TEXTBOOK OF

PALLIATIVE MEDICINE
AND SUPPORTIVE CARE

THIRD EDITION

Edited by
Eduardo Bruera, MD, FAAHPM
Professor and Chair, Department of Palliative,
Rehabilitation and Integrative Medicine, The University of Texas
MD Anderson Cancer Center, Houston, Texas, USA

Irene J. Higginson, OBE, BMedSci, BMBS, PhD, FMedSci, FRCP, FFPHM

Professor and Director,
Cicely Saunders Institute of Palliative Care,
Policy and Rehabilitation, King’s College London, UK

Charles F. von Gunten, MD, PhD

Vice President, Medical Affairs, Hospice and Palliative Medicine,
OhioHealth, Columbus, Ohio, USA

Tatsuya Morita, MD
Director, Department of Palliative and Supportive Care,
Seirei Mikatahara General Hospital, Hamamatsu, and
Adjunct Professor, Kyoto University, Japan
Third edition published 2021
by CRC Press
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Library of Congress Cataloging-in-Publication Data

Names: Bruera, Eduardo, editor. | Higginson, Irene, editor. | Von Gunten, Charles F., 1956- editor. |
Morita, Tatsuya, editor.
Title: Textbook of palliative medicine and supportive care / edited by Eduardo Bruera, Professor and
Chair, Department of Palliative, Rehabilitation and Integrative Medicine, The University of Texas,
MD Anderson Cancer Center, Houston, Texas, USA, Irene Higginson, OBE, BMedSci, BMBS, PhD,
FMedSci, FRCP, FFPHM Professor and Director, Cicely Saunders Institute of Palliative Care, Policy
and Rehabilitation, King’s College London, UK, Charles F. von Gunten, MD, PhD, Vice President,
Medical Affairs, Hospice and Palliative Medicine, OhioHealth, Columbus, Ohio, USA, Tatsuya Morita,
MD, Director, Department of Palliative and Supportive Care, Seirei Mikatahara General Hospital,
Hamamatsu, and Adjunct Professor, Kyoto University, Japan.
Description: Third edition. | Boca Raton : CRC Press, 2021. | Summary: “This new edition provides the
essential clinical guidance both for those embarking upon a career in palliative medicine and for those
already established in the field. A team of international experts here distil what every practitioner
needs to know into a practical and reliable resource”-- Provided by publisher.
Identifiers: LCCN 2020049406 (print) | LCCN 2020049407 (ebook) | ISBN 9780367642037 (hardback)
| ISBN 9780429275524 (ebook)
Subjects: LCSH: Palliative treatment.
Classification: LCC R726.8 .T464692 2021 (print) | LCC R726.8 (ebook) | DDC 616.02/9--dc23
LC record available at https://lccn.loc.gov/2020049406
LC ebook record available at https://lccn.loc.gov/2020049407

ISBN: 978-0-367-64203-7 (hbk)

ISBN: 978-0-429-27552-4 (ebk)
ISBN: 978-0-367-22546-9 (pbk)

Typeset in Warnock Pro

by KnowledgeWorks Global Ltd.
 CONTENTS

List of contributors�������������������������������������������������������������������������������� vi 18. Home palliative care................................................................137

Heather Grant and Dana Lustbader

1. The development of hospice and palliative care.................. 1 19. Palliative care unit.................................................................... 143
Kate Kirk Karen Macmillan, Kelley Fournier, Beth Tupala, and
Kim Crowe Mackinnon
2. Palliative care as a public health issue................................... 7
Irene J. Higginson and Massimo Costantini 20. Multidimensional patient assessment............................... 149
Marvin Omar Delgado-Guay and Alexander Harding
3. Palliative care as a primary care issue................................. 17
Scott A. Murray, Sebastien Moine, and Kirsty Boyd 21. Tools for pain and symptom assessment...........................167
Victor T. Chang
4. The future of palliative medicine...........................................25
Charles F. Von Gunten and Irene J. Higginson 22. Quality of life assessment in palliative care.....................189
Richard Sawatzky and S. Robin Cohen
5. Palliative care and supportive care....................................... 33
Eduardo Bruera 23. Pathophysiology of chronic pain.........................................199
Sebastiano Mercadante
6. Ethics in the practice of palliative care................................ 39
Nelia Jain and James A. Tulsky 24. Causes and mechanisms of pain in palliative
care patients................................................................................207
7. Undergraduate education in palliative medicine............. 47 Michal Kubiak, Marieberta Vidal, and Suresh K. Reddy
Linh My Thi Nguyen
25. Opioid analgesics......................................................................221
8. Graduate education for nonspecialists................................ 51 Geana Paula Kurita, Stein Kaasa, and Per Sjøgren
Fiona Rawlinson and Ilora G. Finlay
26. Assessment and management of opioid side effects......235
9. Challenges of research in palliative and supportive Shalini Dalal
medicine......................................................................................... 61
Irene J. Higginson 27. Adjuvant analgesic medications..........................................249
Jessica Geiger
10. The population: Who are the subjects in palliative
medicine research?..................................................................... 71 28. Alternative routes for systemic opioid delivery..............255
Claudia Bausewein and Fliss E.M. Murtagh Raffaele Giusti, Monica Bosco, Maurizio Lucchesi,
and Carla Ida Ripamonti
11. Study designs in palliative medicine....................................77
Massimo Costantini 29. Interventional pain procedures in palliative care..........271
Po-Yi Paul Su, Ann Cai Shah, and Sarah Gebauer
12. Outcome measurement in palliative care........................... 85
Joan M. Teno 30. Pain management in pediatrics............................................285
Kevin Madden
13. Ethics in palliative care research........................................... 95
Jonathan Koffman and Emel Yorganci 31. Pain in the older adult.............................................................293
Linh My Thi Nguyen and Michelle Peck
14. Adoption of palliative care: The engineering of
organizational change.............................................................107 32. Neuropathic pain......................................................................301
Winford E. (Dutch) Holland and Eduardo Bruera Paolo Marchettini, Fabio Formaglio,
and Marco Lacerenza
15. Principles of measuring the financial outcomes of
specialist palliative care programs......................................115 33. Bone cancer pain and skeletal complications..................313
J. Brian Cassel and Thomas J. Smith Yoko Tarumi

16. Population-based needs assessment for patients 34. Breakthrough (episodic) pain in cancer patients...........323
and those important to them, such as families............... 119 Shirley H. Bush
Irene J. Higginson and Richard Harding
35. Somatic symptoms, symptom clusters, and
17. Models of palliative care delivery........................................127 symptom burden.......................................................................333
Eduardo Bruera and Jessica H. Brown David V. Nelson and Diane M. Novy

iii
iv Contents

36. Pain in patients with alcohol and drug 54. Infections in palliative care...................................................525
dependence.................................................................................337 Rudolph M. Navari
Leah Couture, Malisa Dang, and Danielle Noreika
55. Pediatric palliative wound care:
37. Cachexia–anorexia syndrome...............................................343 The unique anatomy and physiology
Paul Zelensky, Mallika Dammalapati, of neonatal skin......................................................................... 531
and Egidio Del Fabbro Ann Marie Nie and Joyce M. Black

38. Nausea/vomiting.......................................................................357 56 Mouth care..................................................................................539

Sebastiano Mercadante Flavio Fusco

39. Constipation...............................................................................365 57. Fistulas.........................................................................................547

Charu Agrawal and Karina Shih Maurizio Lucchesi, Fabio Fulfaro, Raffaele Giusti,
and Carla Ida Ripamonti
40. Jaundice........................................................................................375
Nathan I. Cherny 58. Assessment and management of lymphedema................553
Ying Guo and Mark V. Schaverien
41. Malignant bowel obstruction................................................381
Carla I. Ripamonti, Alexandra M. Easson, 59. Hypercalcemia...........................................................................563
and Hans Gerdesh Kimberson Tanco and Saima Rashid

42. Endoscopic treatment of digestive 60. Hemorrhage................................................................................569

symptoms.....................................................................................395 Timothy Fuller, Kencee Graves, and Jen-Yu Wei
Pasquale Spinelli
61. Spinal cord compression.........................................................579
43. Mechanism, assessment, and management Maitry Patel, Adrian Cozma, Edward Chow, and
of fatigue......................................................................................401 Srinivas Raman
Sean Hutchinson and Sriram Yennurajalingam
62. Clinical features and management of superior
44. Breathlessness............................................................................421 vena cava syndrome..................................................................587
Claudia Bausewein and Sara Booth Álvaro Sanz, María Luisa del Valle, and Carlos Centeno

45. Other respiratory symptoms (cough, hiccup, 63. Acute pain and management.................................................593
and secretions)...........................................................................433 Mellar P. Davis
Regina M. Mackey and Francisco Loaiciga
64. Suicide.......................................................................................... 613
46. Depression/anxiety..................................................................441 Daniel C. McFarland, Yesne Alici,
Tatsuo Akechi and William S. Breitbart

47. Delirium.......................................................................................455 65. Cancer: Radiotherapy..............................................................623

Yesne Alici and William S. Breitbart Adrian Cozma, Maitry Patel, Edward Chow,
and Srinivas Raman
48. Sleep disturbances in advanced cancer
patients.........................................................................................467 66. Chemotherapy, hormonal therapy, targeted agents,
Delmer A. Montoya and Sriram Yennurajalingam and immunotherapy.................................................................639
David Hui
49. Counseling in palliative care...............................................477
Sophie A. McGilvray and David W. Kissane 67. Integrative medicine in supportive
and palliative care.....................................................................649
50. Hope in end-of-life care.........................................................485 Gabriel Lopez, Santhosshi Narayanan, Wenli Liu,
Cheryl L. Nekolaichuk and Lorenzo Cohen

51. Dehydration and rehydration...............................................493 68. Neurological diseases..............................................................655

Robin L. Fainsinger Tobias Walbert and Joel Phillips

52. Fever, sweats, and hot flashes................................................501 69. End-stage congestive heart failure......................................663
Ahsan Azhar and Shalini Dalal Sam Straw, Klaus K. Witte, and Mark T. Kearney

53. Pruritus........................................................................................ 515 70. Geriatric palliative care..........................................................669

Michael Tang, Katie Taylor, and Andrew Thorns Kimberson Tanco and Maxine De La Cruz
Contents v

71. Advanced chronic obstructive pulmonary 86. Peripheral neuropathy and neurotoxicity......................... 811
disease..........................................................................................677 Sheetal Shroff, Akhil Shivaprasad, and Ivo W.
Daisy J.A. Janssen, Lynn F. Reinke, Tremont-Lukats
and J. Randall Curtis
87. Sex and sexuality....................................................................... 819
72. Other infectious diseases: Malaria, rabies, Mary K. Hughes
tuberculosis................................................................................687
Richard Harding, Rene Krause, and Sue Marsden 88. Managing communication challenges with
patients and families................................................................825
73. Practical resources for palliative care Anthony L. Back
development in countries with limited
resources: An IAHPC perspective.......................................697 89. Supportive and palliative care for patients
Liliana De Lima with HIV infection....................................................................831
Richard Harding, Elizabeth J. Chuang,
74. Prognostic indicators of survival.........................................705 and Peter A. Selwyn
Morena Shkodra, Augusto T. Caraceni, Marco Maltoni,
and Caterina Modonesi 90. Implantable cardiac devices..................................................841
Laura J. Morrison
75. Palliative sedation.................................................................... 717
Nathan I. Cherny A.M. 91. Supportive care for patients with advanced
chronic kidney disease............................................................861
76. Staff stress and burnout in palliative care........................727 Sara N. Davison
Aimee E. Anderson and Eduardo Bruera
92. Palliative care in the emergency department..................873
77. Spiritual care..............................................................................735 Travis DeVader and Tammie Quest
Marvin Omar Delgado-Guay
and Alexander Harding 93. Optimal Symptom Management in Hematopoietic
Stem Cell Transplantation.....................................................879
78. Family caregivers and cultural sensitivity........................743 Katie N. Kanter, Allison Kestenbaum,
Rony Dev and Ali Haider Thomas W. LeBlanc, and Eric J. Roeland

79. Bereavement............................................................................... 761 94. The end of therapy: Building the psychosocial
Victoria H. Raveis and spiritual bridges to survivorship.................................897
Marvin Omar Delgado-Guay
80. Children of palliative care patients.....................................769 and Paige Farinholt
Estela Beale and Sujin Ann-Yi
95. Rehabilitation in the acute and chronic
81. Neutropenic fever.....................................................................777 care setting..................................................................................909
Hiroshi Ishiguro and Harumi Gomi George J. Francis and Ki Y. Shin

82. Side effects of radiation therapy...........................................783 96. Long-term cognitive function...............................................913

Michael Wang, Elizabeth Barnes, and Alysa Fairchild Asao Ogawa

83. Cardiac and pulmonary toxicities 97. Gonadal functions and reproductive health.................... 919
of treatments..............................................................................791 Koji Kawai, Miyuki Harada, Yutaka Osuga, and
Marieberta Vidal Hiroyuki Nishiyama

84. Oral complications of cancer therapies.............................795 98. Pulmonary rehabilitation......................................................925

Siri Beier Jensen and Deborah P. Saunders Ryo Kozu

85. Dermatologic side effects.......................................................803 Index......................................................................................................929

Jen-Yu Wei and Michael Goodblatt
 LIST OF CONTRIBUTORS

Charu Agrawal Joyce M. Black Carlos Centeno

Oncology Supportive Medicine College of Nursing Palliative Medicine
Baylor College of Medicine University of Nebraska Medical Center Clínica Universidad de Navarra
Houston, TX, USA Omaha, NE, USA University of Navarra
Pamplona, Spain
Tatsuo Akechi Sara Booth
Department of Psychiatry and Department of Palliative Care Victor T. Chang
Cognitive-Behavioral Medicine Addenbrookes Hospital VA New Jersey Health Care System
Nagoya City University Graduate School Cambridge University Hospitals NHS Rutgers New Jersey Medical School
of Medical Sciences Foundation Trust NJ, USA
Nagoya, Japan Cambridge, UK
Nathan I. Cherny
Yesne Alici Monica Bosco Cancer Pain and Palliative Medicine
Department of Psychiatry and U.O. Cure Palliative-Dipartimento Cure Service
Behavioral Sciences Primarie Department of Medical Oncology
Memorial Sloan Kettering Cancer AUSL Piacenza, Piacenza, Italy Shaare Zedek Medical Center
Center Jerusalem, Israel
New York, NY, USA Kirsty Boyd
Primary Palliative Care Research Group Edward Chow
Aimee E. Anderson Usher Institute of Population Health Department of Radiation Oncology
Department of Palliative Care Sciences and Informatics Odette Cancer Centre
MD Anderson Cancer Center University of Edinburgh, UK Sunnybrook Health Sciences Centre
Houston, TX, USA Toronto, ON, Canada
William S. Breitbart
Sujin Ann-Yi Department of Psychiatry and Elizabeth J. Chuang
Department of Palliative Care Behavioral Sciences Department of Family and Social
MD Anderson Cancer Center Memorial Sloan Kettering Cancer Center Medicine Montefiore Medical
Houston, TX, USA New York, NY, USA Center
Albert Einstein College of Medicine
Ahsan Azhar Jessica H. Brown Bronx, NY, USA
Department of Palliative, Scientific Development Team
Rehabilitation, and Integrative Department of Palliative Care Lorenzo Cohen
Medicine MD Anderson Cancer Center Department of Palliative, Rehabilitation,
The University of Texas MD Anderson Houston, TX, USA and Integrative Medicine
Cancer Center The University of Texas MD Anderson
Houston, TX, USA Shirley H. Bush Cancer Center
Department of Medicine Houston, TX, USA
Anthony L. Back Division of Palliative Care
Fred Hutchinson Cancer Research University of Ottawa S. Robin Cohen
Center Bruyère Research Institute Program in Palliative Care
University of Washington Ottawa Hospital Research Institute Departments of Oncology and Medicine
Seattle, WA, USA Bruyère Continuing Care McGill University
Ottawa, Canada Montreal, Quebec, Canada
Elizabeth A. Barnes
Department of Radiation Oncology Augusto T. Caraceni Massimo Costantini
University of Alberta and Cross Cancer Palliative Care, Pain Therapy and Azienda USL-IRCCS di Reggio Emilia
Institute Rehabilitation Unit Reggio Emilia, Italy
Edmonton, Alberta, Canada Fondazione IRCCS Istituto Nazionale
dei Tumori Leah Couture
Claudia Bausewein di Milano, Milan, Italy Division of Hematology, Oncology and
Cicely Saunders Institute Palliative Care
of Palliative Care, Policy & J. Brian Cassel Virginia Commonwealth University
Rehabilitation Division of Hematology, Oncology & Richmond, VA, USA
King’s College London, UK Palliative Care
Virginia Commonwealth University Adrian Cozma
Estela Beale School of Medicine University of Toronto
Philadelphia, PA, USA Richmond, VA, USA Toronto, ON, Canada

vi
List of contributors vii

J. Randall Curtis María Luisa del Valle Fabio Formaglio

University of Washington School of Radiotherapy Centro di Medicina del Dolore
Nursing Hospital Clínico Universitario Istituto Scientifico and Ospedale San
Department of Biobehavioral Nursing de Valladolid Raffaele
and Health Informatics Valladolid, Spain Milan, Italy
Cambia Palliative Care Center of
Excellence Marvin Omar Delgado-Guay Kelley Fournier
Harborview Medical Center, and Department of Palliative, Rehabilitation, Tertiary Palliative Care Unit
Department of Medicine and Integrative Medicine Grey Nuns Community Hospital
University of Washington School of The University of Texas MD Anderson Covenant Health
Medicine Cancer Center Edmonton, Alberta, Canada
Seattle, WA, USA Houston, TX, USA
George J. Francis
Shalini Dalal Rony Dev Department of Clinical Neurosciences
Department of Palliative, Department of Palliative, Rehabilitation and Department of Oncology
Rehabilitation, and Integrative and Integrative Medicine Cumming School of Medicine
Medicine Division of Cancer Medicine University of Calgary
The University of Texas MD Anderson MD Anderson Cancer Center Calgary, Alberta, Canada
Cancer Center Houston, TX, USA
Houston, TX, USA Fabio Fulfaro
Travis DeVader Department of Clinical Oncology
Mallika Dammalapati Department of Emergency Medicine Policlinico “Paolo Giaccone”
Support Services and Department of Palliative University Hospital
Virginia Commonwealth University Medicine Palermo, Italy
Massey Stormont-Vail HealthCare
Richmond, VA, USA Topeka, KS, USA Timothy Fuller
Internal Medicine
Malisa Dang Alexandra M. Easson University of Utah Health
Division of Hematology, Oncology and Department of Surgery Salt Lake City, UT, USA
Palliative Care University of Toronto
Virginia Commonwealth University General Surgery and Surgical Flavio Fusco
Richmond, VA, USA Oncology Struttura Semplice Dipartimentale Cure
Mount Sinai Hospital and Princess Palliative
Mellar P. Davis Margaret Cancer Centre Sistema Sanatorio Regione
Palliative Services Toronto, Ontario, Canada Liguria, Genova, Italy
Geisinger Medical Center
Danville, PA, USA Robin L. Fainsinger Sarah Gebauer
Department of Oncology Department of Anesthesia and
Sara N. Davison University of Alberta Perioperative Care
Department of Medicine Edmonton, Canada UCSF
University of Alberta San Francisco, CA, USA
Edmonton, Alberta, Canada Alysa Fairchild
Department of Radiation Oncology Jessica Geiger
Maxine De La Cruz University of Alberta and Cross Cancer Hematology and Medical Oncology
Department of Palliative, Rehabilitation, Institute Cleveland Clinic
and Integrative Medicine Edmonton, Alberta, Canada Cleveland, OH, USA
The University of Texas MD Anderson
Cancer Center Paige Farinholt Hans Gerdesh
Houston, TX, USA Department of Palliative, Weill Cornell Medical College
Rehabilitation, and Integrative Department of Medicine and
Liliana De Lima Medicine Gastrointestinal Endoscopy Unit
International Association for Hospice The University of Texas MD Anderson Memorial Hospital for Cancer and Allied
and Palliative Care Cancer Center Diseases
Houston, TX, USA Houston, TX, USA New York, NY, USA

Egidio Del Fabbro Ilora G. Finlay Raffaele Giusti

Palliative Care Department of Pharmacology, Medical Oncology Unit
Virginia Commonwealth University Radiology, Oncology and Palliative Azienda Ospedaliero Universitaria
Massey Cancer Center Medicine Sant’Andrea
Richmond, VA, USA University of Cardiff, UK Roma, Italy
viii List of contributors

Harumi Gomi David Hui Koji Kawai

Center for Global Health Associate Professor Department of Urology
Mito Kyodo General Hospital University Department of Palliative Care, Institute of Clinical Medicine
of Tsukuba Rehabilitation, and Integrative University of Tsukuba
Tsukuba, Japan Medicine Ibaraki, Japan
Department of General Oncology
Michael Goodblatt The University of Texas MD Anderson Mark T. Kearney
Palliative Care Cancer Center Leeds University School of Medicine
Providence St Peter Hospital Houston, TX, USA Leeds, UK
Olympia, WA, USA
Sean Hutchinson Allison Kestenbaum
Heather Grant Department of Palliative, Rehabilitation University of California San Diego
OPTUM Supportive Care and Integrative Medicine La Jolla, CA, USA
New York, NY, USA Division of Cancer Medicine
MD Anderson Cancer Center Kate Kirk
Kencee Graves Houston, TX, USA Cambridge, UK
Internal Medicine
University of Utah Health Hiroshi Ishiguro David W. Kissane
Salt Lake City, UT, USA Department of Medical Oncology Cunningham Centre for Palliative Care
International University of Health and Research
Ying Guo Welfare Hospital University of Notre Dame Australia
Department of Palliative, Rehabilitation, Tochigi, Japan St Vincent’s Hospital
and Integrative Medicine Sydney
The University of Texas MD Anderson Nelia Jain Sacred Heart Hospital and Palliative
Cancer Center Department of Psychosocial Oncology Care Service
Houston, TX, USA and Palliative Care Darlinghurst, NSW, Australia
Dana-Farber Cancer Institute, and
Division of Palliative Medicine
Ali Haider Jonathan Koffman
Brigham and Women’s Hospital
Department of Palliative, Rehabilitation Cicely Saunders Institute of Palliative
Boston, MA, USA
and Integrative Medicine Care, Policy and Rehabilitation
Division of Cancer Medicine King’s College London, UK
Daisy J.A. Janssen
MD Anderson Cancer Center
Department of Research & Education
Houston, TX, USA Ryo Kozu
CIRO, Centre of expertise for chronic
Department of Rehabilitation
organ failure
Miyuki Harada Medicine
Department of Health Services
Department of Obstetrics and Research Nagasaki University Hospital,
Gynecology CAPHRI School for Public Health and Japan
Faculty of Medicine Primary Care
The University of Tokyo, Japan Faculty of Health Medicine and Life Rene Krause
Sciences School of Public Health and Family
Alexander Harding Maastricht University Medicine
Department of Palliative, Rehabilitation, Maastricht, the Netherlands University of Cape Town,
and Integrative Medicine South Africa
The University of Texas MD Anderson Siri Beier Jensen
Cancer Center Department of Dentistry and Oral Health Michal Kubiak
Houston, TX, USA Faculty of Health Internal Medicine at Centegra
Aarhus University Rosalind Franklin University of Medicine
Richard Harding Aarhus, Denmark and Science
Cicely Saunders Institute of Palliative Chicago, IL, USA
Care, Policy & Rehabilitation Stein Kaasa
King’s College London, UK Institute of Cancer Research and Geana Paula Kurita
Molecular Medicine Multidisciplinary Pain Centre
Winford E. (Dutch) Holland Norwegian University of Science and Rigshospitalet Copenhagen
Holland Management Consulting Technology and European Palliative University Hospital
Houston, TX, USA Care Research Centre Trondheim, Copenhagen, Denmark
Norway
Mary K. Hughes Marco Lacerenza
Psychiatry Department Katie N. Kanter Centro di Medicina del Dolore
The University of Texas MD Anderson Massachusetts General Hospital Cancer Istituto Scientifico and Ospedale San
Cancer Center Center Raffaele
Houston, TX, USA Boston, MA, USA Milan, Italy
List of contributors ix

Thomas W. LeBlanc Marco Maltoni Scott A. Murray

Duke Cancer Institute Palliative Care Unit Emeritus Professor of Primary
Durham, NC, USA Istituto Scientifico Romagnolo per lo Palliative Care
Studio e la Cura dei Tumori (IRST)
University of Edinburgh, UK
Wenli Liu IRCCS
Department of Palliative, Meldola, Italy
Rehabilitation, and Integrative Fliss E.M. Murtagh
Medicine Paolo Marchettini Cicely Saunders Institute of
The University of Texas MD Anderson Centro di Medicina del Dolore Palliative Care, Policy &
Cancer Center Istituto Scientifico and Ospedale San Rehabilitation
Houston, TX, USA Raffaele King’s College London, UK
Milan, Italy
Francisco Loaiciga
Santhosshi Narayanan
Michael E. Debakey VA Medical Center Sue Marsden
Department of Palliative, Rehabilitation,
Texas Hospice North Shore
Houston, TX, USA Auckland, New Zealand and Integrative Medicine
The University of Texas MD Anderson
Gabriel Lopez Daniel C. McFarland Cancer Center
Department of Palliative, Rehabilitation, Department of Psychiatry and Houston, TX, USA
and Integrative Medicine Behavioral Sciences
The University of Texas MD Anderson Memorial Sloan Kettering Cancer Rudolph M. Navari
Cancer Center Center
Division of Hematology Oncology
Houston, TX, USA New York, NY
University of Alabama at Birmingham
Maurizio Lucchesi Sophie A. McGilvray School of Medicine
Oncology and Hematology Unit Cunningham Centre for Palliative Care Experimental Therapeutics Program
Nuovo Ospedale delle Apuane Research UAB Comprehensive Cancer Center
Massa University of Notre Dame Australia Birmingham, AL, USA
Pulmunology Unit – Pneumo-Oncology St Vincent’s Hospital
Service Sacred Heart Hospital and Palliative
Cheryl L. Nekolaichuk
Azienda Ospedaliero-Universitaria Care Service
Department of Oncology
Pisana Darlinghurst, NSW, Sydney, Australia
Pisa, Italy University of Alberta
Sebastiano Mercadante Edmonton, Canada
Dana Lustbader Pain Relief and Palliative Care
OPTUM Supportive Care La Maddalena Cancer Center David V. Nelson
New York, NY, USA Palermo, Italy Department of Psychology and
Philosophy
Regina M. Mackey Caterina Modonesi
Sam Houston State University
Family Medicine UOC ONCOLOGIA-Azienda ULSS6
Mayo Clinic EUGANEA (Veneto) Huntsville, TX, USA
Rochester, MN, USA Ospedali Riuniti Padova Sud
Padova, Italy Linh My Thi Nguyen
Kim Crowe Mackinnon Department of Internal Medicine
Tertiary Palliative Care Unit Sebastien Moine Division of Geriatric and Palliative
Grey Nuns Community Hospital Primary Palliative Care Research Medicine
Covenant Health Group
McGovern Medical School
Edmonton, Alberta, Canada Usher Institute of Population
Houston, TX, USA
Health Sciences and
Karen Macmillan Informatics
Tertiary Palliative Care Unit University of Edinburgh, UK Ann Marie Nie
Grey Nuns Community Hospital College of Nursing
Covenant Health Delmer A. Montoya University of Nebraska Medical Center
Edmonton, Alberta, Canada Aultman Hospital Omaha, NE, USA
Canton, OH, USA
Kevin Madden Hiroyuki Nishiyama
Department of Palliative, Rehabilitation Laura J. Morrison
Department of Urology
and Integrative Medicine Hospice and Palliative Medicine
Division of Cancer Medicine Yale University School of Medicine Institute of Clinical Medicine
MD Anderson Cancer Center and Yale-New Haven Hospital University of Tsukuba
Houston, TX, USA New Haven, CT, USA Ibaraki, Japan
x List of contributors

Danielle Noreika Victoria H. Raveis Mark V. Schaverien

Inpatient Palliative Care Services New York University Department of Palliative,
Hospice and Palliative Medicine New York, NY, USA Rehabilitation, and Integrative
Fellowship Medicine
Division of Hematology, Oncology and Fiona Rawlinson The University of Texas MD Anderson
Palliative Care School of Medicine Cancer Center
Virginia Commonwealth University University Hospital of Wales Houston, TX, USA
Richmond, VA, USA Chair
Specialty Training Committee for Wales Peter A. Selwyn
Diane M. Novy Palliative Medicine Department of Family and Social
Department of Pain Medicine Consultant in Palliative Medicine Medicine
Division of Anesthesiology, Critical Care, for City Hospice Montefiore Medical Center
and Pain Medicine Cardiff, UK Albert Einstein College of Medicine
MD Anderson Cancer Center Bronx, NY, USA
Houston, TX, USA Suresh K. Reddy
Department of Palliative, Ann Cai Shah
Asao Ogawa Rehabilitation and Integrative Pain Management Center
National Cancer Center Hospital East Medicine UCSF
National Cancer Center Division of Cancer Medicine San Francisco, CA, USA
Tokyo, Japan MD Anderson Cancer Center
Houston, TX, USA Karina Shih
Yutaka Osuga MD Anderson Cancer Center
Department of Obstetrics and Lynn F. Reinke Houston, TX, USA
Gynecology Department of Veterans Affairs
Faculty of Medicine Puget Sound Health Care System
Ki Y. Shin
The University of Tokyo, Japan Health Services R&D
Department of Palliative,
University of Washington School of
Rehabilitation, and Integrative
Maitry Patel Nursing
Medicine
Radiation Oncology Department of Biobehavioral Nursing
The University of Texas MD Anderson
Princess Margaret Cancer Center and Health Informatics
Cancer Center
Toronto, ON, Canada Seattle, WA, USA
Houston, TX, USA
Michelle Peck Carla Ida Ripamonti
Akhil Shivaprasad
Department of Internal Medicine ssd Oncologia-Cure di Supporto al
paziente Stanley H. Appel Department of
Division of Geriatric and Palliative
Medicine Fondazione IRCCS Neurology
McGovern Medical School Istituto Nazionale dei Tumori Houston Methodist-Weill Cornell
Houston, TX, USA Milan, Italy College of Medicine
Houston, TX, USA
Joel Phillips Eric J. Roeland
Henry Ford Health System Massachusetts General Hospital Morena Shkodra
Detroit, MI, USA Cancer Center Palliative Care, Pain Therapy and
Boston, MA, USA Rehabilitation Unit
Tammie Quest Fondazione IRCCS Istituto
Department of Emergency Medicine Álvaro Sanz Nazionale dei Tumori
Division of Geriatrics and Gerontology Medical Oncology di Milano
Emory University School Hospital Universitario del Rio Hortega Milan, Italy
of Medicine Valladolid, Spain
Atlanta, GA, USA Sheetal Shroff
Deborah P. Saunders Stanley H. Appel Department of
Srinivas Raman Health Sciences North Neurology
Odette Cancer Centre North East Regional Cancer Center Houston Methodist-Weill Cornell
Sunnybrook Health Sciences Centre Department of Dental Oncology College of Medicine
University of Toronto Northern Ontario School Texas A&M College of Medicine
Toronto, ON, Canada of Medicine Houston, TX, USA
Sudbury, Ontario, Canada
Saima Rashid Per Sjøgren
Department of Supportive Richard Sawatzky Multidisciplinary Pain Centre
Care Medicine, Moffitt Trinity Western University School of Rigshospitalet Copenhagen University
Cancer Center Nursing Hospital
Tampa, FL, USA Langley, BC, USA Copenhagen, Denmark
List of contributors xi

Thomas J. Smith Joan M. Teno Michael Wang

Sidney Kimmel Comprehensive Cancer Division of General Internal Medicine
Center and Geriatrics
Johns Hopkins Medical Institutions School of Medicine
Baltimore, MD, USA Oregon Health Sciences University
Portland, OR, USA
Pasquale Spinelli
International Medical System and Andrew Thorns
Services Milan, Italy Palliative Medicine
Pilgrims Hospices
Sam Straw Canterbury, UK
Leeds University School of Medicine
Leeds, UK Ivo W. Tremont-Lukats
Department of Neuro-Oncology
Po-Yi Paul Su MD Anderson Cancer Center
Department of Anesthesia and The University of Texas
Perioperative Care Houston, TX, USA
UCSF
San Francisco, CA, USA James A. Tulsky
Department of Psychosocial
Kimberson Tanco Oncology and Palliative Care
Department of Palliative, Rehabilitation, Dana-Farber Cancer Institute, and
and Integrative Medicine Division of Palliative Medicine
The University of Texas MD Anderson Brigham and Women’s Hospital
Cancer Center Boston, MA, USA
Houston, TX, USA
Beth Tupala
Michael Tang Tertiary Palliative Care Unit
Department of Palliative, Rehabilitation Grey Nuns Community Hospital
and Integrative Medicine Covenant Health
Division of Cancer Medicine Edmonton, Alberta, Canada
MD Anderson Cancer Center
Houston, TX, USA Marieberta Vidal
Department of Palliative,
Yoko Tarumi Rehabilitation and Integrative
Department of Oncology Medicine
Division of Palliative Care Medicine Division of Cancer Medicine
University of Alberta MD Anderson Cancer Center
Edmonton, Alberta, Canada Houston, TX, USA
Department of Radiation Oncology
University of Alberta and Cross Cancer
Institute
Edmonton, Alberta, Canada
Jen-Yu Wei
Internal Medicine
University of Utah Health
Salt Lake City, UT, USA
Klaus K. Witte
Leeds University School of Medicine
Leeds, UK
Sriram Yennurajalingam
Department of Palliative, Rehabilitation
and Integrative Medicine
Division of Cancer Medicine
MD Anderson Cancer Center
Houston, TX, USA
Emel Yorganci
Cicely Saunders Institute of Palliative
Care, Policy and Rehabilitation
King’s College London, UK
Paul Zelensky
Palliative Care
Virginia Commonwealth University
Massey Cancer Center
Richmond, VA, USA

Katie Taylor Tobias Walbert

Hospice in the Weald Henry Ford Health System
Tunbridge Wells, UK Detroit, MI, USA
1
THE DEVELOPMENT OF HOSPICE AND PALLIATIVE CARE

Kate Kirk

Contents
The “ready minds”..................................................................................................................................................................................................................2
Global growth of the modern hospice movement...........................................................................................................................................................3
Recognition.............................................................................................................................................................................................................................4
The need remains...................................................................................................................................................................................................................4
References................................................................................................................................................................................................................................5

In May 2014, WHO World Health Assembly Resolution 67.19

called for palliative care to be strengthened “as a component of WHO DEFINITION OF PALLIATIVE
comprehensive care throughout the life course.”1 This was the CARE (REVISED 2002)
first global resolution on palliative care, and the call to integrate
it into national health policies and programs was adopted unani- Palliative care is an approach that improves the quality of life
mously by the representatives of the 194 Member States attend- of patients and their families facing the problem associated
ing the Geneva meeting. with life-threatening illness, through the prevention and
The resolution meant that palliative care was now included relief of suffering by means of early identification and impec-
in the definition of universal health coverage, and in the WHO cable assessment and treatment of pain and other problems,
Global Monitoring Framework and action plan for the preven- physical, psychosocial, and spiritual. Palliative care:
tion and control of noncommunicable diseases 2013–2020. It
also meant that medications typically used for pain and symp- • provides relief from pain and other distressing
tom control in palliative care would be included in WHO’s Model symptoms;
Essential Medicines lists for both adults and children. From poli- • affirms life and regards dying as a normal process;
cies to education, and from funding to basic support, Resolution • intends neither to hasten or postpone death;
67.19 called for Member States to integrate palliative care across • integrates the psychological and spiritual aspects
all aspects of their health systems, and for the Director-General of patient care;
of WHO to drive the necessary programs and projects to help • offers a support system to help patients live as
Member States to support implementation. actively as possible until death;
Prior to this, palliative care had become a recognized human • offers a support system to help the family cope
right when the UN Committee on Economic, Social and Cultural during the patients illness and in their own
Rights adopted General Comment No. 14 in 2000. This General bereavement;
Comment asserted the right to “attention and care for chroni- • uses a team approach to address the needs of
cally and terminally ill persons, sparing them avoidable pain and patients and their families, including bereave-
enabling them to die with dignity.” 2 The WHO definition of pal- ment counseling if indicated;
liative care, as revised two years later (see Box 1.1), included the • will enhance quality of life, and may also posi-
family, underscoring a concept familiar to those working in the tively influence the course of illness;
field, that of “total pain.” • is applicable early in the course of illness, in con-
For a medical specialty barely 25 years old where it is recog- junction with other therapies that are intended to
nized, and still unrecognized in many countries, the 2014 WHO prolong life, such as chemotherapy or radiation
Resolution was a major step. And yet, the origins of hospice and therapy, and includes those investigations needed
palliative care go back centuries. to better understand and manage distressing
The first hospices were simply places for pilgrims to rest. Given clinical complications. 3
the rigors of the journeys these guests were undertaking, caring
for the sick became an integral part of the comfort hospices pro-
vided. The idea of a hospice being a home for the “incurable” took conditions such as heart failure, respiratory and neurological dis-
root in the 19th century, when such homes were first established eases, and HIV/AIDS.
in France and Ireland. So while palliative care has only recently As with many leaps of progress, an idea starts to take root in a
taken its rightful place in the world of medicine, the hospice care number of different places and in the minds of different people at
it is intimately linked with and derives from is hardly new. around the same time. But it takes a particular individual to shake
But what is new is the modern hospice, and indeed the inven- things up—to challenge the fundamental assumptions around
tion of the term “palliative care” to encompass all aspects of car- an area of practice or scientific enquiry and cause the necessary
ing for patients with life-limiting conditions—not just cancer paradigm shift by pointing researchers in a new direction and to
(although that is typically the assumption for hospices) but also new sources of evidence.

1
2 Textbook of Palliative Medicine and Supportive Care
The history of hospice and palliative care is one such paradigm
shift that did, indeed, start to grow in several places in the 1950s.
However, it is impossible to write about how the field devel-
oped without focusing on the work of my late aunt, Dame Cicely
Saunders OM, DBE, FRCP, FRCN.
In his Foreword to a selection of her published letters, Professor
Balfour Mount asserted that “Dame Cicely … has been the cata-
lyst for a paradigm shift in global health care.”4 When accepting
the Templeton Prize in 1981, Cicely herself pointed out that “[t]
here are not too many original ideas around but there is often a
new pattern to be discovered if we search with ready minds and
ask some questions.”5
Asking questions, as Cicely did enthusiastically throughout her
life, underpins the development of what we recognize as hospice
and palliative care today.
The “ready minds”
Looking back, it is easy to see a chain of events that led logically,
indeed inexorably, to World Health Assembly Resolution 67.19,
but without the “ready minds” and questioning stance of a few key
individuals, the chain may never have been completed. Indeed,
without Cicely’s unusual career path, it might never have been
started.
Cicely initially went up to Oxford University in 1938 to study
Politics, Philosophy and Economics, but at the outbreak of World
War II, she left her studies and trained as a nurse at the Nightingale
Home and Training School at St. Thomas’ hospital in London. To
her great disappointment, her nursing career was cut short by an
increasingly aggravated back injury, and in 1944 she went back to
Oxford to finish her degree. After graduating, realizing she could
not go back to the nursing she loved, she qualified as what she saw
as the next best thing, a Lady Almoner, or Medical Social Worker,
and began working in this new role in St. Thomas’ in 1947.
The next key moment was in 1948, when she met David Tasma,
a Polish Jew who had come to England shortly before war broke
out, but was now dying of cancer. He was alone, having lost con-
tact with his family back in Poland, and Cicely spent consider-
able time with him. A bond formed between them over lengthy
and far-ranging conversations, particularly over how the dying
were cared for, and how much better things could be. A vision of
a place where death was not a medical failure but instead part of
a journey, and deserving of equal care, was born. When he died,
Tasma left Cicely a sum of money toward her vision, apparently
telling her that “I will be a window in your home.”6
After Tasma’s death, Cicely added two more important pieces
to her journey and both would inform her next step. First, she
started volunteering at St. Luke’s Hospital for Advanced Cases
in London. As a Lady Almoner, she had occasionally had to send
patients to what were often referred to as “homes for the dying,”
and St. Luke’s was one of them. Her nursing vocation remained,
and volunteering reconnected her to that vocation. It also gave
her time to investigate more closely how dying patients were
cared for. In particular, she saw what could be done with differ-
ent regimes for pain-killing drugs, and the use of the so-called
Brompton cocktail, an undefined mixture of morphine, codeine,
sodium amytal, alcohol, and other ingredients.
The second crucial change at this time was to combine her
duties as an Almoner with acting as medical secretary to Norman
“Pasty” Barrett, a consultant thoracic surgeon who played a piv-
otal role. Cicely discussed her observations from St. Luke’s with
Barrett and explained that she was thinking of going back into
nursing to test her ideas. He pointed out the obvious, that a nurse
would not be able to challenge the establishment, and that “it is
doctors who desert the dying.” 7 If she wanted to change things,
she should go to medical school.
Cicely was the oldest in her class by almost a decade when she
began training as a doctor in 1951, once more at St. Thomas’. During
her training, she began monitoring and recording her observations
of, and conversations with, dying patients. Most of her “founda-
tional” patients, as she termed them, were suffering from cancer.
Her experience as a nurse, social worker, and now trainee doctor
gave her unique insights into the constraints and problems around
their care, and the wider ramifications of their situation.
In 1958, an article by Cicely entitled “Dying of Cancer” was
published in the St. Thomas’s Hospital Gazette. In it, she detailed
the cases of four dying patients and the issues associated with
their care, good and bad. She concluded with her thoughts on the
care of the dying and an early vision of how modern hospice care
might evolve.
It appears to me that many patients feel deserted by their
doctors at the end. Ideally the doctor should remain the
centre of a team who work together to relieve where they
cannot heal, to keep the patient’s own struggle within his
compass and to bring hope and consolation to the end.8
Once qualified, Cicely took a position as physician at St. Joseph’s
Hospice, another of London’s homes for the dying, where she
worked for the next seven years. Over that time, she started
to do more detailed research into the use of painkillers. She
interviewed and recorded notes on over one thousand patients,
building a formidable set of qualitative and quantitative data,
and began to write about the benefits of giving regular doses of
painkillers in contrast to the established practice of either wait-
ing until the patient could bear the pain no longer or sticking to
a strict timetable. She also began to develop relationships with
other workers in the field, both in the UK and internationally,
principally North America, writing to and talking to as many
people as possible about her ideas. These included her concept of
total pain—that the dying patient, and their family, should have
not only their medical needs addressed, but also their psychologi-
cal, social, and spiritual needs as well—which reflected her rare
combined experience as a nurse, social worker, and now physi-
cian. As she wrote in 1966:
…a patient, trying to describe her pain, says simply, “It
began in my back, but now it seems that all of me is wrong.”
This kind of “total” pain has physical, mental, social and
spiritual elements. Neither she in her words nor we in
our approach and treatment can deal with any of these
separately.9
With David Tasma’s legacy still waiting to be spent, Cicely was
increasingly focused on how she could establish her own hospice,
one where she could combine the best possible care with research
and teaching. In 1963, she was awarded a nursing fellowship,
which she used to travel to the US, where she visited the National
Institutes of Health in Maryland and a number of hospitals, talk-
ing to professionals from all parts of the medical spectrum. As
she wrote in her report of the trip:
I found it a great asset that I was able to go in my three-
fold capacity of nurse, social worker and doctor. It made
The Development of Hospice and Palliative Care
my own approach a broad one and also made me “one of
them” when I discussed problems with each of the different
professions.10
An additional grant from the Ella Lyman Cabot Trust enabled
Cicely to extend her 1963 tour—crucially giving her the time to
meet some other “ready minds,” including Florence Wald, dean of
the Yale School of Nursing. Subsequent trips to the US included
a six-week lectureship at Yale in 1966, which included two more
important meetings. She renewed her acquaintance with psychia-
trist Colin Murray Parkes, who would add crucial expertise to her
plans. She also met Elisabeth Kübler-Ross, who was already con-
ducting the interviews that would inform her seminal 1969 work,
On Death and Dying. Kübler-Ross would note in her book:
It may not be a coincidence that one of the doctors best
known for the total care of the dying patient, Cicely
Saunders, started her work as a nurse and is now physician
attending the terminally ill in a hospital set-up especially
designed for their care.11
That “hospital set-up” that Kübler-Ross referred to was St.
Christopher’s Hospice in Sydenham, South London. Fired up by
the publication of a 1960 report to the UK Government on the
care of the terminally ill by Glyn Hughes, Cicely had redoubled
her efforts to raise funds and gather support from a broad range
of stakeholders in order to realize her vision.
St. Christopher’s Hospice admitted its first patients in July,
1967. Funded by various philanthropic organizations and indi-
viduals, and with a contribution from the UK’s National Health
Service, research and education were at the heart of activities
from the beginning. Cicely continued the research she had begun
at St. Joseph’s, and brought in others to develop new projects.
One of these was Robert Twycross, who joined St. Christopher’s
as a Clinical Research Fellow in Therapeutics in 1971. Twycross
undertook a series of seminal studies documenting the use of oral
morphine, as given to patients in the Brompton cocktail, and also
comparing the efficacy of morphine, diamorphine, and metha-
done in controlling pain. For the first time, there was robust,
evidence-based confirmation that controlled doses of morphine
could be used to replace the Brompton cocktail.
Many other key developments in the field came after visits
to St. Christopher’s. These included that of Florence Wald, who
spent four weeks working there in 1969. After going back to the
US, Wald and a few colleagues joined forces to plan and develop
the Hospice Home Care program in New Haven, Connecticut,
which launched in 1974. This first hospice program in the US was
initially concerned solely with providing home care but opened
its first in-patient beds in 1980.
Canadian physician Balfour Mount was another early visi-
tor to St. Christopher’s. He was inspired to make contact after
organizing a discussion group for his church to talk about the
Kübler-Ross book, On Death and Dying. The description of St.
Christopher’s in the book intrigued him and he determined to
visit. Cicely famously tried to put him off when he telephoned her
in September, 1973. First of all, she refused to take his call, say-
ing she was just going for lunch and he could call her back later.
When that didn’t deter and Mount persisted in calling again, she
told him:
I know you. You want to come over to London with your
wife, see a few plays, have a quick run around the hospice
3
and then go back. Well, I won’t have it. I’ll tell you what,
leave your wife at home; be prepared to come for a week,
role up your sleeves and get to work, and I’ll have you.12
Mount visited St. Christopher’s as soon as it could be arranged,
and went back again the following year for a longer stay. Having
undertaken a review of the care of the dying in his own hospital,
the Royal Victoria in Montreal, Mount wanted to develop a way
of bringing hospice care into the hospital setting. Eventually, in
1975 Mount set up a pilot project in the Royal Victoria that intro-
duced the term, “palliative care.” The hospital’s Palliative Care
Service was the first of its kind.
David Clark points out in his biography of Cicely that, although
initially unconvinced by the term, she soon changed her mind and:
…quickly embraced [the term] in the coming years and
readily cited Mount and Montreal as its source … the neol-
ogism was to prove hugely consequential as it entered into
use across the world and sounded out the message that hos-
pice principles could be practised in many contexts. It was
not the setting that was important, but rather the approach
to care that was being adopted.13
Apart from the many visitors to St. Christopher’s itself who went
away inspired to “do their bit” for the care of the dying, there are
numerous other incidences where a meeting with Cicely, a lecture
she gave, even singing in the same choir, had an impact on the
development of palliative care. When Mary Baines (a contempo-
rary of Cicely’s at medical school and one of the first physicians
at St. Christopher’s), surveyed a group of doctors prior to attend-
ing a Wellcome Trust Witness Seminar on the development of
palliative medicine in the UK, she found that half of them had
chosen their career in palliative medicine after meeting Cicely.14
Not surprisingly, therefore, it is impossible to name all of the peo-
ple who were inspired by Cicely and went on to contribute to the
expansion of the modern hospice movement and the subsequent
development of palliative medicine. The previous edition of this
book provides many more names and details, but it, too, is far
from complete.
Global growth of the modern
hospice movement
St. Christopher’s served as a model modern hospice, but Cicely
never intended it to be copied exactly. Instead, she encouraged
any who expressed a desire to create something similar to spend
time at St. Christopher’s and then go away and tailor provision to
local conditions.
Today, there are around 220 hospices in the UK.15 Most are
independent and rely on charitable funding for over two-thirds
of their operating costs. In the US, there were over 3,000 hos-
pice programs by the time of Florence Wald’s death in 2008.
The introduction of Medicare hospice benefits in 1980 was a
key trigger for the growth of in-patient provision, and in 2017,
the National Hospice and Palliative Care Organization recorded
4,515 Medicare-certified hospices operating in the US. It also
reported that 1.49 million Medicare beneficiaries had one day
or more of hospice care in the same year, over half those days of
care were delivered in the home, and around 65% of the recipients
were 80 years of age or over.16
The 2012 Atlas of Palliative Care in Latin America cited an
overall figure of 44 in-patient beds per million inhabitants across
4 Textbook of Palliative Medicine and Supportive Care
the 19 countries in the region.17 This ranged from a high of 11
per million population in Argentina to zero in Cuba, El Savador,
Honduras, Nicaragua, Panama, and Peru. Similarly, eight coun-
tries had no home care provision, and very few had any provision
in community centers. A 2017 review of end-of-life care in Latin
America found national palliative laws in four countries, and that
six countries still had no hospice.18
Looking more broadly, the 2014 joint Worldwide Palliative
Care Alliance and WHO Global Atlas of Palliative Care at the
End of Life assessed end-of-life-care provision under 4 categories
and found that 75 countries were in Group 1, with no known hos-
pice or palliative care activity. Many of these were islands where
populations were small and overall health provision challeng-
ing, but the list also included countries such as Liechtenstein,
Monaco, and Syria.19 A further 23 countries were in the “capacity
building” phase, but only 20 countries had reached category 4b,
advanced integration of hospice and palliative care.
Recognition
Hospices are, of course, only part of the picture. In fact, it is the
growing recognition of palliative care as not only a human right
but also a medical specialism that has arguably had the greatest
effect on the care of the dying worldwide.
As with any other medical specialty, in order to be recognized,
palliative medicine had to develop the foundations of a profes-
sion, including research, peer-reviewed journals, associations of
practitioners, education, and certification.
In the UK, the Association of Palliative Care and Hospice
Doctors was formed in 1985, and palliative medicine was first
recognized as a sub-specialty by the Royal College of Physicians
in 1987. Seven years of research, education, and development
later, it became a specialty in its own right.
Established in 1991, the position of Sainsbury Professor of
Palliative Medicine at the United Medical Schools of Guys and
St. Thomas’ Hospitals in London was the first Chair in Palliative
Medicine in Europe.20 By 2005 there were nine such positions
throughout the UK, and three Chairs had been created for pallia-
tive care within social sciences.
The UK’s National Institute for Clinical Excellence published
its first guidance on palliative care, for patients with cancer, in
2004. Its most recent set of quality standards for end-of-life care
include not only various forms of cancer but also COPD, chronic
heart failure, chronic kidney disease, and dementia.21
The European Association for Palliative Care was established
at an international congress in Milan in December 1988 and
recognized as a nongovernmental organization of the Council
of Europe 10 years later. By this time, palliative care was begin-
ning to appear in legislation in several European countries, and in
2003, the Council of Europe incorporated recommendations for
the provision of palliative care.
The American Academy of Hospice and Palliative Medicine
(originally the Academy of Hospice Physicians) was also founded
in 1988 and now claims over 5,000 members.
In the 2006 edition of this book, Ryndes and Von Gunten
pointed out that, as of 2004, the US was awaiting a decision on
whether palliative care would be considered a medical specialism.
A combination of various programs and initiatives supported the
claim, and the authors commented that “[f]ormal recognition is
seen as likely” at a meeting of the American Board of Medical
Specialities in that year.22 In fact, it was two years later, in 2006,
when palliative medicine was finally recognized as a subspecialty
of internal medicine.23
Although the first Canadian Chair of Palliative Medicine was
established at the University of Alberta in 1987, an application to
confirm palliative care as a specialty in Canada was turned down
in 1995. It was only in 2017 that legislation in Canada led to the
publication of the Framework on Palliative Care in Canada by
Health Canada in 2018. The report pointed out that, while there
were a number of programs aimed at delivering and improving
palliative care in place across the provinces and territories of
Canada, there was no national strategy, despite the appointment
of a minister with special responsibility for Palliative and End-
of-Life Care in 2001.24 The report also noted that the Canadian
Institutes of Health Research had put $16.5 million into palliative
care research between 2004 and 2009, and a further $494 million
in funding for aging research between 2012 and 2017 included
some funds directed to palliative care. Nevertheless, a fundamen-
tal weakness in the advancement of palliative care as a profession
remains:
Unfortunately, the core palliative care competencies of
skilled communication, expert pain and symptom man-
agement, and psychosocial assessment remain, at best, a
small part of most medical school and residency training
programs in Canada.25
Elsewhere, progress is equally variable. The African Palliative
Care Association, launched in 2004, reports that 21 out of 47
African countries have “no identified hospice or palliative care
activity,” and only four countries “could be classified as having
services approaching some measure of integration with main-
stream service providers.”26 Similarly, the Asia-Pacific region sees
progress in some countries but barriers in others, particularly
associated with availability of opioids.
However, there is some encouragement to be drawn from
efforts to at least improve education and training, especially for
those in low- and middle-income countries. Online and distance
courses, such as the Stanford Palliative Care Always program,
aimed at cancer specialists, and projects such as that established
by the Lien Collaborative for Palliative Care, to train trainers in
order to build capacity,27 at least keep progress moving in the
right direction.
The need remains
Despite efforts by national and international bodies to put pallia-
tive and hospice care on the health agenda, the unmet need is still
high. WHO estimates that “worldwide, only about 14% of people
who need palliative care currently receive it.”28 The same WHO
Factsheet also points to the increased demand for palliative care
as populations around the world age and greater numbers of peo-
ple live with complex conditions in their later years.
There is still a shortage of academic leaders for capacity build-
ing, and research remains challenging for a number of reasons,
including ethical considerations, difficulty of predicting time to
dying, frailty of patients, and the subjectivity of measuring fac-
tors such as quality of life. The Cicely Saunders Institute, opened
in 2010 in London, strives to address all of these challenges in a
multidisciplinary organization that reflects the origins of the spe-
cialty in nursing, social work, and medicine, but despite efforts
here and elsewhere, much remains to be done.
The Development of Hospice and Palliative Care
Speaking personally, I feel that Cicely would be pleased at how
far we’ve come but also frustrated at how far we still have to go.
As anyone who met her would know, she would also be rolling
up her sleeves alongside us and encouraging us to get on with it.
References
1. World Health Organization. Strengthening of Palliative Care as a
Component of Comprehensive Care Throughout the Life Course. Sixty-
Seventh United Nations World Health Assembly, 2014. http://apps.
who.int/gb/ebwha/pdf_files/WHA67/A67_R19-en.pdf
2. Committee on Economic, Social and Cultural Rights (CESCR), 2000.
CESCR General Comment No. 14: The Right to the Highest Attainable
Standard of Heatlh (Art. 12). Office of the High Commissioner for
Human Rights. Para 25. https://www.refworld.org/pdfid/4538838d0.
pdf
3. WHO Definition of Palliative Care. https://www.who.int/cancer/
palliative/definition/en/
4. Clark D. Cicely Saunders, Founder of the Hospice Movement, Selected
Letters 1959–1999. Oxford: Oxford University Press, 2002, p. v.
5. Saunders C. Templeton Prize Speech. In: Saunders C, ed. Cicely
Saunders: Selected Writings 1958–2004. Oxford: Oxford University
Press, 1981, p. 158. 2006.
6. Saunders C. A place to die. Crux 1973–1974;11(3):24–27. In: Saunders
C, ed. Cicely Saunders: Selected Writings 1958–2004. Oxford: Oxford
University Press, 1973, p. 125, 2006.
7. Clark D. Cicely Saunders: A Life and Legacy. Oxford: Oxford University
Press, 2018, p. 72.
8. Saunders C. Dying of cancer. St Thomas’s Hosp Gaz 1958;56(2):37–47.
In: Saunders C, ed. Cicely Saunders: Selected Writings 1958–2004.
Oxford: Oxford University Press, p. 11.
9. Saunders C. The last frontier. Frontier, Autumn 1966, pp. 183–186. In
Saunders C, ed. Cicely Saunders: Selected Writings 1958–2004. Oxford:
Oxford University Press, 1958, p. 87, 2006.
10. Saunders C. Report of tour in the United States of America (Spring),
unpublished. In Clark D. Cicely Saunders: A Life and Legacy. Oxford:
Oxford University Press, 1963, p. 171, 2018.
11. Kübler-Ross E. On Death and Dying. 50th anniversary ed. New York:
Scribner, 1969, p. 234.
12. Mount BM. Snapshots of Cicely: Reflections at the end of an era.
J Palliat Care 2005;21(3):133–135.
13. Clark D. Cicely Saunders: A Life and Legacy. Oxford: Oxford University
Press, 2018, p. 218.
14. Overy C, Tansey EM, eds. Palliative medicine in the UK c. 1970–2010.
Wellcome Witness to Twentieth Century Medicine, vol. 45. London: Queen
Mary, University of London, 2013, p. 9. http://www.histmodbiomed.org/
sites/default/files/92239.pdf
5
15. Hospice UK, 2019. Hospice UK highlights 2017–2018. p. 2. https://www.
hospiceuk.org/docs/default-source/about-us-documents-and-files/
hospiceuk_highlights-2018_web.pdf?sfvrsn=0
16. NHCPO, 2019. NHCPO Facts and Figures 2018 edition (Revised
7-2-2019) (no page numbers). https://39k5cm1a9u1968hg74aj3x51-
w pengine.netdna-ssl.com/w p-content/uploads/2019/07/2018 _
NHPCO_Facts_Figures.pdf
17. Pastrana T, De Lima L, Wenk R, et al. Atlas of Palliative Care in Latin
America. International Association for Hospice and Palliative Care,
2012, p. 8. https://cuidadospaliativos.org/uploads/2013/12/Atlas%20
of%20Palliative%20Care%20in%20Latin%20America.pdf
18. Soto-Perez-de-Celis, E, Chavarri-Guerra Y, Pastrana T, Ruiz-Mendoza
R, Bukowski A, Goss PE. End-of-life care in Latin America. J Global
Oncol 2017;3(3):261–270. https://www.ncbi.nlm.nih.gov/pmc/articles/
PMC5493222/
19. Worldwide Palliative Care Alliance. Global Atlas of Palliative Care.
WPCA, 2014, p. 36.
20. Overy C, Tansey EM, eds. Palliative Medicine in the UK c. 1970–2010.
Wellcome Witness to Twentieth Century Medicine, vol. 45. London:
Queen Mary, University of London, 2013, p. 115. http://www.histmod-
biomed.org/sites/default/files/92239.pdf
21. NICE, 2017. End of life care for adults. Quality Standard: Related Quality
Standards. NICE. https://www.nice.org.uk/guidance/qs13/chapter/
related-nice-quality-standards#related-nice-quality-standards
22. Ryndes T, Von Gunten, CF. The development of palliative medicine in
the USA. In: Bruera E, et al. eds. 2006. Textbook of Palliative Medicine.
London: Hodder Arnold, 2006, p. 33.
23. American Board of Medical Specialities, 2006. ABMS estab-
lishes New Subspecialty Certificate in Hospice and Palliative
Medicine. Press release, October 6, 2006. https://web.archive.org/
web/20101116144358/http://abms.org/News_and_Events/downloads/
NewSubcertPalliativeMed.pdf
24. Health Canada, 2018. Framework on Palliative Care in Canada. https://
w w w.canada.ca/en/health-canada/services/health-care-system/
reports-publications/palliative-care/framework-palliative-care-canada.
html
25. Morrison RS. A national palliative care strategy for Canada. J Palliative
Med 2017;20(Suppl 1):S-63–S-75. https://www.ncbi.nlm.nih.gov/pmc/
articles/PMC5733738/
26. African Palliative Care Association, 2019. Frequently Asked Questions.
https://www.africanpalliativecare.org/foot-menu/faqs/
27. Spruyt O. The status of palliative care in the Asia-Pacific region. Asia-Pac
J of Oncol Nurs 2018;5:12–14. https://www.ncbi.nlm.nih.gov/pmc/articles/
PMC5763429/
28. WHO, 2018. Palliative Care. https://www.who.int/en/news-room/
fact-sheets/detail/palliative-care
2
PALLIATIVE CARE AS A PUBLIC HEALTH ISSUE

Irene J. Higginson and Massimo Costantini

Contents
Introduction............................................................................................................................................................................................................................7
What is public health?...........................................................................................................................................................................................................7
Public health: New approaches.....................................................................................................................................................................................7
Public health approach to palliative care...........................................................................................................................................................................8
Patient and public involvement as part of the public health response..................................................................................................................8
Moving to palliative care as a human rights issues and the need for universal health coverage to include palliative care........................8
Public health challenges in palliative and supportive care............................................................................................................................................9
Escalating global palliative care need...........................................................................................................................................................................9
Response to population aging in the context of palliative care.............................................................................................................................10
Palliative care during epidemics and pandemics.....................................................................................................................................................10
Inequities.........................................................................................................................................................................................................................11
Poverty and deprivation..........................................................................................................................................................................................11
Extending palliative care beyond cancer.............................................................................................................................................................11
Other disadvantaged groups..................................................................................................................................................................................11
Effectiveness and cost-effectiveness of palliative care............................................................................................................................................12
Research...........................................................................................................................................................................................................................12
Concluding thoughts: Addressing palliative care through an expanding public health paradigm.....................................................................13
References..............................................................................................................................................................................................................................13

Introduction
Palliative care is increasingly recognized as an important pub-
lic health issue.1-5 Public health is the science of protecting and
improving the health of people and their communities. This is
achieved by promoting healthy lifestyles, researching disease and
injury prevention, and detecting, preventing, and responding to
common diseases and health concerns. Overall, public health is
concerned with protecting the health of entire populations. These
populations can be as small as a local neighborhood, or as big as
an entire country or region of the world.
Death and the end of life affect everyone in society. Despite
the continuing advances in prevention and curative treatments,
everyone will eventually die. Despite this, until recently pal-
liative care received very little attention in the field of public
health. This may be because public health focused on infec-
tious diseases, and on preventing illness and premature deaths.
However, the rise in non-communicable and chronic infectious
diseases, variations in access to care, evidence of inequities,
and the escalating need make palliative care a crucial public
health issue that requires response. Our societies are aging with
changes in population structures, and an increasing number
of older people with complex needs and chronic illness. This
requires a response that mobilizes communities, takes preven-
tative measures, and increases access to services, broadening
the focus of palliative care from patients and families to include
a societal approach.
This is set in the context where care at the end of life comprises
a large component of health-care resources; depending on the
methods used, around 20% of total health-care costs are spent
in the last year of life.6–8 Costs increase toward the end of life,
especially the last 3 months of life when, in many high income
countries, 80% of health-care costs are spent in the hospital.9
This chapter provides an introduction to the core principles of
public health and provides examples of public health solutions to
challenges of palliative care development.
What is public health?
The definition of public health as “the art and science of pre-
venting disease, prolonging life and promoting health through
the organized efforts of society,” first introduced in England in
1988,10 has been used by the World Health Organization (WHO)
and others since. Public health has further been interpreted as
“…a collective action of State and Civil Society to protect and
improve the health of individuals. It is a notion that goes beyond
population or community-based interventions and includes the
responsibility of ensuring access by citizens to quality health
care. It does not approach public health as an academic discipline
but rather as an interdisciplinary social practice.”11
The key element that distinguishes public health from clinical
care is being accomplished through social and political action,
as opposed to action targeted at the individual or family level.
Examples of public health include vaccination programs, smok-
ing awareness campaigns, professional education, reform of pub-
lic laws impacting health (such as alcohol tax), and many other
societal interventions.
Public health: New approaches
The definition of what constitutes a public health issue has evolved
with time. Because public health focuses on major causes of mor-
bidity and mortality, it must evolve as the causes of morbidity and

7
8 Textbook of Palliative Medicine and Supportive Care
mortality change. For example, public health approaches in the
18th and 19th century focused on sanitary and environmental
reforms, and antibacterial therapies to curb transmission of com-
municable diseases—like cholera, tuberculosis and malaria—
which were the main causes of morbidity.
In its earliest western incarnation, after John Snow closed the
famous London water pump and ended a cholera outbreak, public
health’s ambition did not extend much beyond what is now con-
sidered basic infectious disease epidemiology. The epidemiologi-
cal transition to noncommunicable diseases in the 20th century
necessitated the development of new public-health approaches to
addressing the problems posed by these killers of the new age.
As understanding of the determinants of health became more
sophisticated, so did public health practice. Disciplines of health
services research, sociology, economics, psychology, nutrition,
anthropology, and others are now considered by many to be
important in understanding the health of individuals and, hence,
populations and societies. The 1988 Acheson Report, commis-
sioned by the UK Minister of Health to review and summarize
health inequalities and to recommend priority areas for policy
development and interventions to reduce them, noted that their
work was based on a socioeconomic model of health that rec-
ognized that main determinants of health could be described
as layers of environmental and social influence over the fixed
individual constitutional factors. Similarly, the US Institute of
Medicine in their seminal report on the Future of Public Health
defines health as a “public good” because “many aspects of human
potential such as employment, social relationships, and political
participation are contingent upon it.”12 One area of action identi-
fied by this report was to adopt a population health approach that
considers multiple determinants of health.
The aging of societies and challenges of maintaining health
and function in a mostly older population, together with anti-
biotic resistances and new epidemics of poor health and ill-
nesses due to obesity, pollution, and other concerns, as we
see in the 21st century, requires a further evolution of public
health. New public health has emerged with one of its main
themes being that interventions be conducted with people
rather than on people. One main difference between the new
and old public health is that the professional dominance of
those from the outside—assuming that that they knew what
is best for the community—was challenged. For example, in
old public health, health professionals adopted an institution-
alized view toward hospice and end-of-life care (viewing death
and dying as experiences requiring “containment”). However,
the ideas of the new public health and community empower-
ment promote moving away from the focus on “containment”
to highlighting social and collective responsibility.
Public health approach to palliative care
As a health issue that affects everyone is amenable to population-
based and public sector interventions, and has the potential to
reduce suffering on a massive scale, palliative and end-of-life care
is an important public health issue. The disciplines of palliative
and supportive care, with their understanding of the interrela-
tionships between physical, spiritual, emotional, and practical
domains of human existence and suffering, fit quite comfortably
into an approach to population health that recognizes multiple
biopsychosocial determinants of health and enduring health
problems. It has made this philosophy the cornerstone of clinical
practice for decades.
Patient and public involvement as part
of the public health response
The current public health approach to palliative care includes
these ideas and is an integral part of the wider global health
promotion campaign. New initiatives are currently being devel-
oped which aim not only to promote the involvement of the
community in their care, but also to involve them in research.
An example of such initiatives is the “patient, family and public
involvement (PPI) in palliative care research” initiative at the
Cicely Saunders Institute in London. The aims of the PPI initia-
tive are primarily to improve the quality impact, and clinical
relevance of palliative-care research, and to demystify precon-
ceptions, and raise awareness of palliative care and palliative-
care research.13–16 Public involvement in palliative care has
evolved from a view that patients were too ill to be involved, to
innovative methods including face-to-face events, and on-line
fora.17
Moving to palliative care as a human rights
issues and the need for universal health
coverage to include palliative care
Palliative care encompasses, but extends beyond, end-of-life
care. WHO has defined palliative care as “…an approach which
improves quality of life of patients and their families facing life-
threatening illness through the prevention and relief of suffering
by means of early identification and impeccable assessment and
treatment of pain and other problems, physical, psychological
and spiritual.”18
A palliative approach then should be applied along all stages
of serious illness regardless of the immediacy of death. To do
otherwise can rightly be considered a failure to provide qual-
ity care. In this light, the public health mandate of palliative
care becomes even larger and more complex: the target for
palliative interventions is not just the result of a calculation
based on incidence of death but, rather, on prevalence of life-
threatening and serious disease in a defined population or geo-
graphic area.
Early initiatives outlined the principles and practice of pallia-
tive care as a human right.19 WHO guidance, such as Palliative
Care for Older People, and Palliative Care: the Solid Facts, pro-
vided the foundations for a wider evidence-based public health
approach to palliative care, supporting the growing recognition
of palliative care as a human right.18,20,21 The guidance provided
an imperative for governments in many countries to address pal-
liative care as part of universal health coverage and include it
within public health strategies.18,20–22
In 2014, the Worldwide Palliative Care Alliance produced the
Global Atlas of Palliative Care.23 The Atlas calculated global pal-
liative care needs and charted the response in different countries.
It reaffirmed that access to palliative care, including access to
pain relief, is a human right. The Atlas noted that palliative care
is highly effective at relieving the pain and suffering of people
living with and affected by life-limiting illness, greatly enhanc-
ing their ability to live to the fullest until the end of life, and yet
without increasing health-care costs. It highlighted that millions
of people worldwide cannot access this type of care, resulting in
grave suffering, and recommended:
1. Development of a research agenda to map and improve
the evidence base around palliative care. Special attention
should be afforded to populations such as children, older
people, and marginalized groups.
Palliative Care as a Public Health Issue 9

2. Comprehensive analysis to identify gaps in existing guid-
ance on palliative care across levels of care in health and
community systems and disease groups.
3. Scale-up, leadership, and accountability, with palliative
care becoming a part of universal health care, with mea-
surable benchmarks.
The Sixty-seventh World Health Assembly, in 2014, considered
and approved resolution WHA67.19, to strengthen palliative
care as a component of integrated treatment throughout the
life course. Member States were urged to develop, strengthen,
and implement “palliative care policies to support the compre-
hensive strengthening of health systems to integrate evidence-
based, cost-effective and equitable palliative care services in the
continuum of care, across all levels, with emphasis on primary
care, community and home-based care, and universal cover-
age schemes.” 24 This has prompted further initiatives to recog-
nize palliative care as a public health challenge, which must be
addressed. 5,25
Public health challenges in
palliative and supportive care
Escalating global palliative care need
The world’s population is growing. It is expected to grow from
7.79 billion in 2020, by a rate of 1.05% (2020) to 0.67% (2039) per
year, reaching 9.20 billion in 2040. Population growth is predicted
to slow slightly each year ranging 0.37–0.66% per year, reaching
10.15 billion population by 2060. Most of the population increase
will be in what are currently considered lower and middle income
countries.26 Note that we cannot assume that country incomes in
2020 will remain the same by 2040 or 2060.
While the growth of the world’s population is well recog-
nized, the projected growth in the number of annual deaths is
only recently being recognized. In 2008 Gomes et al. published
the first landmark predictions that identified that not only was
the population growing but the numbers of deaths annually were
predicted to grow from around 2018 onward.27 This change was
brought about by earlier “delaying of deaths” into later life with
a fall in annual deaths up to around 2003, and a surge in births
during the 1950s, increasing the population in certain age groups.
Subsequent research led to projections, which by 2019 gave a
much better picture of the likely future needs for palliative and
end-of-life care in many countries and globally.28–32
The total number of deaths worldwide is predicted to increase
by 79% from 57 million in 2016 to over 101 million in 2060
according to the WHO global mortality predictions.28 Assuming
that each death affects at least 5 other people, we have calculated
that end-of-life issues are estimated to affect at least 3.6% of the
world’s population each year in 2020, and 5% (i.e., 1 in 20 people)
each year in 2060. There are predicted increases in the numbers
of deaths and in need for palliative care in many countries, such
as by 2040 a 25% increase in England, 33 by 2050 a 26% increase in
Germany, 32 and by 2060 a 70% increase in Brazil, 34 see Table 2.1
for summary examples.
The causes and nature of death have changed, altering the
provision of care and impacting health-care systems. There are
three important changes driving an increasing role for palliative
care, with a public health approach. First, more people are dying
from chronic diseases rather than from acute illnesses. In 1900
in many countries, the leading causes of death were communi-
cable diseases, including tuberculosis and diarrheal diseases in
children. Nowadays, the top predicted causes of death are usually
heart disease, cerebrovascular disease/stroke, dementias, chronic
respiratory disease, respiratory infections, and lung cancer. Non-
communicable diseases and the later more chronic phases of
some communicable diseases (notably HIV/AIDS) are ever more
prevalent, requiring symptom relief and emotional, social, and
spiritual support. Second, people are living longer with these
chronic or multimorbid conditions, suggesting that they require
palliative care, symptom management, support for decision-mak-
ing and for those important to them and their families for longer
periods that in the past. Third, people are dying increasingly at
older ages and this is projected to increase. Some countries, such
as Portugal and Japan already have a high proportion of older
people in their societies.26,31,35 In England and Wales by 2040,
53.6% of those who die will be aged 85 years and over, compared
with only 38.8% in 2014.
The projections research have produced estimates of need for
palliative care, showing increases in need ranging from 42% to
112% depending on the region and methods of calculation.28–34
These increases in need have implications for where and how care
is provided, in particular the number of hospice, community and
hospital beds, and support for patients at home. In many coun-
tries, there has been a trend away from hospital death to more
home and care home deaths. However, for these trends to con-
tinue, the numbers of deaths at home and in care homes will
increase, with the majority of people supported outside hospital
by 2040. This leads to priorities relevant to public health: (1) to
increase and upskill a community health and social care work-
force through education, training, and valuing of care work; (2)
to build community care capacity through informal caregiver

TABLE 2.1  Growth in Numbers of Who Will Die and in Need for Palliative Care, Selection of Published Modeled Projections
Increase in Number
Country/Region Time Period of Annual Deaths Modeled Impacts Authors and Reference
England and Wales 2014–2040 25.4% A 42.4% increase in need for palliative care Etkind et al.33
England and Wales 2014–2040 26.8% Need to provide services for 134,390 more deaths each Bone et al.30
year
Scotland 2016–2040 15.9% A 60% increase in community and social care provision Finucane et al.29
is needed
Portugal 2010–2030 NA Hospital deaths will increase by 27.7–52.1% Sarmento et al.31
Germany 2009–2050 26.0% Implications for hospital care Simon et al.32
Brazil 2000–2040 70.0% 76% increase in palliative care need Santos et al.34
Global 2016–2060 79.0% 87% increase in serious health related suffering Sleeman et al.28
Sources: Source data used from Refs. [28–34].
10
support and community engagement; and (3) to stimulate a real-
istic public debate on death, dying, and sustainable funding.29,30
Projections of the future burden of serious health-related
suffering suggest that by 2060, 48 million people will need
direct palliative care each year.28 This approach uses the Lancet
Commission on Palliative Care and Pain Relief definitions of
serious health-related suffering, 36 combined with WHO mor-
tality projections (2016–2060) and estimates of physical and
psychological symptom prevalence in 20 conditions most often
associated with symptoms requiring palliative care.28 This pro-
jection of 48 million people represents 47% of all deaths globally
and is an 87% increase from 26 million people in 2016. Further,
83% of these deaths will occur in what are currently low-income
and middle-income countries. Serious health-related suffering
will increase in all regions, with the largest proportional rise in
low-income countries (155% increase between 2016 and 2060).
Globally, serious health-related suffering will increase most rap-
idly among people aged 70 years or older (183% increase between
2016 and 2060). In absolute terms, it will be driven by rises in
cancer deaths (16 million people, 109% increase between 2016
and 2060). The condition with the highest proportional increase
in serious-related suffering will be dementia (6 million people,
264% increase between 2016 and 2060).28 If a different defini-
tion, based on a more comprehensive approach to determine
palliative care needs are applied, where 63–82% of all deaths
have palliative care needs37 (rather than only 48%), the escala-
tion in need is much more marked. In these instances the num-
bers of deaths are growing annual, due to prolonged survival
and an earlier boom in births, leading to 15–30% increases in
annual deaths by 2040.29,33
Response to population aging in
the context of palliative care
Life expectancy is increasing in most countries, and populations
are living longer and are on average older. In 2018, for the first
time in history, persons aged 65 or above outnumbered children
under five years of age globally. Projections by the United Nations
suggest that the number of people aged 80 years and over world-
wide will triple, from 143 million in 2019 to 426 million in 2050.
By 2050, one in six people in the world will be over age 65 (16%), up
from one in 11 in 2019 (9%). Regions where the share of the popu-
lation aged 65 years or over is projected to double between 2019
and 2050 include Northern Africa and Western Asia, Central
and Southern Asia, Eastern and South-Eastern Asia, and Latin
America and the Caribbean. By 2050, one in four persons living
in Europe and Northern America could be aged 65 or over.26
While the number of deaths is expected to increase, the poten-
tial support ratio, which compares numbers of persons at working
ages to those over age 65, is falling around the world. In Japan this
ratio is 1.8, the lowest in the world. An additional 29 countries,
mostly in Europe and the Caribbean, already have potential sup-
port ratios below three. By 2050, 48 countries, mostly in Europe,
Northern America, and Eastern and South-Eastern Asia, are
expected to have potential support ratios below two. These low
values underscore the potential impact of population aging on the
labor market and economic performance, as well as the fiscal pres-
sures that many countries will face in the coming decades as they
seek to build and maintain public systems of health care, pensions,
and social protection for older persons.26 This will place pressures
on health and social care systems to provide care and support.
The number of informal caregivers may also decrease. This is
in part due to women, who have traditionally been relied on to
Textbook of Palliative Medicine and Supportive Care
care for people at the end of life, more frequently being in for-
mal employment. Social changes such as smaller family size, dis-
persed families, and increased divorce rates have made informal
caregiver availability less self-evident. Research from different
countries and in different conditions finds that informal caregiv-
ers provide considerable care at the end of life, often more than
formal care. 38–42 If the activities and support of informal caregiv-
ers needed to be paid for, this could lead to an increase of 250%
(for people with advanced illness and breathlessness)40 or 300%
(in the case of people with early onset dementia). 39
Given this unprecedented global aging it is vital to align health
and social care for older populations to support the dual priorities
of living well, while also experiencing increasing or fluctuating
illnesses and ultimately the end of life.5 This objective is not in
conflict with those of palliative care in its origins, as Dame Cicely
Saunders said, “we will do all we can to help you live well, even at
the end of life.” It is also important to remember that many older
people continue to make substantial contributions to society, and
continue in good health until a very old age.
Nevertheless, it is imperative to develop and evaluate new mod-
els of care that respond to the changing (and often very elderly)
populations needing palliative care that are effective, appropriate,
and affordable.
A review recently identified two overarching classifications
of service models but with different target outcomes: Integrated
Geriatric Care, emphasizing physical function, and Integrated
Palliative Care, focusing mainly on symptoms and concerns.
Areas of synergy across the overarching classifications included
person-centered care, education, and a multiprofessional work-
force.43 Both approaches highlight the urgency to integrate
the care continuum, with service involvement triggered by the
patient’s needs and likelihood of benefits. Economic analyses
that span health and social care and take a societal approach
to care costs, including informal caregivers, are critical. New
models of care, such as short-term integrated palliative care,
appear promising for these populations and have effectiveness
and cost-effectiveness in randomized trials44–49 and appear to
promote patient and family dignity.48
Palliative care during epidemics and pandemics
Palliative care is an important component of health care in epidem-
ics and pandemics, contributing to symptom control, psychologi-
cal support, and supporting triage and complex decision-making.50
The hospice and palliative care sector are capable of responding
flexibly and rapidly to epidemics and pandemics. This has been
evident in the SARS, MERS, Ebola, and COVID-19 epidemics and
pandemics.51 A useful framework is to consider the availability
and response in terms of systems (policies, training and protocols,
communication and coordination, and data), staff (deployment,
skill mix, and resilience), space (community provision and use of
technology), and stuff (medicines and equipment as well as per-
sonal protective equipment).51
Palliative care services do not have capacity to care for all those
in need but can help by ensuring protocols for symptom man-
agement are available, and training non-specialists in their use;
being involved in triage; considering shifting resources into the
community; considering redeploying volunteers to provide psy-
chosocial and bereavement care; facilitating camaraderie among
staff and adopting measures to deal with stress; using technology
to communicate with patients and caregivers; and adopting stan-
dardized data collection systems to inform operational changes
and improve care. It is essential that public health services,
Palliative Care as a Public Health Issue
planners, and governments recognize the essential contribution
of hospice and palliative care to epidemics and pandemics, espe-
cially in instances where the disease is not curable. While preven-
tion and treatment are of course important, care and symptom
management for those affected are also vital.
The 2020 COVID-19 pandemic is a particular instance where
palliative care was even more vital. The population most affected
was older, frailer people, and in some countries, such as the UK,
especially those in care homes.52,53 The excess deaths and suffer-
ing may not only relate to the number of people known to have
the disease. As was seen in many countries, excess mortality was
far greater than would be expected from the number of people
affected by the disease and may have been double the number of
reported deaths.54 This may be due to missed diagnoses, and also
the consequences of measures to control infection or strain on
health-care services. Thus, there is a need to ensure that palliative
care is integrated into the health-care system response. However,
essential equipment, including availability of personal protective
equipment, syringe drivers, appropriate medicines, and setting-
specific guidance are essential.
Inequities
Poverty and deprivation
Evidence suggests that people in the lowest socio-economic class
tend to die younger, with poorer quality of life than those in higher
socio-economic classes.55–57 Also, there are more hospital deaths in
areas of high socio-economic deprivation, despite preferences to the
contrary.56–58 Perhaps because it tends to be more difficult to raise
charitable funds for home and hospice care in deprived areas,
the level of palliative care provision may be inversely proportional to
the level of need—the inverse care law. In addition to the complex
range of factors that contribute toward the inverse care law, knowl-
edge and awareness of palliative care and related services also appear
to be important here. Koffman et al. surveyed 252 cancer patients at
2 hospitals in London and found that the least materially deprived
patients were significantly more likely to recognize and describe the
term palliative care (OR = 8.4; p = 0.002) and understand the role of
Macmillan nurses (OR = 6.68; p < 0.0001)—when compared with
their most deprived peers.59 People with lower education levels also
have poorer access to palliative care.60
A recent systematic review analyzed data from 209 studies
from a wide diversity of countries. Compared to people living
in the least deprived neighborhoods, people living in the most
deprived neighborhoods were more likely to die in hospital ver-
sus home (OR 1.30, 95% CI 1.23–1.38, p < 0.001), to receive acute
hospital-based care in the last 3 months of life (OR 1.16, 95% CI
1.08–1.25, p < 0.001), and to not receive specialist palliative care
(OR 1.13, 95% CI 1.07–1.19, p < 0.001). For every quintile increase
in area deprivation, hospital versus home death was more likely
(OR 1.07, 95% CI 1.05–1.08, p < 0.001), and not receiving special-
ist palliative care was more likely (OR 1.03, 95% CI 1.02–1.05, p <
0.001). Compared to the most educated (qualifications or years
of education completed), the least educated people were more
likely to not receive specialist palliative care (OR 1.26, 95% CI
1.07–1.49, p = 0.005).61 Although the observational nature of the
studies included and the focus on high-income countries limit
the conclusions of this review, the results bear out the social ineq-
uity of access to palliative care, which still needs addressing after
it was first identified in 1994.62,63 Worryingly, Sleeman’s recent
analysis of access to inpatient hospices suggests that the trend
may be heading in the wrong direction in the UK.64 People who
are homeless also seem to have poorer access to palliative care.65
11
Extending palliative care beyond cancer
Although early studies of the need for people at the end of life
included different diseases, the response of palliative care is often
more focused in cancer in most countries.66 This leads to inequi-
ties, where people with non-cancer conditions, but similar levels
of symptoms, often miss out on the best in palliative care. For
example, research shows that patients with many different pro-
gressive chronic diseases have similar symptom profiles. Five
symptoms—pain, breathlessness, fatigue, anorexia, worry—are
common among more than 50% of patients with advanced can-
cer, acquired immune deficiency syndrome, chronic heart failure,
end-stage renal disease, chronic obstructive pulmonary disease,
multiple sclerosis, motor neuron disease, Parkinson’s disease, and
dementia; 9–11 different symptoms are prevalent across all these
conditions.67,68 There appeared to be a common pathway toward
death for malignant and non-malignant diseases. Despite this,
access for patients with diseases other than cancer is often limited.
For example, people with progressive lung diseases have poorer
access to palliative care, despite having similar problems with
symptoms, need for information and support.69,70 A similar pat-
tern is for patients with neurological disease, such as Parkinson’s
disease or multiple sclerosis,71–73 heart disease,74–77 renal and liver
failure,78–81 HIV/AIDS,82,83 and many other conditions.
In recent years, dementia has become a major health challenge
worldwide and accounts for increasing health resource use, par-
ticularly in developed countries.84 In 2005, the global prevalence
of dementia was estimated to be 23.4 million, with an incidence of
4.6 cases annually (a new case every second).85 The prevalence of
dementia is expected to reach 81.1 million people by 2040, most
of whom will live in developing countries (60% in 2001, rising to
71% by 2040).85 Research suggests that symptoms of dementia are
similar to those of cancer; however, patients with dementia expe-
rience these symptoms for longer periods than those with can-
cer.86 “Patients with dementia often receive poor end-of-life care,
with inadequate pain control and without access to the palliative
care services that patients with cancer are offered.”87
Other disadvantaged groups
Age is linked to disadvantaged groups by diagnosis, as people
with non-cancer conditions tend to be older. In many countries,
older patients and their caregivers do not have equal access to
palliative care when compared with younger patients.88 This may
partly be accounted for by the fact that the majority of patients
receiving palliative care are cancer patients—who, on average, are
younger—but age appears to be an independent factor, both in
place of death and access to specialist care. A systematic review
by Burt and company on the effect of age on referral to special-
ist palliative care reported that “older people were less likely to
be referred to, or to use, specialist palliative care.”89 Although
this direct age discrimination is important, the main concern is
perhaps that of indirect discrimination through failure to pro-
vide adequate palliative care to older people in the hospital. A
European population-based survey by Gomes et al. found that
between 51% and 84% of people across seven countries would
prefer to die at home if they had advanced cancer.90 Despite this,
34–63% of deaths occurred in hospital, and older people were
found to be more likely to die in the hospital when compared
with their younger counterparts.91 Furthermore, a UK national
end-of-life care survey of 473 bereaved informal caregivers found
that 75.6% of the under 85s were reported to have had an official
record of preference for place of death, but this was only true for
12
39% of the oldest old (people aged 85 years and over).92 The study
also found that being over the age of 85 was associated with a 64%
reduction in the odds of dying at home (OR = 0.36).92
Other disadvantaged groups include black and minority eth-
nic groups;93–95 people with learning disabilities; lesbian, gay,
bisexual, and transgender groups;96 prisoners; refugees, asylum
seekers, and others.97 There is also regional variation in access to
palliative care.97
Effectiveness and cost-effectiveness of palliative care
The effectiveness of palliative care can be considered at two levels.
There is the general issue of the effectiveness of expert palliative
care services and approaches, and there is also the effectiveness of
individual new interventions, services, or approaches, including
those that train those less experienced in palliative care.
There is now quite good evidence to support expert (or spe-
cialist) palliative care multiprofessional teams. High-quality and
randomized trial evidence reveals that palliative care services
improve outcomes and are effective, cost-effective, and high
value (outcomes/costs).1–4 These appear to improve symptom
control, reduce depression and psychological distress, in some
instances improve patient quality of life, and may improve sur-
vival.4,98–103 They also can reduce caregiver burden.46 However, it
should be stressed that these studies were carried out on services
staffed usually by experts trained in palliative care. Therefore, it
is important that as palliative care services develop more widely,
outcomes are assessed on a routine basis—to ensure that the pal-
liative care services continue to achieve high-quality outcomes
for patients and families. Otherwise, there may be a temptation
for funders and commissioners of services to cut corners.104,105
There is, however, less evidence that specific training programs
or pathways adapted from hospices and palliative care services
and provided to generalists can improve care. The Liverpool care
pathway failed to provide evidence of significant patient or care-
giver benefits in a cluster randomized controlled trial.106 Many
other training systems are in development but are not yet well
evaluated. Equally, new techniques and treatments often need
evaluation.
It is important for palliative care interventions to be routinely
subjected to economic evaluation for at least two reasons. First, eco-
nomic evaluation can enable comparisons between palliative care
services to determine the most efficient use of currently allocated
resources. “Services that can be shown to be relatively ineffective and
costly can be replaced by those that achieve more for less.”107
Second, and most importantly, palliative care will always
compete with other health-care services for the same funds. It
is the responsibility of health policy makers to consider “value
for money” when deciding what services to fund. Arguing for
special consideration based on an intrinsic value of a service is
rarely sufficient. Failure to demonstrate the cost-effectiveness of
interventions can result in weak arguments in the competition
for scarce resources.107 Moreover, the WHO resolution on pallia-
tive care urges member states to develop and implement policies,
which support the integration of cost-effective and equitable pal-
liative care services in the continuum of care, across all levels.108
Therefore, to enable health policy makers to provide the resources
required to meet the needs of dying patients, it is necessary for
the palliative care community to provide information on the
“value for money” of palliative care. Economic evaluation using
cost-utility analysis—which compares interventions in terms of
their cost per quality-adjusted life years (QALYs) gained—is a
common means of providing such information.109,110
Textbook of Palliative Medicine and Supportive Care
However, economic evaluations, particularly cost-utility analy-
sis of palliative care, are relatively rare, partly due to the diffi-
culties of estimating costs and outcomes. For example, a 2014
review of the cost-effectiveness of palliative care found that the
majority of studies focused only on costs (cost analysis), only
one study reported cost-effectiveness analysis, and none of the
studies report cost-utility analysis.111 The authors conclude that
in most cases, palliative care was significantly cheaper than
comparators.111 “Economic evaluation of palliative interven-
tions poses some challenges, both for palliative medicine and for
economics.”107
A major challenge around measuring cost in palliative care is
that it is difficult to attribute true costs (and outcomes) to one
particular service or intervention because, within a single episode
of illness, palliative-care patients are usually cared for by various
providers in different settings, simultaneously.112 Also, because
palliative-care patients have complex needs and demands, it is
necessary to adjust for need and complexity (case-mix) when
comparing costs between providers. It is reassuring that in a num-
ber of countries, palliative care funding models which account for
case-mix are being developed, such as the Australian National
Sub-acute and Non-acute Patient system,113,114 and the current
development work on a palliative-care “currency” in the UK.115
Although issues exist around measuring cost, the measure-
ment of outcomes is arguably more challenging in the context
of economic evaluations—particularly cost-utility analysis—of
palliative care. This may partly be because some of the goals of
palliative care—such as improving the quality of the experience
of death—may be incompatible with how the QALY is estimated
(i.e., centered around maximizing healthy or quality-adjusted
life-years). There has been a lot of debate on the appropriateness
of the QALY as an outcome measure in cost-utility analyses of
palliative care services.107,116–120 A major criticism of the QALY
framework is that standard tools, such as the EQ-5D121,122 and
SF-6D122—which have preference weights that enable the estima-
tion of QALYs—are “generic” in nature, and so, do not capture
specific domains that are important to palliative care.117,119 Several
validated palliative-care-specific outcome measures exist, such
as the Palliative Care Outcome Scale (POS),123 and the McGill
Quality of Life Questionnaire,124 which capture important pal-
liative care domains. Recent research with the POS is develop-
ing preference weights, so that this can be used as an economic
measure.125
Research
Clearly, tracking the scope of pain and suffering should be a vital
concern that benefits public health and the public good. There
is a clear need to develop an evidence base for policy and pro-
grams.126,127 Documenting chronic illness, pain, and symptoms
and their management through epidemiologic and demographic
and health surveys should be integral in high, middle, and low
income countries.128 Research is needed to identify salient char-
acteristics of successful palliative care programs.127 Studies must
be performed that describe and analyze practice, policy, and
advocacy to inform future developments and research for build-
ing programs that achieve the varied goals of palliative care—that
is, achieving the best quality of life for patients and their families.
To minimize risk of failure, it is important that new or expanding
palliative care projects in developing countries understand both
the successes and failures of existing programs. Several issues
recently identified as research topics for investigation include
availability of pain-relieving drugs, pain and symptom control,
 Palliative Care as a Public Health Issue
access to services, education and training, identification of rel-
evant needs and determination of outcomes for care at the com-
munity level, and evaluation of the impact of education of policy
makers and program directors about palliative care. Given the
magnitude of palliative care required by people living in devel-
oping regions of the world, programs must also consider cover-
age and not simply strive to provide high-quality care to a few
patients. End-of-life and palliative care research is currently allo-
cated a minute proportion of research funding (e.g., 0.24% of can-
cer research funding in the UK and 1% in the United States).129 To
ensure high-quality research outputs, investment in end-of-life
care research is urgently needed.
Concluding thoughts: Addressing
palliative care through an expanding
public health paradigm
Public health focuses on health promotion and prevention of dis-
ease and has often seen pain and suffering as removed from the
public health paradigm, left to be addressed by tertiary care in a
biomedical/clinical model. Although WHO and others have long
argued a broadening of the concept of health that includes how
well people are able to perform their daily tasks, only recently has
daily functioning begun to be included routinely in the assess-
ment of people’s health status through measures of health-related
quality of life. Simple measures have been tested and adapted
for use in a wide variety of settings including lower income set-
tings.123,130–136 Investigators are going beyond the traditional para-
digm that views health only in terms of adherence to or deviation
from physical or biochemical markers. Instead, they are including
in their assessment of health people’s own reports of their sense
of well-being and their ability to perform valued social roles.
Indeed, there is some evidence that these more patient-centered
KEY LEARNING POINTS
• Palliative care is now recognized as a core public
health issue.
• The need for palliative care is escalating, with ris-
ing numbers of deaths annually across the globe,
population aging and changes in chronic diseases
and multimorbidity.
• Estimates of growth in palliative care need range
from 40% to 87% between now and 2060.
• Although palliative care is now recognized as a
core human right, and should be part of univer-
sal health care (with a World Health Assembly
declaration in 2014), there are still inequities in
access.
• Inequities in access to palliative care in particular
affect groups, such as those with socioeconomic
disadvantage, non-cancer diagnosis, elderly, cul-
tural minorities, those with lower education,
homelessness, and those who are lesbian, gay,
bisexual, or transgender.
• There is good evidence that palliative care is
effective, cost-effective, and adds value (costs/
outcomes), but new models may need to evolve to
respond to the populations of the future.
BK-TandF-BRUERA_9780367642037-200160-Chp02.indd 13
13
measures are better markers of illness than traditional biologi-
cal measures.137 Therefore, pain and suffering should be mea-
sured through epidemiological and social science methods as a
critical health condition that should be tracked just as we track
infectious diseases. By expanding the public health paradigm to
include and promote palliative care, we further the goals of public
health—prevention of disease and prolonging life in society. As
life expectancy increases and medical advances are being made,
people are living longer with chronic diseases. Therefore, an inte-
grated model of palliative care has practical and pragmatic impli-
cations for public health universally. Marginalizing those in need
of palliative care services to clinical specialists or ignoring them
entirely creates a society in dire need of public health action and
intervention.
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76. Harding R, Selman L, Beynon T, et al. Meeting the communication and
information needs of chronic heart failure patients. J Pain Symptom
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77. Selman L, Harding R, Beynon T, et al. Improving end-of-life care for
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78. Mazzarelli C, Prentice WM, Heneghan MA, Belli LS, Agarwal K,
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80. Murtagh FE, Addington-Hall JM, Higginson IJ. End-stage renal dis-
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81. Murtagh FE, Higginson IJ. Death from renal failure eighty years on:
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88. Lock A, Higginson I. Patterns and predictors of place of cancer death
for the oldest old. BMC Palliat Care 2005;4:6.
89. Burt J, Raine R. The effect of age on referral to and use of specialist pal-
liative care services in adult cancer patients: A systematic review. Age
Ageing 2006;35(5):469–476.
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death if faced with advanced cancer: A population survey in England,
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Oncol 2012;23(8):2006–2015.
91. Cohen J, Bilsen J, Addington-Hall J, Lofmark R, et al. Population-
based study of dying in hospital in six European countries. Palliat Med
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92. Hunt KJ, Shlomo N, Addington-Hall J. End-of-life care and pref-
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93. Price RA, Parast L, Haas A, Teno JM, Elliott MN. Black and Hispanic
patients receive hospice care similar to that of white patients when in
the same hospices. Health Aff (Millwood) 2017;36(7):1283–1290.
94. Calanzani N, Koffman J, Higginson IJ. Palliative and End of Life Care
for Black, Asian and Minority Ethnic Groups in the UK. London: Marie
Curie Cancer Care, 2013.
95. Koffman J, Higginson IJ. Accounts of carers’ satisfaction with
health care at the end of life: A comparison of first generation black
Caribbeans and white patients with advanced disease. Palliat Med
2001;15(4):337–345.
96. Bristowe K, Hodson M, Wee B, et al. Recommendations to
reduce inequalities for LGBT people facing advanced illness:
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97. Wee B. Models of delivering palliative and end-of-life care in the UK.
Curr Opin Support Palliat Care 2013;7(2):195–200.
98. Gomes B, Calanzani N, Curiale V, McCrone P, Higginson IJ.
Effectiveness and cost-effectiveness of home palliative care services for
adults with advanced illness and their caregivers. Cochrane Database
Syst Rev 2013;6:CD007760.
99. Paiva CE, Faria CB, Nascimento MSDA, et al. Effectiveness of a pal-
liative care outpatient programme in improving cancer-related symp-
toms among ambulatory Brazilian patients. Eur J Cancer Care (Engl)
2012;21(1):124–130.
100. Harding R, List S, Epiphaniou E, Jones H. How can informal caregiv-
ers in cancer and palliative care be supported? An updated systematic
literature review of interventions and their effectiveness. Palliat Med
2012;26(1):7–22.
101. Gomez-Batiste X, Porta-Sales J, Espinosa-Rojas J, Pascual-Lopez A,
Tuca A, Rodriguez J. Effectiveness of palliative care services in symp-
tom control of patients with advanced terminal cancer: A Spanish,
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Symptom Manage 2010;40(5):652–660.
102. Higginson IJ, Finlay IG, Goodwin DM, et al. Is there evidence that pal-
liative care teams alter end-of-life experiences of patients and their
caregivers? J Pain Symptom Manage 2003;25(2):150–168.
103. Finlay IG, Higginson IJ, Goodwin DM, et al. Palliative care in hos-
pital, hospice, at home: Results from a systematic review. Ann Oncol
2002;13(Suppl 4):257–264.
104. Teno JM, Casarett D, Spence C, Connor S. It is “too late” or is it?
Bereaved family member perceptions of hospice referral when their
family member was on hospice for seven days or less. J Pain Symptom
Manage 2012;43(4):732–738.
105. Teno JM, Gozalo PL, Lee IC, et al. Does hospice improve qual-
ity of care for persons dying from dementia? J Am Geriatr Soc
2011;59(8):1531–1536.
106. Costantini M, Romoli V, Leo SD, et al. Liverpool care pathway for
patients with cancer in hospital: A cluster randomised trial. Lancet
2014;383(9913):226–237.
107. Normand C. Economics and evaluation of palliative care. Palliat Med
1996;10(1):3–4.
108. WHO. Strengthening of palliative care as a component of integrated
treatment within the continuum of care. In: 134th Session: Document
EB134.R7, 2014. http://apps.who.int/gb/e/e_eb134.html (Accessed 03
Jun 2014).
109. Earnshaw J, Lewis G. NICE guide to the methods of technology
appraisal: Pharmaceutical industry perspective. PharmacoEconomics
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110. Drummond MF, Sculpher MJ, Torrance GW, O’Brien BJ, Stoddart GL.
Methods for the Economic Evaluation of Health Care Programmes,
third ed. Oxford: Oxford University Press, 2005.
111. Smith S, Brick A, O’Hara S, Normand C. Evidence on the cost and
cost-effectiveness of palliative care: A literature review. Palliat Med
2014;28(2):130–150.
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112. Murtagh FEM, Groeneveld IE, Kaloki YE, Calanzani N, Bausewein C,
Higginson IJ. Capturing activity, costs, and outcomes: The challenges
to be overcome for successful economic evaluation in palliative care.
Progress Palliat Care 2013;21(4):232–235.
113. Gordon R, Eagar K, Currow D, Green J. Current funding and financ-
ing issues in the Australian hospice and palliative care sector. J Pain
Symptom Manage 2009;38(1):68–74.
114. Palmer KS, Agoritsas T, Martin D, et al. Activity-based funding of hos-
pitals and its impact on mortality, readmission, discharge destination,
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115. Team NEFSFP. Developing a new approach to palliative care funding: A
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2014).
116. Gomes B, Harding R, Foley KM, Higginson IJ. Optimal approaches
to the health economics of palliative care: Report of an international
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117. Normand C. Measuring outcomes in palliative care: Limitations of
QALYs and the road to PalYs. J Pain Symptom Manage 2009;38(1):27–31.
118. Round J. Is a QALY still a QALY at the end of life? J Health Econ
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capability: The spread of ideas in health economics. Soc Sci Med
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123. Hearn J, Higginson IJ. Development and validation of a core out-
come measure for palliative care: The palliative care outcome scale.
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125. Dzingina M, Higginson IJ, McCrone P, Murtagh FEM. Development of
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126. Cassel JB, Kerr KM, Kalman NS, Smith TJ. The business case for pallia-
tive care: Translating research into program development in the U.S. J
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127. Evans CJ, Harding R, Higginson IJ. ‘Best practice’ in developing and
evaluating palliative and end-of-life care services: A meta-synthe-
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128. Harding R, Selman L, Powell RA, et al. Research into palliative care in
sub-Saharan Africa. Lancet Oncol 2013;14(4):e183–e188.
129. Sleeman KE, Gomes B, Higginson IJ. Research into end-of-life cancer
care–investment is needed. Lancet 2012;379(9815):519.
130. Murtagh FE, Ramsenthaler C, Firth A, et al. A brief, patient- and proxy-
reported outcome measure in advanced illness: Validity, reliability and
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Palliat Med 2019;33(8):1045–1057.
131. Guo P, Gao W, Higginson IJ, Harding R. Implementing outcome mea-
sures in palliative care. J Palliat Med 2018;21(4):414.
132. Bausewein C, Daveson BA, Currow DC, et al. EAPC white paper on
outcome measurement in palliative care: Improving practice, attaining
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come measurement. Palliat Med 2016;30(1):6–22.
133. Harding R, Selman L, Agupio G, et al. Validation of a core outcome
measure for palliative care in Africa: The APCA African palliative out-
come scale. Health Qual Life Outcomes 2010;8:10.
134. Eisenchlas JH, Harding R, Daud ML, Perez M, De Simone GG,
Higginson IJ. Use of the palliative outcome scale in Argentina: A cross-
cultural adaptation and validation study. J Pain Symptom Manage
2008;35(2):188–202.
135. Veronese S, Rabitti E, Costantini M, Valle A, Higginson I. Translation
and cognitive testing of the Italian Integrated Palliative Outcome
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136. Ellis-Smith C, Higginson IJ, Daveson BA, Henson LA, Evans CJ,
BuildCare. How can a measure improve assessment and management
of symptoms and concerns for people with dementia in care homes? A
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One 2018;13(7):e0200240.
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Higginson IJ. Longitudinal validity and reliability of the Myeloma
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2017;26(11):2931–2947.
3
PALLIATIVE CARE AS A PRIMARY CARE ISSUE

Scott A. Murray, Sebastien Moine, and Kirsty Boyd

Contents
Primary palliative care has a sixfold potential to deliver better end-of-life care.....................................................................................................17
First potential of palliative care in primary care: Caring for people with all life-threatening conditions..........................................................17
Second potential of palliative care in primary care: An integrated palliative care approach from diagnosis of life-threatening
conditions rather than toward the end............................................................................................................................................................................18
Third potential of palliative care in primary care: Meeting all dimensions of need (physical, psychological, social, and spiritual)............19
Rapid functional decline...............................................................................................................................................................................................19
Intermittent, fluctuating decline.................................................................................................................................................................................20
Gradual decline...............................................................................................................................................................................................................20
Fourth potential of palliative care in primary care: Making a difference in the community................................................................................20
Fifth potential of palliative care in primary care: Reaching to all in need in economically poorer countries and learning from
them about bringing death back to life............................................................................................................................................................................21
Sixth potential of palliative care in primary care: Supporting family caregivers in their time of caring and subsequent bereavement.....21
Facilitating factors for strong primary palliative care...................................................................................................................................................22
Caring for all in the last year or phase of life..................................................................................................................................................................22
References..............................................................................................................................................................................................................................22

BOX 3.1  DEFINITIONS USED IN THIS CHAPTER

Key worker: Health or social care professional with responsibility for organizing the care of an individual patient.
Palliative care approach: An approach that generalist health and social care providers can adopt whereby they consider all
dimensions of the person’s care and life experience and plan holistic care for the future as well as the present with them.
Primary palliative care1: Primary palliative care is palliative care practiced by primary health-care workers, who are the
principal providers of integrated health care for people in local communities throughout their life. It includes early identifica-
tion and triggering of palliative care as part of integrated and holistic chronic disease management, collaborating with specialist
palliative care services where they exist, and strengthening underlying professional capabilities in primary care.
Specialist palliative care: Services whose core activity is the provision of palliative care. The main role of specialist pallia-
tive care is to manage patients and families with more complex and challenging needs while supporting and training generalist
palliative care providers.
Terminal care: Care in the last days or week of life or care in the dying phase.
Transition in care: A change in setting or place of care or a change in the focus of care from being largely curative to being
more supportive and palliative.

Primary palliative care has a sixfold
potential to deliver better end-of-life care
The first potential is to identify and treat people with any serious
or life-threatening condition taking palliative care beyond cancer
and adapting it to meet the diverse needs of the growing num-
bers of people dying with non-malignant conditions. The second
potential is to help people earlier rather than later, not just in
the very terminal stage but from diagnosis of a life-threatening
illness. The third potential is to care for all aspects of the person,
all dimensions—physical, psychological, social, and spiritual—
as good family practitioners already do. The fourth potential is
to have reliably good palliative care available in all community
settings: residential and care homes and people’s own home. The
fifth potential is making end-of-life care available for people in
all nations, especially the poorer countries. Finally, primary care
teams can support family caregivers in their time of caring and
subsequent bereavement, as they are frequently cared for by the
same primary care team.
First potential of palliative care in
primary care: Caring for people with
all life-threatening conditions
In more economically developed countries, most people die after
a longish period of disability with the top three causes of death
now being cancer, organ failure, and frailty/dementia.2 This can
be illustrated by noting that a family physician in the UK, who has
on average about 1,800 patients on his or her registered list, has 18
deaths on average per year. If we only take into account the under-
lying cause of death (i.e., the disease or injury leading directly to
death), then five of these deaths are from cancer, seven from organ

17
18
FIGURE 3.1  The three main trajectories of decline at the end
of life. Number of deaths in each trajectory, out of the average 18
deaths each year per UK general practice list of 1,800 patients.
(Adapted from Murray SA and Sheikh A, BMJ 2008; 336:958–959.)
failure (such as chronic obstructive pulmonary disease, heart fail-
ure, liver failure, renal failure), and four from frailty or progres-
sive neurological conditions (including dementia). The presence of
multimorbidity is now normal3: it is included in annual mortality
data as contributing causes of death but most people still follow
one of three typical trajectories of decline. Only about 2 out of the
18 are likely to die totally unexpectedly (Figure 3.1).4 So around
90% of deaths are in people with progressive conditions and pri-
mary care teams have the opportunity to adopt a palliative care
approach with most of these people in a timely way.
For these three main categories of dying, the implications for
palliative care provision are quite different as the patients’ needs
differ. The rapid trajectory (typically cancer) follows a more pre-
dictable course with a short decline toward the end. Hospice
care fits well with people dying with cancer and can meet their
needs.5 Conversely, patients with an intermittent trajectory (typi-
cally organ failure) may have a gradual decline over 2–5 years, but
during that period, there are acute episodes and frequent hospital
admissions. Such patients may die rapidly at any time but, in con-
trast with advanced cancer, are not expected to die in the next few
months. Prognostic uncertainty and funding constraints mean
such patients rarely benefit from specialist palliative care except
close to death and usually when in hospital. The gradual frailty
trajectory is variable and may last for many years from the onset of
difficulties in functional activities of daily living and/or cognitive
impairment associated with dementia. The needs of this group are
for holistic care and long-term support at home, caregiver sup-
port, and nursing care at home or in care homes. In many coun-
tries, support for this group is inconsistent. Therefore, to meet the
end-of-life needs of all patients reliably, we must provide support
to people with all illnesses, and primary care is uniquely placed to
identify patients with one or more advanced progressive condi-
tions. There is a challenge for specialist palliative care to redesign
services so that they are configured to meet the typical needs of
people on the three archetypal trajectories, providing access based
on needs not diagnosis. An emphasis on education and integrating
with primary care are the obvious ways to take this forward.
Textbook of Palliative Medicine and Supportive Care
Second potential of palliative care in
primary care: An integrated palliative care
approach from diagnosis of life-threatening
conditions rather than toward the end
With cancer, traditionally there was a period when a cure was
the aim and then, when this was no longer possible, palliative
care intervened. The new and better concept is that supportive
and palliative care should start at diagnosis of a life-threatening
illness and gradually increase while disease-modifying manage-
ment may change its focus or decrease (Figure 3.2). This model
and understanding can be applied to all people with progres-
sive conditions including organ failure and frailty.6,7 As debility
increases, from specific illnesses or general frailty, people can be
considered for a palliative approach while continuing with dis-
ease-modifying treatment. Provision of palliative care should be
triggered not by diagnosis, or even prognosis, but by a growing
burden of illness and related needs. Another specific trigger for
considering a holistic palliative approach might be admission to a
residential or nursing care home, as this transition is to increase
supportive care. Alternatively, for people at home the need for
more practical care and support for the patient and or caregiver
can be a trigger for review of overall care and care planning.
In the organ failure and frailty trajectories, it can be more dif-
ficult to conceptualize and decide when a palliative care approach
might be clinically appropriate. However, examining a typical
organ failure trajectory, it is evident that events or triggers such as
a hospital admission might be utilized to consider moving from
a chronic disease management approach (stage 1) to a proactive,
supportive, and palliative care approach (stage 2). Then when the
patient reaches the last days of life, terminal care can be planned
in stage 3, as illustrated in Figure 3.3. Alternatively, there might
be clinical indicators such as breathlessness at rest or other per-
sistent symptoms despite optimal disease management to trigger
stage 2. Some clinicians use the surprise question to help them
identify when care goals might need review. This question is
FIGURE 3.2  Supportive and palliative care should start at diag-
nosis of life-threatening disease. (From Murray, S.A., Kendall, M.,
Boyd, K., and Sheikh, A, Illness trajectories and palliative care,
BMJ, 330, 1007–1011,2005, Copyright 2005, with permission
from BMJ Publishing Group Ltd.)
Palliative Care as a Primary Care Issue
FIGURE 3.3  Caring for people with organ failure: Three progressive stages in advanced illnesses.
commonly stated as: “Would I be surprised if this patient were
to die in the next year?” If the answer is “no,” this means that
the patient is probably sufficiently at risk of dying and is ready
for anticipatory care planning to be started just in case. Research
has shown that patients are living with both preparation for death
and hopes for the future, as they often describe dual narratives of
illness.8
Several tools have been developed for use in primary care to
help doctors and community nurses identify patients as they
transition to a point when a supportive and palliative care
approach is beneficial.9 A tool used increasingly in primary care
and other care settings around the world is the Supportive and
Palliative Care Indicator Tool (SPICT). It consists of evidence-
based clinical indicators of deteriorating health, both condition
specific and generic. These point to a growing burden of illness-
related suffering such that introducing palliative care would be
of benefit. SPICT is available for download from an open access
website (http://www.spict.org.uk). There are translations in 10
languages and a free application is also available (https://www.
spict.org.uk/spictapp/). SPICT can be used opportunistically at
patient consultations or by scanning patient disease registers or
primary care records to identify such patients for a comprehen-
sive needs assessment and a palliative care approach including
proactive future care planning.10,11 SPICT also offers guidance on
communication and care planning.
Treatments and potentially distressing interventions that
are no longer of benefit late in the course of all these types
of illnesses, when the person is in the last days of life, can be
prevented by diagnosing imminent death and caring for the
patient and family using an individualized, holistic, end-of-
life care plan. This approach ensures that communication
with patient and family is central, goals of care are clear, and
treatments and tests that are not consistent with the agreed
care goals or are of greater burden than benefit are stopped.
Plans are made to manage any symptoms or problems that
might develop, including as needed prescription of medica-
tions. Family, spiritual, religious, cultural, and other needs are
considered and addressed. Earlier discussions in primary care
about thinking ahead and planning for when a person deterio-
rates and might die can reduce the risks of over-treatment and
having to make such decisions in a crisis.
19
Third potential of palliative care in primary
care: Meeting all dimensions of need
(physical, psychological, social, and spiritual)
Family physicians are skilled at providing patient-centered
care in the context of family and community and are trained
in person-centered communication. When the doctor–patient
relationship is well established, the trust and mutual under-
standing that are essential to the therapeutic relationship are
already present. This also helps patients receive support and
care starting from the time of diagnosis of the potentially fatal
illness, when psychological and existential distress may be
especially acute.12–14
It is now recognized that everyone has spiritual needs when
faced with serious life-threatening illness. An internationally
accepted definition states, “spiritual needs are needs that relate
to the meaning and purpose of life.”8 People may or may not use
religious vocabulary to express such needs. If the spiritual issue
or need causes the person distress, it becomes spiritual distress.
Each of the above typical trajectories of physical decline has
different patterns of multidimensional distress illustrated below
(see Figures 3.4–3.6).14
Rapid functional decline
In people with advanced cancer, social functioning typically
declines in parallel with physical decline, whereas psychologi-
cal and spiritual wellbeing often fall together at four key times:
around diagnosis, at discharge after initial treatment, as the ill-
ness progresses, and in the terminal phase (Figure 3.4). Patients
and family members report that the time around diagnosis is one
of the most traumatic, psychologically and existentially, with fur-
ther emotional turmoil as the patient gets more ill.
Thus, all people whose cancer is life-limiting, but still treat-
able, should be considered for palliative care from diagnosis.
Patients report finding it supportive for professionals to sim-
ply acknowledge that this initial adjustment time can be very
challenging. Some, but not all, value being able to talk about
the likely course of events for people with their condition.
Waiting for physical decline later on misses the opportunity to
provide well-coordinated palliative care integrated with other
treatments.
20
FIGURE 3.4  Wellbeing trajectories in patients with rapid functional decline (typically progressive cancer).
Intermittent, fluctuating decline
In people with life-limiting, long-term conditions or multiple ill-
nesses, social and psychological decline both tend to track the physi-
cal decline, while spiritual distress fluctuates more and is modulated
by other influences, including the person’s capacity to remain resil-
ient (Figure 3.5). People may die suddenly during an exacerbation or
when still functioning relatively well, so death is often perceived as
unexpected, although it has been predictable as a risk for some years.
During the increasingly frequent exacerbations of heart, lung, liver, or
renal failure, patients and their caregivers are anxious, need informa-
tion, and often have social problems. Support for these needs might
reduce or shorten hospital admissions.
Gradual decline
People who have frailty or a progressive neurological disease typi-
cally experience a gradual physical decline from a lower baseline15
Psychological and existential wellbeing sometimes fall in response
to changes in social circumstances or an acute physical illness but
a decrease in social, psychological, or existential wellbeing can
herald global physical decline or death (Figure 10.6). Some older
people reach a tipping point when they feel unable to live usefully
or with dignity and experience increasing psychological and exis-
tential distress before dying.
Actions to promote optimum physical health should be com-
bined with help to engage with social support and care that lets
people maintain a sense of self and purpose. Allowing people
to raise and discuss their greatest fears—of losing indepen-
dence, developing dementia, or being a burden to others—is
FIGURE 3.5  Wellbeing trajectories in patients with intermittent decline (typically organ failure or multimorbidity).
Textbook of Palliative Medicine and Supportive Care
person-centered, early palliative care. Anticipating likely changes
and planning future care can reduce distress while promoting a
realistic understanding of normal ageing.
Understanding multidimensional trajectories can help family
practitioners address difficult questions such as “How long have
I got?” which patients sometimes ask early in the illness trajec-
tory. A response could be “It’s hard to know how long, but can
we talk about what might happen and how we support people as
things change?” If uncertainty is acknowledged and worries are
explored, patients and caregivers can ask for information and feel
empowered by knowing more about what the future may hold.
Fourth potential of palliative care in primary
care: Making a difference in the community
In many economically developed countries, only about 20–25%
of people die at home. However, surveys indicate that many more
people would prefer to die at home, if possible. The Gold Standards
Framework, developed in the UK, is being used by many primary
care teams there and in other countries to deliver primary pal-
liative care in the community. It gives a framework for general
practitioners and community nurses to organize and coordinate
care within their practices. In the UK National Health Service,
all patients are registered with a specific practice, and this frame-
work is based on creating a register of all patients identified for
supportive or palliative care within each practice. It highlights
the 7Cs, seven aspects that are vital for quality palliative and
Palliative Care as a Primary Care Issue 21

FIGURE 3.6  Wellbeing trajectories in patients with gradual decline (typically frailty or cognitive decline).

end-of-life care in the community: communication, coordina-
tion, control of symptoms, continuity of care, continued learning,
caregiver support, and care in the dying phase.16
The three main steps of the Gold Standards Framework
approach and indeed of primary palliative care are the following:
• Identify which patients would benefit from more support.
• Assess their current and future clinical and personal/fam-
ily needs.
• Plan their future care.
This framework has been adapted for nursing care homes, and
this is also associated with positive outcomes such as less hos-
pital admissions in the last weeks of life and more frequent
documentation of advance care plans and resuscitation status
information.
Other interventions that have improved palliative care in
the community include case conferencing with specialist pal-
liative care.17,18 Training of family residents in palliative care in
Canada has proved effective.19 Work in Australia led by prac-
tice nurses has resulted in much improved care planning. 20
Groundwork for what successful integration of primary deliv-
ery of palliative care in primary care practices might entail in
the USA is reported.15
development known as health promoting palliative care is start-
ing to make dying much more than a “medical” issue. This calls
for community involvement in end-of-life care and encourages
people and the community to talk more openly and be more
involved in many aspects of care at the end of life. This approach
argues that if death and dying were brought more into the open, it
would be much easier to plan for a good death. Such an approach
can be cultivated by family practitioners in their local communi-
ties, or hospices in their localities.22
Sixth potential of palliative care in primary
care: Supporting family caregivers in their
time of caring and subsequent bereavement
Family caregivers are frequently cared for by the same primary
care team as the patient. Research has revealed that family care-
givers of patients with lung cancer can experience a similar
dynamic pattern of needs as the people they care for, so this must
be acknowledged and addressed23 (Figure 3.7). In the UK, gen-
eral practitioners are encouraged to identify and keep registers of
people who have a significant caring role and to assess their needs
and support them.24

Fifth potential of palliative care in primary

care: Reaching to all in need in economically
poorer countries and learning from
them about bringing death back to life
As primary care is the only level of care available to most people
in less developed countries, its potential must be maximized and
enhanced, ideally by international collaborations to let end-of-life
care reach most people there. In Africa, few countries have pallia-
tive care services integrated within their national health services,
although Uganda, Kenya, and Rwanda lead the way.21 But most
African countries have vibrant communities where members visit
the dying to comfort and support them practically. Economically
developed countries can learn much from talking about death
and dying, visiting people, and supporting our friends and neigh-
bors in the community at the end of life. FIGURE 3.7  Trajectories of physical, social, psychological, and
Initially in Australia and now developing internationally spiritual wellbeing in family caregivers of patients with progres-
in India, Canada, and some European countries, an exciting sive lung cancer, from diagnosis to death.
22
Facilitating factors for strong
primary palliative care
Factors that facilitate palliative care in the community include
a strong primary care system with large group practices where
primary care physicians, nurses, and other professionals work
together. Such practices can identify patients eligible for pallia-
tive care proactively and provide multidisciplinary care to people
living at home. There should be a reimbursement system that
values home visits, rapid access to telephone support, and longer
appointments for people with complex needs. Integration with
hospital and emergency care is vital to promote continuity of care
and information throughout the 24 hours. Given adequate train-
ing (adapted to the constraints and the context of primary care),
resources, and access to specialist support, family practitioners
can provide end-of-life care to most patients. Providing primary
palliative care can help fast-track the extension of the palliative
care approach to people with non-malignant conditions. A tool-
kit to help establish palliative care by primary care professionals
in their own country or state or region is available on the web
page of the European Association for Palliative Care Primary
Care Reference Group at: https://www.eapcnet.eu/eapc-groups/
reference/primary-care.25
Recent WHO initiatives have strongly supported palliative care
to be integrated in chronic disease management.26 Furthermore,
palliative care has been recognized as one of the core components
of universal health coverage, and it should be available for those
in need at the primary level.27 Recommendations for the integra-
tion into primary health care with guidance on how to do so are
detailed in a guide published by the WHO.28
Caring for all in the last year or phase of life
So, palliative care can address many of its most pressing chal-
lenges through primary care. It can first go beyond cancer and
help people at the end of life no matter what the illness. We
shouldn’t offer palliative care according to diagnosis or even
prognosis but based on need for holistic care and care planning.
The second challenge primary palliative care can meet is to help
KEY LEARNING POINTS
• There is great potential for palliative care to be
delivered in the community, by primary care doc-
tors and community nurses.
• Primary care teams can reach many more people
with palliative care needs than can specialists
and also earlier in the course of the illness.
• Palliative care specialists should prioritize deliv-
ering training, advice, and support for hospital
and community generalists.
• Primary care is well placed to provide high-quality
palliative care for patients:
• With all life-limiting conditions
• From early in the course of the illness
• With all dimensions of need
• In care homes and at home
• In all countries, including lower income settings
• And to support family caregivers
Textbook of Palliative Medicine and Supportive Care
earlier rather than later, when input is strategic and formative and
when emotional needs are often acute. Third, we can help patients
with all dimensions of need in the community, going beyond the
physical to the social, psychological, and spiritual. Fourth, we can
help more people live and then die where they want to be, often at
home or in a familiar care home. Fifth, we can assist lower income
countries in setting up systems and training community staff to
meet substantial needs for good pain and symptom control while
learning from them how to talk more openly about dying and how
to promote wellbeing in the face of death. Finally, palliative care
based in the community can take the lead in supporting family
caregivers and engaging and encouraging local communities to
be actively involved in caring for friends and neighbors in the last
phase of life.22
References
1. Munday D, Boyd K, Jeba J, et al. Defining primary palliative care for
universal health coverage. Lancet 2019;394:621–622. doi: 10.1016/
S0140-6736(19)31830-6.
2. Lunney JR, Lynn J, Foley DS, Lipson S, Guralnik JM. Patterns of func-
tional decline at the end-of-life. JAMA 2003;289:2387–2392.
3. Aiden H. Multimorbidity. Understanding the challenge. A report for
the Richmond Group of Charities. London: The Richmond Group of
Charities, 2018.
4. Murray SA, Sheikh A. Making a difference campaign. BMJ
2008;336:958–959.
5. Murray SA, Kendall M, Boyd K, Sheikh A. Illness trajectories and pal-
liative care: Clinical review. BMJ 2005;330(7498):1007–1011.
6. World Health Organization. Palliative Care: The Solid Facts.
Copenhagen, Denmark: WHO, 2004.
7. Murray SA. Meeting the challenge of palliation beyond cancer. Eur J
Palliat Care 2008;15:213.
8. Murray SA, Kendall M, Grant E, Boyd K, Barclay S, Sheikh A. Patterns
of social psychological and spiritual decline towards the end-of-life in
lung cancer and heart failure. JPSM 2007;34:393–402.
9. Maas EAT, Murray SA, Engels Y, Campbell C. What tools are available
to identify patients with palliative care needs in primary care: A sys-
tematic literature review and survey of European practice. BMJ Support
Palliat Care 2013;3(4):444–451. doi: 10.1136/bmjspcare-2013-000527.
10. Mason B, Boyd K, Steyn J, Kendall M, Macpherson S, Murray SA.
Computer screening for palliative care needs in primary care: A
mixed-methods study. Br J Gen Pract 2018;68(670):e360–e369.
11. Boyd K and Murray SA. Recognising and managing key transitions in
end of life care. BMJ 2010;341:649–652.
12. Cavers D, Hacking B, Erridge SE, Kendall M, Morris PG, Murray SA.
Social, psychological and existential well-being in patients with glioma
and their caregivers: A qualitative study. CMAJ 2012;184(7):E373–
E382. doi: 10.1503/cmaj. 111622.
13. Kendall M, Cowey E, Mead G, Barber M, McAlpine C, Stott DJ.
Outcomes, experiences and palliative care in major stroke: a mul-
ticentre, mixed-method, longitudinal study. CMAJ 2018;190(9):
E238–E246.
14. Murray SA, Kendall M, Mitchell G, Moine S, Amblàs-Novellas J, Boyd
K. Palliative care from diagnosis to death. BMJ 2017;356:j878. doi:
10.1136/bmj.j878.
15. Nowels D, Jones J, Nowels CT, Matlock D. Perspectives of primary care
providers toward palliative care for their patients. J Am Board Fam
Med 2016;29:748–758.
16. Gold Standards Framework (GSF) Prognostic Indicator Guide (PIG).
http://www.goldstandardsframework.org.uk/ 2012 (Accessed 24 Oct
2019).
17. Hollingworth S, Zhang J, Vaikuntam BP, Jackson C, Mitchell G. Case
conference primary-secondary care planning at end of life can reduce
the cost of hospitalisations. BMC Palliat Care 2016;15:84. doi: 10.1186/
s12904-016-0157-9.
18. Arora S, Smith T, Snead J, Zalud-Cerrato S, Marr L, Watson M. Project
ECHO: An effective means of increasing palliative care capacity.
AJMC 2017. Available from: https://www.ajmc.com/journals/evidence-
based-oncology/2017/june-2017/project-echo-an-effective-means-of-
increasing-palliative-care-capacity.
Palliative Care as a Primary Care Issue
19. Pereira J, Palacios M, Collin T, Wedel R, Galloway L, Murray A. The
impact of a hybrid online and classroom-based course on palliative
care competencies of family medicine residents. Palliat Med 2008.
22(8):929–937. doi: 10.1177/0269216308094561.
20. The Advance Project. The Advance Project Toolkit, 2019. Available
from: https://www.theadvanceproject.com.au/. (Accessed 24 Oct
2019).
21. Grant L, Downing J, Luyirika E, Murphy M, Namukwaya L, Kiyange
F. Integrating palliative care into national health systems in Africa:
A multi-country intervention study. J Glob Health 2017;7:010419. doi:
10.7189/jogh.07.0104.
22. Sallnow L, Richardson H, Murray SA, Kellehear A. The impact of a new
public health approach to end-of-life care: A systematic review. Palliat
Med 2015;30(3):200–211. doi: 10.1177/0269216315599869.
23. Murray SA, Kendall M, Boyd K, Grant L, Highet G, Sheikh A. Archetypal
trajectories of social, psychological, and spiritual wellbeing and dis-
tress in family care givers of patients with lung cancer: Secondary anal-
ysis of serial qualitative interviews. BMJ 2010;340:c2581. doi:10.1136/
bmj.c2581.
23
24. Carduff E, Jarvis A, Highet G, Finucane A, Kendall M, Harrison N.
Piloting a new approach in primary care to identify, assess and support
carers of people with terminal illnesses: A feasibility study. BMC Fam
Pract 2016;17(1):1–9.
25. Murray S, Moine S. Toolkit for the Development of Palliative Care in
Primary Care, EAPC, WONCA, 2019. Available from the web page of
the EAPC Primary Care Reference Group: https://www.eapcnet.eu/
eapc-groups/reference/primary-care.
26. World Health Assembly. Strengthening of palliative care as a com-
ponent of comprehensive care throughout the life course. Resolution
WHA67.19 adopted by the sixty-seventh World Health Assembly.
Geneva: WHO, 2014. Available from: http://apps.who.int/gb/ebwha/
pdf_files/wha67/a67_r19-en.pdf
27. World Health Organization, United Nations International Children’s
Fund. Declaration of Astana. Global Conference on Primary Health
Care. Astana, Kazakhstan, October 25–26, 2018. Geneva and New
York: WHO and UNICEF, 2018.
28. World Health Organization. Integrating Palliative Care and Symptom
Relief into Primary Health Care. Geneva: WHO, 2018.
4
THE FUTURE OF PALLIATIVE MEDICINE

Charles F. Von Gunten and Irene J. Higginson

Contents
Introduction..........................................................................................................................................................................................................................25
Palliative medicine now......................................................................................................................................................................................................25
Future of palliative medicine.............................................................................................................................................................................................27
Meeting individual patient and family needs...........................................................................................................................................................27
Responding to demographic changes of escalating need.......................................................................................................................................27
Developing a unique physician role............................................................................................................................................................................27
Distinct body of knowledge....................................................................................................................................................................................27
Publication of scholarly research..........................................................................................................................................................................28
Graduate medical education..................................................................................................................................................................................28
Professional association..........................................................................................................................................................................................28
Practice patterns and professional role................................................................................................................................................................28
Challenges for the future....................................................................................................................................................................................................29
Health-care policy..........................................................................................................................................................................................................29
Professional boundaries................................................................................................................................................................................................29
Developing new and appropriate models of care in response to the different trajectories of illness and diseases and to new diseases.....29
Fund-raising and/or remaining part of statutory funded care....................................................................................................................................30
Training............................................................................................................................................................................................................................30
Research...........................................................................................................................................................................................................................30
Summary................................................................................................................................................................................................................................31
References..............................................................................................................................................................................................................................31

Introduction organized programs for clinical care, education, and research. In

A reliable forecast for the future requires a hard look at the pres-
ent. Therefore, we will structure this chapter in three parts. First,
we will broadly summarize the current state of palliative medi-
cine in the world. Details of the development of palliative medi-
cine in various parts of the world have been described in other
chapters in this textbook. Second, we will summarize the case
for a future that rests on a response to three features: the needs
of patients and families, demographic changes, and the physician
role in palliative medicine as a distinct subspecialty. Third, we
will describe the challenges that palliative medicine must face in
the future if it is to prosper.
Palliative medicine now
The need for palliative care in the world is immense. Of 57 mil-
lion deaths in 2016 worldwide, 6 of the top 10 were from non-
communicable diseases.1 The vast majority will suffer from pain
and other symptoms as well as psychosocial or spiritual problems
that palliative care will address. Surely, the governments of the
world will want to ensure that palliative medicine is part of the
health system response to their public’s needs.2
The current state of that response around the world can be
summarized as highly variable. Part of the issue is that there
isn’t a common language to describe palliative care services or
the physician role. 3 Another is that each country has a different
approach to the provision of health care for its citizens.4 In some
countries, the field is a recognized specialty or subspecialty with
many others, a broad program of clinical care has emerged with-
out the official recognition that grounds the discipline in the aca-
demic foundation of health care or the financing of health care. In
the poorest nations, the most basic tools for the relief of suffering
are unavailable.
This lack of progress is despite the fact that in 2014, at the
World Health Assembly, all member countries voted in favor of
and together passed resolution 67.19 (2014). This resolution is
that countries integrate palliative care into national health poli-
cies—by revising laws and processes to improve access to opioids
and provide palliative care services through primary health care
as well as through community settings with adequate resources. 5
The number of countries speaking strongly for the resolution was
impressive. However, a review published in 2019 by the World
Health Organization found that by 2017, only 56% of countries
reported that their national non-communicable disease policy
includes palliative care, with this figure ranging from 37% of
countries in the Western Pacific region to 82% of countries in the
South-East Asia region. Some countries did not have a national
non-communicable disease policy. Just over two-thirds (68%) of
countries reported they had funding for palliative care, with this
proportion much higher in high-income countries (93%) than
low-income countries (29%).5
One way to look at this is from an institutional change model.
In such a model, an innovation (such as palliative medicine) is
developed in one location (such as England, Ireland, Australia,
Singapore, Canada, or the United States) and then gradually
spreads to other institutions as its merits become known. There is

25
26
good evidence for this. From a handful of hospices worldwide in
the 1970s and 1980s, the number of hospices and palliative care
programs has grown to involve every continent of the world in
more than 100 countries. The total number of hospice or pal-
liative care initiatives is in excess of 8,000 and includes hospice
inpatient units, hospital-based palliative care services, commu-
nity-based teams, and day-care centers. In England and Wales,
over 100,000 new patients were cared for by the 288 palliative
home care teams in 2014, and 40,000 were cared for in one of
the 193 inpatient hospice or palliative care units, with 2,881 beds.
Of those cared for in inpatient hospices, just below 90% had can-
cer; of those cared for by home care teams, the proportion was
around 86%, with 14% having conditions other than cancer. The
mean length of stay in inpatient units was around two weeks.6
Trend analysis found that the number of annual inpatient hospice
deaths increased from 17,440 in 1993 to 26,032 in 2012, account-
ing for 3.4% of all deaths in 1993 and 6.0% in 2012. Half of hospice
decedents were men; mean age was 69.9 (standard deviation: 12.4)
years. Just 5.2% of all hospice decedents had non-cancer diagno-
ses, and even though the likelihood of non-cancer conditions
increased slightly over time, absolute numbers remained small.
The proportions admitted to hospices from the more deprived
areas fell slightly over time.7 Just below half (44%) of patients who
are admitted are discharged from inpatient care when their rea-
sons for admission are addressed. This is usually to homes, where
many receive ongoing support. In the same year, the number of
cancer deaths in England was around 140,000, suggesting that
around 65% of patients with cancer receive care from a palliative
care/hospice home care team, and 18% die in a hospice.6
In addition, over 85,000 new patients are seen by hospital
palliative care teams each year; many of these go on to receive
home care and/or hospice care. Hospital palliative care teams see
more patients with non-cancer conditions—on average, around
22% of patients are cared for, but this ranges from 0% to almost
50%.8 The 2019 EAPC Atlas identified 803 specialized palliative
care services for adults in the United Kingdom, and 6,388 spe-
cialized services across all Europe (a median of 0.8 adult services
per 100,000 inhabitants).9 Note, however, that the number of ser-
vices per inhabitant is difficult to interpret, as this does not take
account of the size of the services. In the United States, where
hospice care is delivered by teams primarily in patient’s homes,
an estimated 1.1 million patients who died received hospice care
in 2011.10 This corresponds with about 45% of all deaths in the
United States. In contrast with England, 38% of patients served
by hospice programs have cancer; the remainder dies from heart
disease, lung disease, or other conditions. The number of hospi-
tals in the United States who report a palliative care team has
increased to 66%.6
Another way to look at the current state of affairs is from an
economic point of view. Those countries that have most devel-
oped palliative care are comparatively wealthy countries where
palliative care is paid for after other services are covered. Even
in countries where palliative care and hospice are widely devel-
oped, such as the United Kingdom, much remains to the chari-
table sector. This may in part explain why the areas with higher
deprivation have lower in-patient hospice access,7 as in these
areas charitable hospices are more difficult to establish. In the
United Kingdom, 75% of the inpatient hospices are managed by
charities, with the National Health Service covering on average
34% of their costs. In the United Kingdom, place of death varies
considerably according to patient characteristics. Multivariable
analysis found that hospital deaths for all causes combined were
Textbook of Palliative Medicine and Supportive Care
more likely for people aged 75+ years, those who lived in London,
those who were divorced, single and widowed, those who lived in
more deprived areas, and those who died in autumn, winter or
at New Year.11 This variation by region, age, marital status, and
area deprivation suggests that inequities exist, which services and
better care planning could seek to address. In poorer countries
where it hasn’t yet developed, health-care funds are spent in other
ways. In this worldview, any money spent on palliative care in
developing countries can be construed as a failure to provide the
standard health care available in other countries. In other words,
patients who can’t get standard health care are given morphine in
order to ease their otherwise preventable death.
An international comparison of formal care costs (health and
social care) in the last three months of life in three high-income
countries found that hospital care accounted for >80% of total
care costs; community care 6–16%, palliative care 1–15%, despite
all those included in the study having some access to specialist
palliative care. The total mean care costs per person with can-
cer/non-cancer were US$37,250/US$37,376 (the United States),
US$29,065/US$29,411 (Ireland), US$15,347/US$16,631 (England).
Formal care costs differed markedly between the countries, as
did cost distributions. Costs were most homogeneous in England.
Interestingly 10% of decedents used ˜30% of total care costs.
Poverty and poor home care appeared to drive high costs in the
last three months of life.12 This suggests that improving commu-
nity palliative care may improve care value, especially as pallia-
tive care expenditure was low.
Finally, the development of palliative medicine can be viewed
from a public health point of view. An argument can be made that
the most significant health-care developments of the past cen-
tury relate to health promotion (e.g., nutrition), prevention (e.g.,
sanitation, smoking cessation), and palliation (e.g., pain relief).
The universality of end of life needs (it is something that happens
to everyone, like birth) and the variation in palliative care access
are two main reasons why palliative care is increasingly regarded
as a public health issue (see Chapter 20). In this model, pallia-
tive medicine is fundamental to health care and even the poorest
countries should assure their citizens with it.
A further way to consider palliative medicine is the extent that
it remains relevant during periods of major strain on health and
social care. The role of palliative care during epidemics, pandem-
ics, or similar such events, such during as the COVID-19 pan-
demic, can highlight this. There is quite limited understanding
and research into the role of palliative care in epidemics or pan-
demics. A rapid review conducted at the start of the COVID-19
pandemic identified only 10 observational studies.13 Countries
involved in this research were mainly: West Africa, Taiwan,
Hong Kong, Singapore. There were only two studies outside of
these regions, one from the USA, which was based on simulated
experiences, and a survey from Italy, conducted at the start of the
pandemic to understand the “readiness” of hospice and palliative
care services.14
There is a great risk that during pandemics and epidemics, or
other crises, palliative care is overlooked. Indeed, as was pointed
out in the Lancet, palliative care was not mentioned in the World
Health Organization response.15,16 This overlooks the fact that
the relief of suffering, supporting complex decision-making, and
managing clinical uncertainty are key attributes of palliative care
and are also essential components of the response to epidemics
and pandemics.13 However, several of the public health measures
implemented during a pandemic, which are designed to slow the
spread of the virus, also in crease barriers for families and limit
The Future of Palliative Medicine
interdisciplinary support.17–20 There is a risk of shortage of medi-
cines supply, equipment such as syringe drivers and personal pro-
tective equipment, and potentially staff, if staff become unwell
due to infection themselves, which all limit the response.13,21,22
The bereavement issues are also potentially immense. In the con-
text of a new disease, research and international collaboration are
essential. Early data described some of the challenges faced by
patients with COVID-19. The most prevalent symptoms seemed
to be breathlessness (67%), agitation (43%), drowsiness (36%),
pain (23%), and delirium (24%). More than half of the patients
in one palliative care service needed subcutaneous infusions to
control symptoms, frequently opioids and a benzodiazepine.23
International collaboration and a minimum data set would accel-
erate finding answers to new questions as any new disease or pan-
demic develops.
Future of palliative medicine
The future of palliative medicine rests on the responses to three
features.
Meeting individual patient and family needs
People with serious chronic illness, and their families, experience
a remarkably similar set of needs that are relatively independent of
the specific disease or diseases from which they suffer. These can
be categorized in the physical, psychological (emotional), social
(practical), and spiritual (existential) domains. The prevalence of
symptoms such as pain, breathlessness, and fatigue ranges from
50% to 80%.24 Psychological conditions such as depression and
anxiety affect both patient and family. The effect of the social
domain, including family and community relationships and sup-
port, and the need for services can be provided. This includes the
patient’s and family’s need for information and training. Finally,
the spiritual or existential domain that involves the search for
meaning is often affected by serious illness.
Fortunately, there is growing evidence that palliative care is an
effective response to these needs. When pain and symptoms are
controlled, information is shared, family and caregivers are sup-
ported, services are coordinated, and health-care outcomes are
improved at a reasonable cost.
Responding to demographic
changes of escalating need
People in both the developed and developing world are aging.
People live longer and the proportion of those living more than
65 years into very old age is also increasing rapidly. The pattern
of disease from which these people die is now characterized by
chronic progressive illnesses, including the frailty syndrome of
advanced age. This means there will be more people needing
health care toward the end of life.
There are three significant changes driving this escalating need.
The first is the predicted rise in the number of annual deaths from
non-communicable diseases, with increases of around 15–30% in
the next 15 years in many countries.25–28 This crescendo in annual
deaths is brought about by both a delaying of deaths until later
life due to earlier prevention, and a 1950s boom of births in many
countries. The second is that people are living longer with their
chronic diseases, with increasing multimorbidity, symptoms, and
problems, experienced for longer periods of time.25 The third is
the increasing evidence that specialist palliative care earlier in the
course of illness, integrated with existing services, can prevent
problems, is effective and valued by patients and those important
to them, and may lead to cost-savings.29–34
27
The imperative question is, what is the correct response to
this increased need? Especially when the rise in people needing
palliative care will pressurize existing community and hospital
services even further.28,35 Palliative medicine is likely to have a
critical role in (1) helping to increase and upskill a community
health and social care workforce through education, training,
and valuing of care work; (2) building community care capacity
through informal caregiver support and community engagement;
and (3) to stimulate a realistic public debate on death, dying and
sustainable funding.28 This will require evidence of effectiveness,
in particular of new models of care designed to respond to the
populations of tomorrow. These would need to be implemented
in different contexts with an available workforce. Models such as
early short term palliative care, and increasingly an integration
with rehabilitation approaches, are likely to be needed for these
populations.29,36,37 Recent evidence also suggests that palliative
care is particularly effective when needs are complex and multi-
morbidity is prevalent. 38
At the same time as this growth of people who need care, there
is a decrease in the number of both formal and informal caregiv-
ers. Innovative ways of providing care are needed. One compo-
nent of that plan is palliative care.
Developing a unique physician role
The development of the palliative medicine role within the mul-
tiprofessional teams who deliver palliative care within hospitals,
inpatient units, nursing facilities, or patient’s homes is a signifi-
cant development of the past 50 years. The future of palliative
medicine rests on the strength of the case for the field as a distinct
specialty. The specialty of palliative medicine has moved from an
emerging discipline to a recognized area of expertise in some
parts of the world. It is formally recognized as a distinct specialty
in a growing number of countries, for example, in Great Britain,
Ireland, Poland, Australia, Canada, and the United States. Sub-
specialty recognition is also increasing, but levels of training vary.
Around half (29/51) of the European countries considered in the
2019 European Association for Palliative Care (EAPC) Atlas of
Palliative Care have an official accreditation process for physi-
cians in palliative medicine organized by national competent
authorities. However, this varies from palliative medicine being
recognized as a separate specialty in a handful of countries (such
as Great Britain, Ireland, Poland), to a sub-specialty (11/51) or as a
special field of competence (13/51) with quite short training pro-
grams.9,39 We can expect similar recognition in other countries
for the following reasons.40–42
Distinct body of knowledge
A distinct body of scientific knowledge in palliative medicine has
accumulated over the past 40 years.43 The emergence of special-
ized journals, well-regarded textbooks, and formal curricula is an
indicator. This textbook is but one repository. That knowledge is
expressed in a variety of scientific and academic endeavors. For
instance, the Cochrane Collaboration has a pain, palliative care,
and supportive care review group that has produced over 270
reviews.44 In 2004, the UK government published guidance from
the National Institute of Clinical Excellence on supportive and
palliative care in cancer.45 The guidance had reviewed the evidence
for the effectiveness of 13 areas of supportive and palliative care,
including communication, information, psychological support,
specialist palliative care, end-of-life care, and rehabilitation.46 In
2018, the National Consensus Project for Quality Palliative Care
published its fourth revision of the clinical practice guidelines
28
for quality palliative care based on an extensive evidence review
and consensus process with the major US palliative care orga-
nizations.47 Addressing the needs of policy makers, the World
Health Organization’s European Office produced an evidence-
based guidance on palliative care in two complementary book-
lets. Palliative Care: The Solid Facts48 dealt with general palliative
care issues, future needs, and evidence, and Better Palliative Care
for Older People49 dealt with the need to address the demographic
changes in society and take a public health approach to palliative
care. Most recently, the Institute of Medicine in the United States
is revisiting its landmark report from 1997 on the state of end-of-
life care in the United States and in 2019 undertook a consensus
study to explore current state and barriers to advance progress.50
The EAPC and National Associations within Europe have devel-
oped white papers and guidance on many aspects of care and pol-
icy as have other national and international organizations based
in Taiwan, Australia, Singapore, New Zealand, Canada, Africa,
India, and many other regions.
The major skills central to palliative medicine are the assess-
ment and management of physical, psychological, and spiritual
suffering faced by patients with life-limiting illnesses and their
families. Communication and teamwork are also critical skills in
palliative medicine.
Publication of scholarly research
New knowledge is being discovered at an expanding rate. Research
in the area of palliative medicine appears in at least eight inter-
national specialized peer-reviewed journals: Journal of Palliative
Care, Journal of Pain and Symptom Management (including sup-
portive and palliative care, the United States), Journal of Palliative
Medicine (the United States), Palliative Medicine (the United
Kingdom), American Journal of Hospice and Palliative Care (the
United States), Palliative and Supportive Care (the United States),
Progress in Palliative Care (Australia), BMC Palliative Care (a
web-based rapid publication from biomedcentral.com, an inter-
national group), and Supportive Care in Cancer (Switzerland).
More than one curriculum for palliative medicine has been pub-
lished.51–54 Models to guide clinical palliative care have been dis-
seminated, 55 and a number of well-regarded textbooks are now
available56–58 of which the Oxford Textbook of Palliative Care is
now in its fourth edition. In fact, the Oxford University Press has
prioritized being a market leader in publishing in palliative care,
with Oxford Scholarship Online-palliative care as a search tool.59
Graduate medical education
New specialties are characterized by defined training programs
that prepare the holder of an undergraduate medical degree for
independent practice. Specialty training programs are usually
of 3–4 years length after general medical training. In the United
Kingdom, individuals begin the four-year training program in
palliative medicine once they have completed their medical
degree and around three years of general medical posts, includ-
ing hospital medicine. The Association for Palliative Medicine of
Great Britain and Ireland has over 1,000 physician members, of
which 450 are in training, 100 are associate members registered
in other medical specialties or general practice, and the rest are
consultants (fully qualified) or associate specialists (complet-
ing a shorter program60). There is a national training program,
with regionally organized advertising and monitoring. In Great
Britain, Palliative Medicine is one of the larger medical special-
ties, now being the 12th largest specialty within medicine, with a
Textbook of Palliative Medicine and Supportive Care
similar number of physicians to oncologists.40 However, palliative
care and palliative medicine are minute in terms of clinical aca-
demic training or established academic positions, opportunities,
new knowledge, or priority for policy makers.41,42
In the United States, there are 85 programs in operation with a
total of 234 physicians in training.61
In Australia, palliative medicine specialists are Fellows of the
Royal Australasian College of Physicians and have completed the
College’s training program in palliative medicine, a Fellow of the
Australasian Chapter of Palliative Medicine, or both. The College’s
training program comprises three years of full-time equivalent
(FTE) training in either a pediatric or adult setting under the
supervision of a Palliative Care physician. Successful trainees are
accredited as a palliative medicine physician in Australia or New
Zealand. In Australia, medical practitioners may also complete
a six-month Clinical Diploma in Palliative Medicine, but this
qualification does not result in specialist accreditation. In 2017,
there were 249 specialist palliative medicine physicians employed
in Australia, representing 1 in 140 employed medical specialists,
and 1.0 FTE per 100,000 population, respectively. 39
Professional association
New specialties are also characterized by professional associa-
tions. The American Academy of Hospice and Palliative Medicine
(AAHPM) is the professional association for physicians in pal-
liative medicine. AAHPM currently has 5,000 physician mem-
bers.61 The Association for Palliative Medicine of Great Britain
and Ireland has over 1,000 members. The EAPC is a member-
ship organization composed, in part, by members of the national
associations of countries throughout western and central Europe.
Palliative Care Australia is the national peak body for palliative
care in Australia representing all those who work toward high-
quality palliative care for all Australians. The body works closely
with consumers, its Member Organizations, and the palliative
care workforce, to improve access to, and promote the need for,
palliative care. Palliative Care Australia was launched in 1998,
developing from the Australian Association for Hospice and
Palliative Care Inc., which started in 1991. Similar associations
have formed in Southeast Asia, Africa, South America, and most
parts of the globe.
Practice patterns and professional role
The 1997 Institute of Medicine report, Approaching Death:
Improving Care at the End of Life, delineated a three-tiered struc-
ture for professional competence:
1. A basic level of competence in the care of the dying patient
for all practitioners.
2. An expected level of palliative and humanistic skills con-
siderably beyond this basic level.
3. A cadre of superlative professionals to develop and provide
exemplary care for those approaching death, to guide oth-
ers in the delivery of such care, and to generate new knowl-
edge to improve care of the dying.52
These three levels correspond to the primary, secondary, and ter-
tiary levels around which medical care is commonly organized.
Primary palliative care (a term used mainly in the United States;
in the United Kingdom and much of the rest of Europe, the term
used is the palliative care approach, or generalist palliative care,
and here, primary palliative care refers to palliative care in the
The Future of Palliative Medicine
primary care setting, i.e., the community, organized by general
practitioners and family doctors) is the responsibility of all phy-
sicians. This includes basic approaches to the relief of suffering
and improving quality of life for the whole person and his or her
family. Secondary (referred to also as specialist) palliative care is
the responsibility of specialists and hospital or community-based
palliative care or hospice programs. The role of the secondary
specialist or program is to provide consultation and assist the
managing service. Tertiary palliative care is the province of aca-
demic centers where new knowledge is created through research,
and new knowledge is disseminated through education, as well as
providing a clinical service.
The major competencies of the specialist level palliative medi-
cine practitioner can be summarized under the broad patient-
centered goals of
• relief of symptom and suffering
• promotion of quality of life for patients and families in the
context of life-threatening illness
• promotion of the development and growth possible at the
end of life
While the knowledge domains and skills of palliative medicine
overlap to some extent with the knowledge, attitudes, and skills
that characterize other disciplines that care for patients with
advanced illnesses, the specialty practice of palliative medicine
is distinguished from other disciplines by its focus on the com-
mon features and symptoms associated with life-limiting disease.
Palliative medicine reaches across many disease categories and
organ systems to concentrate on relieving the burden of illness.
The palliative medicine specialist acquires and applies (1) a
higher level of clinical expertise in addressing the multidimen-
sional needs of patients with life-threatening illnesses, including
a practical skill set in symptom control interventions; (2) a high
level of expertise in both clinical and nonclinical issues related to
death and dying; (3) a commitment to an interdisciplinary team
approach; and (4) the strong focus on the patient and family as the
unit of care. The specialist level competency required of practi-
tioners in palliative medicine complements the core competency
that should be maintained by other disciplines.
Challenges for the future
There are a number of challenges that confront the future of the
field. These include the response of health-care policy makers, the
definition of the boundaries of the specialty, and the training of
the new physicians that are needed.
Health-care policy
The future of palliative medicine requires a social and political
impetus that is beyond the scope of medicine and firmly in the
sphere of government. For palliative medicine to prosper, health-
care policy must place much greater emphasis on the care of peo-
ple of all ages who are living with and dying from a range of serious
chronic diseases. The structure of health care as if these prevalent
illnesses are acute and curable must be changed. Therefore, pub-
licly funded palliative care services as a core part of health care is
needed; it cannot be an add-on extra. Those services must meet
the needs in the rural and urban community dwelling public as
well as in nursing homes and hospitals, including intensive care.
Those services must be based on need rather than on specific dis-
eases or prognosis. Finally, health-care policy must provide for
29
the development of new knowledge through research. Despite
the prevalence of palliative care need, national research budgets
are paltry. Surely, we don’t want to be using the same tools and
treatments in 50 years that we have now. The low level of invest-
ment in research—less than 1% of research funding in cancer is
spent on palliative or end of life care, and this percentage is likely
even lower in other conditions41—limits growth here. There is an
urgent need for palliative care practitioners, hospice and pallia-
tive care services, charities, and governments to prioritize high-
quality research and invest in this.
The example of Australia is particularly insightful here. In
Australia, resourcing of palliative care has moved to a needs-based
approach, with services receiving core funding and not having to
rely on charitable income for the bulk of their day-to-day running
costs. However, moving toward more core funding will bring with
it a responsibility for specialist palliative care services to monitor
and report their outcomes and to show the additional quality of
care provided and complexity of patients and families cared for.
Professional boundaries
A significant issue that confronts the future of the field is whether
it focuses on a condition (the dying patient) or relates to a broader
set of competencies that can be integrated across the spectrum
of serious and chronic illness. The roots of palliative medicine in
hospice care for the dying would lend itself to the former. The
experiences of hospital-based and outpatient office-based pallia-
tive medicine physicians suggest that the skills are more broadly
applicable than just for the dying. Furthermore, good symptom
management and psychosocial care require earlier palliative care
intervention. Many patients and families should not have to wait
until they are confirmed to be at the end of life to be offered the
palliative care expertise in symptom control or emotional, social,
or spiritual support. New models of palliative care are exploring
how it can be integrated with other specialties, so that patients
can receive potentially life-extending treatment at the same time
as symptom relief and psychosocial and spiritual support.
Palliative medicine is practiced within the context of a team.
Some would say it cannot be practiced without a team. Yet, the
broad interdisciplinary nature of palliative medicine makes it
more challenging to define the boundaries of the specialty than
for those with a disease focus (such as oncology), an organ focus
(such as cardiology), or a technical skill (such as surgery). As
with other fields, there are areas of overlap with other specialties
and subspecialties. Delineating and negotiating those boundar-
ies are an important aspect of the maturation of the discipline.
There is little argument that palliative medicine is primarily a
consulting specialty to the other primary disciplines. There is
no agenda, expressed or implied, that all suffering and dying
patients be cared for by physicians board certified in palliative
medicine.
Developing new and appropriate models of
care in response to the different trajectories
of illness and diseases and to new diseases
Although the symptom and problem profile of patients with dif-
ferent chronic progressive conditions are similar, the trajectory of
diseases is likely to vary. In addition, caring for older people, an
increasing part of the palliative care population, has specific chal-
lenges—notably iatrogenic disease, multiple pathology, and diffi-
culties in prognostication. The early models of palliative care may
have to evolve to care for these patients. In particular, the model
30
of consultation and palliative care offered for periods throughout
the illness, rather than at a particular prognostic point, may have
to develop. It will be a challenge for palliative medicine to develop
and test such models of care while maintaining existing services.
Some new models, such as short-term palliative care, are being
developed and tested. These test ways to offer palliative care ear-
lier in the course of the illness, but in the short term, integrated
with other services. Evidence to date is preliminary but suggests
benefits. For example, a randomized trial of early palliative care
in oncology for patients with lung cancer found quality of life
and survival benefits. 34 Early palliative care for people severely
affected by multiple sclerosis appeared to have benefits in terms
of reduced caregiver burden and improved symptom control and
lower overall costs, without worsening, and possibly improving,
survival. 37
The Salzburg Global Seminar on “Rethinking Care Toward the
End of Life” brought together 66 health leaders from 14 coun-
tries to engage in cross-cultural and collaborative discussions
across several future focused themes including patient/family/
caregiver engagement, integrating health and community-based
social care, eliciting and honoring patient preferences, building
an evidence base for palliative care, learning from system failures,
and delivering end-of-life care in low-resource countries. Lessons
learned from this seminar include proposals for learning from
low-resource countries, wider use of existing evidence-based
quality measures, improving research, training and educa-
tion, and respecting the personal agency of patients and their
families.62
The COVID-19 pandemic, and future pandemics, highlights
the need for palliative care and hospice services to respond
rapidly to changing needs of patients and in society.13,14,63–65
A framework for rapid adaptation could include consideration
of systems (e.g., policies, training), staff (employed and volun-
teers), space (community versus inpatient, technology), and
resources (medicines and equipment).13,64,66 To that we would
add evidence (from research into problems and evaluation of
solutions).
Fund-raising and/or remaining
part of statutory funded care
Currently, much of palliative care is provided within the volun-
tary sector and not-for-profit organizations. These have a contin-
ued battle to raise funds to stand still—and provide a continued
service to the community. The charitable sector is set to become
more competitive in years to come and is subject to fluctuations
in response to economic changes. Becoming part of the statutory
sector or receiving increased statutory funds removes some of the
freedom of previously voluntary units, although it provides more
security. Achieving the right balance here can be a challenge,
especially as national charity organizations in some countries
(e.g., the charity commission in the United Kingdom) provide
guidance that charities should not undertake tasks that should be
provided by statutory services. Perhaps more and more, the role
of charitable organizations will be to innovate and discover better
treatments and ways to care, while they advocate for the statutory
sector to pick up the funding of the services they have proven,
through good research, as effective and cost effective.
Training
Another challenge to the field is to build enough capacity within
training programs to train the next generation of specialists.
Textbook of Palliative Medicine and Supportive Care
The current interest in developing training programs is hearten-
ing, but financial resources are scarce and competition for them
is strong. In England, palliative care posts can go unfilled for
want of trained specialists. In the United States and many other
countries, where the field is emerging, there are similar short-
ages. This will remain the case unless the field is recognized and
sufficient capacity built into national and international programs
for training medical professionals. There is an inherent challenge
here, because the field needs the best dedicated and bright clini-
cians who have undergone sufficient training. Therefore, a bal-
ance needs to be struck between filling posts and filling them
with sufficiently experienced and qualified individuals who have
the ability to deliver the services and development, and to engage
in the research and education needed. Palliative medicine clini-
cians often find themselves in leadership roles and so have to not
only provide clinical care but be versed in managing and moti-
vating staff, strategically developing their services, engage in the
implementation and generation of new knowledge, and often
negotiating contracts and teaching other doctors. They also need
to educate others, as there are not sufficient palliative care clini-
cians to meet all the needs. Burnout is likely to be a problem in
palliative care, especially if clinicians are isolated and asked to
cover services 24 hours, without backup or peer support, as well
as to deal with issues of staff management and service develop-
ment (see the Burnout chapter in this book). Equally, problems
can arise in clinical academic posts, where filling posts with
individuals without sufficiently robust trackrecords or from
fields outside of palliative medicine can lead to loss of respect for
the field or a distraction of effort away from palliative medicine
patients. International networks for capacity building and sup-
port might help to improve and motivate individuals within the
field, but they would require resourcing.
Research
A major challenge for the future of palliative medicine is to
become a strong specialty for the future. Robust knowledge has
to be a central key to this. The COVID-19 pandemic also high-
lighted the need for international research collaboration, and
having a research infrastructure so that new knowledge about
any new condition could be quickly generated. During the pan-
demic this was a challenge for palliative care.
If the specialty is to contribute to the future care of patients
and families, then the evidence base for the treatment of many
symptoms and problems needs to be improved. Unfortunately,
research has been and continues to be relatively neglected.
There has been inadequate funding in all countries, a hesitancy
on the part of some ethics committees and Institutional Review
Boards to fully support research, and a reluctance of some staff,
who entered the specialty because they felt it did not involve
research. There are problems too because of the nature of
research in palliative care, which is often difficult because of
ethical concerns, the intangible nature of many aspects to be
measured (e.g., fatigue, quality of life, quality of death), and the
fact that patients are ill and difficult to interview. They may live
for unpredictable times. Weighed against this, we should recog-
nize that there have been enormous achievements in research in
palliative medicine in the last decades, despite these problems
and the lack of resources. This is a tribute to the few centers
and individuals who are researching the field. In the future, an
improved training in appraising and participating in research is
needed for doctors and nurses entering the field. There is now
evidenced-based guidance and statements on the conduct and
The Future of Palliative Medicine
reporting of research in palliative care, such as the Medical
Research Council generate guidance, MORECare.67 MORECare
includes additional recommendations such as on ethical issues
encountered in research, 68 how and when to measure out-
comes, 69 how to manage missing data,70 and how to integrate
and publish mixed methods.67 The MORECare guidance is
listed on the EQUATOR network to improve the conduct and
reporting of health research are increasingly being used by edi-
tors, researchers, clinicians, and academics.71 It is not expected
that everyone will conduct research, but all will need to appraise
it and may increasingly be part of large studies organized in ter-
tiary centers.72
Summary
In summary, there can be a bright future for palliative medi-
cine. There is a widespread need within society and this is set
to escalate in the future. There is now a body of good-quality
evidence that shows that palliative medicine within pallia-
tive care programs can meet the need. The challenge is clear.
The field needs to grow to sufficient size to be a sustainable
response. It also needs to develop mechanisms to meet the
challenge of the changing population and in particular the
increase in the elderly population and changed trajectory of
illness; it needs to continually improve the caliber and skills
of those in the field, through training, and to invest substan-
tially in research to discover and test better methods of care
and treatment, and to build research capacity.
KEY LEARNING POINTS
• Palliative medicine is highly variable in the world.
• The evidence base supports the effectiveness of
palliative care.
• The demographic changes in the world’s popula-
tions (living longer with more chronic ultimately
fatal disease and increasing numbers of deaths)
require expanded palliative care services.
• Research in palliative care is vital. This was high-
lighted especially during the COVID-19 pan-
demic, where responses to a new disease resulted
in a need for evidence to be gathered urgently.
• It is vital in the coming years that palliative care
moves from being an add-on extra to become a
core component of health care. To do this, it will
have to become needs-based, evidence-based,
and report its outcomes. The development of a
unique palliative medicine role for the physician
within multiprofessional teams is a phenomenon
likely to develop in most countries.
• Expanding clinical services to meet the needs of
patients and families will require modifications
in patterns of care and new models of care and
expansion of the numbers of trained physicians
and other professionals needed to provide pallia-
tive care.
• Collection of internationally agreed data on out-
comes and the issues faced by patients and fami-
lies will be key for the field in the future.
31
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42. Sleeman KE, Leniz J, Higginson IJ, Bristowe K. Is end-of-life care a
priority for policymakers? Qualitative documentary analysis of health
care strategies. Palliat Med 2018;32(9):1474–1486.
43. von Gunten CF, Lupu D. Development of a medical subspecialty in pal-
liative medicine: Progress report. J Palliat Med 2004;7(2):209–219.
♦ 44. http://papas.cochrane.org/palliative-care-database, 2019 (Accessed 19
Aug 2019).
⋆ 45. National Institute of Clinical Excellence (NICE). Improving Supportive
and Palliative Care for Adults with Cancer—The Manual. London, UK:
National Institute of Clinical Excellence, 2004.
♦ 46. Gysels M, Higginson IJ. Improving Supportive and Palliative Care
for Adults with Cancer: Research Evidence. London, UK: National
Institute of Clinical Excellence, 2004. www.nice.org.uk/pdf/csgsre-
searchevidence.pdf (Accessed 7 Sept 2013).
⋆ 47. National Consensus Project for Quality Palliative Care. Clinical
Practice Guidelines for Quality Palliative Care, 2019. https://www.
nationalcoalitionhpc.org/ncp/ (Accessed 19 Aug 2019).
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48. Davies E, Higginson IJ. Palliative Care: The Solid Facts. Denmark:
World Health Organization, 2004.
49. Davies E, Higginson IJ. Better Palliative Care for Older People.
Denmark: World Health Organization, 2004.
50. National Academy of Sciences, 2019. Nationalacademies.org/hmd/
Activities/Aging/TransformingEndofLife.aspx (Accessed 19 Aug
2019).
51. Billings JA, Block SD, Finn JW, et al. Initial voluntary program stan-
dards for fellowship training in palliative medicine. J Palliat Med
2002;5(1):23–33.
♦ 52. Field MJ, Cassel CK, eds. Approaching Death: Improving Care at the
End of Life. Washington, DC: National Academy Press, 1997, p. 208.
♦ 53. Emanuel LL, von Gunten CF, Ferris FD, eds. The Education for
Physicians on End-of-life Care (EPEC) Curriculum, 1999. www.epec.
net (Accessed 3 Apr 2013).
54. Schonwetter RS, Hawke W, Knight CF, eds. Hospice and Palliative
Medicine Core Curriculum and Review Syllabus. American Academy
of Hospice and Palliative Medicine. Dubuque, IA: Kendall/Hunt
Publishing Company, 1999.
55. Ferris F, Balfour H, Bowen K, et al. A model to guide patient and family
care: Based on nationally accepted principles and norms of practice. J
Pain SymptManage 2002;24(2):106–123.
56. Berger AM, Portenoy RK, Weissman DE. Principles and Practice of
Palliative Care and Supportive Oncology. Philadelphia, PA: Lippincott-
Raven, 2002.
57. Doyle D, Hanks GW, MacDonald N, eds. Oxford Textbook of Palliative
Medicine, 3rd edn. Oxford, England: Oxford University Press, 2003.
58. Portenoy RK, Bruera EB, eds. Topics in Palliative Care, Vol. 5. New
York: Oxford University Press, 2001.
59. Oxford University Press, 2019. https://global.oup.com/academic/prod-
uct/oxford-scholarship-online—palliative-care-9780199642748?cc=
us&lang=en& (Accessed 19 Aug 2019).
60. Association for Palliative Medicine. 2012 Accounts. Southampton, UK:
Association of Palliative Medicine, 2013 (Accessed 7 Sept 2013).
61. American Academy of Hospice and Palliative Medicine, 2013. www.
AAHPM.org/fellowship/directory.html (Accessed 4 Apr 2013).
62. Bangerter LR, Griffin JM, Eagan A, et al. Recommendations from the
Salzburg global seminar on rethinking care toward the end of life. Int J
Qual Health Care 2018;30(5):408–413.
63. Adams C. Goals of care in a pandemic: Our experience and recommen-
dations. J Pain Symptom Manage 2020;60:e15-e17.
64. Arya A, Buchman S, Gagnon B, Downar J. Pandemic palliative care:
Beyond ventilators and saving lives. CMAJ 2020;192(15):E400–E404.
65. Chidiac C, Feuer D, Naismith J, Flatley M, Preston N. Emergency pal-
liative care planning and support in a COVID-19 pandemic. J Palliat
Med 2020;23(6):752–753.
66. Fausto J, Hirano L, Lam D, et al. Creating a palliative care inpatient
response plan for COVID-19: The UW medicine experience. J Pain
Symptom Manage 2020;60(1):e21–e26.
67. Higginson IJ, Evans CJ, Grande G, et al. Evaluating complex interven-
tions in end of life care: The MORECare statement on good practice gen-
erated by a synthesis of transparent expert consultations and systematic
reviews. BMC Med 2013;11:111. doi: 10.1186/1741-7015-11-111(111).
68. Gysels M, Evans CJ, Lewis P, et al. MORECare research methods guid-
ance development: Recommendations for ethical issues in palliative
and end-of-life care research. Palliat Med 2013;27(10):908–917.
69. Evans CJ, Benalia H, Preston NJ, et al. The selection and use of outcome
measures in palliative and end-of-life care research: The MORECare
International Consensus Workshop. J Pain Symptom Manage.
2013;46(6):925–937.
70. Preston NJ, Fayers P, Walters SJ, et al. Recommendations for managing
missing data, attrition and response shift in palliative and end-of-life
care research: Part of the MORECare research method guidance on
statistical issues. Palliat Med 2013;27(10):899–907.
71. Oriani A, Dunleavy L, Sharples P, Perez Algorta G, Preston NJ. Are
the MORECare guidelines on reporting of attrition in palliative care
research populations appropriate? A systematic review and meta-anal-
ysis of randomised controlled trials. BMC Palliat Care 2020;19(1):6.
72. Center to Advance Palliative Care. 2019. www.capc.org (Accessed 19
Aug 2019).
5
PALLIATIVE CARE AND SUPPORTIVE CARE

Eduardo Bruera

Contents
Introduction..........................................................................................................................................................................................................................33
Palliative medicine as an emerging medical specialty..................................................................................................................................................33
Role of supportive care.......................................................................................................................................................................................................34
Interdisciplinary nature of palliative medicine..............................................................................................................................................................34
Levels of palliative medicine..............................................................................................................................................................................................35
Conclusions...........................................................................................................................................................................................................................36
References..............................................................................................................................................................................................................................36
Web Resources......................................................................................................................................................................................................................37

Introduction Palliative medicine as an

Palliative care programs have three distinct characteristics:
• Multidimensional assessment and management. This
includes the assessment and management of a large num-
ber of physical symptoms, psychosocial distress, and func-
tional, spiritual, financial, and family concerns.
• Interdisciplinary care. This includes the pivotal role of a team
including physicians, nurses, social workers, pastoral care-
givers, occupational therapists and physiotherapists, phar-
macists, counselors, dieticians, and volunteers who work
together in an integrated fashion for the delivery of care.
• Emphasis on caring for patients and their families. In
the first palliative care programs, it was realized that the
majority of physical and emotional care near the end of life
is provided by the patient’s family. Thus, programs were
developed that aimed to support those families with coun-
seling, education, respite, and bereavement care.
Physicians have had a major role in the development of pallia-
tive care programs in the United Kingdom and other areas of the
world. They came from multiple specialties including family
medicine, oncology, pain medicine, surgery, neurology, psychia-
try, and geriatrics. These physicians are integrated with the other
medical disciplines to establish palliative care teams in programs
that were mostly based in the community.
During the first two decades of the development of palliative
care, there was an impressive and global expansion of clinical
programs. It soon became clear that some of the most seriously ill
patients died in acute care hospitals and cancer centers, and palli-
ative care programs progressively expanded from the community
into major academic centers. The body of knowledge of palliative
care started to progressively develop and the need for research
became apparent. The growth in clinical programs, the variety of
settings where palliative care was delivered, and the expanding
body of knowledge and need for research led to the development
of the specialty of palliative medicine.
emerging medical specialty
Dr. Cicely Saunders started the modern hospice movement in
the 1960s at St. Christopher’s Hospice in the United Kingdom,
focusing on improving care for patients at the end of life. With
increasing clinical knowledge and research, this led to the estab-
lishment of a professional discipline with expertise in symptom
management, psychosocial spiritual care, patient–clinician com-
munication, complex health-care decision making, and caregiver
support.1 In the 1970s, Dr. Baulfor Mount coined the term pal-
liative care to describe his hospice program in Canada, and this
term has since gained worldwide acceptance.2
To date, palliative medicine has achieved specialty or sub-
specialty status in the United Kingdom (since 1987), the United
States, Canada, and Australia. In addition, there are active
efforts to establish palliative medicine as a subspecialty in many
European countries and several countries in Latin America and
Asia. The move toward accreditation is highly important because
it allows palliative care practitioners to obtain standardized
training and to be recognized for their expertise, clinical pro-
grams to set benchmarks for their operations, institutions, and
governments to allocate health-care resources, and researchers to
properly evaluate the structures, processes, and outcomes associ-
ated with palliative care services.
The only nation where the specialty of palliative medicine has
existed long enough to allow for some evaluation of its impact
is the United Kingdom, where physicians need to complete four
years of specialty training to be qualified as palliative medi-
cine consultants. Hospice and palliative medicine have been an
accredited specialty in the United States since 2009, requiring
physicians to complete a one-year clinical fellowship program
with an optional second year focusing on research. The consensus
among physician groups in most of the world is that the develop-
ment of the specialty of palliative medicine is of great importance
for the further development of the field, particularly in acute care
institutions and universities.

33
34 Textbook of Palliative Medicine and Supportive Care

FIGURE 5.1  Conceptual framework for supportive care, palliative care, and hospice care.

Role of supportive care was less likely to cause distress in patients and families compared
to palliative care and that they were more likely to refer patients
The term supportive care first emerged in the early 1990s and was to a supportive care service. Based on this finding, we changed
defined by Page et al. as the following: our program name to supportive care in 2007.7 In a before and
after name change comparison, we found that the name change
The provision of the necessary services for those living to supportive care was associated with more inpatient referrals, as
with or affected by cancer to meet their informational, well as earlier referrals in the outpatient setting.8 There is strong
emotional, spiritual, social or physical need during their evidence that early access to palliative care improves multiple
diagnostic treatment or follow-up phases encompassing clinical, quality, and financial outcomes.9,10 Consult teams and
issues of health promotion and prevention, survivorship, outpatient centers with the name supportive care are perceived
palliation and bereavement.… In other words, supportive by physicians as less likely to reduce patient and family hope and
care is anything one does for the patient that is not aimed more likely to result in early referrals.11
directly at curing his disease but rather is focused at help-
ing the patient and family get through the illness in the
best possible condition. Clearly this type of help would
Interdisciplinary nature of
need to be broad in scope and as varied as the individuals palliative medicine
requiring it. 3
Figure 5.2 illustrates the main disciplines involved in the pal-
liative circle of care. Each of these disciplines is responsible for
Others have used supportive care in a narrower sense to describe
developing its own body of knowledge and for contributing to
the management of treatment-related adverse effects, such
the integration of this body of knowledge with that of the other
as chemotherapy-induced nausea and vomiting, oral muco-
sitis, peripheral neuropathy, and skin rash.4 For instance, the
Multinational Association of Supportive Care in Cancer has
traditionally focused on the treatment of antineoplastic therapy-
related adverse effects and has now expanded its scope to include
palliative care domains such as psychosocial/spiritual care and
communication, as well as survivorship care.
Given the significant overlap and confusion around the
description of supportive care, palliative care, and hospice care, 5
we recently completed a systematic review to identify defining
features for these three terms and developed a preliminary con-
ceptual framework unifying these terms along the continuum
of care (Figure 5.1).4 Hospice care focuses on providing care for
patients at the end of life (i.e., last six months) predominantly in
the community setting. Palliative care includes not only hospice
care services, but also acute care programs in hospitals providing
care for patients with advanced diseases. Supportive care is the
most encompassing term that spans survivorship care services
to bereavement programs for patients throughout the disease
trajectory.
Given that supportive care includes palliative care, it is some-
times used interchangeably to describe palliative care programs
or services. We recently surveyed oncologists and mid-level pro-
viders about their perception of palliative care and supportive
care.6 A majority of the respondents reported that supportive care FIGURE 5.2  Palliative circle of care.
Palliative Care and Supportive Care 35

FIGURE 5.3  Main medical and nonmedical disciplines that influenced the body of knowledge in palliative medicine.

disciplines within the circle. The effective growth and interac-
tions of these disciplines result in increased knowledge in pallia-
tive care, which in turn improves care for patients and families.
In this theoretical model, palliative medicine is the medical com-
ponent of the multidimensional and interdisciplinary domain
known as palliative care.
Figure 5.3 shows that there are many important contributors
to the body of knowledge of palliative medicine. These contribu-
tors have not only included subspecialties of medicine, but a large
contribution to the knowledge of medicine has also been made
by disciplines such as nursing, rehabilitation, psychology, social
work, pastoral care, and nutrition.12 It is desirable to have repre-
sentatives of these disciplines as part of the research and educa-
tion in palliative care. It is likely that with the regular interaction
as part of the palliative care circle, these disciplines will continue
to influence the growth of palliative medicine in the future.
Levels of palliative medicine
As palliative care matures into a professional discipline with spe-
cialized knowledge and skills, the practice of palliative care can
be divided into three categories based on the level of involvement
in clinical care, education, and research.13 Box 5.1 summarizes
the similarities and differences between primary, secondary, and
tertiary palliative care. Palliative medicine specialists are not nec-
essarily expected to see all patients with progressive, incurable
diseases or their families. In most cases, the physician in charge
of the primary care of the patient, either their family physicians
(such as in Canada, the United Kingdom, and Australia4) or their
primary specialists (such as in the United States,14,15 most of con-
tinental Europe,16 and the developing world17), can deliver the
principles of palliative care assessment and management. These
primary care physicians can access a number of other palliative
care disciplines for the patient including nursing, social work,
pastoral care, counseling, rehabilitation, or volunteer services. To
ensure a high base level of primary palliative care delivery, we
need to increase the intensity of palliative care training among
medical students and postgraduate trainees.
When patients present with physical or psychosocial distress
that cannot be appropriately controlled by their primary care
physician, involvement of secondary palliative care by a spe-
cialized team is advised. They can provide episodic care, such
as consultations, or collaborative care by following up with the
patient in an integrated manner with the primary physician.18,19

BOX 5.1  PRIMARY, SECONDARY, AND TERTIARY PALLIATIVE CARE

Primary palliative care Secondary palliative care Tertiary palliative care

Personnel Primary care or specialists (e.g., Specialist palliative care teams Specialist palliative care teams
oncologists, cardiologists)
Roles Provision of primary care and basic Provision of specialist palliative Provision of specialist palliative care
palliative care care as consultants and primary care
Settings Community, hospitals, academic Hospitals (palliative care clinics and Academic centers (palliative care
centers palliative care inpatient units)
consultations)
Complexity of patient cases + ++ +++
Involvement in palliative – +/– +++
care education
Involvement in palliative – +/– +++
care research
36 Textbook of Palliative Medicine and Supportive Care

The palliative medicine specialist will then be able to access all

other members of the palliative care team as required. KEY LEARNING POINTS
A small percentage of patients are severely distressed, and this
requires that the palliative medicine specialist becomes the pri- • Palliative care programs have three main charac-
mary care physician. This will take place both in the ambulatory teristics: multidimensional assessment and man-
care setting and particularly in palliative care units.20–22 In many agement, interdisciplinary care, and emphasis on
cases, the most important contribution of the palliative medicine the patient and their families.
specialist is to provide the sophisticated assessment and correct • Palliative medicine was initially established as a
management plan that will help the team develop the most effec- specialty in the United Kingdom in 1987.
tive interventions. Tertiary palliative care specialists are not only • Palliative medicine specialists integrate with
active in the provision of complex care, but also active in edu- multiple other disciplines in the delivery of pal-
cating the next generation of clinicians and conducting palliative liative care.
care research.23 • Palliative medicine specialists provide clinical
These different levels of delivery of palliative care are not differ- care in the most complex situations, graduate and
ent from the role of other medical specialists in the management postgraduate education, and research.
of different diseases. For example, it would not be reasonable to
expect that cardiologists provide primary care to all patients with
The university affiliation will allow palliative medicine specialists
arterial hypertension or that endocrinologists provide primary
to have the necessary protected time for conducting academic
care to all patients with type 2 diabetes. In most countries in the
activities, the possibility to influence the development of under-
world, their own primary care physicians provide the majority
graduate and postgraduate curricula, and the possibility to estab-
of care for these patients. However, the specialist is available for
lish research teams by interacting with experts in methodology,
consultation for a major proportion of these patients and for pri-
content, and biostatistics affiliated with different universities.
mary delivery of care in the most refractory situations.
The degree of use of the palliative medicine specialist as a
consultant will be linked to the level of expertise of the primary Conclusions
physician. Some primary physicians will have acquired enough
Since the establishment of the specialty of palliative medicine
education and experience in palliative care to be able to resolve a
in the United Kingdom in 1987, similar efforts have been made
large proportion of clinical problems, whereas others will have a
in a number of countries. Palliative medicine specialists have
much lower threshold for consultation. The best indicator for the
been instrumental in the development of scientific organizations
appropriate utilization of palliative medicine specialty services
and meetings, peer-reviewed journals, and textbooks, and in the
will be the level of physical and psychosocial distress in patients
development of a curriculum for the undergraduate and post-
and families in each institution and/or region.
graduate teaching of palliative medicine for physicians. These
Palliative medicine specialists are extremely important for
specialists have also linked with other health-care professionals
undergraduate and postgraduate education.24–27 They are also
and volunteers to maintain the multidimensional and interdisci-
responsible for the continuing medical education of those pri-
plinary nature of palliative care.
mary care physicians already working in the community. The
The nature and content of the teaching curriculum, the finan-
adoption of new assessments and pharmacological and non-phar-
cial viability of the different palliative specialist positions in
macological interventions by primary care physicians will heav-
different countries, and the overall body of knowledge are not
ily depend on the clinical and educational leadership of palliative
completely defined for this young medical specialty. As pallia-
medicine specialists in every community. Physicians adopt new
tive medicine is progressively adopted by acute care facilities and
diagnostic tests, medications, and procedures mostly as a result
academic institutions, the need for palliative medicine specialists
of the clinical leadership and education of those who have spe-
is likely to grow exponentially during the next decade in most
cialized in these specific areas of knowledge.
parts of the world. Unfortunately, the vast majority of universi-
Finally, palliative medicine specialists are responsible for the
ties and large medical centers don’t have independent clinical and
development of the body of knowledge that will result in changes
academic palliative care departments; therefore, research and
in the assessment and treatment of patients and families.26
education progress have been much slower for this emerging spe-
Although most physicians will use analgesics, antiemetics, and
cialty compared to the traditional biomedical disease-centered
drugs for the management of delirium on a regular basis, there is
specialties.
a huge need for a small number of specialists with great dedica-
tion to the discovery of new assessments and treatments for pain,
emesis, and delirium in palliative care. Individuals who are fully References
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Mount BM. The problem of caring for the dying in a general hospital: The
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Hui D, De La Cruz M, Mori M, et al. Concepts and definitions for “sup-
opments in assessment and management of clinical problems. portive care,” “best supportive care,” “palliative care,” and “hospice
Ideally, a significant proportion of palliative medicine specialists care” in the published literature, dictionaries, and textbooks. Support
Care Cancer 2013;21(3):659–685.
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Hui D, Mori M, Parsons H, et al. The lack of standard definitions in the
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6. Fadul N, Elsayem A, Palmer JL, et al. Supportive versus palliative care:
what’s in a name? A survey of medical oncologists and midlevel provid-
ers at a comprehensive cancer center. Cancer 2009;115(9):2013–2021.
7. Bruera E, Hui D. Conceptual models for integrating palliative care at
cancer centers. J Palliat Med 2012;15(11):1261–1269.
8. Dalal S, Palla S, Hui D, et al. Association between a name change from
palliative to supportive care and the timing of patient referrals at a
comprehensive cancer center. Oncologist 2011;16(1):105–111.
9. Hui D, Hannon BL, Zimmermann C, Bruera E. Improving patient and
caregiver outcomes in oncology: Team-based, timely, and targeted pal-
liative care. CA Cancer J Clin 2018;68:356–376.
10. Hui D, Bruera E. Integrating palliative care into the trajectory of can-
cer care. Nat Rev Clin Oncol 2016;13:159–171.
11. Wong A, Vidal M, Prado B, et al. Patients perspective of timeliness and
usefulness of an outpatient supportive care referral at a comprehensive
cancer center. J Pain Symptom Manage 2019;58(2):275–281.
12. Hui D, Parsons HA, Damani S, et al. Quantity, design, and scope of the
palliative oncology literature. Oncologist 2011;16:694–703.
13. von Gunten CF. Secondary and tertiary palliative care in U.S. hospi-
tals. JAMA 2002;287(7):875–881.
14. Morrison RS, Meier DE. Clinical practice: Palliative care. N Engl J Med
2004;350(25):2582–2590.
15. White KR, Cochran CE, Patel UB. Hospital provision of end-of-life ser-
vices: Who, what, and where? Med Care 2002;40(1):17–25.
16. Centeno C, Gomez-Sancho M. Models for the delivery of palliative
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17. Wenk R, Bertolino M. Models for the delivery of palliative care: The
Argentine model. In: Bruera E, Portenoy RK, eds. Topics in Palliative
Care. Oxford, UK: Oxford University Press, 2001, pp. 39–54.
18. Yennurajalingam S, Atkinson B, Masterson J, et al. The impact of
an outpatient palliative care consultation on symptom burden in
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19. Yennurajalingam S, Urbauer DL, Casper KL, et al. Impact of a pallia-
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Web Resources
Edmonton Regional Palliative Care Program: www.palliative.org
International Association of Hospice Care: www.hospicecare.com
6
ETHICS IN THE PRACTICE OF PALLIATIVE CARE

Nelia Jain and James A. Tulsky

Contents
Disclosure and truth telling...............................................................................................................................................................................................39
Advance care planning........................................................................................................................................................................................................40
Requests for treatment of unproven, limited or no benefit.........................................................................................................................................41
Responding to intractable terminal suffering.................................................................................................................................................................42
Conclusion.............................................................................................................................................................................................................................43
References..............................................................................................................................................................................................................................44

Excellent palliative care demands careful attention to diagnostic,
prognostic, and therapeutic challenges. The palliative care clini-
cian must demonstrate sensitivity to psychosocial and spiritual
concerns and thoughtful, empathic communication with patients
and families. Yet, even when these are skillfully done, patients
and providers may still meet ethical dilemmas along the jour-
ney through serious illness. Some dilemmas are subtle and, per-
haps, not recognized. Others are easily apparent and may lead to
conflict. This chapter will discuss several of the more common
and vexing ethical issues that arise in the care of patients with
advanced serious illness. These include truth telling; when and
how to engage in advance care planning; responding to requests
for treatments of unproven, limited, or no benefit; and, finally,
consideration of aggressive measures for responding to intrac-
table suffering. The following case raises each of these dilemmas.
The case is typical, and the problems are not profound. Yet, they
reflect the thorny issues that arise in the real daily practice of pal-
liative care.
S.K. is a 68-year-old retired, Korean born, university pro-
fessor who is admitted to the hospital with pneumonia and
chest pain. Chest CT reveals a 4 cm lesion obstructing the
right upper bronchus and several rib lesions suspicious for
malignancy. As the physician approaches the patient’s hos-
pital room, he is pulled aside by Mr. K’s son and daughter
who wish to know the result of the CT scan. They request
that the doctor not share the results with their father if it
means he might have cancer.
Disclosure and truth telling
Truth telling is fundamental to respectful patient care and a nec-
essary component of informed consent. By fully including patients
in all decision-making, health-care professionals honor patient
autonomy. Truth telling also engenders trust in the medical
profession and promotes shared decision-making. Surveys con-
sistently show that most patients wish to receive as much infor-
mation as possible,1,2 perhaps as a way to cope with uncertainty. 3,4
In one typical survey of 2,850 British patients, over 1,000 of them
receiving palliative care, nearly 90% stated they would like to be
told most or all information about their illness. 5 Information
allows patients to plan their futures and to make decisions. Lack
of information may heighten their fear and anxiety, as the truth is
often not as bad as what might be imagined, and they may lose the
opportunity to achieve important goals prior to death. In addi-
tion, the secrecy and collusion necessary to withhold information
may present a significant challenge to clinicians and families. Yet,
patients also desire an individualized approach to receiving bad
news and discussing prognosis.6 Furthermore, clinicians should
anticipate variations in patients’ informational needs throughout
the course of their illness.7
Most patients prefer to participate actively in decision-making
yet also wish to receive a physician’s advice regarding recom-
mended options. Physicians must strike a balance between con-
veying the ambiguity that clouds medical decision-making and
helping patients find the best options for themselves. Disclosure
of serious diagnoses and their repercussions appears to vary
widely. Physicians do not always share prognosis, and when they
do, they tend to bias optimistically.8 Although withholding infor-
mation or providing an overly optimistic assessment of illness
may be deceptive, legitimate reasons for the practice also exist.
Patients may find it too difficult to hear bad news or may con-
sciously defer all decision-making to their families. While such
perspectives may challenge notions of patient autonomy, in fact,
autonomy dictates that patients also have the right to not hear or
to defer responsibility to others.
Cultural issues also impact patient expectations and the
importance of individual autonomy. While in most Western
societies, common practice is to answer patients’ questions hon-
estly and to share relevant information about their medical con-
dition, prognosis, and therapeutic options, significant variation
exists worldwide.9,10 In many societies, decision-making is local-
ized in the family and individual autonomy is not recognized.
Blackhall surveyed members of four distinct ethnic groups in
the United States and found widely disparate perspectives on
whether a patient should be told a diagnosis of metastatic cancer.
Only 47% of first-generation Korean Americans and 65% of first-
generation Mexican Americans believed that patients should be
told, whereas European Americans (87%) and African Americans
(88%) were more likely to want to hear this news directly them-
selves.11 In some cultures, the delivery of bad news may determine
how patients confront illness and being told the wrong informa-
tion can cause harm. For example, in Navajo society, the concept
of hozho or living in beauty may be considered to be violated by
statements that are viewed as negative.12 Such observations imply
that, in different cultures, personal autonomy carries different

39
40
levels of importance. That said, patients’ preferences are not sim-
ply a reflection of their ethnic background, and there are no iden-
tifiable predictors of such preferences.
To avoid assuming patients’ preferences inaccurately, clini-
cians should ask patients directly, “How much information are
you interested in hearing about your illness?” Patients can specify
what they wish to hear and subsequently receive only the amount
of information they desire. If a patient expresses ambivalence,
clinicians should offer information that fulfills the reasonable
patient standard, conveying the information a reasonable patient
would need to know to make rational decisions.13 Regardless of the
extent of information desired, clinicians should convey medical
facts and recommendations in an empathic manner. Attending to
the emotional responses evoked by patients and families during
these conversations will help the clinician determine the pace at
which information should be delivered.
Advance care planning
Mr. K. is treated for his pneumonia and biopsy reveals non-small
cell lung cancer, metastatic to rib. He receives radiation to his
lung and ribs and feels much better. He is seen six weeks later in
his doctor’s office, and the physician wonders whether this would
be a good opportunity to begin advance care planning.
Advance care planning is the process by which patients,
together with their families and health-care providers, consider
their values and goals and articulate preferences for future care.14
Although it could refer simply to signing a form in a lawyer’s or
doctor’s office, ideally, advance care planning creates an opportu-
nity for patients to explore their own values, beliefs, and attitudes
regarding quality of life and medical interventions, particularly
as their condition changes. Patients may speak with loved ones,
physicians, spiritual advisers, and others during the process. This
reflective work can help patients learn more about what they can
expect as their disease progresses and gain a sense of control over
their medical care and their future.15
An important aspect of advance care planning is the process
of naming a surrogate, also referred to as a health-care proxy.
Patients with serious illness are at risk for losing decisional capac-
ity at any stage of their illness, with greater risk in more advanced
stages. Decisional capacity should be assessed using a systematic
framework, evaluating a patient’s ability to comprehend medical
information regarding one’s condition, apply relevant information
to one’s situation, demonstrate a logical reasoning process in mak-
ing medical decisions, and express a clear choice that is consis-
tent with previously expressed values and beliefs.16,17 Assumptions
regarding a patient’s decisional capacity should not be made based
on underlying or comorbid conditions (e.g., depression or cognitive
impairment). Patient ambivalence may be expected, particularly
in later stages of illness, and does not reflect a lack of decisional
capacity.18 Furthermore, the burden of proof required to establish
a patient’s decisional capacity is proportionate to the level of risk
and consequence of decision at stake, with higher stakes decisions
such as those regarding life-sustaining interventions occurring
more frequently in the care of seriously ill patients.19
Earlier conversations with patients ensure that patients have
the ability to directly express their values and preferences in
the context of their illness as well as identify trusted surrogate
decision makers. When a patient loses decision-making capac-
ity, health-care teams turn to surrogate decision makers to assist
with medical decision-making. The ethical standard expected to
be met by health-care proxies is one of substituted judgments,
Textbook of Palliative Medicine and Supportive Care
where the surrogate’s understanding of the patient’s values and
preferences is used to guide medical decision-making. Clinicians
and loved ones who have been involved in the advance care plan-
ning process know the patient’s goals and values better and make
medical decisions that are more likely to align with the patient’s
values and preferences.
Written advance directives formalize patient preferences and
values elicited from advance care planning conversations and
include living wills or other statements of patient preferences, as
well as durable powers of attorney for health care, which name
health-care proxies. Do-not-attempt resuscitation orders are
written by physicians to operationalize one specific set of prefer-
ences articulated by patients and their proxies. More recently, a
newer directive, often referred to as Physician Orders for Life-
Sustaining Treatment (POLST), has been initiated in many US
states as a way of ensuring that patient preferences are enacted
in practice.20 POLST documents are actual medical orders,
respected by emergency medical services and local health-care
institutions, which implement a scope of treatment for a particu-
lar patient. Advance care planning and documentation has been
promoted widely in the United States and other countries, par-
ticularly in response to high-profile cases in which patients in a
vegetative state have been kept alive despite a presumption that
such treatment violated their preferences.21
When the patient’s illness has progressed to its final stages,
health-care providers can use the groundwork from these earlier
discussions to make specific plans about what is to be done when
the inevitable worsening occurs. Engaging in advance planning
affords patients reassurance that they will be cared for at the end
of life in a manner that is consistent with their preferences.
Although patients and families agree that advance care plan-
ning is important, clinicians are often reluctant to raise the sub-
ject with their patients and often do so later than patients may
desire.22 While clinicians are often worried that patients will be
put off by a discussion about advance care plans, most patients
want to discuss these issues early in the course of their disease
and believe the doctor should raise the topic.23 The root cause of
much of physicians’ reluctance stems from lack of training in how
to have these discussions. With training, physicians can feel more
comfortable having these discussions, can learn how to deal with
patients’ emotional responses, and can have effective discussions
that the physician will find truly helpful in caring for patients.24,25
Clinicians also struggle with the timing of initiating such conver-
sations as they attempt to balance patients’ and families’ readi-
ness for conversations against other factors such as a patient’s
risk for loss of decisional capacity further downstream in the ill-
ness trajectory.26,27 By introducing conversations early, and shift-
ing the focus away from specific medical interventions toward
an exploration of patients’ values and goals, clinicians may find
patients and families more willing to engage in these discussions.
Clinicians also cite time constraints as a barrier to conduct-
ing advance care planning conversations. While time constraints
are difficult to overcome, there are multiple strategies that clini-
cians may implement. Patients and families are often receptive to
advance care-planning discussions with multiple members of the
health-care teams. Enlisting nurses and social workers to initiate
these conversations, particularly those with longstanding relation-
ships with the patients and families, can help increase the frequency
of advance care planning discussions and offload the responsibility
from any one particular team member.28,29 The use of booklets, vid-
eos, and other tools to introduce the concepts involved in advance
care planning may help physicians efficiently use their time to
Ethics in the Practice of Palliative Care
answer specific questions patients may have and to guide patients
through the process.30,31 Finally, the introduction of advance care
planning billing codes allows physicians to dedicate clinic and hos-
pital visits to addressing advance care planning.32
Advance care planning conversations can result in increased
patient and family satisfaction, higher rates of known and fol-
lowed end-of-life care wishes, and decreased anxiety, stress, and
depression among their family members. 33 In addition, advance
care planning can lead to increased completion of advance
directives, decreased utilization of aggressive treatments in late
stages of illness, and improved quality of life and prioritization
of comfort-focused care at the end of life. 34,35 Unfortunately,
the impact of advance directives on actual resuscitation events
remains unclear, with most of the older literature showing mini-
mal effect. 36–43 This may be due to several causes. Discussions
often do not occur or are not recorded in ways that may have a
lasting effect.44 Some of the barriers to successful implementa-
tion have been procedural when, for example, documents are not
available when needed. More importantly, problems arise with
deciding in advance about specific interventions,45 the adequacy
of communication,46 the willingness of health-care providers to
follow patient preferences,41,44 and patient and family misunder-
standings about the process. More recent data including utiliza-
tion of POLST forms to reflect patient wishes suggest higher rates
of patients receiving goal-concordant care.47
Entering these conversations may feel awkward, but if they are
viewed as conversations about hopes, fears, and goals rather than
decisions for specific preferences, they may be easier to engage.
For example, Mr. K. could be asked how he has been doing since
his hospitalization, his response to learning his diagnosis, and the
impact on his hopes and worries for the future. By careful explo-
ration of patients’ values, health-care providers can help patients
discover their preferences. From such discussions, health-care
providers can help patients consider specifically whether there
are certain treatments that they might wish to forgo and to think
about the circumstances under which they might forgo them.
Nevertheless, there will be some patients who are not ready to
discuss advance directives. Health-care providers must be sen-
sitive to these patients. Advance care planning is a process that
should be offered to patients, not forced upon them.
Requests for treatment of unproven,
limited or no benefit
Mr. K. chooses to undergo chemotherapy and receives
carboplatin and gemcitabine. However, he experiences a
significant decline and his tumor progresses. He then tries
nivolumab but is hospitalized with shortness of breath and
hypoxia, and nivolumab is stopped due to concerns for
immune-mediated pneumonitis. At this point, his oncolo-
gist tells him that there are no more proven treatments left
and that he would not suggest more treatment given his age
and poor responses to previous agents. Mr. K asks, “isn’t
there anything else? What about an experimental drug?”
Mr. K. has exhausted the proven treatments for his cancer. Even
though he has experienced significant side effects from his treat-
ment, he does not want to die and is willing to consider other
options. Such options range in efficacy from unproven or question-
able benefit to limited benefit to clear lack of benefit. Clinicians
will often be in the position of making recommendations about
treatments of unclear benefit, raising the question of how to best
41
engage patients in informed consent. The principle of therapeutic
proportionality may serve as a useful guide to clinicians facing
this quandary. Clinicians should take into consideration the level
of aggressiveness and invasiveness of the intervention in question
along with the severity of risks imposed on the patient and weigh
these against the patient’s prognosis and any potential benefit.
Treatments of unproven benefit such as phase I clinical trials
are not meant to be therapeutic and, historically, approximately
5% of patients enrolled in such trials for cancer agents achieve a
response.48,49 Nevertheless, most patients enroll with the intent
of achieving therapeutic benefit.50,51 This may be due, in part, to
a lack of adequate disclosure practices by trial investigators.52 As
treatment intent shifts from emergent to elective to experimen-
tal, the standards for disclosure are higher. Increasingly, it is rec-
ognized that patients choosing to enroll in phase I trials may have
different values than those who do not enroll, and although they
understand the prognostic data presented to them, they maintain
a more optimistic perspective and believe that they will be the
ones to gain benefit.53,54 In fact, many now argue that hospice care
and phase I trials ought to coexist simultaneously.55,56
In addition to clinical trials, there are other medical advances
such as high flow oxygen therapy or total parental nutrition that
are more routinely utilized in the care of seriously ill patients that
may confer some benefit; however, the amount of benefit with
respect to quality of life and quantity of life is unknown. With rap-
idly changing medical technologies, clinicians have a harder time
counseling patients solely on the basis of weighing burdens versus
benefits. There may be a lack of consensus amongst treating cli-
nicians regarding the risks and benefits of specific treatments, or
patients and families may strongly wish to pursue an intervention
despite a clinician’s reservations. In these instances, a “time-limited
trial” of a particular intervention with observation for specific
clinical outcomes over a pre-specified period of time may be a
useful approach. This allows clinicians to maintain a therapeutic
relationship with patients and their families and help to diminish
conflict. If the intended clinical outcome is not observed, patients
and families should be counseled to withdraw the trial interven-
tion. In contrast, the majority of alternative, ineffective treatments
are far less accepted. Although belief systems vary among patients
and clinicians, the primary issue here is one of informed consent
and trying to ensure that patients do not encounter more harm
than good in reaching out to such treatments. Furthermore, these
discussions present opportunities for clinicians to reframe the
conversation around what can be done that will benefit patients
and families, such as intensive supportive and comfort-focused
care in the case of patients with terminal illness.
Mr. K. becomes progressively more debilitated. He decides
not to pursue unproven therapies and accepts a comfort-
focused approach to care, including a DNR order. He has
been spending an increasing percentage of his time in bed
when he develops a fever and cough and stops eating and
drinking. His family wonders whether he is again suffering
pneumonia and asks if he can receive antibiotics. In addi-
tion, they question whether a feeding tube should be placed
or if intravenous hydration would be helpful.
Even when patients have elected to pursue a comfort-focused
approach to care, they and their care providers may struggle
over the exact limitations of treatment. Antibiotics are particu-
larly interesting because they tend to be among the least refused
of medical interventions.57,58 Their use is high even in palliative
42
care units, where they are administered to as many as 30–40% of
patients with comfort care plans.59–61 The literature suggests that
antibiotics can play a role in symptom relief, yet must be balanced
against the burdens of side effects and cost. 59,60 In the case of
Mr. K., pneumonia may be his terminal event, with or without the
use of antibiotics. He and his family will need to decide whether
IV antibiotics are worth a trip to the hospital or even whether it’s
worth trying to administer them at home. His symptoms of cough
and fever can be managed with antitussives and antipyretics—it is
not clear if adding another few days or weeks to his life will meet
his goals at this point. Such decisions become highly individual-
ized with no correct answers.
Tube feeding has not shown a significant benefit for most
patients with terminal illness.62 In contrast, considerable debate
exists as to the benefits of artificial hydration. Recent evidence
suggests that subcutaneous hydration can alleviate common
symptoms of terminal illness with minimal burden.63 Guidelines
established by the European Association for Palliative Care rec-
ommend a three-step approach.64 Step I includes assessing a vari-
ety of clinical factors, Step II involves an assessment of pros and
cons to establish a well-defined goal of therapy and end point, and
Step III requires periodic reevaluation of the decision.
When receiving requests for unproven, limited, or ineffec-
tive therapy, physicians should counsel patients openly and not
hesitate to give an opinion based upon their knowledge of the
intervention and the patient’s values. It is keenly important to
acknowledge the patient’s affect and recognize that requests
for unproven or ineffective treatments are frequent proxies for
patient distress and difficulty coping with impending death. A
common pitfall is responding to such distress by offering more
therapy rather than engaging the patient’s emotional state. Even
in situations where there is a low clinical likelihood of a patient
being a candidate for more treatment, patients are often told,
“we’ll wait until you’re stronger.” In these situations, clinicians
may defer recommending comfort-focused care and access to
intensive support services including hospice to avoid engaging
in difficult conversations. A more productive technique to use
in this situation is the wish statement.65 By letting patients know
that “I wish I had a more effective treatment to offer you,” clini-
cians can both align themselves with patients, while implicitly
acknowledging that this goal cannot be met.
In these settings, clinicians struggle to promote hope in the
patient with advanced disease and to support a positive out-
look.1 Incorrectly, they fear that discussing death may distress
patients.8,66–69 As a result, doctors frequently convey overly opti-
mistic prognoses or do not give this information at all.70 Fearing
the loss of hope, patients frequently cope by expressing denial
and may be unwilling to hear what is said.71 Not unexpectedly,
patients with more optimistic assessments of their own prognosis
are more likely to choose aggressive therapies at the end of life.72,73
Yet, perhaps more importantly, patients who have had no con-
versation about end-of-life issues at all are most likely to receive
aggressive interventions prior to death.74
Physicians should recognize that it is not their job to correct
the patient’s hope for an unrealistic outcome.75 Hope is the frame
within which patients construct their future.76 It may be a desire
for a particular outcome or it may be, more broadly, trust or reli-
ance. The key question is whether the patients’ construction of
hope is interfering with appropriate planning and behavior.
Clinicians, at their best, can provide an empathic, reflective pres-
ence that will help patients to draw strength from their existing
resources. Together, the physician and the patient can “hope for
Textbook of Palliative Medicine and Supportive Care
the best but prepare for the worst.” 77 Helping the patient and fam-
ily manage their hope and their resources in a realistic way may
leave the family in the best possible shape after their loss.
Responding to intractable terminal suffering
Mr. K’S illness progresses, and he is bedbound with fluc-
tuating consciousness. He requires large quantities of
opioids for pain and dyspnea. The patient’s daughter is
concerned that the medication may hasten his death and
resists the hospice nurse’s suggestion to increase it further.
Meanwhile, the son feels that his father had completed
all he needs to do and is just lingering uncomfortably. He
wants to know how much longer his father has and whether
there is anything that can be done to stop the waiting.
One of the major barriers to aggressive symptom management at
the end of life is a clinician’s feelings of inadequacy in respond-
ing to suffering. Some clinicians fear that providing intensive
symptom management will hasten death. Others struggle with
distinguishing between emotional, physical, spiritual, and exis-
tential suffering. Clinicians may feel helpless in these situations,
leading them to withdraw from patients and their families or
experience significant moral distress. Instead, clinicians should
“turn towards” their patients’ suffering, opening themselves up
to understanding the type and extent of suffering from a place
of curiosity and engagement, and ensuring non-abandonment.78
Clinicians should also utilize an interdisciplinary team to ensure
patients’ needs are assessed from a whole-person perspective.
Despite best efforts, clinicians will encounter patients who expe-
rience intractable suffering at the end of life and may be in the
position of considering options of last resort to provide relief.
Moral clarity on these issues is critically important to ensure that
no inappropriate boundaries are overridden and to give reassur-
ance to ethical providers who are working hard to take the best
care of patients.79
Many clinicians and family members are unsure where pain
control ends and euthanasia begins. In situations such as Mr. K.’s,
clinicians generally rely on the principle of double effect to jus-
tify their actions. This centuries-old ethical framework allows
one to perform beneficial actions with potentially harmful con-
sequences as long as four requirements are met.80 The act itself
must not be immoral; it must be undertaken only with the inten-
tion of achieving the possible good effect, without intending the
possible bad effect even though it may be foreseen; it does not
bring about the possible good effect by means of the possible bad
effect; and, lastly, it is undertaken for a proportionately grave rea-
son. The principle of double effect has been very useful in medi-
cal practice generally and palliative care in particular because it
helps many clinicians overcome barriers to prescribing adequate
pain relief and it provides a legal defense for opioid prescriptions
at the end of life.81
Several problems exist with double effect.82 It can be difficult
to distinguish between intended and foreseen consequences,
particularly regarding death at the end of life. Conscientious cli-
nicians not sure of their actions may be tormented by the out-
come. Furthermore, the principle of double effect prioritizes the
absolute prohibition against patient death over patient autonomy.
Advocates applaud the principle for exactly this reason. Yet those
who wish to allow greater flexibility for ending patient suffering
at the end of life find double effect to be constraining. Finally, as
Ethics in the Practice of Palliative Care
discussed in the preceding chapter, because the skilled titration
of opioids ought not increase the risk of death, some argue that
double effect is not really a relevant consideration in these cases.83
Others argue that when someone is known to be dying and the
focus of care is a good death, a somewhat shortened time to death
is not a bad effect, and double effect doesn’t hold.84
Intractable suffering that does not respond to routine inten-
sive palliation requires consideration of less frequently used
treatments. In one practice, termed palliative sedation, patients
are deeply sedated to the extent needed to decrease awareness
of refractory symptoms.85 This intervention is intended for dying
patients, typically with a prognosis of days to weeks, with unbear-
able symptoms unresponsive to other therapies.86 Ethically, this
practice is permissible under the principles of double effect and
therapeutic proportionality. These standards are met as the pri-
mary intention is to titrate sedating medications to a sufficient
decrease in a patient’s awareness to relieve intolerable suffering
after all other strategies have been exhausted. In the Netherlands,
and perhaps elsewhere, the practice precedes a substantial num-
ber of deaths.87 In the United States and most other countries, it
still remains fairly rare and is reserved for intractable physical
suffering. Use of palliative sedation for refractory existential suf-
fering remains controversial due to persistent ambiguity in the
definition, assessment, and treatment of existential suffering.88
Because death is certain if sedation is not withdrawn, some people
view this as a form of euthanasia, particularly those who believe
in an absolute prohibition of hastening death.89 An important
consideration in distinguishing palliative sedation from practices
that directly hasten death is the intention behind the practice.
Given that sedation is the means of relieving suffering rather than
the intent, palliative sedation remains a distinct theoretical entity
from other last resort practices at the end of life.90 Whatever the
specific ethical justifications, there is a growing consensus in
favor of the practice under appropriate circumstances, and it is
legal in the United States and many other countries. Concerns
remain about potential abuses,91 yet the existence of institutional
policies provides some safeguards.83
With regard to hastening death, other practices exist, and a
detailed discussion of their history, merits, and risks is beyond
the scope of this chapter. Briefly, these would include voluntary
cessation of eating and drinking, physician-assisted death, and
euthanasia. Prior to delving into the specifics and availability of
these last resort options with patients, clinicians should make
every effort to explore the reasons underlying a patient’s request
for hastened death. Any reversible or treatable factors should be
addressed, including ensuring patients and families have access
to high-quality palliative care.
Any competent patient who is approaching the end of life
and confronting overwhelming suffering may choose to volun-
tarily stop eating and drinking.79 This difficult and potentially
unpleasant option takes tremendous conviction.92 Nevertheless,
some take advantage of this because it is legally protected under
a patient’s right to refuse medical interventions and avoid bodily
invasion, and there is a growing ethical consensus in support of
the practice. While the lack of requirement for physician involve-
ment removes a significant barrier to patients, clinician supervi-
sion is helpful to address any symptoms such as severe thirst or
delirium that may arise during later stages of the process.93
In contrast to voluntarily stopping eating and drinking, which
has received relatively little attention, physician-assisted death
has been at the center of heated debates, including decisions by
the US Supreme Court. In the United States and many European
43
nations, there is a majority public support for this practice,94–96 yet
considerable controversy exists over its appropriateness.97,98 At the
time of this writing, the practice is legal in eight US jurisdictions,
Canada, and in at least two European nations, although it is tac-
itly approved in others. The practice requires a competent patient,
which is perceived as a safeguard to abuse, and somewhat distances
the agency of physicians, which many prefer. However, physician
aid in dying is distinct from voluntarily stopping eating and drink-
ing as a participating clinician is required to have an active role
in providing the means for a patient to intentionally hasten his or
her death. Ethical arguments supporting physician-assisted death
are primarily founded on the basis of patient autonomy (a person’s
right to choose how to die) and beneficence (a clinician’s responsi-
bility to relieve intolerable suffering). In contrast, critics argue that
physician-assisted death challenges the limits of patient autonomy
under the physician’s responsibility to non-maleficence, particu-
larly as the intent of this practice is hastened death. Additional
concerns include the potential to disrupt the integrity of the pro-
fession as well as the potential for abuse.
Euthanasia is the practice whereby someone other than the
patient, usually a physician, administers a lethal agent to directly
hasten a death. This practice is perceived differently in different
countries.99 In the United States, euthanasia is distinguished from
physician-assisted suicide and no ethical consensus exists.94 It is
illegal everywhere within the United States and likely to be pros-
ecuted. In the Netherlands, Belgium, Canada, and some other
countries, the public response to the two practices is fairly simi-
lar and more accepting. From a practical perspective, euthanasia
does not require a competent patient, which has raised concerns
about safeguards to abuses of vulnerable patients.100
As Mr. K lays dying, his daughter may be reassured knowing
that aggressive use of opioids is entirely within the accepted stan-
dard of care as the intent is focused on controlling his pain and
other symptoms. The son’s position is also understandable. It is
very difficult to sit at such a vigil and wait for a patient to die. The
patient’s son may be reassured that nothing more need to be done
to extend his father’s life, such as giving hydration or antibiot-
ics. Clinicians have a responsibility to remain present for patients
and families throughout the illness trajectory and be prepared to
respond to all forms of suffering encountered at the end of life.101
Regardless of whether or not clinicians practice in a jurisdiction
where physician-assisted death is legalized, they will undoubtedly
encounter a patient requesting options for hastened death and
should be prepared to respond to these requests in an empathic
and respectful manner.102 The debate about assisted dying will
continue to play out in the press, courts, and legislatures. Yet, in
the end, individual patients, families, and health-care providers
confront real-life situations that must be resolved within the con-
straints of individual moral values and the law. All efforts should
be focused on the patient’s comfort and helping the family find
meaning during these last moments.
Conclusion
Ethical challenges lie in the paths of all patients, families, and
health-care providers dealing with a life-limiting illness. At dif-
ferent points of an illness, these may range from truth telling to
requests for assisted dying. Health-care providers must enter into
such issues without assumptions about patient preferences and
with an open mind to learn the underlying issues. Careful listen-
ing, clear thinking about the ethical issues at stake, and empathic
communication will help resolve many such dilemmas.
44
KEY LEARNING POINTS
• Truth telling engenders trust and is a central
aspect of good palliative care, yet patients vary
considerably in their preferences for information.
• Advance care planning can serve multiple goals
for patients, families, and health-care providers
in addition to communicating preferences for
future treatment.
• Requests for unproven, limited, or ineffective
therapies may reflect patient distress and appro-
priate responses should respond to a patient’s
emotional state, not just the underlying question.
• Treating suffering at the end of life is an obliga-
tion for all clinicians and should be addressed
with intensive symptom management and inter-
disciplinary support, with treatments that hasten
death reserved only as options of last resort.
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7
UNDERGRADUATE EDUCATION IN PALLIATIVE MEDICINE

Linh My Thi Nguyen

Contents
Introduction..........................................................................................................................................................................................................................47
Core competencies..............................................................................................................................................................................................................47
Europe������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������47
United States..............................................................................................................................................................................................................48
Canada�����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������48
Colombia....................................................................................................................................................................................................................49
Current status of undergraduate education....................................................................................................................................................................49
Summary and recommendations......................................................................................................................................................................................50
References..............................................................................................................................................................................................................................50

Introduction or the palliative care approach, applies to undergraduate medical

The integration of palliative care in undergraduate training for
health-care professionals was strongly encouraged by a World
Health Assembly. As such, clinicians and educators may be called
upon to provide competency-based curriculum and instruction
in undergraduate settings both in classrooms and at patients’
bedsides.
A general fund of knowledge pertaining to core competen-
cies, accreditation standards, and measurable outcomes may
help curricular and instructional development in these unique
learning environments. National and international investiga-
tors and working groups have proposed competencies developed
from expert opinion and surveys of health-care professionals and
educators. Some recommendations are specific to undergraduate
medical education, whereas others apply to all health-care pro-
fessions working in a setting where palliative care is delivered.
This chapter will describe the different conceptual frameworks of
competencies, research regarding the current status of palliative
care teaching in undergraduate education, and tips for developing
palliative care teaching.
Core competencies
Because the European recommendations for core competencies
include all health-care professionals, this framework is presented
first, followed by competencies for medical students in the United
States and Canada, and finally competencies for nursing and
medical students in Colombia.
Europe
The European Association for Palliative Care (EAPC) has out-
lined core competencies that health- and social-care profession-
als should possess who are involved in palliative care in a two-part
white paper.1,2 This expert opinion paper is intended for practitio-
ners and educators. The EAPC advocates for a three-tier frame-
work for practitioners in an academic environment. The agreed
levels of education reflect the scope and focus of professionals in
the delivery of palliative care: (1) palliative care approach, (2) gen-
eral palliative care, and (3) specialist care (Table 7.1). The first tier,
students. However, EAPC has emphasized that these proposed
competencies are important for all practitioners, irrespective of
their specific discipline.
The EAPC has identified core constituents that frame the
application of palliative care principles and best practices. 3 These
core constituents are the background and framework for the ten
proposed core competencies. Successful application of the EAPC
core competencies requires an understanding of the core con-
stituents of palliative care. The core constituents are autonomy,
dignity, relationship between patient and health-care profession-
als, quality of life, position toward life and death, communica-
tion, public education, multiprofessional approach, and grief and
bereavement.
First, the EAPC suggests key questions that need be asked
before competence can be applied: (1) What is the current posi-
tion of palliative care within the national or hospital system?
(2) What is the capacity of the individual or learner to achieve
competency in palliative care? (3) What resources are available
to enable the individual or learner to learn and practice skills?
(4) Are the baseline standards available against which compe-
tency can be determined? Next, educators must consider the
definitions of competencies. EAPC proposes one clear and mean-
ingful definition of competency which is “a cluster of related
knowledge, skills, attitudes that affects a major part of one’s job
(a role or responsibility), that correlates with performance on the
job, that can be measured against well-accepted standards, and
that can be improved via training and development.”4 Finally, the
core question of educators should be, “What is my expectation
of the learners following this educational program and how well
equipped are they now to carry out the duties expected of them?”
In that context, educators can now apply the 10 competencies
that a practitioner in the field of palliative care must be able to
demonstrate (1) apply the core constituents of palliative care in
the setting where patients and families are based; (2) enhance
physical comfort through the patients’ disease trajectories;
(3) meet patient’s psychological needs; (4) meet patients’ social
needs; (5) meet patients’ spiritual needs; (6) respond to the needs
of family caregivers in relation to short-, medium-, and long-term
patient care goals; (7) respond to the challenges of clinical and

47
48
TABLE 7.1 Levels of Education Reflecting the Scope and
Focus of Professionals Involved in the Delivery of
Palliative Care
Palliative care approach
• A way to integrate palliative care methods and procedures in settings
not specialized in palliative care (e.g., internal medicine, elderly care,
etc.)
• Should be made available to general practitioners, staff in general
hospitals, nursing, and nursing facility staff
• May be taught through undergraduate learning (i.e., students
undertaking their primary education in any health-care discipline
including medicine) or continuing professional development
General palliative care
• Provided by primary care professionals and specialists treating
patients with life-threatening diseases who have good basic
palliative care skills and knowledge (e.g., primary care, geriatricians,
nurse practitioners, oncologist, geriatricians, and clinical nurse
specialists)
• Should be made available to professionals who are involved more
frequently in palliative care but do not provide palliative care as the
main focus of their work
• May be taught at undergraduate or postgraduate level or through
continuing professional development
Specialist palliative care
• Provided in services whose main activity is the provision of
palliative care (e.g., professionals working solely in the field of
palliative care who care for patients with complex and difficult needs
and, therefore, require a higher level of education, staff, and
resources; specialist palliative care provided by specialized services
for patients with complex problems not adequately covered by other
treatment options)
• Taught at a postgraduate level and reinforced through continuing
professional development
ethical decision-making in palliative care; (8) practice compre-
hensive care coordination and interdisciplinary teamwork across
all settings where palliative care is offered; (9) develop interper-
sonal and professional shills appropriate to palliative care; and
(10) practice self-awareness and undergo continuing professional
development. The second part of the EAPC white paper describes
in more detail the 10 core interdisciplinary competencies in pal-
liative care.
Because of the different models in different countries, reflect-
ing different levels of palliative care as a distinct clinical practice,
the core competencies proposed by the EAPC should be consid-
ered for palliative care practice and education in Europe. Other
countries including the United States, Canada, and Colombia
have proposed palliative care competencies for medical students.
United States
In 2014, the Association of American Medical Colleges (AAMC)
released, “Core Entrustable Professional Activities for Entering
Residency” to address concerns that some medical school grad-
uates were not prepared for residency and that there had been
no agreement in the undergraduate medical education commu-
nity about a common core set of behaviors that could/should
be expected of all graduates. The drafting panel considered the
two prevailing conceptual frameworks in the literature, com-
petencies, and Entrustable Professional Activities (EPAs) and
Textbook of Palliative Medicine and Supportive Care
proceeded with EPAs. In the literature, the relationship between
competencies and EPAs has been explained: EPAs are considered
units of work, while competencies are the abilities of individuals.
The disadvantage of competencies is that they may be abstract,
whereas the benefits of EPAs are that they are defined as units
of professional practice, defined as tasks or responsibilities that
trainees are entrusted to perform unsupervised once they have
attained specific competence. The drafting panel was charged
to delineate those activities that all entering residents should be
expected to perform on day 1 of residency without direct super-
vision, regardless of specialty. In this “Version 1.0,” AAMC has
recommended 13 EPAs which describes each activity and the
functions of the new interns, expected behaviors, and vignettes
for pre-entrustable learners and entrustable learners.
Of interest to palliative medical education is EPA 10 which
states that new interns will recognize a patient requiring urgent
or emergent care and initiate evaluation and management.
Furthermore, EPA 10 states that a function of the new intern is to
“clarify patient’s goals of care upon recognition of deterioration
(e.g., do not resuscitate, do not intubate, comfort care).”
In the same year, 2014, other authors published comprehensive
palliative care competencies for medical students, in other words,
primary palliative care competencies. Schaefer et al. surveyed 71
palliative experts to assess ratings and rankings of proposed com-
petencies and competency domains. 5 The proposed competencies
were derived from existing hospice and palliative medicine fel-
lowship competencies and revised to be developmentally appro-
priate for students. Authors identified 18 competencies, of which
7 were proposed as essential graduation competencies, according
to the survey results.
The seven essential competencies were (1) describes ethi-
cal principles that inform decision-making in serious illness,
including the right to forgo or withdraw life-sustaining treat-
ment and the rationale for obtaining a surrogate decision maker;
(2) reflects on personal emotional reactions to patients’ dying and
deaths; (3) identifies psychosocial distress in patients and fami-
lies; (4) explores patient and family understanding of illness, con-
cerns, goals, and values that inform the plan of care; (5) defines
the philosophy and role of palliative care across the life cycle
and differentiates hospice from palliative care; (6) demonstrates
patient-centered communication techniques when giving bad
news and discussing resuscitation preferences; and (7) assesses
pain systematically and distinguishes from nociceptive from neu-
ropathic pain syndromes.
In 2016, for undergraduate nursing students, the American
Association of Colleges of Nursing endorsed the palliative care
competencies published in the document, “CARES: Competencies
And Recommendations for Educating undergraduate nursing
Students.”6,7 The article outlines 17 competencies new nurses
need to have completed by the end of their undergraduate nurs-
ing education. Additional recommendations were published,
and subsequently, the online curricula was made available.8
The End-of-Life Nursing Education Consortium-Undergraduate
Curriculum meets the competencies for primary palliative care
at the undergraduate level, is composed of six 1-hour online mod-
ules, and requires passing a knowledge assessment at the end of
each module.9
Canada
The national undergraduate competencies for palliative and end-
of-life care were developed through a project called Education
Future Physicians in Palliative and End-of-Life Care, subsequently
Undergraduate Education in Palliative Medicine
updated through a multi-stage process that included invited stake-
holders to comment, and validated by 60 individuals and organi-
zations.10 The goal was to graduate every medical student with the
knowledge, skills, and attitudes appropriate to meet patients’ pri-
mary palliative care needs. There were several key changes from
the original project to the update project which included the shift
from “palliative care,” which historically was provided at end of
life primarily to patients with cancer, to a “palliative approach
to care,” which starts earlier in the course of a life-threatening
malignant or non-malignant illness. Competencies, or focused
objectives, that address changes in the practice environment to
include safe and appropriate use of opioid prescribing, changes in
laws around medical assistance in dying, and the growing use of
cannabinoids for symptom management.
From general to specific, the Canadian framework is composed
of key competencies, enabling competencies, specific objectives, and
elements of the undergraduate curriculum that may facilitate learn-
ing of competencies. The key competencies for graduating medical
students are (1) describe a palliative approach to care; (2) address and
manage pain and other symptoms; (3) participate in appropriate care
for the dying patient and their family; (4) participate in appropriate
care for the pediatric patient with palliative care needs and their
family; (5) address psychosocial and spiritual needs; (6) address end-
of-life decision-making and planning using a basic bioethical and
legal framework; (7) communicate effectively with patients, families,
and other caregivers; (8) collaborate as a member of an interprofes-
sional team; (9) attend to multi-dimensional sources of suffering;
and (10) demonstrate self-awareness and self-care in caring for ter-
minally ill patients.
The elements of the curriculum that may facilitate palliative
care competencies are outlined for each competency. These ele-
ments may well help educators with curriculum mapping and
help learners with revisiting important topics (e.g., pain physi-
ology and pathophysiology, pharmacology, management of pal-
liative care/oncological emergencies). This outlined curriculum
offers suggestions on the timing of specific objectives such as
during the pre-clerkship or clerkship years and examples of
instructional methods such as small group case-based teaching,
standardized patients, and technology-supported methods (e.g.,
simulations and videos).
Colombia
Pastrana, Wenk, and De Lima, in Colombia, encouraged the
distribution and promotion of their consensus-based pallia-
tive care competencies for undergraduate medical and nursing
schools to universities and academic decision makers.11 Using
the International Association for Hospice and Palliative Care
(IAHPC) List of Essential Practices (LEP),12 as guidance and
the Recommendation of the EAPC for the Development of
Undergraduate Curricula in Palliative Medicine,13 36 participants
from 16 medical and 6 nursing schools from 18 universities in
Colombia were asked to discuss and define palliative care com-
petencies at the undergraduate level. The group identified core
competencies in six main categories: (1) definition and principles
of palliative care, (2) identification and control of symptoms, (3)
end-of-life care, (4) ethical and legal issues, (6) psychosocial and
spiritual issues, and (6) teamwork. The main categories were fur-
ther divided into subcategories and, finally, the competencies.
There is significant agreement between the competencies
identified by the Colombian participants with the IAHPC LEP.
However, the Colombian participants added specific competen-
cies not included in the IAHPC LEP: knowledge of medications
49
such as essential medications for palliative care, medications to
be used with caution, opioid rotation, risk factors in opioid abuse,
opioid equianalgesia, dilutions, conversions, drug-drug interac-
tions; knowledge of palliative sedation including definitions,
recognizing refractory symptoms, administration, operational
aspects of palliative sedation, and communication. Conversely,
the Colombian participants did not include the IAHPC LEP com-
petencies related to wounds, ulcers, skin rash and skin lesions,
dry mouth, mucositis, and cough, fatigue, anorexia, anemia, som-
nolence, and sweating.
Pastrana et al. note that these competencies are much more
detailed and specific as opposed to the EAPC core competencies,
which are more broad and general. The authors discuss Miller’s
pyramid of clinical competence, which consists of four levels:
knows, knows how, shows, and does. They note that educational
needs vary from learner to learner and in different countries.
For instance, for students who engage in clinical practice after
graduation, the core competencies should focus mainly on clini-
cal aspects, whereas students who must go through residency, the
core competencies can balance palliative care philosophy, human-
istic aspects of care, along with basic clinical competencies.
Current status of undergraduate education
Fitzpatrick et al. conducted a systematic review in 2017 of pallia-
tive care in undergraduate medical education published between
2001 and 2015.14 The review included all original articles about
medical schools with palliative care teaching. Excluded from the
systematic review were studies regarding graduate medical edu-
cation, postresidency training, or continuing medical education
and nursing and allied health students. The systematic review
identified 124 articles. The results of the thematic analysis showed
common themes (number of original articles): curricular content
(n = 15), curricular development (n = 7); comparison of multiple
teaching institutions (n = 14) versus module or curriculum in a
single teaching institution (n = 53); hospice learning (n = 16). The
articles included different instructional methods: technology or
e-learning (n = 2), simulation (n = 4), novel methods (n = 17), and
interprofessional teaching (n = 13). Some articles addressed sev-
eral themes and were counted more than once in these results.
The authors observed that there was greater consistency in the
content being delivered as part of end-of-life education. Among
the most frequently taught topics were attitudes toward death
and dying, communication skills, and pain management. Among
the less frequently addressed topics were pediatric care and reli-
gious and cultural issues. Institutions utilized a broader range of
teaching modalities. The authors concluded that significant prog-
ress had been made.
In 2016, Head et al. reported the overall progress and cur-
rent direction of palliative medical education published in the
English literature between 2005 and 2015. They included 151
articles, summarized palliative medical education efforts outside
the United States and notable innovative education efforts, and
described the number of learners involved, student time, teach-
ing methodologies, level of evaluation (according to Kirkpatrick’s
levels of evaluation), and study outcomes such as learner reported
outcomes and increases in knowledge. Head et al. recognized
that end-of-life education is mandated by Liaison Committee
on Medical Education (LCME) accreditation standards but that
palliative care is surprising absent from the LCME accreditation
standards. To add to the confusion, content related to pallia-
tive care has been added to the United States Medical Licensing
50
TABLE 7.2 Tips for Developing Palliative Care Teaching in
Undergraduate Medical Education
• Compulsory and integrated across the course
• Ensure all students see patients with palliative care needs and those
that are dying
• Back up teaching with compulsory formative and summative
assessments
• Secure support from within the university
• Ensure all students visit a hospice and/or inpatient palliative care
facility
• Develop key learning objectives and competencies
• Involve palliative care specialists
• Join up with interest colleagues in other specialties
• Develop variety and innovation in teaching methods
• Utilize the hidden curriculum to promote learning
• Enable some students to spend more time in palliative care
• Encourage interprofessional learning
Exam. Head et al. argue that because the only LCME requirement
specifies end-of-life care, the misconception that palliative care
and end-of-life care are synonymous will continue. In summary,
authors found that medical students value palliative medicine,
describe the weaknesses of the current approaches to palliative
care educational efforts, and identify barriers to drive initiatives.
They also offer specific recommendations for a comprehensive
palliative care curriculum focused on competency development
that is integrated throughout the four years of medical education.
Summary and recommendations
There have been significant advances in undergraduate educa-
tion in palliative medicine in terms of defining competencies.
The EAPC has published core competencies for all health-care
professions. Colombians authors have proposed competencies for
medical and nursing students, and the United States and Canada
have proposed competencies specifically for medical students.
Systematic reviews and other reviews have described the cur-
rent status of undergraduate medical education. However, less is
known regarding other disciplines and allied health professionals.
Boland, Barclay, and Gibbins have offered practical tips for pal-
liative care teaching for undergraduate medical students, some of
which may applied to nursing and other allied health students.15
Textbook of Palliative Medicine and Supportive Care
References
1. Gamondi C, Larkin P, Payne S. Core competencies in palliative care:
An EAPC white paper on palliative care education—Part 1. Eur J
Palliat Care 2013;20(2):86–91 (Accessed 9 Oct 2019).
2. Gamondi C, Larkin P, Payne S. Core competencies in palliative care:
An EAPC white paper on palliative care education—Part 2. Eur J
Palliat Care 2013;20(3):140–145 (Accessed 9 Oct 2019).
3. Radbruch L, Payne S. White paper on standards and norms for
hospice and palliative care in Europe: Part 1. Eur J Palliat Care
2009;16(6):278–289 (Accessed 12 Oct 2019).
4. Parry SB. The quest for competencies. Training 1996;33(7):48.
5. Schaefer KG, Chittenden EH, Sullivan AM, et al. Raising the bar
for the care of seriously ill patients: Results of a national survey
to define essential palliative care competencies for medical stu-
dents and residents. Acad Med 2014;89(7):1024–1031. doi: 10.1097/
ACM.0000000000000271.
6. O’Connor B. CARES: Competencies and recommendations for educat-
ing undergraduate nursing students preparing nurses to care for the
seriously ill and their families. J Profess Nurs 2016;32(2):78–84. doi:
10.1016/j.profnurs.2016.02.008.
7. O’Connor B. AACN endorses palliative care competencies and rec-
ommendations for undergraduate nursing education. J Profess Nurs
2016;32(2):77–77. doi: 10.1016/j.profnurs.2016.02.006.
8. Ferrell B, Malloy P, Mazanec P, Virani R. CARES: AACN’s new com-
petencies and recommendations for educating undergraduate nursing
students to improve palliative care. J Profess Nurs 2016;32(5):327–333.
doi: 10.1016/j.profnurs.2016.07.002.
9. ELNEC-Undergraduate Curriculum. https://elnec.academy.
reliaslearning.com/ELNEC-Undergraduate-Curriculum.aspx.
10. Palliative Care Competencies for Undergraduate Medical Students in
Canada. https://www.cspcp.ca/wp-content/uploads/2018/06/Palliative-
Care-Competencies-Undergrad-2018-EN.pdf (Accessed 23 Oct 2019).
11. Pastrana T, Wenk R, De Lima L. Consensus-based palliative care com-
petencies for undergraduate nurses and physicians: A demonstrative
process with Colombian universities. J Palliat Med 2016;19(1):76–82.
doi: 10.1089/jpm.2015.0202.
12. De Lima L, Bennett MI, Murray SA, et al. International association for
hospice and palliative care (IAHPC) list of essential practices in pal-
liative care. J Pain Palliat Care Pharmacother 2012;26(2):118–122. doi:
10.3109/15360288.2012.680010.
13. European Association for Palliative Care Task Force on Medical
Education. Recommendation of the European Association for Palliative
Care for the development of Undergraduate Curricula in Palliative
Medicine at European Medical Schools, 2013.
14. Fitzpatrick D, Heah R, Patten S, Ward H. Palliative care in undergradu-
ate medical Education—How far have we come? Am J Hosp Palliat Med
2017;34(8):762–773. doi: 10.1177/1049909116659737.
15. Boland JW, Barclay S, Gibbins J, Boland JW. Twelve tips for developing
palliative care teaching in an undergraduate curriculum for medical
students. Med Teach 2019:1–7. doi: 10.1080/0142159X.2018.1533243.
8
GRADUATE EDUCATION FOR NONSPECIALISTS

Fiona Rawlinson and Ilora G. Finlay

Contents
Introduction..........................................................................................................................................................................................................................51
Domains of learning and learning styles.........................................................................................................................................................................51
Reflective practice................................................................................................................................................................................................................53
Giving feedback to graduate learners..............................................................................................................................................................................53
Role of the educator in a graduate program...................................................................................................................................................................54
Reflective case study (portfolio learning)........................................................................................................................................................................55
Organizing a graduate program........................................................................................................................................................................................55
The graduate student in context........................................................................................................................................................................................56
Planning sessions—A practical approach.......................................................................................................................................................................56
The role of the lecture...................................................................................................................................................................................................56
Flipped classroom..........................................................................................................................................................................................................56
Small group learning.....................................................................................................................................................................................................56
Communication skills.........................................................................................................................................................................................................56
Role-play..........................................................................................................................................................................................................................57
Communication skills case study—The Cardiff 6-point toolkit as a teaching tool.................................................................................................58
Teaching ethics.....................................................................................................................................................................................................................58
Information technology and online learning..................................................................................................................................................................59
Massive open online courses (MOOC’S)..................................................................................................................................................................59
The role of the clinical placement...............................................................................................................................................................................59
Conclusion.............................................................................................................................................................................................................................59
References..............................................................................................................................................................................................................................60

Introduction following an encounter with a patient, which develops into a

The global need for palliative care skills continues to increase.1,2
Health-care professionals are likely to be involved in the care of
patients with life-threatening illness and who are facing death
soon after graduation in their chosen discipline. The World
Health Assembly in 2014 Resolution 67.19 urged member states
to include palliative care as an integral part of education pro-
grams for all health-care professionals according to their role. 3
The proportion of graduates who embark on a career in specialist
palliative care is small, yet almost all branches of clinical medi-
cine will involve the management of patients with incurable and
potentially life-threatening disease. A white paper from EAPC in
2013 suggests three levels of palliative care delivery that can aid
the development of education programs4 (Box 8.1). Furthermore,
10 core constituents of palliative care are identified which need to
be addressed in such education programs4 (Box 8.2).
An emphasis on developing lifelong learning skills begins in
many undergraduate curricula today. Once qualified, the focus
shifts more toward those skills and less to a need to pass exami-
nations, although many disciplines—in particular postgraduate
medicine—include end-point summative assessments as proof of
competence.
For the purposes of this chapter, the term “graduate educa-
tion” refers to training that occurs at any stage following profes-
sional registration, and “nonspecialist” refers to training that is
not part of a specialty training curriculum in palliative medicine.
Graduate education may be delivered on an opportunistic basis
learning opportunity, a set study session or short course, or as
part of a delivered curriculum for a higher qualification such as a
postgraduate certificate, diploma, or masters. Organizations such
as the Quality Assurance Agency in the United Kingdom (UK)
define different levels of education depending on the level of criti-
cal thinking and innovation employed within that education.
An essential feature of all graduate programs for palliative
medicine is keeping the patient and their family at the heart of
all education initiatives and with an aim that such sessions will
result in a positive impact on the palliative care that patients and
family receive.
Domains of learning and learning styles
A graduate program needs to focus around the four key domains
in learning5:
1. Knowledge and understanding
2. Skills and competencies
3. Attitudes and professional behavior
4. Personal and professional development
Objective assessment of these competencies is easier in the first
two domains (knowledge and understanding, and skills and com-
petencies) than the others, although the importance of attitude
and professional behavior should be an underpinning ethos in
any graduate program. A curriculum will include information

51
52 Textbook of Palliative Medicine and Supportive Care

BOX 8.1  EUROPEAN ASSOCIATION FOR PALLIATIVE CARE AGREED LEVELS OF

PALLIATIVE CARE KNOWLEDGE (FROM REFERENCE [4] WITH PERMISSION)
*PALLIATIVE CARE APPROACH
A way to integrate palliative care methods and procedures in settings not specialized in palliative care. Should be made avail-
able to general practitioners and staff in general hospitals, as well as to nursing services and nursing home staff. May be taught
through undergraduate learning or through continuing professional development.

*GENERAL PALLIATIVE CARE

Provided by primary care professionals and specialists treating patients with life-threatening diseases who have good basic
palliative care skills and knowledge. Should be made available to professionals who are involved more frequently in palliative
care, such as oncologists or geriatric specliats, but do not provide palliative care as the main focus of their work. Depending on
discipline, may be taught at an undergraduate or postgraduate level or through continuing professional development.

*SPECIALIST PALLIATIVE CARE

Provided in services whose main activity is the provision of palliative care. These services generally care for patients with com-
plex and difficult needs and therefore reuquire a higher level of education, staff, and other resources. Specialist palliative care is
provided by specialized services for patients with complex problems not adequately covered by other treatment options. Usually
taught at a postgraduate level and reduced through continuing professional development.

deemed to be formal (set by the organizer), informal (developed
by the learner in response to the formal curriculum), or “hidden.”
The “hidden curriculum” is a side effect of an education session.
For example, the values and beliefs conveyed in the classroom
and the social environment and its impact should not be underes-
timated. The way the session is facilitated, the language and atti-
tude of the facilitator toward whichever aspect of care of seriously
ill or terminally ill patients is being discussed will influence the
quality of learning.
Different teaching methods will be better suited to the differ-
ent domains; a combination of teaching methods may be more
effective. A lecture may impart facts and increase “knowledge,”
but understanding does not develop until the application to, and
facts of, clinical scenarios are explored, understood, and applied.
Without understanding, cold “facts” may be applied inappropri-
ately or even dangerously to an individual clinical situation, par-
ticularly the one that is complex.
Although those embarking on a career in palliative medicine
may recognize the need for broad learning methods such as
BOX 8.2  EUROPEAN ASSOCIATION FOR
PALLIATIVE CARE CORE CONSTITUENTS
OF PALLIATIVE CARE (FROM
REFERENCE [4] WITH PERMISSION)
• Autonomy
• Dignity
• Relationship between patient and health-care
professionals
• Quality of life
• Position toward life and death
• Communication
• Public education
• Multi-professional approach
• Grief and bereavement
role-play and reflective practice, older learners and those who
are used to didactic teaching may struggle initially with reflec-
tion or self-directed learning, manifesting their concerns with
attitudinal barriers. Before the development of learning can
occur, the learner needs to have insight into why their attitude
appears inappropriate and negative, understand the fundamental
reasons within themselves behind their behavior, and ultimately
inherently wish to change. Those who feel there is nothing wrong
with their attitude or approach may have not even begun to con-
template the need to change which will make success unlikely.6
Many problems of team working are linked to attitudinal difficul-
ties that may be revealed in course tutorials, small group work,
role-play, or in interactions with the course administrative staff
when the student’s aggressive or awkward approach is manifest.
For all students, sensitive effective feedback is a potent driver to
learning.
Learning outcomes on a graduate program are driven by the
core competencies that have to be attained and, therefore, are
assessed by the end of the program. The EAPC core competencies
outlined previously provide a comprehensive collection of attri-
butes. A fixed learning agenda, however, will not address sudden
needs driven by situations arising from the clinical workplace,
and graduate learning is usually driven by a powerful “need to
learn.” It is useful to allow graduates to set some of their own
learning needs and outcomes as they go through a program and
to reflect on what they are learning.7 This is particularly impor-
tant for the graduate learner who is undertaking palliative care
training for application within their own branch of medicine. For
example, the learning outcomes of a cardiologist are likely to be
different to those of an oncologist, since they care for patients
with different diseases, therapeutic options, and disease trajec-
tories. Allowing the student to identify their own learning needs
within their clinical context promotes a more meaningful and
successful learning process. Such learning outcomes, particularly
when defined by the graduate, may not be easily assessed within
the context of the graduate course itself. This applies particularly
to practical skills, such as draining an ascetic or pleural effusion,
Graduate Education for Nonspecialists
although an imaginative curriculum will allow such assessment
from the student’s workplace to be fed into the overall assessment
on the graduate program.
Adults are more likely to learn if they wish to learn and they
view the learning to be purposeful. The interaction between
learner and the learning material will promote learning, whether
in a face-to-face or online environment. Adult learning styles will
determine how different graduates learn most effectively on a
course.8 The many different facets of adult learning continue to
be researched, and a number of self-assessment tools are avail-
able for students to explore their own preferred learning style in
order to achieve maximum success. However, care is needed in
order to avoid this approach simply leading to strategic learning.
The effective course organizer will include materials delivered
in a variety of styles and use teaching methods aimed to address
a diverse collection of learning styles. For example, in palliative
care teaching on nausea and vomiting, some learners prefer a dia-
grammatic approach to the receptors involved, and others prefer
to learn from tables or from text.
Reflective practice
Reflective practice, described in the early 1930s and champi-
oned by Kolb9 and Schon,10 is now a recognized tool for learn-
ing and is integrated into most course designs. The reflective
practice cycle moves through the stages of having an experience
(concrete experience), reflecting on that experience (reflective
observation), integrating ideas and facts, learning from the
reflections to inform the future (abstract conceptualization),
and finally putting those ideas into practice (active experimen-
tation), which, in turn, provides an “experience” and so the cycle
or perhaps, more accurately, a spiral of learning starts again.
There remains some global disparity—an integrated approach is
generally seen within Western cultures, especially the UK, the
United States, Canada, and Australasia, but less so in countries
where a more traditional lecture-based approach to education
remains.11 Awareness of this important distinction is useful in
order that an educator can plan and deliver the most appropri-
ate material in the most appropriate way for learners working in
a particular culture or region.
Reflection involves the learner in thinking about what they are
doing, developing insight into their own approaches to a problem,
analyzing the way that they tackle the problem, and looking criti-
cally at the outcome. It then involves reflecting on that process,
paying particular attention to what is being learnt and how prac-
tice can be developed.
The learner also needs to think about and draw on related
knowledge and experiences to be able to criticize, restructure, and
apply these principles for further learning. Boud defined reflection
as “an important human activity in which people recapture their
experience, think about it, mull it over, and evaluate it.”13 Schon
calls this type of thinking reflection-on-action. This review of
past experiences leads to a critical analysis of what led the learner
to change their way of practice; sometimes, reflection during the
course of a process (reflection-in-action) involves modifications
while dealing with a problem. It is important that reflection is
encouraged in a nonthreatening way so that the learner does not
become demoralized. Although mistakes or unsatisfactory out-
comes often provide the best stimuli for learning, such events
need to be handled sensitively and appropriately. Much learning
can be effectively undertaken by reflecting on ordinary situa-
tions as they arise, thereby building on good practice. This can
53
be particularly important for the learner who lacks confidence.
When mistakes have occurred, the learner should be encouraged
to reflect on what they would do differently next time, rather than
on what they did wrong.
In palliative care, clinical situations are often complex, and
there can be many different ways of approaching the problem.
Emotionally charged situations can leave the clinician feeling
inadequate, upset, and sometimes with unrealistic expectations
of himself or herself as a practitioner. Supportive nonjudgmental
reflection with colleagues can form part of a “debrief” and help
develop alternative future strategies for dealing with a similar
situation.
Greenwood has been particularly critical of Schon’s module
because it failed to recognize the importance of reflection-before-
action.14 In palliative care, such a reflective approach before act-
ing integrates all previous experiences, with acquired knowledge
and understanding, to empower the practitioner to behave differ-
ently from previously.
Giving feedback to graduate learners
“Feedback is given with the intent to improve performance for
learning rather than to criticize or to judge.”15
Feedback on learning can be formal or informal and can fol-
low an observed procedure or encounter, be part of an education
session, or be in response to a written piece of work—either as an
assessment or as part of an online learning or professional devel-
opment portfolio.
Feedback is an essential part of the reflective learning process;
giving effective constructive feedback is a core communication
skill for educators and should follow some key principles as out-
lined in Box 8.3.
Various frameworks for delivering feedback have developed
over the last 30 years in response to the changing culture and
ethos of health-care education. Table 8.1 outlines the different
attributes. Pendleton’s method of feedback provided an early set
of rules by which feedback could be given.17 However, because
BOX 8.3  PRACTICAL PRINCIPLES
FOR GIVING EFFECTIVE FEEDBACK
(ADAPTED FROM REFERENCES [15,16])
Create the appropriate setting so that feedback is not
unexpected.
Give feedback as soon after the event as possible.
Generally, give feedback on a one-to-one basis, espe-
cially if there is a need to highlight poor performance.
Focus on observable behavior (or on what is written).
Feedback needs to be objective. (If you are giving writ-
ten feedback, still focus on observable behavior or written
facts.)
Initially focus on what went well, areas of strength.
Explore alternative strategies with the person for the
event or the procedure and how they might access support/
resources to enable further development. If necessary, sup-
port the learner in creating a plan for further development
using clear objectives.
Remember giving feedback is a form of interpersonal
communication and needs to be considered and planned
as such.
54 Textbook of Palliative Medicine and Supportive Care

TABLE 8.1  Attributes of Different Feedback Frameworks

Pendleton17
1. Check what the learner wants
and whether is ready for feedback
2. Let the learner give comments or
background to the material that
is being assessed
3. Asking the learner what they felt
they did well or were particularly
happy with
4. Tutor’s ± peer feedback on what
they feel went well
5. Asking the learner what they felt
could be improved
6. Tutor ± peer feedback on what
they feel could be improved
7. Develop an action plan for
improvement
8.   Summarize learning and action plan
Calgary—Cambridge (Silverman)
“agenda led—outcome
Kurtz et al.18 based”—SET-GO18 Alexander19
What is the trainee agenda Feedback based on What am I doing well?
What was Seen?
What outcome is the learner wanting What else was seen? What do I need to do to improve?
to achieve?
Encourage self-assessment and What does the learner and others
self-problem solving think?
While group problem solving Clarify the goals
Descriptive objective feedback on Learner ± group discussed and offers
what went well and what might be alternatives of how to achieve the
done differently goals
Suggest alternatives ± trial of
alternatives (e.g., role-play in a
communication skills scenario)

learners often focus on what did not go well, rather than recog-
nizing strengths to be developed, there is a risk that the frame-
work could become formulaic and thus a barrier to reflection and
learning. Silverman, Kurtz, and Draper18 developed an agenda-
led, outcome-based approach, which has been further worked
into a simple framework by Steve Alexander, namely, “What am I
doing well? And what do I need to improve?”.19
In all cases, feedback should be expected, descriptive, bal-
anced, objective, nonjudgmental, and timely.
Role of the educator in a graduate program
Educators delivering a graduate program need to be aware of
adult learning theories and the need to respect learner autonomy,
yet still give guidance. All educators need clear guidance about
what is expected of them and be familiar with different methods
of delivering education that will encourage learners, in addition
to styles that should be avoided as they lead to barriers to learning
and demoralization. Facilitators need to be aware of the culture
and clinical context within which the learners are working. For
example, teaching ethics or communication skills in a country
where “collective autonomy” is the norm will be different from a
more Western approach.
Where students are being tutored in groups, confidentiality
of the group discussions becomes important and each mem-
ber of the group must be treated with respect by other group
members. Setting “ground rules” for group work and ideally
asking the group to discuss and form these rules themselves
is an important step. Each member should have time to par-
ticipate, and care should be taken that no particular member
of the group dominates. This is particularly important in small
groups of learners from different cultures. A quieter member of
a group may notice and listen particularly closely—these attri-
butes can be a useful way to encourage their participation in
the group discussion. The most effective teaching occurs in a
safe environment where the individual feels supported and good
practice is reinforced. However, sometimes, where individuals
lack insight, the tutor may need to speak on a one-to-one basis
with the student to help that student identify particular prob-
lems that they are having. Such difficult conversations should be
held outside of the group setting.
The role of the hidden curriculum is demonstrated in the
choice of faculty which delivers palliative care teaching. Using
members of the multidisciplinary team, either giving combined
or in separate sessions, gives a strong message to learners about
the benefit of the multidisciplinary team in delivering palliative
care.
Finally, educators themselves need to develop reflective prac-
tice on their teaching skills. Bad habits and overfamiliarity with
content can mean that attention to learners’ changing needs is
missed. Simple peer review of teaching on a regular basis can be
an important part of an educators’ portfolio. Attending to profes-
sional development that matches, for example, the GMC promot-
ing excellence themes of
• Learning environment and culture
• Educational governance and leadership
• Supporting learners
• Supporting educators
• Developing and implementing curricula and assessments
will ensure a comprehensive teaching portfolio of skills.20
For those who wish to formalize teaching, specific training in
medical education and validation as a teacher by organizations
such as the Higher Education Authority in the UK or the UK
Academy of Medical Educators is also worth considering. There
is increasing evidence on the effectiveness of different teaching
methods—educators need to be up-to-date with education and
teaching theory and base their lesson plan and interventions on
evidence-based practice where possible.
Graduate Education for Nonspecialists
Reflective case study (portfolio learning)
The most powerful stimulus to learn is the need to know, which
makes reflective learning, recorded in a portfolio format, a par-
ticularly powerful teaching tool for the individual and for a clini-
cal team. Reflection has become an integral part in some national
training and professional registration portfolios aided by a formal
documentation process.
A portfolio allows personalization of the learning experience,
particularly when postgraduates come from a wide range of
clinical settings and with varying clinical resources. Each stu-
dent in a group may pursue areas they define as their greatest
area of need, with supportive supervision. Although the tutor
is usually unable to verify the details of a case described, the
learning objectives will be met by a focus on the learning objec-
tives set by the student.
The learner can present their learning in a format relevant
to the topic, laid out in a way that allows the tutor to follow
the learning process. In groups, peer review of such a portfolio
can ensure shared learning about the topic and on how to tutor
others, particularly when students have come from a tradition
of didactic teaching and are unfamiliar with more facilitative
styles of teaching that recognize that learning is a dynamic,
lifelong process and respects the unique contribution of each
person.
Organizing a graduate program
When planning graduate education, five distinct phases need to
be addressed:
• Needs assessment
• Precourse planning
BOX 8.4  ELEMENTS OF A SUCCESSFUL
REFLECTIVE PORTFOLIO (FROM
REFERENCE [21] WITH PERMISSION)
• Factual case histories around which the learning
usually occurs.
• References to diverse sources, e.g., textbook read-
ing, literature search, lay press, conversations
with colleagues.
• A record of the clinician’s own decision-making
processes, including details of decisions made
and how the learner arrived at the decision.
• Documentation as to how the learner felt at the
time and sources of stress or doubts are as use-
ful as the outcome since the personal feelings of
the learner will influence how they were able to
approach a problem.
• Ethical considerations.
• Illustrative items such as photographs, drawings,
quotations, and poetry may clarify points being
made. Care must be taken over anonymization
and permission from the patient for such items
to be used.
• Some form of indexing is important, so the
learner and supervisor can follow the learning
process and refer to specific items at a later date.
55
• Course delivery
• Assessment (especially if the course is part of an Institution
Higher award such as PG Certificate or Diploma)
• Evaluation after the course to allow modification and con-
firm that the course has met its own aims and objectives,
particularly the impact on the clinical practice
A robust system of internal and external quality assurance (QA)
underpins all education programs to make sure that agreed stan-
dards are being met (or exceeded) and that good practice is shared.
This is of the utmost importance for the following reasons:
• There are many postgraduate courses available and QA
ensures the students have chosen a course that meets
appropriate standards.
• QA confirms an agreed standard of training has been deliv-
ered by the organization.
• With several postgraduate courses becoming quotable
qualifications, QA is essential to confirm the qualification
is of sufficient standard required by medical governing
bodies.
• It allows for the course to be flexible and develop over time,
to reflect the changes in the specialty, market, and teaching
resources.
Careful pre-course planning is essential; fundamental decisions
about the course include its curriculum and format. This may be
in response to a needs assessment for that region or country that
could use preexisting needs assessment tools22 or be in response
to developing health policy and curricula in that region. Planning
should not be done by one individual in isolation but rather with
the involvement of a committee of potential course tutors and
facilitators. In established courses, including a student represen-
tative and, depending on the course content and aims, a patient
representative will also add diversity and ensure a comprehensive
approach. The overall aims and ethos of the course need frequent
review in order to reflect changing culture and education and pal-
liative care practices.
The curriculum, specific expected learning outcomes, and
course delivery should take into account the needs of the learners
and the resources available to meet them.23 Graduates have differ-
ent levels of palliative medicine knowledge and experience. Some
may be general practitioners or specialists wishing to expand
their palliative medicine skills, while others may be wanting to
follow a specialist career in palliative medicine. The number of
learners intended on the course and their geographical location
will have significant impact on resources and course delivery.
Distance learning and web-based courses are more practical for a
cohort of learners from a wide geographical distribution, but this
will not necessarily be the most effective way to teach communi-
cation skills or ethics.
Many countries have a core curriculum of learning needs and
descriptors of competencies that need to be achieved during
the course.24–29 Several courses based upon these competencies
have run successfully within the UK. For example, the Cardiff
MSc course has trained over 3000 postgraduates at Diploma or
Masters level within its 30 years of activity. Although curricula
that have been developed by national organizations can serve as
“guideposts,” they may not address the specific needs and culture
of an individual. 30 Clinicians from a wide variety of clinical, geo-
graphical, and cultural backgrounds have highlighted communi-
cation skills, multi-professional team working, and psychological
56
aspects of care, which are particularly relevant to their clinical
practice.22 These topics lend themselves best to reflective prac-
tice and role-play, which need face-to-face small group tutorials
rather than distance learning or lecture formats.
Clear goals of learning, or learning outcomes, should state
explicitly the skills and competencies that the learner is expected
to be able to demonstrate. Feedback on any work undertaken is
essential, and adult learners should be encouraged at all times to
be reflective in the way that they approach a topic.
Assessment of learning in a multi-professional holistic patient-
focused approach to care requires valid tools to assess reflec-
tive practice, portfolio learning, and the medical humanities.
Role-play in communication skills training is often met with
trepidation, often manifest as resistance, which is overcome by
experienced, skilled facilitators/tutors to provide the support and
input inevitably required.
Any teaching program needs regular evaluation to ensure
that it is educationally effective in improving clinical practice,
responsive to the changing and individual needs of partici-
pants, provides competent teaching in theory and practice, and
enables students to make a difference in their clinical prac-
tice. 31 Structured feedback should be incorporated throughout
the course, which gives opportunities for learners (directly and
through student representatives) and tutors to contribute to
the course’s evolution through feedback, collated and reviewed
annually.
The graduate student in context
In selecting graduates for a formal training program, it is impor-
tant to know what has motivated the student to come forward
and wish to learn. Some may have recognized a personal learning
need as part of reflective practice and professional development
within appraisal, while others may be motivated by their own
experience within their own friends or family, or a professional
situation where they felt that their practice needed developing.
Students may have come from a wide range of clinical situa-
tions. While in Western Europe and the United States, libraries,
journals, and Internet access abound, in many low- and middle-
income countries, there is still limited access to journals in librar-
ies, and Internet access may still be unreliable.
It is also important to know about the practice conditions of
learners. While it can be useful for learners to be exposed to
a wide range of ways of practicing, including some high-tech
interventions, for those practicing in developing areas, most of
their meaningful understanding and competency development
will occur in relation to techniques and actions that they can
instigate in their own work environment. Furthermore, there
may be differences in access to drugs in common use in other
countries, as well as culture-specific spiritual and communica-
tion issues that may challenge Western palliative care service
models. Using the public health model to underpin education
to support developing services in low- and middle-income
countries will enhance education and training for sustainable
services. 32
Planning sessions—A practical approach
Dale’s Pyramid of Learning has been widely cited as a caution
against lecture-based education as the single delivery method
for education. 33 This view remains contentious because of the
Textbook of Palliative Medicine and Supportive Care
original methodology that developed the model, but the debate is
thought-provoking. 34
Using a framework such as Gagne’s nine events of instruction,
an effective lesson plan can be devised. 35
Of key importance is setting out the aims and objectives at the
start of the session, which can be referred to as the session ends
to help consolidate learning. For effective education, it is useful
to plan and match activities and interaction to these outcomes
and ensure that time allocation is appropriate for each element.
Starting and ending the session on time is particularly impor-
tant for those undertaking sessions within their clinical working
environment.
The role of the lecture
Lectures remain effective ways of delivering consistent facts
to a large collection of people at the same time, although tak-
ing account of Dale’s Pyramid of Learning outlined previously.
Interactive tasks can be incorporated within a lecture, such as
group work, case discussions, or interactive voting. There is
increasing capacity for the lectures to be recorded, either an
aide memoir for learners who might want to go back and clarify
a point, or using a technique such as “flipped learning,”36 where
learners are asked to review a lecture and then participate in
group work for further discussion.
Flipped classroom
Increasingly, innovative ways of combining teaching methods
are being explored. Flipped classroom refers to a technique
where learning materials—reading materials or recorded pre-
sentations—are circulated to learners in advance of small group
discussions. 36 In the busy clinical environment, it may be a chal-
lenge for learners to secure study time in advance of a session
in which the material is explored—however, with appropriate
pre-session information and guidance, the flipped classroom
approach may be useful as a way to catch up on a session which
has been missed.
Small group learning
Several core skills and an understanding of group dynamics will
increase small group learning. The importance of setting up an
effective learning environment has already been discussed. Small
group work is not necessarily synonymous with “problem-based
learning” (PBL). PBL is a specific teaching technique using small
group work to achieve specified outcomes. 37,38
Communication skills
The importance of communication skills is widely recognized
in palliative care. Communication problems faced by graduates
working in oncology are not resolved by time and clinical expe-
rience, 39 and there is strong evidence that training courses can
significantly improve key communication skills40 to deal with
the complex difficulties encountered in palliative care clinical
practice.
Palliative care consultations are often the most challenging in
clinical practice, since they may involve breaking bad news and
talking about dying and loss39,41 and be undertaken by clinicians
who themselves may be at different points in their own learning
or experience of grief and loss.
Observing, teaching, and giving feedback on communica-
tion skills is challenging in this sensitive environment. Intrusive
observation of such sensitive consultations, with recording
Graduate Education for Nonspecialists
FIGURE 8.1  Dale’s Pyramid of Learning. (From Reference [33] with permission.)
devices or the presence of additional observers, may disrupt the
flow of the consultation and hinder the patient’s openness within
discussions. Since the palliative care consultation is potentially
difficult and may have wide ramifications if badly handled, the
trainer must create a safe learning environment where the trainee
can feel comfortable making mistakes without repercussions and
protect potentially vulnerable patients. It necessarily follows that
the use of real patients is not always appropriate.
Role-play
Role-play using either actors or colleagues as patients has long
been established as a useful tool for developing communication
skills.42 It is best done as a small group of learners with one or
more trained facilitators. It is important to keep the groups small
enough to ensure that everyone has the opportunity to role-play
in the time allocated. People are initially wary of role-play, since,
for many, it is unlike any other training they may have encoun-
tered. Maintaining a small group with attention to the psycho-
logical safety of participants will help them feel more comfortable
in the process.
Role-play allows people to train for situations they rarely
encounter, but when they do, they need to be prepared. The skills
for breaking bad news or dealing with anger are best learned prior
to encountering these situations in practice. In the real world, one
will not get a second opportunity to tackle a difficult consultation
from scratch, over and over again. Role-play affords the learner
this luxury.
57
There are several basic principles that should underpin any
such learning session:
• Clearly established rules of role-play
• Strict adherence to confidentiality
• Safe environment
• Avoidance of role-playing situations that are potentially
distressing for learners
• Option to call “time-out” at any point
• Opportunity for all learners to participate
• Nonconfrontational feedback
• Time for those involved to “come out of role” after a session
• Review of learning points and debrief at the end of each
session
A crucial aspect of role-play is the ability to give feedback
as has already been outlined—this feedback is vital to the
development.
The skills to facilitate such sessions sometimes need to be
very sophisticated, so training is strongly recommended before
embarking on this teaching style. Most learning of value will
occur from the role-play itself and the feedback session.
Some graduate programs may choose to develop summative
assessments to highlight particular areas that need developing,
for example, using trained simulated patients or selected vid-
eotaped consultations, although care is needed with patient’s
58 Textbook of Palliative Medicine and Supportive Care

BOX 8.5  A SAMPLE LESSON PLAN

Title of the session

VENUE
DATE
Number and
background of learners
Total TIME for whole
session
Event within the Time allotted within
lesson35 the session Example
Gain attention A picture, quotation, case scenario
Inform learners of the State the aims and objective of the session (this section may be used as an opportunity to
objective ascertain with the learner(s) if there are other objectives that you may or may not have time to
cover at the time, and if not, these may inform a future session. The educator needs to be ready
to adjust the session however, if there has been a critical incident which would need to take
priority as a session.
Stimulate recall or prior A case discussion, or set tasks, or ask questions to the group
learning
Present stimulus Provide some factual material matched to the learning outcomes for the session
material
Provide learner Questions or group work around the material—use cases or scenarios and real life situations if
guidance possible
Elicit performance Ask questions based on the factual material and feedback from learners if there have been
(practice) interactive tasks. Role-play or a practical procedure
Provide feedback Respond to queries and use effective feedback principles
Assess performance Ask specific questions around the session—these could be formally assessed using online
interactive devices or a formal survey or test
Enhance retention The learner needs to be stimulated to remember the session—this could be by case description
or further quotations. It is also a useful moment in which to prompt the learner to outline
how their practice will change as a result of the session and where their learning needs to go
next using the Kolb reflective cycle

confidentiality and legal requirements of data protection over developed a 6-point tool kit to help learners focus on aspects
storage and transfer of such information. of effective communication skills during role-play.43 It
allows participants to reflect-in-action on techniques they
Communication skills case study—The may use to address specific challenges they face during the
consultation.
Cardiff 6-point toolkit as a teaching tool Using the toolkit and encouraging learners to recognize elements
Recognizing that each patient encounter is unique and that a of a role-play consultation that demonstrate the separate aspects in
toolkit of skills is useful for all situations, Cardiff University any consultation type (e.g., anger, denial, breaking bad news, manag-
ing hope, and uncertainty) can be a powerful prompt to reflection.
Discussions also focus on other aspects of communication—with
families, within teams and with other health-care professionals.
BOX 8.6  CARDIFF 6-POINT TOOLKIT The learning outcomes of a communication skills session in pal-
FOR COMMUNICATION IN PALLIATIVE liative medicine can focus beyond the patient and family encoun-
CARE (© CARDIFF UNIVERSITY, FROM ter to encompass team and interprofessional communication.
REFERENCE [43] WITH PERMISSION)
1. Listening/use of silence
2. Reflection
Teaching ethics
3. Summarizing Ethical dilemmas abound in care of patients at the end of life.
4. Question style Ethical decision-making is never straightforward, so mastering
5. Comfort reflection will help the learner function better within zones of
6. Language indeterminate practice or as Schon10 describes it as “the swamp.”
Ethical decision-making needs a sound understanding of the
Graduate Education for Nonspecialists
BOX 8.7  COMMUNICATION SKILLS
MODULE LEARNING OUTCOMES (© CARDIFF
UNIVERSITY—REPRODUCED WITH PERMISSION)
At the end of the module, the students will be able to
• Demonstrate nonverbal ways of
• Facilitating a patient feeling comfortable and
safe
• Opening up a communication
• Helping a patient disclose their problems
• Demonstrate all six elements of the Cardiff
6-point toolkit
• The use of open questions
• Listening/use of silence
• Reflection
• Summarizing
• Question style—open, closed, and hypothetical
• Comfort
• Language
• Demonstrate the process of checking that a
patient has understood information
• Apply the process of closure of a consultation
• Demonstrate a stepwise approach to breaking
bad news
• Demonstrate respect of the patient and the
patient’s concerns
• List potential barriers to communication with
patients, patients’ families, and other health-care
professional (HCP) colleagues
• Suggest ways to overcome barriers to
communication
• Reflect on their own communication style
• Analyze the processes they use in a consultation
principles of autonomy, beneficence, nonmaleficence, and justice
within the patient’s clinical context.44 Gillon has also highlighted
the wide issues around each decision, which require the clinician
to reflect on the “scope” of application of the decision-making
process and its outcomes.45 Although a formal lecture may appear
useful to inform on fact and principle, the complex decision-
making around each case requires ongoing reflection-in-action
by both tutor and learner. Being aware of the legal framework of
the learner’s country will also help the teaching to be within a
practical clinical context.
Information technology and online learning
Information technology has impacted health-care education
worldwide, ranging from complete course delivery online to using
it to complement learning. Clarity about what the learner should
gain from the use of the specific technology is necessary, however.
Distance learning postgraduate courses were established to
save learners from having to take time away from the workplace
and were originally organized as correspondence courses, with
learning material packs mailed regularly and completed assign-
ments duly returned. Such courses have moved toward web-based
learning, where learners are able to access course material, sub-
mit assessments, and access tutor support online. More impor-
tantly, it allows professionals from diverse localities and cultures
59
to learn while practicing clinically in their own environment,
learning alongside each other, and sharing ideas and experiences
under the supervision of a suitably qualified facilitator.
The benefits go far beyond those of administrative convenience;
e-mail allows students’ direct access to tutors for guidance and
submission of assignments, and web-based chat rooms for stu-
dents encourage informal sharing of ideas, avoiding the distance
learner studying in isolation. As technology has improved and
high-speed Internet facilities are more widely available, courses
are able to offer greater resources online, including video pod-
casts on core topics, copies of course lectures, and the opportu-
nity for tutorials through videoconferencing.46,47 Learners tend to
prefer face-to-face teaching to videoconferencing, especially for
learning about sensitive subjects. However, research suggests that
learning outcomes are similar for both modalities.48
With almost all academic journals and major medical texts avail-
able online, the ubiquitous personal computer has greatly increased
access to “facts,” but not with concomitant teaching for wise deci-
sion-making in complex situations. Videoconferencing can link
learners across the globe across cultural and political barriers.
Massive open online courses (MOOC’S)
The massive open online courses (MOOC’S) have the potential to
deliver palliative care education at no cost to learners on a global
scale. In view of the urgent need for palliative care education at all
levels, this advance has been recognized as a potential response
to this need. They have cost implications in their development—
especially as they are “open access,” so do not generate revenue,
and the same meticulous attention to detail is needed in their
planning as in face-to-face sessions. Although useful to impart
some information, they are no substitute for effective analysis and
reflection to gain an in-depth understanding of the subject.
Some examples of online learning courses are from the
International Children’s Palliative Care Network,49 e-cancer pro-
grams, and50 e-ELCA in the UK.51
The role of the clinical placement
An attachment to a palliative care team or face-to-face clinical
contact with palliative care delivery in any setting will help one
to consolidate clinical skills. Although distance learning and
blended learning will achieve, when appropriately constructed,
many of a curriculum’s competencies, observation and reflec-
tion in the clinical workplace will aid in the understanding and
application of these skills. Time is the key resource necessary
here—both for the student observer and for the supervision and
discussion of reflection and feedback. Clear expectations and
necessary governance of such placements is crucial.
Conclusion
As palliative care becomes increasingly integrated into medical
and surgical specialties, the education opportunities available to
graduate health-care professionals need to increase. The nature of
palliative medicine with holistic, multi-professional patient-cen-
tered care requires new learning techniques alien to the didactic
method of training many are accustomed to. Communication
skills, bereavement care, ethical decision-making, and spiritual
care may be better learned by role-play and reflective practice.
Distance-learning courses and using technology facilitate geo-
graphically diverse groups of professionals learning together,
particularly when combined with face-to-face group work in a
blended learning environment. With an inevitable increase in
60
palliative care graduate programs aimed at the nonspecialist, the
need for robust QA becomes ever more important. The pursuit of
delivering palliative care education to as many nonspecialists as
possible should not compromise the importance of all palliative
care education being of a high standard such that the training
given to nonspecialists can be applied practically to the better-
ment of our patients.
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44. Beauchamp TL, Childress JF. Principles of Biomedical Ethics, 3rd edn.
New York: Oxford University Press, 1989.
45. Gillon R. Medical ethics: four principles plus attention to scope. BMJ
1994;309(6948):184–188.
46. Regnard C. Using videoconferencing in palliative care. Palliat Med
2000;14(6):519–528.
47. Lynch J, Weaver L, Hall P, et al. Using telehealth technology to sup-
port CME in end- of-life care for community physicians in Ontario.
Telemed J E Health 2004;10(1):103–107.
48. van Boxell P, Anderson K, Regnard C. The effectiveness of palliative
care education delivered by videoconferencing compared with face-to-
face delivery. Palliat Med 2003;17(4):344–358.
49. International Children’s Palliative Care Network e-Learning
Programmes. Available from: http://www.icpcn.org/icpcns-elearning-
programme/ (Accessed May 19, 2019).
50. Ecancer – e-Learning Courses for Health Care Professionals. Available
from: https://ecancer.org/education/course/1-palliative-care-e-learning-
course-for-healthcare-professionals-in-africa.php (Accessed May 19,
2019).
51. e-Learning to Enhance Education and Training for End of Life Care
e-ELCA. Available from: https://www.e-lfh.org.uk/programmes/end-
of-life-care/ (accessed December 30, 2019).
9
CHALLENGES OF RESEARCH IN PALLIATIVE AND SUPPORTIVE MEDICINE

Irene J. Higginson

Contents
Introduction..........................................................................................................................................................................................................................61
The value of planning, protocol, feasibility, and pilot studies.....................................................................................................................................61
Scientific challenges.............................................................................................................................................................................................................62
Setting the aims and objectives and/or hypothesis or research question...........................................................................................................62
Study design....................................................................................................................................................................................................................62
Selection and recruitment............................................................................................................................................................................................63
Measurement, interviews, and data collection........................................................................................................................................................64
Missing data and attrition............................................................................................................................................................................................65
Clinical, organizational, and practical challenges.........................................................................................................................................................66
Animal models: issues in translating findings to people..............................................................................................................................................66
Ethical issues and dealing with Institutional Review Boards......................................................................................................................................66
Involving users in research: consumer collaboration...................................................................................................................................................67
Reporting the results...........................................................................................................................................................................................................67
Conclusions...........................................................................................................................................................................................................................67
References..............................................................................................................................................................................................................................68

Introduction
All research, whatever the field, faces scientific, practical, and eth-
ical challenges. Palliative and supportive medicine are no excep-
tion.1,2 The challenges in palliative and supportive care are often
greater than those of other fields of medical research, because of
the nature and complexity of the problems faced by patients and
their families, the services they receive, and the settings of care
and way that patients’ conditions can change dramatically in a
short period of time. This is particularly so for palliative medicine
and research among patients who are at the end of life.
There is often a web of challenges that the investigator has to
face. As much as possible, problems should be anticipated and
prepared for in advance to minimize their impact. But not every
difficulty can be anticipated; sometimes problems must be dealt
with as they arise. Often, it requires great courage, skill, and hard
work to overcome the setbacks that occur during the course of
a study and to minimize the effect these have on the quality of
the results. Many of the challenges described here apply equally
to clinical audits, quality assurance, and total quality manage-
ment projects. 3 An audit where the design is not appropriate, or
a quality assurance review that collects information from a very
biased sample of people, suffers from the same weaknesses and
limitations as a research study with these problems.4 The wealth
of studies already conducted in palliative care and the evidence
base to date demonstrate that successful research and audit are
possible. 5,6
The value of planning, protocol,
feasibility, and pilot studies
The protocol should lay out what is planned in the study, step
by step. Increasingly study proposals for grants, and some study
protocols, include a list or register of the possible problems, how
likely they are and anticipated actions should they arise. The pro-
tocol should specify exactly what will be done and consider deci-
sion points, for example, if there is falling recruitment, that are
triggered.
Careful piloting of the methods and testing the feasibility
studies can test and determine possible solutions and may
uncover further challenges that need to be planned for. Pilot
and feasibility studies nowadays are an expected early step in
research studies, after a good literature review and appropriate
patient and public involvement. Their standing is such that in
2015 a new online journal called “Pilot and Feasibility Studies”
was launched to provide a dedicated place for publication of
this important developmental, allowing all to learn from these
activities, as well as a forum for discussion of methodological
issues.7
Although the terms are often used imprecisely, there is nowa-
days a recognized distinction between feasibility and pilot stud-
ies. Feasibility studies are usually described as “pieces of research
done before a main study in order to answer the question Can this
study be done? They are used to estimate important parameters
that are needed to design the main study.” A pilot study is usu-
ally considered “a smaller version of the main study used to test
whether the components of the main study can all work together.
It is focused on the processes of the main study, for example, to
ensure that recruitment, randomization, treatment, and follow-
up assessments all run smoothly.” 7,8
The objectives of feasibility and pilot studies should be differ-
ent from those of the future definitive study and should stipulate
the issues of uncertainty to be addressed in preparation for the
future large-scale study. Moreover, pilot and feasibility studies
are not designed (or powered) to address the effectiveness of an
intervention and should not become mini-randomized controlled
trials that mirrored the main trial, except on smaller numbers of
participants, often in one center as that is easier. Instead, they are

61
62
commonly used to assess one or more of the seven main objec-
tives in planning a study:
1. to test the integrity of the study protocol for the future trial
(which gives a valid reason for randomization),
2. to gain initial estimates for sample size calculation,
3. to test data collection forms or questionnaires,
4. to test randomization procedure(s),
5. to estimate rates of recruitment and consent,
6. to determine the acceptability of the intervention, and
7. to select the most appropriate primary outcome
measure(s).9
There are recommended guidelines for reporting pilot and feasi-
bility studies, including an extension to the CONSORT statement
for randomized trials, and guidance in non-randomized stud-
ies.10–12 An example of the use of feasibility studies can be seen in
a recent feasibility study for a randomized trial of a repurposed
pharmaceutical treatment. This was able to determine the rates
of recruitment and consent, meet prior feasibility criteria for con-
tinuing to a main trail, estimate blinding levels, test the primary
outcome, and obtain data to enable a more accurate sample size
calculation.13
The “Scientific challenges” section considers the main steps in
research, the challenges, and possible ways to overcome them.
Scientific challenges
Setting the aims and objectives and/
or hypothesis or research question
All research is driven by a question or idea that the investigator
wants to answer or better understand. Focusing one’s ideas on
what is to be explored and what can be investigated in a study is
an important step, requiring knowledge of clinical concerns, lit-
erature review, and self-discipline. It is better to decide to answer
a question or explore an issue that can be achieved realistically
within the resources and timescale available than to attempt to
answer a whole multitude of questions that are very broad and
cannot be adequately covered within the study. Time spent refin-
ing the aims and objectives and then considering if these can be
answered by the right study design is a fundamental step in any
study. In a study following a grounded theory method (in qualita-
tive research), the process varies from that above, but guidance is
available.14
That said, it is important that the research question or aim
builds on existing work and takes it further, rather than simply
repeating earlier small studies. One of many challenges within
palliative care research is that there are many small studies that
describe levels of need and problems, often repeatedly, without
these being taken further to develop and test solutions to those
problems.15 This may be partly as a result of a lack of funding
and capacity in the field, as sustainable funding and capacity are
needed to ensure that research builds from one investigation to
the next.16 A further challenge is that many new interventions
and services are complex, and even more simple interventions are
offered to patients and/or their families with complex needs or
circumstances. The new MORECare (Methods Of Researching
palliative and End of Life Care) statement on the evaluation of
interventions in palliative and end of life care proposes that a the-
oretical framework is developed to help both develop interven-
tions and understand how it may be affecting outcomes.17 This is
an important step: a theoretical model will help to understand the
Textbook of Palliative Medicine and Supportive Care
potential benefits and harms of any intervention or new service or
treatment, and also what components are key to its success.
Study design
Choosing the most appropriate design for a study’s aims and
objectives is then one of the most important decisions that any
researcher can make.18 Always the aims and research questions
should lead the design. For example, there is no point attempting
to test the efficacy of a new drug treatment by conducting a sur-
vey of patient’s views of the drug. While such a survey might give
interesting information about acceptability, side effects, actual
use, and patient views, it will not give information about efficacy
(i.e., whether the drug works better than the current best prac-
tice, in controlled conditions). Chapter 23 outlines the different
research designs and options for the researcher.
Certain study designs are problematic in palliative care, and
perhaps the most often discussed is the randomized controlled
trial. These have experienced such severe problems that the trial
failed.19 Nowadays, trials, especially crossover trials, for drug
treatments in palliative care are more often used,20,21 although
there can be difficulties with recruitment, attrition, and mea-
surement (see below). However, trials of nondrug interventions
often face additional difficulties in maintaining a difference
between intervention and control, and because they are difficult
to blind can have problems of contamination and disappoint-
ment (if patients feel they are not receiving a service they wish
to receive).22–24 There is a growing body of literature showing that
although a well-conducted randomized controlled trial is the gold
standard method in evaluative research, alternative quasi-exper-
imental and observational methods can yield valuable results if
their biases can be accounted for or controlled.17,18,25,26.
Successful randomized trials have been conducted, for exam-
ple, communication skills training,27 breathlessness support ser-
vices,29,30 community palliative care teams, 31,32 or early palliative
care different disease groups. 33–36 A broader range of trial meth-
ods have been developed, including cluster randomized trials, 37–39
fast-track trials, and wait list controlled trials (both of which need
careful timing and are often possible only among patients with
longer life expectancy)40–47 and N of 1 trials.48–50 Careful reading
of the designs of others, including those researching outside of
palliative care, and their successes and failings, can often pro-
vide useful guides. 51 In addition, once a design is chosen, there
are now many statements that help guide their conduct and
reporting. The EQUATOR network (Enhancing the QUAlity and
Transparency Of health Research, found at https://www.equator-
network.org/) is an international initiative that seeks to improve
the reliability and value of published health research literature by
promoting transparent and accurate reporting and wider use of
robust reporting guidelines. It contains reporting guides now for
almost every study design used. Examples include the CONSORT
statement for randomized trials52–55 and the STROBE statement
for observational studies.56–60 But there are many more, includ-
ing reporting guides for qualitative studies, published protocols,
systematic reviews, prognostic studies, case reports, quality
improvement studies, and economic evaluations. I often find
these reporting guides useful when planning a study and even
writing a grant application, as they serve as a useful reminder of
the key aspects to plan.
Increasingly mixed-method study designs (combining quanti-
tative and qualitative methods) are being used in health services
and clinical research. These methods have much to offer pallia-
tive care.17,61,62 The quantitative approaches can count numbers of
Challenges of Research in Palliative and Supportive Medicine 63

TABLE 9.1  Priority Sequencing Model Offering Four Ways of Combining Qualitative and Quantitative Data in Mixed Method
Studies Depending on Priority and Sequencing
Quantitative Component Priority
Smaller component is preliminary 1. Qualitative preliminary
qual—QUANT
Purposes: smaller qualitative study helps guide the
data collection in a principally quantitative study
Example: initial qualitative interview study helps
plan methods for recruitment in a larger survey or
trial
Smaller component is follow-up 3. Qualitative follow-up
QUANT—qual
Purposes: Smaller qualitative study helps evaluate
and interpret the results from a principally
quantitative study
Example: qualitative interviews after completion of
survey or trial to aid understanding of the results
Source: Adapted and updated from Morgan DL.70
Qualitative Component Priority
2. Quantitative preliminary
quant—QUAL
Purposes: Smaller quantitative study helps guide the
data collection process in a principally qualitative study
Example: survey of hospices and palliative care services
helps the selection of hospices for in-depth case study
4. Quantitative follow-up
QUAL—quant
Purposes: Smaller quantitative study helps evaluate and
interpret results from a principally qualitative study
Example: survey of hospital palliative care teams
informs generalizability of results of qualitative study
in one team.

affected patients and provide external validity, whereas the quali-
tative methods can help one to understand the more intangible
aspects of symptoms, feelings, or treatment effects and provide
internal validity.63–69 A key in the mixed-method study is to plan
in advance the way in which the methods will be combined. In
the priority sequencing model, four ways of combining methods
are described (see Table 9.1).70 However, methods can also be
combined simultaneously, using a nested or imbedded design,
perhaps examining some aspects of the data in more depth. This
combination should also be described in the analysis plan. The
MORECare statement gives specific suggestions as to how the
mixed methods may be combined and reported.17
Selection and recruitment
Many studies in palliative care, whatever the design, can have
problems with patient selection and recruitment. Selection (or
sampling) bias occurs when the group of patients selected for
or included in the study is different from the total population of
interest. For example, we might wish to study the management of
pain in patients toward the end of life, but the way that we are able
to recruit patients means that we exclude patients in the last week
of life—because they could not participate in interviews, or for
some other reason. There are many reasons why selection or sam-
pling bias may occur, some of the common types and their effects
are shown in Table 9.2. Chapter XX considers the patient popula-
tion in greater depth and the issues and problems of recruitment,
including among disadvantaged groups.
Further recruiting patients who are often quite ill, or caregiv-
ers who are distressed and/or bereaved can be difficult.71 Many
research studies assessing the efficacy of drug treatments have
automatically excluded elderly people (even those over 65 years),
and those with multiple pathologies, because of the difficulties
of recruiting individuals who are ill. In palliative care, excluding
people in these categories would remove almost the entire sample,
leading to considerable selection bias (see Table 9.2). However,
recruiting ill or frail people into research studies requires skill,
time, and energy. It involves winning the hearts of professionals
who may refer patients to the study, and interviewing patients
and families in a way that makes them feel prepared to take part
and continue to be involved.
Jordhoy et al. have written useful guidance on methods of
improving recruitment,1,72 including ensuring staff awareness,
regular updates, feedback, etc. (see Chapter 26 for useful tips, and
Chapter 22 for more information on selecting the patient popula-
tion). In palliative care, interviewers must be sensitive and flex-
ible when attempting to recruit patients. There may need to be
three or four visits to patients to secure one interview (because
patients are ill, factors change, and patients may prefer the inter-
viewer to come back at a different time). In one study at King’s
College London, among patients with advanced cancer, in one
instance, more than 10 contacts were required to secure a com-
plete interview, despite the patient are wishing to be involved in
the study.73 The MORECare statement gives suggestions as to how
the recruitment can be optimized.17 A recent qualitative study
investigated motivations for recruitment and retention in a trial
of a pharmaceutical treatment in palliative care—motivations,
especially for retention in the study included lack of burden-
some questionnaires, which were deemed as relevant; continuity
of relationship with the interviewer or research nurse; a person-
centered approach to individuals in the study; and an easy to take
medication.74
Despite the difficulties of recruitment in palliative care,
many patients in palliative and supportive care do wish to be
involved in research and to tell their story, particularly if they
feel it may help others in their situation in the future. Equally
families, both contemporaneously and during bereavement,
may also wish to be involved. A recent systematic review found
evidence in many countries and investigations that patients
and families often welcome the opportunity to be involved.
Including some open questions in any questionnaires, to allow
the participant to “tell their story” or make comments as they
wish is recommended.75,76 Also recommended is working with
patients and families using the services and with clinicians to
plan recruitment.17
A common challenge in palliative care is establishing suitable
criteria for recruitment to the study. If prognosis is used, then
past experiences suggest that patients may be referred too late
for the study. In one instance, when patients with a prognosis
of less than 1 year were to be referred to the study, one in four
patients had died before the interviewer could recruit them.22 The
criterion of the clinician “not being surprised if the patient had
died within 1 year” has been suggested as likely to be more suc-
cessful.77 Validation work has suggested that this is a feasible and
effective tool in cancer and some other conditions,78–80 although
64 Textbook of Palliative Medicine and Supportive Care

TABLE 9.2  Common Biases (i.e., Systematic Rather Than Random Errors) That Can Be Encountered in Palliative Care Research
Type of Bias Definition
Sampling bias The inclusion of subjects that distort the nature of those that would have been chosen by chance.
—Selection bias The selection of subjects that distort the nature of those that would have been chosen by chance, for example,
selection by nurses or doctors or patients suitable for interview. There are many ways this can occur, but the
selection of any sample is likely to result in sample bias, especially in palliative care where patients may become
too ill to contact, or may not be in contact with particular services from which patients are selected (e.g., clinic,
hospital, primary care doctor), or may be excluded because staff feel they are too ill for interview.
—Nonresponse bias The biasing of the sample due to the nature of those who do not respond being different to those who do
respond. For example, relatives who are most distressed may (or may not) respond to a questionnaire.
—Attrition/dropout bias The biasing of the sample due to subjects being lost to follow-up because they choose not to be involved in the
study, or become too ill for interview, move away, or die. Some attrition bias is inevitable in palliative care.
—Missing data bias The biasing of the responses due to some subjects not responding to some questions. For example, if the most
distressed patients do not answer questions about depression, there is in effect a nonresponse by some of the
samples to some of the questions.
Measurement bias The collection of data or measurements that distort the nature of the data collected from its true state.
—Recall bias The biasing of data collected because of inaccurate or varied recall, perhaps for some events more than others, or
because of varied time (e.g., 1 year vs. 6 weeks) or events.
—Poor measurement tools, The use of measurement tools that introduces bias because they are not valid or reliable in certain situations or
validity/reliability among certain cultures.
—Digit preference bias The use of measurement tools that introduce bias because respondents choose particular digits in their answers,
for example, a scale of 1–100; most people tend to use numbers that end in 0 (10, 20, etc.).
—Observer/researcher’s bias The systematic error introduced by an expectation or belief on the part of the observer or researcher (this can be
quite unconscious and is most common when researchers are not blinded to situations, although it can occur
even then).
—Subject bias The systematic error introduced by an expectation or belief on the part of the research subject (this can be quite
unconscious and is most common when subjects are not blinded to situations, although it can occur even
then).
—Hawthorne effect The change in behavior made by people (e.g., staff or patients) when they know they are being studied. The effect
was first noticed in the Hawthorne plant of Western Electric. Production increased not as a consequence of
actual changes in working conditions introduced by the plant’s management but because management
demonstrated interest in such improvements.
Reporting bias The reporting and publication of research findings in a way that distorts the dissemination of findings toward
more positive or negative findings.
—Publication bias The publication or nonpublication of research findings, depending on the nature and direction of the results. In
general, positive studies are more often published than negative ones.
—Language bias The publication of research findings in a particular language, depending on the nature and direction of the
results. Research findings in some languages, particularly those in English, are more accessible.
—Funding bias The reporting of research findings, depending on how the results accord with the aspirations of the funding
body. Further, there may be a considerable hidden bias in the nature of research supported, whereby certain
investigations are not funded.
—Selective outcome reporting bias The selective reporting of some outcomes but not others, depending on the nature and direction of the research
findings. For example, positive findings are reported, but a lot of negatives ones are not.
—Time-lag reporting bias The delayed (or rapid) publication of research findings, depending on the nature and direction of the results.
—Developed-country bias The publication of findings, depending on whether the authors were based in developed or in developing
countries.
Note: Main categories of bias are shown in bold; subcategories/causes of this type of bias are shown in the table. Note that there are over 100 different types of biases that are
known, but three main categories, sampling, measurement, and reporting, include most types.

it may not be acceptable in some cultures and there is variability
in how different disciplines use it.81 Prognostication is very dif-
ficult but a range of estimated survival is more likely to be cor-
rect than any absolute assessment.82 Further work is improving
our prognostic assessments, by providing information on other
relevant factors.83 Other recruitment criteria, such as the nature
of problems or functional assessment, or a combination of these,
may also be needed1,84 (see Chapters 22 and 26). Careful pilot-
ing or preliminary qualitative work testing different approaches
may shed light on the most effective strategies and methods for
recruiting the research subjects, and the information and updates
needed for staff and subjects.
Measurement, interviews, and data collection
A constant challenge in palliative care research is to find mea-
sures that detect relevant changes and yet are suitable among
very ill populations. This creates a tension between attempt-
ing to capture individual detail—by using long standardized
measures or conducting qualitative interviews—and having
short interviews—with short measures and/or short qualitative
Challenges of Research in Palliative and Supportive Medicine
interviews. In the end, the researcher must balance the amount
of information that can realistically, reliably, and validly be col-
lected with the ideal needed. Often the plan of analysis is help-
ful here, as well as referring back to the aim, objectives, and/
or hypothesis of the research. The analysis plan helps to clarify
how the data will be used, and this in turn clarifies what needs
to be collected.
There are now many hundreds of quality of life instruments and
a range of palliative outcome scales, which have been developed
or validated specifically for palliative care. Chapter 24 provides
more details of individual scales and outcome measurement. In
addition, there are several books on quality of life assessment
and reviews of the measures.85–91 The European Community
supported project PRISMA-assessed potential outcome mea-
sures and measurement tools used in research and clinical prac-
tice.92–94 It identified not only common tools but also a problem
of many different tools being used, with a lack of consistency.93,95
Therefore, there is now every opportunity for researchers and
clinicians to use validated and tested scales. Only if a thorough
systematic review reveals that no fully or partially suitable scale is
available, should a new scale be developed. The MORECare state-
ment makes recommendations of the key features required of
outcome measures in research studies, their timing, and whether
proxy or patient is used.17,96
Less frequently qualitative researchers publish their topic
guides that are generally developed for specific lines of enquiry.
Such publication is useful, for conducted open qualitative inter-
views is a highly skilled activity. Listening to the tapes of, or
reading or typing the transcripts of highly skilled qualitative
interviews is very instructive.
In general, interviews should be kept as short as possible, and
in some instances, the researcher should order the questions
or scales so as to collect the more important information first.
Missing data for some questions among some patients will be
inevitable, and researchers should minimize this for the primary
outcomes of their study. When patients become very tired there
or do not wish to continue interview, the data collection should be
terminated, because collection will become unreliable if patients
cannot concentrate. It may be necessary to return to complete the
interview if the person is willing.
Deciding the primary outcome of the study is vital. Many
journals and funders will require a single primary outcome—
which is the basis of the sample size calculation, and the pri-
mary analysis, especially in randomized trials, and will place
great weight on the significance or not of those results. Thus, the
choice of the primary outcome is critical, as it must be respon-
sive to change that is expected by the intervention. Many out-
come measures as not as well validated as expected or exist in
multiple formats. For example, exploration of the widely used
numerical rating scale to assess breathlessness suggests that
this was not a unidimensional measure and highlighted multi-
ple wording in questions. In fact, the scale does represent quali-
tative comments from patients, and so probably is appropriate
in many circumstances, but care is needed regarding these pre-
viously assumed properties.97 A recent debate has also emerged
regarding the overreliance of statements of statistical signifi-
cance, and especially a single P value of <.05, in the reporting
of trials. A group of leading statisticians has suggested “retiring
statistical significance,” and instead an emphasis on estimates
and the uncertainty in them, with an explicit discussion of the
lower and upper limits of their intervals, and when P values are
reported, using precision (for example, P=.021 or .13).98,99
65
Missing data and attrition
Missing data in palliative care studies is inevitable. Indeed, the
recent MORECare statement reverses usual thinking about miss-
ing data and argues that a lack of missing data may mean that
the study has not recruited the correct population. Missing data
should be anticipated and planned for in advance. Data may be
missing for individual questions (for example, if the patient did
not wish to answer a question or scale) or for individual sub-
jects (for example, in a longitudinal patients may miss a follow-
up interview because they are away or because of illness, or they
may be lost to follow-up because they become too ill to partici-
pate in the study, or they die). The most important thing is to
understand the reason for the missing data and in which subjects
it occurs.17,100
Any missing data may bias the results (see Table 9.2). Therefore,
missing data should never be ignored. In general, missing data
should be classified and explored in three categories:
1. Data missing completely at random (i.e., there is no dis-
cernable pattern to the missing data with any variable in
the data set).
2. Data missing at random (i.e., there is no relationship
between the missingness of data with the outcome vari-
ables of interest, but there is a relationship with one of the
other variables that do not appear to be related to the expo-
sure or outcome variable). For example, in an evaluation of
palliative day care, we found missingness was associated
with whether patients had smoked or not, although there
was no relationship with pain, symptoms, quality of life,
hope, diagnosis, or any clinical variables.
3. Data missing not at random (i.e., the missingness of the
data is associated with an important variable in the study,
e.g., diagnosis or very importantly one of the outcome vari-
ables, e.g., quality of life).
As attrition is such a common problem in palliative care, the
MORECare statement has also proposed a new classification for
attrition in palliative care studies. This defines three main catego-
ries of attrition, depending on its cause:17,100
• Attrition due to death (ADD)
• Attrition due to illness (ADI)
• Attrition at random
The way missing data due to attrition is managed will be differ-
ent depending on its cause.17,100 A review of 119 trials in palliative
care found a total attrition of 29% (95% CI 28–30%). The main
reason for attrition, applying the MORECARE classification was
ADD (weighted mean 31.6% [SD 27.4]) with ADI as the second.
Importantly, the study did not observe significant differences in
missing data between total attrition in non-cancer patients and
cancer patients and recommended the use of the classification to
aid analysis and interpretation of results.101
The field of research into missing data and its effects is grow-
ing rapidly. New techniques are being developed (e.g., imputation
and modeling) to handle missing data.1,102,103 There is now even a
website and group dedicated to understanding and advancing the
handling of missing data (at www.missingdata.org.uk).
The old notion of just ignoring the missing data is now rarely
acceptable, unless there is minimal missing data. Any analysis
conducted with missing data excluded from the analysis is in
effect assuming that those subjects with missing data will give
66
the same results as those with complete data. Thus, there is an
implicit imputation, even if the researcher has not formally car-
ried one out. And even if data is missing completely at random,
missing data will reduce the sample size and may mean that the
study becomes underpowered. Missing data should always be
reported and understood. In palliative care, the pattern of miss-
ing information can often say much about the sample and the
subjects. If modeling or imputations are undertaken, often sev-
eral imputations are advisable, followed by a sensitivity analysis,
to determine the effects of different approaches.
Clinical, organizational, and
practical challenges
Challenges in this area can occur in all forms. There may be con-
cerns among colleagues or reluctance to refer patients for stud-
ies in palliative care, both by specialists outside of palliative care
and those within the field. This may be because of concerns about
the nature of the questions, or a belief that palliative care equates
with end of life care, and so patients should only be included in
studies when they are very close to death. Interviews may have
to be organized around clinical treatments. Patients may not
clearly distinguish between new services or interventions and
the research interview, if both are introduced at the same time.
The Hawthorne effect (see Table 9.2) is likely for a wide range of
reasons.
In addition, there are many practical challenges to consider
in a palliative care research project. There may need to be travel
to patients’ homes to conduct interviews, and the nature of the
home may make it difficult to ensure that patients and cares can
be interviewed separately. Sometimes the only way to achieve
separate patient and caregiver interviews is to have two inter-
viewers, but in some homes, this is not possible. Travel time and
costs must be accounted for.
During the course of any study, things will change. New treat-
ments or services may be introduced, which may require a change
in the recruitment or inclusion criteria. Staff within the clinical
service will change, which may mean there is a need to educate
the new staff. Even the researchers on a study may leave because
of being offered a post elsewhere, finding the work not as inter-
esting as they thought or they may fall ill. A common problem in
palliative care research is if the researcher suffers from a personal
bereavement, he begins to find interviewing difficult (see below,
impact of research). Senior investigators and research teams are
often crucial here, they have seen this problem before and there
maybe several individuals who can help out with the study or who
can at least speak with the funding body and others to let them
know what is happening.
The potential effects of interviews on those conducting them
should also be considered in terms of safely and emotional effects.
During interviewing patients in the community, the safety of
interviews, especially in more deprived and dangerous areas,
should be considered. Community clinical services may provide
useful information. Using mobile phones, keeping lists of places/
people to be visited, agreeing buddies who will check where-
abouts, and in difficult circumstances, joint interviewing can be
helpful. Conducting interviews, transcribing and even analyzing
data (including collected by post) can also be potentially distress-
ing for researchers, particularly those who do not have clinical
experience to make them aware of services that might be avail-
able for others. Often a system of support—even if mutual within
Textbook of Palliative Medicine and Supportive Care
a department—is helpful. At times of particular stress, e.g., fol-
lowing a bereavement, as for clinical staff, it may be that the per-
son should not conduct the interviews.
Using a project advisory group (PAG) can also be helpful. The
PAG usually comprises relevant clinical and investigations and,
depending on the scale of the project, may be small (2 or 3 indi-
viduals) or for complex projects may be large (involving several
centers, representatives of the funding body, external experts,
and users/patients). The PAG may be established by the funding
body or by the investigators. It regularly meets and oversees the
progress of the project and provides a forum to discuss challenges
as they arise, monitor research ethics, governance, and progress
and consider the relevance of findings to patients, policy, and
practice. For clinical trials, there are formal committees that
need to be established to steer overall trial conduct and to moni-
tor data quality and safety for participants. In smaller studies that
are not trials of pharmacological treatments, these functions can
be taken into the PAG role. Using external experts and patients/
families or consumers is desirable in PAGs.
A final practical challenge is obtaining funding for the study.
Many funding bodies do not see palliative care as a priority,
and many scientific assessors on grant-awarding bodies are not
aware of the specific outcome measures and methods needed. In
Canada, a specific palliative care program has been established
within the National research boards, which has international
expert assessors. This is a good model for other countries, as only
with specific programs dedicated to a field can the best studies
be supported.
Animal models: issues in
translating findings to people
Often work with animal models involves the artificial induce-
ment of the problem under study in the animals (e.g., the cancer
is induced in the animal). Then the researchers measure param-
eters that they believe are sufficiently close to or reflect those of
interest in humans. The animals are killed at a point when they
are thought to be suffering. There are many challenges in animal
model studies. Specific guidance exists in many countries as to
the welfare of animals, and it is beyond the scope of this chapter
to consider that here. Research using animal models requires a
model sufficiently close to the situation experienced in humans
to be developed in the animals. For example, to study hyperten-
sion, types of rats are bred specially that develop high blood pres-
sure. To study problems in cancer, the cancer is often artificially
induced. One of the apparent problems is being able, in animals,
to induce sufficiently similar problems to those faced by humans
and to find ways to measure them. Caution is therefore needed
when extrapolating from animal studies to human beings. A fur-
ther problem is that there are many concerns of palliative care, for
example, symptoms such as breathlessness or fatigue, emotional,
social and spiritual worries, and issues related to the delivery of
services, for which no relevant animal model can be developed.
Ethical issues and dealing with
Institutional Review Boards
The ethical challenges in palliative care research are wide-rang-
ing, and for this reason, Chapter 25 deals with this subject in
detail. Common ethical issues that can arise occur at the point
of consent (ensuring that full information is given, and the time
Challenges of Research in Palliative and Supportive Medicine
taken for consent within the interview), during the interview,
when researchers may uncover problems that they feel they need
to act on, and dealing with distressed individuals. Nevertheless,
it is arguably unethical to make decisions for patients about
whether or not they should be given the option of being involved
in research if they wish. The MORECare ethical work concluded
that it is ethically desirable and, in some instances, may be uneth-
ical not to offer patients the opportunity to decide if they want to
be involved in research.75,76,104,105
Institutional Review Boards (IRBs) or Ethics Committees will
need to approve the research (and in many instances the audit) to
be undertaken and will require detailed project information. They
will cover not only research among patients but also staff surveys
and any action that is not part of routine good clinical practice.
Allowing sufficient time within a study for the review is essential.
Ethical committees and IRBs vary in their approach and are often
not familiar with palliative care and survey research and so may
initially be reluctant to pass a study. Often considerable persis-
tence and explanation are needed, although often their sugges-
tions and advice improve the study. If in doubt about whether the
study requires IRB approval, it is sensible to take advice from the
chair of the committee. Chapter 24 provides further guidance.
Involving users in research:
consumer collaboration
There is a growing view, on the part of many patients, families,
caregivers, and research investigators that the involvement of
patients and families/relevant others in research is helpful and
good practice. Some charities that support research have user
forums that help to decide on research priorities, questions, and
the review of potential grants. For example, at King’s College
London, a study funded by the Multiple Sclerosis Society (United
Kingdom) was reviewed by users as well as scientific experts dur-
ing planning and was monitored by a PAG involving users, scien-
tific experts, and clinicians. A user chaired our PAG. The notion
of collaboration with users of services, patients, and families is
especially helpful. Ideally, the research should be collaboration
with users, who bring their own knowledge of the condition and
situation to the field. Increasingly, short job descriptions are
developed to aid the role to be clear. National bodies, such as
the UK National Institute of Health Research (NIHR), have also
begun to recommend this approach and to establish and support
user forums. For example, INVOLVE is a national advisory group
that supports greater public involvement in NHS, public health,
and social care research. It is funded by and part of the NIHR. It
shares knowledge and learning on public involvement in research
(see http://www.invo.org.uk).
However, there can be particular challenges in involving users
in palliative care research and audit—patients are often quite ill,
may need special facilities, and cannot be recruited in all cir-
cumstances. Increasingly, it is recognized that users involved in
appraising research need some development or training, so that
they can understand some of the concepts involved. This, and
the course of a research study over 1–3 years, takes time. But it
is completely unrealistic to expect palliative care patients to be
involved for this period of time. Involving users who are not pal-
liative care patients, for example, involving cured cancer patients,
can be problematic, because these users—although very familiar
with some of the problems in care—have not experienced the spe-
cific issues faced by palliative care patients. Other proxies, such as
67
bereaved relatives, or representatives from relevant patient bodies
and in some instances relevant clinicians may overcome this to
some extent but bring other challenges. The ways to involve users
in palliative care needs more development and testing. The guide
by Small provides a good introduction.106
Reporting the results
Many challenges can arise in the final stage in a research project—
reporting the results (see Table 9.1 and Chapter 25). It can be dif-
ficult to write the chapter up fully within the word limit required
for many journals, and there is often a time lag between complet-
ing the study, analyzing the data, and finally getting the paper out.
However, dissemination is an important part of all research, differ-
ent audiences should be considered, and a dissemination strategy
should be developed in the original protocol.
Conclusions
There are many challenges in conducting research in palliative
care, which means that research in palliative care needs skills,
training, effort, and links to those with expertise in dealing with
such issues. Some of the challenges are similar to those in other
fields (especially, for example, psychiatry and health services
research), whereas some challenges are especially unique (for
example, the problem of attrition and issues of involving users).
There are growing numbers of units that are becoming skilled
and experienced in conducting research in palliative care, which
have sufficient expertise and infrastructure to begin to support
KEY LEARNING POINTS
• Research in palliative care faces a complex web
of scientific, practical, organizational, and clini-
cal challenges.
• Many of these challenges are common to those
faced in other fields, but some (e.g., attrition and
missing data) are especially likely in palliative
care.
• The MORECare statement gives a practical
framework that can be used by those planning
research in palliative or supportive care to help
ensure the best possible design.
• Scientific challenges include setting aims and
objectives, study design, outcome measures,
recruitment, follow-up, attrition, and dealing
with missing data.
• Practical and other challenges include selling the
project to others, interviewing patients in vari-
ous settings and different contexts, managing
changes in treatments and/or services and/or
staff, ethical issues and involving users.
• Many challenges can be avoided or their effects
minimized by careful planning and piloting,
developing a project advisory group, and working
within or with units that possess relevant pallia-
tive care research expertise and skills.
• Research is important to palliative care, to
develop the knowledge and discover improved
treatments and care.
68
others in their research training. In the future, bringing research-
ers, clinicians, and users together—through collaboratives, rota-
tions,107 and ideally institutes devoted to palliative care—will
help to improve the infrastructure for researchers, especially new
investigators. Successfully completed studies are rewarding, both
for investigators and more importantly for patients and families.
Research can begin to discover better, more effective, efficient,
and humane ways of providing care and treatments to benefit
patients and families.108–110 But failed studies are demotivating for
investigators and take valuable time from patients, families, and
clinical staff.111,112 Good research in palliative care can overcome
many of the challenges, although there is a need to find better
ways to deal with some of the problems of recruitment, attrition,
outcome measurement, and missing data.
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2012;26(3):242–249.
95. Harding R, Higginson IJ. PRISMA: a pan-European co-ordinating
action to advance the science in end-of-life cancer care. Eur J Cancer
2010;46(9):1493–1501.
96. Harding R, Simon ST, Benalia H, et al. The PRISMA Symposium 1:
outcome tool use. Disharmony in European outcomes research for pal-
liative and advanced disease care: too many tools in practice. J Pain
Symptom Manage 2011;42(4):493–500.
97. Evans CJ, Benalia H, Preston NJ, et al. The selection and use of outcome
measures in palliative and end-of-life care research: the MORECare
international consensus workshop. J Pain Symptom Manage 2013.
98. Lovell N, Etkind SN, Bajwah S, Maddocks M, Higginson IJ. To what
extent do the nrs and CRQ capture change in patients’ experience of
breathlessness in advanced disease? findings from a mixed-methods
double-blind randomized feasibility trial. J Pain Symptom Manage.
2019;58(3):369–381.e7.
99. Amrhein V, Greenland S, McShane BB. Statistical significance gives
bias a free pass. Eur J Clin Invest 2019;49(12):e13176.
100. Amrhein V, Greenland S, McShane B. Scientists rise up against statis-
tical significance. Nature 2019;567(7748):305–307.
101. Preston NJ, Fayers P, Walters SJ, et al. Recommendations for managing
missing data, attrition and response shift in palliative and end-of-life
care research: part of the MORECare research method guidance on
statistical issues. Palliat Med 2013.
102. Oriani A, Dunleavy L, Sharples P, Perez Algorta G, Preston NJ. Are the
MORECare guidelines on reporting of attrition in palliative care research
populations appropriate? A systematic review and meta-analysis of ran-
domised controlled trials. BMC Palliat Care 2020;19(1):6.
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103. Neymark N, Kiebert W, Torfs K, et al. Methodological and statistical
issues of quality of life (QoL) and economic evaluation in cancer clini-
cal trials: report of a workshop. Eur J Cancer 1998;34(9):1317–1333.
104. Robinson PG, Donaldson N. Longitudinal analysis of quality of life
data. In: Carr AJ, Robinson PG, Higginson IJ, eds. Quality of Life.
London: BMJ Books, 2003, pp. 101–112.
105. Gysels M, Shipman C, Higginson IJ. Is the qualitative research inter-
view an acceptable medium for research with palliative care patients
and carers?. BMC Med Ethics 2008;9:7.
106. Gysels M, Shipman C, Higginson IJ. “I will do it if it will help others:”
motivations among patients taking part in qualitative studies in pallia-
tive care. J Pain Symptom Manage 2008; 35(4):347–355.
107. Small N, Rhodes P. Too Ill To Talk? User Involvement and Palliative
Care. London: Routledge, 2000.
108. von Gunten CF, Von Roenn JH, Gradishar W, Weitzman S. A hospice/
palliative medicine rotation for fellows training in hematology-oncol-
ogy. J Cancer Educ 1995;10(4):200–202.
109. Breitbart W, Bruera E, Chochinov H, Lynch M. Neuropsychiatric syn-
dromes and psychological symptoms in patients with advanced cancer.
J Pain Symptom Manage 1995;10:131–141.
110. Corner J. Is there a research paradigm for palliative care?. Palliat Med
1996;10:201–208.
111. Ripamonti C. Management of dyspnea in advanced cancer patients [see
comments]. Support Care Cancer 1999;7(4):233–243.
112. Higginson I. Research degree supervision: lottery or lifebelt. Critical
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113. Higginson I, Corner J. Postgraduate research training: the PhD and
MD thesis. Palliat Med 1996;10:113–118.
10
THE POPULATION: WHO ARE THE SUBJECTS IN
PALLIATIVE MEDICINE RESEARCH?

Claudia Bausewein and Fliss E.M. Murtagh

Contents
Introduction..........................................................................................................................................................................................................................71
Patients...................................................................................................................................................................................................................................71
Diagnosis..........................................................................................................................................................................................................................72
Prognosis..........................................................................................................................................................................................................................72
Need..................................................................................................................................................................................................................................72
Comorbidities.................................................................................................................................................................................................................72
Patients with cognitive impairment...........................................................................................................................................................................72
Population-based research...........................................................................................................................................................................................73
Family caregivers..................................................................................................................................................................................................................73
Professional caregivers........................................................................................................................................................................................................73
General public.......................................................................................................................................................................................................................73
Criteria for the description of the palliative care population......................................................................................................................................74
Conclusion.............................................................................................................................................................................................................................74
References..............................................................................................................................................................................................................................75

Introduction to curative treatment.”3 This was later changed to patients “fac-

Palliative care research has grown out of its infancy with increas-
ing numbers of published studies annually. Nevertheless, there
is a continuous need for high-quality research to understand the
changing concepts of palliative care both in oncological and non-
oncological diseases, evaluate interventions, and increase the evi-
dence base for palliative care.1 The main focus of palliative care
research is the patients, but there is also research interest in the
needs and the situation of informal and professional caregivers,
and the views and opinions of the general public regarding issues
of end of life care.
In general, the choice of the palliative care population is driven
by the research question that impacts both methods and type of
study. Considering the specific characteristics of participants
is crucial when planning a study. These need to be determined
through clear inclusion and exclusion criteria in preparing the
study. But it is also a central responsibility of researchers to
describe the characteristics of their research, including partici-
pants in a way that helps clinicians to determine under what cir-
cumstances the findings can be applied to their patients2; that is,
to provide clinicians with some insight into the generalizability
of the research findings. This is important as populations differ
widely, and evidence derived in one population may or may not
apply to other populations.2
This chapter focuses on the challenge of defining the popu-
lation to be studied and the specific characteristics of patients,
caregivers, and the general population in the research context.
Patients
Definitions of palliative care are often vague when describing the
patient population. In 1990, the WHO definition of palliative care
included patients with “having a disease that is not responsive
ing the problems associated with life-threatening disease.”3 The
White Paper on standards and norms of the European Association
for Palliative Care defines palliative care as “not restricted to pre-
defined medical diagnoses, but should be available for all patients
with life-threatening diseases.”4 The latest definition of palliative
care originates from the International Association for Hospice
and Palliative Care (IAPHC) in 2019 and refers to “individuals
across all ages with serious health-related suffering due to severe
illness.”5 In a footnote, suffering and severe illness are further
specified with suffering defined as “health-related when it is
associated with illness or injury of any kind” and severe illness
understood as “any acute or chronic illness and/or condition that
causes significant impairment, and may lead to long-term impair-
ment, disability and/or death.”
In research, this inconsistency how to define the palliative
care patient population is also reflected in a lack of consensus
concerning the attributes of illnesses needing palliation and the
ambiguous use of the adjective “palliative.”6 None of the defini-
tions name a specific disease but all include the improvement of
physical, psychological, social, and spiritual needs.
Researchers and clinicians have in some ways redefined what
characterizes a “palliative care patient.” In the early stages of pal-
liative care, attention was focused on cancer patients near the
end of life. Over recent years, however, there has been a shift to
extending palliative care provision to patients with non-cancer
diagnoses and also acknowledging the need for and benefit from
offering it to patients earlier in the disease trajectory.7 Today,
there is a strong demand that needs and not diagnoses and/or
prognoses are the most relevant factors for provision of palliative
care services.8 However, in research, depending on the research
question, both diagnoses and prognoses may play an important
role, and increasingly often alongside newer indicators of need,
such as symptom and/or problem severity.

71
72
Diagnosis
Similar to the provision of palliative care to cancer patients,
research studies focused either on specific cancer populations such
as lung or gastrointestinal cancer7,9 or on mixed populations across
cancer entities.10,11 With changing concepts and widening pallia-
tive care to all patients with chronic medical conditions, there was
increasing interest in understanding the specific needs of individ-
ual patient groups, e.g., patients with chronic kidney disease,12,13
chronic heart failure,14 or chronic obstructive pulmonary disease
(COPD),15 also in comparing these groups to cancer patients.16,17
Studies focusing on one specific population give detailed informa-
tion on this group but have limited generalizability to the whole
palliative care population. In contrast, there might be considerable
heterogeneity in studies with mixed patient groups making find-
ings harder to interpret. Furthermore, different conditions follow
different disease trajectories13,18 which has a potential impact not
only on patients’ retention in the study but also on the comparabil-
ity of data as, for example, patients in cross-sectional studies may
be at different stages in their disease trajectory. Ideally, the date of
data collection should be related to a fixed point in the patients’
disease trajectory, and commonly, death is used as the most obvi-
ous fixed point. However, this has the drawback of being identified
only retrospectively, and being often difficult to anticipate, even in
the relatively late stages of illness.
Prognosis
Basing the definition of palliative care patients in research on
prognoses raises further challenges. If inclusion criteria are con-
fined to those with relatively poor prognoses, there is a risk of
excluding a group of healthier patients whose inclusion would
have improved the generalizability of the study results. In addi-
tion, if prognosis alone is used to define study eligibility, sub-
stantial inaccuracies must be overcome in the predictions of
prognosis, even using the best available models as tools.19–21 In
patients with nonmalignant disease, e.g., COPD or heart failure,
prognoses are even more challenging and in some conditions
survival is worse than in cancer patients.22,23 Physicians are not
only reluctant to make prognostic estimates but also tend to
overestimate life expectancy.19,24 Compared to earlier in the dis-
ease trajectory, physicians can prognosticate slightly more accu-
rately the closer a patient is to death, yet clinicians rarely can say
with certainty whether an individual likely will live another day,
week, or month.25 Imprecision of prognosis also poses challenges
for researchers as healthier patients with specific needs may be
excluded and overestimation of survival time may lead to attri-
tion and dropout if patients become too unwell.
The “surprise question” (Would you be surprised if the patient
would die in the next year?) that is often used in clinical prac-
tice to identify palliative care patients might also be too crude
and its accuracy has been questioned.26 Steinhauser et al. used
an alternative approach choosing clinical criteria associated with
an estimated 50% 1-year survival for patients, e.g., stage IV can-
cer, NYHA stage III or IV congestive heart failure, and COPD
with hypercapnia (pCO2 ≥ 46) and requirement of one emergency
room visit or hospitalization within the previous year.25
Need
In palliative care, support and interventions usually focus on
patients’ needs (and of those important to them, such as caregivers
or families) rather than diagnoses or prognoses alone. Therefore,
many studies test the efficacy of interventions to improve symp-
toms such as pain or breathlessness and define the study population
Textbook of Palliative Medicine and Supportive Care
based on the presence of a specific symptom or symptom cluster.
As many of these symptoms occur across conditions, these stud-
ies often include patients not only with one disease. For example,
a number of studies into relief of breathlessness included patients
with COPD, malignancies, and chronic heart failure.27,28 This again
introduces heterogeneity into the study. This can be overcome
by stratifying the analysis by disease group, but if sub-analysis is
intended, the sample size of the subgroups needs to be high enough
to allow meaningful results and conclusions. However, the dis-
ease heterogeneity may be more representative of the populations
encountered in palliative care improving a study’s external valid-
ity. The increase in the prevalence of comorbidities in our popu-
lations will make pure single disease studies more challenging in
the future. The overall prevalence of the symptom also needs to be
considered as recruitment of patients with a very common symp-
tom such as pain or breathlessness will be much quicker compared
to recruitment of patients with rare symptoms such as itch or diar-
rhea. Differential prevalence, when a symptom is more common in
one condition rather than another, may also need to be considered
carefully, lest subgroups become very unbalanced.
Comorbidities
Increasingly, as populations across the world age, palliative care
patients have multiple comorbid conditions, rather than one
single or predominant diagnosis. These changing patterns and
combinations of multiple diseases have implications, not only for
clinical care but also for research. Just as the primary diseases
and stage of disease need to be carefully described that general-
izability of evidence can be assessed, so too, do the comorbidi-
ties (both the type and the severity of conditions) also need to
be clearly outlined. Ideally, a specific comorbidity index such as
the Charlson comorbidity index (CCI) or Elixhauser comorbid-
ity measure (ECM) is used.29,30 ECM outperformed the CCI in
predicting both short- and long-term mortality in a systematic
review but CCI seems to be more feasible.29,31
This ensures that the study population in palliative care studies
is well characterized, enabling assessment of relevance and gen-
eralizability, and this will become more important over the com-
ing years, given the aging populations of developed countries.
Patients with cognitive impairment
In palliative care patients, high levels of cognitive impairment
are frequently observed, particularly toward the end of life.32,33
Cognitive impairment will comprise the patients’ capacity to con-
sent to participate in research. Level of impairment of capacity
will vary, and it depends on the research question and inclusion
and exclusion criteria whether participants with impaired capac-
ity will be included in or excluded from a study. If it is planned
to include patients with cognitive impairment, risks and benefits
for patients associated with study participation need to be con-
sidered with greater effort to protect participants in high-risk
patients. 34,35 Cognitive impairment may be difficult to identify
in palliative care research because of varying cognitive function
over time. 36 This is particularly important in longitudinal studies
when patients are followed over time. Even if patients have the
capacity to consent at the time of enrollment, they may not retain
that capacity throughout the study. 37 In patients with greater risk
of cognitive impairment, formal assessment of capacity might be
necessary. Specific tools have been developed to aid assessment
and decision about study inclusion. 38,39
During the last weeks and days of life, patients may not have
capacity to give consent to take part in a research study.40 The
The Population: Who are The Subjects in Palliative Medicine Research?
following issues should be considered40: First, research risks and
benefits must be reevaluated in the context of lack of capacity;
how much risk is the individual participant exposed to by partici-
pating, and is the overall likely benefit of the research substan-
tial? Second, the precise role of a proxy, such as a relative, in the
consent process must be considered. Third, incapacity is variable
and not always total: a participant may be able to give consent at
some level, and it is important to include this within the consent
process. Last, alternative consent procedures might be necessary,
especially in the final days of life, such as the advanced consent
suggested by Rees and Hardy.41
Population-based research
So far, we have considered research that recruits participants
(be they patients, caregivers, clinicians, or public) into studies.
However, another way of researching palliative care is to use
existing large datasets to address epidemiological or population-
based research questions.42 Death registration data,43,44 other
national or regional data sources such as health-care utilization
data,45 hospital episode statistics,46 or social care data47 have
been increasingly used over recent years. Increasing numbers of
studies using “big data” have been published in relation to pal-
liative care and death48,49 and will provide further insights into
the future. The advantages of such studies are the extent and
inclusivity of the data available for inclusion, without the need
for collecting primary data and all the resources this requires.
It is also often possible for a complete dataset to be used, i.e.,
the whole population is included, rather than a study sample.
However, secondary use of large datasets also has limitations;
often, for instance, that data is collected for another reason than
research, and does not include the most relevant variables, or
extend as far as a researcher might hope. 50 Large datasets are
perhaps most useful when linked datasets are used, such as com-
bined health-care and social care datasets47 or combined acute
hospital and community health-care datasets.45 Issues that arise
in these studies include information governance (where unique
patient identifiers are needed to link datasets) and the amount of
missing data (some routinely collected data sources are detailed
and complete, but many have large amounts of missing or ques-
tionable data). Some studies conducted in this way may be eco-
logical studies (where the unit of analysis is the population) or
at least use population-level, rather than individual-level, vari-
ables; it is important then that any inferences about the nature of
individuals in this type of study are not assumed to apply at the
individual level.
There is increasing interest in developing national or regional
clinical datasets, which may then not only allow national bench-
marking and quality improvement, but also have the potential to
support clinical research. Examples are the Australian Palliative
Care Outcomes Collaborative, which collects national outcomes
data in palliative care (see http://www.pcoc.org.au/) and uses
standardized validated clinical assessment tools, or the Danish
Palliative Care Database.51 Although the focus to date has been
on improving quality and outcomes, there is considerable poten-
tial for clinical research to be supported too.
Family caregivers
In palliative care, the units of care are patients and their fami-
lies. Although the specific characteristics and needs of family
caregivers are increasingly in the focus of research, less than
10% of studies published in the palliative care literature targeted
73
caregivers/family members as research topics. 52 There are still
huge gaps in the understanding and knowledge of the caring
experience. 53,54 Specific issues are a need for the evolution of
intervention development focused on improving family care-
giver support, attention to marginalized family caregivers, and
strategies to assist health professionals to identify family care-
givers who have significant psychosocial issues. 55 As the role of
informal family caregivers increases, we need larger research
studies with robust designs to reflect—not only the support
needs of the main caregiver—but also better insight into the
role of an extended network of caregivers, including friends,
neighbors, and the wider community. This research should
link with wide community initiatives, such as compassionate
communities. 56,57
Defining the informal caregiver population is a challenge as
every patient might have a number of caregivers which might
not necessarily be related to family structures.54 Also, they
might not identify themselves as caregivers.54 Research in fam-
ily caregivers can be conducted during the patient’s illness and
post-bereavement, after the death of the patient. Special con-
siderations are necessary for each phase for family caregivers’
involvement during research. During the patients’ illness, care-
giver burden is usually high with physical, psychological, social,
and financial consequences.58 For some, involvement in research
might add to the burden, and for others, it might be a relief to
have a voice and be able to share their experiences. When caregiv-
ers are approached via patients, patients often function as gate-
keepers because they do not want to add more burden to their
caregivers. To foster caregivers’ autonomy, they should be given
the choice directly whether they want to participate in research
or not. When caregivers are approached after the death of the
patient, e.g., in a mortality follow-back survey, this can evoke
distressing emotions to some, but some might find it a positive
and useful experience.59 There is debate about the best timing to
approach bereaved caregivers and time frames used vary from 3
to 9 months post-bereavement.60,61
Professional caregivers
A fair amount of palliative care research is conducted in health-
care professionals with about 20% of palliative care studies pub-
lished in 2007 being conducted in this population.52 Health-care
professionals can either provide specific information about the
characteristics and care of their patients62 or can be research
objects themselves with the aim of improving competencies63 or
assessing their views and experiences on a specific topic such as
outcome measurement.64
General public
Although not directly affected by palliative care, the general
public comprises another potential research population as their
opinion influences policy makers and they are potential future
patients and caregivers. Studies can be specifically designed to
approach the general public to study their views such as in a tele-
phone survey where European citizens were asked about their
preferences for end of life care65 or acceptance of euthanasia.66
Essential for the generalizability of these studies is the selection
of a representative sample, e.g., through probability sampling. A
number of methods are available to ensure representativeness,
such as simple random sampling, stratified random sampling, or
cluster sampling.
74 Textbook of Palliative Medicine and Supportive Care

TABLE 10.1  Reporting of Characteristics of Study Participants

Domain Subdomain Measure
Individual participant’s Age Mean (SD), median (range)
demographics (across groups) Gender Percentage
Socioeconomic indices Nationally accepted indices
Educational level
Ethnicity
Patients Diagnoses Cancer: entity, stage; nonmalignant disease: type, stage
Comorbidities Charlson comorbidity index, Elixhauser comorbidity measure
(ECM)
Performance status Australian KPS or ECOG
Symptoms: Physical, psychosocial, spiritual Validated symptom/problem measures, e.g., POS/IPOS, MSAS,
EORTC QLQ C15/30
Validated symptom-specific measures
FICA Spiritual History Tool
Cognitive status Mini-Mental State Examination (MMSE), Montreal Cognitive
Assessment (MoCA), MacArthur Competency Assessment Tool
modified for clinical research (MacCAT-CR)
Setting Home, hospital, hospice, palliative care unit, long-term care home
Days from referral to death Mean (SD), median (range)
Caregivers Caregiver burden Validated measure, e.g., Zarit Burden inventory
Health-care professionals Professional background
Experience in palliative care (years) Mean (SD), median (range)
General public Marital status
Living arrangements
Urbanization levels
Religion/denomination
Financial situation
Source: Adapted from Currow DC et al., J. Pain Symptom Manage 2012;43(5):902.

Criteria for the description of the
palliative care population
In order to understand the population under study and to be
able to judge the generalizability of the results, there is a need
for explicit and clear description of key characteristics of the
study sample. In a study coding characteristics of palliative care
research, the most frequently reported sub-domains were patient
age, gender, diagnosis, and patient performance status.2 Rarely
reported sub-domains included socioeconomic indices, ethnic-
ity, and time from referral to death.2 Overall, there was significant
underreporting even of most basic patient demographic factors.
Given wide local differences in the people referred to, and the
structure of palliative care services, the poor reporting of basic
descriptive factors can be expected to complicate or impede the
application of newly found knowledge in this field.2 Currow et al.
suggest that it is feasible to report standard study descriptors that
can aid with evaluation of generalizability in supportive and pal-
liative care.2 Table 10.1 suggests a number of characteristics of
study participants which should be included when reporting pal-
liative care research.
To understand the sample of a study and put the results in con-
text, reference to the wider population from which the sample
is drawn is necessary. The sample is described as the numera-
tor whereas the population is the denominator.67 Researchers
consistently fail to report information on the population they
recruited their sample from, as demonstrated in a review of
published research literature where articles provided data only
for people participating in the study; no article provided data
for people referred to the service or for the total population of
people with life-limiting illnesses from whom the service popula-
tion was drawn.2 Demographic and clinical characteristics of the
population are both important and necessary, in order to com-
pare the sample with the population, and understand substantial
differences which might constrain generalizability. In qualita-
tive research, the sampling frame (population from which the
qualitative study sample is drawn) is more often considered—in
part because of the different intentions of sampling in qualita-
tive research (to ensure diversity rather than representativeness,
within the sample).
Conclusion
It is in the nature of palliative care for patients to have multiple
symptoms and other problems, with diversity in the severity and
interactions between these problems. Palliative care populations
are therefore inherently heterogeneous. Although it can there-
fore be challenging to define the population for palliative care
research, and some degree of heterogeneity cannot be avoided,
the recommendations discussed earlier, if adopted, would help to
markedly improve many existing or current studies. If data is col-
lected on the nature of the population, subgroup and sensitivity
analysis will be possible to understand and describe the popu-
lation and its potential variability. A balance is needed between
narrower inclusion criteria, targeting more specific populations
when appropriate, and broader inclusion criteria, to achieve suc-
cessful recruitment (and reach the required sample size) and to
maintain generalizability of findings. Careful consideration of
The Population: Who are The Subjects in Palliative Medicine Research? 75

the population to be targeted for any study, use of detailed and 18. Lunney JR, Lynn J, Foley DJ, Lipson S, Guralnik JM. Patterns of func-
well-justified inclusion and exclusion criteria, and thorough tional decline at the end of life. JAMA 2003;289(18):2387–2392.
19. Christakis NA, Lamont EB. Extent and determinants of error in doc-
description of the study population (using criteria such as those tors’ prognoses in terminally ill patients: prospective cohort study.
proposed by Currow), including the denominator population, BMJ 2000;320(7233):469–472.
would all help to raise the standard of the increasing amount of 20. Teno JM, Harrell FE, Jr., Knaus W, et al. Prediction of survival for older
palliative care research being undertaken. hospitalized patients: the HELP survival model. Hospitalized Elderly
Longitudinal Project. J Am Geriatr Soc 2000;48(5 Suppl):S16–S24.
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21. Simmons CPL, McMillan DC, McWilliams K, et al. Prognostic tools
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those near the end of life, and those with limited capacity. There Manage 2017;53(5):962–970 e10.
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Identification of the predictors of cognitive impairment in patients
8. Department of Health. End of Life Care Strategy. London: Department
with cancer in palliative care: a prospective longitudinal analysis.
of Health, 2008.
Support Care Cancer 2017;25(3):941–949.
9. El-Jawahri A, Greer JA, Pirl WF, et al. Effects of early integrated pallia-
34. Casarett DJ. Assessing decision-making capacity in the setting of pal-
tive care on caregivers of patients with lung and gastrointestinal can-
liative care research. J Pain Symptom Manage 2003;25(4):S6–S13.
cer: a randomized clinical trial. Oncologist 2017;22(12):1528–1534.
35. Wohleber AM, McKitrick DS, Davis SE. Designing research with
10. Teunissen SC, Wesker W, Kruitwagen C, de Haes HC, Voest EE, de
hospice and palliative care populations. Am J Hosp Palliat Care
Graeff A. Symptom prevalence in patients with incurable cancer: a sys-
2012;29(5):335–345.
tematic review. J Pain Symptom Manage 2007;34(1):94–104.
36. Bruera E, Franco JJ, Maltoni M, Watanabe S, Suarez-Almazor M.
11. Koffman J, Higginson IJ. Accounts of carers’ satisfaction with health care
Changing pattern of agitated impaired mental status in patients with
at the end of life: a comparison of first generation black Caribbeans and
advanced cancer: association with cognitive monitoring, hydration,
white patients with advanced disease. Palliat Med 2001;15(4):337–345.
and opioid rotation. J Pain Symptom Manage 1995;10(4):287–291.
12. Murtagh FE, Addington-Hall J, Edmonds P, et al. Symptoms in the
37. Casarett D, Ferrell B, Kirschling J, et al. NHPCO task force state-
month before death for stage 5 chronic kidney disease patients man-
ment on the ethics of hospice participation in research. J Palliat Med
aged without dialysis. J Pain Symptom Manage 2010;40(3):342–352.
2001;4(4):441–449.
13. Murtagh FE, Sheerin NS, Addington-Hall J, Higginson IJ. Trajectories
38. Grisso T, Appelbaum PS, Hill-Fotouhi C. The MacCAT-T: a clini-
of illness in stage 5 chronic kidney disease: a longitudinal study of
cal tool to assess patients’ capacities to make treatment decisions.
patient symptoms and concerns in the last year of life. Clin J Am Soc
Psychiatr Serv 1997;48(11):1415–1419.
Nephrol: CJASN 2011;6(7):1580–1590.
39. Folstein MF, Folstein SE, McHugh PR. “Mini-mental state”. A practical
14. Blinderman CD, Homel P, Billings JA, Portenoy RK, Tennstedt SL.
method for grading the cognitive state of patients for the clinician. J
Symptom distress and quality of life in patients with advanced conges-
Psychiatr Res 1975;12(3):189–198.
tive heart failure. J Pain Symptom Manage 2008;35(6):594–603.
40. Karlawish JH. Conducting research that involves subjects at the
15. Habraken JM, van der Wal WM, Ter Riet G, Weersink EJ, Toben F,
end of life who are unable to give consent. J Pain Symptom Manage
Bindels PJ. Health-related quality of life and functional status in end-
2003;25(4):S14–S24.
stage COPD: a longitudinal study. Eur Respir J 2011;37(2):280–288.
41. Rees E, Hardy J. Novel consent process for research in dying patients
16. Habraken JM, ter Riet G, Gore JM, et al. Health-related quality of life
unable to give consent. BMJ 2003;327(7408):198.
in end-stage COPD and lung cancer patients. J Pain Symptom Manage
42. Davies JM, Gao W, Sleeman KE, et al. Using routine data to improve pal-
2009;37(6):973–981.
liative and end of life care. BMJ Support Palliat Care 2016;6(3):257–262.
17. Saini T, Murtagh FE, Dupont PJ, McKinnon PM, Hatfield P, Saunders
43. Cohen J, Bilsen J, Miccinesi G, et al. Using death certificate data to
Y. Comparative pilot study of symptoms and quality of life in can-
study place of death in 9 European countries: opportunities and weak-
cer patients and patients with end stage renal disease. Palliat Med
nesses. BMC Public Health 2007;7:283.
2006;20(6):631–636.
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44. McNamara B, Rosenwax LK, Holman CD. A method for defining and
estimating the palliative care population. J Pain Symptom Manage
2006;32(1):5–12.
45. Dumont S, Jacobs P, Turcotte V, Anderson D, Harel F. The trajectory of
palliative care costs over the last 5 months of life: a Canadian longitu-
dinal study. Palliat Med 2010;24(6):630–640.
46. Quinn MP, Cardwell CR, Rainey A, et al. The impact of admissions for
the management of end-stage renal disease on hospital bed occupancy.
Nephron 2009;113(4):c315–c320.
47. Bardsley M, Georghiou T, Chassin L, Lewis G, Steventon A, Dixon J.
Overlap of hospital use and social care in older people in England. J
Health Serv Res Policy 2012.
48. Janssen DJA, Rechberger S, Wouters EFM, et al. Clustering of
27,525,663 death records from the United States based on health con-
ditions associated with death: an example of big health data explora-
tion. J Clin Med. 2019 Jun 27;8(7):922. doi: 10.3390/jcm8070922.
49. Rajaram A, Morey T, Dosani N, Pou-Prom C, Mamdani M. Palliative
care in the twenty-first century: using advanced analytics to uncloak
insights from big data. J Palliat Med 2019;22(2):124–125.
50. Hunt LJ, Lee SJ, Harrison KL, Smith AK. Secondary analysis of existing
datasets for dementia and palliative care research: high-value applica-
tions and key considerations. J Palliat Med 2018;21(2):130–142.
51. Groenvold M, Adsersen M, Hansen MB. Danish palliative care data-
base. Clin Epidemiol 2016;8:637–643.
52. Wheeler JL, Greene A, Tieman JJ, Abernethy AP, Currow DC. Key
characteristics of palliative care studies reported in the specialized lit-
erature. J Pain Symptom Manage 2012;43(6):987–992.
53. Payne S, Carers ETFoF. White Paper on improving support for family
carers in palliative care: part 2. Eur J Palliat Care 2010;17(5):286–290.
54. Grande G, Stajduhar K, Aoun S, et al. Supporting lay carers in
end of life care: current gaps and future priorities. Palliat Med
2009;23(4):339–344.
55. Hudson PL, Zordan R, Trauer T. Research priorities associated with
family caregivers in palliative care: international perspectives. J Palliat
Med 2011;14(4):397–401.
56. Kellehear A. Compassionate communities: end-of-life care as every-
one’s responsibility. QJM 2013;106(12):1071–1075.
Textbook of Palliative Medicine and Supportive Care
57. Gomez-Batiste X, Mateu S, Serra-Jofre S, et al. Compassionate com-
munities: design and preliminary results of the experience of Vic
(Barcelona, Spain) caring city. Ann Palliat Med 2018;7(Suppl 2):S32–S41.
58. Payne S, Grande G. Towards better support for family carers: a richer
understanding. Palliat Med 2013;27(7):579–580.
59. Koffman J, Higginson IJ, Hall S, Riley J, McCrone P, Gomes B. Bereaved
relatives’ views about participating in cancer research. Palliat Med
2012;26(4):379–783.
60. Addington-Hall J, McPherson C. After-death interviews with sur-
rogates/bereaved family members: some issues of validity. J Pain
Symptom Manage 2001;22(3):784–790.
61. Costantini M, Beccaro M, Merlo F. The last three months of life of
Italian cancer patients. Methods, sample characteristics and response
rate of the Italian Survey of the Dying of Cancer (ISDOC). Palliat Med
2005;19(8):628–638.
62. Meeussen K, Van den Block L, Echteld M, et al. Advance care planning
in Belgium and The Netherlands: a nationwide retrospective study via
sentinel networks of general practitioners. J Pain Symptom Manage
2011;42(4):565–577.
63. Shipman C, Burt J, Ream E, Beynon T, Richardson A, Addington-Hall
J. Improving district nurses’ confidence and knowledge in the princi-
ples and practice of palliative care. J Adv Nurs 2008;63(5):494–505.
64. Bausewein C, Simon ST, Benalia H, et al. Implementing patient
reported outcome measures (PROMs) in palliative care–users’ cry for
help. Health Qual Life Outcomes 2011;9:27.
65. Gomes B, Higginson IJ, Calanzani N, et al. Preferences for place of
death if faced with advanced cancer: a population survey in England,
Flanders, Germany, Italy, the Netherlands, Portugal and Spain. Ann
Oncol 2012;23(8):2006–2015.
66. Cohen J, Marcoux I, Bilsen J, Deboosere P, van der Wal G, Deliens
L. Trends in acceptance of euthanasia among the general pub-
lic in 12 European countries (1981-1999). Eur J Public Health
2006;16(6):663–669.
67. Teno JM, Coppola KM. For every numerator, you need a denomina-
tor: a simple statement but key to measuring the quality of care of the
“dying”. J Pain Symptom Manage 1999;17(2):109–113.
11
STUDY DESIGNS IN PALLIATIVE MEDICINE

Massimo Costantini

… the question being asked determines the appropriate research architecture, strategy, and tactics to be used—not tradition,
authority, experts, paradigms, or schools of thought.
Sackett DL, Wenneberg JE 19971

Contents
Introduction..........................................................................................................................................................................................................................77
Study designs.........................................................................................................................................................................................................................78
Observational studies....................................................................................................................................................................................................78
Experimental and quasi-experimental designs........................................................................................................................................................78
Quasi-experimental designs...................................................................................................................................................................................79
Experimental designs...............................................................................................................................................................................................79
Other study designs.......................................................................................................................................................................................................79
Study aims..............................................................................................................................................................................................................................80
Descriptive studies.........................................................................................................................................................................................................80
Analytical observational studies..................................................................................................................................................................................81
Studies to assess the effectiveness of an intervention.............................................................................................................................................81
Conclusions and future priorities.....................................................................................................................................................................................82
References..............................................................................................................................................................................................................................82

Introduction • To assess the effectiveness of interventions aimed at modify-

The objectives of this chapter are to define and discuss study
designs commonly used for quantitative research in pal-
liative care. Quantitative research uses the epidemiological
approach to define and shape all the aspects of a study, includ-
ing its design. Epidemiology is the study of disease and health
in human populations. 2 In palliative medicine, according to
the World Health Organization definition, we focus on two
populations of interest: patients and their loved ones, usually
relatives or friends, facing the problems associated with life-
threatening illness.
Within these specific areas of interest, the general aims
of epidemiologic research in palliative medicine are the
following:
• To describe needs and problems of people at the end of their
lives and of their families in terms of frequency, risk fac-
tors, and trends.
• To explain the causal relationships between the develop-
ing of one or more health indicators—of structure, pro-
cess, output, or outcome—and one or more study factors
or exposures. The study factors are the potential determi-
nants of the indicator(s) and include characteristics of the
subject, the disease, or the environment. The outcome in
palliative medicine is one or more components of the mul-
tidimensional concept of quality of life or other issues that,
directly or indirectly, can help to better know and improve
the quality of care.
ing the distribution of the problems in the population of
interest by prevention of new occurrences, effective treat-
ment of existing cases, or, in general terms, improving
quality of life of affected persons.
The choice of appropriate study design is probably the most
important factor for the quality of a study. We can define a
study design as the strategy adopted to describe a problem (in
descriptive designs), to test hypotheses and evaluate strengths
of associations (in analytical designs), or to assess the effec-
tiveness of an intervention (in experimental designs). Each
study design has its own methodology and can investigate spe-
cific aims (Table 11.1).
Epidemiologic research makes use of observational, quasi-
experimental, and experimental studies. In observational studies,
there is no artificial/experimental manipulation of the study fac-
tors (also known as independent variables), and their associations
with events/outcomes of interest (i.e., dependent variables) are
described and analyzed as they naturally occur. Whenever there
is an artificial manipulation of an intervention, the study is either
(1) experimental if the study factor is randomly allocated to study
subjects or (2) quasi-experimental if the intervention is allocated
without randomization.2
Any attempt to rank study designs according to their inherent
value makes little sense, since it is the main objective that defines
the most appropriate design for a specific study (Table 11.1).1 This
chapter seeks to help the researcher to identify the most appro-
priate design for answering a specific question.

77
78
TABLE 11.1  Types and General Aims of the Principal Study
Designs
Study Design Methodology General Aim
Cross-sectional Observational Descriptive–analytic
Retrospective cohort study Observational Analytic–descriptive
Prospective cohort study Observational Analytic–descriptive
Case–control Observational Analytic
Quasi-experimental Experimental Analytic
without
randomization
Experimental Experimental with Analytic
randomization
Study designs
In all study designs, the investigator must be concerned with
avoiding any effect or inference tending to produce results that
depart systematically from true values. In other words, one
should avoid any kind of bias (i.e., a systematic error) at any stage
of the research, from the study design, its conduct, the statisti-
cal analysis, and the publication of the results. More than 100
biases have been described.4 A conceptually appealing classifica-
tion identifies two general classes of biases. The first, selection
bias, includes any error that arises in the process of identifying
the study population. The second, information bias, refers to any
systematic error in the measurement of information on exposure
or outcome.
Observational studies
There are three basic observational designs: cross-sectional,
cohort, and case–control studies. The differences between them
are related to the sampling frame and the time frame.
In a cross-sectional study, subjects are selected from the target
population at a particular point in time, regardless of their expo-
sure and disease status, and the associations among independent
and dependent variables are evaluated.2 This type of study can be
conducted at a specific point in time (e.g., prevalence of breath-
lessness at a specific date), at a fixed point during the course of
events (e.g., prevalence of breathlessness at hospice admission), or
in a specific time window (e.g., prevalence of breathlessness dur-
ing the last week of life). As exposure and outcome are assessed
simultaneously, it is difficult to demonstrate a temporal relation-
ship between the two.
In a case–control study, samples of subjects with (cases) and
without (controls) a defined condition are identified and the
groups are compared with respect to prior exposure to one or
more study factors.2 The validity of this design depends on the
ability to draw a valid sample of cases and controls from the
target population. In palliative care, it is difficult to identify the
whole population of palliative patients and appropriately sample
cases and controls (e.g., patients with and without a symptom).
This design is seldom used in palliative care research and will not
be discussed in this chapter. Of note, however, it is possible to
nest a case–control study within a larger and predefined cohort.
In a nested case–control study, cases are retrospectively or pro-
spectively identified as they occur within the cohort. Each case is
time-matched with one or more controls selected from those
who have not developed the problem of interest within the same
cohort. For example, 210 patients with heart failure who received
palliative care (the cases) were sampled from 7496 hospitalized
patients within the Veterans Aging Cohort Study. Cases were
Textbook of Palliative Medicine and Supportive Care
matched by age, discharge date, and left ventricular ejection frac-
tion to 1042 patients with heart failure who did not receive pal-
liative care (the controls).5 Characteristics of the patients and the
disease were identified and the distributions analyzed in cases
and controls. The nested case–control design, as compared to
a cohort design, is advantageous as it requires less subjects to
include in the study with comparable statistical efficiency, when
collection of information for cases and controls is time consum-
ing or expensive.
In a cohort study (also called longitudinal study), samples of
subjects with and without specific characteristics of exposure
are followed forward in time from exposure to outcome, and
the outcome in persons exposed to the study factor (exposed) is
compared with the outcome in persons not exposed to the study
factor (unexposed).2 A cohort study can be done “prospectively,”
where the study population is identified at the time the study
starts and then followed over a certain period to assess the out-
come, or “retrospectively,” where the study population of exposed
and unexposed is identified in the past and the occurrence of the
outcome is evaluated in the period elapsed from the time when
exposure was assessed to the present. The latter is also termed as
historical prospective study.
The choice of a retrospective or prospective design is based
on logistic and scientific considerations. Retrospective studies
require much less time and resources, because all events have
already occurred when the study is initiated. In palliative care,
retrospective cohort studies are difficult to perform because
information on exposure or outcomes is usually not available
retrospectively. The assessment of “hard outcomes,” such as
hospitalizations or place of death, or the availability of histori-
cal databases of routinely collected outcome measures, such as
the Integrated Palliative care Outcome Scale,6 can make this
approach feasible. Conversely, data collected for purposes other
than research may be of questionable accuracy and reliability,7
and information on potential confounders (variables that have a
hidden effect on the outcome variables) are often missing.
A specific design is the after-death approach, where information
is collected after the death of the patient from a proxy that was
close to the patient during the period of observation. The proxy
can be a family member who attended the patient during the last
period of life8 or a professional informed on some dimensions of
end-of-life care received by the patient, for example, the GPs in the
SENTI-MELC surveys.9 This cross-sectional design—similar for
some characteristics to a retrospective cohort design—has been
used in a number of influential studies8–12 to estimate the multi-
dimensional problems experienced by patients during their last
period of life. The strength of this design lies in the possibility to
evaluate a representative sample of patients with advanced and ter-
minal disease, as the sample is built after deaths have occurred.
This approach overcomes many of the problems of the studies per-
formed directly on the patients and allows to generalize the results
to the whole population of terminally ill patients. There are at least
two weaknesses of this type of study. First, the process of defining
the cause of death is often unreliable, especially for elderly and non-
cancer patients, even when death certificates are used.13 Second,
the assessment of the outcomes from bereaved loved ones or from
professionals, several months after patient’s death, may result in a
too much distortion of the results.14
Experimental and quasi-experimental designs
In experimental and quasi-experimental designs, an interven-
tion is deliberately introduced to observe its effects (the artificial/
Study Designs in Palliative Medicine
experimental manipulation of the study factor). The general aim
of these designs is to investigate the efficacy (or the effective-
ness) of the intervention. Random allocation of the intervention
between groups of patients discriminates experimental (with
randomization) from quasi-experimental (without randomiza-
tion) studies.2 All quasi-experimental and experimental studies
are, by definition, prospective.
Quasi-experimental designs
A variety of quasi-experimental designs have been proposed:
some are not very reliable, and others, more sophisticated, allow
in some situation a strong causal inference.15 The validity of the
study design depends on the degree of control that the researcher
has over several elements of the study design such as the assign-
ment of the patients to different treatments, the measurement of
the outcomes, the choice of comparison groups, or the applica-
tion and the scheduling of the treatment.15
The uncontrolled before–after design is characterized by two
measurement points: one before and one after the intervention,
without any external control group. This study design is com-
monly used in health service research, for example, in phase 2
studies for assessing complex intervention.16 This approach
is considered inadequate to evaluate the causal relationship
between the intervention and the outcomes.17
In the classical nonequivalent groups design, the two (or more)
groups are identified from convenience (patients of different ser-
vices, hospitals, health districts) or according to their voluntary
behavior. The researcher can also compare the subjects of the
experimental group with subjects who received a different inter-
vention for the same condition at a different time, generally an
earlier period (the so-called historical controls). In these studies,
the control group is selected to be as similar as possible to the
intervention groups for all characteristics but the intervention.
Matching or stratifying for relevant characteristics or adjusting
for baseline values of the outcomes can increase the compara-
bility between groups, although it is not possible to adjust for
unknown variables that influenced the association between the
intervention and the outcome(s).
These designs can prove severely biased results when the subjects
themselves determine the intervention they receive. People who
choose a new therapy or to be followed by an experimental service
are likely to be different for many characteristics related to the out-
come of interest. Observed differences between the two (or more)
groups may not have resulted from the intervention but it might
have been due to one or more confounding. Designs less amenable
to selection bias are those in which the two groups are selected for
factors not related to their preference for the intervention.
Experimental designs
In experimental studies, the population of units selected for the
study is split into two (or more) groups using randomization. This
procedure ensures that chance alone determines the groups to
which each unit is assigned. Each group is assigned to a different
intervention, and outcomes in the groups are compared to infer
the relative effects of the intervention(s).
Randomization implies that the probability of receiving each of
the possible interventions under study is the same for each unit
being entered into the study. Notably, this probability does not
need to be the same for all interventions being compared, and allo-
cation ratios different from 1:1 can be chosen for various reasons
79
(convenience, costs, organizational problems, etc.), although this
may increase the required sample size. Randomization is a pow-
erful tool that, if appropriately used, protects the study from the
risk of selection bias. Note that randomization does not guarantee
that the two groups are identical, even in large samples. However,
it does guarantee that the distribution of known and unknown
characteristics, in the two groups, is determined by chance alone.
Two experimental designs commonly used in palliative care
research are: the parallel group design and the crossover design. In
the parallel design, patients are randomly allocated to receive the
intervention(s) of interest (the experimental group) and the best
available treatment (the control group). Only if no effective treat-
ment for the condition under study is available should the control
group receive either a placebo or no treatment.18 In a random-
ized crossover trial, patients are randomly allocated to different
sequences of treatments.19 In the simplest design (AB/BA design),
half of the patients are randomly allocated to receive treatment A
followed by B and half to receive the treatment B followed by A.
Other study designs
In randomized cluster trials, the randomization unit is rep-
resented by the clusters (for instance, a GP, a ward, a service, a
health district, each with their own clusters of patients and fami-
lies).20 This means that all the individuals belonging to that group
will receive the same treatment and that different groups, at ran-
dom, will receive different treatments. Cluster trials are a key tool
in the process of evaluation of complex interventions that oper-
ate at a group level and that cannot be delivered to individuals.
Two main types of cluster trial can be identified. In the first type,
the intervention involves the implementation of a program tar-
geted to the health professionals, with the aim of finding a ben-
efit for patients. The randomized cluster trial performed in Italy
for assessing the effectiveness of the Liverpool Care Pathway21
(Figure 11.1) or the ACTION study aimed at assessing the effects
of the Advance Care Program Respecting Choices on the quality
of life of patients with advanced lung or colorectal cancer22 are
two examples. In the second type, the clusters are communities
randomized to receive or not to receive the intervention. These
“large field trials” are characterized by a relatively small number
FIGURE 11.1  The randomized cluster trial assessing the effec-
tiveness of the Liverpool Care Pathway in 16 Italian general medi-
cine wards. (Adapted from Shadish WR, et al. (ed) Experimental
and Quasi-Experimental Designs. Boston, MA: Houghton Mifflin
Company, 2002.)
80 Textbook of Palliative Medicine and Supportive Care

FIGURE 11.2  The classical stepped wedge cluster trial design. (Note: Gray cells are the intervention periods and blank cells are the
control periods. Data on outcomes are collected in all cells from time 1 to time 5.)

of clusters each enrolling many subjects. The study aimed at
assessing the effects of Advance Care Planning on nursing home
staff on 14 nursing homes in Flanders, Belgium is an example.23
In cluster trials, observations on individuals of the same cluster
tend to be correlated, and these studies require more participants
to obtain equivalent statistical power. A specific extension to
cluster randomized trials have been developed for the CONSORT
statements.24
A promising study design is the stepped wedge cluster trial,
where the intervention is implemented sequentially to clusters of
individuals, over several time periods.25 The order in which the
clusters of individuals receive the intervention can be randomized.
At the end of the study, all clusters have received the intervention.
At each time period, outcomes are collected for all clusters, and
a new cluster receives the intervention (Figure 11.2). This study
design is advantageous when there are practical reasons that sup-
port the choice to implement the intervention in stages, avoiding
some clusters not receiving the intervention at the end of the study.
A specific extension to stepped wedge cluster trials have been
developed for the CONSORT statements.26
Most recently in palliative care, the possibilities of performing
randomized fast-track trials have been explored.27,28 In this type
of study, all individuals are offered the intervention, but they are
randomized to either receive it immediately (the fast-track arm)
or to receive the standard intervention (or no intervention) for a
first period of time and then the intervention (the control arm)
(Figure 11.3). The overlapping periods of evaluation of the out-
comes in the two arms allow us to contrast the effectiveness of
the intervention after the first period. At this point, the post-
intervention assessment (in the fast-track arm) is contrasted
against the pre-intervention assessment (in the control arm). The
main analysis is not different from that required for a classical
parallel randomized trial. More complex statistical analyses are
required to use the assessments of the second period for deter-
mining the long-term impact of the intervention and the interac-
tion between time and intervention.27
Study aims
Descriptive studies
Descriptive studies describe “patterns of problem occurrence” in
relation to variables such as person, place, and time. In palliative
care, they have been used to describe the needs and problems
encountered by patients and their families during the advanced
and terminal phase of disease.29
Two basic designs are used: cross-sectional and longitudinal
studies. The first design, regarded as primarily descriptive, pro-
vides a snapshot of the health experience of a population at a
given time. The simplest design is relatively inexpensive and quick
as compared to longitudinal studies. It provides estimates of the
prevalence of all factors measured. Studies estimating unmet
care needs of advanced cancer patients and their informal care-
givers, 30 or the prevalence of severe communication problems
among patients followed by palliative care services31 are classical
cross-sectional descriptive studies.
Longitudinal studies represent the best way to describe the
natural history of a disease, in terms of outcomes relevant for pal-
liative care. The main advantage of a longitudinal design is that
the individual development of the outcomes of interest over time
can be studied. In palliative care, most outcomes should be mea-
sured in the same individual on different occasions and viewed in
a dynamic prospective over time and the statistical analysis of its
results can be very complex. 32
Apart from statistical problems, in longitudinal studies,
researchers are to deal with several methodological issues related
to the validity of the results of their descriptive study. A descriptive

FIGURE 11.3  The fast-track study design assessing the effectiveness of a new palliative care intervention for patients affected by
multiple sclerosis. (Note: Gray cells are the intervention periods and blank cells are the control periods. Data on outcomes are col-
lected at the five points. The effectiveness analysis was performed by comparing the outcomes at T3 (the gray arrow) adjusted for the
baseline [T].) (Adapted from Higginson IJ, et al. Postgrad Med J 2011;87:769.)
Study Designs in Palliative Medicine
study is valid inasmuch as it can describe what it intends to in
the population from which the sample is drawn. Selection and
information bias can compromise the ability of a study to provide
information generalizable to the population of interest.2
Information bias is a particularly sensitive issue in palliative
care, as it is difficult to measure without distortion of the “subjec-
tive point of view” of patients experiencing a progressive func-
tional and cognitive decline. As far as selection bias is concerned,
there is a theoretical and practical difficulty to identify the popu-
lation of terminally ill patients of a specific geographic area.
Analytical observational studies
Analytical studies are epidemiological investigations in which
the association between a dependent variable (the outcome of
interest) and one or more independent variables is evaluated, and
possible cause–effect relationships are assessed. Although some
implicit or explicit type of comparison exists in all study designs,
analytical studies are primarily planned for determining if the
frequency of an outcome is different for people exposed to a study
factor (exposed) or not exposed to the factor (unexposed).
The presence of an association does not imply that the relation-
ship between variables is one of cause and effect. We can speak of
causal association only when an induced change in the quantity
of the study factor results in a corresponding change in the quan-
tity of the outcome. In theory, causality can be demonstrated only
through appropriately designed experiments. Therefore, in obser-
vational studies, assessing whether the observed association (or
the lack of one) represents a cause–effect relationship is a matter
of determining the likelihood that alternative explanations could
account for the observed results. In this process, at least three
explanations should be considered:
• The observed association could be due to the play of chance.
• The association could be the result of a systematic error in the
selection of the study subjects (selection bias) or in the assess-
ment of exposure and/or the outcome (information bias).
• The association could be due to the effect of an extraneous
factor associated with the study factor that independently
affects the risk of outcome (confounding).
A well-designed and conducted longitudinal study allows a valid
inference about risk factors influencing the outcome(s) of interest.
A number of variants of the basic design can be used, sometimes
very difficult to design and analyze.2 The most important weak-
ness remains the unavoidable presence of a systematic distortion
in the estimate of effect resulting from the manner in which sub-
jects are selected for the study population (selection bias).
Studies to assess the effectiveness of an intervention
A fundamental objective of epidemiology, in the area of palliative
medicine, is to produce knowledge that might be or is useful to
prevent and control patients’ and families’ problems during the
terminal phase of disease.
Although the randomized clinical trial represents the gold
standard for the assessment of the effectiveness of an interven-
tion, observational and quasi-experimental designs can provide,
with different degree of feasibility, validity, and generalizability,
useful information for establishing whether (and to what extent)
an intervention is effective both in clinical and in health services
research. The feasibility of a trial depends on its acceptance by all
the subjects involved into the research. 33
Two criteria are used to assess the quality of a trial: internal
and external validity. The internal validity implies an accurate
81
measurement of the effect apart from random errors, but all stud-
ies, including randomized ones, are subject to some type of bias.
The procedure used to allocate subjects to the different treat-
ments is the major source of bias. In all nonrandomized studies,
some selection bias is unavoidable, but in observational studies
and in poorly designed quasi-experimental studies where there is
little or no control on allocation procedures, the risk of selection
bias is very high.
Another major source of bias in palliative care studies derives
from the patients effectively analyzed for the outcome. In ran-
domized clinical trials, the principle of “intention to treat anal-
ysis” is recommended to preserve the internal validity. This
approach should be extended, whenever is possible, to all effec-
tiveness studies. According to the “intention to treat principle,”
all randomized (or registered) patients should be included in
the analyses of results, independent of their effective eligibility,
received treatment, adherence and compliance to the treatments,
and compliance to the assessment procedures. In palliative care
research, the attrition rate is usually high, the contamination of
exposure (especially in health services research) is frequent, and
it is associated with a high baseline symptom burden. 34
External validity refers to the generalizability and applicabil-
ity of study results. In this regard, an important distinction is
that between the efficacy and the effectiveness of an intervention,
because it defines the general aim of the study. 35 Efficacy is the
extent to which a specific intervention produces a beneficial result
under ideal conditions. Effectiveness assesses the same beneficial
effect in the field, estimating if it does what it is intended to do for
a defined population. The studies require different study designs:
explanatory to assess the efficacy and pragmatic to assess the
effectiveness of an intervention (Table 11.2).
Explanatory studies are aimed at providing the proof of prin-
ciple that the intervention works (or does not work) under the
most favorable conditions. On the other hand, pragmatic studies
are interested in assessing the effectiveness of the intervention in
a scenario as similar as possible to everyday practice.
In clinical research, explanatory randomized studies (both the
crossover and the classical parallel design) on selected patients
should be considered as the first option to assess the efficacy of a
new intervention. Problems in recruitment could be overcome by
implementing collaborative networks of high-quality palliative
care units. For these studies, the internal validity is crucial, and
if the planned sample size is not attained, they can be combined
with other studies in a systematic review.
When the clinical question becomes more pragmatic and
refers to the ability of the intervention to work in clinical every-
day practice, the best design is often a quasi-experimental or an
TABLE 11.2  Differences between Explanatory and Pragmatic
Trials
Explanatory Design Pragmatic Design
(The Aim is Efficacy) (The Aim is Effectiveness)
Selected patients Patients as similar as possible to the
common clinical practice
Sophisticated study protocol Very simple study protocol
Intensive follow-up Follow-up as in clinical practice
Multiple and complex end points Simple end point (reflecting the
benefit to the patient)
High-quality centers Generic centers
Minimal sample size Large sample size
82
KEY LEARNING POINTS
• As the design of a study is the strategy of answer-
ing a clinical or epidemiological question, it is the
question that determines the appropriate study
design.
• In studies regarded as primarily descriptive,
selection and information bias (with a differ-
ent degree according to the study design) can
compromise the ability of the study to provide
information generalizable to the population of
interest.
• In analytical observational studies, the archi-
tecture of the study design should allow the
researcher to assess if the observed associations
represent cause–effect relationships or if alterna-
tive explanations could account for the observed
results (chance, bias, and confounding).
• Studies aimed at assessing the efficacy or the
effectiveness of an intervention require different
study designs: explanatory for assessing the effi-
cacy and pragmatic for assessing the effectiveness.
• In clinical research, explanatory randomized
studies should be the first option to assess the
efficacy of a new intervention, followed by more
pragmatic quasi-experimental or observational
designs aimed at assessing the beneficial effect
on the field. For health service research, the ques-
tions are often intrinsically pragmatic.
• Cluster randomized trials or alternative designs,
such as stepped wedge and fast-track trials, have
been shown to be feasible and valid options in
palliative care research. These study designs
should be considered as the first option for the
assessment of the effectiveness of a complex
intervention.
• The perfect study design for answering a specific
question is not always feasible, and often the
choice will be based on a compromise between
feasibility, validity, and generalizability.
observational study. For health services research, the problems
are more complicated. Most of the questions are intrinsically
pragmatic, and pure randomized explanatory trials are very dif-
ficult to conceive. It is difficult to randomize selected series of
patients, avoiding any contamination between the groups. To
assess the effect of a service, several outcomes with their valid,
reliable, and sensitive tools should be available and the best tim-
ing of the assessments should be clearly defined. Moreover, new
activities are difficult to standardize, so that it is often difficult
to be certain that the effect (or the lack of effect) is not due to the
intrinsic quality of that specific team.
Conclusions and future priorities
In this chapter, the various study designs commonly used in pal-
liative care research were reviewed and discussed in terms of
feasibility, validity, and potential biases. Further methodological
research is much needed in palliative care research and particu-
larly in three critical areas:
Textbook of Palliative Medicine and Supportive Care
• The validity of the “after-death designs” and their ability to
produce an accurate portrait of the care provided to dying
patients
• Advantages and disadvantages of quasi-experimental
designs in palliative care research to assess the effec-
tiveness of an intervention and the identification of the
study designs that can provide a high level of internal
validity
• The problems encountered in designing, conducting, and
analyzing randomized cluster trials, stepped wedge trials,
and the fast-track trials and their role in assessing complex
interventions in palliative care
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2. Kleinbaum DG, Kupper LL, Morgenstern H. (eds.) Epidemiologic
Research. New York: Van Nostrand Reinhold, 1982.
3. Sepúlveda C, Marlin A, Yoshida T, Ullrich A. Palliative care: the World
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2002;24(2):91–96.
4. Sackett DL. Bias in analytic research. J Chronic Dis 1979;32:51–63.
5. Feder SL, Tate JP, Akgün KM. The Association between HIV infection
and the use of palliative care in patients hospitalized with heart failure.
Am J Hosp Palliat Care 2019;36(3):228–234.
6. Murtagh FE, Ramsenthaler C, Firth A, et al. A brief, patient- and proxy-
reported outcome measure in advanced illness: validity, reliability and
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Palliat Med 2019;33(8):1045–1057.
7. Johnson JC, Kerse NM, Gottlieb G, et al. Prospective versus retrospec-
tive methods of identifying patients with delirium. J Am Geriatr Soc
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8. Costantini M, Beccaro M, Merlo F. The last 3 months of life of Italian
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9. Penders YW, Onwuteaka-Philipsen B, Moreels S, et al. Differences in
primary palliative care between people with organ failure and people
with cancer: an international mortality follow-back study using quality
indicators. Palliat Med 2018;32(9):1498–1508.
10. First national VOICES survey of bereaved people. London, U.K.: NHS
Medical Directorate/End of Life Care, July 3, 2012. Available from
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survey-of-bereaved-people-key-findings-report-final.pdf (Accessed
April 5, 2013)
11. Cartwright A, Hockley L, Anderson JL. (eds.) Life Before Death.
London, U.K.: Routledge and Kegan Paul, 1973.
12. Teno JM, Clarridge BR, Casey V, et al. Family perspectives on end-of-
life care at the last place of care. JAMA 2004;291:88–93.
13. Gau DW, Diehl AK. Disagreement among general practitioners regard-
ing cause of death. Br Med J 1982;284:239–445.
14. McPherson CJ, Addington-Hall JM. Judging the quality of care at
the end of life: Can proxies provide reliable information? Soc Sci Med
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15. Shadish WR, Cook TD, Campbell DT. (eds.) Experimental and Quasi-
Experimental Designs. Boston, MA: Houghton Mifflin Company,
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16. Sedgwick P. Before and after study designs. BMJ 2014;349:g5074.
17. Simon S, Higginson IJ. Evaluation of hospital palliative care teams:
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18. Meinert CL, Tonascia S. (eds.) Clinical Trials: Design, Conduct, and
Analysis. New York: Oxford University Press, 1986.
19. Senn S. (ed.) Cross-Over Trials in Clinical Research. London, U.K. :John
Wiley & sons, Ltd, 2002.
20. Campbell MJ, Donner A, Elbourne D. Design and analysis of cluster
randomized trials. Stat Med 2001;20:329–496.
21. Costantini M, Ottonelli S, Canavacci L, et al. The effectiveness of the
Liverpool Care Pathway in improving end of life care for dying cancer
patients in hospital. a cluster randomised trial. BMC Health Services
Res 2011;11:13.
Study Designs in Palliative Medicine
22. Gilissen J, Pivodic L, Wendrich-van Dael A, et al. Implementing the
theory-based advance care planning ACP+ programme for nursing
homes: study protocol for a cluster randomised controlled trial and
process evaluation. BMC Palliat Care 2020;19(1):5.
23. Rietjens JAC, Korfage IJ, Dunleavy L, et al. Advance care planning – a
multi-centre cluster randomised clinical trial: the research protocol of
the ACTION study. BMC Cancer 2016;16:264.
24. Campbell MK, Piaggio G, Elbourne DR, Altman DG, CONSORT
Group. Consort 2010 statement: extension to cluster randomised tri-
als. BMJ 2012 Sep 4;345:e5661.
25. Hemming K, Haines TP, Chilton PJ, Girling AJ, Lilford RJ. The stepped
wedge cluster randomised trial: rationale, design, analysis, and report-
ing. BMJ 2015;350:h391.
26. Hemming K, Taljaard M, McKenzie JE, et al. Reporting of stepped
wedge cluster randomised trials: extension of the CONSORT 2010
statement with explanation and elaboration. BMJ 2018;363:k1614.
27. Higginson IJ, Costantini M, Silber E, Burman R, Edmonds P. Evaluation
of a new model of short-term palliative care for people severely affected
with multiple sclerosis: a randomised fast-track trial to test tim-
ing of referral and how long the effect is maintained. Postgrad Med J
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Marie Fallon, Stein Kaasa, Russell K. Portenoy, and David C. Currow
(eds.). Oxford Textbook of Palliative Medicine (5 edn). Oxford: Oxford
University Press, 2015.
30. Wang T, Molassiotis A, Chung BPM, et al. Unmet care needs of
advanced cancer patients and their informal caregivers: a systematic
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care: a comparison of team assessment in three European countries. J
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32. Twisk JWR. (ed.) Applied Longitudinal Data Analysis for Epidemiology.
Cambridge, U.K.: Cambridge University Press, 2003.
33. Cook AM, Finlay IG, Butler-Keating RJ. Recruiting into pallia-
tive care trials: lessons learnt from a feasibility study. Palliat Med
2002;16:163–165.
34. Hui D, Glitza I, Chisholm G, Yennu S, Bruera E. Attrition rates, rea-
sons, and predictive factors in supportive care and palliative oncology
clinical trials. Cancer 2013;119(5):1098–1105.
35. Schwartz D, Lellouch J. Explanatory and pragmatic attitudes in thera-
peutical trials. J Chronic Dis 1967;20:637–648.
12
OUTCOME MEASUREMENT IN PALLIATIVE CARE

Joan M. Teno

Contents
Why measure outcomes?....................................................................................................................................................................................................85
What is quality of care for seriously ill and dying persons?........................................................................................................................................86
What are the sources of information to judge the outcomes of care?.......................................................................................................................86
What tool should be used?.................................................................................................................................................................................................89
Whose outcomes are measured?......................................................................................................................................................................................91
How do you use process and outcome measures in an audit?....................................................................................................................................91
What to do with conflicting outcome measures?..........................................................................................................................................................91
Conclusion.............................................................................................................................................................................................................................92
References..............................................................................................................................................................................................................................92

Why measure outcomes?
The key to achieving excellence in palliative medicine is a pro-
cess of self-reflection that measures the end results of care. To not
know the outcomes of care is simply not an acceptable medical
practice. Without knowledge of the outcomes of care, the qual-
ity of care will not be improved. Excellent quality of care is only
achieved through a process of ongoing research that examines
the outcomes of palliative care programs and medical treatments,
audits that help to shape quality improvement efforts to change
medical practice, and publicly reported quality indicators.
Auditing the quality of care is not just applicable to industrial
nations. Rather, program evaluation is important in developing
nations as well with limited resources.1 While outcome measures
that examine new medications or other treatments are essential
for the development of the evidence base of palliative medicine,
the focus of this chapter will be on the use of measurement in
health services research, quality improvement, and publicly
reported quality indicators.
An outcome measure examines the “end results” of care. The
“end results” are the impact of medical care on the dying person
and/or family. For the seriously ill and aged, it is important to
measure the outcomes of care to acknowledge the important role
of informal caregivers, usually close family members, and medi-
cal care must attend to the needs of both the seriously ill persons
and those of their family. This view is ratified in the World Health
Organization2 definition of palliative medicine as achieving the
best possible quality of life for dying patients and their families.
Outcome measures are the ultimate judge of the quality of care.
Achieving those outcomes is based on ensuring that processes of
care are in place to achieve the desired outcomes. A process mea-
sure examines what health providers “do” for dying persons and
their family. Often, process measures can be a proxy for outcome
measures that can only be examined years later (e.g., the treatment
of hypertension and prevention of strokes). Ultimately, the quality
of care is based on the outcomes of care. However, the focus on
achieving quality of care is to ensure that correct processes of care
are undertaken for the right person at the right time.
A recent international European and African survey of clini-
cians identified reasons why staff wanted to use outcome mea-
sures. For those who used tools, most reported favorable outcome
measurement experiences. For clinical purposes, the main advan-
tage for doctors was assessment/screening and clinical decision-
making for nurses. For research, doctors were most influenced by
a measure’s comparability with national/international literature
followed by its validation in palliative care. For nurses, validation
in palliative care was followed by tool access. 3
The natural reaction of staff to outcome measurement is fear
that the results will be misinterpreted that they are providing
inadequate care. Often, that is hardly the case. Outcome mea-
surement should not be used to “punish” staff. The vast majority
of people come to work every day to do the best possible job within
the constraints of current health-care systems. It is important
that the outcome measurement is not used to blame staff. Rather,
outcomes are the result of complex interactions. It is important
that the people assessing the quality of care approach the exami-
nations of outcomes from this perspective. For example, a local
hospice found that 80% of decedents were dying in the hospital as
opposed to at home. One interpretation of these results is that the
staff is not doing their job in providing adequate supportive care
that allows a person to die at home. In this particular example, a
further exploration of semistructured interviews with the staff
about the barriers to people dying at home revealed that all home
deaths were being treated by the local authorities as potential
homicide. Families had learned to avoid the embarrassment of
having their loved ones’ death be treated as a homicide investi-
gation by insisting that the dying person was transferred to an
acute care hospital. The solution is not blaming the staff but mak-
ing changes to the system of care (e.g., developing an inpatient
hospice unit and working with the police to change how expected
home deaths should be treated) to ensure that dying persons
and their family are receiving medical care consistent with their
needs and expectation. This is an important lesson. Achieving
excellence in end-of-life care requires a critical examination of
the systems and processes of care alongside the outcomes.

85
86
What is quality of care for seriously
ill and dying persons?
Having a serious illness that raises the possibility of mortality is
unique and sentinels time of life, unlike any other time period.
Consider the following two clinical cases and the implications for
measuring the quality of care:
• A 45-year-old man presents with acute anterior wall myo-
cardial infarction. One proposed measure of quality of care
by the Center for Medicaid and Medicare Services, the
branch of the U.S. government that oversees health-care
services, is whether he is discharged with an aspirin.4
• For a person of the same age and gender with stage IV lung
cancer, the development of quality indicators that exam-
ine both the outcomes and process of care is much more
difficult. Not all persons will want active treatment. The
vast majority of 45-year-olds without a contraindication to
aspirin would want to take it given the evidence of its effi-
cacy. Seriously ill persons with lung cancer are faced with
important trade-offs where their preferences are important
for measuring the outcomes of care.4
The importance of patient preferences is reflected in the Institute
of Medicine’s proposed definition of quality of care as “the degree
in which health services for individuals and populations increase
the likelihood of the desired health outcome and are consistent
with current professional knowledge.”5 Over the past century,
the majority of deaths have been from chronic, progressive ill-
nesses, often involving a decision that weighs the quality versus
quantity of life. There is an evolving consensus regarding what
are the key goals and domains to examine the quality of care for
seriously ill and/or dying persons. Table 12.1 outlines a synthesis
of the goals and domains of high-quality palliative care based on
the U.S. National Consensus Project, Canadian Palliative Care
Organization proposed key domains and processes of care, the
National Quality Forum, A National Framework for Palliative
and Hospice Care Quality, 5 and work by Teno et al.6,7 As docu-
mented in Table 12.1, there are four “Cs” of a system perspective
of examining the quality of care. High-quality palliative care is
(1) competent that is safe and right care at the right time and right
locus of care, (2) compassionate, (3) coordinated across health-
care providers and settings of care, and (4) cost-effective.
To date, various sources of evidence have been used to for-
mulate definitions of quality of medical care for the seriously ill
and dying. Professional bodies that rely on expert opinion, such
as the National Hospice and Palliative Care Organization8 or
the Canadian Palliative Care Organization, have proposed key
domains and processes of care that define quality of palliative
and/or hospice care. Newer proposed definitions of the quality
of care have involved the input of consumers.9,10 While there is
agreement on many key domains, dying persons and their fami-
lies provide a unique perspective that should be accounted for in
definitions of quality of care. Based on experts and focus groups
with dying persons and family members, Teno et al. have devel-
oped a model of quality medical care entitled patient-focused,
family-centered medical care (see Table 12.1).9 Under this
model, high-quality medical care is achieved when health-care
providers:
• Provide the desired physical comfort, symptom control,
and emotional, social, and spiritual support
Textbook of Palliative Medicine and Supportive Care
• Promote shared decision-making, including advance care
planning for future periods of impaired decision-making
capacity
• Treat the dying person with dignity and respect
• Attend to the needs of the family for information and skills
in providing care for the dying person
• Support the family at a time prior to and after the patient’s
death
• Listen to and respond promptly to quality concerns regard-
ing the provision of care by that health-care organization
• Advocate for the best possible quality of life and quality of
care for the dying patient
• Coordinate care across health-care providers and settings
of healthcare given the increasing fragmentation of the
healthcare of the dying person
Over the past decade, a consensus has been emerging regarding
what are the key domains to examine both the processes and out-
comes of care. Future research is needed to link both structure
and process measures to the key outcome measures (Table 12.1
proposes key structural and process measures of care that poten-
tially are related to key outcomes). Such research will be criti-
cal as palliative medicine grows as a subspecialty recognized for
scientific evidence base that identifies key processes of care and
treatment that lead to improve outcomes.
What are the sources of information
to judge the outcomes of care?
A key step in measuring the outcomes of care is the decision on
what is the source of information to judge the outcomes of care.
Each source has both advantages and limitations. Often, an audit
will need to draw from multiple sources of information to provide
a more comprehensive view of care of the seriously ill and dying.
The available sources of information on the outcomes of the qual-
ity of care are as follows:
• The medical records either paper or electronic, e.g., one
could examine whether patients in pain receive medica-
tions for pain.
• Administrative data, e.g., site of death based on death cer-
tificate data, billing data regarding medical procedures or
visit, etc.
• Staff reports of the outcomes of care, e.g., pain noted on the
minimum data set (MDS).
• Interviews with dying persons and/or their families con-
ducted prior to and after the patient’s death.
• Independent assessment of the quality of care performed
by experts.
Each source involves trade-offs of strengths, limitations, and
financial costs.
The medical record is a legal record that reflects health-care
providers’ documentation of the patient’s condition and treat-
ment decisions. The absence of documentation of a process of
care in a chart audit of medical records does provide valuable
information, given the legal standard that if it is not documented,
it was not done. However, the medical record does reflect that
bias of a health-care provider. For example, the documentation
that discharge medications were reviewed with the patient and
family may not indicate that the patient and family understood
TABLE 12.1  Components of High-Quality Palliative Care

Outcome Measurement in Palliative Care

1. Competent Care
Domain and Supporting
Evidence from 30 Existing Example of Measure from Family
Goal Guidelines Structure Process Outcome Evaluation of Hospice Care Survey
Plan of care is based Patient- and family-centered Qualified interdisciplinary staff Interdisciplinary assessment and The patient preferences and “At any time while [PATIENT] was
on goals, values, and care (N = 21) (70%)8,19,26–52 with appropriate certification care incorporates the goals and goals of care are honored. The under the care of hospice, did any
needs of the patient Shared decision-making and and excellent knowledge and aligns the values and needs of patient and family felt their hospice team member do
and family advance care planning (N = 24) assessment skills the patient and family concerns and needs are anything with respect to
(80%)2,8,26,28,32,34,35,38,50,53 Clear policy and procedures for Care plan is documented and addressed end-of-life care that was
documentation of goals of care updated Regularly reviewed, shared with inconsistent with [PATIENT’S]
Continuity of care plan with the family and other health- previously stated wishes?”
healthcare transitions care providers
Screening, Physical well-being (N = 30) Policy and procedures are in The patient screened for needs The patient receives their “How much medicine did
assessment, care (100%)2,8,26–53 place for screening of Among those with a concern, an desired level of physical [PATIENT] receive for [HIS/
planning, and Psychological well-being (N = symptoms and needs for in-depth assessment is done comfort and emotional support HER] pain? Would you say less
monitoring of 28) (93%)2,7,19,,21–43,45,46 emotional support, appropriate utilizing standardized The family receives their desired than what was wanted, just the
physical and Social well-being (N = 20) assessment, care planning, and measurement tools emotional support prior to and right amount, or more than [HE/
emotional symptoms (67%)7,19–21,23,26,36,38–41,46 monitoring of treatment plan An individualized plan of care after the death of their loved SHE] wanted?”
are done with the Spirituality and transcendence Qualified interdisciplinary team, Plan is monitored for whether it one “How much emotional support
goal that the patient (N = 21) including physician, nurse, is achieving the patient and The patient is able to connect did the hospice team provide to
receives desired (70%)2,7,19–21,23,25–29,31,34,36–39,46 social worker, pharmacist, and family goals with significant persons and you after [PATIENT’S] death?
amelioration and Grief (N = 19) spiritual counselor that is Relationship and involvement bring closure to their life, if Would you say less than what
emotional support (63%)2,7,19–25,29–34,38,42,46 available 24 hours a day, 7 days fostered with patients’ clergy desired was wanted, the right amount, or
a week. and religious advisors more attention than you
wanted?”
Practical and legal Financial and practical aspects Appropriate staff and referral Screened, assessed, and The patient and family receive “Did staff provide too much, too
aspects of care are of care (N = 16) sources to address the patient provided with appropriate the needed support in the little, or just enough support
addressed (53%)2,7,19,20,22,24,26,30–32,35,37, 41,46 and family concerns. services practical and legal aspects of around practical issues of what
Policy and procedure for the patient’s care. might happen after [PATIENT’S]
screening for these concerns death?”
The family member is Caregiver well-being (N = 16) Staff with appropriate education Family handouts instructing in The family receives the needed “How confident did you feel about
supported in the role (53%)2,19,,22,25–33,35,,40,43,46 in supporting caregiving care support in their caregiving role doing what you needed to do in
as caregiver taking care of [PATIENT]?
Would you say very confident,
fairly confident, or not
confident?”
Care is culturally Care that is patient- and Staff trained in diversity and Sensitive communication that Care is consistent with the “Did any member of the hospice
sensitive to spiritual family-centered culture respects the patient and family patient values and cultural team talk with you about your
beliefs, values, and Translators available 24 hours, 7 values and cultural traditions customs religious or spiritual beliefs?”
customs of the days a week Translator services utilized to “Did you have as much contact
patient and family ensure that language is not a of that kind as you wanted?”
barrier

87
(Continued)
TABLE 12.1  Components of High-Quality Palliative Care (Continued)

88
1. Competent Care
Domain and Supporting
Evidence from 30 Existing Example of Measure from Family
Goal Guidelines Structure Process Outcome Evaluation of Hospice Care Survey
Recognize and Multiple domains that included Staff that are trained to The patient who is actively dying Medical record notes the patient “Did you or your family receive
appropriately shared decision-making, appropriately recognize the is recognized as such. The is actively dying. The family is any information from the
manage the dying symptom management, and patient as dying and educate family is notified and educated notified and receives age- hospice team about what to
patient emotional support the family about what to expect on what to expect. For patient appropriate education on what expect while [PATIENT] was
Provide information Appropriate range of services, on hospital-based palliative to expect while the patient is dying?”
and support to those including the relationship of care service, the patient and dying “Would you have wanted more
who care for that hospital-based palliative care family are informed of the Evidence-based symptom information about what to
dying person service with hospice to ensure option of hospice care amelioration and emotional expect while [PATIENT] was
that the patient and family support provided to the patient dying?”
needs are met while the patient and family
is dying
2. Compassionate
Care
Domain and Evidence for that Example of Measure from
Domain from Existing Family Evaluation of Hospice
Goal Guidelines Structure Process Outcome Care Survey
The dying patient is Personal dignity (N = 17) Appropriately trained staff Assess patient’s notions of self The patient and family are “How often did the hospice team
treated with dignity (57%)2,19,22,25,27,29–33,35,42,44,47 and values treated with dignity and treat [PATIENT] with respect?
and respect Care for the patient in ways that respect Would you say always, usually,

Textbook of Palliative Medicine and Supportive Care

promote and support the sometimes, or never?”
patient’s concept of dignity and
respect
3. Coordinated Care
Care coordination Coordination and continuity of Policy and processes are in place Timely communication of Information continuity among “Was there any problem with
should occur across care (N = 21) to ensure seamless transitions patient goals and plans of care staff such that new caregivers hospice doctors or nurses not
the disease (70%)2,7,19–21,23–25,29–33,36–42,46 in the settings of care when there is transition in are aware of the goals of care, knowing enough about
trajectory, settings of health-care settings plan of care, and what they [PATIENT’S] medical history to
care, and health-care should monitor the patient for. provide the best possible care?”
providers An appropriate member of staff “While under the care of
is seen as in charge of overall hospice, was there always one
care nurse who was identified as
being in charge of [PATIENT’S]
overall care?”
Source: Data from Surgeons ACo, Principles Guiding Care at the End of Life, www.facs.org/fellows_info/statements/; previously published In JAMA6 which was adapted from the National Consensus Project47 and National Quality
Forum, A National Framework and Preferred Practices for Palliative and Hospice Care Quality4 and Teno and colleagues.8
Outcome Measurement in Palliative Care
how properly to take the medications after discharge from the
hospital.
Administrative data may range from information used for
the purpose of billing to death certificate data. Similarly, these
data sources reflect the perspective of the health-care providers.
However, these data are often available at minimal costs and can
provide important overall descriptive information for program
planning. For example, aggregate death certificate data can pro-
vide important information on the site of death that can allow for
examining changes in the location of death with time as well as
differences among subpopulations such as leading cause of death,
age groups, or ethnicity. This information, however, does not
provide definitive information on the quality of care. It is impor-
tant for tracking changes, and information on site of death can
provide both hospice and palliative care programs with impor-
tant information to strategize on where to provide services. For
example, the state of Rhode Island, United States, went from 25th
to 2nd in the nation for nursing homes as the site of death.11 This
in itself may not indicate poor quality of care but provides impor-
tant information for health-care providers regarding the impor-
tance of developing programs in nursing homes on care of the
dying persons.
In the United States, all nursing homes are required to com-
plete the Resident Assessment Instrument for every nursing
home resident at the time of admission, every quarter, and with
significant changes in health status. Although the intent of this
assessment is care planning, it represents an important source
of information to examine some of the key domains. However,
the important limitation similar to the other sources of data is
ascertainment bias (e.g., pain is underreported when compared
to an expert assessor of pain). Given the important role of patient
preferences, surveys of dying persons and/or family provide an
important source of information about the quality of care. There
are important limitations of the typical satisfaction survey item
that asks the respondent to rank a particular aspect of care on a
scale from “excellent” to “poor.” The distribution is often skewed
given the reluctance of respondents to use “fair” or “poor.” In
addition, research has found that a respondent will rate that care
is excellent despite reporting severe pain, reflecting the lowered
expectations that the respondents have for the level of pain con-
trol that can be achieved among the dying. A third limitation is
that the typical rating question does not provide information to
guide improvement. Knowing that 85% of bereaved families rated
TABLE 12.2  Purpose of Outcome Measurements
Purpose of Measure
Research
Main audience Science community
Focus of measurement Knowledge
Confidentiality Very high
Evidence base to justify use Builds off existing evidence to generate
of the measure new knowledge
Importance of psychometric Extremely important to that research effort
properties
Source: Adapted from Solberg et al.11 and modified from Journal of Pain and Symptom Management,48 Teno JM, Byock I, Field MJ. Research agenda for developing measures
to examine quality of care and quality of life of patients diagnosed with life-limiting illness. White paper from the Conference on Excellent Care at the End of Life
through fast-tracking Audit, Standards, and Teamwork (EXCELFAST), September 28–30, 1997, 75–82, Copyright 1999 with permission from The U.S. Cancer Pain
Relief Committee.
89
an aspect of care as “very good” does not provide information
that allows the health-care provider to improve. However, know-
ing that one in four people did not understand how to take their
pain medications provides a target for improvement that has face
validity. Such data can provide information that raises awareness
of the opportunity to improve.
In Europe and Africa, a European Community-funded network,
Preferred Reporting Items for Systematic Reviews and Meta-
Analyses (PRISMA), working with the European Association for
Palliative Care, the African Palliative Care Association, and vari-
ous clinical and academic groups from different countries, has
assessed and recommended ways forward in outcome measure-
ment in research and practice.12,13 Their work found that one of
the major barriers to outcome use is the lack of training for staff
and recommended that online resources should become freely
available.14 The main uses of outcome measures in these contexts
were assessing patients’ symptoms/needs, monitoring changes,
evaluating care, and assessing family needs.15 Further consensus
work involving 32 professionals from 15 countries and 8 different
professional backgrounds identified: (1) the need for standardiza-
tion with improvement of existing patient-reported outcomes
measures (PROMs), for example, with a modular system and an
optional item pool; (2) the aspects of further development with a
multiprofessional approach taking into account cultural sensitiv-
ity especially for translated versions; and (3) the need for guid-
ance, training, and resources.13
What tool should be used?
The key to selecting a measurement tool is to first clearly state the
goals of measurement. Table 12.2 notes that the audience, focus
of measurement, evidence base to justify the use of the measure,
and psychometric properties vary based on the intended use of
an outcome measure. A measure as part of an audit for a quality
improvement–intended audience is the team working on improv-
ing the quality of care, and the focus of measurement is to provide
information that will help select the target for improvement, raise
awareness of the opportunity to improve, and monitor whether
the quality improvement effort is achieving its stated goals. A
measure for public reporting (or accountability) is held to higher
standards given the focus is to provide consumers and payers
with information to select health-care providers.16 It is important
that the chosen measure is under the control of that health-care
Improvement Accountability
Quality improvement team Payers, public
and clinical staff
Understanding care process Comparison
Very high Purpose to compare groups
Important Extremely important in that proposed
domain ought to be under control of
that institution
Important within that setting Valid and responsive across multiple
settings
90
institution and the psychometric properties have been validated
across multiple settings of care. Detailed guidance on tool selec-
tion is included in the PRISMA guidance, which can be freely
downloaded.17
The selection or development of the measurement tool should
receive careful consideration. Too often, researchers and per-
sons conducting an audit ignore the critical steps of ensuring
the reliability and validity of the chosen or developed measures.
Reliability examines the reproducibility of the measure. Two dif-
ferent nurses using the same chart abstraction tool getting dif-
ferent results would indicate a concern with the reliability of the
tool. Achieving reliability is a key step, but not sufficient evidence
of the validity of a measurement tool. A measurement tool is valid
if there is evidence that it measures the constructs that it purports
to measure. Essentially, you are asking, “Is the tool measuring the
‘truth’”? Often, there is no “gold standard” to judge the validity
of the measurement tool. In that situation, the measurement tool
should present evidence of the content or face validity, construct,
and potentially criterion validity if a “gold standard” exists.
The content validity essentially asks whether the measurement
tool is examining the right constructs. To meet the goal of con-
tent validity, there should be evidence that the development of
the measurement tool was based on a systematic review of the
literature and involved experts in the field and that theoretical
model informed the selection of items to include in the outcome
measure. Construct validity tests whether known relationships
hold with the measurement tool. For example, a survey that
examines patient perceptions of the process of care regarding
pain management should have at least a moderate correlation
with the respondents’ overall satisfaction with pain management.
Criterion validity examines whether the measure is associated
with an accepted “gold standard” or predicts future outcomes.
Over the past decade, there have been increasing numbers of
measures to examine key outcome measures for the seriously
ill or dying. Previously, a structured literature review was con-
ducted by the staff at the Center to Improve Care of the Dying
and Center for Gerontology and Healthcare Research18 and
updated by Lorenz et al.19 for the National Institutes of Health
conference on the State of the Science of End-of-Life Care in
December 2004. Each key domain has several potential outcome
measures with the majority of measures having psychometric
properties reported. However, there are still two important areas
for research. First, the responsiveness of measures is often not
documented. Responsiveness examines the degree to which an
intervention or historical event results in change in the outcome
measure. For example, a change in policy regulation that limits
access to opioids would be expected to result in different reports
of bereaved family members regarding unmet needs for pain
medications. Second, many of the instruments have been devel-
oped and validated in a population of English-speaking people
only. Future research needs to examine whether the same con-
structs hold in different cultures and, when appropriate, have the
instrument translated into other languages.
More recently, the European Commission–funded network
PRISMA conducted literature reviews, surveys of clinicians,
and consensus workshops to assess the state of the art of out-
come measures used in research and practice across Europe
and Africa. One of the main challenges found in the PRISMA
project was the large number of tools used only a few times or
by a few people. For example, of the 311 European and African
participants who completed an online survey, 99 tools in clini-
cal care and audit and 94 in research were cited by less than
Textbook of Palliative Medicine and Supportive Care
10 participants.12 Further data revealed that respondents require
the number of potential tools to be rationalized and that brief
tools are favored.12 PRISMA concluded that too often rather than
use or adapt an existing measure, individuals would attempt to
develop their own measure, without validation. However, the
survey also identified that three outcome measures were com-
monly used by over 1 in 4 respondents for clinical practice and
over 1 in 10 for research: the Karnofsky Performance Scale (KPS),
followed by the Edmonton Symptom Assessment Scale (ESAS,
available at www.cancercare.on.ca/common/pages/UserFile.
aspx?fileId=13262) and the Palliative care Outcome Scale (POS,
downloadable free from www.pos-pal.org). Measures were used
twice as often in clinical practice as in research.15 The group rec-
ommended that these should be developed further with core and
then add-on measures. In Africa, the main reason for not using
outcome measures was a lack of guidance/training on using and
analyzing measures, with 49% of 168 respondents saying that they
would use the tools if this was provided. Forty percent of those
using outcome measures in clinical practice used POS, and 80%
used them to assess, evaluate, and monitor change. The POS was
also the main tool used in research, with the principle criteria for
use being validation in Africa, access to the tool, and time needed
to complete it. Challenges to the use of tools were shortage of
time and resources, lack of guidance and training for the pro-
fessionals, poor health status of patients, and complexity of OM
(Outcome Measurement). Researchers also have problems ana-
lyzing outcome measurement data, which needs to be addressed
in the future.20
Another common mistake in measurement is the attempt to
examine every possible outcome. Rigorous data collection on a
small number of items is far superior to any effort that collects a
lot of items in a manner where there are concerns about the accu-
racy of the data collection. This can result in time-consuming
data collection and raises important concerns in terms of respon-
dent burden, especially when one is interviewing seriously ill or
dying persons. Parsimony is important. Winnowing should be
based on the goals of measurement and the realization that exam-
ining multiple outcomes raises the possibility that one outcome
will be statistically significant based on chance alone. While time
is one aspect of individual respondent burden, a second concern
is the number of subjects on which data collection occurs. The
PRISMA network surveys and consensus found that clinicians
and researchers most commonly want brief outcome measures
with 8–10 questions.12 All three most commonly used outcome
measures in the PRISMA survey were 10 items or fewer. In order
to see if the measures could be shortened further, PRISMA sur-
vey respondents were asked to rate the most important questions.
Respondents prioritized brief measures that included physical and
psychological domains.3 The most favored questions were about
pain, symptoms, and emotional and family aspects. There were no
differences in the choice of the most important questions between
doctors and nurses or between researchers and clinicians.15
For the purpose of a quality improvement effort, a small num-
ber of cases collected from a random sample can provide enough
data to guide efforts to select targets for and monitor the rate
of improvement. The sample size for research or accountability
should be based on the effect size that is required to be able to
measure the level of statistical significance and the probability
that you want to be able to find that difference. Statistical soft-
ware packages such as nQuery Advisor 4.0 (Statistical Solutions,
United States) allow for estimation of the sample size with these
three parameters.
Outcome Measurement in Palliative Care
Whose outcomes are measured?
A key specification of any proposed outcome measure is choos-
ing a numerator (e.g., the number of people with a moderate or
excruciating level of pain) and denominator (e.g., all people who
are not comatose). At face value, this can seem quite simplistic.
However, the difficulty is determining who should be counted
among the “dying” or the denominator. This decision has
important implications. Numerous studies have reported the
limitation of physicians in prognostication 21 and that prognostic
guidelines can be overly specific, but not sensitive.22 Thus, care-
ful consideration must be given to the specification of the sam-
ple. For the dying person, the last month of life often involves
transitions in care and flare of symptoms such as pain and dys-
pnea. Often, a dying person is not able to give interviews during
the last month of life. One solution is the mortality follow-back
survey that uses death certificates to determine the denomi-
nator and contact the next of kin. This represents an efficient
data collection strategy with important, acknowledged limita-
tions.23 With this strategy, the denominator is clearly defined.
However, family members more accurately report on factual
information and their interactions with health-care providers.
Those observations are valuable. Families are less accurate in
reports of symptoms and other subjective patient outcomes.24
This limitation needs to be acknowledged, but one should not
ignore the perceptions of bereaved family members. Dame
Cicely Saunders, the founder of the modern hospice movement,
eloquently stated, “How people die remains in the memories of
those who live on.” 25
The Institute of Medicine proposed overall dimensions to
examine the quality of care: safe, effective, timely, patient cen-
tered, efficient, and equitable. To date, safety measures have
focused on the safety concerns in acute care hospital. Careful
thought needs to be given to adaptation of these measures to
hospice and palliative care settings. For example, a safety mea-
sure that identifies medication errors is an important goal.
Considering the example of a nurse who gives the wrong dosage
of medication in an acute care hospital, no one would argue that
this is an important safety concern for which a hospital should
be held accountable. In contrast to the following situation in a
hospice, a family caregiver of a hospice patient asks a neighbor
to watch the patient while he or she does a quick errand. The
neighbor mistakenly gives 10 times the amount of morphine. Is
the hospital responsible for the actions of this next-door neigh-
bor? A second concern with safety measures is at the end of life,
patient preferences and disease trajectory may make some safety
measures not applicable. For example, some medications may
be appropriate for the dying patient, but their side effect profile
raises concern in those persons not close to death. Patients may
not choose certain treatments (e.g., tight control of diabetes)
based on their preferences regarding care at this time of their
life. As palliative medicine becomes part of integrated health-
care system, careful consideration needs to be given to which
safety and other system-wide measures developed in other set-
tings of care are applicable to palliative care.
How do you use process and
outcome measures in an audit?
Health-care providers often may view an audit as being equiva-
lent to trying to speak a foreign language. A metaphor that may
be helpful to think about the components of the key steps of
91
an audit is terms of the routine history and physical exam. As
part of routine history and physical exam (H and P), one asks a
review of systems. A first key step in an audit is to use a mea-
surement tool (e.g., a bereaved family survey) that will exam-
ine a number of domains of quality of care with the goal of
identifying an opportunity to improve or in the metaphor of
the routine H and P a symptom that you need to explore with
further history, physical exam, and potentially laboratory tests
that are needed to arrive at a diagnosis. Similarly, the next step
after identifying an opportunity to improve, based on bereaved
family survey, is to collect more data to understand the key
leverage process of care that would change the quality of care.
Considering pain management in the acute care hospital, big
key processes are as follows: (1) the patients are screened for
pain (e.g., asking the patient to rate the pain on scale of 0–10);
(2) among those screened positive, an in-depth assessment is
done; (3) a care plan is formulated with both nonpharmacologi-
cal and pharmacological treatments; and (4) finally, the effec-
tiveness of that treatment is monitored. An abstraction of the
medical record could examine each of these key processes of
care. Once you arrive at a diagnosis or the key processes of care
to improve, your next step is to come up with a care plan or
potential intervention to change that key process of care that
would alleviate pain. Often, this involves multiple small tests of
interventions that are tested in plan, do, check, and study cycles
that achieve your targeted measure of improvement in the out-
come measure. Once you arrive at a satisfactory treatment plan,
you would monitor the patient condition by screening their con-
dition periodically. Similarly, one monitors the quality measure
as part of your set of measures that you examine on a periodic
basis. Further guidance on this is available in the PRISMA proj-
ect outcome guidance.17
What to do with conflicting
outcome measures?
Often a research effort involves examining multiple sources of
data to evaluate an intervention, such as the palliative care team,
or to conduct an audit of the quality of care that a hospice deliv-
ers. Sometimes the results are in conflict. In my experience,
this is more likely in an audit or quality improvement effort. For
example, an audit of nursing home pain management may use the
MDS (i.e., an assessment form completed by nursing home staff),
chart review (e.g., whether a complete pain assessment was done
on admission to the nursing home), and interviews with cogni-
tively intact nursing home residents regarding their observations
of staff efforts in their pain management. Often, these results
are in apparent conflict. For example, a nursing home could
have a 10% prevalence of moderate pain, with the chart review
indicating that only 30% of residents had a complete pain assess-
ment done on admission and reporting that 45% of the nursing
home residents had to wait too long for pain medications. The
low prevalence of moderate pain seems in conflict with the other
two results. However, this discrepancy is most likely explained by
ascertainment bias, in that staff of the nursing home completes
the MDS pain items and often they underreport the pain. The
other two indicators provide tangible opportunities for improve-
ment. The goal should be that 100% of the people should have a
complete pain assessment on admission with as low as possible
number of nursing home residents reporting they have to wait too
long for pain medication.
92
KEY LEARNING POINTS
• Assessment of processes and outcomes is an
important and essential part of examining the
quality of palliative care in all settings.
• Consumer preferences are an important aspect of
examining the quality of end-of-life care.
• Valid and reliable measures are needed whatever
the purpose. Measures should also be responsive
to change.
• Short and easy-to-use measures are available,
especially the ESAS and the POS. Both measures
are short, well–validated, and used internation-
ally in clinical practice and research.
• Free online guidance is available on how to
select and implement outcome measures
(http://www.csi.kcl.ac.uk/files/Guidance%20
on%20Outcome%20Measurement%20in%20
Palliative%20Care.pdf).
• Strengths and limitations of various sources of
information need to be considered in the selec-
tion of measures and interpretation of results.
• Different purposes of measurement mean that
different measures may need to be used.
• It is unwise and usually impractical to try to mea-
sure everything. Rather, a small amount of qual-
ity information collected on a random sample of
subjects can guide quality improvement efforts.
Clinicians favor outcome measures with 8–10 ques-
tions, and priority questions are concerned with
pain, symptoms, emotional and family aspects.
Conclusion
Knowledge and use of outcome measure is an important tool
for health-care providers with an interest in palliative and hos-
pice medicine. Both process and outcome measures can provide
important information to guide efforts to improve quality of
care. Outcome measures are the key to generating new scientific
knowledge of the efficacy of medical treatments and interven-
tions and to improving clinical care. A key step in the selection of
a measurement tool is to be clear on the goals of measures includ-
ing the proposed definition of the quality of care, the proposed
source of data, and consideration of the bias and perspective of
the source of data. The choice of measurement tools should be
based on knowledge of the reliability and validity of the measure.
The mistake of collecting information about every possible out-
come should be avoided. Rather, a focused data collection effort
on a small number of subjects can provide valuable information
for quality improvement efforts. Guidance is now available to
overcome some of the key barriers to outcome measurement use.
It is recommended to use established validated short tools (which
are freely available on the Internet) rather than invent new tools.
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37. Lynn J. Measuring quality of care at the end of life: A statement of prin-
ciples. J Am Geriatr Soc 1997;45(4):526–527.
38. Focus on ethics. Care of the dying patient—Guidelines for nursing
practice. Nebr Nurse 1995;28(2):34.
39. Ruland CM, Moore SM. Theory construction based on standards
of care: A proposed theory of the peaceful end of life. Nurs Outlook
1998;46(4):169–175.
40. Saunders C. The philosophy of terminal cancer care. Ann Acad Med
Singapore 1987;16(1):151–154.
93
41. Singer PA, MacDonald N. Bioethics for clinicians: 15. Quality end-of-
life care. CMAJ 1998;159(2):159–162.
42. Wanzer SH, Federman DD, Adelstein SJ et al. The physician’s respon-
sibility toward hopelessly ill patients. A second look [see comments]. N
Engl J Med 1989 Mar 30 1989;320(13):844–849.
43. Committee VB, ed. Ethical Issues in Long-Term Care. VA National
Headquarters, Washington, DC: National Center for Clinical Ethics,
1996.
44. Center TH, ed. Guidelines on the Termination of Life-Sustaining
Treatment and the Care of the Dying. Bloomington, IN: Indiana
University Press, 1987.
45. Cassel CK, Foley KM, eds. Principles for Care of Patients at the End of
Life: An Emerging Consensus among the Specialties of Medicine. New
York: Milbank Memorial Fund, 1999.
46. Task Force on Palliative Care. Last acts, A national coalition to improve
care and caring at the end of life. Precepts of Palliative Care. December
1997. Accessed July 1, 2014. http://www.aacn.org/WD/Palliative/
Docs/2001Precep.pdf.
47. Surgeons ACo. Principles Guiding Care at the End of Life. www.facs.
org/fellows_info/statements/, accessed July 1, 2014.
48. Research AfHCPa, ed. Clinical Practice Guidelines for the Management
of Cancer Pain. AHCPR Publication No. 94–0592; 2001.
49. The American Medical Association, Eight “Elements of Quality Care
for Patients in the Last Phase of Life”; subsequently published in the
editorial “Caring to the End: Conscientious End-of-life Care Can
Reduce Concerns about Care of the Terminally Ill,” American Medical
News (December 15, 1997). For more information, see the AMA Web
site: http://www.ama-assn.org. Accessed July 1, 2014.
50. ANA Board of Directors. Position Statement of Registered Nurses
Roles and Responsibilities in Providing Expert Care and Counseling
at the End of Life. June 14, 2010. Accessed July 1,2014. http://www.
nursingworld.org/mainmenucategories/ethicsstandards/ethics-
position-statements/etpain14426.pdf.
51. American Pain Society Taskforce on Pain S, and End of Life Care.
Treatment of Pain at the End of Life: A Position Statement from the
American Pain Society. www.ampainsoc.org/advocacy/treatment.
htm.
52. Palliative care in neurology. The American Academy of Neurology
Ethics and Humanities Subcommittee [see comments]. Neurology
1996;46(3):870–872.
53. Life IOMCoCatEo, ed. Approaching Death: Improving care at the End
of Life. Washington, DC: National Academy Press, 1997.
13
ETHICS IN PALLIATIVE CARE RESEARCH

Jonathan Koffman and Emel Yorganci

Contents
Introduction..........................................................................................................................................................................................................................95
A historical perspective to research ethics.....................................................................................................................................................................95
Research ethics committees...............................................................................................................................................................................................97
Practical approach to research ethics..............................................................................................................................................................................98
The specific ethical challenges in palliative care research...........................................................................................................................................98
Research-related distress and vulnerability of research participants..................................................................................................................98
Research burden: balancing risk against benefit....................................................................................................................................................100
Consent and capacity..................................................................................................................................................................................................100
Confidentiality and anonymity..................................................................................................................................................................................101
Ethical considerations among socially disadvantaged, patient or population groups....................................................................................102
Methodological challenges.........................................................................................................................................................................................103
Conclusion...........................................................................................................................................................................................................................104
References............................................................................................................................................................................................................................104

Introduction psychosocial, and service- and policy-related situations seen in

Palliative care has at its core not only the discipline of rigorous
symptom control but also the need for patient-centered commu-
nication, holistic care of the patient and their family, the consid-
eration of advance care planning, including advance directives,
patient preferences for place of care and death, and respect for
spiritual and religious beliefs of the patient and family.1 Palliative
care as a specialty remains unique in its contribution to patient
and family care. However, the fundamental ethical principles
underpinning the conduct of medical research are identical to
those in primary, secondary, and tertiary care. Where or how the
research takes place should not affect the standards laid down
in national and international guidelines such as the Declaration
of Helsinki and the Belmont Report (as discussed later). However,
the application of these guidelines and their underlying princi-
ples may have implications for types of research carried out in
palliative care. Given that palliative care is relatively still in its
nascency, the research conducted is increasing in volume. This
includes exploration of disease groups and symptoms associated
with advanced disease that are potentially amenable to palliative
care interventions,2–4 the context in which care is provided, 5–7
cost effectiveness of service provision, and provider effects,
including how care is delivered and received by an increasingly
diverse society.8,9 The impact of the proliferation of “evidence-
based guidelines” for managing advanced disease is also an all-
pervading concern.10
One of the most useful issues raised by the “State-of-the-
Science Conference” summary statement in 2004 was the
ethical concerns associated with palliative and end-of-life
research.11 Expansion of research in palliative care requires
more than merely transposing traditional clinical trials, meth-
ods of health services research, or epidemiological methodolo-
gies into the specialty. New methods and research approaches
need to be developed and refined to explore the complex clinical,
palliative care. There has been some discussion of the theo-
retical and practical problems of research in palliative care and
approaches to developing high-quality rigorous research12–14 but
less discussion of the ethical issues raised. Research in palliative
care may raise different ethical questions to other specialties,
including the nature of the study design, issues of consent, the
balance of benefits versus the risks of involvement in research,
what is considered potential harm, and the importance of confi-
dentiality. In this chapter, we apply the historical perspective of
ethics in relation to medical research to palliative care, appraise
the application of international codes that guide ethical frame-
works in palliative-care-related research, describe a practi-
cal approach to research ethics, and discuss important ethical
challenges when undertaking palliative care research. Box 13.1
defines some key terms.
A historical perspective to research ethics
There are historical reasons why the regulation of clinical and
health research involving patients differs from the regulation
of normal clinical practice. The horrific medical experiments
conducted by a number of doctors under the Nazi regime led to
the first internationally agreed guidelines on research involv-
ing people, the Nuremberg Code of 1947.15 This consisted of 10
principles that were finally incorporated into the Declaration of
Helsinki produced by the World Medical Association in 1964, an
international body set up soon after the Second World War to
represent doctors and funded by national medical associations.
The Declaration has been revised eight times since 1964, the last
being on 201316 (see Box 13.2).
The Declaration has been significant in its influence in setting
ethical standards for medical and human research.16, 17 However,
the latest version has not been without its critics. In particular,
disagreement has focused on clauses 29 and 30 (see Box 13.2)

95
96 Textbook of Palliative Medicine and Supportive Care

and concern has been voiced about the potential exploitation of

BOX 13.1  KEY TERMS
• Research is defined as any form of disciplined
enquiry that aims to contribute to a body of
knowledge or theory.
• Research ethics refers to the moral principles
guiding the research, from its inception to
the completion and publication of results and
beyond.
• Human participants (or subjects) are defined as
including living human beings, human beings
who have recently died (cadavers, human
remains, and body parts), embryos and fetuses,
human tissue and body fluids, and human data
and records (such as, but not restricted to, medi-
cal, genetic, financial, personnel, criminal, or
administrative records and test results including
scholastic achievements).
research subjects in developing countries.18 These clauses have also
been criticized for being too crude and obsolete, and that they may
even be damaging to the very research subjects they are intended
to protect by unintentionally limiting research in those countries.19
This has specific implications in palliative care research, and par-
ticularly for research that takes place in developing countries.20 The
reasons for this include increasing evidence that double standards
are frequently adopted in the quality of clinical trials that could
never pass ethical muster in the sponsoring country.21
The current version of the Declaration now includes all forms of
medical research.22,23 It has, for example, changed its designation
from “recommendations for doctors,” to that of “ethical principles
for everybody involved in research.” Medical research, in general,
and palliative care research are frequently an interdisciplinary exer-
cise, and there are times when research is either inadequately con-
ceptualized or not addressed at all in the Declaration of Helsinki.
The focus of the Declaration was originally and still is, the conduct of
human experiments: the frequent use of the term “experimentation”
in the current version of the Declaration is just one manifestation of

BOX 13.2  EXTRACTS FROM THE DECLARATION OF HELSINKI (2013) WITH

PARTICULAR CONSIDERATIONS IN PALLIATIVE RESEARCH (OUR IN ITALICS)16
1. The World Medical Association has developed the Declaration of Helsinki as a statement of ethical principles for medi-
cal research involving human subjects, including research on identifiable human material and data.
2. While the primary purpose of medical research is to generate new knowledge, this goal can never take precedence over
the rights and interests of individual research subjects.
3. It is the duty of physicians who are involved in medical research to protect the life, health, dignity, integrity, right to
self-determination, privacy, and confidentiality of personal information of research subjects. The responsibility for the
protection of research subjects must always rest with the physician or other health-care professionals and never with
the research subjects, even though they have given consent.
4. In medical practice and in medical research, most interventions involve risks and burdens.
5. The design and performance of each research study involving human subjects must be clearly described and justified
in a research protocol.

The protocol should contain a statement of the ethical considerations involved and should indicate how the principles in this
Declaration have been addressed. The protocol should include information regarding funding, sponsors, institutional affiliations,
potential conflicts of interest, and incentives for subjects and information regarding provisions for treating and/or compensating
subjects who are harmed as a consequence of participation in the research study.
In clinical trials, the protocol must also describe appropriate arrangements for post-trial provisions.

1. Participation by individuals capable of giving informed consent as subjects in medical research must be voluntary.
Although it may be appropriate to consult family members or community leaders, no individual capable of giving
informed consent may be enrolled in a research study unless he or she freely agrees.
2. The benefits, risks, burdens, and effectiveness of a new intervention must be tested against those of the best proven
intervention(s), except in the following circumstances:
Where no proven intervention exists, the use of placebo, or no intervention, is acceptable; or
Where for compelling and scientifically sound methodological reasons, the use of any intervention less effective than
the best proven one, the use of placebo, or no intervention is necessary to determine the efficacy or safety of an interven-
tion and the patients who receive any intervention less effective than the best proven one, placebo, or no intervention will
not be subject to additional risks of serious or irreversible harm as a result of not receiving the best proven intervention.
Extreme care must be taken to avoid abuse of this option.
3. In advance of a clinical trial, sponsors, researchers, and host country governments should make provisions for post-
trial access for all participants who still need an intervention identified as beneficial in the trial. This information must
also be disclosed to participants during the informed consent process.
Ethics in Palliative Care Research
this. Doll states that the Declaration only really applies to “research
in which patients are required to take drugs or have invasive proce-
dures” (a relatively small part of palliative research) but that “even
here, however, some of the principles show a lack of understanding
of what their effects would be if rigidly applied.”23
Research ethics committees
The Declaration of Helsinki stipulates that any research involv-
ing any human subjects should be reviewed by a properly
constituted institutional review board (IRB) or research eth-
ics committee (REC). As a result, many countries throughout
the world now have strict regulations governing the forma-
tion and procedure of such bodies. The Netherlands, Belgium,
and the United States have specific legislation in this area.24–27
Until recently, the United Kingdom adhered to a regulatory
system controlled by the government, but not by legislation. 28
Following implementation of the European Union’s Clinical
Trials Directive in 2004, the UK RECs now have a basis in law.
Their accountability is also clearly defined: they are answer-
able to a Health Research Authority with the National Research
Ethics Service (NRES) at its core.
Both RECs and IRBs are responsible for ensuring that they act
independently within their institutions. They must attempt at all
time to be free from bias and undue influence from the institu-
tion in which they are located, from the researchers whose pro-
posals they consider, and from the personal or financial interests
of their members.29,30 This independence is founded on its mem-
bership, on strict rules governing conflict of interests, and on
regular monitoring of and accountability for decisions made. The
membership of an IRB or REC must ensure that it has the range
of expertise and the breadth of experience necessary to provide
competent and rigorous review of the research proposals submit-
ted to it and to do so from a position that is independent of both
the researchers and the institution in which it is located. They
should be multidisciplinary and comprise both men and women,
as well as reflecting other aspects of diversity within society.31
There must also be members who have broad experience of, and
expertise in, the areas of research regularly reviewed and who
have the confidence and esteem of the research community.
This can be problematic with palliative care research given the
limited number of ethics committee members who have experi-
ence conducting research in this area. End-of-life care is typically
characterized by a focus on symptom control with minimum
interference and intervention. A number of IRBs and RECs have
been shown to be reluctant to approve studies in this group of
patients. Specifically, IRBs in the United States have been incon-
sistent in the rates of allowing research involving adults lacking
capacity regardless of the risks and benefits, and in who could act
as a consultee within the studies. 32 However, lack of standard-
ization and subjective nature of IRB and RECs’ decision-making
processes leads to variability in requisites within palliative care
research and across other disciplines, such as mental health and
emergency medicine. It has been suggested that this might be
so because of misconception that research studies may detract
from the ethos of care, that studies are unlikely to be supported
by previous good research in the field, and because of the per-
ceived vulnerability of research participants. A systematic review
exploring the experiences and views of patients and caregivers
about participation in palliative care and end-of-life research
demonstrated the ethical concerns regarding patients’ partici-
pation in research to be generally unjustified. 33 While a minor
97
proportion of patients and carers experienced distress from par-
ticipating in research, for most of the participants, research par-
ticipation was a positive experience. In a recent feasibility trial
that examined care delivered to patients with clinically uncertain
recovery and who were near end of life, no participants reported
any negative impact from partaking in the trial. Moreover, they
were minded to share views with the researchers that support
notions of altruism in their decision to participate. 34 The general
public’s attitudes toward studies involving individuals near end
of life and implications of acting as a consultee on behalf of an
adult who lacks capacity for research participation have also been
shown to be positive. 35,36 Specifically, many people state that they
would like to be considered for research studies, including ran-
domized controlled trials (RCTs) even if they lost mental capac-
ity. 37 While benefits and risks to the patient are considered when
people act as consultees, actual burden to themselves has been
identified at being the least influential factor in informing their
research participation. 35
For all their good, IRBs and RECS are not without their critics.
It has been stated that they are risk-averse38 and that they con-
centrate disproportionately on the information about a study
that will be given to potential participants. 39 This includes the
manner in which consent is recorded (the expectation is usually
a signed consent form for each participant) and the justification
and special procedures required for studies involving children or
mentally incompetent or otherwise vulnerable adults. However,
given the emphasis on the production of information sheets for
clinical trials or other research, there are still some participants
who do not fully understand the information they have been
given as part of the procedure to obtain consent for their par-
ticipation.40,41 Health-care professionals who have worked with
adults with impaired capacity have highlighted the importance
of easy-to-read participant information sheets and avoidance
of unnecessary formal mental capacity assessments.42 As with
research involving children or other “vulnerable” patients,43,44
the closer scrutiny of research involving patients with advanced
disease may necessitate that palliative care researchers need to
invest more time, effort, and creativity in developing consent
procedures to obtain approval for their studies to take place.45
This may bring benefits in the protection of patients, but it may
also result in fewer evaluated interventions and services for
these groups. In recent years, studies exploring the provision
of information in different formats, methods for enhancing
understanding, and maximizing the autonomy in palliative care
research have increased. Evidence suggests providing informa-
tion in various formats, such as written and oral to be an effec-
tive way of enhancing understanding about study participation
(REF). Patients and carers prefer receiving succinct and only
the relevant information during their decision-making pro-
cess and receiving any extra information later. A multicenter
study exploring the views of participants regarding the type and
extent of the information presented prior to biomedical research
participation suggested a participant-oriented approach that
focuses on the elements participants are most interested in and
avoids unnecessarily lengthy information sheets with unwanted
details.46 However, regulatory bodies such as The European
Union General Data Protection Regulation (GDPR) (REF) is now
demanding presentation of lengthy and detailed information to
the patients and carers. This may make it difficult to implement
evidence-based practices for informing potential participants.
Frameworks governing research must be refined to enhance
ethical conduct of palliative care research.47
98 Textbook of Palliative Medicine and Supportive Care

Practical approach to research ethics
Three broad areas of ethical concern outlined by Foster (2001)
have been identified in relation to research:
1. Duty of care to research participants
2. Respect for the rights and autonomy of research participants
3. The scientific validity of the research (without which no
research can be ethically justified)
These areas approximate to different moral and philosophical
traditions. “Duty of care” derives from duty-based deontologi-
cal thinking, which acknowledges that there are rules of conduct
which ought to be followed, not because of the ends that are likely
to be achieved, but by the nature of those involved and their inher-
ent responsibilities. “Respect for rights” derives from rights-based
deontological traditions, which recognize the right of each person
to self-determination and autonomy. Emphasis on the scientific
validity of research draws on “goal-based” moral theory (conse-
quentialism) which judges the moral worth according to predicted
or actual outcomes. These different but complementary philo-
sophical approaches have been used by Claire Foster to derive a
framework for the consideration of research ethics,38 and this can
be a useful way to review any specific research project. Dilemmas
or tensions usually occur because of conflict between these dif-
ferent moral approaches; in palliative research, it is particularly
important to recognize the reasons why conflict arises, the moral
arguments in support of each approach, and then aim to achieve an
acceptable balance between these different ethical demands.
These three broad areas of ethical concern can more simply
be viewed as based on key ethical principles39,40 and each prin-
ciple should be applied in the context of any one research study
(Table 13.1). However, ethical considerations should be wider
than just the single research study or group of studies. Allocation
of research resources, cost-effectiveness (of both research and
the interventions evaluated), population benefit (and harm),
and overall public health must all be considered, and here the
concepts of justice and equity become important. The experi-
ence of individual research participants and the conduct of the
researcher themselves are also important considerations, which
introduce concepts of fidelity, trust, and truthfulness.
The specific ethical challenges
in palliative care research
There has been extensive debate about whether research in pal-
liative care raises ethical challenges unique to the specialty.30, 41
Ethical challenges in palliative research include research-related
distress and the perceived vulnerability of participants; research
burden for ill patients; consent and capacity issues; ensuring confi-
dentiality and anonymity; and methodological challenge of produc-
ing high-quality research, including the contribution of the RCT.
Research-related distress and vulnerability
of research participants
In Foster’s ethical framework, 38 it is duty of care which requires
that distress and vulnerability are given careful ethical consid-
eration. It is often perceived that interviews, surveys, or ques-
tionnaires about end-of-life care may be distressing to those
interviewed, whether patients or their unpaid informal caregiv-
ers. Indeed, patients with advanced disease often experience
many distressing symptoms and are frequently fatigued, frail,
depressed, and heavily dependent on others.42–45 Questions,
therefore, need to be raised as to whether it is ethical to engage
these patients in research at a time when they may wish to make
use of their remaining time with their family and friends. Given
that many of these patients will not stand to benefit directly
from the research they are involved in, it could be argued that it
is unreasonable and unethical for them to offer their remaining
time.48 This concern is amplified when considering that patients
with advanced disease, who may be experiencing many distress-
ing symptoms and are functionally compromised, represent a
captive audience who can be exploited.49 Some have therefore
argued that research involving dying patients as a result of their
vulnerability is ethically unacceptable.48
Few would currently accept that position, and a contrary argu-
ment, that it is unethical not to undertake palliative research
because this diminishes the ability to provide patients with a high

TABLE 13.1  Ethical Principles Guiding Medical Research

Ethical Principles Derived from Refs [39, 40]
Respect for autonomy: This implies self-rule but is probably better described as
deliberated self-rule, a special attribute of all moral agents. If we have autonomy,
we can make our own decisions based on deliberation. In healthcare, respecting
people’s autonomy has many prima facie implications. It requires consulting people
and obtaining their agreement before we do things to them
Beneficence: Whenever health-care professionals try to help others, they inevitably
risk harming them. Those who are committed to helping others must, therefore,
consider the principles of beneficence and aim at producing net benefit over harm.
Nonmaleficence: An obligation not to inflict harm intentionally that is distinct from
that of beneficence—an obligation to help others. In the codes of medical practice,
the principle of nonmaleficence (primum non nocere) has been a fundamental tenet
Justice: This is often regarded as being synonymous with fairness and can be
summarized as a moral obligation to act based on fair adjudication between
competing claims.
Scope: There may be an agreement about substantive moral commitments and
prima facie moral obligations of respect for autonomy, beneficence,
nonmaleficence, and justice. Yet there still may be a disagreement about their scope
of application, that is, about to whom we owe these moral obligations
Ethical Principles Derived from Ref [41]
Respect for persons: Incorporates at least two ethical
convictions: first, those individuals should be treated as
autonomous agents; second, persons with diminished
autonomy are entitled to protection
Beneficence: Persons are treated in an ethical manner not only
by respecting their decisions and protecting them from harm,
but also by making efforts to secure their well-being. Such
treatment falls under the principle of beneficence
Justice: Who ought to receive the benefits of research and bear
its burdens? This is a question of justice, in the sense of
“fairness in distribution” or “what is deserved.” An injustice
occurs when some benefit to which a person is entitled is
denied without good reason or when some burden is imposed
unduly. Another way of conceiving the principle of justice is
that equals ought to be treated equally
Ethics in Palliative Care Research
standard of evidence-based care, is much more widely accepted.
There is no doubt, however, that it is sensible to pay additional
attention to the rights of palliative patients who take part in
research, and the ways in which those rights will be protected,
in the same way, that other vulnerable groups such as the elderly
or cognitively impaired are considered. This approach has been
adopted in a number of countries, with, for example, the Office
of Human Research Protections in the United States classifying
terminally ill patients as a “special class” for research purposes.49
Incorporating the “user voice” is another way to endeavor to pro-
tect the rights of vulnerable research participants and ensure that
the patient perspective influences research goals.50
Although some research bodies50 have highlighted that special
care should be taken where research participants are considered
vulnerable, there is confusion about what this term implies and
how it should be applied to research in general and palliative care
in particular. Definitions of “vulnerable populations” vary, and
they are usually identified as those with limited cognitive abilities
or diminished autonomy.51–53 Vulnerable populations, however,
may possess autonomy but lack the capacity to communicate
opinions regarding participation in research. Moreover, this
definition does not adequately engage with the context (social as
well as medical) of research participants, which may create situa-
tions of vulnerability. Kipnis presents a more helpful definition of
vulnerability as being a condition “intrinsic” or “situational” that
puts some individuals at greater risk of being used in research in
ethically inappropriate ways.54 Within these two domains, Kipnis
developed six caution areas intended to identify those consid-
ered vulnerable and advice on how researchers should manage
them in research studies. The emphasis of this taxonomy is on
conducting clinical trials. While each vulnerability category
acts as a signal for researchers to initiate study safeguards, the
taxonomy also serves as a checklist of criteria to potentially pre-
vent the inclusion of these groups. This supports the principle
of fairness, highlighted by the Belmont Report55 to exercise care
among those who, historically, were selected inappropriately for
research. However, there are also concerns about the unfair dis-
tribution of benefits of research. Protections that surround vul-
nerable populations may have unintended consequences. First,
the principle of justice, often regarded as being synonymous with
fairness, is compromised as they are denied the opportunity to
contribute to the research process.56 Second, being excluded from
research potentially deprives them of the benefits and outcomes
of being studied.57 Therefore, medical advances may not be rele-
vant to their needs or situation. These polarized positions should
represent a concern for researchers and members of RECs since
it is not always apparent what to do when confronted with those
considered vulnerable or those who are not.
This delineation is important but fails to sufficiently protect
those not considered to explicitly inhabit these groups. Recent
research identifies tensions in this current understanding of vul-
nerability, which warrants further consideration.58 First, inter-
pretations of vulnerability need to take into consideration the
relative importance of participants’ individual and situational
characteristics that can include the following: (1) communicative
vulnerability, (2) institutional vulnerability, (3) deferential vul-
nerability, (4) medical vulnerability, and (5) social vulnerability.
These are not exclusive categories, and importantly, researchers
and IRBs and RECs should be aware that it is possible to populate
more than one. Second, as with current debates about capacity59
outlined in the 2005 UK Mental Capacity Act,60 it is possible that
vulnerability need not be viewed as a “once-and-for-all” label;
99
participants can be vulnerable in certain circumstances and not
in others. Third, the timing and location of research (institution
or home) and, very importantly, the individual personality of
participants may govern reactions or responses to the research,
which may move them into areas associated with vulnerability.
All these circumstances may create situations of caution where
research should be viewed more flexibly and sensitively.
Most agree that it is unethical “not” to undertake palliative
research, because the absence of research means patients cannot
be provided with a high standard of evidence-based care. While
the aim is to protect vulnerable patients, excluding the adults
who lack capacity from trials leads to the under-representation
of this population, hence affecting the feasibility and replicabil-
ity of “evidence-based” interventions in clinical practice.61 There
is no doubt, however, that it is sensible to pay additional atten-
tion to the rights of palliative patients who take part in research
and the ways in which those rights will be protected, in the same
way that other vulnerable groups such as the elderly or cogni-
tively impaired are considered. This approach has been adopted
in a number of countries, with, for example, the Office of Human
Research Protections in the United States classifying terminally
ill patients as a “special class” for research purposes.62,63
Incorporating the “user voice” is another way to protect the
rights of vulnerable research participants and ensure that the
patient perspective influences research goals.64 Over the years,
the funding bodies,65 RECs, and researchers have started to
increasingly recognize the importance of involving patients and
carers at all stages of the research studies. A systematic review
and a meta-analysis66 exploring the impact of patient and public
involvement (PPI) on recruitment and retention in clinical trials,
concluded that PPI is likely to improve enrollment to clinical tri-
als, especially if the research is informed by individuals who have
lived experiences of the health condition being studied. Due to
uncertain nature and complex trajectories of health conditions
of patients with palliative care needs and their carers, involving
them at all stages of research could be more challenging com-
pared to other areas of health research due to practical issues.
However, with innovative techniques, such as creating an online
PPI forum for palliative care research,67 issues could be mini-
mized, while providing equitable opportunities to individuals to
make meaningful contributions to research.
In research studies, participants should agree to take part in
the study voluntarily, while knowing that they can decide to stop
whenever they want, without providing any reasons. However,
patients and family members may feel obliged to agree to par-
ticipate in research studies if they are approached by their pri-
mary health-care provider/clinician. In addition, patients and
carers may believe that their research participation decision will
have an impact on any current or future treatment and care they
receive. Second, some patients may be experiencing severe pain
and rely on health-care professionals to administer pain relief in
addition to tending to very intimate care needs. It has therefore
been suggested that this entirely appropriate reliance on health-
care professionals means that it is unethical to ask patients to
participate in research as they may well feel coerced into doing
so, or maybe unwilling to give an honest appraisal of the care
they have received.68 Other evidence does not support this; on
the contrary many patients and their informal caregivers are very
willing to participate in research. 52–54 A simple solution, which is
nowadays accepted as good practice is for patients and families
to be approached for research participation by either an inde-
pendent clinician or a researcher. By reinforcing their rights and
100
shifting the approach and recruitment process to individuals who
are not directly responsible for their care, this potential coercion
could be reduced. The reasons that may account for this include
altruism, defined as a desire to increase a third party’s welfare.69
Other important interrelated factors may involve gaining a sense
of purpose from participation, and finding the overall experience
of being involved in research cathartic and helpful.70–72
Although mortality follow-back research has been shown to
carry a small risk of distress, this has been shown to be much
less than expected, and this distress was often outweighed by
the benefits of open discussion.58 Seamark et al. have also dem-
onstrated low levels of distress in postbereavement interviews. 59
While participants, such as bereaved relatives of cancer patients
experience distress when taking part in research studies, they
view their overall involvement as a positive experience, highlight-
ing altruistic and therapeutic benefits.73
Overall, the current literature highlights reasons for why
excluding the palliative patient population would be unethical,
including honoring individuals’ autonomy,68,74 while overwhelm-
ingly providing support of including palliative care patients and
families in research studies.75,76 Related to the framework pro-
posed by Claire Foster, 38 not offering an opportunity to this pop-
ulation to have their input in evidence base negates their right to
make their own decisions, and limit the benefits they may experi-
ence from merely participating in a research study.77
Research burden: balancing risk against benefit
The risks and benefits of research in palliative care are often hard
to assess comprehensively because of the limited preexisting evi-
dence. The frequent heterogeneity of study populations also makes
weighing up risk and benefit difficult. In general, palliative research
participants are likely to be at greater overall risk because of their
advanced disease and the nature of end-of-life care.
As previously mentioned, IRBs and RECs have tended to be
reluctant to permit palliative patients to be burdened, and profes-
sionals may “gate-keep” to protect patients from research because
of perceptions about their frailty and distress, which concur with
the perception of this research group as vulnerable, as discussed
above. Additionally, even when studies are approved, extensive
gate-keeping by health professionals and relatives for individuals
who lack capacity may create future barriers to recruitment.78,79
Gate-keeping could be minimized by involving the health-care
professionals, providing service to users in all stages of research,
having appropriate inclusion criteria and consent processes in
place, not directly involving health-care professionals in par-
ticipant recruitment process, and considering other research
responsibilities of the health-care professionals.80
Consent and capacity
Informed consent and the patients’ capacity to consent are prereq-
uisites if any research in palliative care is going to be conducted.
In order for consent to be valid, it must be informed, voluntary,
and given by research participants with full decision-making
capacity. Until recently, however, there has been little consider-
ation or practical advice for palliative care research regarding the
methodological challenges of informed consent.81 However, the
process of consent deserves additional consideration in pallia-
tive care research due to the perceived vulnerability of a popu-
lation often seriously ill. Palliative care patients may have high
levels of cognitive impairment and hence potentially impaired
capacity,82 creating ethical challenges regarding their inclusion.
Previously, there has been little consideration or practical advice
Textbook of Palliative Medicine and Supportive Care
for palliative care research regarding the methodological chal-
lenges of informed consent;81 however, an increased interest in
more inclusive research to improve the acquisition of knowledge
in palliative care is emerging.83 With the introduction of the
Mental Capacity Act (MCA) 2005 in England and Wales, some
clarification is given in terms of research guidance.
In order for consent to be valid, it must be informed, voluntary,
and given by a research participant with full decision-making
capacity. Research consent procedures need to be planned care-
fully, with detailed consideration of the expected prevalence
of impaired capacity, and how capacity should be assessed. An
important question is how extensive and detailed assessment
of decision-making capacity should be. This depends to a large
extent on the level of impairment of capacity expected within a
study population, whether participants with impaired capacity
will be included in or excluded from the research, and the risks
and benefits associated with the research—higher risk demand-
ing correspondingly greater effort to protect the rights of par-
ticipants.81 Palliative patients often have high levels of cognitive
impairment and hence potentially impaired capacity,63 so exclu-
sion from research is self-defeating. If a formal assessment of
capacity is required (only likely in those studies associated with
greater risk), then a number of tools have been developed or mod-
ified84 to guide the decision-making process about which patients
may be eligible for inclusion in a study. However, at the time of
writing, the lack of a gold standard for capacity assessment tools
have been highlighted by three systematic reviews.75,76,85 Health-
care professionals regarded the existing tools as time-consuming,
and administration of a formal capacity assessment was shown to
reduce recruitment.86 Furthermore, if the tools were not aligned
to the decisional requirements for each study’s nature, taking into
account the risks and potential direct or indirect benefit of par-
ticipation, they were deemed to add little value.
When a research subject does not have the capacity, as is com-
mon in the last days or weeks of life, then several considerations
are important.68 First, ethical consideration of the research risks
and benefits must be reevaluated in the context of lack of capac-
ity; how much risk is the individual participant exposed to by
participating, and is the overall likely benefit of the research sub-
stantial? Second, the precise role of a proxy, such as a relative, in
the consent process must be considered. Third, incapacity is vari-
able and not always total: a participant may be able to give con-
sent at some level, and it is important to include this within the
consent process. Last, alternative consent procedures might be
necessary, especially in the final days of life, such as the advanced
consent suggested by Rees and Hardy.45
The England and Wales MCA 2005 set out that participants
who lack capacity must meet one of the following two require-
ments: the research has some chance of benefiting the person and
the benefit must be in proportion to any burden caused by taking
part; or the research would provide knowledge about the cause,
treatment, or care of people with the same or similar impairing
conditions.87 The concepts outlined in the MCA were designed to
inform the development of the best practice in the assessment of
capacity and processes of consent, opening up the spectrum of
research to include populations such as those receiving palliative
care. An important question is how extensive and detailed assess-
ment of decision-making capacity should be, which depends to a
large extent on the level of capacity expected within a study pop-
ulation and the necessity to include participants who have limited
mental capacity in the research. Literature informed from the
discipline of psychiatry has highlighted the importance of both
Ethics in Palliative Care Research
formal84 and informal88 methods of capacity assessment and the
impact these methodologies can have on research findings.89
The literature of research including people with varying
degrees of capacity to make research participation decisions is
rapidly growing. Obstacles faced around potential participants’
capacity to consent have been observed and, in many instances,
successfully resolved in other health research areas such as
emergency medicine and mental health. Areas of contention
still arise, however, and several considerations are important.90
First, ethical consideration of the research risks and benefits
must be reevaluated in the context of lacking or limited capac-
ity; how much risk is the individual participant exposed to by
participating, and is the overall likely benefit of the research
substantial? Second, the precise role of a proxy, such as a rela-
tive, in the consent process and whether, in heightened emo-
tional states, they have full decision-making capacity themselves
must be considered. Third, incapacity is variable and not always
total: a participant may be able to give consent at some level, and
it is important to include this in the consent process. Fourth,
how to ethically tackle an individual’s right to withdraw if he
or she loses capacity during the course of the research.45 Based
on these considerations and a review of literature, the consent
processes that are recommended for palliative and end-of-life
care studies are shown in Table 13.2. Clinical trials which do
not involve investigational medicinal products (non-CTIMPs)
are common in palliative care, and toolkits for supporting the
consenting processes have been developed especially for trials
whose potential participants are anticipated to have varying
degrees of capacity to consent.
FIGURE 13.1  Process of seeking consent toolkit.
101
In order to overcome ethical issues faced in palliative and
end-of-life care research, Gysels and colleagues conducted a con-
sultation workshop using the MORECare Transparent Expert
Consultation approach.47 Experts in ethical issues and stakehold-
ers in palliative care research were invited for devising recom-
mendations (See Table 13.3).
Confidentiality and anonymity
Most clinical or health research involves collecting patient
data that should always be kept confidential and anonymous.
Palliative care research is no exception. A researcher could be
found negligent if reasonable precautions were not taken to
ensure that all information gained during a study was not stored
in a secure manner or that the identity of a research subject is
compromised. Further, information resulting from a part of a
study should only be shared with a third party unless there is
explicit consent of the research subject. This requirement is
underpinned by the ethical principle of autonomy. In quanti-
tative studies, these obligations are more straightforward, with
the use of unique identifying codes in place of names. In quali-
tative research, however, the data collection process requires
more prolonged face-to-face contact and makes researcher–par-
ticipant anonymity more challenging. Pseudonyms can be used
in place of actual names in written reports and publications.
Participant confidentiality can be further protected through
the omission of identifying key contextual details and circum-
stances. However, the reality of small sample sizes and the
detailed descriptions which accompany this information may be
recognizable to some readers familiar with the setting. With the
102
TABLE 13.2  Recommended Consent Processes for Patients Who might be Approached for Palliative or End of Life Care
Research Studies
The Trajectory of Mental Capacity for Making an Informed
Research Participation Decision
Adults with capacity (e.g. adults with cancer)
The individual is deemed to have capacity to make an informed and
voluntary decision regarding research study participation
Adults with capacity who might require enhancement with
different domains of informed decision-making (e.g. adults with
moderate dementia)
The individual might not have the full capacity to make an informed
consent at the moment of approach; however, a cognitive domain
(understanding, retaining, weighing up, and communicating
decision) could be enhanced to enable them for meeting the legal
requirement for having capacity to provide informed consent
Adults with capacity who are anticipated to lose capacity during
research participation (e.g., inpatients with an uncertain illness
trajectory/prognosis)
The individual has the capacity to (i) provide informed consent at
the moment of approach for study participation, and (ii) provide
what they would wish to happen if they lose capacity in advance
Adults with fluctuating capacity (e.g., adults with delirium)
The individual has the capacity to provide informed consent at the
first encounter, however, due to their condition, they might not
possess the capacity for voluntary participation at the consecutive
time points throughout the research study
Adults who lack capacity (e.g., adults with advanced dementia)
Individuals from the population of interest are unable to provide
informed consent
Adults who are likely to regain capacity following enrollment to
the research study (e.g., adults with an infection)
Individuals from the population of interest must be entered to the
study when they are lacking capacity (e.g., a medicinal intervention
study with individuals who had an unplanned admission to the
emergency department). However, the individual is expected to
recover from their condition and gain the capacity to provide
informed consent after the enrollment to the research study
a According to the Mental Capacity Act 2005,60 individuals can provide “consent” for themselves and a consultee can advise on whether the person would have liked to partici-
pate in the research study.
b The term “consultee” is used (in line with the Mental Capacity Act 2005) to encompass terms used in various countries including “proxy” and “surrogate.”
increased use of large-scale, population-based databases for pal-
liative care research, ethical considerations for confidentiality
and anonymity of patients’ information should be revised.97 To
ensure patients’ protection, RECs should enhance their under-
standing of technical details, confidentiality, and anonymity
requirements necessary for big-data research studies.
Textbook of Palliative Medicine and Supportive Care
Consent (or Consultee Declarationa) Process to be Followed
Informed consent
Following the provision of necessary information about the study, opportunity
to ask questions, and sufficient time for decision-making, informed consent is
obtained in written or oral formats
Enhanced informed consent
The aim of an enhanced informed consent process is to maximize the
individual’s autonomy and their ability to make an informed decision. It could
include techniques such as the use of multiple formats to provide
information,91–94 having social support present during the consent process93,94
and iterative learning95
Advanced consent
Informed consent is obtained with anticipation that the person might lose
capacity during the study. The individual is also asked to nominate a consultee,
a person the researcher could approach to provide views on the continued
participation in the research study, if and when the person loses capacity
Process consent
This is an ongoing consensual process, which starts with informed consent,
followed with reiteration of the validity of the informed decision at all stages
of the research study, by monitoring and assessing the capacity of the
participant. Process consent is generally paired with the advanced consent
process to ensure that the participant can continue to participate in the study
if this was their stated wish instead of being excluded from the study purely on
the basis of lacking capacity
Consulteeb declaration
A consultee (personal consultee—someone who knows the potential
participant, nominated consultee—when a personal consultee is not available;
someone independent from the research study, who does not know the
potential participant personally, who has been assigned as a consultee at the
beginning of the study) is asked to provide their opinion, to their best
knowledge, on whether or not the potential participant would have wanted to
take part in the research capacity, had they had capacity. Consultees should be
supported throughout the process regarding the potential risks and benefits of
participation in the research study
Deferred consent
In deferred consent process, the process of obtaining informed consent regarding
study participation is postponed to a time where the individual has the capacity.
The process of deferred consent follows the reverse order of first obtaining
informed consent, then enrollment to the study, and is only acceptable in studies
with a population of interest who is expected to regain capacity. Although
deferred assent has been performed previously,96 individuals who do not regain
capacity or die are likely to be excluded from the study
Ethical considerations among socially
disadvantaged, patient or population groups
Ill health, chronic diseases, high levels of comorbidity, polyphar-
macy, cognitive impairment, and fatigue frequently challenge or
prevent an individual’s ability to consent and then participate in
palliative care research. However, there are other patients- and
Ethics in Palliative Care Research 103

TABLE 13.3  Summary of MORECare Recommendations for Ethical Issues in Palliative and End-of-Life Care Research47
Research Study and Recruitment
Research protocols require carefully considered flexibility to accommodate the fluctuating symptoms or levels of competence often experienced by
patients receiving palliative care (e.g., flexible recruitment strategies and data collection methods)
Wide inclusion criteria in studies on palliative and end-of-life care are needed in order to include those who are more difficult to reach (e.g., older
people, the bereaved, those with fluctuating capacity). Therefore, a sensitive approach to recruitment is required that demonstrates empathy, is
responsive to an individual’s level of understanding and emphasizes the voluntary nature of participation
Greater development of clearly defined roles that combine clinical and researcher activities is needed in order to improve research–practice interface
and aid recruitment
Collaboration with Service Users
Ethical and governance applications are enhanced by collaborative working with competent lay user representatives throughout the project, by
developing Participant Information Sheets (regarding proportionality and the clarity and acceptability of language), developing/reviewing the
suitability of data collection tools, a lay summary in the ethical application and by accompanying researchers to the research ethics committee (REC)
review on the application for end-of-life care research. RECs require clear codes of conduct, standards, and competencies for assessing and
facilitating research in palliative and end-of-life care
Research ethics network
The establishment of a Research Ethics Network for palliative and end-of-life care research could further develop methods and guidance on
undertaking and facilitating research at the end of life
Consent Processes
To enhance processes of consent requires palliative and end-of-life care organizations to create a research-aware culture for practitioners by sensitively
informing practitioners and patients on admission to a service that the organization is actively involved in research
To enhance processes of consent requires palliative and end-of-life care organizations to create a research-aware culture for practitioners by adopting
a policy of consent to consent (a screening procedure to identify people interested in taking part in a research study)
A continuous process of consent, in which the original written consent does not necessarily need to be repeated, is required to ensure sensitivity to
changes in an individual’s attitude, ability to participate and careful monitoring of signs of verbal or nonverbal distress.

population-related factors that may operate in isolation or in com-
bination to further complicate this situation. Historically, palliative
care research has focused on patients with cancer, while overlook-
ing the palliative needs of patients who lived with other chronic
and terminal illnesses. Additionally, research in certain groups
of the population such as neonates/newborns, children, refugees,
and prisoners has its unique challenges, as these individuals are
perceived as being in an even more vulnerable position.98–100 It has
been suggested that very old patients, those with learning disabili-
ties, and those from black and minority ethnic communities, to
name just a few, may be excluded from the research.94,101–105
Older people represent a heterogeneous group where compe-
tency and capacity vary considerably. Indeed, many will have no
problem with consent and will be able to participate in research.
At a purely practical level, however, others may be excluded as a
result of their inability to consent due to poor vision or hearing
problems.104,105 The type of research older people are invited to
engage with also needs to be considered. It has been suggested
that frail older people, who would probably not be competent
enough to be included in a pharmaceutical trial because they may
have difficulties understanding the extent of their involvement
and possible implications for their health, may still be eligible
to participate in research if it involves noninvasive, semistruc-
tured interviews, in which they can discuss their experiences of
advanced disease or service use.106
In the past, individuals with learning disabilities were some-
times chosen as research participants precisely because they
were less capable of understanding what was being done to
them and were less likely to object.107 There are many different
kinds and degrees of learning disability, and many patients,
depending on the extent of the disability, will be able to con-
sent on their own behalf.108 Ensuring that the consent is indeed
informed may be more difficult and require special skills in
conveying the relevant information, but it should be attempted
wherever at all possible. Even if a patient can give consent, it
is always advisable to have the patient’s relative as a witness to
the consent process.
To date, there has been very little published research about
engaging patients from black and minority ethnic communities
and refugees in palliative care research.109 Since these popula-
tion groups have traditionally been socially excluded from the
mainstream health services research, they have been referred
to as “invisible” or “elusive” populations. Their notable absence
and unheard voices in research, therefore, reflect their position
on the periphery of the society.110 Where they are identified and
recruited, research considerations include those described earlier.
Heterogeneity will be evident, and naturally, many will be able
to consent. Those who do not possess adequate language skills
either may be excluded from the research or may have to rely
upon family members or advocates to translate for them. Given
the many sensitivities associated with palliative care, researchers
need to be aware that confidentiality may become compromised,
or in order to prevent this, the respondent, the family member, or
advocate may distort realities to protect privacy.
Finally, similar to other areas of health, palliative care has also
been affected by the consequences of historical exclusion and under-
representation of women in clinical studies.111 These exclusions had
an impact on women’s diagnoses, treatment outcomes, and pain
management. To ensure that evidence-based practices are relevant
to the population, in addition to women, LGBT individuals should
also be included in the studies,112 and gender relevancy should be
taken into account in all aspects of palliative care research.
Methodological challenges
The type of research methodology employed during palliative
care research poses interesting ethical questions. While quanti-
tative studies often place considerable time and energy demands
on dying patients, participation in qualitative studies, that
104
frequently explore issues in considerable detail, may create an
emotional burden for patients and their families.113 Qualitative
interactions often become highly personal, and interpersonal,
and in that context, may be even more intrusive than with quanti-
tative approaches.114 The researcher comes to know the interview-
ees in a more intimate manner. Interviews that raise issues such
as terminal illness, suffering, and loss may bring research partici-
pants’ feelings to the fore that may have been previously largely
suppressed. These undisclosed problems may then be exposed
to serious consequences. Johnson and Plant115 and others69 have
reported that, in their interviews with cancer patients, partici-
pants sometimes reported they were emotionally troubled as a
result of reminders of their diagnosis, experienced upset feelings
in response to talking about their illness, and began to question
if their condition might be more serious than they had assumed.
RCTs raise particular issues in palliative research. Traditionally,
the RCT has been viewed as the gold standard for conducting
clinical research.116 Proponents of RCTs argue that where there
is uncertainty, randomization minimizes the risks of exposure
to unevaluated hazards. While in very select situations RCTs
have been successfully employed in palliative care research, for
example, examining the management of pain,117 breathlessness,118
and the psychological interventions,119 they are not without their
problems13 or ethical challenges.120 Randomization can partially
involve relinquishing individualized care and for some patients,
the forgoing of potential benefits to new treatment or care.
McWhinney and colleagues endeavored to minimize the poten-
tial of the latter121 during an evaluation of a palliative care home
support team based on inpatient unit. Patients in the study group
received a service immediately, while those in the control group
received the service a month later. The two groups were then com-
pared after a period of one month using measurement of symp-
toms levels and patients’ quality of life. The trial however failed.
KEY LEARNING POINTS
• Historically, research involving human subjects
was not governed by guiding ethical principles.
This had catastrophic consequences for those
involved in some notorious research studies.
• International guidelines, notably the Declaration
of Helsinki, relating to health research now advo-
cate ethical review, and IRBs and RECs are almost
a worldwide phenomenon.
• In many countries, IRBs and RECs now have a
basis in law, their accountability is clearly defined,
and their performance is regularly audited.
• Ethical regulation of medical research on humans
provides essential reassurance that the risk of
harm has been minimized for all participants.
• Palliative care research raises unique method-
ological and therefore ethical challenges. These
include research-related distress and the per-
ceived vulnerability of participants; research bur-
den for ill patients, many of whom may be close
to death or their relatives who are experiencing
grief; consent and capacity issues; ensuring con-
fidentiality and anonymity; and the methodologi-
cal challenge of producing high-quality research,
including the contribution of the RCT.
Textbook of Palliative Medicine and Supportive Care
The reasons advanced for this included high rates of attrition
due to death, and low compliance rates due to very sick and weak
patients. Knowing this, health professionals too may have been
reluctant to cooperate with the study, discouraging recruitment.
However, by incorporating consent and data collection processes
such as involvement of consultees, and tailoring the RCTs to the
specific population’s needs and circumstances, successful RCTs
can be conducted. Furthermore, methodological adaptations,
such as using cluster or stepped-wedged RCT design especially for
the testing of complex interventions, or using propensity score-
matching and conducting a comparison of two matched groups
from routine data109 could be more suitable alternatives. Finally, by
conducting feasibility studies palliative care researchers can refine
and increase the likelihood of a success of definitive RCT, or derisk
conduct of a technically impractical RCT.34
Conclusion
The ethical issues in palliative care research need to be under-
stood in the context of the historical background of research eth-
ics, and the national and international frameworks which already
exist to inform ethical standards in research. Having said this,
both impose some constraints on present day palliative research,
having developed primarily for research in different contexts.
Imaginative and intelligent ways to refine existing research
methodologies, develop new ones, and to work with the vul-
nerabilities of palliative research participants need to be found.
There are ways to respect patient autonomy, minimize harm, and
reduce research burden, but these are not always easy to find, nor
encouraged within existing structures for ethical review.
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14
ADOPTION OF PALLIATIVE CARE: THE ENGINEERING
OF ORGANIZATIONAL CHANGE

Winford E. (Dutch) Holland and Eduardo Bruera

Contents
Elements of the framework..............................................................................................................................................................................................107
Organization as a mechanical system............................................................................................................................................................................107
Organizations as ongoing theatrical performances..............................................................................................................................................107
Five requirements for engineering change..............................................................................................................................................................108
Requirement one: Engineering and communicating the change vision...........................................................................................................108
Requirements two through four: Engineering the organization’s mechanical components.........................................................................108
Requirement five: Using project management to guide the engineering of change.......................................................................................109
Diffusion of innovation.....................................................................................................................................................................................................109
Leadership in organizational change.............................................................................................................................................................................111
Pulling it all together: a palliative care success story............................................................................................................................................111
Palliative care success story continues….................................................................................................................................................................112
References............................................................................................................................................................................................................................113

Imagine that you have just been named to the faculty of a distin-
guished medical institution. Further imagine that you have been
asked by the director of the institution to “help us implement pal-
liative care in our institution.” What would you do? How would
you do it? With whom would you work? Whom might you avoid?
What missteps would you want to avoid?
Hopefully, many of the readers of this book will be asked
exactly that question: “Can you help us implement palliative
care?” The goal of this short chapter is to offer a framework for
thinking about such an implementation, as well as some practical
tools that might be used to make such an implementation pos-
sible in a relatively short period of time.
Elements of the framework
While most of us spend our time inside a large organization, we
usually do not spend much time thinking about the organization.
What is an organization? What is it made of? What do we mean
when we talk about “changing the organization?” When we say
that we want to implement palliative care in an organization,
what does that mean?
The following three subject areas can form a framework for envi-
sioning and then changing an organization and how it operates:
3. The role of leadership in creating change in an organization:
Leaders cause things to happen in an organization. Leaders
take direct actions on the moving parts of an organization;
they influence organization members to enable the organi-
zation to make changes like implementing palliative care
on an institutional basis.
The following sections of this chapter will explore in more detail
these three key framework ideas, providing both understanding and
action steps that can be used to implement, or “engineer,” an innova-
tion in an institution in an effective and efficient way. The last section
of the chapter will “pull it all together” to illustrate how the actions
can be used for real-world implementation of palliative care.
Organization as a mechanical system
Implementing a change, like the introduction of palliative care,
requires us to know something about what an organization is
from a structural or systematic point of view—the mechanics of
organizations. In today’s world of work, we must be able to do two
things at the same time—use the organization to get today’s busi-
ness done and change the organization so that we can be ready to
do tomorrow’s business.

1. The organization as a mechanical system: A large organiza-
tion can be thought of as a mechanical system made up of
concrete “moving parts”—parts that can be altered to cause
the organization to function in a different way, like deliver-
ing a new service such as palliative care to the institution’s
clients. As a metaphor, organizations can be thought of as
“theater companies” performing in continuous “plays.”
2. The diffusion of innovation within a social organization:
Innovations—ideas that are new to an organization—dif-
fuse through an institution in a patterned way over time,
with some organization members far more inclined to
adopt an innovation like palliative care than others.
Organizations as ongoing theatrical performances
We see an organization as an ongoing play, where organization
members are the cast and crew doing a satisfying performance
for clients/patients. Using the scenario of changing plays from
“Romeo and Juliet” to “My Fair Lady” as an example of what hap-
pens in organizational change is a helpful framework for manag-
ers and employees to easily grasp the changes involved in moving
a theater company from one performance to another—from
learning new scripts to changing costumes and sets, all the way
to the full dress rehearsal before opening.
Once this theater metaphor is learned, our students of change
management can use it to understand why many changes they

107
108
have seen go awry! More importantly, it becomes easy to under-
stand the single most important concept in organizational
change—that organizations are structured, mechanical systems
with concrete moving parts that must work and change together.
Translating the theater metaphor to organizations, students can
see the four primary structural elements:
1. Vision, like the play’s storyline and script
2. Work processes, like the roles in the play
3. Plant/equipment/tools (PET), like costumes and sets
4. Performance agreements, like contracts for actors
While it is easy to comprehend the “work process—role” and
the “PET—props” connections, it does take some stretch to see
that the “agreements for performance,” like actor contracts, are
an attribute of the organization and not the “employees—actors”
themselves. In our experience, the most difficult part of organiza-
tional change for many companies is to understand the idea that
change is designed to alter the roles that people play in the orga-
nization, not to alter people themselves. Failure to grasp the idea
that change hinges on altering roles and subsequent performance
agreements that we make with employees is the most common
downfall of organizational change.
For an organization to change, all four mechanical attributes
of the organization must change—in concert—or there will be no
change (Figure 14.1). Vision alteration, work process alterations,
PETs alterations as well as performance agreement changes are
all done in a social setting. All the alterations have to be done by
people who are involved and committed to (1) making the altera-
tions and (2) working in the new organization after the alterations
are made. Managing the people dynamics can be challenging,
but it is doable as long as leaders of the change understand the
mechanical things that must be done to achieve organizational
change.
Five requirements for engineering change
As discussed, the way any organization works at a given point in
time is the direct and inescapable result of the configuration of
the firm’s vision, work processes, physical plant, and performance
system (agreements with employees and their competence to per-
form to those agreements). Just as in a mechanical system, the
FIGURE 14.1  Mechanical elements of an organization.
Textbook of Palliative Medicine and Supportive Care
way the organization operates cannot change without a change in
its key components.
Calling these needed alterations “requirements” allows us to
see change as a true engineering challenge. These four altera-
tions, along with disciplined project management, make up what
we call the five requirements for engineering change. The critical
part of organizational change is the unglamorous, detail-oriented
hard work of engineering.
Requirement one: Engineering and
communicating the change vision
The first requirement of organizational change is to engineer a
vision or picture of the organization’s desired future that will be
valid, complete, feasible, resourceful, and engaging. In this case,
the detailed vision would picture the continued growth and suc-
cess of the institution, showing palliative care as a core practice
that serves patients and families well and at a decreased cost of
serving those same patients in intensive care. Once detailed,
the vision should be tested with members of the organization to
ensure that it is an understandable picture of the desired future.
To ensure that the organization is positioned to really hear and
digest the vision, we construct a case for change that describes, in
some detail, the potential consequences of keeping the organiza-
tion exactly the way it is now.
An institution bent on implementing palliative care would be
able to describe a time in the near future when such care was an
integral part of the organization’s services, providing a real alter-
native to end-of-life care in an intensive care facility. In addition,
reasons for implementing palliative care, including benefits to
patients and families, as well as institutional economics, should
be clearly detailed.
Once the change vision and the case for palliative care are
complete, the next step is to communicate with all organization
members multiple times using multiple media. First and fore-
most would be direct communication by the CEO that explains
why palliative care will be critical for the institution’s continued
success. The CEO’s message can be picked up in today’s world of
communication: the institution’s website as well as its internal
communication programs. Palliative care brochures, signage, and
even slogans, pins, and badges could complement the face-to-face
communication of the vision.
Technically, this communication requirement is not complete
until all management levels have worked through the vision and
the case for change, and translated them into action terms for
their level and function, as well as for their individual associ-
ates. The final step in this requirement is to test each employee’s
understanding of the translation of the palliative care vision for
his/her job. Without this test, leaders of the change can hardly
know if they are ready to move on to the next requirements of
altering the other mechanical components of the organization.
Failure to communicate the palliative care vision and case
for change would be like the director of a theater company who
selects the next new play but who does not talk about the play,
what it is, how it was selected, or about the future success of that
play. Would you think that this director’s approach would get
their theater company off to a great start?
Requirements two through four: Engineering
the organization’s mechanical components
Requirements two through four call for the physical alteration of
the institution’s work processes, its physical PET, and the employee
performance system. The first step in this alteration process is to
Adoption of Palliative Care: The Engineering of Organizational Change
create an inventory of the organization’s current components—
work processes, PET, and performance agreements with employ-
ees—and identify those elements that will not be in sync with the
palliative care vision of the future organization. Once identified,
each of the elements must be physically altered and tested. It is
these alterations of the existing components, along with the addi-
tion of new work processes (e.g., billing procedures for palliative
care), physical plant (e.g., dedicated palliative care beds), and per-
formance agreements (e.g., job descriptions for personnel servicing
palliative care beds) that will become the “stuff” of the changed
organization that will include palliative care.
Development and negotiation of new performance agreements
for all affected managers and employees is critical at this point
to ensure they are signed up for palliative care in the institu-
tion. Organizations and theater companies alike deal with the
reality that some employees, or actors, will not elect to sign up
for the change. Completing these alterations is akin to the work
that must get done in the theater company to ensure that the new
play is translated into individual roles and scripts for the newly
assigned cast, that the new costumes and sets have been con-
structed, and that the actors have been put under formal contract
and rehearsed for the new play.
The final step in each of these three requirements is to system-
atically dismantle or remove those elements that will not be a part
of the new organization’s structure. Old work processes, proce-
dures, tools, and equipment will need to be removed from the
workplace to ensure they will not be used again. This dismantling
includes the often-forgotten step of directly and formally can-
celing any agreements with managers and employees for perfor-
mance in the old organization that did not contain palliative care.
For example, we might want to verbally and in writing cancel the
institutional procedure that assigned end-of-life patients to the
intensive care unit or to that designated wing.
We want to cancel the agreements that our employee had for
doing work the old way (without palliative care) now that they
have already been signed up for doing work the new way (with
palliative care as a main-stream service). This final dismantling
is akin to the director removing all vestiges of the last play (old
scripts, costumes, and props) to ensure that they will not be inad-
vertently used in the new production. Included in this disman-
tling step is the cancellation of any cast contracts that would have
tied them to the old play.
Requirement five: Using project management
to guide the engineering of change
Even though employees are clear on the vision that is to be imple-
mented, they need day-by-day or week-by-week instructions or
action plans to guide them through the many steps of organiza-
tional change (e.g., “Remember gang, this is the week for costume
fittings; leads come in on Wednesday, dancers on Thursday”).
Employees need an action plan that tells them “what to do on
Monday morning …” to go forward with the coordinated imple-
mentation of the new vision.
These action plans must be a part of a critical project manage-
ment plan and master schedule that lays out all the engineering
work to be done for the organizational change to embrace pallia-
tive care. Critical to the action planning requirement is the trans-
lation of action plans on a weekly or monthly basis for all involved
managers and employees so that they are clear on their roles in
(1) transitioning to the new organization and (2) playing new
or altered roles in that new organization. Failure to keep action
plans updated and communicated would be like the director who
109
does not lay out and communicate detailed plans and schedules
for reading the new roles, signing contracts, fitting new costumes,
or rigging new props.
Project management of change is first and foremost a case of
deciding exactly and precisely what alterations will be required
in each of the components and then how the required alterations
are to be made. The physical change piece is all about making
the required alterations and ensuring that they were done … and
done right.
The engineering challenge in this project management require-
ment is to ensure that all of the required modifications to vision,
work processes, physical plant, and performance agreements
have been done in a thorough, comprehensive manner. While it
may be a technical challenge to keep track of all of the needed
alterations, particularly if the organization is large, it is techni-
cally not difficult to find out exactly where the organization is
during an organizational change.
Knowing where we are in engineering change to include pallia-
tive care is a matter of auditing the status of required alterations
and dealing with the reality of what we find:
• Either work processes have been altered to include pal-
liative care or they have not. New procedures that allow
people to bill for palliative care have been written and dis-
tributed or they have not. The old processes and their sup-
porting procedures that do not include palliative care have
been dismantled/destroyed or they have not.
• Either new tools (beds devoted to palliative care) are
assigned and are working or they are not. Either the guide-
lines for operating the new palliative care suite have been
written and distributed or they have not.
• And either the performance contract for each and every doc-
tor, nurse, and administrator impacted by the introduction
of palliative care has been altered and negotiated with each
of them or it has not. Either each and every manager and
employee has been trained on the new palliative care admis-
sion processes and new suite or they have not, and so on.
So ends this section of the framework that deals with the orga-
nization as a mechanical system, a system that can be literally
engineered from one configuration to another. But organizations
vary in their susceptibility to engineering, as explained in the
next section.
Diffusion of innovation
While the mechanical approach to leading an organizational
change, such as the introduction of palliative care, is simple and
straightforward to describe, there are organizational situations
in which it is an oversimplification. In professional organizations
where there is a high degree of individual autonomy, another
framework element has much to offer.
A major social study area for the past few decades has been
the “diffusion of innovation”—the way and rate at which some-
thing new to an individual or organization gets adopted by the
members of the organization. The basic idea is that an innova-
tion spreads rather slowly across a social system, like a healthcare
institution, by traveling from member to member. Key elements
of the diffusion theory include:
1. The innovation: An idea or practice (e.g., palliative care)
that is perceived as new by individuals or the institution.
110
FIGURE 14.2  Categories of adopters of innovations.
2. Communication channels: The means by which messages
about the innovation get from one individual to another
(formal and informal communication between depart-
ments and members of the medical community).
3. Time: The relative time an innovation takes to be adopted
by an individual or group.
4. Social system: A set of interrelated units (departments) that
are engaged in accomplishing a common goal (providing
healthcare to patients—the institutional goal).
In studying the diffusion process, researchers have been able to con-
sistently identify individuals who have very different rates of adop-
tion. The classic categories of adopters are as follows (Figure 14.2):
1. Innovators
2. Early adopters
3. Early majority
4. Late majority
5. Laggards
Researchers identified several characteristics dominant in
innovators:
• Venturesome; desire for the rash, the daring, and the risky
• Ability to understand and apply complex technical knowledge
• Ability to cope with a high degree of uncertainty about an
innovation
Characteristics identified in early adopters:
• Integrated part of the local social system
• Greatest degree of opinion leadership in most systems
• Serve as role models for other members or society
• Successful and respected by peers
Characteristics identified in the early majority:
• Interact frequently with peers
• Seldom hold positions of opinion leadership
• Deliberate before adopting a new idea
• Constitute one-third of the members of a system
Characteristics identified in the late majority:
• Are naturally cautious and skeptical
• Pressure from peers
Textbook of Palliative Medicine and Supportive Care
• Economic necessity
• Constitute one-third of the members of a system
Characteristics identified in the laggards:
• Are isolates and possess no opinion leadership
• Point of reference in the past
• Suspicious of innovations
• Innovation–decision process is lengthy
The practical significance of these categories has not been lost on
the advertising and sales communities who routinely take advan-
tage of innovator categories. Change leaders can also take advan-
tage of the research by treating different populations within their
institutions differently.
For example, when an innovation like palliative care is first intro-
duced into a department or institution, health-care professionals
produce an “adoption reaction.” Thinking simply, about a third of the
community is likely to have an open, even positive reaction, while
another third might have a very closed or even negative reaction. A
middle third might be observable as those professionals who lean no
way or the other, as if waiting for the next act. In fact, this middle third
is likely to be doing just that: waiting to see how the introduction goes.
From the point of view of the change leader(s), working with
the three communities takes very different levels of energy and
produces varying degrees of results:
• First-third (innovators and early adopters): Working with
them is simple, straightforward, and positive. Reasonable
suggestions about palliative care and its adoption are
heard, evaluated, and frequently acted on.
• Second-third (majority adopters): Working with them is
frequently frustrating, since they are less into “listening,
trying, and evaluating ideas” than they are into “watching
the success (or lack of success)” of the first-third.
• Third-third (late majority and laggards): Working with this
group is usually argumentative, frequently unfriendly, and
sometimes downright nasty and unpleasant.
Change leaders assigned and/or committed to the implementa-
tion of palliative care have the choice of the populations they
address. Diffusion of innovation research would suggest the tactic
of working with the first-third (innovators and early adopters) to
gain as much implementation success as possible and then allow-
ing nature to take its course as those in the first-third do the job of
influencing others through their own work and social channels.
Adoption of Palliative Care: The Engineering of Organizational Change
Leadership in organizational change
Organizational change does not happen without leadership …
and lots of it! We have not seen success in change when the orga-
nization’s leadership, at all levels, was unwilling to take respon-
sibility for setting a direction or was lacking the courage and
commitment needed to carry out that direction. Decisive leader-
ship at the highest level of the organization is essential for suc-
cessful change.
The leader who is unable or unwilling to pick a new future for
the organization, describe that future in some detail, and then steer
toward that future is destined to keep the organization right where
it is. The bottom line is simple: organizational change takes leader-
ship, from both the boss and his/her collaborators (Figure 14.3). The
final word, however, is that the boss must be the one who brings the
energy and excitement to organizational change, along with the per-
sonal leadership to get collaborators on board.
There are three critical sources of leadership that must be
engaged for successful organizational change: the chief executive,
key managers at the departmental level, and health-care profes-
sionals. Each leadership source has a primary mission to accom-
plish in an organizational change to implement palliative care.
The chief executive is the “chief change officer” for the organi-
zation. Period. No one else in the organization has the author-
ity and stroke to make change happen. No one else has the legal
responsibility for the enterprise. No one else can be held account-
able for the performance of the organization before, during, and
after organizational change.
The chief executive’s primary change mission is to develop (or
select) the desired future for the organization and express it as the
vision that includes palliative care, just like the director’s job is to
select a script that will result in a successful play. In addition, the
executive must resource with time, dollars, and personal commit-
ment the palliative care vision as it is being implemented.
The chief executive must also develop his/her own altered exec-
utive role as it will need to be played for palliative care to become
a reality. Actions speak louder than words, but we are talking
about something more than that. What the chief executive does
on a day-to-day, week-to-week, and month-to-month basis must
routinely include the vision of palliative care if that vision is to
FIGURE 14.3  The change leadership acts on the mechanical
attributes of organizations.
111
become a reality (e.g., the CEO asks the controller to add “revenue
from palliative care” to the document top management uses to
hold their monthly revenue review; the zero will stand out like a
sore thumb but make the CEO’s expectation clear).
The middle managers serve as the organization’s source of
energy and initiative for altering work processes, altering the
physical plant, and altering the performance management sys-
tem to include palliative care. This category will likely include the
organization’s department directors as well as the palliative care
leader(s) who have taken on primary responsibility for day-to-day
operations and guiding the implementation effort.
The organization’s middle managers are directly and personally
responsible for completing the changes needed to get palliative
care into operation. Their job is to be the “chief change communi-
cator and director” for their part of the institution. Their primary
change mission is threefold:
• Relentlessly communicate the palliative care vision to their
department.
• Guide their department’s health-care professionals as they
complete the organization’s move to palliative care includ-
ing professional education and training.
• Develop their own altered management and professional
role as they will need to be played for palliative care to be
a reality.
The health-care professionals in the organization will do the
majority of the change engineering needed to alter the organiza-
tion’s mechanical attributes. It is the workers who will physically
do the detailed alternations needed in work processes and physi-
cal plant and develop the new organizational roles that enable
palliative care. The primary change mission of the involved pro-
fessionals must, however, be focused on the alteration and devel-
opment of their own roles and skills needed for their success as a
part of the palliative care vision.
Pulling it all together: a palliative care success story
Take for example, the introduction of palliative care at MD
Anderson Cancer Center (MDACC) in Houston. The chief execu-
tive made the decision to move toward palliative care and hired a
leading physician to come to MD Anderson and “run the show.”
Upon arrival, the newly appointed palliative care department
head encountered stiff resistance and many logistical obstacles
that were almost impossible to overcome. At the end of the first
18 months, progress in gaining acceptance of palliative care was
very slow, and the third-third population of resisters (laggards)
had made themselves heard all the way to the top. The situation
was uncomfortable enough for the department head to say “that
he felt like he had parachuted in behind enemy lines.”
In an effort to move the ball, MD Anderson retained the ser-
vices of a change consultant to work directly with the department
head and his palliative care team of department member physi-
cians and administrators. The steps taken included the following:
• Instruction of and consultation with the palliative care
team in the change concepts that are described in this
chapter. The department head stated that the consultations
and training has “opened a window into the world of orga-
nizations” that allowed him to better see and understand
the actions that he and his team needed to take.
• Decision of the palliative care team to “ignore the third-
third detractors” and to find and work with “first-third”
112 Textbook of Palliative Medicine and Supportive Care

professionals only (i.e., working only with those who were
relatively positive and eager to look at palliative care as a
treatment alternative).
• Formation of a palliative care steering team made up of
volunteer senior physicians/faculty members (all of whom
were first-third).
• Arranging an early meeting/workshop of the steering com-
mittee to hear directly from the MDACC chief executive.
The chief executive explained to the steering team his rea-
son for moving the institution toward palliative, his rea-
sons for selecting the department head, and his vision of
palliative care as a legitimate and important treatment
modality for the institution.
• These key, friendly members helped establish a vision, mis-
sion, and strategic plan of action and not only provided
extremely useful feedback but by the same process they
were sold.
• The palliative care team and steering team worked directly
with administrative officers of the institution to ensure
that processes were in place to handle business and sched-
uling aspects of palliative care (i.e., to ensure money would
start flowing).
• With a palliative vision and strategic plan in place, the
department was able to launch communication and public
relations programs, clinical education sessions, as well as
consultations inside and outside MDACC.
• These programs initially focused on the first-thirds. As a
result of positive acceptance by the first-thirds, members of
the second-third group began to sign up, and before long,
the first two-thirds were chiding members of the third-
third as “being behind the times.”
• The result of this was a large growth in referrals to the pal-
liative care program that have succeeded in fully establish-
ing it as a viable clinical and financial program. Note the
rapid rate of palliative care consultations in Table 14.1.
• The palliative care initiative has continued to increase
in use and popularity, with consultations continuing to
increase, while the number and cost of deaths in internal
care continue to decline.
Blending the messages from the three framework elements is
essential for the effective change. The essential message of this
chapter, therefore, is for leaders to:
1. Take strong, aggressive, visible action
2. To work with “first-third” managers and professionals
3. To alter the mechanical attributes of the organization that
will enact palliative care
In summary, key to the success of the effective and efficient
introduction of palliative care will be the continuing partnership
between the committed chief executive and leaders in the man-
agement cadre. Dedicated action in the engineering framework
described in this chapter, along with huge doses of “blood, sweat,
and tears,” should lead to another palliative care success story.
And there is one.
Palliative care success story continues…
Palliative care at MDACC had continued to grow at a rapid rate
over the first 5 years, but in 2010, growth began to plateau. After
checking and double checking what they had been doing to con-
tinue to attract new patients, the leader of palliative care and his
direct reports held what could be called a “focus group” to talk
about future growth. Invited attendees were several first-third
physicians (innovators and early adopters whose input led to a
new hypothesis: that some physicians were not comfortable mak-
ing a referral to palliative care lest they be seen as “giving up on
the patient”).
Information from the focus group energized the palliative care
leadership to think through their approach again. They reached
the conclusion that their brand needed to be altered from “pal-
liative care and pain management” to “palliative care and reha-
bilitation medicine.” They also changed the name of the facility
they were using to the Supportive Care Center that “focuses
on improving quality of life for MD Anderson Cancer Center
patients and their families.”
The palliative care team used the same change management
approach they had used to stand up their initial practice, but
now they knew what would work, and they were able to get all
their needed change alterations underway in short order. They
initiated a new communication plan focused on the supportive
care center; they revised “processes, labels, buttons, and badges”
to include supportive care; they rethought their space require-
ments, and added supportive care words to job descriptions of
their health-care professionals.
News of the rebranding spread like wildfire through the physi-
cian community and the physicians reacted accordingly. Figure 14.4
shows the total number of patient encounters seen by the palliative/
supportive care service from 2007 to 2014, along with the percent-
age growth each year compared with the prior year. As shown, both
inpatient and outpatient palliative/supportive care services increased
in total patient activity. Even more impressive is that in a recent study
(ref 3) by the MDACC palliative care team, 72% of patients perceived
that the referral to palliative care occurred in a timely manner and
83% of patients found the referral useful. These data show that dedi-
cated leadership, passionate professionals, a proven road map for
change, a lot of creative thinking, and energetic workers can move
mountains.

TABLE 14.1  Impact of Palliative Care Services on Overall Hospital Mortality at The University of Texas MD Anderson Cancer
Center (from ref [1] with permission)
1999 2000 2001 2002 2003 2004
Consultations prior to inpatient death under services other than palliative 8 17 54 106 112 95
care service (PCS)
Inpatient death under primary care of the PCS NA NA NA 54 123 169
Total number of patients accessing palliative care before death 8 17 54 160 235 264
Percent of patients accessing palliative care before death 1% 3% 8% 24% 35% 35%
(8/583) (17/657) (54/671) (160/657) (235/689) (264/764)
Total number of palliative care inpatient visits (death and discharges) 800 1006 3396 5476 6489 6689
Adoption of Palliative Care: The Engineering of Organizational Change 113

FIGURE 14.4  Increase in total patient activity for both inpatient and outpatient palliative/supportive care services at The University
of Texas MD Anderson Cancer Center from 2007 to 2014. (From Reference [2] with permission.) Abbreviation: FY, fiscal year.

KEY LEARNING POINTS
1. The introduction of palliative care can be seen as a
mechanical problem that can be engineered; organi-
zational moving parts must be identified and altered.
2. Individuals have different rates of change accep-
tance. Plan to work with the most eager supporters
of palliative care first.
3. Changing an organization’s way of operating
requires aggressive, visible, hands-on leadership.
The boss must want and support palliative care.
4. Get the physical assets needed for palliative care in
place early on so that the organization can see tan-
gible organizational commitment.
5. Involvement of professionals must be done at every
step of the way.
References
1. Elsayem A, Smith ML, Parmley L, Palmer JL, Jenkins R, Reddy S,
Bruera E. Impact of a palliative care service on in-hospital mortality in
a comprehensive cancer center. J Pall Med 2006;9(4):894–902.
2. Dalal S, Bruera S, Hui D, Yennu S, Dev R, Williams J, Masoni C,
Ihenacho I, Obasi E, Bruera E. Use of palliative care services in a ter-
tiary cancer center. Oncologist 2016;21:110–118.
3. Wong A, Vidal M, Prado B, Hui D, Epner M, Balankari VR, De La
Cruz VJ, Cantu H, Zapata KP, Liu DD, Williams JL, Lim T, Bruera E.
Patients perspective of timeliness and usefulness of an outpatient sup-
portive care referral at a comprehensive cancer center. J Pain Symptom
Manage 2019;58(2):275–281.
15
PRINCIPLES OF MEASURING THE FINANCIAL OUTCOMES
OF SPECIALIST PALLIATIVE CARE PROGRAMS

J. Brian Cassel and Thomas J. Smith

Contents
First principle: Financial outcomes are a positive secondary effect of patient—centered outcomes...............................................................115
Second principle: Understand the utilization and context........................................................................................................................................115
Third principle: Research has shown that SPC reduces utilization and costs.......................................................................................................117
Fourth principle: Inpatient SPC reduces costs for hospitals, while outpatient SPC can avoid them for payers............................................118
Conclusions.........................................................................................................................................................................................................................118
References............................................................................................................................................................................................................................118

Of all the imperatives and outcomes for specialist palliative care
(PC) (SPC) programs in hospitals, one would hope that financial
issues would rank as among the least important. Surely the other
motivations for SPC and effects thereof—humanitarian, moral,
ethical, clinical, to name a few—should be paramount. The hos-
pice and PC innovators and paradigm shifters in the 1960s and
1970s responded to the unmet needs of patients, focusing on the
relief of suffering and creating the ability to provide for a “good
death” when death is inevitable and imminent. The primary moti-
vation of these innovators was to reduce pain and suffering and,
secondarily, to cease futile interventions that create more burden
for the patient than benefits.1 Be that as it may, measuring the
financial impact of SPC may be crucial for ensuring sustained
financial resources continue to be made available for training
SPC professionals and sustaining SPC programs.2,3
First principle: Financial outcomes
are a positive secondary effect of
patient—centered outcomes
Outcomes for SPC may represent a variety of perspectives, includ-
ing patient, family, other care providers, the hospital, payers, and
society. Improvement in the bio-psycho-social-spiritual experi-
ence for the patient is the central rationale for SPC involvement
and is the primary locus of outcomes to be measured. The word
“primary” here has multiple meanings—it is most important, it is
first to occur, and it is a necessary step in producing further posi-
tive outcomes. Secondary and tertiary outcomes ripple outward
from this primary locus of impact (see Figure 15.1). This is not
to say that all clinical effects (e.g., reduced pain) will automati-
cally produce hospital-level financial and operational effects, but
it is to say that financial outcomes are dependent upon clinical
impact.
The first principle of measuring the financial impact of SPC,
then, is to measure it as a consequence of patient-centered clini-
cal and psycho-social-spiritual outcomes. Financial outcomes
are secondary effects of these, and therefore, in practice, SPC
program leaders should measure the patient-centered and social
outcomes first, before turning to institutional outcomes such as
lower costs or fewer Intensive Care Unit (ICU) days.
Second principle: Understand
the utilization and context
With responsibility for the small fraction of hospitalized patients
who are SPC-appropriate diffused across all providers, disci-
plines, and cost centers, most hospital administrators will have
little understanding of the nature of their care and the costs and
reimbursement thereof. As a result, the SPC-appropriate popula-
tion is almost entirely “under the radar” for administrative and
clinical leaders in most institutions. Even the health services
research that examines the high cost and high intensity of typical
hospital care near the end of life4–6 will not necessarily resonate
with hospital administrators who are concerned about their own
patients and providers. One of the critical differences that PC
programs make, clinically, is to halt that diffusion of responsibil-
ity and to provide accountability for the nature and cost of the
care of such patients.
An analysis that can help to make the responsibility more
salient is presented in Table 15.1.
The first two columns represent the SPC-relevant population
as operationally defined as dying or being at high risk of death
during that inpatient episode. These 10% of hospitalizations
drive 26% of total bed days, 64% of ICU days, 33% of direct costs,
and 100% of the losses incurred from limited Medicare reim-
bursement. In the United States, the vast majority of SPC cases
are reimbursed by third-party payers, 8 which limit their pay-
ments per hospitalization prospectively.9 Therefore, this kind of
analysis can make the financial risk of “usual care” quite salient
for hospital administrators. Similar approaches can be used in
other countries and health systems where at least some infor-
mation about costs and payments per bed day can be measured
or inferred. Delving into the baseline or status quo is important
not only for eventual program evaluation but also for program
development in which it may help the nascent PC team better
understand what they could change, and it may help administra-
tors understand the costs of caring for this previously unknown
or unrecognized patient population. Conducting and sharing
financial analyses on the target population—dying or high-risk
patients—may itself be an educational intervention for adminis-
trators and department chairs, whose attention may be drawn to
that population for the very first time. From such analyses can

115
116 Textbook of Palliative Medicine and Supportive Care

TABLE 15.1  Hospitalizations of Adults, FY2011, Virginia Commonwealth University Health System, Categorized into Three
Distinct Groups, with the First Two Groups Representing the SPC-Relevant Population
All Adult Patients, All Payers Deaths High-Risk Survivors All Other Admits Total
Cases 812 1,964 24,584 27,360
Percentage of cases 3 7 90 100
Average DRG weight (case-mix index) 4.03 4.12 1.53 1.79
Percentage ICU days 20 44 36 100
Percentage total days 6 20 75 100
Average LOS 11.9 16.8 5.1 6.2
Direct cost/day $3064 $2220 $1683 $1867
Direct cost/case $36,335 $37,348 $8,628 $11,512
Direct cost/case (ratio) 4.2× 4.3× 1
Percentage cases with Medicare 49 52 30 33
All Adult Patients, Who Had Medicare Deaths Medicare High-Risk Survivors All Other Medicare Admits Total Medicare
Medicare as Their Primary Payer
Medicare cases 396 1030 7469 8895
Percentage of Medicare cases 4 12 84 100
Total costs/case $52,948 $49,109 $15,413 $20,986
Reimbursed/case $48,347 $44,256 $15,440 $20,242
Net margin (sum) ($1822,204) ($4998,219) $197,960 ($6622,463)
Source: Adapted from Cassel et al., Measuring the intensity, cost, and duration of palliative care-relevant cases among all hospitalizations in three US and UK hospitals.
Research Paper Presented at American Academy of Hospice and Palliative Medicine, New Orleans, LA, 2013.
Notes: DRG, “Diagnosis Related Group”; LOS, “Length of Stay”.

FIGURE 15.1  The specialist palliative care measurement model. The primary and secondary outcomes, starting with the patient,
ripple outward to others. The tertiary impact on institutions is a function of clinical impact. (Adapted from Cassel JB. Palliat Med
2013;27(2):103.)
Principles of Measuring The Financial Outcomes of Specialist Palliative Care Programs
come more strategic and comprehensive approaches to caring
for this subpopulation scattered in all departments and units
of a hospital.
This is a critical point for understanding why cost avoidance has
been so important for the development and expansion of SPC pro-
grams in US hospitals: cost-containment in the context of a fixed-
price reimbursement structure has a direct effect on the hospital’s
net margin. It is that impact that is then balanced with the modest
investment or subsidy that the SPC program needs, in order to show
a budget-neutral program that greatly reduces pain and suffering for
patients and families. This brings us to the third principle.
Third principle: Research has shown
that SPC reduces utilization and costs
A variety of financial and operational outcomes have been mea-
sured in the past two decades including costs, length-of-stay, inten-
sity of care (e.g., ICU days), revenues, and quality or performance
metrics such as readmission rates and mortality rates. These have
all been demonstrated or discussed as domains of interest in stud-
ies of SPC and related interventions. Higginson’s early reviews10,11
covered both SPC and related interventions that included utiliza-
tion outcomes (e.g., bed days; costs) in studies dating from 1998.
Smith’s recent review12 specifically on financial and economic out-
comes covers 46 studies published from 2002 to 2011. The latter
review found that, generally, SPC and similar interventions resulted
in significantly lower health-care costs, despite wide variation in
cost measures, methodological quality, and type of intervention.
Research in the United States on cost and utilization outcomes
has generally taken one of the two approaches: a short-term effects
(impact within the same hospitalization as the SPC encounter) and
long-term effects (impact over weeks and months following SPC
involvement, whether inpatient or community based). Short-term
effects on direct costs have been demonstrated repeatedly.8,13–16
Our first study13 was one of the earliest US studies to show that
transfer to a PC unit was associated with within-patient significant
reductions in the hospital’s direct costs per day, and also compared
to non-PCU deaths in the same hospital. White,14 also from our
program at VCU, showed that “usual care” for dying patients was
not associated with a drop in direct costs in the final days, and that
when SPC was involved, the greatest reduction in direct costs was
for patients transferred from ICUs. Penrod15 showed lower direct
costs, and less ICU utilization, among SPC patients in a military
veterans (public) health system and used propensity scores to
more rigorously match “usual care” patients to those that received
SPC. Those three studies had two limitations: they were limited
to patients who died during the index admission, and they were
limited to single sites or health systems. The Morrison et al.8 study
of eight hospitals overcame both of those limitations while con-
tinuing the use of direct costs as the appropriate cost measure,
and examining both survivors and decedents. For both survivors
and decedents, both within-patient and between-patient analy-
ses demonstrated significant reductions in direct costs, with the
matching of SPC and “usual care” groups using propensity scores
to minimize selection bias. Gade17 overcame the limitations inher-
ent in observational studies with a randomized controlled trial
of inpatient SPC, but this study did not demonstrate short-term
effects on costs or length of stay (within the index admission) for
SPC recipients. Albanese16 closely replicated the Smith13 study and
demonstrated significant reduction in direct costs for an inpatient
SPC unit, especially for patients transferred from ICUs, for whom
117
the cost reduction was almost five-fold greater than patients from
acute units. Morrison18 analyzed SPC impact but used total costs
that include indirect costs. This is the wrong cost measure to use
for such research, as it inflates the purported cost reduction attrib-
uted to SPC involvement.
Much of the research cited earlier is from observational and
quasi-experimental studies. At least five true randomized con-
trolled trials (RCTs) have been conducted on clinical SPC inter-
ventions that measured cost impact:
• Brumley19 compared palliative home care (n = 145 followed
for an average of 196 days) to usual home care (n = 152 fol-
lowed for average of 242 days) for home-bound patients with
chronic obstructive pulmonary disease, congestive heart
failure, or cancer. SPC patients had greater satisfaction,
were more likely to die at home, and had lower health-care
costs (net difference of US$7552 per patient) due to fewer
Emergency Department (ED) visits and hospitalizations.
• Gade17 compared inpatient SPC consultation (n = 275) to
usual inpatient care (n = 237) among patients hospital-
ized with a life-limiting disease; utilization and costs were
assessed across the 6 months following discharge. SPC
patients had greater satisfaction, were readmitted at the
same rate as control patients but used ICU less if readmit-
ted to the hospital, and had lower health-care costs (net dif-
ference of US$6766 per patient) following discharge.
• Higginson20 compared fast-tracked SPC (n = 25) to SPC
delivered after a delay of 3 months (n = 21) for patients
with severe multiple sclerosis. SPC was delivered in both
home and community (clinic and hospital) settings. SPC
patients’ caregivers had lower ratings of burden, and lower
total costs of care (net difference of £1789 per patient) after
12 weeks; those costs included both costs of formal health-
care as well as of informal caregiving.
• Temel randomized 151 non-small cell lung cancer patients
to usual care versus usual care plus an interdisciplinary
monthly PC team visit. Patients in the PC arm had more
prognostic awareness, less depression and anxiety, less
aggressive end of life care, less intravenous chemotherapy
in the last 60 days of life, lived 2.7 months longer,21 and cost
several thousands of dollars less per person.
• Zimmermann randomized 24 Ontario oncology clinics to
usual care, or usual care plus a PC team, with 461 random-
ized patients. By the third and fourth month, all the study
endpoints favored the group that had concurrent PC, includ-
ing quality of life, spiritual well-being, symptom severity, and
satisfaction with care. Data on cost has not been reported
yet, but hospitalizations were not increased.25
These five RCTs of SPC are notable for a number of reasons. First,
they were conducted using longitudinal assessments of health-
care costs in the 3–8 months following introduction of the SPC
intervention (not just cost reduction during a hospitalization).
They were conducted in the context of a non-fee-for-service sys-
tem: a health maintenance organization for Brumley19 and Gade,17
and England’s National Health Service for Higginson.20 All three
showed significant reductions in health-care costs, owing pri-
marily to a reduction in hospital costs.
These studies make the case that it is not inpatient SPC which
by itself reduces later ED visits and hospitalizations but rather
the provision of home care or hospice which does so. Inpatient
SPC teams by themselves can do little to manage symptoms or
118
head-off emergencies for patients outside the hospital. This leads
us to the fourth principle.
Fourth principle: Inpatient SPC reduces
costs for hospitals, while outpatient
SPC can avoid them for payers
For the most part, hospitals in the United States are reimbursed
for inpatient care by government payers (Medicare and Medicaid)
in such a way that reducing direct costs for a few days at the end of
a long and costly admission will reduce the hospital’s net loss but
will not affect the expenditures from the payers, which are pro-
spectively determined and not affected by LOS or costs incurred.
Thus, there is a financial incentive built into the inpatient pay-
ment model that has led hospitals to subsidize and support
inpatient SPC teams, which helps to improve patient care while
reducing exposure to net losses for the costliest admissions. There
is a financial incentive for entities to support the intervention of
outpatient or community-based SPC and hospice involved earlier
in the disease course,21 but it is not necessarily an incentive for
hospitals; it is, however, one for third-party payers. Third-party
payers do see less expenditure when there are fewer ED visits
and hospitalizations and when symptoms and crises are man-
aged at home, by outpatient visits, or in hospice instead.22 Note
that four US studies that took a longer term measure of utiliza-
tion and costs—Brumley,19,23 Gade,17 and Enguidanos24 —were all
conducted in the context of a health maintenance organization
which sees hospitalizations as costs, and not as revenue oppor-
tunities. Similarly, the Higginson RCT on multiple sclerosis20
and most other non-US studies take this longer term view, which
makes sense in countries with government-based and govern-
ment-funded health systems. In such settings, one does not need
to parse direct and indirect costs (which are often not available in
health systems outside the United States) and can focus instead
on the frequency, duration, and intensity of hospitalizations.7
Conclusions
Studies have demonstrated cost reduction for inpatient SPC and
avoidance of hospitalizations for hospice and outpatient or com-
munity-based SPC. One can measure financial impact merely as
a proxy for intensity of health-care utilization or as a crucial fac-
tor for garnering support for SPC programs and providers. Either
way, one should always put financial analyses in the larger con-
text of the primary and secondary outcomes that SPC achieves
for patients and the individuals around them.
KEY LEARNING POINT
• SPC may reduce costs of care as a secondary
effect of better patient care.
• SPC-relevant patients have high costs and long
hospitalizations.
• Inpatient SPC reduces direct costs of care dur-
ing those hospitalizations, and this can result in
a substantial improvement in hospital financial
outcomes and resource utilization.
• Outpatient, community-based SPC and hospice
reduce costs for payers by reducing hospitalizations.
Textbook of Palliative Medicine and Supportive Care
References
1. Seymour JE. Looking back, looking forward: the evolution of palliative
and end of life care in England. Mortality 2012;17(7):1–17.
2. Murray E. How advocates use health economic data and projections:
the Irish experience. J Pain Symptom Manage 2009;38(1):97–104.
3. Cassel JB. The importance of following the money in the development
and sustainability of palliative care. Palliat Med 2013;27(2):103–104.
4. Teno JM, Gozalo PL, Bynum JP, et al. Change in end-of-life care for
Medicare beneficiaries: site of death, place of care, and health care
transitions in 2000, 2005, and 2009. JAMA 2013;309(5):470–477.
5. Alemayehu B, Warner KE. The lifetime distribution of health care
costs. Health Serv Res 2004;39(3):627–642.
6. Barnato AE, McClellan MB, Kagay CR, Garber AM. Trends in inpa-
tient treatment intensity among Medicare beneficiaries at the end of
life. Health Serv Res 2004;39:363–375.
7. Cassel, Kerr, Skoro, et al. Measuring the intensity, cost and duration of
palliative care-relevant cases among all hospitalizations in three U.S.
and UK hospitals. Research Paper Presented at American Academy of
Hospice and Palliative Medicine, New Orleans, LA, 2013.
8. Morrison JD, Penrod JB, Cassel M, Caust-Ellenbogen A, Litke L,
Spragens DE. Meier for the Palliative Care Leadership Centers’
Outcomes Group. Cost savings associated with hospital-based palliative
care consultation programs. Arch Intern Med 2008;168(16):1783–1790.
9. Quinn K. New directions in Medicaid payment for hospital care.
Health Aff (Millwood) 2008;27(1):269–280.
10. Higginson IJ, Evans CJ. What is the evidence that palliative care teams
improve outcomes for cancer patients and their families? Cancer J
2010;16(5):423–435.
11. Higginson IJ, Finlay I, Goodwin DM, et al. Is there evidence that pallia-
tive care teams alter end-of-life experiences of patients and their care-
givers? J Pain Symptom Manage 2003;25:150–168.
12. Smith S, Brick A, O’Hara S, Normand C. Evidence on the cost and
cost-effectiveness of palliative care: A literature review. Palliat Med
2013;28(2):130–150.
13. Smith TJ, Coyne P, Cassel JB, Penberthy L, Hopson A, Hager MA. A
high volume specialist palliative care unit and team may reduce in-
hospital end of life care cost. J Palliat Med 2003;6:699–705.
14. White KR, Stover KG, Cassel JB, Smith TJ. Non-clinical out-
comes of hospital-based palliative care. J Healthcare Manage
2006;51(4):253–267.
15. Penrod JD, Deb P, Luhrs C, et al. Cost and utilization outcomes of
patients receiving hospital-based PC consultation. J Palliat Med
2006;9:855–860.
16. Albanese TH, Radwany SM, Mason H, Gayomali C, Dieter K. Assessing
the financial impact of an inpatient acute palliative care unit in a ter-
tiary care teaching hospital. J Palliat Med 2013;16(3):289–294.
17. Gade G, Venohr I, Conner D, et al. Impact of an inpatient palliative
care team: a randomized control trial. J Palliat Med 2008;11:180–190.
18. Morrison RS, Dietrich J, Ladwig S, Quill T, Sacco J, Tangeman J, Meier
DE. Palliative care consultation teams cut hospital costs for Medicaid
beneficiaries. Health Aff (Millwood) 2011;30(3):454–463.
19. Brumley RD, Enguidanos S, Jamison P, et al. Increased satisfaction
with care and lower costs: Results of a randomized trial of in-home
palliative care. J Am Geriatr Soc 2007;55:993–1000.
20. Higginson IJ, McCrone P, Hart SR, Burman R, Silber E, Edmonds PM.
Is short-term palliative care cost-effective in multiple sclerosis? A ran-
domized phase II trial. J Pain Symptom Manage 2009;38(6):816–826.
21. Temel JS, Greer JA, Muzikansky A, et al. Early palliative care for patients
with metastatic non-small-cell lung cancer. NEJM 2010;363:733–742.
22. Kelley AS, Deb P, Du Q, Aldridge Carlson MD, Morrison RS. Hospice
enrollment saves money for Medicare and improves care quality
across a number of different lengths-of-stay. Health Aff (Millwood)
2013;32(3):552–561.
23. Brumley RD, Enguidanos S, Cherin DA. Effectiveness of a home-based
palliative care program for end-of-life. J Palliat Med 2003;5:715–724.
24. Enguidanos S, Vesper E, Lorenz K. 30-Day readmissions among seri-
ously ill older adults. J Palliat Med 2012;15(12):1356–1361.
25. Zimmermann C, Swami N, Krzyzanowska M, et al.. Early palliative
care for patients with advanced cancer: A cluster randomised con-
trolled trial. Lancet 2014 May 17;383(9930):1721–1730. doi: 10.1016/
S0140–6736(13)62416–2. Epub 2014 Feb 19.
16
POPULATION-BASED NEEDS ASSESSMENT FOR PATIENTS AND
THOSE IMPORTANT TO THEM, SUCH AS FAMILIES

Irene J. Higginson and Richard Harding

Contents
Introduction........................................................................................................................................................................................................................119
Uses of population-based needs assessment................................................................................................................................................................119
What is need?......................................................................................................................................................................................................................119
Concepts of need, supply, and demand in health care........................................................................................................................................ 120
Alternative approaches to needs assessment......................................................................................................................................................... 120
Epidemiological data-based needs assessment reviews.......................................................................................................................................121
Epidemiologically based needs assessment............................................................................................................................................................122
Incorporating the evidence base and other views.......................................................................................................................................................123
Population-based needs assessment for future populations: local, national, and global....................................................................................123
Limitations of needs assessment.....................................................................................................................................................................................124
Conclusion and future issues...........................................................................................................................................................................................124
References............................................................................................................................................................................................................................125

Introduction
As palliative care services develop all across the globe, those plan-
ning, funding, and delivering services for populations of people
will seek to ensure that services are developed in a way to meet
the needs of patients and families. This is a group of the popula-
tion that is often least able to make their needs known—as Hinton
said, “the dissatisfied dead cannot noise abroad their concerns.”
So it is often left to patient groups and professionals to advocate
for them. Policy makers and planners responsible for the health-
care services to a population have to make decisions that involve
a range of health services. One way to help to plan services is to
undertake a population-based needs assessment. This approach
emerged in the late 1990s,1 based on the numbers of people dying
from progressive illnesses and their likely symptoms. Population-
based needs assessment evolved to include estimates based on the
prevalence of symptoms and problems using more focused data
from different conditions.2–6 A further advance of needs assess-
ment in the field of palliative care began in 2008 with the first
future projections of need for palliative care, using predicted
population changes in demography and mortality.7
This chapter explains the concepts of needs and shows various
methods of needs assessment. It highlights some of the pitfalls
and factors that should be considered in the different approaches.
Needs assessment in this context takes as its starting point a
community that requires palliative care, rather than individual
patients.2 It is concerned with how many people need what types
of services, where and when. The assessment of an individual
patient has occasionally been described as a needs assessment,
but this is a component of assessment to help clinical care, often
screening for problems,8 and is not considered here.
Uses of population-based needs assessment
Population-based needs assessment has successfully under-
pinned the methods of the Global Atlas for Palliative Care9 in
2014 and the Lancet Commission on palliative care and pain
relief in 2018, both of which recommended universal coverage of
palliative care.10
What is need?
Contributions to the definitions of need come from the fields
of sociology, epidemiology, health economics, and public health
as well as from clinicians. Two main underpinning theories are
those of Bradshaw and Maslow.2 Bradshaw outlined a “taxonomy
of social need.” This distinguished between felt need (what people
want), expressed need (felt need turned into action), normative
need (as defined by experts or professionals), and comparative
need (arising where similar populations receive different service
levels).11 Raised within these distinctions are the questions of
who determines need (professional, politician, or public), what
are the influences of education and media in raising awareness
about health problems, and what are the cultural effects on need.
Social and cultural factors have an enormous impact on levels of
morbidity and on health and the expression of health need. This
is particularly important in the global context as there are enor-
mous differences in need according to the income level of the
country and the specific needs of those living in low- and middle-
income countries (e.g., school fees and food security).12,13
The theory of Abraham Maslow of human motivation (devel-
oped originally in 1943) and his related hierarchy of needs has
been widely applied in social science and health care. It has also
been adapted for palliative care by Zalenski et al.14 Their five levels
of the hierarchy of needs adapted for palliative care are (1) dis-
tressing symptoms, such as pain or breathlessness; (2) fears for
physical safety, of dying or abandonment; (3) affection, love, and
acceptance in the face of devastating illness; (4) esteem, respect,
and appreciation for the person; and (5) self-actualization and
transcendence. The idea of a “fixed” hierarchy in Maslow’s theory
is now challenged. Recent research suggests that the so-called
higher order (self-esteem and self-actualization) and the so-called

119
120 Textbook of Palliative Medicine and Supportive Care

lower order (physiological, safety, and love) needs of Maslow’s

hierarchy of needs are not universal and may vary by age, cul-
tures, and circumstances,15,16 which likely include their illness.

Concepts of need, supply, and demand in health care

The abovementioned definitions of need do not take account of
whether there is an effective remedy or treatment (i.e., supply) that
can be provided for the problem experienced by the patient. Any
assessment of the health needs of a community must take this
into account. Thus, needs assessment includes both the health
problem (whether felt, expressed, normative, or comparative—or
a combination of these) and an effective humane and accessible
FIGURE 16.2  Ideal relationship between need, supply, and
remedy or treatment for this problem.17 The remedy can include
demand.
prevention, treatment, rehabilitation, and palliation. The modern
epidemiological approaches to needs assessment take account of
both health need and effective treatment.18 Figure 16.3 shows one hypothesis, where supply is smaller than
Demand in health care is a function of expressed need, demand and need. Research from the United States supports
although economists would define it as “What people would be this theory, arguing that need and demand are outstripping sup-
willing to pay for in a market or might wish to use in a system of ply.19,20 As the evidence of effective palliative care services and
free health care.” Demand, therefore, is influenced by the nature treatments increases and includes more populations, such as
of information available to patients and communities, the social those with multimorbidity,21,22 this gap will widen.
and educational backgrounds, the media, and the influence of
Alternative approaches to needs assessment
doctors and nurses. Furthermore, for any patient or family, inter-
Three main approaches to needs assessment have been devel-
pretation of information would be affected by the severity of his
oped.2 These can be used independently or in combination. A
or her illness and his or her concern about that illness. The sup-
comparative needs assessment contrasts the services received
ply of health services has been influenced by historical patterns;
by a population in one area with those elsewhere. Thus, if one
political pressures; and pressures from health-care professionals,
area has, for example, 40 hospice beds per million population,
public, media, and patients.
it might be seen as less well provided that an area with say 70
Stevens and Raftery have argued that the need for health care
beds per million population. However, such an assessment is
should be defined as “the population’s ability to benefit from
clearly limited, as it does not take account of differences between
health care.”18 They argue that need, supply, and demand partly
the populations, nor of which model of care (more beds or more
overlap but also differ. Figure 16.1 demonstrates the differences
home nursing) is most effective for the population; so, it is not
and overlap and shows eight different potential situations.18 In
recommended unless part of the assessment using other needs
the central area, need is both demanded and supplied. However,
assessments.
there may be supply where there is no need, there may be care
The corporate approach to needs assessment is based on
demanded but not needed, and there may be demand and sup-
the demands, wishes, and alternative perspectives of interested
ply without need. The aim of a needs assessment in this context
parties, including professionals, politicians, patients, and the
is to bring the circles to more closely overlap, as in Figure 16.2,
public. A variety of interview schedules and tools in many areas
so that need is demanded and supplied. The Stevens and Raftery
of health care have been developed to aid this approach.23 This
hypothesis has one major flaw, however. It makes a rather sim-
approach commonly involves surveys of professionals24–26 and
plistic assumption that need, demand, and supply are of equal
may also survey the public, patients,27 or a combination of views
size, and that reorganization of health care is a matter of lining
(for example, professionals and public).28 For example, Currow
up need, demand, and supply. In reality, this is not likely to be
the case. As part of the MSc in palliative care at King’s College
London, students from different countries report how they feel
need, demand, and supply are related and sized in their countries.

FIGURE 16.1  Relationship between need, supply, and demand: FIGURE 16.3  Are the areas of need, demand, and supply of
need = ability to benefit from health care. equal size one hypothesis?
Population-Based Needs Assessment for Patients and Those Important to Them, Such as Families 121

et al. surveyed 3,027 randomly selected South Australians on the

need for, uptake rate of, and satisfaction with specialist pallia-
tive care services. One in three people surveyed (1069) indicated
that someone “close to them” had died of a terminal illness in
the preceding 5 years—of those who identified that a palliative
service had not been used (38%, 403), reasons cited included fam-
ily/friends provided the care (34%, 136), and the service was not
wanted (21%, 86). Respondents with higher income and those
with cancer were more likely to report that a specialist palliative
care service had been used.29 Currow et al.’s approach utilized the
views of proxies, i.e., not directly the patients but bereaved care-
givers or others. The corporate approach has the potential advan-
tage of gauging the patient’s (or their families’) perspectives and
FIGURE 16.4  Three main components of an “epidemiologi-
capturing expressed need. However, surveying only professionals
cally based” approach.
captures only normative need; and there is the added problem that
expressed need is determined by the individual’s understanding
of services, which is dependent on the provision of information
often giving age- and sex-specific rates or standardized according
about palliative care. Such information can be highly varied both
to the national population.
within and between countries and should be considered when
The epidemiological approach to needs assessment’24 combines
interpreting a corporate needs assessment.
elements of epidemiology and health economics and is a triangu-
Epidemiological data-based needs assessment reviews lation of three components: incidence and/or prevalence, health
The third approach to needs assessment is the epidemiologi- service effectiveness and cost-effectiveness, and information and
cally based assessment. Epidemiological data has been applied in views about existing services. Information allows governments,
health-care planning for many years.17,30 Data on the incidence health-care funders and planners to determine the direction they
(the number of new cases arising in a given period) and preva- wish to pursue in the future (see Figure 16.4).
lence (the total number of cases existing at one time) of diseases, Because any needs assessment will usually make incremental
and demographic information on population structure and likely rather than dramatic changes to existing services and because
changes, was used by health-care planners to determine the there is little information on effectiveness and prevalence, it is
extent and impact of health problems. Epidemiological studies usually recommended that this approach is combined with the
are also concerned with the quality of measurements, including more simple comparative and corporate approaches described
the validity and reliability of tests. Population comparisons are earlier. The main components of the epidemiologically based
usually more clearly made using rates rather than crude numbers, approach to needs assessment are shown in Table 16.1.

TABLE 16.1  Components of the Epidemiological Approach to Needs Assessment (see further ref. 5)
Component
Statement of the context of the problem
Subcategories
Prevalence and incidence
Services available
Effectiveness and cost-effectiveness of services
Models of care and local assessment
Outcomes, targets, information, and research
Description
The problem in its context, including labels attached to the disease or service, e.g., international
classification of disease codes and health-care resource groups (HRGs). The context should relate
the disease to the services it impinges upon.
A division of the health problem into categories that are of value to purchasing, planning, or
providing health care. Often this is based on severity or type of problem presenting. Conventional,
medical subcategories sometimes do not help.
Prevalence and incidence data, including that available for the subcategories described and/or need
for treatment. It considers variations by age, sex, region, socioeconomic, and ethnic status.
Description of existing services defining the components, including the structures and processes as
clearly as possible.
The efficacy (benefits achieved under study—usually ideal conditions), effectiveness (the benefit
achieved in the real world), and efficiency (output or outcome of health care per unit of money
expended). Efficacy is considered first and the quality of the evidence is graded according to the
strength of design of the studies. This is followed by a statement of the strength of recommendation
to support or reject the use of the service or procedure based on the strength of the evidence.
Alternative models of providing services to meet patient’s needs. For example, one model might be
orientated toward prevention, one toward treatment, and a third model, toward education of
existing staff. An appraisal of the models and their application in different social, geographical, and
health-care settings is included.
Here local assessment of individual wishes or local data on the preferences/wishes of patients and
families can be used. It may help to decide between the amounts of different models provided.
Outcome measures or targets that might prove useful in practice to monitor services plus other
information and research needs.
122 Textbook of Palliative Medicine and Supportive Care

Epidemiologically based needs assessment TABLE 16.2  Number of Deaths in the Population during 1 Year
In several countries, now epidemiologically (or population) based for the Most Common Causes (Note: Total population =
needs assessments have developed. These all provided standard 1 million, estimate for developed country)
definitions of palliative and end-of-life/terminal care and use Cause of Death Men Women Total
national and local data on the incidence and prevalence of can-
cer, other diseases and likely symptoms to estimate the numbers Neoplasms 1460 1340 2800
of patients and families needing palliative care. The absolute Circulatory system 2430 2620 5050
numbers of patients dying from cancer and other diseases likely Respiratory system 600 630 1230
to have a palliative period are available from many government Chronic liver and cirrhosis 30 30 60
statistical departments in higher income countries. Applying Nervous system and sense organs** 90 90 180
the prevalence of symptoms to this population gives estimates of Senile and presenile organic conditions 20 20 40
the range of problems and the size of population needing care. Endocrine, nutritional, metabolic, 190 120 310
A challenge is the presumption of availability of reliable routine immunity
data, which may not be available in lower income countries, and Total of these diseases 4820 4850 9670
on locally collected symptom prevalence data. A cross-national
Total deaths from all causes 5360 5640 11,000
comparison of place of death for people living with HIV found
death certification detail varied greatly, for example, the potential Note: Deaths in those aged under 28 days excluded * and ** for breakdown of main
responses for “place of death” were different between countries, groups (see next).
making comparison challenging. 31 A systematic review found
(e.g., extension of palliative care to more non-cancer condi-
that most evidence for symptom burden has been collected in
tions), changing patterns of hospital/home care, and mul-
high-income countries. 32
tiple, rather than single, causes of death as important. Murtagh
Murtagh et al. identified and compared the main approaches
et al. therefore refined methods (using updated ICD-10 causes
to population-based needs assessment. 33 Three main approaches
of death, underlying/contributory causes, and hospital use)
were identified:
to estimate the need for palliative care and developed an
improved approach.
1. Higginson used cause of death/symptom prevalence and,
A first key change is that the ICD 10 codes can be more clearly
using pain prevalence, estimates that 60.28% (95% confidence
specified. These are outlined next, which expanded those used by
interval = 60.20–60.36%) of all deaths need palliative care.
both Higginson and Rosenwax, except for Rosenwax’ most exten-
2. Rosenwax used the International Statistical Classification
sive—which was all causes of death except poisoning, injury, and
of Diseases and Related Health Problems-10th Revision
maternal, neonatal, or perinatal deaths. The proposed diseases of
(ICD-10) causes of death/hospital-use data5,6 and estimates
Murtagh et al. were malignant neoplasm, heart disease, including
that 37.01 (95% confidence interval = 36.94–37.07%) to
cerebrovascular disease, renal disease, liver disease, respiratory
96.61% (95% confidence interval = 96.58–96.64%) of deaths
need palliative care, and
3. Gómez-Batiste used percentage of deaths plus chronic disease
data and estimates that 75% of deaths need palliative care. TABLE 16.3 Cancer Patients: Prevalence of Problems (Per
1,000,000 Population, Developing Country Context)
In the original Higginson protocol, a standard population size % with Symptom in Estimated Number
is used, for example, 1 million people. Within such a popula- Symptom Last Year of Life* in Each Year
tion, if the age and gender mix is similar to that of a developed
country, there are approximately 2800 cancer deaths per year Pain 84 2,357
and 6900 other deaths, some of which may have a period of Trouble with breathing 47 1,318
advancing progressive disease, when palliative care would be Vomiting or feeling sick 51 1,431
appropriate. Table 16.2 shows the number of deaths within a Sleeplessness 51 1,431
population during 1 year for the most common causes, and Mental confusion 33 926
Tables 16.3 and 16.4 show the likely prevalence of problems Depression 38 1,065
for patients with cancer or patients with progressive nonma- Loss of appetite 71 1,992
lignant diseases. Many regions or countries would have their Constipation 47 1,318
own actual data on the number of deaths, and it would be bet- Bedsores 28 785
ter to use these. Loss of bladder control 37 1,038
These prevalence data can then be contrasted with the num- Loss of bowel control 25 701
bers who are receiving different services in an area. Rosenwax et al. Unpleasant smell 19 533
developed three estimates of the potential palliative care popu- Severe family anxiety/ 33 930
lation, minimal, midrange, and maximal, through focus groups, worries
interviews, and the literature.5,6 The minimal estimate was based Severe patient anxiety/ 25 700
on underlying cause of death, with a restricted list, the midrange worries
incorporated hospital admission data, while the maximal esti- Total deaths from cancer 2,805
mate included all deaths except poisoning, injury, and maternal, * Symptoms as per Cartwright and Seale study, 51,52 based on a random sample of
neonatal, or perinatal deaths. deaths and using the reports of bereaved caregivers. Anxiety as per Field et al.,53
Murtagh et al. established an expert panel review of the Bennett et al.,54 Higginson et al.,55 Addington Hall et al.56
three main approaches. 33 This identified changing practice Note: Patients usually have several symptoms.
Population-Based Needs Assessment for Patients and Those Important to Them, Such as Families 123

TABLE 16.4  Patients with Progressive Nonmalignant Disease: conditions associated with end-of life and (2) chronic or acute,
Prevalence of Problems (Per 1,000,000 Population, life-threatening or life-limiting health conditions, diseases,
Developing Country Context) and injuries. It defined “serious health-related suffering” as
having physical, psychological, social, and spiritual compo-
% with Symptom in Estimated Number
nents and defined its report as focusing on the first two (physi-
Symptom Last Year of Life* in Each Year
cal and psychological).10
Pain 67 4599
Trouble with breathing 49 3363
Vomiting or feeling sick 27 1853 Incorporating the evidence
Sleeplessness 36 2471 base and other views
Mental confusion 38 2608
Depression 36 2471 In addition to the data on the prevalence of symptoms, an
Loss of appetite 38 2608 epidemiologically based needs assessment includes data on
Constipation 32 2196 the effectiveness of different models of palliative care. Rather
Bedsores 14 961 than attempt new systematic literature reviews, a variety of
Loss of bladder control 33 2265 high-quality systematic reviews and meta-analyses are avail-
Loss of bowel control 22 1510 able.21,34–41 These show that specialist palliative care has ben-
Unpleasant smell 13 892 efits, particularly in terms of pain and symptom control, patient
Severe family anxiety/ 33 2200 and caregivers satisfaction or psychological well-being, 34,37,42,43
worries 25 1600 and often results in economic savings.21 The evidence base in
Severe patient anxiety/ lower income countries and across a wider range of diseases is
worries now also emerging. 35,44–46
Total deaths from other 6,864 Gaps identified between the epidemiological information on
causes, excluding need and the services currently provided can then be appraised
accidents, injury and against the evidence and any comparative or corporate data. The
suicide, and causes very gaps may also suggest lines of enquiry in a survey of patient,
unlikely to have a caregiver, or professional views—e.g., would they prefer more
palliative period home care, hospital support or in-patient care developed. This
then suggests options for the future development of palliative
* As per Cartwright and Seale study,51,52 based on a random sample of deaths and
care services.
using the reports of bereaved caregivers. Anxiety as per Field et al,53 Bennett et al,54
Higginson et al,55 Addington Hall et al.56
Note: Patients usually have several symptoms.
Population-based needs assessment
for future populations: local,
disease, neurodegenerative disease, Alzheimer’s dementia and national, and global
senility, and HIV/AIDS.
However, limiting those included to only these underly- Populations across the world are changing, influenced partly
ing causes of death may miss some who need palliative care. by worldwide aging as a result of prevention of many infec-
Therefore, the group tested applying not only underlying cause tious and earlier stage diseases, and also treatments into later
of death, but any mention of these conditions as contributing to stages of disease. These population-based future needs assess-
the death. When only underlying cause of death was used, this ments consider the likely numbers of people needing palliative
suggested that a minimum of 63.03% (95% confidence interval = care who may die in future years, up to 2040 or beyond.7,47 This
62.95–63.11%) of all deaths needed palliative care. If any men- method calculates age- and sex-specific proportions of deaths
tion was included, the data more closely reflected levels of need from defined chronic progressive illnesses to estimate the prev-
as suggested by hospital activity in the last months of life (as in alence of palliative care need in the population. It determines
the model developed by Rosenwax et al., but without needing this average annual change in need and combines these with offi-
level of information). Simply including any death with these con- cial mortality and disease prevalence forecasts to model future
ditions as a primary or contributory cause of death gave lower palliative care. Such an approach in England and Wales found
and upper midrange estimates between 69.10 (95% confidence that projected deaths will rise by 25.4% by 2040, and pallia-
interval = 69.02–69.17%) and 81.87% (95% confidence interval = tive care need could increase by 42% in that period.47 Using the
81.81–81.93%). 2018 Lancet Commission definitions of serious health-related
It seems therefore that simple death registration data using suffering requiring palliative care, Sleeman et al. estimated
both underlying and contributory causes can give reliable esti- population-based projections of global palliative care need by
mates of the population-based need for palliative care, without world regions, age groups, and health conditions. This research
needing symptom or hospital activity data. In high-income coun- estimated that by 2060, an estimated 48 million people (47% of
tries, 69–82% of those who die need palliative care.4 This has the all deaths globally) will die with serious health-related suffer-
advantage of not requiring data linkage, from hospital activity, ing, an 87% increase from 26 million people in 2016. Serious
an issue which proved problematic when attempting to use the health-related suffering is projected to increase in all regions,
Australian method of needs assessment in Canada. with the largest proportional rise in low-income countries, and
The 2018 Lancet Commission on global palliative care most rapidly among people aged 70 years or older.48 This dou-
included in those needing palliative care: (1) all health bling of the burden of serious health-related suffering by 2060
124
requires population-based palliative care responses. Future pre-
dictions and their implications in a broader range of countries
and settings are considered further on palliative care as a public
health issue.
Limitations of needs assessment
Although the approach provides a useful model for exam-
ining health needs, it is based on assumptions that limit its
conclusions:
1. The overlapping circles of need, demand, and supply
shown in Figure 1 imply that if only need, demand, and
supply can be lined up, then need and demand will be
satisfied by supply. If demand and need are larger than
supply, they cannot be met completely, even if improved
alignment is of value. A needs assessment, where the
supply of palliative care is limited, will lead to a demand
for more resources, and health planners may not be pre-
pared for this.
2. The data available to undertake the needs assessment is
often limited. Epidemiological studies have often been
more concerned with the etiology of diseases than the
scope for benefit or need for services. For this reason,
most of the epidemiological data is reliant on estimates
from death registrations and estimates of the prevalence
of symptoms in selected populations. Death registra-
tions may not be available (particularly in low- and mid-
dle-income countries) and can be inaccurate, especially
among older people, where there may also be multiple
causes of death. Such data does not take account of the
trajectory of illness and the time period that services are
needed for. Thus, those undertaking the needs assessment
must take these limitations into account when presenting
the data.
3. Effectiveness and cost-effectiveness studies may be carried
out in communities different from that where the service
is concerned. For example, in palliative care, the well-
designed randomized control trials occurred in the United
States and not the United Kingdom. Thus, methods of
needs assessment are needed for developing contexts and
require some further development.
4. Effectiveness and cost-effectiveness are key components
in an epidemiological approach. However, humanity,
equity, acceptability, appropriateness, and accessibility
are also essential in determining the quality of the ser-
vice. However, it could be argued that without efficacy and
effectiveness these are of no value (one would not want a
humane service which had no effectiveness or was even
harmful). Nevertheless, these are important components
of care and, given that effectiveness data is often limited,
excluding such components weakens the approach. A cor-
porate assessment is often very useful in exploring aspects
of appropriateness, acceptability, and humanity, while a
comparative assessment may throw light on accessibility.
These approaches can be combined with the epidemiologi-
cally based needs assessment.
5. The model of needs assessment for palliative care is cur-
rently focused more on adults and on using patients as the
main determinant. More work is needed to develop needs
Textbook of Palliative Medicine and Supportive Care
KEY LEARNING POINTS
• There are four main elements of needs—felt,
expressed, normative, and comparative.
• Need, supply, and demand for services may not
overlap.
• There are three common approaches to needs
assessment, all of which have been used in pal-
liative care.
• A comparative needs assessment determines
need by a comparison of supply between areas,
a corporate needs assessment, by taking views
from local stakeholders.
• Both of these approaches can tend to confirm the
status quo and are limited in scope, rather than
identify groups who are missing out on care more
fundamentally.
• An epidemiological approach to population-
based needs assessment examines the incidence
and prevalence of problems, the effectiveness of
services and its availability, and views on these.
• The most recent epidemiological approaches to
population-based needs assessment can be based
on underlying and contributing cause of death
and suggest that between 69 and 82% of the popu-
lation need palliative care.
• Population-based needs assessments have been
used to underpin the major reports and recom-
mendations for universal health coverage to
include palliative care.
• The epidemiological approach can be combined
with future predictions that are increasingly
relevant.
assessments for children—although work is underway in
Wales.49 Equally, assessment of how well families are sup-
ported should be considered.50
Conclusion and future issues
The epidemiologically based needs assessment approach to
planning palliative care services has emerged in the last decade.
It has three main components: incidence and/or prevalence of
a disease or condition, effectiveness and cost-effectiveness of
services, and review of existing services. It can be combined
with corporate and comparative approaches to needs assess-
ment. This information is combined and culminates in recom-
mendations for particular procedures or interventions based on
standard criteria for the quality of evidence and an appraisal of
alternative models of care.
As the approach is time-consuming and subject to limitations,
some guidance is available, especially on the effectiveness of mod-
els of care and on incidence and prevalence guidance. However,
there is a need to further develop approaches to needs assessment
in developing countries and those where there is little palliative
care. Ideally, a template is needed, which can be applied to differ-
ent settings. Presentation of the data to local groups (statutory
and voluntary and at public meetings) can help to facilitate dis-
cussion about where services should develop in the future.
 Population-Based Needs Assessment for Patients and Those Important to Them, Such as Families
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30. Knox D. Epidemiology in Health Care Planning. Oxford: Oxford
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33. Murtagh FE, Bausewein C, Verne J, Groeneveld EI, Kaloki YE,
Higginson IJ. How many people need palliative care? A study devel-
oping and comparing methods for population-based estimates. Palliat
Med 2013;28(1):48–49.
34. Brighton LJ, Miller S, Farquhar M, et al. Holistic services for people
with advanced disease and chronic breathlessness: a systematic review
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35. Evans CJ, Ison L, Ellis-Smith C, et al. Service delivery models to maxi-
mize quality of life for older people at the end of life: a rapid review.
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36. Higginson IJ, Evans CJ. What is the evidence that palliative care teams
improve outcomes for cancer patients and their families? Cancer J
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37. Gaertner J, Siemens W, Meerpohl JJ, et al. Effect of specialist pallia-
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and meta-analysis. BMJ 2017;357:j2925.
38. Gysels M, Higginson IJ. Improving Supportive and Palliative Care for
Adults with Cancer: Research Evidence. London: National Institute of
Clinical Excellence, 2004.
39. Harding R, Higginson IJ. What is the best way to help caregivers in
cancer and palliative care? A systematic review of interventions and
their effectiveness. Palliat Med 2003;17:63–74.
40. Gysels M, Higginson IJ, Richardson A. Communication train-
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a systematic review of training methods. Support Care Cancer
2005;13:356–366.
41. Harding R, Easterbrook PE, Karus D, Raveis VH, Higginson IJ,
Marconi K. Does palliative care improve outcomes for patients with
HIV/AIDS? A systematic review of the evidence. Sex Transm Infect
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42. Higginson IJ, Finlay IG, Goodwin DM, et al. Is there evidence that pal-
liative care teams alter end-of-life experiences of patients and their
caregivers? J Pain Symptom Manage 2003;25:150–168.
43. Hearn J, Feuer D, Higginson I, Sheldon T. Systematic reviews. Palliat
Med 1999;13:75–80.
44. Harding R, Karus D, Easterbrook P, Raveis VH, Higginson IJ,
Marconi K. Does palliative care improve outcomes for patients with
HIV/AIDS? A systematic review of the evidence. Sex Transm Infect
2005;81(1):5–14.
45. Lowther K, Higginson IJ, Simms V, Gikaara N, et al. A randomised
controlled trial to assess the effectiveness of a nurse-led palliative
care intervention for HIV positive patients on antiretroviral ther-
apy: recruitment, refusal, randomisation and missing data. BMC
Res Notes 2014;7:600.
46. Harding R. Palliative care as an essential component of the HIV care
continuum. Lancet HIV 2018;5(9):e524–e530.
47. Etkind SN, Bone AE, Gomes B, et al. How many people will need pallia-
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49. Noyes J, Edwards RT, Hastings RP, et al. Evidence-based plan-
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51. Cartwright A. Changes in life and care in the year before death 1969-
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experiences of terminally ill patients. Palliat Med 1991;5:207–214.
17
MODELS OF PALLIATIVE CARE DELIVERY

Eduardo Bruera and Jessica H. Brown

Contents
Introduction........................................................................................................................................................................................................................127
Patient and family needs...................................................................................................................................................................................................127
Interdisciplinary care....................................................................................................................................................................................................... 128
Different settings for palliative care delivery............................................................................................................................................................... 128
Home������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������128
Outpatient centers..................................................................................................................................................................................................129
Consult teams in acute care facilities................................................................................................................................................................. 130
Palliative care units.................................................................................................................................................................................................131
Inpatient hospices...................................................................................................................................................................................................132
Consult teams in nursing homes.........................................................................................................................................................................132
Integration of care..............................................................................................................................................................................................................132
Conclusion.......................................................................................................................................................................................................................... 134
References........................................................................................................................................................................................................................... 134

Introduction of life, fatigue was reported to be the most common symptom,4,5

Increasing evidence points to the benefits of earlier integration of
palliative care into the plan-of-care for advanced diseases.1,2 The
optimal method in which to deliver palliative care depends on
the needs of the patient and their family, as well as the resources
available at that particular location. After a brief presentation of
the different settings of palliative care delivery discussed else-
where in this book, this chapter will attempt to provide an inte-
grated vision for palliative care programs capable of delivering
high rates of access and seamless care to patients in the palliative
stages of their illness and to their families.
Patient and family needs
Palliative care is appropriate at every stage of the disease whether
or not the patient is seeking curative treatment. By introducing
palliative care earlier in the disease process, it becomes possible
for health-care professionals to detect subtle shifts that take
place and help the patient and his family to adapt to the dis-
ease progression, redefine the goals of care, and reframe hope.
Therefore, understanding patient and family needs and expecta-
tions is very important for the patient’s care. Hui classified the
patient’s supportive/palliative care needs as emotional, social,
physical, spiritual, and informational and highlighted that they
are all associated with each other.1 Lack of adequately address-
ing these needs and expectations leads to further distress and
conflicts between patients, family members, and health-care
workers. 3
Terminally ill patients develop a number of devastating physi-
cal and psychological symptoms3 that imply the need for access to
an interdisciplinary palliative care service in order to achieve bet-
ter symptom control and psychosocial and spiritual support until
death. Patients need to have good symptom control in order to
improve their quality of life (QOL). 5 Among symptoms at the end
and pain, depression, and anxiety were reported to be the most
distressing for advanced cancer patients.4
Patients expect to be treated with dignity and respect and not
as a disease, and they also appreciate physicians who listen to
them and allow them to express their personal concerns and feel-
ings.6 Most patients expect truth telling from their physician in
an honest, timely, and sensitive manner as well as the continuity
of care and ability to participate in their plan of care, especially
when more than one option is available.6 They need interdisci-
plinary help while coping with the physical, financial, psychoso-
cial, and spiritual impact of their disease. Finally, most terminally
ill patients seek to live the remainder of their life as fully as pos-
sible until death overtakes them, rather than marking time, wait-
ing to die.6
Assisting families in meeting their needs will also lead to an
improvement in the patient’s care. Informational needs were
identified as the most important among other needs.7 Given
et al. identified three types of needs for family members of
a dying person 8: need for information regarding the disease;
need for assistance with how to structure care activities; and
continued guidance to alleviate stressors, burden, and associ-
ated depression.
Families should be provided with clear information about
physical care and comfort measures, what to expect and how
to manage symptoms as the disease progresses, treatments and
their side effects, the patient’s emotional response, and com-
munity resources. Families need assistance in monitoring and
reporting symptoms, nutritional considerations, transportation,
coordination of care, financial concerns, and coping with escala-
tion of care as the patient’s disease status declines without forget-
ting their psychosocial needs, as well as the respite care. Effective
communication between physicians and patients, along with the
patients’ families, secures the trusting partnership and helps to
ease the patient’s burden.5

127
128
Interdisciplinary care
Providing interdisciplinary care is critical in order to meet all
of the multidimensional needs of patients and their families.
Members of the interdisciplinary team (IDT) may come from
the following disciplines: occupational therapy, physical therapy,
music therapy, speech therapy, nutrition, pharmacy, clinical psy-
chology (counselor), social work, and chaplaincy (Figure 17.1).9
One strength of the IDT is the shared responsibility, decision-
making, and leadership in the support of the patient and their
family. Key aspects of the IDT are communication and collabo-
ration.10 Each team member must understand their role, be able
to carry out necessary baseline assessments, communicate their
thoughts and ideas, and work with the other members to provide
exceptional multidimensional interventions. Notably, not all
disciplines are necessary to ensure comprehensive coordinated
care for each patient. Literature suggests that the palliative care
physician and the nurse are required as core members, and other
health professionals are added as determined by the needs and
resources.11 Ultimately, the needs of the patient and family should
dictate the composition of the palliative care IDT.
In some settings (e.g., acute care hospitals), not all disciplines
are readily available. Therefore, outpatient facilities, inpatient
hospices, and acute palliative care units (APCUs) should ideally
take place geographically within acute care facilities that already
have these health-care professionals available. Otherwise, if out-
patient centers and inpatient hospices operate somewhere else,
it may be necessary to make the appropriate transportation
arrangements to allow the different disciplines to see the patients
in case these facilities do not have their own IDT.
Interdisciplinary care may be very difficult, if not impossible,
to conduct at home or in a nursing home (NH) because of the cost
of transportation of all the different disciplines to the patient’s
location. However, the possibility of video interactive techniques
for access to a social worker, counselor, pastoral care, and other
FIGURE 17.1  Disciplines that may be involved in the palliative
care interdisciplinary team (IDT).
Textbook of Palliative Medicine and Supportive Care
members of the IDT will be a promising way to stay in touch with
the patients and their families. These techniques have been used
in psychiatry for various purposes.12,13 Studies need to be done in
palliative care telemedicine to assess cost-effectiveness of these
techniques, as well as patients’ and families’ satisfaction.
The best level of palliative care delivery consists of having
multiple disciplines involved in each setting to provide care that
meets the needs of patients and families. The following para-
graphs discuss the different settings of palliative care and their
integration into a seamless network that every patient can access.
Different settings for palliative care delivery
Home
While most patients die in the hospital or an NH, surveys indi-
cate that more than 70% of people would prefer to die at home.14
Despite the existence of different models internationally, home
palliative care provides patients the possibility of a QOL and
death at home if it is the preferred place to spend his or her last
days. This setting has its own advantages and limitations and can
be challenging as well as rewarding for the patient and the family.
Grant and Lustbader discuss these issues in depth in Chapter 18.
At home, most patients have more autonomy, privacy, and free-
dom, and they also feel safer at home than anywhere else.15 The
family can potentially anticipate the loss, have a better bereave-
ment, and familiarize with death by learning that death is a nor-
mal stage of life.15 Care at home at the end of life can also reduce
the cost of care: it prevents unnecessary admissions to acute
hospitals and skilled nursing facilities and avoids an unnecessary
use of the emergency department by having nurses (backed up
by a palliative care specialist) on call 24 hours/day, 7 days/week
to provide a rapid response to changes in symptoms in the last
days of life.16
On the other hand, care at home may be difficult or impos-
sible if the patient does not wish so, lives alone or far away, cannot
afford the care expenses, or needs higher skilled care; if his family
is physically or emotionally tired, cannot deal with uncontrolled
symptoms, or cannot provide him with 24-hour care; or if the
home does not meet the minimal comfort needs.17
When providing home palliative care, the team should be able
to get early referrals, have access to an inpatient hospice unit for
possible direct admission, provide medications and home equip-
ment for the patient, be able to assess and control symptoms
using universal tools, and document visits and phone calls on the
patient’s chart.
The responsible caregiver (RC) is the member of the family who
is in better condition (health, relation, proximity, and available
time) to carry out and coordinate the care.18 The education of
the RC must be done progressively, with simple verbal, written,
and audio or video-taped instructions about how to administer
medications; evaluate symptoms, diet, hydration, hygiene and
evacuation, and position and dressing changes; organize family
tasks; and recognize death. To prevent frequent hospitalization,
the RC needs support from the medical team for (1) the best pos-
sible symptom control, (2) the availability of the team and access
to easy admissions 24/7, (3) establishment of a caring plan and a
schedule of activities, (4) anticipating the changes that can occur
in the patient’s condition, (5) reducing doubts and uncertainty,
and (6) providing material resources.
Usually, 1 month of care should include approximately two
medical visits per week, two nursing visits per week, two psychol-
ogy/counseling interviews for the patient and two for the family
Models of Palliative Care Delivery
per month, and the provision of oral and parenteral opioid anal-
gesics. When the patient’s condition is stable, medical and nurs-
ing visits can occur once weekly; in the terminal phase, one or
more visits are needed per day. However, available services can
vary dramatically in different areas of the world, particularly
regarding access to medical care.
Volunteer collaboration increases both team activity and
interaction with the community.19 After their selection and
training, the volunteers can help in evaluating patients at home
or on the phone, educate RC, offer practical support (house-
keeping, transport, etc.), and provide company for the patient
and family.
The home hospice service enables patients to live at home in
the last days of life. The demand for such services is expected
to increase in the future because of the aging population.20 This
rapidly growing concept can be a source of ethical dilemmas.21 It
is very important to have a complete discussion with the patient
and family regarding the choices and wishes of where to receive
end-of-life care, with the possibility of changing choices at any
time22: patients and families should be aware that home pallia-
tive care does neither medicalize nor technify the dying process,
and home palliative care should not be an intrusion to the pri-
vacy of their home, nor should it disturb the family life.23 Because
nonprofessional caregiving is crucial to effective end-of-life care
for patients who wish to die at home, early recognition of fam-
ily distress, validation of their role, and effective communication
by physicians may ease their burden and avoid physical illness,
emotional distress, financial hardship, and early mortality in the
caregivers.24 Furthermore, several important needs of the patient
should be recognized and met to make home death a priority. In
a recent survey that asked advanced cancer patients to rank their
end-of-life wishes, home death was toward the bottom of the
list (ranked number 28 out of 35).25 These findings highlight the
many aspects that need to be taken into account initially before
a patient can die comfortably at home. Indeed, a study by De La
Cruz et al. showed that 80% of patients with advanced cancer
had at least one moderate-to-severe symptom, as measured using
Edmonton Symptom Assessment System (ESAS), during the
last week of life in the home setting.26 Therefore, it is of critical
importance that these symptoms are appropriately addressed in
the home setting to ensure patients and their families are relieved
of suffering and symptom burden.
Outpatient centers
The number of outpatient palliative care clinics has significantly
increased over the past decade, mostly due to the growing body of
knowledge that demonstrates the benefits of early palliative care
interventions.27–30 Outpatient clinics allow patients to have access
to palliative care at an earlier phase in the disease process27,31
which ultimately leads to an improvement in the patients QOL.
For example, patients with advanced cancer often develop dev-
astating physical, psychosocial, and existential distress32–36 asso-
ciated with the disease or its treatment. 32,34,35 These symptoms
cannot be controlled appropriately33 in a standard setting based
on a physician/nurse team with a waiting area and small private
examining rooms, which do not allow interactions between the
members of different disciplines. Therefore, interdisciplinary out-
patient symptom control and palliative care clinics were devel-
oped to unify members from different disciplines in a team that
combines their assessments and formulates a plan of care33,34 that
meets the needs of patients and families in the same visit and at
the same place. The outpatient palliative care clinic helps patients
129
and their families to avoid the distress generated by the visits to
several offices located in different areas of an acute hospital.
Hui identified various outpatient settings that deliver pal-
liative care, including (1) interdisciplinary specialist palliative
care in stand-alone clinics, (2) physician-only specialist pallia-
tive care in stand-alone clinics, (3) nurse-led specialist palliative
care in stand-alone clinics, (4) nurse-led specialist palliative care
telephone-based interventions, (5) embedded specialist pallia-
tive care with variable team makeup, and (6) advanced practice
providers-based enhanced primary palliative care. 37 Each set-
ting has strengths and limitations that might make it particularly
suitable to certain clinical situations. For example, Bakitas et al.
found that the delivery of palliative care via nurse-led telephone-
based interventions was advantageous for patients in a rural area
where it was difficult to access interdisciplinary outpatient pallia-
tive care clinics. 38,39 However, interdisciplinary specialist pallia-
tive care clinics remain the gold standard for outpatient palliative
care delivery due to their ability to provide multidimensional care
to the patient and their family.
There are some specific characteristics of successful outpatient
palliative care delivery:
1. Just-in-time access: Patients need to access these consult
programs without lengthy appointments or waiting time.
It is important to encourage a drop-in approach.
2. Physical facility: The rooms need to have enough space for
a full size bed since palliative care patients are frequently
severely symptomatic and cannot tolerate long periods on
examining tables. These rooms also need enough space for
families to be able to sit comfortably with the patient. Privacy
is important for the different discussions that take place.
3. Availability of team members: A successful outpatient pal-
liative care program requires rapid access to different dis-
ciplines. Physicians and nurses are generally ineffective in
identifying problems that require interdisciplinary inter-
ventions. 33 Therefore, palliative care patients and families
should ideally be provided access to as many disciplines
as possible during the course of an initial outpatient con-
sultation. Further follow-up may not be required by all
disciplines.
One problem associated with outpatient palliative care centers is
the lack of timely referrals. In one study, El Osta et al. showed that
the median time between the first palliative care visit and death
of advanced cancer patients was 42 days.40 However, the period of
advanced cancer diagnosis by medical oncologists to death was
250 days, suggesting that there were considerable opportunities
for earlier referral. One reason for the delayed referral of advanced
cancer patients to palliative care was the name of the service. An
anonymous survey showed that medical oncologists and midlevel
providers were more likely to refer patients to a service named
supportive care than palliative care.41 Therefore, the outpatient
palliative care program at MD Anderson is named the Supportive
Care Center. This center is operated by board-certified palliative
care specialists in all cases, and it delivers a full range of sup-
portive and palliative care services to patients at all stages of their
disease trajectory. In a study conducted by Dalal et al. comparing
outcomes after 6 months of the name change, we observed an
overall 41% increase in referrals of both inpatients and outpatients
after adjusting for institutional growth.42 In a more recent study,
Dalal et al. found that total patient activity continued to increase
each year from 2007 to 2014 in both inpatient and outpatient
130
palliative/supportive care services.43 These findings suggest that
the change in name allowed the oncologists who were reluctant
to refer patients due to the name palliative care to refer more of
their patients to both outpatient and inpatient services after the
name was changed to supportive care.
In their retrospective study, 32 Strasser et al. compared the
assessment of 138 consecutive patients with advanced cancer
referred to the outpatient clinic and 77 patients referred to a tra-
ditional pain and symptom management clinic. The two groups
were similar in tumor type, demographics, and symptom bur-
den. Patients of both clinics were evaluated using the same tools:
ESAS,44 Cut Down, Annoyed, Guilty, Eye-Opener (CAGE) ques-
tionnaire,45 and Mini-Mental State Questionnaire46 (MMSQ).
In addition to a physician and a nurse, the patient was assessed
by a social worker, physical and occupational therapist, pharma-
cist, clinical nutritionist, pastoral care worker, and psychiatric
nurse practitioner. The outpatient clinic had no waiting area, and
patients had their own private rooms with a full-sized bed and a
bathroom. After the patient’s evaluation, the IDT discussed the
assessment, interventions, and recommendations in a team con-
ference. The patient, as well as his oncologist and primary care
physician, received a handwritten and audio-taped47 form of the
team conference. A follow-up visit was scheduled within 1–2
weeks of initial assessment32 and monthly thereafter; otherwise,
follow-ups were provided per patient or family needs at the out-
patient clinic32 or over the phone. 33 Patients from the outpatient
clinic received a total of 1066 nonphysician recommendations
(median 4 per patients, range 0–37) in a 5-hour assessment. In 83
patients interviewed after the outpatient clinic visit, satisfaction
was rated as excellent in the following areas: caring team mem-
bers, adequate assessment, treatment plan, useful recommenda-
tions, and time spent.
In contrast, the duration of the pain and symptom manage-
ment clinic assessment, done only by a physician and a nurse, was
30–45 minutes. There were no nonphysician recommendations
given; instead, eight patients were referred to specialists in psy-
chiatry, three to rehabilitation, and three to social work. 32
In conclusion, the interventions of an interdisciplinary half-day
symptom control and palliative care clinic can result in the reduction
of the physical and psychosocial distress of patients with advanced
cancer,32,33 high number of physician and nonphysician specific care
recommendations,32 and high levels of patient satisfaction.32,33
Few studies have evaluated the outcomes of the outpatient
palliative care consult on the treatment of cancer pain at the
first follow-up visit. Yennurajalingam et al.48 reviewed 1612
consecutive cancer patients whose symptoms were evaluated at
the outpatient palliative care center between January 2003 and
December 2010 at the first referral (or baseline) and at the first
follow-up visits to determine the pain intensity changes after the
palliative care intervention. The median of the first follow-up visit
from baseline was 15 days. They found that 462 (29%) patients had
no-to-mild pain intensity, 511 (32%) patients had moderate pain
intensity (4–6), and 639 (39%) patients had severe pain intensity
(7 or above) at baseline ESAS. A total of 728 (45%) patients had
their pain improved at the first follow-up (at least 2 points or at
least 30% intensity reduction from the baseline); among them 228
(31%) patients still reported pain scores of 4 or above at the first
follow-up. Among the patients with no-to-mild pain intensity,
147 (32%) had worse pain at the first follow-up visit.
Using the same patient database, Kang et al.49 showed that
patients with no-to-mild symptom intensity at baseline ESAS
had worse symptoms at the first follow-up, whereas patients with
Textbook of Palliative Medicine and Supportive Care
moderate-to-severe symptom intensity at baseline ESAS had a
significant improvement of their symptoms at the first follow-up.
Of note, the latter patients still had a symptom intensity rated 4
or above on ESAS at the first follow-up.
While these findings are encouraging, a considerable amount
of patients remain in moderate-to-severe symptom distress, dem-
onstrating that frequent follow-up visits should be required to
optimize symptom control for patients.
Consult teams in acute care facilities
Consult teams in acute care facilities act as a bridge between the
palliative and active models50,51 of care by providing access to pal-
liative care services at a time when the patient is still receiving
active treatment.
In a retrospective study, 50 Jenkins et al. reviewed the charts of
100 consecutive cancer patients who had been referred to a pal-
liative care consult team within an acute care hospital during a
6-month period. The palliative care consult team consisted of a
physician and a nurse trained in palliative care and available on
a full-time basis. Demographic characteristics, including rea-
son for admission and disease status upon admission, length of
stay, length of time from consult to discharge, admission loca-
tion, and code status on admission and discharge were recorded.
Symptom acuity, cognitive status, and risk for substance abuse
were evaluated, respectively, using the ESAS,44 CAGE45 question-
naire, and MMSQ.46 Medications before and after the consult
were compared to the recommended medications; compliance of
the primary team with the consult team recommendations was
assessed. Five patients were not palliative at the time of the con-
sult. Only 46/95 (48%) were known to have untreatable cancer at
the time of their admission. The CAGE questionnaire for alco-
holism and the MMSQ were abnormal in 19/78 (24%) and 40/91
(44%), respectively. The most intense symptoms, as measured by
the 100-mm scales of the ESAS, were fatigue (72 ± 24), appetite
(60 ± 32), and well-being (50 ± 29). Eighty-nine of the 95 patients
were living at home prior to admission and 34/95 (36%) were able
to return home. The median length of time between consultation
and discharge was 6 days50 (5 days in a recent study52 carried out
by O’Mahony et al.). Twenty patients died during hospitalization,
23 were transferred to a PCU, and the remaining 18 were dis-
charged to another hospital or long-term care facility. Two-thirds
of the patients were on dimenhydrinate as antiemetic by their
primary team, 4% of the patients had neuroleptics ordered before
the consult compared with 19% for whom neuroleptics were rec-
ommended, 22% of the patients were not prescribed opioids, and
54% were prescribed opioids on an as-needed basis. The patients’
physician complied with the palliative care consult team’s recom-
mendations in 122/137 cases (89%).
Hospitalization of terminally ill patients is a pivotal time in
their disease course. In this study, 50 52% learned that they were
palliative during this hospitalization. The consult team was able
to rapidly assess and treat patients, verify a terminal diagnosis,
and ensure that medical options have been exhausted. By provid-
ing alternative palliative care resources and placement options,
the consult team helped in reducing the number of patients
admitted to the hospital for social reasons, 50 hospital charges, 52
length of stay, 50,52 and interunit transfers.52 Using the tools cited
earlier,44–46 the consult team was able to help the primary team
in detecting the missed delirium in about half of the patients and
assessing and managing cancer pain, as well as opioid side effects
and other symptoms related to the cancer, more effectively. The
high rate of adherence to the consult team’s recommendations50,52
Models of Palliative Care Delivery
suggests that the primary team was able to incorporate palliative
care approaches into the management of acute patients. Higher
adherence rate (>90%) was reported in a recent study carried out
by O’Mahony et al. after evaluating data regarding 592 consecu-
tive patients seen by their palliative care consult team during a
16-month period.52
Additionally, timely referral to palliative care consult teams has
been shown to dramatically reduce the amount of time patients
spend in the hospital, leading to a decrease in overall health-care
charges. In a recent retrospective study, Macmillan et al. looked
at early palliative care consults in patients with various chronic
medical conditions, including cancer, at a university-affiliated
community-based urban acute care hospital.53 They found a
significant difference in the median length of stay for patients
referred to palliative care consultation services within 24 hours
of being admitted to the hospital versus patients not referred (4.2
days versus 9.7 days, P < .001). Consequently, the total cost of hos-
pital charges significantly decreased from $95,300 (patients not
referred) to $38,600 (patients referred within 24 hours). These
results further support the early referral of patients to palliative
care, along with displaying the importance of palliative care con-
sult teams in acute care facilities.
Palliative care units
A PCU, more recently called an APCU, is designated for termi-
nally ill patients who require intensive involvement of a specialist
IDT able to manage their complex problems. von Gunten defined
it as an academic medical center where specialist knowledge for
the most complex cases is practiced, researched, and taught.54
Given the complexity of the physical, psychosocial, and spiritual
nature of the PCU patient population, the ideal location for such a
unit is in an acute care hospital that offers a full range of diagnostic
and interventional procedures, along with support services includ-
ing specialty and subspecialty consultations. The PCU staffing
includes palliative care specialists, nurse practitioners, registered
nurses, research nurses, licensed practical nurses, nursing atten-
dants, a chaplain, a social worker, a physical therapist, an occupa-
tional therapist, a pharmacist, a clinical dietician, a palliative care
counselor, a clerk, and volunteers. The optimal unit size for staff-
ing efficiency is 16–24 beds and the minimum size is 10–12 beds.55
Fournier discusses this setting in depth in Chapter 26.
One example of a PCU is the Edmonton Regional Palliative
Care Program (ERPCP) PCU in Canada.56 The ERPCP is a pub-
licly funded program that provides a comprehensive range of
palliative care services, including home care and specialist con-
sultation in the community, long-term care, hospices, ambulatory
care, and acute care settings. Its PCU is located in an acute care
teaching hospital, and it has 14 beds. Amenities include a patient
smoking room, a family lounge, a kitchenette, a quiet room,
and a conference room. Family members may stay overnight if
they wish, and pets are allowed. Referrals are screened after a
direct patient assessment by the palliative care consultants. Such
patients are referred for acute symptom control, emotional and
family distress, difficult discharge planning, and rehabilitation.
As discussed in Chapter 26, the PCU is intended to be a short-
term place of care until symptoms have stabilized sufficiently
to allow discharge of the patient to another palliative care set-
ting; the expected length of stay is less than 2 weeks. The goal of
admission and its temporary nature should be discussed with the
patients and their families. Most patients are asked to agree elec-
tively to a do-not-resuscitate status prior to admission. Discussing
do-not-resuscitate status is a valuable opportunity to clarify the
131
patient’s and family’s understanding of the illness, prognosis, and
goals of care.57 The tools used daily for assessment are ESAS,44
CAGE questionnaire,45 MMSQ,46 Edmonton Staging System
(ESS) for cancer pain, 58 Edmonton Labeled Visual Information
System59, Edmonton Functional Assessment Tool60 (EFAT), pal-
liative performance score61 (PPS), and constipation score.62 A
family conference coordinated by the social worker and attended
by the team, the patient, family members, and friends whom the
patient wishes to involve is often advisable to clarify goals and
establish plans of care and further discharge to a more appro-
priate palliative care setting that will satisfy their needs. Patients
have the option not to be present at the family conference.
For those patients who are discharged home, clear and timely
communication with community health-care providers (e.g.,
primary care physician, home care manager, and pharmacist) is
critical. Transfer to a hospice may pose a difficult transition for
the patients and their families because of their need to adjust
to a new environment and staff and most importantly because
they may view hospice as a lower level of care and feel a sense of
abandonment.63 These concerns may be alleviated by explaining
to them that the fact that the patient does not require treatment
in a PCU is a positive outcome and that the option of coming back
is possible if the symptoms exacerbate and the patient decides so.
The PCU provides an excellent environment for research in
which all the IDT’s medical members are expected to partici-
pate. Since patients are under direct care of the medical team,
the process of screening and recruiting them for studies becomes
easier. The PCU of the ERPCP receives undergraduate and post-
graduate medical trainees from the University of Alberta on a
regular basis. Clinical teaching is enhanced by journal club,64
held three mornings a week, during which time-relevant articles
to palliative care are presented and discussed. Other educational
activities include tests taken before and after the residents’ PCU
rotation,61 seminars, weekly grand rounds, and presentations
from other specialists sharing their expertise as applied directly
or indirectly to palliative care.
In order to determine the optimal setting of palliative care deliv-
ery, Casarett et al.64 conducted a nationwide telephone survey with
one family member of each of the 5901 patients who died in one of
the 77 Veterans Administration medical centers that offered pal-
liative care consultation services and dedicated PCUs between
July 1, 2008, and December 31, 2009. The survey consisted of
one global rating item and nine core rating items describing the
patient’s care in the last month of life. Families of patients who
received care in PCUs were more likely to report excellent care
than the ones who received a palliative care consultation (adjusted
proportions: 63 vs. 53%; OR (Odds Ratio), 1.52; 95% CI (Confidence
Interval), 1.25–1.85; P < .001). The authors found that care received
in PCUs offered more improvements in care through communi-
cation, providing physical, emotional, and spiritual support than
those achieved with the palliative care consultations during the
last month of life.
Another example is the APCU at MD Anderson, which was
established in 2003 and has since demonstrated an increase in
overall hospital mortality rate, financial feasibility, and successful
reduction of distressing symptoms in advanced cancer patients.65
Another APCU was established in 2007 at the Montefiore
Medical Center, for the treatment of all patients with palliative
care needs.66 Typical characteristics of these APCUs include a
private room that can accommodate the patient and a companion,
a conference room for family and staff meetings, and the presence
of an IDT. Studies show that both APCUs provide cost-effective
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palliative interventions for patients with advanced cancer (MD
Anderson) or chronic illnesses (Montefiore Medical Center).65,66
Inpatient hospices
Hospice is a model designed to provide care at the end of life.
The goal of hospice is to palliate the suffering at the end of life by
addressing the emotional, social, physical, and spiritual needs of
the patient and their family. Inpatient hospice care is the highest
level of care within a hospice program. It is designed to control
physical suffering and support family and patients when such
care is not manageable at home.
The majority of inpatient hospices are staffed by at least one
full-time physician trained in palliative medicine, nurses, physio-
therapists, occupational therapists, social workers, and chaplains
and offer bereavement support services. In addition to providing
inpatient end-stage care, patients are admitted for symptom con-
trol, rehabilitation, and sometimes respite care.
Statistically, five independent factors were found to predict
inpatient hospice care: pain in the last year of life, constipa-
tion, breast cancer, being under 85 years of age, and being
dependent on others for help with the activities of daily liv-
ing between 1 and 6 months before death. 67 Hinton demon-
strated a higher rate of admission from patients receiving PHC
over those that were living alone or with unfit relatives and
those with breast cancer. 68 One study of data relating to cancer
deaths showed that patients accessing palliative care services
were significantly younger and had longer survival times from
diagnosis. 69 An analysis of place of death of cancer patients
demonstrated an increased likelihood of dying in a hospice if
they lived close by.70
In the United States, cancer diagnosis accounted for 30%
of hospice admissions during 2017 while non-cancer diseases
accounted for 70%: end-stage heart disease and dementia were
the most two common terminal illnesses.71 While routine home
care was the most common level of hospice care, accounting for
approximately 98% of all hospice days in 2017, inpatient hospice
care only accounted for approximately 1.5% of days.72 One reason
for this is that compared to home hospice care, inpatient hospice
care is not cost-effective, which creates a huge barrier for the use
of such services.
Consult teams in nursing homes
More than 25% of Americans die in an NH.73 Considerable evi-
dence indicates that NH residents do not receive optimal end-
of-life care,74,75 their pain is undertreated,76 and they are often
transferred to an acute care setting to receive aggressive rather
than palliative treatment in the last weeks of life.77,78 Therefore,
families express dissatisfaction with the end-of-life care that their
loved ones receive in NHs.79 Hospice care may improve the qual-
ity of end-of-life care for NH residents, but it is underutilized by
this population, in part because physicians are not aware of their
patients’ preferences.74
Casarett et al. carried out a randomized controlled trial of 205
NH residents and their surrogate decision makers in 3 US NHs
to determine whether it is possible to increase hospice utilization
and improve the quality of end-of-life care by identifying residents
whose goals and preferences are consistent with hospice care.74
A structured interview identified NH residents whose goals for
care, treatment preferences, and palliative care needs made them
appropriate for hospice care. Of the 205 NH residents, 107 were
randomly assigned to receive the intervention, and 98 received
usual care. Intervention residents were more likely than usual
Textbook of Palliative Medicine and Supportive Care
care residents to enroll in hospice within 30 days (21/107 [20%]
vs. 1/98 [1%]; P < .001 [Fisher exact test]) and to enroll in hospice
during the follow-up period (27/207 [25%] vs. 6/98 [6%]; P < .001).
Intervention residents had fewer acute care admissions (mean:
0.28 vs. 0.49; P = .04 [Wilcoxon rank sum test]) and spent fewer
days in an acute care setting (mean: 1.2 vs. 3.0; P = .03 [Wilcoxon
rank sum test]). Families of intervention residents rated the resi-
dent’s care more highly than did families of usual care residents
(mean on a scale of 1–5: 4.1 vs. 2.5; P = .04 [Wilcoxon rank sum
test]).
In conclusion, by increasing early access to hospice care in an
NH setting by a simple and prompt communication interven-
tion, pain will be better controlled, inappropriate medications
as well as physical restraint use and acute hospital’s admissions
will decrease, and families’ satisfaction of end-of-life care will
increase.74
Integration of care
Figure 17.2 summarizes the different components of palliative
care delivery. Home is considered the center of palliative care
delivery since most patients and their families prefer to stay at
home as long as possible,23 and during all the early stages of the
illness, patients receive all their care while residing at home.
From home, a patient can be moved to an acute care hospital
(e.g., patient develops hematemesis), to a PCU (e.g., control of
severe symptoms or psychosocial distress), or even to an inpa-
tient hospice unit in case the RC becomes ill or needs a respite.
Of note, patients can also be transferred from one setting to
another within this model based on their as well as their family
needs (e.g., after controlling an acute exacerbation of a right arm
pain in a PCU, a patient can be moved to an inpatient hospice
unit while awaiting his caregiver to recover from a severe flu; the
same or a different patient can be transferred from an inpatient
hospice unit to an acute care hospital after a hip fracture second-
ary to a fall from his bed; again, the same or a different patient
can be transferred from a surgery floor to a PCU if he/she devel-
ops a delirium that the surgeon cannot manage appropriately).
In any of these settings, the discharge plan would be directed,
FIGURE 17.2  Home as the center of palliative care delivery.
Models of Palliative Care Delivery
if practical and desirable, toward returning the patient home to
spend his last days surrounded by his loved ones.
During the past several decades, terminally ill patients were
increasingly dying in acute care settings.80–82 With the recent
changes in healthcare, there is greater emphasis on providing care
at home and supporting families to enable more home deaths.82,83
Since home death may not be simple, practical, or desirable in
every family situation,82–85 there is a need for an objective way to
assess the viability of a home death in each family situation. Home
death is not universal and has its limitations. Decreased support,
symptom distress, and inability of the PHC and caregivers to meet
patients’ needs make peaceful death at home impossible. Also,
patients and caregivers can change their minds about their desire
for a home death as their circumstances change.17,86 In these cases,
the patient has to be moved to a higher skilled setting.
Indeed, the most important aspects of this model are the dif-
ferent arrows connecting the different settings of care. The flow
of the patient needs to be seamless, and this is facilitated by using
compatible assessment tools, similar treatment and counsel-
ing protocols, and frequent communication among the different
teams, using videoconferencing, regular teaching rounds, or bus
rounds. However, the different settings do not need to have a uni-
fied ownership or administrative structure to be able to meet the
goal of seamless patient and family care.
Inpatient care can be delivered, in decreasing order of patient
and family distress, at the PCU, by consult teams in acute care
hospitals, or in hospices. In a review of admission data for all
patients discharged from the ERPCP from November 1, 1997 to
October 31, 1998, patients with high symptom distress, positive
screening for alcoholism, and poor prognostic indicators of can-
cer pain (ESS66 > 0/5) were referred to the PCU, while those with
a lower level of distress, negative screening for alcoholism, and
better prognostic indicators (ESS = 0) were treated in acute care
hospitals, hospices, and the community.4
The availability of a palliative care consult team allows patients
access to palliative care at an early stage of their illness, when they
are still receiving active treatment and are still candidates for car-
diopulmonary resuscitation.50 It has reduced significantly hospi-
tal charges52 as well as length of stay, 50,52 interunit transfers, 52 and
admissions for social reasons.50
Integration of palliative care requires action at different levels
of palliative care delivery and education: (1) educating patients,
families, and referring physicians on the benefits of palliative care
and simultaneous care; (2) increasing the availability of outpa-
tient palliative care clinics to enhance earlier referral to palliative
care; (3) increasing the availability of PCUs to improve symptom
control and emotional suffering at the end of life; (4) encouraging
physicians to participate regularly in family conferences and pal-
liative care educational rounds, and similarly encouraging pallia-
tive care specialists to attend physician boards to increase earlier
referral to palliative care; (5) enhancing the education of medical
fellows in core competencies related to palliative care to prompt
more timely referrals to palliative care; and (6) dedicating more
resources toward research in the models of palliative care inte-
gration and clinical outcomes.
The availability and degree of integration of palliative care at US
cancer centers vary widely between NCI and non-NCI designated
cancer centers despite the significant increase in the number of
palliative care programs in the past decade. Hui et al.27 conducted
a survey of 71 NCI and 71 non-NCI designated cancer centers
between June and October 2009. NCI-designated cancer centers
were significantly more likely to have a palliative care program
133
(98 vs. 78%; P = .002), at least one palliative care physician (92 vs.
74%; P = .04), an inpatient palliative care consultation team (92 vs.
56%; P < .001), and an outpatient palliative care clinic (59 vs. 22%;
P < .001). Few centers had dedicated palliative care beds (23%) or
an institution-operated hospice (37%). The median (interquartile
range) reported durations from referral to death were 7 (4–16),
7 (5–10), and 90 (30–120) days for inpatient consultation teams,
inpatient units, and outpatient clinics, respectively. Executives
were supportive of stronger integration and increasing palliative
care resources. A more recent survey showed that while there
had been an increase in the number of outpatient palliative care
clinics between 2009 and 2018 (59 vs. 95%; OR 13.1, 95% CI 2.6–
66.8; P = .0004), there was no significant growth in PCUs (26 vs.
40%), inpatient palliative care consultation team (92 vs. 90%), or
institute-run hospice (31 vs. 18%).87 Possible reasons for the slow
growth of PCUs include issues with staffing, space, and funding.
In the outpatient setting, the interdisciplinary outpatient clinic
allows a better integration of care between a cancer center and
community-based physicians and nurses. It also allows patients
access to multiple disciplines that are not available outside ter-
tiary centers. 33
The two main issues in deciding the setting of care are the
level of distress and available support. The patient’s distress may
be physical, psychosocial, or spiritual and can be measured with
the ESAS,44 the Memorial Delirium Assessment Scale (MDAS), the
McGill Quality of Life Questionnaire88 (MQOL), the EFAT,60 the
PPS,61 the constipation score,62 and others. The level of support
can be determined by the structure and function of the family,
financial status, medical insurance, and overall physical condi-
tion of the home.
If there is worsening of the physical and the psychosocial dis-
tress, the patient has to be transferred to an acute care hospital
where he/she will have access to many disciplines (e.g., consult
teams or PCU). Once the distress is controlled, the patient can
be moved to the community or home if they have good social and
financial support. Otherwise, a transfer to an inpatient hospice
unit would be more appropriate. If the distress could not be alle-
viated or the support could not be provided, the patient would not
be able to return home and might die in an acute care hospital or
in the inpatient hospice unit (Figure 17.3).
The MDAS is a widely used and validated screening tool for
delirium in cancer patients. In a pilot study conducted by Fadul et
al.,89 31 palliative care health professionals obtained the correct
diagnosis of delirium in 90–100% of the time on three simulated
patients’ scenarios after they received a training session on the
MDAS. The authors concluded that MDAS provided an accurate
test to diagnose delirium once palliative care health professionals
were trained on how to use it. Further research in the palliative
care clinical setting is needed to further confirm these results.
MDAS has replaced MMSQ and is being used by our palliative
care providers as a tool to diagnose delirium.
In summary, palliative care services should match the needs of
patients and families. These services can be provided in an inpa-
tient or outpatient setting. Inpatient care can be delivered in PCUs,
acute care hospitals, and the inpatient hospice units. Outpatient
care can be delivered at home, in NHs, or in outpatient clinics.
No single palliative care program needs to have all of these
components. These settings can be owned by one institution or
can have different owners to integrate palliative care delivery.
Most importantly, every palliative care patient should be able to
have access to any of these settings in a seamless way appropriate
to their needs.
134
FIGURE 17.3  Matching palliative care services to the patient
and family needs.
To reach a seamless network for the delivery of care, palliative
care programs should have resources: agreement between dif-
ferent settings, bus rounds, common assessment tools, common
treatment guidelines, and regular communication (audiovisual:
patient care and education).
Conclusion
In more than 30 years since the inception of the modern hospice
movement, a number of clinical programs have emerged. These
programs have demonstrated their value in a number of specific
patient populations.
One of the greater challenges has been to make it possible for
patients in different regimens of the world to access the system
that is most appropriate to their needs (i.e., home care as com-
pared to inpatient hospice or inpatient acute care facility). In
addition, a setting that is appropriate for a patient at a certain
time, that is, a patient’s comfort at home with home care, may be
inappropriate when there is complete family burnout or severe
aggravation of symptom distress.
One of the greatest challenges is to have seamless care so that
patients at any given time are able to receive palliative care in the
setting that is most appropriate to their needs. There has been
significant progress in recognizing that the different settings
described in this chapter are complementary rather than compet-
itive. There is still considerable need for research on the best way
to integrate these different programs into a seamless network.
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18
HOME PALLIATIVE CARE

Heather Grant and Dana Lustbader

Contents
Introduction........................................................................................................................................................................................................................137
Identifying the seriously ill population..........................................................................................................................................................................137
Scope of service..................................................................................................................................................................................................................138
Models of home palliative care........................................................................................................................................................................................138
Metrics and measurement...............................................................................................................................................................................................139
Barriers.................................................................................................................................................................................................................................140
Conclusion...........................................................................................................................................................................................................................140
References............................................................................................................................................................................................................................140

Introduction payers, provider groups, and community resources). Factors used

Home palliative care programs have experienced rapid growth,
largely driven by the failure of a complex and poorly coordinated
health-care system to adequately meet the needs of people with
serious or complex chronic conditions. These individuals often
find themselves in the emergency department or hospitalized
for medical conditions that could be more safely managed at
home.1 Unfortunately, frail medically complex patients are often
instructed to go to the emergency department as medical prac-
tices are poorly equipped to manage these patients, especially
during off hours or weekends. Functional limitations and inad-
equate social support make it challenging for vulnerable patients
to prioritize or even get to their physician’s office for care.2 These
patients are too sick to benefit from telephonic only case-man-
agement programs that deliver monthly outbound calls but fail
to provide in-home support or 24/7 availability with bidirectional
calling. 3 While seriously ill, these patients are not terminally ill
or willing to forgo disease-directed therapies and are, therefore,
not eligible for hospice care, which also requires a prognosis of
6 months or less to live.4
In an effort to fill the health-care void between single organ
disease management and hospice, home palliative programs
have emerged. 5 They have formed through a variety of orga-
nization types, including large hospital health systems,6 home
health agencies, hospice providers, accountable care organiza-
tions (ACOs), and venture funded start-ups.7 The primary goal of
these home-based programs is to provide comprehensive patient
and family centered medical care where people live: in the home,
assisted living, or long-term care facility. Innovative new value-
based payment models are evolving to better support the grow-
ing demand. This chapter explores enrollment triggers, models,
quality metrics, and challenges in the delivery of home palliative
care services.
Identifying the seriously ill population
There are more patients who could benefit from home palliative
care than there are available resources. Therefore, the specific
population to be served should be identified based on the needs
of the overall population and various stakeholders involved (e.g.,
to identify a seriously ill population include specific advanced
diseases, number of chronic comorbidities, being mostly home-
bound, frailty, and health-care utilization patterns. Using claims
data, one study evaluated a fee for service Medicare population
and found that for the 4% of beneficiaries who had a serious ill-
ness, at least one activity of daily living impairment and at least
one hospitalization in the prior 6 months, the average annual
health-care cost per beneficiary was $34k and the average 1-year
mortality rate was 30%.8 Others have found the seriously ill popu-
lation to have an average health-care cost of over $60k per year.
This high-cost, high-need population can be identified through
predictive modeling for home palliative care services. Triggers
for enrollment can include evidence of recent care fragmentation
(e.g., hospital admission or emergency department visit in the
prior 6 months) plus at least one of the following serious illnesses:
1. Advanced cancer (e.g., poor prognosis, metastatic, or
hematologic)
2. Heart failure (e.g., requiring home oxygen or ejection frac-
tion <40%)
3. Chronic obstructive pulmonary disease (COPD)
4. Advanced neuromuscular disease (e.g., Parkinson’s dis-
ease, amyotrophic lateral sclerosis)
5. Stroke requiring rehabilitation in a skilled nursing facility
(SNF)
6. Dementia with dysphagia, aspiration pneumonia, or weight
loss
7. Diabetes with severe complications (e.g., ischemic heart
disease, renal disease, peripheral vascular disease)
8. Hip fracture and age >80 years
9. End stage renal disease (ESRD)
10. Multimorbidity with 5+ chronic conditions
Predictive models often use payer claims data that includes seri-
ous illness International Classification of Diseases (ICD-10) diag-
nosis codes, utilization of hospital, emergency department and
SNFs, pharmacy, and demographic data including zip codes,
which correlate with social determinants of health-related risk.
When combined with markers of frailty such as the ordering
of a wheelchair, commode, or hospital bed, the evaluation of

137
138
functional status from an in-person visit and predictive models
can be useful to identify a seriously ill population likely to benefit
from home palliative care. The limitations to using algorithms for
identifying an eligible population include payer claims lag, poor
correlation between ICD-10 codes and disease burden, difficulty
capturing frailty, and the inability to identify those lacking social
support.
The surprise question may also be used to identify high risk
patients: Would you be surprised if this patient died within a
year? If the answer is no, they may be eligible and benefit from
home palliative care services. While this question performs well
in ESRD9,10 and cancer populations,11 it fell short in a primary care
setting.12 Prognosis alone may not account for symptom burden,
functional decline or the need for other psychosocial support ser-
vices in the home. It is difficult to identify a cohort of people that
reliably die in the future, especially early in the disease trajec-
tory. Less than 10% of those who end up dying within a given year
have an annual mortality prediction of greater than 50%.13 Most
people with a serious illness and high health-care spending are
not in their final year of life.14
Some home palliative care programs rely on direct referrals
from physicians, nurse case managers, or other providers. Often
these referrals are clinically appropriate but can occur late,
sometimes days or weeks before death when the patient is better
served by a direct referral to a hospice program for terminal care.
When this occurs, many non-hospice home palliative care pro-
grams make a direct referral to a local hospice provider to avoid a
delayed hospice transition during the dying process.
Cost is another potential trigger for identification of high-need
patients since over half of all health-care spending for a Medicare
population is concentrated in the sickest 5% of the population.15
Importantly, not all high-cost patients remain high cost over
time. In one study of Medicare beneficiaries, only 28% identified
as high cost, remained high cost over a 3-year period. On average,
persistently high-cost patients spent $64,434 compared to $4,538
for never high-cost patients.16 Factors that correlate with high-
cost persistency in a Medicare population include age <65 years;
dual eligible (Medicare and Medicaid); Black or Hispanic race;
ESRD; comorbidities of heart failure, or diabetes.
Home palliative care is not a one size fits all model.17 After
the initial visit, patients can be stratified by risk level for decom-
pensation, hospital admission, or death within the next 90 days.
Risk can be designated as high, medium, or low with a typical
patient distribution in each level of 20% high, 50% medium, and
30% low risk. High-risk patients can be seen in the home every 2
weeks, medium risk every 4 weeks, and low risk every 6 weeks.
Patients move between risk levels based on medical acuity, care-
giver factors, functional decline, and care transitions. Patients
are automatically high risk if they are being considered for hos-
pice enrollment, experiencing disturbing symptoms, have an
acute issue (e.g., COPD exacerbation, urinary tract infection, and
decompensated heart failure) or have recently been discharged
from a hospital or SNF. Some home palliative care programs dis-
enroll non-homebound low risk patients and refer them to outpa-
tient primary care, if they are found to have no serious illness and
no hospital admissions over a 6-month period.
Scope of service
When starting a new home palliative care program, one should
conduct a needs assessment, define the target population, estab-
lish the type of service being delivered, develop a sustainable
Textbook of Palliative Medicine and Supportive Care
business plan, outline a staffing model, and select key qual-
ity metrics to measure. The type of service being delivered can
include domains outlined by the National Consensus Project for
Palliative Care Clinical Practice Guidelines.18 Core domains and
services include
1. Medication reconciliation and management
2. Pain and symptom management
3. Advance care planning often with documentation of
Medical Orders for Life Sustaining Treatment (MOLST)/
Physician Orders for Life Sustaining Treatment (POLST)
4. Coordination of care with the patient’s other physicians
including specialists
5. Transitions of care management across settings
6. Caregiver training and support
7. Responding reliably to urgent or acute issues with 24/7
availability by phone
8. Planning for end of life, including timely hospice transi-
tions when appropriate
9. Counseling and information about community resources,
private hire home health aides, meal delivery programs,
and help with transportation needs
10. Spiritual assessment and support
11. Attention to social determinants of health
These services are provided in collaboration with the patient’s
other physicians. Some home palliative care programs provide
primary care services including prescribing refills of mainte-
nance medications when the patient is becoming homebound or
when primary care services are not readily available.
Interdisciplinary team (IDT)-based person-centered care is the
most common approach to home palliative care. Staffing models
for home palliative care teams may vary according to geographic
location, finances of the program, and needs of the population
being served. Team members may include physicians, nurse prac-
titioners, physician assistants, nurses, social workers, community
workers, and sometime pastoral care. Some patients report that
while spiritual concerns should be assessed, their needs are best
met by their own local communities of worship.19 The number of
home visits a single provider can offer is usually between 2 and
5 per day depending on drive time, patient acuity, and burden of
clinical documentation.
Models of home palliative care
A variety of innovative models of home palliative care have
evolved to fill voids in serious illness care.20 One model identified
terminally ill homebound patients with COPD, heart failure, or
advanced cancer and a prognosis of 1 year or less to live plus one
or more hospital admissions in the prior 12 months. This model
of home palliative care significantly increased patient satisfaction
while reducing the use of medical services and costs at the end of
life. Patients were also more likely to die at home.21
Some ACOs are well positioned for population health includ-
ing the care of patients with serious illness. Aligned financial
incentives can support and accelerate the growth of palliative
care services because expert management of a high-cost, high-
need population results in better outcomes with significant
financial incentives for the ACO. One of the first home pallia-
tive care programs in the northeast began in Medicare Shared
Savings Program ACO.22 This home palliative care program uses
a nurse, social worker model with physician oversight and heavy
Home Palliative Care
reliance on telepalliative care to ensure increased access to ser-
vices, especially during off hours. Another home palliative care
program in California grew out of a home health agency and col-
laborates with the hospital inpatient team to facilitate care transi-
tions from hospital to home.23
When caring for vulnerable individuals at home, lines blur
between home palliative care and home primary care.24 Home
primary care models often target a population that overlaps
with patients in need of palliative care services such as those
with debilitating or chronic progressive disease associated with
significant symptom burden. When palliative care providers
take on the primary care role, questions may arise regarding
optimal program length of stay (LOS), responsibility for main-
tenance medication prescribing, and preventative services such
as cancer screenings or the provision of flu vaccinations. The
Department of Veterans Affairs has one of the oldest home-
based primary care programs and is associated with a 25%
reduction in hospital admissions. While a longitudinal model
of care, principles of palliative care are integrated into the pro-
gram including advance care planning and symptom manage-
ment.25,26 Other models include those affiliated with integrated
health-care systems and also offer intensive home-based care
including hospital at home models for the in-home treatment of
specific conditions like community acquired pneumonia, heart
failure, COPD exacerbation, and cellulitis.27
Hospice agencies also provide non-hospice home palliative care
services to patients not terminally ill or eligible for their hospice
benefit.28 Innovative models of home palliative care have also been
supported by certain Medicare Advantage health plans which
often pay a case rate or monthly rate for members enrolled in home
palliative care programs.29
There are international models of home palliative care in
Canada, Western Europe, New Zealand, and Australia. A
Canadian model uses technology and personal support workers
to provide overnight in-home care to seriously ill patients and
are in contact with nursing staff via a smartphone application
for guidance in care.30 The Australia government funds palliative
care programs that provide community health workers, health
professionals, and caregivers in the home. 31 In India, a nongov-
ernmental agency provides home palliative care with an IDT of
physicians, nurses, and social workers with a focus on family
caregiver support. 32 In response to an audit of home palliative
care access, New Zealand allocated funds to address the educa-
tional gaps in nursing and medical school curricula. 33
Telepalliative care is the delivery of palliative care and clini-
cal information using telecommunication technologies. 34 The
use of telemedicine (e.g., video calls) increases access to pal-
liative care services for homebound individuals or those living
in rural areas. 35–37 Video visits also reduce clinician drive time,
thereby increasing availability to provide more patient encoun-
ters per day.
Telepalliative care use cases:
1. Symptom Assessment and Management—Palliative care
clinicians may perform video visits with patients and care-
givers to manage new or ongoing symptoms.
2. Advance Care Planning—Family meetings can be done
using videoconferencing. In this way, family members
living elsewhere may be included in a virtual serious ill-
ness conversation. Other members of the IDT can also
be brought in to participate on the video call to guide the
discussion.
139
3. Building Trust—Ongoing regular video visit “check-ups”
between palliative care clinicians, patients, and their fam-
ily caregivers builds trusting relationships.
4. Education—Video technology can be used for education
and training of new or less skilled team members. Palliative
care mentors not physically in the home during the visit
can provide guidance with serious illness communication,
assessments, or medical management to on site clinical
staff via a video call.
5. Caregiver Support—Emotional support can be provided
to the patient as well the caregiver. The ability to see the
patient or caregiver allows the provider to give detailed
feedback and praise for the difficult job of caregiving. “I see
how well cared for your mom looks, and her hair is so beau-
tifully styled. Did you do that?”
6. Remote Monitoring—Digital health products that provide
biometric data, wearable fall sensors, and smart speakers
that detect coughing or agonal breathing patterns show
promise in helping to manage patients with high-burden
conditions. 38 Technology is only as good as the quality and
reliability of the clinical response it prompts; monitoring
alone offers only limited benefit.
Metrics and measurement
Measuring the quality of care delivered is a foundational element
to any home palliative care program.39,40 Quality indicator sets
have been developed by the National Consensus Project Clinical
Practice Guidelines, National Quality Forum, and the National
Center for Quality Assurance.41 Metrics used to track and improve
home palliative care quality include the following measurements of
the program: (1) structure, (2) process, and (3) outcomes.
From a structural perspective, home palliative care programs
comprised an IDT, including physicians, nurses, and social work-
ers. They meet regularly, usually weekly, for IDT meetings to
review cases and quality initiatives. Most home palliative care
teams provide 24/7 coverage at least by telephone or telemedicine
for urgent issues.
Process metrics are measured by attesting to an action or
assessment being completed and can be tracked by checking a
box.42 These measures can often reach their target quickly as they
do not describe an outcome, but simply that a task was performed.
Process measures:
1. Assessment for physical symptoms
2. Discussion of emotional, psychological, and spiritual needs
3. Documentation of a health care proxy
4. Completion of a MOLST/POLST form
5. Social determinants of health assessed
Outcome metrics are more challenging to measure and include
improved care coordination, patient and caregiver satisfaction,
and increased days at home by reducing hospital admissions and
SNF days. Hospitalization, particularly for frail elders is associ-
ated with significant risk for harm, including medication errors,
functional decline, delirium, and nosocomial infection. The met-
ric of days at home highlights the importance of keeping people
well managed and at home.43
Another outcome measure is hospice utilization. While opti-
mal hospice median LOS has not been well established, care
transitions occurring in the final days of life are distressing for
patients and their loved ones. The median hospice LOS is longer
140
for patients served by a home palliative care program compared
to those receiving usual care.44,45 While home palliative care is
associated with increased hospice utilization, decedents enrolled
in a home palliative care program showed the increased number
of days at home at the end of life was independent of hospice utili-
zation but rather a direct result of the program reducing hospital
admissions.46 Interestingly, an overall reduction in all-cause mor-
tality in chronically ill older adults was associated with enroll-
ment in a community-based nursing intervention suggesting that
longitudinal in-home care may also help medically frail older
adults live longer.47
The ability to reduce total cost of care is an important out-
come.48 Several studies have demonstrated significant cost
savings with home palliative care largely driven by a reduction
in hospital admissions.49,50 Lustbader et al. showed a cost sav-
ings of $12,000 for decedents enrolled in their home palliative
care program when compared to patients who died without
palliative care services. 51 Another study demonstrated net sav-
ings, including program costs per patient per month, of $4258
for cancer, $3447 for heart failure, and $2690 for dementia. 52
The 14 practices participating in Medicare’s home-based pri-
mary care program, Independence at Home, which serves
Medicare beneficiaries with two or more high-cost chronic
conditions and functional impairment, was associated with a
16% cost savings in the final 3 months of life compared to a
control group. 53
Outcome measures:
1. Days at Home—Measures the number of days a patient is
out of a hospital or institutional setting and at home.
2. Total Per Capita Cost of Care—Includes all medical
expenses related to cost of care but excludes pharmaceuti-
cal costs.
3. Patient Experience—Survey that emphasizes patient expe-
rience, quality of communication with providers, patient
rating of provider care, getting timely appointments, and
reliable access to care when needed.
Barriers
Several barriers exist to adequately meet the need for home
palliative care services. Perhaps the greatest threat is the work-
force shortage of palliative care trained physicians, nurses, and
social workers. 54 This workforce valley is magnified by declin-
ing physician numbers as they leave the field early due to burn
out coupled with an inadequate physician pipeline to meet the
growing medical demand of an aging population. These forces
will not recover unless public policies that support high-value,
team-based palliative care are implemented. 55 Many providers
are unfamiliar with basic palliative care skills and often con-
fuse it with hospice. This is changing as more training pro-
grams incorporate core palliative care competencies into their
curriculum. 56
A second barrier to broader expansion for home palliative care
programs is drive time involved in serving a rural population.
Often referred to as “windshield time,” this nonproductive time
increases program costs due to decreased visits per day and can
make it difficult to recruit a workforce willing to spend hours in
a car each day. Leveraging telemedicine and utilizing community
health workers have helped increase the availability of home pal-
liative care to rural areas.
Textbook of Palliative Medicine and Supportive Care
A third barrier to palliative care access in the home is the lack of a
viable reimbursement model that rewards outcomes.57 Instead, we
have a payment model that financially rewards high-intensity care
and hospitalization.58 Better outcomes like keeping people healthy
and at home require timely and reliable response for symptom
burden or disease progression, especially during off hours. Most
payment models provide insufficient funds to support the compre-
hensive whole person care required for medically complex individ-
uals.59 As innovative payment models and incentives for high value
care evolve, more home palliative programs will emerge.60
Conclusion
Patients with serious or chronic complex conditions have diffi-
culty in accessing palliative care services when they need them and
where they live. Disease progression, functional impairment, and
symptom burden result in burdensome hospital admissions, added
suffering, and higher health-care costs. Home palliative care pro-
grams provide a team-based approach to care and provide support
to the patient and their loved ones in the home. These programs are
associated with improved clinical outcomes and lower health-care
costs. The need for in home palliative care services will continue
to grow since by 2050, 20% of the United States population will be
over the age of 65, and many more individuals will become func-
tionally impaired and homebound. Patients with advanced illness
want to have medical care that is aligned with their preferences and
values, reliably delivered where they live—at home.
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19
PALLIATIVE CARE UNIT

Karen Macmillan, Kelley Fournier, Beth Tupala, and Kim Crowe Mackinnon

Contents
Introduction........................................................................................................................................................................................................................143
Context.................................................................................................................................................................................................................................143
Patient selection.................................................................................................................................................................................................................143
Staffing..................................................................................................................................................................................................................................144
Assessment..........................................................................................................................................................................................................................145
Ward routine.......................................................................................................................................................................................................................145
Discharge planning............................................................................................................................................................................................................145
Education and research.....................................................................................................................................................................................................145
Outcomes.............................................................................................................................................................................................................................146
Discussion and the wider international context..........................................................................................................................................................146
Conclusion...........................................................................................................................................................................................................................147
References............................................................................................................................................................................................................................147

Introduction
The term palliative care unit (PCU) usually applies to a group
of beds designated for the care of patients with terminal illness,
located in an acute care hospital. Various models of PCUs are pos-
sible, depending on local needs, resources, system characteristics,
and philosophies of care. In some countries, these are also called
hospices within hospitals, but the term PCU is more widespread
and therefore is adopted in this chapter. Potential options in the
design of a PCU are listed in Table 19.1, each of which presents
advantages and disadvantages.1,2 Reasons for admission to a PCU
may include symptom control, end-of-life care, respite care, spe-
cial treatment and investigations, and rehabilitation.4 However,
the availability of diagnostics, procedures, support services, and
consultants in an acute care hospital makes PCUs particularly
suited to the care of patients with problems of a complex nature.
A tertiary PCU (TPCU) is a distinct type of PCU, defined as
an “academic centre where specialist knowledge for the most
complex cases is practiced, researched and taught.”1,5 The pur-
pose of this chapter is to describe and discuss the role, structure,
and operation of a TPCU, using the authors’ unit in Edmonton,
Canada, as an example to provide detailed information on staff-
ing and processes. The final section considers the wider interna-
tional context and evidence.
TABLE 19.1  Options in the Design of PCUs
Design Element
Location Inside main hospital
Admission policy Open (any physician)
Visiting hours Open
Source of admissions Direct from home
Range of procedures, Unlimited
tests
Do-not-resuscitate Required
status
Source: From Reference [1], with permission.
Context
The TPCU in Edmonton is an integral component of the Alberta
Health Services, Edmonton Zone Palliative Care Program
(EZPCP).5,6 This publicly funded program provides a compre-
hensive range of palliative care services, including home care and
specialist consultation in the community, long-term care, ambu-
latory care, and acute care settings. It also supports designated
units in long-term care facilities (i.e., hospices) for patients who
have a life expectancy of 3–4 months or less.
The TPCU is located in an acute care teaching hospital. It
consists of 20 private and semiprivate rooms in a dedicated geo-
graphical area. Amenities include a family lounge with kitchen-
ette, a laundry room, a quiet room, and a conference room. Family
members may stay overnight if they wish, and pets are allowed.
Patient selection
Admission criteria for the TPCU are listed in Box 19.1. The role
of the TPCU is to provide care for the subset of patients who
have the most complex problems and who require the intensive
involvement of a specialist interdisciplinary or interprofessional
team. The problems may be in the physical, psychological, social,
or spiritual domains. Although no limitations are placed around
diagnosis, the vast majority of patients have cancer as their pri-
mary illness. Unlike the hospice setting, life expectancy is not
Options specified. However, the TPCU is intended as a temporary place
Outside main hospital
of care until symptoms have stabilized sufficiently to allow dis-
charge to another setting. Patients are asked to agree to a do-not-
Closed (specialist only)
resuscitate status prior to admission; the pros and cons of this
Limited
policy will be reviewed later in this chapter.
In-hospital transfer only Referrals to the EZPCP are screened by the palliative care
Limited therapies consultants covering the various settings. The consultant deter-
mines, after direct assessment of the patient, whether or not a
Not required referral to the TPCU is indicated. The goals of admission to the
TPCU and the temporary nature of the admission are discussed
with the patient and family. The consultant is also responsible for

143
144 Textbook of Palliative Medicine and Supportive Care

TABLE 19.2  Staffing of the TPCU at Edmonton, Canada

BOX 19.1  ADMISSION CRITERIA FOR Type of Staff Full-Time Equivalent
THE TPCU, EDMONTON, CANADA
Registered nurses 14.3 (3–4 per shift)
• Intensive, interdisciplinary intervention required Licensed practical nurses 8.4 (3 per shift)
for severe symptom problems for which manage- Nursing attendants 8.4 (2 per shift)
ment has not been successful.
Physicians 2.5 (7 days/week)
• Symptoms require ongoing monitoring/
Chaplain 1.0
assessment.
Social worker 0.8
• When stable, patient will be discharged to the
most appropriate care setting. Psychologist 0.6
• Average length of stay is 34 weeks; exceptions are Physical therapist 0.8
expected. Occupational therapist 0.8
• Age 18+. Music therapist 0.7
• Accepts DNR status. Dietician 0.2
• Goal of care designation is either M1 or M2 Pharmacist 0.2
(medical care) or C1 or C2 (comfort care). Clinical educator 1.0
Program manager 1.0
Unit clerks 2.2
Secretaries 1.0
confirming and documenting that the patient accepts a do-not-
resuscitate status and has discussed their preferred goals of care
designation, which is reviewed later in this chapter. nursing model and work 8-hour shifts. The complexity of the
Once admission has been agreed upon, the patient’s health patient population necessitates the inclusion of a chaplain, social
records are forwarded to the TPCU. The referrals are triaged to worker, psychologist, physical therapist, occupational therapist,
determine priority. Patients are usually scheduled for admission music therapist, pharmacist, and dietician as core members of the
on weekday mornings. This allows sufficient time for a compre- team. The program manager is responsible for the organizational
hensive assessment and discussion of the goals and plan of care administrative responsibilities of the TPCU, including the triage
(Box 19.2) with the patient and family. However, admissions for process for admissions to the unit. The clinical educator supports
problems requiring urgent intervention can be accommodated 24 the team’s educational needs. The unit clerks, secretaries, and vol-
hours a day, 7 days a week. unteers play an essential supporting role.
Other hospital support services, such as respiratory therapy,
are often involved. The TPCU has a formal arrangement with
Staffing
an anesthesiology service at another acute care hospital for sup-
Staffing of the TPCU is described in Table 19.2. The patients port for procedures such as spinal administration of analgesics.
are admitted under the care of physicians who are specialists Patients may also be referred to the regional cancer center for pal-
in palliative medicine, one of whom also assumes the medical liative oncological therapies. Other specialists may be accessed
administrative responsibilities. The nurses function in a team from within the hospital as needed.

BOX 19.2  GOALS OF CARE DESIGNATIONS IN ALBERTA (BY COURTESY

OF COVENANT HEALTH, EDMONTON, ALBERTA, CANADA)
Palliative Care Unit
TABLE 19.3  Assessment Tools Used on the TPCU at Edmonton, Canada
Tool Domain Measured
ESAS-r 5 Intensity of common symptoms
Folstein mini-mental state examination11 Cognition
CAGE questionnaire13 History of alcoholism
ECS-CP7 Prognosis for achieving pain control
Constipation score15 of retained stool Quantity and location
Morphine equivalent daily dose Type, dose, and route of opioid
Palliative Performance Scale version 217 Performance status
Assessment
The tools routinely employed on the TPCU are listed in Table 19.3.
Many were developed on the TPCU itself.7–14 The tools have been
adopted in all the settings of the EZPCP.
The Edmonton Symptom Assessment System Revised (ESAS-r)
is a validated tool for measuring the intensity of common symp-
toms in palliative care patients.7 Besides providing important
clinical information on a daily basis, it has been successfully
utilized for audit and research purposes.9 The mini-mental state
examination16 is used because cognitive failure is an extremely
common and potentially distressing complication in palliative
care patients, but one that is easily missed without the use of a
screening tool.17 Identification of a history of alcohol abuse with
an instrument such as the CAGE questionnaire18 is important
because of this condition’s underdiagnosis and association with
poor pain outcomes.18b,19 The Edmonton Classification System
for Cancer Pain (ECS-CP) is a clinician-rated assessment tool
for classification of five pain features—mechanism of pain, inci-
dent pain, psychological distress, addictive behavior, and cogni-
tive function. It is a standardized, comprehensive, and simple
approach, which is used to improve clinical assessments and man-
agement of cancer pain. The assessment informs resource alloca-
tion decisions in clinical programs through early identification of
patients with complex pain syndromes. It improves communica-
tion in the interdisciplinary team members. It is a valuable tool
for accurately predicting the complexity of pain management.13
As constipation is a frequent problem in this patient population,
the constipation score is used to objectively quantify and locate
stool, based on a plain abdominal radiograph.20,21 The type, total
dose, and route of opioid are recorded daily to track patient prog-
ress. The Palliative Performance Scale version 2 (PPSv2) describes
functional status.22
Ward routine
At the beginning of the day, the nurses’ observations of the
patients during the previous two shifts are relayed to the medi-
cal and interdisciplinary teams. The physicians then spend the
morning assessing the patients and negotiating a plan of care for
the day. Interaction with the team occurs on an ongoing basis. A
team conference is held once a week during which the admissions
of the previous week are discussed in detail and a comprehen-
sive management plan is formulated. The progress of the other
patients is also reviewed, and plans are adjusted accordingly.
While discussions with patients and families take place
throughout the course of admission, a designated family confer-
ence is often advisable to clarify goals and establish plans of care.
The conference is coordinated by the social worker and attended
145
Team Member Responsible Frequency
Nurse Daily
Physician On admission and weekly
Physician On admission
Physician On admission
Physician On admission and as needed
Physician Daily
Physician On admission and weekly
by the team, the patient, and all family members whom the
patient wishes to involve.
Discharge planning
Approximately 20% of the patients admitted to the TPCU are
eventually discharged to other settings compared to 50% in 2002;
this represents the increasing complexity of patients admitted
to the TPCU and the inability to manage these patients in other
settings. Some may be able to return home. Usually, a discharge
home is preceded by a family conference that includes the home
care case manager. It is important that the patient and family
understand who will be responsible for care once the discharge
has taken place. The primary roles of the family physician and the
home care case manager are therefore emphasized. If the success
of the discharge is in question, a trial discharge is recommended,
whereby the patient’s bed on the TPCU is retained for a few days
in case the patient needs to return. Once the patient has been
discharged, a medical summary is immediately entered into our
health systems database for review electronically by the family
physician, and a copy is faxed to the home care office. Patients
whose symptoms have stabilized but who are unable to return
home may be transferred to a hospice.
A significant number of patients remain on the TPCU until
death. Some cannot be discharged because of progressive dete-
rioration, whereas others have ongoing needs that cannot be
met in any other setting. For example, hospices do not have the
resources required to manage spinal analgesics, total parenteral
nutrition, or complex respiratory care.
Education and research
All members of the team are expected to participate in educa-
tion and research. Most of the physicians have appointments in
the Division of Palliative Care Medicine of the Department of
Oncology, University of Alberta.
The TPCU receives undergraduate and postgraduate medi-
cal trainees from the University of Alberta on a regular basis.
A total of four residents and fellows may be accommodated at
a given time. Family medicine residents undertake a mandatory
2-week palliative medicine rotation on the TPCU. An analysis of
multiple-choice-question examinations given to family medicine
residents at the beginning and the end of their palliative care
rotations demonstrated a significant improvement in knowl-
edge.23 Oncology residents also spend part of their compulsory
4-week palliative medicine rotation on the TPCU. Residents in
the 1-year palliative medicine program spend 6 months on the
TPCU. Elective rotations are open to residents from other pro-
grams and to medical students. Learners from other disciplines
146
such as nursing, social work, occupational therapy, physiother-
apy, and music therapy are also welcome. The TPCU has a long
history of training palliative care specialists from across Canada
and around the world.
Clinical teaching is complemented by journal club, held three
mornings per week, during which time articles with relevance
to palliative care are presented and discussed. A survey revealed
that a majority of trainees found this activity to be of value for
education, clinical practice, and development of critical appraisal
skills.24 Other educational activities include seminars and weekly
program-wide rounds, which incorporate medical, interdisci-
plinary, and research topics. Presenters from other specialties are
invited to share their expertise as applied directly or indirectly to
palliative care, thus fostering the exchange of knowledge between
different health-care fields.
Funding for research on the TPCU is derived from a variety
of sources. The priority given to this activity is reflected in the
numerous examples of innovations in symptom assessment and
treatment developed in this setting.4–15,25–27
Outcomes
Patients on the TPCU are significantly younger and have signifi-
cantly higher frequency of positive CAGE scores, poor prognosis
for achieving good pain control, and severe symptoms. This sug-
gests that patients were being appropriately selected for admis-
sion to this setting.
In 2018, the total number of patients admitted to the TPCU
represented 7% of all patients seen by the EZPCP compared to
17% in 2002.29 Median length of stay was 14 days and bed occu-
pancy was 83% compared to 91% in 2002. Eighty-eight percent of
patients died on the TPCU, while 14% and 3% were discharged to
the home and hospice settings, respectively. The changes in these
outcomes are related to an increase of beds on the TPCU from
14 to 20 and the additional consult services available throughout
the zone. With increased specialists and expertise, many complex
symptoms can be managed in other care settings, decreasing the
need for admission to a tertiary-level setting. The annual budget
for the TPCU is approximately $4750,000, of which 85% is used to
fund salaries (excluding physician salaries, which are paid from a
separate source). Another 8% is directed toward drugs, while the
remainder is allocated for supplies.
Discussion and the wider
international context
TPCUs fulfill a unique clinical role in the continuum of care
for patients with terminal illness. They are designed to care for
patients with the most complex problems of a physical, psycho-
logical, social, or spiritual nature. In a comprehensive, integrated
palliative care program, approximately 10% of patients would be
appropriate for admission to such a unit.
Given the complexity of the patient population, the ideal loca-
tion for such a unit is in an acute care hospital that offers a full
range of diagnostic and interventional procedures (e.g., magnetic
resonance imaging, endoscopy), support services (e.g., respira-
tory therapy), and specialty and subspecialty consultation (e.g.,
anesthesiology, surgery, internal medicine, and psychiatry). For
units that admit cancer patients predominantly, access to onco-
logical consultation and therapy is essential. Indeed, it is possible
for such units to be situated in cancer centers, although access for
patients with diagnoses other than cancer may be limited. In the
Textbook of Palliative Medicine and Supportive Care
opinion of some administrators, the optimal unit size for staffing
efficiency is 16–24 beds and the minimum size is 10–12 beds. 30
The issue of requiring a do-not-resuscitate status for admission
(GCD M or C) to a PCU is controversial. This policy is based on
the finding that the chance of success of cardiopulmonary resus-
citation, defined as survival to discharge from hospital, is nil in
patients with metastatic cancer. 31 Agreement on this issue prior
to admission lessens the chance of subsequent confusion about
the overall goals of care. Furthermore, patients and families are
spared the distress of experiencing or witnessing a resuscitation
attempt. However, this policy may pose a barrier to care for those
patients who could benefit from the unit’s services but are not
willing to accept a do-not-resuscitate status. Moreover, some
palliative care specialists perceive that selected patients may
be appropriate for resuscitation, depending on prognosis, qual-
ity of life, and the patient’s wishes. 32 Whatever decision is made
regarding policy, discussion of do-not-resuscitate status presents
a valuable opportunity to clarify the patient’s and family’s under-
standing of the illness and prognosis, as well as goals of care. 33
In order that the limited resources of the TPCU may be used
for the appropriate patients, a process for screening referrals is
required. Direct assessment of the patient by a palliative care
consultant is preferred. Besides determining whether or not the
patient’s concerns warrant admission to this specialized setting,
the consultant is able to prepare the patient and family for the
type of care that will be provided on the unit. Meticulous commu-
nication between the referring and receiving teams is important
for continuity of care and to minimize unnecessary duplication
of assessments.
Given the complex nature of the patients’ problems, a special-
ist interdisciplinary team is required. The team should comprise
members who together can address the breadth of concerns of
the patients and families referred to the TPCU. Consultants from
other specialties also make a significant contribution to the care
of patients on a TPCU.
A disciplined approach to assessment and documentation of
patient’s and family’s concerns is essential for achieving the goals
of admission. First, it is a fundamental step in identifying and
characterizing the patient’s issues. Second, it allows for tracking
of the patient’s course over time and outcomes of interventions.
Third, it facilitates communication of the patient’s situation to the
various care providers involved. Finally, the data collected may be
used for program management, quality assurance, and research.
As much as possible, the tools should be validated, easy to under-
stand, not burdensome to complete, and clinically useful. Also,
they should capture the multidimensional nature of patients’
concerns. Ideally, the same tools should be used in all associated
health-care settings, as the use of a common language facilitates
transfer of care between settings and allows for comparisons to
be made among settings.28,29 The acuity and complexity of the
patients admitted to the TPCU necessitate frequent assessment,
rapid adjustment of therapies, timely communication between
team members, and careful coordination of efforts. The patient
and family must be recognized as being central to the team.
In order for the TPCU beds to remain readily accessible to
patients requiring admission, an effective and proactive discharge
planning process is required. Options for discharge depend on
local resources. For those patients who are discharged home,
clear and timely communication with community health-care
providers (e.g., primary care physician, home care manager, and
pharmacist) is critical. Transfer to a hospice often poses a difficult
transition for the patients and families, not only because of their
Palliative Care Unit 147

need to adjust to a new environment and staff, but also because

they may view hospice as a lower level of care and feel a sense KEY LEARNING POINTS
of abandonment. 34 These concerns may be alleviated by noting
that the fact that the patient no longer requires management on • Different models of PCUs in acute care hospitals
the TPCU is a positive outcome, providing reassurance that the are possible.
patient’s needs can be adequately met in hospice, and arranging • A PCU admits patients with the most complex
for families to view the hospice through virtual tours. Depending problems.
on the resources available outside the TPCU, there may also be • The key roles of a PCU are clinical care, educa-
patients who stay despite stable symptoms because their needs tion, and research.
cannot be met in any other setting. Some of these patients may • Effective use of a PCU requires a process for
remain on the TPCU for a prolonged period of time. selecting appropriate patients and for discharg-
As a setting for the management of the most complex cases, ing them.
the TPCU has an inherent mandate to transfer its knowledge to • Successful management of these patients requires
others as well as to advance the state of that knowledge. These a specialist interdisciplinary team and access to
roles are facilitated by locating the unit in a teaching hospital and diagnostic and interventional procedures, sup-
by appointing the staff to faculty positions in the university. The port services, and consultants.
TPCU presents a number of advantages as a learning environ- • A disciplined approach to assessment and docu-
ment. It provides learners with the opportunity to be exposed to mentation is essential for achieving the goals of
a broad range of problems in palliative care, to follow patients admission.
closely, to gain experience dealing with distressed families, and to
work with an interdisciplinary team, all under the direct super-
distinction between acute palliative care services and hospice ser-
vision of experts in the field. The potential disadvantage is that
vices is essential for reimbursement purposes.39
the patients and problems encountered on the TPCU are highly
selected and not necessarily representative of those encountered
in other practice settings. Also, the interventions performed on Conclusion
the TPCU may not be transferable to other settings because of
By providing specialist interdisciplinary care for the most com-
resource limitations. The TPCU provides an environment that is
plex patients, TPCUs fulfill a unique and leading role in clinical
well suited to the conduct of research. Since the patients are under
care, education, and research within palliative care programs,
the direct care of the team, the process of screening and recruit-
health-care systems, and academic centers. Further study is
ing for studies may be simpler. If the study involves medically
needed to clarify the impact of such units on clinical, economic,
complex interventions or monitoring, this may be most readily
and academic outcomes.
achieved in an acute care setting such as the TPCU. However,
patients on a TPCU have a greater degree of symptom distress
and therefore may not be well enough to participate in studies.
In addition, the results may not be generalizable to other pallia-
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The economic impact of PCUs has also been described. In a 5. Brenneis C, Bruera E. Models for the delivery of palliative care: the
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report from a 23-bed PCU in a comprehensive cancer center, costs
Care, Vol. 5. New York, NY: Oxford University Press, 2001, pp. 3–23.
were shown to exceed revenues if length of stay was greater than 6. Fainsinger R, Brenneis C, Fassbender K. Edmonton, Canada: a regional
10 days. Also, cost was inversely proportional to patient census.41 model of palliative care development. J Pain and Symptom Manage
Analysis from a palliative care inpatient service in another com- 2007;33(5):634–639.
prehensive cancer center revealed that mean daily charges were 7. Bruera E, Kuehn N, Miller MJ, et al. The Edmonton Symptom
Assessment System (ESAS): a simple method for the assessment of pal-
38% lower than in the rest of the hospital.39 Both units are charac- liative care patients. J Palliat Care 1991;7:6–9.
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discharge planning, high patient volumes, short lengths of stay, Strasser F. A multi-centre comparison of two numerical versions of the
and low mortality rates. Economic outcomes have been described Edmonton Symptom Assessment System in palliative care patients. J
Pain Symptom Manage 2011;41:456–468.
for a different model of PCU, located in an acute care facility but
9. Bruera E, Kuehn N, Miller MJ, Selmser P, Macmillan K. The Edmonton
providing terminal care for patients with a variety of diagnoses. symptom assessment system (ESAS): a simple method for the assess-
Charges and costs were 66% lower for days on the unit, compared ment of palliative care patients. J Palliat Care 1991;7:6–9.
with days in hospital prior to transfer to the unit, and almost 10. Bruera E, Sweeney C, Willey J, et al. Perception of discomfort by rela-
60% lower for patients who died on the unit versus matched con- tives and nurses in unresponsive terminally ill patients with cancer: a
prospective study. J Pain Symptom Manage 2003;26:818–826.
trols who died elsewhere in the hospital.42 Economic issues are 11. Bruera E, Schoeller T, Wenk R, et al. A prospective multicenter assess-
of course influenced by the funding mechanisms particular to ment of the Edmonton Staging System for cancer pain. J Pain Symptom
each health-care system. For example, in the United States, the Manage 1995;10:348–355.
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12. Fainsinger R, Nekolaichuk C, Lawlor P, Neumann C. Edmonton
Classification System for Cancer Pain Administration Manual.
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ClinicaNnfo/AssessmentTools/Edmonton0/o20Classif ìcation0/
o20System0/o20for0/o20Cancer0/o20Pain0/o20(ECS-CP)0/o20Man-
ual0/o20Sept10-final.pdf.
13. Fainsinger RL, Nekolaichuk C, Lawlor P, et al. An international mul-
ticentre validation study of a pain classification system for cancer
patients. Eur J Cancer 2010;46(16):2865–2866.
14. Walker P, Nordell C, Neumann CM, Bruera E. Impact of the Edmonton
labeled visual information system on physician recall of metastatic
cancer patient histories: a randomized controlled trial. J Pain Symptom
Manage 2001;21:4–11.
15. Dudgeon DJ, Harlos M, Clinch JJ. The Edmonton Symptom Assessment
Scale (ESAS) as an audit tool. J Palliat Care 1999;15:14–19.
16. Folstein MF, Folstein S, McHugh PR. ‘Mini-mental state’: a practical
method for grading the cognitive state of patients for the clinician. J
Psych Res 1975;12:189–198.
17. Bruera E, Miller L, McCallion J, et al. Cognitive failure in patients
with terminal cancer: a prospective study. J Pain Symptom Manage
1992;7:192–195.
18. (a) Ewing J. Detecting alcoholism: the CAGE questionnaire. JAMA
1984;252:1905–1907; 18(b) Parsons H, Delgado-Guay M, Osta B, et al.
Alcoholism screening in patients with advanced cancer: impact on
symptom burden and opioid use. J Palliat Care 2008;11(7):964–968.
19. Bruera E, Moyano J, Seifert L, et al. The frequency of alcoholism among
patients with pain due to terminal cancer. J Pain Symptom Manage
1995;10:599–603.
20. Starreveld JS, Pols MA, Van Wijk HJ, et al. The plain abdomi-
nal radiograph in the assessment of constipation. Z Gastroenterol
1990;28:335–338.
21. Bruera E, Suarez-Almazor M, Velasco A, et al. The assessment of con-
stipation in terminal cancer patients admitted to a palliative care unit:
a retrospective review. J Pain Symptom Manage 1994;9:515–519.
22. Anderson F, Downing GM, Hill J, et al. Palliative performance scale
(PPS): a new tool. J Palliat Care 1996;12:5–11.
23. Oneschuk D, Fainsinger R, Hanson J, Bruera E. Assessment and knowl-
edge in palliative care in second year family medicine residents. J Pain
Symptom Manage 1998;14:265–273.
24. Mazuryk M, Daeninck P, Neumann CM, Bruera E. Daily journal club:
an education tool in palliative care. Palliat Med 2002;16:57–61.
25. Bruera E, Fainsinger R, MacEachern T, Hanson J. The use of methyl-
phenidate in patients with incident cancer pain receiving regular opi-
ates. A preliminary report. Pain 1992;50:75–77.
26. Bruera E, de Stoutz N, Velasco-Leiva A, et al. The effects of oxygen on
the intensity of dyspnea in hypoxemic terminal cancer patients. Lancet
1993;342:13–14.
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27. de Stoutz ND, Bruera E, Suarez-Almazor M. Opioid rotation (OR) for
toxicity reduction in terminal cancer patients. J Pain Symptom Manage
1995;10:378–384.
28. Bruera E, Neumann C, Brenneis C, Quan H. Frequency of symptom
distress and poor prognostic indicators in palliative cancer patients
admitted to a tertiary palliative care unit, hospices, and acute care
hospitals. J Palliat Care 2000;16:16–21.
29. Regional Palliative Care Program Annual Report April 1, 2002–March
31, 2003 and April 1, 2003–March 31, 2004. 2005. Available from:
www.palliative.org (Accessed September 7, 2005).
30. von Gunten CF, Ferris FD, Portenoy R, Glachen M, eds. CAPC Manual:
Everything You Wanted to Know About Developing a Palliative Care
Program but Were Afraid to Ask, 2001. Available at www.capcmssm.
org (Accessed September 7, 2005).
31. Faber-Langendoen K. Resuscitation of patients with metastatic cancer.
Is transient benefit still futile? Arch Intern Med 1991;151:235–239.
32. Thorns AR, Ellershaw JE. A survey of nursing and medical staff views
on the use of cardiopulmonary resuscitation in the hospice. Palliat
Med 1999;13:225–232.
33. von Gunten CF. Discussing do-not-resuscitate status. J Clin Oncol
2001;19:1576–1581.
34. Maccabee J. The effect of transfer from a palliative care unit to nurs-
ing homes—are patients’ and relatives’ needs met? Palliat Med
1994;8:211–214.
35. Ross C, Cornbleet M. Attitudes of patients and staff to research in a
specialist palliative care unit. Palliat Med 2003;17:491–497.
36. Rees E, Hardy J, Ling J, et al. The use of the Edmonton symptom assess-
ment scale (ESAS) within a palliative care unit in the UK. Palliat Med
1998;12:75–82.
37. Lo RSK, Ding A, Chung TK, Woo J. Prospective study of symptom con-
trol in 133 cases of palliative care inpatients in Shatin Hospital. Palliat
Med 1999;13:335–340.
38. Mancini I, Lossignol D, Obiols M, et al. Supportive and palliative
care: experience at the Institute Jules Bordet. Support Care Cancer
2002;10:3–7.
39. Elsayem A, Swint K, Fisch M, et al. Palliative care inpatient service in
a comprehensive cancer center: clinical and financial outcomes. J Clin
Oncol 2004;22:2008–2014.
40. Cohen SR, Boston P, Mount BM, Porterfield P. Changes in qual-
ity of life following admission to palliative care units. Palliat Med
2001;15:363–371.
41. Davis MP, Walsh D, Nelson KA, et al. The business of palliative medi-
cine—part 2: The economics of acute inpatient palliative medicine. Am
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42. Smith TJ, Coyne P, Cassel B, et al. A high-volume specialist pallia-
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Palliat Med 2003;6:699–705.
20
MULTIDIMENSIONAL PATIENT ASSESSMENT

Marvin Omar Delgado-Guay and Alexander Harding

Contents
Introduction........................................................................................................................................................................................................................149
Distressing symptoms.......................................................................................................................................................................................................149
Frequency of symptoms....................................................................................................................................................................................................151
Multidimensional assessment.........................................................................................................................................................................................151
Disease status......................................................................................................................................................................................................................152
Assessment tools................................................................................................................................................................................................................153
Assessment of delirium and cognitive impairment....................................................................................................................................................156
Assessment of physical function.....................................................................................................................................................................................156
Assessment of psychological distress.............................................................................................................................................................................157
Mood disorders..................................................................................................................................................................................................................157
Somatization.......................................................................................................................................................................................................................158
Chemical coping.................................................................................................................................................................................................................158
Spiritual assessment..........................................................................................................................................................................................................158
Family/caregiver assessment...........................................................................................................................................................................................159
Social, financial, and cultural assessment.....................................................................................................................................................................160
References............................................................................................................................................................................................................................161

Introduction
Supportive and palliative care aim to decrease symptom burden
and alleviate psychosocial distress in patients and families. There
has been significant growth of supportive/palliative care services
and increasing international awareness of the role of supportive
and palliative care for patients with advanced illness and their
caregivers.1–3
Studies have showed that supportive/palliative care is associ-
ated with improved symptom control, mood, and better quality
of life (QOL); in the context of an appropriate health resource use,
increased patient and caregiver satisfaction, health-care savings,
and possibly even better survival.4–10
A patient’s experience of advanced illness is complex—from
suffering physical symptoms, to coping, financial concerns,
caregiver burden, social and family changes, and spiritual con-
cerns (Figure 20.1). Suffering is a state of distress that occurs
when the intactness or integrity of the person is threatened or
disrupted. Much of this suffering is often left unaddressed when
healthcare is focused on the disease rather than the person with
the disease.11
These issues should be managed through an interdisciplin-
ary approach, with the focus of care being the patient and the
family rather than the disease. Physicians must work together
with many other professionals, such as nurses, psychologists,
chaplains, occupational therapists, physical therapists, nutrition-
ists, social workers, pharmacists, and volunteers, to provide care
and support.12 This enables a multidimensional evaluation that
includes assessment of the patient’s clinical and psychosocial, and
spiritual characteristics, identification of specific prognostic fac-
tors related to symptoms, and the patient’s self-reported symp-
tom burden (Figure 20.2).
This chapter aims to bring together and summarize the differ-
ent components of multidimensional bedside clinical assessment
in supportive/palliative care and its importance for symptom
control, QOL, and decision-making. The type of assessment tool
and the intensity of assessment will vary according to the patient
population (e.g., cancer patients and geriatric patients), the set-
ting (palliative care unit, outpatients, home, etc.), and a variety of
issues related to the team composition, culture, etc. The reader is
referred to specific chapters in this book for a more comprehen-
sive assessment and the use of specific tools for each particular
symptom.
Distressing symptoms
Symptoms are inherently subjective. They are perceptions,
usually expressed by language.13 Patient self-report is the
primary source of information of symptom presence and
severity.
The physical and psychological symptoms experienced by
patients with advanced-stage cancer are not uncommon, yet these
issues are frequently addressed improperly in the conventional
care setting.13–15 Communication between clinicians and caregiv-
ers and pain management continues to be less than adequate dur-
ing the process of dying. One group reported that only 54% of 357
ovarian cancer patients with pain received high-intensity analge-
sic medication near their time of death,16 suggesting that there is
room for improvement in the care of ovarian cancer patients at
the end of life.
Improving communication with caregivers will allow cli-
nicians to inform, educate, and identify areas of distress that
they might encounter during the care of their patients.17,18 This
approach empowers patients and their families to exercise their

149
150 Textbook of Palliative Medicine and Supportive Care

FIGURE 20.1  Multiple distressing symptoms, factors, and complications that affect the quality of life in patients with advanced
illness.

FIGURE 20.2  Multidimensional approach to evaluate patients with advanced illness and with multiple distressful symptoms.
Multidimensional Patient Assessment
decision-making options and self-control while balancing the
benefits and risks of treatments, with the goal of improved QOL
near its end.
For clinicians, the interaction with patients facing life-threat-
ening illness can be a rewarding experience, although it remains
one of the most challenging aspects of their work. Formal train-
ing about communication remains low during residency or fel-
lowship and even specialists receive limited proper training
about communication with these patients with different cultural
and ethnic backgrounds.19–21 The benefit of good communication
on patient care and outcomes is unequivocal, whereas deficien-
cies in communication are associated with medical errors and a
negative patient experience.22
It is always important to prepare oneself for the patient
encounter, always trying to create a supportive environ-
ment, using appropriate nonverbal behaviors, and expressing
empathy. 23
Communication is frequently difficult in advanced and ter-
minally ill patients because of delirium or severe sedation due
to drugs, metabolic abnormalities, infections, brain metas-
tases, etc. 24 Proxies may be considered as an alternative or
complementary source of information, especially during end-
of-life care. 25 However, numerous studies have demonstrated
that observer and patient assessments are not highly corre-
lated, and that the accuracy of a clinician’s assessment cannot
be assumed. 26–28
Health-care providers often underestimate the severity of pain
and other symptoms.25,29 In studies of patients with terminal
cancer assessed by health-care workers as compared with the
patients, agreement was higher for physical than psychologi-
cal and cognitive symptoms, there was a greater agreement on
absence rather than on the presence of a symptom24 and the vari-
ation in symptom scores was minimal when at least two individu-
als contributed in the assessment. 30
Data about concordance of patient proxies’ reports suggests
that a patient’s and their family members’ reports of patient
pain and performance status were highly correlated, although
family members consistently reported more pain and disabil-
ity.27 Another study that assessed patients and their spouse
caregivers suggests that caregivers agree with patients on objec-
tive measures with observable referents (e.g., ability to dress
independently) but disagree with subjective aspects of patients’
functioning (e.g., depression, fear of future, and confidence in
treatment).28
Frequency of symptoms
Patients with advanced illnesses have an extraordinarily
high frequency of physical and psychological complaints that
impact the QOL. Symptoms may vary with age, sex, primary
tumor, and extent of disease. 31 In different studies 32,33 con-
ducted in cancer patients referred to a palliative medicine
program both as inpatients or outpatients, the median num-
ber of symptoms per patient was 11 (range 1–27). The 10 most
prevalent symptoms were pain, lack of energy, dry mouth,
dyspnea, feeling drowsy, anorexia, insomnia, feeling sad, con-
stipation, and greater than 10% weight loss. The frequency of
these 10 symptoms ranged from 50 to 84%. The most common
symptoms were also the most severe. Gastrointestinal symp-
toms were also common in non-gastrointestinal primary site
cancers. Specific symptoms were influenced by age, sex, or
151
performance status. For example, males had more dyspha-
gia, hoarseness, 10% weight loss, and sleep problems; females
had more early satiety, nausea, vomiting, and anxiety. In a
sample of 504 outpatients with acquired immune deficiency
syndrome (AIDS) was observed multiple symptoms (mean of
16) with higher symptom distress. The most prevalent symp-
toms were worrying, fatigue, sadness, and pain. Patients with
intravenous drug use as an HIV transmission factor reported
more symptoms and higher overall and physical symptom
distress. 34
Multidimensional assessment
It is always important to perform a comprehensive and multi-
dimensional assessment in all patients with advanced illness
with multiple symptoms. 35–37 Production of a symptom is the
process by which nociception occurs. There are three steps
in the experience of symptoms: production, perception, and
expression. In the case of cancer pain, for example, J recep-
tor stimulation in the lung results in the production of dys-
pnea or the afferent stimulus from the gastrointestinal tract
or central nervous system results in the production of nausea.
Production can be significantly different in one individual to
another and in different areas within the same individual (e.g.,
some patients have multiple bone metastases of which only
one hurts). Perception is the process by which the symptom
reaches the brain cortex. This can also differ significantly from
one individual to another (in the case of pain, endorphins, or
descending inhibitory pathways can significantly confound
the intensity of the pain perceived). Unfortunately, these two
stages cannot be measured. Finally, the expression of the dis-
tress is the only measurable part of the experience and is a
target of therapy. However, this stage can also vary from one
individual to another due to beliefs about the symptom experi-
ence, intrapsychic factors such as depression or somatization,
and even cultural factors. 35,38–40
In summary, although it is important to measure the inten-
sity of a certain symptom such as pain, fatigue, or nausea, it is
important to recognize that this intensity of expression does
not have the same unidimensional value of, for example, blood
glucose in the control of diabetes, or blood pressure in the con-
trol of arterial hypertension. Interpreting the intensity of pain
expression as being only the expression of nociception would
deny that in addition to variability in nociception, there is a
great variability in both perception and expression. Rather,
symptom expression should be interpreted as a multidimen-
sional construct. In a given patient, a score of 8 out of 10 in
pain intensity could be the result of nociception plus a certain
level of somatization, coping chemically, and mild delirium.
The multidimensional assessment should help in the recog-
nition of the contribution of the different dimensions to the
patient’s symptom expression and thereby assist in the plan-
ning of care. A purely unidimensional interpretation of inten-
sity of pain would result in assuming that 100% success can
be achieved with the simple use of higher and higher doses
of analgesics. This simplistic approach could result in massive
doses of opioids, opioid-related toxicity, and excessive reliance
on pharmacologic, as compared with non-pharmacologic,
approaches to symptom control. A number of tools (Table
20.1) can be used to assess the contribution of different dimen-
sions of the patient’s symptom expression. 35,38–40
152 Textbook of Palliative Medicine and Supportive Care

TABLE 20.1  Multidimensional Assessment of Patients with Advanced Illness in the Supportive/Palliative Care Setting
Dimension Assessment
1. History Stage of the cancer/illness
Recent chemotherapy and/or radiotherapy or other therapy
Self-rated symptoms scales
Characteristics, intensity, location, aggravating factors of distressful symptoms
2. Performance status Karnofsky Performance Scale or Eastern Cooperative Oncologic Group Scale scores
3. Activities of daily living (ADL) and instrumental Assessment of ADL (bathing, dressing, and undressing, eating, transferring from bed to
activities of daily living (IADL) chair, and back, voluntarily control urinary and fecal discharge, using the toilet, and
walking)
Assessment of IADL (light housework, preparing meals, taking medications, shopping for
groceries or clothes, using the telephone, and managing money)
4. Assessment of distressful symptoms (pain, Edmonton Symptom Assessment System (ESAS-FS)
fatigue, anorexia, nausea, dyspnea, insomnia, Abdominal X-ray to assess constipation vs. bowel obstruction (consider abdominal CT scan)
drowsiness, constipation)
5. Assessment of psychosocial symptoms: anxiety/ Anxiety/depression (ESAS-FS)
depression Identification of Mood disorder during interview
6. Family/caregiver’s distress Assessment for family/caregiver distress during the interview
Sociocultural and financial issues evaluation
7. Assessment of delirium Memorial Delirium Assessment Scale (MDAS)
Mini-Mental State Examination (MMSE)
Confusion Assessment Method (CAM)
8. Assessment of spiritual distress/spiritual pain Spiritual Assessment SPIRITual History; FICA
Self-rated spiritual pain (pain deep in the soul/being that is not physical)
Identification of Spiritual distress during interview
9. Assessment of chemical coping C.A.G.E. questionnaire
10. Evaluation of medications and possible interactions (polypharmacy)
11. Physical examination

Disease status tests, or specialist referral may be appropriate to understand

Good symptom assessment precedes effective symptom treat-
ment. Symptom assessment is very important because symp-
toms directly affect patient distress, QOL, and survival.13
Symptoms can be related to disease, treatment, concurrent
comorbid illnesses, or a combination of all three.13,41 The early
stages of cancer are associated with considerable symptomatol-
ogy, and the symptom burden (symptoms and their interference
with life) increases with cancer stage, possibly reflecting tumor
burden.41–43 One important point to consider is that symp-
tom burden decreases patient QOL.13,44 QOL is a multidimen-
sional construct with specific emotional, physical, and social
aspects.45–47 The presence of symptoms affects but does not nec-
essarily determine QOL.13
An initial step in the multidimensional assessment of the
patient seen by the supportive and palliative care team involves
a complete medical history that reviews the disease diagnosis
(cancer, AIDS, end-stage chronic obstructive pulmonary dis-
ease, congestive heart failure, or renal disease, etc.), the chro-
nology of disease-related events, previous and current therapies,
and all relevant medical, surgical, and psychiatric problems. A
detailed history includes current and prior use of prescription
and nonprescription drugs, “alternative” medical therapies, drug
allergies, and previous adverse reactions. The patient should be
questioned about prior treatment modalities for each symptom
and their perceived efficacy. Symptom assessment must include
a thorough physical examination and review of the available
laboratory and imaging data. Specific imaging, laboratory
the pathophysiology of symptoms and their relationship to the
disease.13,42,211
The Edmonton Labeled Visual Information System (ELVIS) 48
is a pictorial representation that has been developed and tested
to improve the physician’s ability to comprehend and remem-
ber the basic details of the patient’s disease status and prior
treatments (Figure 20.3). This instrument is a simple one-page
line diagram that is used to graphically document the extent of
disease in advanced cancer. It consists of two figures, of which
one is used to document visceral and soft-tissue disease and
the second, portraying the skeleton, is used to document bony
disease. The diagrams are simple and require the user to draw
in, as necessary, sex-specific organs such as breasts, ovaries,
the uterus, or testes, as well as other structures that have not
been included. White space is provided to add labels to the
visual representations and to document type and date of dif-
ferent treatments.
Supportive and palliative care specialists need to be knowl-
edgeable about the natural history and treatment of patients
referred to their care. This allows for the appropriate recognition
of patients referred to the supportive and palliative care team
who might significantly benefit from disease-modifying therapy,
or occasionally even curative therapy. For example, a patient with
advanced testicular cancer or Hodgkin disease may be severely
symptomatic and appropriate for a palliative care referral.
However, this patient should also immediately be referred to an
oncologist because there is potentially curative therapy available.
Similarly, a patient with opportunistic symptomatic infections
Multidimensional Patient Assessment
FIGURE 20.3  Edmonton Labeled Visual Information System (ELVIS).
related to AIDS with no history of previous triple antiviral ther-
apy should be treated by the palliative care team in coordination
with an AIDS specialist.
Assessment tools
In the process of instrument selection, the physician must
carefully consider the goals of assessment and the practicality
and acceptability of the assessment instrument by the patient
with advanced illness. Assessment tools allow for the identi-
fication of many more symptoms than do simple unstructured
evaluations.49,50
Simple assessment tools are the most appropriate for patients with
advanced illnesses. These patients may be weak and experiencing
symptoms that make it difficult to complete a time-consuming and
complex assessment tool.
153
Assessment tools are not only useful to diagnose and evaluate
the intensity of the symptoms but also to monitor the effective-
ness of therapy and to screen for side effects of medications. They
play a role in the early identification of poor prognostic factors
that can hamper the management of the symptoms of advanced
illness. Assessment tools should be used regularly, especially
when patients experience new symptoms, an increase in the
intensity of preexisting symptoms, or when therapy changes. The
results should be documented in the patient’s chart to ensure
accuracy in the monitoring of the symptoms.
Efficient symptom-assessment instruments include the
Edmonton Symptom Assessment Scale (ESAS), the Memorial
Symptom Assessment Scale (MSAS), the Rotterdam Symptom
Checklist51 (RSCL), and the Symptom Distress Scale (SDS).
The ESAS52–56,212 is used to assess 10 common symptoms (pain,
fatigue, nausea, depression, anxiety, drowsiness, shortness of
154
breath, appetite, sleep problems, and feeling of well-being) expe-
rienced by patients with cancer or chronic illness over the past
24 hours. In this scale, the patient rates the intensity of symptoms
on a 0–10 numerical scale, with 0 representing “no symptom” and
10 representing the “worst possible symptom.” It was developed
in 1991 to evaluate the intensity of the most frequent physical
and psychological symptoms in cancer patients receiving pallia-
tive care and was rapidly adopted by many cancer and supportive
and palliative care programs (Figure 20.4a).57 It is widely used in
supportive and palliative care research. Its ease of use and visual
representation make it an effective and practical bedside tool56,57
that allows the health-care provider to track symptoms over time
with regard to intensity, duration, and responsiveness to therapy.
There have been independent validations of this tool in pallia-
tive care and cancer patients by a number of different authors and
FIGURE 20.4  Edmonton Symptom Assessment Scale (ESAS-FS) (a) and Edmonton Symptom Assessment Scale revised version
(ESAS-r) (b).
Textbook of Palliative Medicine and Supportive Care
in a variety of different languages, for example, in English,49,58–62
Italian,63 French,64 German,65 Spanish,66 Korean,67 and Thai.68
Two recent reviews on ESAS studies have found limited psycho-
metric evidence that supports the need for further validation
studies.69,70
Based on concerns raised in the literature61,70–72 and the find-
ings of the think-aloud study, a revised version of the ESAS, the
ESAS-r, was created. The ESAS-r retains the core elements of the
ESAS (9 common symptoms, option of adding a 10th symptom,
11-point numerical rating scales), with key revisions focusing on
(1) symptom assessment time frame, specified as “now;” (2) ter-
minology: brief definitions have been added to some symptoms
and “appetite” has been changed to “lack of appetite” to express
the concept as a symptom; (3) item order: related symptoms (e.g.,
tiredness and drowsiness, nausea and appetite, and depression
Multidimensional Patient Assessment
FIGURE 20.4  Edmonton Symptom Assessment Scale (ESAS-FS) (a) and Edmonton Symptom Assessment Scale revised version
(ESAS-r) (b). (Continued)
and anxiety) are grouped together, and “well-being” is now the
9th symptom at the end of the instrument; and (4) format: hori-
zontal lines over the numbers have been removed (Figure 20.4b).73
The ESAS was further augmented to address symptoms of spir-
itual distress and financial distress. These additional measures
were added to evaluate aspects of patient’s distress that are highly
prevalent but rarely assessed by health-care practitioners. Studies
of spiritual distress find that greater than 40% of advanced cancer
patients report it. Spiritual pain is associated with higher ratings
for pain, depression, and financial distress.213,214 These findings
were taken into account when developing the next iteration of the
tool, the ESAS-FS, which includes two questions addressing spiri-
tual distress and financial distress.
The ESAS has been validated against a widely used scale, the
Hospital Anxiety and Depression Scale (HADS), for assessing the
presence of depression and anxiety in advanced cancer patients.74
155
The ideal cutoff point of ESAS of 2 out of 10 is sensitive for the
presence of depression and anxiety in patients in the palliative
care setting.
The MSAS, a lengthier assessment tool, is mostly used for
research purposes. With the MSAS, patients rate the frequency,
severity, and distress associated with 32 physical and psychologi-
cal symptoms.75 There is a short-form MSAS76 (MSAS-SF) that
captures the patient-rated distress associated with 26 physi-
cal symptoms and the frequency of 4 psychological symptoms.
Another tool that can be completed in 2–4 minutes and contains
both QOL and survival information is the condensed MSAS,77
which provides equivalent information that approximates to
the original 32 items. The symptoms identified by Chang et al.77
are also included in other widely used clinical symptom assess-
ment instruments, such the ESAS, RSCL, and SDS. This report
is also one of the first to demonstrate that scales from a shorter
156
instrument can be predictive of survival, and that there is a core
of symptoms that provide most of the information about health,
QOL, and survival. The SDS is a patient-rated instrument that
assesses the intensity, frequency, and distress level associated
with nine physical and two psychological symptoms.78,79 It is
important to recognize that the research instruments may differ
from those used for clinical practice.77
Assessment of delirium and
cognitive impairment
The presence of cognitive impairment, whether as a result of
delirium or dementia, presents a major impediment in the assess-
ment of symptoms in patients with advanced disease.80 Delirium
is an important source of distress to patients, family members,
and caregivers. Patient assessment becomes difficult, com-
munication of patients with caregivers and family members is
impaired, the patient’s expression of their symptoms is usually
increased, and they are usually unable to participate in their
own care.81 The frequency of delirium in patients with advanced
cancer varies from 28 to 40% on admission.82,83 Eventually, up to
83% of patients develop delirium in their final days, and 10–0% of
them may require palliative terminal sedation.84,85 In some stud-
ies, delirium was not detected in up to 61% of the cases of patients
referred to palliative care services.86,215
The diagnosis of delirium is made on the basis of acute onset,
fluctuation in course, reduced sensorium, attention deficit, and
cognitive and perceptual disturbance, which occurs in the pres-
ence of an underlying organic derangement.81,87
Historically, the Mini-Mental State Examination (MMSE)88
was used in multiple studies on cognitive failure in cancer patients
with delirium.89,90 However, it only assesses cognitive function,
and because of its high rates of false negatives and false positives,
individual scores should be interpreted with caution and fol-
lowed by more detailed assessments.91 For example, two delirious
patients with an MMSE score of 14 of 30 can range from being
completely lethargic to completely agitated and unmanageable.
Different tools have been developed and validated for screen-
ing or monitoring the course of delirium, such as the Memorial
Delirium Assessment Scale92,93 (MDAS), the Delirium Rating
Scale,94,95 and the Confusion Assessment Method96,97 (CAM). The
MDAS is a 10-item, 4-point, clinician-rated instrument (possible
range, 0–30). It was originally designed to measure severity but
can be used as a diagnostic tool. It has been validated in inpatient
palliative care settings with a sensitivity of 97% and a specificity
of 95% at a cutoff score of 7.
Based on the level of psychomotor activity, there are three
subtypes of delirium: hyperactive, hypoactive, and mixed, which
is the most frequent form of presentation.98,99 Misdiagnoses
of hypoactive delirium as depression or agitated delirium as
anxiety disorder is not unusual. The emotional lability, disin-
hibition, and psychomotor agitation components of delirium
are frequently interpreted as worsening pain by relatives, and
sometimes by medical and nursing staff,100 especially in the
absence of any objective cognitive testing. Fainsinger et al.101
described a “destructive triangle” created as a result of the fam-
ily’s misinterpretation of the patient’s delirium as pain, and
their consequent desire for nursing and the physician’s efforts
to “do something.” The doctor may be placed under pressure to
relieve the patient’s and family’s distress. This emotional over-
load may lead to an increase in the opioid dose and aggravate the
Textbook of Palliative Medicine and Supportive Care
agitation, in particular when the opioid is already implicated as
a precipitant.102
Delirium can result in misinterpretation of symptoms and
emotional expression and conflict between the patient’s family
and health-care professionals, or even among different health-
care professionals with regard to the patient’s behavior. Once the
diagnosis of delirium has been confirmed by a thorough medi-
cal assessment, it is important to appropriately inform the differ-
ent disciplines in the team about the presence of this syndrome
because a number of pharmacologic, rehabilitation, and counsel-
ing interventions may be inappropriate in patients with severe
cognitive failure or delirium. Education for the family will also be
important to help them understand the inhibited expression of
physical or emotional distress in a cognitively impaired or deliri-
ous patient.
A multidimensional assessment in this setting will lead to cog-
nitive testing and the recognition of delirium. This assessment
may result in more appropriate interventions, such as opioid rota-
tion or dose reduction, and prescription of a neuroleptic for the
symptomatic treatment of delirium.103
Assessment of physical function
The majority of patients with advanced and terminal illness have
impaired ability to perform everyday functions during the vari-
ous stages of the disease. Functional status is an independent pre-
dictor of survival.104 It is also essential for planning the setting of
care, which can be the home, hospice, or acute service.
The Karnofsky Performance Scale105 (KPS) and the Eastern
Cooperative Oncology Group106 (ECOG) have been used widely
in the assessment of physical function in cancer patients. The
KPS is considered a “gold standard” for assessment of func-
tional status in cancer patients.107,108 However, in patients with
advanced cancer in palliative care setting assessments, these
instruments tend to generate clustering of scores at the extreme
end of impairment. Consequently, newer instruments such as
the Edmonton Functional Assessment Tool109 (EFAT) and the
Palliative Performance Scale110 (PPS) have been developed. The
EFAT includes domains such as pain, mental alertness, sensory
function, communication, and respiratory function, in addition
to domains that more directly reflect physical function, such as
balance, mobility, wheelchair mobility, activity, activities of daily
living, and dependence performance status. This information can
give physicians prognostic information about the patient. For
example, a bedridden patient with severe pain due to a pathologi-
cal hip fracture has a much better potential for recovery than a
patient bedridden due to cachexia and delirium. The EFAT was
updated and validated in 2001 and continues to see use in stud-
ies of palliative care.111 The PPS is essentially a modification of
the KPS and assesses ambulation, activity, self-care, intake, and
conscious level.112
An objective assessment of physical functioning constitutes
part of the multidimensional symptom assessment in palliative
care. Impairment in physical functioning and distressing physi-
cal symptoms such as pain have the potential to adversely affect
psychosocial function.113,114 Physical and occupational therapy
assessments may reveal deficits and suggest interventions that
can be essential to maintaining functional capacity, ensur-
ing patient safety, conserving energy, and decreasing fatigue.
A speech therapy assessment can provide valuable information
regarding swallowing function, while a nutritional assessment by
a dietician can aid in determining caloric intake.
Multidimensional Patient Assessment
The assessment of physical function in supportive and pal-
liative care will allow for the identification of simple measures
such as special wheelchairs, ramps if there are steps in the home,
bathroom supplies, a trapeze for bed mobility, or the need for a
formal rehabilitation approach. On the other hand, in some cases,
decreased function may be associated with conditions such as
severe incidental pain, delirium, dyspnea with minimal efforts, or
irreversible neurological damage, and in these cases, appropriate
adaptation to the loss in function, and patient and family educa-
tion will be the most appropriate course of action. Therefore, the
assessment of physical function needs to be integrated with an
understanding of the underlying disease status, symptom con-
trol, and psychosocial distress.
Assessment of psychological distress
The perception of different symptoms, such as pain or fatigue,
may be accentuated by the emotional or psychological dis-
tress of the patient. Psychological distress impairs the patient’s
capacity for pleasure, meaning, and connection; erodes QOL;
amplifies pain and other symptoms115; reduces the patient’s
ability to do the emotional work of separating and saying good-
bye; and causes anguish and worry among family members and
friends. Finally, psychological distress, particularly depression,
is a major risk for suicide and for requests to hasten death.116 On
the other hand, severe undertreated physical distress leads to
severe psychological distress. Untreated or undertreated pain,
nausea, dyspnea, or other uncomfortable physical symptoms
can profoundly disturb mood, sleep and make it impossible for
patients to relate appropriately to their family and their health-
care professionals.
A psychological assessment should be done to evaluate mainly
mood and coping. It is important for a team’s members to become
familiar with each of these areas and to recognize when there
are issues that need further assessment and/or intervention by
another health-care discipline. Medical staff often fails to rec-
ognize and address psychological distress, and this negatively
impacts QOL.115,116
Patients with advanced and terminal diseases have a variety of
ways of coping with their diagnosis, including fear, anger, avoid-
ance, denial, intellectualization, intense grieving, and existential
questioning. The distinction is often difficult to make between
the normal psychological burden that exists in relation to physi-
cal and psychological distress and certain aspects of psychopa-
thology such as somatization, anxiety, adjustment disorder, and
depression.117 In addition, physical symptoms of depression (such
as fatigue, anorexia, and sleep disturbance) may be attributable to
the disease itself.
Numerous factors act as barriers to recognition and treatment
of psychological symptoms. Both patients and clinicians believe
that psychological distress is a normal feature of the dying pro-
cess and fail to differentiate natural, existential distress from
clinical depression. Physicians often lack clinical knowledge and
skills to identify depression, anxiety, and delirium, especially in
terminally ill patients where the diagnostic clues are confounded
by coexisting medical illness and appropriate sadness. Patients
and clinicians often avoid exploration of psychological issues
because of time constraints and concerns that such exploration
will cause further distress. Physicians are reluctant to prescribe
psychotropic agents, which can have additional adverse effects,
and therefore may hesitate to diagnose a condition that they feel
they cannot treat successfully. Finally, when caring for dying
157
patients, physicians may feel a sense of hopelessness that can lead
to therapeutic nihilism.114,118
Mood disorders
Mood disorders are among the most prevalent and important of
the psychiatric illnesses.119,120 Depression coexists with a number
of physical symptoms in patients with advanced cancer. Its fre-
quency varies widely, but it is considered to be present in approxi-
mately 25% of these patients.120–125 In a recent meta-analysis, it
was reported that the prevalence of adjustment disorder alone
was 15.4% and of anxiety disorders 9.8%, while the prevalence
of all types of depression combined was of 24.6%, depression
or adjustment disorder 24.7%, and all types of mood disorder
29.0%.126 Also it was reported that the prevalence of depression
diagnosed by the Diagnostic and Statistical Manual of Mental
Disorders (DSM) or International Classification of Diseases
(ICD) criteria was 16.3%; for DSM-defined major depression, it
was 14.9% and for DSM-defined minor depression 19.2%. The
prevalence of adjustment disorder was 19.4%, anxiety 10.3%, and
dysthymia 2.7%. Combination diagnoses were common; all types
of depression occurred in 20.7% of patients, depression or adjust-
ment disorder in 31.6%, and any mood disorder in 38.2%.126 The
European Journal of Cancer published findings noting a 5-fold
increase in the prevalence of depression in advanced cancer
patients compared to the general population.216
Mood disorders in medically ill patients are underdiagnosed
and are therefore undertreated.123–127 To improve the accuracy of
screening for depression, several self-reporting tools have been
created that are easy to administer without extensive training.128
Lloyd-Williams et al.128 showed the association between depres-
sion and physical symptoms in patients with advanced cancer
using a 7-item verbal rating scale.
The clinical interview is the gold standard for diagnosis of
depression.129,130 Chochinov et al.131 found that the single question
“Are you depressed?” provides a sensitive and specific assessment
of depression in terminally ill patients. Another useful question
is “Have you often been bothered by having little interest or plea-
sure in doing things?” The first question targets mood, while the
latter is an indicator of anhedonia.132 A patient who responds
affirmatively to any of these questions is likely to receive a diag-
nosis after a comprehensive interview.133,134
HADS135,136 is a brief, self-administered, widely used screen-
ing tool to measure psychological distress in patients. It is sensi-
tive to change, both during the course of disease and in response
to medical and psychological interventions. HADS consists of
14 items on two subscales (7 for anxiety and 7 for depression).
Ratings are made on 4-point scales representing the degree of
distress during the previous week. The two scales are then scored
separately. A score of 7 or less indicates non-cases, 8–10 doubtful
cases, and 11+ definite cases for anxiety and/or depression (with
ranges of 0–21 for each subscale). Also, a one-third cutoff of the
range (a score of 14–15) has been proposed as the indicator for
severe disorder. In different studies, HADS showed good reliabil-
ity and validity in assessing symptom severity, anxiety disorders,
and depression in somatic, psychiatric, and primary care patients
and even in the general population.135,136
Patients who are at increased risk for developing psychiat-
ric complications are those with low-performance status, those
receiving certain cancer treatments, and those with uncon-
trolled physical symptoms, functional limitations, lack of social
support, and past history of psychiatric disorder, substance
158
abuse, or family history of depression or suicide.137,138 Clinicians
should always remain vigilant for mood complications, not just
depression.
Somatization
Somatization is broadly defined as the somatic manifestation of
psychological distress. This should be distinguished from the
“somatization disorder” in the somatoform disorders section of
Diagnostic and Statistical Manual (DSM)-IV.139 Somatoform dis-
orders are rare in cancer patients and have a restrictive set of cri-
teria.140,141 Somatization is closely related to depression, anxiety,
personality disorders, and cognitive impairment.142–144 Patients
who somatize will have a tendency to express pain intensity as
higher, will have poorly defined etiology after appropriate inves-
tigations, will describe pain “all over the body,” and derive little
benefit (but often toxicity) from pharmacological treatment.145 In
addition to a history of affective disorder, a history of functional
somatic syndromes146 (e.g., chronic pelvic pain, irritable bowel
syndrome, fibromyalgia, tension headache, and chronic fatigue
syndrome) and the simultaneous presence of multiple highly
intense symptoms (high ESAS scores in multiple domains) are all
signs suggestive of somatization. Because of the absence of a gold
standard, the diagnosis of somatization is made based on a num-
ber of repeated observations, and after extensive discussion with
the patient and family.147
Patients who somatize frequently express increased symp-
tom intensity associated with stressors, and many patients are
unaware of this coping mechanism. It is important to recognize
that in most palliative care patients, somatization consists of
the increased expression of a symptom for which there is a clear
pathophysiological mechanism, rather than the expression of
symptoms for which there is no demonstrable pathophysiology,
as is the case for somatoform disorders.
Chemical coping
Patients who have a past or active history of substance abuse pres-
ent a special problem for symptom management. Their history of
abuse reflects maladaptive coping strategies that frequently lead
to excessive expression of symptomatology. Several studies sug-
gest that patients who cope chemically tend to express a higher
degree of symptoms.148–150 In patients with pain, this is often mis-
interpreted as nociception and may lead to an escalation of opi-
oids and opioid-induced neurotoxicity.151
Patients who have a history of alcohol or drug use are suscep-
tible to addiction when prescribed opioid analgesics152; whereas,
in patients without such a history, the use of opioids to control
cancer pain very rarely results in abuse or addiction. The fre-
quency of addictive disorders in the USA ranges from 3 to 16%
with the higher rates reflecting prevalence of alcoholism.153,154
In cancer patients, frequency of alcoholism rises in up to 28% of
patients.155,156
Alcoholism is strongly linked with other addictive substances,
including tobacco and illicit drugs,157 and the aberrant use of these
substances to help cope with life stressors is defined as chemical
coping.158 A history of chemical coping is an independent poor
prognostic factor for pain control using opioid analgesia.159
The CAGE160 alcohol questionnaire is frequently used as a
brief screening tool for the detection of alcohol abuse. A positive
screen for alcohol abuse and dependence is made with two posi-
tive answers of the four questions with an average sensitivity of
Textbook of Palliative Medicine and Supportive Care
0.71 and specificity of 0.90.161 A positive screen should be followed
by a proper diagnostic evaluation using standard clinical criteria.
The questions refer to lifetime experience and not to any specific
or limited time frames in the patient’s history. To improve the
validity of the CAGE results, the questionnaire should be com-
pleted as part of the initial assessment, in particular before asking
the patients about amounts of alcohol or drugs ingested.
The 14-item Screener and Opioid Assessment for Patients with
Pain (SOAPP)162 was created as a promising brief self-report mea-
sure to capture important information in order to identify which
chronic pain patients may be at risk for problems with long-term
opioid medication. Each of the items is rated from 0 = “never” to 4 =
“very often.” A cutoff score of 8 of 56 or higher indicates a high risk
of opioid abuse. The SOAPP revealed five factors labeled (1) history
of substance abuse, (2) legal problems, (3) craving medication, (4)
heavy smoking, and (5) mood swings.163
It has been reported that tobacco use was associated with
higher opioid use.164 Also, patients who had a history of tobacco
abuse had more severe symptoms of pain and dyspnea and were
more likely to be prescribed strong opioids before palliative care
consultation.164
Relative to the general population, individuals who smoke are 4
times more likely to be addicted to alcohol, and alcoholic patients
are 3 times more likely to be dependent on nicotine.165 In addi-
tion, patients with a history of opioid addiction reportedly had a
3-fold or greater increased frequency of tobacco use.166 Despite
alcohol and nicotine having different mechanisms of action,
recent research suggests that both drugs may share the ability to
modulate the endogenous opioid system.167 A history of abuse of
either alcohol or tobacco may indicate an individual’s predisposi-
tion to chemical coping.
Cancer patients are living longer, and those with chronic pain
may be treated with opioids for prolonged periods. In the past,
assessment of risk factors for addiction may have been overlooked
in patients with cancer, because it was believed they had a short
life expectancy. Identifying patients who are at risk for chemical
coping has important clinical implications, including the need for
close monitoring of opioid use, consideration for early referral to
pain specialists or palliative care physicians, and management by
an interdisciplinary team to avoid inappropriate escalation, neu-
rotoxicity, and side effects of strong opioids. Before prescribing
pain medications, clinicians need to carefully screen for behav-
iors that place patients at risk for addiction or chemical coping,
including past history of alcohol, prescription drug, or nonpre-
scription drug abuse.168
Spiritual assessment
Spirituality is recognized as a factor that contributes to health
in many people and is an important component in the care of
patients with life-threatening illnesses, such as cancer, and con-
gestive heart failure.169–172 Spiritual and religious beliefs can
affect the way patients cope with their illnesses creating distress
and worsening the burden of the illness.169,173–177 Spirituality is a
dimension of personhood, a part of our being and religion is a
construct of human making, which enables the conceptualiza-
tion and expression of spirituality.178,179 A key goal of support-
ive and palliative care services is to alleviate patient suffering.
Suffering is a biopsychosocial, multidimensional construct that
includes physical, emotional, as well as spiritual pain. The spiritu-
ality and religiosity field is important to consider when we evalu-
ate patients with advanced and terminal illness, because it can
Multidimensional Patient Assessment 159

TABLE 20.2  FICA Tool for Spiritual Assessment

FICA Tool
F—Faith, belief, meaning
I—Importance and influence
C—Community
A—Address in care
Questions
Do you consider yourself spiritual or religious?
Do you have spiritual beliefs that help you cope with stress?
What gives your life meaning
What importance does your faith or belief have in your life?
On a scale of 0 (not important) to 5 (very important), how would you rate the importance of faith/belief in your life?
Have your beliefs influenced you in how you handle stress?
What role do your beliefs plan in your health-care decision-making?
Are you a part of a spiritual or religious community?
Is this of support to you and how?
Is there a group of people you really love or who are important to you?
How would you like your health-care provider to use this information about your spirituality as they care for you?

influence coping strategies and QOL. The presence of spiritual
pain can be an important component of the patients with chronic
or acute pain and other physical and psychological symptoms.180
Spirituality can be defined as “the aspect of humanity that refers
to the way individuals seek and express meaning and purpose and
the way they experience their connectedness to the moment, to
self, to others, to nature, and to the significant or sacred.”169 The
spirituality is a dimension of personhood, a part of our being,
while religion is a construct of human making, which enables the
conceptualization and expression of spirituality179; this encom-
passes structured belief systems that address spiritual issues,
often with a code of ethical behavior and philosophy.181
Spiritual needs should be met in an individualized recipro-
cal process. Patients like conversations that allow them to set
the pace and agenda. Patients selected simple questions such as
“What principles do you live by?,” “Do you have a personal faith?,”
and “Have you ever prayed about your situation?” as useful ways to
start discussions. Most importantly is that attention to religious/
spiritual issues has been shown to have a significant influence on
several important indicators of quality care. Several studies have
documented the positive relationship between meeting spiritual
needs and patient satisfaction.182,183 Several other findings suggest
that attention to spiritual needs improves QOL and reduces the
use of aggressive care at the end of life.184
Spiritual assessment is a conversation in which the patient is
encouraged to tell and explore their spiritual story. As in spiri-
tual screening, there are several options in the literature for tak-
ing a spiritual history. It is to be patient centered and guided by
the extent to which the patient chooses to disclose his/her spir-
itual needs. There are several tools available for taking a spiri-
tual history, including the Systems of Belief Inventory-15R,185
Brief Measure of Religious Coping,186 Functional Assessment of
Chronic Illness Therapy-Spiritual Well-Being,187,188 SPIRITual
History,189 HOPE,190 and FICA Spiritual History.191 Some of these
instruments are intended primarily for research, whereas the
others have been used primarily in the clinical setting for non-
chaplain clinicians.
The SPIRITual History tool,189 with the acronym SPIRIT,
includes six domains that are explored: S for spiritual belief sys-
tem, P for personal spirituality, I for integration with a spiritual
community, R for ritualized practices and restrictions, I for impli-
cations for medical care, and T for terminal events planning. The
six domains include 22 items that may be covered in as little as
10–15 minutes or integrated into general interviewing over sev-
eral appointments.
The FICA tool (Faith, Importance, Community, Address
in care) developed at the George Washington Institute for
Spirituality and Health (Table 20.2) has been tested and vali-
dated.191 It is recommended that it be incorporated into the social
history section of the overall history and physical. In incorpo-
rating this area into a history, providers should be conscious of
not imposing their own beliefs on the patient or trying to answer
any questions or concerns that the patient may have in this area.
Such questions and concerns should be referred to as a profes-
sional chaplain. They also should be clear that this process does
not oblige them to discuss their own beliefs and practices. The
main goal of this process is to understand the role of spiritual and
religious beliefs and practices in the patient’s life and the role they
play in coping with illness. As in the screening, a basic goal of the
history is to diagnose spiritual distress, which should be referred
to the professional chaplain.192,193 Through active listening, a rela-
tionship is established between the patients and providers, and/
or the professional chaplain. The chaplain then extracts themes
and issues from the story to explore further with the patient.
These themes might include meaning, making God as judge vs.
God as comforter, grief, despair, and forgiveness. This assessment
should result in a spiritual care plan that is fully integrated into
the patient’s and family’s total plan of care, which should be com-
municated to the rest of the treatment team.193
Family/caregiver assessment
Chronic illness from advanced disease has an impact on all the
family members. The distress created with the knowledge of a
limited life span, the patients’ relationship with their world and
with their families/caregivers changes. The patient’s role/s within
the family, as a provider, a caregiver, a parent, a spouse, or a sexual
partner, may be challenged. Therefore, the particular issues and
needs of family members, in addition to the patient, must also be
assessed.194 Although the family is traditionally defined by individ-
uals of blood relationship, a broader definition of family/caregiver
is most appropriate, best defined as those individuals considered as
a family by the patient.195,196 The family/caregiver assessment is par-
ticularly important for patients who will receive care at home. The
willingness of the family to deliver care at home is the most impor-
tant predictor of a home death.197 Family members will be involved
in all aspects of patient care at home, including hygiene, reposi-
tioning, and administration of multiple medications. Knowledge
of the family’s structure and function will help clinicians organize
medications and other aspects of care.
160
Furthermore, because care will be provided by family members
in the home setting, the family should also be consulted and edu-
cated about the diagnosis, treatment options, the illness trajec-
tory, symptom burden and treatment, and caregiving.198
A genogram or family tree facilitates the understanding of a
particular family’s structure and dynamics. It helps to identify
the family structure in a clear and comprehensive way. It high-
lights relationships and strengths and weaknesses and can often
clarify some of the family norms around disease/illness and cop-
ing. Family communication patterns, roles, and coping methods
are components of family functioning affected by the cancer. For
example, family members frequently do not share their thoughts
or concerns with one another in an effort to protect each other.
These “conspiracies of silence’ may complicate coping, and they
should be diagnosed and treated.199
Caring for a person with cancer is demanding and overwhelm-
ing and can be a stressful experience that may erode the physical
and psychological health of the caregiver.200 For example, care-
givers who provide 24-hour day care often experience cumula-
tive sleep disruption, and fatigue is common.201 Also, caregivers
of patients with cancer-related pain report even higher levels of
depression, tension, and mood disturbances than caregivers of
pain-free patients.202,203 Therefore, to address and manage these
issues, these patients should be managed together with psy-
chologists and social workers, and this is important to reduce
the psychological distress of caregivers. The patient–family unit
is expected to make decisions about treatment options, goals of
care, advance directives, and finances. The importance of advance
care planning for the patient and family is stressed, and this is
best addressed early in the course of illness and frequently reas-
sessed. Early discussions regarding prognosis, likely the course of
the disease, events to anticipate, and clarifying advanced direc-
tives all can serve to mitigate subsequent dilemmas and increase
control and lessen angst.
Ultimately, the level of family care available will be the main
defining factor in discharging a patient back to the community
or to an institution. Family meetings should be conducted in the
majority of cases when a palliative care team discharges a patient
home.
Involvement of family caregivers is essential for optimal treat-
ment of cancer patients at the end of life, especially in ensuring
treatment compliance, continuity of care, and social support.204
For example, family members who fear drug addiction or respira-
tory depression may under-medicate a patient even though the
patient is experiencing unrelieved pain.
Other more structured tools to evaluate family/caregiver dis-
tress involve the Zarit Burden Interview205 and the Brief symptom
Inventory.206
In the Zarit Burden Interview,205 “caregiver burden” is an all-
encompassing term to describe the physical, emotional, and
financial toll of providing care. It is the most widely referenced
scale in studies of caregiver burden and has been demonstrated to
have high internal consistency (Cronbach’s α = 0.94).
The Brief Symptom Inventory and its short form206 provide an
overview of a caregiver’s symptoms and their intensity at a spe-
cific point in time. The BSI is an 18-item self-reported symptom
inventory designed to reflect the psychological symptom patterns
of psychiatric and medical patients and non-patients. This inven-
tory reports profiles of nine primary symptom dimensions and
three global indices of distress. Each item is rated on a 5-point
scale of distress ranging from 0 (not at all) to 4 (extremely). The
depression and anxiety subscales of the BSI are well established.
Textbook of Palliative Medicine and Supportive Care
The approximate completion time for these items is 5 minutes.
The internal consistency estimates of these two subscales are 0.85
(depression) and 0.81 (anxiety). Estimates of the construct valid-
ity of these subscales also are satisfactory.
Social, financial, and cultural assessment
A number of socioeconomic factors have great influence on the
expression of symptoms, psychosocial distress, family dynamics,
and even overall access to health-care professionals and medi-
cations. Socioeconomic status is one of the main predictors of
home death,207 and it is particularly important in countries where
there is no universal access to healthcare such as the United
States. However, socioeconomic status can also be an indepen-
dent predictor of home death in other countries. The appro-
priate assessment of social and cultural needs will provide for
better counseling, better planning of the site of care, enhanced
communication, and even better adherence to pharmacological
therapy. Culturally competent communication skills are neces-
sary in health-care settings so that quality of care is promoted
and the opportunities for distress are minimized. For example,
patients with limited coverage for medications may not be able to
afford some expensive opioid analgesics or antibiotics, and it may
be preferable to prescribe less expensive medications to ensure
adherence to the treatment. Even patients with adequate insur-
ance incur substantial burdens related to uncovered services such
as transportation or home care, lost salaries and work, household
modifications, and alternative treatments.208
One of the less frequently explored effects of cancer is its
impact on personal finances and the contribution of financial-
related distress to overall suffering and QOL. Financial issues
have been recently found to be the second most frequent source
of distress identified by cancer patients in a community cancer
center context (22%).209
A substantial proportion of patients and families experience
adverse financial events during this period, probably due to the
increased direct out-of-pocket expenses related to cancer diagno-
sis and to loss of income secondary to functional status decline,
KEY LEARNING POINTS
• In clinical practice, patients present with mul-
tiple symptoms require simultaneous assessment
and management. The presence of these symp-
toms and the distress they cause are linked for
the patient to the disease experience.
• Our primary goal is to improve quality of life
for both advanced illness patients and the fam-
ily/caregiver, and we offer treatments to relieve
symptoms, pain, and distress.
• In order to treat advanced illness patients, we
first listen and seek to understand their symptom
experience, and the psychological and spiritual
sources of suffering.
• It is very important to have an effective strategy
that requires a multidimensional assessment of
and a specific plan for each patient, with an inter-
disciplinary approach, respecting the treatment
goals and the patient’s wishes.
Multidimensional Patient Assessment
among others.210 Forty-two percent of advanced cancer patients
will exhaust their savings within 2 years of their diagnosis.217
The assessment of the impact of financial distress on QOL in
patients with advanced cancer and the identification of possible
associations and explanations are of paramount importance.
Patients with financial distress have higher mortality rates com-
pared to similar patients.218 Developing tools and strategies to
correctly assess these domains will help us better understand
what is happening to our patients and identify possible interven-
tions to ease their suffering and improve their QOL.
In some cases, a simple social assessment will reveal that
patients may benefit from a disabled parking sign, application for
benefits, preparation of a will or funeral arrangements, or assis-
tance with financial planning. These issues can greatly improve
the QOL for the patients and their communication with health-
care professionals and their family.
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21
TOOLS FOR PAIN AND SYMPTOM ASSESSMENT

Victor T. Chang

Contents
Introduction�����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������168
Fundamentals of symptom measurement and assessment tools����������������������������������������������������������������������������������������������������������������������������168
Biological underpinnings�������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������168
Theoretical underpinnings of symptom instruments������������������������������������������������������������������������������������������������������������������������������������������168
Clinimetrics������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������168
Psychometrics��������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������168
Item response theory��������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������168
Properties of symptom assessment instruments��������������������������������������������������������������������������������������������������������������������������������������������������168
Validity and reliability�������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������168
Responsiveness������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������169
Scales������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������169
Dimensions�������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������169
Types of response categories�������������������������������������������������������������������������������������������������������������������������������������������������������������������������������169
Single symptom versus multisymptom instruments��������������������������������������������������������������������������������������������������������������������������������������170
Specific symptom instruments���������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������170
Appetite�������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������170
Constipation�����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������170
Delirium������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������170
Depression��������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������170
Dysphagia���������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������171
Dyspnea�������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������171
Fatigue���������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������171
Nausea���������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������171
Pain���������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������171
Multiple symptom instruments�������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������172
Applications of symptom instruments�������������������������������������������������������������������������������������������������������������������������������������������������������������������������172
Clinical trials����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������173
Patient prioritization/screening�������������������������������������������������������������������������������������������������������������������������������������������������������������������������������173
Prognosis�����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������173
Symptom clusters��������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������173
Symptom burden���������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������173
Quality of care��������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������173
Treatment outcome����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������173
Symptom monitoring�������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������173
Cultural considerations����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������173
Special populations�����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������173
Practical issues�������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������173
Research and practical tools�������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������173
Availability of instruments����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������174
Choosing an instrument��������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������174
Caregivers and patients ratings��������������������������������������������������������������������������������������������������������������������������������������������������������������������������������174
Mode of administration���������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������174
Translation of instruments����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������174
Validation����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������175
Implementation of tools���������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������175
Unexplored areas/Future directions�����������������������������������������������������������������������������������������������������������������������������������������������������������������������������175
Propose an ideal tool package with good psychometric properties and minimal overlap���������������������������������������������������������������������������������175
How to select a tool����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������175
References���������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������176

167
168
Introduction
The field of symptom assessment and the variety of tools avail-
able for pain and symptom assessment have expanded dra-
matically. The importance of symptoms was recognized by the
convening of a National Institutes of Health (NIH) symposium
to discuss the target symptoms of fatigue, pain, and depres-
sion.1 All palliative care personnel assess and manage pain and
symptoms.2 Symptom tools provide an organized approach to
symptom assessment. While both symptom and quality of life
tools emphasize patient-rated outcomes, symptom tools dif-
fer from quality of life instruments in emphasis on symptoms
rather than general physical, social, or emotional well-being.
This distinction is becoming blurred as symptom subscales are
developed for specific diseases and therapies, especially in the
Functional Assessment Cancer Therapy (FACIT) and European
Organization for Research Treatment Cancer (EORTC) fam-
ily of quality of life instruments. The purpose of this chapter
is to provide a brief background and describe some of the more
well-known symptom assessment instruments. The vivid and
unusual descriptions provided by patients in clinical encoun-
ters are not routinely captured by these tools. As palliative
care becomes integrated with general medical care, symptom
assessment has become incorporated into clinical trials and
drug approvals, and expanded into many noncancer diseases.
The findings from studies with symptom instruments have
important implications for routine medical care. The impact of
symptom assessment globally will increase as new translations
become available and symptom assessment becomes accessible
through mobile platforms.
Fundamentals of symptom
measurement and assessment tools
Biological underpinnings
Best understood for pain, the perceived intensity of a sensory
stimulus is proportional to the rate of firing by sensory nerves
and the number of nerves which send impulses. Sensory impulses
reach the cerebral cortex where they may be recognized, and
trigger various responses such as evaluative (severity), affective
(unpleasantness or distress), and behavioral (agitation).
Theoretical underpinnings of symptom
instruments
Clinimetrics
It is a field that focuses on the quality of measurements in clinical
medicine. 3 Descriptive statements (mensuration) are combined
to express a numerical summary (quantification).4 The descrip-
tive statements are chosen on the basis of clinical relevance, usu-
ally by clinicians, and can be eclectic with a variety of symptoms,
physical findings, and laboratory findings. An example is the
Apgar score, where five items (i.e., heart rate, skin color, respira-
tory effort, muscle tone, and reflex irritability) are combined to
form a score to describe the condition of a newborn.5
Psychometrics
The degree to which a respondent agrees with items (statements)
allows an inference about whether the respondent has a particu-
lar, otherwise unmeasurable, psychological state (latent trait),
such as pain, anxiety, or depression. Another analogy is the
Textbook of Palliative Medicine and Supportive Care
blind men describing an elephant. Each blind man is an item
and the latent trait is the elephant. The extent of agreement
between items commonly determined with Likert scale (e.g.,
not at all, a little bit, somewhat, quite a bit, and very much). The
intraclass correlation coefficient (Cronbach’s alpha) is a measure
of self-consistency between the statements; alpha levels of 0.70
or greater are considered acceptable. Factor analyses and other
statistical techniques are used to analyze the collection of state-
ments to see whether they measure one factor, and are therefore
unidimensional, or more than one factor. Longer instruments
with more items are preferred to minimize variation and maxi-
mize the Cronbach’s alpha.
Item response theory
In this very simplified explanation, item response theory (IRT)
starts with the concept of item difficulty and the percentage of
respondents who respond correctly to a test item. Similar to
psychometrics, IRT estimates a latent trait. The correspondence
between the item difficulty and the latent trait is described by
the item–characteristic curve (ICC) which is usually sigmoid
shaped. Easier items are on the left of the trait scale and more
difficult items on the right. IRT models estimate the difficulty
parameter for each item from questionnaire data, where the
difficulty parameter is the trait level needed to answer the item
correctly 50% of the time. The different kinds of IRT models
differ in the numbers and types of parameters used to describe
the ICC. The attractiveness of this approach lies in its ability
to recognize that different items are different, and its versatil-
ity through the availability of item banks. Potential improve-
ments in symptom assessment include shorter questionnaires,
computerized adaptive testing, and comparisons of different
instruments. Questionnaires will not be as dependent on the
population being tested. This is an area which is being real-
ized in the revision of existing instruments, and the implemen-
tation of the NIH’s Patient Reported Outcome Management
Information System (PROMIS; www.nihpromis.org) with an
assessment center to aid clinical trials, 6 a collaborative effort by
the European Association for Palliative Care7 and the develop-
ment of patient rated outcome version of the Common Clinical
Toxicity Criteria; further developments are anticipated in the
future. 8–10
Properties of symptom assessment instruments
This section presents basic information about common terms
used in discussing instruments. Symptom instruments rely upon
patient’s ratings and descriptions of symptoms. For more detailed
discussions the reader is referred to references.11–14
Validity and reliability
Validity means that the instrument measures what it claims to
measure. Measures of validity include face validity (items that are
easy to understand), content validity, criterion validity, and con-
struct validity. Content validity asks how the items in the instru-
ment represent the symptom that the instrument is trying to
measure. For example, a pain instrument might include a rating
of pain severity.15 Criterion validity is shown by correlation with
other accepted measures of the symptom in question. Criterion
validity can be demonstrated by expected agreement (conver-
gent validity) or expected disagreement (divergent validity). As
symptoms are not directly observable, a construct is a definition
Tools for Pain and Symptom Assessment
of what is being measured, such as the symptom, by a group of
related observations. Construct validity is an assessment of how
well the construct, and the symptom instrument based on the
construct, measures the symptom.16,17 In construct validity, the
relationships between these observations are tested to see if they
are present as expected.
More recently the concept of validity has been extended to
consider the patient population and clinical setting studied
with an instrument, and whether an instrument or a group of
instruments are appropriate for a palliative care population.18,19
Validation of instruments used in an electronic format represents
another new area of research.20
Reliability implies freedom from error, and is defined as the
true variance divided by the true variance and variance from
repeated administration of the instrument. Reliability can be
measured by the degree of reproducibility (test-retest) and self-
consistency (Cronbach’s alpha).21
Responsiveness
Responsiveness of the instrument to changes has received
increased attention, along with the notion of minimal clinically
significant difference. Measures of clinically significant differ-
ences are important for sample size estimation in trials designed
to improve symptom control or quality of life. They also illustrate
the transformation of symptom instruments into outcome mea-
sures. Much of the work to date has been done with quality-of-life
measures, where the minimal clinically important difference has
been defined as “the smallest difference in score in the domain
of interest which patients perceive as beneficial and which would
mandate, in the absence of troublesome side effects and excessive
cost, a change in the patient’s management.”22
Anchor-based and distribution-based methods have been used
to define clinically important differences.23 Anchor-based meth-
ods use established clinical criteria or patient ratings as ways to
anchor interpretations of difference scores. An example is the
Performance Status rating. Distribution-based methods rely
upon the statistical aspects of the score distributions.24 A half of
the standard deviation may be a good approximation of the mini-
mally important difference (MID).25 Recent recommendations
have been to use multiple approaches and to base the MID on
patient-based and clinical anchors.26
It has been suggested that instruments which are designed to
evaluate the patient at a point in time may not be the optimal
instruments for measuring changes because of the large num-
ber of items.27 An alternative approach is the transition rating,
a single item where the patient is asked to rate the change he or
she perceives in the target measure. This can be expressed as a
percentage, as a 7-point Likert scale ranging from very much
worse to very much better, and as visual analogue scales (VAS).
Likert scale and VAS approaches were equivalent in one study.28
While the ability of the patient to remember his previous symp-
tom status has been questioned, this approach is quick, sensitive,
and corresponds to the usual clinical conversation between the
patient and health-care provider. The minimum difference has
been estimated as 0.5 on a 7-point scale. The magnitude of the
transition score is correlated with the pretreatment score.29
Scales
Nominal scales have items that cannot be combined. Ordinal
scales have graded categorical responses. Numerical scales ask
the respondent to assign a number. Numerical scales can be
169
interval scales, where the difference between the numerical
values is a number (e.g., weight), or a ratio scale, which con-
tains a true zero. The type of scale determines the kinds of
data analysis to be done.
Dimensions
Symptoms have dimensions. A medical history will ask about
the presence of a symptom, exacerbating and alleviating events,
temporal variation, descriptors, and relief. A palliative symptom
history can additionally include severity, frequency, duration, dis-
tress, effect on function, and associated meanings for the patient.
Many of these terms are self-explanatory.
It remains an open question as to how many dimensions
are needed. Is one dimension enough? Severity tends to be the
dimension most commonly used followed by distress. However,
symptoms are not always categorized easily by just one dimen-
sion. In speaking with a patient who has breakthrough bone
pain, he/she may have difficulty deciding whether the severity
or frequency, or both are important. This has led to interest in
the use of multidimensional symptom instruments, such as the
Memorial Symptom Assessment Scale.
To summarize, potentially important dimensions of a symp-
tom include frequency, severity, distress, duration, and associated
meanings.
Types of response categories
Visual analogue scales
The symptom of interest is represented by a straight line 10 cm
long. Anchors are no symptom on one end and worst symptom on
the other end. The patient marks off with a straight line the sever-
ity of the symptom. Horizontal and vertical VAS scales have been
described. VAS are one of the oldest forms of symptom assess-
ment approaches and have the advantage of providing a continu-
ous variable for subsequent analyses. 30 VAS scales have been used
for many symptoms. Disadvantages include a tendency for the
marks to bunch up in the middle, and physical problems in com-
pleting the form in case of patients with impaired eyesight and/
or motor disability. Mechanical VAS scales have been described,
where patients move a marker along the line.
Numerical rating scale
Patients are asked to rate the symptom on a numerical scale,
such as 0–5 or 0–10. However, not all patients are able to express
themselves numerically. In one study, 10% of hospice patients
were unable to use a numerical rating scale for pain. 31 VAS and
numerical rating scales can yield similar results. 32
Categorical rating scales
Patients are asked to categorize the symptom by severity or other
attributes. The simplest is a dichotomous response, yes/no. These
categories often are “none,” “a little bit,” “somewhat,” “quite a bit,”
and “very much” in the Likert version. Other categories have also
been described. This presents an alternative for patients who can-
not give numerical values.
Ranking
Patients are asked to rank symptoms in order of priority. This
provides a different way of characterizing symptoms and may
help the interviewer set priorities for symptom control. Patients
in palliative care may have many severe symptoms and may have
difficulty ranking symptoms.
170
Pictorial approaches
Best known examples include the FACES design for children, 33
and the use of symbols such as fire to characterize intensity.
These approaches are appropriate in populations where the abil-
ity to read may be a barrier.
Descriptors
Patients select from a list of adjectives to capture qualitative
aspects of the symptoms.
Cutpoints
When the response is given as a numerical value, the cutpoint
helps to identify a threshold number where the interpreta-
tion or clinical importance of the rating changes. Usually, a
cutpoint is where severity of the symptom changes markedly
from mild to moderate or moderate to severe. 34 Cutpoints for
pain, fatigue, and additional symptoms have been derived on
the basis of interference caused by the symptom in the daily
activities. 35
Single symptom versus multisymptom
instruments
Many instruments are devoted to information about only one
symptom. As palliative care patients may have multiple symp-
toms, instruments which assess multiple symptoms have been
developed. A related question is how many symptoms should be
routinely covered? By the time patients reach palliative care sta-
tus, patient stamina can last for 5–10 questions at most. Many
symptoms—e.g., pain, tiredness, nausea, difficulty sleeping,
drowsiness, dry mouth, shortness of breath, and sadness—are
common to most of the multisymptom instruments.
Specific symptom instruments
A very large number of symptom instruments have been devel-
oped. This section presents information on many widely used
instruments, but there are few, if any, standard instruments.
Appetite
The Visual Analog Scale (VAS) is a 10-cm line where the left
represents no appetite and the right anchor is 100% appetite. 36
The North Central Cancer Treatment Group Patient
Questionnaire37 has seven items and a VAS score for quality of life.
The Functional Assessment of Appetite Cancer Therapy38 is
a subscale that has 12 items rated on a Likert scale. It has been
translated into Chinese39 and Spanish,40 and has been further
developed into validated shorter versions in non-small-cell lung
cancer patients.41,42
Constipation
The Constipation Assessment Scale is a validated eight-item
scale for assessment of constipation in cancer patients,43 and has
been translated into Italian.44
Delirium
The Confusion Assessment Method (CAM)45,46 is based upon
Diagnostic and Statistical Manual (DSM)-III criteria and non-
psychiatrist clinicians can use an algorithm of four items—acute
onset and fluctuating course, inattention, and either altered level
of consciousness or disorganized thinking. The CAM has been
translated into Chinese,47 French,48 German,49 Korean, 50 Polish, 51
Textbook of Palliative Medicine and Supportive Care
and Portuguese languages.52 Versions have been developed for
adult intensive care unit (ICU [the CAM-ICU])53,54 and translated
into Arabic, 55 Chinese, 56 French, 57 Greek, 58 Japanese, 59 Korean,60
Spanish,61 Swedish,62 and Thai63 and for pediatric ICU patients
as well.64 In addition, versions have been developed in Brazilian,
Portuguese,65 German,66 Spanish,67 and also a preschool version68
in Japanese.69
The Delirium Rating Scale (DRS)70 is a 10-item instrument
with clinician-rated symptoms. The DRS has been translated
into Japanese71 and validated for adolescents.72 A revised longer
16-item version has been developed with improved sensitivity
and specificity.73 The DRS-98 has been translated into Chinese,74
Dutch,75 Japanese,76 Korean,77 Portuguese,78 and Spanish79 and
studied in the pediatric population.80
The Memorial Delirium Assessment Scale (MDAS)81 is
a 10-item tool which can be used for diagnosis, severity, and
repeated assessments. A cutoff score of 13 is diagnostic and a
cutoff score of 7 has been proposed for advanced cancer patients
in a palliative care setting.82 The MDAS has been translated into
Italian,83 Japanese,84 Korean,85 and Spanish,86 and has been stud-
ied in an ICU87 and at a tertiary referral center.88
The Mini Mental Status Exam89 was originally developed as
a screening test for dementia, and has been used as a screen for
other cognitive dysfunctions. Norms should be adjusted for age
and educational level.90,91 The instrument has been translated
into Chinese,92 French,93 Gujarati,94 Hebrew,95 Hindi,96 Japanese,97
Korean,98 Sinhalese,99 Spanish,100 and other languages.101 Shorter
versions have been developed with IRT approaches.102,103
Other special situations include hepatic encephalopathy in
patients with advanced liver disease.104
In a comparison of 12 different delirium tools, the CAM was
felt to be the best diagnostic tool and the DRS was rated best for
screening symptom severity. The CAM-ICU was recommended
for ICU patients and the MDAS for cancer patients.105 This area
has been recently reviewed.106–108
Depression
Depression instruments have served primarily as screening
instruments and have been used in epidemiologic surveys.
Single-item VAS have correlated well with depression tools.109
Screening questions: Single-110 and two-question screens111
have been validated. In one literature review of depression
screening tools for use in a palliative care population, the authors
concluded that the single question “Are you depressed?” had the
highest sensitivity and specificity, and identified a cutoff value of
20 and 13 for the Hospital Anxiety and Depression Scale and the
Edinburgh Postnatal Depression Scale, respectively.112 This still
remains an area for further study.
The Beck Depression Inventory113 is a 21-item instrument
where the patient rates the severity of attitudes and symptoms
over 1-week period. In 1996, the Beck Depression Inventory
II was released to conform to the DSM IV criteria.114 The Beck
Depression Inventory has been translated into modern standard
Arabic,115 Chinese,116 Czech,117 German,118 Greek,119 Icelandic,120
Japanese,121 Persian,122 Russian,123 and Spanish languages.124
The Center for Epidemiologic Studies on Depression
(CES-D)125,126 has a validated instrument with 20 items and asks for
patient-rated frequency and has been studied in cancer patients.
The CES-D has been translated into Brazilian, Portuguese,127
Chinese,128,129 Eritrean,130 French,131 Greek,132 Italian,133
Japanese,134,135 Luo,136 Spanish,137 Turkish,138 Vietnamese,139 and
Tools for Pain and Symptom Assessment
Zambian languages.140 A ten-item version has been introduced141
and translated into South African languages.142
The Geriatric Depression Scale (GDS)143 is a 30-item instru-
ment which can be administered by telephone144 and has
been translated into Arabic,145 Chinese,146 Hindi,147 Italian,148
Korean,149 Sinhala,150 Spanish,151 Swedish,152and Turkish.153 A
Geriatric Depression Scale Short Form with 15 items has been
validated154 and translated into Arabic,155 Danish,156 French,157
Greek,158 Korean,159,160 Persian,161 Spanish,162 and Tamil.163
IRT analysis led to a 7-item version for Asian patients.164 A
shorter 5-item version has been reported165 and translated into
Chinese.166 The GDS may not be valid in patients with moderate-
to-severe dementia.
The Hamilton Depression Rating Scale167 is a 17-item sever-
ity rated scale and is widely used in trials of antidepressants.
It has been translated into Chinese,168 Turkish,169 and Urdu.170
A 6-item version has been developed171,172 and translated into
Chinese.173 This instrument has been validated in advanced can-
cer patients.174
The Hospital Anxiety Depression Scale (HADS) is a validated
instrument that has two subscales.175 Patients rate frequency of
symptoms for 14 items; 7 related to anxiety and 7 for depression.
The HADS is widely used in Europe and has been translated into
Arabic,176,177 Chinese,178,179 Finnish,180 French,181 German,182,183
Greek,184 Hungarian,185 Japanese,186 Malayalam,187 Maltese,188
Nepali,189 Persian,190 Portuguese,191 Punjabi,192 Slovenian,193
Spanish,194 and Urdu.195
The Zung Self-Rating Depression Scale is a 20-item instru-
ment.196 The Zung scale has been translated into Arabic,197
Azerbaijani,198 Chinese,199 Czech,200 Dutch,201 Finnish,202 Greek,203
and Urdu,204 and has been studied in India205 and Spain.206 A
shorter 12-item version has been translated into Dutch.207 Both
have been validated in ambulatory cancer patients.208,209
The Patient Health Questionnaire (PHQ) 9 is a criterion-
based instrument that has been widely used in general medicine
settings as a screening tool for depression.210,211 The PHQ-9 has
been translated into Chinese,212 Korean,213 Luganda,214 Somali,215
and Thai languages,216 and has been implemented in India217 and
Kenya.218 It has been used to screen for depression in cardiac219
and palliative care populations.220 A two-item version, the PHQ-
2, has also been developed.221
An area of ongoing interest is the applicability of these tools
in palliative care patients. The cutoff points have not been
derived for palliative care patients, and other issue is that the
patient’s self-report may be influenced by stress and the desire
to be socially acceptable.222 Another area is whether subscale
scores from multisymptom instruments can be used to screen
for depression.223
Dysphagia
Most studies have used an ordinal scale for measuring dyspha-
gia in five categories: no symptoms, can take solids, can take soft
food, can take liquids only, and cannot swallow at all. Many stud-
ies do not specify whether this is patient rated or observer rated.
The EORTC and the FACIT each have modules for malignant
dysphagia.224,225
Dyspnea
The Borg Scale measures symptoms with a vertical scale from
zero to ten anchored by descriptive words and requires an exer-
tional test.226
171
A VAS is a validated measure of dyspnea,227 as is a numeric rat-
ing scale.228
The Chronic Respiratory Questionnaire229 and the
St George’s Respiratory Questionnaire230 are quality-of-life
instruments for patients with chronic obstructive pulmonary
disease (COPD), with an emphasis on dyspnea. The Chronic
Respiratory Questionnaire has 20 items and has been trans-
lated into Arabic,231,232 Chinese,233 German,234 Japanese,235
Portuguese,236 and Spanish.237 A shorter version of the Chronic
Respiratory Questionnaire has also been developed.238
The St George’s Respiratory Questionnaire has 50 items and has
been translated into American English,239 Chinese (Cantonese),240
Chinese (Mandarin),241 French,242 Japanese, Luganda,243 Persian,244
Polish,245 Portuguese,246 Spanish,247 and Swedish.248 The MID for
the St George’s Respiratory Questionnaire is estimated at 4 on a
scale of 0 to 100.249 Psychometric properties250 and responsiveness
to changes in COPD251 have been recently reviewed.
Descriptions of many other instruments can be found in the
reviews in references.252–255
Fatigue
To date, most measures of fatigue have been based on cancer-
related fatigue.
A single item of distress from fatigue correlated well with
responses to the Brief Fatigue Inventory and the FACIT Fatigue
model.256
The Numeric rating scale (0–10) has been studied as part of
the Brief Fatigue Inventory. A cutoff for worst fatigue of 3 or usual
fatigue of 2 separates mild from moderate fatigue.257
The Brief Fatigue Inventory258 assesses fatigue severity and
interference using a numeric rating scale. It has been trans-
lated into Amharic,259 Chinese,260,261 Filipino,262 Indonesian,263
Italian,264 German,265 Greek,266 Japanese,267 and Korean.268
The Piper Revised Fatigue Scale269 contains 22 items and 4
subscales: behavioral/severity, affective meaning, sensory, and
cognitive/mood. It has been translated into Chinese,270 Dutch,271
French,272 Italian,273,274 Korean,275 Spanish,276 and Swedish.277,278
The FACIT Fatigue module279 is a 13-item subscale with Likert
responses that has been used for epidemiologic purposes and as
an outcome measure in clinical trials. It has been translated into
Farsi280 and German.281
Readers are referred to articles in the reference list for more
detailed reviews.282–285
Nausea
The development of a solid accepted methodology for measur-
ing chemotherapy-related nausea and vomiting and response has
helped advance the field of palliating chemotherapy-related eme-
sis. Nausea is measured with a VAS and vomiting is quantitated
as the number of episodes per 24-hour period.286
Pain
VAS scale: A mark of more than 30 mm is more than mild
pain.287 A clinically significant change was estimated at 13 mm
for patients with initial VAS scores of 34 and 28 mm for patients
with initial VAS scores greater than 67.288,289
Numerical Rating Scale of 0–10: Analysis of pain severity in
a multinational sample suggests that 1–4 may be mild pain, 5–6
moderate pain, and 7–10 severe pain.290 Changes in severity of 2 may
correspond to a minimally clinically significant difference.291,292
Pain reports on numerical scales and VAS are comparable.293
172
The Brief Pain Inventory (BPI)294 and the Brief Pain
Inventory Short Form are widely used validated pain instru-
ments. The instrument contains a body diagram, numerical
rating scale ratings of pain severity, relief, and interference
with function. The BPI has been translated into Amharic, 295
Chinese, 296,297 Farsi, 298 German, 299 Greek, 300 Hindi, 301 Italian, 302
Japanese, 303 Norwegian, 304 Spanish, 305 Xhosa, 306 and other
languages. 307
The McGill Pain Questionnaire308,309 has a present pain
intensity item and 20 sets of descriptors to assess for sen-
sory, affective, and evaluative components of pain. It has been
translated into Amharic, 310 Arabic, 311 Brazilian, Portuguese, 312
Chinese, 313 Danish, 314,315 Dutch, 316 Finnish, 317 Flemish, French, 318
German, 319,320 Greek, 321 Italian, Japanese, 322,323 Norwegian, 324
Polish, Slovak, 325 and Spanish. 326,327 The McGill Short Form has
17 items: present pain intensity, pain severity VAS, and ratings of
15 descriptors. 328 It has been translated into Arabic, 329 Czech, 330
Greek, 331 Japanese, 332,333 Persian, 334,335 Portuguese (Brazilian336)
Swedish, 337 and Turkish. 338
The Memorial Pain Assessment Card339 has one item for
the each of the dimensions of severity, mood, relief, and a set of
descriptors, and has been translated into Spanish. 340,341
Neuropathic pain scales have been developed where patients
rate the presence and severity of pain descriptors. The purpose of
these research scales is to screen for neuropathic pain. 342–344 These
include: the Neuropathic Pain Scale, 345 the Leeds Assessment of
Neuropathic Signs and Symptoms346 (translated into Arabic, 347
Chinese, 348 Greek, 349 Japanese, 350 Korean, 351 Portuguese, 352
Spanish, 353,354 and Turkish355), the Neuropathic Pain Diagnostic
Questionnaire (DN4)356 (translated into Arabic, 357 Chinese, 358
Dutch, German, Greek, 359 Hungarian, 360 Japanese, 361 Korean, 362
Persian, 363 Portuguese, 364 and Thai), 365 and the Neuropathic Pain
Questionnaire, 366 the Short Form of which has been translated
into Arabic367 and Turkish. 368
An important new area for oncologists is the recognition of
chemotherapy-related peripheral neuropathy. Two instruments
are widely used in studies, the EORTC Chemotherapy-Induced
Peripheral Neuropathy Scale369 and the FACT Neurotoxicity
Subscale. 370 This area has been reviewed. 371,372
Instruments for breakthrough pain include the Breakthrough
Pain Questionnaire, 373 a pediatric version, 374 the Breakthrough
Pain Assessment Tool, 375 and the Alberta Breakthrough Pain
Assessment Tool. 376
Multiple symptom instruments
Originally developed for cancer patients, these instruments are
being studied and adapted for patients with other advanced ill-
nesses. This section presents some of the more widely used
instruments, readers are referred to reference [377] for a more
detailed review. 377
The Symptom Distress Scale (SDS) introduced the concept
of distress to symptom assessment. 378 The SDS has 13 items,
with 11 symptoms; pain and nausea are each assessed twice.
Variations include the Adapted Symptom Distress Scale 2379 and
the Symptom Experience Scale380 The Adapted Symptom Distress
Scale has 31 items for 14 symptoms and includes symptom occur-
rence. The SDS has been translated into Chinese, 381 Dutch,
Italian, 382 Korean383 Spanish, and Swedish. 384 The SDS has been
studied in patients receiving cancer chemotherapy, home care, 385
and in a variety of other settings. 386
Textbook of Palliative Medicine and Supportive Care
The Edmonton Symptom Assessment Scale (ESAS)387 is a val-
idated nine-item VAS scale with eight symptoms and a well-being
item;388–390 a newer version is the ESAS-R, with a numerical rating
scale and summary scores. 391 Brazilian, Portuguese392 Chinese393
French394 Italian, 395 Korean396 Norwegian, 397 Spanish, 398 Thai, 399
Flemish,400 and German401 versions have been developed.
The ESAS-R has been translated into French,402 Icelandic,403
Japanese,404 and Spanish.405 Cutpoints406 and minimal clinically
important differences407 have been defined. The ESAS has been
studied in multiple settings, including hospice, palliative care
consultation teams,408 home care,409 quality improvement, 395
and the ICU410 and implemented for automated screening in
Ontario.411
The MD Anderson Symptom Inventory (MDASI)412 was
derived from hierarchical cluster analysis on patient responses.
A core number of 14 items accounted for 64% of the variance in
symptom distress. Patients are asked to rate the severity of 13
symptoms and 6 interference items with a numeric rating scale. It
has been translated into Amharic,413 Arabic,414 Chinese,415 Farsi,416
French,417 German,418 Japanese,419 and Russian.420 Fourteen mod-
ules for specific categories of cancer patients have been developed
to supplement the items in the MDASI.421
The Memorial Symptom Assessment Scale (MSAS) is a vali-
dated patient-rated instrument in which patients rate symptom
severity, distress, and frequency for 32 highly prevalent physi-
cal and psychological symptoms.422,423 Each symptom is rated
on a Likert scale and scored from 0 to 4 ranging from “no” to
“very much.” The MSAS subscales include: the Global Distress
Index (GDI), the Physical Symptom distress (PHYS), and the
Psychological Symptom distress (PSYCH). In the MSAS Short
Form, patients rate symptom distress for physical symptoms and
symptom frequency for psychological symptoms.424–426 In the
condensed MSAS, the number of items has been reduced to 14.427
The MSAS has been used in cancer chemotherapy,428 hospital
settings,429 hospice,430 ICU,431 patients with hematologic malig-
nancies,432 heart failure,433 COPD,434 chronic renal disease,435
and in longitudinal studies.436 The minimal clinical significant
difference has been estimated for the MSAS Short Form.437 A
caregiver version438 and a children’s version have been devel-
oped.439 There are translated versions in Arabic (Lebanese),440
Brazilian, Portuguese,441 Chinese,442,443 Indonesian,444 Swedish,445
Turkish,446 Arabic (Israeli), Dutch, English, French, German,
Hebrew, Italian, Polish, Spanish and Turkish.447 Ths MSAS
Short Form has been translated into Chinese,448,449 Korean,450
Spanish,451,452 and Turkish.453
The Rotterdam Symptom Checklist454 is a validated 34-item
instrument where patients rate distress. A physical and a psycho-
logical symptom subscales are described. It has been translated
into French,455 Italian,456 Spanish,457 and Turkish.458 A modified
version has been validated in an American population of can-
cer patients.459 This instrument has been used extensively in
European cancer chemotherapy trials and symptom intervention
studies.
Disease-specific multisymptom instruments have been devel-
oped, including the Lung Cancer Symptom Scale460 and the
Myeloproliferative Symptom Assessment Form.461
Applications of symptom instruments
Epidemiology and descriptive studies: Symptom surveys with
the ESAS, MSAS, and other instruments have established that
multiple symptoms are highly prevalent in both treatment462
Tools for Pain and Symptom Assessment
and palliative care settings. Descriptive longitudinal studies
with symptom instruments are now being reported.463–465 The
application of information technology has enabled larger scale
collection, such as in Canada,466 or with hospital information
systems.467
Improvement of symptom recognition: Surveys of symptom
data concurrently gathered with the symptom tools show that
routine symptom assessment by doctors and nurses often misses
significant data.468–471 There is a growing consensus that the use
of symptom instruments is feasible and contributes important
information.
Clinical trials
A core set of symptoms has been recommended for cancer treat-
ment trials.472
Patient-rated adverse events: Patient and clinician reports
differ.473 The National Cancer Institute has developed patient-
reported symptoms as a separate component—the Toxicity
Assessment for clinical trials.474 It has been translated into
Danish,475 Japanese,476 Korean,477 and Spanish,478 and has been
studied in different modes of administration.479
Drug labeling indications: The Food and Drug Administration
and the European Medicine Agency have provided guidance for
industry on the role of symptom assessment measurements in
pharmaceutical trials.480,481
Patient prioritization/screening
Symptoms represent an important approach to identifying
patients for early palliative care. One British study used data from
a symptom checklist to suggest that patients with lung cancer
or brain tumors should be on high priority for specialist pallia-
tive care.482 Another British study found differences in symptom
patterns by service component of patients referred to a hospice
inpatient service, a community team, an NHS hospital support
team, and an outpatient service, suggesting that different symp-
tom management strategies may be needed for different patient
groups.483
Prognosis
Patient ratings of symptoms can add prognostic information.484
In studies of patients with cancer, individual symptoms as well
as combinations of symptoms provide prognostic information in
addition to that provided by the Karnofsky Performance Score.485
Physical symptoms may carry more of the prognostic informa-
tion.486 Larger-scale analyses from clinical trials suggest that
symptoms and quality of life are prognostic.487,488
Symptom clusters
Symptom clusters are one way of understanding the multiple
symptoms reported by patients with advanced illness. Factor
analyses with the MSAS, Rotterdam Symptom Check List, and
the Canberra Symptom Scorecard489 have shown two major
groups of symptoms—physical and psychological symptoms. The
use of multisymptom instruments is a logical step in establish-
ing the presence of these clusters.490 Symptom clusters have been
studied in advanced cancer patients491 in different phases of can-
cer care, such as chemotherapy,492 and in noncancer areas, such as
heart failure493 and kidney disease.494
Symptom burden
Patient ratings of symptom severity and interference have
enabled measurements of symptom burden, a concept that is easy
to understand and clinically useful.495,496
173
Quality of care
Tools may also be important to the program as evidence for the
quality of care given, where the act of symptom assessment is
taken as the process. In this concept, tools may be important as a
way of evaluating the structure of the program.497 More recently,
symptom assessment has become an integral part of quality of
care standards by many organizations within the United States,
including the National Quality Forum498 and the National
Comprehensive Cancer Network.499
Treatment outcome
Tools can serve by recording the outcomes of symptom manage-
ment in different settings.
Symptom monitoring
The combination of symptom tools and new computerized
technology has led to the concept of symptom monitoring500
or surveillance. A symptom monitoring program could cover
more areas of patient concern, identify symptoms before they
become severe, complement measures of tumor response, and
assist in clinical decision-making. Randomized trials in cancer
patients have shown that real-time symptom assessment during
chemotherapy administration can improve quality of life and
survival.501,502
Studying the relationship of symptoms to other aspects of pal-
liative care, such as spirituality503 and dignity.504
Cultural considerations
The wording of items and comparisons of scores across different
sites afford opportunities for assessing the effect of culture. To
date, instruments for screening of depression have received more
attention, 505–507 and less differences have been found for general
symptoms.508
Special populations
In patients who are unable to communicate, the ascertainment
of symptoms becomes more difficult. This is especially true for
the pediatric, geriatric, and ICU populations. One approach has
been the development of behavioral measures of pain which can
be recorded by observers.
For pediatric patients, behavioral scales include the
FLACC509,510(translated into Brazilian Portuguese, Hebrew, 511
Japanese, 512 and Korean513) and for demented patients, the
PainAD514 (Translated into Brazilian, Portuguese, 515 Chinese, 516
German, 517 Italian, 518 Spanish, 519 and Turkish520) and Pain
Assessment for the Dementing Elderly.521 Pain behaviors have
been described for ICU patients in reference [522].522
More recent recommendations have included a hierarchy of
approaches, whereby findings with these and other instruments
are combined with other clinical data.523
Practical issues
The selection of tools for pain and symptom assessment reflects a
balance, as elsewhere, between what is possible and what is desir-
able. These considerations include the nature of the organization
and the uses to which the information from the tool will be put.
Research and practical tools
The difference between research and practical tools lies in their
purpose and function. Most instruments in use started out as
research tools to better describe symptom(s). As such, these
174
reflected concepts about the symptom, tended to be longer, stud-
ied healthier patients, and were administered by research person-
nel. These studies have provided many insights into symptom
epidemiology and their relationship to other aspects of patient
experience, and demonstrated feasibility. In the clinical context,
pragmatism is emphasized, and time and personnel are limited.
As instruments move from research to clinical application, there
is then an evolutionary pressure for the development of shorter
and simpler instruments which can be rapidly administered and
interpreted.
Research Practical
Comprehensive Screening
Based upon specific theories Empirical
Longer Shorter
Wide choice of answers Yes/No
Specific Global
Multiple item Single item
Patient rated Observer rated
Paper/electronic Paper/electronic
Patient stamina is decisive. Many terminally ill patients may
be unable to answer more than a handful of questions. In one
study of patients with terminal cancer at an American hos-
pital, only half were able to complete one of the three instru-
ments offered—the McGill Pain Questionnaire, the Memorial
Pain Assessment Card, or the Faces Pain Rating Scale. 524 In a
study of hospice inpatients, only 30 out of 71 patients with pain
were available to participate in a study where they were asked to
answer a 6-item questionnaire about pain, with each item scaled
from 0 to 10. The ratings were completed without difficulty and
showed good reproducibility one hour later. 525 Hospice patients
may have individual preferences for categorical responses to
numerical scales. 526
Availability of instruments
In addition to the time honored practice of contacting the develop-
ers of an instrument or finding the journal, many instruments may
be viewed on websites. These include, the MAPI Research Institute
www.eprovide.mapi-trust.org, www.qolid.org), the Robert
Wood Johnson Promoting Excellence in End of Life Care (www.
promotingexcellence.org), and the Toolkit of Instruments to Measure
End-of-Life Care (www.chcr.brown.edu/pcoc/Physical.htm)
Another source for symptom items can be quality of life instru-
ments, such as the FACT system, 527 the EORTC QLQ-C30, 528 or
the RAI-PC529 which have developed disease-related modules.
The first two have been translated into many languages and have
symptom items. More recently, PROMIS and pro-CTCAE items
have become available and may be helpful.
Choosing an instrument
Criteria for an ideal pain instrument, as listed by Chapman and
Syralja, apply for symptom instruments in general. These crite-
ria include: (1) minimal patient burden, (2) understandable by
patients, (3) produce a wide range of scores, (4) sensitive to inter-
ventions, (5) demonstrate appropriate reliability and validity, and
(6) availability of appropriate norms. Their principles of selection
are equally applicable. These ultimately depend on the needs of
the clinician and limitations of the patient population. The prin-
ciples include: (1) Define the goal of assessment (complexity of
Textbook of Palliative Medicine and Supportive Care
problem and information required); (2) Decide which dimensions
are appropriate for the problem at hand (severity, behavior, and
function); (3) Select subparts of instruments that are most suit-
able; (4) Consider development of a clinical database—layout to
be suitable for analyses; (5) Consider automated data collection;
(6) Avoid too much data; (7) Be sure the test instruments fit the
patient population; and (8) Take care to collect responses to all
items on the forms.530
For newer palliative care programs, selecting a short and easily
available tool is a good starting point after assessing initial goals.
For research purposes, the instrument is guided by the underly-
ing scientific question and the type of measurement needed. For
pharmaceutical trials, current recommendations are influenced
by regulatory guidelines.531 These include developing a model of
how components of patient-reported outcomes are expected to
change, and selection of tools accordingly.532
Sometimes the question arises as to when a new tool is needed.
Despite the large number already developed, for a particular
research question, there may not be an available instrument.
Depending upon the circumstances and resources available, one
may take a standard instrument with additional items, 533 adapt an
instrument from another field, or start afresh.534,535
Caregivers and patients ratings
Ideally, patients should be the source of information about symp-
toms, but they become unable near the end of life. The role of
caregivers or other proxies in symptom assessment has been an
area of ongoing research and has been studied with symptom
scales.536–539
Mode of administration
A tools is originally completed by the patient, or an interviewer,
and it is helpful to check the patient’s understanding of the
items.540 For pencil-and-paper instruments, checking the forms
for missing items after a patient has finished can save time.
Tools can now be completed by the patient in a variety of ways
including pen and paper, telephone, computer, internet, interac-
tive voice response, touch tablet, 541 and other modalities. Much
recent research has been on the feasibility of obtaining symptom
data by different forms of electronic interface.542,543 The flexibility
of modern information technology will enable symptom assess-
ment on a large scale and in new ways.544,545
Translation of instruments
Even within the same language, symptoms and aspects of
symptoms may be difficult to describe for the purposes of a
symptom questionnaire (e.g., British vs. American English).
These problems are magnified further when translations are
attempted, as different connotations may be associated with
the symptom or the items in the second language. 546 However,
it may be easier to translate an instrument than to develop
one. Linguistic validation refers to the translation, and cross-
cultural adaptation includes both translation and assessment
of psychometric properties.
If the reader would like to translate an instrument, it is advis-
able to work with the group that developed the original instru-
ment. The goal is to obtain semantic, idiomatic, experiential
and conceptual equivalence in translation. Fundamentally,
the instrument is translated into the new language, then back-
translated into the original language by a second team, and then
retranslated into the new language by a third team. After each
translation, the instrument is reviewed by a committee.547,548 The
Tools for Pain and Symptom Assessment
translated instrument is tested on speakers (health-care workers
and/or patients) to determine ease of use and comprehension.
More thorough efforts may lead to nine or more steps.549 The
quality of a linguistic validation is the performance and docu-
mentation of each of the translation steps.550 Guidelines have
been developed551–553 including manuals, 554,555and the subject is
recently reviewed.556,557
Validation
In a new population, or with a new language, the tool should be
validated. A representative sample of at least 40 patients should
complete the tool, a reference tool known to be valid, and have
their performance status and demographic data recorded.
Practical aspects, such as ease of administration and comprehen-
sion should also be recorded. These data can then be analyzed for
validity.558 For instruments to be used in multinational trials, a
sample size of 200 patients has been recommended.559
Implementation of tools
Many palliative care professionals are not familiar with symptom
instruments.560 Principles of implementation by Higginson561 are
applicable to symptom tools. These include: (1) Measures that
form a part of treatment planning and evaluation are more likely
to influence clinical decision-making than monitoring alone; (2)
Are the symptoms relevant?; (3) How long does it take to com-
plete?; (4) Will it measure differences?; (5) who will use the mea-
sures?; (6) Involve staff and patients; (7) Plan and begin training in
both the use of the measure and associated clinical skills. I would
add that a plan of action for symptom control should be in place
or no improvements will result.
Subsequent experience has led to additional emphasis on
understanding the purpose and context of implementation, and
attention to how the data will be gathered and reported.562 The
perspective of symptom assessment implementation as a modifi-
cation and requiring the support of a health-care system will be
increasingly relevant.563
Unexplored areas/Future directions
With the increasing importance of symptom assessment and
other patient-reported outcomes for clinical use, health services
research, intervention trials, and the availability of newer meth-
odologies and modes of administration, symptom assessment
will be an active area for the foreseeable future.
An emerging area will be deciding what kind of symptom
assessment, instrument, and method of administration is most
applicable for palliative care patients. A second area is the imple-
mentation of symptom assessment into the field of palliative
medicine and into general medical practice.564 A third area will
be finding where IRT-developed approaches fit into the general
world of symptom assessment instruments. A fourth area will be
how the large scale of symptom data acquisition made possible
by informatics will affect symptom analysis and management.
A fifth area may be reconciling the different demands put upon
symptom instruments as the result of more stringent develop-
ment criteria, different applications (e.g., screening vs. clinical
trial), and different populations. A sixth area will be whether
the number of instruments continues to increase, or some form
of consolidation starts to take place. A seventh area is whether
the distinction between quality of life and symptom assessment
remains. An eighth area to follow will be to what extent instru-
ments originally designed for advanced cancer patients can be
175
used in patients with other advanced illnesses. A ninth area is the
role of symptom instruments in electronic health records, apps,
and the Internet. The tenth area is the implementation of symp-
tom assessment in routine practice, and its role in the integration
of palliative care.
Propose an ideal tool package with
good psychometric properties
and minimal overlap
How is it done at certain centers?
MD Anderson:565 Edmonton Symptom Assessment Scale,
Mini Mental Status Exam, CAGE Questionnaire, 566 Morphine
Equivalent Daily Dose, and Functional Impairment Measure567
Institut Jules Bordet:568 Mini Mental Status Exam, Memorial
Delirium Assessment Scale, Edmonton Functional Assessment
Tool, 569 and Edmonton Symptom Assessment Scale
University of Cologne:570 Mini Mental Status Exam, Brief Pain
Inventory, Medical Outcome Study Short Form-12571
Duke University:572 FACT G, FACIT F, MDASI.
Ontario Province Palliative Care Improvement Project:573
Edmonton Symptom Assessment Scale
How to select a tool
No instrument is perfect and the package depends upon the local
needs of the patients (types of disease and prevalence of symp-
toms), resources available to the staff (manpower, time), and pur-
pose (research or practice or screening).
Areas of practical interest at intake include the ability of the
patient to make decisions, the presence of key symptoms, and a
performance status rating. Additional instruments can be added
depending upon the interest of the group. At follow-up, we need
to screen for new symptoms and determine if older symptoms
have changed.
If the reader is planning to set up a palliative care program, it
is better to select an available validated instrument (or module)
and add items than to pick and choose items from different tools.
The reader may wish to try out different tools on few patients to
see which one works best in terms of comprehension and ease of
administration.
Possible combinations are presented below.
Better KPS Worse KPS (KPS<50%)
Research Practice / Screening
Symptoms RSCL, MSAS ESAS, CMSAS, SDS,
MDASI
Pain BPI, McGill SF Numeric Rating Scale
Depression HADS Screening questions PHQ 9
Noncommunicative PAINAD PAINAD
Mental Status CAM CAM
MDAS
Note: BPI, Brief Pain Inventory; CAM, Confusion Assessment
Method; ESAS, Edmonton Symptom Assessment Scale; HADS,
Hospital Anxiety Depression Scale; KPS, Karnofsky Performance
Score; MSAS, Memorial Symptom Assessment Scale; MDAS,
Memorial Delirium Assessment Scale; PHQ, Patient Health
Questionnaire; RSCL, Rotterdam Symptom Checklist; SDS,
Symptom Distress Scale.
176
KEY LEARNING POINTS
• Many validated and reliable tools are available
for various symptoms. Responsiveness is being
established.
• The usefulness and validity of these tools in dif-
ferent populations continues to require further
study.
• The items of the symptom instruments selected
should be perceived as useful, easy to under-
stand, easy to answer, and easy to interpret.
Follow-up plans for symptom treatment should
be developed.
• Symptom tools are versatile in their applications.
• The choice of symptom tools depends on the
priorities set by the palliative care staff and the
stamina of the patients.
• Application of these instruments to clinical care
is the next challenge.
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557. Acquadro C, Patrick DL, Eremenco S, et al. International Society
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Functional Assessment Tool: preliminary development and evaluation
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573. Gilbert JE, Howell D, King S, et al. Quality improvement in can-
cer symptom assessment and control: the Provincial Palliative Care
Integration Project (PPCIP). J Pain Symptom Manage 2012;43:663–678.
22
QUALITY OF LIFE ASSESSMENT IN PALLIATIVE CARE

Richard Sawatzky and S. Robin Cohen

Contents
Introduction�����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������189
What is quality of life?������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������189
Use of measurement tools�����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������191
How can QOL measurement tools support clinical practice?���������������������������������������������������������������������������������������������������������������������������������191
What do you need to consider in deciding how to assess QOL?����������������������������������������������������������������������������������������������������������������������������192
QOL measurement validation����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������193
Construct validity��������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������193
Psychometrics��������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������193
Utility�����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������193
Social consequences���������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������194
Measuring QOL throughout the disease trajectory���������������������������������������������������������������������������������������������������������������������������������������������������194
QOL measurement tools�������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������194
Patient QOL�����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������194
Family caregiver QOL������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������195
To keep in mind when interpreting QOL scores��������������������������������������������������������������������������������������������������������������������������������������������������������195
The future���������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������196
References���������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������196

Introduction expectations and their actual situation.”2–4 This definition implies

The ultimate goal of palliative care is to optimize the quality of
life (QOL) of people living with a life-threatening illness and that
of those important to them, such as their families. Assessment of
QOL is therefore necessary if we are to provide the best care pos-
sible and ensure that we are eliminating unnecessary suffering.
This chapter focuses on the use of measurement tools to facili-
tate QOL assessments by drawing attention to the perceptions
and priorities of patients and family caregivers in health-care
research and clinical decision-making. We hope to clarify the
concept of QOL at the end of life, explicate the use of measure-
ment tools to facilitate QOL assessments, identify the questions
you must ask yourself when deciding how to assess QOL, and
discuss important measurement validity considerations for the
selection and use of QOL measurement tools.
What is quality of life?
The WHO Quality of Life Working Group defined QOL as “indi-
viduals perceptions of their position in life in the context of the
culture and value systems in which they live and in relation to
their goals, expectations, standards, and concerns.”1 Although
this definition is argued across and within disciplines, there is
general agreement that QOL is a perception. How else might we
explain situations where two people who have similar physical
circumstances and are close to death may judge their QOL to
be very different? For example, one person may judge QOL to be
good and cherishes each day, while the other feels that life is not
worth living. Consistent with this focus on perception, QOL has
also been defined as “the discrepancy or gap between a person’s
that QOL can be enhanced (or the gap can be decreased) either by
improving the actual situation (e.g., reduced pain) or by decreas-
ing expectations where the actual situation cannot be improved
(e.g., alter expectations to retain full physical functional status).
Furthermore, good QOL is not merely the absence of problems,
but involves an evaluation of both the positive and negative
aspects of a person’s life as well as the value or weight the person
places on each aspect.2,5–7
Health-care professions consider QOL an important out-
come in many situations. However, a careful look at many of
the QOL measurement tools used in health care reveals that
health, which the WHO defines as “a state of complete physi-
cal, mental and social well-being, and not merely the absence
of disease,”8 rather than QOL is being measured.9 The concept
of health-related QOL, which we and others consider a misno-
mer, 5,9 was introduced to broaden the focus of health measures
by including aspects of physical, social, and mental health, while
at the same time excluding aspects of life perceived as unre-
lated to health care, such as spirituality and life satisfaction.
Consequently, health-related QOL involves limiting the concept
of QOL to certain aspects of the person whose QOL we want
to assess. However, we cannot separate health-related physical,
psychological, and social aspects of a person’s life from other
essential aspects, such as existential well-being or spirituality.
Among the other aspects of significant importance to the QOL
of people who are in need of palliative care is their experience
with health care and the extent to which health care addresses
their individual needs.10,11 Whole person care involves recogniz-
ing and understanding that all aspects of the person are inter-
related, affecting one another. For this reason, we believe that
the notion of health-related QOL as a concept that is distinct

189
190
from QOL does not have a match in reality. Instead, we view
health-related QOL as a field of study that focuses on aspects of
a person’s QOL in the context of health research.
The complexity of the concept of QOL, including but not lim-
ited to the fact that QOL is a perception of one’s position in life,
and that contexts, goals, and expectations create that perception,
means that QOL is created by the interaction of external circum-
stances with who the person is. This complexity has two important
implications for QOL assessment. First, people may adapt to their
situation, resulting in a change in the frame of reference by which
they appraise their QOL. When this occurs, the meaning of their
QOL appraisal will not be consistent over time, resulting in a
phenomenon known as response shift. Second, we cannot assume
that the meaning of QOL is the same for all people. Consequently,
there will be individual differences in the meaning and interpre-
tation of QOL appraisals.
1. Response shift or adaptation.2 People have an amazing
capacity to adapt to new and/or more difficult circum-
stances. This is a powerful way of coping with a challeng-
ing situation, which is in part largely out of our control.
Response shift here refers to the situation in which the
frame of reference by which people appraise their QOL
(or other patient-reported outcomes), changes over time.
People may have (a) changed their internal standards
(called recalibration), (b) focused on areas in which they are
doing better and de-emphasized the importance of areas in
which they are not doing well (called reprioritization), or
(c) changed what areas they call to mind when they answer
“How is your QOL?” (called reconceptualization).2 There is
evidence of response shifts occurring in people with a life-
threatening illness, both early in the disease trajectory and
at more advanced phases.12–15
Research has shown that ignoring response shift
could lead to the inability to detect treatment effects
on patient-reported outcomes, such as QOL.16 If we are
truly interested in subjective well-being, and recognize
QOL as a perception, then the fact that response shift
or adaptation is affecting our assessment of QOL is not
a problem. Response shift could be viewed as a thera-
peutic outcome. However, when we are determining the
effect of an intervention on QOL, then if there is dif-
ferential response shift in two groups we are comparing,
it is important to know how response shift or adapta-
tion is affecting our assessment of QOL. For example,
in the context of an intervention study, people who
receive an intervention that leads to reduced symptoms
may be less prone to response shift (they do not need to
adapt as their situation has improved), whereas people
who do not receive this intervention may experience
response shift as a result of adapting to living with wors-
ening symptoms. The net result is that the two groups
of people may assess their QOL similarly. In the case of
the intervention group, this will be because the situa-
tion has improved; whereas, in the case of the control
group, it will be because they have changed their expec-
tations or evaluation of the situation. Both are coping
well, but the effectiveness of the intervention will be
hidden. Conversely, some interventions may be designed
to promote adaptation and may therefore intentionally
induce response shift.17 Supporting this idea of differ-
ential response shift, Kvam and colleagues18 found that
Textbook of Palliative Medicine and Supportive Care
response shift plays a greater role in evaluating QOL
when the condition of people with multiple myeloma
deteriorates than when it improves.
Clearly the possibility of response shift must be
taken into account when using QOL measurement tools
in empirical studies and to inform clinical practice.
Although further study is needed, significant progress
has been made during the past decade to establish reliable
statistical and research design approaches to detect, mea-
sure, and accommodate response shift in QOL measure-
ment, and to identify people who experience response
shift.19,20 Each method has advantages and drawbacks.
Items that directly measure change (e.g., “Has your social
life changed for better or worse?,” with responses rang-
ing from “a lot worse” to “a lot better”) have been used
to help interpret changes in scores on standardized QOL
measures. However, response shift has also been shown
to affect these direct measures of change, and in different
ways depending on whether there is improvement or dete-
rioration.21 Other approaches to response shift detection
rely on statistical methods, including structural equation
modeling.22 The choice of method can lead to different
results and interpretations. Although the research on
response shift is ongoing, palliative care practitioners and
researchers need to be aware of the phenomenon and take
into account that change scores in QOL measures cannot
always be taken at face value.
2. Individual differences in the meaning and interpretation
of QOL appraisals. While response shift pertains to a
change in the meaning of QOL within individuals over
time, differences in the meaning of QOL can also be pres-
ent between individuals or groups. People from different
cultural backgrounds and with different experiences in
life may not interpret the questions that we use to assess
QOL in the same way. Such different interpretations may
be the result of cultural, developmental, gender or person-
ality differences, or because of differences in health and
illness experiences or life circumstances. If ignored, these
differences could distort the comparison of QOL scores
between individuals or different groups of people.23,24
Consequently, the measurement scores may not mean the
same thing for different people, resulting in a phenom-
enon known as “differential item functioning,” or a lack
of “measurement invariance.” A variety of approaches
have been used to identify and accommodate differential
item functioning in patient-reported outcomes and QOL
measurement.25,26 Although significant methodological
advances have been made, we need to better understand
the various factors that influence how people, particu-
larly in contexts of palliative care, interpret and respond
to questions about their QOL. This knowledge is crucial
to accurately interpret differences in QOL measurement
scores between individuals and groups with different
backgrounds and life experiences.
In summary, when assessing QOL, it is important to recognize
that different people may not ascribe the same meaning and
interpretation to the questions used in QOL measurement tools.
In contexts of research and health-care decision-making, this
means that QOL measurement scores should be evaluated for
response shift and differential item functioning prior to infer-
ring conclusions about differences in QOL over time or among
Quality of Life Assessment in Palliative Care
different groups of people. In clinical practice and interpretations
of QOL assessments at the individual level, this means that the
scores should not be taken at face value but rather must to be
clarified and discussed with the patient.
Use of measurement tools
A variety of tools are available to measure QOL for purposes
of research and health-care decision-making. The term “QOL
assessment” often refers to the use of QOL measurement tools
in clinical practice. This can be facilitated through the use of
both standardized and individualized measurement tools.27
Standardized QOL measures have fixed questions and fixed
response options. Examples include a wide variety of patient-
reported outcome measures (PROMs) and patient-reported
experience measures (PREMs). PROMs consist of standardized
sets of questions for obtaining patients’ assessments of health
outcomes relevant to their QOL (e.g., symptoms, functional
status, health status, and psychological, social, and existential
well-being).28,29 PREMs consist of questions that measure sat-
isfaction and experiences with the health care provided, which
are also relevant to their QOL (e.g., respect, communication,
coordination of care, emotional support, and access). 30 Similar
measures exist to assess the QOL of family caregivers. For most
of these standardized measures, answers to these questions can
be combined to obtain summary scores of overall QOL, dif-
ferent QOL domains (e.g., physical, social, psychological, and
existential aspects of QOL), or both. Some standardized mea-
sures may ask people to rate the importance of various items or
domains. However, weighting the responses by the importance
assigned to specific domains or questions by each participant
has not seemed to change the results when studying the QOL of
groups of people, and it therefore is rarely used as it adds to par-
ticipant burden. 31,32 In contrast, individualized QOL measures
ask each person to first name the areas of their life that are most
important to their QOL and to subsequently rate their experi-
ence and importance of each named area. 33,34 These measures
can be particularly useful in clinical practice to focus assess-
ments and monitoring on those areas that are most important
to the person. However, comparisons with other individuals and
populations are more challenging due to different areas being
measured for different people.
Whether it is best to use standardized or individualized QOL
measures depends on the purpose of QOL assessment. While
there are individual differences in the meaning and interpreta-
tion of QOL assessments, there appears to be sufficient com-
monality among people regarding the QOL domains that are
generally considered to be important. For example, most people
want to be physically comfortable, be neither depressed nor anx-
ious, be comfortable with their place in the world, etc. In addi-
tion, differences in aspects of QOL that are unique to particular
disease populations can be accommodated using standardized
disease-specific QOL measures. Nonetheless, standardized
measures remain limited in the extent to which they are able
to represent accurately differences in individuals’ perspectives
of their QOL. Individualized measures may therefore be more
informative if the purpose is to obtain a measure of an indi-
vidual’s QOL from his or her point of view. However, individual-
ized measures are limited in the extent to which the QOL scores
of an individual can be meaningfully compared with those of
other people. Thus, to inform clinical practice, some combination
of standardized measures (to obtain accurate comparisons with
191
a reference group) and individualized measures (to better under-
stand the meaning of QOL from an individual’s point of view)
may be most beneficial.
The utilization of QOL measures, some of which are com-
posed of long lists of questions, has been constrained by the
time and energy required by people to complete them. Recent
methodological advances, including item response theory,
item banking, and computerized adaptive testing are increas-
ingly being utilized to tailor QOL assessments to individuals,
thereby reducing the number of items. Computerized adap-
tive tests involve administering items based on an individual’s
responses to previous items such that accurate assessment can
be achieved while administering just a few items. Different
items from a common pool of items (an item bank) are admin-
istered to different people to produce a standardized and yet
individualized measure. Computerized adaptive tests thus
have the advantage of achieving accurate assessments with
reduced response burden by exposing individuals to fewer
items and by avoiding items that are not relevant or appli-
cable given responses to prior items. Examples of computer-
ized adaptive tests applicable to people with life-threatening
illness include the European Organisation for Research and
Treatment of Cancer (EORTC) CAT Core35 as well as those
that are part of the Patient-Reported Outcomes Measurement
Information System (PROMIS). 36,37
How can QOL measurement tools
support clinical practice?
The clinical usefulness of QOL measurement tools has been
examined in many different health-care settings and popula-
tions, including people living with cancer, and those who are in
need of palliative care. 38–41 Despite variation in population and
measurement tool used, giving clinicians the results of a QOL
or health status measure, completed by their patient just prior
to their appointment has been reported to: improve clinician–
patient communication40,42,43; make the clinician aware of patient
problems of which they were otherwise unaware, especially psy-
chological problems44; and change the care plan.44,45 The worse
or more complex the patient’s condition, the more useful this
assessment is for communication and management.46 Contrary
to clinicians’ expectations, interviews in which the QOL assess-
ment information is considered do not take more time44,47 In
palliative care, use of QOL measures in practice helps to detect
patient problems,45 enhances the collaboration among staff,42 and
can lead to improved emotional and psychological outcomes.48
Relational use of QOL measures by clinicians as part of routine
care has potential to enhance person-centered care practices.49
However, despite these benefits, clinicians have also expressed
concerns and tensions regarding the use of QOL measures in
routine care.50–52
There are several general guidelines and frameworks for
integrating QOL measurement tools into clinical practice set-
tings.53–55 Successful integration requires educational support
regarding clinicians’ knowledge, skills and attitudes for using
QOL assessment information to enhance person-centered care,
as well as considerations pertaining to workflow and organiza-
tional context.56–58 Clinical use of QOL measurement tools may
also be supported by electronic health record systems (both
personal health records and electronic medical records) that
are increasingly being designed to: (a) routinely collect QOL
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assessments from patients, (b) guide interpretation of QOL
scores, and (c) integrate QOL assessment data with other clinical
data to inform health-care decision-making.58–60
What do you need to consider in
deciding how to assess QOL?
Here are some questions you must answer in order to decide how
best to assess QOL for your purpose:
1. What level of QOL information do I need? You may
only want an answer to the question: how is your QOL?
However, for many purposes, more detailed information
is required, and you will want to know in what areas (or
QOL domains) the person is doing well, and in what areas
they are doing poorly. This is especially important in pallia-
tive care, where there is an inevitable decline in some areas
such as physical well-being, but there may be improvement
in others such as relationships or existential well-being. If
you only measure overall QOL over time, it may remain
steady despite large changes in different domains. In this
case you would select either a measurement tool that has
well-established subscales for different domains (standard-
ized measure with psychometrically sound subscales) or
one that allows the person to name the domains important
to their QOL and rate their status in each one (individual-
ized measure).
2. Am I interested in using QOL measurement scores at the
individual level to assess individual people at point of care,
or at aggregate levels (e.g., for research, program evaluation,
or quality improvement)? It is important to select measure-
ment tools that have been developed and validated for pur-
poses that correspond with your intended use. Validation
research on QOL measurement tools has predominantly
focused on their use at aggregate levels. However, there is
increasing interest in using these tools at the individual
level to inform clinical practice.40,55 If your interest is to
use tools in clinical practice, it is best to select tools that
have validity evidence supporting this particular type of
use. However, given the current state of the field, and the
need for more evidence, this may not yet be available. In
this situation, you may want to consider contributing to the
field by collecting evidence based on your clinical use of
QOL measurement tools that you find to be particularly
promising. Regardless of the tool used, it is important to
interpret scores from standardized QOL measures based
on conversations with the patient and/or their family
caregivers and by considering patients’ unique situations.
Individualized measures are particularly valuable if you
want to focus on measuring what is most important to the
individual person.55
3. Am I interested in comparing groups of people? If yes, do
these people have the same disease or different diseases?
If you are comparing groups of people with different dis-
eases, is the importance of each QOL domain likely to be
the same or different? If the domains of QOL differ for the
two groups, the content of a standardized measure will
not be equally valid for both groups, and an individualized
measure is required. A standardized measure can be used
if QOL domains are the same and of equal importance for
both groups, or if you want to only measure the distinct
Textbook of Palliative Medicine and Supportive Care
QOL domains (i.e., you do not need an overall QOL
score). In all situations, where possible, you should select
tools for which differential item functioning, or measure-
ment invariance, between the groups of interest has been
examined.
4. Do I need information regarding everyone in the group, or
is it acceptable to have only information regarding people
capable of completing a questionnaire? If you are in the
camp that agrees that QOL is subjective, then it is clear
that the person whose QOL is being measured is the best
person to rate their own QOL. However, the physical or
cognitive status of many palliative care patients precludes
them being able to participate in rating their QOL. In this
case, proxy measures may be considered. Ideally, someone
who knows the patient well will rate the patient’s QOL
on their behalf. This may be a member of the staff or the
family. However, proxy measures are known to differ from
the patient’s own ratings, and the difference tends to be
greatest for areas that are less concrete (such as existen-
tial wellbeing) and where the patient is doing poorly. Many
studies have been conducted regarding proxy measures,
and the results are inconsistent.61–63 There is no perfect
solution in palliative care. You will have to balance the
limitations of using proxy measures against the limitation
of assessing only those who are well enough to complete a
questionnaire.
5. How do I interpret a change in scores? What amount of
change in the scale is clinically meaningful to the patient?
A statistically significant difference in scores between
groups or over time is not necessarily an important one.
Some researchers suggest relying on statistically deter-
mined measures of the minimal clinically important differ-
ence, which appears to be similar across many QOL studies
with different populations and represents about 0.2–0.5
standard deviations, or 5–10% of the scale range.64 Others
suggest that anchor-based approaches are more appropri-
ate for determining minimally important differences.65 The
ideal is to put the change in scores into a clinically mean-
ingful context (e.g., an improvement in score of 25% or two
points on Psychological Subscale X corresponds to the dif-
ference between someone who is clinically depressed and
someone who is not really enjoying every day but is not
depressed). Some measurement tools provide information
about score interpretation. For example, the difference in
score between bad, average, and good days is known for the
McGill Quality of Life Questionnaire.66 However, if you
expect a more subtle change due to your intervention or
difference between groups, you may need to be creative and
think of ways of asking the person completing the ques-
tionnaire to directly rate the importance of the change or
indicate what it means clinically (e.g., if measuring physical
functioning, what can you do now that you could not do
before?).67–70 In addition, in some circumstances response
shift must be taken into account.
6. Do I want to assess QOL to help a particular patient or fam-
ily caregiver? If so, do I just want an initial assessment, peri-
odic assessments, or do I want to track change in QOL over
time? Will the answers to a formal assessment be useful
(e.g., the scores), or should I use the QOL measurement tool
as a guide for what to ask, without focusing on the numbers
generated? For clinical purposes, QOL measures cannot
replace a good, thorough clinical interview. However, QOL
Quality of Life Assessment in Palliative Care
measures are helpful as an initial interview guide or to flag
areas that need further attention.27,45,71–73 Although several
studies suggest that QOL measures are useful in clinical
practice, further research is needed to guide their success-
ful implementation in palliative care clinical practice.
7. How much can I expect my participants to do? Can they
complete the questionnaires on their own—do they have
the strength, concentration, sight, and reading skills? Or
does someone need to read the questions to them? Or, is
it too long even if read to them? You may want to consider
using a short-form or a computerized adaptive test specifi-
cally designed to reduce response burden when collecting
QOL data. However, further research is needed for such
abbreviated measurement tools to be developed and vali-
dated for use in palliative care.
8. Will response shift (adaptation) interfere with my inter-
pretation of the answer, or is the extent to which it occurs
irrelevant to my question? If a response shift may greatly
influence your conclusions, ideally you would plan some
way of measuring the degree of response shift to help
you interpret your data.2 Including a change question, or
“then-test,” may be helpful, but it is important to consider
that the same factors that cause response shift may also
influence individuals’ interpretations and responses to the
change question. The then-test may also be influenced by
recall bias. Other statistical methods may be required to
reliably detect and adjust for response shift if the purpose
is to obtain an accurate evaluation of change in QOL over
time (e.g., intervention research).
9. If assessing over time, how will I use the data from the
different times of data collection? How will I handle the
inevitable missing data? There are many well-established
statistical approaches to dealing with missing data in QOL
measures.74,75 However, most approaches assume some
degree of randomness in the patterns by which the data
are missing. In palliative care it is important to consider
that most of our missing data are not missing at random:
usually data are missing because the patient has become
too ill to respond or has died, or the patient’s deteriora-
tion means that the family caregiver no longer has time to
complete the questionnaire. Although there is no perfect
solution, guidelines, and advances in statistical methods
are increasingly being developed to minimize the possibil-
ity of biased results in palliative care research.76,77 When
reviewing results of studies, or conducting your own, it is
important to investigate explanations for missing data and
use appropriate statistical methods to minimize bias.
10. What time frame should the questions refer to? It is impor-
tant that your questions clearly indicate the time period
that people are to consider when answering. QOL mea-
sures developed for the general population often refer to
the past month, while those that are disease-specific often
use a time frame of the past week. However, because QOL
often changes so rapidly near the end of life, a 2-day time
frame may be better.
QOL measurement validation
Meaningful QOL assessment requires that we understand peo-
ple’s responses to the questions or items that comprise QOL
measurement tools. That is, the use of individuals’ responses to
193
questions for QOL assessment requires that we understand how
these responses relate to the construct (e.g., overall QOL or a par-
ticular domain) that we wish to measure. Zumbo78 describes four
elements of this explanatory perspective of measurement valida-
tion as the basis for establishing such an understanding: validity,
psychometrics, utility, and social consequences.
Construct validity
Any assessment of QOL needs to have construct validity: you
need to be assessing QOL, and not some other construct (such
as health status). To what extent can you legitimately make infer-
ences about people’s QOL based on their responses that are used
as assessment indicators of QOL? This includes establishing the
various domains that comprise QOL, the “why” and “how” of
individual’s responses to questions for the assessment of QOL,
and understanding the factors that explain QOL (antecedents)
and those that are influenced by it (consequences). There is not
complete agreement in the literature as to which domains are
relevant to the QOL of palliative care patients, but there is a gen-
eral consensus that QOL comprises at least the physical, psycho-
logical, social/relationship, and existential/spiritual domains.79,80
Other domains such as cognitive functioning, 81,82 environment,81
and communication have been found to be important in some
studies.79,81 The experts as to what content is most relevant to
QOL are members of the groups of people whose QOL is to be
measured (e.g., patients; family caregivers for their own QOL).
Consequently, when assessing QOL in different cultures, valid-
ity needs to be established for each culture that differs in ways
related to QOL and what is important to it. It is not enough to
know that the translation of the scale or interview is accurate and
embraces the same concepts, it is necessary to be sure that the
interview or questionnaire includes all relevant content and only
relevant content.
Psychometrics
An important element of measurement validation involves the
use of statistics to examine the statistical relationships between
QOL and its assessment indicators (i.e., items or questions of
a measurement tool or questionnaire). This includes the use of
factor analysis techniques to determine the dimensional struc-
ture of a set of assessment indicators (e.g., to create subscales)
and evaluation of the indicators’ trustworthiness (test-retest and
internal consistency reliability).83 In addition, modern statistical
approaches, such as item response theory and latent variable mix-
ture models, are increasingly used to establish assessment scales
and evaluate the extent to which assessment properties might
be different for different groups of people.25 A foundational prin-
ciple is that psychometric evaluation in one population may not
be directly applicable to another (e.g., people from a different cul-
ture or age group) and should ideally be re-examined.
Utility
In the context of measurement validation, utility refers to evi-
dence resulting from the use of measurement tools. QOL mea-
surement tools have been created for a variety of purposes. Some
tools are specifically designed to evaluate changes in QOL in dif-
ferent groups (e.g., for use in clinical trials), whereas other tools
are more appropriate for measuring QOL of larger populations
(e.g., for epidemiological studies). Some QOL measurement tools
are particularly appropriate for use in clinical practice (e.g., to
monitor treatment effectiveness or identify particular areas of
needs). The term “clinimetrics” is sometimes used to refer to the
validation of measurement tools from a clinical point of view.84,85
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Measurement tools have also been developed for purposes of
economic analysis where the focus is on determining the value
placed on QOL. 86 In economic evaluations of QOL, such val-
ues are often expressed as “utilities” that range from 100% (per-
fect health/QOL) to 0% (health/QOL equivalent to death). It is
important to consider, however, that the utility scores do not
represent an individual person’s QOL from their point of view,
but rather the value that is placed by a reference group on that
person’s condition (i.e., health state) as defined by the result of
the QOL assessment. Consequently, we do not regard a util-
ity score as a QOL assessment. The key point here is that QOL
measurement tools are developed to maximize the usefulness
(utility) and accuracy (sensitivity and specificity) for specific
intended purpose(s). When using a QOL measurement tool, it
is therefore important to determine whether this is the most
appropriate tool for your purpose.
It is also important to ensure that the QOL measurement tool is
acceptable to the person whose QOL is being assessed. The ques-
tions must not be distressing. They may raise important feelings
and even bring tears, but if these appear to be a welcome open-
ing, by the person, to discuss important issues with the assessor,
then we do not consider it distressing, provided they are given the
opportunity to discuss these issues. We and others have infor-
mally noted that many palliative care patients find QOL assess-
ments therapeutic. A formal study demonstrates this to be true
for family caregivers as well.87 The measurement tool must also be
within the limits of the strength and other capabilities (e.g., read-
ing, or else the opportunity to have it read aloud) of the person
whose QOL is being assessed.
Social consequences
The use of QOL measurement tools requires careful consider-
ation of both intended and unintended consequences.88 Tools
have often been designed to make visible some aspects of QOL
from the respondent’s point of view for purposes of research or
clinical decision-making. However, the selected aspects of QOL
that are made visible, and those that have not been made visible,
could have unintended consequences. For example, some QOL
measures include a subscale measuring existential or spiritual
domains, whereas others do not. If existential or spiritual domains
are important for an individual, then excluding an assessment of
this domain could have detrimental consequences. Clinicians
may not adequately take existential or spiritual needs into account
when such these are not made visible. Conversely, tools that reveal
complex existential or spiritual needs may cause clinicians to
address these needs without having adequate expertise to do so.
As another example, some tools may reveal aspects of QOL that
are important in particular cultural groups. This could lead to the
needs of other cultural groups being underrepresented. Another
unintended consequence could occur when people who have
experienced response shift are inadvertently penalized for not
demonstrating a decline in QOL scores over time, for example by
not being offered an intervention that would alleviate a problem
(e.g., pain) so that they don’t have to adjust to it.
Measuring QOL throughout
the disease trajectory
Since palliative care is appropriate from diagnosis on, ideally we
would have QOL measurement tools that are valid throughout
the disease trajectory.89 However, construct validity, psychomet-
ric properties, and the ability to respond to all questions may
Textbook of Palliative Medicine and Supportive Care
vary along the trajectory, due to response shift and deteriorat-
ing physical status as the disease progresses. For example, women
with a recurrence of breast cancer describe their experience and
concerns now that the cancer has recurred as quite different from
what they were when they were first diagnosed and thought that
they could be cured. They describe different kinds of adaptations
needed and a reprioritizing of various aspects of their life. They
also now grieve for an anticipated future that won’t be lived and
experience anxiety about the dying process.14 However, other
studies suggest that while a reprioritization may occur at dif-
ferent disease stages, physical, psychological, social, and spiri-
tual/existential well-being are contributors to QOL at all stages
(although they may not be so named).82,90,91 It may be that there
is more inter-individual variability in what is important to QOL
than there is across disease stages.
Many measurement tools used at earlier stages of the dis-
ease and into long-term survivorship tend to focus primarily
(although not always exclusively) on physical symptoms and
functioning.92,93 Those commonly used further along the disease
trajectory tend to measure the social and spiritual/existential
domains as well. QOL measurement tools commonly used ear-
lier in the disease trajectory tend to be longer than those used
at later stages, when the patient’s capacity to complete the ques-
tionnaires becomes a central concern. Few studies have tried to
follow patients throughout the disease trajectory, in part because
the research questions of interest at different phases tend to dif-
fer and in part because of feasibility issues. Another issue that
requires study is whether a change in scores has the same mean-
ing at different stages of the disease trajectory. There is evidence
that differences in scores are larger when there is deterioration
than when there is improvement in QOL.21,66,69 One solution to the
problems of re-prioritization and length of the measurement tool
might be to use an individualized measure of QOL, as the domains
will always be important to the respondent. However, the ability
to measure change in particular domains becomes more compli-
cated when the domains measured shift over time (as a result of
reprioritization).
QOL measurement tools
A full review of QOL measurement tools is beyond the scope of
this chapter. Reviews and compendiums of QOL measurement
tools in the palliative care setting are available.94,95 All tools to
date have some limitations. Below we briefly mention a few tools
that have been most commonly used for the assessment of the
QOL of patients and family caregivers in palliative care.
Patient QOL
The McGill Quality of Life Questionnaire (MQOL),96,97 which has
recently been revised98 and expanded,99 is among the most widely
used QOL measurement tools for studies of people near the end
of life and was developed specifically for people with a life-threat-
ening illness. The European Organisation for the Research and
Treatment of Cancer Quality of Life Questionnaire-Cancer, 30
items (EORTC QLQ-C30)93 and Functional Assessment of Cancer
Therapy-General (FACT-G, later called FACIT-G)90 have been
widely used in studies of people undergoing anti-cancer treatment,
the population for which they were designed. These latter two tools
are also commonly used in palliative care studies aimed at physi-
cal symptom management, where they are often combined with
add-on modules for different cancer sites or diseases. In addition,
to make these tools more suitable for palliative care, the EORTC
Quality of Life Assessment in Palliative Care
developed a short form (EORTC PAL)100 and an add-on module has
been developed for the FACT to create the FACIT-PAL,101 although
neither has yet been widely used. While standardized QOL mea-
surement tools developed for people at the end of life measure the
existential/spiritual domain (e.g., MQOL contains a validated exis-
tential well-being subscale), measurement tools developed for use
primarily with people undergoing anti-cancer treatment often do
not. Because of the increasing recognition of the spiritual domain
as important to QOL, additional modules for measuring this aspect
of QOL have been developed for the FACIT102 and the EORTC.103
QUAL-E is another non-disease-specific measurement tool devel-
oped for people at the end of life.104 Standardized measures that
have been developed for general populations, like the SF-36105 to
assess health and the General Health Questionnaire (GHQ) to
assess mental health,106 have been used to compare people with
different diseases. However, these generic measures have not been
designed for use with palliative populations. In addition, individu-
alized QOL measures have been developed to focus assessments
on those areas that are most important to the person. Examples of
individualized measures include the Schedule for the Evaluation
of Individual Quality of Life (SEIQoL),107 the Patient-Generated
Index (PGI),108 and the Measure Yourself Medical Outcome Profile
(MYMOP) questionnaire.109
Two other commonly used measurement tools focusing on key
outcomes and symptoms that impact on QOL are worthy of men-
tion: the Palliative care Outcome Scale (POS) and the Edmonton
Symptom Assessment Scale (ESAS). These tools are not designed
to provide an overall QOL assessment, but rather to assess some
of the domains relevant to QOL affecting the person and those
important to them. The POS110 (also see: https://pos-pal.org) is a
widely used tool for measuring outcomes of palliative care from
the person’s point of view. Recently a new integrated version, the
Integrated Palliative care Outcome Scale (IPOS) has developed,111
bringing together more symptom elements into the existing psy-
chosocial, spiritual, and health-care support items. Additional
POS modules for different diseases are also available. The ESAS112
and its more recently revised version (the ESAS-R)113 is a widely
used clinical tool designed to routinely assess intensity of par-
ticular symptoms and overall wellbeing in palliative care. There
have been many studies supporting validity and reliability of the
ESAS-R for its intended purpose of supporting routine and fre-
quent symptom assessments in palliative care settings.114
Since palliative care is much less developed for life-threatening
illnesses other than cancer, there is a concomitant relative lack
of studies on QOL measurement in these non-cancer palliative
care populations,48 although these are increasing (e.g., chronic
obstructive pulmonary disease, heart failure).92,115 Unfortunately,
the same mistake regarding content validity is often made as
when studies of “QOL” in cancer first began, i.e., the tendency is
to focus mainly on physical symptoms and functioning or health,
rather than the broader concept of QOL. Fortunately, there are
exceptions.116,117
There is increasing emphasis on the importance of focusing
QOL measurement tools on those QOL domains that are identi-
fied as important by patients. The following eight domains have
been identified as being of particular importance for people who
are receiving palliative care: physical; personal autonomy; emo-
tional; social; spiritual; cognitive; health care; and preparatory.118
Overall, there continues to be an important need for research on
the construct validity of QOL measures for all life-threatening
illnesses from a person-centered point of view. This includes the
need for validation research within different cultural populations,
195
contexts of care, points of time, and purposes (including research,
clinical practice, and health services decision-making).119
Family caregiver QOL
There has been less research regarding the QOL of family care-
givers than that of patients. The Caregiver Quality of Life-Cancer
measure (CQOLC),120 the Caregiver Quality of Life Index,121 and
the Quality of Life in Life-Threatening Illness-Family Caregiver
(QOLLTI-F)122 have all been developed to measure the QOL of
family caregivers of people at the end of life. Measures of outcomes
that form part of, contribute to, or are related to family care-
giver QOL are useful in many situations. Some have been devel-
oped specifically for caregivers, such as the Caregiver Reaction
Assessment (CRA),123 or measures of caregiver burden (e.g., Zarit
Burden Interview).124,125 Others are generic tools and may be used
for both patients and caregivers, such as those designed to assess
general health (e.g., SF-36 or its free parent version, the Rand-36)
or mental health alone (e.g., GHQ; Center for Epidemiological
Studies Depression Scale (CES-D),126 or social support (e.g., Social
Support Questionnaire).127 While the generic tools do not capture
all aspects of QOL important to end-of-life caregivers, they allow
comparison to norms for the general and other populations.
To keep in mind when
interpreting QOL scores
Just as with many medical tests, there are conditions that may
invalidate QOL scores from well-developed measurement tools
or make them difficult to interpret. These cautions apply espe-
cially if QOL scores are being used to inform care plans or con-
tribute to research evidence.
• QOL assessment questions may not be interpreted as
intended and different people may not interpret these ques-
tions in the same way. Individual differences in the meaning
and interpretation of QOL appraisals must be considered.
• Individuals may not have the same frame of reference
by which they appraise their QOL at different points in
time. Response shift and adaptation should be taken into
account when interpreting the meaning of QOL assess-
ments over time.
• Construct validity is an important consideration, as differ-
ent tools may not be measuring the same QOL construct
(i.e., some tools might focus predominantly on symptoms
and functioning whereas others include questions pertain-
ing to a broader understanding of QOL).
• Some measurement tools use response scales that need
to be reverse scored (e.g., the best QOL is not always at
the same end of the rating scale, or we may wish to avoid
the respondent developing a habit of checking off the
same answer without carefully considering the item).
This can be confusing, resulting in the wrong answer
being selected, especially when fatigue or medication
decreases cognitive acuity.
• If possible, when there are scores that are counter-intuitive,
it is best to speak with the respondent to determine their
understanding of the item and their intended answer. This
is especially important when standardized QOL measure-
ment tools are used in clinical practice. For research pur-
poses, studies can be designed as mixed-methods studies,
with a qualitative component intended to inform interpre-
tation of the QOL scores.
196
The future
Despite the need to interpret QOL scores carefully, QOL assess-
ment has brought renewed focus in health care on what is
important to people whose QOL is in jeopardy. While existing
instruments to assess QOL or aspects of it have limitations, much
work and financial resources have gone into developing them and
gathering information about their properties and behavior in the
field. Since developing new instruments is resource-intense over
a long period, it is usually preferable to work with and toward
improving existing measures and better understanding how they
function in new circumstances. We look forward to a future where
patients and family caregivers are understood and described not
only in terms of their disease and symptom status, but also in
terms of their QOL. Only then can palliative care really begin to
address whole person care.
KEY LEARNING POINTS
• Improving QOL is the main goal of palliative
care, therefore assessing it is critical if we want to
understand the extent to which we are achieving
our goals.
• QOL assessment pertains to the whole person.
QOL is a perception. It is not a specific set of exter-
nal circumstances, but rather the interaction of the
person with external and internal circumstances.
• The “best” way of assessing QOL will depend on
your purpose in assessing it. There is no perfect
way to assess QOL in palliative care. Choose the
best way, or combination of ways, and be aware of
its strengths and limitations.
• Consider family caregiver QOL in addition to
patient QOL.
• While it is important to expand our knowledge
about the QOL instruments that have been devel-
oped and improve them, several are sufficiently
developed and studied to be used for either
research or clinical purposes.
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23
PATHOPHYSIOLOGY OF CHRONIC PAIN

Sebastiano Mercadante

Contents
Introduction�����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������199
Physiopathology of nociceptive pain�����������������������������������������������������������������������������������������������������������������������������������������������������������������������������199
Spinal cord��������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������200
Physiopathology of neuropathic pain���������������������������������������������������������������������������������������������������������������������������������������������������������������������������201
Pathophysiology����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������201
Chronic pain and plastic changes of the central nervous system����������������������������������������������������������������������������������������������������������������������������202
Descending modulation of nociception�����������������������������������������������������������������������������������������������������������������������������������������������������������������������203
Chronic pain states and opioid activity������������������������������������������������������������������������������������������������������������������������������������������������������������������������203
References���������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������205

Introduction complication of infiltration of tissue by tumor or tissue injury as

Cancer pain syndromes are commonly classified as somatic, vis-
ceral, or neuropathic in origin. Pain may be due to tumor infil-
tration of local structures or antineoplastic therapy, or it may be
unrelated to the tumor. Recognition of pain syndromes is essen-
tial for the adequate management of cancer pain. Basic science
research on the mechanisms of pain has been helpful in providing
the scientific rationale for new approaches to cancer pain manage-
ment. Cancer pain is a complex issue. While it is initially a signal of
ongoing injury associated with the onset or recrudescence of dis-
ease or may be caused by some diagnostic procedures, it subsides
after oncological treatments. However, with the progression of the
disease, the causes cannot be adequately eliminated and pain per-
sists or worsens. In this phase, cancer pain no longer serves a bio-
logical purpose of alerting the organism to the presence of harmful
stimuli. Rather it assumes the status of a chronic disease and is
associated with alterations in mood and pain behavior. The differ-
ences between acute and chronic pain include peripheral responses
of the organism and central nervous system modifications induced
by the chronic afferent volley of nociceptor activity.1
In the presence of damage of tissues, peripheral nerves transmit
their information from the body tissues to the spinal cord, where
neurons transmit in turn the information to the brain while
simultaneously triggering reflexes that withdraw the body part
involved in the painful stimulus. The higher brain centers orga-
nize the appropriate behaviors to restore health by protecting and
facilitating the healing of the damaged body site. As healing pro-
gresses, pain tends to spontaneously diminish. Thus, in healthy
individuals, pain is highly adaptive and has survival-oriented
purposes. However, pain may be the consequence of a dysfunc-
tion of the peripheral or central nervous system, or may develop
after prolonged and intense stimuli from damaged tissues.
The clinical picture of cancer pain varies depending on the
pathophysiological mechanisms, which depend on the charac-
teristics and progression of disease and the preferential sites of
metastases. Traditionally, the pain related to malignant disease
has been classified as nociceptive-inflammatory (somatic and
visceral) and neuropathic. Somatic and visceral pains involve
a direct activation of nociceptors, and these pains are often a
a consequence of oncological treatments. Neuropathic pain is a
complication of injury to the peripheral or central nervous system.
This type of pain is often poorly tolerated and more difficult to con-
trol. In clinical conditions that occur following the injury, infec-
tion, or inflammation of peripheral nerves, sensory processing
in the affected body region gets abnormal. Environmental stimuli
that would not normally result in the sensation of pain now do so,
and painful stimuli elicit exaggerated perceptions of pain.
Although nociceptive and neuropathic pains depend on sep-
arate peripheral mechanisms, they are both significantly influ-
enced by changes in the central nervous system function. It is
now clear that cancer pain is a more complex entity, particularly
regarding the response to analgesics, where numerous factors
play a role. However, it remains unclear whether cancer pain is
a unique type of pain or merely a subtype of inflammatory or
neuropathic pain, as in cancer pain models there are changes
in transmitters commonly produced in either neuropathic or
inflammatory pain state.2
Physiopathology of nociceptive pain
Nociceptors are terminal peripheral branches of sensory nerve
fibers that are sensitive to noxious stimuli. C-polymodal receptors
with unmyelinated afferent axons respond to different noxious
stimuli, including mechanical, thermal, or chemical.4,5 Pain from
soft tissues, such as muscles and joints, is induced by a variety of
these stimuli and is mediated by somatic nerves. This results in
well-localized sensation that is clearly perceived. Different neuro-
physiological understandings of visceral pain have been reported.
Visceral afferents are considered polymodal, providing excitatory
responses to different stimuli, including inflammation, stretch-
ing, and distension. Thus, visceral nociceptors do not evoke con-
scious perception necessarily, but have a wide range of responses
activated in the presence of inflammation or tissue injury. Distinct
classes of nociceptive sensory receptors innervating abdominal
internal organs have been hypothesized. They include the high-
threshold receptors, which are mainly mechanical and activated
by stimuli within the noxious range, and the low-threshold recep-
tors, which are activated low-intensity stimuli.

199
200
The high-threshold receptors encode the peripheral noxious
events in the viscera. Prolonged and intense stimuli, for example
the presence of hypoxia or tissue inflammation, sensitize these
receptors, activating also previously silent receptors. The activity of
afferents and the excitability of dorsal horn neurons are increased
when stimuli are persistent. This is due to a process of sensibi-
lization of afferents, determined by the local release of chemical
substances in ischemic or damaged tissues. A critical level of pre-
ceding activity in the afferents is required to induce the facilitation
of dorsal horn neuronal responses via central mechanisms.6
Afferent neurons transmit visceral sensory information to the
spinal cord and have cell bodies that reside in the dorsal root gan-
glia, travelling through the paravertebral ganglia and the prever-
tebral ganglia. Clinically, visceral pain tends to diffuse because of
a lack of a specific visceral sensory pathway and a low proportion
compared with those of somatic origin. Thus, distribution of vis-
ceral pain differs from that reported with somatic pain. While some
spinal neurons are involved in the localization of pain and project
it to the brain, other groups of neurons have short ascending pro-
jections sending collateral connections into many spinal segments.
Thus, the activation of visceral afferents produces changes in the
excitability of various spinal sites, activating the somatic nocicep-
tive sensory pathway. Supraspinally, the brain may misinterpret the
activity in the viscero-somatic neurons. These convergent recep-
tive fields at spinal level are multidermatomal, mainly centered in
the dermatome corresponding to the spinal segment stimulated.
These fields are larger than the receptive fields receiving only
somatic input.7,8 These dermato-anatomical aspects explain the
poor localization of visceral pain and the tendency to refer pain in
other areas of the body. Pain originating from any viscus is difficult
to differentiate from the pain originating in another viscus.
In cancer patients with abdominal diseases and intraperitoneal
masses, the most common sources of pain are mechanic stimuli,
for example torsion or traction of mesentery, distension of hollow
organs, stretch of serosal and mucosal surfaces, or compression of
some organs. There are several clinical abdominal pictures show-
ing that visceral pain is produced when the intraluminal pressure
of hollow organs is maintained above certain pressure thresholds.
For example, obstruction or inflammation within the biliary tract
or pancreatic duct leads to pain directly, as a consequence of an
increased intraluminal pressure associated with inflammation and
the release of sensitizing substances. The stretch of liver capsula
produces pain. Distension of the gallbladder induces a deep epi-
gastric pain, with inspiratory distress, and vomiting. A paradoxical
opioid-induced visceral pain is due to the spasm of the sphincter
of Oddi. Indeed, analgesia induced by opioids may counterbalance
this effect, as they increase the pressure threshold necessary to
activate the sensation of pain.9 Similarly, colicky pain is commonly
observed with a ureteral obstruction and subsequent distension
of the ureter and renal pelvis, as it occurs in the presence of an
abdominal-pelvic mass that compresses or invades the ureters. A
better localization of stimulus is evident when the disease invades
a somatically innervated structure such as the parietal peritoneum.
According to the different stages of disease, initially, visceral pain
may be poorly localized and dull because of the wide divergence of
visceral afferents in the spinal cord. Thereafter, the poorly localized
visceral pain may change and becomes more localized as visceral
afferent input increases due to the spinal facilitation or activation of
visceral nociceptors. When somatic structures, for example mus-
cles or peritoneum, are involved, a greater localization occurs.10
The peripheral component of primary afferent neurons has
been traditionally considered limited to the activation and
Textbook of Palliative Medicine and Supportive Care
transduction of sensory input. However, it has a role also in the
modulation and integration of nociceptive input.6 Following
tissue injury, chemical mediators or ligands of nociceptor ori-
gin (substance P, cholecystokinin [CCK]) or from nonneuronal
sources (acetylcholine, prostaglandin, or bradykinin) are released
close to nociceptors that are activated and sensitized. Many of
these nociceptors are inactive under normal circumstances, but
can be recruited under specific pathological conditions such as
inflammation. The chemical mediators change the transduction
sensitivity of nociceptors, resulting in a decreased threshold for
activation and increased response to suprathreshold stimulus,
that is, the peripheral sensitization.
Spinal cord
In the dorsal root ganglion, the cell bodies of primary afferent
fibers give rise to axons that enter the spinal cord through the
dorsal root. The axon of the A and C fibers may ascend or descend
as much as three levels before entering the dorsal horn. Lamina
II, the substantia gelatinosa, is the area with most terminations
of C and Aδ fibers, being the primary site of nociceptive affer-
ent processing. In the dorsal horn, neurons sending fibers to the
higher center and those descending are connected with interneu-
rons in a local circuitry.
In the dorsal horn, there are two major groups of neurons which
respond to nociceptive stimuli. The first class is represented by
specific nociceptive neurons, prevalent in the superficial lamina
and responding only to noxious stimuli. Their receptor fields are
mild, varying from one to several square centimeters. They have
a weak activity in encoding the intensity of noxious stimuli. The
second one is represented by the wide dynamic range (WDR)
neurons, which respond to a wide range of stimuli from Aδ and
C fibers proportionally, the rate of firing escalating with increas-
ing intensity of stimulation. These neurons are prevalent in the
dorsal horn, are largely distributed in all lamina, and have a large
receptor field. Due to these characteristics, WDR neurons play a
relevant role in the process of central sensitization and the plas-
ticity of the spinal cord.
The primary afferent neurons are the gateway by which sen-
sory information from peripheral tissues is transmitted to the
upper centers. While Aδ and C nociceptors have been identified
in fibers innervating somatic structures, in the viscera the situa-
tion is less clear. In cutaneous tissue, thermal, mechanical, and
chemical stimuli producing tissue damage stimulate unmyelin-
ated polymodal transducers of Aδ and C fibers. The majority of
large-diameter myelinated A and B fibers normally transport
non-noxious stimuli. The small-diameter sensory fibers (unmy-
elinated C fibers and myelinated Aδ fibers) are specialized sen-
sory neurons that have the function of detecting and converting
chemical or physical stimuli into electrochemical signals that are
finally transmitted to the central nervous system.
A repeated and intense stimulus induces the release of sev-
eral inflammatory mediators capable to decrease the activa-
tion threshold, to increase the response to any stimulus, or to
induce the development of spontaneous activity. With increase
of the intensity, high-threshold receptors are activated. Sustained
stimuli or damage to the nerve lead to a release of several pep-
tides such as substance P contained within primary afferents.
Substance P facilitates the production of nitric oxide (NO) as
well as the degranulation of mast cells. These substances are
vasodilators promoting extravasation and release of bradykinin.
Bradykinin in turn is an algogenic substance, because it is able
to sensitize nociceptors by means of prostaglandin E2 and other
Pathophysiology of Chronic Pain
inflammatory molecules, such as cytokines. Prostaglandins have
a limited algogenic activity, but may facilitate the sensitization
of nociceptors to other substances. Taken together, the effects
of these mediators induce a peripheral hyperalgesia, which is
responsible for the peripheral sensitization of nociceptors. 3
Many silent receptors may become excitable in these condi-
tions and their recruitment is able to amplify the stimuli. The
phenotype of sensory neurons may change. Substance P induces
an overexpression of neurokinin-1 receptor in a subset of neu-
rons. Primary hyperalgesia is mediated by peripheral mecha-
nisms and is characterized by an augmentation of sensitivity to
noxious stimulation at the site of the injury. On the other hand,
secondary hyperalgesia is related to central activity or sensiti-
zation, and as such extends beyond the area of the injury. This
occurs because of the expansion of receptive fields of dorsal horn
neurons, consequent to a prolonged excitation of dorsal horn
cells. Concomitantly, the expression of c-fos in the superficial
dorsal horn increases. Moreover, peripheral nerve lesions lead to
the abnormal expression of receptors and channels, thus result-
ing in ectopic discharges from neurons.
After injury to somatic, visceral, and neural structures, there
may be an alteration in the response of the autonomic nervous
system, which may react by novel sprouting of sympathetic effer-
ents and formation of rings around dorsal root ganglia. Central
neural mechanisms are also involved, leading to a constellation of
peripheral vasomotor and sudomotor changes.4 Immune system
cells, including macrophages, neutrophils, and T cells, either in
the tumor mass or produced as a reaction, sensitize or directly
excite primary afferent neurons. Local acidosis produced by can-
cer cells can activate or express further nociceptors. Moreover,
tumor necrosis factors and inflammatory cells are able to express
opioid receptors, which may influence the response to opioids by
initial sequestration first and then by the release of NO, known as
hyperalgesic agent.5
Physiopathology of neuropathic pain
Neuropathic pain defines the type of pain due to a disease or a
lesion associated with an alteration of the function of the somato-
sensitive system at the level of the peripheral and/or central ner-
vous system, in the absence of a stimulation of the nociceptors
by a tissue trauma.6 Following a peripheral lesion, the Aδ and C
afferent fibers become abnormally sensitive developing a spon-
taneous pathological activity leading to peripheral sensitization.
This is associated with an overexpression of sodium and calcium
channels, the release of various receptor proteins, and growth
factors from degenerate fibers. This process causes secondary
alterations in the central processes, leading to a state of hyper-
excitability in the spinal cord with consequent central sensitiza-
tion. The descending pathways lose their activities of control, and
excitatory activity prevails on the inhibitory one, thus exacerbat-
ing the state of spinal cord excitement.7
Peripheral neuropathic pain occurs when the dysfunction
affects the first neuron, while central pain is originated from dys-
functions in the central nervous system. In neuropathic pain due
to damage to nerve structures associated to disease progression,
complex frameworks are observed, mostly in a mixed frame, with
variable aspects over time due to the dynamism of lesions and
signs of the manifestation.
These observations explain both the heterogeneity of the clini-
cal pictures, and the individual responsiveness to commonly
used drugs. In fact, patients with neuropathic pain have shown
201
less responsiveness, even if not absolutely, to opioids and a greater
propensity to develop side effects.8
Pathophysiology
From the neurophysiological point of view, there are several
mechanisms of neuropathic pain that arise after a damage of the
first neuron and include:
1. Peripheral nerve lesions, both demyelinating and axonal,
are able to make peripheral nerve fibers hyperexcitable, for
example the hyperexcitability of the regenerating nerve
endings after an axonal lesion of the nerve. This hypersen-
sitivity manifests itself as a result of chemical, mechanical,
and thermal stimuli, which generate pain probably due to
the formation of ectopic sites in the injured areas as well as
at the level of the sensory ganglion.
2. The first nociceptive neuron can give rise to ectopic dis-
charges even after adrenergic sensitization phenomenon.
The adrenergic stimulus can be induced by an increased
efferent sympathetic activity or by the normally circulating
catecholamines.
3. Spontaneous activity in nociceptors C is responsible for
continuous pain and above all for sensitization of spinal
neurons. The spontaneous activity of myelinated fibers
A (which generally carry harmless sensations) generates
spontaneous paresthesias and, after central sensitization,
dysaesthesia and pain.
4. The second neuron can be of two types: specific, with
exclusive connections with nociceptive neurons at the
level of the posterior horn in the spinal cord, or conver-
gent, connected both with nociceptive fibers and fibers that
normally transport tactile sensitivity (Aβ). The hyperexcit-
ability of the neurons of the posterior horn of the spinal
cord follows the phenomenon defined by the term “spinal
cord hypersensitivity”, caused by the increase of afferents
coming from the first neuron. The events that occur at the
spinal level are represented by an inhibition exerted by
the inhibitory gamma-aminobutyric acid (GABA) system
and by the descending serotonergic and adrenergic inhibi-
tory systems, by a possible reduced efficacy of opioids at
the receptor level, and by the activation of N-methyl-
D-aspartate (NMDA) receptors. Therefore, the noxious
stimuli that reach the dorsal horns increase neuronal excit-
ability with an exaggerated response to subsequent stimuli.
5. At peripheral level, sensitization of adjacent neurons can be
observed for the antidromic release of algogenic substances.
6. Glia has traditionally been considered a connective struc-
ture for neurons. In recent years, a more relevant function
has been attributed to glia, concerning the neuronal homeo-
stasis, the immune response, and above all it has been rec-
ognized to have a role in the modulation of pain. Following
activation, glia initially produces a variety of neuro-
excitatory substances, including interleukin 1 and 6 (IL1
and IL6) and tumor necrosis factor, particularly following
experimentally induced nerve lesions. Activation of toll-like
receptors type receptors produces the pro-inflammatory
cascade similar to that documented with interleukins.
Knock-out studies, in animals without such receptors, or
the use of antagonists for such receptors, have produced the
prevention of the development of allodynia in experimen-
tal models of neuropathic pain, confirming the role of these
receptors in the phenomenon of hyperexcitation. Opioids
202 Textbook of Palliative Medicine and Supportive Care

are also able to induce analgesia and at the same time to
activate the glia, through the overexpression of the toll-like
receptors. Therefore, glia may condition opioid analgesia by
reducing its flow rate or inducing tolerance and addiction.9
Chronic pain and plastic changes
of the central nervous system
Chronic pain, regardless the initial etiology, produces important
changes in the central nervous system. A prolonged stimulus
from the periphery through the stimulation of either nociceptors
or ectopic firing after neural damage leads to repetitive activa-
tion of C fibers. This results in an augmentation of activity in
dorsal horn wide dynamic range neurons and a strong increase
in the magnitude of the responses evoked by subsequent stimuli.
Thus, increased input from injured neurons, ectopic nerve action
potentials, and sensitization of nociceptors by the peripheral
nerves produces tonic input to the spinal cord.
Central sensitization and a windup phenomenon at the spi-
nal and supraspinal levels have been described to explain the
pathophysiological background of chronic pain conditions due
to persistent peripheral stimuli or nerve injury.10 The existence
of peripheral hyperalgesia has a bearing on the induction of cen-
tral hypersensitivity in the spinal cord. The enhanced release of
substance P and other neurokinins may provide the mechanisms
by which the NMDA receptor for the excitatory amino acids
becomes more easily activated. These transmitters cooperate to
activate spinal cord neurons. The release of peptides, such as sub-
stance P, into the spinal cord on afferent stimulation removes the
magnesium block of the channel of the NMDA receptor and thus,
allows glutamate to activate the NMDA receptor in the range of
persistent pain states. 3 The ion channel for the NMDA receptor
allows vast amounts of calcium to enter into the neurons, result-
ing in an amplification of the response underlying central hyper-
algesia. The repetition of a constant intensity C fiber stimulus
induces the phenomenon of windup, that is, the switch from a low
level of pain-related activity to a high level without any change in
the inputs arriving from the peripheral nerves. This results in the
prolongation and amplification of nociceptive activity even after
the cessation of the peripheral input.
The activation of such receptors is involved in the development
and maintenance of injury-induced central hyperactive states by
initiating a variety of intracellular processes. These principally
consist of an increase in the concentration of intracellular calcium,
activation of protein kinase C (PKC), and the calcium–calmodulin-
mediated production of NO, leading to neuronal excitability in
a complex manner. It has been suggested that feedback by NO
increases the release of C fiber transmitters, further enhancing
pain transmission. PKC translocation and NO production may
enhance postsynaptic neuronal excitability, leading to the devel-
opment of hyperactive states. Furthermore, PKC and NO may
activate presynaptic NMDA receptors localized on primary affer-
ent fibers by removing the magnesium blockade of the NMDA
receptor. In so doing, even small amounts of excitatory amino acid
ligands may allow the opening of calcium channels, with further
activation of a second pool of PKC (Figure 23.1). Increases in intra-
cellular calcium and activation of PKC also result in c-fos expres-
sion in postsynaptic dorsal horn neurons as well as in supraspinal
areas. This is considered to be a third messenger, probably involved
in encoding a variety of cellular responses that are responsible for
the neural changes associated with hyperalgesia.11 This has been
demonstrated by similar time courses of c-fos expression and the

FIGURE 23.1  Activation of N-methyl-D-aspartate receptors increases intracellular Ca2+ concentration and subsequent intracellular
activation of protein kinase C (PKC) and nitric oxide (NO). Substrate phosphorylation by PKC or NO-mediated protein kinase may
produce the enhanced activity of glutamate receptor–Ca2+ complex, with the development of hyperactive states. PKC and NO-mediated
protein kinase actions may produce uncoupling of G-protein with mu opioid receptor (MORj), thus reducing morphine antinociception.
Pathophysiology of Chronic Pain 203

FIGURE 23.2  Normal synaptic transmission: Presynaptic activation produces the exocytosis of glutamate which binds to postsynap-
tic receptors: (i) α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors, leading to the opening of Na+ and K+ channels and
resulting in depolarization; (ii) metabotropic receptors, causing the binding of GTP to G-proteins and activation of second messengers
(protein kinase C, adenyl cyclase); and (iii) N-methyl-D-aspartate receptors, potentially opening ion channels. Mg2+ blocks the ion flux.

development of hyperalgesia.12 Whereas the entry of calcium can
also activate phospholipases and lead to the spinal production of
prostanoids, persistent activation of excitatory amino acid recep-
tors within the spinal cord may contribute to central hyperexcit-
ability. This is because irreversible morphological changes may
occur with the loss of function of spinal cord inhibitory interneu-
rons. These excitotoxic processes may result in disinhibition phe-
nomena, reinforcing the central hyperactivity state.13
Peripheral nerve injury also results in a number of dorsal
horn effects, such as changes in the distribution and density of
α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid recep-
tors (better known as AMPA), release of neurotrophins, sprout-
ing of central terminals, and loss of inhibitory neurons containing
GABA.3 Mechanisms of normal synaptic transmission, and intense
and prolonged activation are shown in Figures 23.2 and 23.3.
Similar mechanisms are presumably operating at the supraspinal
level, although available data are less clear. Pain activates brain
structures, such as the periaqueductal gray matter of the mid-
brain (which is involved in blood pressure regulation, respiration,
vasomotor control, and metabolic homeostasis), and the thala-
mus (which is a major relay in the transmission of nociceptive
information). Prolonged activation of these structures can have a
strong impact on psychological function, also inducing complex
cognitive responses.
Descending modulation of nociception
Brainstem descending pathways constitute a major mecha-
nism for modulating nociceptive transmission at the spinal
level. The rostral ventromedial medulla (RVM) includes the
nucleus raphe magnus and adjacent lateral reticular formation.
A biphasic descending modulation of nociception has been pos-
tulated through the activation of facilitation and inhibition of
nociceptive processes, consequent to activation of two types
of cell groups, on-cell and off-cell, respectively. Descending
pathways are activated by tissue injury to counteract the cas-
cade of events that ultimately contribute to the development of
inflammatory hyperalgesia. Opioidergic circuits are involved
in descending inhibition of nociception, increasing the activ-
ity of the antinociception-inhibiting off-cells, and decreasing
the activity of the nociceptive-facilitating on-cells of the RVM.
Studies suggest that descending serotonergic and noradrenergic
pathways differently suppress the responses of spinal neurons.14
The organization and functional significance of the facilitatory
network is less known and is possibly involved in pronocicep-
tive mechanisms. For example, prolonged administration of
opioids induces neuroplastic changes, resulting in the enhanced
ability of CCK to excite facilitatory pathways from the RVM,
and/or upregulation of dynorphin levels, evoking the release of
excitatory transmitters from primary afferents (Figure 23.2).15
Ventrolateral periaqueductal gray matter could be one of the
sites where the repeated administration of opioids induces opi-
oid tolerance. There is evidence that endogenous or exogenous
opioids lead to an enhancement of CCK activity, which in turn
attenuates the antinociceptive effect of opioids and may be
one of the mechanisms responsible for opioid tolerance.16 The
dynamic plasticity of descending pathways may render the sys-
tem vulnerable and lead to pathological consequences.
Chronic pain states and opioid activity
Opioids inhibit or block the excitation of dorsal horn cells by
depressing firing through both presynaptic and postsynaptic
inhibitory effects in the spinal cord.17 The physiological targets of
both exogenous and endogenous opioids are receptors coupled to
G-proteins: m, d, and k receptors. The acute effects of the opioids
204 Textbook of Palliative Medicine and Supportive Care

FIGURE 23.3  Intense and prolonged activation causes an abnormal release of glutamate. More α-amino-3-hydroxy-5-methyl-4-
isoxazole propionic acid (AMPA) receptors are activated, limiting the Mg2+ block on N-methyl-D-aspartate receptors. Ca2+ ions flow
through these channels, interacting with the second messenger enzymes, resulting in more availability of AMPA receptors as a conse-
quence of gene activation. Phosphorylation of ion channels makes the cell more excitable. Retrograde messengers also act on presyn-
aptic nerve terminals, causing the release of more glutamate.

include inhibition of cAMP formation, activation of inward K+
channels, and inhibition of voltagegated Ca channels. These lead
to presynaptic hyperpolarization, inhibition of excitatory neu-
rotransmitter release, and activation of descending antinocicep-
tive pathways.18
Chronic administration of mu-opioid agonists can lead to the
development of analgesic tolerance. Tolerance has been defined
as a reduction in effect following prolonged drug administration
that results in a decrease of drug potency, characterized by a shift
to the right in the dose–response curve. The term tolerance itself
has been used to describe multiple processes. While associative
tolerance is related to conditioning, pharmacological tolerance
is related to specific drug actions. Pharmacological tolerance
may be dispositional, due to pharmacokinetic changes or phar-
macodynamics. The latter is more common and characterized
by a decline in analgesia related to complex processes of neural
adaptation. There is a large intraindividual and interindividual
variability in the development of tolerance. This phenomenon
develops at varying rates and can occur both after acute dosing or
accrue more gradually with chronic dosing. Tolerance to adverse
effects has its own favorable aspect as it allows enlarging the ther-
apeutic window. From a clinical perspective, the development of
tolerance may become the “driving force” for dose escalation that
can be constant during long-term administration and can have
an accelerated phase at the beginning of the treatment as well as
at other times during the course of treatment. Tolerance may be
a major contributing factor in declining opioid effects, and may
create a situation of poor responsiveness if adverse effects occur
as the dose is increased.19
There are some factors influencing the development of toler-
ance, including the drug interactions with the opioid receptors,
doses, and frequency of administration. Many mechanisms con-
tribute to opioid tolerance at a behavioral level. These processes
include the upregulation of drug metabolism (that is metabolic
tolerance), the desensitization of receptor signaling, the downreg-
ulation of receptors, and the compensatory/opponent processes.20
From a clinical perspective, analgesic tolerance is noteworthy as
the management of such patients during acute episodes of care
is a challenge because they will have a significantly longer length
of hospital stay, are more likely to be readmitted within 30 days,
and have a higher risk of mortality and comorbidities.21 Indeed,
the progressive increase of opioid doses can induce or exacerbate
undiagnosed opioid-induced hyperalgesia (OIH), which in turn
favor the occurrence of behavioral analgesic tolerance and is
often misdiagnosed as a progression of disease producing pain.
Opioids generate opponent processes in both nociceptive cir-
cuits and circuits modulating mood. The involvement of different
circuits contributes to the production of an addicted state favor-
ing the hedonic aspects of drug taking. Among these adverse
effects, prolonged opioid therapy is associated with tolerance
and OIH, which are relevant for the inevitable consequences on
the clinical responses. Analgesic tolerance refers to a progressive
decrease of analgesia produced by an opioid given chronically. As
a consequence, it often results in the need to increase the dose to
maintain the same level of the previous analgesia. For OIH, there
is a development of hypersensitivity to painful stimuli associated
with opioid therapy, resulting in exacerbation of pain sensation,
rather than a relief of pain.
It is relevant to distinguish tolerance and OIH.22 Tolerance is
exhibited to most opioid effects but not to miosis and constipa-
tion. The increase in doses overcomes this problem and the patient
will be relieved of his pain. In OIH, there is a state of nociceptive
Pathophysiology of Chronic Pain
sensitization induced by an acute as well as a prolonged exposure
of opioids. The level of pain experienced might be the same or often
might be different. However, it cannot be resolved by increasing
the dose of the drug, which instead can aggravate the pain. This
phenomenon can be relieved only by decreasing the dose of opioid
or discontinuing it while using other strategies to compensate the
underlying pain condition. This clinical eventuality is quite com-
plex, as a negative feedback loop can be elicited so that the devel-
opment of tolerance often induces physicians to increase opioid
doses. This decision, in turn, facilitates the development of OIH.
The clinical implications are that dose escalation in chronic opioid
therapy might cause OIH, producing a vicious cycle of opioid esca-
lation and anxiety both for physician and patient.
As it becomes clear that chronic pain, particularly cancer pain,
is able to specifically modify the response of the central nervous
system, recent data indicate a close relation between cancer disease
and its metabolic and immunological consequences, and plastic
changes of the central nervous system associated with the con-
comitant chronic administration of opioids, which require better
knowledge of molecular events underlying such mechanisms. An
integrated approach that takes into account information from both
experimental work and the bedside is recommended.
KEY LEARNING POINTS
• The clinical picture of cancer pain varies depending
on the pathophysiological mechanism, which fur-
ther depends on the characteristics and progression
of disease, and the preferential sites of metastases.
Although the pain related to malignant disease can
be classified as nociceptive-inflammatory and neu-
ropathic, they are both significantly influenced by
changes in the central nervous system function.
• It is now clear that cancer pain is a more com-
plex entity, particularly regarding the response
to analgesics, where numerous factors play a role.
• Central sensitization and a windup phenomenon
at the spinal and supraspinal level have been
described to explain the pathophysiological back-
ground of chronic pain conditions.
• Brainstem descending pathways constitute a
major mechanism for modulating nociceptive
transmission at the spinal level.
• The dynamic plasticity of descending pathways
may render the system vulnerable and lead to
pathological consequences.
• Opioids produce inhibition or block excitation of
dorsal horn cells within the spinal cord. Repeated
administration of opioids produces a decrease in
analgesia, an effect termed “tolerance.”
• Prolonged opioid treatment not only results in a
loss of opioid antinociceptive efficacy but also leads
to activation of a pronociceptive system character-
ized by a reduction of nociceptive threshold.
205
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antinociceptive effects of morphine: implications for common intra-
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lecystokinin in the tolerance induced by morphine microinjections
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18. Varga EV, Yamamura Hi, Rubenzik et al. Molecular mechanisms of
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tor trafficking and morphine tolerance by receptor oligomerization.
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development of morphine tolerance and dependence. Life Sci
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24
CAUSES AND MECHANISMS OF PAIN IN PALLIATIVE CARE PATIENTS

Michal Kubiak, Marieberta Vidal, Suresh K. Reddy

Contents
Introduction�����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������207
Specific pain syndromes in patients with cancer��������������������������������������������������������������������������������������������������������������������������������������������������������209
Tumor hemorrhage�����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������209
Tumor infiltration of bone�����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������209
Skull metastasis�����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������210
Cervical spine metastasis�������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������211
Thoracic spine metastasis������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������211
Lumbar spine and sacral metastasis������������������������������������������������������������������������������������������������������������������������������������������������������������������������211
Carcinomatous meningitis����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������211
Tumor infiltration or trauma to peripheral nerve, plexus, root, and spinal cord������������������������������������������������������������������������������������������������212
Brachial plexopathy�����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������212
Brachial plexopathy in Pancoast tumors����������������������������������������������������������������������������������������������������������������������������������������������������������������212
Lumbosacral plexopathy��������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������212
Pain syndromes associated with cancer therapy��������������������������������������������������������������������������������������������������������������������������������������������������������213
Postsurgical injury to peripheral nerves�����������������������������������������������������������������������������������������������������������������������������������������������������������������213
Post thoracotomy pain�����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������213
Post mastectomy pain�������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������213
After radical neck surgery�����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������213
Post amputation pain��������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������213
Chemotherapy-related pain syndromes�����������������������������������������������������������������������������������������������������������������������������������������������������������������213
Immunotherapy-related pain syndromes���������������������������������������������������������������������������������������������������������������������������������������������������������������214
Post radiation therapy pain���������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������214
Noncancer pain syndromes and mechanisms�������������������������������������������������������������������������������������������������������������������������������������������������������������215
End-stage liver disease and pain������������������������������������������������������������������������������������������������������������������������������������������������������������������������������215
End-stage renal disease and pain�����������������������������������������������������������������������������������������������������������������������������������������������������������������������������215
Human immunodeficiency virus and pain�������������������������������������������������������������������������������������������������������������������������������������������������������������216
Oropharyngeal pain����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������216
Esophageal pain�����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������216
Abdominal pain�����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������216
Anorectal pain�������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������217
Chest pain syndromes������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������217
Neurological pain syndromes�����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������217
Headache�����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������217
Neuropathies����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������217
Rheumatological pain syndromes����������������������������������������������������������������������������������������������������������������������������������������������������������������������������217
Opioid-induced hyperalgesia������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������217
Calciphylaxis����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������218
Acknowledgments.............................................................................................................................................................................................................218
References���������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������218

Introduction include treatment side effects and coexisting pain conditions3,8

Pain due to cancer is one of the most common symptoms expe-
rienced by palliative care patients, as shown by many studies in
this patient population.1–3 The consequences of undertreatment
of pain are daunting, yet pain is underdiagnosed and under-
treated for many reasons.4,5 One of the main reasons for under-
treatment of pain in patients with cancer continues to be a lack
of appropriate pain assessment.6,7 In cancer, pain is predomi-
nantly caused by the tumor and its consequences. Other reasons
(Box 24.1). Pain syndromes are also highly prevalent among non-
cancer conditions such as end-stage liver disease (ESLD), end-stage
renal disease (ESRD), human immunodeficiency virus (HIV)/
acquired immune deficiency syndrome (AIDS), neurological/auto-
immune disorders, chronic obstructive pulmonary disease (COPD),
and heart failure (HF).9,10 In these situations, pain may result from
chronic degenerative disorders of the spine and joints11–13: central
pain is because of spinal cord injury and neuropathic pain due to
metabolic, infective, and other causes14–16 (Box 24.2).

207
208 Textbook of Palliative Medicine and Supportive Care

BOX 24.1  COMMON CLINICAL PAIN BOX 24.2  NONCANCER PAIN SYNDROMES
SYNDROMES AND THEIR CAUSES
Headache
Tumor pain
• Migraine
• Bone pain due to metastasis (somatic pain) from • Tension-type headache
breast, prostate, and other cancers • Cluster headache
• Plexopathy pain (neuropathic pain) due to • Miscellaneous
Pancoast tumor/pelvic tumor
• Abdominal pain (visceral pain) due to pancreatic Facial pain
cancer and liver metastasis
• Chest wall pain due to mesothelioma (somatic • Trigeminal neuralgia
and neuropathic pain) • Temporomandibular joint pain
• Glossopharyngeal neuralgia
Cancer treatment pain • Postherpetic neuralgia (PHN)
• Myofascial pain syndromes
• Postchemotherapy pain syndromes
• Peripheral neuropathy due to cisplatin and paclitaxel Neck pain

Postirradiation pain syndromes • Discogenic radicular pain

• Whiplash injury pain syndrome
• Chronic throat pain due to radiation-induced • Cervicogenic pain
mucositis • Facet joint pain syndrome
• Chronic abdominal pain due to radiation-induced
enteritis in fistulas Thoracic pain syndromes
• Radiation-induced plexopathy pain
• Costochondritis
Postsurgical pain syndromes • Intercostal neuralgia
• PHN
• Postmastectomy pain syndrome • Facet joint pain syndrome
• Postradical neck dissection pain syndrome • Chronic shoulder pain: frozen shoulder; rotator
• Phantom limb pain syndrome cuff tear

Noncancer pain Abdominal pain

• Chronic low back pain due to degenerative • Chronic pancreatitis

process in the spine • Chronic peptic ulcer disease
• Pain secondary to osteoarthritis and rheumatoid • Postcholecystectomy syndrome
arthritis • Crohn’s disease
• Migraine headaches • Irritable bowel syndrome

Pelvic pain

Pain results from the activation of nociceptors by a variety of • Chronic interstitial cystitis
chemical mediators released from damaged cells. The mediators • Chronic testicular pain
include potassium, serotonin, bradykinin, and histamine and • Chronic prostatitis pain
are usually associated with the redness and swelling of inflam- • Chronic pelvic pain from inflammatory pelvic
mation. In addition, cells may be sensitized by other substances disease
such prostaglandins, leukotrienes, and substance P. Sensitization • Endometriosis-related pain syndromes
can extend to areas away from the original damage, resulting in
hypersensitivity of the area. Low back and lower extremity pain
Cancer pain can occur after activation of peripheral nocicep-
tors (somatic and visceral “nociceptive” pain) or by direct injury • Central pain
to peripheral or central nervous structures (neuropathic or “deaf- • Lumbosacral spine disease: myofascial; disk-
ferentation” pain). In addition, both nociceptive and neuropathic ogenic; osteoporotic; facet joint pain syndrome
pain may be modified by the involvement of the sympathetic ner- • Peripheral vascular disease and ischemic pain
vous system, resulting in sympathetically maintained pain (SMP) syndrome
or complex regional pain syndrome type 1 (CRPS). Each of these • Dorsal tunnel syndrome
painful states has somewhat unique clinical characteristics that • CRPS
may aid in its identification and directed treatment. A key step, • Phantom limb pain
therefore, in the evaluation of a cancer patient with pain is to
(Continued)
Causes and Mechanisms of Pain in Palliative Care Patients
BOX 24.2  NONCANCER PAIN
SYNDROMES (Continued)
Medical diseases causing pain
• Chronic fatigue syndrome
• Sickle cell disease
• Peripheral neuropathy pain (e.g., diabetes)
• Rheumatoid arthritis, multiple sclerosis,
osteoarthritis
HIV/AIDS pain syndromes
• Headache (e.g., cryptococcal meningitis)
• Oral cavity pain secondary to candidiasis, herpes
simplex, or Kaposi’s sarcoma
• Chest pain secondary to candidal esophagitis
• Chronic abdominal pain from infections such as
cryptosporidiosis, cytomegalovirus (CMV), cho-
lecystitis, pancreatitis
• Pain syndromes related to Kaposi’s sarcoma
• Neuropathic pain syndromes (e.g., predomi-
nantly sensory neuropathy (PSN), myelopathy,
radicular pain from Guillain–Barré syndrome)
elicit a careful history of the quality, nature, and location of per-
ceived pain, as the descriptors may provide valuable clues to the
etiology of the complaint.
Somatic pain results from the involvement of bone and mus-
cle structure. Metastatic bone disease is the most common pain
syndrome in patients with cancer. There are many components
of metastatic bone pain including inflammatory, nociceptive,
and neuropathic factors. Afferent myelinated A-delta fibers and
unmyelinated C fibers are present in the bone, with their density
being greatest in the periosteum.17
Cancer cells invading the bone can produce a wide array of
chemical mediators including prostaglandins, nerve growth factors
(NGF), endothelin, interleukin-6, and bradykinin to name a few.
Prostaglandins along with NGF have found to be increased at the
sites of bone metastasis.18 Recent studies have hypothesized that
NGF are associated with sprouting of nerves and formation of neu-
romas within the bone. Pharmacotherapies that block NGF binding
are currently being studied; although more research is still needed
in order to evaluate their long-term efficacy and safety profile.19
Conversely, prostaglandins have been studied more extensively
and are known to mediate osteolytic and osteoclastic metastatic
bone changes. Prostaglandin E2 is known to sensitize nocicep-
tors and produce hyperalgesia. These observations have resulted
in the use of steroidal and nonsteroidal anti-inflammatory drugs
(NSAIDs) for metastatic bone pain. Reports have suggested that
NSAIDs are uniquely effective.20
Visceral pain is also common in patients with cancer, and pre-
sumably results from stretching or distending or from the pro-
duction of an inflammatory response and the release of analgesic
substances in the vicinity of nociceptors. Visceral pain commonly
occurs at cutaneous sites, thus misleading the examiner, particu-
larly since those cutaneous sites may be tender to palpation. This
property likely results from convergence of visceral and somatic
afferent information onto common neuronal pools in the dorsal
209
horn of the spinal cord.21 Neuropathic pain from neural injury,
such as brachial plexus infiltration by tumor, is often severe. The
pain is described as paroxysms of burning or electric-shock-like
sensations, which may result, at least in part, from spontaneous
discharges in the peripheral nervous system and central nervous
system (CNS).
Somatic, visceral, and deafferentation pain may be modified
by the sympathetic nervous system. SMP is often suspected
when pain is severe in intensity (even after relatively trivial tis-
sue insults) and described as burning in quality, with associated
features of allodynia, hyperpathia, brawny edema, and osteopo-
rosis.22 Several mechanisms involving both peripheral and CNSs
have been postulated to explain SMP. For example, one periph-
eral mechanism may be the development of ephaptic connections
at sites of tissue injury such that efferent sympathetic impulses
produce activation of afferent nociceptive pathways. Others have
postulated that traumatic injury to peripheral tissues may pro-
duce sensitization of spinal cord nociceptive neurons, which may
then be secondarily activated by efferent sympathetic activity.
It is common for patients with cancer to present with mixtures
of the pain types described earlier. Furthermore, the pattern of
pain intensity is often not constant, but rather includes episodes
of pain exacerbations on a background of continuous pain, called
“breakthrough” pain (see Chapter 54).23
Specific pain syndromes in
patients with cancer
There are several specific pain syndromes that may present dif-
ficult diagnostic and therapeutic problems, of which the pallia-
tive care specialist needs to be aware during the evaluation of the
cancer patient with pain.24 The characteristic clinical features of
these syndromes are summarized in Box 24.3 and discussed in
following sections. Please note that notable but short-lived pain
syndromes, such as mucositis, that complicate chemotherapy and
radiation therapy, and the acute pain associated with diagnostic
and therapeutic procedures, such as bone marrow aspiration, are
not included in Box 24.3.
Tumor hemorrhage
Tumor hemorrhage can present as an acute pain syndrome in cancer
patients and might need urgent treatment. This syndrome is com-
mon in hepatocellular carcinoma, presenting usually with severe
right upper quadrant (RUQ) pain and it could be a potential life-
threatening complication when the tumor ruptures. Another exam-
ple is an ovarian cancer causing bleeding inside the tumor leading to
severe flank pain.25,26 Other intra-abdominal malignancies can also
present with acute bleeding into the tumor causing pain.
Tumor infiltration of bone
Pain from invasion of bone by either primary or metastatic tumor
is the most common cause of pain in patients with cancer. Several
important pain syndromes are often misdiagnosed because physi-
cians are unfamiliar with the characteristic signs and symptoms,
and plain X-rays of the involved areas may show normal findings.
The pathophysiology of metastatic bone pain is poorly under-
stood. Although most patients with bone metastasis report pain,
a large proportion of patients with radiographic evidence of dis-
ease deny pain. This has been best studied in breast cancer,27 but
210 Textbook of Palliative Medicine and Supportive Care

BOX 24.3  CLINICAL CHARACTERISTICS OF INTRACTABLE CANCER PAIN SYNDROMES

• Tumor-related infiltration of bone: Acute and chronic nociceptive pain.

• Skull-base metastasis: Severe head pain (usually referred to vertex or occiput) with associated cranial nerve deficits.
Bone scan and plain films of the skull may show normal findings.
• Vertebral metastasis: Significant risk of associated spinal cord compression. Of patients with back pain and vertebral
body metastasis, 30% will eventually develop epidural spinal cord compression, and pain alone may precede root or
spinal cord signs by many months.
• Pelvis and long bones: Risk of pathological fracture with weight-bearing activities; orthopedic consultation helpful.
• Tumor-related infiltration of nerve: Acute and chronic neuropathic pain.
• Brachial/lumbosacral plexopathy: May occur by contiguous spread of tumor or by hematogenous dissemination;
radiographic studies are helpful to distinguish from radiation-induced plexopathy.
• Spinal cord compression: Neurological emergency requiring prompt treatment with corticosteroids, radiation therapy,
and/or surgery.
• Meningeal carcinomatosis: Headache and meningeal signs. Causes significant pain in about 15% of patients.
• Visceral tumor infiltration: Acute and chronic visceral pain that is poorly localized and widely referred. Common
examples include pancreatic carcinoma, liver metastasis, and pleural effusion.
• Therapy-related postsurgical pain: Chronic pain that persists well beyond healing of the incision and may or may not
be associated with recurrent disease.
• After thoracotomy: May be associated with recurrent tumor or may occur as a chronic intercostal neuralgia.
• After mastectomy: Occurs in 5% of women; more common in women undergoing modified radical procedure with
axillary dissection; intercostal brachioradial neuralgia is one cause.
• After radical neck surgery: Mechanisms unclear; chronic infection may play a role.
• After amputation: Stump pain and phantom phenomena are common; role of preventive analgesic and anesthetic
therapies is under investigation.

is also true in prostate cancer. Tumor growth in bone may pro-
duce pain by several mechanisms which are as follows:
• Relatively rapid growth causing expansion of the mar-
row space and increased interosseal pressure (beyond
50 mmHg). In theory, this may activate mechanoreceptive
nociceptors in bone. In addition, elevation or invasion of
the periosteum may also activate nociceptors that inner-
vate this structure.
• Weakening of the bone leading to fractures.
• Edema and inflammation associated with tumor growth
in bone may liberate chemical mediators that activate
nociceptors.
• Recent data regarding mechanisms of bone destruction
emphasize that osteoclasts may be stimulated by a number
of humoral factors associated with tumors. For example,
carcinomas may secrete prostaglandins18 which would
have the dual role of activating osteoclasts and sensitizing
nociceptors. These observations have provided a rationale
for the use of corticosteroids and NSAIDs for the manage-
ment of metastatic bone pain.28
Metastatic bone pain is often associated with neurological dys-
function because of the close anatomical relations between the
brain and cranial nerves and the skull vault, and the spinal cord
and its roots and the vertebral column. Therefore, characteristic
clinical syndromes may be identified by the site of bony involve-
ment, the coexistence of mechanical instability secondary to
fractures, and neurological dysfunction caused by tumor infiltra-
tion of contiguous neurological structures. Bone metastasis to
the hip and pelvis often produces local pain that is exacerbated
by movement, especially when bearing weight. In addition to
palliative radiotherapy, this type of “incident pain” may require
specific orthopedic interventions.
Spread of cancer to the vertebral bodies and calvarium, espe-
cially the base of the skull, often produces distinctive neuro-
logical syndromes. These are important to recognize early so
that prompt initiation of antitumor treatments, especially radi-
ation, may avoid neurological impairment. For example, local
and radicular back or neck pain is the predominant symptom in
epidural spinal cord compression, complicating vertebral body
metastasis in these locations. Pain may be the only symptom of
impending spinal cord compression and often precedes motor
weakness and bowel or bladder incontinence by days or weeks.
The spinal cord is compromised by growth of the tumor in an
anterior direction from the vertebral body. Irreversible spinal
cord injury may occur when the vascular supply is compromised
as a result of severe compression. Thoracic spine vertebral body
metastases often produce bilateral radicular pain and sensory
symptoms (a “band-like” squeezing sensation across the upper
abdomen or chest) because of the close proximity of the thoracic
nerve roots to the vertebral body. On the other hand, metastases
in the cervical or lumbar spine may produce unilateral pain and
sensory loss as the vertebral bodies are wider in these areas and
lateral extension of the tumor may compress only one root at
the time.
Skull metastasis
Spread of tumor to the calvarium may produce neurological symp-
toms by two mechanisms. Metastases to the skull vault, which
grow to compress the sagittal sinus, may produce a syndrome of
severe headache with associated papilledema and seizures caused
by elevation in the intracranial pressure (ICP). If untreated, focal
neurological deficits may occur, secondary to venous infarction
Causes and Mechanisms of Pain in Palliative Care Patients
of the brain. The cause of metastatic sagittal sinus occlusion is
usually obvious and is easily confirmed by magnetic resonance
imaging (MRI) of the brain. The gadolinium-enhanced MRI will
not only demonstrate the tumor metastasis, but will also dem-
onstrate the blood clot in the sagittal sinus. It is noteworthy that
nonmetastatic sagittal sinus occlusion may also occur in prostate
cancer as a complication of a hypercoagulable state induced by
diethylstilbestrol treatment.
Tumor metastasis to the base of the skull may also produce dis-
tinct neurological syndromes.29 Bone metastasis to this portion
of the skull often produces severe headache referred to the top
of the head or the occiput. Also, single or multiple cranial nerve
palsies usually accompany basal skull metastasis. For example,
clival metastasis often compresses the hypoglossal nerve, pro-
ducing unilateral weakness of the tongue and deviation of the
tongue to the side of the lesion when protruded from the mouth.
Bone metastasis to the middle cranial fossa may compress and
infiltrate the facial nerve, producing ipsilateral weakness of the
upper and lower face. Tumor invasion of the jugular foramen will
produce severe head pain with associated dysphagia, dysphonia,
and hoarseness caused by dysfunction of the glossopharyngeal
and vagal nerves, which exit the skull base through this foramen.
Involvement of foramen ovale may result in compression of tri-
geminal nerve leading to facial pain.
Small lesions at the skull base may not be visible on plain X-rays
or bone scans. It is mandatory that computed tomography (CT)
scans with bone windows and 5-mm sections are done to dem-
onstrate the tumor. It is sometimes necessary to do MRI scans
of the base of the skull when CT scans are negative.24⋆ Radiation
therapy directed to the base of the skull is the preferred treat-
ment. Again, prompt recognition of these syndromes and aggres-
sive treatment is indicated to prevent irreversible cranial nerve
palsies that often produce devastating neurological impairments.
Cervical spine metastasis
Metastatic disease involving the odontoid process of the axis
(first cervical vertebral body) results in a pathological fracture.
Secondary subluxation occurs and results in spinal cord or brain-
stem compression. The symptoms are usually severe neck pain
radiating to the posterior aspect of the skull to the vertex, exac-
erbated by movement. The diagnostic evaluation may require
MRI as plain X-rays and bone scans may not show the problem.
Imaging procedures must be carried out carefully to ensure spi-
nal stability.
Pain in C5–C6 is characterized by a constant dull aching pain
radiating bilaterally to both shoulders with tenderness to percus-
sion over the spinous process. Radicular pain in a C7–C8 distri-
bution occurs most commonly unilaterally in the posterior arm,
elbow, and ulnar aspect of the hand. Paresthesias and numb-
ness in the fourth and fifth fingers, progressive hand and triceps
weakness are the neurological signs. Horner’s syndrome suggests
paraspinal involvement. The diagnostic evaluation must be done
carefully. Plain X-rays are often negative since this area is visual-
ized poorly in these, therefore, CT or preferably MRI scans are
necessary to define metastatic disease.
Thoracic spine metastasis
The onset of back pain in association with band-like tighten-
ing across the chest or upper abdomen or radicular arm or leg
pain may be the first sign of impending spinal cord compression.
Motor and sensory loss occurs later, and autonomic disturbances
producing bladder and bowel incontinence occur later still. Thus,
211
the evaluation of the patient should begin at the onset of pain
for the best chance to preserve motor and sphincteric function.
This should include plain X-rays of the entire spine, focused on
the symptomatic area, and an MRI. This is necessary because
there is about a 15% incidence of another epidural lesion. 30
Corticosteroid therapy should be started even before the radio-
logical evaluation, since this may decrease pain and protect the
spinal cord from further compression caused by edema from the
tumor or radiotherapy. Even if metastatic disease is found on
plain spine films, the MRI should be done to define the extent
of tumor invasion in the epidural space because this will influ-
ence the size of the radiation therapy ports and will determine
the dose and duration of corticosteroid therapy. If anterior ver-
tebral body subluxation has occurred and there is bony com-
pression of the spinal cord, surgical decompression is indicated,
if the patient’s medical condition permits. This is usually fol-
lowed by radiation therapy. Surgery is usually not attempted as
a primary modality of treatment because the results of radiation
therapy and corticosteroid treatment are usually equal to surgi-
cal decompression. 30 This is especially true if a simple posterior
decompressive laminectomy is done. However, if patients have
recurrent spinal cord compression in a previously irradiated
port, then an anterior spinal approach with removal of tumor
from the vertebral body, decompression of tumor from the spi-
nal canal, and restructuring of the vertebral body with methyl
methacrylate should be considered. 31
Lumbar spine and sacral metastasis
Dull and aching mid-back pain exacerbated by lying or sitting
and relieved by standing is the usual presenting complaint of
L1 metastasis. Pain may be referred to the hip, both paraspi-
nal lumbosacral areas, and to the sacroiliac joint or superior
iliac crest. Aching pain in the low back or coccygeal region
exacerbated by lying or sitting, relieved by walking, is the com-
mon complaint with sacral metastases. Associated symptoms
include perianal sensory loss, bowel and bladder dysfunction,
and impotence.
Local invasion of tumor from the pelvis into the sacrum may
produce the syndrome of perineal pain, which is often difficult
to manage. This syndrome is characterized by local pain in the
buttocks and perirectal area, which is often accentuated by pres-
sure on the perineal region such as that caused by sitting or lying
prone. In its most extreme form, the patient cannot sit to eat meals
or lie flat to sleep, and may spend much of their time standing.
Because of the critical role of the parasympathetic sacral innerva-
tion to normal bladder and rectal sphincter function, continence
is impaired early in the course of this syndrome, perhaps even
before significant weakness can be discerned in the legs.
Carcinomatous meningitis
Cancer arising outside the nervous system can metastasize to the
CNS, including the meninges. Leptomeningeal disease occurs in
approximate 5% of cancers. When meningeal disease presents
as a late complication of malignant disease, the general prog-
nosis is poor. The patients can present with different pain syn-
dromes including headaches, cranial neuropathies, back pain, and
radiculopathies. These particular symptoms are produced by the
tendency of malignant cells in the cerebrospinal fluid (CSF) to con-
gregate in specific sites such as in the base of skull producing cra-
nial neuropathies, obstructing CSF flow, and leading to raised ICP.
They can also accumulate in the base of spine producing back pain,
leg weakness, radiculopathies, and bowel/bladder disturbance.32,33
212
Tumor infiltration or trauma to peripheral
nerve, plexus, root, and spinal cord
These syndromes present with radicular pain in the neck, chest,
or trunk and the differential diagnosis includes tumor infiltration
of the peripheral nerves, and surgical injury, partial, complete or
secondary to direct surgical interruption or traction, and nerve
compression secondary to musculoskeletal imbalance, diabetic
peripheral neuropathy, acute herpes zoster, and PHN.
Pain is characterized by constant burning pain with hypo-
esthesia and dysesthesia in an area of sensory loss. The most
common causes are tumor compression in the paravertebral or
retroperitoneal area or in association with metastatic tumor in
rib causing intercostal nerve infiltration. Pain is usually the first
sign of tumor infiltration of nerve and presents as either a local,
radicular, or referred pain. Local and radicular pain is seen with
tumor infiltration or compression of nerve peripheral to the para-
spinal region, whereas referred pain with or without a radicu-
lar component is seen with tumor infiltration of the paraspinal
region and more proximal areas. Associated autonomic dysfunc-
tion causing loss of sweating and loss of axonal flair response to
pin scratch can help define the site of the nerve compression or
infiltration. The pain is characterized initially by a dull, aching
sensation with tenderness to percussion in the distribution of the
nerve. Mild paresthesia or dysesthesia can occur as the next sen-
sory symptom followed by the late appearance of motor symp-
toms and signs.
As tumor invades the perineurium or compresses nerve exter-
nally, the nature of the pain changes to a burning, dysesthetic
sensation. A careful neurological examination followed by a CT
scan to define the site of nerve compression is the diagnostic pro-
cedure of choice. Electromyography (EMG) can help to define the
site of nerve involvement, but it is not diagnostic. Rib erosion and
retroperitoneal and paraspinal soft-tissue masses are the most
common associated findings. In patients with paraspinal tumor,
MRI scanning is often necessary to exclude epidural extension.
Antitumor therapy is the first-line therapy when possible, but
interim pain management with analgesics is almost always nec-
essary. Steroids may provide a useful diagnostic test, and provide
both anti-inflammatory and antitumor effects, or may act to
reduce local swelling and relieve pain.
Brachial plexopathy
Brachial plexopathy in patients with cancer may occur due to
metastatic spread of tumor to the plexus or radiation injury pro-
ducing transient sensory and motor symptoms. More prolonged
neurological dysfunction may result from previous radiation
therapy to a port which has included the plexus, involvement
of the plexus by radiation-induced tumor such as malignant
schwannoma or fibrosarcoma, and trauma to the plexus during
surgery and anesthesia.
Tumor infiltration and radiation injury are the most common
causes. 34 A review of 100 cases suggested that there are reliable
clinical signs and symptoms to distinguish metastatic plexopathy
from radiation injury. The characteristics of the pain are quite
different and a useful distinguishing clinical sign. 35 MRI has been
advocated as a better means to image the brachial plexus, 35 and
may be a useful means to diagnose metastatic brachial plexopa-
thy. Rarely, biopsy of the brachial plexus may be necessary to dis-
tinguish from radiation fibrosis versus a recurrent tumor or a new
primary tumor. 36 However, biopsy is not always definitive.
Textbook of Palliative Medicine and Supportive Care
Metastases to the brachial plexus most commonly involve
the lower cords of the brachial plexus, giving rise to neurologi-
cal signs and symptoms in the distribution of the C8, T1 roots.
In contrast, radiation plexopathy most commonly involves
the upper cords of the plexus, predominantly in the distribu-
tion of the C5–C7 roots. Severe pain is most commonly asso-
ciated with metastatic plexopathy, and Horner’s syndrome is
more commonly associated with metastatic plexopathy than
radiation plexopathy. A significant number of patients with
metastatic plexopathy show epidural extension of disease. A
primary tumor of the lung, the presence of Horner’s syndrome,
or involvement of the whole plexus should alert the physician
to the possibility of epidural extension and warrant immediate
MRI. Neither a negative surgical biopsy nor observation for sev-
eral years for other metastases rules out recurrence of tumor or
a new primary tumor. 36
Brachial plexopathy in Pancoast tumors
Brachial plexopathy in Pancoast tumor, as described by Kanner
et al., 37 is an integral part of the disease. Pain in the distribution
of C8–T1 is an early sign and is part of the clinical diagnosis of
Pancoast syndrome. Pain is the most reliable sign to follow as it
closely reflects progression of disease and may be the only sign of
epidural cord compression. Plain X-rays and bone scans are not
reliable diagnostic tests for this disorder, and MRI yields the most
important diagnostic information. As many as 50% of patients
develop epidural cord compression, with pain being the earliest
and most consistent clinical symptom. In patients who present
with Pancoast syndrome and involvement of the brachial plexus,
the initial diagnostic workup should include MRI to determine
the extent of tumor infiltration. Initial antitumor surgery should
be directed at radial removal of all the local tumors and secondary
treatment with external radiation therapy and brachytherapy. 38
The Pancoast syndrome is commonly misdiagnosed and con-
fused with cervical disk disease, which appears in less than 5% of
patients in a C8–T1 distribution.
Lumbosacral plexopathy
Lumbosacral plexus tumor infiltration most commonly occurs
in genitourinary, gynecological, and colonic cancers. Pain varies
with the site of plexus involvement. Radicular pain occurs in L1–
L3 distribution (i.e., anterior thigh and groin) or down the poste-
rior aspect of the leg to the heel when in an L5–S1 distribution. In
some instances, there is only referred pain without local pain over
the plexus. Common referred points are the anterior thigh, knee,
and lateral aspect of the calf. These areas are commonly pain-
ful, but the origin of the pain is in the plexus. Pain is the earliest
symptom, followed later by complaints of paresthesia, numbness,
and dysesthesia leading to motor and sensory loss.
Jaeckle et al. 39 have described the clinical symptoms and natu-
ral history of this disorder in a review of 85 patients with lumbo-
sacral plexopathy. In this study, the pain was noted to be of three
types: local in 72 of 85 patients, radicular in 72 of 85 patients, and
referred in 37 of 85 patients. Local pain in the sacrum or sciatic
notch occurred in 59% of patients followed by low back pain in
27% and pain in the groin or lower abdominal quadrant in 21%.
Pain referred to the hip or flank occurred in patients with upper
plexus lesions, whereas pain in the ankle or the foot occurred
in patients with a lower plexopathy. Typically, the pain precedes
objective sensory, motor, and autonomic signs for weeks to
months, with a mean of 3 months. Also, initially, the CT scan may
be negative. Unilateral and bilateral plexopathy with significant
Causes and Mechanisms of Pain in Palliative Care Patients
motor weakness is commonly associated with epidural exten-
sion, and both CT and MRI are necessary to define the extent of
tumor infiltration and/or epidural compression. Plain X-rays are
not often helpful because the lumbosacral plexus lies within the
substance of the psoas muscle and is not radio-dense.
Pain occurs in 40% of patients with leptomeningeal metasta-
ses40 and is of two types:
1. Headache with or without neck stiffness
2. Back pain localized to the low back and buttock regions
There may be associated confusion, delirium, cranial nerve
palsies, radiculopathy, and myelopathy. Diagnostic workup
should include MRI with contrast to determine enhancement
in the basal subarachnoid cisterns and rule out hydrocepha-
lus; MRI to rule out bulk disease on nerve roots which might
require focal radiation therapy; and a lumbar puncture to
determine CSF glucose, protein, cell count, cytology, and bio-
chemical markers.
Pain syndromes associated
with cancer therapy
This category includes those clinical pain syndromes that occur
in the course of or subsequent to treatment of cancer patients
with the common modalities of surgery, chemotherapy, or radia-
tion therapy.
Postsurgical injury to peripheral nerves
Four distinct pain syndromes involving the peripheral nerves
occur following surgery in patients with cancer.
Post thoracotomy pain
This pain occurs in the distribution of an intercostal nerve fol-
lowing surgical interruption or injury. The intercostal neuro-
vascular bundle courses along a groove in the inferior border of
the rib. Traction on the ribs and rib resection are the common
causes of nerve injury during a surgical procedure on the chest.
Kanner et al. 37 prospectively followed 126 consecutive patients
undergoing thoracotomy and defined several groups of patients.
In the majority of patients (79 patients), immediate postopera-
tive pain was reduced at approximately 2 months, but in 13 of the
79 patients, recurrence of the pain occurred. Recurrence of
tumor in the distribution of the intercostal nerves was the cause
of recurrent pain. The immediate postoperative pain is charac-
terized by an aching sensation in the distribution of the incision
with sensory loss with or without autonomic changes. There is
often exquisite point tenderness at the most medial and apical
point of the scar with a specific trigger point. In another group
(20 of the 126 patients), pain persisted following the thoracotomy
and increased in intensity during the follow-up period. In this
group of patients, local recurrence of disease and/or infection was
the most common cause of increasing pain. In the third group,
18 of the 126 patients had stable or decreasing pain that resolved
over time and did not represent a difficult management problem.
Thus, persistent or recurrent pain in the distribution of the
thoracotomy scar in patients with cancer is commonly associ-
ated with recurrent tumor. However, a small number of patients
will have a traumatic neuroma at the site of their previous tho-
racotomy scar, but this should not be the initial consideration in
evaluating such cancer patients.
213
Post mastectomy pain
Post mastectomy pain occurs in the posterior arm, axilla, and
anterior chest wall following any surgical procedure on the breast
from lumpectomy to radical mastectomy.41 It may be more likely to
occur from axillary dissection and lymph node dissection.42 There
is marked anatomical variation in the size and distribution of the
intercostal brachial nerve accounting for its variable appearance
of this syndrome in patients undergoing mastectomy.41 The pain
results from interruption of the intercostal brachial nerve, a cuta-
neous sensory branch of T1–T2. The pain may occur immediately
following the surgical procedure or as late as 6 months following
surgery. It is characterized as a tight, constricting, burning pain
in the posterior aspect of the arm and axilla radiating across the
anterior chest wall. The pain is exacerbated by the movement of the
arm and relieved by the immobilization of the arm. Patients often
posture the arm in a flexed position close to the chest wall and are
at risk to develop a frozen shoulder syndrome if adequate pain and
postsurgical rehabilitation are not implemented early on.
Approximately 5% of women undergoing surgical procedures
on the breast develop the syndrome. The nature of the pain and
the clinical symptomatology should readily distinguish it from
tumor infiltration of the brachial plexus. The syndrome appears
to occur more commonly in patients with postoperative compli-
cations who are at risk for local fibrosis in and about the nerve fol-
lowing surgery, following wound infection or seroma. Typically,
a trigger point in the axilla or on the anterior chest wall may be
found and this is usually the site of the traumatic neuroma. Breast
reconstruction does not alter the tight, constricting sensation in
the anterior chest wall that is associated with this syndrome.
After radical neck surgery
Prospective studies of pain after radical neck dissection are lack-
ing. In any patient in whom the pain occurs late, that is, several
months following the surgical procedure, and particularly any
pain occurring several years following the surgical procedure,
reevaluation is necessary to exclude recurrence of tumor.
Post amputation pain
Loss of a body part is often followed by psychological adjustment
which may include a grief reaction.43 The physiological phenom-
ena of nonpainful and painful phantom sensations referred to
the missing part, pain in the scar region after limb amputation,
and involuntary motor activity also occur. Many patients note
more sensations in the distal phantom limb or in the nipple of the
phantom breast. A phantom visceral organ may be associated with
functional sensations, for example, the urge to urinate or defecate.
There are a few reports on the course of post amputation pain in
malignant disease. In a study of 17 patients with cancer who under-
went forequarter amputation, none of the seven survivors had
pain, requiring the use of analgesics after an average of 69-months
follow-up.44 Larger surveys of post mastectomy patients reveal that
at least 10% experience chronic phantom breast pain, more than
is generally believed.45 Increasing pain in the cancer amputee may
signify disease progression or recurrence.46,47
Chemotherapy-related pain syndromes
Painful dysesthesias follow treatment with several chemothera-
peutic agents, in particular, the vinca alkaloid drugs such as
vincristine and vinblastine. Cisplatin and taxol are also toxic to
peripheral nerves.48,49 These agents produce a symmetrical poly-
neuropathy as a result of a subacute with chronic axonopathy. Pain
214
is usually localized to the hands and feet and is characterized as
burning pain exacerbated by superficial stimuli which improves
as the drug is withdrawn. Aseptic necrosis of the humeral and
more commonly femoral head is a known complication of chronic
steroid therapy.50 Pain in the shoulder and knee or leg is the com-
mon presenting complaint, with X-ray changes occurring several
weeks to months after the onset of pain. The bone scan and MRI
are the most useful diagnostic procedures.
PHN51 can be thought of as a post chemotherapy pain syn-
drome since immunocompromised patients are at risk for acute
zoster infection or a recurrence of latent zoster. Persisting pain
after healing of the cutaneous eruption of herpes zoster infection
has generally three components:
1. A continuous burning pain in the area of sensory loss
2. Painful dysesthesias
3. Intermittent shock-like pain
Older patients are at greater risk of this complication.
Immunotherapy-related pain syndromes
With the relatively recent advent of immunotherapy use in the
treatment of cancer there have been a considerable side effects
documented, including pain. These side effects also known
as immune-related adverse events (IrAEs; see Box 24.4) have
been found to be less frequent with programmed death 1(PD-
1)/programmed death-ligand 1(PDL1) antibodies such as ave-
lumab, nivolumab, pembrolizumab, atezolizumab, durvalumab
compared to anticytotoxic T-lymphocyte antigen-4 (CTLA-4)
BOX 24.4  CLINICAL CHARACTERISTICS
OF IMMUNOTHERAPY/AUTOIMMUNE-
RELATED PAIN SYNDROMES
• Guillain–Barré syndrome: symptoms usually
start with neuropathic pain localized to the lower
extremities followed by progressive symmetrical
muscle weakness.
• Polymyalgia-like syndrome: symptoms may
include pain and stiffness in proximal upper and
lower extremities.
• Myositis: muscle pain, weakness, and soreness.
• Colitis: peritoneal signs, cramping, distended
abdomen, diarrhea, melena/hematochezia.
• Hepatitis: RUQ pain along with jaundice, nausea,
emesis.
• Myocarditis/pericarditis: chest pain, arrhythmia,
palpitations with dyspnea.
• Inflammatory arthritis: inflammation of joints
leading to joint pain; morning stiffness lasting
>30–60 minutes with decreased range of motion,
swelling, erythema.
• Pneumonitis: dyspnea, nonproductive, cough
with chest pain/tightness.
• Peripheral neuropathy: asymmetric or symmetric
sensory, motor, or sensory motor deficit. Numbness
and paresthesia may be painful/painless.
• Aseptic meningitis/encephalitis: headache, nuchal
rigidity, photophobia, confusion, and seizure.
Textbook of Palliative Medicine and Supportive Care
inhibitors like ipilimumab.52 IrAEs resemble autoimmune disor-
ders, the mechanism is thought to be related to the activation of
T cells to self-antigen resulting in a response against normal tis-
sue. This process generates elevated levels of CD-4 T-helper cell
cytokines or cytolytic CD8T cells within normal tissue which can
illicit significant amounts of inflammation, precipitating a pain
response.53 The median time of presentation for IrAEs has found
to differ depending on the immunotherapy used. For example, a
randomized phase 3 control study published in 2015 by Robert
et.al. comparing pembrolizumab with ipilimumab in advanced
melanoma showed a median time of 40 and 64 days, respectively.54
Keeping this in mind, physicians should remain alert to the pos-
sibility that IrAEs may present months to years into therapy and
further studies are needed to better understand these toxicities.55
A multidisciplinary panel organized by the American Society of
Clinical Oncology have generated a grading system ranging from 1
to 4 for IrAEs along with treatment recommendations and guide-
lines. Patients experiencing minor grade 1 IrAEs may be moni-
tored, while patients presenting with more severe grades of 2–4 are
recommended to have their immunotherapy held as well as start-
ing them on corticosteroids. Patients refractory to corticosteroid
therapy may even require tumor necrosis factor (TNF)-α inhibitor
(infliximab) if symptoms do not resolve with steroids.52
Post radiation therapy pain
These syndromes are becoming less common as the sophistication
with which radiation therapy portals are planned decreases the
likelihood of radiation overdose to tissues and spares surround-
ing normal tissues. Nonetheless, radiation fibrosis of peripheral
neural structures, such as the brachial and lumbar plexus, still
occurs and radionecrosis of bone is occasionally seen.
Radiation fibrosis of the brachial plexus was discussed pre-
viously. Pain occurring in the leg from radiation fibrosis of the
lumbar plexus is characterized by the late onset of pain in the
course of progressive motor and sensory changes in the leg.56,57
Lymphedema, a previous history of radiation therapy, myokymia
on EMG, and X-ray changes demonstrating radiation necrosis of
bone may help to establish this diagnosis.
Pain is an early symptom in 15% of patients with radiation
myelopathy.58,59 Some patients may have the Lhermitte sign, signi-
fying transient demyelination in the posterior columns, which does
not necessarily predict the development of myelopathy. Pain may
be localized to the area of spinal cord damage or may be a referred
pain with dysesthesias below the level of injury. The neurological
symptoms and signs often start as Brown–Séquard syndrome, a
lateral hemisection of the cord, such that pain and temperature
sensation are lost contralateral to the side of weakness. Position
and vibration sensation are lost ipsilateral to the side of weakness.
The incidence of myelopathy increases with increasing radiation
exposure and approaches 50% with 1500 ret exposure. The latency
from completion of radiation to the onset of symptoms of myelopa-
thy ranges from 5 to 30 months, with an average of 14 months in
most series.
A painful enlarging mass in an area of previous irradiation
suggests a radiation-induced peripheral nerve tumor.60–63 In one
study, seven of nine patients who developed radiation-induced
nerve tumors presented with pain and progressive neurologi-
cal deficit with a palpable mass involving the brachial of lumbar
plexus; these nine patients developed their tumors 4–20 years
following radiation therapy. Neurofibromatosis is associated
with an increased risk for the development of radiation-induced
peripheral nerve tumors.60
Causes and Mechanisms of Pain in Palliative Care Patients
Noncancer pain syndromes and mechanisms
Like cancer pain syndromes, noncancer pain syndromes may be
nociceptive or neuropathic in nature. Internists and family physi-
cians deal with common degenerative, musculoskeletal pain syn-
dromes along with specialist assessment as indicated. Palliative
care specialists are likely to encounter pain in patients with
ESLD, ESRD, and HIV infection/AIDS.
Although pain syndromes in other conditions such as HF,
COPD, and dementia are not well described, it is thought that
these conditions in themselves along with other underlying medi-
cal comorbidities contribute to the experience of pain.64 There is
less evidence for the effective treatment of pain HF, COPD, and
dementia patients and treatment is based on the practitioner’s
experience and considered best practices.65
End-stage liver disease and pain
The final stage of chronic liver disease is known as ESLD (see
Box 24.5). Cirrhosis is the process of hepatic fibrosis of normal
liver architecture that leads to ESLD. The damage done to the
liver at this point is permanent and can lead to several devastat-
ing complications including hepatopulmonary syndrome, spon-
taneous bacterial peritonitis (SBP), ascites, encephalopathy, and
hepatorenal syndrome.66 Theses complications in turn can result
in significant symptom burden including pain. It is estimated that
in 2015 approximately 633,323 of population in the United States
suffered from cirrhosis.67 Liver transplantation continuous to be
the only curative option for a specific group of patients.66
A systemic review and meta-analysis done by Penk et al.
showed that prevalence of pain in ESLD patient’s ranged from
30–79%. The most common locations of pain were noted to be
the abdomen and lower back.68
Abdominal pain discomfort and nagging or stabbing pain is
frequently reported by cirrhotic patients and is thought to be
secondary to the compression of adjacent abdominal or thoracic
organs from hepatomegaly/splenomegaly or by the distention of
the hepatic capsule itself.69 The liver capsule is a visceral structure
BOX 24.5  CLINICAL CHARACTERISTICS
OF PAIN IN ESLD
• Hepatomegaly/splenomegaly: nociceptive pain
due to distention of the hepatic capsule, compres-
sion of adjacent abdominal or thoracic organs
leading to chronic abdominal pain.
• Tense ascites: generalized abdominal discomfort,
slower bowel transit times, and decreased gas-
tric emptying leading to dyspepsia and epigastric
pain.
• Spontaneous bacterial peritonitis: generalized
peritoneal abdominal pain associated with fever
and malaise.
• Portal vein thrombosis: thrombosis of portal
veins presenting with RUQ abdominal pain.
• Fibromyalgia-like syndrome: widespread muscu-
loskeletal pain associated with fatigue and mood
disorders.
• Mastalgia: excess estrogen leads to breast pain
and/or tenderness.
215
which supplies pain signals by afferent nerves via the celiac plexus
to the CNS. These sensory visceral afferent fibers are activated
when there is insult to the hepatic capsule.70
Other etiologies of abdominal pain in ESLD include tense ascites.
Tense ascites may lead to slower bowel transit times and decreased
gastric emptying leading to dyspepsia and epigastric pain. Patients
that develop ascites are also at risk for developing SBP with an inci-
dence reported anywhere from 7–30%.71 SBP can cause worsen-
ing abdominal pain along with fever, malaise, and altered mental
status. When suspecting SBP, patients should have an immediate
diagnostic paracentesis along with antibiotic treatment.69
Liver cirrhosis patients are also at an increased risk for portal
vein thrombosis (PVT). Patients with PVT may complain of pro-
gressively worsening abdominal pain most commonly reported
in the right upper abdominal quadrant. PVT in cirrhotic patients
is thought to be due to increased intrahepatic vascular resistance,
reduced portal vein velocity, and hypercoagulability state.72 One
study reported that up to 15.9% of cirrhotic patient’s awaiting
liver transplantation had PVT.73
Musculoskeletal pain and fibromyalgia-like syndromes is com-
monly reported in cirrhotic patients. It is hypothesized that this
may be secondary to the release of pro-inflammatory cytokines
leading to a constant state of systemic inflammation.69 Muscle
cramps also tend to lower the quality of life in cirrhotic patients.
Researchers postulate that the higher prevalence of cramping in
cirrhotic patients may be due to function, energy metabolism
along with plasma volume electrolyte abnormalities.74
End-stage renal disease and pain
ESRD (see Box 24.6) is most commonly defined as the irrevers-
ible decline in kidney function requiring renal replacement in the
form of peritoneal dialysis, hemodialysis, or kidney transplant.75
Data collected in 2017 estimated the prevalence of ESRD to be
746,557 cases in the United States alone.76 Pain is considered to be
BOX 24.6  CLINICAL CHARACTERISTICS
OF PAIN IN ESRD
• Calciphylaxis: rare and serious disorder char-
acterized by systemic medial calcification of the
arterioles that leads to ischemia and subcutane-
ous necrosis.
• Dialysis-related amyloidosis: deposition of β2
microglobulins on articular and visceral surfaces
leading to pain syndromes such as CTS, bone
cysts, scapula–humeral periarthritis, joint arthro-
plasty, and destructive spondyloarthropathy.
• RLS: unpleasant sensations in the lower extremi-
ties most frequently observed at night, at rest,
and made better with movement.
• Uremic neuropathy/diabetic neuropathy: distal
symmetrical sensorimotor polyneuropathy.
• Renal osteodystrophy: disturbance in calcium,
phosphate, vitamin D, and PTH homeostasis
leading to bone pain, joint pain, deformities, and
bone fracture.
• Dialysis-associated pain: arteriovenous fistula
pain, cannulation discomfort, and dialysis-
related headaches.
216
one of the most prevalent symptoms in ESRD patients. A review
by Davidson et al. evaluating symptoms in hemodialysis revealed
that overall 58% patients experienced pain with 49% reporting
moderate to severe pain.77 Another study reported chronic pain
prevalence as high as 92%78.
The etiology of pain in ESRD is directly related to the complica-
tions of the disease process. These pain syndromes consist of but are
not limited to neuropathic, ischemic, and musculoskeletal pain.75
The etiology for neuropathic pain in ESRD is variable. Both
diabetic and uremic neuropathy may present as a distal symmet-
rical sensorimotor polyneuropathy. Incidence of uremic neuropa-
thy is reported to be 10–83% in patients with renal failure in the
United States.79 The pathophysiology of uremic polyneuropathy is
not fully understood. Treatment consists of renal transplant and
early initiation of hemodialysis when indicated. Diabetes contin-
ues to be the leading cause of ESRD in the United States, with the
peripheral nervous system being affected in roughly two-thirds
of diabetic patients. 80
Patients on long-term dialysis are at risk of developing
dialysis-related amyloidosis which can lead to carpal tunnel
syndrome (CTS), bone cysts, scapula–humeral periarthritis,
joint arthroplasty, and destructive spondyloarthropathy.75 The
process of dialysis is thought to induce a pro-inflammatory
environment through the production of cytokines (IL-6, IL-1,
TNF-alpha) and activation of the complement cascade. This in
turn increases the production of low-molecular-weight fibrils
known as β2 microglobulins. When in high concentration, β2
microglobulins deposit on articular surfaces leading to painful
degenerative joint disease. 81
Bone morphology alterations due to defective mineralization,
and bone turnover are commonly seen in ESRD patients.82 The
disturbance in calcium, phosphate, vitamin D, and parathyroid
hormone (PTH) homeostasis leads to a disorder known as renal
osteodystrophy. Renal dystrophy may lead to symptoms such
as bone pain, joint pain, deformities, and bone fractures.83 The
major treatments for renal osteodystrophy at this time are phos-
phate binders, vitamin D compounds, and calcimimetics.84
Other pain syndromes that can impact quality of life in ESRD
patients include muscle cramps and restless leg syndrome (RLS).
Muscle cramps occur in 33–85% of patients on Hemodialysis
(HD), theories on the pathomechism include volume contrac-
tion, electrolyte abnormalities, hypoxia, carnitine deficiency,
and hypotension.85 RLS is characterized as the urge to move the
legs due to unpleasant sensations, usually during rest/inactivity,
worsening at night, with relief provided by movements.
The prevalence of RLS is higher in dialysis populations
(20–30%) than in the general population (5–10%).86 Risk factors
for developing RLS include female gender, long-term dialysis use,
iron deficiency, and use of tricyclic antidepressants/dopaminer-
gic antagonists, sleep hygiene, correcting iron deficiency, avoid-
ance of antidopaminergic medications, and possibly starting
dopamine agonists such as pramipexole or ropinarole.87
Human immunodeficiency virus and pain
Pain is a common symptom in HIV/AIDS patients. With the
increasing burden of this disease in Africa and Asia, palliative
care specialists are likely to encounter these pain syndromes.
Pain syndromes encountered in HIV/AIDS patients are diverse in
nature and etiology. The most common pain syndromes include
painful sensory peripheral neuropathy, pain due to extensive
Kaposi’s sarcoma, headache, oral and pharyngeal pain, abdomi-
nal pain, chest pain, arthralgias and myalgias, and painful
Textbook of Palliative Medicine and Supportive Care
dermatological conditions.88–93 Hewitt and colleagues in 1997
demonstrated that although pains of a neuropathic nature (e.g.,
polyneuropathies, radiculopathies) certainly comprise a large
proportion of pain syndromes encountered in AIDS patients,
pains of a somatic and/or visceral nature are also common clini-
cal problems.92 The etiology of pain syndromes seen in HIV dis-
ease can be categorized into three types:
1. Those directly related to HIV infection or consequences of
immunosuppression
2. Those due to AIDS therapies
3. Those unrelated to AIDS or AIDS therapies
In studies to date, approximately 45% of pain syndromes encoun-
tered are directly related to HIV infection or consequences of
immunosuppression; 15%–30% are due to therapies for HIV- or
AIDS-related conditions and to diagnostic procedures; and the
remaining 25%–40% are unrelated to HIV or its therapies.90,92
Oropharyngeal pain
Oral cavity and throat pain is common, accounting for approxi-
mately 20% of the pain syndromes encountered in one study.94
Common sources of oral cavity pain are candidiasis, necrotiz-
ing gingivitis, and dental abscesses and ulcerations caused by
herpes simplex virus (HSV), CMV, Epstein–Barr virus (EBV),
atypical and typical mycobacterial infection (MAI), cryptococ-
cal infection, or histoplasmosis. Frequently no infectious agent
can be identified and painful recurrent aphthous ulcers are
encountered.95
Esophageal pain
Many HIV/AIDS patients experience dysphagia or odynophagia,
most commonly caused by esophageal candidiasis. Ulcerative
esophagitis is usually a result of CMV infection but can be idio-
pathic. Infectious causes of esophagitis include HIV, papovavirus,
HSV, EBV, Mycobacterium, Cryptosporidium, and Pneumocystis
carinii. Kaposi’s sarcoma and lymphoma have both been reported
to invade the esophagus, resulting in dysphagia, pain, and ulcer-
ation.95 Nonsteroidal medications as well as zidovudine and zal-
citabine have been implicated in esophagitis.
Abdominal pain
The abdomen is the primary site of pain in 12–25% of patients
with HIV infection.96 Infectious causes of abdominal pain pre-
dominate and include cryptosporidiosis, Shigella, Salmonella,
and Campylobacter enteritis infections, CMV ileitis, and MAI.
Perforation of the small and large intestine secondary to CMV
infection has been described.97 Repeated intussusception of the
small intestine has been seen in association with Campylobacter
infection.98 Lymphoma in the gastrointestinal tract can pres-
ent with abdominal pain and intestinal obstruction.95,98 Other
causes of abdominal pain in HIV-positive patients95 include ileus,
organomegaly, spontaneous aseptic peritonitis, toxic shock, her-
pes zoster, and Fitzhugh–Curtis syndrome (perihepatitis in asso-
ciation with tubal gonococcal or chlamydia infection).
Many antiretroviral agents are responsible for gastrointestinal
symptoms, but lactic acidosis, a rare but serious complication of
some highly active antiretroviral therapy (HAART) regimens,
can present with abdominal pain.99 Didanosine, zalcitabine, and
stavudine can cause pancreatitis, whereas patients taking indi-
navir are at increased risk for nephrolithiasis. Cholecystitis is a
painful condition that may occur in HIV-infected patients as a
result of opportunistic infection.100 CMV and Cryptosporidium
Causes and Mechanisms of Pain in Palliative Care Patients
are the most common infectious agents. Drug-induced hepatic
toxicities as well as viral hepatitis as coinfection may lead to
abdominal pain. Pancreatitis is an extremely painful condition
often related to adverse effects of HIV-related therapies such
as didanosine, stavudine, and dideoxycytidine.101 Intravenous
pentamidine is also associated with pancreatitis. Other causes
of pancreatitis include CMV infection, MAI, cryptococcal lym-
phoma, and Kaposi’s sarcoma.
Anorectal pain
Perirectal abscesses, CMV proctitis, fissure-in-ano, and human
papilloma virus and HSV infection often cause painful anorectal
syndromes.
Chest pain syndromes
Chest pain is a common complaint in patients with HIV disease,
comprising approximately 13% of the pain syndromes encountered
in a sample of ambulatory AIDS patients.92 The index of suspi-
cion for coronary artery disease, even in young patients with no
other risk factors, must be high if the patient is being treated with
HAART. In immunosuppressed patients, infectious causes of chest
pain should be considered, particularly in the presence of fever
and some localizing sign such as dysphagia, dyspnea, or cough.
Infectious causes of chest pain include pneumocystis pneumonia,
esophagitis (CMV, candidiasis), pleuritis/pericarditis, and PHN.
Opportunistic cancers, Kaposi’s sarcoma, or lymphoma invad-
ing the esophagus, pericardium, chest wall, lung, and pleura may
also be sources of chest pain. Rarely, pulmonary embolus or bac-
terial endocarditis may be the cause of chest pain.
Neurological pain syndromes
Pain syndromes originating in the nervous system include head-
ache, painful peripheral neuropathies, radiculopathies, and
myelopathies. The HIV infection is highly neurotropic, invading
CNS and peripheral nervous system structures early in the course
of HIV disease. Consequently, many complications of HIV/AIDS
and opportunistic infections result in neurological pain, and
many commonly used HIV/AIDS medications can also be impli-
cated in neurological pain. Rarely, cerebrovascular events (e.g.,
thalamic stroke) occurring in hypercoagulable states can result
in central pain syndromes.
Headache
Headache is extremely common in the HIV/AIDS patient and can
pose a diagnostic dilemma for providers in that the underlying
cause may range from benign stress and tension to life-threatening
CNS infection.95 The differential diagnosis of headache in patients
with HIV disease includes:
• HIV encephalitis and atypical aseptic meningitis
• Opportunistic infections of the nervous system
• AIDS-related CNS neoplasms
• Sinusitis
• Tension
• Migraine
• Headache induced by medication (particularly azathio-
prine [AZT])
Toxoplasmosis and cryptococcal meningitis are the two most
commonly encountered opportunistic infections of the CNS that
cause headaches in patients with HIV infection. More benign
causes of headache in the patient with HIV infection include
217
AZT-induced headache, tension headache, migraine with or
without aura, and unclassifiable or idiopathic headache.102
Neuropathies
Neuropathic pain occurs in about 40% of AIDS patients.90,92 The
most common painful neuropathy seen is the PSN of AIDS.
However, other potentially painful neuropathies in HIV/AIDS
patients can have other viral and nonviral causes or may be caused
by demyelination leading to Guillain–Barré syndrome, nutri-
tional deficiencies, alcohol, and HIV therapies.103 Predominantly
symmetrical sensory neuropathy of AIDS is the most frequently
encountered neuropathy. This is typically a late manifestation
occurring most often in patients with an AIDS-defining illness.104
The prevalence of this neuropathy in hospice populations ranges
from 19 to 26%.105,106 The predominant symptom in about 60% of
patients is pain in the soles of the feet. Paresthesia is frequent and
usually involves the dorsum of the feet and soles. Most patients have
signs of peripheral neuropathy and, although the signs progress,
the symptoms often remain confined to the feet.107,108 Although
patients’ complaints are predominantly sensory, electrophysiologi-
cal studies demonstrate both sensory and motor involvement.
Rheumatological pain syndromes
In studies conducted by the Memorial Sloan-Kettering group,
over 50% of pain syndromes were classified as rheumatological in
nature including various forms of arthritis, arthropathy, arthral-
gias, myositis, and myalgias.92
The most frequently reported arthritis is a reactive arthritis or
Reiter’s syndrome.109–113 Acute HIV infection may present with a
polyarthralgia in association with a mononucleosis-like illness.
There is also a syndrome of acute severe and intermittent artic-
ular pain, often referred to as HIV-associated painful articular
syndrome, which commonly affects the large joints of the lower
limbs and shoulders. Psoriasis and psoriatic arthritis have been
reported in patients with HIV infection.114 Septic arthritis has
been reported in patients with HIV disease, including arthritis
due to bacterial infections and infections with Cryptococcus neo-
formans and Sporothrix schenckii.109,110
Opioid-induced hyperalgesia
Opioid-induced hyperalgesia is a state of nociceptive sensitiza-
tion that is caused by exposure to opioids. It is characterized by a
paradoxical response when a patient receiving opioids for the treat-
ment of pain may actually become more sensitive to certain pain-
ful stimuli and, in some cases, experiences pain from ordinarily
nonpainful stimuli (allodynia). The phenomenon of opioid-induced
hyperalgesia, linked to the development of analgesic tolerance, has
been clearly demonstrated in animal models and has relevance in
the clinical setting.115,116 Patients who demonstrate a loss of opioid
effect in the absence of progressive illness (i.e., develop analgesic
tolerance) or develop a syndrome of worsening or more diffused
pain during a period of aggressive opioid escalation may be demon-
strating opioid-induced hyperalgesia. Clinicians should be aware
of this phenomenon, which often occurs when moaning arising
due to delirium at the end of life is mistaken for pain and extra
boluses of opioids are given. All patients with worsening or more
diffuse pain during a period of aggressive opioid escalation should
be evaluated for delirium- and opioid-induced hyperalgesia. When
suspected, it is reasonable to consider opioid rotation or the use of
a nonopioid strategy for pain control.
 218
Calciphylaxis
Calciphylaxis is a rare and serious disorder characterized by sys-
temic medial calcification of the arterioles that leads to ischemia
and subcutaneous necrosis.117 Calciphylaxis most commonly
occurs in patients with ESRD who are on hemodialysis or who
have recently received a renal transplant. Calciphylaxis should be
suspected in patients with skin lesions characterized by painful,
nonulcerating subcutaneous nodules or plaques, nonhealing ulcers,
and/or necrosis, which are most commonly present in the thigh and
areas of increased adiposity.118,119 Ulceration carries a mortality of
greater than 80%. There should be an aggressive program of wound
care, adequate pain control, and avoidance of local tissue trauma.
Acknowledgments
Thanks to Sunny Kuriakose for his help in the preparation of this
manuscript.
KEY LEARNING POINTS
• Pain is the most common symptom for which pal-
liative care specialists are consulted.
• Pain is classified into nociceptive and neuropathic
pain in broad terms, but the majority of cases are
mixed type.
• Pain in cancer is caused by tumor, treatment, or as
coexisting chronic pain.
• Tumor size may not correlate with pain intensity.
• There are well-defined pain syndromes described in
the literature based on the cause and the location.
• Metastatic bone pain is often associated with neu-
rological deficit due to close proximity between
skull and cranial nerves, and spinal cord and its
roots with vertebral column.
• Not all bony metastatic sites hurt.
• Detailed history with emphasis on neurological
examination will lead to early diagnosis of spinal
cord compression.
• Suspect epidural disease with new-onset neck and
upper or lower back pain.
• Critical assessment of pain syndrome helps with
optimal pain management, avoiding erroneous
polypharmacy.
• A new pain or a sudden change in intensity of
existing pain in cancer patient is invariably due to
recurrence.
• Headache should always raise suspicion for base of
skull metastasis or leptomeningeal disease.
• Exclude constipation as the cause of increased
abdominal pain.
• Exclude infection as the cause of intractable pain,
especially in head and neck cancers.
• Pain syndromes in HIV/AIDS often follow similar
pattern as cancer. But neuropathic pain, and rheu-
matic and musculoskeletal pain syndromes predom-
inate, with high incidence of psychosomatic issues.
• Delirium can masquerade as pain.
• Generalized body pains may be a sign of somatization.
BK-TandF-BRUERA_9780367642037-200160-Chp24.indd 218
Textbook of Palliative Medicine and Supportive Care
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25
OPIOID ANALGESICS

Geana Paula Kurita, Stein Kaasa, and Per Sjøgren

Contents
Introduction�����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������222
Morphine����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������222
Absorption��������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������222
Pharmacokinetics��������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������223
Elimination�������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������223
Pharmacokinetics of M6G and M3G����������������������������������������������������������������������������������������������������������������������������������������������������������������223
M6G and analgesia������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������223
M3G: Antagonism of antinociception and neurotoxicity�����������������������������������������������������������������������������������������������������������������������������223
Clinical aspects������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������223
Methadone�������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������223
Absorption��������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������224
Pharmacokinetics��������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������224
Elimination�������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������224
Clinical aspects������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������224
Oxycodone�������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������224
Absorption��������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������224
Pharmacokinetics��������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������224
Elimination�������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������224
Clinical aspects������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������224
Fentanyl�������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������224
Absorption��������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������225
Pharmacokinetics��������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������225
Elimination�������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������225
Clinical aspects������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������225
Buprenorphine�������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������225
Absorption��������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������225
Pharmacokinetics��������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������225
Elimination�������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������225
Clinical aspects������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������225
Opioid equivalency and switching��������������������������������������������������������������������������������������������������������������������������������������������������������������������������������225
Long-term potential unintended consequences of opioid treatment��������������������������������������������������������������������������������������������������������������������226
Physical dependence���������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������226
Tolerance�����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������226
Opioid-induced hyperalgesia������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������227
Addiction����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������227
Immune system�����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������227
Reproductive system���������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������228
Summary�����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������228
References���������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������229

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222 Textbook of Palliative Medicine and Supportive Care

Introduction emerged. However, the clinical and genetic complexity of

Opioids are a class of substances derived from opium poppy
(Papaver somniferum), which when used properly can help to
decrease pain intensity and consequently, improve quality of life.
The main constituent, the alkaloid called morphine, was isolated
by Sertürner in 1803 and it remains the “gold standard” when
effects of other opioid analgesics are to be compared.
The mechanism of action of opioids is based on inhibition of
the ascending nociceptive signal transmission from the dorsal
horn in the spinal cord. The periaqueductal gray region is a major
anatomical locus for opioid activation of descending inhibitory
pathways to the spinal cord and is an important site for opioid-
receptor-mediated analgesia. However, opioid receptors are also
present in peripheral nerves.5
The concept of a specific opioid receptor was established in the
middle of the twentieth century based on the stereospecificity and
availability of selective antagonists to the analgesic actions.1 Studies
identified three main types of opioid receptors in the central ner-
vous system (CNS): μ (mu), δ (delta), and κ (kappa). Additional
receptors have been reported (e.g., sigma, epsilon, and orphanin)2
as well as subtypes of opioid receptors (e.g, µ1-3, κ1-3, δ1,2).100
Until recently, it was thought that most opioids provided
analgesia by activation of μ-receptor, reflecting their similar-
ity with morphine. However, variability in their efficacy, side
effects, and cross-tolerance in humans has resulted in the
assumption of μ-receptors subtypes and opioid interaction
with other molecular targets.101,102 New findings suggest that
μ-receptor-based drugs are not all the same; they exert their
analgesic action by not only a specific interaction with one
or more subtypes of the three main opioid receptors, but may
also interact with several pain-related receptor subtypes with
different activation profiles (Table 25.1). 3,103 Another explana-
tion for the discrepancy concerning the effects of the different
opioids may be genetic variability. In the last decade, accord-
ing to the paradigm of precision medicine, a growing number
of candidate-gene studies searching for associations between
genetic variability and efficacy or side effects of opioids have
responses to opioids has until now resulted in limited clinical
applicability.4,104
According to the World Health Organization (WHO)105 and
European Society for Medical Oncology106 guidelines for manage-
ment of cancer pain in adults and adolescents (2019), any opioid
may be used for pain relief. Availability/acceptability, drug indus-
try marketing in different regions worldwide, and challenges of
non-medical opioid use, misuse, and abuse have influenced pre-
scription patterns substantially.
Examples of weak opioids in current use are codeine and tra-
madol, whereas strong opioids are largely represented by mor-
phine, hydromorphone, oxycodone, oxymorphone, methadone,
fentanyl, and buprenorphine. In this chapter, the most widely
used and clinically relevant strong opioid analgesics in palliative
medicine are described.
Morphine
Morphine used to be the first-line opioid for cancer relief,6,7 but
recent WHO guidelines have stated, according to the available
evidence, that most commonly used strong opioids have little
difference regarding analgesic efficacy and side effects in cancer
pain.105 Morphine is a pure opioid agonist with affinity primarily
to the μ receptors and, to a lesser degree, to the δ and κ recep-
tors (see Table 25.1). Morphine can be administered by the oral,
rectal, intravenous, intramuscular, subcutaneous, epidural, intra-
thecal, and intracerebroventricular routes.
Absorption
After oral administration, morphine is almost completely
absorbed from the gastrointestinal tract. 8 The rate of absorp-
tion from the gut depends on the pharmaceutical formulation.
Immediate-release morphine tablets reach their maximum
plasma concentrations within an average of 60–70 minutes
and sustained-release morphine tablets designed for twice
or thrice daily administration within an average of 140–200
minutes.9,10

TABLE 25.1  Primary Receptor Binding and Pharmacologic Data of Important Opioids in Palliative Medicine
Potential New Bioavailability Metabolism/ Safety in Renal
Opioid Pathways Interactions103 Average (%) Major Metabolites Excretion Failure
Morphine μ-Receptor agonist CB1 partial agonist 30.6 M3G3 Hepatic/renal/gut Not safe
M6Ga
Methadone μ-Receptor agonist – 80 Pyrrolidineb Hepatic/gut Safe
Oxycodone μ-Receptor agonist – 60 Oxymorphonea Hepatic/renal Uncertain
Nororxycodoneb
Oxymorphone μ-Receptor agonist DOR/KOR partial 10 Oxymorphone- Hepatic/renal Uncertain
agonist 3-glucuronidec
6-OH-oxymorphonea
Fentanyl μ-Receptor agonist 50–90 Norfentanylb Hepatic/renal Hepatic/renal
p-Hydroxy(phenethyl)
fentanyla
Buprenorphine μ-Receptor agonist CB1 inverse agonist, 50 Norbuprenorphineb Hepatic/renal Safe
κ-Receptor antagonist monoamine
transporter activator
Note: M6G, morphine-6-glucuronide; M3G, morphine-3-glucuronide.
a Active.

b Inactive.

c Uncertain.
Opioid Analgesics
Pharmacokinetics
About 20–38% of morphine is bound to plasma proteins, primar-
ily albumin.11 The mean volume of distribution varies between
2.1 and 4.0 L/kg in cancer patients and healthy individuals,
decreasing to half the value in elderly individuals.12–14 In cancer
patients and healthy individuals, mean elimination half-life var-
ies between 1.6 and 3.4 hours and mean systemic plasma clear-
ance between 9 and 33 mL/kg/minutes.13–15
Extensive first-pass metabolism after oral morphine adminis-
tration results in a low and variable bioavailability between 19
and 47%14,16 (see Table 25.1). The two most important metabolites
quantitatively and qualitatively are morphine-3-glucuronide
(M3G) and morphine-6-glucuronide (M6G) (see Table 25.1).
M3G has no analgesic effect; however, it has been reported to
antagonize morphine analgesia and produce side effects includ-
ing hyperalgesia,107 while M6G has been reported to produce
higher analgesic effect than morphine. Regardless of the route
of administration, approximately 44–55% of a morphine dose is
converted into M3G, 9–10% to M6G, and 8–10% is excreted
in the urine unchanged.14,108 The major pathway for morphine
metabolism is conjugation with the co-substrate uridine-
diphosphate (UDP)-glucuronic acid. The process is catalyzed by
UDP glucuronyltransferase (UDPGT) and takes place mainly in
the liver, although a part takes place in the kidneys, gut, and
brain as well16,17 (see Table 25.1). UDPGTs are a multienzyme
family, and it has been demonstrated that the UGT2B7 is likely
to be the major isoform responsible for morphine glucuronida-
tion, capable of catalyzing the glucuronidation process at the
three as well as six positions.18,19 During long-term treatment,
neither dose level nor treatment length seems to influence gluc-
uronidation of morphine20 ; however, varies among individuals,
and studies have proposed that genetic variability seems to play
a role.21–23
Elimination
During the process of glucuronidation, morphine is made more
hydrophilic, and the enhanced water solubility eases its excre-
tion via the kidneys (see Table 25.1). In a study of patients with
renal failure who were given intravenous morphine, plasma
concentrations of M3G and M6G were observed to be sev-
eral fold greater in these patients than in a control group with
normal renal function.24 The clearance of the metabolites is
significantly correlated to the creatinine clearance.25 As a con-
sequence of the accumulation of M3G and M6G in patients with
renal impairment, toxic effects of morphine metabolites may be
expected 26,27 (see Table 25.1).
Pharmacokinetics of M6G and M3G
In healthy volunteers, the plasma protein binding of M3G and
M6G has been found to be low upto 15 and 11%, respectively.
Formation of the metabolites takes time, and Tmax for M6G and
M3G occurs later than for morphine. After long-term adminis-
tration of morphine to cancer patients, the cerebrospinal fluid
(CSF) and plasma ratios for M3G and M6G range between 0.08
and 0.18 and 0.07 and 0.15, respectively.29,30
M6G and analgesia
Animal studies demonstrated that, although M6G and mor-
phine were almost equally potent after peripheral administra-
tion, the analgesic potency of M6G was 100-fold higher than
morphine after intracerebroventricular injection. 31 Further, it
223
was suggested that prolonged analgesia may be due to attenu-
ated brain penetration of M6G, 31,32 its retention in the extracel-
lular fluid, 32 and consequently slower rate of elimination from the
brain compared to morphine. 33 An analysis of existing in vivo and
in vitro studies (n = 23) with mixed populations regarding ratios/
concentrations of morphine and metabolites, mostly after single
doses of morphine, observed a major contribution of M6G to the
overall analgesic effect (from 85.4 to 96.6%), depending on route
of administration.109 In patients with cancer, only a few clinical
studies have found evidence for M6G being a contributor to the
analgesic efficacy observed after morphine administration, 35,36
whereas other clinical studies have been unable to demonstrate
this.20,30,37,38 In general, these studies are confounded by uncon-
trolled psychological factors, assessment of pain as an outcome,
level of morphine exposure and different patient populations
(related to pain mechanism) among others.
M3G: Antagonism of antinociception
and neurotoxicity
M3G appears to have no μ-agonist properties, and therefore
appears to be devoid of analgesic activity; however, associa-
tions with exacerbation/attenuation of the effects of morphine
and induction of side effects have been reported. In some stud-
ies, subcutaneous or intracerebroventricular administration of
M3G prior to or after the administration of morphine or M6G
has been shown to reduce the antinociceptive response of the
two analgesic agents. 39,40 Moreover, symptoms of hyperalgesia,
allodynia, and myoclonus have been reported in patients with
cancer treated with high doses of morphine administered by
several different routes44,45; although these side effects have also
been associated with other opioids.46 In contrast, other studies in
rodents,41,42 healthy volunteers,47 and patients with cancer110 have
not found any influence of M3G on morphine analgesia and/or
induction of side effects.
Clinical aspects
An update of a Cochrane review111 on the use of oral morphine
concluded that despite poor evidence, it has similar efficacy
compared to other opioids and the frequent side effects did not
implicate in high rates of treatment discontinuation. Studies
in patients with cancer have suggested that a variety of genetic
polymorphisms may be responsible for pain relief variability;
however, the literature is still inconsistent.112 A large cross-
sectional study conducted to analyze the influence of genetic
variability on opioid mechanisms did not show any association
between 112 single nucleotide polymorphisms in 25 candidate
genes for opioid actions and the efficacy of commonly used
opioids, including morphine.4 A recent meta-analysis includ-
ing 12 studies examining the association between OPRM1
A118G (rs1799971) polymorphism and opioid analgesia demon-
strated that patients with cancer pain carrying G allele (AG +
GG) required higher opioid doses compared to those with AA
homozygous.112
Methadone
Methadone is a long-acting μ-receptor agonist, with pharmaco-
logical properties qualitatively similar to those of morphine (see
Table 25.1). Earlier reports of severe toxicity of methadone have
given rise to misconceptions and render its effective use in cancer
224
pain difficult.48,49 With better understanding of the pharmaco-
kinetics and the clinical challenges of methadone, it has subse-
quently been found to be a safe, effective, and cheap alternative
to other opioids when prescribed by physicians experienced in its
use. Methadone is administered by the oral, rectal, and intrave-
nous routes. It is not suitable for subcutaneous administration
because of the high frequency of local reactions.50
Absorption
Methadone is a synthetic opioid almost completely absorbed when
administered orally and rectally.51 Its oral bioavailability is higher
than morphine and ranges from 41 to 99%52,53 (see Table 25.1).
It is a lipophilic drug and is subject to considerable tissue distri-
bution.54 The peripheral tissue reservoir sustains plasma concen-
trations during long-term treatment.55 Methadone is extensively
metabolized through P450 system in the liver to inactive metabo-
lites via N-demethylation56 (see Table 25.1). In most countries,
methadone is used in a racemic mixture of S and R enantiomers,
although the latter form has significantly longer elimination half-
life, larger volume of distribution, slower clearance, and more
analgesic potency.57,58
Pharmacokinetics
Methadone is characterized by a rapid and extensive distribution
phase (half-life, 2–3 hours) followed by a slow elimination phase
(b-half-life, 15–60 hours). After oral administration, measurable
concentrations appear in plasma after 30 minutes.54 There is a
large inter-individual variation of the elimination phase, which
can cause accumulation and potential toxicity.59
Elimination
Methadone is mainly excreted by the fecal route and only a minor
part is eliminated in the urine (see Table 25.1). Renal clearance
is enhanced by lowering the urinary pH.60 As the elimination is
primarily via feces, significant accumulation is not likely in renal
failure (see Table 25.1).
Clinical aspects
It has been demonstrated that methadone can block
N-methyl-D-aspartate (NMDA) receptor, which may theoret-
ically be advantageous in management of neuropathic pain.113
In addition, methadone has been used extensively for opioid
switching or rotation in patients with cancer and improve-
ments have been reported in terms of pain relief and toxici-
ties. 3,61,62 A major problem encountered when switching to
methadone from another opioid is the huge inter-individual
variations in the equianalgesic ratio of methadone to other
opioids. Most research regarding the use of methadone for
cancer-related pain has focused on identifying safe conver-
sion ratios that can be used to switch to methadone from
other strong opioids. Due to methadone’s complex pharma-
codynamic/pharmacokinetic profile several switching meth-
odologies have been proposed. Whichever method is used,
patients require close clinical monitoring during the initial
weeks after switching to methadone.114 Moreover, arrhyth-
mias associated with its use has been reported.115 Nevertheless,
Cochrane and systematic reviews have indicated that metha-
done has similar analgesic efficacy as morphine and fentanyl
in adults with cancer pain, but the quality of the evidence is
still weak.113,116 Recently, methadone has also been used as a
first-line opioid in cancer pain. Despite the weak evidence,
five randomized controlled trials compared low and higher
Textbook of Palliative Medicine and Supportive Care
doses of methadone with oral morphine and transdermal fen-
tanyl and found similar analgesic and side effects between
those drugs.116
Oxycodone
Oxycodone (4,5 α-epoxy-14-hydroxy-3-methoxy-17-
methylmorphinan-6-one hydrochloride) can be administered
by the oral, rectal, intramuscular, and intravenous routes. It is a
μ-receptor agonist, but a small part of its antinociceptive effects
may be mediated by the δ, κ, and nociception/orphanin FQ pep-
tide receptors (see Table 25.1). Its metabolite oxymorphone
(14-hydroxydihydromorphinone) is a powerful analgesic, 10 times
more potent than morphine and considered highly addictive, which
was the reason to recommend removal of the product from the US
market by the Food and Drug Administration (FDA) in 2017.117
Absorption
Oral oxycodone bioavailability in humans is about 60% (range
50–87%)63,64 (see Table 25.1). Oxycodone is extensively metabo-
lized by the liver to the active metabolite oxymorphone and to
the possibly inactive, but quantitatively most prevalent metabo-
lite, noroxycodone119 (see Table 25.1).
Pharmacokinetics
Oxycodone’s physicochemical properties, liposolubility, and
protein-binding capacity are similar to those of morphine.66 Tmax
of oxycodone is approximately 1 hour and the mean half-life after
single dose is 3.5–5.65 hours.64,66 The half-life is not influenced
by the route of administration.64 Analysis of bioavailability of
immediate-release tablets demonstrated Cmax twofold higher
than with controlled-release tablets; Tmax was earlier (1.3 and
2.6 hour) and t½ was shorter with immediate-release tablets
(3 hour) than controlled-release tablets (4–5 hours).118
Elimination
Oxycodone is metabolized in the liver and both oxycodone and
its metabolites are mainly excreted via the kidneys. Systematic
reviews concerning the effects of oxycodone in patients with can-
cer and renal impairment106 and in patients with liver disease121
found weak clinical evidence regarding safety. However, oxyco-
done seems to be less toxic than other opioids and WHO guide-
lines have recommended to reduce oxycodone dose as much as
possible and to monitor patients with liver or renal insufficiency
closely105 (see Table 25.1).
Clinical aspects
Oral equianalgesic ratios of oxycodone to morphine have varied
due to interindividual differences in oral bioavailability, unequal
non-cross-tolerance, and sex differences in the metabolism of
oxycodone.70,71,122 However, recommendation for opioid switch-
ing during long-term treatment is 1:1.5.7,122
A Cochrane systematic review has indicated that the evidence
is still very weak regarding effectiveness and tolerability of oxy-
codone in adults with cancer, but data suggest that it can be used
as first-line oral opioid for cancer pain relief.123
Fentanyl
Fentanyl is a synthetic phenylpiperidine derivative and a chemi-
cal congener of the reversed ester of meperidine. It has selective
Opioid Analgesics
high affinity for the μ-receptor, where it acts as a pure agonist72
(see Table 25.1). Fentanyl has a short duration of action and is
therefore administered continuously by the transdermal, sub-
cutaneous, or spinal routes or used on demand by the intra-
venous and transmucosal routes. The transdermal therapeutic
system (TTS) is designed to release fentanyl at a slow and con-
stant rate of 72 hours. Nasal and buccal delivery devices, have
rapid onset with a clinical meaningful response rate in approxi-
mate 20–50% of patients after 10 minutes and in 50–90% after
30 minutes.7
Absorption
Transdermal fentanyl’s mean bioavailability is around 92%
(range 57–146%), although marked inter-individual variation
is demonstrated73 (see Table 25.1). Although fentanyl has been
detected in the blood 1–2 hours after initial application of
TTS, a considerable delay (17–48 hours) between patch appli-
cation and occurrence of Cmax is also apparent. The delay has
been attributed to accumulation of the drug in the skin under
the TTS before diffusion into the systemic circulation. Steady-
state concentrations are achieved after application of the sec-
ond patch.74
Transmucosal fentanyl includes buccal, sublingual, and
intranasal routes. The different formulations may imply phar-
macokinetic differences, but they are all capable of avoiding
first-pass metabolism. Buccal/sublingual formulations result
in overall bioavailability between 50–80% and concentra-
tions are maintained for 2 hours. Intranasal formulation
has a much higher bioavailability of 90% due to nasal cavity
characteristics.124
Pharmacokinetics
Fentanyl is predominantly metabolized in the liver and produces
norfentanyl and other inactive metabolites124 (see Table 25.1). It is
highly lipid soluble, thus rapidly transferring across the blood–
brain barrier and into the CNS. This is reflected in the half-life for
equilibration between the plasma and the CSF of approximately
5 minutes.75
Elimination
Renal elimination of fentanyl is prolonged after transdermal appli-
cation compared with intravenous administration (see Table 25.1).
Elimination half-life values vary from 5 to 25 hours depending on
route of administration and release system used.124
Clinical aspects
The relative analgesic potency of intravenous fentanyl to mor-
phine is approximately 1:100, and the transdermal fentanyl to oral
morphine during long-term administration is 1:150.F Recently,
oral transmucosal and intranasal fentanyl have become more
frequently used for breakthrough pain due to the rapid onset of
action and shorter duration of effect.7
Difficulties have been observed with oral transmucosal fen-
tanyl as absorption may be reduced in case of low saliva produc-
tion or liquid ingestion before application, which may alter oral
pH. Moreover, it may be challenging to administer in patients
with cognitive or physical dysfunction, which may decrease com-
pliance with treatment.124 Two major difficulties have been iden-
tified with the transdermal route: a delay of 12–24 hours occurs
in obtaining steady-state plasma concentrations and a prolonged
period of continued fentanyl effect following removal of the
patch.76
225
Buprenorphine
Buprenorphine is a semisynthetic opioid derived from thebaine,
a natural opium alkaloid structurally similar to morphine. It has
a potent analgesic effect due to agonist activity and a high bind-
ing affinity for μ-opioid receptors. In addition, an antagonistic
activity can be seen on the κ and δ receptors. Buprenorphine is
an opioid with a potency 25–30 times that of morphine.77 It can
be administered via sublingual, transdermal, and intramuscular
routes. Its high analgesic potency, lipophilicity, and low molecular
weight make it ideal for transdermal delivery systems.78 No ceil-
ing effect has been demonstrated, except for respiratory depres-
sion.79 Efficacy is dose-related and the duration of sublingual or
parenteral analgesia is long, approximately 6–8 hours. However,
the transdermal application may be most relevant in cancer pain
and therefore only this administration route and form will be
mentioned in the following.
Absorption
Transdermal buprenorphine has a similar time of onset as trans-
dermal fentanyl, but a longer duration of action (up to 7 days).
Therefore, this formulation of the buprenorphine patch can be
changed twice weekly on fixed days.80
Pharmacokinetics
Buprenorphine pharmacokinetics varies according to admin-
istration route. Approximately one-third of buprenorphine is
metabolized predominantly by cytochrome P450 3A4 in the
liver, yielding the active metabolite norbuprenorphine—about 40
times less potent.80
Elimination
In case of hepatic impairment, the half-life of the drug is pro-
longed, but because of the low activity of the metabolites, this
is of low clinical relevance. Nevertheless, careful monitoring
of patients with hepatic impairment is recommended. In cases
of renal impairment, no clinically important accumulation of
metabolites has been observed; therefore, a dose reduction is not
necessary.80
Clinical aspects
A Cochrane review analyzed the effectiveness and tolerability
of buprenorphine for pain in adults and children with can-
cer.125 Nineteen controlled studies with different designs were
examined; 11 were randomized and 5 of them showed analge-
sic effects of sublingual and transdermal buprenorphine com-
pared to other analgesic substances; however, no dose–response
relationship was observed. The evidence was of very low qual-
ity, precluding firm conclusions. Therefore, buprenorphine was
suggested as a fourth-line option compared to morphine, oxy-
codone, and fentanyl.123
Opioid equivalency and switching
Opioid switching is indicated when a decrease of opioid clini-
cal efficacy (despite dose increase) and/or unmanageable adverse
effects are observed for a period. In addition, issues regarding
compliance with treatment and route of administration may
require opioid switching. The concept is to substitute the current
opioid with another opioid, which can provide a more advanta-
geous analgesia/toxicity profile. However, switching opioids may
226
TABLE 25.2  Examples of Common Ratios and Ranges of Conversion with Oral Morphine for Opioid
Switching (see Further Mercadante and Bruera 2016, Treillet et al. 2018)122,126
Mercadante and
Route Opioid Bruera 2016126
Oral Methadone 5–10
Oxycodone 1.5
Hydromorphone 5 1.35–5
Transdermal Fentanyl 100
Buprenorphine 70
be a clinical challenge. First, assessment is based on patient’s
report and physician’s clinical judgment, depending very much
on the professional expertise to decide the moment for opioid
switching. Second, opioid pharmacological properties and char-
acteristics of the patient (age, comorbidities, concomitant medi-
cations in use, genetic factors, etc.) may interfere with analgesic
response.126,127 Third, opioid equipotency is dynamically depen-
dent on duration and dose exposure.128 Last but not least, there
is no consensus regarding opioid dose conversion due to lack of
evidence (Table 25.2).122 Therefore, individualized assessment/
therapeutic plan and careful monitoring are essential, especially
in cases of high doses of opioids.126
Long-term potential unintended
consequences of opioid treatment
Apart from providing analgesia and other potentially desired
effects, opioids also induce traditional side effects (nausea, seda-
tion, constipation, itching, etc.). However, long-term opioid
treatment may also have other consequences that should be con-
sidered in palliative care including physical dependence, toler-
ance, opioid-induced hyperalgesia (OIH), addiction and abuse,
and suppression of immune and reproductive systems.
Physical dependence
Physical dependence is a pharmacological phenomenon and
an expected consequence of use of opioids. It is defined by the
appearance of withdrawal symptoms when the opioid dose is
reduced or abruptly discontinued during long-term treatment
and/or when there is decreasing level of opoids in blood. 81,82
Some withdrawal symptoms, such as physical symptoms
(sweating, tremor, diarrhea, lacrimation, rhinorrhoea, nausea/
vomiting, and pain) may resolve within days, while others, such
as dysphoria, irritability, insomnia, and anxiety can last for
months or years. The behavioral transformation of cellular phe-
notypes leading to dependence and tolerance (see below) consist
of multiple adaptive responses, beginning at the opioid receptor
itself and modulating multiple signaling pathways in response
to continuous exposure to the opioid. Therefore, opioid recep-
tors desensitize and downregulate mediated by kinases and
receptor-associated proteins such as β-arrestins, which modu-
late the µ-receptor.129 Further, opioid-induced activation causes
microglia and astrocytes to release pro-inflammatory chemo-
kines, cytokines, ATP or NO, which in turn also may contrib-
ute to opioid tolerance and dependence, as well as OIH.130,131
Physical dependence and addiction may be associated as the
development of addiction may be driven by a learned association
Textbook of Palliative Medicine and Supportive Care
Treillet et al. 2018122 Fallon et al. 2018106
– 5–12
1.5 1.5
5–7.5
70–78 100
75
of seeking withdrawal relief by the continuous use of opioids. A
diagnostic distinction between dependence and addiction may
be difficult in some patients on long-term opioids with the avail-
able criteria, creating a diagnostic and therapeutic dilemma for
patients and their physicians.132 Intermittent withdrawal phe-
nomena, breakthrough withdrawal symptoms, or on-off phe-
nomena, which may appear as increased pain, are common in
patients using short-acting opioids on demand. 83 It may also
be a diagnostic challenge to distinguish between real physical
pain and pain elicited from withdrawal. In general, withdrawal
symptoms may appear after discontinuation of 3 weeks of daily
opioid consumption, but in some individuals it may appear even
after shorter periods of treatment.133 Opioid withdrawal symp-
toms can, to some extent, be prevented by gradually tapering off
the opioid until complete discontinuation.
Tolerance
Pharmacologically, tolerance may develop with the repeated
use of opioids and is characterized by the necessity of increased
doses in order to maintain the drug effects. Some opioid side
effects (nausea, respiratory depression, and sedation) may also
be subject to tolerance development.128 Clinically, tolerance to
the analgesic effect is problematic, whereas tolerance to side
effects may be useful to allow for dose increase when required
to improve analgesia. However, the effects on the bowel, includ-
ing constipation, or on the endocrine system, including testos-
terone depletion do not seem to decrease over time. Tolerance
results from adaptive mechanisms at the cellular, synaptic, and
network levels, where adaptations due to homeostatic mecha-
nisms tend to restore normal function in spite of the contin-
ued perturbations produced by opioid agonists. Some major
research concepts for the explaining and treating opioid toler-
ance have been launched.
The first is the determination of cellular responses by the
agonist–receptor complex but not by activated receptor alone. When
this concept is applied to opioid tolerance, it implies that different
opioids that work on the same receptor may induce different cell
responses to cause tolerance. This theory may explain the well-
known asymmetric cross-tolerance between drugs that activate
the same receptor, but have different intrinsic activities (e.g., a
patient who develops morphine tolerance may have good analge-
sic effects from methadone) and a commonly used technique of
opioid rotation for patients requiring chronic opioid use.84 Along
this line, different β-arrestins have been found to mediate cell
responses after different opioids, which are all μ-receptor ago-
nists. Thus, β-arrestins may be intracellular targets for modifying
cell responses such as tolerance induced by individual opioids.
Opioid Analgesics
The second concept is that receptor internalization and recycling
reduce opioid tolerance. If this is proved to be true in humans,
one simple way to reduce opioid tolerance in clinical practice
would be to combine morphine with a sub-analgesic dose of an
opioid with high intrinsic efficacy (these opioids usually induce
receptor internalization). The development of drugs that induce
receptor internalization, but do not activate opioid receptors,
may be another useful approach to reduce morphine tolerance.85
The third concept is that morphine exposure results in a strong
upregulation of spinal microglia.134 Alpha2-adrenoreceptor ago-
nists (e.g., clonidine) and NMDA antagonists (e.g., ketamine or
dextromethorphan) can minimize tolerance development. In
addition, opioid rotation and multimodal analgesia are other
alternative approaches.86
Opioid-induced hyperalgesia
OIH is broadly defined as a state of nociceptive sensitization
caused by an exposure to opioids. The condition is character-
ized by a paradoxical response whereby a patient receiving opi-
oids for the treatment of pain might become more sensitive to
certain painful stimuli. The type of pain experienced by an indi-
vidual might be the same as the underlying pain or different from
the original underlying pain, and typically, OIH produces dif-
fuse pain, which extends to other areas of distribution, than the
preexisting pain. Thus, the original pain type may be amplified,
combined with a state of more generalized hyperalgesia/allodynia
resembling neuropathic pain. Several studies have documented
hyperalgesia in response to different types of systemic or intra-
thecal opioids at high doses, and reported that pain was further
potentiated after dose increase.135 While there are several pro-
posed central and peripheral mechanisms, such as alpha-2 adre-
noceptors and the endocannabinoid system, the NMDA-receptor
activation seems to be crucial for the development of OIH, and
therefore the opioid receptors may not exclusively be involved in
the development of OIH.136 Indeed, several studies have reported
the downregulation of spinal glutamate receptors after prolonged
opioid exposure, resulting in spinal neuron sensitization.137-139
From the first anecdotal reports on OIH, a dose reduction or
switching to other opioids has been suggested as an effective
remedy in cancer patients. The switching has not only abolished
the OIH, but also substantially reduced other opioid toxicities.
The beneficial rotation to methadone has most frequently been
explained by the assumption that methadone has a weak NMDA
receptor antagonism, which could explain the effect.87,88 However,
studies of opioid addicts on methadone maintenance have also
shown that methadone can elicit and worsen OIH.135 The poten-
tial involvement of the NMDA receptors in generation of OIH
has promoted the use of more specific NMDA-receptor-blocking
agents. The most powerful available of these is ketamine, which
has been used to reduce OIH in humans.89,90
Addiction
Addiction is a phenomenon distinct from physical dependence
and tolerance.140 Addiction in the context of opioid therapy
for pain constitutes a constellation of maladaptive behaviors
including loss of control over use, preoccupation with opioid
use despite adequate pain relief, and continued use of the drugs
despite apparent obvious adverse consequences due to their
use.140 Other suggestive signs of addiction may be unwilling-
ness to terminate opioid treatment even if other treatment pos-
sibilities are offered, preference for short-acting opioids used on
227
demand, and not being interested in other treatment possibili-
ties. Previous studies have indicated that the prevalence of opi-
oid addiction varies up to 7.7% in cancer-related pain depending
on the subpopulations studied and the criteria used.141 However,
a recent North American study analyzed the frequency and fac-
tors predicting risk for aberrant drug-related behavior among
729 opioid treated patients with cancer, who received an out-
patient supportive care consultation at a comprehensive cancer
center; out of them 20% were at risk of aberrant opioid use and
11% of drug and alcohol use.142
The success of opioid therapy in patients with advanced can-
cer has set the stage for extending the same treatment principles
to the treatment of all chronic pain, due to the search for more
effective alternative treatments to manage “intractable” chronic
noncancer pain, lack of adequate pain treatment knowledge in
health professionals, and heavy marketing promotion from the
pharmaceutical industry. For the chronic noncancer pain popula-
tions, a high risk of addiction and the overdose related causalities
combined with poor pain relief outcomes and reporting of severe
toxicity have increasingly been associated with long-term opioid
therapy.143 Thus, well-designed population studies have almost
exclusively provided the evidence of prevalence of opioid-related
addiction > 20%.143,144 Especially in the United States, the con-
sumption of opioid analgesics has increased dramatically since
1990, making up one-third of global annual opioid consumption
despite having only 5% of the global population. This dramatic
rise has been associated by an increase in the number of opioid-
related deaths as an illegal market of heroin and fentanyl as well
as diversion of opioid analgesics have blossomed up.147 This so-
called opioid epidemic may not be ensconced within US borders
as many other western countries have been moving in the same
direction.146 Although opioids are the cornerstone of cancer pain
management, both in palliative and supportive care, more sys-
tematic empirical knowledge is needed concerning addiction in
“chronic” cancer patients. That includes identification of risk fac-
tors for opioid addiction as well as development of efficient opioid
tapering off programs.
Regarding opioid addiction, the µ-opioid receptor gene
encodes the receptor targets for some endogenous opioids and
studies about µ-opioid receptor polymorphisms have contrib-
uted substantially to knowledge of genetic influences on opi-
oid addiction. Monoaminergic system genes and other genes of
the endogenous opioid system, particularly genes encoding the
dopamine, serotonin, and norepinephrine transporters, and
dopamine β-hydroxylase, have also been studied.148 Clarke et al.
analyzed the role of rs1076560 in opioid dependence by genotyp-
ing 1,325 opioid addicts. The single nucleotide polymorphism
(SNP), 1076560 of the DRD2, was associated with increased risk
for drug dependence when combined opioid-addicted ancestral
samples were examined.149 There exist numerous positive studies
for many candidate genes associated with all reward deficiency
syndromes behaviors, especially involving alcoholism,150 and it
is possible that opioids are also associated. Particularly, pharma-
cogenomic identification of candidate genes may result in future
pharmacogenomic personalized solutions, and improved clinical
outcomes in terms of analgesic response, optimal side effect pro-
files and avoidance of addiction.
Immune system
Long-term opioid use has been suspected to be associated with
increased risk of infections151 and development and progression
228
of cancer diseases, respectively.152 The observations of poten-
tial immune suppression have mainly been based on an
animal- and in vitro studies153,154 as well as short-term opioid use
in humans.155,156 Studies have indicated that opioids may modu-
late and suppress both the innate and adaptive immune system by
involving the immune cells directly and the neuroendocrine sys-
tem indirectly. Regarding the immune cells the composition and
function of T lymphocytes (T cells), B lymphocytes (B cells) and
natural killer cells (NK cells) seem to be influenced.130,158 Further,
a reduced number of the different cell types has been shown,
which may be mediated by modulation of the toll-like receptors
(TLRs).159 The TLRs play a central role in the innate immune
system by detecting microbes and activating the immune cell
response.160
Studies have shown that opioids are TLR4 agonists,161,162 which
can produce immune signals involving a neuroinflammatory reac-
tion, which in turn may reduce analgesic effects.161 The µ-receptor
is also expressed on peripheral cells such as lymphocytes, which
may explain the suppression of NK cell activity during morphine
administration.162 Further, other studies have shown that mor-
phine can suppress cytokine production by interacting with the
surface receptors.163 A recent systematic review found indica-
tion that long-term opioid treatment alters the immune system
in chronic noncancer pain patients. These alterations involved
reduction of NK cells and IL-1β production.164 In addition, dif-
ferent opioids seem to act differently on the immune system, as
exemplified through methadone, which may be less suppressive
than morphine.91,92
Clinical data regarding the effects of opioids on cancer devel-
opment and progression are limited. A study in breast cancer
patients found a polymorphism in the gene encoding MOR,
which confers decreased response to opioids, and was corre-
lated with longer breast cancer-specific survival,165 whereas
high MOR receptor expression has been associated with shorter
survival in prostate cancer.166 Most clinical studies have mainly
focused on the effects of perioperative opioid use and a few
studies have focused on the long-term effects of opioids on
cancer development in chronic noncancer pain conditions and
progression of disease in patients with cancer. The outcomes of
these studies are inconclusive.167–173 Finally, an enhanced sensi-
tivity to viral and bacterial infections has been demonstrated in
drug abusers.93
However, for the time being due to lack of sound clinical
research, there is little if any clinical evidence that opioids poten-
tial effect on the immune system should influence the traditional
clinical practice on pain management in cancer care.
Reproductive system
Among patients treated with opioids intrathecally, Abs et al.94
found decreased libido or impotence in almost all the men
and significantly lowered serum testosterone levels. Decreased
libido was present in about 70% of women receiving opioids, and
all premenopausal females developed amenorrhea or an irreg-
ular menstrual cycle. Serum luteinizing hormone, estradiol,
and progesterone levels were significantly lower in the opioid-
treated group than among the controls. Finch et al.95 and Roberts
et al.96 have also found decreased libido and testosterone lev-
els in men, and it can be concluded that opioids administered
intrathecally may induce hypogonadotropic hypogonadism,
which is of clinical importance for the majority of men and
in premenopausal women. A study in men on methadone or
Textbook of Palliative Medicine and Supportive Care
buprenorphine maintenance treatment (MMT, BMT) inves-
tigated the prevalence and etiology of hypogonadism. Men on
MMT had high prevalence of hypogonadotrophic hypogonad-
ism, whereas the extent of hormonal changes associated with
buprenorphine needs to be explored further in larger studies.97
The decline in production of sex hormones can cause a negative
effect on patients’ sex life since a low level of testosterone, in
both genders, negatively influences sexual desire and fertility.174
Other studies have indicated that a differential effect of gender
on bone mineral density might be explained in part by differ-
ences in gonadal function during long-term opioid therapy. A
study of individuals in MMT indicated that low levels of testos-
terone are associated with accelerated bone loss particularly in
men,98 but hypogonadism has also been reported in women dur-
ing treatment with oral opioids.99 In summary, these findings
may suggest that individuals receiving long-term methadone,
and maybe other opioids, are at increased risk of osteoporosis
and physicians should consider evaluating the skeletal health of
such individuals, including the estimation of absolute fracture
risk. Controlled longitudinal studies of bone mineral density
and bone turnover are indicated to define the timing and pace of
the bone loss. Furthermore, future studies of hypogonadism in
opioid-treated individuals should examine the potential benefits
of dose reduction, choice of opioid medication, and sex hormone
replacement therapy.175 Finally, there is increasing evidence that
opioid treatment may cause varying degrees of hypopituitarism,
which may involve cognitive deficiencies, fatigue, decreased
libido, depression, and insomnia.176,177 Although some of these
effects are well-known as opioid-induced effects, the indirect
contribution from hypopituitarism has not yet been established.
Summary
This chapter discussed the history and recent evidence regard-
ing opioid receptors along with clinical observations of individual
responses and incomplete cross-tolerance to different opioids.
The up-to-date pharmacology of the most commonly used strong
opioids—morphine, methadone, oxycodone/oxymorphone, fen-
tanyl, and buprenorphine—has been reviewed. Important clinical
issues associated with long-term administration of these drugs
are highlighted.
KEY LEARNING POINTS
• Variability regarding opioid efficacy, side effects,
and cross-tolerance in different patients suggest
μ-receptors subtypes and opioid interaction with
other molecular targets.
• Pharmacogenetic knowledge of opioid effects is
still limited.
• Morphine may still be the first drug of choice;
however, selection of opioids should be based on
clinical assessment and the respective pharmaco-
kinetics/dynamics of each opioid analgesic.
• New routes of fentanyl and buprenorphine
administration have been developed, but titra-
tion difficulties and clinical relevance are still
discussed.
Opioid Analgesics
• Long-term opioid treatment has other conse-
quences than the “classic” side effects. In pallia-
tive medicine, physical dependence, tolerance,
OIH, and addiction should also be consid-
ered as these may be related to poor treatment
outcomes.
• New research concerning the potential influ-
ence of long-term administration of opioids
on the immune and reproductive systems is
needed.
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26
ASSESSMENT AND MANAGEMENT OF OPIOID SIDE EFFECTS

Shalini Dalal

Contents
Introduction....................................................................................................................................................................................................................... 235
Opioid-mediated gastrointestinal side effects............................................................................................................................................................. 235
Constipation................................................................................................................................................................................................................. 236
Assessment and management of constipation...................................................................................................................................................... 236
Nausea................................................................................................................................................................................................................................. 238
Assessment and management of opioid-induced nausea................................................................................................................................... 238
Sedation.............................................................................................................................................................................................................................. 238
Driving and opioids.....................................................................................................................................................................................................239
Opioid-induced neurotoxicity.........................................................................................................................................................................................239
Cognitive impairment and delirium.........................................................................................................................................................................239
Hallucinations...............................................................................................................................................................................................................239
Myoclonus and seizures..............................................................................................................................................................................................239
Hyperalgesia and allodynia....................................................................................................................................................................................... 240
Mechanism of opioid-induced neurotoxicity........................................................................................................................................................ 240
Assessment of OIN..................................................................................................................................................................................................... 240
Management of OIN....................................................................................................................................................................................................241
Respiratory depression......................................................................................................................................................................................................241
Opioid-induced bladder dysfunction............................................................................................................................................................................ 242
Pruritus and allergic reactions........................................................................................................................................................................................ 242
Opioid-induced endocrine and immune effects......................................................................................................................................................... 242
Opioid effects on immune function........................................................................................................................................................................ 243
Physiological and psychological responses to opioid use................................................................................................................................... 243
References........................................................................................................................................................................................................................... 244

Introduction
Opioids are the cornerstone of pain management in the palliative
care setting. Successful pain management with opioids requires
that adequate analgesia be achieved without excessive side effects.
Approximately 10–30% of patients treated with opioids do not
have a successful outcome due to either excessive side effects
and inadequate pain relief or a combination of both.1 All opioids
have the potential for side effects (Table 26.1), which may com-
pel some patients to decrease or discontinue opioids. The most
common include constipation, nausea, and sedation, while dose-
limiting side effects typically involve the central nervous system
(CNS) and include cognitive impairment, delirium, and myoclo-
nus. In recent years with the increased long-term use of opioids
such as in the chronic nonmalignant pain situation, effects of
prolonged use on the endocrine, particularly on sex hormones,
and the immune system are being increasingly recognized and
researched. The clinical importance of these effects for palliative
care patients is not yet clear.
The concept of individualizing analgesic therapy to the patient’s
pain syndrome with close monitoring of treatment outcomes
(pain relief, side effects of treatments) and changing clinical cir-
cumstances is fundamental to achieving success with pain man-
agement. Depending on these assessments, opioids are titrated or
switched to another to maintain a favorable balance between effi-
cacy and side effects.1 Further, some opioids may be better suited
than others among vulnerable patients, such as the elderly or ter-
minal cancer patients, who may already have or be at increased
risk for impaired renal and hepatic functions. Assessment of
hydration status and renal functions plays an important role
when using opioids in palliative care patients.
Greater compliance is likely if clinicians educate patients/fam-
ily of anticipated side effects and discuss plans for management.
Side effects may be limited by using appropriate opioid doses,
coadministration of adjuvant analgesics if indicated, and use of
medications to prevent/manage expected side effects.
Opioid-mediated gastrointestinal side effects
The etiology of opioid-induced gastrointestinal (GI) effects is
multifactorial and predominantly mediated by three opioid
receptors, mu-, delta-, and kappa-, which are widely distrib-
uted in the myenteric and submucosal neurons throughout the
GI tract.2–4 Opioids modify GI function by interacting with
these opioid receptors, thereby reducing neuronal excitability
and neurotransmitter (acetylcholine) release, with an overall
inhibitory effect on motility and secretion.2–6 Major physiologi-
cal effects include inhibition of gastric emptying and increased
gastric acid secretion; delayed colonic transit, increased colonic
tone/segmentation, increased colonic absorption, and decreased
secretion; increased pyloric and anorectal tone; and increased
gall bladder contraction with decreased secretion, and spasm of

235
236 Textbook of Palliative Medicine and Supportive Care

TABLE 26.1  Opioid Side Effects uremia, hypercalcemia), neurological lesions, prolonged immo-
bility, dehydration, or other medications (such as anticholiner-
Gastrointestinal
gics, antacids, or antidepressants). The etiology of constipation
• Nausea in the palliative care setting is discussed in detail in Chapter 59.
• Constipation
Central nervous system Assessment and management of constipation
• Sedation Assessment should include a history of the frequency and dif-
• Opioid-induced neurotoxicity ficulty of defecation and consideration of other possible con-
• Severe sedation tributors. Physical examination should include palpation of the
• Delirium abdomen, and a rectal examination may be needed. Occasionally,
• Hallucinations an abdominal X-ray may be required if the history is unclear.11,12
• Myoclonus and seizures Constipation-specific instruments that assess the impact
• Hyperalgesia and allodynia and severity of the condition include the Patient Assessment
Cutaneous
of Constipation Quality of Life (PAC-QOL) and the Patient
Assessment of Constipation Symptoms (PAC-SYM) question-
• Pruritis
naires. The PAC-QOL and PAC-SYM instruments have been
• Sweating
shown to be reliable, valid, and responsive measures of constipa-
Respiratory/cardiac
tion and opioid-induced constipation, respectively,13,14 and pre-
• Respiratory depression
dominantly used in research setting.
• Non-cardiogenic pulmonary edema
All patients receiving opioids should be counseled about opi-
Autonomic oid-induced constipation and have an individualized bowel regi-
• Dry mouth men plan in place. This may include a combination of measures,
• Urinary retention as illustrated in Table 26.2. Therapeutic interventions include the
Endocrine administration of oral laxatives, suppositories, rectal enemas,
• Hypogonadism peripherally restricted opioid receptor antagonists, and manual
• Hypopituitarism disimpaction. Oral laxatives include bulk agents, osmotic agents,
Immune contact cathartics, lubricants, and prokinetic agents.
Lower doses of opioids, or weaker opioids such as codeine,
are just as likely to cause constipation, and clinicians should,
therefore, base laxative prescribing and titration on bowel func-
tion rather than opioid type and dose.15 There is no single cor-
sphincter of Oddi. 3,4 The inhibitory effect on colonic secretions
rect approach to laxative prescribing in palliative care. Although
also appears to involve complex mechanisms involving 5-HT2
there are various recommendations in the literature on initiat-
receptors, α2-adrenoreceptors, and noradrenaline release.7 These
ing patients on a bowel regimen, the most important point to
effects may result in a myriad of GI symptoms that include early
remember is that regimens should be individualized and titrated
satiety, nausea and emesis, abdominal bloating and cramping,
to response. One approach to constipation prevention and man-
and constipation (passage of hard stool, infrequent stool, strain-
agement is presented in Table 26.3.
ing during bowel movement, and incomplete evacuation). In
While there are no studies revealing the superiority of one
addition, opioid-induced gallbladder effects may result in biliary
approach over the other, the most common treatment, the
pain and delayed digestion. This constellation of opioid-induced
palliative care setting, is the use of a bowel stimulant such as
GI symptoms is referred to as opioid-induced bowel dysfunction, 3
senna, with or without a stool softener. Additionally, milk of
of which constipation is the most frequently reported and dis-
magnesium oral concentrate, polyethylene glycol, or lactulose
tressing symptom in patients taking opioids.8

Constipation
Constipation is the most common side effect of opioid use9 and
TABLE 26.2  Prevention and Management of Opioid-Induced
should be anticipated, monitored, and treated throughout the
Constipation
duration of opioid therapy. In the noncancer setting, approxi-
mately 40% of chronic opioid users for pain management develop Nonspecific measures
constipation.8 This frequency is higher in patients with advanced • Maintaining adequate hydration
illness such as cancer, where more than 90% of patients on opi- • Maintaining ambulatory status
oids develop constipation.9,10 Often dismissed as a trivial side • Diet rich in fruit and vegetables, fiber
effect, constipation can adversely impact patient’s quality of life • Availability of privacy during defecation
and make patients avoid or reduce the opioid dose, resulting in • Opioid sparing regimens
decreased analgesic benefits. Untreated and severe constipation Therapeutic measures
can lead to partial or complete bowel obstruction with attendant • Laxatives: e.g., sennosides, bisacodyl, poly
issues of severe morbidity. Unlike many of the other opioid side • Rectal suppositories, enemas
effects such as nausea and sedation that may occur on opioid ini- • Prokinetic agents: e.g., metoclopramide
tiation, constipation usually does not improve over time, and the • Peripherally restricted opioid receptor antagonists: e.g.,
majority of patients will require therapy. Frequently, several other methylnaltrexone (parenteral administration)
factors predisposing to constipation coexist in palliative care • Manual disimpaction
patients, such as autonomic failure, metabolic disorders (such as
Assessment and Management of Opioid Side Effects 237

TABLE 26.3  Suggested Approach for the Prevention and Management of Opioid-Induced Constipation and Nausea
Side Effect Prevention
Constipation Unless there are existing alterations
in bowel patterns such as bowel
obstruction or diarrhea, all patients
receiving opioids should be started
on laxative bowel regimen and
receive education for bowel
management.
2. Stimulant laxative ± stool
softener: e.g.: senna 8.6 plus
docusate 50 mg
4. Ensure adequate fluids, dietary
fiber and exercise if feasible.
5. Prune juice following by warm
beverage may be considered.
Nausea and Titrate opioid dose slowly and
vomiting steadily.
Make antiemetics available with
opioid prescription.
Metoclopramide 10 mg PO
For patients at high risk of nausea,
consider around the clock regimen
for 5 days and then change to PRN.
Management
1. Assess potential cause that can cause constipation (such as recent opioid dose increase,
use of other constipating medications, new bowel obstruction)
2. Increase senna and/or docusate tablets and add 1 or both of the following:
a. Milk of Magnesia oral concentrate: 10 mL PO every 2–4 times daily
b. Polyethylene glycol: 17 g in 8 ou beverage once daily
c. Lactulose 15–30 cc every 4–6 hours
3. If no response to above, do digital rectal examination (DRE) to rule out low impaction.
Continue above steps AND
• If impacted: disimpact manually if stool is soft. If not, soften with mineral oil fleets
enema before disimpaction. Follow up with milk of molasses enemas until clear with
no formed stools.
• Consider use of rescue analgesics before disimpaction.
• If not impacted on rectal examination, patient may still have higher level impaction,
and if history is appropriate consider abdominal imaging and/or administer milk of
molasses enema along with magnesium citrate 8 oz PO.
Please note: DRE, manual disimpaction, and enemas may be contraindicated in several
circumstances such as the presence of colitis, neutropenia, thrombocytopenia, or
coagulopathy.
Investigate other causes of nausea (e.g., constipation, bowel obstruction, chemotherapy, or
other medications) and treat per guideline.
Initiate around the clock antiemetic regimen.
Example Metoclopramide 5–10 mg PO, IV, or subcutaneously around the clock every 4–6
hours.
Add or increase non-opioid or adjuvant medications for additional pain relief so that opioid
dose can be reduced. If analgesia is satisfactory, reduce opioid dose by 25%. Consider opioid
rotation if nausea remains refractory

may be initiated and titrated until a large bowel movement
occurs. Bisacodyl suppository, a milk-and-molasses enema, or
a fleet enema may be required. Bulk-forming laxatives should
be avoided in patients unable to maintain adequate fluid intake.
Nondrug approaches, such as increasing fluid intake and
increasing physical activity, should be implemented if feasible
but are seldom sufficient by itself.
Occasionally, it may be required to switch opioids. There is pre-
liminary evidence to suggest that transdermal fentanyl may be
less constipating than morphine and oxymorphone.16,17 In a ret-
rospective study of laxative use, laxative doses needed were sig-
nificantly lower with methadone than with equianalgesic doses of
morphine or hydromorphone.18 Tapentadol, a mu-opioid recep-
tor agonist that also inhibits norepinephrine reuptake has been
shown to have a more favorable GI side effect profile than oxyco-
done in several studies.19–21
Two peripherally restricted opioid receptor antagonists, meth-
ylnaltrexone and alvimopan, do not cross the blood–brain barrier at
therapeutic doses and selectively counteract opioid-inducing con-
stipating effects without reversal of analgesia. Methylnaltrexone,
a quaternary ammonium derivative of naltrexone, has been inves-
tigated in several clinical studies, including two phase III studies
of patients with advanced illness.22–25 In the study by Thomas et
al.,24 133 patients with terminal illness (cancer or other end-stage
disease) on opioids for 2 or more weeks with opioid-induced consti-
pation despite the use of laxatives for 3 or more days received meth-
ylnaltrexone (at 0.15 mg/kg) or placebo subcutaneously (s.c.) every
other day for 2 weeks. Methylnaltrexone was found to be superior
(P < .0001) to placebo on the primary outcomes of laxation (defeca-
tion) within 4 hours after the first dose (48 vs 16%), and laxation
within 4 hours after two or more of the first four doses (52 vs 9%).
For those who responded to methylnaltrexone, the median time
to laxation was 30 minutes. Methylnaltrexone was well tolerated,
with transient abdominal cramping and flatulence being the most
common adverse events. Methylnaltrexone for s.c. use has been
approved by regulatory agencies in the United States, Canada, and
the European Union for the management of opioid-induced consti-
pation in patients with late-stage, advanced illness who are receiv-
ing chronic opioid therapy.26 The usual dosing schedule is one dose
every other day, as needed, but no more frequently than one dose in
a 24-hour period. The recommended dose of methylnaltrexone is
8 mg for patients weighing 38–62 kg or 12 mg for patients weigh-
ing 62–114 kg. Patients whose weight falls outside of these ranges
should be dosed at 0.15 mg/kg.
238
Alvimopan is an orally administered peripherally restricted
mu-opioid receptor antagonist approved for short-term use
in hospitalized patients for the management of postoperative
ileus in patients undergoing bowel resection. It is not approved
for the management of opioid-induced constipation. While
several studies in chronic noncancer pain patients have sug-
gested benefit, 27,28 a recent double-blind, placebo-controlled
trial conducted over 12 weeks in 485 patients with noncancer
pain found no statistically significant difference in the propor-
tion of patients with spontaneous bowel movements (primary
outcome) between the three groups: alvimopan 0.5 mg once
daily (63%), alvimopan 0.5 mg twice daily (63%), or placebo
(56%, P > .05). 29
Naloxone, a peripherally acting opioid antagonist with low
systemic bioavailability (<3%) following oral administration,
acts almost exclusively on opioid receptors in the GI tract.4
Combining opioids with naloxone is emerging as a promising
approach for managing opioid-induced constipation. Several
studies in the noncancer pain population, including three ran-
domized, placebo-controlled phase III trials, 30–35 have dem-
onstrated beneficial effects of combined oxycodone–naloxone
tablets as compared to oxycodone alone. In cancer patients, a
recent randomized, double-blind, active-controlled, double-
dummy, parallel-group study36 of 185 patients was randomized
to receive up to 120 mg/day of combined oxycodone–naloxone
PRN or oxycodone pro re nata (PRN) alone over 4 weeks. After
4 weeks, the combination group provided superior bowel func-
tion (as measured by bowel function index) and 20% lower
laxative intake, as compared to oxycodone alone, without com-
promising analgesic efficacy or safety.
Tegaserod is a promotility agent, which acts as an agonist at
serotonin type 4 (5-HT4) receptors in the GI tract. It normalizes
impaired motility in the GI tract, inhibits visceral sensitivity,
and stimulates intestinal secretion. Tegaserod is approved by the
Food and Drug Administration for short-term treatment only of
constipation-predominant irritable bowel syndrome in patients
below 65 years of age. Its use in palliative care patients has not
been investigated.
Nausea
The exact prevalence of opioid-induced nausea is not known but
estimated to be approximately 25%. 37 Nausea with or without
vomiting usually occurs when patients are initiated on opioids for
the first time or when the dose is substantially increased. In most
patients, this responds well to antiemetic medication and disap-
pears spontaneously within 3 or 4 days. 38 Occasionally, patients
experience chronic and severe nausea; this may be more likely in
those receiving higher doses of opioids, or when there are other
contributing etiologies for nausea.
Opioids cause nausea by a number of mechanisms, including
stimulation of the chemoreceptor trigger zone and vomiting
center, and increasing the sensitivity of the vestibular cen-
ter. 39 In addition, opioids reduce GI motility causing gastro-
paresis and constipation that may also contribute to nausea.
Chronic nausea has been associated with the accumulation of
active morphine metabolites such as morphine-6-glucuronide,
which can occur with higher doses of opioids or in the pres-
ence of renal insufficiency.40 Although not as well defined as
the other neuronal inputs, the cortex has direct input into the
vomiting center through several types of neuroreceptors. A
Textbook of Palliative Medicine and Supportive Care
patient may remember unpleasant feelings of nausea associ-
ated with past opioid therapy. When presented with the sight,
smell, or even anticipation of taking an opioid again, a strong
nausea reflex may result.
Assessment and management of
opioid-induced nausea
As there are many potential causes of nausea and vomiting in
patients receiving palliative care, it is important to search for and
treat potential contributing factors in addition to opioid use. It
is recommended that antiemetic medication be available to all
patients who commence opioid therapy or when there is a sig-
nificant dose increase. A number of different antiemetic medica-
tions can be used to effectively to treat opioid-induced nausea and
vomiting in palliative care patients, such as dopamine antagonists
metoclopramide and haloperidol.41–43
As a prokinetic agent, metoclopramide may also help in symp-
toms of early satiety and constipation. In the cases of persis-
tent or refractory nausea, opioid rotation should be considered.
Persistent nausea should always trigger a search for coexisting
contributors such as constipation, metabolic alterations (hyper-
calcemia), other emetogenic therapies, and brain metastasis. For
the management of opioid-induced nausea, a recent systematic
review concluded that there is limited evidence to prioritize
between symptomatic treatment and opioid adjustments (opioid
rotation or route change) in cancer patients.44
Sedation
Sedation is common following opioid initiation or significant
dose increase and usually resolves after a few days. Providing
reassurance to the patient/family is usually sufficient. However,
in the presence of comorbidities such as dementia, metabolic
encephalopathy, brain metastases, or other sedating medications,
sedation is more likely to persist. Management should involve
the treatment of reversible causes of sedation and discontinua-
tion of other sedating medications. If pain is well controlled, the
opioid dose may be reduced. Opioid rotation and/or addition of
a psychostimulant may be appropriate if sedation is refractory.
Excessive sedation may also be a feature of opioid-induced neuro-
toxicity (OIN), discussed later in greater detail. Psychostimulants
may be helpful in patients who have persistent sedation and allow
for continued use of opioids and even opioid dose increase when
sedation is a dose-limiting factor.45–50 Psychostimulants should
not be prescribed in patients with known psychiatric disorders,
or if they are exhibiting delirium, hallucinations, or paranoid
behaviors. They are also relatively contraindicated with a history
of substance abuse or hypertension. The best type and dose of
psychostimulant for the treatment of opioid-induced sedation
has not been determined. Methylphenidate has been the most
extensively studied of the group for this indication and is usually
commenced at a dose of 5 mg twice daily. A beneficial effect is
usually evident within 2 days of treatment, and the dose can be
increased to 10 mg twice daily. Morning and noon administra-
tion are recommended in an attempt to minimize potential sleep
disturbance. Donepezil, a cholinesterase inhibitor, was found in
an open-label study to reduce sedation and fatigue with cancer
pain and opioid-induced sedation.49 A retrospective study of 40
patients receiving opioids (mainly for cancer pain) also found a
reduction in sedation with donepezil treatment in majority (73%)
patients50; however, tolerance to donepezil was reported to occur
in approximately 116 patients.
Assessment and Management of Opioid Side Effects
Driving and opioids
Opioids have the potential to interfere with driving ability by
impairing psychomotor skills and/or cognitive function. An evi-
dence-based review of driving-related skills in opioid-dependent/
tolerant patients concluded that the majority of studies found
no evidence of impaired driving-related skills. 51 However, the
review grouped three different populations of patients on opioids
together: the former addicts on maintenance programs, patients
with chronic nonmalignant pain, and patients with chronic can-
cer pain. The majority of studies reviewed were carried out in the
former population, and there was some lack of consistency in the
findings of studies in cancer patients.
In palliative care populations, the situation is more com-
plicated. The underlying disease as well as other medications
and treatments may contribute to the impairment of skills that
are considered to be important for driving. A number of stud-
ies looking at cognitive function and psychomotor abilities
have been carried out in cancer patients receiving opioids. 52–56
In some studies, when compared with healthy controls, can-
cer patients receiving opioids have been found to have delayed
continuous reaction times. 54,56 However, in studies comparing
cancer patients receiving stable opioid doses with those not
receiving opioids, there appears to be some evidence that both
populations are similar in terms of psychomotor and cognitive
skills. 52,53 When both these groups were compared to healthy
controls, some deficits were found. 52 A study looking at the
influence of opioid use, pain, and performance status on neu-
rophysiological function found that both pain and performance
status appeared to affect neurophysiological tests; long-term
use of opioids did not in itself appear to negatively affect these
tests. 55 Controlled studies of actual driving ability in cancer
patients on opioids have not been carried out. Further research
is needed in this area.
In general, cancer patients receiving opioids should be advised
that their ability to drive may be compromised and that they
should not drive if they feel drowsy or sedated. In addition,
patients should be advised to avoid driving for 4–5 days after ini-
tiation of opioid medication or after a dose increase. They should
also be informed that other medications used to treat symptoms
can cause sedation and to check with their physician before driv-
ing if in doubt. Advising a patient to do a driving test may be
appropriate if there is concern about a patient’s driving ability
and they are anxious to continue driving.
Opioid-induced neurotoxicity
OIN refers to a constellation of neuropsychiatric symptoms
such as excessive sedation, cognitive impairment, delirium,
hallucinations, myoclonus, seizures, and hyperalgesia. 57–59 In
some situations, these symptoms may be indistinguishable
from those of disease progression or inadequate analgesic con-
trol and lead to further escalation in opioid dose, resulting in
a vicious cycle that may further worsen OIN. If any of these
symptoms are present in a patient taking opioids, OIN should
be suspected. Risk factors for OIN are presented in Table 26.4.
Terminally ill patients are especially at risk for OIN due to
the high prevalence of cognitive decline due to their disease,
use of psychoactive medication, dehydration, and renal and
metabolic impairments in these patients. Individual features
of OIN are discussed further. These can be present alone or in
any combination.
239
TABLE 26.4  Risk Factors for Opioid-Induced Neurotoxicity
• Large doses of opioids
• Extended period of treatment with opioids
• Rapid opioid dose escalation
• Dehydration
• Renal failure
• Underlying delirium or dementia
• Infection
• Concomitant use of other psychoactive drugs (e.g., benzodiazepines)
• Older age
Cognitive impairment and delirium
Impaired cognition and delirium is frequently present in termi-
nally ill patients, is usually progressive, and is a cause of immense
distress to patients and families.60–64 Clinical features of delirium
are presented in Table 26.5. Although restlessness and agitation
is the most commonly recognized feature of delirium, it is not
essential to its diagnosis. The two essential components of delir-
ium diagnosis are disordered attention (arousal) and cognition,
in contrast to dementia that does not have alteration in attention
or arousal.
Delirium has multiple contributing etiologies such as end-
organ failure, dehydration, and the accumulation of toxic opioid
metabolites.60,65,66 Opioid use is a major contributor to delirium
in frail terminally ill patients who may have renal failure or
impaired fluid intake.66,67 Nonagitated or hypoactive delirium is
often missed by health-care professionals when no objective test-
ing is performed.68,69
Hallucinations
In OIN, hallucinations are typically visual in nature, although
tactile hallucinations are not uncommon. Auditory hallucina-
tions may also occur. The overall prevalence of hallucinations in
the palliative care setting is unknown. The prevalence of visual
hallucinations has been reported as 1%,70 while more recent work
has reported the figure to be nearer 50%.71 Hallucinations are
commonly associated with cognitive impairment but are occa-
sionally seen in patients who have not experienced cognitive
impairment.72
Myoclonus and seizures
Myoclonus is a sudden, shock-like involuntary movement
or twitching caused by active muscular contractions, which
may involve a whole muscle or may be limited to a small num-
ber of muscle fibers.73 It has been postulated that generalized
TABLE 26.5  Clinical Features of Delirium
• Disorientation to time, place, or person
• Memory impairment
• Reduced attention, easy distractibility
• Altered arousal
• Increased or decreased psychomotor activity
• Restlessness, anxiety, irritability
• Disturbance of sleep–wake cycle
• Affective symptoms (sadness, anger, emotional lability, euphoria)
• Altered perceptions (misperceptions, delusions, hallucinations)
• Disorganized thinking
• Myoclonus
• Acute onset and fluctuation during the course of the day
240
myoclonus is a type of tonic-clonic seizure.74 Myoclonus is one
of the more frequently observed features of OIN, and if present,
there should be a high index of suspicion for the diagnosis. It
has been described following administration of most commonly
used opioids but is more common with opioids that have active
metabolites such as morphine,75,76 hydromorphone,77,78 and
meperidine.79,80 However, myoclonus has also been described
with fentanyl74,75 and methadone. It has been proposed that
myoclonus results from accumulation of neurotoxic opioid
metabolites.77 Myoclonus may occur more commonly in patients
who have impaired renal functions.
Hyperalgesia and allodynia
Abnormally heightened pain sensations can occur with the use
of opioids. These are characterized by a lowering of the pain
threshold (hyperalgesia) and pain elicited by normally innocu-
ous stimulation (allodynia). 81 Hyperalgesia may present as an
exaggerated nociceptive response to a painful stimulus or as
a worsening of the underlying pain syndrome, termed para-
doxical pain. 82 This paradoxical pain may be misinterpreted
by clinicians and the opioid dose increased further, result-
ing in worsening OIN. Opioid-induced hyperalgesia and allo-
dynia should be suspected when pain increases despite opioid
escalation, presence of pain all over, and increased sensitivity
to touch. Mechanisms involved include increase in excitatory
nonanalgesic opioid metabolites and N-methyl-d-aspartate
(NMDA) activation. 81,83
Mechanism of opioid-induced neurotoxicity
The precise mechanism of OIN is not fully understood, but likely
to involve multiple mechanisms. The accumulation of neuro-
excitatory opioid metabolites has been postulated to be the main
underlying cause of the opioid-induced toxicity. These effects are
not mediated via the mu-receptor, and therefore, mu-receptor
antagonists are not usually useful unless there is excessive seda-
tion from accumulation of the parent drug. Another important
proposed mechanism is CNS sensitization due to opioid acti-
vation of the NMDA receptors in the CNS that can initiate an
FIGURE 26.1  Potential co for induced neurotoxicity/delirium in terminal illness.
Textbook of Palliative Medicine and Supportive Care
imbalance between the excitatory and inhibitory neurons, result-
ing in aberrant nerve activity.84,85
Morphine, hydromorphone, and fentanyl have all been found
to cause agitation, myoclonus, hyperalgesia, and tonic-clonic
seizures in animals when administered systemically or intrathe-
cally. 85,86 Morphine followed by hydromorphine have received
the most scrutiny. Both are metabolized to active metabolites
that are devoid of analgesic properties, morphine-3-glucuro-
nide (M3G) and hydromorphone-3-glucuronide, respectively,
which have been postulated to be responsible for some of the
neuro-excitatory effects. 87,88 These metabolites are usually elim-
inated by the kidneys and usually do not accumulate to pro-
duce toxicity. However, in the presence of renal impairment, or
rapidly escalating high doses, these can accumulate and result
in manifestations of OIN such as myoclonus, hallucinations,
allodynia, and hyperalgesia. However, there is also conflicting
reports where M3G failed to produce excitatory and antianal-
gesic effects in rats. 89 In a phase I study of healthy volunteers,
M3G did not elicit any clinical effects when given alone.90 The
possibility of interindividual variation in metabolism of opioids
and the impact of renal functioning on metabolite elimination
are likely some of the many factors responsible for conflicting
findings. Further research is required to gain a better under-
standing of the pathophysiology of OIN.
Assessment of OIN
Numerous risk factors predispose patients to the development
of OIN, which are summarized in Table 26.4 and Figure 26.1. A
detailed medication history should include the dose/duration of
opioid therapy, the onset of OIN features in relation to opioid ini-
tiation or dose increase, the use of psychoactive medications (e.g.,
benzodiazepines, tricyclic antidepressants) or drugs that may
impair renal function. Examination should look for signs of infec-
tion, dehydration, and jerking movements that should be noted.
Cognitive function should be assessed as a matter of routine. It is
important to enquire specifically about hallucinations. A num-
ber of tools exist to assess cognitive function.62 Although no gold
standard tool has been identified, the mini-mental state exami-
nation91 has been widely used in this population.92 Other tools
Assessment and Management of Opioid Side Effects
TABLE 26.6 Key Approaches to Management of Opioid-
Induced Neurotoxicity
• Maintaining adequate hydration (oral or parenteral)
• Treat reversible causes as clinically appropriate for the setting (such
as antibiotics for infection, bisphosphonates for hypercalcemia)
• Opioid rotation. Opioid reduction may be considered if the patient
reports no pain
• Use of adjuvant analgesics (e.g., NSAIDs or anticonvulsants) if
appropriate
• Discontinuation of psychoactive or sedating medications
• Symptomatic treatment (e.g., haloperidol for hallucinations or
agitation)
• Reassurance and explanation
include the memorial delirium assessment scale (MDAS)93 and
the delirium rating scale (DRS).94 Delirium assessment is covered
in more detail in Chapter 70. If OIN is suspected and appropriate
for the clinical circumstance, blood should be sent for biochemi-
cal and hematological analyses to exclude for infection, renal fail-
ure, or hypercalcemia.
Management of OIN
OIN is frequently managed by correction of identifiable and
reversible factors contributing to OIN, hydration, opioid rota-
tion, and symptomatic medications directed toward controlling
patient distress (Table 26.6).
Dose reduction or discontinuation of opioids may usually not
be an option for the management of OIN due to the presence of
uncontrolled pain or dyspnea. Opioid rotation, the term used
for substituting one opioid for another, is usually preferred and
allows for the reduction of neurotoxicity symptoms while simul-
taneously retaining or improving analgesia.1,58,60,91,92 However,
opioid rotation has not been systematically studied in random-
ized controlled trials, and this evidence is mainly from observa-
tional or uncontrolled trials.93
For the management of specific OIN symptoms, haloperidol
is considered first-line therapy for patients who have agitated
delirium because of its efficacy and low incidence of cardiovascu-
lar and anticholinergic side effects. Chlorpromazine can be used
if sedation is required, although hypotension may be a concern.
Benzodiazepines are best reserved for refractory situations, as in
some patients, it may paradoxically worsen delirium.
Preliminary studies conducted in advanced cancer suggest
that hydration intervention may help in delirium prevention, or
its reversal when delirium is attributed to dehydration or opioid
toxicities.94–96 By switching opioids and providing hydration, the
parent opioid and its toxic metabolites are allowed to be excreted.
Once OIN has been recognized and treated, steps must be taken
to reduce the risk of further episodes.
Respiratory depression
Respiratory depression is a potentially fatal side effect of opi-
oids. It primarily occurs in opioid-naïve patients who are
administered high doses of opioid. Fortunately, tolerance to
respiratory depressing opioid effects develops within days of
opioid use and is extremely rare in patients on chronic opioids.
The majority of studies have been conducted in the postopera-
tive setting, where the incidence of clinically recognized and
relevant respiratory depression is about 1–2% in postoperative
patients receiving opioids.97–99 However, close monitoring in
241
patients who are at high risk of respiratory depression is advised
such as patients with morbid obesity, sleep apnea, advanced age,
and those with multiple comorbidities.100 In rare circumstances,
respiratory depression has been observed in opioid-tolerant
patients such as when there is sudden reduction of opioid
requirements following a successful neurolytic block resulting
in reduced pain,101 or following opioid rotation to methadone
where the equianalgesic conversion ratio may not be certain,102
or in the presence of renal failure due to the buildup of mor-
phine metabolites.103 Therefore, it is important to revaluate opi-
oid dosing requirements in the palliative care patient where any
of these scenarios may occur.
The management of respiratory depression involves reducing
or omitting the next regular opioid dose, or stopping an infu-
sion temporarily, to allow plasma levels to reduce with a plan
to recommence the infusion at a lower dose. Naloxone, a non-
selective competitive opioid antagonist,104 should be adminis-
tered in patients with symptomatic respiratory depression in a
diluted solution, and in small increments to avoid symptoms of
opioid withdrawal. It is administered parenterally due to its low
bioavailability with oral administration. Opioid-induced seda-
tion in the absence of respiratory depression is not an indica-
tion of using naloxone. Naloxone in these patients can result
in opioid withdrawal syndrome and severe pain.105 Naloxone
is indicated only if there is significant respiratory depression,
that is, a respiratory rate of less than 8 breaths/minute, and
if the patient is barely arousable and/or cyanosed. Table 26.7
summarizes the use of naloxone in opioid-induced respiratory
depression. Naloxone has a shorter half-life than most opioids;
therefore, it is important to observe patients carefully over a
period of hours. Additional administration of naloxone may be
required if the respiratory rate falls or clinical status changes.
One must take care to distinguish opioid-induced respiratory
depression from respiratory changes at the very end of life,
which are to be expected and need no intervention. Research
into new treatments/and or approaches to prevent opioid respi-
ratory depression without affecting analgesia are ongoing with
agents such as serotonin agonists, ampakines, and the antibiotic
minocycline.100
TABLE 26.7 Management of Opioid-Induced Respiratory
Depression
Management of opioid-induced respiratory depression
1. Discontinue opioid (e.g., stop opioid infusion if ongoing)
2. Provide supplemental oxygen
3. Dilute 1 mL ampoule of naloxone (e.g., 0.4 mg/mL) with 9 mL of
saline.*
4. Give 0.5–1 mL of above-diluted mixture either IV or SC and
repeat**every 1–2 minutes until the 5. respiratory rate increases to
above 8–10/minutes
5. The aim is for partial opioid reversal but not a complete reversal
6. Additional small amounts can be given at appropriate intervals to
maintain an adequate respiratory rate
7. If no change with naloxone, there may be other causes for respiratory
depression
* Giving the complete ampoule will result in an acute withdrawal from the opioid
and cause immediate reversal of analgesia.
** Repeat doses are required due to the short half-live of naloxone.
242
Opioid-induced bladder dysfunction
Opioid-induced bladder dysfunction (difficulty voiding or urinary
retention) is recognized as a side effect of opioid therapy but has
not been well researched in the palliative care setting. Two stud-
ies conducted in the postoperative setting reported prevalence
estimates of approximately 4% for urinary retention requiring
catheterization and 18% of urinary retention.106,107 The mecha-
nism of urinary retention is still not completely understood but is
likely due to opioid-induced decreased detrusor muscle tone and
force of contraction, decreased sensation of bladder fullness and
urge to void, and inhibition of the voiding reflex. These effects
likely involve both central and peripheral opioid effects,108–110 and
shown to be reversed by naloxone.111 A more recent study demon-
strated reversal of opioid-induced bladder changes by the periph-
erally restricted opioid antagonist methylnaltrexone.112
Pruritus and allergic reactions
Hypersensitivity reactions to opioids are rare. Patients may
report being “allergic” to opioids, and it is important to distin-
guish between “true’’ immune-mediated reactions (rare) and
reactions that mimic an immune allergic response (nonallergic or
pseudoallergy). Patients often consider side effects (e.g., nausea,
sedation) to be an allergy; hence, it is important to check what
problems a specific opioid has caused for an individual patient.
The prevalence, severity, and pathophysiology of opioid-
induced pruritus depend on the type of opioid, dosage, and route
of administration. Pruritus (itching) occurs in 2–10% of patients
treated with systemic opioids, is usually mild, and self-limited.
The frequency of pruritus increases with increasing opioid dos-
ages.113 The likely mechanism involves direct mast cell degranu-
lation, with histamine release causing local itching and a typical
weal and flare response. While all opioids may cause direct his-
tamine release, morphine, codeine, and meperidine are more
potent offenders than others. Histamine release also may be
associated with vasodilation, which is more common in volume-
depleted patients. This is not a contraindication to opioid use, and
an alternative opioid may be well tolerated. Antihistaminics may
be added for use on as needed basis.
Neuraxially administered opioids, especially morphine, have
higher pruritus risk and appear not to be mediated via histamine,
but via mu-opioid receptors.114–118 Pruritus invoked by intrathe-
cal morphine is of longer duration and is difficult to treat.119
Treatment options remain a challenge, and much of the research
has emerged from surgical patients who received neuraxial opi-
oids and have looked at agents as prophylaxis rather than treat-
ment.116 Naloxone and naltrexone, both mu-opioid receptor
antagonists, have demonstrated antipruritic effects, but their
usage is limited by decreased analgesic effects.119–121 Nalbuphine,
a mixed opioid-receptor agonist–antagonist, was shown to be
effective without compromising analgesia, but its usage is lim-
ited due to its sedating effects.122–124 Serotonin (5-HT3) receptor
antagonists (ondansetron, dolasetron) have demonstrated mixed
results with respect to their effectiveness in pruritus manage-
ment, with some studies suggesting benefit,125–128 and others that
do not.129–131 Dopamine D2-receptor agonists, droperidol and
alizapride, have demonstrated some benefit in the management
of pruritus prophylaxis.132,133
Type 1 hypersensitivity reactions are IgE mediated, resulting
in the immediate systemic release of potent mediators that result
in hypotension, bronchospasm, angioedema, hives, and vascular
Textbook of Palliative Medicine and Supportive Care
collapse. Fortunately, these events are extremely rare with opioid
use. Emergent management with epinephrine, steroids, and his-
tamine blockers is instituted. Patients with prior IgE-mediated
allergic reaction should not be rechallenged with the offending
opioid. For both these immune-mediated reactions, an allergist
may be consulted to identify appropriate alternatives. Opioids
from an alternative chemical class may also be considered.
Opioid-induced endocrine
and immune effects
Evidence is emerging that opioids have potential effects on the
functioning of endocrine and immune systems. The most com-
monly reported effects are suppression of gonadal function and
immune suppression.
Opioid effects on gonadal hormones and sexual function: A
growing number of studies conducted in the settings of opioid
addiction (e.g., heroin abuse), opioid addiction treatment (such
as methadone maintenance programs), and the use of opioids for
the management of chronic noncancer pain have demonstrated
that opioids suppress gonadal hormone secretion in men and
women.134–145 Potential symptoms of opioid-induced hypogonad-
ism include loss of libido, infertility, fatigue, depression, anxiety,
loss of muscle strength/mass, osteoporosis, and compression
fractures, in both men and women; impotence in men; and men-
strual irregularities and galactorrhea in women.
Several of these studies suggest that the effect of opioids is
rapid, dose dependent, and reversible on discontinuation of
opioids. In the study by Mendelson et al., total testosterone lev-
els declined within 7–9 hours of single oral dose of 30–80 mg
of methadone, suggesting a rapid decline in testosterone levels
within hours of opioid ingestion.137 Among subjects with heroin
abuse, one study demonstrated normalization of testosterone
levels 1 month after cessation of heroin use.139 Another study
showed a dose–response effect, in that subjects on lower doses of
methadone (10–60 mg/day) had no evidence of testosterone level
suppression, whereas patients on higher doses (80–150 mg/day)
did.137 One case series described amenorrhea and galactorrhea in
female heroin addicts.140
In men with nonmalignant chronic pain, a case–controlled
observational study found chronic opioid therapy to be associ-
ated with a dose-dependent decline in total testosterone levels in
74% of opioid users.145 In this study, of the men who reported nor-
mal erectile function before opioid use, 87% of men who reported
normal erectile function prior to opioid initiation reported either
severe erectile dysfunction or diminished libido after starting
opioids.
In women with nonmalignant pain treated with sustained-
action oral or transdermal opioids,146 low levels of FSH and LH,
estradiol, and adrenal androgens (testosterone and dehydroepi-
androsterone sulfate) production have been demonstrated.
A recent prospective study conducted in men and women
attending a pain clinic for chronic nonmalignant pain demon-
strated males to have lower free testosterone (FT) and prolactin
levels in opioid users, and in women lower FT. In both groups,
there was no relationship between symptoms of sexual dysfunc-
tion and abnormal hormone levels or opioid use.147
A single preliminary study conducted in men with opioid
addiction has suggested that buprenorphine may not have the
same gonadal suppressive effects as methadone.141 In this study,
those treated with buprenorphine (n = 17) had significantly higher
Assessment and Management of Opioid Side Effects
testosterone and a significantly lower frequency of sexual dys-
function compared with patients treated with methadone (n = 37)
and did not differ from healthy controls (n = 51).
There are no prospective studies that have evaluated the effects
of opioids on gonadal hormones or sexual functions in the pallia-
tive care patients. Among male cancer survivors without evidence
of disease, and on opioids for chronic pain, a cross-sectional study
(n = 20) demonstrated abnormally low testosterone levels.148 In a
follow-up case–control study, 18 (90%) of 20 patients who were
taking more than 200 mg of morphine daily or equivalent opi-
oids for chronic pain exhibited abnormally low testosterone lev-
els, compared with 40% in the matched control group (n = 20).149
Median testosterone and luteinizing hormone levels were signifi-
cantly lower in the opioid group and were associated with sexual
dysfunction, anxiety, depression, and overall decreased QoL.
Among patients with advanced cancer, a retrospective chart
review demonstrated that chronic use of even lower doses of
opioids (morphine 30 mg or more) was associated with low tes-
tosterone levels in men.150 Prospective studies are needed to bet-
ter characterize the effect of opioids on gonadal hormones and
sexual function in cancer patients.
Opioid effects on immune function
In animal experiments and opioid addicts, chronic opioid use has
been shown to induce immune suppression and increase the rate
of infection.151 In vitro studies demonstrate alterations in several
immune parameters, induced by the direct effects of morphine
and other opioids on immune cells. These include impaired che-
motaxis, phagocytosis, and intracellular killing of neutrophils
and monocytes, reduced effector cell responses in B and T cells,
as well as increased apoptosis in lymphocytes and phagocytic
cells. Currently, the mechanisms that modulate these changes are
not well understood. It has been suggested that opioid interaction
with opioid receptors in the CNS and endocrine axis (HPA and
sympathetic nervous system), as well as its direct interaction with
opioid receptors on immune cells are likely involved. The immu-
nomodulatory effects of morphine are attenuated significantly in
mu-opioid receptor knockout mice.
Current evidence suggests that not all opioids have the same
immunological effects.152 For instance, tramadol and buprenor-
phine do not appear to share the immunosuppressive effects dem-
onstrated by morphine and fentanyl. Tramadol rather has been
shown to have an immune-enhancing effect on several immune
parameters such as NK cell activity, lymphoproliferation, and
cytokine production when administered to healthy animals.153
When tramadol was compared to morphine in experimental mod-
els of neuropathic pain154 and surgical-induced suppression of NK
activity,155 tramadol preserve NK cell activity, while morphine sup-
pressed it. In rat experiments, morphine but not buprenorphine
has been shown to suppress NK cell activity and T-cell and macro-
phage functions.156,157 In a model of surgery stress, buprenorphine
was able to prevent all the biochemical and immune alterations
usually associated with pain.158 In another experiment, fentanyl,
but not buprenorphine, was shown to suppress NK activity, lym-
phoproliferation, and cytokine production.159
Several studies conducted in tumor experimental models
suggest opioids such as morphine and fentanyl influence tumor
spread by their effects on immune function, while these have not
been shown with tramadol and buprenorphine.152 Fentanyl, for
instance, at doses shown to suppress NK cell activity, was shown
to increase metastatic disease in MADB106 mammary adeno-
carcinoma tumor model.160 These effects were more pronounced
243
when surgery was also performed, suggesting an additive effect on
immunosuppression.158,160 In contrast, tramadol and buprenor-
phine were not associated with these effects. The relevance of
these findings in the palliative care population is unclear, and
further research is warranted in this area.
Physiological and psychological
responses to opioid use
Tolerance and physical dependence are expected physiological
responses to chronic opioid use. Tolerance is characterized by
decreasing opioid analgesic effects, requiring increased opioid
doses to achieve the same degree of pain relief. In terminally ill
patients, it may not be possible to know whether the develop-
ment of tolerance, disease progression, or both is contributing
to higher opioid requirement. Tolerance also develops to several
opioid side effects, including nausea and respiratory depression,
but not to constipation. Physical dependence manifests as devel-
opment of withdrawal symptoms on abrupt opioid cessation, such
as increased pain, agitation, insomnia, diarrhea, sweating, and
palpitations. Physical dependence is frequently and incorrectly
thought of as addiction. Withdrawal symptoms can be prevented
by gradually tapering opioids.
In contrast to the aforementioned physiological responses,
addiction and pseudo-addiction are psychological and behav-
ioral responses toward opioids that patients may or may not
develop. Addiction is compulsive use of drugs for nonmedical
reasons, characterized by a craving for mood-altering drug
effects, not pain relief. Suggestive aberrant behaviors include
forgery of prescriptions, denial of drug use, stealing opioids
from others, selling/buying opioids on the street, and using
prescribed drugs to get “high.” Addiction is uncommon in the
chronic pain, and postoperative and cancer pain settings,161–163
and opioids should not be withheld for fear that a patient will
become addicted. If terminally ill patients request a strong
analgesic, it is likely they have inadequate pain control. Pseudo-
addiction is an “iatrogenic” phenomenon resulting from inad-
equate pain management by clinicians. Patient’s behavior is
geared toward obtaining pain relief, such as requesting stronger
pain medications, asking several providers for opioids, and fre-
quently visiting the emergency center for pain relief. The clini-
cian’s response should always be to reassess the pain, reassure
the patient, and treat pain adequately.
Opioids are potential drugs of addiction. Psychological depen-
dence is a key feature of addiction and involves compulsive
behavior to obtain and take a drug for its psychological effects.
Hence, psychological dependence involves substance misuse or
abuse. Fear of addiction is common in patients and physicians
and can lead to underuse of opioids in palliative care populations.
Opiophobia should not prevent opioids being prescribed where
they are needed. In clinical practice, psychological dependence
and opioid abuse are rare in patients who do not have a preexist-
ing history of drug or alcohol abuse.162,164 Physical dependence is
often confused with psychological dependence. However, physical
dependence (the appearance of withdrawal symptoms and signs
when a drug is abruptly discontinued) is common when patients
have been taking opioids for a period of time; this does not mean
that a patient is addicted to an opioid. Abrupt discontinuation or
dramatic reductions in opioid doses should be avoided. If a major
dose reduction or discontinuation is desired, doses should be
gradually reduced over several days. The management of pain in
patients with drug and alcohol dependence is discussed in detail
in Chapter 55.
244
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120. Okutomi T, Saito M, Mochizuki J et al. Prophylactic epidural nalox-
one reduces the incidence and severity of neuraxial fentanyl-induced
pruritus during labour analgesia in primiparous parturients. Can J
Anaesth 2003;50:961–962.
121. Lockington PF, Fa’aea P. Subcutaneous naloxone for the prevention of
intrathecal morphine induced pruritus in elective Caesarean delivery.
Anaesthesia 2007;62:672–676.
122. Charuluxananan S, Kyokong O, Somboonviboon W et al. Nalbuphine
versus propofol for treatment of intrathecal morphine-induced pruri-
tus after cesarean delivery. Anesth Analg 2001;93:162–165.
123. Charuluxananan S, Kyokong O, Somboonviboon W et al. Nalbuphine
versus ondansetron for prevention of intrathecal morphine-induced
pruritus after cesarean delivery. Anesth Analg 2003;96:1789–1793,
table of contents.
124. Kendrick WD, Woods AM, Daly MY et al. Naloxone versus nalbu-
phine infusion for prophylaxis of epidural morphine-induced pruritus.
Anesth Analg 1996;82:641–647.
125. Yeh HM, Chen LK, Lin CJ et al. Prophylactic intravenous ondan-
setron reduces the incidence of intrathecal morphine-induced
pruritus in patients undergoing cesarean delivery. Anesth Analg
2000;91:172–175.
126. Borgeat A, Stirnemann HR. Ondansetron is effective to treat spinal or
epidural morphine-induced pruritus. Anesthesiology 1999;90:432–436.
127. Iatrou CA, Dragoumanis CK, Vogiatzaki TD et al. Prophylactic intra-
venous ondansetron and dolasetron in intrathecal morphine-induced
pruritus: a randomized, double-blinded, placebo-controlled study.
Anesth Analg 2005;101:1516–1520.
128. Charuluxananan S, Somboonviboon W, Kyokong O et al. Ondansetron
for treatment of intrathecal morphine-induced pruritus after cesarean
delivery. Reg Anesth Pain Med 2000;25:535–539.
129. Korhonen AM, Valanne JV, Jokela RM et al. Ondansetron does not
prevent pruritus induced by low-dose intrathecal fentanyl. Acta
Anaesthesiol Scand 2003;47:1292–1297.
130. Wells J, Paech MJ, Evans SF. Intrathecal fentanyl-induced pruritus dur-
ing labour: the effect of prophylactic ondansetron. Int J Obstet Anesth
2004;13:35–39.
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131. Yazigi A, Chalhoub V, Madi-Jebara S et al. Prophylactic ondansetron is
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Anesth 2002;14:183–186.
132. Horta ML, Ramos L, Goncalves ZR. The inhibition of epidural
morphineinduced pruritus by epidural droperidol. Anesth Analg
2000;90:638–641.
133. Naji P, Farschtschian M, Wilder-Smith OH et al. Epidural droperidol
and morphine for postoperative pain. Anesth Analg 1990;70:583–588.
134. Facchinetti F, Volpe A, Farci G et al. Hypothalamus-pituitary-adrenal
axis of heroin addicts. Drug Alcohol Depend 1985;15:361–366.
135. Khan C, Malik SA, Iqbal MA. Testosterone suppression by heroin. J
Pak Med Assoc 1990;40:172–173.
136. Malik SA, Khan C, Jabbar A et al. Heroin addiction and sex hormones
in males. J Pak Med Assoc 1992;42:210–212.
137. Mendelson JH, Mendelson JE, Patch VD. Plasma testosterone levels
in heroin addiction and during methadone maintenance. J Pharmacol
Exp Ther 1975;192:211–217.
138. Daniell HW. Narcotic-induced hypogonadism during therapy for her-
oin addiction. J Addict Dis 2002;21:47–53.
139. Mendelson JH, Mello NK. Plasma testosterone levels during chronic
heroin use and protracted abstinence. A study of Hong Kong addicts.
Clin Pharmacol Ther 1975;17:529–533.
140. Pelosi MA, Sama JC, Caterini H et al. Galactorrhea-amenorrhea
syndrome associated with heroin addiction. Am J Obstet Gynecol
1974;118:966–970.
141. Abs R, Verhelst J, Maeyaert J et al. Endocrine consequences of long-
term intrathecal administration of opioids. J Clin Endocrinol Metab
2000;85:2215–2222.
142. Doleys D, Dinoff BL, Page L et al. Sexual dysfunction and other side
effects of intraspinal opiate use in the management of chronic noncan-
cer pain. Am J Pain Manage 1998;8:5–11.
143. Finch PM, Roberts LJ, Price L et al. Hypogonadism in patients treated
with intrathecal morphine. Clin J Pain 2000;16:251–254.
144. Paice JA, Penn RD, Ryan WG. Altered sexual function and decreased
testosterone in patients receiving intraspinal opioids. J Pain Symptom
Manage 1994;9:126–131.
145. Daniell HW. Hypogonadism in men consuming sustained-action oral
opioids. J Pain 2002;3:377–384.
146. Daniell HW. Opioid endocrinopathy in women consuming prescribed
sustained-action opioids for control of nonmalignant pain. J Pain
2008;9:28–36.
147. Wong D, Gray DP, Simmonds M et al. Opioid analgesics suppress
male gonadal function but opioid use in males and females does not
correlate with symptoms of sexual dysfunction. Pain Res Manage
2011;16:311–316.
148. Rajagopal A, Vassilopoulou-Sellin R, Palmer JL et al. Hypogonadism
and sexual dysfunction in male cancer survivors receiving chronic opi-
oid therapy. J Pain Symptom Manage 2003;26:1055–1061.
149. Rajagopal A, Vassilopoulou-Sellin R, Palmer JL et al. Symptomatic
hypogonadism in male survivors of cancer with chronic exposure to
opioids. Cancer 2004;100:851–858.
150. Dev R, Hui D, Dalai S et al. Association between serum cortisol and
testosterone levels, opioid therapy, and symptom distress in patients
with advanced cancer. J Pain Symptom Manage 2011;41:788–795.
151. Risdahl JM, Khanna KV, Peterson PK et al. Opiates and infection. J
Neuroimmunol 1998;83:4–18.
152. Sacerdote P, Franchi S, Panerai AE. Non-analgesic effects of opioids:
mechanisms and potential clinical relevance of opioid-induced immu-
nodepression. Curr Pharm Des 2012;18:6034–6042.
153. Sacerdote P, Bianchi M, Manfredi B et al. Effects of tramadol on immune
responses and nociceptive thresholds in mice. Pain 1997;72:325–330.
154. Tsai YC, Won SJ. Effects of tramadol on T lymphocyte proliferation
and natural killer cell activity in rats with sciatic constriction injury.
Pain 2001;92:63–69.
155. Gaspani L, Bianchi M, Limiroli E et al. The analgesic drug tramadol
prevents the effect of surgery on natural killer cell activity and meta-
static colonization in rats. J Neuroimmunol 2002;129:18–24.
156. Ben-Eliyahu S, Page GG, Yirmiya R et al. Evidence that stress and sur-
gical interventions promote tumor development by suppressing natu-
ral killer cell activity. Int J Cancer 1999;80:880–888.
157. Gomez-Flores R, Weber RJ. Differential effects of buprenorphine
and morphine on immune and neuroendocrine functions following
acute administration in the rat mesencephalon periaqueductal gray.
Immunopharmacology 2000;48:145–156.
Assessment and Management of Opioid Side Effects
158. Franchi S, Panerai AE, Sacerdote P. Buprenorphine ameliorates the
effect of surgery on hypothalamus–pituitary–adrenal axis, natural killer
cell activity and metastatic colonization in rats in comparison with mor-
phine or fentanyl treatment. Brain BehavImmun 2007;21:767–774.
159. Martucci C, Panerai AE, Sacerdote P. Chronic fentanyl or buprenor-
phine infusion in the mouse: similar analgesic profile but different
effects on immune responses. Pain 2004;110:385–392.
160. Shavit Y, Ben-Eliyahu S, Zeidel A et al. Effects of fentanyl on natural
killer cell activity and on resistance to tumor metastasis in rats. Dose
and timing study. Neuroimmunomodulation 2004;11:255–260.
247
161. Fishbain DA, Rosomoff HL, Rosomoff RS. Drug abuse, dependence,
and addiction in chronic pain patients. Clin J Pain 1992;8:77–85.
162. Porter J, Jick H. Addiction rare in patients treated with narcotics. N
Engl J Med 1980;302:123.
163. McQuay HJ. Opioid use in chronic pain. Acta Anaesthesiol Scand
1997;41:175–183.
164. Passik SD, Kirsh KL, McDonald MV et al. A pilot survey of aberrant
drug-taking attitudes and behaviors in samples of cancer and AIDS
patients. J Pain Symptom Manage 2000;19:274–286.
27
ADJUVANT ANALGESIC MEDICATIONS

Jessica Geiger

Contents
Introduction....................................................................................................................................................................................................................... 249
Corticosteroids.................................................................................................................................................................................................................. 249
Antidepressants................................................................................................................................................................................................................. 249
Tricyclic antidepressants........................................................................................................................................................................................... 250
Serotonin–norepinephrine reuptake inhibitors (SNRIs).......................................................................................................................................... 250
Anticonvulsants................................................................................................................................................................................................................. 250
N-Methyl-d-aspartate (NMDA) receptor antagonists.............................................................................................................................................. 250
Alpha2-adrenergic agonists..............................................................................................................................................................................................251
Sodium channel blockers.................................................................................................................................................................................................251
Cannabinoids......................................................................................................................................................................................................................251
Topical agents.....................................................................................................................................................................................................................251
Medications specific for bone pain.................................................................................................................................................................................252
Osteoclast inhibitors...................................................................................................................................................................................................252
Receptor activator of nuclear factor kappaB ligand (RANKL) therapies..........................................................................................................252
Medications specific to pain from bowel obstruction................................................................................................................................................252
Anticholinergic medications......................................................................................................................................................................................252
Somatostatin analog....................................................................................................................................................................................................252
Conclusion...........................................................................................................................................................................................................................252
References............................................................................................................................................................................................................................252

Introduction be effective for treating bone, inflammatory and neuropathic

The pain pathway is a complex process with many neurotrans-
mitters and receptors involved. As such, medications other than
opioids can be effective as adjuvant analgesics. The definition of
adjuvant analgesics is as follows: “medications whose primary
indication is not the management of pain, but have analgesic
properties.”1 Some of the medications used as adjuvants have
indications for specific pain diagnoses, and others are used off-
label. Adjuvant analgesic and “coanalgesic” are interchangeable
as both terms refer to using these medications in addition to
opioids.
Adjuvant analgesics are an option on every step of the World
Health Organization’s (WHO) three-step ladder for cancer pain
relief.2 These medications are added to a regimen to improve pain
control and potentially decrease the opioid requirement. 3
Adjuvant analgesics span multiple medication classes with dif-
ferent mechanisms of action, which allows the clinician to target
different areas on the pain pathway to decrease the pain experi-
ence for the patient. Selection and dosing of adjuvant analgesics
in populations with serious illness comes mainly from clinical
experience and data extrapolated from studies in patients with
non-cancer-related pain. Some of the medications used as adju-
vants have indications for specific pain diagnoses, while others
are used off-label.4
Corticosteroids
Steroids are frequently used to manage pain, nausea, fatigue,
and anorexia in palliative care, which makes them very useful
and versatile medications. 5 For pain management, steroids can
pain, as well as pain caused by bowel obstruction, organ capsule
stretch, lymphedema, and headache caused by increased intra-
cranial pressure.6 Steroids affect the pain experiencing through
anti-inflammatory effects and impact transduction in the pain
pathway.
Dexamethasone is the preferred agent among palliative care
providers due to the long half-life and low mineralocorticoid
effect.7 The long half-life allows for once daily dosing of dexa-
methasone. The low mineralocorticoid effect leads to less fluid
retention. If dosing any steroid twice daily, give the second dose
in the early afternoon to avoid sleep disturbances.
A generally accepted starting dose for dexamethasone is 4 mg;
equivalent doses of alternate steroids are in Table 27.1. Higher
doses of steroids may be necessary if pain is severe or a patient is
experiencing metastatic spinal cord compression.8
Side effects of glucocorticoids include sleep disturbances,
hyperglycemia, and hypertension. Acutely, the most worrisome
glucocorticoid toxicity is delirium or adverse mood effects. Long-
term use is associated with the potential for many adverse effects,
including myopathy, Cushingoid symptoms, diabetes, osteo-
porosis, and prolonged adrenal suppression. In the context of
advanced illness, the risks are balanced by the need to provide
symptomatic relief.
Antidepressants
The most commonly used antidepressant medications for neuro-
pathic pain control in palliative care span two medication classes.
Tricyclic antidepressants (TCAs) and serotonin–norepinephrine
reuptake inhibitors (SNRIs).9 There is very little evidence that

249
250 Textbook of Palliative Medicine and Supportive Care

TABLE 27.1  Corticosteroid Profiles

Generic Name Equivalent Dose (mg) GA MA Peak Effect (hours) Half-Life (hours)
Cortisone 125 0.8 0.8 2 Plasma: 0.5
Hydrocortisone 100 1 1 1 Biologic: 8–12
Prednisone 25 4 0.8 2 Plasma: 2.5
Prednisolone 25 4 0.8 1 Biologic: 18–36
Methylprednisolone 20 5 0-0.5 1–2
Dexamethasone 4 30 0 1–2 Plasma: 2
Biologic: 36–54
Abbreviations: GA, glucocorticoid activity; MA, mineralocorticoid activity.

supports other classes of antidepressants for use in pain manage-
ment, but this is largely due to a lack of research testing other
categories of antidepressants.
Tricyclic antidepressants
Studies have shown that this class of medications can be effec-
tive as an adjuvant analgesic.10 There are two groups of TCAs into
secondary and tertiary amines. Examples of secondary amines
are nortriptyline (active metabolite of amitriptyline) and desip-
ramine. The tertiary amines include amitriptyline, imipramine,
and doxepin. All TCAs can cause sedation and anticholinergic
side effects, but these side effects are less with secondary amines.
Postural hypotension, heart block, and arrhythmias are also
potential side effects of TCAs. Consider a careful risk versus ben-
efit analysis before utilizing these medications in the elderly.9
TCA dosing for pain relief is less than that required to treat
depression, and effects for pain management can be seen quicker
than improvements in mood. Common starting doses for tricy-
clic antidepressants can be seen in Table 27.2 Dose these at bed-
time due to the potential to cause sedation. The exact mechanism
of action for how TCAs work for pain management is not clearly
defined, but it is thought that they act on descending pain path-
ways (modulation) through the inhibition of norepinephrine and
serotonin reuptake, interaction with histamine H1 receptors, as
well as interaction with sodium channels.11
Serotonin–norepinephrine
reuptake inhibitors (SNRIs)
SNRIs that have been studied for analgesic effect include duloxetine,
milnacipran, venlafaxine, and desvenlafaxine.9 Both duloxetine and
venlafaxine have been studied for the treatment of pain and have
been found to be effective.12 Both duloxetine and venlafaxine are
recommended as first-line agents for neuropathic pain, suggested
starting doses for these medications can be found in Table 27.3.13–15
The side effect profile for SNRIs is more favorable than that of
the TCAs. Side effects of SNRIs include nausea, somnolence, and
sexual dysfunction. As with the TCAs, the effect of pain relief can
be seen faster than mood changes.
TABLE 27.2  Antidepressants
Generic Name Starting Dose
Amitriptyline 25 mg QHS
Nortriptyline 10 mg QHS
Desipramine 12.5 mg QHS
Imipramine 25 mg QHS
Doxepin 3 mg QHS
TABLE 27.3  SNRIs
Generic Name Starting Dose
Duloxetine 60 mg daily
Venlafaxine 37.5 mg daily
SNRIs cannot be abruptly discontinued, taper over several
weeks to avoid discontinuation syndrome. Duloxetine requires a
renal dose adjustment in CrCl less than 30 mL/minutes.
Anticonvulsants
Gabapentin and pregabalin, commonly referred to as gabapen-
tinoids, are the two anticonvulsant medications with the most
evidence for use as an adjuvant analgesic, specifically targeted
at neuropathic pain. Use of these medications has been studied
for the treatment of diabetic neuropathy, chemotherapy-induced
neuropathy, as well as other cancer-related neuropathic pain.16–18
Gabapentinoids work by decreasing the influx of calcium into a
cell, which affects depolarization. Preventing depolarization
of a cell membrane disrupts pain signaling. Specifically, these
medications bind to the alpha 2 delta protein of voltage gated
calcium channels.19 Recommended starting doses are provided
in Table 27.4. Gabapentin and pregabalin can both be titrated to
doses of 2700—3600 and 300—600 mg, respectively. Titration
should occur no more frequently than every few days to a week to
allow the patient time to adjust to the new dose. Both medications
require renal dose adjustments.
Side effects of the gabapentinoids include somnolence, dizzi-
ness, confusion, and peripheral edema.
Of the other anticonvulsants that could be considered for pain
management, carbamazepine, and oxcarbazepine might be use-
ful for trigeminal neuralgia, though drug–drug interactions may
limit use.20,21
N-Methyl-d-aspartate (NMDA)
receptor antagonists
N-Methyl-d-aspartate (NMDA) receptors mediate excitatory
nerve transmission in the brain. Medications that act as NMDA
receptor antagonists bind to the receptor and decrease channel
TABLE 27.4  Anticonvulsants
Generic Name Starting Dose
Gabapentin 100–300 mg QHS
Pregabalin 25–75 mg QHS
Adjuvant Analgesic Medications
opening time, which affects and slows the transmission of an
excitatory signal, such as pain. NMDA receptor antagonists can
be especially helpful in neuropathic pain. Ketamine and metha-
done are common examples of NMDA receptor antagonists.22,23
Ketamine is a dissociative anesthetic that can provide pain relief
in sub-anesthetic doses.24 Both ketamine and methadone can be
given via a variety of routes, including oral, sublingual, and par-
enterally. Additionally, ketamine is effective for topical pain relief.
Side effects of ketamine include increased heart rate and blood
pressure, nausea/vomiting, hypersalivation and psychomimetic
inclusive of emergence phenomenon, vivid dreams/hallucina-
tions, and anxiety.25
Methadone is an additional medication that interacts with the
NMDA receptor. The pharmacologic profile of methadone is com-
plex. Refer to Chapter 43 (opioid analgesics) for additional details
on methadone dosing, monitoring, and safety considerations.
Dosing for both of these medications is variable, and starting
doses are dependent on other clinical factors.
Limited studies exist for using other medications with NMDA
receptor antagonistic properties such as memantine, amanta-
dine, and dextromethorphan.26
Alpha2-adrenergic agonists
Alpha2-adrenergic agonists prevent signal transmission to the
brain. Both clonidine and tizanidine fall into this category of
medications. The most common use of clonidine is to treat
hypertension. Tizanidine is antispasmodic. These medications
interact with the alpha2 receptor and inhibit norepinephrine
release.27 Epidural clonidine has been shown to be effective for
pain reduction both postsurgically and in patients with severe
cancer pain.28,29
Tizanidine can be useful in the setting of muscle spasms and
an appropriate starting dose would be 2–4 mg daily. Studies have
shown that it can be useful for back and neck pain in combination
with other analgesics. 30
Both clonidine and tizanidine can cause somnolence and hypo-
tension, which can be potential barriers to their use.
Sodium channel blockers
Lidocaine was developed in 1943 and the original use was as a
local anesthetic. The earliest report of pain relief was published
in 1961. 31 Lidocaine blocks sodium channels, which makes the
medication a useful anesthetic and anti-arrhythmic. The sodium
channel blockade is also beneficial for modulating neuropathic
pain, which makes lidocaine a useful analgesic. Additionally,
lidocaine is an NMDA receptor antagonist, which is also ben-
eficial for treating pain. Lidocaine infusion has been utilized
in perioperative pain, sickle cell disease, neuropathic pain, and
refractory cancer pain. 32–34
Lidocaine infusion is well tolerated, and in most circum-
stances, free of adverse effects; the infusion can be stopped or
dose decreased to manage the toxicity. While lidocaine levels can
predict toxicity, in the clinical setting, the lidocaine levels do not
guide treatment, and thus lidocaine levels are usually not moni-
tored. Common adverse effects include perioral numbness, seda-
tion, light-headedness, tinnitus, and headache. Arrhythmias are
also a potential side effect.
As with the previously mentioned NMDA receptor antago-
nists, lidocaine dosing is variable and starting doses are depen-
dent on various clinical factors.
251
TABLE 27.5  Cannabinoids
Generic Name Starting Dose
Dronabinol 2.5–5 mg daily
Nabilone 1–2 mg BID
Cannabinoids
Recent studies suggest that cannabinoids can be useful for pain and
spasticity.35 Cannabinoids interact with the body’s endocannabi-
noid system through the CB1 and CB2 receptors.36 CB1 receptors
are located both peripherally and in the central nervous system;
CB2 receptors are located in peripheral organs and tissues.
Dronabinol (synthetic tetrahydrocannabinol [THC]) and
nabilone are available options in the United States. Nabiximols
are available in other countries and are undergoing clinical tri-
als for use in cancer pain. 37 Dronabinol and nabilone both have
approved indications other than pain, but there is some evidence
that they have analgesic efficacy. 38 Starting doses for dronabinol
and nabilone can be found in Table 27.5. Nabiximols is an oromu-
cosal spray that contains both THC and cannabidiol. The most
common side effects of these medications are dizziness, drowsi-
ness, and cognitive impairment.
Cannabinoid use in pain management is evolving and addi-
tional studies are needed to determine the appropriate place in
therapy.
Topical agents
Topical analgesic preparations can be especially useful as there
is minimal systemic absorption, which means there are minimal
systemic side effects. These formulations are especially helpful in
easily localized pain.
Lidocaine, in the form of a patch, gel, or cream, is a common
topical formulation. The approved indication for Lidocaine 5%
patches is the treatment of postherpetic neuralgia. 39 Other types
of easily localized pain near the surface of the skin may also
respond to lidocaine patches. Up to three of the topical patches
can be applied at the same time and the patches can be cut. The
most common reaction is a local skin reaction to the adhesive on
the patch. If a patient tolerates the adhesive, the patch can remain
in place for up to 24 hours.
Topical capsaicin, a component of chili peppers, is an addi-
tional option for pain relief. This medication works by depleting
substance P, which leads to decreased pain perception. In order
for capsaicin to be most effective, regular application is required.
Capsaicin is available in a low concentration cream (0.075–
0.1%) as well as a high concentration (8%) patch. There is evidence
that the 8% patch is helpful for pain associated with postherpetic
neuralgia.40 The lower concentration cream can be useful for joint
and neuropathic pain. Burning and redness at the application site
are common side effects. Patients should wear gloves or wash
their hands immediately after application to prevent transfer of
the cream to other parts of the body.
Nonsteroidal anti-inflammatory (NSAID) medications are also
available in topical formulations such as creams and patches and
are effective for the treatment of musculoskeletal pain.
Other compounded combination topical creams include TCAs,
gabapentin, ketamine, clonidine, and others, but data to support
these medications is lacking.
 252
Medications specific for bone pain
Osteoclast inhibitors
Bisphosphonates are medications that reduce bone resorption by
causing osteoclast apoptosis, which can prevent the development
of bone lesions. This class of medications includes pamidronate,
zoledronic acid, ibandronate, and clodronate. Evidence shows
that these medications are effective in reducing the severity and
frequency of skeletal-related events in patients with bone metas-
tases from a variety of types of cancers.
Side effects of bisphosphonate therapy include flu-like symp-
toms, symptomatic hypocalcemia, and transient renal impair-
ment. Severe side effects include osteonecrosis of the jaw and
femoral fracture.
The evidence for using bisphosphonates to treat bone pain from
cancer is mixed. It is thought that the impact on pain control is
due to the prevention of bone lesions.41
Receptor activator of nuclear factor
kappaB ligand (RANKL) therapies
Denosumab is a targeted RANKL inhibitor that also inhibits
bone resorption, but in a different manner than that of bisphos-
phonates. This medication works by binding the RANKL and
inhibiting it. This causes decreased osteoclasts on bone surfaces.
Denosumab can also reduce the frequency and severity of skele-
tal-related events, similar to bisphosphonates. 34
Medications specific to pain
from bowel obstruction
Anticholinergic medications
Anticholinergic medications work by decreasing gut motility and
secretions. This medication class included scopolamine, glycopyr-
rolate, and hyoscyamine. Literature supports the use of scopol-
amine as an effective medication for treating pain in the setting of
inoperable malignant bowel obstruction.42 Anticholinergic agents
that cross the blood–brain barrier, such as scopolamine and hyo-
scyamine, have a higher potential to cause side effects, which
include constipation, somnolence, and confusion. Glycopyrrolate
only minimally crosses the blood–brain barrier, which can lead
to decreased side effects.
Somatostatin analog
Octreotide is a somatostatin analog that inhibits secretions from
the GI tract and pancreas. It also decreases motility. Affecting the
aforementioned actions can cause decreased pain as well as other
symptoms associated with a bowel obstruction such as nausea
and vomiting.
The side effects of octreotide are minimal and the medica-
tion has a favorable safety profile. Octreotide can be adminis-
tered via intermittent subcutaneous boluses or as a continuous
infusion.
Conclusion
Adjuvant analgesics can be beneficial in many types of pain either
alone, or in conjunction with opioids. Additional clinical trials
are needed in populations with serious or life-threatening medi-
cal conditions, but this lack of evidence should not stop clinicians
from using adjuvant analgesics as first-line agents. Evidence from
available literature in chronic pain can be extrapolated to the
BK-TandF-BRUERA_9780367642037-200160-Chp27.indd 252
Textbook of Palliative Medicine and Supportive Care
palliative care patient population. Consider using these medica-
tions as appropriate (neuropathic, bone, inflammatory, and bowel
obstruction pain), especially in patients whose pain is not respon-
sive to opioids.
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2017;34:571–575.
25. Gorlin AW, Rosenfeld DM, Ramakrishna H. Intravenous sub-anesthetic
ketamine for perioperative analgesia. J Anaesthesiol Clin Pharmacol
2016;32:160–167.
26. Aiyer R, Mehta N, Gungor S, et al. A systematic review of NMDA
receptor antagonists for treatment of neuropathic pain in clinical prac-
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27. Helander EM, Menard BL, Harmon CM. et al. Multimodal analgesia,
current concepts and acute pain considerations. Curr Pain Headache
Rep 2017;21:1–10.
28. Abdel Hay J, Kobaiter-Maarrawi S, Tabet P, et al. Bupivacaine field
block with clonidine for postoperative pain control in posterior
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29. Eisenach JC, DuPen S, Dubois M, Miguel R, Allin D. Epidural cloni-
dine analgesia for intractable cancer pain. The epidural clonidine study
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30. van Tulder MW, Touray T, Furlan AD, Solway S, Bouter LM. Muscle
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31. Bartlett EE, Hutserani O. Xylocaine for the relief of postoperative pain.
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37. Parmar JR, Forrest BD, Freeman RA. Medical marijuana patient coun-
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39. Gammaitoni AR, Alvarez NA, Galer BS. Safety and tolerability of the
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28
ALTERNATIVE ROUTES FOR SYSTEMIC OPIOID DELIVERY

Raffaele Giusti, Monica Bosco, Maurizio Lucchesi, and Carla Ida Ripamonti

Contents
Introduction........................................................................................................................................................................................................................255
Subcutaneous route...........................................................................................................................................................................................................255
Rectal route........................................................................................................................................................................................................................ 257
Sublingual and buccal routes...........................................................................................................................................................................................259
Sublingual route...........................................................................................................................................................................................................259
Buccal route.................................................................................................................................................................................................................. 260
Intranasal administration.................................................................................................................................................................................................261
Intravenous route...............................................................................................................................................................................................................261
Transdermal route............................................................................................................................................................................................................ 263
Topical opioids................................................................................................................................................................................................................... 265
References........................................................................................................................................................................................................................... 266

Introduction of opioid for treatment of cancer pain. Patients were randomly

Almost 70% of patients with cancer-related pain requires an
alternative route for opioid administration hours and months
before death.1,2
Several routes for opioid administration have been explored. 3
This chapter describes the most commonly used and avail-
able routes (Table 28.1) that can substitute for oral opioid
therapy. It provides a summary of factors affecting choice of
opioid for use in palliative care in terms of benefits, indica-
tions, and safety, taking into account the European Society
of Medical Oncology (ESMO) recommendations regarding
opioids administration for the management of moderate and
severe pain4 (Table 28.2).
Subcutaneous route
The rate of absorption of a drug strongly depends on the blood
flow to the site of absorption. In normal conditions, the perfu-
sion of subcutaneous (SC) tissue is similar to that of muscles.
However, the rate of absorption is slower. The main factors deter-
mining the SC absorption are the solubility of the drug, the site of
the injection, the surface exposed, the blood pressure, the pres-
ence of cutaneous vasoconstriction, edema, or inflammatory pro-
cesses in cachectic patients and those with disturbed peripheral
circulation.
Figure 28.1 shows the plasmatic concentration of morphine
when administered via continuous SC infusion or as oral slow-
release tablets.
A survey of US hospices found that the most common indica-
tions for the use of continuous SC infusion were pharmacological
management (95%), poor intravenous (IV) access (56%), no oral
intake (38%), dehydration (8%), infusion of saline (2%), and nutri-
tion (1%).5
SC opioid administration can be performed both intermit-
tently (ISCI) and continuously (CSCI). In a randomized, double-
blind crossover trial, Watanabe et al.6 compared CSCI and ISCI
assigned to receive opioid by CSCI by portable pump or ISCI by
Edmonton injector for 48 hours, followed by crossover to the
alternative modality for 48 hours. There were no differences
between CSCI and ISCI in mean visual analog score for pain,
nausea, or drowsiness; categorical rating score of pain; number
of breakthrough opioid doses per day; global rating of treatment
effectiveness; or adverse effects. In all cases, patients and inves-
tigators expressed no preference for one modality over another.
Another review demonstrated that CSCI is effective and safe for
use in terminal illness.7 Consistently with this evidence, CSCI
is a standard practice in palliative medicine and the preferred
route when oral administration is not possible. However, CSCI is
contraindicated in patients with coagulation disorders, cognitive
failure, with a history of substance abuse, and should be avoided
or used with caution in immunocompromised patients.8 Several
other factors should be considered when deciding whether to
use the SC route for a patient. Although the infusion needle can
remain in place for up to 1 week,9,10 this route may require more
frequent site rotation than a central IV, but site changes can be
easily accomplished. Although there may be limited peripheral
venous access sites, availability of SC access sites is virtually
unlimited. Infectious complications are less frequent and less
severe than with the IV route; local complications are rare but
may occur, especially in patients with diabetes.11
Most studies of SC opioid administration have used mor-
phine or hydromorphone. These drugs have short half-lives
and hence reach the steady state rapidly. Waldmann et al.12
reported that the blood levels of morphine during continuous
SC infusion are similar to those reached during continuous IV
infusion. Another study in healthy volunteers provided dif-
ferent results, indicating that the bioavailability of morphine
and of its main metabolites is significantly lower after SC than
after IV administration. Despite this observation, the authors
concluded that the SC route is an effective method for the sys-
temic administration of morphine.13 No clear differences seem
to exist between SC morphine and hydromorphone from both

255
256 Textbook of Palliative Medicine and Supportive Care

TABLE 28.1  Potential Applications of Alternative Routes for Systemic Opioid Administration
Transdermal Fentanyl
Symptoms Sublingual Rectal CSIa IV Buprenorphine Transmucosal
Vomiting ++ ++ ++ ++ ++ –
Bowel obstruction ++ ++ ++ ++ ++ –
Dysphagia ++ ++ ++ ++ ++ –
Cognitive failure x + ++ ++ ++ –
Diarrhea ++ x ++ ++ ++
Hemorrhoids anal fissures ++ x ++ ++ ++ –
Coagulation disorders ++ ++ x ++ ++ –
Severe immunosuppression ++ ++ x + ++ –
Generalized edema ++ ++ x ++ x –
Frequent dose changes ++ x ++b ++b x –
Titration ++ + ++b ++b x –
BTcP ++ ++ ++b ++b x ++§
+, may be indicated; ++, recommended; x, not recommended; –, not indicated.
a Continuous subcutaneous infusion.

b Patient-controlled analgesia, PCA. BTcP = Breakthrough cancer pain.

§ Specific for BTP or acute pain in patients who are taking regular doses of opiates.

the pharmacokinetics and pharmacodynamic point of view.14,15
Such a toxicity is manageable by changing the position of the
needle and infusing dexamethasone concurrently with the
methadone.16,17
In general, it is recommended the infusion be performed by
using a 25- or 27-ga butterfly needle inserted in the anterior chest
or abdomen. Sites that interfere the least with the patient’s mobil-
ity and are not easily accessible by patients should generally be
selected. The volume of fluid that can be administered per hour
is a limiting factor; Pirrello et al.18 reported the “nursing norm” as
3 mL/hour and infusion rates should not exceed 5 mL/hour unless
hyaluronidase is added to the infusion, in which case larger infu-
sion rates can be utilized.
Table 28.3 provides a summary of the remaining literature
regarding the SC route. Of particular importance, studies by
Watanabe et al.,6 Vanier et al., and McDonald et al.19,20 compare
continuous versus intermittent SC delivery. Oosten et al.21 com-
pared SC and/or transdermal fentanyl for moderate-to-severe
cancer-related pain. Hunt et al.22 found SC morphine to pro-
vide effective analgesia with less severe nausea and vomiting in
patients who did not achieve satisfactory pain relief with oral
morphine.

TABLE 28.2  Opioid Administration According to the ESMO Recommendations for Moderate-to-Severe Pain (From Reference
[4] with Permission)
Recommendation
The opioid of first choice for moderate-to-severe cancer pain is oral morphine
The average relative potency ratio of oral to IV morphine is between 1:2 and 1:3
The average relative potency ratio of oral to SC morphine is between 1:2 and 1:3
The SC route is simple and effective for the administration of morphine, diamorphine, and hydromorphone, and it should be the first-choice
alternative route for patients unable to receive opioids by oral or transdermal routes
IV infusion should be considered when SC administration is contraindicated (peripheral edema, coagulation disorders, poor peripheral circulation,
and need for high volumes and doses)
IV administration is an option for opioid titration when rapid pain control is needed
Fentanyl and buprenorphine (via the TD or IV route) are the safest opioids in patients with chronic kidney disease stages 4 or 5 (estimated glomerular
filtration rate <30 mL/min)
A different opioid should be considered in the absence of adequate analgesia (despite opioid dose escalation) or in the presence of unacceptable opioid
side effects
Individual titration, e.g., normal-release morphine administered every 4 hours plus rescue doses (up to hourly) for BTcP, is recommended in clinical practice
Immediate and slow-release oral morphine formulations can be used to titrate the dose. Titration schemes for both types of formulation should be
supplemented with immediate-release oral opioids, prescribed as required for BTcP
Immediate-release opioids should be used to treat BTcP that is opioid-responsive and for which background cancer-pain management has been optimized
Transmucosal fentanyl formulations (oral, buccal, sublingual, and intranasal) have a role in unpredictable and rapid-onset BTcP
There are indications for standard normal-release oral opioids (e.g., morphine) that include a slow-onset BTcP or a preemptive administration of oral
opioids 30 minutes before a predictable BTcP triggered by known events
The regular dose of slow-release opioids can be adjusted to take into account the total amount of rescue morphine
Abbreviations: TD, trans dermal; BTcP, breakthrough cancer pain; GFR, glomerular filtration rate; IV, intravenous; SC, subcutaneous.
Alternative Routes for Systemic Opioid Delivery
FIGURE 28.1  Pharmacokinetics of oral and SC morphine: continuous subcutaneous infusion.
Rectal route
The main mechanism of absorption from the rectum is passive
diffusion. This is probably no different from that in the upper part
of the gastrointestinal (GI) tract despite the fact that the rectum’s
pH (7–8), surface area (rectum is small, 200–400 cm2, with no
villi), and fluid content differ substantially from the upper GI
tract.23 The rectum is drained by the superior rectal vein into the
portal system and by the middle and inferior rectal veins into the
inferior cava vein. It is impossible to predict the quantity of drug
that will bypass the hepatic filter, because there are several exten-
sive anastomoses between the superior rectal vein that drains to
the portal system and the median and inferior rectal veins that
drain toward the systemic circulation.24 Rectal drug vehicles may
be liquid or solid.25 The absorption of aqueous and alcoholic solu-
tions may occur very rapidly, but the absorption of suppositories
is generally slower and very much dependent on the nature of the
suppository base, the use of surfactants, and other factors such
as the presence/absence/quantity of fecal mass and the total vol-
ume content inside the rectum. Although an almost complete
absence of pre-systemic metabolism has been found for intrar-
ectal lidocaine in humans, several other drugs have been found
to metabolize equal to or more than orally when administered on
intrarectal route.23 Davis et al.25 reviewed the clinical pharmacol-
ogy and therapeutic role of suppositories and rectal suspension of
opioids and other analgesics.
Bioavailability studies have shown considerable interindividual
variation. Johnson et al.26 found that after 24 hours of rectal and
IV administration of 10 mg of morphine chloride in eight patients,
the bioavailability of morphine after rectal administration was
53 ± 18% of the values obtained after IV administration. The
257
authors conclude that, probably, first-passage elimination of mor-
phine was partially avoided by the rectal administration, since a
previous study suggested that the bioavailability of oral morphine
is 37%.27 The bioavailability of free morphine and morphine-
6-glucuronide was found to be comparable after oral, sublabial,
and rectal administration of morphine in cancer patients.28–30
In a comparative study31 between 10 mg of morphine sulfate
in oral solution and rectal suppository carried out in 10 patients
with cancer pain, a significantly higher mean concentration of
free morphine was found after rectal administration at all evalu-
ation times throughout a period of 4.5 hours, whereas there were
no differences between the routes in mean morphine-3-glucuronide
concentrations. These data suggests the presence of some avoid-
ance of first-pass metabolism. Moolenar et al. 32 studied the rectal
absorption of morphine hydrochloride from different aqueous
solutions with different pH values in seven volunteers. Kaiko
et al. 33 carried out a randomized crossover multiple-dose study in
14 healthy men to compare the bioavailability of 30 mg of mor-
phine sulfate tablets administered orally and rectally. The results
suggest that there is a slower rate of absorption for administered
rectally than when given orally.
Pannuti et al. 30 found similar efficacy with oral, rectal, and sub-
lingual application of morphine in a controlled study with 102
patients who received treatment for at least 10 days. Maloney34
reviewed the experience with 39 terminally ill patients who
received slow-release morphine as a rectal suppository. Good
pain control was reported in all cases. In two patients, the slow-
release morphine tablets were administered into a colostomy, and
in one case, a female patient with diarrhea received the tablets
intravaginally. No local side effects using the standard commer-
cial preparation of 30 mg tablets were reported.
258 Textbook of Palliative Medicine and Supportive Care

TABLE 28.3  Selected Studies of Importance Regarding Subcutaneous Opioid Administration

First Author (Ref.) Study Design N Route(s) Medication Summary of Results
Watanabe 6 Randomized, 12 SC, by both continuous Hydromorphone, Analgesia and side effects were similar
double-blind, infusion (CSCI) and morphine, oxycodone between the two delivery methods
crossover regularly scheduled
intermittent injections
(ISCI)
Pirrello18 Retrospective chart 32 SC Recombinant human Infusion rates of up to 500 mL/hour for
review hyaluronidase (for the bolus dosing, and repeated dosing of up to
enhancement of 7 days were obtained
medication infusion)
Bruera, 198816 Randomized, crossover 25 SC Morphine, Analgesia and side effects were similar
hydromorphone between the two delivery methods
Vanier19 Randomized, double- 8 SC Hydromorphone Although the two delivery methods
blind, crossover resulted in similar pain intensity, patients
who received the patient-controlled
(intermittent) delivery required a lower
mean hydromorphone dose than patients
receiving continuous infusion
McDonald20 Prospective 164 SC Morphine, F Subcutaneous morphine provided effective
analgesia with less severe nausea and
vomiting in patients who did not achieve
satisfactory pain relief with oral morphine
Oosten21 Prospective 52 SC, transdermal Fentanyl Pharmacokinetics of subcutaneous and
transdermal fentanyl; the absorption rate
constant for subcutaneous and
transdermal fentanyl was 0.0358 and
0.0135 h(−1), respectively. Moderate-to-
large interindividual and inter-occasion
variability was found. Around rotation
from subcutaneous to transdermal
fentanyl, measured and simulated plasma
fentanyl concentrations rose and
increasing side effects were observed
Hunt22 Randomized, double- 23 SC Morphine, fentanyl Similar pain scores were observed with
blind, crossover morphine and fentanyl but patients had
more frequent bowel movements while
receiving fentanyl
Zecca, 2015137 Randomized double 114 Buccal, SC Morphine, fentanyl Trial did not show noninferiority of
dummy noninferiority fentanyl versus morphine
trial

Long-term rectal administration of high-dose sustained-
release morphine tablets is reported by Walsh and Tropiano.35
Based on this case, the correct mg relative potency conversion
ratio for rectal to IV morphine during repeated dosing appears to
be 3:1, which is similar to that for the conversion from oral to IV.
For rectal-to-oral morphine dosing, the conversion ratio seems
to be 1.1.
Table 28.4 reports the randomized controlled trials (RCTs) on
rectal morphine compared to oral or SC morphine.36–39
Few data are available on the analgesia and tolerability of
rectally administered methadone. A study40 was carried out to
assess the pharmacokinetics and pharmacodynamics of 10 mg
of methadone hydrochloride administered rectally in six opioid-
naive cancer patients whose pain no longer responded to treat-
ment with nonsteroidal antiinflammatory drugs given at fixed
times. The pharmacokinetics of rectal methadone showed rapid
and extensive distribution phases followed by a slow elimination
phase. The plasmatic concentrations presented a great intrain-
dividual variability, with no correlation between analgesia and
plasmatic methadone concentration. Pain relief was statistically
significant already after 30 minutes and continued more than 8
hours after administration.
In a prospective, open study, Bruera et al.41 demonstrated
that custom-made capsules and suppositories of methadone
are safe, effective, and low cost in 37 advanced cancer patients
with poor pain control receiving high doses of SC hydromor-
phone. These patients had significant improvement in pain
control with minimal toxicity, using doses higher than those
reported in the literature. This study also demonstrated a
large interindividual variation between methadone dosage
and plasma level. Rectal methadone can be considered an
effective, safe, and low-cost therapy for patients with cancer
pain where oral and/or parenteral opioids are not indicated
or available.
Alternative Routes for Systemic Opioid Delivery 259

TABLE 28.4  RCTs on Rectal Morphine Compared to Oral or SC Morphine

Authors (Ref.) Study Design
Bruera et al.36 Double blind crossover
Babul et al.37 Double blind crossover
De Conno et al.38 Double blind, double
dummy, crossover
single-dose study
Bruera et al.39 Randomized double-
blind crossover
Abbreviations: SC, subcutaneous; CSI, continuous subcutaneous infusion; CR, controlled release; IV, intravenous.
No. of Patients Route 1 Route 2 Results
23 CR morphine sulfate, SC morphine, rectal/ Comparable analgesia and side
suppository every parenteral ratio 2.5:1 effects
12 hours
27 CR morphine, CR morphine tablets No difference in pain and
suppository every every 12 hours, sedation; small but significant
12 hours conversion rate 1:1 difference in nausea in favor of
rectal administration
34 opioid naives Rectal morphine Oral morphine Rectal morphine had a faster
prepared as conversion rate 1:1 onset of action and longer
microenema duration of analgesia than an
acute dose of oral morphine.
No significant difference in
intensity of sedation, nausea, or
number of vomiting episodes
between the two routes.
12, 6 evaluable CR morphine sulfate, CR morphine sulfate, There was no significant
suppository every suppository every 24 difference between the q12h
12 hours hours and q24h treatment groups in
symptom (pain, nausea,
sedation) intensity, adverse
effects, and patient choice

Mercadante et al.42 in a randomized double-blind clinical trial
compared oral tramadol versus rectal tramadol to compare the
analgesic activity and tolerability of tramadol by oral and rectal
administration in a double-blind double dummy crossover trial.
No differences in pain intensity (PI) and relief scores, or in other
symptoms between the two treatments efficacy as judged by the
clinician in patient compliance, or on patient satisfaction regard-
ing treatment were found.
Ritschel et al.43 have determined the absolute bioavailabil-
ity of rectal administration of hydromorphone suppository in
humans. The low bioavailability and large interindividual varia-
tion observed when hydromorphone is administered rectally is
due to various factors, namely, the type of preparation, the pH
of the solutions used, the presence of feces in the ampulla, the
condition of the mucosa, the placement of the agent, and the con-
current use of lubricants.
The colostomy administration route of opioids is not recom-
mended. The results of the study of Hojsted et al.44 comparing the
pharmacokinetics of hydrochloride morphine administered via
rectal and colostomic routes demonstrated that the bioavailabil-
ity via colostomy showed a very wide variation, but the mean value
as compared to rectal administration was 43% (range 0–127%).
The authors suspect that the main reason for lower bioavailabil-
ity may be poor vascularization of the colostomy, adsorption of
morphine to feces, and the presence of first-passage elimination.
A handful of articles describing the use of rectal administra-
tion of hydromorphone,45,46 oxymorphone,47,48 and oxycodone49,50
were identified. However, due to the paucity of studies, no con-
clusions supported by literature can be drawn for these opioids.
Small studies51,52 and case report53 that evaluated the efficacy of
rectal methadone compared with SC hydromorphone were also
identified. The results of these studies suggested that rectal meth-
adone might be useful for some patients.
Although the studies on the rectal route reported similar effi-
cacy and tolerability with SC or IV route, 3 the rectal route of drug
administration may present some disadvantages: (1) presence of
feces or diarrhea when used chronically causing discomfort and
reduced absorption, (2) difficulty in titration and individualiza-
tion of the doses, (3) interruption of absorption because of defeca-
tion, and (4) presence of painful anal conditions.
Rectal route could be administered successfully in patients
with breakthrough pain (BTcP) and in some clinical situations
how reported in Table 28.4.
Sublingual and buccal routes
Sublingual route
The mouth has many areas with a potential for transmucosal
administration: sublingual (beneath the tongue), buccal (between
the gingival edge of the upper molars and the cheek), and gingi-
val (between the gingival edge of the incisors and the lip). The
permeability is greatest in the sublingual area and lowest at the
gingival level.
The surface of the buccal and sublingual area is small (200
cm 2), with a pH of 6.2–7.4. However, this region is rich in blood
and lymphatic vessels and the possibility exists for rapid absorp-
tion with direct passage into the systemic circulation avoiding
the hepatic first-pass metabolism. 5 The sublingual mucosa com-
prises a small fraction of the 200 cm 2 of oral mucosa, but it is
the most permeable region in the oral cavity. In contrast to the
buccal mucosa, which is comprised of 40–50 cell layers and is
500–800 m thick, the sublingual mucosa comprises fewer cell
layers and is only 100–200 m thick. And unlike the gingival
mucosa, the sublingual mucosa is nonkeratinized, thus elimi-
nating an important barrier to drug absorption. In nonkera-
tinized mucosa, the outermost epithelial layers pose the major
barrier to drug absorption.
The conditions for the penetration of the drug improve with
the smallness of molecules, a high concentration of nonionized
drug, and a high degree of lipophilicity.
260
Lipophilic drugs such as buprenorphine, fentanyl, and metha-
done are better absorbed than polar ones. 54 Salivary pH also plays
a role in drug absorption.
Normal pH of saliva is 6.5–3 but is influenced by a number
of factors, including mouth-breathing, nutritional status, age,
recent beverage consumption, vomiting, chemotherapy, stomati-
tis, and decreased salivary flow rate.
Drugs that are highly lipophilic, such as fentanyl and metha-
done, are well absorbed sublingually. Hydrophilic drugs such
as morphine and hydrocodone are poorly absorbed; thus, most
of the efficacy of sublingually administered hydrophilic opioids
results from the drug being swallowed.55–57
Sublingual use of lipophilic opioids is indicated for patients
who cannot swallow, above all when a rapid effect is necessary,
for example, for BTcP.
The preferred preparations are tablet form rather than liquids
and pastes, which can spread all over the mouth and consequently
increase the possibility of swallowing the drug. Saliva affects the
absorption of the drug by dilution and by increasing the likeli-
hood of the drug being swallowed before absorption.
Buprenorphine is one commercial opioid formulated in a sub-
lingual preparation. Single-dose, crossover studies have shown it
to be 15 times as potent as morphine in terms of total analgesic
effect.58
Robbie59 treated 141 cancer patients with sublingual buprenor-
phine in doses of 0.15–0.8 mg for an average of 12 weeks. This
treatment was effective in most of the patients, particularly those
with pain from head and neck cancer. Drowsiness was the most
common side effect, followed by dry mouth and nausea.
De Conno et al.60 found that patients previously treated with
sublingual or IM buprenorphine required a dose of morphine sig-
nificantly higher than those treated with other opioids (codeine,
oxycodone, dextropropoxyphene, and pentazocine) to obtain the
same pain relief.
There are still some controversies on the efficacy of sublingual
morphine61 because of the lack of controlled clinical studies. The
very few reports on the clinical effects of sublingual and buccal
morphine are related to one-time dosage or anecdotal experience.
Whitman62 reports that 70–80% of 150 patients with cancer pain
who were treated with sublingual morphine (10–30 mg q3–4h)
obtained “adequate to good pain control.” The main side effects
reported were intolerance to the taste of the drug and occasional
confusion or unpleasant dreams.
The routine utilization of sublingual hydrophilic opioids, such
as morphine, is not supported by the literature
Weinberg et al.54 administered sublingual methadone, 5 mg
(0.8 or 5 mg/mL) to healthy volunteers, and measured the quan-
tity of drug in the saliva expectorate after 10 minutes. Methadone
absorption was 35% at pH 3.5 and 75% at pH 8.5, a statistically sig-
nificant difference. The absorption of methadone at even the lower
pH was significantly greater than it was for morphine, oxycodone,
hydromorphone, levorphanol, and heroin. Bioavailability was not
influenced by the concentration of the methadone solution.
Disadvantages of sublingual route include bitter taste, burning
sensation, possible ulceration, and need to retain the drug sublin-
gually for several minutes. Patients are required to avoid eating or
drinking until the medication is completely dissolved.
Fentanyl’s potency, lipophilicity, and clinical efficacy have
made it the object of intense interest for a variety of transmucosal
applications.
There are several rapid acting fentanyl formulations in the
treatment of breakthrough pain in patients with cancer.63
Textbook of Palliative Medicine and Supportive Care
The effects of sublingual fentanyl citrate (SLFC) were assessed
in 11 hospices in patients with cancer-related BTcP.57 SLFC was
started at 25 μg (using parenteral formulation of 50 μg/mL),
and the dose was progressively increased by 25 μg till the pain
was controlled. The maximum dose used was 150 μg as volumes
greater than 3 mL were difficult to retain sublingually. Fifty-five
percent of patients reported pain reduction after 10 minutes and
82% after 15 minutes. Compared to the usual breakthrough med-
ication (mostly normal-release morphine), SLFC was better (46%),
the same (36%), or worse (18%). No systemic adverse effects were
reported. SLFC may be an option for patients unable to tolerate
oral morphine in treating BTcP.
Newly developed galenic formulation with a higher early sys-
temic exposure and a shorter Tmax compared with oral transmu-
cosal fentanyl citrate (OTFC) makes these products a particularly
suitable formulation for the management of BTP in opioid-treated
cancer patients due to the very rapid onset of action.64
Sublingual fentanyl at a dose of 25 μg after 3, 6, and 9 minutes
produced pain relief, with a minimal sedation in one patient pre-
viously treated with oral morphine and with sublingual fentanyl.65
Sufentanyl 25 μg is approximately equianalgesic to 70–100 mg
sublingual morphine, whereas 50 μg sublingual fentanyl is about
7–10-mg sublingual morphine.66
Currently, three formulations of buccal fentanyl are available: a
lozenge on a handle (OTFC), an effervescent fentanyl buccal tablet
(FBT), and a fentanyl buccal soluble film (FBSF). OTFC incorporates
fentanyl into a lozenge that is sucked, and FBT incorporates fentanyl
into an effervescent tablet that is placed in the buccal cavity. FBSF is
a film containing fentanyl that is placed on the buccal mucosa. These
products are indicated for breakthrough pain in patients with cancer
who are already receiving and who are tolerant to opioid therapy for
their underlying persistent pain. Extensive research has been con-
ducted on each of these prod-cuts during their development prior
to regulatory agency approval and in post–marketing surveillance.
Thus, pharmacokinetics, efficacy, and safety data from transmucosal
fentanyl product use are well described.67–70
OTFC is a synthetic opioid agonist manufactured in a matrix
of sucrose and liquid glucose base and fitted onto a radiopaque
plastic handle.
In a multicenter, randomized, double-blind, placebo-controlled
trial of OTFC for cancer-related BTcP carried out by Farrar
et al.,71 OTFC produced significantly larger changes in PI and bet-
ter pain relief than placebo. In another controlled dose titration
study72 in cancer patients treated with OTFC, 74% of them were
successfully titrated.
In a double-blind, double dummy, randomized, multiple
crossover study, Coluzzi et al.73 compared OTFC and immedi-
ate-release morphine sulfate for the management of BTP in 134
outpatients receiving a fixed scheduled opioid regimen equiva-
lent to 60–1000-mg/day oral morphine or 50–300 μg/hour trans-
dermal fentanyl. Sixty-nine percent of patients (93/134) found a
dose of OTFC successful, and it proved to be more effective than
the immediate-release oral morphine in treating BTP.
Mucositis, local infections, and dry mouth may limit the use or
reduce the absorption of the drug. Absolute availability is about
50%; however, the percentage absorbed by mouth and available for
treating BTP is about 25%, because 75% of the drug is swallowed.74
Buccal route
Although the prevalence of use of the buccal route in palliative
care has not been reported in the literature, the buccal route is
commonly used in this population.
Alternative Routes for Systemic Opioid Delivery
Fentanyl is also available as a rapidly disintegrating sublingual
tablet that is quickly absorbed and produces a fast onset of anal-
gesia, as documented in two randomized double-blind clinical
trials compared with placebo.75
FBT is a formulation of transmucosal fentanyl designed to pro-
vide a rapid penetration of fentanyl through the buccal mucosa
by using effervescence to cause PH shifts that enhance the rate
and extent of fentanyl absorption. FBT is absorbed in approxi-
mately equal proportions through the buccal mucosa and the GI
tract, whereas, with OTFC, the proportion absorbed through the
buccal mucosa was lower (22%) than that absorbed gastrointes-
tinally (78%). Thus, the drug immediately available to treat BTP
is double that of OTFC (48 vs 22%). Compared with OTFC, FBT
has greater bioavailability (65% FBT vs 47% OTFC) and more is
absorbed transmucosally (48% FBT vs 22% OTFC).76
The clinical efficacy of FBT in treating BTcP associated with
cancer pain has been well established in two randomized,
placebo-controlled trials in opioid-tolerant cancer patients. The
two studies, one with 123 patients and the other with 125 patients,
received FBT in a double-blind fashion. Both documented clini-
cally significant improvement in pain scores versus placebo. The
significant greater reduction (P < .05 and P < .0001, respectively)
in PI was achieved after FBT administration compared with pla-
cebo as early as 15 and 10 minutes, respectively.
Interestingly, patients with moderate or severe pain at baseline
generally experienced greater improvements in pain than those
with mild pain.
In the studies with FBT as well as in other studies where
BTP was treated with an orally fast-acting morphine tablet, an
effervescent solution, 31 or with OTFC, there was no simple lin-
ear relationship between the effective dose and the dose of the
background opioid regimen. Not only does such an approach
lack a solid base of evidence, but also accumulating data sug-
gests that the optimal dose of BTP medication may bear little
relationship to the around-the-clock dose.77 Such results under-
line the need to titrate individually to effectiveness rather than
calculate the percentage of an existing opioid regimen as previ-
ously suggested.78
The various transmucosal fentanyl products are not bioequiva-
lent due to differences in absorption characteristics. Therefore,
it is recommended that initial dosing begin with the lowest dose
and that when switching from one formulation (product type) to
another, re-titration should be considered in a monitored setting.
Intranasal administration
The nasal mucosa is the only location in the body that provides
a direct connection between the central nervous system and the
atmosphere. Anatomically, human nasal cavity fills the space
between the base of the skull and the roof of the mouth; above,
it is supported by the ethmoid bones and, laterally, by the eth-
moid, maxillary, and inferior conchae bones. The human nasal
cavity has a total volume of 15–20 mL, and a total surface area of
approximately 150 cm2. These nasal vestibular characteristics are
desirable to afford high resistance against toxic environmental
substances, but, at the same time, the absorption of substances,
including drugs, becomes very difficult in this region.79,80
Drugs administered to the nasal mucosa rapidly traverse
through the cribriform plate into the central nervous system by
three routes: (1) directly by the olfactory neurons, (2) through
supporting cells and the surrounding capillary bed, and (3)
directly into the cerebrospinal fluid (CSF).81
261
Drugs sprayed onto the olfactory mucosa are rapidly absorbed
by three routes: by the olfactory neurons, by the supporting cells
and the surrounding capillary bed, and into the CSF. For some
drugs, administration by nasal spray results in a greater ratio of
CSF to plasma concentration than does IV or duodenal adminis-
tration, giving evidence for diffusion of these compounds through
the perineural space around the olfactory nerves, a compartment
known to be continuous with the subarachnoid space.
An open-label, uncontrolled study evaluated the pharmacoki-
netics, safety, and efficacy of a single 40-mg dose of nasal mor-
phine gluconate administered to 11 cancer patients in response to
an episode of BTP.82 This treatment was associated with effective
plasma morphine concentrations, rapid onset of pain relief, and
minor side effects (nasal irritation). Patient satisfaction ratings
were high.
As morphine administered nasally shows a bioavailability of
the order of 10% compared with IV administration, a novel chi-
tosan-morphine nasal formulation has been produced and tested
in both healthy volunteers and in 14 cancer patients with BTP.83,84
Morphine was rapidly absorbed (T-max of 15 minutes or less),
with a bioavailability of nearly 60%.
The efficacy of intranasal fentanyl spray (INFS) was compared
with that of OTFC for the relief of cancer-related BTcP in an
open-label, crossover trial. INFS constitutes a promising new
treatment option for BTcP, having demonstrated a rapid onset of
action (median 7 minutes) for the relief of dental postoperative
pain,85 and a clinically important reduction in pain at 10 minutes
post-administration in cancer patients with BTcP.
NFS offers unique advantages over existing treatment options
in cancer pain management. The pharmacodynamic profile of
INFS fits very closely with the temporal characteristics of BTcP,
and the present study has shown that “meaningful” pain relief
was obtained faster in patients treated with INFS than with
OTFC. INFS was easy to use, with the majority of patients prefer-
ring INFS over OTFC. It was well tolerated with a safety profile
that is typical for this group of opioids.
INFS represents a considerable improvement in the clinicians’
armamentarium for the treatment of BTcP.
An intranasal fentanyl formulation that uses pectin as a pene-
tration enhancer (fentanyl pectin nasal spray [FPNS]) is currently
marketed in Europe and was recently approved in the United
States. This formulation was designed to deliver fentanyl in a
manner intended to match the characteristics of a breakthrough
pain episode. Its efficacy, safety, and effectiveness in the treat-
ment of breakthrough pain have been upheld.86–88
Disadvantages of this route include the potential for side effects
such as nasal congestion, nasal irritation, rhinitis, upper respira-
tory infection, sinus congestion, and local irritation. The maxi-
mum volume of intranasal opioids should not exceed 150 μL,
which for some opioids may require a higher concentration than
the IV preparation to reach the effective dose.89 Studies of differ-
ent doses and formulations of intranasal fentanyl have been pub-
lished for patients with breakthrough cancer pain90–98; the most
relevant RCTs are summarized in Table 28.5.
Intravenous route
IV administration of opioids permits complete systemic absorp-
tion and produces rapid analgesia that is correlated to lipid
solubility (10–15 minutes for morphine and 2–5 minutes for
methadone) but of short duration. This makes it necessary to
repeat infusions at least every 4 hours.
262 Textbook of Palliative Medicine and Supportive Care

TABLE 28.5  Selected Most Important Randomized Controlled Trials Regarding Intranasal Opioid Administration
First Author (Ref.) Study Design n Route(s) Studied Medications Studied Summary of Results
Mercadante 85 Randomized, 139 Intranasal, oral Fentanyl Intranasal was associated with faster
open-label crossover transmucosal “meaningful” analgesia and greater patient
preference than was oral transmucosal
administration
Portenoy86 Randomized, double-blind, 114 Intranasal, oral FPNS as compared
a Fentanyl pectin nasal spray produced
placebo-controlled with morphine (at significantly better pain intensity scores
crossover least 60 mg) than placebo in as early as 5 minutes after
administration; significantly better summed
pain intensity difference (SPID) scores from
10 minutes until 60 minutes; and
significantly better pain relief scores from
10 minutes. More than 90% of episodes
treated with FPNS did not require rescue
medication compared with 80% of episodes
treated with placebo. No problematic nasal
effects occurred, and 87% of patients opted
to continue receiving FPNS in a follow-on
open label study.
Portenoy87 Multicenter, open label 356 Intranasal FPNS
a The safety profile of FPNS was typical of that
seen with other opioids and nasal
assessments revealed no nasal toxicity.
Rescue medication was not required for
94% of FPNS-treated episodes and more
than 90% of patients did not require an
increase in dose from their initial dose
Taylor88 Randomized, 114 Intranasal FPNS
a FPNS produced significantly better pain
placebo-controlled, intensity scores at 5 minutes than placebo
double-blind (P < .05). Patient satisfaction for
convenience and ease of use was reported
by 70% and 68% of patients, respectively,
and 87% of patients continued treatment
with FPNS after the study
Kaasa93 Randomized, open-label, 19 Intranasal Fentanyl Intranasal fentanyl demonstrated quick
two-period, crossover onset and was well tolerated in managing
breakthrough pain
Kress94 Phase III, double-blind, 139 Intranasal Fentanyl Intranasal fentanyl facilitated rapid onset of
randomized, placebo activity and was clinically effective in
controlled, crossover managing breakthrough pain
Fallon95 Phase III, double-blind, 110 Intranasal, oral Fentanyl Compared with IRMS, FPNS significantly
randomized, controlled, improved mean PID (15) scores. 57.5% of
crossover FPNS-treated episodes significantly
demonstrated onset of PI improvement by
5 minutes and 95.7% by 30 minutes
Abbreviation: INFS, intranasal fentanyl spray.
a FPNS: fentanyl pectin nasal spray.

Thus, this route of administration is painful for the patient,
time-consuming for the nursing staff, and difficult to carry out
in the home-setting.
Bolus administration can be substituted by continuous IV
infusion (CIVI) using a pump. This type of administration is very
frequent in the cancer population during hospitalization above
all in those with central venous catheters. CIVI of opioids has
been reported to be effective and safe in managing cancer pain in
patients who are less responsive to analgesics administered at the
maximum tolerated dose by other routes.99,100 PCA is also pos-
sible by IV route.101
The most frequently used drugs are short-acting opioid ago-
nists such as morphine, hydromorphone, and fentanyl.102
Although morphine is the drug of choice, clinical experience
has shown that other drugs, such as methadone, hydromorphone,
and fentanyl, can also be used successfully.103,104
The choice of a drug for CIVI depends on the previous anta-
lgic treatment and on the pharmacokinetic profile of the drug
employed. If the patient refers to a good analgesia with a particu-
lar opioid but presents adverse effects to a bolus administration,
this is a suitable candidate for CIVI with the same drug. On the
other hand, if the patient presents adverse effects at plasmatic
Alternative Routes for Systemic Opioid Delivery
peak and also refers poor or the absence of analgesia, the CIVI
must be initiated with a different opioid. In choosing an analgesic
drug, its half-life is, by far, the most important pharmacokinetic
factor. For this reason, morphine and hydromorphone, both hav-
ing short half-lives, are the preferred infusion drugs. With the
use of long half-life medication such as methadone, the delay to
steady state may result in the slow onset of analgesia when CIVI
is increased or in the late appearance of toxicity after analgesia
appears.
The opioid dosage at the beginning of treatment depends
on the patient’s pharmacological intake. Patients treated with
repeated parenteral doses can switch to CIVI with the same
drug using the same daily dosage, whereas the administration of
a different opioid would require a dosage reduction of between
1/2 and 2/3.
Portenoy et al.100 reviewed the clinical experience of 36 patients
who received CIVI. Mean doses during CIVI were equivalent to
maximum morphine initial doses of 17 mg/hour (range 0.7–100),
with maximum doses reaching 69 mg/hour (range 4–480) and
52 mg/hour (range 1–480) at the end of the treatment. Pain relief
was acceptable in 28 CIVIs, unacceptable in 17, and unknown in
one. The most important side effects, beginning or progressing
during the CIVIs, were sedation, confusion, constipation, and
myoclonus. This review suggests that CIVI is safe; that analge-
sia may require rapid dose escalation; and that, while not all the
patients had an acceptable analgesia; failure of CIVI with one
medication because of incomplete cross-tolerance could be fol-
lowed by effective analgesia obtained with a different opioid.
Oral and IV oxycodone were compared in a single-dose study.105
Although IV oxycodone produced a faster onset of pain relief,
the duration of analgesia was about 4 hours with both routes of
oxycodone administration; IV oxycodone produced significantly
more adverse effects.
The pharmacokinetic of IV methadone showed rapid and exten-
sive distribution phases followed by a slow elimination phase.106
Manfredi et al.107 described the dramatic beneficial effects of IV
methadone in four patients in whom IV morphine and hydromor-
phone failed to produce adequate pain relief despite titration to
dose-limiting side effects. All the patients had long-lasting pain
relief without significant side effects at a methadone dose equal
to 20% of the hydromorphone dose. Fitzgibbon et al.108 described
the successful use of large doses of IV methadone administered
by PCA and continuous infusion for pain refractory to large doses
of IV morphine. Morphine was stopped, and treatment with
methadone via PCA was initiated (incremental dose 10 mg every
6 minutes) with a continuous infusion of methadone at a rate
of 40 mg/hour. On day 3, methadone was decreased to 200 mg,
with a good pain management and no adverse effects. The patient
was discharged after 5 days with a dose of 220 mg/day (average
daily methadone was approximately 1/10 that of morphine). After
6 weeks, the dose was increased up to 400 mg/day, with good pain
control and no adverse effects.
Even if the titration with strong opioids is commonly per-
formed using immediate-release oral morphine every 4 hours,
there are some clinical situations such as severe pain where pain
relief has to be achieved as quickly as possible. Tables 28.6109–111
and 28.7112,113 show the studies reporting “fast titration” result-
ing in rapid pain relief of moderate-to-severe pain in cancer
patients treated with bolus doses of IV morphine or fentanyl
and then switched to oral morphine or transdermal fentanyl.
These authors show that “fast titration” with IV opioids is effec-
tive and safe.
263
At the Memorial Sloan Kettering Cancer Center in New York,
the patients on transdermal fentanyl presenting severe episodes of
pain are switched (TTS removed) to CIVI of fentanyl using a trans-
dermal: IV conversion of 1:1. PCA IV fentanyl is used to adminis-
tered rescue on demand doses (50–100% of the CIVI rate).
Continuous parenteral (SC or IV) opioids improved analgesia
and tolerability in 71% of cancer patients previously treated with
oral opioids (codeine, tramadol, morphine, and methadone) or
with transdermal fentanyl. On the basis of this study, parenteral
opioids may be considered a good alternative to spinal opioids.114
CIVI of opioids used in cancer-related pain is specifically
indicated in cases of generalized edema, coagulation disor-
ders, increased frequency of SC local site infections, reduced
peripheric circulation, when frequent IM or IV injections are
required to maintain pain control, in the presence of prominent
“bolus effects” on repetitive injection, and when rapid titration of
drug doses is required to produce rapid pain relief.
Data of literature115,116 show that EV and SC routes are equi-
analgesic for most patients when administered as a continuous
infusion. Pain control and side effects are quite and acceptable.
There are several considerations for using the IV route. This
route may have limited availability (especially in the home/nurs-
ing home setting) and can limit patient freedom/mobility. The
IV route generally requires a higher level of patient and nursing
involvement, training, and education; and skilled nursing may be
required if the patient/family is unable to care for a catheter.117
Transdermal route
Substances with high lipid solubility and molecular weight below
800–1000 Da (kDa) can pass through the skin. The absorption
rate varies according to different factors such as the type of the
vehicle, the skin characteristics (the thickness of stratum cor-
neum) and conditions, the body surface.
Currently, the only approved transdermal opioids in many
countries are fentanyl and buprenorphine.
Among opioids, the potent synthetic drug “fentanyl citrate” is
particularly suitable for transdermal administration, and its util-
ity in pain therapy has been extensively evaluated. Transdermal
fentanyl systems (TTS) are available in four release programs
of 12, 25, 50, 75, and 100 μg/hour, depending on the patch size,
and the drug is released continuously for 3 days. A substantial
amount of fentanyl remains in used systems even after 3 days of
application.118 When a TTS is removed, fentanyl continues to be
absorbed into the systemic circulation from the cutaneous depot.
However, opioid withdrawal symptoms may occur after discon-
tinuation of TTS administration, as well as after conversion from
other opioids to TTS.119,120
Pharmacokinetic studies demonstrated that the rate of absorp-
tion of fentanyl from the transdermal delivery is constant, begin-
ning 4–8 hours after placement of the patches. Steady state is
reached on the third day. However, a wide individual variabil-
ity exists.121 There is a lag period after patch application before
plasma concentrations approach therapeutic levels. This lag
period is highly variable, with a mean value of about 13 hours.122
The TTS should be changed every third day. However, published
data show that application intervals have to be shortened in about
25% of patients at 48–60 hours because on the third day of each
patch period, the need of rescue doses of short release oral mor-
phine was major of first and second day.123 In 11–43% of patients
during long-term treatment, the patch had to be changed every
48 hours.121
264 Textbook of Palliative Medicine and Supportive Care

TABLE 28.6  Intravenous Titration (Dose Finding) with Morphine for Severe Cancer Pain
Study Design and Patient Initial Morphine Dosage Following Dosage
Authors (Ref.) Population and Route and Route Results
Radbruch et al. 109 Prospective study. 26 IV PCA pump programed Oral SR morphine q12h; Mean PI (NRS 0–100):
inpatients with uncontrolled for 24 hours: 1-mg bolus, dose on the basis of the At entry: 67
pain, on step II opioids lock-out interval of previous IV requirements. After 5 hours: 22
5 minutes. Max. dose of IV-PO conversion 1:2 At day 7: 17
12 mg/h BTP treated with IV PCA At day 14: 12
until stable analgesia was Mean morphine dosage (IV PCA) in
reached the first 24 hours: 32 mg (range
4–78) mean daily morphine dosage
(PO + IV PCA for BTP) at PCA
termination (range 2–6 days):
139 mg (range 20–376) mean
morphine dosage (PO) at day 14:
154 mg (range 20–344)

• No significant adverse events

Mercadante et al.110 Prospective study. Forty-five IV bolus (2 mg every 2 Oral SR morphine; dose on Mean PI (NRS 0–10):
inpatients with severe (NRS minutes), repeated until the basis of the previous IV At entry: 8.1
≥ 7) and prolonged pain. At analgesia or adverse effects requirements After 9.7 minutes: 3.0 with a mean
entry, 30 patients were on were reported IV-PO conversion: 1:3 for IV morphine dosage of 8.5 mg
step II opioids and 15 were lower IV dosages, 1:2 for Mean daily oral morphine dosage at
on step III opioids higher IV dosages time to discharge: 131 mg
The same IV dose was (107–156) + 10.8 mg (IV extra
maintained for BTP in the doses). No significant adverse
first 24 hours events
Harris et al.111 RCT. IV group: IV group: Percentage of patients achieving
62 strong opioid naïve in 1.5 mg bolus every Oral IR morphine q4h, on satisfactory pain relief:
patients PI NRS > 5 10 minutes until pain relief the basis of the previous IV After 1 hour: IV group, 84%;
Patients were randomized to (or adverse effects) requirements oral group, 25% (P < .001)
receive IV morphine Oral group: IV: PO conversion 1:1. After 12 hours: IV group 97%;
(n = 31) or oral IR IR morphine 5 mg every Rescue dose: the same dose oral group 76% (P < .001)
morphine (n = 31) 4 hours in opioids naive pts every 1 hour max. Oral After 24 hours: IV group and
10 mg in patients on weak group: follow the same oral group similar IV group:
opioids. Rescue dose: the scheme Median morphine dosage (IV) to
same dose every 1 hour achieve pain relief: 4.5 mg (range
max 1.5–34.5). In the same group,
mean morphine dosage (PO) after
stabilization: 8.3 (range 2.5–30)
mg Oral group:
Median morphine dosage to achieve
pain relief: 7.2 (2.5–15) mg.
No significant adverse events
Abbreviations: IV, intravenous; PCA, patient-controlled analgesia; NRS, numerical rating scale; step II of the WHO analgesic ladder; BTP, breakthrough pain.

For stable, chronic, cancer pain, this formulation offers an
interesting alternative to oral morphine.124–126 In comparison
with oral morphine, TTS fentanyl seems to cause fewer GI side
effects, with special reference to constipation.127,128 Its useful-
ness in chronic, nonmalignant pain is also strongly suggested
by recently published papers.129,130 Of course, this formulation is
contraindicated during the titration phase, or to control BTP.
The permeability coefficient for fentanyl is affected by tempera-
ture. A rise in body temperature to 40°C may increase the absorp-
tion rate by about one-third.127 Acute toxicity related to increased
absorption secondary-to-high temperature has been reported.
The partial agonist buprenorphine is another ideal candidate
for delivery via a transdermal patch.131 In the currently available
formulation (buprenorphine transdermal delivery system), this
drug is incorporated in a polymer adhesive matrix, from which
it is released through the skin. Transdermal buprenorphine
has a bioavailability of about 50%, which is comparable to that
observed after sublingual administration.132
Although comparative analysis between the analgesia and the
tolerability of TD and oral opioids shows that transdermal opi-
oids are at least equivalent to the oral opioids,133 it is well known
that transdermal fentanyl and transdermal buprenorphine are
best reserved for patients whose opioids requirements are sta-
ble.134 They are usually the treatment of choice for patients who
are unable to swallow, patients with poor tolerance of morphine,
and patients with poor compliance.
An important characteristic of the pharmacokinetics of TD
buprenorphine is its safe use in patients with renal impairment.
Alternative Routes for Systemic Opioid Delivery 265

TABLE 28.7  Intravenous Titration (Dose Finding) with Fentanyl for Severe Cancer Pain
Study Design and Patients
Authors (Ref.) Population
Soares et al.112 Prospective study. Eighteen
outpatients’ PI NRS ≥7,
on oral morphine therapy
for at least 2 weeks.
Excluded patients with
BTP and neuropathic
pain
Grond et al.113 Prospective study. 50 GI
or head and neck cancer
patients with severe pain.
Excluded patients with
BTP and opioid
unresponsive pain
Abbreviations: IV, intravenous; NRS, numerical rating scale; BTP, breakthrough pain; GI, gastrointestinal; TTS, transdermal therapeutic system; SC, subcutaneous.
a PCA IV fentanyl (mg/day)     TTS fentanyl (mg/day)
Initial Morphine/Fentanyl
Dosage and Route
Repeated IV bolus in four
steps, with 5-minute
intervals.
Evaluation of pain and side
effects after each step.
Dosage: Oral morphine
converted to IV morphine
(dose ratio 1:3) and then to
IV fentanyl (dose ratio 1:100).
Steps 1 and 2: 10% of the total
IV morphine taken in the
previous 24 hours
• Steps 3 and 4: steps 1 and
2 dosage increased by 50%
Previous opioids were
discontinued and PCA IV
fentanyl started: demand
dose 50 μg, lock-out time
5 minutes, hourly max dose
250 μg
Following Dosage and Route
The protocol was not
performed to find future
doses of opioids
The management of pain
after the fast titration with
fentanyl was as follows:
Nine patients increased the
previous morphine dose.
• Three patients switched
to the opioid
• Five patients switched to
the route. Five patients
received ketamine
infusion
On the second day TTS
applied with a rate delivery
calculated from the PCA
dosea of the first 24 hours +
IV fentanyl for rescue doses
during first and second day,
thereafter oral or SC
morphine for rescue doses. If
PI increased at the end of the
72 hours period and an
increase of the TTS dose was
ineffective, the systems were
changed every 48 hours
Results
100% of patients achieving
satisfactory pain relief.
Mean time to achieve pain relief:
11 minutes (range 5–25 minutes)
PI less than 4 mean previous oral
morphine dosage 276 mg (range
180–600).
Mean IV fentanyl required to
achieve pain relief: 214 μg (range
60–525).
No significant adverse events
The patients were treated for 66 ±
101 days (3–535)
The mean delivery rate was 5.9 ±
4.1 mg/day
The mean PI decreased from
initially 45 ± 21–19 ± 15 in the
titration phase and 15 ± 11 during
long-term treatment.
Three patients had moderate
respiratory depression moderate
or severe constipation in 40% of
the patients prior to study, in 18%
during titration period and in 10%
during long-term treatment

0.2–0.6 0.6
0.6–1.0 1.2
1.0–1.4 1.8
1.4–1.8 2.4

Moreover, hemodialysis does not affect buprenorphine plasma
levels, and this result leads to a stable analgesic effect.135,136
In 2015, Zecca et al. assessed the relative bioavailability of
fentanyl from two different transdermal systems by evaluating
plasma drug concentrations after single administration with a
randomized single center open label cross over trial in 36 healthy
volunteers. He demonstrated that the 90% confidence intervals of
the AUC ratio (116.3% [109.6, 123.4%]) and C(max) ratio (114.4%
[105.8, 123.8%]) were well included in the acceptance range and
the C(max) ratio also met the narrower bounds of 80–125%.
There was no relevant difference in overall safety profiles of the
two preparations investigated, which were adequately tolerated,
as expected for opioid-naïve subjects.137
Topical opioids
The use of topical opioids in the treatment of pain in malignant
and nonmalignant oropharyngeal mucositis and ulcers is based
on the discovery of peripheral opioids receptors that may be
enhanced by the presence of inflammation.138,139 Moreover, mor-
phine and its metabolites are largely undetectable systemically
when applied topically to skin ulcers.140 Kalso et al.141 have found
the efficacy of peripheral opioids injections for local analgesia,
such as intra-articular morphine after knee surgery.
In a pilot randomized study, Cerchietti et al.142 evaluated the
role of morphine oral rinses administered with 15 mL of either 1
per 1000 or 2 per 1000 morphine solution in patients with painful
chemoradiotherapy-induced stomatitis. Rinses with 2 per 1000
morphine solution showed better pain relief (median 80%) than
those with 1 per 1000 (median 60%, P = .0238). No morphine
was detectable in the blood through GC–MS analysis. The most
important side effect due to oral morphine rinses was burning
sensation.
In a next study, Cerchietti et al.143 randomized 22 patients with
painful mucositis due to chemoradiotherapy for head and neck
cancer to receive morphine mouthwash (MO; 1/4 patients) or
magic mouthwash (MG) composed by equal parts of lidocaine,
diphenhydramine, and magnesium aluminum hydroxide (12
patients). Patients on morphine mouthwashes compared with
MG group (1) had a lesser number of days (3.5) with pain (P =
.032); (2) had a significantly lower intensity of pain (P = .038); (3)
did not require strong opioids to relieve pain; (4) showed signifi-
cant difference in the duration of severe functional impairment
(P = .017); and (5) had less local side effects (P = .007).
266
Topical morphine administered as mouthwashes during
chemoradiotherapy may be considered effective in reducing pain-
ful mucositis in head and neck cancer patients.
Opioids such as morphine144 and diamorphine145 have also
been used to reduce pain in patients with ulcers as gel applica-
tions by means of Intransite Gel®, which is an aqueous gel that
in contact with a wound absorbs excess exudates and produces a
moist environment at the surface.
Zeppetella and Ribeiro144 randomized 21 hospice patients with
painful ulcers to receive topically either morphine (morphine sul-
fate injection 10 mg/mL in 8-g IntraSite gel) or placebo (water
for injection 1 mL in 8-g IntraSite gel). Topical morphine pro-
duced significantly lower pain, as assessed by numerical rating
scale (NRS) score, compared with pretreatment period and pla-
cebo group (P < .001) and showed no difference in rescue doses
requirement. Patients reported some local effects such as itching
and burning sensation.
Topical gels, also used for painful wound care, provide periph-
erally acting analgesia without central side effects common in
systemic opioids.146
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29
INTERVENTIONAL PAIN PROCEDURES IN PALLIATIVE CARE

Po-Yi Paul Su, Ann Cai Shah, and Sarah Gebauer

Contents
Introduction........................................................................................................................................................................................................................271
Nerve blocks........................................................................................................................................................................................................................271
Definitions.....................................................................................................................................................................................................................271
Methods of block/duration of effect.........................................................................................................................................................................272
Transient nerve blocks..........................................................................................................................................................................................272
Neurolytic nerve blocks........................................................................................................................................................................................272
Effect of blocks on components of pain...................................................................................................................................................................272
Contraindications, risks, and practical considerations........................................................................................................................................273
How a block is performed..........................................................................................................................................................................................273
Autonomic blocks..............................................................................................................................................................................................................273
Celiac plexus/splanchnic plexus blocks...................................................................................................................................................................273
Superior hypogastric blocks.......................................................................................................................................................................................275
Other sympathetic blocks...........................................................................................................................................................................................275
Peripheral somatic nerve blocks.....................................................................................................................................................................................275
Side effects of peripheral nerve blocks....................................................................................................................................................................275
Head, face, and neck peripheral nerve blocks........................................................................................................................................................276
Upper extremity peripheral nerve blocks................................................................................................................................................................276
Chest and abdominal peripheral nerve blocks.......................................................................................................................................................277
Groin and pelvis peripheral nerve blocks...............................................................................................................................................................277
Lower extremity peripheral nerve blocks................................................................................................................................................................277
Neuraxial analgesia............................................................................................................................................................................................................278
Introduction..................................................................................................................................................................................................................278
Epidural analgesia.........................................................................................................................................................................................................278
Anatomy...................................................................................................................................................................................................................278
Efficacy......................................................................................................................................................................................................................278
Complications and cost considerations.............................................................................................................................................................278
Intrathecal analgesia....................................................................................................................................................................................................278
Anatomy...................................................................................................................................................................................................................278
Efficacy......................................................................................................................................................................................................................279
Complications and cost considerations............................................................................................................................................................ 280
Botulinum toxin for pain management........................................................................................................................................................................ 280
Mechanism of action.................................................................................................................................................................................................. 280
Studies of botulinum toxin........................................................................................................................................................................................ 280
How botulinum toxin injections are performed................................................................................................................................................... 280
Side effects and risks of botulinum toxin injections............................................................................................................................................ 280
Conclusion.......................................................................................................................................................................................................................... 280
References............................................................................................................................................................................................................................281

Introduction Nerve blocks

Most patients with cancer pain can be treated using the World
Health Organization (WHO) analgesic stepladder (Zech et al.
1995). Approximately 10–25% will need an interventional proce-
dure for pain management, which is considered the fourth step
of the WHO stepladder (Miguel 2000). An interventional tech-
nique may be considered due to intolerance of systemic medi-
cations or pain despite optimal medical management (Miguel
2000). In general, the goals of these procedures are to decrease
pain severity and interference, and to improve the quality of life
of the patients (Rork et al. 2013).
Definitions
Broadly speaking, regional anesthesia is the administration of
medication to produce a sensory block in a specific area of the
body (Rork et al. 2013). Regional analgesia provides pain relief,
though not necessarily complete numbness. Colloquially, these
terms are often used interchangeably, but mechanistically, these
terms reflect the differential blockade of motor, sensory, and
nociceptive nerves. In this chapter, regional anesthesia refers to
techniques that provide either anesthesia or analgesia. Neuraxial
anesthesia is one aspect of regional anesthesia specific to the

271
272
spinal cord and the adjacent nerve roots and is covered in the later
portion of this chapter.
Moreover, most regional anesthesia procedures, regardless of
the type of nerve they affect (autonomic or somatic) or their effect
on the nerve (neurolytic or transient), are referred to as “nerve
blocks.” Autonomic nerve blocks almost always block transmis-
sion of the sympathetic system. Depending on the composition of
peripheral somatic nerves (motor, mixed motor and sensory, or
sensory nerves), blocking these nerves will have their respective
clinical effects.
Methods of block/duration of effect
Nerve blocks traditionally imply a one-shot delivery of local anes-
thetic to the target nerve.
Transient nerve blocks
Transient nerve blocks are performed with local anesthet-
ics, which work by blocking sodium channels. The duration of
action depends on the type of local anesthetic with some lasting
less than an hour to most of the day (French and Sharp 2012).
The limited duration of action of local anesthetic nerve blocks
allows the nerve block to be promptly evaluated, and undesired
effects such as unwanted motor paralysis are rapidly reversed.
Local anesthetic nerve blocks are frequently used as diagnostic
tools to assess potential benefits and side effects of specific nerve
targets prior to other interventions (Yuen et al. 2002). In some
cases, local anesthetic has the potential to decrease sensitization,
which is a feature of chronic pain, and thereby exert a treatment
effect longer than the pharmacologic half-lives of the local anes-
thetic itself (Arner et al. 1990; Blumenthal et al. 2011; Okell and
Brooks 2009). Addition of adjuncts to the local anesthetic such
as clonidine can extend the duration of action of local anesthetic
(Popping et al. 2009).
Peripheral nerve catheters can be placed in close proximity to
the target nerve to provide a conduit for the delivery of medi-
cation such as local anesthetic, an adjunct, or an opioid. This
method can provide relief for days, weeks, or even months (Esch
et al. 2010; Pacenta et al. 2010). Studies in postoperative patients
with peripheral nerve catheters attached to an electronic or
spring-powered pump with prefilled medication show that their
catheters can be easily managed at home, though the reservoir
may require repeated refills for longer infusions (Ilfeld 2011a).
The most commonly encountered complication includes catheter
dislodgement, obstruction, or fluid leakage at the catheter site.
These complications may be reduced by using subcutaneous tun-
neling, anchoring device, or liquid adhesive (Ilfeld 2011b).
There is clinical evidence that clonidine itself exerts thera-
peutic effects in chronic neuropathic pain through its effect as
an alpha-2 agonist (Kumar et al. 2014). Steroids are of particular
interest as they can also extend the duration of action of local
anesthetic (Pehora et al. 2017). The analgesic mechanism of ste-
roids is thought to be due to its anti-inflammatory properties, and
inhibition of ectopic neuronal firing. Despite its widely adopted
use in the treatment of chronic pain, evidence regarding its clini-
cal effectiveness is not substantial (Desmet et al. 2013; Murphy
et al. 2000; Wong et al. 2010).
Neurolytic nerve blocks
Neurolysis causes nerve injury and temporary denervation of
the target tissues. This can be accomplished by applying ther-
mal energy as in the case of radiofrequency ablation, or by
Textbook of Palliative Medicine and Supportive Care
applying chemical agents such as phenol or alcohol (Hsu 2014).
Both approaches cause Wallerian degeneration of the nerve fiber
distal to the lesion along with the myelin sheath. Denervation is
only temporary but typically lasts months because axons regen-
erate at a rate of 1–5 mm/day (Tetzalff and Bisby 1989). Another
common characteristic between chemical and thermal neurolysis
is their indiscriminate nature; sensory, motor neurons, and sur-
rounding tissues will all be affected.
Thermal ablation
Radiofrequency ablation generates an area of coagulative necrosis at
a temperature between 60 and 90°C along the active tip of an insu-
lated needle. In order to maximize the neurolysis, the tip should
be placed parallel to the target nerve—a rather challenging task if
the nerve is not directly visualized (i.e., fluoroscopy). One potential
shortcoming is incomplete lesioning of the target nerve leading to
faster reinnervation (compared to chemical neurolysis) and inflam-
mation (neuritis) which can lead to symptoms of pain, paresthesia, or
paralysis (Joo 2013). Sensory stimulation testing may be performed,
but motor stimulation testing must always be conducted prior to
ablation to minimize the risk of unwanted motor deficits.
A nondestructive alternative to radiofrequency ablation,
termed “pulsed radiofrequency ablation,” was described in 1995.
In contrast to radiofrequency ablation inducing coagulative
necrosis, pulsed radiofrequency ablation delivers high-voltage
bursts interrupted by silent phases to allow for heat elimination,
thereby keeping the target tissue temperature below 42°C and
preventing tissue damage. The exact mechanism of pulsed radio-
frequency ablation remains unclear but is thought to be medi-
ated by modulating electrical fields to affect neurons by altering
gene expression (Bryd and Mackey 2008). Pulsed radiofrequency
ablation is extremely safe; there are no reported adverse effects
reported except those associated with needle placement. The evi-
dence for its efficacy in clinical practice is mixed, but literature
regarding this technique continues to grow (Facchini et al. 2017).
Chemical ablation
Phenol (6–10%) and alcohol (50–100%) cause nonselective
destruction of tissues by the denaturation of neuronal proteins
and can cause vascular injury that can alter the nerve regenera-
tion process. Phenol may have a shorter duration of action than
alcohol and has a theoretically higher risk of neuroma formation;
however, it is non-painful on injection, and more viscous and
hyperbaric compared to alcohol, which may be useful in certain
clinical situations (Jackson and Gaeta 2008). Potential complica-
tions from chemical neurolysis include necrosis of the skin and
other nontarget tissue, neuritis, anesthesia dolorosa, and pro-
longed motor paralysis. Local anesthetic may be injected first
to assess for efficacy, then neurolysis with alcohol or phenol may
follow at the time of the diagnostic block or within a few weeks
(Jackson and Gaeta 2008). Given the aforementioned risks, the
American Society of Anesthesiologists and the American Society
of Regional Anesthesia and Pain Medicine recommend against
the use of chemical neurolysis in the routine treatment of chronic
noncancer pain (ASA and ASRA 2010).
Effect of blocks on components of pain
Cancer pain can be nociceptive, neuropathic, somatic, visceral/
autonomic pain, or a combination (Portenoy 2011). In addition,
Interventional Pain Procedures in Palliative Care
cancer patients are also susceptible to noncancer-related pains,
such as ischemia, immobility, or wounds (Klinkenberg et al.
2004). Peripheral nerve blocks are often used to address pain of
somatic origin, and autonomic nerve blocks are reserved for sus-
pected visceral or sympathetically mediated pain. The etiology
of visceral pain is complex, and the visceral afferent fibers often
travel with autonomic fibers (Cervero and Laird 1999). Decisions
about which nerve(s) to block must consider the likely pathophys-
iology of the pain generator(s).
Contraindications, risks, and
practical considerations
Most risks of nerve blocks are related to the possible puncture
of major vessels and organs near the target nerve, or failure of
the block. Nerve damage and infection are also possible, although
rare (Ilfeld 2011b). The procedural risk of bleeding depends on
the type of procedure as well as the potential consequences of
bleeding. The bleeding risk of most peripheral nerve blocks is low,
whereas autonomic blocks (stellate, splanchnic, celiac, lumbar,
and hypogastric) are considered intermediate, and neuraxial pro-
cedures (epidurals and intrathecal pumps) are considered high
bleeding risk (Narouze et al. 2018).
Many cancer patients are on anticoagulants for the treat-
ment or prevention of venous thromboembolism. Management
of anticoagulants for patients on antithrombotic or antiplatelet
therapy for pain interventions is a frequent clinical dilemma. In
general, for low bleeding risk procedures, patients may be able to
continue their anticoagulants. For intermediate and high bleed-
ing risk procedures, a multidisciplinary approach is warranted to
balance the risks of venous thromboembolism and bleeding and
may require bridging of anticoagulation, for example (Horlocker
et al. 2018; Narouze et al. 2018).
There is little evidence for a maximum safe international
normalized ratio (INR) or minimum platelet count for neuro-
lytic blocks (Raj et al. 2004). The American Society of Regional
Anesthesia suggests an INR of 1.4 or less for deep plexus or
peripheral blocks (Horlocker et al. 2010). However, less restric-
tive guidelines are proposed for injection sites in areas amenable
to compression (Horlocker et al. 2010). Local infection or tumor
invasion in the path of the nerve block is generally considered
to be a contraindication (Chambers 2008; Horlocker et al. 2010).
Blocks near major vessels or in highly vascular regions should
be performed in a closely monitored setting due to the risk of
hemodynamic collapse with intravascular injection, bleeding, or
other serious complication. Several large studies have established
the incidence of local anesthetic systemic toxicity in peripheral
blocks to be 1 in 1,000 and is dependent on the type of block
(Auroy et al, 1997).
In the palliative care population, the need for prone positioning
or transport to a radiology or gastroenterology suite may be sig-
nificant barriers to care (Bhatnagar and Gupta 2011). Suboptimal
positioning due to patient factors adds a degree of procedural
complexity for the interventionalist. Some patients may require
sedation to tolerate the procedure at a cost of increased proce-
dural risk (Bahn and Erdek 2013).
How a block is performed
Traditionally, fluoroscopy has been used to advance a small-
bore needle to the target nerve. This technique relies on the
relative location of the nerves to bony landmarks visible on fluo-
roscopy. Peripheral nerve stimulation has historically been used
273
to guide nerve localization by using the association between
electrical current and needle-to-nerve distance to elicit prefer-
ential motor nerve response; this technique remains a popular
technique alone or in combination with ultrasound techniques
(Klein et al. 2012).
There is an increasing prevalence in the use of ultrasound-
guided approach to nerve blocks. Ultrasound allows for direct
visualization of neural target, surrounding vascular, and soft
tissue structures and offers dynamic live visualization of the
needle during the procedure (Ilfeld 2011a). CT-guided and
endoscopic ultrasound approaches have also become more
popular (Bhatnagar et al. 2012, Wyse et al. 2017). Current data
do not suggest that one method of nerve localization is mark-
edly safer or more effective than another for most patients
(Arcidiacono et al. 2011; Nagels et al. 2013). One should con-
sider all the various available techniques to achieve the desired
block based on the patient’s characteristics. For example, can
the patient tolerate prone positioning, or does the patient’s
tumor burden distort his/her soft tissue anatomy relative to
bony landmarks?
Autonomic blocks
General visceral afferent fibers conduct sensory information
(including pain) from internal organs, glands, and blood vessels
back to the central nervous system. These fibers are responsible
for the sensation of “visceral” (or referred) pain. General visceral
afferents travel from the internal organs along with sympathetic
efferent fibers passing through prevertebral ganglion to the para-
vertebral ganglion, where they then enter the dorsal horn of the
spinal cord via the dorsal root ganglion. The convergence of gen-
eral visceral afferents with somatic nociceptive afferents in the
dorsal horn contributes to referred pain. Visceral afferent fibers
also travel along in parallel with parasympathetic nerves, but
these afferents have not been implicated in mediating pain (Ko
and Burchiel, 2015). As prevertebral ganglion and paravertebral
ganglion are anatomical hubs for the general visceral afferents,
they are the targets for autonomic blocks. The paired chain of
paravertebral ganglion (also known as the sympathetic trunk)
forms from the lower cervical levels down to the level of the
sacrum, and they are located just lateral to the vertebral bodies.
There are three prevertebral ganglia (celiac ganglia, superior mes-
enteric ganglia, and inferior mesenteric ganglia) that are located
ventral to the aorta and are in between the abdominal/pelvic
organs and the sympathetic trunk (Figure 29.1). Nerve blocks
will affect not only visceral afferents but also sympathetic effer-
ent fibers with resultant “sympathectomy” and overall increase
in parasympathetic tone (i.e., vasodilation leading to potential
hypotension).
Celiac plexus/splanchnic plexus blocks
Celiac plexus blocks (and neurolysis) are among the most well-
studied nerve blocks for cancer pain stemming from tumors of
the pancreas, stomach, gallbladder, and liver (De Leon-Casasola
2000; Mauck and Rho 2010). The plexus is located anterior to
the aorta at the level of the L1 vertebrae, inferior to the origin
of the celiac artery (Mauck and Rho 2010). The celiac plexus
contains autonomic and visceral fibers that innervate the vis-
cera of the upper abdomen and often travel together (Erdek
et al. 2010). Traditionally, this block is performed using the
transaortic approach, although there is no statistically sig-
nificant difference in clinical efficacy with retrocrural and
274 Textbook of Palliative Medicine and Supportive Care

FIGURE 29.1  Visceral afferentation. Visceral afferent fibers travel from the internal organs along the sympathetic and parasympa-
thetic fibers to the spinal cord. Visceral cancer pain can result from distension, ischemia, inflammation, and traction from cancer mass
in abdominal and pelvis. (From Cousins MJ, Carr DB, Horlocker TT, Bridenbaugh PO, eds. Cousins and Bridenbaugh’s Neural Blockade
in Clinical Anesthesia and Pain Medicine, 4th ed., Philadelphia, PA: Lippincott Williams &Wilkins, p. 852, Figure 39.5 with permission.)
Interventional Pain Procedures in Palliative Care
FIGURE 29.2  A posterior approach to the splanchnic nerves and celiac plexus. (From Cousins MJ, Carr DB, Horlocker TT,
Bridenbaugh PO, eds., Cousins and Bridenbaugh’s Neural Blockade in Clinical Anesthesia and Pain Medicine, 4th ed., Philadelphia,
PA: Lippincott Williams & Wilkins, with permission.)
splanchnic approaches (targeting at the level of paravertebral
ganglions) (Figure 29.2; Ischia et al. 1992). This block can be
performed in the prone, supine, or lateral positions depending
on technique used (De Leon-Casasola 2000). A meta-analysis
of 21 studies showed that approximately 90% of patients receive
partial or complete short-term pain relief, and the majority have
longer term relief (Eisenberg et al. 1995). A landmark random-
ized, double-blind, placebo-controlled trial of 100 patients com-
pared neurolytic celiac plexus blocks to systemic opioid therapy.
The study showed a sustained improvement in pain scores but
no difference in quality of life or survival in the neurolytic celiac
plexus group (Wong et al. 2004). Most studies have found that
patients continue to require opioids in addition to the neuro-
lytic celiac plexus block, though the total opioid requirements
decrease after a neurolytic celiac plexus block (Arcidiacono et al.
2011; Mercadante et al. 2003). There is debate regarding whether
this technique should be used early in the course of illness or
when medical therapy fails (De Oliveira et al. 2004; Tempero
et al. 2010). Diarrhea, hypotension, and transient localized pain
are the most common complications, and major complications
occur less than 2% of the time (Eisenberg et al. 1995). One nota-
ble major complication associated with celiac plexus block is
anterior spinal cord syndrome through disruption of the lumbar
arteries leading into the artery of Adamkiewicz. The mechanism
behind acute spinal cord ischemia may include acute thrombosis
from needle injury or vasospasm in response to injected alcohol
neurolysis (Davies 1993).
Superior hypogastric blocks
Patients with pelvic pain from gynecologic, colorectal, and blad-
der pelvic tumors may respond to superior hypogastric blocks
(Kroll et al. 2014). The superior hypogastric blocks target the
paravertebral ganglions between the L5 vertebral body and
the sacrum. The largest study to date included 227 patients
with mostly gynecological cancer, 159 of whom had a reduc-
tion in pain with a diagnostic block and therefore received a
neurolytic hypogastric block (Plancarte et al. 1997). Seventy
275
percent of patients had adequate pain relief for at least 3 weeks,
though 38% required a second neurolytic superior hypogastric
block (Plancarte et al. 1997). Mean opioid use also decreased
(Plancarte et al. 1997). Major complications seem to be uncom-
mon (Bosscher 2001).
Other sympathetic blocks
Lumbar sympathetic blocks (paravertebral ganglions at the L2
and L3 vertebral bodies) have shown mixed results for painful
lower extremity ischemia (Sanni et al. 2005). Ganglion impar
blocks (located ventral to the sacrococcygeal junction, where the
paired sympathetic trunks converge into a single small ganglion)
are used for perineal pain in prostate, colorectal, and vulvar can-
cers (Agarwal-Kozlowski et al. 2009; Eker et al. 2008; Ho et al.
2006). Stellate ganglion blocks (located at the level of the C6 and
C7 tubercles) are typically used for sympathetically mediated
pain of the head and neck, though there are also case reports and
series supporting its use in palliative care patients for refractory
angina (Chester et al. 2000; Moore et al. 2005), postmastectomy
pain (Nabil Abbas et al. 2011), and hot flashes in breast cancer
survivors (Haest et al. 2012). Sphenopalatine ganglion is a com-
plex neural center comprising somatosensory, sympathetic, and
parasympathetic fibers. Neurolysis of this ganglion has been
reported with success for the treatment of pain for advanced head
and neck cancers (Varghese and Koshy 2001).
Peripheral somatic nerve blocks
Side effects of peripheral nerve blocks
The main side effect of peripheral somatic nerve block is the loss
of motor function that accompanies the loss of sensation when
mixed motor and sensory nerves are targeted. This may be miti-
gated by the choice of a lower concentration anesthetic, but full
motor function is not guaranteed. For some patients, this may
limit mobility, such as with a femoral nerve block, and for others,
it may limit the ability to perform personal care, such as with a
brachial plexus block.
276 Textbook of Palliative Medicine and Supportive Care

Head, face, and neck peripheral nerve blocks
The trigeminal nerve (fifth cranial nerve) provides sensory and
motor contributions to the face and head region. The ophthalmic
branch (V1) and maxillary branch (V2) are purely sensory nerves,
but the mandibular branch (V3) is a mixed sensory and motor
nerve controlling the muscles of mastication. The trigeminal
ganglion (also known as Gasserian ganglion) is the sensory gan-
glion for the trigeminal nerve, and it is located in Meckel’s cave
in the temporal bone. Targeting of the terminal sensory branches
or the trigeminal ganglion is often used in the treatment of head
and neck cancer (Shapshay et al. 1980). Because the trigemi-
nal ganglion lies within cerebral spinal fluid, small amounts of
local anesthetic can inadvertently cause total spinal anesthesia
(Feldstein 1989).
The occipital region to the top of the head is innervated by
the greater, lesser, and third occipital nerves arising from the
upper cervical region (C1–3). Head and neck cancer-associated
headaches may be due to entrapment of these nerves or irrita-
tion due to tumor invasion. Occipital nerve blocks are effective
in treating a variety of headache disorders. Blockade of these
nerves is easy to perform and safe with only minor side effects
(Nagar et al. 2015).
Upper extremity peripheral nerve blocks
The brachial plexus, in which nerve roots from C5 to T1 form
trunks, divisions, cords, and then peripheral nerves, innervates
the upper extremity (Gorlin and Warren 2012). Blocks can be
performed at various levels of the brachial plexus. Colloquially,

TABLE 29.1  Nerve Blocks

Example of
Location of amenable Selected side effects
Pain Treatment Options pathophysiology Effect of treatment and complications Duration of Effect Setting
Upper GI/ Celiac plexus block Pancreatic cancer Sympatholysis, Diarrhea, orthostasis Months (neurolytic) Interventional pain,
abdomen decreased visceral radiology, or
pain endoscopy suites
Neuraxial anesthesia Abdominal wall Analgesia of several Equipment failure Months (catheter) Bedside (external),
(thoracic or upper tumor abdominal interventional pain
lumbar) dermatomes suite (implanted)
Pelvis Superior Ovarian cancer Sympatholysis, Need for repeat block Months (neurolytic) Interventional pain
hypogastric plexus decreased visceral or radiology suites
pain
Neuraxial anesthesia Abdominal wall Analgesia of several Possible loss of Months (catheter) Bedside (external),
(lumbar) tumor dermatomes ambulation depending interventional pain
on location of catheter suite (implanted)
Shoulder Interscalene block Tumor of the Analgesia of Diaphragmatic Hours (single shot); At bedside in
(single shot or humerus shoulder hemiparesis weeks (catheter) hospital
catheter)
Cutaneous lesions
Analgesia below the Risk of pneumothorax Hours (single shot); At bedside in
of the elbow and
shoulder and diaphragmatic weeks (catheter) hospital
forearm hemiparesis; likely loss
of arm movement
Elbow/forearm Supraclavicular, Trauma, AV fistula Analgesia below the Loss of arm movement Hours (single shot); At bedside in
infraclavicular mid-humerus weeks (catheter) hospital
Bier block Trauma Analgesia below the Loss of forearm Hours At bedside in
tourniquet movement hospital, possibly at
home
Hand Wrist block Trauma Analgesia of hand Loss of hand movement Hours (single shot At bedside, at home
only) or in hospital
Fingers Digital block Trauma Analgesia of finger Loss of movement in that Hours (single shot At bedside, at home
finger only) or in hospital
Leg and knee Femoral nerve block Femoral neck Analgesia of Difficulty with Hours (single shot); At bedside in
fracture anterior thigh and ambulation weeks (catheter) hospital
knee, very little
analgesia below the
knee
Lower leg Popliteal sciatic Tumor of the lower Analgesia below the Difficulty with Hours (single shot); At bedside in
(with or without leg knee ambulation weeks (catheter) hospital
saphenous block)
Foot Ankle block Diabetic foot Analgesia of the foot Difficulty with Hours (single shot At bedside, at home
wounds, dressing ambulation only) or in hospital
changes
Interventional Pain Procedures in Palliative Care
various brachial plexus blocks are most often referred to by the
anatomic location at which the brachial plexus is blocked. For
example, axillary block refers to brachial plexus nerve block at the
level of the axillary artery—not to be confused with nerve block of
the axillary nerve. Brachial plexus infusions have been reported
for pain of tumor growth in the bone, skin, and soft tissues of the
arm, and for Pancoast tumors (Buchanan et al. 2009; Pelaez et al.
2010; Turnbull et al. 2011; Vranken et al. 2000, 2001).
Interscalene brachial plexus blocks are performed at the roots
and proximal trunks of the brachial plexus (at the level of C6
vertebral body) to provide analgesia to the shoulder and upper
arm. This block often fails to provide analgesia to the hand due
to incomplete coverage of the inferior roots and trunks (Gorlin
and Warren 2012). A successful block always results in a hemi-
paresis of the diaphragm due to proximity of the phrenic nerve,
with an associated 25% decrease in pulmonary function and sub-
jective dyspnea (Fujimura et al. 1995; Horlocker et al. 2014). This
procedure is therefore contraindicated in individuals with respi-
ratory insufficiency or known contralateral phrenic nerve palsy.
Recurrent laryngeal nerve palsy may occur and lead to hoarse-
ness or airway obstruction. Horner’s syndrome (ptosis, miosis,
and anhidrosis) may occur secondary to blockade of the stellate
ganglion (Horlocker et al. 2014).
Supraclavicular brachial plexus blocks are performed at
the trunks of the brachial plexus just above the clavicle and
provide analgesia to the elbow, forearm, and hand. Prevalence
of pneumothorax is highest at this level between 0.5 and 6%,
but this risk has decreased dramatically with the use of ultra-
sound (Bhatia et al. 2010). Additional risks include Horner’s
syndrome, and phrenic nerve palsy (Maga et al. 2012).
Infraclavicular brachial plexus blocks offer similar distribu-
tion of coverage as supraclavicular blocks. Infraclavicular
blocks are performed at the level of the cords as the brachial
plexus emerges beneath the clavicle toward the axilla. Due to
its depth beneath the pectoralis muscles, it is a favorable loca-
tion for indwelling catheters.
Axillary brachial plexus blocks are performed at the branches
of the brachial plexus landmarked by the axillary artery near the
medial aspect of the upper arm. Brachial plexus block at this level
provides reliable analgesia to the wrist and hand with a low com-
plication rate (Maga et al. 2012).
The brachial plexus terminates into individual peripheral
nerves. In addition to the previously described techniques of
ultrasound and neurostimulator, the individual peripheral
nerves can also be blocked using field blocks such as in wrist
blocks where local anesthetic is infiltrated near the course of
radial, median, and ulnar nerves (Delaunay and Chelly 2001).
Specific anatomic areas innervated by peripheral nerve can be
further isolated such as a digital block—a single subcutaneous
injection of 2–3 mL of local anesthetic at the palmar aspect
of the base of the finger is effective, safe, and easy to perform
(Cannon et al. 2010).
Chest and abdominal peripheral nerve blocks
Intercostal nerves run along the underside of each rib. Intercostal
nerve blocks and neurolysis can be effective in the management
of intractable cancer-associated chest wall pain such as from
metastatic disease (Matchett 2016). In 25 patients with metastatic
rib lesions who received intercostal nerve blocks, 80% of patient
noted optimal local pain control and 56% reported reduction in
opioid use (Wong et al. 2007). The dreaded complication is pneu-
mothorax, but the reported incidence is about 0.07% in a large
277
series of anesthesiologist (Horlocker et al. 2014). In the abdo-
men, the nerves from the thoracolumbar spinal columns pass
laterally in between the internal oblique muscle and the trans-
versus abdominis to innervate the abdominal wall. This plane
forms the basis for the transversus abdominis plane (TAP)
block in the treatment of abdominal wall pain. TAP block can
be effectively utilized in pain of the mid-to-lower abdominal
region (McDonnell et al. 2007). Complications from TAPS
blocks are rare. There are case reports of liver injury after TAP
blocks, and in theory, the spleen and kidneys are also at risk
(Young et al. 2012).
When multiple ipsilateral thoracic or lumbar dermatomes are
targeted, paravertebral blocks may be performed. This block is
performed by injecting local anesthetic on either side of the tho-
racic vertebral column, which will block ipsilateral somatic and
sympathetic nerves in multiple contiguous dermatomes above
and below the level of injection (Cheema et al. 1995). Indwelling
catheters can easily be placed using this approach. Paravertebral
blocks are often used to decrease postoperative pain after mastec-
tomies (Schnabel et al. 2010) and appear effective in preventing
chronic mastectomy-related pain (Andreae and Andreae 2013;
Hussain et al. 2018). Paravertebral blocks have also been used
with great success in treating post-thoracotomy pain (Kirvela and
Antila 1992). Due to potential sympathectomy, hypotension has
been reported to occur in about 4.6% of cases, and pneumothorax
in about 0.5% of cases (Coveney et al. 1998).
Erector spinae plane block is the most recent development in
regional anesthesia, first described in 2016 in the treatment of pain
from metastatic disease of the ribs. It has also been reported to
be effective in the treatment of post-thoracotomy pain syndrome
(Forero et al. 2017). This regional technique can be effective for
both thoracic and abdominal dermatome coverage. This interfas-
cial plane block produces extensive multi-dermatomal analgesia
due to its action on the ventral and dorsal rami of thoracic spi-
nal nerves similar to paravertebral blocks (Forero et al. 2016). In
theory, this block is performed at a location with no structures
at risk of needle injury (i.e., pneumothorax), although in practice,
this complication has been reported in the literature (Tsui et al.
2019). Indwelling catheters can also be easily placed for long-term
continuous erector spinae plane block (Ramos et al. 2018).
Groin and pelvis peripheral nerve blocks
Pudendal nerves are responsible for the somatic innervation of the
pelvis. This nerve is formed from the S2, S3, and S4 nerve roots.
Pain from invading pelvic tumors, pudendal nerve entrapment by
pelvic mass, or radiation-induced pudendal neuropathy can be
potential indications for this nerve block. Parts of the genitalia
are also innervated by the pudendal nerve. However, ilioingui-
nal, iliohypogastric, and genitofemoral nerves from the lumbar
plexus (contributions from L1, L2 nerve roots) also contribute to
the groin, inner thigh, and genital region. Often a combination of
careful clinical history taking, neurologic exam, and diagnostic
blocks is required to identify the target peripheral nerve(s).
Lower extremity peripheral nerve blocks
Historically, lower extremity blocks were less popular than
blocks for upper extremity because of the safety and efficacy of
neuraxial anesthesia. Furthermore, nerves of the lumbosacral
plexus are often deeper and not anatomically clustered like the
brachial plexus for easy targeting. The femoral nerve is formed
from the L2 to L4 nerve roots, and blocks are performed at
the inguinal crease to provide analgesia for the anterior thigh,
278
femur, and knee (Murray et al. 2010). Femoral nerve blocks and
catheters have been reported for pathologic fractures, and bone
and muscle tumors (Koshy et al. 2010; Pacenta et al. 2010). The
femoral nerve becomes a pure sensory saphenous nerve as it
passes distally through the adductor canal. Mobilization and
ambulation are both less inhibited by performing the femoral
nerve block at the level of the adductor canal without significant
changes in pain in a study of patients undergoing knee surgeries
(Karkhur et al. 2018).
The sciatic nerve is formed by contributions from the L4 to
S3 nerve roots via two major nerve trunks—tibial and common
fibular trunks. Sciatic nerve block is most commonly performed
proximal to the crease of the knee posteriorly where the tibial and
common fibular nerves separate and provide analgesia below the
knee, except for the medial aspect of the lower leg in the saphe-
nous nerve distribution (Creech and Meyr 2013).
Ankle blocks are easy to perform without ultrasound or
nerve stimulator guidance by injecting local anesthetic poste-
rior to the medial malleolus, near the dorsalis pedis artery, and
posterior to the lateral malleolus and infiltrating the anterior
joint line between the malleolus. This usually successful block
provides anesthesia to the entire foot with few complications
(Rudkin et al. 2005).
Neuraxial analgesia
Introduction
Neuraxial analgesia is a specific subset of regional anesthesia spe-
cifically involving the delivery of medication around the spinal
cord or the exiting nerve roots. This can occur at the level of epi-
dural space or the intrathecal (subarachnoid) space. As the site
of action of many medications is located at the level of the spinal
cord, neuraxial analgesia requires only a fraction of the systemic
drug concentrations. Neuraxial analgesia should be considered
when patients’ pain cannot be controlled with systemic medica-
tions, or if the side effects of systemic medications are intolerable.
All neuraxial procedures are considered high risk for bleed-
ing. Bleeding within the neuraxis can lead to a rare but poten-
tially catastrophic consequence of spinal hematoma. The most
common neurologic symptom is progressive sensory or motor
dysfunction in 68% of patients, or bowel/bladder dysfunction in
8% of patients. Only 38% of patients had partial or good neurologic
recovery, although spinal cord ischemia appeared to be reversible
in patient who underwent decompressive laminectomy within
8 hours of neurologic symptoms (Vandermeulen et al. 1994). Most
hemorrhage into the neuraxis occurs in the epidural space; this is
likely due to the extensive venous plexus located in the epidural
space. Other variables such as needle size, location along the neur-
axis, and placement of catheter can also affect the risk of bleed-
ing (Horlocker et al. 2018). The incidence of spinal hematoma from
epidurals is less than 1 in 150,000, and it is less than 1 in 200,000
in spinal anesthetics (Horlocker and Wedel 1998)—however, this
calculation is based on patients not receiving anticoagulants/
thromboprophylaxis. Management of bleeding risk factors, includ-
ing patient characteristics and antithrombotic or thrombolytic
therapy, must be considered in neuraxial procedures.
Epidural analgesia
Anatomy
The epidural space is a potential space inside the spinal canal,
surrounded by the ligamentum flavum or vertebral periosteum
Textbook of Palliative Medicine and Supportive Care
for the external wall, and dura mater of the spinal cord for the
inner wall. There are spinal nerves, fatty tissue, and venous plexus
inside the cavity. The epidural space starts from the foramen
magnum to the sacral hiatus. Similar to nerve blocks, medica-
tion can be delivered to the epidural space via a “single shot,” or
more commonly in the management of cancer pain, via a cath-
eter sterilely placed into the epidural space to allow for continu-
ous delivery of the medication. The epidural space can serve as
a repository for medications to affect the traversing nerve roots,
diffuse across the dura to affect the adjacent spinal cord, or act
systemically after being absorbed by the surrounding vasculature
(George 2006).
Efficacy
Epidural catheters have proven to be highly efficacious; it is
routinely employed in the treatment of labor and postsurgi-
cal pain. Many studies have also reported on the success of
epidural catheters for the treatment of cancer-related pain not
responsive to systemic medications. In two studies, 100% of
patients with epidural catheters experienced successful pain
relief (Driessen et al. 1989; Hogan et al. 1991). In another
study by Smitt et al. (1998), adequate pain relief was obtained
in 76% of patients. The placements of the epidural catheters in
these studies provided coverage of the neck, shoulder, upper
extremities, thoracic, abdominal, lower extremities, and pel-
vic pains.
Complications and cost considerations
Some complications are associated with the epidural medica-
tion. In patients receiving local anesthetic, higher concentra-
tion is associated with sensory blockade, and motor blockade at
even higher concentrations. Postural hypotension was reported
in 9% of the patients but was only present in the first 24 hours
(Du Pen et al. 1992). Other complications increase with long-
term epidural therapy. One of the most commonly cited com-
plication is the high incidence of catheter dislodgement or
breakage (Driessen et al. 1989; Hogan et al 1991). Deep infec-
tion was reported in as many as 43% of patients; thus, these
authors recommend this therapy only for patients with a short
life expectancy (Smitt et al. 1998). To try to minimize the risk
of migration as well as infection, the epidural catheter can be
tunneled subcutaneously (Burstal et al. 1998; Bomberg et al.
2016). Additionally, long periods of epidural infusion may result
in epidural adhesions or fibrosis, which impairs distribution of
medications or result in occlusion-related complications (Crul
and Delhaas 1991). Epidural infusions require a larger volume
of infusion compared to intrathecal infusions. This results in
higher frequency of refills and health-care needs which may
prove to be an obstacle in a home care setting. Bedder et al.
(1991) compared epidural to intrathecal drug delivery systems
and found that intrathecal drug delivery system becomes more
cost effective beyond 3 months.
Intrathecal analgesia
Anatomy
The intrathecal space (also known as subarachnoid space) is
deep to the epidural space and dura mater. It contains the spi-
nal cord, cerebral spinal fluid, and is continuous with the brain
and intracranial cavity. The administration of analgesic drugs
directly into the intrathecal space is superior to the epidural
Interventional Pain Procedures in Palliative Care
TABLE 29.2 Clinically used intrathecal medications and
their respective drug targets (modified from Stearns
et al. 2005)
Drug Target Intrathecal Medication
Opioid receptor Morphine*, hydromorphone, fentanyl,
sufentanil, methadone, buprenorphine
Sodium channels Bupivacaine, ropivacaine,
levobupivacaine, tetracaine
GABA receptor Baclofen*, midazolam
NMDA receptor Ketamine, methadone
Calcium channels Ziconotide*
Alpha-2 receptor Clonidine, dexmedetomidine
Other (rarely used) adjuvants Octreotide, adenosine, gabapentin,
ketorolac, neostigmine
* Indicates FDA-approved intrathecal medications.
space in many aspects. By directly administering opioids into
the intrathecal space, it can directly bind the opioid receptors
on the spinal dorsal horn. Accordingly, the dose of intrathecal
opioids is approximately one-tenth the fraction of the epidural
dose, which is approximately one-tenth the fraction of the sys-
temic intravenous dose on average. There is an expected 1:300
conversion ratio between intrathecal and oral opioid doses.
Although many novel opioids, analgesics, and local anesthetics
are commonly used in intrathecal therapy, only three medica-
tions are approved by the US Food and Drug Administration
(FDA) for intrathecal use: morphine, ziconotide, and baclofen
(for spasticity). Table 29.2 lists intrathecal medications used
in clinical practice and its respective drug targets. Current
intrathecal therapy guidelines by the North American
Neuromodulation Society (PACC guidelines) recommend trial-
ing on-label monotherapy first, before combination therapies if
possible. Additionally, the guidelines acknowledge that in can-
cer pain, combination therapy may be warranted as first-line
strategy considering the age, type of pain, and anticipated dura-
tion of therapy (Deer et al. 2017).
A percutaneous intrathecal catheter can be placed with rela-
tive ease typically under fluoroscopic guidance. The catheter is
then connected to an external pump. This is considered only a
temporary treatment limited by the need for frequent monitoring
for infection, catheter migration, and restrict patient mobility.
In order to continue intrathecal therapy long term, an indwell-
ing catheter and infusion pump need to be surgically implanted;
the pump is typically implanted in the anterior lower abdomi-
nal region (Figure 29.3). Per PACC guidelines, depending on the
patient’s clinical prognosis, patients may undergo direct pump
implantation without first undergoing a trial. The infusion pump
serves as a reservoir for intrathecal medication (typical reservoir
volumes are 20 or 40 mL) and can either be a fixed-rate pump or
a programmable pump to deliver the medication. The reservoir is
refilled percutaneously. Advantages of fixed-rate pumps include
cheaper cost, and the pumps are not dependent on battery opera-
tion so do not need to be replaced. Programmable devices allow
flexibility in the medication delivery, interrogation of the pump
in the setting of suspected pump malfunction, which is not pos-
sible with the fixed-rate pumps. However, programmable devices
are battery driven. The typical life of the pump is between 5 and
8 years and will require a surgical replacement of a new pump at
the end of each service life.
279
FIGURE 29.3  Medtronic SynchroMed programmable intra-
thecal drug delivery pump. (Courtesy of Allen W. Burton.)
Efficacy
Intrathecal therapy can reduce cancer pain severity, alleviate
medication-related toxicities, and improve survival of cancer
patients. In a randomized control trial of patients with refrac-
tory cancer pain, over 200 patients were assigned to receive either
intrathecal therapy or medical management (Smith et al. 2002).
At the 4-month follow-up, 85% of intrathecal therapy group
achieved at least 20% reduction in pain score or 20% reduction
in toxicity, statistically significantly higher than 71% of con-
ventional medical group. The intrathecal group had significant
reductions in fatigue and depressed level of consciousness. At
6 months, the intrathecal group had statistically improved sur-
vival, with 54% alive compared with 37% of the medical group.
In another prospective, open-label, multicenter study with 119
patients with refractory cancer pain or uncontrollable side effects
implanted with intrathecal pump, clinical success (as defined as
50% reduction in pain severity, use of systemic opioids, or opioid
complications) was reported in at least 83% of patients at 1–4-
month follow-up (Rauck et al. 2003). In the largest randomized,
placebo-controlled, cross over study of ziconotide which included
predominantly cancer patients (95 patients; and 13 with refrac-
tory pain related to AIDS) who had elevated pain severity scores
despite systemic or intrathecal therapy. The ziconotide group
had significantly improved pain severity compared to placebo,
and those patients who cross over into the ziconotide group also
developed statistically significant improvement in pain severity
(Staats et al. 2004).
Intrathecal therapy should be considered in patients whose
pain cannot be adequately controlled with optimized medical
and other procedural therapy, or who experience intolerable side
effects to such therapy. However, not all patients are appropri-
ate for intrathecal therapy. Other aspects of patient selection,
including psychologic factors (anxiety, depression, patient expec-
tations), life expectancy, associated medical comorbidities, con-
current chemotherapy and radiation treatments, and social and
health-care support, can influence the appropriateness for intra-
thecal therapy (Deer et al. 2011). The decision to proceed with
intrathecal therapy is complex and requires consideration of a
multitude of patient dimensions in order to achieve the optimal
outcome (Sterns et al. 2005).
280
Complications and cost considerations
Complications of intrathecal therapy can be divided into phar-
macological, mechanical, surgical, and refilled-associated com-
plications. In a retrospective study of intrathecal therapy–related
complications, the most common complication is associated with
pharmacologic reactions (Bhatia et al. 2013). Due to the potency
of medications in the central nervous system, even small changes
in dose can result in significant clinical effects. Four classic side
effects of intrathecal opioids are pruritus, nausea and vomit-
ing, urinary retention, and respiratory depression (Chaney 1995).
Ziconotide may cause dizziness, nausea and vomiting, gait imbal-
ance, nystagmus, and confusion. Ziconotide carries a black box
warning for severe psychiatric symptoms and neurologic impair-
ment (cognitive impairment, hallucinations, changes in mood
or consciousness). Patient with preexisting history of psychosis
should not be treated with ziconotide (Ziconotide 2006). Acute
intrathecal baclofen withdrawal can be potentially life threatening
(Coffey et al. 2002). Local anesthetic at high doses can be poten-
tially neurotoxic and can cause motor, sensory, and autonomic
dysfunction, including urinary retention (Bottros and Christo
2014). Mechanical complications relate to dysfunction of the intra-
thecal pump, which ultimately results in a reduction of medica-
tion leading to withdrawal or overdose of medication which can
head to hemodynamic instability, respiratory depression—both
of which can potentially result in death. Examples of mechanical
complications include intrathecal catheter kinking, motor stalls
in the pump, and formation of catheter tip granulomas. Surgical
complications include bleeding, infection, cerebrospinal fluid leak-
age, and seroma formation. Incidence of surgical site infection is
reported between 1 and 10% of implants with an average of 3–5%
in larger systemic reviews (Deer et al. 2016). Pump refills can open
windows for error, including wrong medication or concentration,
reprogramming errors, or deposition of medication, outside the
reservoir into the pocket leading to systemic toxicity and overdose.
Intrathecal drug delivery systems for cancer are character-
ized by high initial cost followed by low maintenance costs. In
comparison, non-intrathecal-based pain management therapies
are associated with steadily cumulative cost. Several studies have
examined the cost-benefit analysis of intrathecal therapy. In one
study retrospectively comparing patients on high opioid therapy
with patients with intrathecal therapy, the cost equivalence was
reached in as early as 3 months, and on average by 6 months;
intrathecal drug therapy was deemed cost-beneficial after this
period (Brogan et al. 2013). A Canadian study under universal
health-care settings also found the cost-benefit to favor intra-
thecal drug therapy if administered for 7 months or longer com-
pared to high-cost oral therapy in cancer pain (Ottawa Hospital
Research Institute 2016). An economic evaluation of the United
States claims data of over 500 patients comparing the use of intra-
thecal therapy with conventional medical treatment to conven-
tional medical treatment alone, the intrathecal therapy group
accumulated cost savings of over US$60,000 over the conven-
tional medical treatment (Stearns et al. 2019). These cost savings
reflect a decrease in emergency room visits and hospitalization in
the intrathecal therapy group.
Botulinum toxin for pain management
Mechanism of action
Botulinum toxin irreversibly binds to the cholinergic nerve ter-
minal and causes flaccid paralysis that lasts 3–6 months due to
the inhibition of neurotransmitter release (Chen 2012; Dressler
Textbook of Palliative Medicine and Supportive Care
2012). Traditionally, the analgesic effect of botulinum toxin was
considered to be secondary to muscle relaxation. More recent
studies show direct analgesic effects of botulinum toxin possi-
bly by reduction in pain neurotransmitters, reduction in local
inflammation around the nerve endings (Park and Park 2017),
and modulation of afferent sensory nerve firing (Yuan et al.
2009). Botulinum toxin is approved by the FDA for the treatment
of cervical dystonia, upper limb spasticity, urinary incontinence
due to neurologically associated detrusor overactivity, primary
axillary hyperhidrosis, blepharospasm, strabismus, and chronic
migraine. Its use in directly treating pain and other abnormal
muscle spasms is considered off-label.
Studies of botulinum toxin
Botulinum toxin was first approved for spasticity and similar
muscle disorders, and in recent years, interest has grown sur-
rounding additional uses of the medication (Chen 2012). A retro-
spective review of cancer patients with spasticity suggested that
the majority received benefit from botulinum (Fu et al. 2013). It
seems to improve disabilities in patients with poststroke spastic-
ity, but data on pain relief are mixed (Lim et al. 2008; Marciniak
et al. 2012). One prospective study of 48 patients who received
botulinum injection prior to mastectomy showed a decrease in
postoperative pain (Layeeque et al. 2004). There are reports of
botulinum toxin being used successfully in painful radiation
fibrosis syndrome (Stubblefield et al. 2008) and radiation proctitis
(Vuong et al. 2011). A meta-analysis of two double-blind, cross-
over study of diabetic patients with painful neuropathy of the feet
showed decreased neuropathic pain scores with higher doses of
botulinum toxin (Yuan et al. 2009; Ghasemi et al. 2014; Lakhan
et al. 2015). In the two randomized controlled trials of botulinum
toxin for postherpetic neuralgia, there was a significant improve-
ment in pain severity (of at least 50% reduction in pain scores) and
improvement in sleep quality compared to control groups (Xiao
et al. 2010; Apalla et al. 2013).
How botulinum toxin injections are performed
Botulinum toxin injections have been performed on a wide
variety of muscles throughout the body, including skeletal and
smooth muscle such as the bladder (Seth et al. 2013). In the case
of spasticity or myofascial pain, the medication is injected into
the hypertonic or painful muscle, and the amount used may
vary depending on the size of the muscle (Argoff 2002). Accurate
placement may be aided by electromyography and/or ultrasound
(Lim et al. 2011).
Side effects and risks of botulinum toxin injections
Botulinum toxin is generally safe with a wide therapeutic win-
dow. Complications include local weakness and the exacerbation
of preexisting weakness such as Lambert–Eaton syndrome (Lu
and Lippitz 2009). Autonomic side effects have been reported
(Dressler and Benecke 2003), as well as flu-like symptoms
(Baizabal-Carvallo et al. 2011) and uncommon autoimmune con-
ditions (Dressler 2012).
Conclusion
Owing to the increased awareness of the WHO cancer pain treat-
ment guidelines, we have witnessed significant advancements in
the management of patients with cancer pain. However, empha-
sis on pharmacologic tools and lack of understanding of interven-
tional pain procedures have resulted in reduced utilization of these
interventions as treatment modalities. We impressed the plethora
 Interventional Pain Procedures in Palliative Care
of safe interventional pain procedures that can be effectively used
to treat cancer pain, to decrease side effects from systemic pharma-
cologic therapies, and to improve patients’ quality of life.
Cancer pain differs from chronic, nonmalignant pain in its pro-
gressive nature and the deterioration of the patients’ general con-
dition. Given this time pressure, selection of interventional pain
procedures should be decided in a timely manner and reviewed
frequently to align with patients’ goals of care.
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30
PAIN MANAGEMENT IN PEDIATRICS

Kevin Madden

Contents
Introduction....................................................................................................................................................................................................................... 285
Brief overview of pediatric palliative care.................................................................................................................................................................... 285
Brief overview of pain management in pediatrics...................................................................................................................................................... 286
Pain in pediatric palliative care...................................................................................................................................................................................... 286
Assessment of pain in children with developmental considerations................................................................................................................ 286
Infants (0–1 years of age)..................................................................................................................................................................................... 286
Toddlers and preschoolers (2–5 years of age)................................................................................................................................................. 287
Children (6–11 years of age)............................................................................................................................................................................... 287
Teenagers and adolescents (12–17 years of age)............................................................................................................................................. 287
Children with neurologic injury......................................................................................................................................................................... 288
Treatment of pain in pediatrics................................................................................................................................................................................ 289
Dosing and cautionary medications.................................................................................................................................................................. 289
Assessment of type of pain.................................................................................................................................................................................. 289
Adjuvants................................................................................................................................................................................................................ 289
Non-pharmacologic interventions.................................................................................................................................................................... 290
Special considerations...................................................................................................................................................................................................... 290
Nonmedical opioid use...............................................................................................................................................................................................290
Conclusion.......................................................................................................................................................................................................................... 290
References........................................................................................................................................................................................................................... 290

Introduction
Pain is one of the most common symptoms reported by children
who receive palliative care.1–4 The assessment of pain in children
can be particularly vexing, giving the varying abilities of children
to accurately report their experience. The parent is often called
upon to help the clinician understand the child and their pain,
but it is crucial to involve the child as much as possible in the
assessment and treatment of their pain. Despite (at times) their
young, age children are remarkably observant and knowledge-
able about their bodies and how they feel. The greatest difficulty
in obtaining an accurate picture of a child’s pain is to gain the
trust of the child. While there are comprehensive resources
available5–7 to gain a more in-depth understanding of how pain
is managed in children who receive palliative care, this chapter
is intended to give an overview of the differences in the care of a
child. Specific attention will be given to developmental aspects
of children, as this is often the key to establishing therapeutic
rapport with a child.
Brief overview of pediatric palliative care
Pediatric palliative care is a model of care that shares many simi-
larities to adult palliative care in that both attempt to maximize
the best quality of life by mitigating physical, psychological, emo-
tional, and spiritual suffering. These goals are achieved through an
interdisciplinary team approach, using the unique skills of physi-
cians, nurses, nurse practitioners, psychologists, chaplains, social
workers, pharmacists, bereavement specialists, art/music thera-
pists, nutritionists, and physical and occupational therapists.8
Both pediatric and adult palliative care tend to patients with life-
threatening illnesses with a possible cure, progressive conditions
without curative therapy, and irreversible medical conditions that
are not always progressive (Table 30.1).
There are, however, a few notable and crucial differences
between pediatric and adult palliative care. First, the nature of
caring for children is inextricably linked with working with the
parents of the child. While the child is the patient, the philosophy
of family-centered care is the primary lens through which all care
is viewed. “Family-centered care” is a philosophy that is rooted
in the understanding that the child’s primary source of strength
and support is the family. It also prioritizes the perspectives and
information provided by families and children when making
decisions about clinical care.9 The goal-concordant care of a child
will be compromised without the alignment of a child and fam-
ily’s values with any proposed therapeutic intervention, including
the assessment, recommended treatment, and ongoing manage-
ment of a child’s pain syndrome. This longitudinal relationship
can only successful and sustained with substantial trust between
the family and the pediatric palliative care team.
Second, while the dominant medical condition in adult pal-
liative care was cancer, pediatric oncology illness only accounts
for approximately 20% of children who receive pediatric pallia-
tive care.10 The predominant primary clinical conditions of chil-
dren who receive pediatric palliative care in the United States
are overwhelmingly either genetic/congenital conditions (41%)
or neuromuscular disorders (39%). Most of these children have
some level of cognitive impairment and are dependent on medical
technology.10 These characteristics of children with life-limiting
or life-threatening illnesses only underscore the essential role of

285
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TABLE 30.1  Spectrum of Illnesses—Adult versus Pediatric Palliative Care

Life-Threatening with Progressive Conditions Irreversible but not always
Possible Cure without Curative Therapy Progressive
Adult Cancer ALS COPD
Palliative care Sepsis Dementia Intracranial hemorrhage
Pediatric Cancer Cystic fibrosis Non-accidental trauma
Palliative care Sepsis Sickle cell disease Cerebral palsy

the parent in the provision of medical care and medical decision- to treat a child’s pain undoubtedly includes in-depth knowledge
making, as these children often cannot express their opinion in of the child and the family to maximize the supports that cannot
an age-appropriate, developmentally normal, way. be provided by medication.

Pain in pediatric palliative care

Brief overview of pain
management in pediatrics
One of the primary obligations of pediatric palliative care physi-
cians is to minimize pain, although there is a complicated his-
torical legacy that continues to influence our current practices.
As recently as the 1970s and 1980s, pain in infants and children
was thought to be different than in adults and therefore grossly
underrecognized and undertreated.11 At best, it was treated dif-
ferently; at worst, it was not treated at all. Early studies show that
children received far less opioid for pain after surgical procedures
or other painful interventions than adults, even when accounting
for differences in age and weight.12–15 Furthermore, it was com-
mon for neonates to only receive neuromuscular blocking agents
without general anesthesia during surgical procedures. This prac-
tice came to light only due to the extraordinary advocacy by a
parent of an infant who died following cardiac surgery.16–18 This
led to the first published statements by the American Society of
Anesthesiologists19 and the American Academy of Pediatrics20
that the administration of anesthesia and analgesia is both safe
and ethically warranted in neonates.
Shortly thereafter, the effort began to deem pain as the “fifth
vital sign.”21 This work ushered in an era of increased vigilance
to recognize and treat pain, not just in pediatrics but in adults
as well. Accordingly, opioid prescription rates in adults soared
over the last 25 years22–24 and this led to a dramatic increase in
opioid-related deaths25,26 in adults. Curiously, during the same
time period, the opioid prescription rates for children remained
relatively.27
Despite the reassurance of stable opioid prescription rates,
children are just as prone to nonmedical opioid use (NMOU)
as adults. Adolescents have an increased incidence of persistent
opioid refills after common surgical28,29 and dental30 procedures.
Pediatric and adolescent cancer survivors are more likely to have
NMOU, 31 as well as more likely to fill opioid prescriptions when
compared to healthy peers without cancer. 32 Taking the evidence
as a whole, there is a renewed drive for a multimodal strategy of
pain management. “Total pain” is a complex phenomenon with
physical, psychological, spiritual, and social components that are
influenced by the child’s sociocultural environment, their stage
of developmental, and many other contextual factors. 33 Opioids,
when indicated, are part of a larger plan that includes adjuvant
medications, regional anesthesia and analgesia, and harness-
ing the power of non-pharmacologic interventions such as the
involvement of psychology, Child Life services, music and art
therapy, integrative medicine, and many other interventions that
will be discussed in this chapter. The most successful prescription
Pain is one of the most common symptoms experienced by chil-
dren receiving palliative care1 and often is the one most dreaded
by children and their families. Poorly treated pain can have a cas-
cading effect on the child, starting with the obvious detrimen-
tal effect of their physical well-being and moving to affect their
psychological and emotional health. Children with uncontrolled
pain often limit their participation in activities they once derived
joy and a source of meaning from, and they can socially withdraw
from their family and friends. The attentive assessment and treat-
ment of a child’s pain syndrome improves the quality of life of the
child and diffuses out to enhance the quality of the larger family
dynamic.
As with adults, pain is an integrated construct with physical
and psychological dimensions. How a child experiences pain is
modulated by many factors, most prominently their experience
with painful events. Every child uniquely experiences pain, and
they develop behaviors to help them cope with both the anticipa-
tory anxiety as well as the actual painful stimuli itself. The physi-
cal, psychological, and personal factors related to pain contribute
to the experience of pain, and a comprehensive approach to pain
will address all of these aspects.
Perhaps, the most significant difference between children and
adults concerning pain is the vast developmental range that pedi-
atrics encompasses. From the infant for whom we rely strictly on
behavioral observational scales and parental input to the school-
aged child whose world is a unique blend of fantasy and reality to
the stereotypical adolescent who is reluctant to share worries and
concerns to the children with a neurologic injury who may lack
the capacity to communicate with words, knowledge of normal
child developmental milestones is absolutely essential to navigate
the range of expression of pain in children. In short, attending to
the developmental level of the child increases the efficacy of the
intervention. 34
Assessment of pain in children with
developmental considerations
Infants (0–1 years of age)
Fundamentally, infants do not have the capacity to know some-
thing exists independently without seeing, touching, or hearing
it. Consistent attachment to a parent or other caregivers is inte-
gral for them to develop a healthy sense of security. Infants with
significant pain are frequently hospitalized, which can isolate the
child from their parent or caregiver. At this age, the most note-
worthy way that children experience loss is through prolonged
separation from their primary caregiver; this can lead to deep
levels of emotional and psychological stress with an impact that
Pain Management in Pediatrics
can extend into childhood and beyond. Effective pain control
serves dual purposes: to relieve pain in the infant and to empower
parents to feel that they can offer comfort to their child through
the administration of medication or other non-pharmacological
treatments such as the use of weighted blankets. 35 Successful con-
trol of pain allows the infant to feel secure, which then reinforces
the healthy bonding between the parents and the child.
The challenge in assessing pain in infants is the limited
range of discernible behaviors they possess. Many common
behavioral expressions of pain overlap with expressions that
indicate other common needs, such as being hungry or simply
having a soiled diaper. To objectively quantify these behav-
iors, the Face, Legs, Activity, Cry, Consolability (FLACC) scale
was developed and contains five categories of pain behaviors,
including facial expression, leg movement, activity, cry, and
consolability. While initially developed to monitor postopera-
tive pain, 36 it has been co-opted to be the primary tool used by
pediatricians to quantify pain and evaluate the intervention
provided, in infants.
Toddlers and preschoolers (2–5 years of age)
The world of a toddler and preschooler becomes more imagina-
tive, and children can start to use and understand symbols that
signify larger truths that they cannot verbally communicate. To
children at this age, all stories are real, and the lessons gleaned
have their place in the story of the child’s life. Younger children
in this age group begin to develop autonomy, while older children
focus on initiative and guilt. The importance of the latter concept
cannot be overstated if one is to understand children at this age.
Illness, and the pain that can accompany it, is often interpreted
as a punishment for “bad” behavior and hospitalization can be
seen as a rejection.
Children in this age group are beyond the simple behaviors
measured by the FLACC scale. Still, not all of them will be cog-
nitively ready to use unidimensional self-report measures such
as visual analog scales (VAS) or “faces” scales. Most VAS scales
require children to possess three fundamental cognitive abili-
ties1: proportionality2 conceptualization of pain across a gradient
and3 translate that understanding to the visual representations.
Faces scales show cartoon faces with expressions of increasing
distress.
The two most commonly used “faces” scales are the Wong-
Baker FACES® Pain Rating Scale37 and the Faces Pain Scale. 38 The
Wong-Baker FACES® Pain Rating Scale is the most widely used
faces scale and does not require children to comprehend the
concept of magnitude or the ability to arrange items in order by
magnitude. It has been validated and used in children as young
as 3 years of age. One potential implicit bias, however, is the two
anchor points. 39 A pain score of 10 shows a crying face, and some
children may underrate their pain as they may concretely process
that a pain score of 10 must include crying. Similarly, but at the
opposite end, pain scores of 0 and 2 show a smiling face, and some
children may overrate their pain as they may concretely process
that a pain score of 0 or 2 must include smiling. Often this can
be alleviated by instructing the child that they do not need to be
smiling for a score of 0 or 2, and they do not need to be crying for
a score of 10. Overall, children prefer the Wong-Baker FACES®
Pain Rating Scale, but the Faces Pain Scale has the more robust
validation testing.40
Given the difficulties and uncertainty in the precision of a
child’s self-reporting their pain, it is imperative to ask the parents
287
their assessment of the severity of their child’s pain. Fear can be
a significant confounder when trying to assess pain in this age
group accurately. Some easy ways to establish trust and rapport
with a child at this age are as follows:
1. Get down to their eye level when speaking with them—
literally. Sit on the floor, if needed. Introduce yourself,
and tell them you are there to talk to them and their
parents.
2. Get down to their experiential level—ask them to play.
Playing with a child reassures them you have an interest in
who they are. Less mindful providers will direct the major-
ity of the time spent in the room at the parent.
3. Most importantly, speak to them, not at them. Use truthful
but straightforward phrases. Reassure them. You are not
there to inflict more pain. When performing the physical
exam, tell them you do not expect anything to hurt (if that
is truthful), but if they are discomforted during the exam
to let you know.
Once trust is established with the child, the combination of
physician observation and examination, child reporting aspects
of pain, and parent reporting the same composes a rich tapes-
try of information upon which sound clinical practice can be
grounded in.
Children (6–11 years of age)
Children at this age are starting to comprehend the body’s func-
tions, and so they may be insistent about knowing details. They
have also begun to internalize the concept of “work”—school-
work and chores around the home support a developing auton-
omy. This increased autonomy is coupled with an increased
ability to be reliable reporters of their experience in the world,
including their perception of pain. Caution should be exercised,
however, as the school-aged child still straddles two worlds:
the logical, “schooled” world of work, organized play, and peer
involvement and the private world which largely remains imagi-
native, is largely still mythical, and challenging to access. One
particularly relevant aspect of the private worlds of children
with life-threatening or life-shortening illnesses is that they
often possess an intrinsic desire and need to take care of oth-
ers, particularly parents and siblings. This may be manifested
as the underreporting of their pain severity. Children can see
themselves and their illness as a burden to their family. In the
spirit of “taking care of them,” children may underreport their
pain to spare their parents the psychological stress of knowing
their child continues to suffer.
The increased cognitive capabilities allow for the use of VAS
or faces scales in the assessment of pain. Children at the older
end of this age spectrum may be cognitively ready to go beyond
simple VAS or faces scales and use multidimensional symptom
assessment scales. The most widely known tool is the Memorial
Symptom Assessment Scale (MSAS).2,3 The MSAS assesses three
dimensions of a symptom, including pain, severity, frequency,
and level of distress. The main drawback is the time needed to
complete, limiting its utility in daily practice.
Teenagers and adolescents (12–17 years of age)
The transition from child to teenager and adolescence ush-
ers in a period of enormous neurodevelopmental change. These
changes include the nascent development of abstract thinking
288 Textbook of Palliative Medicine and Supportive Care

TABLE 30.2  Revised Face, Legs, Activity, Cry, Consolability (r-FLACC) Scale
Scoring
0 1 2
Face No particular expression or smile Occasional grimace or frown, withdrawn Frequent to constant quivering chin, clenched jaw.
disinterested. Sad, appears worried. Distressed looking face, expression of fright/panic.
Legs Normal position or relaxed. Usual Uneasy, restless, tense. Occasional Kicking, or legs drawn up. Marked increase in
tone and motion to limbs. tremors. spasticity, constant tremors, jerking.
Activity Lying quietly, normal position, Squirming, shifting back and forth, tense. Arched, rigid, or jerking. Severe agitation, head
moves easily. Regular, rhythmic Tense/guarded movements, mildly banging, shivering, breath holding, gasping,
respirations. agitated, shallow/splinting respirations, severe splinting.
intermittent sighs.
Cry No cry (awake or asleep) Moans or whimpers; occasional complaint. Crying steadily, screams or sobs, frequent
Occasional verbal outbursts, constant complaints. Repeated outbursts, constant
grunting grunting.
Consolability Context, relaxed Reassured by occasional touching, hugging, Difficult to console or comfort. Pushing caregiver
or being talked to, distractible away, resisting care, or comfort measures.

Source: From Reference [57] with permission.

Note: Each of the five categories (F) Face, (L) Legs, (A) Activity, (C) Cry, (C) Consolability is scored from 0 to 2, which results in a total score between 0 and 10. Differences
from original FLACC scale highlighted in bold text.

and the ability to engage in higher order reasoning, maturation
of personal identity, and growing independence.41,42 They strive
to locate themselves within the world, make sense of their experi-
ences, and contemplate a sense of the mysterious as available and
full of potential. It is also a time of impulsive decision-making43
and intensified feelings of invulnerability. Simultaneously, teen-
agers and adolescents also show a strong desire to be in control
of their pain, echoing their neurodevelopmental trajectory of
growing autonomy. The physician needs to be keenly aware of
the conflicting drives of autonomy and poor decision-making, as
this can cause conflict between the all involved—the physician,
the patient, and the parents. Flexibility, patience, but also clear
boundary setting, is important to help navigate this challenging
dynamic. In the end, the clinician must elicit trust from the teen-
ager to understand their pain and develop a clear plan44 —this is
true for all patients but can be more complicated in this particu-
lar group of patients.
By this age, patients have full capacity to use the VAS, faces
scales, and multidimensional tools discussed previously. For the
clinician, it is a time to allow for emotions, respect and honor
privacy, support independence, and even to take on the chal-
lenging role as confidant. The “split-visit,” where the teenager
or adolescent is separated from the parent, may yield important
information. The split-visit is a model of confidentiality that can
facilitate transparent conversations that would not occur if the
parent were present.45
Children with neurologic injury
Children with cognitive impairment represent a large proportion
of patients that receive pediatric palliative care10,46 and experience
pain more regularly than children without neurologic injury.47–49
Their underlying injury can cause lifelong and progressive muscu-
lar spasticity that requires intensive physical therapy, occupational
therapy, braces, and splints to minimize the severity. Despite these
interventions, most children with neurologic injury will require
multiple orthopedic procedures50 during their lifetime to allay the
pain associated with spasticity and minimize the risk of pathologic
factures due to perilous combination of increased muscle tone with
osteopenia from prolonged immobilization.
The primary challenge when working with children with neu-
rologic injury is the accurate assessment of pain.35,51 It is known
that these children receive fewer analgesic medications when com-
pared to their non-cognitively impaired cohort.52,53 The assessment
tools above are not clearly intended for use in this patient popula-
tion, although given the range of what neurologic injury can mani-
fest as they may be helpful. For those who are noncommunicative,
the Individualized Numeric Rating Scale (INRS)54–56 and revised
(r-FLACC)57 can help guide the clinician. The r-FLACC (Table 30.2)
modifies the FLACC to include common behaviors exhibited by
children with cognitive impairment. The INRS uses a combination
of numeric rating scales and the FLACC scale, and the parent iden-
tifies typical pain behaviors specific to their child that corresponds
to specific pain intensities (Figure 30.1).

FIGURE 30.1  Individualized Numeric Rating Scale (INRS). (From Reference [54] with permission.)
Pain Management in Pediatrics
Treatment of pain in pediatrics
Adult palliative care providers report that the two domains
they feel uncomfortable in when working with children are in
addressing conflicts involving children and the administration
of medications, including pain medications.58 Adherence to the
World Health Organization’s Pain Relief Ladder is applicable in
children as well as adults. Step 1 in the ladder is to use a non-
opioid medication such as acetaminophen or the various nonste-
roidal anti-inflammatory drugs such as ibuprofen, naproxen, or
celecoxib. Depending on the etiology of pain, these medications
may be more effective than opioids in alleviating pain. 59 If pain
is not adequately controlled, step 2 is the initiation of opioids.
One must keep in mind that only approximately 20% of all drugs
approved by the United States Food and Drug Administration
(FDA) are labeled for pediatric use, and there are currently no
general guidelines on opioid usage for analgesia in pediatrics. The
Centers for Disease Control and Prevention opioid prescribing
guidelines for pain states “[T]here is limited evidence for children
and adolescents, and the population is outside the scope of the
guideline.”60 Despite this, the basic and fundamental principles of
pain management in children and adults are remarkably similar.
There are standardized recommended starting doses in opioid-
naïve patients (Table 30.3), and the same methods familiar to
adult practitioners are used to calculate breakthrough dose, opi-
oid rotation, and dose escalation in children. There are, however,
a few caveats to consider.
Dosing and cautionary medications
The most essential difference between children and adults in the
administration of medication is that all children receive medica-
tions on a weight-based calculation, indexed by body weight in
kilograms. Adult practitioners should feel reassured that every
day virtually all pediatric physicians look up medication doses
simply because of the enormous range of precise weight-based
dosing—one should feel no shame in looking up doses. Infants
< 6 months of age generally require approximately 25–50% lower
initial opioid dosing, but this should be reflected in whatever pro-
fessional reference one choses to use. With regards to providing
medications to children in pain, it is important to remember that
most children cannot reliably swallow tablets or pills until 7 or
8 years of age. Liquid preparations of short-acting opioids (and
methadone) are extensively used in pediatrics.
One must exercise caution with some specific opioids in chil-
dren. Acetaminophen with codeine is a medication best avoided.
Codeine is a prodrug with little intrinsic pharmacologic activ-
ity and is metabolized to morphine by the cytochrome P450
TABLE 30.3  Opioid Dosing in Children
Initial PO Dosing Initial IV Dosing
Hydromorphone 0.04–0.06 mg/kg 0.015 mg/kg
q 3–4 hours (max 2 mg/dose) q 2–3 hours (max 0.6 mg/dose)
Methadone 0.1 mg/kg q 12 hours (max 5 mg/dose) 0.1 mg/kg q 12 hours (max 5 mg/dose)
Morphine 0.2–0.3 mg/kg 0.05–0.1 mg/kg
q 3–4 hours (max 15 mg/dose) q 2–3 hours (max 5 mg/dose)
Oxycodone 0.1–0.2 mg/kg N/A
q 3–4 hours (max 10 mg/dose)
289
(CYP) pathway. There is significant variability in the activity of
the CYP2D6 enzyme, with some children essentially having no
activity to those who are “ultrarapid metabolizers”. The children
who are ultrarapid metabolizers convert codeine to morphine
very quickly and are at risk for unexpected respiratory depres-
sion and death.61–63 The FDA issued a “contraindication” for
codeine and said that it should not be used to treat pain in chil-
dren younger than 12 years of age. They also added a “warning”
that codeine should not be used in adolescents between 12 and
18 years of age who are obese or have comorbidities such as
obstructive sleep apnea or severe lung disease.64 Lastly, fentanyl
transdermal patches are both attractive and potentially problem-
atic. The transdermal route obviates the issue of a child who can-
not swallow a tablet or pill but must be used very cautiously as
the percentage of subcutaneous fat in children is much lower than
in adults. This may lead to an unanticipated rapid absorption of
fentanyl in a younger or cachectic child.
Assessment of type of pain
Another significant difference is in the assessment of pain.
Children, as in adults, are subject to both nociceptive and neu-
ropathic pain. Unfortunately, neuropathic pain can be very dif-
ficult to describe under the best of circumstances and is only
more challenging when one considers the limited vocabulary of a
child. An average 3-year-old child possesses about 1000 words, a
10-year-old child 12,000 words, and an 18-year-old child 22,000
words. By contrast, a 30-year-old child has about 30,000 words
in their vocabulary. Children simply may not have the words to
describe the sensations that accompany neuropathic pain. They
often need prompting (Some children I work with have used the
following words to describe what it feels like. Let me know if
any of these sound like what you are feeling.), although it is not
unusual for a frustrated child to only say “It just feels weird” or “It
just feels different.”
Adjuvants
Adjuvants medications that target refractory symptoms, or are
used to augment the use of opioids, are similar to those used in
adults. As with all medications in pediatrics, weight-based dos-
ing is the standard of care. There are some special considerations
to be given when using antidepressant medications, including
selective serotonin reuptake inhibitors, serotonin–norepineph-
rine reuptake inhibitors, and tricyclic antidepressants for the
treatment of depression, anxiety, or neuropathic pain. There is
concern that these medications may increase the risk of suicidal
Available Formulations
• Immediate release: tablet, liquid
• Extended release: tablet
•  IV
• Tablet
•  IV
• Immediate release: tablet, liquid
• Extended release: capsule, tablet
•  IV
•   Immediate release: tablet, liquid
290
ideation and behaviors in children and adolescents,65,66 and the
FDA requires manufacturers of antidepressants to include a
warning that they may increase the risk of suicidal ideation.
The position of the American Academy of Child and Adolescent
Psychiatry is that depression is one of the largest risk factors for
suicide, and that the treatment of depression warrants immediate
assessment and treatment.67 In addition to the pharmacist issuing
a Patient Medication Guide to patients receiving this medication,
it is wise to discuss these risks with the child and parent. It is
strongly recommended that a “safety action plan” be discussed
before starting the medication; the child should identify an adult
they can ask for help if they are experiencing thoughts of harming
themselves. The identified adult should know that the appropriate
next step would be to bring the child to the attention of medical
services to ensure their safety.
Non-pharmacologic interventions
There are innumerable non-pharmacologic interventions that
will benefit a child with pain. By and large, they are very similar
to what is utilized in adult palliative care: aromatherapy, art ther-
apy, massage, meditation, music therapy, occupational therapy,
physical therapy, psychological counseling, and warm and cold
compresses.
There is, however, one specialist that is unique to pediatrics that
any adult provider should consult with when working with chil-
dren in palliative care who have pain: the Child Life Specialist.
A Child Life Specialist provides developmentally appropriate
interventions, including therapeutic play.68 The use of play often
leads the child to disclose information they otherwise would not
that helps inform decisions made by health-care providers. Child
Life Specialists also prepare children for medical procedures that
may elicit pain or anxiety and teach them coping strategies to
minimize distress while supporting the child’s ongoing mastery
of self-initiated coping techniques.
Special considerations
Nonmedical opioid use
While the vast majority of mainstream press coverage and medi-
cal literature is devoted to the NMOU epidemic in adults, there
is evidence that pediatric patients have not been spared in this
public-health crisis. As mentioned earlier, over the period of time
that opioid prescriptions for adults dramatically increased, opi-
oid prescriptions for children remained relatively stable. Over
the same period of time, however, hospitalizations for prescrip-
tion opioid poisonings69–71 and mortality72 related to prescription
opioids increased for all pediatric age groups. It is known that the
future development of a substance use disorder is associated with
the use of prescribed opioids before high school graduation73 and
inversely correlated with the age at first use of an opioid.74 Access
to opioids is surprisingly easy, and approximately one in four high
school seniors reports NMOU.75 Adolescents report the most com-
mon source is from a friend or relative76 likely a consequence of the
documented unsafe storage of opioids by adults77–79 and parents of
children with cancer.80 A repository of opioids is essentially created
that can be easily accessed by all who reside in or visit the home.
This information highlights the need to adopt “universal precau-
tions” when prescribing opioids: in adults consistent and thorough
education about the proper storage, use, and disposal of opioids
improved patient practices in these domains,81 and it would be
prudent to adopt these practices in pediatric practice.
Textbook of Palliative Medicine and Supportive Care
Conclusion
Adult palliative care physicians tasked with the responsibility of
seeing children will generally find that the underlying principles
are universal across the age spectrum. The one area of pediatrics
that is essential for any provider to be familiar with is the devel-
opmental aspects of how children comprehend the world they live
in, how they may or may not be able to accurately report their
pain, and how each age group has specific needs in order for the
proposed interventions to be successful.
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61. Voronov P, Przybylo HJ, Jagannathan N. Apnea in a child after oral
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65. Whittington CJ, Kendall T, Fonagy P, Cottrell D, Cotgrove A,
Boddington E. Selective serotonin reuptake inhibitors in childhood
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68. Munn E, Robison K. Palliative care and the role of child life. Child Life
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69. Gaither JR, Leventhal JM, Ryan SA, Camenga DR. National trends in
hospitalizations for opioid poisonings among children and adoles-
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70. Burghardt LC, Ayers JW, Brownstein JS, Bronstein AC, Ewald MB,
Bourgeois FT. Adult prescription drug use and pediatric medication
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71. Finkelstein Y, Macdonald EM, Gonzalez A, et al. Overdose
risk in young children of women prescribed opioids. Pediatrics
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72. Gaither JR, Shabanova V, Leventhal JM. Us national trends in pedi-
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73. Groenewald C, Palermo T. Legitimate opioid prescription increases
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75. McCabe SE, West BT, Veliz P, McCabe VV, Stoddard SA, Boyd CJ.
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76. Lipari RN, Hughes A. How People Obtain the Prescription Pain
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77. Reddy A, de la Cruz M, Rodriguez EM, et al. Patterns of storage,
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78. Silvestre J, Reddy A, De La Cruz M, et al. Frequency of unsafe storage,
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79. McDonald EM, Kennedy-Hendricks A, McGinty EE, Shields WC,
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80. Madden K, Reddy A, De La Cruz M, Liu D, Bruera E. Patterns of stor-
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81. de la Cruz M, Reddy A, Balankari V, et al. The impact of an edu-
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31
PAIN IN THE OLDER ADULT

Linh My Thi Nguyen and Michelle Peck

Contents
Introduction........................................................................................................................................................................................................................293
Assessment of pain............................................................................................................................................................................................................293
General principles..............................................................................................................................................................................................................293
Pharmacological treatment............................................................................................................................................................................................. 294
General principles....................................................................................................................................................................................................... 294
Nonopioid analgesics...................................................................................................................................................................................................295
Opioid analgesics........................................................................................................................................................................................................ 296
Adjuvant drugs............................................................................................................................................................................................................ 296
Other drugs for pain................................................................................................................................................................................................... 296
Nonpharmacological interventions................................................................................................................................................................................297
References............................................................................................................................................................................................................................298

Introduction least likely to lead to toxicity, side effects, or drug–drug interac-

Older persons are generally defined as aged 65 and older. By age 75,
many people exhibit frailty with chronic illnesses, multimorbidity
(i.e., more two or more chronic conditions), and/or social difficul-
ties.1,2 The prevalence of multimorbidity appears to have increased
in many regions of the world over the past 10–20 years, and it is
anticipated to continue rising, especially among older people (1).
Pain assessment and management in this older and sometimes
frail population is more complex and necessitates individualized
treatment due to both physiologic and pathologic changes such
as sensory and cognitive impairment and disability. Despite these
challenges, pain is usually effectively controlled in this population.
Pain can be acute or persistent in the older adult, and both
types of pain warrant the proper investigation in order to diag-
nose and treat the underlying causes. Often, the terms “persistent
pain” and “chronic pain” are synonymous. Because of the nega-
tive connotations of “chronic pain,” the term “persistent pain”
is sometimes preferred. 3 Persistent pain is defined as pain that
continues beyond the expected time of healing or for at least
3–6 months. Commonly, the etiology of pain is multifactorial.
Classifying the pain mechanism directs therapy and prognosti-
cation (Table 31.1).4,24(2)
Nonpharmacological treatments are often beneficial, low cost,
associated with minimal side effects, and may decrease the dose
and need for pharmacological treatments. A stepwise approach
with acetaminophen (known as paracetamol in many coun-
tries) as first-line pharmacological treatment and a multimodal
approach emphasizing a combination of both pharmacologic
and nonpharmacological treatments were supported by a clini-
cal review of the evidence (3). Key principles of pharmacological
and nonpharmacological management including those published
by the American Geriatrics Society (4),29 British Geriatric Society
and British Pain Society (5), and The Royal College of Emergency
Medicine (non-palliative patients in the emergency department)
(6) are summarized (Table 31.4 and 31.5)(3,7,8).
Geriatric dosing guidelines and consideration of potential inap-
propriate medications may help in selecting drugs and dosages
tions. Of note, older patients appear to be more sensitive to anal-
gesics and especially opioids, 5 and studies suggest elderly patients
with postoperative and cancer pain experience higher pain relief
and longer duration of action of opioids.6,7
Short-term opioids may be effective for both cancer and non-
cancer pain (5) and especially in patients with shorter survival.
However, there is limited evidence supporting the use of long-
term opioid use in older people for chronic non-cancer pain
(9,10). With improvements in both life-prolonging treatment
options and access to palliative care earlier in the trajectory of
disease, many patients may live longer with serious or advanced
disease. Therefore, in this changing palliative population, health-
care professionals must weigh the potential risks of longer opioid
treatment.
For older adults at end of life and/or those that are receiving
mostly palliative rather than curative treatments, professional
organizations endorse opioids in these appropriate situations.
Fear of illicit drug use has produced reluctance of opioids in
health-care providers, patients, and families. The risk of drug
abuse is low in patients taking opioids for medical treatment8,9
and intensive monitoring by a trained health-care team mitigates
the potential for abuse.
Assessment of pain
General principles
The approach to pain management in the elderly is somewhat
more complex and multifactorial, as compared to younger
patients. Older patients may underreport pain or not report it
at all. They also are at higher risk of side effects from drugs and
complications from diagnostic and invasive procedures. Patients
with cognitive impairment are at risk of under treatment of pain
due to their inability to provide an accurate pain history.
The patient’s own pain report and its intensity are most accurate
and reliable, and it may be necessary to ask questions about pain
in different ways in order to elicit a response10(11,12). A verbally
administered numeric rating scale 0–10 is a common first choice.

293
294
TABLE 31.1  Classification and Common Etiologies of Pain
Pain Classification Examples
Nociceptive • Low back pain from facet joint arthritis,
spondylosis
• Osteoarthritis
• Osteoporosis and bone fractures
• Paget’s disease
• Rheumatoid arthritis, polymyalgia rheumatica
• Gout
• Degenerative disk disease
• Chronic tendonitis
• Ischemic disorders (e.g., claudication, peripheral
vascular disease, and coronary artery disease)
• Myofascial pain syndromes
Neuropathic • Peripheral neuropathy (e.g., diabetes, HIV,
chemotherapy, and nutritional)
• Trigeminal neuralgia
• Herpes zoster
• Postherpetic neuralgia
• Poststroke central/thalamic pain
• Postamputation phantom limb pain
• Radicular pain
• Trauma
Mixed or unspecified • Recurrent headaches
• Some vasculitic pain syndromes
• Myofascial pain
• Fibromyalgia
• Chronic low back pain episodic pain
Other • Rare conditions (e.g., conversion reaction)
However, many patients with and without cognitive impairment
may have difficulty with the numeric rating scale. Alternatives
for self-reporting of pain include other verbal descriptor scales,
thermometers, and faces scales. It is important to personalize
the scale, which is appropriate to the individual, and document
the same tool at subsequent assessments.11 Patients may deny
pain; however, they may endorse “discomfort,” “hurting,” or
“aching.”12–14
Many patients with mild-to-moderate cognitive impairment
can self-report with simple assessment tools.15–22 Patients with
sensory or cognitive impairment should be assessed with tech-
niques adapted to the patient’s handicaps.17,23 History should also
be taken from the family and other caregivers (Table 31.2).
Common and misdiagnosed conditions that cause persistent
pain in older adults are myofascial pain syndrome, chronic low
back pain, lumbar spinal stenosis, and fibromyalgia syndrome (2).
Myofascial pain syndrome are best treated using nonpharma-
cological strategies, and their diagnosis can prevent exposing
older adults to potential adverse drug effects and unnecessary
procedures (13). In chronic low back pain, imaging is helpful in
demonstrating the absence of disease (i.e., compression fractures,
metastatic bone disease, and disk space infection) rather than
the cause of pain. Lumbar spinal stenosis may be a potential con-
tributor to pain, but it may not be the most important treatment
target considering the multifactorial etiologies of pain. Imaging
is required prior to surgical intervention, but many adults have
asymptomatic spinal stenosis. In the LAIDBack study, one in five
asymptomatic older adults had moderate-to-severe central canal
stenosis (14). Still, patients should have realistic expectations
Textbook of Palliative Medicine and Supportive Care
Treatment and Prognosis
Usually responds well to traditional approaches,
including common analgesic medications and
nonpharmacological strategies
Does not respond as predictably to conventional
analgesics but may respond to anticonvulsants
or antiarrhythmics
More unpredictable and may require trials of
different medications or combined approaches
May need psychiatric treatment but traditional
analgesic interventions are not indicated
about reduction in pain when undergoing surgery for spinal ste-
nosis. The patients who underwent decompressive laminectomy
in the SPORT investigation experienced on average 17% reduc-
tion in back pain and 14% reduction in leg pain (15). Fibromyalgia
is a common cause of wide spread pain, and generalized osteoar-
thritis should be considered in the differential diagnoses along
with fibromyalgia.
Pharmacological treatment
General principles
Generally, older patients are at higher risk of adverse drug reac-
tions. Age-related changes in older adults result in differences in
drug effectiveness, sensitivity, and toxicity. Therefore, pharma-
cokinetics and pharmacodynamics properties are unique in this
population (Table 31.3).25–28
Older adults have greater analgesic sensitivity; however,
because of the heterogeneity of this population, it is difficult to
predict the therapeutic dose and common side effects. Although
some medications recommend geriatric-dosing or age-adjusted
dosing, generally, it is recommended in the elderly population to
initiate low doses followed by slow upward titration (i.e., start low
and go slow).
Clinicians should refer to specific drug information for the
“geriatric dosing” and “Beers Criteria medication” recommenda-
tions. The drug monographs or point-of-care drug information
references (e.g., Lexicomp or other drug database) provide the age
at which age-adjusted dosing should be consider. For instance,
age-adjusted dosing is suggested at age 65 with one drug, whereas
Pain in The Older Adult 295

TABLE 31.2  Assessment of Persistent Pain another drug’s age-adjusted dosing starts at age 75. In 2019,
History
The American Geriatrics Society updated the Beers Criteria for
Cognitively intact or mild-to-moderate dementia
potentially inappropriate medication use in older adults.29 These
medications are known to cause adverse drug events due to their
• Directly query the patient always. pharmacologic properties and the physiologic changes of aging.
• When screening, use pain synonyms (e.g., burning, discomfort, Not all criteria are applicable in patients receiving palliative and
aching, soreness, heaviness, and tightness). hospice care. Clinicians should use this guide to identify the risks
• Standard pain scale sensitive to the patient’s cognitive, language, and and benefits of each medication and to serve as a reminder for
sensory impairments (e.g., adapted for visual, hearing, foreign close monitoring so that an adverse event can be prevented or
language, and other common handicaps in the elderly). detected early.
• Multidimensional pain scales (e.g., pain disability index and brief pain The least invasive drug route should be used. General prin-
inventory). ciples of both around the clock and as needed medications are
• Patients with limited attention span and cognitive impairment should the same in the older adult. However, for patients with cognitive
receive repeated instructions and adequate time. impairment, the as-needed approach is not a good choice because
• Ask about their worst pain experience over the last week. they are not able to request the medication appropriately. Patients
• In mild-to-moderate cognitive impairment, frame the question in should be premedicated prior to incident pain when possible, and
present tense due to impaired recall. continuous pain requires around the clock administration.
Combing pharmacological and nonpharmacological treat-
Moderate-to-severe dementia or nonverbal ments including integrative or complementary and alternative
• Assess pain via direct observation or history from caregivers
medicine can enhance the analgesic control of persistent pain.
• In patients with advanced dementia, unusual behaviors may indicate pain
Some nonpharmacological strategies have been shown to reduce
• Direct observation scales (e.g., PAINAD)
pain, but these benefits are enhanced when combined with drug
therapies. Physical therapy and patient and caregiver education
Physical exam are important interventions.24
Monotherapy may not attain adequate analgesia, and there-
• Look for deformity, posture, leg length discrepancy. fore, the combination of two or more drugs with complementary
• Look for pain behaviors (e.g., facial expressions, verbalizations/ mechanisms of action may work synergistically to achieve a bet-
vocalizations, body movements, changes in interpersonal interactions, ter outcome with less toxicity as compared to a single drug. This
changes in activity patterns or routines, mental status changes). is known as “rational polypharmacy.”
• Physical function (e.g., measure ADL and performance measure such
as range of motion and get-up-and-go tests) Nonopioid analgesics
• Cognitive function for new or worsening confusion Acetaminophen (paracetamol) is effective for osteoarthritis and
• Delirium assessment (e.g., MDAS and CAM) low back pain, 30,31 and because of its greater safety than non-
• Dementia assessment (e.g., SLUMS, MoCA, and MMSE) steroidal antiinflammatory drugs (NSAIDs), acetaminophen is
Abbreviations: ADL, activities of daily living; BPI, brief pain inventory; CAM, confu- recommended as first-line therapy according to the American
sion assessment method; MDAS, memorial delirium assessment score; MMSE, mini Geriatric Society’s panel on the pharmacological management of
mental status exam; MoCA, montreal cognitive assessment; PAINAD, pain assess- persistent pain in older persons. 32 Additionally, the British Pain
ment in advanced dementia; PDI, pain disability index; SLUMS, St. Louis University Society’s and British Geriatric Society’s evidence-based clinical
Mental Status. practice guidelines advise that acetaminophen (paracetamol) is
effective particularly for musculoskeletal pain and is well toler-
ated (5). A dose titration upward of 1000 mg of acetaminophen
may control pain, and stronger medications may not be needed.
The maximum safe dose is <4 g/24 hours. Some authors have sug-
TABLE 31.3  Key Pharmacologic Changes in the Older Adult
gested a maximum of <3/24 and <2 g/24 hours for patients with
Pharmacologic Concern Normal Aging frailty, over 80 years of age, and who use alcohol on a regular basis.
GI absorption/function • Slowing of GI transit time may prolong For patients with hepatic insufficiency or history of alcohol abuse,
the effects of continuous release drugs. the maximum dose should be reduced by 50–75%. Transient ele-
• Opioid-related bowel dysmotility may vations of alanine aminotransferase observed in long-term users
be enhanced. do not progress to liver dysfunction or failure when maximum
Distribution • Increased volume of distribution for
doses are avoided. 33,34
fat-soluble drugs due to increased
For chronic inflammatory pain (e.g., rheumatoid arthri-
fat-to-lean body weight ratio. Results
tis), NSAIDs are more effective than acetaminophen. 35 Other
in longer effective drug half-life.
potential advantages of NSAIDs are that they may be better for
short-term relief of osteoarthritis pain and short-term low back
Liver metabolism renal • Oxidation is variable and may
pain. 36–39 Although some NSAIDs such as naproxen at over-
excretion decrease. May result in longer half-life.
the-counter dosing may have a good safety profile in the general
• Glomerular filtration rate decreases
population,40 older adults are at higher risk of NSAID side effects
with age. Results in decreased
including gastrointestinal (GI) toxicity,41 which increases in fre-
excretion and prolonged effects of
quency and severity with age.42 The GI toxicity may also be dose
active metabolites.
related and time dependent.43,44 One study implicated NSAIDs as
Anticholinergic side effects • Increased confusion, constipation,
the cause of hospitalization for adverse drug reactions in 23.5% of
incontinence, movement disorders.
cases in older adults.45
296
NSAIDs should be used cautiously in high-risk patients includ-
ing those with kidney disease, which is common in the older
adult due to age-related decreases in glomerular filtration rate,
gastropathy, cardiovascular disease, and intravascularly depleted
states such as congestive heart failure. NSAIDs were previously
recommended on a trial basis; however, newer evidence suggests
this is risky in the older adult. Older patients are at particular risk
for NSAID-related serious or life-threatening GI bleeding and
cardiovascular events, 46 and, therefore, opioids may be a safer
alternative.
Opioid analgesics
Opioid therapy is widely used to treat cancer pain and for
patients at end-of-life and patients with shorter life expectancy.
However, there is debate regarding the long-term benefits of opi-
oids. According to the British Pain Society and British Geriatric
Society’s evidence-based clinical practice guidelines on the man-
agement of pain in older people, in the short term, opioids may
be effective for both cancer and non-cancer pain; however, long-
term data are lacking (5). A systematic review concluded there is
limited evidence supporting the use of long-term opioid use in
older people for chronic non-cancer pain in community-dwell-
ing older adults and a lack of trials in this age group (9). Another
systematic review and meta-analysis of opioids for chronic non-
cancer pain in adults that included 96 randomized clinical trials
concluded that opioid use was associated with statistically sig-
nificant but small improvements in pain and physical function.
This conclusion suggests that the benefit of opioids and nonopioid
alternatives may be similar, although the evidence was from the
studies of only low-to-moderate quality (10).
In addition to the lack of long-term data to support the use of
opioids internationally, opioid abuse and overdose deaths are at
epidemic levels nationally in the United States. Prescribers play a
key role in combatting opioid misuse, abuse, diversion, and over-
dose by recognizing extremely high amounts of opioids, apparent
doctor shopping (i.e. received high amounts of opioids and had
multiple prescribers and pharmacies), and being vigilant about
reviewing the state monitoring databases (16). Based on a survey
conducted, the National Council on Aging recommends commu-
nity-based organizations that serve older adults: increase the use
of standardized screening and assessment tools (to identify those
at risk or who are suffering from opioid use disorders), improve
the health literacy of older adults and their caregivers, offer older
adults alternative approaches to managing chronic pain, incor-
porate the older adult perspective in opioid efforts, raise aware-
ness of the risk factors for financial fraud and abuse, and mobilize
multiple service providers (17).
According to the American Society of Interventional Pain
Physicians (ASIPP) 2017 guidelines for opioids for chronic non-
cancer pain, long-term opioids therapy should be provided
only to patients with proven medical necessity and stability
with improvement in pain and function, independently or in
conjunction with other modalities of treatments in low doses
with appropriate adherence monitoring and understanding of
adverse events (18). Opioids are potentially effective for some
patients and part of a multimodal treatment strategy for both
persistent cancer and noncancer pain.47–51 Opioids are effec-
tive in musculoskeletal disease (e.g., osteoarthritis52 and low
back pain53,54) and neuropathic pain syndromes (e.g., diabetic
peripheral neuropathy and postherpetic neuralgia 55). However,
for chronic low back pain, opioids should only be considered
Textbook of Palliative Medicine and Supportive Care
an option in patients who have failed other treatments (i.e.,
nonpharmacological treatment, followed by NSAIDs, then tra-
madol or duloxetine) and only if the benefits outweigh the risks
and after a discussion of known risks and realistic benefits with
patients according to American College of Physicians’ clinical
practice guidelines (19).
The American Academy of Hospice and Palliative Medicine
(AAHPM) recommends the starting dose for patients who are
elderly, suffering from severe renal or liver disease, should be half
that of the usual dose for opioid-naïve patients. 56 Again, older
patients appear to be more sensitive to analgesics and especially
opioids, 5 and studies suggest elderly patients with postoperative
and cancer pain experience higher pain relief and longer dura-
tion of action of opioids.6,7 “Rational polypharmacy” with agents
with complementary mechanisms of action may be beneficial
particularly if they experience dose-limiting side effects from a
single agent.
The potential for opioid misuse and abuse should always be
evaluated in every patient. However, older age is significantly
associated with lower risk for opioid misuse and abuse. 57–60
Underuse of opioids may be a greater problem than misuse
and abuse due to various patient-related barriers such as fear
of addition, cost, side effects including constipation, and social
stigma. 61
Adjuvant drugs
Antidepressants including tricyclic antidepressants (TCAs) and
mixed serotonin- and norepinephrine-reuptake inhibitors
(SNRIs) have been used in the treatment of chronic neuro-
pathic pain and have increased side effects in older adults.
TCA’s (e.g., amitriptyline, desipramine, and nortriptyline)
were the first agents found to be effective for postherpetic
neuralgia and diabetic neuropathy. Unfortunately, because of
the adverse side effects in the elderly, it is often contraindi-
cated. SNRIs (e.g., duloxetine and venlafaxine) are effective in
neuropathic pain syndromes and fibromyalgia, with a better
side-effect profile as compared to TCAs. In contrast, selective
serotonin reuptake inhibitors (SSRIs) (e.g., sertraline, fluvox-
amine, fluoxetine, citalopram) have not proved to be an adju-
vant pain treatment.
Other drugs for pain
The evidence for the use of these drugs remains limited. As a
group, they are less reliable than opioids and traditional anal-
gesics for persistent pain. The use of these nonopioid, nontradi-
tional drugs is a matter of clinical judgment.62
Muscle relaxants include cyclobenzaprine, carisoprodol,
chlorzoxazone, methocarbamol, and others. It should be noted
that cyclobenzaprine is essentially identical to amitriptyline with
similar adverse effects of amitriptyline. These drugs may relieve
skeletal muscle pain; however, the effects are nonspecific. These
medications do not relieve muscle spasm. If muscle spasms are
the etiology of pain, then benzodiazepines or baclofen should be
considered, because these agents have known effects on muscle
spasm. These drugs are associated with increased risk for falls
in the older adults. Baclofen has been used as a second-line drug
treatment for paroxysmal neuropathic pain and severe spastic-
ity due to central nervous system and neuromuscular disorders.63
Baclofen should be started at a low dose and slowly increased to
minimize common side effects of dizziness, somnolence, and GI
symptoms. Baclofen should not be abruptly discontinued due to
potential for delirium and seizure and requires a slow taper.
Pain in The Older Adult 297

Benzodiazepines do not have evidence to support any analgesic Nonpharmacological interventions

effect in persistent pain.64 The high-risk profile usually outweighs
any potential benefits for pain relief, although they may be justi-
fied for anxiety at the end of life, a trial for muscle spasm, and if
pain coexists with these symptoms.
The use of corticosteroids, calcitonin, bisphosphonates, and
topical analgesics is similar to that of younger patients. Calcitonin
is effective as a second-line agent for neuropathic pain and treats
pain due to osteoporotic vertebral compression fractures and in
patients with bone metastases (20,21). Cannabinoids have limited
evidence, and in the older adult, the therapeutic window appears
to be narrow because of the dysphoria and patients that use
higher doses (Table 31.4).
According to the British Pain Society and British Geriatric soci-
ety guidelines, psychological therapies such as cognitive behav-
ioral therapy (CBT) and behavioral therapy may be effective in
improving chronic pain in improving disability and mood, but
few studies focused on older adults and had small sample sizes
(Table 31.5). Nursing home residents with persistent pain may
benefit from CBT, but there is limited evidence for biofeedback
training, relaxation, mindfulness, meditation, and enhancing
emotional regulation (5).
A systematic review and meta-analysis of psychological
interventions for older adults with chronic pain concluded that

TABLE 31.4  Key Guideline Recommendations for Pharmacological Management of Persistent Pain
Acetaminophen (Paracetamol)

• Consider as initial and ongoing drug therapy especially for musculoskeletal pain and is well tolerated.
• Do not exceed recommended maximum daily dose of 4 g with dose adjustments up to 50–70% required in patients with hepatic dysfunction.
• Effective in osteoarthritis and low back pain.

NSAIDs

• Consider rarely due to their side effect profile that requires them to be used with great caution. Can be used when acetaminophen fails to control
pain. Helpful in inflammatory type of pain.
• Use the lowest dose for the shortest period and review regularly.
• Add either a proton pump inhibitor or misoprostol for GI protection if taking nonselective NSAID or COX-2 selective with aspirin.
• Do not use more than one NSAID.
• Patients taking aspirin should not use ibuprofen.

Opioids

• Short term may be effective, but long-term data are lacking. Must evaluate the risk versus benefit. Long-term complications of use include
suppressed production of pituitary, gonadal, hypothalamic, and adrenal hormones and opioid abuse.
• Treatment is similar to younger patients; however, the elderly may be more sensitive. Increased half-life of the active drug metabolites.
• Weaker opioids such as tapentadol and tramadol have dual mechanism of action (both mu-opioid agonists and norepinephrine reuptake
inhibitors). Tramadol may cause sedation, cognitive impairment, and drug–drug interactions. Tapentadol has only weak effects on serotonin
reuptake but must be used with caution due to hypotension, respiratory depression, and sedation.

Adjuvants

• Tricyclic antidepressants or antiepileptics may be considered for neuropathic pain. However, some recommend tertiary tricyclic antidepressants
(amitriptyline, imipramine, and doxepin) should be avoided due to high risk of adverse effects.
• Antiepileptics/anticonvulsants such as gabapentin and pregabalin are mainly used for neuropathic pain. Renal dosing is required. Gabapentin must
be carefully titrated with 100–300 mg daily, up to a maximum dose of 3600 mg.
• Serotonin–norepinephrine reuptake inhibitors (SNRIs) such as venlafaxine and duloxetine can be used for neuropathic pain.
• Start with lowest possible dose and titrate slowly. Some medications have delayed onset of action and therapeutic benefits (e.g., gabapentin may
require 2–3 weeks).

Other drugs

• Systemic corticosteroids should be reserved for inflammatory disorders or metastatic bone pain. Osteoarthritis is not considered an inflammatory
disorder.
• Topical lidocaine and capsaicin have limited efficacy for localized neuropathic pain. Capsaicin is used mostly as an adjuvant, and the major
disadvantage is the burning sensation. The only FDA-approved indication for topical lidocaine is postherpetic neuralgia.

Emergency Departments (non-palliative)

• Mild pain: Oral acetaminophen (paracetamol) preferred over oral NSAIDs (e.g., ibuprofen) in elderly.
• Moderate pain: As for mild pain plus oral NSAID (if not already given) or codeine (consider lower doses in the elderly).
• Severe pain: Intravenous opioids (elderly appropriate dose reduction) or rectal NSAIDs
• Acetaminophen available as oral, rectal, and intravenous. NSAIDs available as oral, rectal, and intravenous, and intramuscular (e.g., ibuprofen,
naproxen, and diclofenac). Opioids: codeine available as oral and intramuscular, morphine available as oral, intravenous, and intramuscular.
298 Textbook of Palliative Medicine and Supportive Care

TABLE 31.5  Nonpharmacological Interventions for Pain Management in the Older Adult
Intervention Examples Comments
Psychological • Cognitive and behavioral therapies Cognitive behavioral therapy, when delivered by a
• Mindfulness and meditation professional, observed benefits found most desirable with
group-based approaches, long-term efficacy remains
undetermined, limited/weak existing evidence
supporting the use of mindfulness meditation
Therapeutic alliance • Constructive patient/physician collaboration Some positive outcomes in patients receiving general and
rehabilitative medical care, limited/weak existing
evidence in the older population with pain
Assistive devices • Devices and technology designed to assist in personal Some evidence of a reduction in pain when compared to
activities of daily living as part of a home hazard assessment older adults not using devices but can increase pain if
on functional ability misused, rehabilitative therapists can help make device
• Environmental adaptations like bath and toilet rails and recommendations, studies with older adults are lacking
frames
Movement-based • Tai-Chi Increase in activity, use personal preference, motivation,
approaches • Yoga consider barriers, customize and facilitate the exercise
• Gaming technologies program, consider using if approaches are delivered
• Strengthening, flexibility, endurance, and balance appropriately, studies with older adults are lacking
Self-management • Relaxation Self-management education programs, studies with older
• Coping strategies adults are lacking
• Personal exercise
• Adaptation to activities
• Structured group education programs
Complementary • Acupuncture Use as adjunctive therapy, some efficacy among the older
therapies • TENS/PENS population, studies with older adults are lacking
• Massage

psychological interventions that use cognitive behavioral modal-
ities have small benefits, including reducing pain and catastro-
phizing beliefs and improving pain self-efficacy for managing
pain. Group-based approaches showed the strongest results. The
review and analysis included 22 randomized trials with 2608 par-
ticipants with chronic pain ≥3 months and a sample mean age
of 60 or older. The studies evaluated a psychological intervention
that used cognitive behavior modalities alone or in combination
with another strategy (8).
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32
NEUROPATHIC PAIN

Paolo Marchettini, Fabio Formaglio, and Marco Lacerenza

Contents
Introduction........................................................................................................................................................................................................................301
Neuropathic pain syndromes in patients with cancer............................................................................................................................................... 302
Neuropathic pain syndromes due to direct or indirect activity of the tumor................................................................................................ 302
Plexopathies.................................................................................................................................................................................................................. 302
Radiculopathies and myelopathies.......................................................................................................................................................................... 304
Postherpetic neuralgia.......................................................................................................................................................................................... 304
Polyneuropathies......................................................................................................................................................................................................... 304
Iatrogenic neuropathic pain in cancer.......................................................................................................................................................................... 304
Neuropathic pain as a consequence of radiotherapy........................................................................................................................................... 304
Neuropathic pain as a consequence of chemotherapy........................................................................................................................................ 306
Postsurgical neuropathies.......................................................................................................................................................................................... 306
Post–neck surgery syndrome.................................................................................................................................................................................... 306
Pain following breast cancer surgery...................................................................................................................................................................... 306
Post-thoracotomy pain............................................................................................................................................................................................... 306
Therapy................................................................................................................................................................................................................................ 306
References........................................................................................................................................................................................................................... 308

Introduction referred to by their eponyms (Lhermitte, Lasègue, Wassermann,

Diagnosing and treating neuropathic pain is a major challenge for
palliativists, to the same extent as for neurologists, oncologists,
and pain specialists. In 2011, the International Association for the
Study of Pain and its Taxonomy Committee modified the defini-
tion of neuropathic pain as “pain caused by a lesion or disease
of the somatosensory nervous system.”1 This modification avoids
the possible confusion of considering pain from natural activa-
tion of nociceptors as, for example, pain associated with rigidity
or spasticity, a neuropathic type of pain.
Neuropathic pain originates from diseases or trauma to the
peripheral or central somatosensory system.2 Pain and related
neuropathic symptoms exhibit an acute or chronic temporal
profile, the latter being by far more common and disabling. Signs
may fluctuate according to the temporal evolution of the painful
disease, mood and anxiety of the patient, and even weather con-
ditions (as in trigeminal neuralgia and central pain). Neuropathic
pain can be spontaneous (stimulus-independent pain) with an
episodic or continuous temporal profile. Episodic paroxysms are
typical of trigeminal and glossopharyngeal neuralgias, but other
pains in neuropathy may appear as isolated attacks or attacks
of increasing intensity superimposed on continuous pain. 3
Spontaneous symptoms are abnormal tactile and thermal sensa-
tions associated with numbness, tingling, pins and needles, burn-
ing, shooting, or electric shock–like sensation. In addition, the
common aching pain, attributable to the nociceptive component,
may be part of the clinical picture of painful peripheral neuropa-
thies and a frequent complaint in patients with central pain due
to multiple sclerosis4 and syringomyelia. 5
Neuropathic pain is also evoked. The evoking stimulus may
cause massive activation of ectopic sensory discharges by act-
ing on mechanosensitive neural pathways. The maneuvers evok-
ing the latter are improperly called clinical signs and classically
Tinel, Phalen, and Spurling are widely known). Pain may also be
evoked by direct stimulation of terminal nerve endings (stimulus-
dependent pain) unchaining a sequence of spontaneous attacks,
such as trigger zones activation of tic douloureux, or remaining
time locked within the original stimulus, however, with exagger-
atedly intense or distorted quality. Dysesthesia, hyperalgesia, and
allodynia are the terms applied to define aberrant-evoked sensory
phenomena. Such aberrant sensations appear following a lesion in
the peripheral or central somatosensory system; obviously, simi-
lar symptoms originating from anatomically different sites and
causes are likely to have different pathophysiology. Sensitization
of nociceptors, ectopic activity, and multiplication of impulses are
probable peripheral mechanisms of dysesthesia and hyperalgesia.6
Disinhibition of the spinothalamic pathway and, again, ectopic
activity are likely central mechanisms, although the evidence in
humans is still weak. It is at least recognized that central pain and
pain evoked by central stimuli require abnormal spinothalamic
function.7,8 Allodynia is a more complex condition. By definition,
the term implies a painful perception evoked by stimuli (mechani-
cal or thermal) of intensity below nociceptor threshold. Therefore,
allodynia is widely viewed as the clinical “sign” of central sensiti-
zation. However, nociceptor threshold is remarkably lower than
pain threshold, the pain perception requiring temporal and spatial
summation of nociceptive impulses to overcome the endogenous
inhibitory state. Thus, what common experience would reasonably
define as stimulus of painless intensity might be sufficient to acti-
vate nociceptors.9 Hyperactivity and multiplication of discharges
in peripheral nociceptive afferents may well give rise to allodynia
as objectively shown by recordings from nociceptors in patients
with allodynia due to painful neuropathies.10
When considering the somatotopical organization of the periph-
eral and central nervous systems, all neuropathic pains are per-
ceived within the innervation territory of the damaged structure.

301
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Autonomic signs may be a direct consequence of the nerve
injury or a consequence of spinal/supraspinal reflex to nocicep-
tive input, and care should be taken to distinguish between these
phenomena.11 Standard neurophysiological tests such as electro-
myography, nerve conduction studies, evoked potentials, infrared
telethermography, but also quantitative sensory testing, laser-
evoked potentials, microneurography, and skin biopsy supple-
ment the clinical diagnosis, allowing the definition of nerve fibers
or central sensory pathways involved.12
The bulk of literature on neuropathic pain in palliative care
deals with cancer patients, and we have focused the chapter on
this topic. However, pain is among the main complaints also
in non-oncological patients into a palliative care context and
affects up to 30–50% of the patients followed into hospice care
programs.13 Painful neuropathies may occur in several terminal
heart, liver, and renal diseases and in advanced acquired immune
deficiency syndrome (AIDS) patients. Neuropathic pain preva-
lence is much higher between patients affected by neurodegen-
erative disease compared to cancer patients. About 10% of the
patients affected by Parkinson’s disease and complaining of pain
may have a central neuropathic mechanism, and about 25% of
them suffer from painful lumbosacral radiculopathies. Pain hurts
many patients with amyotrophic lateral sclerosis, notably into the
more advanced phases of this disease. In several of ALS patients,
pain is spread over the whole body and has a probable central
neuropathic nature, or could be distributed distally on the limbs
and be consequent to small fibers peripheral neuropathy. Pain is
a frequent symptom in multiple sclerosis, involving about 60% of
the palliative care clinic patients, and in their majority has neu-
ropathic mechanisms.
Neuropathic pain syndromes
in patients with cancer
Most patients with cancer complain of pain in the course of their
disease, in a large prevalence as a consequence of the nervous sys-
tem involvement.14 Direct activity of the growing tumors causes
nerve trunk, nerve plexus, or dorsal roots external compression
and/or infiltration.15 In the early clinical phase, tumor compres-
sion or invasion of the peripheral or central nervous system
stimulates nociceptors embedded in perineurium and meningeal
sheaths. This nociceptive nerve trunk pain16 or meningeal pain
usually responds well to analgesic drugs of nonsteroidal anti-
inflammatory (NSAIDs) and opioid types. In the following phase
of axonal membranes damage, the typical neuropathic symptoms
characterize the clinical picture and require specific treatments
for neuropathic pain. Beyond direct mechanical lesions of ner-
vous tissues, cancers promote nociception through pro-inflam-
matory and algogenic release.17,18 Moreover, mediators secreted
by constituents of the cancer microenvironment enhance sprout-
ing on the nociceptive small nerve fibers embedded within the
cancer.19 These specific mechanisms set apart neuropathic can-
cer pain (NCP) from the other non-oncological neuropathic pain
syndromes and may provide specific clinical presentations and
therapeutic response. Cancers may damage nerves through indi-
rect mechanisms as well, favoring nerve ischemia and infections,
such as herpes zoster, and in toxic, metabolic, and autoimmune
(paraneoplastic) polyneuropathy.
An investigation of neuropathic pain symptoms in cancer
patients is useful not only to target the therapy. A neurological
complication of neoplasm is frequently heralded by pain,15,20 and
Textbook of Palliative Medicine and Supportive Care
a careful neurological examination in cancer pain patients may
disclose cancer recurrence, cancer progression, or other diseases
such as infections.21,22
Cancer patients often complain of neuropathic pain. Into an
overall review of 22 prevalence studies on cancer pain, including
13,683 patients, neuropathic pain prevalence varied from a con-
servative estimate of 19% to a wide estimate of 39.1%, when mixed
pain is also included.23 In a hospital-based prevalence investiga-
tion on 919 Chinese patients with cancer, 454 (49.4%) reported
pain conditions. Among these, 333 (36.2%) exhibited neuropathic
pain symptoms, including 150 with NCP (DN4 ≥ 4).24 In a pro-
spective national multicenter study carried out in France, over
1805 patients with cancer, 509 patients reported chronic daily
pain for more than 3 months with an overall prevalence of 28.2%.
Using the DN4, neuropathic characteristics related to cancer
were present in about 20–25% of patients with chronic cancer
pain, giving an overall prevalence of 4.8%.25 Neuropathic pain
because of cancer treatments has a prevalence of 20.3%, much
higher than in non-NCP. Neuropathic pain nonrelated to cancer
or its treatments has a prevalence of 10.2–19.9%.23,25 A single sur-
vey estimates neuropathic pain prevalence among people affected
by cancer at the end of life to be around 20%, but with an exclu-
sively neuropathic pain diagnosed in only 14% of the patients 26
NCP severity is more intense and associated with greater intel-
lective, social, and physical disability, compared to non-NCP27
NCP in cancer patients is significantly associated with worsened
quality of life28 and may be the stronger prognostic feature of anal-
gesic treatment failure27 Patients with neuropathic pain assume
higher dosages of opioids and adjuvants than non-NCP subjects,
which contribute to more severe mental impairments.27,29,30
Neuropathic pain syndromes due to direct
or indirect activity of the tumor
Classic trigeminal neuralgia is among the presenting symptoms
of malignancies of middle and posterior cranial fossae.31 Most
commonly, bone or meningeal invasion causes constant deep
aching pain overlapping with paroxysmal electric shock–like tri-
geminal pain. With the progression of the illness, neuropathic
pain becomes continuous. Spontaneous deep burning sensation
combined with sensory loss and other focal neurological signs
appear following axonal loss.
Tumor invasion of mandibular canal and inferior alveolar
nerve infiltration generates pain and chin dysesthesia (numb
chin syndrome). This occurs more often with breast metastases
and lymphoma and is a negative prognostic sign (mean life expec-
tancy between 3 and 7 months). 32,33
The intercostal nerve syndrome, caused by metastatic spread
into a rib or by cancer thoracic wall infiltration, is a common pain-
ful syndrome caused by peripheral nerve lesion.34 A period of deep
aching pain in the chest precedes the appearance of a continuous
burning pain with superimposed episodes of shooting pain with
a belt distribution, culminating in the fracture of the rib. Positive
and negative sensory signs may not appear in neurological exami-
nation, for the wide overlapping of the dorsal dermatomes.
Plexopathies
Nerve plexus lesions in cancer frequently lead to pain with a
neuropathic component. Direct invasion by the primary tumor,
dissemination via adjacent lymph nodes, radiotherapy, or surgery
causes the nerve injury.
Cervical plexus involvement happens in primary or metastatic
head or neck tumors, resulting from invasion or compression
Neuropathic Pain 303

from the growing mass or from surgical and/or radiation treat-
ment. Pain and sensory symptoms can arise from the lesser and
greater occipital nerve territories in the occipital region, the pre-
auricular area supplied by the greater auricular nerve, and the
anterior part of the neck and shoulder innervated by the trans-
verse cutaneous and supraclavicular nerves and may project to
the jaw. 32 Typical symptom is the combination of nociceptive and
neuropathic pains with positive and negative sensory symptoms
in multiple nerve territories. 32,35
Brachial plexopathy is frequent in patients with cancer and
occurs often in lymphoma and breast and lung carcinoma. Pain
usually precedes focal neurological signs, even up to 9 months; it
is the most common symptom in 85% of patients. 36 Lower plexus
invasion is by far the most common, as in Pancoast syndrome, due
to apical lung cancer. An aching pain in the shoulder, subscapular
area, and upper back may appear some months before a burning
pain in the armpit. Clinical examination usually reveals sensory
loss in the intercostobrachial nerve territory, of which patients
are frequently unaware. 37 The advanced clinical picture includes
Horner’s syndrome (Figure 32.1) and focal weakness, atrophy,
sensory loss in the hand. Involvement of the upper plexus (C4,
C5, C6 roots) by metastatic breast carcinoma and lymphoma is
less frequent. Pain is localized in the shoulder girdle, worsened
by neck movement, and projected to the radial side of the hand
with tingling, sensory loss, burning, and shooting sensations. 38
The combination of Lhermitte’s sign, Horner’s syndrome, and
panplexopathy strongly suggests epidural extension, which can
occur even in the absence of bony erosion as documented in lum-
bosacral plexopathy. 39A
Painful lumbosacral plexopathy, and its complications, is the
most disabling condition in cancer. Pelvic tumors and meta-
static malignancies usually cause pain in the buttocks and/or
legs following lumbosacral plexus invasion. The insidious onset
of an aching and cramping nociceptive pain typically precedes
and later merges with more specific neuropathic pain symptoms,
and causalgic pain could be difficult to be seen. 39 The anatomi-
cal distribution of weakness and sensory symptoms and signs,
usually appearing after the pain, does not always correlate with
CT imaging—the examination usually reveals wider invasion. 39
Pain is projected to the thigh in the upper plexopathy (L1–L4)

FIGURE 32.1  (a) This 72-year-old woman developed aching pain in the left shoulder followed by projected burning pain in the left
upper limb 4 months prior to examination. The neurological evaluation revealed Horner’s syndrome and signs of left lower brachial
plexus involvement. (b) Telethermography revealed straightforward thermal asymmetry of the face, the left side being warmer than
the right due to sympathetic denervation. (c) Computed tomography (CT) of the pulmonary apex disclosed a Pancoast tumor on the
left side.
304
involvement in about a third of the cases. Pain in the leg, foot,
and buttocks is associated with a lower plexopathy (L5–sacral
dermatomes) and appears in half the cases. Panplexopathy is
rarer and happens in less than a fifth of patients with lumbo-
sacral plexopathy. The presence of pain and neurological signs
of lumbosacral plexopathy with normal findings on the CT of
the abdomen and pelvis calls for a differential diagnosis of men-
ingeal carcinomatosis, epidural cord compression, and cauda
equina compression.
Radiculopathies and myelopathies
Painful radiculopathy in patients with cancer is usually related
to direct compression or invasion of nerve roots by vertebral and
paraspinal cancers or leptomeningeal metastases. There can be
nociceptive focal and neuropathic pain projected along the dis-
tribution of the damaged root.
Pain is the most frequent symptom in leptomeningeal carcino-
matosis and often precedes other symptoms and signs by weeks.
The prevalent picture is a lumbosacral polyradiculopathy, since
tumor cells often seed in the lumbar sac. 39
Local nociceptive pain due to invasion of vertebral body or
epidural space and then neuropathic pain of radicular origin
commonly anticipate the clinical picture of myelopathy. When
the compression extends to the dorsal column of the spinal cord,
generating focal demyelination, the presence of Lhermitte’s sign
confirms the onset of clinical myelopathy. Pure central neuro-
pathic pain originated from compression/invasion of spinotha-
lamic pathways is infrequent. 38 The pain is usually unilateral,
a few myelomers below the affected level—extended down to
the foot or with a patchy distribution, associated with tingling
and allodynia, peculiarly due to cold and spontaneous thermal
sensations.
Postherpetic neuralgia
Postherpetic neuralgia is a painful radiculopathy following her-
pes zoster infection usually in the mid-thoracic dermatomes and
in the ophthalmic branch of the trigeminal nerve. It is more com-
mon in altered immune states, for example, in older people and
in patients with cancer (mainly leukemia and lymphomas), and
it has been shown that the site of the primary tumor correlates
with the site of subsequent herpes zoster infection.40 Neuropathic
pain can be spontaneous with deep aching, burning, and shoot-
ing components or stimulus dependent with allodynia and/or
hyperalgesia.41
Polyneuropathies
Painful peripheral paraneoplastic neuropathies, due to either
indirect cancer activity or the immune reaction against cancer,
are a rare complication of cancer and sometimes anticipate by
weeks or months the uncovering of the tumor. Paraneoplastic
sensory neuronopathy is a disabling condition presenting with
burning and shooting sensation and progressive asymmetrically
distributed numbness, and tingling in the limbs, trunk, and
face. Most frequently, the neoplasm is a small-cell lung cancer
or less frequently a breast carcinoma. Given the high specific-
ity (99.8%) and sensitivity (82%) of anti-Hu antibodies,42 patients
positive to this test, even with no evidence of cancer, should
undergo a CT study of the chest. Moreover, if CT scan is nega-
tive, then FDG-PET should be conducted.43 In some patients,
painful neuronopathy may be associated with mixed axonal
and demyelinating sensorimotor neuropathy. In those cases,
the combination of anti-Hu antibodies and anti-CV2/CRMP-5
Textbook of Palliative Medicine and Supportive Care
antibodies is present.44 With lymphomas, most neuropathies
occur with monoclonal gammopathy, including AL amyloidosis,
POEMS syndrome, type I cryoglobulinemia, and anti–myelin-
associated glycoprotein neuropathies. Early symptomatic man-
agement of neuropathic pain is mandatory. Appropriate and
successful treatment of the underlying cancer is the starting
point of the therapy of paraneoplastic neuronopathy.45 However,
immunomodulatory therapy before or together with antineo-
plastic treatment can be useful in patients with this condition
and has been used even when the underlying tumor cannot be
detected.45,46
Guillain–Barré syndrome is another painful peripheral
nervous system paraneoplastic disorder sometimes heralded
by radicular pains and a nonsystemic vasculitic neuropathy.
This subacute and progressive condition can be associated
with small-cell lung cancer and lymphomas and involves sen-
sory and motor fibers in a symmetric or asymmetric fashion.
Early diagnosis of paraneoplastic vasculitis encourages com-
bined treatment with steroids and cyclophosphamide, which
yields better results than the treatment with steroids alone.46,47
Severe local pain can be related to the inflammatory biochemi-
cal cascade that leads to activation/sensitization of nervi ner-
vorum, followed by ischemia and consequent axonal damage
and neuropathic pain along the anatomical distribution of the
damaged nerve.
Table 32.1 summarizes the neuropathic pain syndromes in the
patient with cancer along with their etiology.
Iatrogenic neuropathic pain in cancer
Bleuler, in 1924, introduced the term “iatrogenic” to define any
disorder “generated or caused by medicine or medical doctors.”
Longer survival times and a more aggressive surgical and medical
treatment of cancer have led to an increase in iatrogenic painful
conditions. Iatrogenic neuropathic pain in cancer patients may
arise because of radiotherapy, chemotherapy, or surgical nerve
lesions.48 Pain in malignancies is often associated with cancer
recurrence. The appearance of a novel painful condition deserves
extensive examination aimed at early diagnosis of the cause of
the pain. Informing the patient that the pain is iatrogenic and
not a direct consequence of the tumor reduces their anxiety and
results in a favorable response to specific treatment.
Neuropathic pain as a consequence of radiotherapy
Radiation may provoke painful myelopathy or peripheral nerve
lesions. High-dose radiotherapy close to the spine causes transient
or, less frequently, delayed progressive myelopathy that occasion-
ally has the features of a central pain syndrome.49,50 Sometimes,
the presenting complaint of a postradiation myeloradiculopathy
is the Lhermitte’s sign.51 Painful brachial plexopathy is the most
common postradiotherapy syndrome. The nerve injury may be
direct or indirect, that is, infarction of the brachial plexus due
to thrombosis of the subclavian artery and its branches.52 High-
voltage radiation may cause acute painful but reversible brachial
plexopathy.53 A delayed, but usually not painful, brachial plexop-
athy due to radiation fibrosis may develop several months after
radiotherapy, with tingling and large fiber sensory loss within the
upper plexus distribution.54 In contrast, recurrent cancer with
invasion of the peripheral nerves is often severely painful with
neuropathic and nociceptive pains. Radiation neuropathy shows
abnormal muscle activity (myokymia) more often than tumor
invasion.55
Neuropathic Pain 305

TABLE 32.1  Summary of Neuropathic Pain Syndromes in the Patient with Cancer and Their Etiologies
Clinical syndrome
Direct activity Nerve compression/invasion Trigeminal neuralgia
of cancer
Glossopharyngeal neuralgia
Intercostal neuralgia
Cervical Postauricular neuralgia
Brachial Compression/ Preauricular neuralgia
invasion
plexopathies
Lumbosacral Anterior part of the neck neuralgia
Upper brachial plexus neuralgia
Pancoast syndrome
Upper lumbar (L1–L4) neuralgia
Lower lumbar (L5–S1) neuralgia
Sacrococcygeal neuralgia
Compression/invasion of nerve root Unilateral pain in the cervical and
lumbosacral radicular territories
Frequently, bilateral distribution in the
thoracic dermatomes
Compression/invasion of spinal cord Rarely, central pain with Brown-Séquard
syndrome
Compression/invasion of thalamocortical Rarely, central pain with thalamic syndrome
projections
Indirect activity Paraneoplastic neuropathies Sensory ganglionopathy
of cancer
Guillain–Barré syndrome
Nonsystemic vasculitis
Brachial plexopathy
Acute herpes zoster Frequently in the thoracic dermatomes,
Postherpetic neuralgia ophthalmic branch of the trigeminal nerve
and in previously irradiated dermatomes
Nerve entrapment due to lymphedema Brachial plexopathy
Ischemic neuropathy/ies Painful mono/multiple neuropathy
Cerebral hemorrhage Central pain with thalamic syndrome
Iatrogenic Postsurgical nerve lesion Post–neck surgery syndrome
neuropathic Intercostobrachial neuralgia
pain in cancer Intercostal neuralgia
Post-thoracotomy pain
Phantom pain
Stump pain
Postradiation neuropathies Painful brachial plexopathy acute and
delayed, rarely painful
lumbosacral plexopathy
Postradiation myelopathy Central pain with Brown-Séquard syndrome
Painful polyneuropathy associated with Distal ascending pain and sensory +
chemotherapy symptoms
Inferior alveolar nerve neuropathy: numb Progressive sensory loss and pain in the nerve Bisphosphonates treatment
chin syndrome territory
Etiology
Middle and posterior cranial fossa
tumors, base of skull metastases
Jugular foramen invasion,
leptomeningeal metastases
Primary or metastatic lung, pleural, rib
cancer
Primary head and neck cancer and
cervical lymph nodes metastases
Lymphoma and cervical lymph nodes
metastases from breast and lung
cancer
Breast metastases and lung cancer
Primary cancer: colorectal,
genitourinary and sarcoma, lymphoma
Metastatic cancer: colorectal, breast,
lymphoma, genitourinary, melanoma,
lung, gastric
Vertebral cancer
Paraspinal invasion
Epidural invasion
Leptomeningeal dissemination
Primary and metastatic cancer
Primary and metastatic cancer
Small-cell lung, ovary, colon, and breast
carcinomas
Small-cell lung cancer, lymphoma
Leukemia, lymphomas, postirradiation
Postmastectomy
Thrombosis, compression/invasion of
small arteries
Primary and metastatic cancer
Neck dissection
Mastectomy
Thoracotomy
Thoracotomy
Limb, breast, rectal amputation
Radiotherapy
Platinum compounds, vincristine,
bortezomib, taxanes, and a
combination of them
306
Nearly half the data reporting on radiation-induced brachial
plexus injury is from breast cancer patients who might show
neurological complication in up to 39% (at 5 years follow-up) or
even 50% of the cases (at 30 years follow-up).56 The critical dose
for inducing brachial plexopathy after breast radiation is 54 Gy.57
High-dose radiation therapy for head and neck cancer also causes
plexus injury in 8–9% of the cases, the incidence increasing to 12%
overall if patients undergoing, in addition, surgical neck dissection
or chemotherapy, or both are included.58
Lumbosacral plexopathy, which is rarely painful, may also fol-
low radiotherapy as a late delayed complication.59
Neuropathic pain as a consequence of chemotherapy
Chemotherapy-induced peripheral neuropathy is a common
complication of chemotherapy. Its prevalence is decreasing
from 68% at 1 month after chemotherapy to 30% at 6 months
or more.60 Neuropathic pain and sensory symptoms are often
the limiting factors in chemotherapy with platinum-based
agents, vinca alkaloids, bortezomib, and the taxanes. The sever-
ity of nerve damage is directly proportional to drug dosage.61–63
Patients with preexisting neuropathy due to diabetes mellitus,
alcohol, hereditary neuropathies, paraneoplastic neuropathy,
earlier treatment with neurotoxic chemotherapy and also obe-
sity, chronic alcohol use, and smoking are thought to increase
vulnerability to develop chemotherapy-induced peripheral
neuropathy.64,65 Ascending distal paresthesia and dysesthesia
together with burning pain and allodynia to cold or mechani-
cal stimuli in a glove and stocking distribution often appear
after chemotherapy. A common mechanism has been proposed
for the toxicity of cisplatin, vincristine, and taxol.66 Vincristine
therapy provokes a predominantly sensory, sometimes auto-
nomic, subacute neuropathy in almost all patients. Cisplatin
neuropathy becomes clinically evident with cumulative dosages
of the drug, nerve deterioration continuing months after drug
withdrawal.67 The widely used paclitaxel is known to provoke
neuropathic pain and sensory dysfunctions that mostly affect
the hands and feet and is related to a myelinated fiber neu-
ropathy preferentially affecting the largest fibers (with spar-
ing of C fibers).66 Bortezomib is a proteasome inhibitor active
against recurrent or newly diagnosed multiple myeloma, 68 and
it is responsible for a primarily length-dependent sensory neu-
ropathy affecting small fibers, often causing severe neuropathic
pain. In up to 30% of patients taking bortezomib, pain and neu-
ral toxicity impose dose modification or cessation of therapy.69
Also, brachial and lumbosacral plexopathies are related to
chemotherapy. Chemotherapy administration through the sub-
clavian or iliac artery may cause an acute painful brachial or
lumbosacral plexopathy, which is sometimes irreversible. This is
probably due to direct damage to small vessels and thrombosis,
which leads to infarction of the nerve plexus.70
Postsurgical neuropathies
Postsurgical neuralgia is a relatively rare event compared with the
large number of nerve injuries provoked by surgical trauma, peri-
operative ischemia, compression, and delayed scar entrapment.
Although reliable clinical data is lacking, the incidence of pain-
ful neuralgia following peripheral nerve injury seems to be about
2.5–5% of the nerve injuries.71
Post–neck surgery syndrome
Neck and nuchal pain may arise because of cutaneous nerve
lesions provoked by surgical interventions for primary or meta-
static head or neck tumor. Pain affects almost 50% of patients,
Textbook of Palliative Medicine and Supportive Care
sometimes weeks after neck dissection.72 According to the aggres-
siveness of tumor and the timing and location of the surgery, the
pain may have nociceptive and neuropathic components. In half
of the patients, the pain subsides in a few months, whereas in the
other half, it lasts for years.72 In studies reporting on pain fol-
lowing neck surgery, 8% of patients complained of shoulder and
arm pain, increasing to around 30% after a 1-year period.72,73,74
Shoulder pain and disability were shown to be proportional to
the surgical extension; they are reduced in modified radical neck
dissection and selective neck dissection compared with standard
radical neck dissection.75 It is likely that the surgical technique
influences the pain occurrence.
The use of bisphosphonates treatment appears to increase the
occurrence of inferior alveolar painful neuropathy.76
Pain following breast cancer surgery
More than 50% of patients have chronic pain syndromes after
breast cancer surgery.77 Acute postoperative pain has both noci-
ceptive and neuropathic components, whereas persistent pain has
predominantly a neuropathic origin. A validated classification of
neuropathic pain following breast cancer surgery has identified
four classes: phantom breast pain, intercostobrachial neuralgia,
neuroma pain, and other nerve injury pains.77 In another study,
pain occurrence correlated significantly with the surgical exten-
sion is infrequent in lumpectomy but is found in up to 72% of
patients who underwent axillary lymph node dissection.78 In
these cases, pain appearance was positively associated with the
number of lymph nodes removed.78 Pain seems to be less frequent
when careful surgical techniques are used, or when surgeons per-
form more interventions, as in hospitals experienced in breast
surgery.79
Post-thoracotomy pain
One year after thoracic surgery, up to 61% of the patients report
post-thoracotomy pain. Chronic pain development is directly
related to the degree of postoperative pain severity.80 This pain
may be due to intercostal nerve lesions or to brachial plexus trac-
tion. Trans-axillary rib resection is one of the causes of brachial
plexopathy.81 Persistent chest pain may also be due to complete
or partial intercostal nerve lesion, sometimes followed by painful
neuroma. Seventy percent of patients undergoing thoracotomy
report severe pain (usually subsiding after 2 months’ time) with a
neuropathic component. Progressive pain, worsening over weeks
or months, and recurrence of chest pain following a pain-free
period are significant negative prognostic symptoms, suspicious
for cancer recurrence.82
Therapy
Pain in cancer patients may have a poor response to analgesic
treatments. An explanation is the high prevalence of neuropathic
pain, often misdiagnosed and not appropriately cured with a
specific neuropathic pain treatment strategy. However, the man-
agement of chronic nonmalignant neuropathic pain, based on
consecutive trials of different drugs, slowly titrated until efficacy
or dose-limiting side effects, is not applicable in the short survival
times of a palliative care context.
Moreover, in palliative care, relief of pain is the priority, while
the preservation of functionality becomes a secondary issue.
Therefore, the overall side effects, and in particular the seda-
tive effects of opioids and adjuvant drugs, may become accept-
able, providing the drugs offer adequate pain control. However,
Neuropathic Pain
the increasing prevalence of cancer survivors83 and long surviv-
ing cancer patients with chronic pain requires a paradigm shift
in cancer pain care toward management models more similar to
those applied in chronic non-cancer pain patients.
Neuropathic pain management is among the priorities in can-
cer and palliative care research. The current recommendation of
care in cancer patients is to follow the World Health Organization
(WHO) ladder, choosing an analgesic regimen based on pain
intensity and adding complementary adjuvant drugs for neuro-
pathic pain syndromes.84,85,86
Nerve trunk pain, that is, the nociceptive component of neuro-
pathic pain syndromes caused by compression, invasion, or acute
nerve ischemia, is treatable with NSAIDs, steroids, and eventu-
ally opioids.14 Conversely, in the experience of most clinicians,
neuropathic pain of the deafferentation type responds poorly to
NSAIDs.
For a long time, opioids were considered barely effective in
neuropathic pain. Since then, several clinical studies have sup-
ported the use of opioids in the treatment of peripheral neuro-
pathic pain. 87,88,89 However, evidence of their effectiveness in
central pain and long-term studies is very weak.89,90
Some opioids are potentially more effective than others are
in neuropathic pain due to their pharmacological properties:
methadone91,92 has weak N-methyl-d-aspartate (NMDA) recep-
tor antagonism and may be a first choice in the neuropathic pain
treatment of cancer patients.
Tramadol has noradrenergic/serotonergic activity and has
some evidence of efficacy in different types of neuropathic pain.93
Tapentadol is a centrally acting analgesic that acts both as a mu-
opioid receptor agonist and a noradrenaline reuptake inhibitor
(NRI).94,95 In clinical trials, tapentadol has proved to be efficacious
in chronic pain of different origins,96,97 and considering the mech-
anisms of action, it promises a role in mixed pain syndromes
(neuropathic and nociceptive) in cancer patients.
Anticonvulsants and antidepressants, commonly referred to
as adjuvant drugs, are considered effective drugs and first-line
treatments for neuropathic pain.98,99,100 Gabapentin is an anticon-
vulsant that binds the alpha2-delta subunits of voltage-gated cal-
cium channels and inhibits calcium cellular influx. Gabapentin
has a well-documented efficacy in peripheral neuropathic
pain.101,102,103,104 Pregabalin shares many of the analgesic proper-
ties of gabapentin and has better kinetics properties. Its efficacy
in neuropathic pain of both peripheral105,106 and central type is
well documented.107–109 By now, gabapentinoids have been con-
sidered for years first-choice drugs in neuropathic pain100 and
are used as monotherapy or in association with opioids in cancer
pain.110
Carbamazepine is an old anticonvulsant that unselectively
blocks sodium channels. It is still considered the gold standard
treatment for trigeminal neuralgia.111 Its analog oxcarbazepine is
also effective in trigeminal neuralgia112 and in painful diabetic
polyneuropathy, with a better tolerability profile.113 A random-
ized, controlled study of oxcarbazepine versus placebo, in patients
with peripheral neuropathic pain, has documented that signs and
symptoms profiles can identify those responding to treatment.
Patients with the “irritable nociceptor” phenotype have a greater
decrease in pain with oxcarbazepine compared to placebo against
those with different phenotypes.114
Lamotrigine is an antiepileptic agent that stabilizes the neu-
ral membrane, blocking voltage-sensitive sodium channels
and inhibiting presynaptic release of glutamate. Its analgesic
efficacy has been shown in trigeminal neuralgia,115 poststroke
307
central pain,116 and human immunodeficiency virus (HIV)-
related polyneuropathy.117
Tricyclic antidepressants (TCAs) were the mainstay of neuro-
pathic pain therapy before the introduction of the new anticonvul-
sants.118 Among these drugs, amitriptyline is the most commonly
prescribed TCAs in neuropathic pain.119 Amitriptyline reduces
pain in diabetic neuropathy,120 central poststroke pain,121 while
in NCP patients, there is no evidence of efficacy.122 In a compara-
tive open-label study of amitriptyline and gabapentin in cancer
patients with neuropathic pain, no difference in pain scores mea-
sured up to 6 months’ follow-up between gabapentin and ami-
triptyline group was found, although in both groups, there was
a significant decrease in pain intensity.123 Randomized trials of
selective serotonin reuptake inhibitors have shown inconstant
efficacy in neuropathic pain.124 The noradrenergic/serotonergic
reuptake inhibitor venlafaxine has shown analgesic efficacy in dia-
betic polineuropathy,125 neuropathic pain after breast cancer sur-
gery,126 and oxaliplatin-induced neuropathic pain.127 Duloxetine,
a more balanced noradrenergic/serotonergic reuptake inhibitor,
has a well-documented activity on diabetic neuropathic pain,128 in
chemotherapy-induced peripheral neuropathic pain,129 and its use
in palliative medicine is rising. Cannabinoids have been proven
to be effective in MS-associated pain130 and, as smoked cannabis,
in HIV neuropathy.131 A lidocaine patch decreases pain and allo-
dynia in postherpetic neuralgia.132 Intravenous lidocaine133 and
parenteral ketamine134 quickly, although only transiently, reduce
pain and may help control episodic neuropathic pain unrespon-
sive to conventional analgesics.
Neuromodulation with spinal drug delivery is a recognized
treatment for patients with severe refractory pain and life expec-
tancy of at least 6 months.135,136 The most commonly used drugs
in neuraxial analgesia are morphine, bupivacaine, clonidine, and
ketamine. Intrathecal ziconotide, an N-type calcium-channel
blocker derived from a sea snail peptide, has shown statisti-
cally significant analgesic efficacy in advanced cancer and AIDS
patients with intractable pain.137 On the other hand, a lack of
cost–benefit efficacy and concomitant poor long-term prognosis
precludes electrical spinal cord stimulation.138
As a general rule, for treating the neuropathic component of
a pain in a palliative care context, the initial approach could be
based on gabapentin (particularly for peripheral pain), or prega-
balin, given “round the clock” in a regular fashion with an appro-
priate titration dose, added to a base therapy with NSAIDs and/or
opioids. Oxycodone, tramadol, tapentadol, and, in a second line,
methadone are preferred opioids. In selected cases, nonrespon-
dents to gabapentinoids, amitriptyline or duloxetine, or other
antidepressants and anticonvulsants are an alternative. Opioids,
such as transmucosal preparations of fentanyl, and sometimes
NSAIDs, are useful rescue medication for treating breakthrough
pain episodes.
Combination therapy with different class analgesics is the rule
in palliative medicine. The use of different pain drugs with syn-
ergistic activity allows gaining a consistent pain relief, with lower
single drug dosages and fewer side effects in shorter time.139–142
Figure 32.2 summarizes our standard approach to treating
neuropathic pain in palliative care patients.
In conclusion, we emphasize the need to identify the cause of
the pain, unravel its neuropathic nature, and possibly hypoth-
esize or search for the mechanisms. A thorough investigation
might lead to a more specific treatment, which even in the pal-
liative stages could be relevant for improving the patient’s auton-
omy, cognition, and dignity.
308
FIGURE 32.2  Management of neuropathic pain in palliative care patients. NB based on the clinical practice at the authors’ center; this
management protocol is not fully supported by randomized clinical trials. *Suggested dosages when given as monotherapy consider reduc-
ing to the minimum effective dose in combination with opioids; bds, twice daily; tds, thrice daily; qds, four times daily; od, once daily; d, day.
KEY LEARNING POINTS
• Neuropathic pain is not a single entity but encom-
passes a variety of different, complex clinical pic-
tures with diverse pathophysiological mechanisms.
• Neuropathic pain is frequently present in cancer
patients in isolation or combined with nocicep-
tive pain (mixed pain).
• Direct and indirect activity of cancer causes dif-
ferent neuropathic pain syndromes depending
on the anatomy and the pathophysiology of the
injured part of the nervous system.
• The number of cancer patients with neuropathic
pain of iatrogenic origin is increasing due to lon-
ger survival times and the more aggressive surgi-
cal and medical treatment.
• Radiotherapy, chemotherapy, and surgery may
cause multiple painful neuropathic syndromes.
• A thorough evaluation of the patient’s pain points
out the most appropriate treatment and enhances
the patient’s ability to cope.
• Treatment of neuropathic pain is moving from
the empirical era to an evidence-based scientific
approach. Adjuvant compounds have become
available for neuropathic pain, supported by clin-
ical studies on their efficacy and tolerability.
• Improved understanding of neuropathic pain
pathophysiology is steering clinical research and
patient management.
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131. Iskedjian M, Bereza B, Gordon A, et al. Metanalysis of cannabis-based
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132. Abrams DI, Jay CA, Shade SB, et al. Cannabis in painful HIV-associated
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135. Mercadante S, Arcuri E, Tirelli W, et al. Analgesic effect of intravenous
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136. Hassenbusch SJ, Portenoy RK, Cousins M, et al. Polyanalgesic consen-
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Symptom Manage 2019;58:645–653.
33
BONE CANCER PAIN AND SKELETAL COMPLICATIONS

Yoko Tarumi

Contents
Introduction........................................................................................................................................................................................................................313
Epidemiology.................................................................................................................................................................................................................313
Clinical characteristics of CIBP.................................................................................................................................................................................313
Mechanism of cancer-induced bone pain.....................................................................................................................................................................313
Bone resorption............................................................................................................................................................................................................313
Bone microenvironment.............................................................................................................................................................................................314
Peripheral nerve to spinal sensitization...................................................................................................................................................................314
Diagnostic approach..........................................................................................................................................................................................................314
Therapeutic approach.......................................................................................................................................................................................................316
Role of analgesic pharmacotherapy..........................................................................................................................................................................316
Role of osteoclast inhibitors in SREs........................................................................................................................................................................317
Non-pharmacological approaches..................................................................................................................................................................................317
Occupational and physical therapy..........................................................................................................................................................................317
Radiotherapy and radiopharmaceuticals.................................................................................................................................................................318
Interventional approaches..........................................................................................................................................................................................318
Long-term effects on bone health and cancer therapy...............................................................................................................................................318
Conclusion...........................................................................................................................................................................................................................319
References............................................................................................................................................................................................................................319

Introduction Clinical characteristics of CIBP

Epidemiology
Bone is the third common most common site for metastatic
malignant disease, after lung and liver.1 The most common site
of bone metastases is the axial skeleton, such as the vertebrae,
pelvis, proximal ends of long bones, and ribs and skull.2 Skeletal
complications (“skeletal-related events” [SREs]) appear over time
during the course of disease. Common SREs are cancer-induced
bone pain (CIBP), pathologic fractures, subsequent surgery or
radiation, hypercalcemia of malignancy, and spinal cord or nerve
root compression. 3 Among cancer pain syndromes, CIBP is com-
mon and highly debilitating.
A point-prevalence study of metastatic bone disease using a
large commercial insurance claims database and a Medicare 5%
sample database in the United States estimated that approxi-
mately 280,000 adults were living with metastatic bone disease,
with 68% of cases occurring with primary breast, prostate, or lung
cancer.4 Based on the Danish National Patient Registry, 1- and
3-year cumulative survival in adults with breast cancer diagnosed
with bone metastasis was 59% and 22%, respectively. 5 Similarly,
1- and 3-year cumulative survival in adults with prostate cancer
with bone metastasis was 47 and 9%, respectively.6 In the same
cohort in Denmark, 0.5% presented with bone metastases at the
time of diagnoses, of whom 43.2% developed an SREs during a
median of 3.4 years of follow-up.7 Five-year survival was 75.8%
for patients without bone metastases, 8.3% for those with bone
metastases, and 2.5% for those with both bone metastases and
SREs.5 These data demonstrate that bone metastases and SREs
are prevalent and impact on survival. The ongoing condition of
bone metastases requires careful management over the course of
many months to years for some patients.
CIBP is the most common source of cancer pain.8 Although CIBP
may be found in the context of an established cancer diagnosis,
it can also be an initial presenting symptom, with or without
constitutional signs, that requires further work-up to establish
the diagnosis of primary cancer. Although bone metastases may
be asymptomatic, CIBP and analgesic use significantly increase
within the 6 months preceding the onset of SREs.9,10
CIBP usually manifests as continuous background pain with
episodes of aggravation of pain, known as breakthrough (cancer)
pain (BT(c)P), episodic pain, or incident pain.11 While interna-
tional consensus is lacking, BT(c)P is considered a transient exac-
erbation of pain, occurring spontaneously or related to a trigger,
on a background of stable and adequately controlled pain.11,12
Background pain may be dull or aching in quality, and well local-
ized. It increases in intensity as the disease progresses and can
usually be treated fairly successfully with standard analgesics. In
contrast, BT(c)P is difficult to treat due to its intermittent nature
with often rapid onset and short duration. Currently, available
analgesic options are often insufficient and cause dose-limiting
adverse effects.13 CIBP can evolve to severe pain with normally
non-painful activities, such as coughing, turning in bed, gentle
touch, or gentle limb movements.14 CIBP has ominous conse-
quences for quality of life and survival. 5,6,15,16
Mechanism of cancer-induced bone pain
Bone resorption
Bone resorption (bone loss) and formation is an ongoing process
occurring in both healthy and cancerous bone, directed by the
influence of endocrine hormones such as parathyroid hormone
(PTH) and 1,25-dihydroxyvitamin D (1,24-(OH)2D3), paracrine

313
314
hormones, and cytokines.17 In the normal bone homeostasis,
remodeling of bone is balanced between resorption and forma-
tion. In the setting of metastasis, the balance is shifted, result-
ing in osteolytic (net resorption) or osteoblastic (net formation)
bone lesions, or both, which disrupts the bone microarchitecture.
Hence, the structural integrity of bone is compromised, eventu-
ally leading to an increased risk of fractures. Bone metastases are
typically characterized as “lytic,” “sclerotic,” or “mixed” according
to the radiographic and/or pathologic appearance of the lesions. 3
Osteocytes, which are the most abundant bone cell type, serve
as the primary mechanosensing cell and may control the initia-
tion of bone remodeling. Osteoblasts have the role to produce
bone matrix by secreting collagen and non-collagenous proteins
and regulate osteoclast differentiation.18 Osteoclasts are respon-
sible for resorbing bone.18
Osteolytic metastases result from the release of agents that
stimulated the activity of osteoclasts by tumor cells in the bone
microenvironment, which is the most common feature of mul-
tiple myeloma (a primary bone tumor), and breast, kidney, and
thyroid cancer. Osteoblastic metastases result from the release of
factors that stimulate osteoblast proliferation, which is the most
common feature of prostate and bladder cancer. Mixed osteolytic
and osteoblastic metastases occur most frequently in breast and
lung cancer. 3,17,18
Bone microenvironment
Upon bone resorption, growth factors such as transforming
growth factor-β (TGF-β) and insulin-like growth factor-1 (IGF-1)
are released. These stimulate cancer cells that have homed to
places with a high bone turnover, to proliferate and release
bone-resorbing factors such as PTH-related protein (PTHrP)
and interleukin-6 (IL-6). Eventually, osteoblasts, osteocytes,
and stromal cells that normally express the receptor activator
of nuclear factor-κB ligand (RANKL) are stimulated to secrete
more RANKL. RANKL binds to the RANK receptor expressed
on osteoclast precursors, promoting their maturation and pro-
liferation.19 Excessive bone resorption is prevented by the decoy
receptor, osteoprotegerin (OPG), produced by osteoblasts; OPG
binds to RANKL, preventing interaction with the RANK recep-
tor.20 RANKL inhibition reduces skeletal tumor burden and dis-
tant metastases.21
The growth of tumor and destruction of surrounding tissue
results in recruitment of inflammatory and immune cells such
as macrophages, mast cells, neutrophils, and T lymphocytes.
These eventually become part of the tumor-associated stromal
cells, together with endothelial cells and fibroblasts. The stromal
cells release growth factors such as cytokines, interleukins, che-
mokines, prostanoids, endothelins, bradykinin, and adenosine
triphosphate that contribute to the overall pain process by sen-
sitizing or directly exciting the peripheral nerves.22 Additionally,
tumor and immune cells secrete prostaglandins and other inflam-
matory cytokines, which can sensitize the peripheral nerves to
pain stimuli directly, and by creating a more acidic environment.
Peripheral nerve to spinal sensitization
The peripheral nerves are an essential element in driving and
maintaining CIBP, especially the interface between the periph-
eral terminal and the local microenvironment in the bone. Bone
has rich myelinated and unmyelinated sensory and sympathetic
fiber innervations. The periosteum is innervated by a dense net-
like mesh network of sensory fibers that detect mechanical distor-
tion of periosteum and bone.23 A further factor in CIBP is spinal
Textbook of Palliative Medicine and Supportive Care
sensitization.24 In healthy bones, the sensory and sympathetic
fibers are not closely located to each other. However, tumor cells
can induce reorganization and sprouting of both fibers, result-
ing in the formation of neuroma-like structures with abnormal
intermingling of the two fibers.25 The remodeling of the sensory
and sympathetic fibers has been speculated to lead to induction of
pain by normally non-painful stimulation of sympathetic nerves,
and to episodes of spontaneous pain.25
At the spinal level, extensive neurochemical and neurobiological
reorganization occurs, including expression of the pro-hyperalge-
sic peptide dynorphin, proliferation of astrocytes, and activation
of pro-nociceptive neuropeptide substance P and the excitatory
neurotransmitter glutamate in the dorsal horn.24 The peripheral
sensory neurons synapse with secondary ascending neurons in
the spinal cord. Normally, most lamina I neurons are nociceptive-
specific neurons that only respond to noxious stimuli, whereas
the vast majority of lamina V cells consist of wide dynamic range
(WDR) neurons that code non-noxious stimuli throughout the
temperature and mechanical range as noxious intensities. In a rat
model of CIBP, the proportion of WDR neurons was increased.26
This results in a hyperexcitable state where normally non-noxious
stimuli produce pain (hyperalgesia/allodynia). CIBP is a mixed-
mechanism pain state exhibiting elements of both neuropathic
and inflammatory pain, but with distinctive modifications to the
tissue and nerves in the periphery, as well as unique neurochemi-
cal changes at the spinal cord level.
The reorganization of the sensory and sympathetic fibers is
likely associated with increased release of nerve growth factors
(NGFs).27,28 NGF has been implicated to have pro-nociceptive
actions, in addition to remodeling of peripheral nerve fibers.
NGF can both increase the expression on the transient receptor
potential cation channel 1 (TRPV1) on the sensory nerves and
sensitize the channel by phosphorylation. NGF and its receptor,
neurotrophic tyrosine kinase receptor type 1 (TrkA), can form a
complex that can be transported retrogradely from the peripheral
terminals to the cell body located in dorsal root ganglion, where
it can initialize synthesis of neurotransmitters (substance P and
calcitonin gene–related peptide) and expression of receptors
(bradykinin receptor, P2X3), channels (TRPV1, acid-sensing ion
channel 3 and sodium channels), transcription factors (activation
transcription factor 3), and structural molecules (neurofilaments
and sodium channel anchoring molecule p11). Moreover, NGF
directly stimulates nociceptors and lowers neuron activation
thresholds by modulating trafficking and expression of voltage-
gated sodium channel (Nav)1.8 and TRPV1.27,28
Diagnostic approach
Besides the general physical examination, musculoskeletal and
neurological examinations should be included, focusing on pal-
pable tenderness in the skeletal system and neurological deficits/
alterations. Patients presenting with back pain, with or without
weakness of the limbs, paresthesia, sensory changes, or bladder or
bowel functional impairment, should be carefully assessed for spi-
nal cord compression or cauda equina syndrome. In all cases, it is
important to emphasize that imaging tests should be interpreted in
conjunction with the clinical picture. Tables 33.1 and 33.2 provide
summaries of the differential diagnoses of CIBP and diagnostic
modalities.
Bone consists of 85% dense cortical bone composed of miner-
als and 15% porous and spongy trabecular bone composed of
collagen and mineral content, which encompasses the marrow
Bone Cancer Pain and Skeletal Complications 315

TABLE 33.1  Common Presentations of CIBP and Differential Diagnosis

Differential Diagnosis to be Considered
Presentation of bone pain Cancer related
Back pain Spinal metastasis
Pancoast syndrome
Spinal cord/thecal sac/cauda equina
compression
Pelvic metastasis or direct invasion
of tumor into pelvic structure
Scapular, posterior rib metastasis
may present as back pain
Retroperitoneal metastases
Hip/femur/humeral pain Impending or actual pathological fracture
Rib pain Rib metastasis or direct invasion
intrathoracic tumor
Headache Skull and base of skull metastasis
Cancer therapy related Nonmalignant
Vertebral compression fracture Osteoporosis
secondary to glucocorticoids, Immobility
antiandrogen/estrogen therapy Paget’s disease
insufficiency fracture related to Other inflammatory conditions
radiotherapy (e.g., sacrum) infectious conditions (e.g.,
septic arthritis)
Avascular necrosis of the femoral Avascular necrosis of the
or humeral head related to femoral or humeral head
glucocorticoid use Stress fracture
Radiation pneumonitis Stress fracture
Post-thoracotomy neuropathy New onset of herpes zoster
pleuritic chest pain related to
multiple etiologies
Chemotherapy, hormone therapy, Temporal arteritis or other
or others vasculitis

component. Most of the red marrow (consisting of hematopoietic
tissue) is located in the axial skeleton (e.g., vertebrae, pelvis, and
proximal femora), while yellow marrow (consisting of fat cells)
is located in appendicular bones. Cancer spreads to bone hema-
togenously, where it first localizes in the marrow. As the lesion
grows, it produces a cortical response, which can be osteolytic or
osteoblastic.
On plain radiographs, bone metastases may appear as areas of
absent density or absent trabecular structure, which represent
osteolytic lesions. Osteoblastic lesions may appear as increased
density and sclerotic lesions or rims. However, because 30–75% of
demineralization must occur before osteolytic lesions in the ver-
tebrae become apparent on plain radiographs, metastatic lesions
may not be visible on an X-ray for several months.29 Plain radio-
graphs are useful for primary investigation of bone metastases,
assessing risk for pathological fracture, and pure lytic disease
such as multiple myeloma, in which bone scintigraphy is com-
monly false negative. The diagnostic sensitivity of this modality
for detecting bone metastases is 44–50%, which is substantially
less than bone scintigraphy. 30
Diagnostic sensitivity and specificity of bone scintigraphy are
62–100% and 78–100%, respectively.29 Bone scintigraphy com-
monly shows an abnormality associated with osteoblastic activ-
ity, whereas it may be negative (cold spots) with purely lytic lesions
or rapidly progressive disease, which allows little chance for new
bone formation. It may also show uptake in conditions such as
osteoarthritis, infection, trauma, or Paget’s disease. Diffuse accu-
mulation of tracer throughout the skeleton may occur in dissemi-
nated skeletal disease (superscan), commonly seen in prostate
cancer, leading to the false impression of a normal scan.
Computed tomography (CT) with bone windows or magnetic
resonance imaging (MRI) can provide detailed information on
the bone and marrow. MRI has better contrast resolution than
CT for visualizing soft tissue and the spinal cord, and CT is disad-
vantaged by the beam hardening artifact that obscures adjacent
soft tissues and bones. The diagnostic sensitivity of CT and MRI

TABLE 33.2  Comparison of Diagnostic Specificity/Sensitivity

Sensitivity Specificity Cost Remarks
Plain radiograph Low (40–50%) High Low Useful in the
• Evaluation of risk for pathological fracture
• Skeletal survey for lytic lesions
Bone scintigraphy High (62–100%) High (78–100%) Moderate Able to screen whole skeletal system
More sensitive than plain radiograph
Provides information on osteoblastic activity and skeletal vascularity
Lack of sensitivity in pure lytic lesions, and specificity in degenerative
change, inflammatory process, and mechanical stress
CT scan High (71–100%) High (85–100%) Moderate Modality of choice for evaluating cortical bone (e.g., ribs)
Soft tissue extension of bone metastases is easily visualized
MRI High (82–100%) High (73–100%) High Highly sensitive for detection of bone metastases
Preferred imaging method for spinal cord compression
FDG-PET scan
18 High High Very high Detects increased metabolic activities of cancer even in early stage or
bone marrow involvement only
316
KEY LEARNING POINTS
• Skeletal-related events (SREs) occur during the
course of cancer and bone metastases. The com-
mon SREs are cancer-induced bone pain (CIBP),
pathologic fractures, subsequent surgery or radi-
ation, hypercalcemia of malignancy, and spinal
cord or nerve root compression.
• CIBP is one of the most common etiologies of
cancer pain. It often presents with BT(c)P that is
difficult to control due to its temporal character-
istics. CIBP may evolve to spontaneous or inci-
dent hyperalgesia and has ominous consequences
on quality of life and survival.
• Cancer stimulates excessive bone resorption
through expression of the receptor activator of
nuclear factor-κB ligand (RANKL) that binds to
RANK receptor expressed on osteoclast precursors.
Tumor cells release cytokines that interact with
osteoblast resulting further osteoclast activities.
• The bone marrow and periosteum are innervated
by a combination of different types of afferent
sensory fibers. In the spinal cord, an increased
proportion of wide dynamic range (WDR) neu-
rons compared with nociceptive-specific neurons
transmit non-noxious stimuli as noxious stimuli,
which is thought to contribute to the unique fea-
ture of hyperalgesia in bone cancer pain.
• The diagnostic sensitivity of plain radiographs
for detecting bone metastases is substantially less
than bone scintigraphy, although they are useful
as a primary investigation and for pure lytic dis-
ease. Magnetic resonance imaging (MRI) may be
considered for the examination of the spinal cord,
rather than to screen for painful bone metastases.
• When CIBP is identified, analgesic relief is the first
step, while approaching non-pharmacologically
whenever possible in order to optimize patients’
function and quality of life. Timely radiotherapy
and surgical intervention may be necessary.
• As survival improves with new cancer therapies,
the prevalence of cancer treatment–induced
bone loss (CTIBL) will increase. Approaches for
CTIBL, including regular screening of bone min-
eral density (BMD), life style modifications, and
use of bone-modifying agents, are considered.
for the detection of bone metastases is 71–100% and 82–100%,
respectively, with specificity of 73–100% for MRI. 30
Whole-body MRI is a new alternative to the stepwise multi-
modality diagnostic process for bone metastases. The introduc-
tion of a rolling platform mounted on top of a conventional MRI
examination table facilitates whole-body MR imaging within
1 hour. A recent systematic review and meta-analysis revealed a
pooled sensitivity and sensitivity of 90.0 and 91.8%, respectively,
for the detection of bone metastases. 31
Positron emission tomography (PET) may have a role in
the early detection of soft tissue or bone metastases. A recent
Textbook of Palliative Medicine and Supportive Care
meta-analysis to evaluate the diagnostic properties of PET or
PET/CT and bone scintigraphy in detecting bone metastases
associated with lung cancer revealed that the pooled patient-
and lesion-based sensitivity and specificity were 93 and 95% for
PET, respectively, compared to 93 and 57% for bone scintigraphy,
respectively. 32
Therapeutic approach
The goals of therapy are to achieve local tumor control and struc-
tural stability of bone while managing pain. This may lead to
the maintenance or restoration of functional independence and
improvement in quality of life while enhancing opportunities for
potentially life-extending therapies. Although it is important to
provide immediate and effective analgesic management, clini-
cians should pay careful attention to possible long-term adverse
effects of pharmacotherapy. Non-pharmacological approaches
should be considered wherever possible.
Role of analgesic pharmacotherapy
The provision of analgesics is the first step to relieve suffering
from CIBP and create a quality of life acceptable to the person.
Analgesic pharmacotherapy should follow the standard of cancer
pain management, in view of the current lack of mechanism-
specific analgesics. This includes the use of nonsteroidal anti-
inflammatory drugs (NSAIDs), opioid analgesics, corticosteroids,
and adjuvant agents.
NSAIDs inhibit the enzyme cyclooxygenase (COX). The COX-1
isoform is found in platelets, the gastrointestinal tract, kidneys, and
most other human tissues. The COX-2 isoform is found predomi-
nantly in the kidneys and central nervous system and is induced
in peripheral tissues by noxious stimuli that cause inflammation
and pain. In addition to peripheral effects, NSAIDs exert a central
action at the brain or spinal cord level. NSAIDs are effective in can-
cer pain,33 although there is no evidence that they are more effec-
tive in CIBP compared to other pain syndromes. Adverse effects of
NSAIDs include gastrointestinal ulceration and renal failure. The
risk of gastrointestinal toxicity is higher with increased age, pre-
vious peptic ulcer disease, comorbidities, use of multiple NSAIDs
(including ASA), and use in combination with a corticosteroid.
Misoprostol, proton-pump inhibitors, and double-dose H2 block-
ers are effective at preventing chronic NSAID-related endoscopic
gastric and duodenal ulcers.34 Renal function should be monitored
on a regular basis, and adequate hydration ensured.
Corticosteroids are frequently prescribed in cancer care for
the management of multiple symptoms. One small random-
ized controlled trial of methylprednisolone versus placebo in
patients with advanced cancer on opioids did not demonstrate
an analgesic effect for pain of any mechanism, including CIBP.35
A multicenter randomized controlled trial in patients receiving a
single fraction of palliative radiotherapy to a painful bone metas-
tasis showed that dexamethasone reduced the incidence of pain
flare. 36 Side effects occur particularly with prolonged use (e.g.,
osteoporosis, myopathy). Therefore, it is preferable to use corti-
costeroids on a short-term basis, while other analgesic interven-
tions take effect. Corticosteroids act directly on osteoblasts and
osteocytes to induce their apoptosis and reduce bone formation
and strength, and also stimulate bone resorption, increase uri-
nary excretion of calcium, and inhibit intestinal absorption of
calcium. 37 Bone loss can be seen in the first 3–6 months of use.
Even low doses, such as prednisolone 2.5 mg/day, are associated
with an increased fracture risk. 38
Bone Cancer Pain and Skeletal Complications
Calcitonin is a hormone that inhibits osteoclastic bone resorp-
tion. It is used in the treatment of hypercalcemia of malignancy
and for management of pain from osteoporotic compression
fractures. A systematic review found only two small clinical
trials evaluating calcitonin in the treatment of CIBP, conclud-
ing that available evidence does not yet support its use for this
indication. 39
Opioid analgesics are commonly used in CIBP. However, they
are not fully effective and have significant side effects with pro-
longed use. Studies in the animal model have further revealed
that CIBP requires higher doses of morphine to control pain
behaviors compared with inflammatory pain.40 High doses
required for neuropathic and incident pain characteristics lead
to significant adverse effects.41 BT(c)P, as discussed earlier, is
significantly associated with bone metastasis, worse pain man-
agement outcome, interference with activities of daily livings,
and decreased quality of life.42 The Alberta Breakthrough Pain
Assessment Tool is one of few validated assessment tools that
incorporates important aspects of BT(c)P (frequency, severity,
and location) and aims to distinguish BT(c)P from uncontrolled
pain.43 BT(c)P should be treated with rescue analgesia that is
50–100% of the regular 4-hourly opioid dose, in immediate-
release formulation.44 The challenge is that BT(c)P generally
has a rapid onset and short duration, while immediate-release
opioid formulations take 30–40 minutes to achieve meaning-
ful pain relief and last 3–6 hours. Transmucosal fentanyl citrate
may provide rapid-onset pain relief that better matches the time
course of BT(c)P due to its lipophilic nature, which allows direct
absorption across mucosa and rapid distribution to tissues and
plasma.45 However, published studies of transmucosal fen-
tanyl in BT(c)P have methodological issues, with potential bias
that limits the ability to identify its clinical superiority against
other immediate-release opioids.45 The cost, tolerability, and
safety of transmucosal fentanyl also prohibit its use in multiple
clinical settings.44,45 The World Health Organization (WHO)
and National Institute for Health and Care Excellence (NICE)
guidelines recommend an immediate-release opioid, such as
morphine, as the first-line treatment for BT(c)P.44,46
Pregabalin and gabapentin are anticonvulsants used for adju-
vant treatment of neuropathic pain.47 Gabapentin, which has a
role in attenuating hyperalgesia, has been demonstrated to nor-
malize CIBP-induced dorsal horn neuronal hyperexcitability and
reduce pain behaviors in the animal model.48 One multicenter
randomized controlled trial compared pregabalin to placebo in
patients with CIBP receiving palliative radiotherapy. No differ-
ences in analgesic outcomes were seen between the two groups,
although it is possible that effects of radiotherapy masked drug
effects.49
Tanezumab is a humanized monoclonal antibody with high
selectivity and specificity for the neurotropin NGF. NGF plays
an important role in pain signaling. A number of cancers
express or are stimulated by NGF. NGF stimulates sensory neu-
rons by binding to two receptors, tropomyosin receptor kinase
A (TrKA) and p75. Two studies examined tanezumab 10 mg
intravenously in the treatment of CIBP requiring background
opioids. Greater efficacy in daily average pain in week 8 was dem-
onstrated with NGF compared with placebo. The improvement
was seen in the group with higher baseline daily pain score and
lower total opioid usage. Adverse events of abnormal peripheral
sensation were reported. 50 Currently, a phase 3 study on efficacy
and safety of tanezumab in CIBP requiring background opioid
therapy is underway. 51
317
Role of osteoclast inhibitors in SREs
Osteoclast inhibitors (a.k.a. bone-modifying agents) such as
bisphosphonates and denosumab have been found to reduce
the frequency of SREs in patients with bone metastases second-
ary to a variety of cancer types. Bisphosphonates are synthetic
analogs of pyrophosphate, which bind to bone matrix and cause
osteoclast apoptosis, thereby reducing bone resorption. Regular
administration of bisphosphonates has been shown to reduce
SREs in patients with breast cancer metastatic to bone and mul-
tiple myeloma.52,53 Evidence of benefit in other types of tumor
metastatic to bone is evolving. A systematic review concluded
that bisphosphonates may delay onset of bone pain, but there is
insufficient evidence to recommend bisphosphonates for imme-
diate analgesic effect.54
Available bisphosphonates include clodronate, pamidronate,
zoledronic acid, and ibandronate (availability varies among
countries). The parenteral route is preferred due to superior bio-
availability, avoidance of gastrointestinal distress, and probably
better analgesic effect. Clodronate is unique in its ability to be
given subcutaneously, which may be advantageous in the pal-
liative care setting.55 Bisphosphonates may harm renal function,
an uncommon event if given according to recommended dos-
ing. An international expert panel endorsed that an intravenous
bisphosphonate should not be administered in combination with
nephrotoxic chemotherapy.56 Another potential complication
is osteonecrosis of the jaw; pretreatment dental assessment and
intervention, and monitoring of dental health during treatment,
are recommended.57 A randomized open-label study in people
with breast, prostate, or multiple myeloma demonstrated non-
inferiority in SREs, pain intensity scores, performance status
scores, incidence of jaw necrosis, and renal dysfunction in the
treatment group receiving zoledronic acid every 12 weeks com-
pared with those receiving standard interval of every 4 weeks.
The levels of a marker of tumor turnover (C-terminal telopeptide)
were greater among the group treated with every 12 weeks.58
Denosumab is a human monoclonal antibody with high affin-
ity and specificity for RANKL.59 By neutralizing RANKL, deno-
sumab inhibits osteoclast formation, function, and survival,
thereby suppressing bone resorption. Studies in breast, prostate,
and other solid tumors have demonstrated delayed time to first
SRE compared to zoledronic acid, pamidronate, and placebo, but
insufficient information exists on its effects on pain.54,60 A sys-
tematic review and meta-analysis of denosumab, although lim-
ited by a small number of included studies, showed a favorable
impact on delaying the time to first SRE and reducing the inci-
dence of radiation to the bone in comparison to bisphosphonates,
with similar efficacy regarding overall survival and time to dis-
ease progression.61 Denosumab’s subcutaneous route of adminis-
tration offers a potential advantage in certain settings. However,
it is significantly more costly than bisphosphonates.
Non-pharmacological approaches
Occupational and physical therapy
Bone metastases are a frequent source of cancer-related physi-
cal impairment that requires the active involvement of the reha-
bilitation team. Rehabilitation focuses on decreasing the stress
or immobilizing compromised bone through the provision of
assistive devices, strength, and balance training. Modification
of the living environment with assistive devices (crutches, walk-
ers, wheelchairs, braces, and grip bars), in addition to non-weight
318
bearing techniques, heat, ice, and sometimes gentle massage,
can help reduce pain. It is critical to rule out concurrent upper
extremity lytic lesions and CIBP prior to prescribing assistive
devices that require the upper extremity support. There is strong
evidence that exercise is safe and beneficial for patients with the
majority of cancer types, regardless of prognosis and age; how-
ever, the evidence was limited to specific symptoms related to
CIBP and BT(c)P.62 Although supporting rehabilitation in people
with bone metastases potentially presents an ethical dilemma,
the alternative to rehabilitation is bed rest, which carries its own
complications such as further deconditioning, muscle contrac-
tures, osteoporosis, thromboembolic disease, infection, and pres-
sure ulcers that can complicate further pain syndromes. A recent
systematic review demonstrated that one-third and half of adults
with cancer, respectively, have difficulty or require assistance to
perform basic and instrumental activities in daily livings.63 The
potential underutilization of rehabilitation in cancer care, com-
pared to other medical conditions such as heart disease or stroke,
has been highlighted. A randomized trial of physical therapy
during radiotherapy in patients with vertebral metastasis demon-
strated improvement in biochemical markers of bone turnover;
pain intensity and quality of life were not outcome measures.64
Radiotherapy and radiopharmaceuticals
External beam radiotherapy is a standard approach to the man-
agement of CIBP that cannot be adequately controlled with anal-
gesics. A systematic review showed that over 60% of patients can
expect at least partial pain relief, and just over 20% can expect
complete pain relief.65 There is no difference in pain relief or
adverse effects between single and multiple fractions. While sin-
gle-fraction radiotherapy may require re-treatment more often
than multiple fractions, it is less burdensome for the patient and
less costly for the health-care system.65 External radiotherapy for
CIBP often takes several weeks to achieve pain reduction.66 The
use of this treatment modality in the final weeks of life may have
limited clinical use and may impair quality of life. A Canadian
population-based analysis found that 4% of CIBP-related radio-
therapy was provided during the last 2 weeks of life. Patients with
lung and gastrointestinal cancer, or those with metastases to the
spine or extremity, were more likely to receive late radiother-
apy.67 Another systematic review noted that the external beam
radiotherapy was utilized in 5–10% of reported studies during
the last month of life. Twenty-six percent of patients who sur-
vived less than 1 month reported palliation of symptom following
radiotherapy.68
Radiopharmaceuticals are radioactive agents, administered
intravenously, that localize to metastatic bone sites and deliver
radiation in a focal manner due to the nature of the radioactivity
emitted (typically beta/electron emission). A systematic review,
including randomized controlled trials of strontium-89, samar-
ium-153, rhemium-186, rhenium-188, and phosphorus-32, dem-
onstrated that radiopharmaceuticals are associated with pain
relief (number needed to treat = 5 to achieve complete relief and
4 for complete plus partial relief).69 The main adverse effects are
leukocytopenia and thrombocytopenia (number needed to harm
= 13). The use of radiopharmaceuticals may best be considered
for patients with multiple painful bone metastases, where pain
control with conventional analgesic regimens is unsatisfactory
and local field radiotherapy is not appropriate. Patient selec-
tion for radiopharmaceutical therapy should consider marrow
function, performance status, recent use of other marrow sup-
pression agents (chemotherapy or external beam radiotherapy),
Textbook of Palliative Medicine and Supportive Care
suitability for alternate interventions, and life expectancy of
more than several months, since onset of analgesia is typically
measured in months.70
Interventional approaches
The goal of surgical intervention is to provide structural stability
and promote immediate functional recovery, weight-bearing, and
rehabilitation, with the least possible morbidity. The indications
for surgical intervention of long bone and pelvic girdle metasta-
ses include impending and pathological fractures and intractable
pain.71 Surgical intervention for spinal metastases is indicated for
patients with spinal instability or spinal cord compression.72
Mirels’ scoring system is a validated tool combining clini-
cal and radiographic factors (associated pain, location, size,
osteoblastic versus osteolytic lesions) to assess fracture risk in
metastatic bone disease. This is necessary because prophylactic
treatment of impending fractures (versus established fractures)
can lead to faster recovery.73 While Mirels’ scoring system has
been criticized for its relatively low specificity, it is reproducible,
applicable, and remains the gold standard.74 Spinal instability is
presumed if there is transitional deformity, vertebral body col-
lapse of >50%, tumor involvement of two of three columns, or
involvement of the same column at two or more adjacent levels.75
Postoperative external beam radiotherapy is necessary in most
cases to obliterate residual microscopic disease and thus prevent
disease progression and further osteolysis.76
A prospective study to evaluate surgical intervention for long
bone metastases with a median Mirels’ score of 10 out of 12 found
that while quality of life indicators did not improve, postoperative
pain and functional scores improved within 2 weeks compared
with preoperative scores, and continuous incremental improve-
ment was observed at 1 year. Overall complications occurred at a
rate of 35% and included wound infection, venous thromboembo-
lism, hardware failure.77 Similarly, systematic reviews report that
surgery can improve outcomes, although with paucity of high-
level evidence and inconsistencies in study design.78,79 In some
patients with pathologic fractures, even if survival is expected to
be in the range of short months to 2 weeks, the benefits of pain
control and quality of life may outweigh the risk of postoperative
complications.77,80 Percutaneous vertebral augmentation (verte-
broplasty, balloon kyphoplasty) stabilizes vertebral bones com-
promised by metastatic bone disease, with the aim of improving
pain control. These interventions too must be carefully consid-
ered, with complications and potential benefits.81
Long-term effects on bone
health and cancer therapy
With advances in screening and therapies, people are living
increasingly longer with the consequences of cancer and its
treatment. In children and adolescents with cancer, the 5-year
survival rate has become 80%, which can lead to impact on
endocrine, metabolic, and skeletal health.82 All cancer therapies
can decrease bone mineral density (BMD), leading to cancer
treatment–induced bone loss (CTIBL).83 Androgen deprivation
therapy results in reduction of circulating testosterone, which
lowers serum estradiol, promoting decrease in BMD and muscle
decrease but increase in fat.83 Aromatase inhibitors (AIs) such
as anastrozole, exemestane, and letrozole deplete circulating
estrogens by inhibiting the aromatization of androgens and their
conversion to estrogens in peripheral tissues.83 In a large popula-
tion-based cohort of older women, there was a higher risk of total
Bone Cancer Pain and Skeletal Complications
nonvertebral fracture but nonsignificant differences in hip frac-
tures among AI users compared to tamoxifen users.84 AI use was
associated with increased overall fracture risk in another large
cohort, with other significant factors, including smoking status,
low body mass index, dementia, and use of corticosteroids.85
Meanwhile, chemotherapies contribute to bone mass loss
either directly, through dysregulation of osteoblast and osteo-
clast differentiation and activity, or indirectly, as a result of the
development of chronic renal disorders and hypogonadism.83
Radiotherapy, glucocorticoids and targeted therapy such as tyro-
sine kinase inhibitors also contribute to damage of bone health.83
In a long-term cohort study in survivors of breast, colorectal, and
prostate cancer matched with noncancer controls, the incidence
of osteoporosis was increased in all survivors. Prostate cancer
survivors had the highest risk of osteoporosis.86 Pelvic radio-
therapy has been found to contribute to insufficiency fractures in
uterine and cervical cancer patients.87
Preclinical models have shown that prolonged exposure to
morphine is associated with increased osteoclast activity, upreg-
ulated interleukins (IL-1 beta), accelerated sarcoma-induced
bone destruction and doubles the incidence of spontaneous
fracture, in a dose- and naloxone-sensitive manner.88 Clinical
studies in chronic noncancer pain have provided evidence for
opioid-induced androgen deficiency in men and profound inhibi-
tion of ovarian sex hormone and adrenal androgen production in
women, which may affect bone health.89 In patients on long-term
opioid maintenance therapy, BMD was significantly lower than in
age- and BMI-matched controls in all age groups.90
The WHO provides a clinical tool, namely, the Fracture Risk
Assessment Tool (FRAX), to evaluate the 10-year probability of
major osteoporotic and hip fractures based on age, sex, body
mass index, clinical risk factors, femoral neck BMD, and other
information in the general population.91 An elevated baseline
FRAX score was highly predictive of vertebral fractures in mul-
tiple myeloma patients.92 Periodic BMD evaluations, regular
exercise, and calcium/vitamin D supplementation as well as the
use of bone-modifying agents are recommended in AI-treated
postmenopausal women, all women with breast cancer with
concomitant fracture-risk factors, and men on androgen depri-
vation therapy.93
Conclusion
The progress in cancer therapeutics has significantly improved
the survival of patients with metastatic bone disease. However,
these therapeutic options have not demonstrated evidence in
reducing the incidence of CIBP and other SREs to date. CIBP is
the most common source of cancer pain that has ominous conse-
quences for prognosis of both quality of life and survival. A high
impact on bone health and consequential CTIBL are associated
with all aspects of cancer therapies in cancer survivors. SREs,
CIBP, and CTIBL demand a multimodal approach in order to
improve and maintain an acceptable quality of life for people liv-
ing with a diagnosis of cancer.
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fracture probability in men and women from the UK. Osteoporos. Int
2008;19:385–397.
92. Atrash S, Dua I, Buros AF, et al. FRAX is a robust predictor of
baseline vertebral fractures in multiple myeloma patients. Bone
2019;121:134–138.
93. Hadji P, Aspro MS, Body JJ, et al. Management of aromatase
inhibitor-associated bone loss (AIBL) in postmenopausal women
with hormone sensitive breast cancer: joint position statement of
the IOF, CABS, ECTS, IEG, ESCEO, IMS, and SIOG. J Bone Oncol
2017;7:1–12.
34
BREAKTHROUGH (EPISODIC) PAIN IN CANCER PATIENTS

Shirley H. Bush

Contents
Introduction�����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������323
Background to terminology and definitions����������������������������������������������������������������������������������������������������������������������������������������������������������323
Etiology of breakthrough pain����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������324
Breakthrough pain mechanisms������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������324
Prevalence and characteristics of breakthrough pain������������������������������������������������������������������������������������������������������������������������������������������������324
Impact of breakthrough pain������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������324
Management of breakthrough pain�������������������������������������������������������������������������������������������������������������������������������������������������������������������������������325
Assessment of breakthrough pain���������������������������������������������������������������������������������������������������������������������������������������������������������������������������325
Primary therapies to treat the underlying cause���������������������������������������������������������������������������������������������������������������������������������������������������325
Optimizing the analgesic regimen���������������������������������������������������������������������������������������������������������������������������������������������������������������������������325
Using “rescue” analgesia for breakthrough pain���������������������������������������������������������������������������������������������������������������������������������������������������325
Routes of administration of opioid “rescue” analgesia for breakthrough pain�����������������������������������������������������������������������������������������������326
Oral route����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������326
Subcutaneous route����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������327
Intravenous route��������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������327
Oral and nasal transmucosal routes������������������������������������������������������������������������������������������������������������������������������������������������������������������327
Fast-acting transmucosal fentanyl preparations���������������������������������������������������������������������������������������������������������������������������������������������327
Other routes�����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������328
Other drugs used for breakthrough pain���������������������������������������������������������������������������������������������������������������������������������������������������������������328
Nonpharmacological approaches����������������������������������������������������������������������������������������������������������������������������������������������������������������������������328
Interventional approaches�����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������328
Future directions���������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������328
Conclusion��������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������329
References���������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������329
BTP chapter: NEW References for 2019 edition��������������������������������������������������������������������������������������������������������������������������������������������������������330

Introduction
The intensity of cancer pain commonly fluctuates over time
and challenges usual cancer pain management using the World
Health Organization (WHO) analgesic “ladder.” It is an impor-
tant common clinical problem, often significantly impacting on
a patient’s quality of life and can be difficult to assess and pre-
dict. A bewildering array of terminology and definitions has been
used to describe this heterogeneous phenomenon, but the lack of
a standardized worldwide definition has led to difficulty in com-
parisons of reported prevalence and management.
Background to terminology and definitions
In 1989, the Edmonton staging system for cancer pain defined
“incidental pain” as “pain aggravated suddenly as a result of
movements, swallowing, defecation or urination.”1 The term was
later changed to “incident pain” in the subsequent Edmonton
Classification System for Cancer Pain (ECS-CP).2 In a seminal
paper in 1990, Portenoy and Hagen developed a working definition
for “breakthrough pain” (BTP) for a prospective survey of cancer
pain patients.3 BTP was defined as “a transitory increase in pain
to greater than moderate intensity, which occurred on a baseline
pain of moderate intensity or less.” Opioid use was not included
in the working definition, but evaluated patients had been on
relatively stable doses of opioids for two consecutive days. Portenoy
and Hagen’s definition of BTP required controlled baseline pain.4
A task group of the Association for Palliative Medicine of Great
Britain and Ireland defined BTP as “a transient exacerbation of
pain that occurs either spontaneously, or in relation to a specific
predictable or unpredictable trigger, despite relatively stable and
adequately controlled background pain.”5 Hagen et al. commented
in their definition of BTP that “it is difficult to characterize BTP
when baseline pain is not controlled”6; however, some authors
consider BTP, irrespective of whether baseline pain is controlled,
as did expert participants in a Delphi survey for the European
Association for Palliative Care Research Network.7,A BTP has also
been defined as pain that “breaks through” the regular doses of an
analgesic schedule.8 This includes “end-of-dose failure,” where pain
worsens before the next scheduled dose of opioid. Conversely, not
all authors think “end-of-dose failure” should be included as a sub-
type of BTP as it signifies that the baseline pain is not controlled.5,7
The term “incident pain” is frequently used to describe the
pain induced by movement.9 The definition is often broadened to
describe a precipitated, stimulus-dependent, or triggered pain.7
McQuay and Jadad classified “incident pain” into two subtypes—
the first was pain on movement that included walking, turning,
lifting, coughing, and deep breathing. The other subtype was inter-
mittent pain not related to activity or movement.10 “Incident pain”

323
324
FIGURE 34.1  Breakthrough pain (BTP) crescendos with
(a) controlled baseline pain and (b) uncontrolled baseline pain.
VRS, verbal rating scale.
has also been used to represent pain with a volitional precipitant,
that is, induced by the patient’s voluntary actions, which should
be predictable. 3
Other terms that have been used include “pain in motion”11
and “transitory pain.”12 In an international survey of 58 clinicians
from 24 countries, where BTP was defined as an episode of “pain
flare,” there was a large variation in the rates of BTP identifica-
tion, suggesting that the concept of BTP varies geographically.13
“Episodic pain” was the term agreed on by an expert working group
of the European Association for Palliative Care (EAPC) in December
2000, as it translated better into different languages.14 “Episodic pain”
was defined as a transitory exacerbation of pain that changes with
time, which could occur with controlled or uncontrolled baseline
pain (Figure 34.1), with the term incident pain reserved for move-
ment-related “episodic pain,” usually due to bone metastases. The
EAPC working group also recognized pains that are volitional and not
induced by a specific movement, for example, swallowing in the pres-
ence of mucositis or touch if hyperesthesia, and nonvolitional pains,
for example, sneezing, coughing, laughing, or myoclonus.14
From these assorted terms and definitions, BTP is the common-
est term that has been used in the published literature.7 BTP can be
more usefully classified into three subtypes: incident pain, sponta-
neous, and “end-of-dose failure.” In a systematic literature review,
incident pain was further characterized into volitional and nonvo-
litional categories.7 Volitional (movement-related) pain is usually
predictable. In contrast, nonvolitional pain (nonmovement related)
is usually unpredictable in nature. Spontaneous pains are indepen-
dent of movement or volition, for example, neuropathic pain.14
Etiology of breakthrough pain
As with cancer pain etiology, BTP may be caused by the cancer
or by the cancer treatment. BTP may also be due to a concurrent
disorder that is unrelated to the patient’s cancer.
Breakthrough pain mechanisms
BTP, like baseline cancer pain, is categorized according to differ-
ent anatomical and pathophysiological pain mechanisms.15 These
Textbook of Palliative Medicine and Supportive Care
mechanistic categories are nociceptive (comprising superficial
somatic, deep somatic, and visceral), neuropathic, and mixed
pain. The BTP may have a different pathophysiology to the base-
line pain.
Prevalence and characteristics
of breakthrough pain
The prevalence of BTP differs enormously depending on the defi-
nition and survey instrument used and the population sampled.
Reported prevalence has been as low as 19%16 to around 90%.17–19
Many studies report prevalence in the range of 40–80%. 3,4,12,20–22,B
Internationally, prevalence has been found to vary according to
region with a reported prevalence of 80.1% from English-speaking
countries, 69.4% from North and Western Europe, 54.8% from
South America, and only 45.9% from Asia.23
BTP is heterogeneous and commonly occurs 2–4 times/
day, 3,19,24,25,C although the range can markedly vary, as in the
reported case of a patient with a rib fracture and cough experi-
encing BTP every minute. 3 Box 34.1 gives the median time for
BTP to peak and the median duration, although the upper limit
of the range for BTP duration can be as long as 2 or even 4 hours.
Most cases of BTP are exacerbations of the baseline pain, but
they can be a worsening of a different pain. A minority of patients
experience more than one type of BTP. The intensity of BTP is
usually moderate-to-severe.25
The onset of BTP is often unpredictable, despite 20–40% being
movement related and 13–30% classified as “end-of-dose fail-
ure.”4,18,21 Neuropathic BTP is significantly briefer and more fre-
quent than nociceptive BTP.12,18
Impact of breakthrough pain
Patients with BTP tend to have higher pain scores and more
intense baseline pain than patients without BTP. Movement-
related BTP, which is commonly due to metastatic bone disease,
is relatively resistant to treatment with analgesics.21,26 Only 6%
of patients with pain secondary to bone metastases, who were
attending a multidisciplinary pain clinic in Denmark, became
pain-free “in motion” after pain treatment.11 In an interna-
tional multicenter validation study of the ECS-CP, patients with
incident pain required more adjuvants and higher final opioid
doses.27 Incident pain was also independently associated with a
longer time to achieve stable pain control.
The presence of BTP significantly impacts on walking and
causes functional interference on the Brief Pain Inventory, mani-
festing as increased levels of depression and anxiety.4,21,23 BTP
often interferes with sleep and impairs quality of life by restrict-
ing social and general activities.17 Uncontrolled BTP reminds
BOX 34.1  FEATURES OF TYPICAL
CANCER BREAKTHROUGH PAIN
• Prevalence—40–80%
• Frequency—Median 3 episodes/day
• Onset—Often unpredictable
• Intensity—Moderate-to-severe
• Median time to peak—5–10 minutes
• Median duration of untreated episodes—
30–60 minutes
Breakthrough (Episodic) Pain in Cancer Patients
patients of their cancer and imparts a sense of loss of control.28
It may necessitate a change in lifestyle or even the discontinua-
tion of work life with accompanying significant psychological dis-
tress. Cancer patients with BTP are more likely to have endured
increased medical costs, due to pain-related hospitalization and
physician visits.29
Management of breakthrough pain
BTP is under-recognized, and its treatment remains subopti-
mal.20,22,30,31 There is a pressing need for further health-care pro-
vider and patient education. 30,32 For the appropriate management
of BTP, a multimodal patient-centered approach is needed while
maintaining a holistic framework. The multidisciplinary and
interprofessional management plan should take account of the
stage of disease, illness trajectory, performance status, and the
patient’s goals of care, including their personal pain target bal-
anced with their desired level of activity. Patients’ and families’
fears and expectations should be explored and ongoing explana-
tion and support provided.
Assessment of breakthrough pain
The comprehensive assessment of the patient and the BTP(s)
experienced should comprise a detailed history, including the
characteristics and mechanisms of the BTP and also the base-
line pain, a thorough clinical examination, and a psychosocial
evaluation. BTP assessment should include an evaluation of its
interference with activities of daily living and quality of life.7 A
daily pain diary recorded by the patient may also form part of the
assessment, in addition to being a useful record in the monitoring
of BTP treatment.
The BTP Questionnaire was designed to characterize BTP.3
However, the assessment algorithm used in the 1999 survey has
only been partially validated.4,7 The Alberta Breakthrough Pain
Assessment Tool (ABPAT-R) is a detailed tool for use in cancer
patients.6 It was designed to use in research as opposed to day-to-day
clinical use and has been validated in a multicenter study of cancer
patients.D The Breakthrough Pain Assessment Tool (BAT) was devel-
oped as a clinical assessment tool.E It was validated in cancer patients
and consists of 14 questions. Patients often find the use of pain scales
difficult and find it easier to describe their BTP in terms of sever-
ity, emotions, or impact, rather than the traditional pain descriptors
(e.g., burning, stinging) used by health-care professionals.28
Primary therapies to treat the underlying cause
Oncological interventions may be appropriate, depending on the
patient’s condition and anticipated prognosis. Radiotherapy is effec-
tive at reducing pain from painful bone metastases (see Chapter 88).
Single and multiple fractionation schedules have been used with
similar efficacy.33 For extensive bone metastatic disease causing
pain, hemibody irradiation has been used. There is some evidence
that radioisotopes, for example, strontium-89 and samarium, relieve
pain over 1–6 months, but with a risk of leucocytopenia and throm-
bocytopenia.34 Bisphosphonates have been shown to be effective in
reducing pain due to bone metastases35,36 (see Chapter 52).
There may be a role for chemotherapy or hormone therapy in
responsive disease. Surgery may also be used palliatively after an
assessment of benefits and attendant risks, for example, stabiliza-
tion of a pathological fracture, or prophylactically for a femur at
risk of fracture. Percutaneous vertebroplasty has been shown to
reduce pain and improve mobility in patients with fractured spi-
nal metastases, who have failed radiation. 37 Some cases of bowel
325
obstruction may be remediable with surgery, thus eliminating
BTP due to colic.
Optimizing the analgesic regimen
Implementation of the principles of the WHO “ladder” should
optimize the treatment of baseline pain. Opioid titration is usu-
ally required, and at times, a change in route of opioid adminis-
tration is needed. BTP then regularly improves as often baseline
pain has been poorly controlled. However, it is important not to
oversedate the patient by increasing baseline opioid analgesia levels
excessively in pursuit of around-the-clock (ATC) control of BTP
crescendos, as the pain signal will often diminish with rest or time
(Figure 34.2a). If opioid side effects are excessive, opioid substitu-
tion or “switching” should be considered (see Chapter 44). Another
strategy to decrease sedation from opioids is the addition of meth-
ylphenidate.16 Increasing the opioid dose or reducing the interval
between opioid doses can manage “end-of-dose failure.” For exam-
ple, a few patients require 12-hourly modified release morphine to
be given every 8 hours or transdermal fentanyl patches changed
every 48 hours, rather than the usual 72 hours.
Depending on the pain mechanism, the use of nonopioid
analgesic regimens will also improve baseline analgesia. Anti-
inflammatory agents, such as nonsteroidal anti-inflammatory
drugs (NSAIDs) and short-term use of corticosteroids like dexa-
methasone, are indicated for pain due to bone metastases and
mucosal or skin lesions. They also provide relief for pain originating
from organ capsules, such as liver capsule inflammation, and from
mesothelial membranes (pleura and peritoneum). Corticosteroids
also have an analgesic effect on neuropathic pain by reducing
edema around peripheral nerves. The regular use of adjuvants for
neuropathic pain, including tricyclic antidepressants and anti-
convulsants, should diminish BTP from this mechanism. Patients
with either multiple bone metastases and severe movement-related
BTP, mucositis, or neuropathic pain have responded to ketamine,
an N-methyl-d-aspartate (NMDA) receptor antagonist, given as a
“burst” subcutaneous infusion for 3–5 days.38
Other drugs used for BTP include antispasmodics, for example,
hyoscine butylbromide for bowel spasm, oxybutynin for bladder
spasm, and diazepam or baclofen for muscle spasm.
Using “rescue” analgesia for breakthrough pain
A “rescue” dose of analgesia should be administered when needed
to “top up” baseline analgesia, either 20–30 minutes before a pre-
dictable BTP as a preemptive dose (e.g., for movement-related pain
or pain with dressing changes) or at the onset of a BTP episode. 39
However, most patients do not take their “rescue” medication
for each episode.40 Frequently, a patient would have concluded
that their prescribed “rescue” opioid medication is pointless, as
their BTP episode would have resolved long before the onset of
the extra pain relief. Usually an immediate release (IR) formula-
tion of opioid is used as “rescue” medication, but sometimes, an
NSAID is prescribed. If a patient is experiencing more than four
BTP episodes per day, an increase in the total daily opioid dose for
baseline pain should be considered.
Properties of an ideal “rescue” analgesic include the following:
• Quick absorption with rapid onset of analgesia and early
peak effect
• A short duration of action, but long enough to treat the
BTP episode
• Minimal side effects
• A good safety profile
326 Textbook of Palliative Medicine and Supportive Care

FIGURE 34.2  Drug management of cancer breakthrough pain (BTP). (a) Increasing the baseline analgesia to meet the peaks of
BTP, leading to oversedation. (b) Rescue doses of analgesia—schematic representation. Legend: IR, immediate release; IV, intravenous;
OTFC, oral transmucosal fentanyl citrate; PCINA, patient-controlled intranasal analgesia.

The drug should target the implicated pain mechanism. The ideal usual oral IR formulation of morphine24 contrasting with under
“rescue” analgesic would be responsive to the peaks and troughs 15 minutes for an effervescent IR morphine preparation.43 Oral IR
of BTP episodes with a rapid on/off effect to counter a fluctuating morphine has a mean Tmax (time at which maximum concentra-
pain trajectory over a short period of time, analogous to the cur- tion is reached) of 1 hour.44 Analgesia then lasts about 4 hours,
rent “gold standard” of intravenous (IV) patient-controlled anal- indicating that the time taken for onset of analgesia and its dura-
gesia (PCA). It should also be easy to self-administer, available for tion are often too prolonged for the majority of BTP episodes.
both inpatients and those in the community and should not be However, in a recent prospective study in a palliative care outpa-
expensive. The choice of drug for the “rescue” dose and the route tient clinic, almost 90% of patients (who had advanced cancer and
used will also be influenced by the accessibility of opioids and
their formulations in different countries. TABLE 34.1  Comparing the Analgesic Onset and Duration
for Different Routes of Administration of Opioids
Routes of administration of opioid “rescue”
Average Time for
analgesia for breakthrough pain
Onset of Analgesia Average Duration of
See Table 34.1 and Figure 34.2b.
Route (minute) Analgesic Effect (hour)
IV, e.g., morphine 5 1–2
Oral route Oral transmucosal/ 5–15 1–2
For patients on an oral regularly scheduled morphine regimen for
intranasal, e.g.,
baseline pain, it has been recommended that the “rescue” dose
fentanyl series
be equivalent to the 4-hourly dose of morphine, that is, 16% of
Subcutaneous, e.g., 10–15 3–4
the current 24-hour dose.41 Other clinicians suggest 5–10% of the
morphine
total daily opioid dose. More recent studies suggest that an indi-
Oral, as IR, e.g., 30 4
vidual’s “rescue” dose should be found by titration.42 The aver-
morphine
age time to meaningful pain relief is around 30 minutes with the
Breakthrough (Episodic) Pain in Cancer Patients
baseline pain ≤ 3/10) reported that their oral IR opioid medica-
tion was effective for their BTP.F
Subcutaneous route
Following a subcutaneous injection of opioid, analgesia begins
within 10–15 minutes and lasts for 3–4 hours.45 Mean time to
pain relief with subcutaneous morphine for BTP is 17 minutes.20
The majority of patients who self-administered subcutaneous res-
cue opioids using a “pain pen” rated its efficacy as good.46
Intravenous route
Pain relief should begin within 5 minutes of IV administration
and last for 1–2 hours.45 On using a fixed ratio of IV morphine
to oral morphine daily dose, given by bolus injection, BTP
intensity was reported to be reduced by more than 50% within
a mean of 16.6 minutes.47 IV administration of “rescue” doses
of opioids has been found to be superior to the transmucosal
route at 15 minutes, with both routes being equally effective at
30 minutes.48 Patients with uncontrolled bone pain have been
successfully and safely managed at home by skilled and acces-
sible staff, using a PCA pump and either the IV or subcutane-
ous route.49
Oral and nasal transmucosal routes
These routes have the advantage of bypassing the first-pass effect
of the liver. The nasal and oral mucosae are highly vascular areas,
enabling rapid absorption and superior bioavailability for those
drugs with suitable physicochemical properties.50–52 Drugs meet-
ing these requirements are lipophilic, with a high permeability
coefficient, and potent. The properties of the fentanyl series of
drugs make them highly suitable for transmucosal administra-
tion. The onset of action for buccal and intranasal fentanyl can
occur within 10 minutes of administration.48 Fentanyl is metabo-
lized by cytochrome P450 (CYP) 3A4. Its use should be avoided
in patients who have received a mono-amine oxidase inhibitor
within the previous 2 weeks due to an increased risk of sero-
tonin toxicity.53 Sufficient saliva is needed for the administration
of sublingual and buccal preparations. Common adverse effects
of transmucosal fentanyl are somnolence, nausea, and dizzi-
ness. Methadone also has a favorable pharmacodynamic profile.
Sublingual methadone has a rapid onset of analgesic effect, occur-
ring with a median onset of 5 minutes.54 (Methadone should only
be initiated by expert physicians who are experienced in its use.)
Buprenorphine can be given sublingually, but sublingual absorp-
tion of morphine is poor due to low lipid solubility and over 90%
ionization.55
Off-label sublingual administration of injectable formula-
tions of fentanyl citrate, 56 sufentanil, 57 and alfentanil58 has been
reported. Volumes of fluid greater than 1–2 mL have been found
to be problematic, due to reflex swallowing. Similarly, off-label
administration of the fentanyl series by intranasal spray has been
reported.58–60 The Tmax for their intranasal single dose adminis-
tration in healthy volunteers is 5–10 minutes, with bioavailabili-
ties of 65–78%.50 The maximum volume for one nostril in a single
administration is 150–200 μL. The use of a patient-controlled
intranasal analgesia (PCINA) device mimics the efficacy of IV
PCA. Morphine has been administered intranasally using chito-
san to enhance penetration.61 Adverse effects of nasal adminis-
tration are mainly systemic opioid-related side effects, as opposed
to nasal toxicity.
327
Fast-acting transmucosal fentanyl preparations
Several proprietary products have been developed. 39,48,62 See
Table 34.2 for characteristics of these preparations. These have
a role in those patients where traditional “rescue” analgesia has
failed, causes excessive side effects, or is not sufficiently respon-
sive to the intensity or temporal profile of their BTP. The propri-
etary formulations are comparatively expensive and availability
will vary according to country. Publication bias needs to be con-
sidered in reviewing the evidence as much of the data on these
products was from pharmaceutical industry–sponsored random-
ized controlled trials (RCTs). 39
The first available proprietary transmucosal fentanyl prepara-
tion was oral transmucosal fentanyl citrate (OTFC). Double-blind
RCTs showed significantly better pain relief compared to placebo
or IR oral morphine.42,63 The Tmax of a 15 μg/kg dose is 22 minutes,
with the duration of effect lasting 1–2 hours.
As the original studies found no fixed relationship between
the total daily dose of scheduled opioid and dose of OTFC
required for the BTP episode, 64,65 individual dose titration of
all of the transmucosal fentanyl formulations was recommen
ded, 5,48,53 but more recent studies have used transmucosal fen-
tanyl products in doses that are proportional to the patient’s
basal opioid dose.66,67 Further evidence is required before this
approach can be routinely recommended.G Lower doses of these
products should be used in older or frail patients, in addition to
slower titration.H
All of the transmucosal fentanyl products should only be
used in adult patients on a regular strong opioid (morphine 60
mg/24 hour PO or equivalent) for chronic cancer pain for at
least 1 week.53 The optimal dose is usually used to treat up to a
maximum of four BTP episodes/24 hour. These products are not
interchangeable, and retitration is essential if switching products.
Education should be given to patients on the use of these prod-
ucts. Safe storage and disposal is also needed. Patients should be
given support, have regular reassessment of their pain and any
adverse effects, and their opioid usage should be monitored.
Cases of local ulcer and dental caries have been reported with
transmucosal preparations. 39 Intranasal opioids should not be
used in patients with recurrent epistaxis, and concurrent use
with vasoconstrictive nasal decongestants should be avoided.53
Data from the long-term use of these products has been reported,I
but more data on long-term outcomes is needed.
There is a potential risk for misuse, abuse, addiction, and
diversion of these medications, especially in high-risk patients.
Prescriptions and aberrant behaviors need to be closely moni-
tored.68 In December 2011, the US Food and Drug Administration
(FDA) approved a shared Risk Evaluation Mitigation Strategy
(REMS) for transmucosal IR fentanyl (TIRF) products. A recent
analysis of the REMS program (including FDA documents
from 2012 to 2017) reported that claims data indicated that
between 35 and 55% of patients prescribed these products had
not received a prescription for 7 days of opioid immediately pre-
ceding the TIRF prescription. 69 In August 2017, the FDA made
changes to some of the required REMS Access Program forms
to meet its goal of ensuring that TIRF products are only pre-
scribed and dispensed to appropriate patients who are opioid
tolerant.
Health-care professionals may lack confidence in the appropri-
ate prescribing and use of these newer pharmacological agents. 32
There remains a need for further clinician education and training
in this area and the development of user-friendly BTP manage-
ment algorithms for day-to-day clinical practice.
328 Textbook of Palliative Medicine and Supportive Care

TABLE 34.2  Characteristics of Fast-Acting Transmucosal Fentanyl Proprietary Formulations53,62,82,83,I

Duration of
Formulation Onset of Action (minute) Action (hour) Bioavailability (approximate) Notes
Oral transmucosal 15 1–2 Overall bioavailability: 50% (25% Consumed slowly over 15 minutes by
Oral transmucosal from rapid oromucosal rubbing compressed sweetened
fentanyl absorption + 25% from slower lozenge (which is attached to a plastic
citrate—OTFC gastrointestinal absorption, after applicator) across the oral,
swallowing remaining dose) particularly buccal, mucosa
Buccal 10 >2 65% Enhanced buccal delivery of fentanyl:
Fentanyl buccal Drug delivery system utilizes
tablet—FBT effervescence to cause pH shifts
Fentanyl buccal 15 >1 70% Small bioerodible polymer film with
soluble film—FBSF the fentanyl-containing layer, which
adheres to patient’s cheek, separated
from saliva by an outer layer
Sublingual 10 >1 70% Tablet rapidly breaks down with a
Sublingual fentanyl bioadhesive component enabling
tablet—SLF carrier particles to adhere to the
sublingual mucosa
Intranasal 5 >1 90% Aqueous solution; multidose device
Intranasal fentanyl nasal spray
spray—INFS
Fentanyl pectin 10 >1 65% Aqueous nasal spray that forms a gel
nasal spray—FPNS on contact with nasal mucosa—this
attenuates the peak plasma
concentration
Note: Earliest statistically significant onset from fentanyl products and placebo studies. Clinically meaningful onset usually takes longer. For further details, see individual product
monographs.

Other routes
The use of nebulized fentanyl has been reported in a small case
series,70 but more evidence is needed to support its use in clinical
practice.
Other drugs used for breakthrough pain
Intermittent subcutaneous midazolam has been used for the tem-
porary sedation of patients with pathological hip fractures and
severe BTP.71 Subanesthetic ketamine, in a subcutaneous bolus
dose of 20–40 mg, may be used before predictable movement-
related BTP, such as difficult dressing changes or repositioning
of a patient with a fractured long bone. It may be combined with
a bolus injection of midazolam.72 The sublingual and intranasal
routes of ketamine have also been utilized in the management of
BTP, as has nitrous oxide.73–75
Nonpharmacological approaches
Psychosocial interventions are a fundamental component of
a multimodal approach to the management of cancer pain.76
Patients frequently use nonpharmacological strategies to relieve
BTP, including repositioning, rest and sleep, movement and
exercise, heat or cold, rubbing and massage, relaxation, visual-
ization, and distraction.12,19,25 Transcutaneous electrical nerve
stimulation has been utilized.77 Referral to physiotherapy and
occupational therapy is beneficial for patients with movement-
related BTP. Orthotic devices, bracing, or aids may be neces-
sary, in addition to lifestyle modification. Acupuncture may
have a potential adjunctive role in the management of BTP, but
more research is needed.78
Interventional approaches
For patients with resistant BTP, anesthetic or neurosurgical
intervention may be required. Techniques used include periph-
eral nerve or neurolytic blocks, spinal (intrathecal or epidural)
analgesia, and percutaneous or open cordotomy.79,80
Future directions
For cancer-related BTP, an internationally agreed upon defi-
nition and simple classification system is still needed for
consistency in characterization. BTP has been identified as
a key variable to be included in a future standardized clas-
sification system for cancer pain. 81 Standardization of the
BTP phenomenon will help further high-quality research and
evidence-based clinical practice. A validated screening tool
and practical BTP assessment instrument should be used in
daily clinical practice to characterize and measure pain inten-
sity over short periods of time, in addition to detailing the
impact on patients. Double-blind RCTs comparing different
transmucosal products are warranted. Future studies should
investigate the appropriate dosing and titration techniques
for “rescue” analgesia and examine the most appropriate man-
agement of different BTP mechanisms.
Breakthrough (Episodic) Pain in Cancer Patients
KEY LEARNING POINTS
• BTP is common and challenges the WHO
“ladder” for pain management.
• Current terminology and definitions are
confusing.
• BTP is typically characterized by both rapid
onset and brief duration.
• Thorough assessment of both breakthrough and
baseline pains is vital.
• ATC analgesia for baseline pain must first be
optimized.
• The parenteral and transmucosal routes are effi-
cacious for “rescue” analgesia, for medications
with appropriate pharmacodynamic properties.
• BTP management should be individualized and
requires both pharmacological and nonphar-
macological therapeutic strategies, as well as a
comprehensive multidisciplinary and interpro-
fessional approach.
Conclusion
Breakthrough (episodic) pain is a common heterogeneous
phenomenon in cancer patients which is often undertreated.
Comprehensive patient assessment and optimization of the con-
trol of baseline cancer pain are essential. The choice of medica-
tion for BTP episodes needs to be appropriate for the postulated
BTP mechanism and characteristics of the individual’s BTP (fre-
quency, speed of onset, duration, etc.) and also guided by patient
preference and medication availability. Nonpharmacological
strategies are a fundamental component of management, as are
the provisions of support and education to the patient. More
research is needed in order to inform multidisciplinary clinical
guidelines to improve the management of BTP in cancer patients.
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35
SOMATIC SYMPTOMS, SYMPTOM CLUSTERS, AND SYMPTOM BURDEN

David V. Nelson and Diane M. Novy

Contents
Introduction�����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������333
Symptom burden���������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������333
Diagnosing somatic symptoms��������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������334
Theories of pain perception��������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������334
Treatment recommendations�����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������335
Summary�����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������335
References���������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������335

Introduction care experienced depression; and depression symptoms were

Somatic symptoms such as pain, fatigue, nausea, headache, dizzi-
ness, and insomnia are common complaints among people seen
in palliative care settings.1–3 Although symptoms such as these
are often described as “somatic” in nature, care must be taken
to avoid any of the pejorative connotations often associated with
the term somatization, which imply a strong potential psycho-
genic etiology that undermines the validity of patients’ reports.4
Rather, it is common for patients in medical settings, includ-
ing pain centers and palliative care settings to endorse somatic
symptoms as well as some emotional, cognitive, and behavioral
symptoms. Among palliative care patients, in particular, these
clusters of symptoms may be part of the complex burden related
to aspects of illness, side effects of medical treatment, or psycho-
logical suffering.
Symptom burden
Patients receiving palliative care typically have a high symptom
burden, with a median of 14 symptoms occurring simultane-
ously.5,6 Fatigue is one of the most commonly reported symptoms
in palliative care patients.7 In a palliative care setting, fatigue was
reported by 84% of cancer patients and in up to 99% of patients
following radio- or chemotherapy.7 Many factors potentially
influence fatigue in cancer patients, including aspects of the dis-
ease, the cancer treatment, and a psychological component of suf-
fering.8 Similarly, large percentages of non-cancer patients (e.g.,
HIV, multiple sclerosis, chronic obstructive pulmonary disease,
heart failure) also report fatigue.1,7,9 This highlights the problems
with classifying symptoms such as fatigue as “somatic” in medical
populations, where patients often have complex symptom profiles
and a high symptom burden.
Empirical evidence supports a relation among symptoms
such as pain, fatigue, nausea, sleep disturbance, and negative
mood states such as depression and anxiety in many medical
settings.10,11 Symptoms often occur in clusters that may inter-
act and that may share overlapping mechanisms and treatment
approaches.12 In palliative care settings, depression and anxiety
have consistently been found to relate to greater reporting of med-
ical symptoms.13,14 For example, research has found that about
one in four patients with advanced cancer receiving palliative
associated with greater symptoms of fatigue and pain.15 Among
patients with chronic cancer pain, anxiety and depression have
been shown to be higher than among those who are not being
treated for cancer-related pain.16,17 In other research on cancer
patients with and without pain, hostility, anxiety, and depression
were found to be more common among those who were expe-
riencing pain. Moreover, among patients with advanced cancer,
negative mood states were found to be associated with greater
fatigue, drowsiness, and pain and lower quality of life.13
The relation between pain and negative mood states has also
been demonstrated in patients with chronic non-cancer pain.
For example, patients with chronic non-cancer pain had T-score
means approximately one standard deviation above the commu-
nity norms for anxiety and depression.18 Strong positive relations
were also found between somatic symptoms and negative mood
states among patients with non-cancer pain.16,17 Consistently,
in literature reviews of studies examining symptom report-
ing among patients with chronic pain, greater depression and
somatic symptoms were found in chronic pain patients, com-
pared to patients without pain.19,20 Patients with chronic medical
illness and comorbid depression have been found to report a sig-
nificantly higher number of somatic symptoms than those with a
chronic medical illness but no depression, even when controlling
for the severity of the medical illness.21
Thus, the relation between negative mood and physical symptoms
is supported by research findings with a wide variety of patients
across various treatment settings. The commonly observed associ-
ations between mood, pain, and other somatic symptoms highlight
the difficulty, if not futility, in attempting to separate these symp-
toms into “real” body symptoms and psychological symptoms.
Moreover, this research highlights the problematic nature of the
“somatic” label, as symptoms such as headache, nausea, and fatigue
have multiple and complex causes and may not fit a traditional
definition of somatization, especially in palliative care populations.
Indeed, studies of somatization per se often operationalize soma-
tization simply as a count of somatic symptoms endorsed, with
the presumption that somatic symptoms reflect the expression or
communication of emotional distress or other psychological fac-
tors.22,23 This presumption ignores the bidirectional influences of
somatic and psychosocial processes and the possibility of shared
underlying mechanisms in symptom clusters.12

333
334
Diagnosing somatic symptoms
Past editions of the Diagnostic and Statistical Manual of Mental
Disorders (DSM) specified diagnostic criteria for somatization
(somatoform) disorders as being largely focused on medically
unexplained or accounted for symptoms. The distinction between
medically explained and unexplained symptoms can be prob-
lematic, and physicians have acknowledged that many patient-
reported somatic symptoms cannot easily be classified as either
medically explainable or unexplainable.16,17 Prevalence rates
for medically unexplained symptoms in pain populations vary
widely, with estimates ranging from 0 to 80%.16,17,24,25 Not only are
there problems with grounding a diagnosis on limited reliability
and high variability, but also such a perspective reinforces mind–
body dualism that is not useful. Furthermore, somatization disor-
ders were associated with a pejorative characterization.
Currently, the DSM-526 has shifted away from giving a men-
tal disorder diagnosis solely because a medical cause cannot be
demonstrated. In the DSM-5, there is a new category of disorders
called somatic symptom and related disorders, and somatization
is not included as a possible diagnosis. The major diagnosis in this
category is somatic symptom disorder. This diagnosis is made on
the basis of physical symptoms and signs (e.g., pain, fatigue, nau-
sea, headache, dizziness, insomnia), emotional suffering (mostly
anxiety and worry), troubling cognition (thoughts about the
seriousness of possible causes of somatic symptom), and abnor-
mal behaviors (possible repeated bodily checking and seeking
medical assistance and reassurance). There is a recognition that
genetic and biological vulnerability, early traumatic experiences,
learning, and cultural and social norms contribute to the disor-
ders in this category. Individual differences in symptom presen-
tation are likely the result of the interactive factors of a complex
biopsychosocial context.
There are five other diagnoses in the DSM-5 somatic symptom
category that appreciate a conceptualization of physical and psy-
chological symptoms as interacting processes. The first of these
is illness anxiety disorder that focuses on the preoccupation with
and anxiety about having an illness or somatic symptom. In the
disorder of psychological factors affecting other medical condi-
tions, the diagnostic criteria include psychological or behavioral
factors that adversely affect the development, exacerbation, or
treatment of a medical condition. Factitious disorder is quite
different in that there is falsification of physical or psychologi-
cal symptoms in the absence of obvious external rewards. Two
diagnoses, other specified somatic symptom and related disorder
and unspecified somatic symptom and related disorder, are used
when full criteria of the more defined diagnoses are not met.
There are two diagnoses in the DSM-5 somatic symptom cat-
egory in which medically unexplained symptoms remain a key
feature. These include conversion disorder (having one or more
symptoms of altered voluntary motor or sensory function incom-
patible with neurological or medical conditions) and pseudocyesis.
In both of those diagnoses, it is possible to demonstrate that the
symptoms are not consistent with medical pathophysiology.27,28
Theories of pain perception
All patients experience illness, pain, and other somatic symptoms
differently. The overall suffering and discomfort experienced
by each patient will depend on multiple factors. These include
aspects of the disease and treatment, how the patient interprets
and experiences illness, pain, other somatic symptoms, and
Textbook of Palliative Medicine and Supportive Care
social support available to them, as well as their level of psycho-
logical distress, depression, and anxiety, and ability to cope with
previous life difficulties. Thus, multiple and complex factors are
involved in the experience of pain and other somatic symptoms.
Regarding pain, theories of pain provide some insight into the
potential mechanisms involved in pain perception. One such
theory proposes that a sensitizing effect on physiological events
in some patients may heighten bodily awareness and increase
pain.29 The support for this theory can be found in research on
patients with chronic pain conditions such as fibromyalgia which
has found that these patients have increased responsiveness and
sensitivity to various sensory stimulation, including pain, audi-
tory tones, and tactile stimuli. 30 A similar perspective presents
a neurobiological model of pain in which a patient’s tendency to
focus on bodily symptoms activates pain facilitation neurons. 31
The activation of these neurons is believed to sharpen the percep-
tion of the painful stimulus. Consistent with this theory, some
people attend to and focus on pain and pain-related stimuli to
a greater degree, a practice that has been found to be related to
greater pain reporting. 32
A third perspective draws from cognitive–behavioral theories
of pain. 33 Cognitive–behavioral perspectives propose that pain
can be examined on three dimensions: (1) an affective dimension
that describes pain-related affect (depression, anxiety, and anger),
(2) a behavioral dimension that includes maladaptive behaviors
related to pain (inactivity, avoiding others), and (3) a cognitive
dimension that includes maladaptive beliefs and thoughts about
pain (e.g., belief that one cannot function when in pain). These
various dimensions all influence a person’s overall experience
of pain. Moreover, this model supports bidirectional relations
between dimensions. As an illustration, negative mood can lead
to changes in pain behaviors, such as inactivity, thus leading to
deconditioning in some patients and increasing the body’s vul-
nerability to illness and injury. 34 Negative mood state may also
affect the interpretation of physical changes, such that the body’s
cues and signals (e.g., heart palpitations, shortness of breath) are
inaccurately interpreted as more enduring symptoms or condi-
tions. 35 Additionally, pain can also influence mood states. For
example, the way in which a person interprets their chronic
pain condition (e.g., the degree to which they believe the pain
will interfere in their life) can influence the later development of
depression symptoms. 36
Other so-called somatic symptoms reflect the complex interac-
tions of physiology and emotional, cognitive, and behavioral pro-
cesses. The phenomena associated with breathlessness provide
another example of the multifactorial nature of such symptoms.5
Chronic or refractory breathlessness is commonly associated
with various advanced diseases (e.g., advanced cancer, COPD)
and is periodically complicated by episodes of severe worsen-
ing. While incompletely understood, it appears that impaired
respiratory mechanics interact with neural networks involving
emotional and sensory perception of breathlessness, as well as
neurological circuits involved in threat perception and fear con-
ditioning and other potential environmental, psychiatric, mood,
and personality contributions. 37
Lastly, cultural, social, and institutional factors that empha-
size physical symptoms rather than psychological factors may
also contribute to a heightened focus on physical symptoms. 38
Research has found that some patients with chronic pain
report certain experiences, such as affective distress, as pain. 38
Additionally, qualitative examination of patient’s and provider’s
beliefs suggests that cultural factors can influence how physicians
Somatic Symptoms, Symptom Clusters, and Symptom Burden
respond to patients’ problems, the relationship between health-
care providers and patients, and how patients respond to illness,
including the reporting of pain and psychological symptoms. 38
Many of these principles also apply more broadly to more com-
plex symptom clusters, although there are controversies and
other competing models guiding current research is this area.12
Treatment recommendations
The discussion presented in this chapter highlights the multi-
faceted and interrelated nature of pain and other physical and
psychological complaints. It is important to recognize that in pal-
liative care, symptoms such as pain, nausea, and fatigue will likely
reflect aspects of the chronic medical condition or its treatment.
Additionally, each patient will experience pain and other bother-
some somatic symptoms differently. The overall suffering and
discomfort experienced by each patient will depend on multiple
factors such as how the patient interprets and experiences illness,
pain, and other somatic symptoms; the social support available
to them; and their level of psychological distress, depression, and
anxiety. Given the high co-occurrence of psychological symp-
toms with physical complaints and research findings presenting
evidence for the interactive nature of these symptoms, the use of
a multidisciplinary treatment approach is recommended. In the
treatment of pain, multidisciplinary teams often include profes-
sionals from pain medicine, palliative care, psychology, social
work, and nursing. Treatment models in which these disciplines
are integrated fully into the treatment team for pain or more com-
plex symptom clusters are ideal, but utilizing these services on a
consulting basis may be necessary in some settings due to finan-
cial, geographic, or institutional constraints. Multidisciplinary
approaches to pain management have consistently been found to
be more effective than other forms of treatment for chronic pain.39
Additionally, research demonstrates that incorporating routine
screening for psychological distress in cancer pain patients leads to
improved detection of psychological symptoms and more appro-
priate referrals to specialized services.16,40 Current recommenda-
tions for assessment and treatment of broader symptom clusters
also focus on multidisciplinary approaches.41,42
A multidisciplinary approach to management may help one to
address potential difficulties that can occur when treating some
patients presenting with somatic complaints—when appropri-
ate, involve other services, including psychology and social work,
in the patient’s treatment. We also recommend using caution
in assigning a somatoform disorder or other psychiatric diag-
noses, as these labels may invalidate patients’ physical symp-
toms or unfairly alter the perception of the patient held by other
BOX 35.1  MANAGEMENT GUIDELINES
FOR SOMATIC SYMPTOMS
• Utilize a multidisciplinary team approach.
• Rule out and/or treat diagnosable medical
disease.
• Assess for psychological distress.
• Consider the cultural and social context.
• Build a collaborative relationship with the patient.
• Provide a caring physician attitude.
• Make appropriate referrals to specialized
services.
335
KEY LEARNING POINTS
• Due to its often pejorative connotations, soma-
tization is not a useful diagnosis and it does not
adequately reflect the complexity of multiple con-
tributing factors inherent in so-called somatic
symptoms.
• The distinction between medically explained and
unexplained symptoms is not required for most
diagnoses in the DSM-5.
• Unexplained symptoms do not necessarily indi-
cate a psychiatric diagnosis.
• Chronic pain patients and large percentages of
other patients with chronic illnesses consistently
report more symptoms, including fatigue and
sleep difficulties.
• Negative mood is associated with greater pain
and physical complaints among patients with
both chronic non-cancer and cancer pain.
• Multidisciplinary approaches to symptom man-
agement are more effective than other forms of
treatment for chronic pain and complex symp-
tom clusters.
providers. Moreover, as demonstrated in this article, diagnosis of
somatization disorders is unreliable and can be complicated in
patients with chronic medical conditions. Symptom management
guidelines, based in part on suggestions presented by Barsky and
Borus43 and Purcell,44 are presented in Box 35.1.
Summary
In summary, somatic symptoms such as pain, fatigue, nausea,
headache, dizziness, and insomnia are common complaints
among people with medical conditions, and they often occur in
clusters. Among palliative care patients, these symptoms may be
related to aspects of the illness, side effects of medical treatment,
or psychological suffering. The new category of somatic symptom
disorder and related disorders of the DSM-5 reflects an appre-
ciation for the close relation between psychological and physi-
cal symptoms and the inherent difficulty with past editions that
classified symptoms as “medically unexplained.” This current
appreciation is especially appropriate for palliative care patients
who commonly have a complex symptom profile and high symp-
tom burden. Negative mood is associated with greater pain and
greater symptom reporting among patients with both chronic
non-cancer and cancer pain. Theories of pain perception offer
insights into the relation between mood, somatic symptoms, and
pain, which suggest that these symptoms are interactive, rather
than distinct, independent symptoms. This conceptualization of
pain and related symptoms clusters supports a multidisciplinary
treatment approach where psychological treatment and other
specialized services are integrated at all stages of care.
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36
PAIN IN PATIENTS WITH ALCOHOL AND DRUG DEPENDENCE

Leah Couture, Malisa Dang, and Danielle Noreika

Contents
Introduction�����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������337
Definitions, diagnosis and prevalence of alcohol and drug dependence and substance use disorder�������������������������������������������������������������337
Screening for substance use disorder in palliative care patients�����������������������������������������������������������������������������������������������������������������������������338
Non-opioid management of pain in palliative patients with SUD��������������������������������������������������������������������������������������������������������������������������339
Opioid management of pain in palliative patients with SUD����������������������������������������������������������������������������������������������������������������������������������339
Substance abuse disorder for patients in the last 6 months of life��������������������������������������������������������������������������������������������������������������������������340
Interdisciplinary team support in palliative patients with SUD������������������������������������������������������������������������������������������������������������������������������341
Naloxone�����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������341
Conclusion��������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������341
References���������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������341

Introduction represented as a range from mild (2–3 criteria), moderate (4–5

Substance use disorder (SUD) is a significant public health con-
cern. In the United States in 2017 SUD affected approximately
19.7 million people aged 12 or older.1 This included 14.5 million
people who had an alcohol use disorder, 7.5 million people who
had an illicit drug use disorder, and an estimated 2.1 million
people who had an opioid use disorder.1 Worldwide the World
Health Organization estimates there were 27 million people
living with SUD in 2016 and approximately 450,000 dying as
a result of drug use in 2015.2 SUD not only impacts the indi-
vidual, contributing greatly to disease burden, but also involves
substantial social and economic costs.1 Even with the challenges
of the opioid crisis, opioids still serve as a mainstay of pain
management for palliative and cancer patients. Many of these
patients experience pain, and the use of opioids and other con-
trolled substances may be necessary for optimal symptom man-
agement.2 Substance abuse disorder can affect all dimensions of
palliative care (Chapter 5);3 therefore, appropriate identification
is important to allow the consideration of support and manage-
ment options.
Definitions, diagnosis and prevalence
of alcohol and drug dependence
and substance use disorder
As with much of medicine, the definition of substance abuse dis-
order is evolving. In the update from the DSM IV to the DSM 5,
the definitions of substance abuse and substance dependence
were merged into a new term of SUD, which was then clarified
into severity depending on the number of criteria met.4,5 The revi-
sions for the DSM-5 were formulated by a multidisciplinary team
of experts whose overall aim was overcoming problems identi-
fied in the DSM-IV to provide an improved approach to SUD.5
Modifications to the DSM-IV included dropping legal problems
as a criterion, adding “cravings or strong desire or urge to use sub-
stance” as a criterion, and changing the diagnostic threshold to
≥2 criteria within a 12-month period. Furthermore, severity was
criteria), and severe (≥6) (Table 36.1).5,6
Prevalence of SUD in populations of patients cared for by
palliative care and hospice teams are less well established. A
recent large retrospective review of National Veteran Health
Administration data showed that of 482,688 patients with cancer,
6.64% had a diagnosed comorbid substance abuse disorder.7 Data
on alcohol and substance abuse in the palliative care population
remains scarce due to limited application of urine drug screen-
ing or implementation of existing screening tools for misuse8;
however, some studies suggest that this problem may be at least
as common in the palliative population.9,10 In a study of termi-
nally ill cancer patients admitted to a palliative care unit, 27%
of those able to be assessed were found to meet the criteria for
alcohol abuse using the Cut Down, Annoyed, Guilty, Eye-Opener
(CAGE) questionnaire as a screening tool.11 Notably approxi-
mately one-third of patients found to have an alcohol use disor-
der had not been diagnosed previously. Other studies have also
suggested that alcoholism is not only prevalent but frequently
undocumented and underdiagnosed in patients with advanced
cancer.12,13 For palliative care providers who manage patients who
have transitioned to cancer survivorship, there may be additional
challenges in creating a long-term pain management plan in the
setting of comorbid SUD.14
While most providers are able to recognize the outward man-
ifestations of substance use, such as the impairment in behav-
ioral control, cravings, and decreased recognition of problems
TABLE 36.1  DSM-IV and DSM-5 Criteria for Substance Use
Disorders (from Reference [5] with Permission)
1 One or more abuse criteria within a 12-month period and no
dependence diagnosis; applicable to all substances except nicotine,
for which DSM-IV abuse criteria were not given
2 Three or more dependence criteria within a 12-month period
3 Two or more substance use disorder criteria within a 12-month
period
4 Withdrawal not included for cannabis, inhalant, and hallucinogen
disorders in DSM-IV. Cannabis withdrawal added in DSM-5

337
338 Textbook of Palliative Medicine and Supportive Care

FIGURE 36.1  Model of interacting circuits in which disruptions contribute to compulsive-like behaviors underlying drug addic-
tion. The overall neurocircuitry domains correspond to three functional domains: binge/intoxication (reward and incentive salience:
basal ganglia), withdrawal/negative affect (negative emotional states and stress: extended amygdala and habenula), and preoccupa-
tion/anticipation (craving, impulsivity, and executive function: PFC, insula, and allocortex). Arrows depict major circuit connections
between domains, and numbers refer to neurochemical and neurocircuit-specific pathways known to support brain changes that
contribute to the allostatic state of addiction. PFC, prefrontal cortex; ACC, anterior cingulate cortex; OFC, orbitofrontal cortex; NAc–
VTA, nucleus accumbens–ventral tegmental area. (From Reference [15], with permission.)

in behaviors and relationships, many providers are less familiar
with the physiologic changes that occur during the development
of SUD. There is growing research regarding the neurobiological
changes that occur during addiction affecting neurotransmission
within the reward structures of the brain, including the nucleus
accumbens, anterior cingulate cortex, amygdala, and basal gan-
glia.15 Understanding these changes can help providers reframe
the behaviors that manifest at least partially from this physiologi-
cal state (Figure 36.1).
Screening for substance use disorder
in palliative care patients
Based on the 2016 CDC Guidelines for Prescribing Opioids for
Chronic Pain, providers should ask all patients about prior alco-
hol and substance use.16 While there is an entire paragraph at
the beginning of these guidelines exempting palliative care and
hospice patients, given that patients with a prior history of SUD
and alcohol abuse are at increased risk for opioid misuse as well as
death from opioid use, it would be clinically appropriate to iden-
tify these patients. The actual use of screening tools in palliative
care is unfortunately low, perhaps in part due to a lack of guide-
lines for opioid prescribing among people with SUD or alcohol
abuse. In a survey of palliative care fellowship directors, 67.6%
stated that their program did not have a written policy regarding
the use of a screening tool for substance abuse.8 Of those that did
have a policy, only 18.9% stated it was required on all patients.8
Multiple screening tools have been validated to identify
patients at increased risk for opioid misuse: the CAGE ques-
tionnaire (as well as the updated version that includes “drugs,”
CAGE-AID), the Opioid Risk Tool (ORT), and the Screener and
Opioid Assessment for Patients with Pain—Revised (SOAPP-R).17
Although small studies have evaluated the prevalence of positive
screening in palliative care populations,10 none of these tools have
Pain in Patients with Alcohol and Drug Dependence
Population of Patients with Cancer
Aberrant Behavior
Diversion
Misuse
Addiction
Chemical
coping
FIGURE 36.2  Spectrum of aberrant opioid-related behavior. (From Reference [17] with permission.)
been specifically designed for patients with life limiting illness.
Identification of patients at risk for opioid misuse allows provid-
ers to have an informed discussion with patients about their spe-
cific potential benefits and risks of opioid therapy (Figure 36.2).
Non-opioid management of pain in
palliative patients with SUD
Although palliative and hospice patients often have pain that
would benefit from opioid management, treatment strategies
should be multimodal as often as possible and not focus solely
on opioids. In some areas of this field, there is a paucity of data
to guide evidence-based practice and guidelines on specific
groups of patients (for example, cancer patients) or chronic pain
are extrapolated for use. This is especially true for non-pharma-
cologic measures where there may be low cost and little risk of
harm. One recent study analyzed the types of non-pharmacologic
therapy and frequency of use in patients with chronic musculo-
skeletal pain. They included clinician-directed forms of therapy
(physical therapy, transcutaneous electrical nerve stimulation,
massage, etc.) as well as self-directed (yoga, pool exercises, herbal
medicines, etc.). The majority of patients (71%) had used at least
one non-pharmacologic measure over the preceding 6 months,
and individual activities were rated as being helpful by more than
half of all users (range 51–79%).18
Technology may offer more opportunities over time for non-
pharmacologic management of substance abuse and symptoms
including pain in palliative care patients. Currently, publications
are few; for instance, a 2019 meta-analysis of virtual reality in
cancer-related symptom management only returned six papers
for review.19 In a more recent small prospective study for cancer
patients, the use of virtual reality to allow patients to “travel” to
a comforting place was associated with significant improvements
in multiple symptoms including pain.20 For more upstream palli-
ative patients with substance misuse disorders, avatars have been
utilized to increase access to treatment.21
Adjunctive medications are commonly utilized in chronic pain
disorders but integration in pain management for palliative care
or hospice patients may be challenging due to comorbid condi-
tions, risks of polypharmacy, or timeline to efficacy. There is a
lack of evidence to guide practitioners who are trying to incorpo-
rate adjunctive medications in palliative pain management. For
instance, a recent review of nonsteroidal anti-inflammatory med-
ications found that study duration and discordance in outcome
339
Abuse
measures limited the ability to identify the areas of efficacy.22 A
randomized, double blind, placebo-controlled trial of additive
duloxetine for 70 patients with cancer-related neuropathy who
were nonresponsive to opioid-pregabalin combination ther-
apy suggested that there may have been some meaningful pain
improvement but concluded that further studies are needed.23
Depending upon the prognosis of the patient, the time to efficacy
may be a potential barrier for making this a treatment strategy.
Although gabapentin and pregabalin are sometimes used in the
palliative care setting, data to support their use is mixed and side
effect profiles are notable.24
Opioid management of pain in
palliative patients with SUD
When considering the use of opioids to manage pain in palliative
care patients with SUD, it is important to consider the unique
aspects of this population and the goals of treatment. As the focus
of palliative care is to reduce suffering in life-limiting illness, it
may be appropriate to very cautiously continue the manage-
ment with opioids even in the setting of active substance abuse,
whereas in other patient populations, this may be an indication
to stop opioids.25 When it is deemed on full assessment appropri-
ate and necessary to continue opioids, other action providers may
take to try to minimize harms, in particular reducing the risk of
overdose, adverse effects, and aberrant behaviors (such as misuse
and diversion).26
Similar to patients being started on opioid therapy for chronic
pain management, palliative care patients should complete a
comprehensive pain and symptom history as the foundation of
creating the management plan (see Table 36.2).26 In addition to
a comprehensive pain assessment, it may be beneficial to assess
for substance abuse using a standardized assessment tool as pre-
viously described. While the identification of active substance
abuse and high-risk behaviors may place patients at risk for opi-
oid misuse, it should not automatically preclude them from start-
ing opioid treatment. Instead, it may help identify patients who
may need more support and monitoring to allow for safe and suc-
cessful treatment. If possible, patients with active SUDs may be
referred to an addiction specialist to help comanage their pain
and SUD.26
The concept of pain agreements is familiar to most providers
caring for chronic pain patients; however, the use of these agree-
ments in palliative care is not well studied. When personalized to
340
TABLE 36.2  Evaluation and Documentation Considerations
for Palliative Patients on Opioid Medications
1. Comprehensive pain history
2. Past medical history including psychiatric or substance use diagnosis
and treatment
3. Family history to include substance use disorders
4. Extensive social history
5. Risk assessment screening tool for all patients (CAGE, SOAPP-R,
ORT, etc.)
6. Review of records in state prescription drug-monitoring program
7. Full physical exam
8. (If applicable) review of outside records of pain management
9. (If applicable) review of urine drug screen results
10. Review of laboratory or imaging data related to pain diagnosis
11. Consideration of non-pharmacological and adjunctive-management
options
12. Documentation of risk assessment and corresponding treatment plan
based on risk assessment
13. (When available/indicated) interdisciplinary team support and access
to addiction specialists and resources
14. (If applicable) consideration for and education on naloxone
15. Informed consent for opioid therapy (to include benefits, risks,
shared goals, and safety parameters); this process many include a
written agreement with the patient
a specific patient and setting it can be a helpful tool in the estab-
lishment of informed consent, development of expectations for
both the patient and provider; setting of functional goals and dis-
cussion of safe opioid use practices.27
Urine drug screening is another modality that is utilized often
in chronic pain patients but is with no specific recommendations
in palliative care populations. This can be beneficial in patient
care, but it should be applied in a structured and supportive man-
ner with a clear understanding of result interpretation.28
General consensus for patients with a history of SUD or high
risk indicators is to begin with short prescriptions to allow for
close monitoring.29 State prescription monitoring plans provide
helpful information on controlled substances that have been
dispensed to patients and should be accessed routinely over the
course of care. 30
For patients being followed for pain management with a his-
tory of SUD, it is important to ask about their substance use at
follow up visits as it may change over the course of their disease
and with changes in their pain management. If patients either
admit to substance use or inappropriate use of their medications
(or if discovered through a UDS), it is important to obtain further
information as all substance use is not equal.29 For example, a
patient with cannabis on a UDS but otherwise appropriate behav-
ior versus a patient with multiple non-prescribed opioids are
not at the same risk for overdose or other serious consequences.
This consistent weighing of benefits and burdens rather than the
strict discontinuance of opioid therapy may be a critical differ-
ence when using opioid therapy in a palliative population versus
patients with chronic pain. 30
Finally, after risk assessment, the above choice of opioid may be
a consideration for patients with an active substance abuse disor-
der and palliative pain-management needs. There are no guide-
lines which direct initial opioid choices in patients with SUD in
palliative or hospice patients and care plans must be individual-
ized. Although methadone has been cited in multiple resources
Textbook of Palliative Medicine and Supportive Care
as beneficial in refractory cancer pain management, 31–33 a recent
white paper has recommended that active illicit drug use or
misuse be considered a contraindication to using methadone. 34
Buprenorphine and buprenorphine/naloxone use has increased
with the opioid crisis over the past several years. A review in 2015
on the effectiveness of buprenorphine for cancer pain recom-
mended consideration as a fourth line agent in specified situa-
tions. 35 Finally, abuse deterrent formations may be considered a
way of decreasing the potential for nonoral abuse. 36
Substance abuse disorder for patients
in the last 6 months of life
One distinct population of patients in palliative care that requires
specific focus is patients approaching death or in the last 6
months of life, and in the community. Palliative care patients
may range anywhere along the spectrum of a life limiting illness.
In the United States, hospice patients are, according to the cur-
rent Medicare benefit definitions, terminally ill with an expected
prognosis of less than 6 months, if the illness runs usual course.
In other countries, these distinctions are not used, but commonly,
patients receiving palliative care and hospice care are in advanced
stages of illness. When patients are at home, which is common for
many palliative care and hospice services, including US hospices,
there is an additional concern of staff safety when caring for the
patient with a potential substance abuse disorder.
Despite estimates of SUD incidence in US hospice upward 25%
and the recognition that these patients may have additional psy-
chosocial support needs. 37,38 There are no guidelines for screen-
ing nor are many organizations caring for patients with advanced
disease routinely performing standardized risk assessments. In
a recent nationwide study of US hospices, although 68% were
assessing for potential substance abuse disorders, most were not
using validated risk assessment tools. 39 Additionally, even when
aberrancy has been noted, there is little to guide practitioners
in publications and state or national guidelines or regulations.
Although a potentially helpful resource, there is little practical
availability of substance abuse providers to follow these patients. 38
As is the case in palliative care extrapolations from SUD, in
other pain, the patients have been applied to managing end-of-
life care in the home setting with a known history of aberrant
behaviors. Communication is paramount and should include
family caregivers who are present in the home. Interdisciplinary
team members can support this process to create a multimodal
pain-management plan with partners’ hospice staff, patients, and
families to regulate medications for safety. Inpatient care can be
utilized when needed to monitor medications and dose titrations
as well as create transition plans to other locations of care. 38
Education is also essential and should include the entire inter-
disciplinary team. Despite the increase in awareness around
substance abuse disorders, there are gaps in training around this
topic for interdisciplinary team members.8,38 As these patients
can be in challenging circumstances, education and training is
critical to provide practitioners with a toolkit to assess for risk
mitigation in their patients.
Consideration of the safe disposal of opioid medications
should also be an area of focus from a public health perspective.
There are resources available on the Internet to guide patients
and families in their local region for safe disposal of unused
medications as well as many pharmacies that will take back
unused medications.
Pain in Patients with Alcohol and Drug Dependence
Interdisciplinary team support in
palliative patients with SUD
Palliative care patients with concurrent pain management needs
and substance abuse disorders may be the most challenging to
manage in daily practice. Unfortunately, as referenced earlier in
this chapter, education on this topic remains underutilized in fel-
lowship training.8 This lack of preparation for management strat-
egies in a challenging patient population may increase distress for
not only the provider but also the patient and family who are also
struggling with these comorbid conditions.
In addition to the lack of guidelines to shape practice for man-
aging pain in the setting of substance abuse in palliative care,
there is also little evidence on provider support strategies for
managing these patients outside of trying to increase education.
Dedicated substance abuse resources are limited in many regions
and may not be accessible for hospice and palliative patients. 38
One novel study by Arthur et al. that investigated ways of pro-
viding support to both patients and the treating palliative care
team in the case of aberrant opioid behaviors was reported in
the Oncologist.40 The “CHAT” (Compassionate High Alert Team)
was created to follow a pilot group of clinic patients who met the
criteria for one or more of eight aberrant behaviors during their
assessment. The team consisted of a palliative care physician and
two or more of the following members: a palliative care nurse,
psychologist or counselor, pharmacist, social worker, and patient
advocate plus potentially a representative from risk or secu-
rity depending on the scenario. The team met to debrief before
and after the patient encounter and conducted the meeting in a
supportive and nonjudgmental manner. Outcomes noted were
decrease in the number of aberrant behaviors per month via chart
abstraction as well as a decrease in median morphine equivalent
daily dose. It was hypothesized that the expertise of multiple pro-
viders to address the complex issues in these patients would be
“likely to prevent burnout in any individual provider who tries to
address the issue alone.”40
Naloxone
Over time, naloxone accessibility in the community has increased
as one of the ways of mitigating the risks of the current opioid cri-
sis. In addition to training programs, for first responders in most
states in the United States to be able to use naloxone between
2010 and 2014, there was a three-fold increase in the number of
laypersons with naloxone kits (52,032–152,283).41 Most states
now have laws to expand naloxone access to laypersons, and
depending on the type of law, this may reduce the risk of fatal
overdose. In a 2019 study in JAMA Internal Medicine, Abouk
et al. reviewed the type of policy in each state (whether the phar-
macist had direct authority to prescribe) as well as fatal and
nonfatal overdoses. States with laws that allowed pharmacists
to directly prescribe had a significant reduction in fatal overdose
compared to states with indirect authority.42 Although these stud-
ies have documented the effects of community naloxone avail-
ability globally to this point, there is little data to guide efforts in
palliative populations. One publication addressed palliative pro-
vider confidence in multiple measures with prescribing naloxone
and managing addiction being the lowest among all variables, but
this paper focused on chronic pain in cancer survivors and not
those with life limiting diseases.43 Most of the existing resources
and laws in the United States also exempt cancer, palliative, and
341
end of life/hospice care patients (SAMSHA, CDC, etc.).44 If nalox-
one is incorporated into care, education on how to use the specific
product is essential and must be undertaken by the prescribing
provider or pharmacist with the patient and family.45 Many states
offer educational brochures that can be shared with patients and
families; for example, Virginia has created the REVIVE program
to use as a resource to guide these conversations (see further
http://www.dbhds.virginia.gov/library/substance%20abuse%20
services/revive%20pharmacy%20dispensing%20brochure%20
v10.pdf).46
Conclusion
Palliative care patients often have complex physical, psychoso-
cial, and spiritual needs. When palliative or hospice situations
also involve substance misuse, they become some of the more
challenging circumstances for teams to manage. Although as
described before, considering risk assessment strategies, multi-
modal therapy, resources in settings of care, and reversal agents
are all tools to apply to these situations—the most powerful is
that of the interdisciplinary team. A highly functioning interdis-
ciplinary team with different backgrounds and strengths—utiliz-
ing all of the strategies above—can help patients and families to
overcome the challenges that a comorbid substance misuse disor-
der brings to serious illness care.
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37
CACHEXIA–ANOREXIA SYNDROME

Paul Zelensky, Mallika Dammalapati, and Egidio Del Fabbro

Contents
Introduction�����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������344
Diagnostic criteria and definitions��������������������������������������������������������������������������������������������������������������������������������������������������������������������������������344
Malnutrition�����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������344
Cachexia������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������344
Sarcopenia��������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������344
Prognostication�����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������345
Poor appetite and nutritional impact symptoms (NIS)���������������������������������������������������������������������������������������������������������������������������������������345
Weight loss�������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������345
Body composition�������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������345
Laboratory biomarkers�����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������345
Inflammation����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������345
Testosterone�����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������345
Mechanisms of cachexia��������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������346
Cachexia and starvation���������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������346
Inflammation����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������346
Peripheral effects���������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������346
Central effects��������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������346
Other mechanisms causing muscle and fat atrophy��������������������������������������������������������������������������������������������������������������������������������������������347
Endocrine dysfunction�����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������347
Metabolic dysfunction, including increased resting energy expenditure��������������������������������������������������������������������������������������������������347
Nutritional impact symptoms�����������������������������������������������������������������������������������������������������������������������������������������������������������������������������347
Assessment�������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������347
Nutrition risk screening and identification������������������������������������������������������������������������������������������������������������������������������������������������������������347
Health-related quality of life�������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������348
Weight and body composition���������������������������������������������������������������������������������������������������������������������������������������������������������������������������������348
Body mass index (BMI)����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������348
Anthropometrics���������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������348
Bioelectrical impedance analysis (BIA)������������������������������������������������������������������������������������������������������������������������������������������������������������349
Imaging��������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������349
Physical performance�������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������349
Management����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������349
Non-pharmacological intervention�������������������������������������������������������������������������������������������������������������������������������������������������������������������������349
Nutritional supplementation������������������������������������������������������������������������������������������������������������������������������������������������������������������������������349
Psychosocial intervention������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������350
Exercise and physical therapy�����������������������������������������������������������������������������������������������������������������������������������������������������������������������������350
Pharmacological management���������������������������������������������������������������������������������������������������������������������������������������������������������������������������������350
Nutrition impact symptoms (NIS)���������������������������������������������������������������������������������������������������������������������������������������������������������������������350
Metoclopramide����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������351
Mirtazapine������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������351
Corticosteroids������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������351
Cannabinoids���������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������351
Thalidomide������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������351
Beta blockade���������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������351
Nonsteroidal anti-inflammatory drugs (NSAIDs)������������������������������������������������������������������������������������������������������������������������������������������351
Androgens���������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������352
Ghrelin and ghrelin agonists�������������������������������������������������������������������������������������������������������������������������������������������������������������������������������352
Combination therapy��������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������352
Conclusion��������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������352
References���������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������352

343
344
Introduction
Cachexia–anorexia syndrome (CAS) is a multifactorial syn-
drome characterized by involuntary loss of skeletal muscle and
fat, reduced quality of life, and decreased survival. CAS occurs
in a variety of seemingly disparate illnesses, including can-
cer, acquired immune deficiency syndrome (AIDS), heart fail-
ure (HF),1 human immunodeficiency virus (HIV), tuberculosis,
malaria, rheumatoid arthritis, chronic obstructive pulmonary
disease (COPD),2 kidney failure, 3 and liver failure. Comorbidities
such as diabetes may contribute to muscle abnormalities in
patients with cancer,4 and in older patients, 5 age-related muscle
loss6 and decreased physical activity exacerbate CAS. Although
epidemiological studies are scarce, the estimated prevalence of
cachexia in Europe, the United States, and Japan is as high as 1%
or 12 million people,7 with mortality rates ranging from 15 to 80%
depending on the type of chronic illness. In developing countries,
cachexia is likely to be a more frequent cause of death in patients
with chronic illness.
Diagnostic criteria and definitions
The conditions of malnutrition, cachexia, frailty, and sarcopenia
overlap may occur in the same individual (8%)8 and are espe-
cially common among older patients. They share features such
as weight loss and/or changes in body composition (BC), and all
are associated with adverse clinical outcomes. A survey from four
European countries found nutrition-related disorders and their
distinguishing features were suboptimally recognized in clinical
practice.9
Malnutrition
Malnutrition is often used as an overarching term that encom-
passes nutrition-related disorders such as starvation, cachexia,
and sarcopenia. Recently, a consensus-based set of criteria for
malnutrition, independent of the clinical setting or etiology,10
recommended the diagnosis of malnutrition be based on either
a low body mass index (BMI) (<18.5 kg/m2) or on the combined
finding of weight loss (>10% indefinite of time or >5% over 3
months) together with either reduced BMI (age-specific) or a low
fat-free mass index (FFMI) using sex-specific cutoffs.
Cachexia
Defining cachexia is challenging since several mechanisms,
including poor appetite, inflammation, and metabolic dysregula-
tion, may contribute variably to decreased muscle and fat in any
individual patient. Furthermore, the patient’s clinical presenta-
tion may span a wide spectrum of weight loss, BMI, symptoms,
and physical performance. The most commonly applied defini-
tions in research and daily practice include the cancer-specific
definition by Fearon11 and a definition by Evans12 that is appli-
cable to all disease states. Importantly, variation in diagnostic
criteria for cachexia will of course alter its clinical prevalence.13
Fearon’s definition for cancer cachexia is largely weight based
and emphasizes direct measures of muscularity, requiring
>5% weight loss within the last 6 months or >2% weight loss in
patients with a BMI <20 kg/m2 or sarcopenia assessed by anthro-
pometry, dual-energy X-ray absorptiometry (DEXA), bioelec-
trical impedance analysis (BIA), or computerized tomography
(CT). The definition identifies loss of skeletal muscle as key in
patients’ functional impairment and highlights the concept of
skeletal muscle mass as both a marker for CAS and an important
Textbook of Palliative Medicine and Supportive Care
therapeutic target. Although most patients with advanced cancer
are consuming diets insufficient to maintain weight in healthy
individuals,14 the Fearon definition does not include anorexia or
nutrition intake among its defining criteria.
Fearon also proposed classification into stages of pre-cachexia,
cachexia, and refractory cachexia based on patient characteris-
tics, endeavoring to identify patients earlier in their illness when
they may be more responsive and less “refractory” to therapeu-
tic agents. Although serum biomarkers were not included in the
framework as criteria for classification, C-reactive protein (CRP),
serum albumin, and testosterone have been associated with prog-
nosis in patients with cancer cachexia.15 Subsequent attempts to
use these laboratory tests for delineating patients into stages of
cachexia have only been partially successful.16,17
An alternative definition for cachexia, proposed by Evans and
not restricted to cancer, does include laboratory tests among the
defining criteria. The Evans definition of cachexia requires weight
loss of ≥5% within 12 months or BMI < 20 kg/m2 and at least three
of the following: decreased muscle strength, fatigue, anorexia,
low FFMI, hypoalbuminemia, anemia (Hb < 12 g/dL), or elevated
CRP.
There is no consensus regarding the preferred definition, as
there are advantages and disadvantages to both. The Fearon defi-
nition is considered to be more pragmatic and suitable for daily
clinical practice,18 while the Evans definition may be a better pre-
dictor of overall survival.19
Sarcopenia
Sarcopenia is considered a “muscle disease or muscle failure’”
rather than purely low muscle mass, arising from adverse muscle
changes that accumulate across a lifetime, commonly in older
adults.20 The European Working Group on Sarcopenia in Older
People (EWGSOP) updated the consensus definition in 2018,
focusing on low muscle strength as the key characteristic of sar-
copenia, with low muscle quantity and quality confirming the
diagnosis, and poor physical performance as indicative of severe
sarcopenia. The EWGSOP updated the clinical algorithm for
sarcopenia (Find-Assess-Confirm-Severity or F-A-C-S) and pro-
vided cutoff points relevant to clinical practice for the variables
that characterize sarcopenia. Sarcopenia is considered primary
or age related when no other specific cause is evident and sec-
ondary when factors other than or in addition to aging, such as
cancer, are evident.
It is important to note that, in BC research, the term sarcope-
nia is often used and refers to a low skeletal muscle mass rather
than the combination of decreased strength and low muscle mass
characterizing the EWGSOP definition. In BC research, sarco-
penia is defined as “appendicular skeletal muscle mass divided
by body height squared in meters (muscle mass index),” two
standard deviations or more below reference values from young,
healthy individuals measured with DEXA. The term myopenia is
proposed as possibly being a more appropriate label for low mus-
cle mass.21
Frailty is a broader concept than sarcopenia, as it encom-
passes a lifetime decline of multiple physiological systems, affect-
ing physical, cognitive, and social dimensions. Diagnostic tools
reflect these multiple dimensions; however, there is some overlap
with sarcopenia, including criteria (low muscle strength and per-
formance) and therapeutic interventions (exercise, optimal pro-
tein intake, vitamin D).
Sarcopenic obesity (SO) is a combination of reduced lean
body mass and excess adiposity. The risk and prevalence of SO22
Cachexia–Anorexia Syndrome
increase with age23 and vary in definition and cutoffs. For exam-
ple, in an outpatient bariatric clinic, the prevalence ranged from
0 to 84.5% in females and 0 to 100% in males, depending upon
the definition applied; and in pancreatic cancer, a meta-analysis
found SO ranged between 0.6 and 25.0% of patients.24
Osteosarcopenia occurs as when the two diseases coexist.
Sarcopenia and osteoporosis are linked in terms of common risk
factors and biological pathways. Patients with osteosarcopenia
may have a higher risk of falls, fractures,25 and frailty, although
further research is required to confirm this.26
Prognostication
Several domains of CAS are associated with poor prognosis,
including decreased appetite, nutrition impact symptoms (NIS),
weight loss, changes in BC, and sarcopenia.27 Inflammation and
low testosterone are also shown to be associated with decreased
survival in patients with cancer cachexia.
Poor appetite and nutritional impact symptoms (NIS)
Poor appetite and other symptoms that impact nutritional intake
have been associated with poor prognosis. A systematic review
of 30 randomized controlled trials (RCTs) in oncology found
that anorexia and pain improved the accuracy of overall survival
prognosis relative to sociodemographic and clinical character-
istics alone.28 A pooled analysis of 17 RCTs confirmed appetite
loss to be a significant independent prognostic factor in patients
with cancer.29 In addition to poor appetite, NIS such as nausea,
depression, anxiety, and drowsiness may worsen energy intake
and, along with the catabolic processes associated with cachexia,
lead to profound losses of muscle and fat. Furthermore, the aggre-
gate burden of symptoms in head and neck patients is a signifi-
cant independent predictor of decreased survival. 30 Although
most of the literature is focused on oncology, a study examin-
ing comorbidities in patients with HF found those with anorexia
had impaired functional capacity (measured by oxygen uptake,
6-minute walk (6MW) test, and short physical performance bat-
tery test) and higher mortality. 31
Weight loss
Weight loss has been valuable as a core criterion in formulat-
ing definitions for cachexia, and recent studies have refined
the prognostic significance of weight loss by incorporating
baseline energy reserves into the prognostic model. There is
substantial evidence that energy reserves are important pre-
dictors of prognosis in patients with solid tumors. A retrospec-
tive study of >8000 European and Canadian patients revealed
a greater percentage weight loss in lower BMI patients who
were associated with shorter survival. Based on these findings,
a grading system combining baseline BMI and weight loss
was able to distinguish survival when applied to a variety of
specific cancers, stages, ages, and performance statuses. 32 A
single weight loss percentage cutoff is no longer appropriate
as a diagnostic criterion since patients have varying degrees of
risk based on their initial BMI.
Body composition
While a higher BMI and energy reserves are a survival advantage
in cancer, there is also an increasing body of evidence showing
high BMI and excess adiposity may be detrimental when present
in patients with low muscle mass (sarcopenia/myopenia). The rea-
sons for the poorer survival are unclear; however, it may be that
patients with low muscle mass are deconditioned due to aging
345
and/or a sedentary lifestyle, or perhaps high fat mass inflates
drug doses in body surface area–based treatments, causing an
increased rate of dose-limiting toxicity. SO is independently asso-
ciated with higher mortality and complications in medical and
surgical cancer treatment across multiple tumor types. 33
Low muscle mass identified on imaging in nonobese patients
is associated with decreased survival in both early-34–36 and late-
stage cancer. More recently, the combination of sarcopenia and
systemic inflammation decreased progression-free survival and
overall survival in patients treated with immunotherapy in phase I
clinical trials. 37
A systematic review of pre-therapeutic sarcopenia found
associations with surgery and chemotherapy complications;
diminished overall survival during chemotherapy; decreased
relapse-free survival after surgery for extrahepatic biliary can-
cer, hematopoietic stem cell transplantation, and hepatectomy;
and decreased progression-free survival after chemotherapy
for hepatocellular carcinoma and metastatic breast cancer. 38 In
ambulatory patients with clinically stable chronic HF, muscle
loss appears to have a more pronounced effect on clinical out-
comes such as physical performance and quality of life than
weight loss alone. 39 Similarly, in stable COPD patients, sarcope-
nia is associated with more severe dyspnea40 and decreased exer-
cise tolerance.41 Sarcopenia in COPD patients is also linked with
abnormalities such as the loss of oxidative muscle fibers, suggest-
ing impaired muscle quality.42
Laboratory biomarkers
Inflammation
Inflammation is thought to be the dominant driver of cachexia,
and a meta-analysis of CT imaging studies and inflammation
showed a consistent association between low skeletal muscle
mass and a systemic inflammatory response.43 The Glasgow
prognostic score (GPS) is a simple, systemic inflammation-based
approach (using CRP and albumin levels) with prognostic value
independent of tumor stage, performance status, and treatment,
in a variety of solid tumors.44 The GPS is also useful for prognos-
tication in non-cancer conditions such as pulmonary fibrosis45
and HF.46 Despite the importance of inflammation as a driver of
cachexia and its role in prognostication, small, preliminary stud-
ies incorporating anorexia scores, CRP, and weight loss have thus
far failed to distinguish between the stages of cancer cachexia
based on survival.16,17
Testosterone
Testosterone may be a useful prognostic indicator in patients
with cancer cachexia; however, the literature is limited to pre-
liminary, retrospective studies with small sample sizes. An asso-
ciation between low testosterone and decreased survival has been
reported in male patients with cancer cachexia.47 Low testoster-
one correlated inversely with CRP levels, dyspnea, and insomnia
in males with >5% weight loss in the preceding 6 months. In other
conditions such as cardiac cachexia, the evidence is more limited.
Some studies show that decreased testosterone is associated with
myocardial damage, lower exercise capacity, and higher mortality
in men with HF48; however, this is inconsistent.
More research is needed to develop a more robust prognos-
tic model that combines the various cachexia domains with
biomarkers such as lymphocyte count, albumin, or CRP lev-
els. As cachexia is common to a variety of diseases, prognostic
models should be tailored to specific diseases, even though
346
some indicators such as inflammation may be applied to most
(but not all) patients.
Mechanisms of cachexia
CAS is characterized by a complex interplay of various mecha-
nisms, leading to loss of muscle and fat as well as poor appetite.
Based on our current knowledge, the aberrant pro-inflamma-
tory response may be the dominant mechanism that drives sys-
temic effects on muscle, fat, and appetite regulation. Additional
mechanisms contributing to the syndrome include endocrine
dysfunction, increased resting energy expenditure (REE), and
diminished caloric intake due to nutritional impact symptoms
(NIS). It is important to note that the various mechanisms for
CAS should not be regarded in isolation, as they appear to be
interrelated.
Cachexia and starvation
Cachexia can be distinguished from starvation by a number of
features, including hormonal abnormalities such as elevated
insulin and ghrelin levels, increased REE in some patients, and
continued weight loss despite caloric supplementation. There
are some key differences between cachexia and starvation (see
Table 37.1), although, for individuals with involuntary weight
loss, a combination of the two conditions may be present simul-
taneously, e.g., a patient with esophageal cancer and dysphagia.
Inflammation
The inflammatory response may be the major factor contribut-
ing to changes in metabolism, protein synthesis, and endocrine
homeostasis in CAS. Immune cells and tumors produce small
proteins called cytokines that act as messengers, with cell signal-
ing effects on the nervous system, peripheral fat, and muscle.49
In spite of robust preclinical evidence, there are inconsistent
findings in the literature concerning cytokine serum levels and
clinical outcomes. Some studies show an association between ele-
vated serum cytokines and cancer cachexia, particularly IL-1β50
and IL-6, 51 while others have shown no correlation between cyto-
kine levels and cachexia52 or weight loss.53 A review of small, early
phase clinical trials showed that anti-IL-6 monoclonal antibody
treatment in patients with multiple myeloma, renal cell carci-
noma, and B-cell lymphoproliferative disorders decreased CRP
levels and the incidence of cachexia.54 The reasons for these dis-
crepancies are unclear; plasma levels do not necessarily reflect
true tissue concentrations, and cytokines may act locally in a
paracrine rather than endocrine fashion. A preliminary study
TABLE 37.1  Starvation versus Cachexia
Starvation Cachexia
Caloric Intake ↓↓ ↓ Cytokines also stimulate pathways in the hypothalamus to
REE ↓ ↓↑ or ↔
Body fat ↓↓ ↓ hormone (α-MSH), which inhibits feeding and increases energy
Lean body mass ↓ ↓
Acute phase reactants ↔ ↑ or ↔
Insulin ↓ ↑
Legend:
↔ Unchanged
↓ Reduce
↓↓ Markedly reduced
↓↑ Increased or reduced
↑ Increased
Textbook of Palliative Medicine and Supportive Care
in non-small cell lung cancer55 found decreased muscle func-
tion in pre-cachectic patients but identified muscle wasting only
once a transition occurred from systemic to local inflamma-
tion and activation of the ubiquitin–proteasome system (UPS)-
mediated proteolysis pathway. Other studies have also indicated
that elevated levels of pro-inflammatory cytokines are only a late
manifestation of disease and that biomarkers such as circulating
monocyte chemoattractant protein-1 (MCP-1) may be more rel-
evant56 earlier in the disease process.
Peripheral effects
Interleukin (IL)-6, tumor necrosis factor (TNF), and inter-
feron (IFN-γ) are thought to have an important role in skeletal
muscle wasting and decreased muscle synthesis. One pathway
for muscle wasting is through downregulation of myosin heavy
chain (MyHC), a myofibrillar protein that supports skeletal mus-
cle structure. In myogenic cell culture, TNF and IFN-γ reduce
myoblast determination protein (MyoD), a nuclear transcription
factor regulating MyHC; and in vivo, INF and TNF selectively
reduced MyHC as compared to other myofibrillar proteins, such
as actin or troponin.57
Another pathway for muscle wasting modulated by cytokines
is the ligase-dependent ubiquitin–proteasome pathway. Several
studies suggest that IL-6 produces skeletal muscle breakdown by
modulating this specific proteolytic pathway.58
There may be cross talk between muscle and fat so that main-
tenance of adipose tissue homeostasis also prevents wasting of
muscle, even in a pro-inflammatory state. Cachectic tumor mouse
models with high levels of circulating cytokines maintained nor-
mal levels of adipose and gastrocnemius muscle59 with genetic
ablation of adipose triglyceride lipase. Other important effects by
cytokines on adipose tissue have emerged in recent years. White
adipose tissue (WAT) lipolysis and white-to-brown transdifferen-
tiation of WAT, resulting in thermogenic gene expression (WAT
browning) and ultimately adipose atrophy, have been identi-
fied in renal and cancer cachexia.60 Animal models reveal that
inflammation mediated by IL-6 might promote cancer cachexia
by regulating WAT lipolysis in early-stage cachexia and browning
in late-stage cachexia.61
Central effects
Systemic pro-inflammatory cytokines affect appetite regulation
and endocrine homeostasis by stimulating the expression of cyto-
kines in the hypothalamus, which can then act through second
messengers.62 Hypothalamic appetite regulation consists of two
major opposing peripheral hormones: leptin and ghrelin. Leptin,
from adipocytes, is anorexigenic, while ghrelin, predominantly
from the stomach, is orexigenic. Cytokines mimic the anorexi-
genic signals of leptin and suppress orexigenic signals from neu-
ropeptides such as ghrelin and agouti-related peptide (AgRP).
release anorexigenic peptides, such as α-melanocyte-stimulating
expenditure.63 Central effects mediated by cytokines through
the hypothalamic–pituitary–adrenal (HPA) axis also produce
effects peripherally; for example, IL-1β causes significant muscle
atrophy64 when administered centrally in animal models. Since
an intact HPA axis appears to be necessary for muscle wasting,
it is possible glucocorticoids may combine with local cytokines
to promote muscle atrophy. In addition, cytokines decrease oral
intake by generating symptoms such as early satiety (via IL-1) and
depression (IL-6).65
Cachexia–Anorexia Syndrome
Other mechanisms causing muscle and fat atrophy
Inflammation, cytokines, tumor factors, and hormones play a
role in altered catabolism and anabolism leading to muscle and
fat atrophy in cachexia. In progressive cancer cachexia, body fat
is lost more rapidly than lean tissue.66 However, both muscle and
fat loss occur by either decreased synthesis, increased degrada-
tion, or both. As noted previously, there is also evidence of “cross
talk” between muscle and fat through various pathways, includ-
ing via parathyroid hormone–related protein and myostatin.67
Myostatin,68 an extracellular cytokine, is a negative regulator of
muscle growth and is upregulated across various diseases impli-
cated with cachectic muscle wasting.69 For muscles specifically, in
addition to the UPS, there are proteolytic pathways that are lyso-
somal, calcium dependent, and caspase dependent.70 Lipolysis
in cachexia is associated with increased expression of zinc-α2-
glycoprotein (ZAG), an adipokine and catabolic marker71,72 found
in COPD,73 renal, and cancer cachexia patients. Additionally,
medications, alcohol,74 and vitamin D75 have been implicated in
the “browning” and atrophy of fat, while corticosteroids76 can
induce subacute and chronic muscle loss.
Endocrine dysfunction
Changes in the response to hormones or altered hormone levels
can contribute to the muscle/fat wasting and poor appetite seen
in CAS. The role of anabolic hormones, such as ghrelin, insulin,
and androgens, as well as catabolic hormones, such as epineph-
rine, norepinephrine, and cortisol, is important to consider in the
development of CAS.
Ghrelin is secreted predominantly by the stomach during fast-
ing, resulting in increased appetite, gastrointestinal motility, and
reduced inflammation. Ghrelin may also activate ghrelin recep-
tors in the terminals of the vagus nerve and trigger neuronal sig-
naling to the nucleus of the solitary tract (NTS) in the brain stem
and indirectly the hypothalamus.77 In addition to stimulating
appetite, ghrelin acts on multiple other mechanisms that cause
muscle atrophy, including downregulating inflammation, p38/C/
EBP-β/myostatin, and activating Akt, myogenin, and myoD.
Ghrelin’s release is inhibited by food-associated stimuli; unex-
pectedly, levels are elevated in patients with cancer cachexia, 56
suggesting they may be ghrelin “resistant.”
Insulin resistance may contribute to the muscle wasting seen
in cancer cachexia, as insulin has the dominant hormonal control
over muscle proteolysis. Specifically, insulin’s signaling pathway
activates molecules that overlap with the ubiquitin–proteasome
pathway so that resistance to insulin results in increased prote-
olysis78 while insulin sensitivity decreases proteolysis.
Adrenal hormones are associated with weight loss and decreased
survival in patients with congestive HF (CHF). Cachectic patients
showed increased levels of epinephrine, norepinephrine, and corti-
sol as compared to control or non-cachectic patients.79 One of the
pathways by which catecholamines may produce wasting includes
the activation of uncoupling protein 1 (UCP1) and increased ther-
mogenesis within brown adipose tissue.80
Metabolic dysfunction, including
increased resting energy expenditure
Metabolic abnormalities in cachexia include mitochondrial dys-
function81 leading to altered amino acid metabolism and an
increased rate of whole-body glycolysis driven by the tumor glucose
demand and increased gluconeogenesis due to lactate production.
347
The use of lactate as a substrate is extremely energy inefficient,
requiring six ATP to produce one molecule of glucose. Reasons
are unclear as to why tumor cells favor this relatively inefficient
process or “Warburg effect” even in the presence of adequate
oxygen. More recent research into the metabolism of tumor cells
suggests there is substantial metabolic heterogeneity within a
tumor, allowing cancer and stromal cells to couple and transfer
metabolites between them to support maximal cellular growth.82
Other elements of metabolic dysfunction have also been identi-
fied; for example, during the development of peritoneal metas-
tases, hypoxia-inducible factor-1α (HIF-1α) plays a key role in
activating both aerobic and anaerobic glycolysis, increasing the
uptake of glucose, lipid, and glutamine into cancer cells. HIF-1α
also stimulates the utilization of glutamine and fatty acids as
alternative energy substrates.83 Increased utilization of energy by
tumors may also be quite substantial84 (estimated at between 100
and 1400 kcal/day) and, along with fat “browning,” could contrib-
ute to the increased REE seen in some, but not all, patients.
Nutritional impact symptoms
Symptoms can exacerbate the cachectic state by decreasing nutri-
tional intake. NIS include nausea, vomiting, constipation, diar-
rhea, early satiety, severe pain, dyspnea, anxiety or depression,
stomatitis, dysgeusia, xerostomia, and dysphagia. Some NIS (e.g.,
depression) may be precipitated by the same endocrine dysfunc-
tion (low testosterone) and pro-inflammatory cytokine response
(increased IL-6) that produce CAS. Other NIS are caused by
the disease itself or by its treatment (e.g., mucositis because of
chemotherapy). A retrospective database review evaluated the
impact of 17 symptoms on 635 patients with head and neck can-
cer referred to a cancer center. 30 Participants were only on oral
intake and using no enteral tube feeding or parenteral nutrition.
Individual symptoms significantly associated with reduced food
intake included loss of appetite, difficulty chewing, dry mouth,
thick saliva, and pain. Importantly, aggregate symptom burden
was found to be an independent predictor of reduced intake,
weight loss, and survival (Figure 37.1).
Assessment
Nutrition risk screening and identification
There is no consensus regarding the use of a particular screen-
ing tool for cachexia. The Patient-Generated Subjective Global
Assessment Short Form (PG-SGA SF) is often used in the
oncology setting and is a valid screening tool in chemotherapy
outpatients. 85 The PG-SGA SF provides additional prognos-
tic value in evaluating patients with cancer, can be completed
by patients in less than 5 minutes, and includes information
about the severity and rate of weight loss, food intake, nutri-
tional symptoms, and functional status. In addition to iden-
tifying patients at risk, self-completion of the PG-SGA SF by
patients increases self-awareness regarding malnutrition risk
after completing the PG-SGA SF.
Among 1001 patients with gastric cancer, a comparison of
four commonly used tools, including the Malnutrition Universal
Screening Tool, the Nutritional Risk Screening 2002, the
Malnutrition Screening Tool (MST), and the Short Nutritional
Assessment Questionnaire (SNAQ), found the MST had the
greatest ability to detect cancer cachexia. However, in a study of
725 patients, abnormal BC (sarcopenia or myosteatosis) identified
on CT imaging was misclassified as “low risk” by the MUST and
348
FIGURE 37.1  Multiple factors contributing to cachexia.
MST in more than 50% of patients. The Nutritional Risk Index
proved to be the most useful in capturing “hidden malnutrition”
among ambulatory oncology patients.86 Tools may need to be tai-
lored to a specific disease or setting; in patients with cirrhosis,
the six-question Liver Disease Undernutrition Screening Tool
was only one of two tools shown to be accurate for detecting mal-
nutrition in cirrhotic patients, 87 and in hospitalized older people,
the Simplified Nutritional Appetite Questionnaire (SNAQ) iden-
tified patients at higher risk of poor outcomes.88
A single tool for evaluating cachexia, sarcopenia, and malnu-
trition would be ideal for clinical practice. Unfortunately, a sys-
tematic review of 38 studies using 22 validated tools found no
single tool that contained all accepted components for all three
conditions.89
Health-related quality of life
The most frequently used questionnaire to assess health-related
quality of life (HRQoL) in cachexia is the anorexia/cachexia sub-
scale (A/CS) of the functional assessment of anorexia/cachexia
therapy (FAACT). Recently, shortened versions for FAACT
and FACT fatigue subscale have been published specifically for
NSCLC,90 and higher cutoff values have been proposed (≤37 for
the FAACT–A/CS and ≤70 for the visual analog scale for appe-
tite, with 100 being a good appetite) in an attempt to improve the
positive predictive value and capture more cachectic patients.91
Although the HRQoL instruments are traditionally confined to
the research setting, it is possible that shortened versions may be
feasible for daily clinical practice.
Textbook of Palliative Medicine and Supportive Care
A relatively new European cancer cachexia questionnaire has
been developed (EORTC QLQ-CAX24), which provides a more
comprehensive assessment and includes 24 items, 5 multi-item
scales (food aversion, eating and weight-loss worry, eating diffi-
culties, loss of control, and physical decline) and 4 single items.92
Weight and body composition
Body mass index (BMI)
BMI (BMI = body weight divided by height in kg/m2) is not useful
in evaluating BC but does provide important information regard-
ing energy reserves and, in combination with percentage weight
loss, has been incorporated into a grading system for predicting
prognosis. Other measures are necessary to evaluate BC and vary
with regard to accuracy, cost, and patient comfort.
Anthropometrics
Anthropometrics to quantify skeletal muscle mass are non-
invasive but require training and are difficult to measure
accurately in obese and very old patients. A simple regional
measure can be used in clinical practice to monitor the impact
of therapy on arm muscle area,93 e.g., (Mid-arm circumference
[MAC] in centimeters) − π × tricipital skinfold thickness [in
millimeters])2/(4 × π) minus a correction factor of 10 for men
and 6.5 for women.
Another very simple test, requiring no equipment and found to
be effective in screening for muscle atrophy in chronic liver dis-
ease, is the “finger-circle test’” that compares the size of the circle
Cachexia–Anorexia Syndrome
made with the bilateral thumb and index fingers of the patient
with that of the calf of their leg.94
Bioelectrical impedance analysis (BIA)
BIA is noninvasive, portable, inexpensive, and uses a constant,
low-level alternating current to measure impedance, consisting
of resistance (water and electrolytes in fluids and tissues) and
the reactance component in tissues (cells and tissue interfaces).
The phase angle, a direct derivative of the reactance and resis-
tance measurements, has correlated with outcome and health
status in diverse cancer populations and even with healthy con-
trols.95 Low sensitivity to detect subjects with reduced muscle
mass is a limitation of BIA96; however, a systematic review
concluded that BIA was a viable alternative to more expensive
imaging modalities. The best use of BIA is for evaluation of indi-
viduals over time and monitoring a change in phase angle as the
disease progresses.97
Imaging
Imaging is useful for assessment of BC and diagnosing sarcope-
nia. Skeletal muscle mass and composition have correlated with
outcomes of muscle function, strength, and physical perfor-
mance. Depending on resources, assessment goals, and patient
comfort, imaging may entail DEXA, CT and magnetic resonance
imaging (MRI), or ultrasound (US).
DEXA
DEXA has been the gold standard for research and clinical prac-
tice, providing information on lean soft tissue and fat at rela-
tively low radiation levels and modest cost. DEXA also provides
useful information regarding bone mineral content so that the
composite musculoskeletal system (i.e., muscle plus bone) can be
evaluated. This is especially important in older persons where the
combination of osteopenia/osteoporosis and sarcopenia (osteo-
sarcopenia) may be a marker for frailer individuals at higher risk
of institutionalization, falls, and fractures.98
CT and MRI
CT scanning has the advantage of producing high-quality images
that also provide measures of tissue composition and quality.99
Disadvantages of CT scans include radiation exposure and higher
cost; however, CT scans may be regarded as a very useful “opportu-
nistic tool”100 since oncology patients often have CT scans done as
part of their routine care. BC analysis of muscle and different adi-
pose tissue depots at the third lumbar vertebra cross-sectional area
correlates with whole BC. Although a radiologist is not required for
evaluation of BC, the CT images and the software for analysis, as
well as trained personnel are required for accurate evaluation.104
In addition to BC assessment, CT or MRI is able to identify
reduced muscle attenuation, an indicator of intermuscular adi-
pose tissue or poor “quality” skeletal muscle. Muscle attenua-
tion or myosteatosis has correlated with survival101 in oncology
patients and recurrence-free survival after resection of pancre-
atic cancer.102 Myosteatosis also is also associated with reduced
aerobic physical fitness in patients undergoing hepatobiliary and
pancreatic surgery.103
Ultrasound
US is inexpensive, can be done repeatedly in the clinic or bedside,
avoids radiation exposure,104 and is a reliable indicator of change
in muscle size, based on preliminary studies. Analysis of rectus
femoris by US was shown to be a reliable index of total quadriceps
349
volume and change in response to an exercise intervention for
chronic kidney disease patients.105
Physical performance
There is no consensus regarding the use of specific tests for mea-
suring physical performance in cachexia; however, assessments
that are relatively brief and associated with cachexia-relevant
outcomes include the short physical performance battery (SPPB),
handgrip strength, stair climb,106 and 6MW test.
Short physical performance battery
The SPPB assesses lower extremity physical performance and
requires between 6 and 10 minutes to complete. A meta-analysis
found the SPPB score <10 was predictive of all-cause mortality,107
and a comparison of five mobility measures in older patients
with cancer found the SPPB was the best measure for predicting
6-month mortality.108 SPPB also demonstrated excellent predic-
tive abilities for functional decline and survival in older women
with breast cancer109 and gynecological cancer,110 respectively.
Recently, a prospective study in patients with HF and preserved
ejection fraction (>80% of patients were mildly frail with an
SPPB score of <10) reported that the SPPB score independently
predicted death or all-cause hospitalization over a 6-month
period.111 Furthermore an SPPB score of <10 is associated with
higher symptom burden in patients with cancer.
Handgrip dynamometry
Handgrip dynamometry has been used in clinical trials of
cachexia112,113 and a predictive model for older oncology
patients.114 To assess maximal handgrip strength (HGS), at least
three attempts are needed if HGS is considered to be a continu-
ous variabl.115 HGS measurements should be interpreted using
region/ethnic-specific reference ranges.116
Six-minute walk test
The 6MW test measures endurance and cardiorespiratory fitness,
and it has been validated in patients with cancer.117 The 6MW
has also been used as an outcome measure in clinical trials for
cancer cachexia118 and in studies of HF patients with cachexia or
sarcopenia. 39
Management
A complex syndrome such as CAS, with multifaceted mecha-
nisms, requires a combined pharmacological and non-pharma-
cological approach to improve protein and caloric intake, gain or
maintain muscle and fat, and boost physical function. The treat-
ment goal for many patients with cachexia is to maintain physical
function and independence. For some individuals, the psychoso-
cial aspects of CAS, such as altered body image and the inability
to enjoy meals with family members, may carry greater impor-
tance. In this section on management, the potential interventions
are for the most part discussed in isolation; however, a multimo-
dality approach should always be considered because it is likely to
be most effective (Figure 37.2).
Non-pharmacological intervention
Nutritional supplementation
Nutritional counseling may alleviate the negative impact of CAS
by reducing anxiety and conflict among patients and families
and by facilitating conscious control over caloric intake.119 When
considering strategies for increasing nutrition intake, emphasis
should be placed on maintaining a daily goal of 1–1.5 g/kg/day
350
FIGURE 37.2  Management of Cachexia–Anorexia Syndrome.
of protein,120 with a focus on protein-rich foods. Poor compli-
ance with supplements suggests that a concentration on food
rather than nutritional supplements should be the approach of
nutritional counseling.121 Based on the guideline recommenda-
tions, the overall caloric intake should range between 25 and
30 kcal/kg/day. This estimation assumes caloric needs are simi-
lar to healthy subjects; however, individual patients may be
hypermetabolic requiring even higher caloric targets. A study of
320 patients with advanced cancer and weight loss found the
majority of patients are consuming diets insufficient to main-
tain weight even in healthy individuals.14 Vitamin D levels should
always be checked in patients with cachexia because prelimi-
nary studies report a high prevalence of vitamin D deficiency in
advanced cancer and an association with fatigue.122
Psychosocial intervention
Psychosocial support has the potential to relieve suffering and
family conflict123 since there is a high prevalence of eating-related
distress.124 Psychological intervention and teaching cognitive
reframing strategies also encourages patients to take control over
eating habits.125 A shift to conscious control over eating is often
useful by reframing eating as a necessity rather than a pleasure
for promoting positive outcomes such as a slowing disease pro-
gression and maintaining strength and stamina.50
Exercise and physical therapy
Exercise has the potential to improve muscle mass, strength,
physical function, fatigue, and quality of life in patients with
Textbook of Palliative Medicine and Supportive Care
cancer cachexia. There are several trials that provide encourag-
ing support for incorporating exercise into CAS management.
A randomized, controlled trial in patients with advanced can-
cer and a life expectancy of <2 years reported improved physi-
cal performance after 8 weeks of exercise.126 Resistance exercise
has been successfully combined with testosterone in age-related
cachexia, producing a greater anabolic effect than either inter-
vention alone;127 a multidisciplinary rehabilitation incorporating
exercise in patients with cancer cachexia improved weight, hand-
grip strength, and 6MW.128 For clinics without a physical thera-
pist, there is potential for other team members to play a greater
role. For example, a nurse-led simple “walk-and-eat” intervention
consisting of 20-minute ambulation 3×/week and weekly nutri-
tional advice resulted in significantly better HGS, walk distance,
and weight compared with a control group receiving neoadjuvant
chemoradiotherapy for esophageal cancer.
Pharmacological management
Nutrition impact symptoms (NIS)
Symptoms such as depression, dysgeusia, severe pain, excessive
drowsiness, nausea, and constipation may contribute appreciably
to poor intake and are associated with adverse outcomes such as
weight loss and decreased survival. 30 There are effective, inex-
pensive pharmacological interventions for symptoms impacting
nutritional intake. Two-thirds of patients referred to a cancer
cachexia clinic reported between two and four NIS, and one in
five patients had five-to-eight NIS. In spite of their advanced ill-
ness, one-third of patients experienced weight gain after referral.
The pharmacological approach to NIS is shown in Table 37.2.
Cachexia–Anorexia Syndrome 351

TABLE 37.2  Pharmacological Management of Nutritional Impact Symptoms

Nutritional Impact Symptom Pharmacological Intervention
Early satiety; bloating; GERD Metoclopramide 10 mg four times daily to q4h po
Second choice: mirtazapine
Constipation Laxatives; for example, polyethylene glycol and senna
Nausea/vomiting Metoclopramide for non-CINV
Olanzapine 10 mg qhs for CINV, depression
Mirtazapine 15 mg qhs for depression, insomnia, and anxiety
Depressed mood or anxiety Mirtazapine first choice
Duloxetine for neuropathic pain
Dysgeusia Zinc supplement trial for 2 weeks
Fatigue Testosterone replacement in men
Vitamin D replacement for both men and women
Severe pain; for example, mucositis Opioid, honey, mouthwash
Abbreviations: CINV, chemotherapy-induced nausea or vomiting; GERD, gastroesophageal reflux disease.

Metoclopramide potentially serious side effects, and MA should be reserved for

Metoclopramide is the drug of choice for nonchemother-
apy-induced nausea or vomiting, early satiety, and bloating.
Metoclopramide has advantages, including increased motility
and accommodation of the stomach, but it is less sedating than
prochlorperazine and promethazine. All dopamine antagonists
carry a risk of extrapyramidal side effects and should not be used
in combination. Except for tardive dyskinesia, extrapyramidal
side effects are reversible, and good clinical practice suggests a
review of benefits and potential risks with patients at initiation
and following 3 months of therapy. An alternative dopamine
antagonist such as olanzapine should be considered if nausea
and vomiting are likely chemotherapy related.129 Olanzapine does
not have the advantage of being a promotility agent but is dosed
more conveniently (10 mg at night) and has demonstrated a mod-
est effect in altering the trajectory of weight loss among patients
with advanced cancer.130
Mirtazapine
Mirtazapine is a good drug of choice for depression or anxiety
in view of potential for improving other symptoms, including
early phase studies for appetite.131 The medication is also nota-
ble for being more sedating at lower doses, and caution should
be exercised, with one preliminary trial reporting sedation and
xerostomia.132
Corticosteroids
Corticosteroids and progestational agents have good evidence
for improving appetite; however, their risk for serious side
effects and their anti-anabolic effects on muscle are problematic.
Corticosteroids should be considered in patients with advanced
cancer, limited prognosis, and a cluster of symptoms that include
fatigue and loss of appetite. Based on two double-blind RCTs
showing improved fatigue and appetite within 7–14 days, it seems
reasonable133,134 to prescribe twice daily dexamethasone (4 mg)
or methylprednisolone (16 mg). The benefit of continuing beyond
2 weeks is unclear, and lower doses or tapering may be clinically
indicated depending on side effects such as hyperglycemia, infec-
tion, and myopathy. A systematic review found megestrol acetate
(MA) improved weight but not quality of life, with more adverse
events when compared to placebo. Because of the increased
risk for thromboembolism, patients should be informed of the
patients placing a high priority on improved appetite, since MA
may have an anti-anabolic effect on muscle. Since some of the
adverse effects may be dose related, it seems prudent to start at a
low dose (e.g., 160 mg/day) and monitor clinical response.
Cannabinoids
Cannabinoids have improved appetite at higher doses in patients
with AIDS135; however, an increased risk of adverse psychotropic
effects is documented in oncology patients taking higher doses
of dronabinol. A multicenter, three-arm study in patients with
advanced cancer also found no significant differences when com-
paring the effects of cannabis extract, dronabinol (2.5 mg twice
daily), and placebo on appetite and quality of life.
Thalidomide
Thalidomide showed promising improvements in lean body mass
and minimal side effects after 4 weeks of 200 mg/day in patients
with pancreatic136 and esophageal cancer.137 Unfortunately, a
subsequent study reported poor tolerability,138 and a systematic
review concluded the evidence was insufficient139 to recommend
thalidomide as a cancer–cachexia therapy.
Beta blockade
Beta blockade has been shown to be an effective therapy for a
number of conditions, including hypermetabolism and wasting
experienced by children hospitalized with burns.140 Blockade with
carvedilol attenuated the development of cachexia in patients
with severe chronic HF,141 and a multicenter phase II study found
espindolol116 reversed weight loss and improved fat-free mass in
patients with cancer-related cachexia.
Nonsteroidal anti-inflammatory drugs (NSAIDs)
NSAIDs, including celecoxib, ibuprofen, indomethacin, and
etodolac, have been used alone or in combination with other
agents for a variety of clinical outcomes related to cancer cachexia.
A systematic literature review identified 11 of 13 trials showing
improvement or stabilization in weight or lean body mass142; how-
ever, the evidence was considered insufficient to recommend use
of NSAIDs outside clinical trials. Even though the trials reported
negligible toxicity, concerns regarding the potential side effects
352
such as hemorrhage and kidney dysfunction support the need for
additional trials to confirm efficacy and safety.
Androgens
Androgens, including testosterone and selective androgen recep-
tor modulators,143 have improved some CAS-related outcomes;
however, the results are inconsistent. Men with cancer have
a high prevalence of testosterone deficiency, possibly due to
medications144 (e.g., opioids, megestrol, corticosteroids), chemo-
therapy, radiation therapy, and chronic inflammation. Low tes-
tosterone levels in men with cancer are associated with greater
weight loss,145 increased fatigue, diminished health-related qual-
ity of life, and decreased survival.146
Two small, double-blind placebo-controlled trials found some
cancer cachexia–related outcomes improved after intramuscular
testosterone injections. In 29 men with advanced cancer, those
given intramuscular testosterone replacement therapy (TRT) had
better performance status and fatigue scores compared to a pla-
cebo injection, but there were no differences in weight, appetite,
or adverse effects.147 A phase II trial in 28 men and women receiv-
ing weekly injections of testosterone or placebo for 7 weeks148
found loss of weight and lean body mass were significantly greater
in the placebo group, while physical performance improved in the
testosterone group.
Ghrelin and ghrelin agonists
Ghrelin and ghrelin agonists have demonstrated efficacy and
safety in a number of preliminary trials for cachexia-related out-
comes in oncology and COPD149; however, a systematic review
recommended additional adequately powered trials to determine
whether ghrelin is effective for patients with cancer cachexia.150
The ghrelin mimetic anamorelin has shown the greatest poten-
tial thus far, with two multicenter studies from Japan reporting
improved lean body mass, weight, and appetite in patients with
lung or gastrointestinal cancer. These reports follow a large, inter-
national phase III trial117 where 12 weeks of anamorelin improved
lean body mass and weight but not HGS, compared to placebo.
Combination therapy
Combination therapy is likely to be the most effective manage-
ment strategy, as monotherapy is unlikely to correct the multiple
abnormalities associated with cachexia. Even an effective single
pharmacological agent would have to be combined with dietary
counseling, supplementation, symptom management, and exer-
cise. Combination therapy should ideally have additive or even
synergistic effects and should be modified to target the specific
mechanisms affecting individual patients, since the contribu-
tion of the different mechanisms of cachexia may vary. Several
multimodality trials have been published showing improved can-
cer-related CAS outcomes, including weight, appetite, lean body
mass, and survival.151
Conclusion
Malnutrition, sarcopenia, and CAS are complex challenges for
researchers and clinicians in daily practice. Improved under-
standing of CAS and its mechanisms allows for the develop-
ment of new targeted agents and better insights into how these
therapies could be incorporated into effective multimodal man-
agement. CAS is also an opportunity for collaboration between
palliative care teams and their oncology colleagues to improve
Textbook of Palliative Medicine and Supportive Care
patients’ quality of life, decrease treatment toxicity, and improve
performance status. Importantly, palliative care teams have the
skill set to implement the necessary basic assessments for CAS,
a comfort with a model of interdisciplinary care that integrates
other health professionals (e.g., dieticians and physical therapists)
and the expertise for optimal management of nutritional impact
symptoms.
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38
NAUSEA/VOMITING

Sebastiano Mercadante

Contents
Introduction�����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������357
Definitions��������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������357
Pathophysiology and causes of nausea and vomiting������������������������������������������������������������������������������������������������������������������������������������������������358
Assessment and diagnosis�����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������359
Specific conditions associated with vomiting�������������������������������������������������������������������������������������������������������������������������������������������������������������359
Chemotherapy-induced nausea and vomiting������������������������������������������������������������������������������������������������������������������������������������������������������359
Disorders affecting the central nervous system����������������������������������������������������������������������������������������������������������������������������������������������������361
Autonomic failure�������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������361
Drug-induced nausea and vomiting������������������������������������������������������������������������������������������������������������������������������������������������������������������������361
Treatment of nausea and vomiting in advanced cancer or non-cancer patients�������������������������������������������������������������������������������������������������361
Prokinetic agents���������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������362
Dopamine antagonists������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������362
Antihistamines�������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������363
Anticholinergics����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������363
Setron family����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������363
Steroids��������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������363
Cannabinoids���������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������363
References���������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������363

Introduction vomiting,1 these symptoms are not necessarily on a continuum,

Nausea and vomiting are common and distressing symptoms
reported by cancer patients and affecting up to 70% of patients in
the last months of life.1 Nausea may also develop at an early stage.
These symptoms have been variably reported in literature accord-
ing to the evaluation methods and stage of disease. Nausea is
often associated with chemotherapy and other oncological treat-
ments and may develop chronically because of the progression
of disease, being multifactorial.2 Nausea may also be reported
in patients with progressive neurological diseases such as cen-
tral nervous diseases, peripheral nervous diseases, dysfunction
of neuromuscular junction, and muscle diseases. 3 Nausea and
vomiting are demeaning, reduce patients’ quality of life, and may
affect compliance with therapy.
Definitions
Three components of vomiting are recognized: nausea, retching,
and emesis.4 Nausea is an unpleasant sensation of the need to
vomit associated with a decrease in gastric tone and peristalsis
and an increase in the tone of duodenum, frequently expressing
autonomic symptoms, such as pallor, cold sweats, tachycardia,
and diarrhea. Thus, nausea is a subjective component and has
dimensions unique to the individual. It is difficult to describe to
another person this experience. Indeed, retching and vomiting
are mediated by somatic nerves and are objective and definitive
signs. It is not clear if nausea and vomiting represent different
points along the spectrum of outputs from the vomiting cen-
ter (VC), or if they are related, but independent, phenomena.
Although nausea is commonly considered a prodromal phase to
as patients can experience nausea without vomiting or can have a
sudden episode of vomiting without background nausea. Nausea
is characterized by a decrease in gastric tone and peristalsis and
is associated with an increase in the tone of duodenum, as an
expression of autonomic stimulation.
Retching and vomiting are mediated by somatic nerves. Retching
is an attempt to vomit without bringing anything up and is charac-
terized by a spasmodic movement of the diaphragm and abdominal
musculature with the glottis closed, denoting the labored rhythmic
respiratory activity that frequently precedes emesis.
Vomiting involves forceful contraction of the abdominal
muscles, contraction of pylorus and antrum, a raised gastric car-
diac activity, a decreased lower esophageal sphincter tone, and
esophageal dilatation. Vomiting is characterized by a pre-ejection
phase, retching, and ejection and can be accompanied by shiver-
ing and salivation.
The intestinal content is commonly present in vomited mate-
rial, implying a possible reverse peristalsis. Hypersalivation and
cardiac rhythm disturbances are the expression of a concomitant
vegetative involvement. It seems that the neural pathways that
mediate nausea are the same pathways that mediate vomiting.5
It may be that mild activation leads to nausea, the more intense
activation leading to retching or vomiting. The distress resulting
from these symptoms may escalate over time with the continuing
symptom experience, regardless of the frequency, duration, and
severity. Although people may experience seemingly identical
symptoms, the cause of the symptoms and each person’s response
to the symptoms may vary so that an accurate assessment of the
individual’s symptoms and recognition of the possible causes
form the basis for customized treatments.

357
358
Pathophysiology and causes
of nausea and vomiting
As the optimal approach to managing nausea and vomiting in
cancer patients should be based on physiopathological mecha-
nisms, it is the need to recognize the principal cause by knowl-
edge of a complex set of neurological activities.
The afferent and efferent reflexes regulating nausea and vomit-
ing are thought to be integrated by two centers at brain stem level.
In the floor of the fourth ventricle, outside the blood–brain
barrier there is the “chemoreceptor trigger zone (CTZ).”6–9 CTZ
should be considered as an interconnecting neural network pen-
etrating into the nucleus of the tractus solitarius8,10 rather than a
specific anatomical area. The CTZ is stimulated by chemical sub-
stances as well as vestibular and vagal afferents. In the CTZ, there
are dopamine (D2), serotonin (5-HT3), acetylcholine (ACH), and
opioids (m2) receptors.2,5–9,11,22
The VC is situated in the medulla oblongata, beyond the blood–
brain barrier. Also, the VC is not a distinct anatomical structure,
but an interconnecting neural receiving afferent information
from many areas, including the CTZ, the glossopharyngeal and
splanchnic nerves, cerebral cortex, thalamus, and hypothalamus.
Moreover, it is stimulated from the vagus nerve that receives
stimuli from mechanoreceptors and activation of 5-HT3 recep-
tors in the gastrointestinal (GI) tract. 3,5
VC is anatomically adjacent to the medullary centers that con-
trol respiration and salivation. The generator, however, is in the
third ventricle, close to the area postrema, which is lying within
the blood–brain barrier and contains emetogenic receptors like
D2 receptors, histaminic (H1) receptors, muscarinic cholinergic
receptors, serotonin (5-hydroxytryptamine [5-HT] 2 and 3) and
m2-opioid receptors.
Intracranial masses are a relevant cause of nausea and vom-
iting. An increased intracranial pressure stimulates the VC on
the floor of the fourth ventricle. Limited lesions may directly
affect their afferent pathways. Indeed, VC may also be stimulated
by a ventricular dilatation without high intracranial pressure.
Infectious diseases of the central nervous system may also pro-
duce vomiting.8
Psychological or emotional factors may also contribute to the
generation of nausea at this level, where there is a group of motor
nuclei, including the nucleus ambiguous, ventral, and dorsal
respiratory groups, and the dorsal motor nucleus of the vagus.
The CTZ is sensitive to chemical stimuli and lies in the floor of
the fourth ventricle in the brain stem and is able to stimulate the
VC.5 This area is outside the blood–brain barrier and is bathed in
the systemic circulation. The CTZ contains emetic receptors for
dopamine (D2), serotonin (5-HT3), acetylcholine (ACHr), and opi-
oids (mu2), which when stimulated provide input for the VC sited
in the third ventricle. High plasma concentrations of emetogenic
substances, such as calcium ions, urea, morphine, and digoxin,
may stimulate dopamine receptors in this area.
The CTZ is also implicated in delaying the reflex of gastric
emptying, and production of taste aversion, which could contrib-
ute to vomiting. Acoustic neuroma, bone metastases at the base
of the skull, brain tumors, or metastases affecting the vestibular
apparatus are possible other causes of vestibular stimulation of
H1 receptors and muscarinic cholinergic receptors. In addition
to the direct afferent pathways from the GI tract to the VC, the
anatomical region of the area postrema receives emetic impulses
from the pharynx, heart, peritoneum, mesenteric vasculature,
Textbook of Palliative Medicine and Supportive Care
BOX 38.1  FACTORS STIMULATING THE CTZ
• Glycosides
• Opioids
• Ergot derivatives
• Chemotherapeutic agents, enterotoxins, salicylates
• Metabolic abnormalities: uremia, hypercalcemia,
hyponatremia, diabetic ketoacidosis
• Hypoxia
• Radiation sickness
and bile ducts. Impulses from these peripheral receptors are also
transmitted directly to the VC.
Anorexia, dehydration, weight loss, abnormal metabolites, and
toxins produced by associated infections may also contribute
(Box 38.1). Moreover, it also receives input from the vestibular
apparatus and the vagus. Drugs, particularly aspirin and opioids,
are able to directly stimulate the vestibular apparatus, which in
turn provides input to the VC. The deeper layers of the area pos-
trema are partly formed of the nucleus tractus solitarius, which
predominantly contains 5-HT receptors and is considered the
main central connection of the vagus. Visceral afferent impulses
arising from the GI tract may reach the medullary VC by way of
the vagus, without traversing the CTZ. 3
Receptors present in the GI tract play another important role in
the pathogenesis and treatment of nausea and vomiting, particu-
larly 5-HT3, 5-HT4, and D2 receptors. Activation of D2 receptors
produces gastroparesis. Vagus receptors include 5-HT3 receptors,
which are emetogenic, and 5-HT4 receptors, which enhance the pro-
pulsion, that translate into a prokinetic effect. This effect is medi-
ated by the cholinergic myenteric plexus so that it could be inhibited
by anticholinergics. Different stimuli, notably bowel distension and
inflammation, may produce a release of 5-HT from enterochromaf-
fin cells contained in the bowel wall. Slowed gastric emptying and
constipation, frequently observed in patients progressively immo-
bilized and anorectic, may similarly activate this process. The acti-
vation of these peripheral receptors leads to the stimulation of the
VC through vagal and sympathetic afferents. Moreover, there
are corticobulbar afferents to the VC that mediate vomiting in
response to some stimuli like smells, sights, and tastes and may play
a role in psychogenic vomiting. Stress, anxiety, and nausea from any
cause induce delayed gastric emptying via peripheral dopaminergic
receptors on the myenteric plexus interneurons.3 Therefore, nausea
and vomiting are influenced by a complex network of central and
peripheral factors that interact with each other.
Thus, vomiting is an integrated somatovisceral activity con-
stituted by a central emetic pattern generator that coordinates
emetic processes, receiving and integrating input from various
sources. The efferent pathways are mainly somatic and involve the
vagus nerve, the phrenic nerves, and the spinal nerves. Changes
in tone and mobility of the stomach during vomiting are likely
mediated by visceral efferent neurons. Once the VC has been suf-
ficiently stimulated, the vomiting reflex is initiated. The person
takes a deep breath that is held, the glottis closes to avoid aspira-
tion of vomitus, the soft palate elevates to close off the nasal pas-
sage, and finally the diaphragm and abdominal muscles contract.
As a consequence, intra-abdominal pressure squeezes the stom-
ach between the two sets of muscles, and the GI sphincter relaxes,
allowing the expulsion of gastric contents.5
Nausea/vomiting
The receptor site affinities of principal antiemetics are listed
in Box 38.2.
Assessment and diagnosis
Like pain, nausea is a subjective experience and presents all of
the problems inherent in measuring pain. Patients with nausea
should be assessed with a visual analog scale (0–10, with 0 = no
nausea and 10 = maximum nausea). Similar assessments and
observations should be made for emesis to try to determine the
severity and the context of the nausea and emesis. The frequency,
time of day, and any associated activities (meals, medications,
and exertion) should be noted. Vomiting can be more objectively
recorded as events.
The physical examination should include a detailed assessment
of the abdomen to exclude a possible peripheral cause, such as
bowel obstruction, an inflammatory process, or gastroparesis.
Any abdominal distention, abnormal bowel sounds, ascites, hep-
atomegaly, or splenomegaly should be noted.
Many factors should be considered when choosing antiemetic
treatment. History, examination, and review of the ongoing drug
regimen are generally helpful in finding the cause of GI symp-
toms in the neurological population. A multitude of medications,
including opioids, digoxin, antibiotics, imidazoles, and cytotox-
ics, can cause nausea and vomiting by acting on the CTZ, whereas
nonsteroidal anti-inflammatory drugs (NSAIDs), iron supple-
ments, antibiotics, and tranexamic acid may damage gastric
mucosa. Opioids, tricyclics, phenothiazines, and anticholinergics
induce gastric stasis. Finally, selective serotonin reuptake inhibi-
tors and cytotoxic drugs may induce 5-HT3 receptor stimulation.
Uncontrolled pain per se may be a cause of nausea and vomiting.
Inquiries about weight loss, appetite, anorexia, and/or cachexia
should be made in order to further assess the nature of the nausea
and emesis and provide insights into their possible etiology. 3,14
In patients with neurological diseases such as diabetic neu-
ropathy, or with advanced cancer, autonomic failure occurs with
gastroparesis, nausea, vomiting, and constipation. Movement-
related nausea with vomiting suggests either vestibular dys-
function or mesenteric traction. Nausea increasing with head
motion, with tinnitus, decreased hearing, or skull tenderness is
suggestive of vestibular involvement due to drug toxicity and
local lesions. The presence of vertigo may be helpful in distin-
guishing the two conditions. Candidal infection may produce
pharyngeal irritation, activating the afferent arm of the vom-
iting circuit via the vagus nerve and should be suspected in
patients taking steroids.
Emesis produced with cough occurs at the end or during a
coughing paroxysm and is associated with chronic pulmonary
disease, esophageal fistulas, and brain metastases. A neuro-
logic examination should be performed to assess the presence of
neurologic signs suggestive of elevated intracranial pressure or
central nervous system metastases. Vertigo and nystagmus are
typical symptoms of a labyrinthitis or other causes of vestibular
dysfunction. Morning vomiting, sometime projectile, associ-
ated with cognitive changes or neurological deficits may be due
to brain tumors or secondaries. Papilledema may be a possible
associated sign. Neck stiffness and headache may be signs of
underlying meningitis. Computed tomography (CT) or magnetic
resonance imaging can confirm the diagnosis. Nausea produced
by hyperglycemia or hypercalcemia is associated with poly-
uria and polydipsia. Patients treated for prolonged periods with
359
steroids for chronic neurological disease may develop Addison
disease after abrupt suspension of medication. 3
Vomiting that occurs after ingesting food is of diagnostic
importance. Patients with gastric outlet obstruction or gastric
atony often will complain of vomiting several hours after eating.
In contrast, patients who vomit as a result of viral gastroenteritis
or psychogenic causes are usually symptomatic in the immedi-
ate postprandial period. Appropriate screening tests include a
biochemistry profile consisting of electrolytes, blood urea nitro-
gen, creatinine, glucose, albumin, and calcium. In patients tak-
ing digoxin or anticonvulsants, the plasma drug levels should be
considered. A pattern of infrequent large-volume vomitus that
relieves nausea suggests a partial bowel obstruction. Abdominal
examination and an abdominal X-ray are helpful to screen for
situations involving sub-obstruction. Abdominal CT and ultra-
sound may be required to complete the investigation. Emotional
experience may trigger psychogenic vomiting.5
Specific conditions associated with vomiting
Chemotherapy-induced nausea and vomiting
Chemotherapy-induced nausea and vomiting is one of the most
feared effects of cancer treatment and is associated with a sig-
nificant deterioration in quality of life. These symptoms also may
result in nonadherence to or dose reductions in chemotherapy.2
Five categories are used to classify this phenomenon: acute,
delayed, anticipatory, breakthrough, and refractory (Box 38.3).
There are different levels of emetic potential of chemotherapeutic
agents. The emetogenic potential is high, in nearly all patients,
with cisplatin, dacarbazine, melphalan in high doses, and nitro-
gen mustard.7 A preemptive treatment with antiemetics is man-
datory for the highest levels.
The incidence of acute emesis, occurring in the first 24 hours after
chemotherapy, reflects several treatment-related factors, includ-
ing the environment in which chemotherapy is administered, the
emetogenicity of and doses of drugs administered, and patient-
related factors. Delayed emesis develops more than 24 hours after
chemotherapy administration. Delayed emesis is more common in
patients who experienced acute emesis and typically occurs after
carboplatin, doxorubicin or cyclophosphamide. For cisplatin, emesis
reaches peak intensity 2–3 days and can last up to a week. Vomiting
that occurs within 5 days after prophylactic use of antiemetic agents
or requires a rescue medication is called breakthrough emesis.
BOX 38.3  CLASSIFICATION OF CINV
CATEGORIES
Type of CINV characteristics
Acute  occurs and resolves within 24 hours.
Peak 5–6 hours
Delayed occurs 1–5 days after cisplatin, carbo-
platin, cyclophosphamide, doxorubicin
Breakthrough acute or delayed, occurs despite pro-
phylactic antiemesis, needs rescue
medication
Anticipatory occurs before chemotherapy
Refractory occurs during chemotherapy, failed pro-
phylaxis and rescue therapy in previous
cycles
360
BOX 38.4  PHARMACOLOGIC AGENTS FOR CINV
• Serotonin receptor antagonists (5-HT3)
Ondansetron, granisetron, palonosetron, polymer-
based granisetron
• Neurokinin-1 receptor antagonists (NK1)
Aprepitant, netupitant, rolapitant, IV aprepitant
• 5-HT/NK1 combination
Netupitant/palonosetron
• Corticosteroids
• Olanzapine
Neurotransmitters, such as dopamine, acetylcholine, hista-
mine, and serotonin, are involved in the emetogenic pathways
stimulated by chemotherapy and radiation. It has been suggested
that chemotherapy causes release of serotonin from enterochro-
maffin cells of the GI tract, which then stimulates emesis via both
the vagus and greater splanchnic nerve as well as stimulating the
area postrema of the brain, which is rich in serotonin receptors.
Thus, serotonin receptors, both central and peripheral, are par-
ticularly important in the pathophysiology of acute emesis, and
drugs that inhibit this group of receptors are the cornerstone of
the prevention and treatment of chemotherapy-related nausea
and vomiting. Contributing factors include emetogenic potential
of the chemotherapy drug combination, dosages, route, time of
day, and length of administration, other therapies, anxiety, previ-
ous episodes, sex, and age.
The antiemetics guidelines of the various national and inter-
national societies have very specific recommendations for the
antiemetic agents that should be used to prevent CINV; these
are based on the emetogenicity of the specific chemotherapeu-
tic agent being given. Box 38.4 lists the various pharmacologic
agents recommended for the prevention of CINV. For patients
receiving highly emetogenic chemotherapy, recommenda-
tions are to use a neurokinin-1 (NK1) receptor antagonist, a
5-hydroxytryptamine type 3 (5-HT3) receptor antagonist, and
dexamethasone; for patients receiving moderately emetogenic
chemotherapy, a 5-HT3 receptor antagonist or dexamethasone
is recommended. 2
Serotonin receptors, both central and peripheral, are par-
ticularly important in the pathophysiology of acute emesis
and drugs that target this group of receptors underpin the
prevention and treatment of chemotherapy-related nausea and
vomiting.
Several 5-HT3 antagonists are commercially available,
including ondansetron, granisetron, tropisetron, dolasetron,
and palonosetron. Many randomized controlled trials have
demonstrated that these agents have equivalent antiemetic
activity and safety at the recommended doses, despite differ-
ences in structure and pharmacokinetic profiles, both orally
and intravenously, due to their good bioavailability following
oral administration. These drugs are well tolerated, and cen-
tral adverse effects are not commonly observed with serotonin
antagonists, unless for constipation which may be of concern
in advanced cancer patients. Palonosetron, compared with
older 5-HT3 receptor antagonists, has a higher potency and a
significantly longer half-life. It is used in a single dose of 0.25
mg for the prevention of acute and delayed nausea and vom-
iting associated with initial and repeat courses of moderately
and highly emetogenic cancer chemotherapy.6 Neurokinin-1
Textbook of Palliative Medicine and Supportive Care
receptor antagonists inhibit the effects of substance P on the
nucleus tractus solitarius.
These agents have been successful in preventing emesis in the
majority of patients. However, they have not been effective in
preventing nausea.15 It seems that neither the serotonin nor the
substance P receptors may have a relevant role in mediating nau-
sea.16 More recently, the addition of olanzapine to an antiemetic
prophylactic regimen has demonstrated very good control of both
emesis and nausea in patients receiving either moderately emeto-
genic or highly emetogenic chemotherapy.17,18 Thus, olanzapine is
recommended in various national and international guidelines
for the prevention of CINV in patients receiving highly emeto-
genic chemotherapy.19 The role of complementary and alterna-
tive therapies for the prevention of CINV remains limited by
the insufficient evidence a recommendation for or against the
use of ginger, acupuncture/acupressure, and other treatments. If
vomiting occurs in subsequent chemotherapy cycles when anti-
emetic prophylaxis and rescue have failed in earlier cycles, it is
known as refractory emesis. In these circumstances, a change in
the prophylactic antiemetic regimen should be considered. If the
patient is receiving highly emetogenic chemotherapy, olanzapine
(days 1–4) may be added to a prophylactic regimen of a 5-HT3
receptor antagonist, an NK1 receptor antagonist, and dexametha-
sone or can be substituted for an NK1 receptor antagonist in com-
bination with a 5-HT3 receptor antagonist and dexamethasone.
If the patient is receiving moderately emetogenic chemotherapy,
an NK1 receptor antagonist may be added to an antiemetic regi-
men of palonosetron and dexamethasone. Patients who develop
nausea or vomiting post-chemotherapy after 1–5 days despite
adequate prophylaxis should be considered for treatment with a
regimen of 3 days of oral or sublingual olanzapine or oral meto-
clopramide. Oral olanzapine was significantly more effective
than oral metoclopramide at controlling both emesis and nausea
in patients receiving highly emetogenic chemotherapy who devel-
oped breakthrough CINV, despite guideline-directed prophylac-
tic antiemesis.15,16
Phenothiazines, metoclopramide, dexamethasone, or olan-
zapine may be effective in the treatment of breakthrough nau-
sea and vomiting. It is very unlikely that breakthrough nausea
and vomiting will respond to an agent in the same drug class
as one that has been used unsuccessfully for prophylaxis. NK1
receptor antagonists, approved as an additive agent along with a
5-HT3 receptor antagonist and dexamethasone for the preven-
tion of CINV, should not be used to treat breakthrough nausea
and vomiting.
Finally, anticipatory nausea and vomiting occurs on the day
or some hours before the expected chemotherapy, and often
symptoms present in particular conditions, such as talking
or thinking about the treatment. It affects a third of patients
attending for chemotherapy. A psychological mechanism of
association is probable and is strongly related to the intensity
of adverse effects associated with the previous chemotherapy
and the number of treatments received. Younger age, expec-
tation, and motion sickness are well-recognized risk factors
for developing anticipatory nausea and vomiting, probably
due to the higher doses used and anxiety. If anxiety is thought
to be a major factor in the CINV, a benzodiazepine such as
lorazepam or alprazolam can be added to the prophylactic
regimen.
There is uncertainty whether cannabis, including extracts
and tinctures, compared with placebo or other antiemetic drugs
reduces nausea and vomiting in patients with cancer requiring
Nausea/vomiting
chemotherapy, although the confidence in the estimate of the
effect was low or very low. In the included studies, many adverse
events were reported and none of the studies assessed the devel-
opment of abuse or dependence.20
Disorders affecting the central nervous system
There are many chronic neurological diseases that may produce
disturbances in central control of gut motility, resulting in GI
syndromes, such as vomiting or intestinal pseudo-obstruction
with or without gastric stasis.
Spinal cord lesions above T5 may isolate the spinal sympathetic
control from the influence of high centers, resulting in a delayed
gastric emptying and delay in duodenal progression. In cases of
long-term loss of function, patients who develop quadriplegia are
more likely to have gut complications than those with paraplegia.
The incidence of gastroesophageal reflux is increased and gastric
emptying impaired. Chronic constipation may worsen the clini-
cal picture possibly facilitating the development of nausea and
vomiting. Neuropathies are frequently encountered in patients
with cancer. 3
Autonomic failure
Autonomic failure is common in advanced cancer patients
with a poor performance status and is often associated with
anorexia–cachexia syndrome. The mechanisms are multifacto-
rial, including tumor invasion of nervous tissue, malnutrition,
damage from chemotherapy or radiotherapy, drugs, and preex-
isting disease. 3
Other disorders may affect the extrinsic GI innervation. There
is evidence that vagal autonomic neuropathy may be responsible
for gastric motor disturbances in diabetic patients with gastro-
paresis. Peripheral neuropathy, manifestations of autonomic
neuropathy, with bladder dysfunction, sweat disorder, ortho-
static hypotension, impotence, nephropathy, and retinopathy,
are frequently found, as gastroparesis is commonly reported in
patients with long-standing, insulin-dependent poorly controlled
diabetes. Other neurological diseases, such as dystrophia myo-
tonica and progressive muscular dystrophy, amyloidosis, collagen
vascular diseases, and autoimmune neurological diseases, are
associated with dysfunction of parietal structures of the GI tract,
inducing intestinal dysmotility, which can precipitate nausea and
vomiting. Radiation injury is another important cause of GI dys-
motility. Early vomiting is probably due to direct mucosal injury,
whereas late vomiting and GI stasis may be related to radiation-
induced inflammation or strictures. Significant GI disturbances
may be associated with thyroid and parathyroid disorders.
Intestinal pseudo-obstruction may develop both in hyperthyroid-
ism and hypothyroidism. The role of GI hormones in disorders of
upper intestinal motility remains unclear.
Drug-induced nausea and vomiting
Many substances may induce nausea and vomiting. Adrenergic
agents, such as β-agonists, generally delay gastric emptying,
whereas b blockers enhance gastric emptying. Clonidine, an α2
agonist, may induce nausea and vomiting. Anticholinergic agents,
such as some tricyclic antidepressants, inhibit contractile activity
and delay gastric emptying.
Dopamine agonists, opioids, digitalis, and chemotherapeutic
agents such as cisplatin remain the major offenders. Opioids have
central and peripheral actions. Centrally, they may stimulate the
emetic center via D2 receptors of the CTZ, richly distributed in
the area postrema. In addition, they induce a relevant delay in
gastric emptying and a delay in intestinal transit. Nausea occurs
361
when there is relaxation of the esophageal sphincter tone, delayed
gastric emptying, and poor duodenum motility. The narcotic
bowel syndrome is characterized by a picture similar to pseudo-
obstruction NSAIDs may induce nausea and vomiting by damag-
ing gastric mucosa and activating peripheral ascending impulses.
A central effect of alcohol on the CTZ has been recognized,
other than the well-known consequence of damage to the gastric
mucosa.11,21
Treatment of nausea and vomiting in
advanced cancer or non-cancer patients
Long periods or repeated episodes of vomiting can lead to dehy-
dration. To avoid this, it is important to replace fluids lost through
vomiting. In some circumstances, it is necessary to administer
fluids and drugs by the parenteral route, either subcutaneously or
intravenously. Treating any identifiable cause of nausea and vom-
iting is the first step. Reversible causes include hypercalcemia,
hyperglycemia, hypocortisolism, hyponatremia, uremia, obsti-
pation, and increased intracranial pressure. Bisphosphonates for
hypercalcemia and dexamethasone for intracranial tumors are
the first-line treatments in these specific conditions. Identifiable
offending drugs should be stopped. A range of environmental
and psychological factors contribute to the experience of nau-
sea. A calm and reassuring environment may be useful, avoiding
exposure to foods precipitating nausea. Control of malodor from
decubitus ulcers is mandatory. Behavioral techniques, relaxation
exercises, and benzodiazepines may be helpful for anticipatory
nausea.
Generally, widely accepted management guidelines are not
available, except for the treatment of nausea and vomiting associ-
ated with chemotherapy (see previously).
The pharmacological treatment of nausea and vomiting in the
palliative care setting does not have solid data to provide specific
recommendations. The fact that different agents cause nausea
and vomiting by different mechanisms prompted researchers
to develop regimens with multiple drugs with different mecha-
nisms of action. Although the mechanism considered to play
the predominant role in the induction of nausea and vomiting is
the activation of the CTZ, GI stimulation or damage, vestibular
and cortical mechanisms, or alterations of taste and smell may
equally contribute in different ways in producing these symptoms
(see Figure 38.1).6,9,10,21,22
Many classes of medication have been used as antiemetics. If
vomiting prevents drug absorption, a non-oral route should be
used at first. Patients should be reevaluated at regular intervals
to optimize the dose or to switch drugs. The choice of medication
depends upon drug receptor selectivity and drug interactions, as
patients are frequently receiving several medications that poten-
tially interact with or antagonize the antiemetics. The afferent
pathway involved and the group of antiemetics that antagonize
the involved neuroreceptors are key factors that influence the
choice of the first drug, i.e., a mechanistic approach should be the
basis for choosing first-line antiemetic drugs. The sites and pos-
sible receptor mechanisms of the principal antiemetic drugs are
listed in Table 38.1.
An important principle is to use combinations of antiemetics
with different modes of action, 3,6,9,21,22 primarily based on starting
with a metoclopramide regimen. On the other hand, antiemet-
ics may have specific adverse effects in patients with neurological
diseases. Moreover, anticholinergic medications may antagonize
362 Textbook of Palliative Medicine and Supportive Care

FIGURE 38.1  Emetogenic pathway and receptors involved: AchM = muscarinic acetylcholine, D2 = dopamine 2, H1 =histamine 1,
NK1 = neurochinin 1, 5-HT2-5-HT3 = 5 hydroxytryptamine 2 and 3, mu = opioid mu.

the prokinetic effects of drugs acting via the cholinergic system
in the myenteric plexus.
In a systematic review of the efficacy of antiemetics in the
treatment of nausea in patients with terminal cancer, uncon-
trolled studies had high response rates (75–93%) to standard
regimens, whereas randomized controlled trials reported much
lower response rates (23–36% for nausea, 18–52% for vomiting),
regardless of an empirical or a more selective clinical approach.22
Antiemetic drugs are commonly grouped into five categories,
including prokinetic agents, dopamine antagonists, antihista-
mines, anticholinergics, and serotonin antagonists. However,
most of them are broad agents working at multiple receptor sites.
Moreover, there are novel and old drugs not included in these
groups, such as corticosteroids, cannabinoids, benzodiazepines,
and neurokinin-1 receptor antagonists.
Prokinetic agents
The prokinetic agents activate 5-HT4 receptors and antago-
nize 5-HT3 receptors and D2 receptors, favoring acetylcholine
release from myenteric plexus neurons in the upper GI tract.
Metoclopramide, in addition to its recognized dopamine antago-
nist action, also has a weak serotonin antagonist activity and can
stimulate GI motility by increasing acetylcholine release, which
explains the potential for central adverse effects, such as extra-
pyramidal reactions. Metoclopramide enhances the transit of
the GI content, speeding gastric emptying, and decreasing small
intestinal transit time, probably by increasing cholinergic activity
through the activation of 5-HT4 receptors. In high doses, metoclo-
pramide also has 5-HT3 receptor antagonist activity. Although, in
the same studies, the efficacy was similar to that observed with
placebo,23 metoclopramide in doses of 60 mg daily has been found
to be quite effective in a cancer population with chronic nausea.
Three percent of patients required to switch to other antiemet-
ics because of extrapyramidal side effects.24 Controlled-release
metoclopramide 40 mg every 12 hours significantly reduced nau-
sea without producing the pertinent adverse effects in patients
with a history of cancer-associated dyspepsia syndrome.25
Metoclopramide use confers an increased risk for the initiation of
treatment generally reserved for the management of Parkinson’s
disease in patients with drug-induced extrapyramidal symptoms.
Domperidone, a D2 antagonist analogous of metoclopramide that
poorly crosses the blood–brain barrier, acts primarily on gastric
D2 receptors and D2 receptors in the CTZ, which are outside the
blood–brain barrier, facilitating gastric motor activity and emp-
tying. Extrapyramidal adverse effects are less likely because it
does not cross the blood–brain barrier.21
Dopamine antagonists
Typically, phenothiazines and butyrophenones are considered
the class of D2 antagonists. Haloperidol has a relatively narrow

TABLE 38.1  Receptor Site Affinities of Principal Antiemetics

Dopamine D2 Histamine H1 Acetylcholine
Antagonist Antagonist Antagonist 5-HT2 Antagonist 5–HT3 Antagonist 5–HT4 Agonist
Metoclopramide ++ + ++
Domperidone ++
Ondansetron +++
Cyclizine ++ ++
Hyoscine +++
Haloperidol +++
Prochlorperazine ++ +
Chlorpromazine ++ ++ +
Levomepromazine ++ +++ ++ +++
Abbreviation: 5-HT, 5-hydroxytryptamine.
Nausea/vomiting
spectrum and is a potent D2 antagonist with negligible anticho-
linergic activity so that it produces less sedation than phenothi-
azines but greater extrapyramidal reactions.21 Haloperidol has
been widely used in the management of nausea and vomiting
due to chemical or toxic causes, non-related to cancer treatment.
Despite the lack of evidence and the need for objective evaluation,
about half of patients are expected to have a benefit.26 Antiemetic
doses are lower than antipsychotic doses. It is less likely then phe-
nothiazines to cause sedation but causes more extrapyramidal
side effects.25
Phenothiazines possess a broader spectrum of activity with
dopaminergic, cholinergic, and histamine receptor antagonism.
Hypotension, sedation, decreased salivary flow are the main adverse
effects. Central and hemodynamic adverse effects are more likely
with major tranquilizers like chlorpromazine. Levomepromazine
is a phenothiazine closely related chemically to chlorpromazine.
Its proved analgesic properties make it unique among the phe-
nothiazines. It is efficacious and generally nonsedative in doses of
5–12.5 mg/day. It is a potent antagonist at 5-HT2, H1, D2, and a1-
receptors. Methotrimeprazine is a phenothiazine antipsychotic
used in palliative care for the management of terminal agitation and
nausea/vomiting. The administration of low-dose methotrime-
prazine proved to be useful in patients with advanced malignancy.26
Olanzapine, an atypical antipsychotic, possesses a unique neu-
rotransmitter binding profile that is similar to methotrimepra-
zine. It blocks multiple neurotransmitters, particularly at the D2
and 5-HT3 receptors. It has been shown to relieve nausea in some
patients with advanced cancer who fail to respond to the usual
antiemetics.27–29
Antihistamines
Drugs belonging to phenothiazine family, including promethazine
and cyclizine, have potential as antiemetics because they exert an H1
receptor antagonism in the VC of medulla, the vestibular nucleus,
and the CTZ, although they belong to. They also have an antimusca-
rinic effect, blocking the cholinergic receptors on intestinal smooth
muscles. Promethazine has been largely used for motion sickness
and vestibular disorders but may also be useful when nausea related
to raised intracranial pressure. The antiemetic dose of prometha-
zine is 25 mg orally or intravenously every 4–6 hours. Cyclizine has
more antimuscarinic activity, making it useful for bowel obstruction
as well as movement-related nausea.22 Cyclizine is effective in nau-
sea associated with motion sickness, pharyngeal stimulation, bowel
obstruction, and increased intracranial pressure. Drowsiness and
antimuscarinic effects are the main adverse effects.9
Anticholinergics
Hyoscine competitively inhibits the action of acetylcholine and
other muscarinic agonists. The primary indication of hyoscine is
motor sickness and labyrinthic disturbances. Because it relaxes
smooth muscle and reduces GI secretions via blockade of mus-
carinic receptors, it is also used for the management of GI symp-
toms in patients with inoperable bowel obstruction. Unlike the
other antimuscarinic agents, hyoscine produces central nervous
system depression in therapeutic doses—manifesting as drowsi-
ness, euphoria, amnesia, disorientation, restlessness, and hallu-
cinations.2 The anticholinergic effects of hyoscine are a potential
problem in the elderly. The butylbromide salt does not cross the
blood–brain barrier and is less sedating.21,22
Setron family
The effect of the setrons on the serotonin-mediated emetic
pathways may lend itself to the management of chronic nausea.
363
Ondansetron, a selective 5-HT3 antagonist, has been used in pal-
liative care setting in patients not responding to conventional
treatments. Although in a case series of patients with advanced
human immunodeficiency disease, the treatment was effective
and well tolerated, 30 in a controlled study, the efficacy of ondan-
setron at relatively large doses was similar to that reported with
placebo.23 Tropisetron-containing combinations or tropisetron
as a single agent is much more effective in the control of emesis in
patients with advanced cancer than the conventional antiemetic
combination of chlorpromazine plus dexamethasone. 31 Not being
antidopaminergic, setrons are potentially useful when the risk of
extrapyramidal reactions is high, such as in children or elderly
people who have neurological diseases with an extrapyramidal
component. They appear to have no effect on motion sickness. 32
Steroids
Dexamethasone has synergistic or additive antiemetic effects
combined with setrons, metoclopramide, or phenothiazines.
The mechanism remains unknown. The antiemetic actions of
dexamethasone are not well characterized, except for use in the
treatment of nausea and vomiting due to increased intracranial
pressure. Adverse effects include glucose intolerance, myopathy,
osteopenia, and infections.9,32
Cannabinoids
Cannabinoids have a low antiemetic efficacy. The mechanism of
the antiemetic effect of cannabinoids is unknown. It has been
hypothesized that an indirect inhibition of the VC in the medulla
occurs as a result of binding to opioid receptors in the forebrain.
Dronabinol has been used in diffuse metastatic disease in the GI
tract mucosa for intractable nausea and vomiting unresponsive
to conventional antiemetics. 33 Cannabinoids commonly used in
cyclic vomiting syndrome, due to its antiemetic and anxiolytic
properties, paradoxically have led to the recognition of a putative
new disorder called cannabinoid hyperemesis syndrome. 34
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39
CONSTIPATION

Charu Agrawal and Karina Shih

Contents
Introduction and prevalence������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������365
Definition����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������365
Assessment�������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������366
Treatment���������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������367
Bulk-forming agents���������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������367
Stool softeners��������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������368
Osmotic laxatives��������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������368
Stimulants���������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������368
Suppositories and enemas�����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������368
Biofeedback������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������368
Other pharmacologic interventions������������������������������������������������������������������������������������������������������������������������������������������������������������������������368
New medications���������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������368
Alternative therapies��������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������369
Recommendations for management�����������������������������������������������������������������������������������������������������������������������������������������������������������������������370
Diarrhea������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������370
Introduction, prevalence, definition������������������������������������������������������������������������������������������������������������������������������������������������������������������������370
Causes����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������370
Assessment�������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������371
Treatment���������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������372
General supportive care���������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������372
Symptomatic management����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������372
Other treatments���������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������372
References���������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������373

Introduction and prevalence
Constipation is a common symptom in the palliative commu-
nity that can exacerbate symptom burden and distress. It can be
due to idiopathic or functional causes as well as other medical
conditions, including their treatment. The median prevalence of
constipation has been found to be 16% in adults,1 and a system-
atic review found the prevalence in North America to be between
2 and 27%.2 In older adults, aged 60–101 years, the prevalence
is greater at 33.5%,1 and up to 50% of nursing home residents. 3
There are estimated 2.5 million physician visits and 100,000 hos-
pitalizations annually for the treatment of constipation result-
ing in significant cost for diagnostics and treatment.4 There is
an annual estimated expenditure of at least 800 million dollars
in the United States for laxatives. Constipation can negatively
impact the quality of life and is often minimized by physicians
and family.5 In a prospective study of hospice in patients taking
strong opioids, 87% required laxatives, while 74% on weak opi-
oids required laxatives.6 Less than half of patients on opioids find
acceptable response to laxatives greater than 50% of the time.7
Definition
Constipation is a clinical diagnosis characterized by stool infre-
quency, incomplete elimination of stool, or difficulty passing
stools. There can also be hard, lumpy, small stools accompanied
by abdominal discomfort, bloating, distention, and pain. Normal
stool frequency can be present with a minimum of 1 stool 3 times
per week or daily.8 Chronic constipation is defined using the
Rome IV criteria (Table 39.1),7,9 a study done in the United States,
United Kingdom, and Canada in adult gastroenterology clinic
patients. Diagnostic sensitivity was 72.2% (with excluding criteria
of irritable bowel syndrome [IBS] and opioid-induced constipa-
tion [OIC]), while specificity was 93.6%, and the diagnosis was
reproducible in 75% of patients.10
Functional constipation with normal transit is the most com-
mon type of constipation, characterized by normal stool fre-
quency but with hard stools.
Slow-transit constipation is defined as infrequent defecation
due to prolonged stool transit in the colon and can be a result of
neuropathic etiology, smooth muscle dysfunction, or both.
Secondary constipation can be due to medications, chronic ill-
nesses, mechanical obstruction, diet, or psychosocial factors.
Outlet constipation (pelvic floor dysfunction) is a result of
dyscoordination of pelvic floor muscles during evacuation or
functional resistance with high anal resting pressure, incomplete
relaxation of anal sphincter, anismus, dyssynergic defecation, or
structural pathology not due to muscle or neurologic pathology.11
Patients with outlet constipation often also have slow-transit
constipation. It is frequently accompanied by increased straining,
soft stools that are difficult to pass, rectal discomfort, and com-
mon need for manual aid to evacuate stool. Outlet constipation

365
366 Textbook of Palliative Medicine and Supportive Care

TABLE 39.1  Rome IV Criteria (See Further Reference [9])
It must have 3 months of symptoms.
It must have two or more of the following symptoms occurring more than
25% of defecations:
• Straining
• Hard stools
• Incomplete evacuation
• Anorectal obstruction or blockage
• Use of manual maneuver for defecation
• Less than three spontaneous bowel movements per week.
Loose stools are rare without laxatives.
It does not meet the criteria for IBS.
The criteria are fulfilled with symptom onset 6 months prior to diagnosis.
is treated with biofeedback relaxation and does not respond to
traditional medical treatment (see Table 39.2).9
Opioids are known to affect gastrointestinal (GI) motility and
secretion via suppression of neural activity. Opioids suppress for-
ward peristalsis, increase non-propulsive segmental contractions,
and raise anal sphincter tone and sphincter tone in both small and
large intestines. There is inhibition of peristaltic reflex by stimu-
lation of receptors along the enteric nervous system as well as
inhibiting postsynaptic acetylcholine receptors. As a result, there
is increased resting tone in circular muscles of the small and large
intestine. There is also an inhibitory effect on motor neurons at
the level of the submucosal plexus causing decreased secretion of
the intestines leading to hard stools.23 Opioids may also vary in
constipating severity possibly due to potency and dosage require-
ment differences to achieve analgesia. There have been reports
of reduction in laxative use after opioid rotation from morphine
to methadone at a lower morphine equivalent daily dose.24 Up to
40% of patients taking opioids for nonmalignant pain experience
constipation, and 90% of patients with malignant pain on opioids
experience constipation.
Assessment
Constipation can be associated with a variety of different causes.
Thus, beginning with a careful history is imperative. A thorough
medication list, including prescription drugs, over the counter
medications, and herbal supplements are important. A detailed
review of systems may elicit possible secondary constipation due
to other comorbidities and also complications of constipation
such as urinary retention from impaction, nausea and vomiting
from obstruction, or delirium.
The type of constipation a patient may be experiencing can be
assessed in context of self-reported history of bowel movements,
including frequency, pattern, characterization, including volume,
consistency, straining, sensation of incomplete emptying, medi-
cation use, or manual manipulation. There should be concern for
overflow diarrhea, liquid stool that leaks around a hard ball of
stool, when a patient has been constipated and then has diarrhea.
A thorough general physical exam is needed to elucidate etiol-
ogy of constipation and elicit any secondary causes of constipa-
tion as well. During the abdominal exam, it is important to assess
distention, tenderness, firmness, and at times a fecal mass may
be palpated in the left side of the abdomen (descending colon).

TABLE 39.2  Causes of Constipation1,2,7,12–15

Associated Conditions Neurologic Conditions Structural Abnormalities Medications
Chronic kidney disease Parkinson’s Pelvic floor dysfunction Antidepressants
Congestive heart failure Cerebrovascular Fecal impaction (5HT3 Antagonists
Chronic pain Disease Patulous anus and TCAs)
Bipolar disorder Dementia Rectal prolapse Antipsychotics
Schizophrenia Spinal cord injury Rectal intussusception Antispasmodics
Depression Sacral nerve pathology Obstructing sigmoidocele Antihistamines
Irritable bowel syndrome Lack of anal reflex Excessive perineal descent Anticonvulsants
Inflammatory bowel Autonomic neuropathy Malignancy related Antiparkinsonian
Disease Hirschsprung’s Mechanical obstruction Antacids
Diverticulosis Malignancy impacting nerves Anal fissure Sucralfate
Chagas disease Spinal ganglion tumors Sympathomimetics
Neural plexus invasion Opioids
Anti-emetics
Ganglionic blockers
Chemotherapy
Vinca alkaloids
Calcium supplements
Iron
Antihypertensives
(calcium channel
blockers and diuretics)
Metabolic Causes Motility Abnormalities Endocrine Conditions Diet
Hypokalemia Amyloidosis Hypothyroidism Anorexia
Hypercalcemia Scleroderma Hyperparathyroidism Dehydration
Hypomagnesemia Immobility Panhypopituitarism Low fiber intake
Diabetes mellitus Excess alcohol, caffeine, or dairy
Foods high in fat or sugar
Constipation
Auscultate for hyperactive or high-pitched sounds that may point
to obstruction, or loss of bowel sounds with ileus. A rectal exam is
helpful to look for hemorrhoids, fissures, tissue masses, prolapse,
assess sphincter tone (decreased tone may point toward neuro-
logical issues), and take the presence and consistency of stool in
vault. The presence of firm stool can indicate impaction, while the
absence of stool can indicate concern for obstruction or proximal
impaction. Asking patients to bear down can help evaluate for
anal dyssynergia. Lab tests such as complete blood count, com-
prehensive metabolic profile, and thyroid studies can assist when
there is concern for secondary causes.
Imaging with a plain abdominal X-ray to assess stool burden
throughout the colon and calculate a “constipation score” can be
helpful in confirming constipation, rule out obstruction, as well
as provide education for patients (Figure 39.1).
For those without a clear diagnosis who do not respond to
symptomatic therapy, there may be a need to refer to a GI special-
ist for advanced studies such as colonic transit studies, colonos-
copy, or manometry.
FIGURE 39.1  On a flat abdominal X-ray, draw two diagonal
lines intersecting at the umbilicus, as shown, transecting the
abdomen into four quadrants corresponding to the ascending,
transverse, descending, and rectosigmoid colons. Assess the
amount of stool in each of the four quadrants using the follow-
ing scoring system: 0, no stool; 1, stool occupying <50% of the
lumen of colon; and 3, stool completely occupying the lumen. The
total score will therefore range from 0 to 12; a score of 7 indicates
severe constipation and requires immediate intervention. (From
Reference [16] with permission.)
367
Constipation-specific instruments have also been developed
to help in evaluation. One of the most used tools is the Patient
Assessment of Constipation—Quality of Life questionnaire that
has been shown to be internally consistent, reproducible, valid,
and responsive to improvements over time.17 This makes the tool
especially valuable for tracking individual patients longitudi-
nally, but of limited value when comparing a group of patients
with constipation versus patients with IBS. In elderly patients
with constipation, the elderly bowel symptom questionnaire
may be more appropriate.18 In a study analyzing constipation in
advanced cancer patients, patient self-rating from 0 to 10, with a
score of 3 or greater, appeared to be a useful tool in screening for
constipation.19
Treatment
The primary focus of treating constipation is the relief of discom-
fort associated with constipation. The secondary focus should
then be achieving soft formed stool without straining with a
desired frequency for 3 times/week. Fecal impaction should also
be addressed.
Initial management should begin with patient education,
behavior modification, and dietary changes. Daily bowel move-
ments are not necessarily the norm and adequate fluid, and fiber
intake can play a role in assisting with healthy bowel movements.
Behavior adjustments such as taking advantage of the gastrocolic
reflex and toileting after meals can aid in alleviating constipa-
tion. Positioning can also make an impact on defecation such as
having a step stool to straighten the anorectal junction. Privacy
and adequate time are also important factors for a healthy envi-
ronment for bowel movements in the hospital setting. Avoiding
bedpans and encouraging activity can also play a role in manage-
ment. Dietary changes such as increasing fluid and adequate fiber
intake, 20–35 g/day, can assist in healthy bowel habits. However,
if there is a need for increasing fiber in the diet, this should be
done gradually and slowly over several weeks and ensuring ade-
quate fluid intake, otherwise bloating and flatulence may result
and lead to low compliance.8 Prunes have also shown to be effec-
tive in alleviating constipation, providing more spontaneous
bowel movements when compared with psyllium,20 and improv-
ing stool consistency. They have also been reported to be gener-
ally well tolerated.
For those who do not respond to initial management, or when
chronic symptoms persist, further laxatives may be needed. If
slow-transit constipation or outlet dysfunction is suspected, spe-
cialist referral may be necessary for further advanced workup of
anorectal function and colonic transit with possible need for sur-
gical intervention for slow-transit constipation.
Bulk-forming agents
Bulk-forming agents are made of synthetic polysaccharides
or cellulose derivatives and include fiber supplements such as
psyllium, methylcellulose, and polycarbophil. Their physiologic
action is a result of resistance to bacterial breakdown in the
gut increasing water absorption and propulsive activity as well
as bacterial proliferation that can contribute toward gas pro-
duction.7 The goal is to achieve softer, larger stools for easier
bowel movements. Adverse effects can include bloating and
gas. Caution is to be considered when prescribing bulk-forming
agents as they can worsen conditions in those with slow-transit
constipation, OIC, and anorectal dysfunction or those unable to
take in adequate fluids.
368
Stool softeners
Stool softeners include docusate and mineral oil and work by low-
ering the surface tension of stool, increasing water in the bowel
to lubricate and soften stools. It is sometimes used in situations
of anal fissure and hemorrhoids. However, in a recent review,
docusate was shown to be no better than placebo in decreas-
ing symptoms of constipation.9 Furthermore, caution should be
taken when prescribing docusate in situations where patients are
unable to increase fluid intake that can lead to further cramp-
ing and inability to produce a bowel movement, OIC, and slow-
transit constipation. Adverse toxicity can occur as docusate can
increase GI or hepatic uptake of other medications. Mineral oil is
advised to be avoided in those with aspiration risk, chronic con-
stipation, and can contribute to stool softener toxicity. There is
also concern for inability to absorb fat-soluble vitamins and peri-
anal irritation with use.
Osmotic laxatives
Osmotic laxatives include polyethylene glycol (PEG) powdered
preparation without electrolytes, PEG electrolyte solutions
(such as GoLYTELY), lactulose, sorbitol (synthetic disaccha-
rides), magnesium citrate, and magnesium hydroxide. These act
via an osmotic effect in the intestinal lumen to increase water
remaining in the lumen for increased stool frequency. In a 2006
systematic review by the American Journal of Gastroenterology,
PEG has had good evidence for its use in constipation 20 and was
more effective and with fewer adverse effects than lactulose in
a meta-analysis of adults up to age 75.7 With sugar-based laxa-
tives, bloating and cramping as well as nausea can occur, with up
to 20% of patients observed with lactulose. Caution should also
be taken with magnesium-based osmotic agents due to potential
for magnesium toxicity with lethargy, hypotension, and respira-
tory depression. Excessive use of electrolyte-based osmotic laxa-
tives can be related to volume overload and should be avoided
in patients with CKD and CHF for the treatment of chronic
constipation.
Stimulants
Stimulant laxatives such as bisacodyl, senna, sodium picosulfate,
and glycerin work to increase intestinal motility and alter elec-
trolyte transport by intestinal mucosa and also to increase fluid
secretion in the bowel. These result in increased stool frequency,
and hopefully reduce symptoms. Due to the prokinetic effect,
stimulant laxatives can be helpful in OIC. It may be beneficial
to take 30 minutes after meals to augment the gastrocolic reflex
for increased effect. Adverse effects can include abdominal pain
and cramping. Melanosis coli is associated with senna laxatives,
and there is concern that prolonged use could damage the enteric
nervous system, but studies have not shown that to be the case.
However, the studies were conducted in patients that had use of
laxative for up to 4 weeks.9 There is also strong evidence that the
use of stimulant laxatives is safe and effective.1
Suppositories and enemas
Suppositories are effective for defecatory dysfunction via liquefy-
ing stools and relieving obstruction. Examples include glycerin
suppositories that are often safe and improve fecal emptying.
Bisacodyl suppositories are another example as well.
Enemas can help alleviate fecal impaction. Manual disim-
paction may be necessary first. Mineral oil enemas can help
soften stool and provide lubrication but can cause anal irrita-
tion. Phosphate enemas should be used with caution due to
hypotension, dehydration, and electrolyte disturbances such as
Textbook of Palliative Medicine and Supportive Care
hyperphosphatemia, potassium disturbances, hypocalcemia,
metabolic acidosis, and prolonged QT interval on EKG.
Biofeedback
Biofeedback is useful in dyssynergic defecation to address
dysfunctional contraction of the pelvic floor muscles and
external anal sphincter during defecation. Anorectal manom-
eters are used to monitor external anal sphincter pressures
and evaluate mental physical capability during defecation.
In a randomized control trial of 88 patients with obstructive
constipation, biofeedback-guided pelvic floor exercises were
found to be superior to PEG for symptom improvement at 6
months follow-up.7
Other pharmacologic interventions
Lubiprostone is FDA-approved for chronic constipation and
constipation-predominant IBS in females as well as OIC in non-
cancer patients. It is a prostaglandin E1 derivative and acts on
chloride channels to increase water into the intestinal lumen.
Adverse effects include headache and nausea in up to 30% of
patients in clinical trials.9
Linaclotide is a minimally absorbed peptide agonist at gua-
nylate cyclase-C receptors that stimulate fluid secretion in the
intestinal lumen resulting in increased motility used for chronic
constipation and IBS. Studies have shown increased frequency
of bowel movements and decreased abdominal pain.22 Adverse
effects include diarrhea.
Peripherally acting mu-opioid antagonists can be considered
when initial measures fail to provide relief. Peripherally acting
mu-opioid antagonists include medications such as methylnal-
trexone, alvimopan, and naloxegol. Naltrexone is also effective
but reverses analgesic effects due to systemic action. Peripherally
acting mu-opioid antagonists have been shown to be effective
for OIC for palliative care patients resistant to other laxatives.25
Naloxegol is approved for patients without cancer. Naloxegol is
made up of naltrexone conjugated with PEG to prevent cross-
ing the blood–brain barrier and avoid reducing centrally acting
opioid analgesia. Methylnaltrexone avoids crossing the blood–
brain barrier due to its methyl group. It is FDA-approved for
constipation in advanced illness in those whose laxatives have
not provided relief. However, it should be avoided in patients
with structural pathologies of the GI tract. It should be avoided
in patients with intestinal malignancy and contraindicated in
intestinal obstruction due to increased risk for bowel perfora-
tion. Alvimopan, although approved for short-term treatment for
post-op ileus, has restricted prescribing due to increased risk of
myocardial infarction.7
New medications
Other medications have recently been developed utilizing other
methods of action that would likely not be used by palliative care
without consultation from gastroenterology specialists.
Selective serotonin agonists (naronapride, prucalopride,
velusetrag) increase gut motility via the activation of submucosal
neurons by acetylcholine release.
Ileal bile acid transporter inhibitors (elobixibat) prevent
absorption of unconjugated bile salts in the distal ileum. Bile
acids then increase colonic secretion of water and electrolytes
through the activation of adenylate cyclase.
Plecanatide is an intestinal secretagogue that is a guanylate
cyclase-C receptor agonist that has a similar mechanism of action
to lubiprostone and linaclotide. They are approved for chronic
idiopathic constipation in adults when conservative therapies
Constipation 369

TABLE 39.3  Medications for the Treatment of Constipation1,7,9

Medication Common Dosage Time to Onset Comments
Bulk-forming agents Start low dose and increase gradually
(soluble fiber) and ensure adequate fluid intake. Side
effects include bloating and distention.
Methylcellulose 19 g daily 12–72 hours
Polycarbophil 1250 mg daily or 4 times a day 12–72 hours
Psyllium 1 tsp or 1 packet daily or 3 times a day 12–24 hours
Osmotic laxatives
Polyethylene glycol 17 g daily 24–48 hours Side effects include cramping and gas.
Lactulose 20 g daily 24–48 hours Side effects include bloating, distention,
and nausea.
Magnesium hydroxide 30–60 mL daily 30 minutes to 6 hours Caution with increasing doses and
magnesium toxicity.
Magnesium citrate 150–300 mL/day 30 minutes to 6 hours Caution with increasing doses due to
magnesium toxicity.
Sorbitol 30–150 mL once 24–48 hours Side effects include bloating, cramping,
nausea.
Stimulants
Bisacodyl 10 mg daily 6–10 hours Side effects include diarrhea and
abdominal pain.
Senna 17.2–34.4 mg 6–12 hours Side effects include abdominal pain.
Intestinal secretagogues
Lubiprostone 24 mg twice a day within 24 hours Side effects include nausea.
Linaclotide 145 µg daily Side effects include diarrhea. Take 30
minutes before the first meal.
Plecanatide 3–6 mg daily
Opioid receptor antagonists
Methylnaltrexone Subcutaneous injection, 8 mg for 30–60 minutes Avoid in patients with intestinal
weight 38–62 kg, 12 mg for weight malignancy, contraindicated in bowel
62–114 kg, 0.15 mg/kg/dose for obstruction due to increased risk of
weight <38 kg or >114 kg qod perforation.
Max 1 dose q24 hours.
Naloxegol 12.5–25 mg daily Take on empty stomach, 1 hour before
the first meal or 2 hours after the meal.
Common side effects include
abdominal pain, diarrhea, nausea, gas,
and headache.

have failed. Studies have shown improvement in pain, straining,
and frequency after 2 weeks of treatment.9
Sodium–hydrogen exchanger 3 transporter inhibitor, tena-
panor, increases sodium levels in the GI tract to increase fluid
volume and lead to increased luminal transit (see Table 39.3).9
Alternative therapies
Abdominal massage has been shown to increase GI motility and
secretions as well as relax sphincters and decrease GI transit time
and enhance rectal load sensation as well as discomfort in pal-
liative, elderly, spinal cord injury, and post-op ileus patients. A
prospective study showed effects were not immediate, but mas-
sage group after 8 weeks had decreased symptoms and increased
bowel movements versus control group of patients.26
There have been some reports of probiotics improving gut tran-
sit time, stool frequency, and consistency in functional constipa-
tion. A systematic review and meta-analysis evaluated 14 studies
of randomized control trials, but due to high heterogeneity and
risk of bias of individual studies, interpretation of the data is still
unclear. Subgroup analysis indicated that the positive effects may
be related in particular to Bifidobacterium lactis. Further studies
are still needed to determine species or strains, doses, frequency,
and duration of treatment for significant efficacy.27
Peppermint oil relaxes smooth muscles in the GI tract via cal-
cium channel inhibition to work as an antispasmodic. Dosages
of 450–900 mg daily divided into 2–3 doses over a period of
1–3 months have been shown to be effective.9 Gastroesophageal
reflux has been an observed side effect that has led to the develop-
ment of enteric-coated formulations to bypass the upper GI tract.28
There have been reports that acupuncture facilitates gastric
motility through parasympathetic activation of the distal colon
at certain acupoints.29 In patients with chronic severe functional
constipation, electroacupuncture was shown to be beneficial
when treated for 8 weeks and its effects persisted for a 12-week
follow-up period, when compared to sham acupuncture. There
is interest in this modality to treat constipation due to its last-
ing effects compared to laxatives, the therapeutic effects of which
stop when the medication is stopped. 30
370
Recommendations for management
In the palliative population, bulk-forming agents are not the pre-
ferred initial therapy for constipation as they can have difficulty
taking in adequate fluids that in turn can make their constipa-
tion worse on these medications. Also, oftentimes these patients
are suffering from slow-transit constipation or OIC, and again
bulk-forming agents can worsen their condition. Instead, it is
recommended to start with a stimulant laxative or an osmotic
laxative and titrate it until achieving a soft bowel movement with-
out straining. Using two medications from different classes is
commonly needed to achieve the desired effect, and these medi-
cations are titrated aggressively to avoid impaction or severe con-
stipation that can lead to complications such as delirium, pain,
and urinary retention.
If unable to produce bowel movements with oral medications,
rectal interventions such as suppositories, enemas, or manual
disimpaction may be needed.
Patients who require pain management with opioids should
be started simultaneously on a stimulant laxative and titrated
to prevent constipation. In the cases of OIC, opioid antagonists
such as methylnaltrexone may be considered, although caution is
advised if there is concern for intestinal obstruction.
Diarrhea
Introduction, prevalence, definition
Diarrhea, although less common than constipation in the pallia-
tive care population, is a cause of significant distress as well and
can cause significant illness with dehydration, electrolyte imbal-
ance, and malnutrition that can lead to compromise of wound
healing and immune function. Hypokalemia, metabolic acidosis,
and alteration of pharmacokinetics with drugs contribute toward
an array of negative consequences from diarrhea. It has been
known to occur in 7–10% of hospice patients31 and can be up to
50–80% of patients on certain chemotherapy (5-FU and irinote-
can), 32 and up to 27% of patients with HIV. 33
Diarrhea is defined as loose stools with increased frequency.
Diarrhea is considered when patients have more than three loose
stools in 24 hours,34 water content of greater than 75%, or increased
stool weight of greater than 200 g (average 50–200 g.31 However,
patients can also have a single large loose stool or frequent small
stools that are normal or hard in consistency and complain of diar-
rhea. Thus, careful assessment and history are important in dif-
ferentiating between constipation and diarrhea as overflow with
constipation can be mistaken for diarrhea as well. Stool weight
is also not as clinically helpful since passage of rectal mucus or
increased water content is common. Symptoms can also include
incontinence and urgency (see Table 39.4.).
Causes
Most often, diarrhea is acute and lasts only a few days as a result
of infections. When it is chronic, lasting over 3 weeks, there
may be underlying pathology and require further workup. In
the palliative care patient, a common cause is laxative imbal-
ance due to aggressive titration to address severe constipation.
TABLE 39.4  National Cancer Institute Toxicity Criteria35
Grade 0 1 2 3
Number of loose stools None 2–3/day 4–6/day moderate cramping nocturnal
above baseline stools
Textbook of Palliative Medicine and Supportive Care
This often resolves within 24–48 hours after temporary cessa-
tion of the laxative.
Chronic conditions associated with diarrhea include con-
ditions of disordered motility such as hyperthyroidism, dia-
betic autonomic neuropathy, and IBS. Inflammatory conditions
include ulcerative colitis, Crohn’s disease, and microscopic coli-
tis. Although infectious etiology is often acute, infections with
HIV or parasitic amebiasis lead to chronic diarrhea.
Common medications that can be related with diarrhea include
antibiotics, magnesium-containing antacids, sweeteners such as
sorbitol, and chemotherapy agents. Chemotherapy-induced diar-
rhea is related to epithelial necrosis and inflammation as well as
loss of absorptive surface and secretory cells. Known agents to
cause diarrhea include 5-fluorouracil, docetaxel, irinotecan, and
capecitabine. There is also targeted therapy associated with diar-
rhea that can be common among patients receiving treatment with
some having severe symptoms. This can be potentiated for patients
on a combination of cancer therapies leading to increased inci-
dence and higher grades of diarrhea.32 Radiation to the abdomen
and pelvis can be associated with diarrhea due to damage of the
intestinal mucosa and release of prostaglandins and malabsorption
of bile salts.34 Diarrhea related to radiation has a peak incidence
in the second or third week of therapy and can continue for sev-
eral weeks after completing therapy or become chronic. Opioid use
can also be related to alternating diarrhea and constipation as with
narcotic bowel syndrome with fecal impaction and leakage around
impacted stool. This can present with incontinence.
Tube feeds are also a common source of diarrhea and can occur
in up to 60% of patients receiving tube feeds.33 The composition of
the formula, osmolality, and feeding rate can all contribute toward
diarrhea. Contamination of tube feeds is also a contributing factor.
Infections are also a common cause of diarrhea, especially in
the immune compromised. For patients with altered normal gut
flora, Clostridioides difficile can propagate and be a cause of diar-
rhea in the setting of antibiotic use, repeated enemas, prolonged
nasogastric tube insertion, and GI tract surgery. There have been
reported cases of infection after chemotherapy without the use of
antibiotics. 34 AIDS-related diarrhea is most commonly caused by
cryptosporidium, cytomegalovirus, microsporidia, Giardia lam-
blia, and Mycobacterium avium–intracellulare. Other bacteria
related to diarrhea with AIDS also include shigella, salmonella, and
campylobacter. The frequency of infection can vary and depend
on the stage of disease. AIDS-related enteropathy without other
enteric infections can also be a cause of diarrhea. Neutropenic
enterocolitis is another cause of diarrhea that can carry high
mortality risk. 38 Broad-spectrum antibiotics are directed to
cover Pseudomonas, Staphylococcus aureus, Escherichia coli, and
Group A Streptococcus. Fungemia is also common in neutropenic
enterocolitis and should be considered especially when patients
do not respond to antibacterial treatment. 34
Malabsorption can occur in cancer of the head of the pancreas
due to reduced fat absorption and result in steatorrhea. Patients
who have undergone Whipple’s procedure or gastrectomy can
experience malabsorption as well. With ileal resection of over
100 cm, there is a decrease in reabsorption of bile acids that can
4
7–9 stools/day severe >10 stools/day parenteral
cramping incontinence support gross bloody stools
Constipation 371

TABLE 39.5  Causes of Diarrhea33,34

Motility Osmotic Inflammatory Secretory
Obstructive tumors Pancreatic insufficiency Infection Infection
Hyperthyroidism Hypoalbuminemia Invasive bacteria Viral
Diabetic autonomic neuropathy Celiac disease Ulcerative colitis Noninvasive bacteria
Irritable bowel syndrome Lactase insufficiency Crohn’s radiation therapy Protozoal
Postvagotomy diarrhea Small intestine bacterial overgrowth Graft versus host HIV
Celiac plexus blockade Dietary Chemotherapy Ulcerative colitis
Nonabsorbable sugars Microscopic colitis
Phosphate products Chemotherapy reactions
Magnesium products Neuroendocrine tumors
Tube feeds VIPomas
Chemotherapy reactions Gastrinomas
e.g., 5-FU Carcinoid
Radiation therapy

cause watery diarrhea. 39 There can also be carbohydrate mal- Assessment

absorption with ileal resection and result in osmotic diarrhea. A complete history should be obtained, including past medical
Colectomy can reduce water absorption and result in diarrhea as history, surgical history, travel history, sexual history, recent
well. Bacterial overgrowth can occur when patients have under- antibiotic use, and medication list. The complete review of sys-
gone various surgical procedures to intestines and cause malab- tems can be helpful in eliciting secondary causes of diarrhea such
sorption. Vagotomy also causes an increase fecal secretion of bile as hyperthyroidism. Special attention should be paid in identify-
acids in some patients and increases water and electrolyte secre- ing complications of diarrhea such as dehydration or symptoms
tion in the colon. Endocrine tumors can cause secretory diarrhea. of electrolyte imbalances.
Watery diarrhea with hypokalemia and achlorhydria can occur It is important to assess diarrhea in the context of a patient’s
with tumors of the adrenal glands, pancreatic islet cells, and self-reported history of bowel movements, including duration,
bronchogenic carcinomas. Gastrinomas and multiple endocrine frequency, volume, consistency, presence of greasy stools that
neoplasia type 1 are also related with diarrhea with Zollinger– float, malodor, nocturnal bowel movements, and presence of
Ellison syndrome. Increased vasoactive intestinal polypeptide blood or mucous. This can help guide the differential signifi-
(VIP) can also cause diarrhea such as in VIPoma and ganglioneu- cantly. Greasy stools that flat is concerning for fat malabsorption,
roblastoma. Carcinoid tumors cause diarrhea with the overpro- nocturnal diarrhea may indicate a secretory cause, and the pres-
duction of serotonin, prostaglandins, bradykinins, and VIP. ence of blood would be concerning for severe inflammation.
Malignancy related to intestinal obstruction and fecal impac- A general physical exam is needed, mostly to elicit secondary
tion or partial obstruction can have alternating diarrhea and causes of diarrhea and complications of diarrhea.
constipation. Abdominal exam should include palpation for masses, dis-
Celiac plexus block is another cause of diarrhea that results in tension, tenderness, firmness, and auscultation of bowel sounds
profuse watery diarrhea due to interruption of innervation of the pattern. A rectal exam can assess for structural anomalies or the
gut resulting in excessive bowel activity (see Tables 39.5 and 39.6.). presence of gross or microscopic blood.
Lab tests may not usually be needed unless there is a concern
for secondary causes. Accordingly, tests such as CBC, CMP,
TABLE 39.6 Causes of Diarrhea: Medications Commonly thyroid function, diabetic workup can be helpful. Further diag-
used in the Palliative Population34,36–38 nostic workup such as stool studies (fecal leukocytes, stool fat
Laxatives Chemotherapy quantification, stool cultures, fecal occult blood, stool osmotic
Antibiotics gap, ova, and parasites) are warranted in the cases of severe ill-
• 5-Fluorouracil ness such as fever, dehydration, presence of blood and/or mucus,
Antiretrovirals
• Irinotecan severe pain, hospitalization, concern for Clostridium difficile
Magnesium-containing antacids
• Capecitabine in the setting of antibiotic use, or in an immunocompromised
Metformin
• Docetaxel patient. Immunoassays for C. difficile toxins A and B are easy to
Levothyroxine
Statins perform and have results available in 2–4 hours. The specificity
Targeted therapy
Metoclopramide can be high, but sensitivity is lower. Diarrhea within 3 days of
NSAIDs • Erlotinib, gefitinib an inpatient admission may be due to acquired bacterial or viral
Mycophenolate • Sorafenib infection, and cultures for organisms such as Salmonella, E. coli,
Proton pump inhibitors • Sunitinib Campylobacter, and C. difficile can be sent, but after this point
Cholinesterase inhibitors • Imatinib diagnostic yield is of value. 39 CT imaging of the abdomen can
• Bortezomib sometimes provide further information as with the case of neu-
tropenic enterocolitis or tumor presence, and ultrasound evalu-
Immunotherapy ation of bowel wall thickness can also help provide prognostic
information.40
• Ipilimumab
For those without a clear diagnosis and do not respond to symp-
• Nivolumab
tomatic therapy, they may need to be referred to GI specialists for
372
advanced studies such as endoscopy, flexible sigmoidoscopy, and
colonoscopy.
Treatment
General supportive care
For mild acute symptoms, rehydration is the main focus and
oral route is more effective than intravenous. Replenishing elec-
trolytes should be a focus with proportional electrolyte concen-
tration solutions and include a glucose source to assist in active
electrolyte transport in the GI tract wall. It is helpful to start
on clear liquids with gradual incorporation of simple carbohy-
drates then eventually protein and fats thereafter as conditions
improve. Avoidance of dairy is helpful due to transient lactase
deficiency with some infections or following antibiotics.41 In the
case of antibiotics, when C. difficile has been ruled out, a course
of probiotics can be helpful in reestablishing normal gut flora
balance.
Symptomatic management
Opioid agonists
Loperamide is considered first-line therapy and has a duration of
action of 8–16 hours. It is given with initial dose of 4 mg and then
2 mg after each loose stool with a maximum of 16 mg per day. As a
mu receptor agonist, it reduces peristalsis in the colon, decreases
secretion in the GI tract, and increases anal sphincter tone. Both
loperamide and codeine have been shown to improve fecal incon-
tinence in patients with diarrhea. Diphenoxylate was less effec-
tive at doing so even with same stool frequencies. 33 Loperamide is
restricted to peripheral action and does not have centrally medi-
ated analgesic effects due to exclusion from the central nervous
system by active transport of the P-glycoprotein of the blood–
brain barrier. Diphenoxylate does cross the blood–brain barrier
and has a subtherapeutic atropine component to prevent aberrant
use but limits maximum dosage. Thus, loperamide is preferred
treatment of choice. Diphenoxylate is given with initial dose of 10
mg then 5 mg every 6 hours with a duration of 6–8 hours.
Somatostatin medications
For diarrhea that does not respond to loperamide, a somatosta-
tin long-acting synthetic such as octreotide can be very effective.
Native somatostatin has a short half and is produced in intesti-
nal D cells of the stomach, pancreas, and gut and acts on epithe-
lial receptors of the gut to block peristalsis and reduce gastric,
biliary, pancreatic, and small intestine secretions. It increases
electrolyte and water absorption through the inhibition of secre-
tion of insulin, glucagon, gastrin, peptide YY, neurotensin, VIP,
and substance P. Octreotide is dosed from 100 to 200 µg tid and
given subcutaneously but can also be provided as a continuous
subcutaneous infusion. Lanreotide is a much longer acting soma-
tostatin analog with dosing every 14 days predominantly used
for acromegaly, and in the palliative care, a population may be
less effective due to continually changing clinical conditions of
patients. 33 Octreotide has been proven to be effective in chemo-
therapy-induced diarrhea, radiotherapy-related diarrhea, and
graft versus host disease.
Specific conditions
Diarrhea that is able to be attributed to specific etiologies war-
rants the treatment of the underlying conditions. Acute diarrhea
where infections are suspected, and patient is immunocompro-
mised, elderly, and prone to opportunistic infections, may need
broad-spectrum coverage and coverage of fungemia. However,
Textbook of Palliative Medicine and Supportive Care
antibiotics should be reserved for these situations and those with
moderate-to-severe and invasive diarrhea. Antibiotics should be
avoided in enterotoxigenic E. coli due to increased risk for hemo-
lytic uremic syndrome. Common symptoms that suggest entero-
toxigenic E. coli include bloody stool with abdominal pain but no
significant fever. Metronidazole is treatment of choice for C. dif-
ficile and also effective in bacterial overgrowth.
Cholestyramine is useful in the cases of ileal resection and
chologenic diarrhea when there is a lack of ability to reabsorb bile
acids. Cholestyramine acts as a bile acid–binding resin.
In the cases of pancreatic insufficiency, such as with pancreatic
cancers of the head of the pancreas, pancreatic enzymes, includ-
ing amylase, lipase, and protease, may need replacement. This
may be more effective in situations where gastric acidity is also
reduced with H2-receptor antagonists. Enteric-coated formula-
tions should thus be avoided.
Carcinoid tumors respond to serotonin antagonists such as
methysergide and cyproheptadine, but cyproheptadine is pre-
ferred due to toxic side effects such as retroperitoneal fibrosis
and cardiac valve dysfunction with methysergide. They are
effective against severe diarrhea and possibly malabsorption.
Somatostatin analogues are also effective in situations of carci-
noid tumors as well.
Chemotherapy- and radiation
therapy–induced diarrhea
Uncomplicated grade 1–2 diarrhea is treated with oral hydration
and loperamide (4 mg initially and 2 mg every 4 hours thereaf-
ter). There should be elimination of dairy as well. Diet should
be gradually advanced after diarrhea resolves, and loperamide
should be continued until the patient is free of diarrhea for
12 hours. 32 In patients in whom diarrhea does not resolve after
24 hours, loperamide doses may be increased to 2 mg every
2 hours, and prophylactic oral antibiotics may be necessary.
However, if patients do not respond to high-dose loperamide after
24 hours, patient follow-up with their physician office is necessary
for further evaluation and started on octreotide.
Complicated diarrhea is characterized by mild-to-moderate
diarrhea but accompanied by moderate-to-severe cramping, nau-
sea, vomiting, worsened performance status, fever, sepsis, blood
in stools, dehydration, neutropenia, or severe diarrhea. These
patients need hospitalization and require IV hydration, octreo-
tide, and antibiotics in addition to thorough evaluation of under-
lying cause. Loperamide should also be stopped.
In radiation-induced diarrhea, cholestyramine and aspirin can
be effective. 34 Chronic radiotherapy-related diarrhea can also
benefit from opioid antidiarrheals, but not in those with obstruc-
tion and there may be a need for antibiotics for bacterial over-
growth that can be evaluated with breath test.
Other treatments
Prostaglandin inhibitors include aspirin, mesalazine, bismuth
subsalicylate, and COX-2 inhibitors. These work to reduce secre-
tions caused by prostaglandin increased intestinal water and
electrolyte secretion. Bismuth subsalicylate is also said to have a
direct antimicrobial effect on enterotoxigenic E. coli. Mesalazine
is used in patients with ulcerative colitis. Bismuth, however, can
produce toxic blood salicylate levels in higher doses. COX-2
inhibitors may be beneficial in alleviating chemotherapy-induced
diarrhea related to reducing PGE2 levels, but more studies are
needed to show significant benefit.42
Constipation
KEY LEARNING POINTS
• Constipation can be a significant cause of distress in
the palliative care population that can be related to
nausea, delirium, urinary obstruction, and anorexia
that can contribute toward increasing health-care
costs by way of health-care system visits and medi-
cations and diagnostics and procedures.
• Multiple etiologies can contribute toward con-
stipation from normal transit to slow transit, or
outlet dysfunction constipation as well as a variety
of secondary causes. A combination of outlet dys-
function as well as slow transit is possible as well.
Hence, underdiagnosis thus still occurs despite
different tools for screening constipation leading
to untreated suffering and impact on quality of life.
• Despite patient education, dietary changes, bulk-
forming laxatives, and behavior modification,
patients often still need laxatives that require
assessment with careful history and exam and
titration of doses with attention to the individual
and their success response as well as the develop-
ment of adverse effects.
• If constipation is still refractory to osmotic
laxatives, stimulant laxatives, or stool soften-
ers, patients may need more aggressive means,
including suppositories or enemas.
• Warm water enemas are suggested over sodium
phosphate enemas due to risk of hypotension,
volume depletion, hyperphosphatemia, hypo- or
hyperkalemia, metabolic acidosis or hypocalce-
mia, and renal failure. Polyethylene glycol has
been shown to be more effective than lactulose
and with fewer adverse effects.
• Opioid administration needs to be accompanied
by prophylactic laxative regimen to prevent fur-
ther symptom burden.
• Constipation may present with atypical symp-
toms such as nausea, abdominal distention,
overflow diarrhea, or acute intestinal pseudo-
obstruction such as Ogilvie’s syndrome.
• Opioid antagonists such as methylnaltrexone
and naloxegol are FDA-approved for the treat-
ment of opioid-induced constipation in patients
with advanced illness. However, they are contra-
indicated in patients with bowel obstruction, and
caution is advised with those at risk of GI perfo-
ration due to concomitant illness or medications
related to perforation.
• Diarrhea can be a cause of significant distress and
malnutrition, and in severe cases with some can-
cer therapies, a cause of increased mortality.
• It is important to be vigilant in identifying cases
of severe diarrhea especially in the cancer treat-
ment patient population.
• Loperamide is a first-line agent that can help alle-
viate symptoms.
• For more severe cases and in a variety of situa-
tions, octreotide can be effective in helping to
treat diarrhea.
373
Probiotics include nonpathogenic microorganisms, including
Lactobacillus rhamnosus, Lactobacillus acidophilus, and bifido-
bacterium. The proposed mechanism of action includes providing
a protective physical barrier from infectious bacteria and degrad-
ing carcinogens and producing anti-inflammatory effects on bowel
mucosa.42 Some trials have seen decreased abdominal discomfort
and reduction in grade 3–4 diarrhea. However, further studies are
still needed to establish evidence that they can be effective, and
caution is needed in immunocompromised patients due to con-
cerns about severe infections and sepsis resulting from probiotics.42
Hange-shashin-to (TJ-14) is a Japanese herbal treatment pre-
pared from seven different medicinal herbs and generally pre-
scribed to treat GI diseases such as diarrhea and gastroenteritis in
Japan.43 It contains baicalin, a beta-glucuronidase inhibitor and
has been studied as an antidiarrheal with irinotecan where its
active metabolite is the cause of diarrhea when microflora in the
intestine inhibit metabolization and biliary excretion.43 TJ-14 has
been seen in some studies to reduce grade of diarrhea and lower
incidence of higher grades.42 However, further studies are still
needed to contribute toward more evidence in this treatment.
Palifermin is a recombinant form of human keratinocyte growth
factor (KGF) that has been approved to reduce the incidence and
duration of severe oral mucositis in patients with hematologic
malignancies who are on myelotoxic therapy requiring hemato-
poietic stem-cell support42 and also been studied in patients with
metastatic colorectal cancer. There have also been some studies
looking into its use as an antidiarrheal, as the binding of KGF to
receptor cells results in proliferation and differentiation of epithe-
lial cells in multiple tissues, including stomach and small intestine.
However, further studies are needed for efficacy and common
adverse reactions include rash and erythema and reversible tongue
thickening, discoloration, and alteration of taste.44
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(Japanese herbal medicine TJ-14) on tolerability of irinotecan: pro-
pensity score and instrumental variable analyses. J. Clin. Med
2018;7(9):246.
44. Rosen LS, Abdi E, Davis ID, et al. Palifermin reduces the inci-
dence of oral mucositis in patients with metastatic colorectal can-
cer treated with fluorouracil-based chemotherapy. J Clin Oncol
2006;24(33):5194–5200.
40
JAUNDICE

Nathan I. Cherny

Contents
Generalized hepatic dysfunction�����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������375
Biliary obstruction������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������376
Clinical presentation��������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������376
Investigation�����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������376
Diagnostic evaluation�������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������376
Blood tests���������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������376
Imaging studies������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������376
Management of biliary obstruction�������������������������������������������������������������������������������������������������������������������������������������������������������������������������������377
Symptomatic management����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������377
Surgical management and Stents�����������������������������������������������������������������������������������������������������������������������������������������������������������������������������377
Endoscopic biliary stent���������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������377
Percutaneous transhepatic cholangiographic (PTC) drainage��������������������������������������������������������������������������������������������������������������������������378
Endoscopic ultrasound–guided biliary drainage��������������������������������������������������������������������������������������������������������������������������������������������������378
Special case: obstruction at the bifurcation of the hepatic ducts����������������������������������������������������������������������������������������������������������������������378
Cholestatic itch (pruritus)�����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������378
Pathogenesis�����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������378
Management����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������378
Anion-exchange resins�����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������378
Rifampicin���������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������379
Opioid antagonists������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������379
Sertraline�����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������379
Medications with limited evidence of benefit�������������������������������������������������������������������������������������������������������������������������������������������������379
General measures��������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������379
References���������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������379

In developed countries, jaundice in patients with terminal ill-
ness is most commonly encountered in advanced malignancy.
In this setting, it is generally caused by obstruction of biliary
drainage, extensive hepatocellular failure due to liver infiltration
by metastases, or a combination of both. Indeed, cancer-related
jaundice is one of the most common causes of severe jaundice; in
a series from Sweden, it accounted for 58 of 173 sequential cases.1
In developing countries, it is more frequently due to end-stage
chronic liver disease.
Generalized hepatic dysfunction
Jaundice is a common feature of generalized hepatic dysfunction.
Intrahepatic cholestasis involves either diffuse injury to small bile
ducts or metabolic derangements in the bile secretory apparatus
at the level of the hepatocyte and canaliculus. Intrahepatic cho-
lestasis is typically not associated with ductal dilatation and is not
amenable to mechanical interventions.
End-stage chronic liver disease or fulminant acute liver dis-
ease: Jaundice is a common feature in both of these scenarios.
In chronic liver disease, there are often other associated clinical
features, including palmar erythema, spider nevi, gynecomastia,
and signs of portal hypertension.
Cancer infiltration: Jaundice caused by extensive tumor infiltra-
tion of the liver by primary liver cancer or intrahepatic metastases
is a sign of very extensive dysfunction and it is usually accompa-
nied by other features of liver failure. Gastrointestinal malignan-
cies are especially prone to spread to the liver because of its portal
venous drainage. Extra-abdominal tumors such as bronchogenic
carcinoma, breast cancer, and malignant melanoma often spread
hematogenously to the liver. Irrespective of the site of origin of the
tumor, jaundice associated with extensive tumor infiltration of the
liver is a sign of far advanced disease and is an adverse prognostic
factor associated with a relatively short anticipated survival.2,3
Patients commonly display signs of incipient encephalopathy,
ascites and have evidence of hypoalbuminemia, and laboratory
findings of coagulopathy. Ultrasonic or computerized tomog-
raphy (CT) imaging of the liver usually demonstrates extensive
involvement of the liver by metastases.
The role of antitumor therapies in this setting depends on the
likelihood of anticipated response, the performance status of the
patient, and the goals of care. Among patients with tumors that
are sensitive to systemic therapies (chemotherapy, hormonal ther-
apy, tyrosine kinase inhibitors, or immunotherapy), occasional
patients will achieve a remission with adequate restoration of liver
function to facilitate resolution of jaundice. In patients with unre-
sponsive disease, liver failure ensues with progression until death.

375
376
Administration of antitumor therapies in this situation requires
great caution, since many agents require dose modification in the
setting of liver failure and some are contraindicated.4
Biliary obstruction
Cancer-related cholestasis: Tumors may obstruct biliary flow
within the liver parenchyma, at the porta hepatis, or at any point
along the common bile duct until the ampulla of Vater.
Proximal obstruction at the ductal confluence may be caused
by cholangiocarcinoma, gallbladder carcinoma, intra biliary
metastases, or adenopathy in the porta hepatis secondary to a
variety of metastases. Rarely sarcoid reaction in hilar lymph
nodes has been associated with obstructive jaundice in cases of
cholangiocarcinoma.5
Obstruction of the common bile duct is most commonly caused
by cancer of the head of pancreas, ampullary carcinoma, or less
commonly cholangiocarcinoma or gallbladder.6 Among patients
with hepatocellular carcinoma, bile duct thrombosis is one of the
main causes for obstructive jaundice, and the reported incidence
is 1.2–9%.7,8 Thrombi can be benign (clots, pus, or sludge), malig-
nant, or a combination of both. Rarely, rupture of hepatocellular
carcinoma into the common bile duct may cause a fluctuating
obstruction by floating tumor debris.9
Extensive tumor metastases within the liver may produce
intrahepatic cholestasis by obstructing smaller intrahepatic
ducts. Diffuse infiltration of malignant cells along hepatic sinu-
soids with consequent cholestasis also may occur, especially in
small-cell carcinoma of the lung and in lymphoma.10
Chronic cholestatic liver disease: Primary biliary cirrhosis and
primary sclerosing cholangitis are both chronic progressive liver
diseases with predominant cholestatic features.
AIDS cholangiopathy: AIDS may be associated with a number of
biliary tract abnormalities.11 Patients with advanced immunodefi-
ciency may develop acalculous cholecystitis, focal distal biliary ste-
nosis at the ampulla of Vater, or multifocal stenoses of the biliary
tree that resembles primary biliary cirrhosis. AIDS cholangiopathy
is strongly associated with colonization of bile with cryptosporidia,
cytomegalovirus, or microsporidia. Patients typically describe right
upper quadrant abdominal pain, diarrhea, and often have abnormal
liver test results, particularly elevated alkaline phosphatase (ALP).
The diagnosis may be suggested when an ultrasound examination
of the gallbladder reveals edema of the wall; endoscopic retro-
grade cholangiopancreatography (ERCP) demonstrates strictures
and delayed emptying and may permit direct sampling of bile for
pathogens. These syndromes are late complications of AIDS which,
although rarely fatal of itself, indicate a poor prognosis.
Chronic graft-versus-host disease: After bone marrow transplan-
tation, chronic graft versus host disease may be associated with an
intrahepatic cholestasis syndrome.12 Liver involvement is charac-
terized by mononuclear infiltration of portal tracts with oblitera-
tion of small bile ductules, similar to that seen in PBC (primary
biliary cirrhosis). Intensive immunosuppression may control the
graft-versus-host reaction, and if this fails, ursodeoxycholic acid
may improve cholestasis; however, the cholestasis often progresses
to biliary cirrhosis.
Clinical presentation
Patients with advanced jaundice experience generalized malaise,
weakness, easy fatigability, nausea, anorexia, and pruritus. Itch is
common but it does not occur in all cases.
Textbook of Palliative Medicine and Supportive Care
Introduction of bacteria into bile above an obstructing lesion
can cause ascending cholangitis; a purulent infection of the
biliary tree and liver. Contributing factors include high bili-
ary pressure and stasis. In the absence of infection, however,
cholestasis may be well tolerated for very long periods of time.
Common presenting features of cholangitis include fever, right
upper quadrant pain, confusion, or hypotension. Chronic bili-
ary obstruction, regardless of cause, eventually leads to cir-
rhosis with all its complications. The mechanism by which an
increased bile secretory pressure leads to cirrhosis has not as
yet been established, but it can occur with either extrahepatic
or intrahepatic obstruction.
Investigation
Clinical evaluation often yields substantial information in the
assessment of the cancer patient who presents with jaundice. It
is important to ascertain the tumor type and history to date, if
known. The presence of pale stools is strongly suggestive of cho-
lestasis. The abdomen is examined for evidence of hepatomeg-
aly, ascites, and features of portal hypertension. Patients should
undergo a brief mental status examination and neurological
examination for evidence of asterixis and features of Parkinson’s
like psychomotor retardation.13,14
Diagnostic evaluation
Blood tests
The diagnosis of jaundice is confirmed by the finding of hyperbili-
rubinemia. Serum bilirubin concentration in normal adults is less
than 1–1.5 mg/dL and varies directly with bilirubin production
and inversely with hepatic bilirubin clearance. A serum bilirubin
value of 3 mg/dL is usually required for jaundice or scleral icterus
to be clinically evident.
Other initial studies should include a complete blood cell count
as well as liver function tests, including activities of ALP and ala-
nine and aspartate aminotransferases (AST and ALP), albumin,
and prothrombin time. Both gamma-glutamyl transpeptidase
(GGT) and ALP are typically elevated in patients with cholesta-
sis; the combination of an elevated ALP and normal GGT sug-
gests that from bone. Conversely, an isolated elevation of GGT
may result from certain drugs (e.g., phenytoin) or alcohol even in
the absence of liver disease.
Imaging studies
Imaging studies help one to identify the presence or absence of
intrahepatic metastases, the presence of intrahepatic or extrahe-
patic cholestasis, and the site of obstruction if present.
Ultrasound: Transabdominal ultrasound is a noninvasive test
that can identify the presence or absence of metastases and deter-
mine whether the intrahepatic and/or extrahepatic biliary system
is dilated. The sensitivity of abdominal ultrasonography for the
detection of biliary obstruction in jaundiced patients ranges from
55 to 91%, and the specificity ranges from 82 to 95%.15 Given the
sensitivity limitations of this approach, a negative US should not
preclude further imaging when there is a compelling clinical sus-
picion of obstruction.
CT: CT may be preferred when precise definition of anatomic
structure and information about the level of obstruction are
desired.15 It provides a more comprehensive analysis of the liver
and extrahepatic abdomen and pelvis than ultrasound. Both CT
and ultrasound may occasionally fail to identify dilated ducts in
Jaundice
obstructed patients with cirrhosis and poorly compliant hepatic
parenchyma or in patients with primary sclerosing cholangitis.
Conversely, the presence of dilated ducts in a patient who has pre-
viously undergone cholecystectomy does not necessarily signify
obstruction.
Magnetic resonance cholangiopancreatography (MRCP):
MRCP is a technical refinement of standard magnetic reso-
nance imaging that permits rapid clear-cut delineation of the
biliary tree without the requirement of intravenous contrast
agents. IV contrast improves the sensitivity of MRCP for the
detection of peribiliary enhancement (seen with cholangitis)
and in the diagnosis and staging of unsuspected pancreatico-
biliary tumors.15 In patients with hilar tumors and bilateral
biliary tree obstruction, MRCP can determine the dominant
ductal drainage for the liver segments for subsequent stent
placement.16 Limitations of this approach include image arti-
facts (caused by fluid within the adjacent duodenum, duodenal
diverticulae, and ascites).
Endoscopic ultrasonography (EUS): EUS is an invasive proce-
dure usually performed in an interventional suite or operating
room under general anesthesia using an endoscope equipped
with an US probe that is advanced in to the duodenum. This
approach allows for detailed US evaluation of the pancreaticobili-
ary tree. EUS is a valuable imaging test for diagnosing and staging
pancreatic cancer. In skilled hands, it is more accurate than spi-
ral CT scanning or MRCP.15 This approach is particularly useful
when no visible mass is observed on routine imaging studies. In
this setting, it has both a high positive and negative predictive
value.17 EUS is particularly useful in the diagnosis of cancer of
papilla of Vater.18
ERCP: ERCP is highly accurate in the diagnosis of biliary
obstruction, with a sensitivity of 89–98% and specificity of
89–100%.15 If dilated ducts are identified, it is generally appro-
priate to visualize the biliary tree directly by ERCP. ERCP
involves passing an endoscope into the duodenum, introduc-
ing a catheter into the ampulla of Vater, and injecting contrast
medium into the distal common bile duct and or pancreatic
duct. Because of significant advances in cross-sectional imag-
ing, in particular, the advent of MRCP and ERCP currently
has more of a therapeutic role.15 Choledochoscopy and bile
duct brushing cytology are potentially useful techniques to
distinguish between obstructions due to intraluminal mass,
infiltrating ductal lesions, or extrinsic mass compression.
Furthermore, if a focal cause for biliary obstruction is iden-
tified (e.g., choledocholithiasis, biliary stricture), therapeutic
maneuvers to relieve obstruction (e.g., sphincterotomy, stone
extraction, dilation, and stent placement) can be performed
during the procedure. ERCP is not a benign procedure and
significant adverse events occur in 0.5–2% of patients. Risks
include respiratory depression, aspiration, bleeding, perfora-
tion, cholangitis, and pancreatitis.
Percutaneous transhepatic cholangiography (PTC): PTC
involves percutaneous passage of a needle through the hepatic
parenchyma and injection of contrast medium into the prox-
imal biliary tree through a peripheral bile duct. PTC is often
preferred when the level of biliary obstruction is proximal to
the common hepatic duct or in which altered anatomy precludes
ERCP. When, however, bile ducts are not dilated, this approach
may be technically difficult and it may be unsuccessful in up to
25% of attempts. As with ERCP, interventional procedures, such
as balloon dilation and stent placement, can be performed at the
time of PTC.
377
Management of biliary obstruction
Symptomatic management
Biliary obstruction that is asymptomatic in a patient who has
a short life expectancy does not require intervention. In many
cases, however, jaundice is associated with symptoms of itch,
anorexia, and fatigue. Indeed, studies that have evaluated the
quality of life of patients before and after the relief of biliary
obstruction highlight improvements in itch, anorexia, fatigue,
and global well-being.19–21
Surgical management and Stents
Historically, the approach to obstructive jaundice has been bili-
ary bypass surgery. However, randomized trials and a meta-anal-
ysis22 have demonstrated that endoscopically placed stents are as
successful as surgical bypass but with lower morbidity and pro-
cedure-related mortality rates and that most can be successfully
managed using stents or percutaneous drains.
Endoscopic biliary stent
Endoscopic placement of biliary endoprostheses can provide
effective drainage without the burden and stigma of an external
drain.23 It is successful in more than 90% of attempts, it is asso-
ciated with procedure-related mortality of about 1%. Transient
complication of cholangitis, fever, or hemorrhage are common
and occur in about 20% of patients attempts.24 Median survival
for stented patients was 4.9 months.23
Combined percutaneous–endoscopic procedures have been
described for patients in whom endoscopic insertion is unsuc-
cessful.25 In this approach, a guidewire and fine-bore catheter is
introduced percutaneously, and the biliary tree is decompressed.
The guidewire is advanced through the obstruction, and into
the duodenum. An endoscopist then introduces a stent over the
guidewire. Once adequate internal drainage has been achieved,
the percutaneously placed guidewire and catheter may be
withdrawn.
Blockage
Stent blockage is a major problem with teflon catheters.
Obstruction has been attributed to the adherence of bacteria to
the wall of the stent, resulting in the production of a biofilm that
traps debris and ultimately occludes the lumen.26,27 Occlusion of
Teflon or plastic endoprostheses generally is managed with repeat
endoscopy and stent replacement. Exchange of endoprostheses
may be done as long as duodenal intubation with an adequate
endoscope remains possible but does require a second endos-
copy. Early prophylactic stent exchange at 3–6 months has been
advocated, but an optimal time has not been defined. In patients
whose stents have occluded but who are not candidates for endo-
scopic replacement, percutaneous stenting may be palliative.
Stent selection
Self-expanding metal prostheses were introduced to overcome
the problem of occlusion. The most commonly used device, the
Wallstent®, consists of a stainless steel mesh that is mounted on
a 9-Fr delivery catheter.27 Metal stents have a larger diameter
(8–10 mm), most are not removable and they are much more
expensive than plastic. They are introduced into the bile duct
enclosed in a sheath which is then retracted enabling the stent
to expand against the wall of the bile duct. However, metal stents
are permanent and much more expensive than plastic. Meta-
analysis of 20 prospective trials in which patients with biliary
378
obstruction were randomized to stenting with either polyethylene
or metal stents found that placement is seen in at least 95% of
patients and is independent of stent material. Expanding metallic
stents were associated with longer stent patency, lower complica-
tions rates, fewer re-interventions, and some survival advantage
in subsets of patients.27
Covered metal stents have lower rates of tumor ingrowth and a
potential advantage of removability.28 These advantages must be
balanced against higher rates of stent migration due to the lim-
ited ability of the stents to embed surrounding tissues because of
the overlying covering.29
Percutaneous transhepatic
cholangiographic (PTC) drainage
Percutaneous drainage can be achieved with an internal–
external catheter that can drain externally or, if the obstruction
can be passed, internally. 30,31 Even when biliary obstructions are
complete, in many instances an interventional radiologist can
negotiate through a stricture with a combination of guidewires
and catheters under fluoroscopic guidance. Transhepatic cath-
eters are designed with side holes both above and below the level
of obstruction in the biliary tree; the tip of the catheter resides
within the bowel, so that bile drains through the catheter across
the obstruction and out of the side holes into the duodenum.
Transhepatic catheters are associated with complications of
obstruction, leakage, and infection. 32 Usually transhepatic bili-
ary catheters are routinely changed every 2 months to avoid any
chance of obstruction. 30
The percutaneous approach to biliary cannulation (PTC) can
also be used to inset expandable metallic stents. 31 Experience
comparing direct stent insertion with an approach of delayed
stenting after initial drainage and dilatation demonstrated sub-
stantially less morbidity with the more direct approach. 33 In a
series of 224 patients, there were no procedure-related deaths,
and the clinical success rate within the first 30 days was 88%. 34
Endoscopic ultrasound–guided biliary drainage
Traditionally, patients who had failed ERCP have been offered
PTC or surgical biliary decompression, both of which are associ-
ated with higher morbidity. Endoscopic US–guided biliary drain-
age has been developed as a less invasive alternative for biliary
drainage. 35,36 In a single-step procedure, it aims to establish bili-
ary drainage using transgastric puncture of the intrahepatic duct
or the common bile duct and placement of a bridging stent to the
gastric lumen. This approach is feasible in patients with inac-
cessible papillae due to duodenal obstruction, surgically altered
anatomy, or hilar block due to cholangiocarcinoma or gallblad-
der cancer. This approach may also be safer than PTC, since the
bile duct is accessed using Doppler to avoid blood vessels in the
needle path. 35 The most common complications are biliary leak-
age and pneumoperitoneum which is usually self-limited. Biliary
leakage may occur predominantly with extrahepatic duct punc-
ture, transluminal drainage, and larger hole. The procedure is
technically complex and it is only performed by specialist endos-
copists who are skilled at both ERCP and EUS. It requires surgical
backup and is not yet widely available.
Special case: obstruction at the
bifurcation of the hepatic ducts
Patients with biliary obstruction at the bifurcation of the hepatic
ducts present a difficult challenge, and there is much controversy
as to the importance of establishing drainage of both liver lobes
in malignant hilar obstruction. A meta-analysis of nine studies
Textbook of Palliative Medicine and Supportive Care
(782 patients) with malignant hilar obstruction concluded that
bilateral stenting had a lower re-intervention rate as compared
to unilateral drainage for high-grade inoperable malignant bili-
ary strictures, with no significant difference in technical success,
and early or late complication rates. 37 If a unilateral approach is
preferred, MRCP can be used to determine the dominant ductal
drainage for the liver segments, thus directing stent placement.
In a series of 35 patients who underwent MRCP, with subsequent
unilateral stent deployment in ERCP, jaundice resolved in 86%.16
Uncovered stents are preferred to avoid occluding drainage from
the contralateral biliary system.
Cholestatic itch (pruritus)
Pruritus is the major symptom of obstructive jaundice. 38,39
Pruritus may occur with any type of liver disease but is primar-
ily associated with acute or chronic cholestasis. It has been esti-
mated to occur in 20–50% of jaundiced patients. The intensity
of the pruritus varies from mild to severe. It can be persistent
or intermittent and it may be generalized or localized to specific
parts of the body, commonly the soles of the feet and palms of
the hands.
Pathogenesis
The pathogenesis of cholestatic pruritus is complex and multi-
factorial. 38,39 Indirect evidence suggests that it may be caused, at
least in part, by dermal itch receptor stimulation by bile acids,
lysophosphatidic acid (LPA), endogenous opiates, and progester-
one derivatives, all of which are often elevated in cholestasis. Not
all jaundiced patients suffer from pruritus, but those with pru-
ritus have highly elevated levels of serum autotaxin (ATX), the
enzyme that converts the lysophosphatidylcholine into LPA.40,41
Interestingly, rifampicin downregulates ATX transcription, and
this may contribute to its efficacy in relieving cholestatic itch. A
central mechanism, associated with altered neurotransmission
in the brain, has also been imputed based on observations that
opioid and serotonin antagonists reduce scratching activity in
cholestatic patients. 38,39 Finally, there is evidence that skin biliru-
bin is correlated with itch severity and that bilirubin may bind to
and activate a Mas-related G protein–coupled receptor (Mrgpr)
on itch-encoding sensory neurons39.
Management
The management of pruritus in this setting is often difficult and
it should involve specific antipruritic therapies along with general
supportive measures.
Anion-exchange resins
Anion-exchange resins, which are given by mouth, bind bile
acids and other anionic compounds in the intestine, resulting
in increased fecal excretion of bound substances. Thus, they
decrease the enterohepatic circulation of bile acids. The most
widely administered treatment for the pruritus of cholesta-
sis has been the basic anion-exchange resin cholestyramine or
colestipol. 39 The bile acid sequestrant, colesevelam, was found to
be ineffective in an RCT.42 The maximum recommended dose of
cholestyramine is 16 g/24 hours. The resins should be taken at least
2 hours apart from other medications so as not to interfere in their
absorption. Cholestyramine is not very palatable and it should be
diluted in water or juice. The most common side effects of resin
treatment are bloating and constipation. It is prudent to moni-
tor the prothrombin time during prolonged the administration
Jaundice
of these agents, because treatment may result in malabsorption
of fat-soluble vitamins.
Rifampicin
Rifampicin (like Phenobarbital, see next) is a pregnane X recep-
tor agonist that strongly induces hepatic microsomal oxidiz-
ing enzymes and biotransformation transporters (i.e., CYP3A4,
UGT1A1, and MRP2) that may promote the metabolism and/or
the secretion of the potential endogenous pruritogens. In addi-
tion, rifampin reduced autotaxin expression that is the essential
enzyme that converts the lysophosphatidylcholine into LPA,
and it competes with bile acid uptake by hepatocytes and modi-
fies secondary bile acid synthesis in the gut lumen (through its
antimicrobial effects). 39 Substantial effectiveness in the relief
of cholestatic itch is supported by multiple small trials and
2 meta-analyses.43,44 When effective, the onset of effect is relatively
rapid. The usual dose is 150–300 mg twice daily.43,44 The long-
term administration of rifampicin for pruritus is generally safe
but, rarely, may be associated with hepatotoxicity. Consequently,
requiring regular monitoring of serum alanine aminotransferase
(ALT) levels is advised.45
Opioid antagonists
The observation that intravenous naloxone can reduce cholestatic
pruritus46,47 prompted subsequent trials of therapy with orally
administered antagonists nalmefene and naltrexone. However,
these agents must not be used in patients receiving opioid-
containing medications or in patients with acute hepatitis, liver
failure, or severe liver dysfunction or patients with underlying
chronic pain syndromes.48
Approaches include naloxone IV (administered as a loading
dose of 0.4 mg followed by 0.01 mg/kg/hour for 24 hours),47 oral
nalmefene (30–120 mg daily),49 and oral naltrexone (12.5–50 mg
daily) subjectively.50,51 These approaches may generated a tran-
sient, self-limited opioid withdrawal-like syndrome that usually
resolves within 48 hours52 which may be attenuated by using an
initial naloxone infusion before switching to oral therapy.53
Sertraline
Sertraline is a selective serotonin reuptake inhibitor antidepres-
sant that may attenuate serotonin-mediated pruritic pathways.
Pruritus is frequently the most debilitating symptom of chole-
static liver diseases. Sertraline was studied in 21 patients with
chronic pruritus due to liver disease: initially with open label,
dose escalation to determine the dose with optimal efficacy and
tolerability and after a washout period, 12 underwent a random-
ized, double-blind, placebo-controlled trial using sertraline dose
(75–100 mg/day) which confirmed efficacy and with a low preva-
lence of adverse effects.54
Medications with limited evidence of benefit
Despite common application in this setting, antihistamines are
rarely effective in this setting.55 Phenobarbital may relieve pru-
ritus in individual patients, but its utility has not been supported
in controlled trials.56 The barbiturate phenobarbital has sedative
effects as well as effects on the liver. This drug nonspecifically
increases the activity of the hepatic microsomal enzyme system
by enzyme induction, and it is hypothesized that it may act by
enhancing the excretion of pruritogens. A systematic review con-
cluded that the 5-HT3 antagonist ondansetron had negligible
379
effect on cholestatic or uremic pruritus on the basis of a limited
number of studies.57 Propofol, at subhypnotic doses of 15 mg, was
reported to ameliorate the cholestatic pruritus in a small placebo-
controlled trial.58,59 Finally in refractory cases, there is limited
data to support the trials of phototherapy, cannabinoids, plasma-
pheresis, fibrate, and newly developed (but still unlicensed) ileal
bile acid transport inhibitors that interrupt enterohepatic circu-
lation of bile acids. 39
General measures
In addition to these specific therapies, simple measures have
been recommended. Such measures include the use of emollients
and mild fragrance-free soaps (e.g., fragrance-free Dove, Basis,
Aveeno), less frequent bathing, wearing light clothing, and fre-
quent cutting of fingernails.
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41
MALIGNANT BOWEL OBSTRUCTION

Carla I. Ripamonti, Alexandra M. Easson, and Hans Gerdesh

Contents
Definition and epidemiology...........................................................................................................................................................................................381
Signs and symptoms MBO: Assessment and differential diagnosis..................................................................................................................382
Management of bowel obstruction............................................................................................................................................................................... 383
Palliative interventional procedures in MBO........................................................................................................................................................ 383
Surgical decision-making.......................................................................................................................................................................................... 384
Nutritional considerations........................................................................................................................................................................................ 385
Stenting and venting procedures............................................................................................................................................................................. 385
Gastroduodenal and proximal jejunal obstruction.............................................................................................................................................. 386
Malignant small-bowel obstruction........................................................................................................................................................................ 386
Malignant colorectal obstruction............................................................................................................................................................................ 386
Drainage percutaneous endoscopic gastrostomy in bowel obstruction...........................................................................................................387
Pharmacological management of symptoms................................................................................................................................................................387
Efficacy of octreotide in patients with GI symptoms due to inoperable malignant bowel obstruction.................................................... 388
Comparative studies between octreotide and scopolamine butylbromide......................................................................................................389
Conclusions........................................................................................................................................................................................................................ 390
References���������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������391

Definition and epidemiology
Bowel obstruction is defined as any process preventing the
movement of bowel contents. Malignant bowel obstruction
(MBO) is defined using the following criteria: clinical evidence
of bowel obstruction (history/physical/radiological examination)
beyond the ligament of Treitz, in the setting of a diagnosis of
intra-abdominal cancer with incurable disease or a diagnosis of
non-intra-abdominal primary cancer with clear intraperitoneal
disease.1,2
MBO may be the mode of presentation of intra-abdominal
and pelvic malignancy or a feature of recurrent disease follow-
ing anticancer therapy. MBO is well recognized in gynecologic
patients with advanced cancer. Retrospective and autopsy studies
found the frequency at approximately 5.5–51% of patients with
gynecological malignancy. 3–8 MBO is particularly frequent in
patients with ovarian cancer where it is the most frequent cause
of death.5,6,8 Patients with stage III and IV ovarian cancer and
those with high-grade lesions are at higher risk for MBO as com-
pared to patients with lower-stage or low-grade tumors.9,10
The reported frequency of bowel obstruction ranges from 10 to
28% in colorectal cancer.2,11
Bowel obstruction can be partial or complete, single or mul-
tiple. Benign causes are reported in nearly half the patients with
colorectal cancer and in approximately 6% of patients with gyne-
cological cancer.2,11 The small bowel is more commonly involved
than the large bowel (61 vs. 33%) and both are involved in over
20% of the patients. 3–7
Symptoms of MBO can result from a variety of mechanical and
functional clinical mechanisms (Table 41.1). Whatever the cause
that prevents the propulsion of the intestinal contents from pass-
ing distally induces a cascade of events producing definitive bowel
obstruction (Figure 41.1). At least three factors occur: (1) accu-
mulation of gastric, pancreatic, and biliary secretions that are a
potent stimulus for further intestinal secretions; (2) decreased
absorption of water and sodium from the intestinal lumen; and
(3) increased secretion of water and sodium into the lumen as dis-
tension increases12,13 (Figure 41.1). As a result of the breakdown of
the sequence and reabsorption in the gastrointestinal (GI) tract,
there is a loss of fluids and electrolytes. The pancreatic, biliary,
and GI secretions accumulate in the bowel above the obstruction
and the volume of secretions tends to increase following intesti-
nal distension and the consequent increase in the surface area,
TABLE 41.1 Clinical Mechanisms Resulting in Malignant
Bowel Obstruction
Mechanical obstruction caused by:
1. Extrinsic occlusion of the lumen from the primary or recurrent
tumor, mesenteric and omental masses, abdominal or pelvic
adhesions (secondary to tumor or surgery), post irradiation fibrosis
2. Intraluminal occlusion of the lumen due to neoplastic mass or
annular tumoral dissemination
3. Intramural occlusion of the lumen due to intestinal linitis plastic
Functional obstruction (adynamic ileus) caused by:
a. Tumor infiltration of the mesentery or bowel muscle and nerves
(carcinomatosis), celiac plexus
b. Paraneoplastic neuropathy in patients with lung cancer
c. Chronic intestinal pseudo-obstruction (CIP): patients with
diabetes mellitus, previous gastric surgery, and other neurological
disorders may have vagal dysfunction and altered extrinsic neural
control to viscera
d. Paraneoplastic pseudo-obstruction

381
382
FIGURE 41.1  Pathophysiology of clinical malignant bowel obstruction.
thus producing a vicious circle of secretion-distension-secre-
tion.12,13 Depletion of water and salt in the lumen is considered
the most important “toxic factor” in bowel obstruction.
Inflammatory edema, fecal impaction, constipating drugs
(e.g., opioids, anticholinergics), and dehydration contribute to
the development of bowel obstruction and worsen the clinical
picture.
Signs and symptoms of MBO: Assessment and
differential diagnosis
In MBO, compression of the bowel lumen develops slowly and
often remains partial. The initial symptoms are frequently peri-
odical abdominal cramps, nausea, vomiting, and abdominal
distension that resolve spontaneously. These episodes are fre-
quently followed by passage of gas or loose stools. GI symptoms
caused by the sequence of distension–secretion–motor activity
of the obstructed bowel (Figure 41.1) occur in different combi-
nations and intensity depending on the site of obstruction and
tend to worsen (Table 41.2). Vomiting can be assessed in terms
of numbers, volume, and overall duration. Other symptoms such
as nausea, pain (both colicky and/or continuous), xerostomia,
somnolence, dyspnea, and even sensation of hunger can be pres-
ent and can be evaluated with visual analog, numerical, or verbal
scales. The assessment of patients with suspected MBO should
Textbook of Palliative Medicine and Supportive Care
consider: (1) other causes of nausea, vomiting, and constipation;
(2) metabolic abnormalities; (3) type and dosages of drugs; (4)
nutritional and hydration status; (5) bowel movements and the
presence of overflow diarrhea; (6) presence of abdominal fecal
masses, distension to all the abdomen or above the obstacle, asci-
tes, as well as painful sites; and (7) presence of feces in the rectal
ampulla (rectal exploration).
From the metabolic point of view, dehydration, electrolyte
losses, and disorders of acid–base balance are frequently associ-
ated with bowel obstruction. The hypovolemic state may induce a
functional renal failure due to a decrease of the renal flow and, as
a consequence, of the glomerular filtration. Different respiratory
patterns may be observed, depending on the level of obstruction.
When the level is high, metabolic alkaloses, hypochloremia and
hypokalemia, due to a prevalent loss of gastric secretions, deter-
mine hypoventilation; if the level of obstruction is distal, the sec-
ondary deficit is global including chloride, sodium, potassium,
and bicarbonates owing to intestinal stasis of biliary, pancreatic,
intestinal, as well as gastric secretions. The dehydration reflects
the accumulation of fluids and electrolytes in the third space.
With a low level of obstruction, including ileum or colon, acidosis
prevails. The diagnosis of intestinal obstruction is established or
suspected on clinical grounds and usually confirmed with radio-
logic imaging.
Malignant Bowel Obstruction 383

TABLE 41.2  Common Symptoms in Cancer Patients with Malignant Bowel Obstruction
Vomiting, Intermittent or Occurs early and copious in upper Odorless biliary vomiting indicates MBO in upper
nausea continuous gastrointestinal obstruction and develops later abdomen. Foul smelling and fecaloid vomiting can
in large-bowel obstruction be the first sign of more distal ileal or colonic
obstruction
Colicky pain Variable intensity and Intense, periumbilical, and frequent pain Severe sudden-onset, localized acute pain that
localization suggests jejunal–ileal level obstruction. Pain is intensifies may be from perforation or an ileal or
(distension due to gas less intense, deeper, and more intermittent in colic strangulation. A pain that increases with
and fluid produced by colon obstruction movement may be due to peritoneal irritation from
the bowel proximal to the beginning of a perforation. These finding may
the obstruction) indicate a surgical emergency.
Continuous Variable intensity and It is due to abdominal distension, tumor mass, Local radiation may help in select circumstances
pain localization intestinal distension, and/or hepatomegaly
Dry mouth Dehydration and metabolic alterations in part
due to decreased oral intake, use of
anticholinergic drugs
Constipation Mechanical or functional causes (see Table 41.1)
Overflow It is the result of bacterial liquefaction of the
(paradoxical) fecal material blocked in the sigma or rectum
diarrhea

Management of bowel obstruction
The management of patients with MBO is one of the greatest
challenges for physicians who care for cancer patients. This man-
agement has to be highly personalized according to the stage of
the illness, the prognosis, the possibility of further antineoplas-
tic therapies, and the general status and choices of the patients.
Figure 41.2 shows an algorithm for a decision-making process in
patients with MBO.
Palliative interventional procedures in MBO
Palliative interventions, either open, laparoscopic, endoscopic, or
with fluoroscopic stenting, may benefit patients with MBO and
are generally considered when bowel obstruction symptoms do
not resolve after 24–48 hours of nasogastric tube (NGT) decom-
pression. Each patient must be assessed individually to decide
whether an invasive intervention is feasible and appropriate.
Although the diagnosis and location of obstruction can be sug-
gested by the history, physical exam, and plain or contrast radi-
ography, cross-sectional imaging by computed tomography (CT)
scanning or magnetic resonance imaging (MRI) is essential in
decision-making. CT will diagnose the site and cause of obstruc-
tion in 70–95% of cases,14 compared to 23% for ultrasound and
7% for plain-film radiography.15 CT will also rule out closed-loop
obstruction and intestinal ischemia, which requires emergency
management. Newer technology in CT scanning such as spi-
ral and multidetector scanners, combined with the intravenous
and oral ± rectal contrast, provides a better global assessment
of the abdomen and pelvis and, when coupled with multiplanar
reconstruction, can help identify the transition point(s) in bowel
obstruction, thereby determining the site, cause, and severity
of obstruction.16,17 MRI may provide similar information, but is
not as widely available as CT scanning, and local expertise in its
use in the assessment of bowel obstruction may be limited. The
expected results with MRI should be similar to CT scanning, but
the data on the sensitivity, specificity, and accuracy are lacking.
Once the site and cause of obstruction are known, a decision
can be made about management. In the face of a clearly incurable
situation, significant patient discomfort and suffering must be
balanced with the need to simplify the care of those patients with
a short time to live. The procedure that is most likely to success-
fully relieve symptoms for the greatest length of time with rea-
sonable morbidity is chosen.18–20
A multidisciplinary working group in Europe reviewed issues
regarding bowel obstruction and published clinical practice rec-
ommendations for the management of MBO in patients with
end-stage cancer.7 A recent Cochrane review did not recommend
significant changes.21 Several groups are prospectively studying
how to reduce the burden of MBO particularly in the ovarian
cancer population which may help informed decision-making in
the future.22–26
Complete surgical resection of a tumor is most desirable.
However, it is only worthwhile if the entire tumor in that area
can be resected with negative margins. The exception can be
ovarian or some GI cancers where intraperitoneal chemotherapy
can treat the residual disease after a “debulking” operation of
all obvious disease. If the tumor cannot be resected, but there is
healthy nonobstructed bowel before and after the site of obstruc-
tion, a side-to-side bypass can be performed. This will restore
bowel continuity and allow the patient to eat and maintain their
nutritional status. In the case of distal obstruction, a stoma can
be created out of the most distal unaffected bowel segment. In
order to maintain one’s nutrition orally, it is necessary to have
a minimum of 100 cm of proximal bowel before a stoma, so the
length of proximal bowel should be measured prior to creating a
proximal stoma. Proximal stomas also have high outputs and may
cause significant fluid balance problems. Finally, in the absence of
any other options, a gastrostomy tube may be placed to avoid the
need for an NGT.27
The likelihood of long-term relief of obstruction after surgery
depends on the location of the bowel obstruction, with large-
bowel obstruction successfully relieved in 80% of cases versus
25% if both large and small bowels are involved.19 The number of
obstructed sites also affects the likelihood of success; a single site
of obstruction has a high likelihood of success as compared to
multiple sites of obstruction. It is worth emphasizing that MBO
384
FIGURE 41.2  Algorithm for assessing and managing a patient with malignant bowel obstruction.
from generalized carcinomatosis is a distinct entity that responds
poorly, or not at all, to surgical intervention and these patients are
not surgical candidates.7,13,28
Surgical decision-making
In addition to the aforementioned technical factors, surgical deci-
sion-making must take into account the individual patient and
their disease. Performance status remains one of the best predic-
tors of lower complication rates and improved survival.29 Patient
factors associated with poor surgical outcomes include advanced
age (both physiological and chronological); poor nutritional sta-
tus, psychological health, and social support; ascites; and/or con-
current illness and comorbidities (Table 41.3). 30 Disease factors
such as tumor type, grade and extent, time from primary presen-
tation, and history of response to and availability of anticancer
treatments also affect decision-making. Slow-growing, well-dif-
ferentiated tumors are more likely to be associated with better
outcomes and longer survival. The best predictor of the future is
the place of the disease in the past and its response to treatment,
Textbook of Palliative Medicine and Supportive Care
due to the biology and inherent growth characteristics of the
tumor. Patients with bulky liver or lung metastatic disease will
generally die sooner than those with localized pelvic or intraperi-
toneal disease and are therefore less likely to benefit from surgery.
The selection of patients who will benefit from these proce-
dures is an ongoing challenge. Because the management of MBO
is rarely an emergency, time can and should be taken to develop
an appropriate individualized treatment plan with the patient
and family. In the face of an incurable, progressive illness, the bal-
ance between honesty and maintaining hope and optimism can
be difficult to achieve but is necessary to avoid futile treatments
and harm to the patient. 31 It may be easier to offer a treatment
just to do something; the more difficult decision may be not to
do something when it is not going to help. However, there is little
guidance on what should be considered a futile treatment as the
definition will vary depending on the patient’s goals and values
and the clinician’s experience.7,32–34
A decision-making approach can be outlined as shown in
Figure 41.2. The clinician first decides which, if any, treatments
Malignant Bowel Obstruction
TABLE 41.3 Prognostic Indicators of Low Likelihood of
Clinical Benefit from Surgery of Malignant Bowel
Obstruction
1. Obstruction secondary to cancer
2. *Intestinal motility problems due to diffuse intraperitoneal
carcinomatosis
3. +Widespread tumor
4. +Patients over 65 years of age in association with cachexia
5. *Ascites requiring frequent paracentesis
6. +Low serum albumin level and low serum prealbumin level
7. +Previous radiotherapy of the abdomen or pelvis
8. +Poor nutritional status
9. *Diffuse palpable intra-abdominal masses
10. +Liver metastases, distant metastases, pleural effusion, or
pulmonary metastases producing dyspnea
11. *Multiple partial bowel obstructions with prolonged passage time
on radiograph examination
12. +Elevated blood urea nitrogen levels, elevated alkaline
phosphatase levels, advanced tumor stage, short diagnosis to
obstruction interval
13. +Poor performance status
14. *A recent laparotomy, which demonstrated that further corrective
surgery was not possible
15. +Previous abdominal surgery, which showed diffuse metastatic
cancer
16. *Involvement of proximal stomach
17. +Extra-abdominal metastases producing symptoms difficult to
control (e.g., dyspnea)
Source: Modified from ref. [7], Ripamonti C, et al. Support. Care Cancer,
19,23,2001. Data from retrospective studies.
*Absolute contraindications to surgery
+ Relative contraindications to surgery
are appropriate or feasible. This can only be done after a thor-
ough evaluation, including imaging, to assess the current state of
the illness, avoiding intraoperative surprises or emergencies. The
patient is asked about their understanding of where they are on
their disease trajectory and about their expectations, goals, and
values. Their current medical condition and expected prognosis
are discussed. All treatment options including surgery, endos-
copy, interventional radiology, and aggressive medical manage-
ment should be discussed, along with the complication rates and
the expected success of each intervention. Reasonable treatment
goals are set and a plan is developed with the patient, whether
this is continued anticancer therapy, withdrawal of inappropriate
therapies, or vigorous palliative care. These goals should address
the relief of suffering and improving quality of life (QOL). This
may take time as the patient comes to terms with their disease.
With careful preoperative planning, it is possible to deter-
mine before the operation in most cases which operation is most
likely to succeed; however, the final decision will be made in the
operating room. The possibility that no surgical procedure may
be possible must also be discussed, and the patient and fam-
ily must be prepared for that option. Finally, there must be a
commitment to ongoing care with a clear care plan whatever
the outcome of the surgery. Several recent papers from large
cancer centers have followed patients prospectively with MBO.
Significant symptom relief can be obtained by selecting appro-
priate patients either for surgery or stenting with minimal pro-
cedural mortality.28–30,35–40
385
Nutritional considerations
Any malignancy may influence a patients’ nutritional status,
whether due to the disease itself or due to anticancer treatments
such as chemotherapy or radiation. Nutritional status in case of
MBO is further impaired by the inability to eat. The European
Society for Clinical Nutrition and Metabolism (ESPEN) defined
severe malnutrition as existing when patients have at least one of
the following risk factors: weight loss ≥10–15% within 6 months,
body mass index (BMI) ≤18 kg/m2, and serum albumin ≤30 g/L
(without evidence of renal and/or liver dysfunction).41 Cachexia
is a catabolic-metabolic state common in advanced cancer, where
the patient is metabolically breaking down intrinsic muscle, pro-
tein, and fat.42 Cachexia is associated with inflammation, hyper-
catabolism, hormonal changes, and the production of tumor
factors. There is no consensus in the literature how to best diag-
nose cachexia. Cachexia is not reversible by increasing nutritional
intake and represents end-stage disease, and therefore, interven-
tions to improve oral intake will not be helpful. Unfortunately, in
advanced cancer patients, cachexia, MBO, and poor nutritional
status are often seen together, and it can be difficult to identify if
the weight loss can be reversed if the obstruction is relieved.
The use of parenteral nutrition (PN) in unrelieved MBO from
advanced cancer is generally not recommended. Recent guide-
lines by ESPEN were published for the use of PN in patients who
will undergo a surgical procedure41 and for cancer patients who
will not undergo a surgical intervention.43 For those patients who
meet the ESPEN definition for severe malnutrition (BMI under
18.5–22 kg/m2 depending on age), in whom a surgery is planned,
and who cannot be enterally fed, ESPEN recommends starting
PN 7–10 days preoperatively to decrease the rate of postoperative
infections, length of stay in hospital, and postoperative mortal-
ity. Short-term postoperative PN is indicated for malnourished
patients who required emergency surgery and therefore could
not receive PN preoperatively.41 For those patients with advanced
cancer and poor nutritional status who will not have surgery, PN
is considered ineffective if the reason for the poor nutritional sta-
tus is not located in the GI tract. Also, PN does not have a role as a
supplement while patients are on either chemotherapy, radiation
treatment, or both therapies simultaneously and also are able to
receive oral or enteral nutrition adequately.43
Once the obstruction is relieved, the value of an oral nutri-
tional support programs for advanced cancer patients is unclear.
Several early reports suggest a benefit for active nutritional inter-
vention in advanced cancer patients.44,45 However, in advanced
head and neck cancer patients undergoing radiation, the group
randomized to the nutritional support program lost less weight
but had an overall poorer outcome,46 and a review of nutritional
support program in lung cancer patients also demonstrated no
survival benefit.47
Stenting and venting procedures
Self-expanding metallic stents (SEMS) for the management of
MBO of the gastric outlet, proximal small bowel, and colon can
provide an important alternative to palliative surgery. SEMS may
be used in the initial presentation of potentially resectable dis-
ease, where the goal of stenting is to convert an emergent oper-
ation to a safer, elective one that can be curative or provide an
opportunity to deliver neoadjuvant therapy prior to a curative
operation.48 For patients presenting with an MBO where cura-
tive treatment is unlikely, stenting can provide a quick and safe
procedure palliating the patient’s symptoms with a very brief or
same day hospital stay.
386
Gastroduodenal and proximal jejunal obstruction
Patients presenting with malignant gastric outlet obstruction
(GOO) or upper small bowel obstruction present with severe
abdominal pain with distension, nausea, vomiting, and dehy-
dration. This is most often seen in advanced pancreatic, gastric,
gall bladder cancers; cholangiocarcinoma; and a variety of extra-
abdominal malignancies, including breast and lung cancer.
The insertion of SEMS under endoscopic or interventional radi-
ology guidance, results in rapid relief of obstruction. Technical
success rates for stent placement are >90% and clinical success for
resolution of nausea and vomiting and improved oral consump-
tion is over 75%.49–54 The overall safety of procedures to insert
SEMS has been considered very acceptable with bleeding and
perforation occurring in about 3–4% in published reports.49–53
Delayed erosion and perforation also occur but are inconsistently
reported.65 The major limiting factor is the ability to reach and
traverse the point of obstruction with an endoscope or guide wire
especially when the obstructing tumor is located beyond the liga-
ment of Treitz. Durable palliation of obstructive symptoms is
variable as a result of multiple factors affecting the patency of the
stents, such as effects of anticancer therapy (chemotherapy and
radiation) on continued tumor growth, the long-term survival
of the patient, and the location and characteristics of the origi-
nal tumor stricture. In one multicenter prospective trial, 56% of
patients experienced an improvement in solid food intake by 1
week, and 80% by 1 month, and this effect lasted till death or last
follow-up in 48%. Also, 66% of patients did not require any re-
intervention, demonstrating the excellent durability of palliative
stenting.55 In the limited comparative studies published, endo-
scopic stent placement has been associated with shorter hospital
stay with lower periprocedural mortality in patients with GOO
secondary to pancreatic cancer56,57 and with more rapid food
intake compared to surgical bypass.56–58 Stent placement has
been effective in palliating symptoms from obstruction with lim-
ited peritoneal carcinomatosis.59
Delayed stent failure can occur due to food impaction or
reobstruction caused by tumor ingrowth: additional cancer
chemotherapy or radiation therapy can prolong the patency
of the stents.60 Stent migration also can occur, sometimes in
association with cancer treatment, if there is reduction in the
size of the tumor.60 In most cases, reobstruction due to tumor
ingrowth can be managed with placement of a second stent or
tumor ablation by Nd:YAG laser or argon plasma coagulator.61–63
In comparative studies, those managed with SEMS in the ini-
tial palliative management of malignant obstruction did just
as well initially as patients managed with surgical bypass but
had a greater need for reintervention because of delayed stent
occlusion. 58,64
The effect of palliative treatments on the patient’s QOL in
malignant GOO has not been widely studied, and those that have
been published show very modest results.66,67 In one prospective,
nonrandomized study, stent placement in the treatment of malig-
nant gastric and/or duodenal obstruction was associated with a
shorter hospital stay than surgical bypass, but both procedures
were associated with improvements in nausea, vomiting, ability
to eat, and several measures of QOL.67 Another prospective study
examining QOL in patients with malignant GOO randomized 27
patients to receive laparoscopic gastrojejunostomy or endoscopic
stent placement. Stent placement was associated with less pain
and shorter hospital stay, with a greater improvement in physi-
cal health following stent placement relative to those managed
surgically.66
Textbook of Palliative Medicine and Supportive Care
When faced with decisions on the best treatment for patients
with malignant gastric or duodenal obstructions, clinicians need
to consider multiple factors including the nature and extent of
the malignancy, prior treatment, medical comorbidities and per-
formance status, the overall prognosis, and the available techni-
cal expertise. Surgical bypass should be the preferred option for
patients with a good performance status, a slowly progressive
disease, and a relatively long life expectancy (> 60 days). If the
site of obstruction is distal in the jejunum or ileum or if there are
multiple sites of obstruction, endoscopic stenting is not likely to
succeed, therefore, surgical intervention or drainage gastrostomy
should be considered. Patients who are best suited for endoscopic
stenting are those with a short proximal tumor at a single site or
those with an intermediate to high performance status and an
intermediate life expectancy > 30 days. In patients with rapidly
progressive disease, evidence of advanced carcinomatosis with
moderate-to-severe ascites, multiple levels of obstruction on
cross-sectional imaging, a poor performance status, or a very
short life expectancy of less than 30 days are best served by medi-
cal palliation of symptoms or the insertion of a drainage percuta-
neous endoscopic gastrostomy (PEG).
The recently described endoscopic ultrasound-guided gastroje-
junostomy (EUS-GJ) offers a potential improvement to endoscopic
stenting with greater durability and longevity. This technique
uses an echoendoscope to visualize, through the stomach wall,
the surrounding organs, to locate the proximal jejunum, punc-
ture into the jejunal lumen, and advance a covered self-expanding
lumen apposing stent, with flanges to anchor the gastric and jeju-
nal wall to prevent migration of the stent into the jejunum.68–70
This quickly creates a stent-assisted stoma between the stomach
and jejunum. Initial case series and prospective registries have
demonstrated a technical success rate of 92% and clinical suc-
cess rate of 85% for relief of obstruction. This technique may be
another minimally invasive alternative for managing patients
with malignant gastric and duodenal obstruction.
Malignant small-bowel obstruction
Most gastroscopes are unable to reach beyond the ligament of
Treitz, and colonoscopes are unable to reach very far retrograde
into the terminal ileum. The recent development of long entero-
scopes that can be advanced far into the small intestine through
an overtube with pleating of the small bowel has permitted some
investigators to report anecdotal success in stenting areas of the
small intestine not previously accessible to standard endoscopes.
With time and increasing experience, the ability to treat mid-
jejunal and ileal points of malignant obstruction may become
more available.70–73 The selection of patients appropriate for such
interventions will, however, remain challenging.
Malignant colorectal obstruction
Malignant large-bowel obstruction can be managed by sigmoid-
oscopy, colonoscopy, or transanal wire-guided approaches under
fluoroscopy alone. Published series have shown technical success
rates for insertion of metallic stents ranging from 80 to 100%, with
clinical improvement in symptoms reported in more than 75% of
patients.48,74,75 Many patients treated with stents have a durable
relief of symptoms until death from progression of disease, but
as has been seen with the use of stents in other parts of the body,
restenosis does occur, usually caused by tumor ingrowth through
the interstices of the stent or stent migration. This can usually be
managed with insertion of another stent, endoscopic dilation, or
laser ablation.74–77
Malignant Bowel Obstruction
Two analyses of pooled data from the multiple reported case
series have been published.78,79 Both report clinical success rates
of 88 and 91%, defined as resolution of obstructive symptoms fol-
lowing the insertion of stents. The limitations to success are a
very proximal location of obstruction in the proximal colon and
the ability to traverse a tortuous or tightly obstructing tumor
with the endoscope or a guide wire. A greater success with stent-
ing primary colorectal cancer has been noted, with lesser success
for obstruction caused by extrinsic compression from metastatic
or locally invasive pelvic tumors.77,80,81
Limited data on cost effectiveness of colorectal stenting are
available in published reports, with some calculations suggesting
a potential reduction in the estimated cost of palliation for such
patients of approximately 50% compared to surgery.78 This is pre-
dominantly attributed to a reduced hospital stay with stenting.
A recent multicenter study was completed demonstrating sim-
ilar results with a newer generation of nitinol SEMS, called the
Wallflex.82 This study, like most others, demonstrates the ease of
use, high technical and short-term clinical efficacy, and low over-
all and serious complication rate. As in stenting in other parts of
the GI tract, these procedures have acceptable published safety
rates, with bleeding and perforation occurring in less than 5% of
cases.78,79,83 One limitation of stent use in malignant colorectal
obstruction is the location of obstruction involving the lower
rectum. Although not widely published, stent placement for
tumors that obstruct the mid or lower rectum may result in relief
of obstruction but an insufficient remaining rectal reservoir,
resulting in the development of intractable tenesmus and incon-
tinence which severely impairs QOL.84 It is best to recognize such
patients as inappropriate for treatment with a stent and consider
performing surgical diversion or other palliative approaches.
The proper evaluation of the efficacy of palliative treatments
requires a careful assessment of the effect of each treatment on
symptoms and the QOL and less attention on survival. In one
prospective, nonrandomized study evaluating the effect of endo-
scopic stenting and surgical diversion in palliating malignant
colorectal obstruction, symptoms improved significantly after
either treatment but were more durable after stenting than after
surgery. Although there was a trend, neither stenting nor surgery
had a significant effect on overall QOL.82 This and other studies
demonstrate how difficult it is to actually quantify the benefits of
therapeutic interventions in the dying patient.
Drainage percutaneous endoscopic gastrostomy in
bowel obstruction
Some patients with significant intraperitoneal disease not ame-
nable to other options experience intractable nausea and vomit-
ing which are relieved by the insertion of NGT. Long-term use
of this tube is, however, associated with severe nasopharyngeal
discomfort, pain with swallowing, speaking, and coughing, or
may be cosmetically unacceptable and confine the patient at
home. In such patients, gastric venting with PEG tube place-
ment has become a widely acceptable alternative for palliat-
ing nausea and vomiting.27,84,85 Endoscopic or radiographically
guided placement of drainage PEG tubes is a rapid and safe
method of achieving symptomatic relief without the risks of a
traditional surgical procedure even in the presence of ascites,
adhesions, or tumor infiltration of the stomach. 84–87 However,
for most patients with MBO from advanced peritoneal carci-
nomatosis, drainage PEG tubes only help to reduce some of the
symptoms associated with MBO and often require additional
efforts at controlling symptoms.
387
Pharmacological management of symptoms
The pharmacological management of bowel obstruction due to
advanced cancer focuses on the treatment of nausea, vomiting,
pain, and other symptoms without the use of an NGT. If a central
venous catheter has been previously inserted, this can be used to
administer drugs for symptom control. Continuous subcutane-
ous infusion of drugs using a portable syringe driver allows the
parenteral administration of different drug combinations, pro-
duces minimal discomfort for the patient, and is easy to use in a
home setting.
Drug therapy comprising analgesics, antisecretory drugs,
and antiemetics, without using an NGT, was first described by
Baines et al.88 Several authors have confirmed the efficacy of this
approach. 3–7 In most MBO patients, oral administration is not
suitable and most drugs can be administered via parenteral con-
tinuous infusion. To relieve continuous abdominal pain, opioid
analgesics via continuous subcutaneous or intravenous infusion
are necessary in most patients. The drugs and dosage has to be
titrated and frequently reassessed for each patient until pain relief
is achieved. Anticholinergics may be administered in association
to opioids to control colicky pain7 (Figure 41.3).
Vomiting can be managed using two different pharmacological
approaches and reduced to an acceptable level for the patient (e.g.,
1–2 times/day): (1) drugs such as anticholinergics (scopolamine
butylbromide [SB], glycopyrrolate) and/or octreotide, which
reduce GI secretions, and (2) antiemetics acting on the central
nervous system, alone or in association with drugs to reduce GI
secretions (Figure 41.3). For example, olanzapine at the dose of
4.9 mg ± 1.2 mg for 23 ± 16 days significantly decreased the aver-
age nausea score in 90% of patients and the vomiting frequency
(p < 0.001) in incomplete bowel obstruction unresponsive to
chlorpromazine, corticosteroids, domperidone, haloperidol,
metoclopramide, or prochlorperazione.89
Another strategy to reduce gastric secretions is the use of
histamine-2 receptor antagonists and proton-pump inhibitors
(PPIs). A meta-analysis based on seven randomized controlled
trials (RCTs) showed both drugs reduced gastric secretions and
ranitidine was the most potent.90 Based on this report, we can-
not make final conclusions, but these findings represent another
tool available in the management of this condition and something
that needs further investigation.
Several authors recommend the use of corticosteroids for the
symptoms due to bowel obstruction because it can reduce peri-
tumoral inflammatory edema, thus improving intestinal motility.
No robust trials have been carried out and administration routes
and dosing of these drugs have not been standardized as yet.
A systematic review showed a tendency but not significant reduc-
tion in symptoms in the steroids group compared to the placebo.
In terms of mortality, there are no differences between both
groups. The role of corticosteroids in treating bowel obstruction
is still controversial.91 However, the coadministration of octreo-
tide, corticosteroids, and metoclopramide produced a prompt
resolution of GI symptoms and recovery of bowel movements
within 5 days.92
SB is a frequently used drug for both vomiting and colicky pain
by some palliative care centers.88,93–95 This drug differs from both
atropine and scopolamine hydrobromide in having a low lipid
solubility. It does not penetrate the blood–brain barrier as much
as these other drugs and, consequently, may produce fewer side
effects, such as somnolence and hallucinations, when adminis-
tered in combination with opioids. The anticholinergic activity
388
FIGURE 41.3  Symptomatic pharmacological approach.
of SB decreases the tonus and peristalsis in smooth muscle and
decreases the secretions in the GI tract. The antiemetic, antise-
cretory, as well the analgesic role of SB administered subcutane-
ously by a syringe driver has been well documented. Dry mouth
is reported to be the most significant side effect, but the patients
tolerated it by sucking ice cubes and drinking small sips of water.
Anticholinergic agents such as scopolamine hydrobromide or
butylbromide and glycopyrrolate reduce colicky pain and the
volume of intestinal secretions. Glycopyrrolate, which is used
as an antisecretory drug in the United States, is more potent
than scopolamine hydrobromide and may be effective in some
patients who fail to respond to scopolamine.96 It has little
central nervous system penetration and is unlikely to cause
the delirium that has been associated with tertiary amine
anticholinergics.
Octreotide, a synthetic analog of somatostatin that has a more
potent biological activity and a longer half-life, has been shown
to inhibit the release and activity of GI hormones, modulate GI
function by reducing gastric acid secretion, slow intestinal motil-
ity, decrease bile flow, increase mucous production, and reduce
splanchnic blood flow. It reduces GI contents and increases absorp-
tion of water and electrolytes at intracellular level via cAMP and
calcium regulation. Submucosal somatostatin-containing neu-
rons, activated by octreotide, inhibit excitatory nerves, mainly
by an inhibition of acetylcholine output. Octreotide has been
shown to have a potent anti-VIP effect resulting in the inhibition
of intestinal secretions.97–99 Also in the in vitro experiments on
rabbit ileum, somatostatin was able to stimulate water and NaCl
absorption, inhibit HCO3 secretion, and inhibit water secretion in
the jejunum.13,100 As a result, muscle relaxation can occur, amelio-
rating the spastic activity responsible for colicky pain. The drug
may therefore break the vicious circle represented by secretion,
distension, and contractile hyperactivity.
Textbook of Palliative Medicine and Supportive Care
Experimental studies suggest that the principal mechanism
of fluid secretion in bowel obstruction depends on VIP-induced
inflammatory events.13,97,101 Another inhibitory mechanism of
hormonal release occurs through the activation of a G protein,
which, on stimulating the potassium channels, determines the
hyperpolarization of the cell, with the consequent blockage of
the flux of calcium to the cell.102 Octreotide may be administered
by subcutaneous bolus or continuous subcutaneous or intrave-
nous infusion. Its half-life is about 1.5 hours after intravenous
or subcutaneous administration and its kinetics are linear. The
recommended starting dose is 0.3 mg/day subcutaneously. The
dose can be titrated upward until symptom control is achieved
in general 0.6–0.9 mg/day. Octreotide is an expensive drug, and
its cost–benefit ratio should be carefully considered, especially
for prolonged treatment. However, the cost of the drug should be
interpreted in the widest possible sense, that is, if the use of a
drug results in a more rapid improvement of GI symptoms that
potentially limits the bed stay or the admission to an inpatient
unit in addition to a better QOL of the patient.103
Efficacy of octreotide in patients with GI symptoms
due to inoperable malignant bowel obstruction
Many studies, although uncontrolled, strongly support the use
of octreotide in reducing GI secretions, nausea, and vomiting in
patients with MBO. 3,5,7,12,104–121 In many cases, the NGT can be
removed. Reported effective doses range from 100 to 600 mcg/
day either as a continuous infusion or as intermittent subcutane-
ous boluses. Octreotide has been coadministered with numerous
other agents including morphine, haloperidol, and SB.
All the authors were able to show the efficacy on emesis in can-
cer patients with intractable continual vomiting due to small-/
large-bowel obstruction that was unresponsive to conventional
therapy (prochlorperazine, metoclopramide, cyclizine, and
Malignant Bowel Obstruction 389

dexamethasone). Octreotide was administered subcutaneously in
association (or not) with opioid analgesics and with antiemetics.
Symptom control was maintained until death. No adverse
effects were attributable to the drugs. The NGT was removed in
most patients.
In the four prospective studies published in 2000–2018,118–121
different antiemetics were used as single agent or in associa-
tion.118 Frequently antiemetics are used in association with cor-
ticosteroids and so it may be the combination rather than the
single drug which was effective.
Octreotide was successfully used for treating nausea and vom-
iting in patients with different primary cancers. 3,5,7,12,104–121
In the presence of marked and diffuse bowel distension, the
administration of octreotide may reduce GI secretions and thus
allow an appropriate site for PEG placement to be obtained.112
These studies, although uncontrolled, support the use of
octreotide in the management of GI symptoms due to inoper-
able MBO. Reported effective doses range from 0.1 to 0.6 mg/
day either as a continuous parenteral infusion or as intermittent
subcutaneous or intravenous boluses. Octreotide, administered
in association, respectively, with morphine or hyoscine butyl-
bromide (HB) or haloperidol (0.5—1.2 mg/mL), does not show
visual precipitation when mixed in the syringe.7 Recognizing that
octreotide is an expensive therapy and considering the fact that
the goal of the treatment is the improvement in the QOL of the
patient and based on the strong evidence available in the litera-
ture that supports a real benefit with the use of this medication,
the authors of this chapter consider that octreotide should be part
of the treatment once the patient is diagnosed despite the cost.
Randomized clinical trials carried out in patients with MBO
are summarized in Table 41.4.122–125 From 2009 to 2018, four ran-
domized trials (three double-blind) were published.122–125 Results
related to octreotide are fairly consistent across studies (see
Table 41.4 for details).
In trials where corticosteroids were not used,119–121,123 there
was an important improvement of nausea and vomiting with
improvements in secondary outcomes as opposed to trials that
included corticosteroids and antiemetics.122,124
Comparative studies between octreotide and
scopolamine butylbromide
Three randomized trials have compared octreotide with SB.126–128
In all of these trials, octreotide was superior in the control of
symptoms compared to SB.
Two randomized prospective studies were carried out to com-
pare the antisecretory effects of octreotide (0.3 mg/day) and SB
(60 mg/day) administered by continuous subcutaneous infu-
sion for 3 days in 17 patients with inoperable bowel obstruc-
tion having an NGT126 and in 15 patients without NGT.127 In
both studies, 50% of the patients were cared for at home and the
other half were hospitalized in surgical wards. In both studies,
the hospitalized patients received significantly more parenteral
hydration (2000 vs. 500 mL daily) with respect to the patients
cared for at home.

TABLE 41.4  Summary of Randomized Controlled Trials122–125

Type of
Standard Therapy n. PT Population Study
Drugs Under Study Co-administered with Cancer Duration Outcomes and Tools Results
Currow Infusion in 24 hours Infusion in 24 hours: 87 patients Double blind, Primary - No difference in number of
DC122 Ocreotide 600 µg Ranitidine 200 mg (45 on OCT): placebo - Pts reported days free of days free from vomiting: 1.87
(OCT) or placebo (P) Dexamethasone 8 mg - No cancer controlled vomiting at 72 hours vs. 1.69 (OCT vs. controls)
Comparative trial Hydration treatments randomized Secondary - Significant decrease in
10/20 mL/Kg - Inoperable 3 days - Vomiting episodes vomiting episodes with OCT
As needed therapies (clinical - Patient-rated global (IRR = 0.4, 95% CI: 0.19–0.86,
- Hyoscine assessment of 2 impression of change p = 0.019)
butylbromide (HB) medical (-3% + 3) - No difference in patient perceived
PRN for colic practitioners) - Survival global improvement and survival
- Opioids for pain - Nausea (NGT-CTCAE) - No difference in nausea or pain
- Haloperidol for - Pain (BPI) - OCT was associated with
nausea - Australian KPS increased need for HB (OR = 2)
Peng X123 SC infusion in 24 Not possible: 96 patients with RCT Primary - OCT significantly reduced
hours of OCT 300 The use of steroids, advanced 3 days - Antisecretive effect secretions > SB(p < 0.05)
µg or scopolamine antiemetics, ovarian cancer between OCT and SB - SB reduced secretions at (T3)
butylbromide (SB) anticholinergics, H2 and NGT Parameters measured daily: - OCT reduced vomiting
60 mg blockers, (48 on OCT): - Number of vomiting significantly more than SB day
comparative trial omeprazole - No cancer episodes 1–3 (p < 0.05)
3.5 L of fluids used treatments - Nausea, dry mouth - Reduction of vomiting with SB
Pain treated - Inoperable drowsiness, continuous occurred at day 3
according WHO (assessment of and colicky pain - OCT reduced nausea at day 2,
guidelines surgeon) By a Likert scale (0 = no, 3, 7 more than SB (p < 0.05)
1 = slight, 2 = moderate, - No change in colicky pain, dry
3 = severe) mouth or drowsiness
- ECOG - Continuous pain was significantly
- Quantity of GI secretions lower with OCT as compared
through the NGT with SB at day 2 and 3 (p < 0.05)

(Continued)
390 Textbook of Palliative Medicine and Supportive Care

TABLE 41.4  Summary of Randomized Controlled Trials122–125 (Continued)

Type of
Standard Therapy n. PT Population Study
Drugs Under Study Co-administered with Cancer Duration Outcomes and Tools Results
Laval G124 On days 1,29,57 Possible therapies The study started Randomized Primary Imbalance with lower KPS in
30 mg IM OCT LAR + Parenteral hydration/ in 2005 and phase II ITT at day 14 octreotide arm
On days 1 to 6 nutrition, finished in 2008 pilot study - Response = < 2 vomiting
• 28 withdrew between
600 µg OCT IR, SC or antiemetics, 102 patients Double blind episode days 10–13,
baseline to day 14
IV and IV bolus antispasmodics, planned and 64 Placebo - No NGT between day
• ITT analysis
methylprednisolone proton-pump enrolled group 10–13
• Response: 12 octreotide, 9
(3 to 4 mg/kg/day) inhibitors, H2 (32 OCT and non- - No anticholinergic until
placebo, (p > 0.05)
anatagonists, 32 P) comparison day 14, withdrawal prior to
• Median survival: 31.5 days
analgesics, and All the patients 14 days day 14
octreotide, 44 days placebo
NGT had peritoneal Secondary
carcinomatosis QoL by ESAS
- Inoperable
(assessment of
surgeon)
Mariani 30 mg lanreotide 80 patients with Double blind Primary More patients on lanreotide than
et al.125 microparticles vs. peritoneal parallel- Proportion of patients placebo were responders but not
placebo carcinomatosis group phase responding on day 7 (1 or statistically significant for the
Patients previously (37 P) 10 days less episodes of vomiting/ primary analysis (ITT )
treated with IV 67 pts (84%) day or no vomiting population and statistically
corticosteroids and completed the recurrence after NGT significant for the supportive PP
proton-pump study removal for ≥ 3 analysis (p < 0.05) and ITT
inhibitors - Inoperable consecutive days analysis on the basis of
(assessment of Secondary investigators’ assessments
surgeon) Frequency of vomiting/ (p < 0.05)
NGT secretions, nausea, Well-being significantly greater
abdominal pain, well- with lanreotide on days 3, 6, and 7
being, safety No difference for secondary
end-points
Abbreviations: SC, subcutaneously; NGT, nasogastric tube; RCT, randomized clinical trial, IM, intramuscular; LAR, long-acting release; IR, immediate release.

In the study of Ripamonti et al.,126 octreotide was shown to
significantly reduce the amount of GI secretions already at T2
(p = 0.016) and T3 (p = 0.020). The NGT could be removed in
all 10 home care patients and in 3 hospitalized patients without
changing the dosage of the drug. In three patients, it was possible
to remove the NGT when the octreotide was added to SB (one
patient) or when the SB dose was doubled and parenteral hydra-
tion was reduced (one patient). Also in these patients, octreotide
showed a trend toward better efficacy than SB.
It can be hypothesized that in the hospitalized patients, the
major difficulty in removing the NGT was associated with the
higher amount of parenteral hydration.
In the second study,127 octreotide treatment induced a signifi-
cantly rapid reduction in the number of daily episodes of vomiting
and intensity of nausea when compared to SB-treated patients,
examined at the different time intervals.
In the third RCT, Mystakidou et al.128 evaluated the efficacy of
octreotide in the management of nausea, vomiting, and abdomi-
nal pain, secondary to MBO in inoperable cancer patients. Sixty-
eight terminally ill patients were enrolled, and the patients were
randomly assigned to two equal groups. One group received SB
60–80 mg/day and chlorpromazine 15–25 mg/day, and the com-
parative group received octreotide 0.6–0.8 mg/day and chlor-
promazine 15–25 mg/day. The drugs were administered via
continuous subcutaneous infusion. Patients on octreotide pre-
sented significant less intensity of nausea and quantity of vomit-
ing episodes. The survival time ranged from 7 to 61 days.128
The association of the two drugs (octreotide and SB) may
reduce GI secretions and vomiting whenever one drug alone is
ineffective.117,126
Recently 2016 updated MASCC/ESMO consensus recommen-
dations on the management of nausea and vomiting in advanced
cancer was published.129 Octreotide is the recommended drug in
MBO, it has to be dosed around the clock and given alongside
an antiemetic (with the committee recommended haloperidol).
If octreotide plus antiemetic is ineffective, the use of anticholin-
ergic antisecretory agents (e.g., SB and glycopyrronium bromide)
and/or corticosteroids is recommended as either adjunct or
alternative interventions. The use of cyclizine or 5-HT3 receptor
antagonists is ill defined in this setting. Metoclopramide is rela-
tively contraindicated in partial bowel obstruction and absolutely
contraindicated in complete bowel obstruction.
Conclusions
Bowel obstruction should be carefully evaluated by expe-
rienced physicians, considering individual and prognostic
factors, as well as life expectancy. Different options may be
chosen depending on the goals of intervention, and the modal-
ities of occurrence of bowel obstruction, as well as the patient’s
conditions. Involvement of patient and family members in this
therapeutic decision-making is mandatory, based on clear
information about the clinical status and the possible evolu-
tion of the clinical course. Further controlled studies on large
Malignant Bowel Obstruction
numbers of patients are needed, looking at the problems from
the epidemiological and prognostic point of view. Comparative
trials performed at different stages of bowel obstruction could
make an important contribution to defining the best treat-
ments in potentially reversible conditions as well as estab-
lished MBO.
KEY LEARNING POINTS
• MBO is the most distressing outcome in patients
with abdominal and pelvic cancer in the advanced
and terminal stage of disease.
• Surgery should not routinely be undertaken in
patients with poor prognostic criteria such as
intra-abdominal carcinomatosis, poor perfor-
mance status, and massive ascites.
• Medical measures such as analgesics, antisecre-
tory drugs, and antiemetics administered alone
or in combination should be used to relieve
symptoms.
• Endoscopic management of MBO should always
be considered.
• An NGT should be used only as a temporary
measure, and a venting gastrostomy should be
considered if drugs fail in reducing vomiting to
an acceptable level.
• Total parenteral nutrition (TPN) should be con-
sidered only for patients who may die sue to star-
vation rather than from tumor spread.
• Parenteral hydration is sometimes indicated to
correct nausea, and regular mouth care is the
treatment of choice for dry mouth.
• A collaborative approach by surgeons and phy-
sicians can offer patients an individualized and
appropriate symptom management plan.
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105. Mercadante S, Avola G, Maddaloni S, Salamone G, Aragona F, Rodolico
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106. Sun X, Li X, Li H. Management of intestinal obstruction in advanced
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107. Khoo D, Riley J, Waxman J. Control of emesis in bowel obstruction in
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108. Mercadante S, Maddaloni S. Octreotide in the management of inop-
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Octreotide in relieving gastrointestinal symptoms due to bowel
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110. Mangili G, Franchi M, Mariani A, et al. Octreotide in the manage-
ment of bowel obstruction in terminal ovarian cancer. Gynecol Oncol
1996;61:345–348.
111. Steadman K, Franks A. A woman with malignant bowel obstruction
who did not want to die with tubes. Lancet 1996;347:944.
112. Sartori S, Trevisani L, Nielsen I, Tassinari D, Righini E. Identification
of a safe site for percutaneous endoscopic gastrostomy placement in
patients with marked bowel distension: May octreotide have a role?
Endoscopy 1994;26:710–711.
113. Mercadante S, Kargar J, Nicolosi G. Octreotide may prevent definitive
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114. Fainsinger RL, MacEachern T, Miller MJ, et al. The use of hypoder-
moclysis for rehydration in terminally ill cancer patients. J Pain Sympt
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115. Shima Y, Ohtsu A, Shirao K Sasaki Y. Clinical efficacy and safety of
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116. Hisanaga T, Shinjo T, Morita T, et al. Multicenter prospective study
on efficacy and safety of octreotide for inoperable malignant bowel
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117. Mercadante S. Scopolamine butylbromide plus octreotide in unrespon-
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42
ENDOSCOPIC TREATMENT OF DIGESTIVE SYMPTOMS

Pasquale Spinelli

Contents
Introduction........................................................................................................................................................................................................................395
Palliative treatments..........................................................................................................................................................................................................395
Surgery.......................................................................................................................................................................................................................... 396
Radiotherapy................................................................................................................................................................................................................ 396
Chemotherapy............................................................................................................................................................................................................. 396
Endoscopy and gastrointestinal symptoms................................................................................................................................................................. 396
Dysphagia, regurgitation, salivation, odynophagia, bleeding, and vomiting.................................................................................................. 396
Palliative endoscopic options for dysphagia.................................................................................................................................................................397
Nasogastric tube...........................................................................................................................................................................................................397
Dilation...........................................................................................................................................................................................................................397
Laser treatment.............................................................................................................................................................................................................397
Photodynamic therapy................................................................................................................................................................................................397
Endoscopic intratumoral injection of alcohol or chemotherapeutic drugs.....................................................................................................397
Cryotherapy...................................................................................................................................................................................................................397
Other treatments (electrocoagulation, argon plasma, and adrenalin injection).............................................................................................397
Prostheses......................................................................................................................................................................................................................397
Percutaneous gastrostomy/jejunostomy.................................................................................................................................................................398
Malignant jaundice............................................................................................................................................................................................................398
Constipation..................................................................................................................................................................................................................398
Palliative endoscopic options for constipation and colon and rectum obstructions.....................................................................................398
Surgery...........................................................................................................................................................................................................................398
Endoscopic options......................................................................................................................................................................................................398
Conclusions.........................................................................................................................................................................................................................398
References���������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������399

Introduction • Consider the side effects of a treatment and weigh up the

The number of patients surviving a long time after the diagno-
sis of a non-curable digestive cancer is continuously increasing.
Most of these patients need to be supported by further treatments
aiming to improve the quality of life.1 It is extremely important
to identify the borders between curable and non-curable cancers
through accurate staging procedures. In patients not curable or
not responding to therapy, the palliation of symptoms is essential,
involving a multidisciplinary team.2
Mistakes in this evaluation can result in giving anticancer
treatments to patients with non-curable diseases and, on the
other hand, deprive a curable patient of proper and effective treat-
ments. This is the source of cases of over- or undertreatments.
Before deciding to propose a palliative treatment, the oncolo-
gist should consider the following points:
• Give the correct information about the curative potentials
of surgery, radiotherapy, chemotherapy, or monotherapy,
immunotherapy, and possible therapeutic combinations
and any other kind of certified treatments.
• Evaluate the risk factors relevant to the circumstances of a
particular patient.
pros and cons, especially the likely quality and duration of
the remaining life of the patient.
• Weigh up the likely impact of the therapeutic procedures
with regard to the expected benefits.
With the availability of a variety of old and new prognostic tools
in the form of clinical, pathological, and molecular tests, the pos-
sibility of identifying the correct stage of a cancer with extreme
precision and predicting the response to an anticancer treatment
are becoming possible.
Palliative treatments
Cancer of the alimentary tract growing inside the digestive tube
and bleeding from ulcerations causes obstructive symptoms,
associated hemorrhage, and consequent anemia. Treatment
opportunities are quite different in intrathoracic (esophageal)
and intra-abdominal tumors3,4
Palliative care should not be limited to the patients with pre-
terminal disease, but greatly expanded, starting with the control
of symptoms as soon as the disease is staged and classified as
incurable.

395
396
Surgery
The classical option to overcome both obstruction and bleeding
in the digestive tube is resective surgery with end-to-end anas-
tomosis. When this is not possible or advisable due to the local
conditions of the lesion or the general conditions of the patient,
the other surgical possibility is a bypass operation.5
Surgery is generally the first option to be considered. From
the surgeon’s standpoint, therapy is considered palliative when
removal of all known tumor sites is not possible. So, the success
of the therapy is determined by restoring the lumen and reducing
bleeding by removing a tumor mass. The operation must be per-
formed through laparoscopic access, achieving the double goal
of minimum trauma and quick recovery.6 The appropriate use of
surgery in these settings can improve the quality of life.
Radiotherapy
This is mainly used for esophageal cancer and cancers of the rec-
tum. External radiotherapy and endoscopic brachytherapy4 are
used to reduce the tumor mass. They can be used in combination
with chemotherapy in selected cases of large cancers to make the
tumor become surgically resectable.
Under specific circumstances, external radiotherapy can be
combined with endoscopic treatments, thus combining endo-
luminal with the extraluminal benefits of mass reduction. In
some cancers causing local symptoms, the irradiation of medi-
astinal tissue surrounding the esophagus and reduction of the
size of the tumor may also result in partial control of pain. The
effect of brachytherapy is ephemeral and generally lasts no more
than 5–12 weeks. Esophagitis is a frequent complication of both
external radiotherapy and brachytherapy and must be treated by
appropriate medical support.
Chemotherapy
Perioperative, adjuvant or neoadjuvant chemotherapy with mul-
tiagent regimens, also in association with radiotherapy, is used to
treat cancers located in the esophagus as well as in stomach, liver,
pancreas, colon, and rectum. The treatments aim to reduce the
size of neoplastic masses and to restore the transit.7 Furthermore,
in patients who have locally advanced, unresectable disease and
in patients in whom tumors are resected with palliative intent,
the duration of survival can be increased with palliative chemo-
therapy and irradiation. The therapy is based on cisplatin, 5-flu-
oruracil, or taxanes plus radiotherapy.
Endoscopy and gastrointestinal symptoms7
Esophagogastrointestinal symptoms may be produced by diges-
tive or by extradigestive tumors. The gastrointestinal tract has
cavities that function as “containers” or as “canals” (stomach,
esophagus, intestine, biliary, and pancreatic tract). Tumors
reduce the space available and impair the functions of contain-
ing (the stomach) and transit (the esophagus and intestine);
moreover, tumors infiltrating and ulcerating the walls of these
cavities cause hemorrhage, obstruction, perforation, and fistula
formation. The most important symptoms of digestive tumors
are dysphagia, odynophagia, salivation, vomiting, jaundice, pain,
constipation, and hemorrhage. All these symptoms can be treated
by endoscopic modalities.
There are different ways to achieve relief from symptoms. The
physician must be able to discuss with the patient the different
symptom relief methods available so that the patient can choose
the one that fits better with the preferred lifestyle. For example,
Textbook of Palliative Medicine and Supportive Care
esophageal stenosis can be relieved by a nasogastric tube, by a
laser or other thermal treatment, by a gastrostomy, by stent inser-
tion or palliative radio-chemotherapy. Patients must be informed
about these options so that they can decide which one is the most
suitable for their way of life.
Dysphagia, regurgitation, salivation, odynophagia,
bleeding, and vomiting
Malignant dysphagia can be related to the presence of primary or
secondary esophageal tumors, or it can be consequent to esopha-
gitis after a surgical treatment or a radiotherapy or chemotherapy.
Dysphagia can be defined as an abnormal swallowing, characterized
by difficulty in transferring solid or liquid food or saliva from the
mouth to the stomach; various degrees of dysphagia are used to eval-
uate the response to the treatment. Beyond the most common causes,
in oncological patients, dysphagia may occur due to the following:
• Neurological reasons, for example, cricopharyngeal dys-
phagia because of recurrent nerve palsy due to perineural
and neural infiltration by tumor tissue; neurological dys-
phagia may also occur due to vagal or sympathetic tumoral
infiltration, with the involvement of the skull base or due
to brain metastases.
• Mucositis related to candidosis, bacterial infection, herpes,
radiotherapy, chemotherapy, gastric or biliary reflux.
• Asthenia/cachexia.
A patient becomes dysphagic when the diameter of the esopha-
geal lumen is less than 14 mm, but an uncertain feeling of trouble
in swallowing is generally complained some weeks or months
before the diagnosis of esophageal cancer.
Esophagoscopy is indicated when a patient complains of dys-
phagia; it allows to locate a tumor, to measure its length, to appre-
ciate the circular extent and the size of the residual esophageal
lumen, and to obtain histological samples. Echoendoscopy is
extremely useful for determining the level of infiltration across
the esophageal wall, the involvement of neighboring anatomical
structures and the eventual presence of metastatic lymph nodes.
Infiltration of the wall interrupts the progression of peristaltic
movements and stops the progression of food; this interruption
causes a variety of symptoms, depending on whether it is partial
or total. Partial obstruction can stop solid food but allow passage
of liquids; total obstruction causes liquids to collect above the site
of the obstruction and the upper esophageal sphincter.7
Long-standing stenoses can cause incompetence—permanent
or episodic—of the upper esophageal sphincter and the regurgi-
tation of undigested material together with inhalation leading to
cough and sometimes pneumonia. Total esophageal obstruction
stops the passage of saliva to the stomach and causes the onset of
another invalidating symptom, the salivation.
The patient complaining of salivation is obliged to spit or drib-
ble continuously and walks around with a bag full of handker-
chiefs, deprived of a social life. Dysphagia can be associated with
odynophagia, generally caused by inflammation of the esophageal
wall or by candidiasis or herpes virus; odynophagia too may cause
salivation. Salivation and regurgitation often cause coughing as
patients attempt to swallow. After insertion of a stent into a ste-
notic esophagus, cough on swallowing disappears because, after
the opening of the esophageal transit, there is no more esophago-
tracheal regurgitation.
Endoscopic treatment can be beneficial for bleeding and vomit-
ing from gastric or extra-gastric (e.g., pancreatic) tumors infiltrate
Endoscopic Treatment of Digestive Symptoms
the gastric wall.16 Malignant ulcerations bleed and produce ane-
mic conditions, speeding up the progression toward cachexia.
To stop bleeding, endoscopic laser photocoagulation, electro-
coagulation, cryotherapy, and injection of sclerosing drugs and/
or adrenalin can be used for cytoreductive as well as hemostatic
purposes. The duration of the effect of these treatments is limited
and the rebleeding is a rule. Vomiting is produced by gastric or
intestinal obstruction. Duodenal obstructions can be treated by
performing a translaparoscopic bypass between the gastric body
and the first jejunal loop, although expandable prostheses are also
used to bypass stenosing lesions. Duodenum and gastric antrum
can be obstructed by primary or metastatic tumors. Malignant
lymph nodes, pancreatic, and ampullary cancers are the most
frequent causes of duodenal obstruction. Together with biliary
tumors, these conditions are responsible for biliary obstruction
and cause malignant jaundice.
Palliative endoscopic options for dysphagia
Nasogastric tube
Treatment of dysphagia and its sequels is based on crossing the
obstacle that prevents the passage of food: This can be achieved by
a nasogastric tube, by restoring the esophageal lumen by dilation,
laser treatment, photodynamic therapy, endoscopic injection of
chemotherapeutic drugs or alcohol, endoluminal brachytherapy,
argon plasma coagulation, cryotherapy, prostheses insertion,
and finally, performing a gastrostomy or jejunostomy. All these
different options have specific indication.8–10 The purpose of
inserting a nasogastric tube is feeding liquid food. The indica-
tion is restricted to cases in which the stenotic obstacle cannot
be dilated more than 4–8 mm; this mainly happens when there
is postoperative or postradiotherapy fibrotic stenosis that makes
forced dilation dangerous as there is a possibility of perforation.
There are several different disadvantages of the nasogastric tube:
Esthetic: the patient is obliged to live with the tube coming out
of the nose.
Functional: the external surface of the tube adheres strictly
to the inner surface of the stenotic tract, and this prevents
saliva from being swallowed, leading to salivation.
Sensuous: with food introduced through the tube, the patient
is unable to enjoy its taste, one of the few pleasant sensa-
tions remaining at this stage of the life.
Patients complain of these disadvantages also after the creation
of a gastrostomy or jejunostomy.
Dilation
Dilation can be performed using pneumatic balloon dilators,
metallic olives, and plastic bougies: All can slide along a previously
introduced guidewire and enlarge the esophageal lumen up to 20
mm. or more.9 The drawback of the dilation is that the stenosis will
recur in 1–3 weeks, and dilations must be frequently repeated.
Laser treatment
This aims to reopen the esophageal lumen through the thermal
coagulation–destruction of the cancer tissue: power laser radia-
tion increases the local temperature of the irradiated tissues and
causes the tissue water to evaporate.10 The neodymium:yttrium
aluminum garnet (Nd:YAG) laser is the most frequently used due
to the depth of the penetration of its radiation (1064 nm) into
the cancer tissue. The treatment is precise and safe in appropri-
ate hands, and the esophageal lumen can be fully restored so as
397
to obtain a satisfactory eating function; the mean duration of the
patency of the lumen is estimated to be 4–8 weeks. Laser treat-
ments were more popular before the end of last century. Most
centers abandoned laser techniques in favor of stents, easier to be
inserted, safer, and maintaining a more durable palliation.
Photodynamic therapy
Photodynamic therapy (PDT) uses intravenously injected pho-
tosensitizing drugs from the group of porphyrins that are selec-
tively fixed by the tumor tissue. The photosensitizer, activated by
light, produces singlet oxygen that is toxic for biological tissues
and causes a necrotic effect;11 unlike the procedures discussed
earlier, which are immediately effective, the necrotic effect of
PDT needs 4–8 days to become apparent, and the relief from
obstruction lasts for 5–10 weeks.12,13 Moreover, patients submit-
ted to PDT have to avoid direct sunlight for 4–6 weeks because of
skin photosensitization.
Endoscopic intratumoral injection of alcohol or
chemotherapeutic drugs
These forms of locally induced necrosis are technically simple,
not expensive14 and do not need special and sophisticated tech-
nologies. Related to tumor bulk 10–20 ml of pure ethanol are
injected under endoscopic visual control into the tumor tissue.15
Among the various chemotherapeutic drugs, mitomycin and
5-fluoruracil are the most frequently used to be injected into the
tumor and provide intensive and durable necrotic phenomena,
especially if the injection is combined with laser therapy.
Cryotherapy
Cryotherapy is based on the sudden reduction of local tempera-
ture in the tumor mass. The reduction of temperature is obtained
using special probes introduced through an endoscope and put
in contact with the tumor. The effect of the sudden reduction in
temperature is that the bleeding stops and tumor necrosis is pro-
duced, so as to temporarily reopen the esophageal transit.15,16
Other treatments (electrocoagulation, argon plasma,
and adrenalin injection)
These kinds of treatments combine the effect of destroying tumor
tissue with stop bleeding. The techniques are based on the effect
of a beam of heat (e.g., laser, electrocoagulation) on a bleeding
surface. In the case of argon-plasma a jet of argon gas switched to
form argon plasma is directed to the tumor surface under endo-
scopic control to coagulate the bleeding source. Transedoscopic
adrenalin injection is also used for immediate stop of a bleeding
artery. Sometimes cryotherapy also can be used.
Prostheses
Introducing a stent after reopening a stenotic tract prevents an
early recurrence of the obstruction. Inserting an expandable
stent is no more traumatic than performing a normal flexible
esophagoscopy.
New 3D printing technique may allow manufacturing person-
alized stents. Drug-eluting stents open a new horizon for these
patients, giving anticancer drugs directly to the tumor simultane-
ously with the reopening of the obstructed lumen. Gemcitabine,
docetaxel, or paclitaxel in bilayer films, progressively releasing
the drugs into the tumor tissue, have been used.
The best results are obtained when the prosthesis does not
interfere with the mechanism of a sphincter (the pharyngo-
esophageal or the cardiac sphincter). When the cardiac sphincter
is infiltrated by the tumor and the prosthesis keeps it open, the
398
natural antireflux mechanism is impaired and the gastric content
flows back into the esophagus. The acid gastric secretion can be
responsible for supra-prosthetic esophagitis and this condition
causes dysphagia even though the esophagus is patent. However,
in patients submitted to gastrectomy, the reflux through the pros-
thesis may give rise to an alkaline esophagitis.16
The evolution of the cancer through the esophageal wall can
develop a fistula, connecting the esophageal lumen with the skin
of the neck, the trachea, a bronchus, the mediastinum, or the
pleural space. Prostheses are equally used in these patients to
bypass the fistula, allowing passage of the oral intake.18
In case of esophagotracheal or esophagobronchial fistula a
stent can be inserted into the respiratory tract avoiding aspira-
tion pneumonia, a frequent cause of death. Generally, plastic
stents introduced with a rigid tracheo-bronchoscope under gen-
eral anesthesia give the solution. Expandable stents can also be
used in patients with inoperable cancers stenosing the gastric
antrum, causing vomiting, with immediate recovery of gastric
transit accompanied by stopping of vomiting.
Percutaneous gastrostomy/jejunostomy
Percutaneous endoscopic gastrostomy (PEG)19 is proposed only
when it is impossible to carry out one of the previously described
procedures. It consists of the insertion of a feeding/venting tube
into the stomach, through the abdominal wall under direct endo-
scopic control. Such a tube can be advanced to reach the jejunum,
thus becoming a jejunostomy and it can also be used for decom-
pressing an obstructed intestine.
Malignant jaundice
Biliary obstruction caused by biliary, pancreatic, metastatic can-
cer or by lymphomas, obstructing the common bile duct or the
hepatic ducts, causes jaundice. Transpapillary biliary cannulation
(ERCP) and the insertion of a stent is the most used procedure of
drainage; in cases of failure, the drainage can be performed under
endoscopic ultrasonographic (EUS) guidance and punction/can-
nulation of the biliary duct.22,23
EUS-guided drainage can be considered as an alternative in
cases of failure of ERCP.21 Palliative treatments alternatives to the
endoscopic ones (surgical and percutaneous) have higher costs
and complications and lower success rate. They are indicated in
case of failure of the endoscopic procedures.
Expandable stents have a low occlusion and complication rate, are
easy to place with low trauma and immediate effect; stools become
well-stained in the 24–48 h after the procedure, the urine loses pro-
gressively its intensive brown color, and itchiness disappears.
Constipation
Constipation is a very frequent symptom; more than 50% of
advanced cancer patients need to be treated for the infrequent pas-
sage of hard stools. The cause should be clarified. When caused
by anticancer chemotherapeutic drugs (mainly vincristine), opi-
oids, metabolic problems such as hypokalemia, or global electro-
lyte imbalances; it is mostly of the type of a dynamic ileus and is
frequently accompanied by generalized abdominal pain. Intestinal
obstruction by endoluminal masses or by extraintestinal compres-
sions is more frequently accompanied by colicky pain.
Palliative endoscopic options for constipation and
colon and rectum obstructions
In oncological patients with longstanding constipation resistant
to common treatments, endoscopy helps in treating the bowel
Textbook of Palliative Medicine and Supportive Care
distension. Colonoscopy with large channel endoscopes allows aspi-
ration of gas, washing fecal materials and to perform the first pallia-
tive treatment by dilation, laser, or stenting in rectum and colon.23–25
Obstruction can also occur due to metastatic involvement of the
mesenteric lymph nodes or diffuse peritoneal nodular metastases,
for example, in papillary carcinomas, mainly ovarian and pancreatic.
Surgery6
Persistence of bowel obstruction has a strong influence on prog-
nostic outcome. Bypass operations and diverting stomas alleviate
symptoms due to obstruction but do not interfere with symptoms
related to the presence of the tumor, such as bleeding and pain. It
must be managed as soon as possible.
Endoscopic options
Patients to be submitted to endoscopic palliation are those with
very advanced and non-removable cancers. They generally appear
in bad general conditions with weight loss, sometimes cachexia
and surgical operations carry a high mortality, about 10%, and
a survival rate of around 5% at 5 years.26 In the case of stenos-
ing lesion infiltrating the bowel wall, a trans-stenotic guidewire
has to be introduced under endoscopic guidance and a dilator slid
on it; once dilation has been achieved, the fecal transit can been
reestablished, the emergency problem overcome, and the bowel
cleaned. If the patient is inoperable, inserting a stent will keep
open the intestinal lumen and maintain the bowel functions with
a durable effect in more than 80% of treated patients. If surgery
can be performed, the stent will be a bridge to surgery. We started
inserting stents in primary rectal tumors and in recurrences in
rectal anastomoses with a success rate of more than 90%. In most
of our cases, patency of the stent lasts until death.
There are different endoscopic possibilities of treatment,
related to the kind of the obstructing lesion and in particular
to its shape and to the tumor bulk, growing into the lumen or
infiltrating the bowel wall. Once the fecal transit has been rees-
tablished, the emergency problem overcome, and the bowel
cleaned, if the tumor is operable, the lesion can be resected or a
bypass operation performed through a laparoscopic procedure,
which is planned for the following days; if the patient is inoper-
able because of high-risk conditions or because the lesion is not
removable, the endoscopic alternative is the only feasible option.
To keep open the intestinal lumen and maintain the bowel func-
tions, an expandable prosthesis must be inserted in these cases
to obtain a durable effect. Insertion of a prosthesis with a correct
technique and indication allows the patency of the large bowel
to be maintained in more than 80% of treated patients. When
inserting stents in primary rectal tumors and in recurrences in
colorectal anastomoses, we reported a success rate of more than
90%.26 In most of our cases, patency of the stent lasts until death.
Conclusions
The features of endoscopic palliation are:
1. Achievement of an immediate result in the control of
symptoms and the restoration of a normal function,
whereas other options of palliation, such as radiotherapy
and chemotherapy, can have important side effects and
need longer times to become effective;
2. Absence of contraindications; and
3. The possible combination of endoscopic treatments with
any other form of treatment.
Endoscopic Treatment of Digestive Symptoms
Palliative treatments, in each case, should be tailored to the indi-
vidual patient, and to the patient’s capability to undergo the treat-
ments, consisting of a decrease or disappearance of symptoms
and of improvement of performance status.
Endoscopic palliative treatments aim to obtain the best pos-
sible quality of life with immediate and durable benefits with neg-
ligible trauma, side effects, and incidence of complications related
to the proposed advantages.27
Although the primary purpose of a palliative procedure is not
to increase survival, the treatment of severe symptoms (nutri-
tional, respiratory or metabolic) very often results in an effective
extension of the survival. Consequently, palliation becomes, in
many cases, not just the simple treatment of symptoms, but offers
the patient a wide range of therapeutic opportunities during the
entire course of the disease.
References
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ing prognosis in patients with esophageal carcinoma. Ann Surg
2003;238:197–202.
2. Moroney MR, Lefkowits C. Evidence for integration of palliative
care into surgical oncology practice and education. J Surg Oncol
2019;120:17–22.
3. Halpern AL, McCarter MD. Palliative management of gastric and
esophageal cancer. Surg Clin N Am 2019;99:555–569.
4. Taggar AS, Pitter KL, Cohen GN, et al. Endoluminal high-dose-rate
brachytherapy for locally recurrent or persistent esophageal cancer.
Brachytherapy 2018;17: 621–627.
5. Freeman RA, Ascioti AJ, Mahidhara RJ. Palliative therapy for patients
with unresectable esophageal carcinoma. Surg Clin North Am
2012;92:1337–1351.
6. Cloyd JM. Minimally invasive surgery for palliation. Surg Oncol Clin N
Am 2019;28:79–88.
7. Baines MJ. Symptom control in advanced gastrointestinal cancer. Eur
J Gastroenterol Hepatol 2000;12:375–379.
8. Shah MB, Schnoll-Sussman F. Novel use of cryotherapy to control
bleeding in advanced esophageal cancer. Endoscopy 2010;42:E46.
9. Spinelli P, Dal Fante M, Mancini A. Endoscopic palliation of malignan-
cies of the upper gastrointestinal tract using Nd:YaG laser: Results and
survival in 308 treated patients. Lasers Surg Med 1991;11:550–555.
10. Spinelli P, Cerrai FG, Meroni E. Pharingo-esophageal prostheses in
malignancies of the cervical esophagus. Endoscopy 1991;23:213–214.
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11. Lightdale CJ. Role of photodynamic therapy in the management of
advanced esophageal cancer. Gastrointest Endosc Clin North Am
2000;10:397–408.
12. Lightdale CJ, Heier SK, Marcon NE, et al. Photodynamic therapy with
porfimer sodium versus thermal ablation therapy with Nd:YaG laser
for palliation of esophageal cancer: a multicenter randomized trial.
Gastrointest Endosc 1995;42:507–512.
13. Shishkova N, Kuznetsova O, Berezov T. Photodynamic therapy in gas-
troenterology. J Gastrointest Cancer 2013;44:251–259.
14. Ramakrishnaiah VP, Ramkumar J, Pai D. Intratumoural injection of
absolute alcohol in carcinoma of gastroesophageal junction for pallia-
tion of dysphagia. Ecancermedicalscience 2014;8:395.
15. Goetz M, Malek NP, Kanz L, Hetzel J. Cryorecanalization for in-stent
recanalization in the esophagus. Gastroenterology 2014;146:1168–1170.
16. Lal P, Thota PN. Cryotherapy in the management of premalignant
and malignant conditions of the esophagus. World J Gastroenterol
2018;24:4862–4869.
17. Pais-Cunha I, Castro R, Libânio D, et al. Endoscopic stenting for pal-
liation of intra-abdominal gastrointestinal malignant obstruction:
predictive factors for clinical success. Eur J Gastroenterol Hepatol
2018;30:1033–1040.
18. Markos P, Markos S, Ivekovic H, Bilic B, Rustemovic N. Self-expandable
metal stent for dysphagia caused by mediastinal masses in patients
with lung cancer. Arab J Gastroenterol 2019;20:28–31.
19. Russel TR, Brotman M, Norris F. Percutaneous gastrostomy: a new
simplified and cost-effective technique. Am J Surg 1984;148:132–137.
20. Classen M, Koch H, Demling L. Diagnostische Bedeutung des endos-
copischen Kontrastdarstellung des Pankreas-gang-systems. Leber
Magen Darm 1972;2:79–81.
21. Costamagna G. Therapeutic biliary endoscopy. Endoscopy 2000;32:209.
22. Aadam AA, Liu K. Endoscopic palliation of biliary obstruction. J Surg
Oncol 2019;120:57–64.
23. Logiudice FP, Bernardo WM, Galetti F, et al Endoscopic ultrasounr-
guided vs endoscopic retrograde cholangiopancreatography bili-
ary drainage for obstructed distal malignant biliary strictures: A
systrematic review and metanalysis. World J Gastrointest Endosc
2019;11:281–291.
24. Krouse RS. Malignant bowel obstruction. J Surg Oncol 2019;120:74–77.
25. Moon S, Yang S, Na K. An acetylated polysaccharide-PTFE mem-
brane-covered stent for the delivery of gemcitabine for treat-
ment of gastrointestinal cancer and related stenosis. Biomaterials
2011;32:3603–3610.
26. Spinelli P, Mancini A. Use of self-expanding metal stents for palliation
of rectosigmoid cancer. Gastrointest Endosc 2001;53:203–206.
27. Spinelli P, Mancini A, Dal Fante M. Endoscopic treatment of gastro-
intestinal tumors: indications and results of laser photocoagulation
and photodynamic therapy. Semin Surg Oncol 1995;11:307–318.
43
MECHANISM, ASSESSMENT, AND MANAGEMENT OF FATIGUE

Sean Hutchinson, Sriram Yennurajalingam

Contents
Introduction....................................................................................................................................................................................................................... 402
Definition of fatigue.................................................................................................................................................................................................... 402
Frequency..................................................................................................................................................................................................................... 402
Mechanism of fatigue................................................................................................................................................................................................. 403
Tumors, host-derived factors, and cytokines........................................................................................................................................................ 403
Muscle abnormalities................................................................................................................................................................................................. 403
Mitochondrial enzymes............................................................................................................................................................................................. 403
Deconditioning............................................................................................................................................................................................................ 403
Central nervous system abnormalities.................................................................................................................................................................... 403
Relationship between fatigue and cachexia........................................................................................................................................................... 404
Infection........................................................................................................................................................................................................................ 404
Anemia.......................................................................................................................................................................................................................... 404
Autonomic dysfunction............................................................................................................................................................................................. 404
Psychological issues.................................................................................................................................................................................................... 404
Metabolic and endocrine disorders......................................................................................................................................................................... 404
Paraneoplastic neurological syndromes................................................................................................................................................................. 404
Other cancer-related symptoms............................................................................................................................................................................... 404
Side effects of cancer treatment............................................................................................................................................................................... 405
Genetics and cancer-related fatigue........................................................................................................................................................................ 405
Assessment of fatigue................................................................................................................................................................................................. 405
Assessment of fatigue in clinical practice............................................................................................................................................................... 405
Management of fatigue.............................................................................................................................................................................................. 407
Cancer............................................................................................................................................................................................................................ 408
Therapies and medications........................................................................................................................................................................................ 408
Chemotherapy and radiotherapy....................................................................................................................................................................... 408
Biological therapy.................................................................................................................................................................................................. 408
Opioids.................................................................................................................................................................................................................... 409
Cytokine modulation.................................................................................................................................................................................................. 409
Treatment of cachexia................................................................................................................................................................................................ 409
Management of autonomic failure.......................................................................................................................................................................... 409
Neurological disorders................................................................................................................................................................................................410
Treating anemia............................................................................................................................................................................................................410
Pain..................................................................................................................................................................................................................................410
Other comorbidities..........................................................................................................................................................................................................410
Infection.........................................................................................................................................................................................................................410
Psychogenic disorders.................................................................................................................................................................................................411
Insomnia........................................................................................................................................................................................................................411
Metabolic and endocrine abnormalities..................................................................................................................................................................411
Hypogonadism..............................................................................................................................................................................................................411
Chronic hypoxia...........................................................................................................................................................................................................411
Symptomatic management of fatigue............................................................................................................................................................................411
Pharmacological management..................................................................................................................................................................................411
Established agents..............................................................................................................................................................................................................412
Corticosteroids.............................................................................................................................................................................................................412
Progestational steroids................................................................................................................................................................................................412
Psychostimulants..........................................................................................................................................................................................................412
Testosterone..................................................................................................................................................................................................................413
Emerging pharmacological agents......................................................................................................................................................................413
Nonpharmacological management..........................................................................................................................................................................413

401
402 Textbook of Palliative Medicine and Supportive Care

Physical activity or exercise..................................................................................................................................................................................413

Acupuncture............................................................................................................................................................................................................414
Cognitive behavorial therapy...............................................................................................................................................................................414
Neurofeedback........................................................................................................................................................................................................414
Light therapy...........................................................................................................................................................................................................414
Nutritional supplements.......................................................................................................................................................................................414
Education.................................................................................................................................................................................................................415
Counseling...............................................................................................................................................................................................................415
Conclusion...........................................................................................................................................................................................................................416
References���������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������416

Introduction
Fatigue is a subjective sensation of weakness, lack of energy,
or becoming easily tired.1–5 It is one of the most common and
chronic symptoms experienced by advanced cancer patients.6
Fatigue is debilitating and profoundly impacts the quality of life
(QOL) of the patients and their families.7 With the availability of
effective treatments for pain and nausea, screening and treatment
of fatigue has become a major focus of symptom management in
advanced cancer.6
Definition of fatigue
Cancer-related fatigue (CRF) is defined as a “distressing persis-
tent, subjective sense of physical, emotional and/or cognitive
tiredness or exhaustion related to cancer or cancer treatment
that is not proportional to recent activity and interferes with
usual functioning”3(NCCN guidelines 2010). In contrast to mus-
cle fatigue, clinical fatigue is a multidimensional phenomenon
and includes three major components: (1) generalized weak-
ness, resulting in inability to initiate certain activities; (2) easy
fatigability and reduced capacity to maintain performance; and
(3) mental fatigue resulting in impaired concentration, loss of
memory, and emotional lability. Despite the distinction to three
major dimensions (physical, affective, and cognitive), it is unre-
solved whether these dimensions are stable and reproduced in
more general settings.8 Due to the limitation in distinction and
reproducibility of various dimensions, there is also an emerging
thought among fatigue researchers about more of having a “case
definition” for CRF that may best capture and describe what con-
stitutes clinically significant fatigue in subgroups of patients with
advanced cancer.2
Frequency
Fatigue is reported as prevalent in most studied populations
including patients with cancer and palliative care patients. The
frequency of fatigue has been reported to be approximately
60–90% in patients with advanced cancer whereas prevalence of
fatigue is around 20–30% in cancer survivors.7,9–15 The wide range
of these estimates likely reflects variable diagnostic criteria used
to define CRF. For example, using an International Classification
of Diseases, 10th revision (ICD-10 definition criteria), the fre-
quency of fatigue was reported to be 49.8%, far less than reported
in previous studies using a number rating scale (NRS) of 0–10.16
Moderate-to-severe persistent fatigue affects the patients’
QOL and ability to perform activities that add meaning to their
life. Fatigue has been associated with other symptoms, includ-
ing pain, anxiety, depression, cachexia, and insomnia. However,
assessment and treatment of this common symptom is difficult,
as it is a complex, subjective symptom and is often underreported.
Most commonly, the assessment of severity can be used to guide
the management (Figure 43.1).
The pathophysiology of fatigue has already been discussed in
the previous chapters and it is clear that fatigue is usually mul-
tifactorial in patients receiving palliative care.4 Physiological,
psychological, and situational factors can contribute to fatigue.
The most frequent contributing factors in patients with advanced

FIGURE 43.1  Contributors to fatigue.

Mechanism, Assessment, and Management of Fatigue
cancer include weight loss, depression, dyspnea, deconditioning,
isolation, and polypharmacy. 3,12,17 Chronic diseases can produce
factors such as circulating cytokines, inflammation, and auto-
nomic failure that may mediate fatigue.18,19
Although few published studies have correlated fatigue and
cytokines near or at the end of life, several lines of evidence
implicate cytokines in the pathophysiology of fatigue.20 First,
cytokine levels are increased in nononcologic conditions char-
acterized by fatigue, such as chronic fatigue syndrome. Second,
fatigue is a major adverse effect of cytokines administered for
therapeutic purposes including interleukins (IL), tumor necrosis
factor α (TNF α), and interferon (INF).21 Finally, upregulation of
pro-inflammatory cytokines is correlated with fatigue in several
malignancies.11,18
In this chapter, we will discuss the mechanism, assessment,
and management of fatigue in advanced cancer patients.
Mechanism of fatigue
The etiology of fatigue is often unclear in the majority of patients
with advanced-stage cancer. Several possible underlying etiolo-
gies of fatigue exist in most patients and the basic pathophysiology
is not well understood. Infrequently, a predominant abnormality
is a main driver to the symptom but more commonly, multiple
abnormalities and other symptoms in cohort contribute to the
genesis of fatigue.
There are complex interactions between the host and tumor
in patients with cancer. These interactions are not clearly under-
stood and can result in fatigue in multiple ways. Figure 43.1 sum-
marizes contributors to fatigue in cancer patients.
Tumors, host-derived factors, and cytokines
Tumors can produce multiple by-products, including proteolytic
and lipolytic factors and cytokines capable of interfering with
close metabolism and inducing fatigue.22 This may also have a
role in the development of cancer-related cachexia. The rela-
tionship between cachexia and fatigue is discussed in another
chapter 37.23
The current growing literature is increasingly supporting the
prevailing hypothesis that the presence of a tumor and/or can-
cer related treatment, such as chemotherapy and/or radiotherapy,
induces dysregulation of pro-inflammatory cytokines, such as
TNF-α, IL-1, and IL-6.24 Furthermore, the cytokines have been
implicated in the pathophysiology of fatigue by acting on multiple
systems, including the brain (hypothalamic–pituitary–adrenal
[HPA] axis, psychological and dopaminergic alterations, sleep),
immune system (humoral and cellular changes), muscles (reduc-
tions in strength and mass), and metabolism.25 However, there
are overall mixed, inconsistent, and nonpersistent outcomes
when cytokine levels and fatigue burden are assessed.
Pro-inflammatory cytokines are further regulated by host-
related factors such as genetic factors. However, the lack of a
clear consensus on the definition of CRF (phenotype), challenges
the methodology used to measure the cytokines, and the lack of
methodology for measuring these cytokines, along with a limited
number of fatigue studies using animal models, contributes to our
little understanding of the link between CRF and inflammation.26
Muscle abnormalities
Impaired muscle function may be a potential major underlying
mechanism of fatigue.27 The cause of fatigue-related muscular
abnormalities may be partially related to cytokine production,
403
but the production of other fatigue-inducing substances by the
tumor or the host has only been hypothesized.
Muscle alterations in patients with tumors are well known.
Cachexia leads to a loss of muscle and fat, which may partially
explain the relationship between cachexia and fatigue.28 Tumor-
free muscle from tumor-bearing animals shows alterations in
the activity of various enzymes, the distribution of isoenzymes,
and the synthesis and breakdown of myofibrillar and sarcoplas-
mic proteins.28 Our group found decreased relaxation velocity,
impaired maximal strength, and increased fatigue after electrical
stimulation of the abductor pollicis muscle via the ulnar nerve in
breast cancer patients compared with normal controls.29
In cancer patients, myopathies can also be induced by medi-
cations. Cyclosporine has been implicated as a cause of mito-
chondrial myopathy and corticosteroids can cause loss of
muscle mass.
A preliminary study comparing 10 patients with advanced-
stage cancer and 12 healthy volunteers determining the contribu-
tion of muscle fatigue to overall fatigue found no alterations in the
muscle contractile property of advanced-stage cancer patients;
therefore, the authors of the study postulated that the early motor
task failure in CRF was primarily due to a central mechanism. 30
However, further studies are needed as more recent studies
targeting the fatigue mechanisms involving muscle found no
correlation between muscle alterations and fatigue. These stud-
ies included supplementation of adenosine triphosphate31 and
L-carnitine. 32
Mitochondrial enzymes
There is a known association between the mitochondria and
fatigue. Specifically, dysfunctions within the mitochondrial func-
tion (enzymes and oxidative/nitrosative stress), energy metabo-
lism, structure, immune response, and genetics interplay with
fatigue. Of the mitochondrial enzymes reviewed, only plasma
CoQ10 levels were found to be significantly and consistently
inversely correlated with fatigue expression. 33
Deconditioning
Prolonged bed rest and immobility lead to loss of muscle mass
and reduced cardiac output. Deconditioning results in wors-
ened muscle mass, which may be compounded by other muscle
abnormalities in patients with cancer. Recent studies have found
that endurance exercise training can reduce fatigue and improve
physical performance in patients who have undergone bone mar-
row or autologous stem cell transplant, cancer survivors, and
transplantation cancer patients undergoing chemotherapy. 34
Central nervous system abnormalities
The mechanisms by which fatigue is induced or perceived in the
central nervous system (CNS) are poorly understood. Primary or
secondary tumors involving the CNS and subsequent invasion of
brain tissue (particularly the pituitary gland, with resulting endo-
crine abnormalities) appear to be possible causes of fatigue in
cancer patients. Disturbed cognitive functioning may be caused
by, but may also contribute, to fatigue.
Brain tumors can cause cognitive dysfunction and other
tumors, such as small cell lung cancers, can also affect brain
function via production of neurotransmitters or hormones.
Antineoplastic treatments, such as radiotherapy and chemother-
apy, and medications used to treat complications of cancer, such
as corticosteroids and opioids, can also impact the CNS. Recent
research findings additionally suggest that inflammatory cyto-
kines play a role in mental fatigue.
404
Other CNS mechanisms that have been proposed include: (a)
circadian rhythm disruptions, which negatively impact arousal
and sleep patterns (prior studies suggest that fatigue is positively
correlated with decreased daytime activity and restless sleep at
night); (b) dysregulation of serotonin and/or its receptors in the
brain due to cancer or cancer treatment; and (c) dysregulation of
the hypothalmo-pituitary axis. 35
Relationship between fatigue and cachexia
Fatigue and cachexia coexist in the great majority of advanced-
stage cancer patients and it is likely that malnutrition is a major
contributor to fatigue. The resulting loss of muscle mass from
progressive cachexia can cause profound weakness and fatigue.
As previously discussed, biochemical and structural muscle
abnormalities are frequently found in advanced cancer patients. 36
Similar abnormalities often are used to explain fatigue associated
with chronic respiratory and cardiac disease.
It is important to note, however, that fatigue can exist indepen-
dently of weight loss. Fatigue is common in patients with breast
cancer and lymphomas, which has a low prevalence of cachexia.
In nonmalignant conditions such as chronic fatigue syndrome
and depression, profound fatigue is generally not associated with
malnutrition. Our group found no correlation between nutri-
tional status and fatigue or weight in a population of breast can-
cer patients. 37 However, severe malnutrition in the absence of
fatigue can be observed in patients with anorexia nervosa and in
some patient populations with solid tumors. Figure 12.1.2 illus-
trates the potential relationship between fatigue and cachexia.
It has been proposed that fatigue and anorexia may be an
expression of the major metabolic abnormalities that occur in
patients with cancer, rather than simply be an expression of mal-
nutrition per se. 38 This situation would be similar to the occur-
rence of a catabolic state owing to a viral infection or in the early
postoperative period whereby patients experience anorexia and
fatigue that are secondary to the metabolic abnormalities rather
than being causes of those abnormalities.
Infection
Fatigue is frequently associated with infections, particularly those
that are recurrent or protracted. It may occur as a prodrome, and
it may outlast the infection by weeks or even months. Chronic
infection and cancer induce the same mediators for cachexia,
including inflammatory cytokines, 38 and they may share similar
mediators for fatigue as well.
Anemia
Anemia is prevalent in cancer patients. Common causes of ane-
mia in cancer patients are myelosuppression by chemothera-
peutic agents, iron deficiency, bleeding, hemolysis, nutritional
deficiencies, and anemia owing to chronic disease. Severe anemia
(hemoglobin < 8 g/dL) is known to be a cause of profound fatigue.
In patients receiving chemotherapy, treating less severe anaemia
has been shown to improve energy levels, activity levels, and
QOL. In a prospective, open-label study of epoetin-alpha in 2,342
anemic patients receiving chemotherapy, mean energy levels,
activity levels, and QOL were found to improve with increases in
mean hemoglobin levels from approximately 9 g/dL to 11 g/dL. 39
The improvements were independent of tumor response and cor-
related with the increases in hemoglobin levels. Although these
data suggest an association between anemia and fatigue, there are
limited studies that specifically assess this relationship in popula-
tions with advanced illness.
Textbook of Palliative Medicine and Supportive Care
Autonomic dysfunction
Autonomic dysfunction is a common complication of advanced-
stage cancer. This syndrome includes malnutrition, delayed gas-
tric emptying, chronic nausea, anorexia, and poor performance
status.40 Postural hypotension has been documented in patients
with a specific type of severe chronic fatigue syndrome. The
association between fatigue and autonomic dysfunction has not
been established in cancer patients and should be investigated in
future research.41
Psychological issues
Anxiety, depression, and psychological distress may contribute
to fatigue.42 However, the nature of these relationships is unclear.
The diagnosis of a major depressive episode in patients with
advanced-stage cancer is difficult because the patients frequently
present with neurovegetative and somatic symptoms that are part
of the disease itself.
Nevertheless, cancer patients presenting with an adjustment
disorder or a major depressive disorder can have fatigue as one
of the prevalent symptoms. Therefore, the role of psychological
factors, including anxiety and depression, in the development of
fatigue among cancer patients needs further research.
Metabolic and endocrine disorders
Endocrine disorders (e.g., diabetes mellitus, Addison’s disease,
and hypothyroidism) and electrolyte disorders (e.g., hypona-
tremia, hypokalemia, and hypercalcemia) are possible causes of
fatigue and in many instances have relatively simple and effective
treatments.
Testosterone deficiency results in the loss of muscle mass,
fatigue, reduced libido, and reduced hemoglobin.43 Androgen
insufficiency in cancer patients can result from anorexia-cachexia
syndrome.44 In addition, chemotherapy and radiotherapy can
cause hypogonadism. Hormonal ablative therapy has been found
to significantly increase the incidence of fatigue in patients with
prostate cancer. In patients with testosterone insufficiency treat-
ment with androgenic anabolic steroids, including testosterone
and its derivatives, has been found to increase muscle mass,
improve energy and libido,45 and increase hemoglobin levels.45
Androgenic anabolic steroids are regularly used for the treatment
of hypogonadism in HIV-infected men.
Abnormalities of the HPA axis concerning corticotrophin-
releasing factor have been postulated as another possible endo-
crine-related cause of fatigue. Corticotrophin-releasing factor
levels increase in situations of physical or emotional stress and
thus may cause fatigue.19 The pro-inflammatory cytokines IL-1,
IL-6, and TNF-α are central mediators of the inflammatory
process that can result in the dysregulation of the HPA axis and
the secretion of mediators that induce such symptoms as pain,
fatigue, anxiety, and depression, leading to an impaired QOL. 35
Paraneoplastic neurological syndromes
Paraneoplastic neurological syndromes are rare but are impor-
tant to recognize, as many of these syndromes can precede the
clinical presentation of a malignancy. They may be partially
reversible with primary treatment of the tumor. Table 43.1 sum-
marizes some of the paraneoplastic neurological syndromes
associated with fatigue.
Other cancer-related symptoms
Various correlative studies have shown that fatigue is associated
with pain, psychological symptoms such as anxiety and depres-
sion, dyspnea, sleep disturbances, anorexia, and constipation.46
Mechanism, Assessment, and Management of Fatigue
TABLE 43.1  Paraneoplastic Neurological Syndromes Associated
with Fatigue
Syndrome Association
Progressive multifocal Lymphoma, leukemia
leukoencephalopathy
Paraneoplastic encephalomyelitis 70% lung, 30% other malignancies
Subacute motor neuropathy e.g., after irradiation in lymphoma
Subacute necrotic myelopathy Lung cancer
Peripheral paraneoplastic Often precedes the primary
neuropathy
Ascending acute polyneuropathy Lymphoma
(GBS)
Dermatomyositis/polymyositis Associated with malignancy in 50%
Eaton–Lambert syndrome Small cell lung cancer
Myasthenia gravis Lymphoma, thymoma (30%)
Amyotrophic lateral sclerosis Primary disorder with fatigue
Abbreviation: GBS, Guillain–Barré syndrome.
However, the intensity of the individual symptoms in a given
patient may determine the symptoms’ ultimate contribution to
the fatigue.47
Side effects of cancer treatment
Treatments for both cancer and the symptoms and conditions
caused by cancer can cause or aggravate fatigue. Worsening of
fatigue is common during chemotherapy and radiotherapy.48
Radiotherapy can result in anemia, diarrhea, anorexia, and
weight loss, and chemotherapy commonly causes anorexia,
nausea, vomiting, and anemia; all these events may contribute
to fatigue. In addition, these treatments have secondary effects
that may cause or exacerbate fatigue; for instance, fatigue may
be a consequence of chronic pain resulting from radiotherapy-
or chemotherapy-induced immunosuppression that predisposes
patients to infection. Such effects may persist for months to years
after the completion of treatment.
Biological response-modifying agents have also been impli-
cated in fatigue; for instance, INF-α was shown to cause fatigue in
70% of patients. In fact, fatigue is the most frequent dose-limiting
side effect in patients receiving biological response-modifying
treatments for cancer. Data from studies using of PD-1 check-
point inhibitors and targeted agents in advanced cancer patients
found significant increase in cancer related fatigue especially in
the first few months of treatment.49,50 However, in these patients
endocrinopathies (a complication with treatment) should be
ruled out as a cause of CRF.49
Opioids such as morphine have significant effects on the
reticular system and are capable of inducing sedation, cognitive
changes, and fatigue in some patients. Box 43.1 outlines can-
cer therapies and drugs that frequently contribute to fatigue in
patients with cancer.
Genetics and cancer-related fatigue
There is preliminary evidence that various single nucleotide poly-
morphisms of pro-inflammatory cytokine genes (which affect the
gene expression levels) are associated with CRF.51 Prior studies
found overrepresentation of the IL-1B—511 CC alleles among
cancer survivors with fatigue.52 Another recent study found a sig-
nificant association between polymorphisms in the TNF-alpha
and IL-6 genes and fatigue.53
405
In summary, evidence clearly shows that fatigue is a complex,
subjective, multidimensional syndrome that can be attributed to
multiple causes. It is particularly important to note that not only
cancer but also cancer treatments, cancer-related symptoms,
metabolic causes, endocrine dysfunction, cytokine dysregulation,
and neuromuscular dysfunction may be among those causes,
making a comprehensive assessment of paramount importance.
Assessment of fatigue
Fatigue is a complex, subjective, chronic multifactorial and mul-
tidimensional symptom.5,54,55 Therefore, a systematic evaluation
is essential. Fatigue assessment involves characterizing its sever-
ity, temporal features (onset, course, duration, and daily pattern),
exacerbating and relieving factors, associated distress, and impact
on daily life; and identifying treatable causes.4,5 Several scales
have been developed to quantify fatigue. These instruments mea-
sure the severity and assess various dimensions of fatigue.
These include the Edmonton Symptom Assessment Scale
(ESAS)-fatigue item, 56 which evaluates the average sever-
ity of fatigue in the last 24 hours (in 0–10 scale wherein “0” in
no fatigue and “10” is the worst fatigue imaginable).5 In addi-
tion to the ESAS-fatigue item, various other scales are com-
monly used. These include EORTC-fatigue items, 57 Brief Fatigue
Inventory, 58 Functional Assessment of Cancer Illness Therapy
(FACIT)-fatigue subscale, 59 and most recent Patient-Reported
Outcomes Measurement Information System (PROMIS)-item
Bank-Fatigue Short Form (PROMIS-SF).60–62 CRF has been clas-
sified into various subtypes based on severity, or cut-off scores.
The NCCN guidelines on CRF recommend a simple 0–10 NRS
be used to assess CRF intensity during past week (0 = no fatigue;
10 = worst fatigue you can imagine).2 Patients can be grouped by
their severity responses into subtypes: 0 = none; 1 to 3 = mild; 4
to 6 = moderate; and 7 to 10 = severe. A CRF severity score of 4
or more can be used to indicate that further workup, referrals,
and treatment may be needed.2,3 Cut-off scores are sometimes
used to identify the optimal level for detecting cases of clinically
significant fatigue defined by exceeding the established threshold
of “caseness.” The cut-off scores, however, vary according to how
they are used to define a subgroup and by the CRF measure used.
For example, a FACIT-F score of 43 or less indicates clinically sig-
nificant fatigue, and on a 0–10 NRS scale a cut off score of 4 or
greater has been used as an eligibility criteria for entry into clini-
cal trials.12,63 The PROMIS-SF is a novel, validated, and efficient
scale that consists of seven items that measure both the expe-
rience of fatigue and the interference of fatigue on daily activi-
ties over the prior week, scores range from 7 to 35 with higher
scores reflecting greater fatigue burden.60 A potential benefit of
PROMIS is that as a multidimensional, accurate, and standard-
ized tool, it allows the opportunity to link legacy CRF measures
such as FACIT-F to the PROMIS fatigue measure and vice versa,
thus enabling comparisons across research results.64 Several mul-
tidimensional instruments are more frequently used in research
rather than routine clinical settings. These include multidimen-
sional fatigue symptom inventory-MFSI-SF, Fatigue symptom
inventory, Multidimensional fatigue Inventory.
Assessment of fatigue in clinical practice
Assessment of fatigue in palliative practice might be a chal-
lenge, and fatigue is probably often neglected or overlooked.65
Physicians’ neglect of fatigue might have historical reasons, but
406 Textbook of Palliative Medicine and Supportive Care

it is probably related to the non-specificity of fatigue as a symp-
tom and also due to the fact that there are limited effective
treatments available. By asking, the physician might fear ending
up in a long consultation, taking several tests, not finding any
treatment options and end up with presenting general advice.
For these reasons, physicians probably don’t address fatigue,
and the lack of documentation on treatment alternatives might
further support such a nihilistic or avoidant approach. The
physicians’ beliefs about fatigue are therefore of relevance.66
However, the prevalence of fatigue, the overall aim of pallia-
tive care to prioritize the patients’ QOL, and the burden fatigue
imposes on the patients and their families both psychologically
and functionally do not support an avoidant approach. In fact,
many patients are relieved just by being asked, they feel assured
by adequate information tailored to their level of knowledge,
and many are well aware of the limited possibilities for doc-
umented treatment alternatives. The clinical assessment of
fatigue as a symptom follows general guidelines for symptom
assessment in palliative care.4,5 Fatigue assessment involves
characterizing its severity, temporal features (onset, course,
duration, and daily pattern), exacerbating and relieving fac-
tors, associated distress, and impact on daily life. To measure
fatigue severity, routine use of a simple NRS such as the fatigue
item in the ESAS might be both useful for the physician and
patient. The PROMIS-F is also another crucial and validated
tool in assessing fatigue for both clinical practice and research.
Fatigue is for most the complex subjective experience, and
hence in patients who are deemed to have clinically signifi-
cant fatigue it is essential to further assess the predominant
dimension, physical, psycho-social or cognitive domain that is
interfering with optimal function. However, evaluation should
include a detailed history and focused physical examination
and laboratory investigations based on clinical suspicion so as
to identify treatable causes (Tables 43.2 and 43.3). 5

TABLE 43.2  Fatigue Specific Instruments in Cancer Patientsǂ

Reliability,
Cronbach
Instruments Coefficient Population Base No. of Items Comments
Unidimensional
Instruments
Functional 0.930.95, Patients with cancer and receiving 41 items, self-administered Multidimensional fatigue subscales
Assessment of Testretest treatment or interview, 10 minutes of Functional Assessment of
Chronic Illness reliability Cancer Therapy, assesses global
Therapy-Fatigue r = 0.87 over fatigue severity and quality of life
(FACIT-F) 37 days
Edmonton Symptom 0.79, Testretest Elderly patients receiving palliative care Patients rate the severity Global fatigue severity
Assessment Scale reliability 0.65 of 9 symptoms including
fatigue on 11-point
(0–10) visual analog
scales, self-administered
or interview, 5 minutes
Profile of Mood 0.89, Testretest Patients with cancer and many chronic 8 items for vigor, 7 items Global fatigue severity
States (vigor and reliability conditions for fatigue
fatigue) r = 0.65
Short Form36Version 0.87 Adults with cancer and other populations 1–2 min for 4-item Vitality, energy level, and fatigue
1 Vitality (Energy/ subscale
Fatigue) Subscale35
PROMIS Fatigue 0.994 Adults with cancer and other populations Each question has five Fatigue frequency, duration and
Short Form response options ranging intensity and Impact of fatigue on
in value from one to five. physical, mental and social
It assesses fatigue over activities*
the past seven days
Brief Fatigue 0.820.97 Patients with cancer and receiving 9 items, self-administered, Severity and effect of fatigue on
Inventory treatment 5 minutes daily functioning in the past 24
hours
Fatigue Symptom 0.90 Patients with cancer and receiving 13 items, Fatigue intensity and duration and
Inventory31 treatment self-administered interference in quality of life in the
past week
EORTC QLQ (FS) 0.80–0.85 Patients with cancer and receiving 3 items, self-administered It has been noted to have a ceiling
treatment effect in advanced cancer patients
and is not recommended as a single
measure in this group

(Continued)
Mechanism, Assessment, and Management of Fatigue 407

TABLE 43.2  Fatigue Specific Instruments in Cancer Patientsǂ (Conitnued)

Reliability,
Cronbach
Instruments Coefficient Population Base No. of Items Comments
Unidimensional
Instruments
Multidimensional Instruments
Multidimensional 0.80 validity Cancer patients receiving radiotherapy, 20-item self-report Multidimensional scale including:
Fatigue Inventory (r ≤ 0.78) patients with chronic fatigue syndrome, instrument general fatigue, physical fatigue,
psychology students, medical students, mental fatigue, reduced motivation,
army recruits, and junior physicians and reduced activity
Multidimensional 0.93 Adults with rheumatoid arthritis, human 16 items, self- Subjective aspects of fatigue
Assessment of immunodeficiency virus-positive adults, administered, 5 minutes including quantity, degree, distress,
Fatigue multiple sclerosis, coronary heart disease, impact, and timing are assessed
or cancer
Multidimensional 0.870.96 Patients with different types of cancer 30-item instrument Global, somatic, affective, cognitive,
Fatigue Symptom and behavioral symptoms of fatigue
Inventory (short
form)
Revised Piper Fatigue 0.85–0.97 Patients with cancer-related fatigue; or 22-item measure Multidimensional, assesses global
Scale chronic hepatitis C infections fatigue severity to evaluate the
efficacy of intervention strategies
Fatigue 0.79–0.89 Adults with cancer and other populations 11-item instrument One of the few multidimensional
Questionnaire instruments that is brief, easy to
use but also has robust
psychometric properties
* http://www.assessmentcenter.net/documents/PROMIS%20Scoring%20SF%20Fatigue%207a.pdf
ǂ Table in part was adapted from ref 5; see also ref. 55.

TABLE 43.3  Assessment Modalities for the Causes of Unexplained Fatigue at the End of Lifea
Medical Condition Assessment Modality
Anemia Complete blood cell count, serum vitamin B12, folate, iron, transferrin saturation, ferritin levels,
fecal occult blood tests, and, if abnormal test result, further evaluation for blood loss
Medication adverse effects and Anticholinergics, antihistamines, anticonvulsants, neuroleptics, opioids, central α-antagonists,
polypharmacy β-blockers, diuretics, selective serotonin reuptake inhibitors and tricyclic antidepressants, muscle
relaxants, and benzodiazepines
Cognitive or functional impairment Assessments such as ADL, IADL, MMSE, and “get up and go” test
Mood disorders Assessment of depression and anxiety following the DSMIV criteria
Adverse effects of primary disease Recent radiation therapy, chemotherapy, surgery
treatment
Malnutrition Serum albumin, prealbumin, cholesterol
Infections Blood cultures, urine culture, chest radiography, HIV antibody, RPR, PPD skin test
Other contributing medical conditions Directed based on clinical finding
Abbreviations: ADL, activities of daily living; DSMIV, Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition; HIV, human immunodeficiency virus; IADL,
instrumental activities of daily living; MMSE, MiniMental State Examination; PPD, purified protein derivative; RPR, rapid plasma reagin.
a Evaluation of fatigue is based on ref. 5; see also ref. 74.

Management of fatigue
To be able to manage fatigue adequately, the contributing fac-
tors, often multiple, need to be determined (Figure 43.1), some
of which may be irreversible. Once appropriate assessment is
completed, the therapeutic approach to fatigue can be divided
into treating underlying causes and symptomatic treatment
(Figure 43.2).
Routine assessment and management of fatigue is essential for
optimal management. The NCCN guidelines for cancer related
fatigue recommend screening all patients at regular intervals. For
mild fatigue, educating the patient and their caregivers along with
close monitoring at regular intervals is advised. When patients
report moderate or severe cancer related fatigue, which is signifi-
cant enough to affect their QOL, a focused history and evaluation
helps to delineate contributing factors (medications/ side effects,
cancer related symptoms such as pain, nausea, drowsiness, lack
of appetite, shortness of breath, emotional distress, sleep distur-
bance, anemia, nutritional deficit/imbalance, decreased func-
tional status, comorbidities). Treating the reversible factors with
the use of evidence-based interventions tailored to individual
needs is important to treating the underlying causes of fatigue
408
FIGURE 43.2  Therapeutic approaches to the management of fatigue.
Cancer
The complex association between cancer and fatigue has not
been completely defined. There is little doubt however, that most
patients with cancer at some time in their illness develop fatigue,
and especially in the terminal phase this is thought to be as a
direct result of the cancer.67–69 In a cross-sectional follow-up study
of 459 Hodgkin’s disease patients, fatigue was significantly higher
than in controls from the general population.70 In patients with
cancer, there is a complex interaction occurring between tumor
and host, which is not well understood but is thought to result in
fatigue in several ways. The mechanism of CRF is described more
in detail in the previous section, but in brief, tumors produce
proteolytic and lipolytic factors, which can interfere with host
metabolism. These factors are thought to play a role in the devel-
opment of cancer cachexia with which there is complex overlap
and interplay with fatigue28 as discussed in other chapters in this
book and also below. Moreover, there may be other substances
induced or released directly by the tumor which can also lead to
fatigue.19,71 Tumors can also act by direct invasion of brain tissue,
particularly the pituitary gland, and cause fatigue by both direct
(disturbance in cognition) or indirect (endocrine disturbances
via the pituitary axis) mechanisms.19 Management in this case is
essentially treating the cancer. The successful treatment of the
malignancy can result in significant and sustained improvement
in fatigue.72 Fatigue is generally perceived as a sign of the pro-
gression of disease by patient and family members, which adds to
anxiety and unnecessary interventions. The patient and caregiv-
ers must be educated about how common fatigue is as a compli-
cation of cancer and its treatment. They must also be counseled
and educated about what to anticipate during and after therapy is
completed with regards to fatigue, and mechanisms by which this
common symptom can be managed.
Many of the cancer therapies and symptomatic treatments of
other effects of the cancer, such as pain, can themselves result
in transient and/or prolonged fatigue and management of this is
discussed below.
Therapies and medications
Chemotherapy and radiotherapy
These treatment modalities in patients with cancer cause a spe-
cific fatigue syndrome.48,73,74 In isolation they both can cause
fatigue but this is augmented further when both modalities are
given concurrently. Bower et al. in a longitudinal study in 763
breast carcinoma survivors found that the patients with both
Textbook of Palliative Medicine and Supportive Care
radiation and chemotherapy were more likely to be fatigued than
radiation alone.75 Fatigue associated with chemotherapy tends
to have a cyclical pattern. It occurs within the first few days of
starting therapy, gets to a peak at about the time the white blood
cell count is at its lowest level then improves in the week or so
thereafter. The cycle is repeated with each cycle of chemotherapy
and worsens with subsequent cycles, suggestive of a cumulative
dose-related toxic effect.73,76 Multiple chemotherapeutic agents
have been studied in fatigue either in isolation or in combination
with most generating some degree of fatigue. Different types of
cancer have also been studied with specific chemotherapeutic
regimens with varying degrees of fatigue noted depending on the
cancer and the regimen.73,77–79 A longitudinal prospective con-
trolled study assessed 104 women with breast cancer receiving
adjuvant chemotherapy and 102 controls. Tools used included the
Functional Assessment of Cancer Treatment-General Quality of
Life questionnaire, with subscales for fatigue and endocrine
symptoms and the High Sensitivity Cognitive Screen. Ninety-
one and 83 patients, and 81 controls were assessable at the end
of 1 and 2 years, respectively. Differences between patients and
controls were significant for both scales. It showed that fatigue,
menopausal symptoms and cognitive dysfunction were impor-
tant adverse effects of chemotherapy that improved in most
patients with time.79 Radiotherapy causes a different pattern of
fatigue when given alone.74 It tends to start more abruptly soon
after treatment and diminishes soon thereafter but may get pro-
gressively worse as therapy continues.80,81 Fatigue has been noted
to diminish but not completely resolve when short breaks in ther-
apy occur, for example at weekends.80
Biological therapy
Biological response modifying agents such as INF-α cause fatigue
in 70% of patients who receive this therapy. 31 Fatigue is one of the
most important dose-limiting side effects of this type of therapy.
The mechanism here is unknown though some investigators have
postulated diffuse encephalopathy may occur. 32,33
Management of fatigue in these situations is essentially symp-
tomatic and nonpharmacological. Patients and their caregivers
need to be counseled and educated prior to commencing ther-
apy about the anticipated fatigue associated with the different
treatment modalities and that treatment related fatigue is not
necessarily correlates to disease progression. Exercise, with-
out overexertion as well as physical and occupational therapy
Mechanism, Assessment, and Management of Fatigue
during treatment can help minimize the sometimes-overwhelm-
ing fatigue and prevent deconditioning. One common side effect
of chemotherapy, which may impact fatigue and has been associ-
ated with symptom improvement if treated early, is anemia. This
will be discussed later in this chapter.
Opioids
A large proportion of cancer patients experiencing pain are on
opioids. This group of medications has significant effects on the
reticular system and can cause sedation, cognitive changes, and
fatigue in some but not all patients. The central acting effects
would explain the mental fatigue, but it is more likely that the
drowsiness or somnolence is what is perceived as fatigue by some
patients.42 A trial of dose reduction if pain is well controlled and
fatigue is becoming the predominant symptom can be effective.
Psychostimulants such as methylphenidate and donepezil have
been used to improve opioid-induced fatigue.82,83 Chronic opi-
oid use have been implicated in causing male hypogonadism and
contributing to symptoms of fatigue.84 If treatment of hypogo-
nadism by hormone replacement or decreasing dose of opioid is
the best approach is yet to be identified.
Cytokine modulation
Circulating cytokines and inflammatory proteins are thought to
be associated with many of the symptoms exhibited in patients
with advanced cancer such as fatigue, pain, depression, cachexia,
and sleep disorders.19,28,85 These products have also been associ-
ated with infections, the effects of cancer treatments including
chemotherapy and radiation therapy, and with the presence of
the cancer itself. One of the mechanisms shown in laboratory
studies by which cytokines mediate symptoms is via a number
of signals through the hypothalamic–pituitary–adrenal axis.86,87
Since fatigue is one of the most common symptoms in advanced
cancer, researchers have proposed that one possible explanation
for fatigue in this patient population is the increased secretion of
pro-inflammatory cytokines, such as IL-2, IL-6, INF-α and TNF-
α, in response to both the disease and its treatment.41,42 Several
lines of evidence support cytokines in the pathophysiology of
fatigue. These include:
• The occurrence of fatigue as a major side effect of cytokines
used in the treatment of cancer patients.48,88
• The elevation of cytokine levels seen in chemotherapy
treatments for cancer.89
• The upregulation of pro-inflammatory cytokines seen
in several malignancies and their correlation with fati
gue.42,48,49
Treatment in this case can be challenging and depends to some
extent on the mechanism. Evidence to date strongly supports
a role for cytokine modulation with agents such as corticoste-
roids, cyclooxygenase (COX) 1 and 2 inhibitors (nonsteroidal
anti-inflammatory drugs, nabumetone) thalidomide, monoclonal
antibodies (anti-TNF, infliximab), and specific soluble receptor
antagonists, some of which are currently being studied to modu-
late the effects of cytokines on the brain and other sites.90,91
Treatment of cachexia
Cachexia has been covered in detail elsewhere in this book but
there are a number of important points to note with cachexia in
association with fatigue.28 There is a complex overlap between
cachexia and fatigue, especially in advanced cancer. Cachexia can
409
be reversible when due to malnutrition or starvation, or in cata-
bolic states such as acute or chronic infections. However, when
due to underlying illness usually in the terminal phase such as
cancer, AIDS, end-stage cardiac disease, or chronic obstructive
airways disease, it is often more difficult to reverse.28,92 The sig-
nificant loss of muscle mass in cachexia could explain the pro-
found weakness and fatigue with which it is associated.93 Of note
though is that fatigue can be present in the absence of significant
weight loss and vice versa where profound cachexia and malnutri-
tion may exist without fatigue.
Treatment for cachexia secondary to malnutrition or starvation
involves nutritional support. Though there is no evidence that
aggressive nutritional therapy improves the QOL in advanced
cancer patients or that parenteral feeding has much impact on
fatigue,92 in patients where cachexia is deemed to be second-
ary to malnutrition these are exactly the measures that should
be employed. In such patients, aggressive nutritional support
can result in reversing the cachexia and associated fatigue. The
majority of cachexia in palliative care patients is unfortunately
irreversible and treatment is often symptomatic. In addition to
established agents in use including progestins (megestrol acetate),
corticosteroids, and prokinetics (metoclopramide), many newer
agents are being studied such as thalidomide, cannabinoids and
omega 3 fatty acids found in fish oils.94 Treatment of secondary
cachexia by treating symptoms like constipation, nausea, dysgue-
sia, dysphagia, early satiety with simple pharmacologic measures
also helps with treatment of cachexia/anorexia and consequent
weight gain.95
Management of autonomic failure
Autonomic failure is a common outcome of advanced cancer,96,97
but can also occur in other non-cancer diseases encountered in
palliative care such as Parkinson’s disease. Symptoms associ-
ated with autonomic failure include postural hypotension with
or without intermittent episodes of syncope, gastrointestinal
symptoms such as nausea, vomiting, diarrhea or constipation,
and anorexia.97 Some of these symptoms may contribute directly
or indirectly to fatigue such as postural hypotension, anorexia,
and persistent diarrhea. A subset of chronic fatigue syndrome has
been associated with autonomic dysfunction, but this association
has not been widely studied in advanced diseases encountered
in palliative care. Low heart rate variability and increased nor-
epinephrine levels have been associated with fatigue in advanced
cancer population. Exercise is known to increase HRV, and hence
might benefit with management of fatigue in advanced cancer
population with autonomic failure.98
Autonomic failure is usually irreversible and can be difficult
to treat in the setting of fatigue. Midodrine, a specific a1 sympa-
thomimetic agent, has been used to manage autonomic failure in
other conditions such as diabetes and might have a therapeutic
role in autonomic failure in the palliative care population. In a
double-blind randomized crossover study with midodrine and
ephedrine, eight patients with refractory orthostatic hypotension
secondary to autonomic failure were assessed. Midodrine pro-
duced a significant increase in both systolic and diastolic blood
pressure with associated improved ability to stand as compared
with ephedrine and placebo.99 Another double-blind, placebo
controlled, four-way crossover trial looked at 25 patients with
neurogenic orthostatic hypotension. Patients were randomized
to receive either placebo or three different doses of midodrine
(2.5, 10, or 20 mg) on successive days. Supine and standing blood
pressures were measured sequentially and midodrine was shown
410
to significantly increase standing systolic blood pressure (peak-
ing at 1 hour after dosing) with a mean score of global improve-
ment of symptoms being significantly higher for midodrine at
doses of 10 and 20 mg compared with placebo.100 Other mea-
sures, including discontinuing all possible contributing medica-
tions, plasma volume expansion with increased salt intake and
use of fludrocortisone, wearing pressure stockings and rising up
in stages and slowly for patients with postural hypotension used
in other causes of autonomic failure might also be applicable in
this patient population.101
Neurological disorders
A number of neurological disorders are associated with fatigue,
some of which may be the primary disease such as amyotrophic
lateral sclerosis, myasthenia gravis, Parkinson disease, multiple
sclerosis, and other demyelinating diseases.2 On the other hand,
some neurological disorders occur as a result of the terminal dis-
ease and may sometimes precede the disease by quite a long time,
such as the paraneoplastic syndromes including Eaton–Lambert
syndrome and dermatomyositis/polymyositis (Table 43.1).102
Treatment here is disease specific, though most of these diseases
are progressive despite treatment and both the disease and asso-
ciated fatigue become irreversible, at which point symptomatic
therapies, both pharmacological and non-pharmacological, are
introduced (see Figure 43.1).
Treating anemia
Anemia is a common entity seen in cancer patients, either as a
complication of chemotherapy or as a disease presentation in
itself, more so with hematological malignancies. Low hemoglobin
and duration of anemia has been found to correlate with nega-
tive symptoms in patients with cancer, including fatigue, QOL,
depression, vertigo. However, in the setting of advanced cancer
the etiology of fatigue is multidimensional and the contribution
of anemia is yet to be defined.17,103 In the patient group in which
mild to moderate levels of anemia may exacerbate fatigue, there
is evidence that treating less severe anemia improves energy lev-
els and QOL, including those receiving chemotherapy. In patients
with advanced disease and in the palliative care patient popula-
tion, anemia is probably over-diagnosed as a cause for fatigue.
Fatigue measured on a scale of 0–10 in a retrospective study of
147 patients seen in palliative care consultation with a median
hemoglobin level of 11.6 g/dL did not show significant correla-
tion between fatigue and hemoglobin level though there was a
trend (p = 0.09).104 There is little doubt that anemia is prevalent in
such disease states, especially advanced cancer, but it is unclear
at what hemoglobin level the treatment of anemia either with
blood transfusions or epoeitin impacts fatigue. Unfortunately,
treatment of anemia in advanced cancer palliative settings has
not been studied with randomized control trial. The two main-
stays of treatment of anemia are blood transfusions or synthetic
erythropoietin.
A. Synthetic erythropoetin: Erythropoetin/darbopoetin
are synthetic drugs administered subcutaneously either
weekly or every three weeks. Several trials in the past have
shown benefit of EPo with respect to decrease in need for
RBC transfusions, improved QOL, Hb levels. In an open
label study 2342 patients from community-based hospitals,
with malignancies undergoing chemotherapy, were treated
with epoetin alfa. A total of 1,047 patients completed the
full 4 months of epoetin therapy and showed significant
Textbook of Palliative Medicine and Supportive Care
increase in mean self-rated scores of energy level, activ-
ity level, and overall QOL. These improvements corre-
lated with the magnitude of the hemoglobin increase.105
Another prospective community-based study with 2,289
patients with nonmyeloid malignancies receiving chemo-
therapy received epoetin for 16 weeks. Patients reported
improvement in QOL parameters which correlated with
significant increases in hemoglobin levels independent of
tumor response. 39 Some authors, however, believe that the
improvement noted in treating this level of anemia may be
secondary to improvement in exertional dyspnea rather
than fatigue per se. Osterborg et al. conducted a placebo
controlled randomised trial of epoetin alpha in severely
anemic transfusion dependent patients with advanced
haematologic malignancy. He concluded an improvement
of QOL and anemia with most benefit seen ≥2 g/dl Hb. In
2008, FDA revisited the safety data and has black box warn-
ing on erythropoetin as several studies in breast, head and
neck malignancies reported decreased survival, VTE and
cardiac risks. The recommendation for use of Epo in cancer
patients is at lowest dose possible to keep Hb around 12 g/
dl and dose reduction for Hb>12.106,107
B. Blood transfusion: In a Cochrane review by Preston NJ et
al. the effect of blood transfusion for treating anemia in
patients with advanced cancer was analyzed.108 12 stud-
ies with 653 participants were identified and the primary
outcome in 5 studies was improvement of fatigue for two
to seven days with the effect waning after 14 days. The
studies used different measures for assesment and quanti-
fication of fatigue. Few patients in some studies died at or
after 14 days of transfusion which could be attributed to
transfusion or simply the patients being sicker. The result
of this review demonstrated the short term response with
concerns about risk and safety of blood transfusion in
advanced disease. In managing fatigue thought to be asso-
ciated with anemia, assessment of the underlying cause as
well as the acuity of anemia becomes important as this may
influence the choice of treatment. The goals of care need
to be determined on an individual basis as well as overall
prognosis since transfusions would give almost immediate
results and erythropoietin could take up to 4 weeks to show
response.109
Pain
Some authors have found a strong correlation between pain
intensity/severity and fatigue in patients with cancer.110 It is
more likely that there is an indirect correlation with chronic
uncontrolled pain causing psychological distress, insomnia,
thus impacting fatigue. Moreover, as mentioned above, some of
the treatment modalities of pain can cause fatigue, for example
opioids. As such, detailed assessment and targeting treatment
toward the associated factors and symptoms, as well as achiev-
ing good pain control, would be the most appropriate manage-
ment here.
Other comorbidities
Infection
Patients with advanced cancer and other advanced disease states
seen in palliative care are at increased risk of infection due to
relative and sometimes profound immunosuppression. Fatigue
is often associated with infections, especially when the course
Mechanism, Assessment, and Management of Fatigue
is protracted or when infections are recurrent. Prolonged viral
infections are especially notorious for producing longlasting epi-
sodes of fatigue.111–113 Fatigue may occur as a prodromal symp-
tom and persist sometimes long after the infection has resolved.
Chronic infection and cancer induce the same cytokine media-
tors for cachexia such as IL-6, TNF α,113,114 so it is possible that
they share similar mediators for fatigue as well due to the over-
lap between cachexia and fatigue described earlier. Vigilance in
avoiding recurrent infections is important here and having a low
threshold for using appropriate antimicrobial therapy can mini-
mize some of these infections.
Psychogenic disorders
Depression and anxiety are discussed in more detail elsewhere
in this book but a few key points are worth mentioning here due
to the strong correlation between these disorders and fatigue.
Symptoms of psychological distress and adjustment disorders
with depressive or anxious moods are much more common in
this patient population than major psychiatric disorders.115 The
incidence of depression in this group tends to be overestimated.
Self-reported scales suggest a prevalence as high as 25%, but
in fact only 6% of cancer patients are estimated to have major
depression and 2% have anxiety disorders.116 Fatigue can be the
prevalent symptom in any of these disorders. It is sometimes dif-
ficult to tease out cause and effect as depression for instance may
be the cause of or occur as a result of fatigue. Some groups have
found significant association between fatigue and psychological
distress but again this is by no means the only variable causing
fatigue, reiterating the multifactorial contributors to fatigue.
Furthermore treatment of depression using antidepressant may
not improve fatigue.117
Treatment here is by and large symptomatic with good expres-
sive supportive counseling though antidepressants may some-
times be indicated especially when depressive mood makes up a
large component of the adjustment disorder.118
Insomnia
Lack of sleep occurs for multiple reasons which themselves may
be indirectly causing fatigue. Sleep may be disturbed because of
uncontrolled symptoms such as pain, depression or anxiety, mild
delirium with sleep cycle inversion, drugs and suboptimal condi-
tions causing poor sleep hygiene. Insomnia is less likely there-
fore to be an independent variable in the etiology of fatigue and
though it can cause fatigue does not cause physical weakness.89
Appropriately assessing the patient and treating the underlying
contributing factors such as pain and psychogenic disorders, as
well as teaching good sleep hygiene, can improve the insomnia
and may sometimes be more effective in the long run than using
hypnotics and sedatives which sometimes may be indicated for
short-term use.118
Metabolic and endocrine abnormalities
These are often very reversible causes of fatigue, which can be easy
to treat.5 It is therefore important when a patient presents with
fatigue to run a simple chemistry panel as part of the work-up.
Abnormalities such as hyponatremia, hypokalemia, hypomagne-
semia, hypercalcemia, and hyper or hypoglycemia can be readily
diagnosed and corrected with simple measures such as hydration
and replacement therapy. A lot of these electrolyte disturbances
cause physical/muscle weakness, which can cause significant
fatigue. Endocrine disorders are easily missed but can also often
be readily reversible or treatable causes of fatigue. Addison dis-
ease for instance causes significant fatigue and although this is
411
now uncommon in Western society, hypoadrenalism per se is still
fairly common. Many drugs can cause secondary hypoadrenal-
ism, which has identical symptoms to the primary disorder, e.g.,
steroids (when discontinued abruptly). Other common endo-
crine disorders such as diabetes and hypothyroidism should also
be excluded and if diagnosed treated promptly with appropriate
replacement therapies.
Hypogonadism
This condition deserves a separate mention from the other
endocrine disorders due to recent research interest in this as a
cause of fatigue with associated loss of muscle mass. Low tes-
tosterone results in loss of muscle mass, fatigue, reduced libido,
and reduced hemoglobin.41,119 Two large patient groups encoun-
tered in palliative care, namely cancer patients and patients
with AIDS, have been found to have testosterone deficiency
which in males can often be easily reversible by replacement
therapy with testosterone. Some antineoplastic therapies as well
as both systemic and intrathecal opioids have been shown to
cause hypogonadotropic hypogonadism41,44,120 and a low thresh-
old for measuring testosterone levels and offering replacement
therapy is key in managing fatigue in this patient population.
Hormonal ablative therapy has been shown to double the inci-
dence of fatigue in men with prostate cancer but of note is that
this is one patient population in which testosterone replacement
therapy is contraindicated.
Chronic hypoxia
The association here with fatigue is probably best studied in
chronic airways disease where oxygen therapy has been shown
to improve QOL in patients with fatigue as one of the symptoms.
In a prospective longitudinal study of 43 consecutive chronic
obstructive pulmonary disease patients fulfilling criteria for
long-term oxygen therapy and 25 patients not fulfilling criteria,
there was significant improvement noted in health-related QOL
in patients on long-term oxygen therapy. This improvement in
symptoms included fatigue, emotional, and mental function and
was sustained over a 6-month period.121
The use of supplemental oxygen in decreasing dyspnea and
fatigue or improving exercise tolerance has not been shown
to be beneficial in cancer patients with mild hypoxemia. A
double-blind, randomized controlled crossover trial with 31
lung cancer patients without severe hypoxemia (O2 saturation
level > 90%) assessed whether or not oxygen is more effec-
tive than air in decreasing dyspnea and fatigue and increas-
ing physical performance. There was no significant difference
observed between treatment and control groups in dyspnea,
fatigue, or physical performance.122 Earlier studies showed
that patients with cancer who had hypoxemia and dyspnea
at rest benefit from oxygen therapy, but further studies are
required to determine whether oxygen therapy could improve
fatigue or exercise tolerance in hypoxia patients with advanced
disease.123
Symptomatic management of fatigue
This can be divided into pharmacological and nonpharmacologi-
cal management.
Pharmacological management
Pharmacological management can be further divided into estab-
lished and emerging agents (Box 43.1).
412
BOX 43.1  PHARMACOLOGICAL
AGENTS FOR FATIGUE
Established agents
• Corticosteroids
• Megestrol acetate
• Psychostimulants, e.g., methylphenidate, modafinil,
dextroamphetamine
• Testosterone
Emerging agents
• Agents that inhibit cytokine action, e.g., thalido-
mide, COX-1 and COX-2 inhibitors (NSAIDs),
selective COX-2 inhibitors, omega 3 fatty acids,
a-melanocyte stimulating hormone
• Agents that block cytokine release, e.g., pentoxi-
fylline, bradykinin antagonists
• Donepezil
• Monoclonal antibodies, e.g., infliximab, soluble
receptor antagonists
• l-Carnitine
Established agents
Unfortunately there is no single agent that can be used to treat
fatigue in advanced diseases effectively. This is probably because
of the multifactorial etiologies contributing to fatigue. However,
a number of agents have been studied and shown to be effective in
treating fatigue, often in combination targeting he multifactorial
and multidimensional etiology of fatigue.
Corticosteroids
Corticosteroids are commonly used in palliative care for the
management of symptoms. The mechanism of action of corti-
costeroids on fatigue is not well understood. Corticosteroids are
presumed to decrease fatigue by their effect on: (a) inflammatory
cytokines such as IL-1, IL-6, TNF-α which have been implicated
in pathogenesis of cancer related fatigue; (b) effect on HPA axis
as dysregulation of HPA axis has been associated with chronic
fatigue syndrome. Some smaller studies have also implicated the
altered cortisol response to stress in cancer patients related to
persistent fatigue and symptom clusters.
Studies have been done on steroids, dexamethasone, and meth-
ylprednisone and have shown improvement in fatigue. Moertel
et al. in a double-blind controlled study with 116 patients with
advanced gastrointestinal cancer, dexamethasone given at a dose
of 0.75 and 1.5 mg four times daily showed improvement in appe-
tite and sense of wellbeing.124 There was however, no associated
weight gain or improvement in performance status. There was also
initial symptomatic improvement in the placebo group but after 4
weeks this disappeared and at this point, dexamethasone showed
a statistically significant advantage over placebo. Other groups
found methylprednisolone caused improvement in activity level
quite rapidly but this was not sustained over a 3-week period. A
newer study by Paulsen et al. revealed methylprednisolone 16 mg
twice daily improved fatigue, anorexia, and patient satisfaction 7
days post administration when compared to placebo.125 Forty ter-
minally ill cancer patients were studied in a 14-day randomized
Textbook of Palliative Medicine and Supportive Care
double-blind, crossover trial comparing methylprednisolone
with placebo. The daily dose was 32 mg and endpoints studied
were pain, appetite, nutritional status, psychiatric status, daily
activity, and performance. Appetite and daily activity increased
in 77 and 21% of patients, respectively, with 71 and 57% reduc-
tion in depression and analgesic use, respectively.126 In a recent
randomized placebo controlled study by Yennurajalingam et
al. 2013 with 84 advanced cancer patients, oral dexamethasone
8 mg/day for 14 days was found to be effective in relieving can-
cer related fatigue as compared to placebo. The mean (standard
deviation) improvement in the FACIT-F fatigue subscale at day 15
was significantly higher in the dexamethasone group than in the
placebo (9 [10.3] vs. 3.1 [9.59], p = 0.008). The numbers of grade
≥3 adverse effects did not differ between groups (17/62 vs. 11/58,
p = 0.27. Corticosteroids to treat fatigue are probably best used on
a short-term basis, as long-term use is associated with increased
incidence of side effects including myopathy which could poten-
tially make fatigue worse. Moreover, studies have shown that the
beneficial effects generally last between 2 and 4 weeks. Other
beneficial effects of steroids that may impact fatigue include the
effect on nausea, appetite, and pain.91
Progestational steroids
Cancer cachexia is known to contribute to fatigue in cancer
patients and weight loss has been associated with increased mor-
tality. A number of studies in terminally ill patients given meges-
trol acetate have shown a rapid improvement within 1 week to 10
days, in a number of symptoms including fatigue, appetite, calorie
intake, and nutritional status. Doses used range from 160 to 480
mg per day. In a randomized, double-blind crossover study with
53 evaluable patients with advanced solid tumors not responsive
to hormone therapy, megestrol acetate given at a dose of 160 mg
three times daily for 10 days reported a significant improvement
in appetite, activity, and wellbeing. There was also significant
improvement in overall fatigue score. There was no significant
change in nausea, nutrition, or energy intake. The mechanism
of action of megestrol acetate is unclear and may be due to the
glucocorticoid or anabolic activity or due to effects on cytokine
release or a combination. In a Cochrane review by Minton et al.
involving three studies on progestational steroids, no benefit of
these for treatment of fatigue was found. Known side effects of
these agent include thromboembolic events), adrenal suppres-
sion with insufficiency upon abrupt discontinuation, hyperten-
sion, hyperglycemia, breakthrough uterine bleeding, and skin
photosensitivity.127
Psychostimulants
Methylphenidate is a known drug therapy for ADD, used mainly
in children and is the most well researched psychostimulant drug
used for the treatment of fatigue as well as additional symptoms
such as sedation and depression in advanced-stage cancer.128
Prior studies found that MP blocks the reuptake of norepineph-
rine and dopamine into the presynaptic neuron by its action on
the dopamine transporter and this results in the increased release
of these monamines into the extraneuronal space.129 While prior
studies have suggested that methylphenidate may result in sig-
nificant improvement in activity level in patients on large doses
of opioids,131–135 and otherwise heterogeneous studies with mixed
results thought so due to small sample sizes due to underpower-
ing,133,134 more recent meta-analysis of larger studies have found
no statistically significant benefit of methylphenidate for fatigue
compared to placebo.133,132 Despite these overall negative results,
Mechanism, Assessment, and Management of Fatigue
future studies are needed to assess the benefits of psychostimu-
lants in a subset of fatigued patients with predominant depressed
mood or sedation.132
Other psychostimulants studied in noncancer palliative groups
include modafinil and amantadine in multiple sclerosis,136 and
armodafinil in human immunodeficiency virus (HIV)137 and
amyotrophic lateral sclerosis (ALS).138 Both agents are postulated
to enhance catecholaminergic signaling and decreased gamma
aminobutyric acid release, primarily at the anterior hypothala-
mus, for the benefits of the treatment of impaired cognition139
and severe fatigue.140 Effect of modafinil on fatigue in cancer
patient was studied by Jeanne-Pierre et al. in a phase III double
blind placebo controlled randomised trial with 631 patients on
chemotherapy.135 Modafinil 200 mg once a day was used and
BFI-3 was utilised as a measure of fatigue in this study. The results
showed a statistically significant response for those with severe
fatigue (BFI score ≥ 7) with average BFI-3 scores 7.2 in modafinil
group as compared to placebo with average score 7.6 (p = 0.033),
although there were no significant differences in BFI-3 in the
patients with mild to moderate fatigue. In a newer, randomized,
well-designed study in non-small cell cancer patients, there were
no significant benefits of modafinil when compared to placebo.141
Modafinil, a psychostimulant, is effective and well tolerated for
the treatment of excessive daytime sleepiness (EDS) in patients
with narcolepsy, and conditions such as Parkinson’s disease and
obstructive sleep apnea. It was studied in HIV positive and ALS
patients, and was found to improve symptoms of fatigue, depres-
sion and sleepiness.142
The newest literature reiterates insufficient evidence to use psy-
chostimulants for the management of fatigue in cancer patients
with or without opioid-related sedation.131
Testosterone
Low testosterone is common in men with advanced cancer. Low
testosterone has been associated with high inflammatory mark-
ers and high symptom burden in patients with advanced cancer.143
Treatment with testosterone replacement has been beneficial in
management of symptoms in non-cancer patients. The use of
testosterone and its derivatives and other androgenic anabolic
steroids have been shown, predominantly in patients with hypo-
gonadism due to HIV disease, to increase muscle mass, improve
energy and libido and increase hemoglobin levels. In a prospec-
tive longitudinal study over a 3-year period, 18 hypogonadal men
who had never been treated were given transdermal testoster-
one. The mean testosterone level reached the normal range by 3
months of treatment and remained normal for the duration of
treatment. Outcomes measured were bone mineral density, fat
free mass, prostate volume, erythropoiesis, energy, and sexual
function. The full effect on bone mineral density took 24 months
but the full effects on the other tissues and energy levels took
3–6 months.45 A randomized, double-blind, placebo controlled
study in a group of hypogonadal men with AIDS wasting looked
at the effect of testosterone administration on the depression
score. Fifty-two hypogonadal males with AIDS demonstrated sig-
nificantly higher scores on the Beck Depression Inventory (BDI)
than matched eugonadal men also with AIDS. The hypogonadal
men were then treated with testosterone and there was a sig-
nificant decrease noted in the BDI score for the 39 patients who
completed the study.144 The correlation between depression and
fatigue has been made earlier and hence by improving depression
in this way, fatigue could potentially improve. Testosterone defi-
ciency has also been shown to occur as a result of cancer therapy
413
including radiation and chemotherapy as well as in the hormonal
treatment of certain cancers such as prostate cancer (where tes-
tosterone replacement is not possible). A preliminary random-
ized controlled study was recently conducted by Del Fabbro et al.
to evaluate the efficacy of testosterone replacement for fatigue in
male hypogonadic patients with advanced cancer.145 A total of 26
patients were evaluated with 12 on replacement and 14 on placebo
for the primary outcome at Day 29. The intervention group had
improvement in fatigue scores (mean [SD] −5.5±19 for placebo
and 3.9 ± 14 for testosterone, p = 0.09). Adverse events were simi-
lar between groups.
Emerging pharmacological agents
Fatigue, as stated earlier in this chapter, is the most common
symptom in palliative patients and yet is probably one of the most
difficult symptoms to treat. Multiple agents have been studied
and found not to be effective in the treatment of fatigue, such
as mazindol, donepezil,146 and L-carnitine.147 With regards the
established agents, results are often short term or they are asso-
ciated with unacceptable side effects, e.g., corticosteroids with
myopathy in long-term use or megestrol acetate with associated
thrombotic risk. This often makes them unsuitable for many in
this patient population. Moreover because of the multifacto-
rial complex etiology of fatigue, it has been challenging to find a
single effective pharmacological agent to treat fatigue. Currently
a number of agents are under investigation for the treatment of
fatigue some of which are discussed below.
Ginseng is a Chinese herbal medicine, which comes in three
forms: Asian (Panax ginseng) and American (Panax quiquefo­
lium), and the Siberian (Eleutherococcus senticosus) variety. It is
presumed to help fatigue by reducing the impact on environmen-
tal stress (adaptogen). However, there are limited studies con-
ducted in cancer patients.
Other emerging and proposed agents for targeting the treat-
ment of fatigue in palliative care include a-melanocyte-stimu-
lating hormone, monoclonal antibodies against TNF-α such as
infliximab, COX-1 and COX-2 inhibitors, to name a few. Herbal
remedies are often used by patients with CRF. Ginkgo biloba, for
example, has some activity against TNF and the potential ben-
efits of natural products in fatigue should also be explored with
good clinical studies.51
Nonpharmacological management
Of the various treatment strategies, exercise has the strongest
empirical support in patients with early cancer and cancer sur-
vivors, with several recent meta-analyses concluding that physi-
cal activity has a moderate beneficial effect on CRF.150 There is
also some support for psychological interventions, with a meta-
analysis showing a small to moderate beneficial effect (stan-
dardized mean difference in the range of 0.10 to 0.30).42 The
few trials that explicitly focused on fatigue, providing education
about fatigue and instruction in self-care, coping techniques,
and activity management, were more effective than nonspecific
interventions.151
Physical activity or exercise
A recent Cochrane review confirmed the beneficial effects of
exercise in the management of CRF.34 In a total of 56 studies in
which 1,461 participants received an exercise intervention and
with 1,187 control participants, exercise was seen to be statisti-
cally more effective than the control intervention (standardized
414
mean difference, −0.27, 95% confidence interval −0.37 to −0.17).
Both aerobic and resistance exercises, such as brisk walking,
cycling, swimming, and weight lifting, are helpful; at least one
30-minute episode per day (at least 150 minutes per week) has
been shown to reduce fatigue levels. In addition, they found that
aerobic exercise significantly reduced fatigue but that resistance
training did not.
There is limited evidence of beneficial effects of exercise in
palliative care patients.152 In a randomized controlled study in
advanced-stage cancer patients, 121 patients were referred to
exercise and 110 were referred to usual care. After 8 weeks of a
standardized 60-minute, twice-a-week intervention, no signifi-
cant differences were found in the primary outcome of physical
fatigue as assessed by a fatigue questionnaire. Statistically signifi-
cant results were noted in the physical performance measures,
including a shuttle walk test and a hand grip strength test; how-
ever, this study had a relatively lower adherence rate (69%) and a
high dropout rate (36%).153 Further research is necessary to deter-
mine the most effective type (aerobic vs. resistance), frequency,
duration, and intensity of exercise in palliative care patients.
In general, exercise should be prescribed for patients with
advanced-stage cancer, if appropriate, as exercise may be benefi-
cial to maintain muscle mass and physical strength, which are
commonly affected due to cachexia related to progressive can-
cer.153 Increase in physical activity may further be beneficial in
improving outcomes, including maintaining independence,
self-reported physical functioning, well-being, self-esteem, and
energy.154
In cases of deconditioning, the physiotherapist can suggest
suitable exercises and encourage increased activity, which may
have beneficial effects from both physical and psychosocial per-
spectives. In addition, if the patient is immobile, a physiothera-
pist can perform passive movements that will help the patient
maintain flexibility and decrease painful tendon retraction.
Occupational therapists can allow patients to remain safe and
increase their activity at home by providing such resources as
ramps, wheelchairs and walkers, elevated toilets, safety devices
for bathrooms, and hospital beds. In addition, these therapists
can give patients and families useful tips that enhance mobility
and help prevent further muscle atrophy, tendon retraction, and
pressure ulcers.
Acupuncture
Several studies have been conducted using acupuncture as an
intervention for CRF (see Chapter 75 Integrative Medicine
in Supportive and Palliative Care).155 Of these, a recent study
by Malossitis et al.156 of patients with breast cancer shows the
most promise. In this study, 75 patients were randomly assigned
to usual care and 227 patients to acupuncture plus usual care.
Treatment was delivered by acupuncturists once a week for 6
weeks through needling three pairs of acupoints for 6 weeks.
The usual care group received a booklet with information about
fatigue and its management. The difference in the mean General
Fatigue score of the multidimensional fatigue inventory, which
was the primary outcome, between those who received the inter-
vention and those who did not was −3.11 (95% confidence inter-
val, −3.97 to −2.25; p < 0.001). The intervention also improved
all other fatigue aspects including Physical Fatigue and Mental
Fatigue, anxiety and depression1 and QOL. The authors of this
study concluded that acupuncture is an effective intervention for
managing CRF and improving patients’ QOL.157
Textbook of Palliative Medicine and Supportive Care
Recent studies also suggest that integrative interventions such
as massage therapy, Qigong/Tai Chi, and Yoga are beneficial in
the treatment of fatigue in cancer patients.158 Further studies are
needed in advanced cancer patients.
Cognitive behavorial therapy
Cognitive behavioral therapy (CBT) and psychosocial interven-
tions (including mindfulness-based stress reduction) have been
known to be effective for improving insomnia in cancer survi-
vors, but have also been shown to be effective modalities for the
treatment of CRF.159,160 Since daytime sleepiness and sleep distur-
bances contribute to CRF,90,161 interventions targeting sleep dis-
turbances could improve CRF. In a recent four arm study of 96
cancer patients with chronic insomnia, it was found that CBT,
or the combination of CBT with armodafinil was associated with
greater reduction in fatigue scores.162 However, further well-
designed studies are needed in a broad variety of palliative care
patients before this approach can be recommended in advanced
serious illnesses other than cancer.
Neurofeedback
Cancer survivors typically experience ongoing symptoms such
as fatigue and cognitive impairments. Neurofeedback is a non-
invasive form of brain training that is noninvasive with minimal
side effects. However, there is currently insufficient data to uti-
lize neurofeedback as effective therapy for management of these
symptoms in cancer survivors though there are promising results
based on a meta-analysis review of multiple randomized control
trials in utilizing this modality.163
Light therapy
Light has a known strong effect of sleep and circadian rhythms
in other medical conditions but its effects on CRF are largely
unknown. Preliminary studies in breast cancer patients have
suggested that bright white light (BWL) prevented CRF from
worsening during chemotherapy when compared to dim red light
(DRL).164 Another preliminary study assessed 36 cancer survivors
who were either post chemotherapy or chemotherapy and radia-
tion for breast cancer, post completion of treatment for gyne-
cologic cancer, or post hematopoietic stem cell transplantation
in which BWL showed a reduction in fatigue whereas DRL did
not. In addition, 55% of patients in the DRL group still reported
residual fatigue post light therapy whereas the BWL arm did not
report any residual fatigue.165
Nutritional supplements
For patients with moderate to severe fatigue who are undergo-
ing cancer treatment, a therapeutic course of American ginseng
is reasonable, as long as there are no potential contraindications
such as drugs that may interact unfavorably with ginseng (such as
anticoagulants).
There is some literature that illustrates the benefits of ginseng.
In a randomized, double blind, dose evaluation pilot study by
Barton et al. with 282 cancer patients, Wisconsin Ginseng (Panax
quiquefolium) was tried in a dose of 750, 1,000, and 2,000 mg/day
in twice daily dosing versus placebo.148 There was no difference
in symptom improvement in patients on 750 mg versus placebo.
Although 40% of patients who completed 8 weeks of treatment
with the 1,000 and 2,000 mg doses noted moderate benefit as
Mechanism, Assessment, and Management of Fatigue
compared to 17% of the patients on the placebo arm. No sig-
nificant toxicities were noted despite patients being on cytotoxic
therapy. In a recently completed study, Wisconsin Ginseng at a
dose of 2,000 mg daily for 2 months was found to effective com-
pare to placebo in reducing fatigue in cancer patients. In a subset
of patients receiving chemotherapy, it was found to be effective
in 4 weeks.149 There were no significant side effects between the
treatment and placebo arm. In another randomized controlled
study, 2,000 mg/day of American ginseng (Panax quinquefolius)
in 364 participants undergoing active treatment across the United
States was associated with improvement in fatigue after 8 weeks
of treatment compared to placebo, especially in patients receiv-
ing active treatment (versus those who had completed treatment)
with no statistically significant differences in toxicities between
the arms.149 Another study examined 50 mg twice daily of gua-
rana (a stimulant derived from the extract of seeds from a plant
in the Paullinia cupana) revealed that there was a significant
improvement in fatigue at days 21 and 49 post administration
with no resulting toxicities.166 Randomized control trials assess-
ing the efficacy of Korean ginseng (Panax ginseng) however have
demonstrated less clear benefits. In one randomized control trial,
Asian ginseng (800 mg daily) was shown to be non-superior to
placebo after 4 weeks of treatment in 112 patients with advanced
cancer.167 By contrast, another randomized control trial in which
438 patients with colorectal cancer being treated with combina-
tion chemotherapy received 2,000 mg/day of Korean ginseng and
had improved fatigue scores at 16 weeks without discernable tox-
icities.168 These findings support Ginseng as a promising nutra-
ceutical agent in the treatment of cancer related fatigue. Further
studies are necessary to characterize the dose, duration, and
selection of patient population of who would most benefit from
ginseng administration.
Education
Educating the patient and caregivers about the possible causes of
fatigue and informing them of how frequent a symptom it is at this
stage in their disease may help them have more realistic expecta-
tions. Also providing them with information about the different
modalities of treatment, some of which can be self-implemented,
such as education about sleep hygiene and progressive limitation
in physical activity can help empower the patient.118,169
In a study by Carolina et al. of colon or gastric cancer from a
comprehensive cancer center, 40 eligible patients were randomly
allocated to intervention which consisted of a patient education
program delivered by nurses aiming to study perception of fatigue
with nursing education. The program included one-to-one educa-
tion, training and counseling, as well as audio-visual and com-
puterized educational materials. The comparison of symptoms
was done between patients who received same treatment and had
same type of cancer. Using FACT-F scale, the nursing interven-
tion group had decrease in level of fatigue as compared to control
group (please complete the data descriptions using p values).
Cognitive behavioral therapy has shown benefit in chronic
fatigue syndrome, neurological disorders, primary insomnia. The
benefits of this therapy in cancer population have been studied as
well. Gielissen et al. conducted a study with 112 cancer survivors
with unexplained fatigue, who were randomly allocated to inter-
vention (CBT) versus no intervention (waiting list)and assessed
at baseline and 6 months. There was significant improvement
in fatigue severity (−13.3; 95% CI, 8.6 to 18.1) and in functional
impairment (−38.2; 95% CI, 197.1 to 569.2) in CBT versus no
415
intervention group. 54% of CBT group had clinically significant
improvement in fatigue severity as compared to 4% of waiting list
group. Similar results were seen with regards to improvement in
functional impairment (50 vs 18% in CBT vs waiting list respec-
tively). In another RCT by Espie et al., with 150 cancer patients,
CBT was used as an intervention to study the effect on sleep qual-
ity with fatigue, QOL as secondary measures. Patients with CBT
intervention had statistically significant improvement in physical
fatigue measured by FACT scale as well as FSI, post-treatment
and at 6 month follow up.
Counseling
Patient education and CBT were found to improve fatigue in
patients with advanced-stage cancer.150 Patients frequently
underestimate the side effect burden at the beginning of cancer
therapy. In one study, only 8% of patients expected tiredness but
86% experienced it.170 This result suggests that many patients
undergo treatment without sufficient information to develop
realistic expectations about what that treatment entails.
Counseling regarding the possible causes of fatigue and the
types of therapeutic options available may allow the patient the
opportunity to develop realistic expectations which may need to
change as the disease progresses.
Patients should be empowered by receiving correct and full
information and by undergoing counseling. They may combat
fatigue by:
1. Adapting their activities of daily living by reducing the
amount of housework they do or by enlisting the help of
others to perform physical duties;
2. Spending more time in bed or, alternatively, exercising
more (the latter if deconditioning is considered to be a con-
tributor to the fatigue);
3. Rearranging their schedules within the day, depending on
their fatigue patterns;
4. Requesting changes in medications perceived to be causing
a loss of energy; and
5. Avoiding expending energy on unnecessary activities.
Counseling a patient about what symptoms to expect, including
fatigue, with disease progression or with cancer treatment helps to
better prepare them for the symptom when it occurs. Studies have
shown that only a small percentage of patients expect fatigue from
their therapy whereas up to 89% of them experience it.121 Counseling
for coping with other symptoms, such as adjustment disorder with
depressed mood and anxiety, which may impact fatigue could also
help with improving fatigue. CBT for insomnia helps with fatigue
Exercise (overexertion/deconditioning) has been discussed in
detail in other chapters of this book. It is important however, to
mention this again briefly here as it does impact the management
of fatigue. Impaired muscle function may be one of the under-
lying mechanisms in fatigue (at least the physical component to
fatigue). There are a number of studies showing muscle altera-
tions in cancer patients and the association between reduced
muscle mass in cachexia and fatigue.122 Prolonged bed rest or
immobility has been shown to cause deconditioning with associ-
ated loss of muscle mass and decreased cardiac output. This state
results in reduced endurance both for normal activities of daily
living and exercise. Normal exercise has been shown to have a
beneficial effect on muscle and cardiovascular fitness; however,
overexertion is a frequent cause of fatigue in non-cancer patients.
416
This is an important problem to recognize in younger cancer
patients who are trying to maintain their social and professional
lives while receiving aggressive antineoplastic therapies such as
chemotherapy and radiotherapy. 3
Several meta-analysis now support the benefits of exercise for
treatment of fatigue in patients receiving cancer treatment and in
cancer survivors. In a Cochrane analysis by Cramp et al. in 2008,
involving 28 RCTs, similar results were compiled. Most of these
studies show a clear benefit of exercise on fatigue are in cancer
survivors, patients with breast cancer, and in patients with less
advanced disease. In a randomized control trial by Oldervoll et al.
in 2011, 231 patients with advanced cancer and life expectancy ≤2
years were randomized to a physical exercise under supervision
versus usual care. The exercise included warm up, circuit train-
ing, stretching and relaxation for 60 minutes twice a week for 8
weeks. The primary outcome was physical fatigue measured by
the Fatigue Questionnaire and physical performance was a sec-
ondary outcome measured by the Shuttle Walk Test (SWT) and
hand grip strength (HSG) test. Analyses showed fatigue was not
significantly reduced (P-0.2) but physical performance (SWT and
HGS test) was significantly improved (p = 0.001 for both) after 8
weeks of exercise. In a smaller study by Bass et al. with 49 hospice
patients with 30 patients receiving kinesitherapy and 19 without
kinesitherapy the results were different. In this study patients
exercised under physiotherapist’s supervision three times a week,
for 20–30 minutes, for 3–4 weeks. The patients in exercise group
had significant improvement in fatigue after 3 weeks (p < 0.0001)
as compared to the control group in which the fatigue deterio-
rated. Hence based of the prior studies exercise improves fatigue
and physical functioning in patients with less advanced disease,
cancer survivors although with advanced illness the type and
amount of exercise needs to be defined.
Exercise is recommended as part of the therapy for fatigue in
cancer patients,123,124 and physiotherapists and occupational ther-
apists can suggest suitable exercises and help achieve increased
activity. The precaution here, however, is that the level of exercise
is appropriate for the patient and does not result in overexertion
and subsequent worsening of the fatigue.125
Multimodal and personalized therapy
In patients with advanced cancer, due to the multidimensional
nature of fatigue, it is unlikely that fatigue can be effectively
treated using a single intervention. A multimodal approach of
combination of pharmacological and non-pharmacological treat-
ments simultaneously should be considered on the basis of a pre-
dominant pathophysiologic mechanism for a given patient.171
For example, a patient with a significant component of physical
fatigue may benefit from a combination of a short course of dexa-
methasone and physical activity tailored to the patient’s needs.
On the other hand fatigue patients with anxiety/depression or
drowsiness may benefit from interventions such as methylpheni-
date, and counseling with or without physical activity. Similarly,
various combinations of treatment that have shown preliminary
beneficial effects on fatigue in patients with advanced-stage
cancer should be considered on an individual basis. These may
include interventions such as cognitive behavioral therapy, edu-
cational interventions, anti-inflammatory drugs, and exercise.
However, further well-designed studies are needed to investigate
the efficacy of multimodal approach in patients with fatigue.
Further studies should also investigate the benefit of personal-
izing fatigue management by targeting both the reversible causes,
Textbook of Palliative Medicine and Supportive Care
KEY LEARNING POINTS
• Fatigue is a common yet complex multifactorial
symptom in palliative care.
• To offer appropriate treatment a detailed assess-
ment is important.
• Treat reversible causes then add in symptomatic
treatment if indicated—pharmacological as well
as nonpharmacological.
• Multiple agents are emerging with constant
research, but it will be difficult to find a single
agent to manage this complex symptom.
as well as nonreversible factors by a combination of treatments
for reversible causes (e.g., hypokalemia), and symptomatic treat-
ments (e.g., use of steroids or methylphenidate).
Conclusion
Fatigue is a multifactorial symptom that is extremely common
in advanced cancer patients. Approach to the management of
this complex symptom must therefore be multidimensional to be
effective. Detailed assessment is key to appropriate management
and, as noted here, there is still a lot of research to be done to offer
adequate therapy to this patient population for such a common
symptom.
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double-blind, dose-finding evaluation: NCCTG trial N03CA. Support
Care Cancer 2010;18(2):179–187.
149. Barton DL, Liu H, Dakhil SR, et al. Wisconsin ginseng (Panax quin­
quefolius) to improve cancer-related fatigue: a randomized, double-
blind trial, N07C2. J Natl Cancer Institute 2013;105(16):1230–1238.
150. Mustian KM, Alfano CM, Heckler C, et al. Comparison of pharmaceu-
tical, psychological, and exercise treatments for cancer-related fatigue:
a meta-analysis. JAMA Oncol 2017;3(7):961–968.
151. Jacobsen PB, Donovan KA, Vadaparampil ST, Small BJ. Systematic
review and meta-analysis of psychological and activity-
based interventions for cancer-related fatigue. Health Psychol
2007;26(6):660–667.
152. Ligibel JA, Giobbie-Hurder A, Shockro L, et al. Randomized trial of a
physical activity intervention in women with metastatic breast cancer.
Cancer 2016;122(8):1169–1177.
153. Oldervoll LM, Loge JH, Lydersen S, et al. Physical exercise for can-
cer patients with advanced disease: a randomized controlled trial.
Oncologist 2011;16(11):1649–1657.
154. Segal R, Reid R, Courneya K, et al. Randomized controlled trial of resis-
tance or aerobic exercise in men receiving radiation therapy for pros-
tate cancer. J Clin Oncol 2009;27:344–350.
155. Garcia MK, McQuade J, Haddad R, et al. Systematic review of acu-
puncture in cancer care: a synthesis of the evidence. J Clin Oncol
2013;31(7):952–960.
156. Molassiotis A, Bardy J, Finnegan-John J, et al. Acupuncture for cancer-
related fatigue in patients with breast cancer: a pragmatic randomized
controlled trial. J Clin Oncol 2012;30(36):4470–4476.
157. Zhang Y, Lin L, Li H, Hu Y, Tian L. Effects of acupuncture on
cancer-related fatigue: a meta-analysis. Support Care Cancer
2018;26(2):415–425.
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158. Hilfiker R, Meichtry A, Eicher M. Exercise and other non-pharmaceu-
tical interventions for cancer-related fatigue in patients during or after
cancer treatment: a systematic review incorporating an indirect-com-
parisons meta-analysis. Br J Sports Med 2018;52(10):651–658.
159. Bower JE, Crosswell AD, Stanton AL, et al. Mindfulness meditation for
younger breast cancer survivors: a randomized controlled trial. Cancer
2015;121(8):1231–1240.
160. Johns SA, Brown LF, Beck-Coon K, et al. Randomized controlled pilot
trial of mindfulness-based stress reduction compared to psychoedu-
cational support for persistently fatigued breast and colorectal cancer
survivors. Support Care Cancer 2016;24(10):4085–4096.
161. Berger AM, Mitchell SA. Modifying cancer-related fatigue by opti-
mizing sleep quality. J Natl Comprehens Cancer Netw: JNCCN
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162. Heckler CE, Garland SN, Peoples AR, et al. Cognitive behavioral ther-
apy for insomnia, but not armodafinil, improves fatigue in cancer sur-
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163. Luctkar-Flude M, Groll D. A systematic review of the safety and effect
of neurofeedback on fatigue and cognition. Integrat Cancer Ther
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164. Neikrug AB, Rissling M, Trofimenko V, et al. Bright light ther-
apy protects women from circadian rhythm desynchroniza-
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2012;10(3):202–216.
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165. Redd WH, Valdimarsdottir H, Wu LM, et al. Systematic light exposure
in the treatment of cancer-related fatigue: a preliminary study. Psycho-
oncology 2014;23(12):1431–1434.
166. de Oliveira Campos MP, Riechelmann R, Martins LC, Hassan BJ, Casa
FB, Del Giglio A. Guarana (Paullinia cupana) improves fatigue in
breast cancer patients undergoing systemic chemotherapy. J Alternat
Complement Med 2011;17(6):505–512.
167. Yennurajalingam S, Tannir NM, Williams JL, et al. A double-blind,
randomized, placebo-controlled trial of Panax Ginseng for cancer-
related fatigue in patients with advanced cancer. J Natl Comprehens
Cancer Netw: JNCCN 2017;15(9):1111–1120.
168. Kim YH, Lim Y, Cho JY, et al. Korean red ginseng to improve can-
cer-related fatigue in colorectal cancer patients with FOLFOX
chemotherapy: a randomized, double-blind, placebo-con-
trolled, parallel, multicenter trial, NCT02039635. J Clin Oncol
2017;35(15_suppl):10008–10008.
169. Reif K, de Vries U, Petermann F, Görres S. A patient education pro-
gram is effective in reducing cancer-related fatigue: a multi-centre
randomised two-group waiting-list controlled intervention trial. Eur
J Oncol Nurs 2013;17(2):204–213.
170. Kirsh KL, Passik S, Holtsclaw E, Donaghy K, Theobald D. I get tired
for no reason: a single item screening for cancer-related fatigue. J Pain
Symptom Manage 2001;22(5):931–937.
171. Bruera E, Yennurajalingam S. Challenge of managing cancer-related
fatigue. J Clin Oncol 2010;28(23):3671–3672.
44
BREATHLESSNESS

Claudia Bausewein, Sara Booth

Contents
Definition.............................................................................................................................................................................................................................421
Experience of breathlessness.......................................................................................................................................................................................... 422
Epidemiology..................................................................................................................................................................................................................... 423
Pathophysiology of breathlessness................................................................................................................................................................................ 423
Assessment and identification of causes of breathlessness...................................................................................................................................... 424
Symptomatic management of dyspnea......................................................................................................................................................................... 425
Nonpharmacological therapies...................................................................................................................................................................................... 425
Interventions affecting the breathing domain....................................................................................................................................................... 425
Breathing techniques and positioning.............................................................................................................................................................. 425
Hand-held fan........................................................................................................................................................................................................ 425
Acupressure/acupuncture................................................................................................................................................................................... 426
Interventions affecting the thinking domain......................................................................................................................................................... 426
Psychotherapy........................................................................................................................................................................................................ 426
Mind–body interventions.................................................................................................................................................................................... 426
Music........................................................................................................................................................................................................................ 426
Interventions affecting the functioning domain................................................................................................................................................... 426
Physical exercise.................................................................................................................................................................................................... 426
Mobility aids........................................................................................................................................................................................................... 426
Neuromuscular electrical stimulation.............................................................................................................................................................. 426
Multicomponent/complex interventions���������������������������������������������������������������������������������������������������������������������������������������������������������������426
Pulmonary rehabilitation..................................................................................................................................................................................... 426
Breathlessness support services..........................................................................................................................................................................427
Pharmacological therapies...............................................................................................................................................................................................427
Opioids...........................................................................................................................................................................................................................427
Anxiolytics.....................................................................................................................................................................................................................427
Benzodiazepines.....................................................................................................................................................................................................427
Antidepressants..................................................................................................................................................................................................... 428
Oxygen................................................................................................................................................................................................................................ 428
References........................................................................................................................................................................................................................... 429

Definition daily experience of breathlessness from the patient’s perspective. 3

Dyspnea is a common and burdensome symptom for patients
with advanced disease. The American Thoracic Society describes
dyspnea as “a subjective experience of breathing discomfort that
consists of qualitatively distinct sensations that vary in intensity.
The experience derives from interactions among multiple physi-
ological, psychological, social, and environmental factors, and
may induce secondary physiological and behavioural responses.”1
It is important to note that the subjective nature of the symp-
tom is stressed along the multidimensional components, which
go beyond solely physical condition and support the importance
of the psychological, social, and spiritual/existential component.
Similar to the concept of “total pain” as described by Dame Cicely
Saunders, “total dyspnea” or “total breathlessness” have been
suggested.2,3 Various terms are used in the context of dyspnea:
difficult breathing, shortness of breath, breathing discomfort,
or simply breathlessness. The term breathlessness is now widely
used in the palliative care and breathlessness literature in prefer-
ence to the biomedical “dyspnea” to emphasize the focus on the
Therefore, this term is used in this chapter also.
When breathlessness is persisting despite management of the
underlying disease, it is sometimes referred to as “refractory
breathlessness.” As this term is implying therapeutic nihilism,
Johnson et al. suggested to name it “chronic breathlessness syn-
drome” to recognize possibilities of management and raise aware-
ness among patients, clinicians, service providers, researchers,
and research funders.4 The chronic breathlessness syndrome is
described as “experience of breathlessness that persists despite
optimal treatment of the underlying pathophysiology and results
in disability for the patient.”4
Breathlessness presents as continuous breathlessness alone
or in combination with episodic breathlessness. The latter is
characterized by a severe worsening of breathlessness intensity
or unpleasantness beyond usual fluctuations in the patient’s
perception. 5 Such episodes are time-limited (seconds to hours)
and occur intermittently with or without underlying continu-
ous breathlessness. Episodes of breathlessness can be predictable
with known triggers such as exertion, emotions, comorbidities, or

421
422
external environment or may apparently be unpredictable.5 Linde
et al. stated that many ostensibly inexplicable episodes are driven
by “fear” or “panic” when investigated.6
Experience of breathlessness
Breathlessness not only impacts on patients’ physical condition,
but also imposes psychological distress, changes social rela-
tionships, and often provokes spiritual-existential concerns for
patients and carers. In the early stages, patients suffer from the
invisibility of breathlessness, later on living with breathlessness
is often seen as an ongoing struggle with unexpected transitions
into acute illness in form of acute exacerbations.7,8 Breathlessness
is frightening and distressing, and many patients suffer from anx-
iety and panic leaving them feeling vulnerable and open to attack
by their breathlessness.9
Breathlessness affects individuals in different ways and in dif-
ferent dimensions which is well demonstrated by the Breathing–
Thinking–Functioning (BTF) model.10,11 This clinical model
conceptualizes the three predominant cognitive and behavioral
reactions to breathlessness that, by causing vicious cycles, worsen
and maintain the symptom as demonstrated in Figure 44.1.
The three domains relating to the model are described in more
detail here:
• Breathing domain: Breathlessness associated with dys-
functional breathing patterns with an increased respira-
tory rate, the need for the use of accessory muscles and
dynamic hyperinflation, leading to inefficient breathing
and increased work of breathing.
FIGURE 44.1  The Breathing–Thinking–Functioning clinical model. (From Reference [10] with permission.)
Textbook of Palliative Medicine and Supportive Care
• Thinking domain: Misconceptions about the nature of
breathlessness, e.g., its causation, and previous experiences
and memories of breathlessness having a profound impact
on the present experience. These negative cognitions and
memories can lead to anxiety, distress, feelings of panic,
and thoughts about dying.
• Functioning domain: People suffering from breathlessness
frequently reduce their physical activity to avoid the sensa-
tion which leads to social isolation, the need for more help
from others and deconditioning of limbs, chest wall, and
accessory muscles.10
When patients are suffering from breathlessness, this affects
informal carers—families and friends supporting the patient—
as well. However, their burden and anxieties are often over-
looked and their presence is taken for granted. Carers of
breathless patients carry out many roles and tasks of caring
such as washing, dressing, managing symptoms, administer-
ing medications, or managing home oxygen as along with doing
all the everyday household work.12 Besides this practical help,
they also provide emotional support.12 The support of carers is
not only a daytime job but includes disturbed nights as well, as
described by Booth et al.13 Carers are lying awake, watching the
patient breathing and observing whether he is still alive. Thus,
it is not surprising that caregivers report severe problems with
sleep quality which have much in common with those of shift
workers and mothers of young children.14 Therefore, when
treating patients with breathlessness, the focus also needs to
be on the carers and their needs, acknowledging their role and
providing education, support, and resources to them as well as
Breathlessness
the patients. Carers need to be encouraged to look after their
own health, both physical and mental.
Epidemiology
Breathlessness is a common symptom in the general popula-
tion with higher prevalence in older age, female sex, and chronic
malignant and non-malignant conditions.15–17 The prevalence var-
ies across conditions from 16–77% in cancer, 56–98% in chronic
obstructive pulmonary disease (COPD), 18–88% in chronic heart
failure, 11–82% in end-stage renal disease, 12–52% in dementia,
and 81–88% in motor neuron disease.18 Large variations are due
to different ways of measurement and different disease stages.
In the last months of life, breathlessness intensity increases
as death approaches, especially in patients with primary lung
cancer.19,20
Based on the Global Burden of Diseases, Injuries and Risk
Factors Study, in 2016, deaths from cancer and noncancer condi-
tions likely associated with breathlessness were as follows: cancer
overall 8.9 million; lung cancer 1.7 million; cardiovascular dis-
ease 17.6 million; chronic respiratory diseases 3,5 million (with
COPD 2.9 million; asthma 0.4 million).21
Breathlessness is associated with shorter survival,22 reduced
will to live,23 reduced physical activity,24 increased emergency
room visits,25 and other health services use.
Pathophysiology of breathlessness
Breathlessness—the uncomfortable awareness of the need
to breathe—is a complex, individual experience of the mind
and the body.26–28 This helps to explain the clear evidence that
FIGURE 44.2  Schematic diagram to outline the genesis of breathlessness. (Reproduced with permission from Reference [32].)
423
breathlessness severity is a better predictor of prognosis than dis-
ease severity measured by quantitative assessments such as pul-
monary function tests.29
Respiration is the only vital function that is both unconscious
and under voluntary control, enabling an individual to talk, sing,
eat, or breathe-hold to swim under water, for example.30 The
respiratory (breathing) center in the medulla and pons gener-
ates a respiratory rhythm which is then modified by connections
through the brain stem and upper spinal cord. It coordinates the
activity of the diaphragm, the intercostal muscles, and accessory
muscles of respiration (see Figure 44.2). The links between dif-
ferent parts of the brain and brain stem and respiratory muscles
continue to be very controversial—it is clear that “the sensation
of breathlessness originates from complex neurophysiological
interplays between the automaticity of the breathing center in the
brain stem, the generation of fear/anxiety in the amygdala and
limbic system and the influence of the higher, cortical thinking
and feeling areas” (very much simplified in Figure 44.2). 31
The sensation of breathlessness is integrated throughout the
central nervous system (CNS), influenced by “peripheral genera-
tors,” such as fluid in the pleural space, fear, and anxiety (originat-
ing in the limbic system) and cognitions and memories associated
with breathlessness from the higher cortical centers. The breath-
lessness associated with planned activities in health, such as run-
ning, is not distressing although it may require much effort and
cause discomfort, because it is interpreted in a different way from
the breathlessness of disease. 33
In neuroimaging studies, breathlessness is associated with
activity in these specific brain areas, but these will feed into
distributive brain networks, rather than acting as discrete enti-
ties. The areas particularly associated with the generation of
424
FIGURE 44.3 The Bayesian brain. (Reproduced from
Reference [35] under Open Access.)
breathlessness within the limbic system and the cerebral cortex
are: (i) the amygdala, an area associated with perceiving threats
to self and arousing anxiety and fear, (ii) the cingulate cortex—
strongly associated with motivation, memory and action, (iii) the
medial-dorsal thalamus, associated with memory all part of the
limbic system, and (iv) the anterior insula, (cerebral cortex) asso-
ciated with interpreting the body’s own perception of “how it is”
known as “interoception.”
In the 1950s, Comroe postulated that breathlessness, “like
pain,” involved not only a “sensory component” from disease
but also the patients “reaction to the sensation,” now called
the affective component. 34 This historic definition is consistent
with the current Bayesian brain hypothesis, 35 see Figure 44.3,
which rejects the idea of the brain as a mere “stimulus con-
version” organ, proposing a model that proposes that the brain
“forms predictions based on previous experience28 and con-
tinuously generating a top-down cascade of neutrally encoded
(mostly non-conscious) hypotheses about the body and the
world.” 35 The stimulus conversion model would imply that a
given quantitative amount of pathology would always gener-
ate the same breathlessness severity, and this is demonstrably
untrue. It is likely that in order for a person to react instantly
to the environment around them, the brain works on a num-
ber of “prior” interpretations of the world, based on previous
experiences and so individuals react to the “brain’s best guess”
of what it is happening to them. 35 These “top-down” interpreta-
tions work in concert with “bottom-up” sensory information
and can be modified over time by new information including
education, so that treating “breathlessness via the brain” has
been proposed. 28,36 Certainly, the idea of “stimulus of the fail-
ing organ” 37 as the sole approach to palliating the symptom has
been rejected although treatment of the underlying disease is
fundamental to managing breathlessness.
A schematic representation of the generation of breathless-
ness is shown in Figure 44.2. The presence of the physical conse-
quences of disease, such as the distortion, stretching, or stiffening
of lung tissue by fluid, inflammation or tumor, or hypoxemia are
transmitted to the breathing center by, for example, pulmonary
stretch receptors and large vessel chemoreceptors (see Table 44.1,
pathology associated with breathlessness). It is thought that the
medullary breathing center sends out a corollary discharge of the
sensation being generated, and the perception of breathlessness
is then modulated by the influences of the higher cortical centers
and the limbic system, including “prior” interpretations of the
experience of breathlessness.
It is clear that the respiratory center receives sensory informa-
tion from multiple sources and breathlessness encompasses many
different qualitative dimensions. Two principle sensations are (i)
Textbook of Palliative Medicine and Supportive Care
TABLE 44.1  Causes of Breathlessness
Infection
Anemia
Deconditioning
Hypoxia
Hypercapnia
Metabolic acidosis
Bronchospasm
Pulmonary edema
Pleural effusion
Restrictive processes (chest wall restriction,
decreased lung compliance)
Pneumothorax
Pulmonary embolus
Muscle weakness (neuromuscular diseases,
cachexia, steroid myopathy, and phrenic
nerve paralysis)
Airway mechanical obstruction
Lymphangitic carcinomatosis
Pulmonary hypertension
Pericardial effusion
Ascites
increased sense of effort, or work of breathing, from, for example,
stiff lungs or narrowed airways; and (ii) air hunger, from changes
in blood gases. Air hunger is far more frightening.
It follows that the impact of breathlessness for a person will
be linked to their individual characteristics as well as disease
severity, and that some of these will be modifiable by physical,
educational, and psychological interventions. These include the
person’s health beliefs, previous experiences, and associations
with breathlessness, psychological status, degree of social con-
nectedness or isolation, poverty, nutritional status, and the sup-
port given by the health-care system. In someone who has been
breathless for some time, secondary behavioral responses, some-
times resulting from the actions of others, such as admonitions
to rest, may have become established. Some of these, although
apparently helpful, may actually increase the impact or severity
of breathlessness.
The central role of the CNS in the perception of breathless-
ness including the importance of cognitions in interpreting it as
well the possibility of altering peripheral generators (e.g., mus-
cle deconditioning) are consistent with a holistic palliative care
approach to managing breathlessness.
Assessment and identification
of causes of breathlessness
A comprehensive clinical history of a patient with breathlessness
should include the following aspects:38
1. Pattern of breathlessness (onset, aggravating factors, char-
acteristics, episodes, triggers)
2. Presence of other symptoms and their importance com-
pared to breathlessness
3. Impact on a person’s quality of life including physical
activities (e.g., walking), ability to self-care, social life, and
psychological status
Breathlessness
4. Current symptomatic treatments for breathlessness
(e.g., hand-held fan) and their efficacy for that person
5. Adverse effects of any treatments used currently or in the
past
6. All comorbidities
7. The person’s understanding and interpretation of the
symptom
8. Carer burden
Assessment of breathlessness needs to incorporate the subjec-
tive experience of the patient; thus, self-report of the symp-
tom is essential. This should include the sensory component
with intensity and severity, the emotional burden reflected in
the unpleasantness of breathlessness and the impact on daily
life. 3 There is currently no universally accepted outcome mea-
sure in either the clinical or research setting which is an obvi-
ous barrier to routine clinical assessment and monitoring of
breathlessness. 3 Two validated measures, the Dyspnoea 12 and
the Multidimensional Dyspnoea Profile (MDP) are suitable for
use in the clinical and research setting and are short enough for
assessment and monitoring. 39–42 The Dyspnoea 12 is a 12-item
measure with 7 physical items and 5 affective items not related
to physical activity. The answering options are on a scale of none
(0), mild (1), moderate (2), or severe (3). The time period relates
to “these days.”39 The MDP is also a 12-item scale using NRS
scores (0–10).41 Seven items relate to overall intensity, unpleas-
antness, and other qualitative sensory descriptions of breath-
lessness (increased muscle work of breathing, tight chest, air
hunger, breathing a lot, requires mental effort), and five rate
emotional responses to the breathlessness (depression, anxiety,
frustration, anger, and fear).41,42
An assessment of a patient with breathlessness should also
include a physical examination with vital signs, cardiac and pul-
monary examination, ascites, and peripheral edema.
Additional studies may include blood tests, pulse oximetry,
echocardiogram, and imaging studies (chest X-ray, computed
tomography, magnetic resonance imaging, positron-emission
tomography, ventilation-perfusion scan).
Although additional diagnostic tests may be important to iden-
tify any treatable causes of breathlessness, one should be aware
that more objective assessments such as respiratory rate, blood
gas analyses, or lung function tests do not measure breathless-
ness and only correlate moderately with the patient’s subjective
experience of breathlessness.
For optimal management of breathlessness, treatment of the
underlying disease and the exclusion of reversible symptoms are
the first step. A list of common causes of breathlessness asso-
ciated with malignant and non-malignant processes causing
breathlessness is presented in Table 44.1.43
Symptomatic management of dyspnea
When breathlessness persists despite optimal management of
the underlying condition, symptomatic treatment is mandatory.
This comprises both nonpharmacological and pharmacological
measures. Earlier in the disease trajectory, nonpharmacological
treatments are the first choice with the aim to improve patients’
self-management and increase physical activity. Later in the dis-
ease when patients suffer from breathlessness at slight exertion
or at rest, the addition of pharmacological measures will often
be necessary.
425
Nonpharmacological therapies
The abovementioned BTF model is helpful to classify available
nonpharmacological interventions for breathlessness as demon-
strated in Table 44.2. These should be proactively introduced to
patients as they are the cornerstone for breathlessness manage-
ment. Not all available interventions will be suitable for every
patient. Thus, it is important to identify the domains of the BTF
model where the patient is most affected and select individually
interventions together with the patient.
Interventions affecting the breathing domain
Breathing techniques and positioning
As breathlessness is causing dysfunctional breathing with
excessive accessory muscle use and upper chest dominance,
readaptation of breathing patterns is essential in breathlessness
management. Breathing control and diaphragmatic breathing
are two commonly used techniques. Diaphragmatic breathing
prolongs and slows inspiration and deliberately increases tidal
volume but should not be advocated in patients with severe
COPD.45 In contrast, breathing control techniques maintain
normal tidal breathing with relaxed upper chest and shoul-
ders.46 Pursed lip breathing is a further frequently used breath-
ing technique and is frequently and often instinctively used by
patients as it is a potential strategy to reduce respiratory rate
and aid recovery, especially in COPD patients.46 For improving
their breathing, physiotherapy is essential for patients to teach
them the right techniques and provide instructions for regular
exercise.
Many patients with COPD adopt a rapid, shallow breathing
pattern, frequently with chest wall and abdominal asynchrony.46
Inspiratory muscles are constantly in a shortened position and
may need to be augmented by accessory muscles with fixation
of the shoulder girdle.46 Patients need to be advised on passively
fixing the shoulder girdle for optimizing ventilatory muscle effi-
ciency and relief of breathlessness.46
Hand-held fan
Airflow directed to the face reduces breathlessness by altering
ventilation.47 This is potentially mediated through cold recep-
tors in the nose arising from the second and third branch of
the trigeminal nerve which give sensory input to affect respi-
ration and decrease breathlessness.47,48 A simple device to pro-
duce such an airflow is a hand-held fan. Its effectiveness has
TABLE 44.2  Nonpharmacological Interventions in Relation
to Breathing-Thinking-Functioning Domain44
Patient Focus Breathing Thinking Functioning
Breathlessness Sensory Affective Symptom
domain perceptive distress impact or
burden
Treatment by Breathing Psychotherapy Physical exercise
primary target techniques and and cognitive Mobility aids
or mechanism of positioning therapies Neuromuscular
effect Hand-held fan Mind–body electrical
Acupressure/ interventions stimulation
acupuncture Music
Multicomponent/ Pulmonary rehabilitation
complex Breathlessness support services
interventions
426
been tested in three randomized controlled trials (RCTs) 49–51
and reduction of breathlessness has been shown in two of
them.49,51 The fan has been reported as a helpful self-manage-
ment strategy and aiding recovery. 52,53 Patients need sound
instructions on how to use the fan and the mechanism of
action behind it. 54
Acupressure/acupuncture
Acupuncture is widely used in traditional Chinese medicine and
its efficacy and practice has been demonstrated.55 A systematic
review examining the effects of acupuncture in breathless patients
suffering from advanced disease, included 12 studies with 597
patients with COPD or advanced cancer and demonstrated that
breathlessness severity decreased significantly. 56 Median treat-
ment duration was 25 days ranging from a single acupuncture
session to treatment over 12 weeks with better treatment effects
in treatment duration of at least 2 weeks.56
Interventions affecting the thinking domain
As anxiety and panic are highly prevalent in patients suffering
from breathlessness, psychosocial support and interventions
addressing these symptoms are crucial. For many patients, active
listening and promotion of the therapeutic alliance is an inter-
vention in itself. 31 Also, education about breathlessness and that
breathlessness in itself does not harm or inevitably means that
the patient is dying.
There is limited evidence of studies testing psychosocial inter-
ventions as most do not measure breathlessness but focus on
anxiety and panic.
Psychotherapy
Different types of psychotherapies have been tested either with
personalized psychoeducational interventions57,58 or cognitive
behavioral therapy (CBT).59–61 In CBT, two studies reported a
significant reduction of breathlessness following CBT, 59,60 but in
one, the effect did not persist during the follow-up period.59 In
Bove’s study, a trend in favor of CBT was shown but results were
not significant after 12 weeks of follow-up.61 In the studies test-
ing personalized psychoeducational interventions, self-reported
breathlessness was unchanged.57,58
Mind–body interventions
Norweg et al. reported in her systematic review small to large
dyspnea improvements resulting from yoga (ES = 0.2–1.21
for intensity; 0.67 for distress; 0.07 for mastery; and −8.37
for functional burden). 62 In a study evaluating an 8-week
mindfulness-based breathing therapy (MBBT) program, the
intervention group did not show any significant reduction of
breathlessness. 63
Music
Studies testing music are referred to as distractive auditory
stimuli (DAS). Two small studies tested DAS in combination
with exercise (either walking or an upper extremity program) in
COPD patients.64,65 In the study testing DAS during walking, a
nonsignificant decrease was observed in the intervention group,
and a nonsignificant increase in the control group.64 In the sec-
ond study, no significant differences between or within groups
were shown.65 Singh et al. compared the effects of music with pro-
gressive muscle relaxation and demonstrated that both groups
Textbook of Palliative Medicine and Supportive Care
were clinically effective in immediately reducing breathlessness.
The improvements in breathlessness and anxiety were higher in
the music group than in the PMR group.66
Interventions affecting the functioning domain
Physical exercise
As many patients experience unpleasant breathlessness especially
with exertion, they reduce physical activity which in consequence
leads to muscle deconditioning which drives further breathless-
ness at lower levels of activity.54 Therefore, physical exercise should
be encouraged in patients with breathlessness. Exercise leads to
improvement of fitness and muscular performance among people
living with and cured of cancer.67 By improving physical capacity,
the level of exertion for any given physical task or activity relative
to capacity becomes proportionally lower, and the level of per-
ceived exertion and symptoms, e.g., breathlessness and fatigue,
is reduced.54 Exercise training has been proposed as the most
powerful means of desensitization to breathlessness.1 A variety
of exercise programs have been studied, but rates of uptake and
completion vary widely, and benefit from intensive, supervised
exercise training may be limited to selected patients, often those
who are fitter and less symptomatic.68 Physical exercise is also a
key component in pulmonary rehabilitation programs.
Mobility aids
Mobility aids such as rollators or walking sticks offer the breath-
less patient additional support and not only allow for walking lon-
ger distances but also improving breathlessness.69,70 An increased
maximal voluntary ventilation by bracing the arms on the walk-
ing aid and adopting a lean forward position are probably respon-
sible for the positive effect of a walking aid on breathlessness.71 In
addition, stabilizing the ribcage may improve accessory muscle
function allowing these muscles to be engaged in respiratory
activities.71
Neuromuscular electrical stimulation
Deconditioning due to physical activity also leads to breathless-
ness and peripheral muscle weakness.72 Therefore, exercise train-
ing is a key component of pulmonary rehabilitation programs
but not all participants with severe COPD are capable of exer-
cise and exercise training.73 Neuromuscular electrical stimula-
tion (NMES) provides an interesting alternative to improve lower
limb muscle performance. Low current is applied to leg muscles,
mainly the quadriceps muscle, by a device causing the muscle to
contract. NMES does not have the same effect as aerobic or weight
training but the aim is to prevent or slow the downward spiral
that can affect the breathless patient, not to reduce breathless-
ness directly.54 Jones et al. demonstrated in a systematic review
including 18 studies with 933 participants in chronic respiratory
disease, chronic heart failure and thoracic cancer that NMES led
to a statistically significant improvement in quadriceps muscle
strength as compared to control equating to approximately 1.1
kg, and an improvement in exercise performance with mixed
results in breathlessness.74
Multicomponent/complex interventions
Pulmonary rehabilitation
There is strong evidence that pulmonary rehabilitation has a sig-
nificant effect on breathlessness, increases functional exercise,
and improves quality of life in COPD patients as demonstrated in
a Cochrane Review including 65 RCTs with 3,822 participants.75
Breathlessness
Programs usually last 8–12 weeks and encompass exercise train-
ing for at least 4 weeks with or without education and/or psycho-
logical support.75
Breathlessness support services
For optimal management of breathlessness several management
strategies outlined above need to be tailored to the individual
patients’ needs. Also, many patients with advanced disease are
not fit enough to participate in a longer pulmonary rehabili-
tation program. Therefore, breathlessness services have been
developed and evaluated over the past 20 years for patients with
advanced disease following the Medical Research Council (MRC)
Framework for complex interventions.76 These relatively new
multi-professional services are usually provided by palliative care,
sometimes in close collaboration with respiratory medicine.77
Services comprise expertise from a medical and physiotherapy
and/or nursing or social work background.77–79 Most services pro-
vide 4–6 contacts over 4–6 weeks.80 Interventions provided to the
patients are physiotherapy including breathing techniques and
positioning, relaxation techniques, self-management strategies,
and medical review. In a meta-analysis of studies testing breath-
lessness services, reductions in Numeric Rating Scale distress due
to breathlessness (n = 324; mean difference [MD] = −2.30, 95% CI
−4.43 to −0.16, p = 0.03) and depression scores measured by the
Hospital Anxiety and Depression Scale (HADS) (n = 408, MD =
−1.67, 95% CI −2.52 to −0.81, p < 0.001) favored the intervention.80
Statistically nonsignificant effects were observed for Chronic
Respiratory Questionnaire (CRQ) mastery (n = 259, MD = 0.23,
95% CI −0.10 to 0.55, p = 0.17) and HADS anxiety scores (n = 552,
MD = −1.59, 95% CI −3.22 to 0.05, p = 0.06).80
Pharmacological therapies
Opioids
Opioids are the preferred treatment for breathlessness with good
evidence.81,82 Endogenous opioids have a modulatory effect on
breathlessness which appears to be mediated by binding to cen-
tral rather than peripheral opioid receptors in the respiratory
tract.83 Their effect can be reduced by naloxone as demonstrated
in a cohort of COPD patients who had a significant increase in
circulating beta-endorphin after exercise which was reversed by
naloxone leading to higher levels of breathlessness.84 Recently,
sustained-release morphine has been licensed in Australia in
patients with distressing breathlessness due to severe COPD, car-
diac failure, malignancy or other cause, after treatments for the
underlying cause(s) of the breathlessness have been optimized
and nonpharmacological treatments are not effective. 31
Over the past 30 years, a number of clinical trials evaluated
the efficacy of opioids in patients with advanced disease. Jennings
et al. published the first systematic review on the effectiveness
of opioids in breathlessness due to advanced disease includ-
ing nine studies with 116 participants.85 The review supported
the use of oral and parenteral opioids to treat breathlessness in
patients with advanced disease but concluded that nebulized opi-
oids are not better than nebulized saline.85 The Jennings review
was updated by Barnes et al. in 2016 including 26 studies with
526 participants.81 The meta-analyses with fixed-effects model
demonstrated a standardized mean difference (SMD) of −0.09
[95% CI −0.36 to 0.19] in the opioid group. The review resulted
in the conclusion that there was only low-quality evidence that
shows benefit for the use of oral or parenteral opioids to palliate
427
breathlessness and no evidence to support the use of nebulized
opioids.81 This review was criticized for the conflicting findings
as they did not account for matched data of crossover trials.82
Ekström et al. reanalyzed the data with a random effects model
and accounted for crossover data. They concluded that opioids
decreased breathlessness (SDM = −0.32; 95% CI −0.18 to −0.47;
I2 = 44.8%) representing a clinically meaningful reduction of 0.8
points (0–10 numerical rating scale) which was consistent across
all meta-analyses.82
For other than oral or parenteral modes of application, such
as intranasal or transmucosal, there are only case series or pilot
RCTs and clinical observations.86–88
Most studies testing opioids on breathlessness included
patients suffering from COPD and breathlessness at rest or mini-
mal exertion limiting daily activities despite optimized treat-
ment.89 In a pooled analysis, younger people or those with worse
breathlessness are more likely to benefit.90
Overall, opioid doses to relieve breathlessness are much lower
compared to analgesic doses. In a dose titration study, 70% of
patients experiencing relief of breathlessness needed 10 mg/24
hours sustained release morphine and 90% responded to 20 mg
or less daily.91 As slow-release opioids with steady state of the
opioid showed slightly larger reductions in breathlessness than
non-steady states,92 starting with sustained-release morphine
seems preferable to short-acting morphine. In opioid-naïve
patients, an adequate dose would be 10 mg/24 hours with dose
titration upward over days and weeks. Similar to pain manage-
ment, immediate-release opioids should be prescribed in addition
for acute episodes of breathlessness but unlike pain management
the titration rate is much lower. In patients who are already on
opioids, e.g., for pain relief, a 25% increase in the baseline opioid
dose for cancer pain provided relief of breathlessness for up to
4 hours.93 In patients with non-oncological disease, e.g., COPD,
lower doses of opioids have been suggested if patients are opioid-
naïve. A starting dose of 1 mg morphine once a day, increasing
to twice daily during the next week and further upward titra-
tion were recommended.94 This is in contrast to the slow-release
doses mentioned above and based on studies mainly with COPD
patients but it might indicate that very low doses are sufficient for
some of these patients.
Side effects are those expected with opioid therapy. In Barnes’
systematic review, participants were 4.73 times more likely to
experience nausea and vomiting compared to placebo, three
times more likely to experience constipation, and 2.86 times
more likely to experience drowsiness.81 Therefore, the same pro-
active prophylaxis as in pain management is necessary, e.g., regu-
lar laxatives to prevent constipation. More importantly, none of
the studies testing opioids in breathlessness reported respiratory
depression or other serious adverse events resulting in hospital
admission or death.85,91 Therefore, regular, low dose, sustained-
release opioids seems to be safe in patients with advanced and
terminal disease.89
Anxiolytics
Benzodiazepines
Benzodiazepines are frequently prescribed for the manage-
ment of breathlessness hoping to reduce coexisting anxiety in
these patients. Furthermore, it is assumed that benzodiazepines
are active at brain structures implicated in the perception of
breathlessness.95 However, a Cochrane review failed to show
any benefit of benzodiazepines.96 Eight RCTs with 214 partici-
pants were included (COPD n = 66; cancer n = 148). Only one
428
study demonstrated a significant positive effect of midazolam
compared to morphine.97 However, this result is conflicting with
another study of the same author group were midazolam was less
effective than morphine.98 In all the other studies, no significant
effect could be demonstrated.
Despite the limited evidence and because of the good clini-
cal experience, benzodiazepines are recommended as second-
line therapy when opioids and other pharmacological measures
are not effective or when patients suffer from additional anxiety
and panic.99 In advanced stages of the disease and in the ter-
minal phase, a combination of opioids and benzodiazepines is
recommended.98,100
Other psychoactive agents such as phenothiazines (pro-
methazine or chlorpromazine) have been studied in patients
with breathlessness.101–103 The potential mechanism of action is
thought to be reduction of anxiety and agitation. Most studies
are quite old (all published before 1990), with small numbers of
participants and of low quality. Only one study demonstrated a
small effect of promethazine for the relief of breathlessness which
was not confirmed in other studies.101
Antidepressants
More recently, antidepressants have come more into a focus of
interest for the relief of breathlessness. Serotonin, a neurotrans-
mitter, plays an important role in the central control of respiration
via multiple receptor subtypes, contributing to chemosensitivity
and mediating ventilatory response to changes in CO2/pH, and
by maintaining regulatory function as part of respiratory neu-
roplasticity.104 The perceived benefit does not appear to relate to
antidepressant or anxiolytic effects, as patients without concur-
rent anxiety and/or depression also reported improvements in
breathlessness.105,106 In consequence, selective serotonin reuptake
inhibitors (SSRIs) could be a potential new treatment option,
especially as there is some upcoming evidence. Two observational
studies using sertraline, an SSRI, reported a subjective decrease
in breathlessness in patients with COPD.105,107 However, a fully
powered RCT in 223 patients with chronic breathlessness did not
show a benefit of 25–100 mg (titrated upward over nine days) ser-
traline over placebo.108
Another commonly used and well-tolerated antidepressant
is mirtazapine, a noradrenergic and specific serotonergic anti-
depressant (NaSSA). Besides action at the α2-receptor, it is also
an antagonist at serotonin (5HT2A/2C/3) and histamine (H1)
receptors.109 Mirtazapine may have direct beneficial effects as it
impacts rapidly on neural circuits involved in vigilance and the
perception of, and the emotional response to, unpleasant stimuli
(of which breathlessness is one) through the process of intero-
ception.104 This assumption is supported by a case series of six
patients who received 15 mg mirtazapine.110 All patients reported
less breathlessness and being able to do more. These effects need
to be tested in a larger randomized controlled study which is cur-
rently underway.
Oxygen
Oxygen is commonly administered to patients suffering from
breathlessness due to advanced disease, often in the belief that
it is beneficial to patients. However, evidence is mixed regarding
the effectiveness of oxygen in relieving breathlessness. In patients
with COPD and chronic hypoxemia, long-term oxygen therapy
(LTOT) is an established measure and recommended in numer-
ous guidelines for prolongation of survival.
Textbook of Palliative Medicine and Supportive Care
In breathless patients with mild or no hypoxemia, evidence is
rather limited. In mildly hypoxemic and non-hypoxemic COPD
patients who would not otherwise qualify for home oxygen
therapy, oxygen can relieve breathlessness when given during
exercise.111 In chronic heart failure, Asano et al. concluded in a
systematic review including 11 studies, that there are scant data
to justify the use of oxygen in individuals with non-hypoxemic
chronic heart failure and chronic breathlessness.112 In intersti-
tial lung disease, Bell et al. demonstrated in a further systematic
review that there are no effects of oxygen therapy on breathless-
ness during exercise, although exercise capacity was increased.113
A systematic review in cancer patients confirmed the lack of evi-
dence to support the use of oxygen for breathlessness.114 Most sys-
tematic reviews criticize mainly small and underpowered studies.
Abernethy et al. studied a mixed population of 239 pallia-
tive care patients with PaO2 > 55 mmHg who were breathless
at rest or with minimal exertion.115 Patients received oxygen or
room air via a concentrator through a nasal cannula at 2 L per
min for 7 days. Both groups experienced a similar reduction of
breathlessness but without a significant difference. The authors
concluded that oxygen provided no additional symptomatic
benefit for the relief of refractory breathlessness compared with
KEY LEARNING POINTS
• Breathlessness is a subjective experience that
derives from interactions among multiple physio-
logical, psychological, social, and environmental
factors. Informal caregivers are severely burned
and need attention of professionals.
• The BTF model conceptualizes the three pre-
dominant cognitive and behavioral reactions to
breathlessness that, by causing vicious cycles,
worsen and maintain the symptom.
• Breathlessness is a complex interaction of mind
and body influences both by peripheral changes
in the lungs as well as cognition and memories.
• Assessment of a patient with breathlessness
should include pattern of breathlessness, impact
on patients’ quality of life including physical
activities, and the person’s understanding and
interpretation of the symptom.
• Treatment of the underlying disease and the
reversible causes are the first step in breathless-
ness management.
• A variety of nonpharmacological therapies are
available with good evidence that can be indi-
vidually tailored to the patients. They should be
employed before starting with pharmacological
treatment.
• For pharmacological therapies, opioids are
the drugs of choice with good evidence.
Benzodiazepines should only be used in combi-
nation with opioids as their evidence is limited.
• Oxygen should only be prescribed to hypoxic
patients. Otherwise, a draught of cool air, e.g.,
generated by a hand-held fan, should be intro-
duced to patients as there is good evidence for the
relief of breathlessness.
Breathlessness
room air and that less burdensome strategies should be consid-
ered after brief assessment of the effect of oxygen therapy on
the individual patient.115 Abernethy’s study implies that airflow
also has a beneficial effect on patients’ breathlessness. This has
been confirmed by a systematic review examining the effect of
airflow on chronic breathlessness. Swan et al. included 16 stud-
ies with overall 929 participants which used airflow as an inter-
vention or a comparator.47 Airflow via a fan at rest, medical air
via nasal cannulae, and medical airflow during a constant load
exercise test before and after rehabilitation all offered signifi-
cant benefit for breathlessness intensity.47 The potential mecha-
nism of effect are stimulation of the second and third branches
of the trigeminal nerve and/or stimulation of nasal mucosa and
upper airway “flow” receptors.47 As the application of oxygen
has known side effects (dry mouth and nose, immobility, CO2
retention, perceived stigma), is expensive and laborious to orga-
nize at home, the indication should be critically reviewed and
restricted to patients with proven hypoxemia. In patients with
mild or no hypoxemia, a hand-held fan should be introduced to
the patient with clear instructions about its use.
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45
OTHER RESPIRATORY SYMPTOMS (COUGH, HICCUP, AND SECRETIONS)

Regina M. Mackey and Francisco Loaiciga

Contents
Introduction....................................................................................................................................................................................................................... 433
Cough.................................................................................................................................................................................................................................. 433
Physiology..................................................................................................................................................................................................................... 433
Pathogenesis................................................................................................................................................................................................................. 434
Etiologies....................................................................................................................................................................................................................... 434
Assessment................................................................................................................................................................................................................... 434
Management strategies.............................................................................................................................................................................................. 435
Supportive: speech therapy................................................................................................................................................................................. 435
Pharmacological: cough suppressor or protrusive or cough enhancers.................................................................................................... 435
Hiccup................................................................................................................................................................................................................................. 436
Physiology..................................................................................................................................................................................................................... 436
Pathophysiology.......................................................................................................................................................................................................... 436
Management strategies...............................................................................................................................................................................................437
Nonpharmacological strategies...........................................................................................................................................................................437
Secretions.................................................................................................................................................................................................................437
Physiopathology of increased respiratory secretions including bronchorrhea.............................................................................................. 438
Management................................................................................................................................................................................................................ 438
Nonpharmacological approach.......................................................................................................................................................................... 438
Pharmacological approach.................................................................................................................................................................................. 438
References............................................................................................................................................................................................................................439

Introduction severe.2,3 Persistent and chronic cough can impact the lives of
patients and their families. It can cause insomnia, fatigue, vomit-
In this chapter, we approach other respiratory symptoms besides ing, worsening of pain, and anxiety.
dyspnea. Starting with the incidence of each symptom in the
palliative medicine population, moving into physiology, patho- Physiology
genesis, and then, we discuss the assessment and management Cough can be a voluntary act or a spontaneous reflex. In the latter,
options. it involves a complex reflex arc with receptors, an afferent path-
We present each symptom with its section and the latest way, a center for process information, the efferent pathway, and
research evidence. In the end, we offer a summary of these symp- this reflex arc ends with effectors.4 These receptors are located
toms and palliative care management approaches in tables to in the respiratory tree and lesser extent in other areas such as
facilitate a quick consult. the esophagus, pericardium, diaphragm, pleura, ear, and para-
nasal sinuses.4 Sensory nerves from larynx, pharynx, and upper
Cough respiratory tract join the vagus nerve, and then enter the nerves
system near the respiratory center, terminating in the medullary
Cough is one of the most common complaints that motivates cough center. The efferent part of the reflex arc is a cholinergic
patients to seek medical attention in the United States. It is a pathway going to the effectors, located on pharyngeal and respi-
natural mechanism that protects the respiratory tract with ratory muscles.5
multiple roles: (1) an important defense mechanism that clears The cough reflex act has four phases; the first one is part of
secretions or foreign body from the airways, (2) important factor afferent, all others are in the efferent pathway. It begins with the
of infection spreading, (3) a life-saving mechanism when keep- receptorial phase when the cough receptors are stimulated and
ing patient consciousness during a potentially lethal arrhythmia send the signal through the vagus nerve. The next is the inspira-
or converting back to the normal cardiac rhythm, or (4) one of tory phase that consists of a contraction of the arytenoid carti-
the most common symptoms for which patients visit a health- lage resulting in the glottis opening with rapid inhalation. This
care provider.1 phase will require an average of 50% of the vital capacity with
Chronic cough is a distressing symptom present in approxi- some variation depending on the stimulation. Following is the
mately 37% of patients with advanced cancer. Approximately compressive phase, happening with the closure of the glottis after
38% of these patients will rate this symptom from moderate to the contraction of the adductor muscle of the arytenoid cartilage,

433
434
which results in the adduction of the vocal cords. At this time, the
abdominal muscles will exhibit a strong contraction, resulting in
an intrapulmonary pressure increase and compression of bron-
chioles and alveolar sacs. The expiratory phase is the final phase,
with the action of abductor muscle of arytenoid cartilages, which
will cause a sudden opening of epiglottis and vocal cords. It will
cause the explosive leakage of air to the outside, with complete
exhalation and relaxation of the diaphragm.4
An effective cough is determined by the operational lung vol-
ume, which relies on the coordination of respiratory and laryn-
geal muscles and lung mechanics.6
Pathogenesis
The ineffectiveness of the cough reflex may occur when respi-
ratory and laryngeal muscles are weakened or uncoordinated,
decreasing the driving pressure, which will result in a low expi-
ratory volume and flows during cough. Neuromuscular disease
such as Parkinson’s disease, quadriplegia, multiple sclerosis,
poliomyelitis, motor neuron disease, Guillain–Barre syndrome,
Charcot-Marie-Tooth disease, myasthenia, Lambert–Eaton syn-
drome, Duchenne muscular dystrophy, etc. may have weakness
or dysfunction of respiratory muscle.4
The other important factor for an effective cough is the tenac-
ity of the mucus and the effectivity of the mucociliary transport
system. The mucus needs to be dispersed into the expiratory gas.
The physical properties of the mucous slug also affect cough effi-
ciency. Cough effectiveness is directly proportional to the depth
of the mucus and is inversely proportional to mucus tenacity (the
product of adhesiveness and cohesiveness).7 The normal func-
tion of the mucociliary apparatus is critical in maintaining an
effective cough, as it is needed to transport secretions from the
periphery to the more proximal airways where they can then be
cleared by cough.4
It is also important to understand the innervation related
to the cough reflex. The majority of bronchopulmonary vagal
afferent nerves are unmyelinated C fibers. 8 These fibers are
further differentiated from lung stretch receptors by their
sensitivity to several different substances such as bradykinin
and activators of the ion channels, transient receptor poten-
tial vanilloid 1 (TRPV1) (e.g., capsaicin, protons), and transient
receptor potential ankyrin 1 (TRPA1) (e.g., ozone, allyl isothio-
cyanate). Several other inflammatory mediators found in the
environment, for instance, prostaglandin E2, ozone, nicotine,
adenosine, and serotonin can play a role as irritants of broncho-
pulmonary C fibers. 8 Mechanical stimulus can be due to touch-
ing or displacement.
Because cough can be the result of an affective behavior, the
social and psychological issues of the patient must be clarified as
a possible cause or effect of coughing.9
Etiologies
The most common etiologies of chronic cough are upper airway
cough syndrome (previously postnasal drip), asthma, and gastro-
esophageal reflux.9,10 Cough may also be a complication of drug
therapy, particularly with angiotensin-converting enzyme (ACE)
inhibitors.
Other less common causes of chronic cough include a number
of disorders affecting the airways (non-asthmatic eosinophilic
bronchitis, chronic bronchitis, bronchiectasis, neoplasm, foreign
body) or the pulmonary parenchyma (interstitial lung disease, lung
abscess). A cause is identified in 75–90% of patients with chronic
cough.11,12 However, some patients may experience chronic cough
Textbook of Palliative Medicine and Supportive Care
of unclear etiology for years, despite extensive evaluation. The eti-
ology of so-called chronic idiopathic cough is unknown; exagger-
ated cough reflex sensitivity has been suggested.
In a palliative care population, there are many malignant and
non-malignant diseases related to chronic cough, for instance,
cardiopulmonary source (tumor, asthma, infection, pulmonary
edema, decompensated congested heart failure (CHF), lymph-
adenopathy, etc.), esophageal origin (gastroesophageal reflux),
medication angiotensin-converting enzyme (ACE) inhibitors,
and treatment-related (radiation therapy to the chest).5 Cough
caused by cancer can be direct (anatomical) or indirect (as the
result of complications). For example, tumor mass obstructing,
lymphangitic carcinomatosis, and related to treatment. An indi-
rect cause could lead to infections (such as pneumonia and bron-
chitis empyema and post obstructive pneumonia, pulmonary
embolism, compressive atelectasis, pleural effusion, or effusion of
the pericardium in superior vena cava syndrome).13 Fistulas from
the esophagus to the respiratory tract in radiation to the chest
can cause cough with swallowing in about 50% of the patients
with this type of lesions.14
Malignant disease from lungs, pleura, airway, mediastinum,
and metastatic to the thorax is likely to cause cough. In patients
with advanced head and neck cancer or lung cancer, cough is
present in 90% of the patients.15
Assessment
Based on duration, cough can be acute, lasting less than 3 weeks
or chronic, lasting from 3–8 weeks or longer. Acute cough is
mostly due to infection; chronic cough is more often simultane-
ously due to more than one condition1 It can also be subdivided in
acute, subacute (3–8 weeks), and chronic after 8 weeks.
As with other symptoms, a detailed history and physical exam-
ination remain the key to diagnosing cough. Starting by trying to
distinguish between acute and chronic cough is very important.
Several of the algorithms of evaluation and management of cough
have been published.13,16 It can be helpful to follow a systematic
assessment approach.
Identifying important associated symptoms, such as nausea,
vomiting, pain (odynophagia, dysphagia), insomnia, weight loss,
lack of appetite, dyspnea, and cough characteristics and timing,
may help elucidate the diagnosis. However, cough characteristics
and timing may not yield significant predictive value in diagnosis.9
Searching for benign causes is still important, even in the can-
cer population. Questions should begin with the most common
causes of cough, regardless of the population. Medication and
smoking history should always be part of the encounter.
Chest X-ray is the main diagnostic test in evaluating cough
when history and physical examination are insufficient. Other
tests and imaging should be followed to rule out life-threaten-
ing diseases. While looking for underlying causes, the provider
should be able to determine the frequency and effectiveness of
the cough.
In patients with chronic cough, the optimal evaluation should
include both subjective and objective methods because they are
potential methods to measure different things.9 The patient’s sub-
jective response will be measured by the intensity of the cough.
It is recommended to use a reliable quality of life instrument to
assess this symptom and treatment. Some assessment tools have
been studied to evaluate cough. Leicester Cough Questionnaire
(LCQ) and the Cough-Specific Quality-of-Life Questionnaire
(CQLQ) were valid and reliable, showing high interclass and
test–retest correlations. Unfortunately, these tools are being used
Other Respiratory Symptoms (Cough, Hiccup, and Secretions)
inconsistently. Because health-related quality-of-life instruments
have been psychometrically tested and visual analog scales have
not, the cough-specific health-related quality-of-life instruments
are recommended as the primary subjective outcome measure.
More studies are needed.17
Management strategies
When planning the management, the treatment of the underlying
diseases is recommended as the first step, when possible.
Stop offending agents: for example, for patients with ACE
inhibitor-induced cough, the medication should be discontin-
ued or replaced with another medication from a different class.
The incidence of ACE inhibitor-induced cough has been reported
to be in the range of 5–35% among patients treated with these
agents. The onset of ACE inhibitor-induced cough ranges from
within hours of the first dose to months after the initiation of
therapy. Resolution typically occurs within 1–4 weeks after the
cessation of therapy, but the cough may linger for up to 3 months.
The only uniformly effective treatment for ACE inhibitor-induced
cough is the cessation of treatment with the offending agent.
Treatment of underlying disease when possible:
• Upper airway cough syndrome: antihistaminic and/or
decongestants. Cough is caused by the nasal and sinuses
secretion dripping down and stimulating the cough reflex.
There is no diagnostic test for it. The confirmation will be
the response to treatment. Antihistaminic with sedating
property has shown good results, but the provider needs to
be aware of sedation and anticholinergic effects these med-
ications may have, especially in the elderly population.18,19
• Asthma: bronchodilator and/or steroids. Asthma and its
variants will respond to B2 agonist and corticoids with dif-
ferent degrees of relief.20,72
• Gastroesophageal reflux: treat as the general population
with proton pump inhibitor.9
• Oncological treatment when appropriate: radiotherapy
may improve cough in non-small-cell lung cancer in about
50% of patients.21 Chemotherapy may also provide cough
palliation, with studies showing 75% of patients achiev-
ing improvement of the cough.22 Other oncology invasive
procedures can be helpful to palliative cough.23 If a can-
cer patient presenting with cough is no longer followed
by oncology, it would be important to discuss with the
patient’s previous oncologist and consider referring back
for evaluation.
Supportive: speech therapy
Chronic cough that does not respond to medical treatment may
respond to speech therapy. There is some evidence that speech
therapy might improve cough with counseling, breathing exer-
cise, and cough suppression techniques.24
Consultation with physical therapy may also be helpful. Chest
physiotherapy teaches techniques to the patient to improve the
clearance of the airway, especially in patients with neuromuscu-
lar diseases.25
Pharmacological: cough suppressor
or protrusive or cough enhancers
Pharmacological treatment of the chronic cough can be either
antitussive, to prevent or eliminate cough, or protrusive, to make
cough more effective. When the cough serves no useful purposes
435
like cleaning airways, the antitussive is used. When the therapy
is directed to the symptom rather than the cause, a nonspecific
antitussive is employed. If the cough is performing a helpful func-
tion, like with bronchiectasis and cystic fibrosis, for instance, the
protrusive can be employed to encourage the cough.9
Using the cough severity to guide the treatment, a mild cough
should be first trial non-pharmacological management, such as
breathing exercises, education, and counseling.24 A peripheral
acting antitussive such as benzoate may be tried if not responsive
to non-pharmacological methods. Benzoate has also been used
on cancer patients with opioid-resistant cough. Benzonatate pre-
sumably anesthetizes stretch receptors in the lungs and pleura.
The recommended dose is 100–200 mg three times daily.5 If the
latter does not produce an acceptable response, or if the cough
is moderate to severe, a centrally acting medication like opioid
could be tried. They are the primary medication for moderate-to-
severe cough in palliative care.
Morphine 5 mg every 4 hours as needed can be started in a
naïve person. If the patient is already on opioids for pain, for
instance, a slow increase of the dose can be trialed.
Although widely used in the past, codeine is metabolized to
morphine by a cytochrome P450 enzyme system, and patients
who have variants of this enzyme are at risk of experiencing
adverse effects of codeine without the benefit.26
Some patients with advanced disease are taking opioids for
pain when they present cough. The dose might be adjusted to try
to control the cough, but there is no evidence supporting a second
opioid added for the chronic cough.
Hydrocodone, a codeine metabolite, can be an alternative for
morphine. A study showed that hydrocodone was well-tolerated
in advanced cancer patients, who presented a greater than 50%
improvement on their cough using hydrocodone 10 mg a day.27
Patients with moderate-to-severe cough unable to take opi-
oid, gamma-aminobutyric acid analogs, such as gabapentin and
pregabalin, are recommended. The evidence for these medica-
tions was from a study conducted on a general palliative care
population. The initiation dose should be low (300 mg/day for
gabapentin and 75 mg/day for pregabalin) and carefully titrated
watching for sedation and dizziness. Other side effects such as
nausea, weakness, tremor, peripheral edema, and others can also
be observed.28
A randomized trial showed improvement of the cough in
patients with idiopathic pulmonary fibrosis (IPF). Thalidomide is
an anti-inflammatory medication with the antiemetic and immu-
nomodulatory effect that can be potentially helpful for a cough
from IPF.29
Guaifenesin is an expectorant shown in a systematic review,
to have very limited benefit in reducing cough intensity and no
benefit from mucolytics. 30
It is important to remember that dehydrated patients may need
additional fluid to be able to effectively use an expectorant. An
efficient cough is also required, which is not always possible, for
instance, in patients with weak muscles due to cachexia or dis-
eases causing muscular weakness.
Mucolytics are expectorants, which means they facilitate the
sputum elimination by breaking the polymer network of the
mucin or the DNA-actin. This way is helping with the mucus
clearance. 31
Carbocysteine is a type of mucolytic with some benefit for
patients with cough due to bronchitis but no benefit for advanced
cancer patients. Another type of mucolytic is the recombinant
DNase, which is not recommended by the American College of
436 Textbook of Palliative Medicine and Supportive Care

Chest Physicians in their 2006 guidelines for use in patients with
cystic fibrosis. 32
Dextromethorphan, an antitussive antagonist of the N-methyl-
D-aspartate receptor (found in most over-the-counter cough syr-
ups), is not indicated for the treatment of chronic cough due to
limited evidence of efficacy. 33
Lidocaine or bupivacaine, both local anesthetics, have been
studied, but they have an unpleasant taste, risk of aspiration,
risk of bronchospasm, short duration of action and frequent
tachyphylaxis. 34,35
Several other therapies have been tried but with uncertain ben-
efit or evidence to support the use.
Hiccup
Hiccups, or singultus (medical term), are caused by synchronous,
repetitive spasm (myoclonic jerks) of one of both hemidiaphragm
and inspiratory intercostal muscle with the inhibition of the expi-
ratory component of the latter (intercostal muscle). As soon as
the contractions start, a sudden closure of the glottis produces
the characteristic sound and sensation.40–43 Soon after the activa-
tion of the hiccup neural pathway, the recurrent laryngeal nerve
stimulates the glottis closure, which gives the characteristic “hic”
sound. It is more frequent in males than females and can occur
every 2–60 minutes.44
Most of the hiccups are benign, and resolves in minutes to
hours,45 but it can last longer, being described as persistent when
lasting more than 48 hours or intractable, after 1 month. The
incidence of this symptom in advance cancer patient is about
1–9%.45–47
This bothersome symptom can affect the quality of life the patient
with serious illness. It can cause sleeping problems, decrease of oral
intake, anxiety, worsen pain, fatigue, depression, etc.
Physiology
The function of hiccups in adults is still unknown. Hiccups are
observed in fetuses after the 8 weeks of gestation also seen in neo-
nates, decreasing frequency over time. Some postulated theories
include protection of the respiratory tract against esophageal gas-
tric reflux.41,44 A recent explanation by Howes in 2012 suggests
that hiccups may have evolved along with other reflexes devel-
oped in mammals that allow them to coordinate suckling milk
and breathing.48
Knowing the neural pathway that controls the reflex, or reflex
arc, involved in the hiccup may help us to understand the pos-
sible causes. The afferent component of the arc reflex consists of
the vagus and phrenic nerves (C2–C4), the pharyngeal branch
of the glossopharyngeal nerve and sympathetic fibers from
T6–12. The central mediation is thought to be located on the
hypothalamus, brainstem near the respiratory center, medial
and dorsal medullary nuclei, and cervical spinal cord some-
where between C3 and C5 segment.40,41,44,45 The efferent path-
way of the arc is given by the phrenic and intercostal nerves.44
Pathophysiology
Like the hiccup function, the pathophysiology of chronic hiccup
is poorly understood. There are more than 110 diseases and sev-
eral medications that may be associated with persistent intrac-
table hiccups, with disturbance of one or more components of the
hiccup arc reflex (Table 45.1).41
The leading causes of hiccups can be:
1. Pathology of the gastrointestinal tract or thoracic struc-
tures: They are related to the anatomical location of the
phrenic and vagus nerves.
2. Conditions involving the central nervous system (CNS)
3. Medication or metabolic causes

BOX 45.1  APPROACH TO MANAGING COUGH IN THE PALLIATIVE CARE POPULATION

Assess with detailed history, examination, and when appropriate, complementary tests, which may be chest radiograph and
spirometry.
Stop ACE inhibitors.
Consider smoking cessation counseling based on prognosis. It can be stressful for a long life smoker and may not add any mean-
ingful result.
Consider benign causes of cough, such as gastroesophageal reflux, upper respiratory infection, asthma, and treat appropriately:

• Upper airway cough syndrome: antihistamines and/or decongestants

• Asthma: most respond to inhaled bronchodilators and inhaled corticosteroids
• Gastroesophageal reflux disease: prokinetics, antacids, and proton pump inhibitors/H2 antagonists36

Consider disease-directed treatment, such as chemotherapy, radiotherapy, etc.

Commence other treatment protocols from Association for Palliative Medicine task group70 (reproduced with permission):

• Inhaled sodium cromoglycate: There are only one small randomized controlled trial from 1996 for patent with lung
cancer and chronic cough. 37 The main limitation is the need to use an inhaler device. New formulation of inhaled
sodium cromoglycate has been studied in an RCT for idiopathic pulmonary fibrosis. 38
• Prescribe an opioid:
a. Morphine: 5 mg every 4 hours PRN
b. Gabapentoid: patient unable to take opioids, gabapentin or pregabalin should be tried. 39

If the patient has a very poor prognosis, consider cough suppression with opioid alone.
Other Respiratory Symptoms (Cough, Hiccup, and Secretions) 437

TABLE 45.1  Etiology of Chronic Hiccup (see further reference [41])

Peripheral Causes (Esophageal
Disorders) Central Causes Metabolic/Toxic Causes Psychiatric Causes
Gastritis, gastric ulcer Brainstem infarction (in particular Corticosteroids Reaction to grief
lateral medullary infarction)
Gastric distension, foreign body, Demyelinating conditions: Electrolyte imbalance Personality disorder
gastric bleeding multiple sclerosis (MS),
neuromyelitis optica (NMO)
Bowel obstruction Neoplasia Uremia malingering
Hepatic and biliary disorders Cerebrovascular diseases Sepsis Anorexia nervosa
Intestinal disease Infections Renal failure Hysteria
Pleural effusion Epilepsy Drugs enuresis
Cardiac infarction, aneurysm, Sarcoidosis Medication
etc.
Mediastinal disease Parkinson’s disease Diabetes
Diaphragmatic hernia Tuberculoma ENT infection
Post operatory Neurosyphilis Goiter

Management strategies Classification:

After considering the possible etiology (Table 45.1), the first
step on management should be assessed for reversible causes.41
Nevertheless, sometimes the cause cannot be found. The next
is the assessment and documentation of how the symptom is
impacting the patient and his/her family, and consideration of
treatment. The evidence on hiccup treatment is sparse and mostly
based on case reports, probably because it is rare and self-limiting.
The respiratory airway is a complex system, hence the neces-
sity to understand a symptom so ubiquitous toward end
of life has been a challenge within the medical commu-
nity, and the following two classifications; even though
TABLE 45.2  Medications Used to Treat Hiccup (see further
reference [41])

Nonpharmacological strategies Drug Evidence Common Side Effects

Launois et al. have a list of possible nonpharmacological manage- Gabapentin: Starting Reported to be effective Drowsiness, sedation,
ment for the hiccup.40 Finally, treatment with medication might dose 100–300 mg in several case series50 ataxia, and anxiety
need to be tried (Table 45.2). TID49
In 1932, Mayo stated that the knowledge about hiccups was Baclofen: 5–60 mg Case series and a small Sedation, drowsiness,
inversely proportional to the available treatments. In patients TID PO, increasing randomized crossover careful with renal
with advanced cancer, the most common causes are gastroesoph- dose by 5 mg every 3 trial impairment
ageal reflux, irritation of the diaphragm all the phrenic nerve, days until effective or
gastric distention, CNS tumors in toxic, metabolic, infection, and maximum dose
iatrogenic.47 reached
While there are many “traditional” remedies for acute bouts Metoclopramide: 10 Used with success Few side effects and
of hiccups, they often involve some form of pharyngeal stimu- mg IV then 10–40 in a case series not a sedative
lation or diaphragmatic splinting, for example, a cold key on mg PO daily of 14 patients
the back of the neck or drinking water from the wrong side with a variety
of a cup, these are unlikely to be successful for the intrac- of conditions51
table hiccup.41 Nonpharmacological interventions that used Haloperidol: 5–10 mg Licensed for use in Extrapyramidal side
with success include phrenic nerve stimulation 52 and phrenic daily PO intractable hiccup but effects and sedation
nerve block. 53 Acupuncture at pressure points has also proven evidence for efficacy (usually at higher
successful. 54 in case reports only. doses)
Commonly used in
Secretions palliative care
Chlorpromazine: Licensed for use in Hypotension,
The accumulation of secretions within the respiratory tract of a
25–50 mg IV in intractable hiccup, dizziness, and
patient around the later stages of a terminal disease can become
30–60 minutes then, small evidence for sedation
a burden for the patient and the caregiver(s); it is also known as
50–60 mg daily PO efficacy
“death rattle” due to its association with imminent death (16–60
Nifedipine: 10–80 Four patients in a series Headache,
hours before death).55–58 In this chapter, we will approach this
mg/day (orally) of seven gained vasodilatation, and
subject based on the following classifications/terminology: pre-
complete relief and a peripheral edema
dominantly salivary secretions (type I), predominantly bronchial
fifth felt improvement
secretions (type II); as well as terms such as death rattle versus
with nifedipine
pseudo death rattle.
438
they share similarities, cite important factors that help us
understand the physiopathological basis of the symptom
in question, such as level of consciousness and other types
of secretions, besides the ones innate to the respiratory
tract:
1. Noisy respiratory secretions (Bennet):57
• Type I due to predominantly salivary secretions: accu-
mulation of upper respiratory tract secretions second-
ary to an impaired swallowing reflex or inability to
swallow.
• Type II due to accumulated bronchial secretions: sec-
ondary to inability to satisfactorily clear the lower
respiratory tract, due to weakness or absence of cough
reflex.
2. Death rattle (Wildiers and Menten): 55
• Type 1 real death rattle: accumulation of respiratory
secretions, associated mainly to a decline in the swal-
lowing reflex or consciousness, due to nonpathological
secretions.
• Type 2 pseudo-death rattle: bronchial or pathologi-
cal pulmonary secretions (e.g., pulmonary effusion
secondary to congestive heart failure or pulmonary
edema). This specific category is likely to not respond
well to ant muscarinic regimens.
Physiopathology of increased respiratory
secretions including bronchorrhea
It is defined as the sound caused by the oscillatory movement of
the upper respiratory airway secretions along with the expira-
tory and inspiratory phases of respiration. As mentioned above,
different authors tend to agree that the presence or combina-
tion of the accumulation of upper respiratory tract secretions
in the bronchi and oropharynx due to loss or decreased cough
or swallow reflexes as well as increased M2 and M3 musca-
rinic acetylcholine receptors leading to partial obstruction of
the airways. 59 The airflow through the secretions produces the
characteristic “death rattle,” which is the result of airway resis-
tance and respiratory rate; decreased expiratory flow of air sub-
sequently augments airway resistance causing an audible noise.
This mechanism is considered hypothetical at the moment
and more research in this regard is recommended by different
authors.60
TABLE 45.3  Anticholinergic medications used in Death Rattle (see further references [67,69,70])
Medication Recommended starting dose (adult)
Scopolamine base transdermal 1 patch every 72h May use 1-3
(hyoscine) patches
Glycopyrrolate 0.2 mg SC every 4-6 hours as
needed. 1 mg PO, then 1-2 mg
every 4-6
Atropine Sublingual (1% ophthalmic solution):
Initial: 1 to 2 drops every 2 to 4
hours; usual dose range: 2 to 4
drops every 2 to 4 hours)
Hyoscyamine (Levsin) 0.125 mg SC/SL then 0.125-0.25 mg
every 4-6h
Textbook of Palliative Medicine and Supportive Care
Bronchorrhea, also a common cause of increased respira-
tory secretions, has a similar symptomatic and broad differen-
tial diagnosis to noisy upper respiratory secretions. Defined as
the production of more than 100 ml of sputum per day, can
be found in chronic obstructive pulmonary disease, pancre-
atic cancer, colorectal carcinoma, cervical adenocarcinoma,
as well as lung cancer (most commonly broncoalveolar carci-
noma [BAC]).60–63 When it comes to BAC, the airway mucin
gene MUSC5AC is highly expressed. Epidermal growth factor
(EGF) ligands also stimulate mucin production, explaining why
EGFR-TK inhibitors have reported rapid and complete resolu-
tion of bronchorrhea.64–67
Management
Nonpharmacological approach
Repositioning the patient in a lateral position, and a more upright
fashion as tolerated, while trying to achieve the maximum level of
comfort with the intervention, providing scheduled mouth care, and
keeping the amount of parenteral fluids to the minimum. The use of
suctioning is appropriate only if the secretions are easy to reach, as it
has been associated with pain and distress. Also, the most important
aspect in the management of secretions toward end of life is to pro-
vide reassurance that the sounds are not distressing for the patient
and that their pharmacological treatment or lack of is not contrib-
uting to his/her life expectancy. Some healthcare systems recur to
educational pamphlets to support this intervention.
Pharmacological approach
The antisecretory properties of anticholinergic medications
are related to their antagonism with muscarinic receptors.
The most common drugs used for the management of termi-
nal secretions are the tertiary amines (e.g., hyoscine, atropine,
and hyoscine hydrobromide) and the quaternary amines (e.g.,
glycopyrronium bromide [glycopyrrolate]) and hyoscine butyl-
bromide). The smaller size of the tertiary amines make them
easier to the medication to cross the brain–blood barrier pro-
moting agitation, sedation, and confusion, whereas both qua-
ternary and tertiary amines can cause more peripheral effects
such as rhythm disturbances, and urinary retention (see
Table 45.3). 68
Special medical management considerations: bronchor-
rhea secondary to malignancy (specifically BAC) responds to
EGFR-TK inhibitors such as gefitinib and erlotinib, as well as the
use of nebulized indomethacin for malignant and nonmalignant
bronchorrhea (eg, panbronchiolitis).69
Side effects comments
Dry mouth, drowsiness, dizziness, Known in the United States as
confusion Scopolamine, generic name is
hyoscine.
Severe xerostomia, decrease The high volume for PO route
absorption of other SL maybe cause difficulty to
medication administer
Delirium, flushing, tachycardia There is no sufficient evidence to
hypotension. support use as first line
treatment, please consider if no
alternative available.
Dry mouth, drowsiness, dizziness,
constipation
 Other Respiratory Symptoms (Cough, Hiccup, and Secretions)
KEY LEARNING POINTS
COUGH
• Chronic cough can be very stressful for patients
and their families.
• Careful assessment to identify the cause is essen-
tial, when possible.
• Remember benign and common causes of
cough.
• For mild cough, start with nonpharmacological
treatment.
• Antitussive agents are available and the reason
for the treatment choice should be weighed care-
fully with patient prognosis and medications side
effects.
• Opioids are the most widely available antitussive
therapy, especially for cancer patients, but may
not be appropriate in early disease.
HICCUP
• Assessment for the underlying cause and remove,
when possible. Check medication profile and
electrolytes (see Box 45.1).
• Also evaluate for gastric distension and reflux,
and start prokinetics and proton pump inhibi-
tors, if indicated. Be aware of medication side
effects, for instance, metoclopramide, a good
prokinetic, may not be used in malignant bowel
obstruction.
• No response to the aforementioned, gabapentin
is becoming the recommended second-line medi-
cation for intractable hiccups.
SECRETIONS
• Noisy respiratory secretions in the setting of
advanced disease are a strong predictor of immi-
nent death.
• Identify differential, as increased secretions in
the end of life setting may be related to other
causes, such as infections, gastrointestinal dis-
eases, or extra pulmonary tumors, that might not
respond to the most common interventions.
• Nonpharmacological interventions such as repo-
sitioning and frequent mouth care should be the
first attempted.
• Consider discontinuation or decrease of intrave-
nous fluids, as they might worsen secretions.
• No antisecretory medication is better compared
to another, also data show that pharmacological
management might not be useful or necessary;
this topic is in need of further research.
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46
DEPRESSION/ANXIETY

Tatsuo Akechi

Contents
Introduction....................................................................................................................................................................................................................... 441
Prevalence, effect, and assessment of depression....................................................................................................................................................... 441
General medical patients................................................................................................................................................................................................. 441
Cancer: A paradigm for serious chronic illness.......................................................................................................................................................... 442
Challenges in the assessment of depression in cancer patients............................................................................................................................... 442
Treatment of depression.................................................................................................................................................................................................. 443
General medical patients........................................................................................................................................................................................... 443
Cancer patients............................................................................................................................................................................................................ 444
Choosing patients for treatment........................................................................................................................................................................ 444
Treatment options................................................................................................................................................................................................. 445
Randomized trials................................................................................................................................................................................................. 446
Unique issues in end-of-life care........................................................................................................................................................................ 447
Managing anxiety.................................................................................................................................................................................................. 448
Conclusion.......................................................................................................................................................................................................................... 450
References........................................................................................................................................................................................................................... 450

Introduction Physicians recognize psychological distress in about two-thirds

The length and quality of life of patients with serious chronic
illnesses, such as cancer, are influenced not only by their
malignant disease but also by comorbid medical and psycho-
logical conditions, such as depression and anxiety. For exam-
ple, previous study investigating the effect of cancer diagnosis
demonstrates that cancer diagnosis can produce acute stress
associated with higher suicide rate and cardiovascular death
especially in the first weeks, and these effects prolong at least
6 months after diagnosis.1 The complexity of care for these
patients makes it particularly challenging to ascertain whether
a patient is struggling with serious depression. Moreover, com-
pared with the statistics on the overall population of general
medical patients, there are fewer data to draw upon that would
help clinicians determine what treatments are effective for
depression in the advanced cancer or other advanced disease
settings. This chapter will examine the assessment and treat-
ment of depression and anxiety in general medical patients
and in patients with cancer.
Prevalence, effect,
and assessment of depression
General medical patients
To better understand how to recognize and treat depression in
patients with cancer, it is useful to first review the existing para-
digms for finding and treating depression in the primary care
setting. Depression is estimated to affect 121 million people
worldwide, and 5.8% of men and 9.5% of women experience a
depressive episode every year.2 The prevalence of major depres-
sion in primary care setting is 5–9%. 3 Depression is two to three
times more common in patients with chronic medical illnesses.4
of the general medical patient population and prescribe anti-
depressants for about half of those distressed patients. 5 Major
depressive disorders can cause severe decrement in health.6
Depressive symptoms are associated with a higher-than-normal
risk of physical decline and with long-term mortality in older
adults;7,8 depression is also a risk factor for diabetes, coronary
heart disease, and stroke,4,9 and it is associated with a greater
use of health-care services.10 In addition, comorbid depression is
associated with increased medical symptom burden, functional
impairment, medical costs, poor adherence to self-care regi-
mens, and increased risk of morbidity and mortality in patients
with chronic medical disorders.4
The standard paradigm for identifying depression in the pri-
mary care setting is to view depression as a syndromal diagnosis
made on the basis of patient history and the exclusion of compet-
ing diagnoses, using criteria from the Diagnostic and Statistical
Manual of Mental Disorders (DSM)-5.11 Major depression is
defined as depressed mood or anhedonia (loss of interest in plea-
surable activities) that lasts for at least 2 weeks plus the presence
of three or four other specific psychological or somatic symptoms.
If two to four rather than more than five symptoms are present,
then the patient may be defined as having minor depression, an
other specified diagnosis in the DSM-IV-TR,12 while this criteria
is not mentioned in DSM-5. The U.S. Preventive Services Task
Force recommends depression screening in clinical practices that
have systems in place to ensure accurate diagnosis and effective
treatment and follow-up. 3 Unfortunately, such systems are not
available in most primary care practices or oncology/hematology
subspecialty practices.
The decision regarding whether to treat a patient for depres-
sion in the primary care setting is not always made on the basis
of rigid diagnostic criteria; it often arises from clinical judgment

441
442
about the severity and duration of symptoms and the likelihood
of spontaneous recovery within a supportive environment.13
Between 50 and 60% of cases of major depression respond to
initial therapy with antidepressants, psychotherapy, or both.13
Although previous study suggests that minor depression has
similar response rates to antidepressants or psychotherapy over
placebo, recent meta-analysis investigating the effect of anti-
depressants on minor depression reveals that there is unlikely
to be a clinically important advantage for antidepressants.14
Depression may be treated by a patient’s primary care physi-
cian, who can use either a collaborative care model that involves
augmentation with one or more visits with a mental health-care
provider or a stepped-care approach in which patients whose
depression does not respond to initial therapy are referred to a
mental health-care provider.15
Depression is the 15th leading cause of disability adjusted life
years (DALY) in the world according to the most recent esti-
mates.16 Moreover, this burden is expected to rise in the next 10
years. Thus, depression is now recognized as an important cause
of long-term disability and dependency.17 It not only produces
serious suffering,18 but also worsens quality of life,19,20 reduces
adherence to medical treatments,21,22 can lead to suicide,23 is a
psychological burden on the family,24,25 and prolongs hospital-
ization.26 Fortunately, depression is treatable, and thus, cost-
effective interventions to improve the detection and treatment of
depression are important.
Cancer: A paradigm for serious chronic illness
Mitchell et al. reported findings with regard to meta-analysis
including 70 studies with 10,071 individuals across 14 countries
in oncological and hematological settings, and they demon-
strated that prevalence of major depression was 14.9% (95% con-
fidence interval: 12.2–17.7), minor depression 19.2% (9.1–31.9),
adjustment disorders 19.4% (14.5–24.8), and dysthymia 2.7%
(1.7–4.0).27 In palliative care settings studies including 24 stud-
ies with 4,007 individuals across seven countries, they also found
that prevalence of major depression was 14.3% (11.1–17.9), minor
depression 9.6% (3.6–18.1), and adjustment disorders 15.4%
(10.1–21.6).27 Thus, the best estimate is that major depression has
a point prevalence of 10–20% in cancer patients, irrespective of
cancer stage. This prevalence is similar to that seen in patients
with other chronic medical illnesses.
Although some comprehensive cancer centers have adequate
behavioral health-care resources, most hospitals and oncol-
ogy clinics rely on general psychiatry and psychology staff and
resources. Limited funding for mental health-care resources is
a serious problem, and care is often fragmented among private
practitioners, for-profit and not-for-profit clinics, and commu-
nity mental health centers.28 This is a report by American psy-
cho-oncologist: the situations, however, are similar or even much
worse in other countries including Asian nations.29 Limited
resources in standard areas of care also affect the research
environment.
Even though it may be ideal to use a two-stage strategy
that combines an assessment of severity with an assessment
of the number of depressive symptoms, it is far more com-
mon to perform only a short instrument to assess symptom
severity in the typical environment where time and resources
are limited. Numerous symptom scales have been used to
assess depression symptom severity at a specific time or over
time. The most commonly reported instruments are shown in
Box 46.1.
Textbook of Palliative Medicine and Supportive Care
BOX 46.1  SELF-REPORT MEASURES
USED TO ASSESS DEPRESSIVE
SYMPTOMS IN CANCER PATIENTS
• Hospital and Anxiety Depression Scale (HADS)
• Zung Self-Rating Depression Scale (ZSRDS)
• Brief version, Zung Self-Rating Depression Scale
(BZSDRS)
• Beck Depression Inventory (BDI)
• Beck Depression Inventory, Short Form (BDI-SF)
• Center for Epidemiologic Studies Depression
Scale (CES-D)
• Brief Symptom Inventory (BSI)
• Rotterdam Symptom Checklist (RSCL)
• Geriatric Depression Scale (GDS)
• Profile of Mood States (POMS)
• Profile of Mood States, Short Form (POMS-SF)
• General Health Questionnaire (GHQ)
• Edinburg Postnatal Depression Scale (EPD)
Challenges in the assessment
of depression in cancer patients
Patients, family members, and health-care providers sometimes
believe that feeling down, depressed, or hopeless is perfectly
natural and understandable in the context of living with can-
cer. Clinicians are encouraged to acknowledge the difficulty and
disappointment that often confront cancer patients and their
families, 30 but depression and hopelessness are not accepted by
expert clinicians as an inevitable consequence of living with can-
cer. In addition, cancer patients often have physical symptoms of
depression (so-called neurovegetative symptoms), such as sleep
disturbance, psychomotor retardation, appetite disturbance,
poor concentration, and low energy, as a consequence of their
underlying illness or treatment, thus confounding the diagnosis
of depression. Indeed, depression is just one of the many symp-
toms that clinicians must recognize and manage in inpatients
and outpatients with cancer. For example, roughly two-thirds of
outpatients with cancer experience pain, and more than a third
report significant disruption in daily function associated with the
pain. 31 For patients with advanced cancer, fatigue, pain, lack of
energy, weakness, and appetite loss are the most frequent symp-
toms, occurring in more than 50% of patients. 32 It may be that
the problem of concurrent symptoms is the most relevant dif-
ference between depression in the general medical setting and
in the cancer care setting. Relatively few cancer care providers
have sufficient knowledge and skills to assess and treat depres-
sion in this context, and it is often difficult to decide whether the
depressive symptoms should be the primary focus of treatment
or whether these symptoms may improve if other problems are
better managed.
The large number of instruments and techniques used to assess
cancer patients for depression does not seem to translate into an
overall improvement in the assessment of depression in this com-
plex population of patients. A “Don’t ask, don’t tell” policy appears
to be in place all too often.28 A list of 11 of the most significant
barriers to the assessment of depression is presented in Box 46.2.
With a growing appreciation for the need to simplify the start-
ing point in assessing depression, the use of 1- or 2-item screen-
ing techniques has become popular (Box 46.3). Chochinov et al. 33
Depression/Anxiety
BOX 46.2  COMMON BARRIERS TO
THE ASSESSMENT OF DEPRESSION
IN PATIENTS WITH CANCER
• Overlap of physical symptoms of depression and
symptoms of cancer or its treatment
• Clinician’s underrecognition of hopelessness,
feelings of worthlessness, or suicidal ideation
• Clinician’s uncertainty about how to interpret
screening instrument cut-offs
• Lack of clinician’s routine discussion with
patients and family about low mood, not like pain
assessment
• Limited understanding by cancer professionals
regarding which patients are most at risk
• Time constraints in busy oncology settings
• Cost constraints limiting access to professionals
with behavioral health training
• Few mental health programs and specialists con-
necting with oncology
• Poor continuity of care over the trajectory of
illness
• Stigma concerning mental illness or weakness
perceived by the patient/family
• Patient/family fear that revealing depression will
lead to undertreatment of the cancer
have studied a simple 1-item survey and found it to have accept-
able psychometric properties in patients with advanced cancer.
Akizuki et al. 34 have described a clever 1-item survey that was
tested in 275 patients and was found to correlate well with both the
Hospital Anxiety and Depression Scale (HADS) (r = 0.66) and the
Distress Thermometer (r = 0.71). At optimal cut-offs, the sensitiv-
ity (80%) and specificity (61%) for diagnosing major depression and
adjustment disorders for this 1-item survey were similar to those
of the HADS and Distress Thermometer. Finally, Whooley et al. 35
have used 2-item screening in medically ill patients who did not
BOX 46.3  EXAMPLES OF 1- OR 2-QUESTION
SCREENING METHODS FOR DEPRESSION
One question
• “Are you depressed?” (Chochinov et al. 33)
• “Please grade your mood during the past week by
assigning it a score from 0 to 100, with a score
of 100 representing your usual relaxed mood.
A score of 60 is considered a passing grade.”
(Akizuki et al. 34)
Two questions
• “Have you often been bothered by feeling down,
depressed, or hopeless?”35
• “Have you often been bothered by having a lack of
interest or pleasure in doing things?” (Whooley
et al. 35)
443
have cancer with an approach that targeted depressed mood and
anhedonia. This 2-item screening approach has been endorsed
by the U.S. Preventive Health Task Force for use in primary care
settings. 3,36 Recent meta-analysis investigating the screening per-
formance of one or two simple verbal questions in the detection
of depression in cancer settings demonstrated the findings as
follows: a simple 1-item “depression” survey, sensitivity of 72%,
specificity of 83%; a simple 1-item “loss of interest” survey, sen-
sitivity of 83%, specificity of 86%; two questions “depression and
loss of interest” survey; sensitivity of 91%, specificity of 86%. 37 The
author concluded that simple surveys perform well at excluding
depression in the nondepressed but perform poorly at confirm-
ing depression and that the “two question” method is significantly
more accurate than either single question. In addition, based on
this finding, the author emphasizes that clinicians should not rely
on these simple questions alone and should be prepared to assess
the patient more thoroughly.
The HADS38 has also been investigated as a screening tool for
depression and anxiety in cancer patients and this instrument
has been translated into more than 20 languages. A meta-analysis
published in 2010 investigating the accuracy of the HADS as a
screening tool in cancer patients demonstrates that the HADS
had a sensitivity of 82% and a specificity of 77% for depression (no
studies for anxiety). 39 The authors conclude that the HADS is rec-
ommended as a screening tool but not case-finding instrument.
In addition to brief screening approaches specific to depres-
sion, a more global approach to distress screening has been devel-
oped by Holland and endorsed by the National Comprehensive
Cancer Network.40,37 This approach involves a thermometer with
a numerical scale ranging from 0 to 10 for the patient to indi-
cate “How much distress you have been experiencing in the past
week, including today?” This is coupled with a 34-item checklist
organized into practical areas, family issues, emotional issues,
spiritual/religious issues, and physical symptoms. This approach
embeds depression screening in a broad context that can be less
stigmatizing to some patients. The drawback of this approach is
that it is not easy to use in face-to-face discussions between the
physician and the patient. Rather, it is well suited to a practice
setting in which other providers are available to do the screening
and initiate an appropriate response to the patient on the basis
of the information provided. In general, the distress screening
approach works best in a resource-rich environment. Now dis-
tress thermometer approach is introduced and used in several
countries.41–46
Non-Western, for example, Japanese, patients still had dif-
ficulty with Western biopsychiatric concepts of depression.
Sadness, worry, and stress, not depression, were more commonly
used terms; thus, mental health providers need more euphe-
misms: worry, maybe sadness, stress, anxiety. These patients are
reluctant to discuss with psychological issues, especially emo-
tional disclosure to their physicians. They would like not to view
their condition as an individual issue. Focusing on community
and contextual factors, such as family, work, financial, and hous-
ing issues, was seen as more acceptable. The physicians might
avoid the term “depression” during these discussions.47
Treatment of depression
General medical patients
Antidepressant therapy and psychotherapy seem to be equally
effective for treating mild-to-moderate depression in the general
444 Textbook of Palliative Medicine and Supportive Care

medical population.48,49 For treating severe depression, antide-
pressant therapy combined with psychotherapy may be better
than psychotherapy alone.48,49 Antidepressants are also effec-
tive for treating depression in patients with concomitant physi-
cal illnesses.50 In 2011, a systematic review of randomized trials
comparing antidepressants with placebo to treat depression in
patients with life-threatening illness was published; the review
comprised 25 studies including more than 1,100 patients with
a variety of life-threatening illness including cancer, renal fail-
ure, chronic obstructive pulmonary disease, chronic heart fail-
ure, Parkinson’s disease, multiple sclerosis, and HIV/AIDS.51
Depression treated with antidepressants was significantly more
likely to improve than that treated with placebo (4–5 weeks, odds
ratio: 1.93; 95% CI: 1.15–3.42; 6–8 weeks, odds ratio: 2.25; 95%
CI: 1.38–3.67; 9–18 weeks, odds ratio: 2.71; 95% CI: 1.50–4.91).
However, at 4–5 weeks, the study also showed that approximately
nine patients would need to be treated to produce one recovery
that would not have occurred with placebo alone (number needed
to treat [NNT] 9; 95% CI: 4.3–81.0). The NNT decreased over
time: 6–8 weeks NNT 6; 95% CI: 3.9–8.8; 9–18 weeks NNT 5;
95% CI: 2.9–9.9.51
Approximately 40 different antidepressants that work by at
least 8 distinct mechanisms of action are available. However,
no single drug or category of drugs has proved most effective
for relieving depressive symptoms or treating the syndrome of
major depression (see Box 46.4, for a summary of antidepressant
agents),48,52 although several previous studies suggest existence of
differences for efficacy and acceptability among second-genera-
tion antidepressants.53,54
Cancer patients
Choosing patients for treatment
The largest barrier to the effective treatment of depression in
patients with cancer is the difficulty in recognizing patients who

BOX 46.4  COMMONLY USED ANTIDEPRESSANTS GROUPED BY MECHANISM OF ACTION

Selective serotonin reuptake inhibitors (SSRIs)

• Sertraline
• Citalopram
• Escitalopram
• Fluoxetine

Comment: These agents are frequently used. They have few anticholinergic or cardiovascular side effects and, therefore, not fatal
in overdose. Sexual dysfunction, insomnia, headache, or nausea may occur with any of these agents.
Noradrenergic and specific serotonergic antidepressants (NaSSA)

• Mirtazapine

Comment: This agent is frequently used for patients with poor appetite and/or insomnia, because they cause sedation and weight
gain. For this reason, it can be dosed at night to improve sleep and given to patients who have poor appetite.
Serotonin and norepinephrine reuptake inhibitor (SNRIs)

• Venlafaxine
• Duloxetine

Comment: In addition to their effect on depression, these agents have been used to decrease the frequency and intensity of hot
flashes and neurotoxicity induced by chemotherapy in cancer patients. Dose-related sustained hypertension is an important
possible side effect to monitor. These may cause sexual dysfunction, insomnia, headache, constipation, or nausea.
Dopamine and norepinephrine reuptake inhibitor

• Bupropion

Comment: This agent is also indicated to improve rates of successful smoking cessation. Sometimes used to avoid the sexual
dysfunction seen with other agents. Does not treat anxiety. Known to lower the seizure threshold. May cause insomnia, agita-
tion, confusion, headache, or weight loss.
Psychostimulants

• Methylphenidate
• Pemoline
• Dextroamphetamine

Comment: These agents are known for the rapid onset of action in terms of antidepressant efficacy. They are activating agents
also used to counteract opioid-induced sedation. Generally given in the waking hours (morning and early afternoon). Should be
avoided in patients with unstable ischemia or cardiac arrhythmias. Drug tolerance, abuse, and dependence can occur. May cause
nervousness, agitation, insomnia, or nausea.
Depression/Anxiety 445

Tricyclic antidepressants

• Nortriptyline
• Amitriptyline
• Doxepin
• Desipramine

Comment: These agents are generally not used because they can cause cardiac arrhythmias, and overdoses are lethal.
Baseline electrocardiography is recommended. Often used as adjuvant analgesics at doses subtherapeutic for depression.
May cause sexual dysfunction, weight gain, anticholinergic effects (dry mouth, sedation, or constipation), or orthostatic
hypotension.

Novel antidepressants

• Agomelatine

Comment: This agent is approved in 2009 for use in the European Union. This drug is thought to act through a combination of
antagonist activity at 5-HT 2c receptor and agonist activity at melatonergic MT1/MT2 receptors.

• vortioxetine

Comment: This agent is first approved in 2013 for use in United States. vortioxetine is a multimodal antidepressant with two dif-
ferent types of pharmacologic targets: serotonin receptors and transporters including 5-HT1a receptor agonist, 5-HT3, 5-HT7,
5-HT1D receptor agnosist, 5-HT1B receptor partial agonist, and inhibitor of 5-HT transporter.

are depressed and need treatment.55,56 The factors associated

with increased risk of depression in cancer patients are shown BOX 46.5  RISK FACTORS FOR
in Box 46.5. Because of the complexity of assessing patients in DEPRESSION IN CANCER
modern cancer care environments, many cases of depression are
missed, and the patients with more severe symptoms, ironically, Social and environmental factors
are more easily overlooked. Investigators in Indiana, USA, work-
ing in the community setting evaluated 1,109 outpatients with • Recent losses (e.g., spouse, family, friends, animals)
cancer and found that physicians were most accurate at correctly • Financial stressors
identifying the absence of depression.56 However, when depres- • Poor social support
sion was severe, only 13% of affected patients were correctly clas- • Sexual and/or physical abuse
sified by their oncologists. In general, oncologists and oncology • Childhood trauma or parental loss
nurses appear to be most responsive to sad, tearful patients with
minor depression rather than patients with a flat affect, feelings of Psychiatric factors
pervasive guilt or worthlessness, or suicidal thoughts. In a sense,
sicker patients may create thicker smokescreens that impede easy • Family and own history of depressive disorder
recognition of the underlying problem. These patients are par- • History of substance abuse
ticularly vulnerable, and their inability to advocate for themselves
may be part of the illness.28 Cancer-related factors
Symptom research is an emerging interest within the discipline
of academic general medicine.57,58 Within this new paradigm, • Advanced stage of disease
symptoms are conceptualized in terms of a functional distur- • Poor performance status
bance of the nervous system. There is a growing appreciation • Poor pain control
for the physical changes in the nervous system associated with
depression and its treatment.59,60,51,52 Understanding depressive Cancer treatment factors
symptoms in the context of symptom science rather than solely
within the standard psychiatric paradigm is being explored in the • Corticosteroids
context of cancer care to try to overcome some of the barriers • Interferon α
to recognition and management of depression in this population. • Interleukin-2
• Amphotericin-B
• Procarbazine
Treatment options • L-Asparaginase
Drugs used to treat depression in cancer patients are quite similar • Paclitaxel
to those used in the primary care setting; these include selective
446 Textbook of Palliative Medicine and Supportive Care

serotonin reuptake inhibitor (SSRIs), serotonin and norepineph-
rine reuptake inhibitor (SNRIs), noradrenergic and specific
serotonergic antidepressants (NaSSA), newer antidepressants,
tricyclic antidepressants, and psychostimulants. The essential
medicines recommended by the International Association for
Hospice and Palliative Care for treatment of depression in pal-
liative care are amitriptyline, citalopram (or any other SSRIs
except paroxetine and fluvoxamine), and mirtazapine (or any
other generic dual action noradrenergic and specific serotoner-
gic antidepressants or SNRIs).61 Specific examples of commonly
used antidepressants grouped by mechanism of action are pre-
sented in Box 46.4. The National Institutes of Health consensus
statement regarding symptom management in cancer states that
“depression related to cancer is not substantially different from
depression in other medical conditions, but treatments may need
to be adapted or refined for cancer patients.”62 One refinement
for patients with cancer, particularly in the palliative care setting,
is the growing interest in the use of psychostimulants to treat
depression.63–65 Especially depressive terminally ill patients with
estimated prognosis of less than a couple of weeks are best treated
by psychostimulants. Another refinement that is often important
to cancer patients is being mindful of potentially important drug
interactions that can occur with antidepressants that are metab-
olized using the cytochrome P450 (CYP) enzyme system of the
liver.66 In particular, agents such as fluoxetine and nefazodone
that inhibit the CYP 3A4 enzyme system may increase the effects
of some commonly used chemotherapeutic agents. Fluoxetine
may also influence and paroxetine (CYP 2D6 inhibitors) can
probably affect on the effect of tamoxifen that is the usual endo-
crine therapy for hormone receptor-positive breast cancer in
premenopausal women.67,68 Moreover, because many patients
with cancer are older adults with complex medical problems,
other coadministered drugs may be influenced by the antide-
pressants. Among commonly used antidepressants for physically
ill patients, sertraline and citalopram may be recommended for
first-line treatment, because these drugs appear to be less poten-
tial for serious pharmacokinetic drug interaction.69
Psychological therapies include psychoeducational inter-
ventions, behavioral therapy including relaxation training,
cognitive behavioral therapy, interpersonal psychotherapy, sup-
portive psychotherapy, group therapy, and supportive-expres-
sive psychotherapy. In practice, all psychological therapies are
patient-centered but very flexibly provided depending on each
patient’s physical condition and needs.70 Electroconvulsive
therapy, an invasive modality known to be effective for severe
depression, is rarely used and has not been studied for depres-
sion in the context of cancer care. Some recent studies have
demonstrated the effectiveness of ketamine71 and scopol-
amine,72 commonly used drugs in palliative care setting, and
light therapy 73 on depression in physically healthy people.
These therapies may be worth for testing their efficacy for
the treatment of depression among cancer patients. Finally,
both pharmacological and psychological therapies have been
shown to be efficacious in treating depression in cancer; it is
unknown that their relative and combined efficacy and their
role in the treatment that is less severe and occurs in associa-
tion with advanced disease.74
Randomized trials
With all of these challenges in mind, it is not surprising that
data from controlled trials regarding the efficacy of treatment of
depression in cancer patients are sparse. Fifteen published con-
trolled randomized trials have investigated the effects of an anti-
depressant drug for depression in cancer patients (Table 46.1). A
total of 1824 patients were included; none of these studies included
children, and eight studies75–83 included women only. The trend
in these studies was in favor of the treatment arm than placebo,
but the small sample size of the individual trials, short follow-up
duration, and lack of reporting of adverse events/tolerability limit

TABLE 46.1 Clinical Trials Comparing Antidepressant with Placebo or Other Antidepressants for Depression in Patients
with Cancer
Inclusion Criteria for
Author Antidepressants Subjects Depression Main Findings
Costa (1985)75 A. Mianserin (N = 36) Women with cancer Major depression Depression is more improved
B. Placebo (N = 37) in mianserin group
Van Heeringen (1996)76 A. Mianserin (N = 28) Early breast cancer Major depression Depression is more improved
B. Placebo (N = 27) patients receiving in mianserin group
radiation therapy
Razavi (1996)82 A. Fluoxetine (N = 45) Mixed cancer patients Major depression or NS
B. Placebo (N = 46) adjustment disorders
Holland (1998)77 A. Fluoxetine (N = 21) Adult women with Major depression or NS
B. Desipramine (N = 17) advanced cancer adjustment disorders
Pezzella (2001)78 A. Paroxetine (N = 88) Adult women with Major depression NS
B. Amitriptyline (N = 87) breast cancer
Tasmuth (2002)79 Venlafaxine (N = 13) Patients with breast None NS
Placebo (N = 13) cancer and
neuropathic pain
Morrow (2003)99 A. Paroxetine (N = 277) Fatigued patients with None Depression is more improved
B. Placebo (N = 272) cancer receiving in paroxetine group
chemotherapy
Fisch (2003)100 A. Fluoxetine (N = 83) Advanced cancer Depressed mood and/or Depression is more improved
B. Placebo (N = 80) patients anhedonia revealed by in fluoxetine group
2-question survey
(Continued)
Depression/Anxiety 447

TABLE 46.1  Clinical Trials Comparing Antidepressant with Placebo or Other Antidepressants for Depression in Patients
with Cancer (Continued)
Inclusion Criteria for
Author Antidepressants Subjects Depression Main Findings
Roscoe (2005)80 A. Paroxetine (N = 44) Breast cancer patients None Depression is more improved
B. Placebo (N = 50) receiving in paroxetine group
chemotherapy
Musselman (2006)81 A. Paroxetine (N = 13) Breast cancer patients Major depression NS
B. Desipramine (N = 11)
C. Placebo (N = 11)
Stockler (2007)101 A. Sertraline (N = 95) Advanced cancer Depressive but not with NS
B. Placebo (N = 94) patients major depression
Cankurtaran (2008)102 A. Mirtazapine (N = 20) Cancer patients Major depression or Depression is more improved
B. Imipramine (N = 13) adjustment disorders in mirtazapine group
or anxiety disorders
Lydiatt (2008)103 A. Citalopram (N = 13) Head and neck cancer Without major NS
B. Placebo (N = 12) patients depression
Navari (2008)83 A. Fluoxetine (N = 90) Early breast cancer Positive after two-item Depressed symptoms are more
B. Placebo (N = 90) patients beginning depression screening improved in fluoxetine group
adjuvant treatment
Ng (2014)65 A. Methylphenidate + Terminally ill cancer Major depression Depressed symptoms are more
mirtazapine (N = 44) patients defined as an (DSM-IV) improved in methylphenidate
B. Placebo + mirtazapine estimated life group
(N = 44) expectancy of less
than 3 months
Abbreviation: NS, not statistically significant.

the conclusions that can be made from this body of research. In
addition, no specific antidepressant has proved more effective
for relieving depression in cancer patients. As the previous sys-
tematic review investigating the effectiveness of pharmacologi-
cal treatment for depression in cancer patients suggested, there
is some evidence that cancer patients with depression are respon-
sive to pharmacological treatment although more data are needed
regarding the safety and efficacy of antidepressants.84,85 Even
though there is some evidence that patients with cancer with
depression may respond to antidepressants in general, more data
are needed regarding the most commonly prescribed antidepres-
sants including SSRIs and SNRIs because physicians tend to treat
patients with cancer in similar way they treat other depressed
patients without comorbidity.86
Psychological therapies are most often applied in addition to
drug treatments for depressed patients, but this kind of therapy
can also be used alone to treat moderate to severe depression.15
In fact, there are very few studies in the medically ill in which
the effect of psychotherapy has been described with sufficient
methodological detail.87 There are several published systematic
reviews and meta-analyses of controlled trials of psychologi-
cal interventions for decreasing psychological distress in can-
cer patients (Table 46.2). Although the findings of these reviews
are not consistent probably due to differences in the focus of the
reviews, the methods used to summarize findings across stud-
ies, and the manner in which recommendations were reached,
psychoeducational interventions, behavioral therapy, cognitive
behavioral therapy, and supportive and supportive-expressive
psychotherapy are effective for ameliorating depression for can-
cer patients.88
It is useful to note that application of unwanted (but received)
intervention has been uniquely associated with poor psychosocial
adjustment.89 As such, clinicians would do well to make support
available to cancer patients but to respect the boundaries that
some patients set regarding such services.
A recent study, investigating the effect of provision of early
palliative care by palliative care team consisting of board-certi-
fied palliative care physicians and advanced-practice nurses for
advanced lung cancer patients on quality of life and psychologi-
cal distress including depression, demonstrated that early pallia-
tive care itself contributes to improvement in quality of life and
ameliorating depression.90 This study suggests the usefulness of
patient-centered early palliative care itself for reducing depres-
sion in cancer patients. In addition, some recent studies dem-
onstrate that collaborative care interventions are also useful for
depression among cancer patients.91–93
Unique issues in end-of-life care
Ambiguity surrounding the definition of end-of-life care makes
this particular literature difficult to interpret and apply. The
1-item screening question “Are you depressed?” explored by
Chochinov involved a cohort of 197 palliative care inpatients and
had perfect sensitivity and specificity of 1.0 in this single study.33,94
However, in a palliative care cohort of 74 patients in the United
Kingdom receiving only palliative and supportive day care, Lloyd-
Williams et al. found that 27% of patients had depression by
semistructured interview criteria, and the single-item screening
question had a sensitivity of 55%, a specificity of 74%, a positive
predictive value of 44%, and a negative predictive value of 82%.94
The similar findings with regard to poor screening performance
of the 1-item screening question are also shown in Japanese study
(a sensitivity of 47%, a specificity of 97%).95 Nevertheless, even use
of the 14-item HADS had significant limitations in another UK
study in a hospice population, as the positive predictive value of
this instrument using a cut-off threshold of 20 was only 48% with
448 Textbook of Palliative Medicine and Supportive Care

TABLE 46.2  Systematic Reviews and Meta-Analysis of Psychotherapy for Depression and Anxiety in Cancer Patients
Effect Size or Results
Author Psychotherapy Included Studies Depression Anxiety Main Findings
Devine 118 Psychoeducation R and Non-R d = 0.54 (95% CI: d = 0.56 (95% CI 0.42 Psychoeducation is effective for both
0.43–0.65) to 0.70) depression and anxiety
Sheard119 Psychological R d = 0.36 (95% CI: d = 0.42 (95% CI: Preventative psychological
intervention 0.06–0.66) (d = 0.19 0.08–0.74) interventions may have a moderate
with positive clinical effect upon anxiety but not
outliers removed) depression
Luebbert120 Relaxation training R d = 0.54 (95% CI: d = 0.45 (95% CI: Relaxation training is effective for
0.30–0.78) 0.23–0.67) both depression and anxiety
Redd121 Behavioral R and Non-R NA Positive results Behavioral intervention is effective for
intervention for side reported in 17 of 19 ameliorating anxiety associated with
effects studies aversive side effects
Barsevick122 Psychoeducation R and Non-R Positive results NA Psychoeducation is effective for
reported in 29 of 46 depression
studies
Newell123 Psychological R No intervention Music therapy can be Music therapy can be tentatively
intervention strategy can be tentatively recommended for reducing anxiety,
recommended recommended although no intervention strategy
can be recommended for reducing
depression
Ross124 Psychological R Positive results Positive results The question of whether psychosocial
intervention reported in 9 of 17 reported in 10 of 24 intervention among cancer patients
studies studies has a beneficial effect remains
unresolved
Akechi125 Psychological R SMD = –0.44 (95% SMD = –0.68 (95% Psychotherapy is effective for
intervention for CI: –0.08 to –0.80) CI: 0.01 to –1.37) depression in advanced cancer
advanced cancer patients
Okuyama126 Psychological R SMD = –0.67 (95% SMD = –0.68 (95% Psychotherapy is effective for
intervention for CI: –1.06 to –0.29) CI: 0.01 to –1.37) depression in advanced cancer
advanced cancer patients
Abbreviations: R, randomized studies; Non-R, nonrandomized studies; CI, confidence interval; SMD, standardized mean difference.

a sensitivity of 77% and specificity of 89%.96 Overall, there are
insufficient data in end-of-life patient populations to distinguish
the assessment issues from those that have been described for
cancer patients in general.97 It should be noted, however, that the
occurrence of counter-transference of hopelessness on the part of
families and clinicians may discourage dying patients from seek-
ing assessment and treatment for depression.98
Regarding the treatment of patients with depression toward
the end of life, several consensus statements have been publis
hed.18,87,98,104 These statements are limited by the paucity of evi-
dence, but several themes emerge across these statements. First,
there should be a low threshold for treating patients with sus-
pected depression using short-term therapeutic trials of care-
fully selected interventions.18,87 In addition, the rapid onset of
the action of psychostimulants makes this class of drugs particu-
larly appealing in patients toward the very end of life although
one guideline does not recommend the use of psychostimulants
due to three being evidence of adverse effects and inadequate evi-
dence of efficacy.104 At all events, because patients’ survival time
largely determines susceptibility to pharmacological treatment
and it is hard to achieve drug response in patients whose survival
time is very limited, possible symptom management including
sleep disturbance and agitation, even not focused on depression
fundamentally, should be provided.105 In addition, novel psycho-
therapeutic interventions focused on issues related to meaning
and/or dignity106–109 have shown promising results in the termi-
nally ill.
Finally, one of the more dreaded issues in managing patients
with serious illness toward the end of life is the problem of
patients who express desire for death. Desire for death statements
may indicate that a patient is depressed or suicidal, but may also
be a way of coping or expressing suffering.110,111 Depressive disor-
ders and delirium are the most common underlying psychiatric
disorders of suicidal ideation in patients with potentially fatal ill-
nesses.112,113 However, the presence of a potentially fatal illness,
by itself, only carries a modest two- to fourfold increased risk for
suicide.23,114 Challenging aspects of assessing patients with desire
for death include evaluation and treatment of depression and
delirium, assessing the adequacy of palliative care overall, and
dealing with broader issues such as personality, family dynamics,
as well as important ethnic and cultural issues.115,116 It is impor-
tant to understand that most patients appreciate being asked
about their mood in depth, including questions about desire for
death or suicide.117
Managing anxiety
Because anxiety is a response to threat, most patients living with
cancer or a serious chronic illness experience some kinds of
anxiety. Thus, anxiety is an inevitable human reaction to serious
Depression/Anxiety 449

medical illness. On the other hand, anxiety ranges from adaptive

to pathological ones. In psychiatry, clinically pathological anxiety
is diagnosed with anxiety disorders including generalized anxi-
ety disorders (GAD), panic disorders, and so on11 and a certain
amount of cancer patients actually have these disorders.127,128
However, in practice, these criteria may be difficult to apply to
cancer patients (e.g., A diagnosis of a DSM-5 (11) defines GAD
requires excessive anxiety and worry, difficulty in controlling the
worry, plus 3 or more additional symptoms of anxiety occurring
more days than not for at least 6 months). Rather anxiety may
be encountered as a component of trauma- and stressor-related
disorders including adjustment disorders and posttraumatic dis-
orders, depressive disorders, delirium, or organic anxiety disor-
der.129–132 In oncology setting, the estimated prevalence of clinical
anxiety is within a range 15–30%.27,133
Symptoms that are uniquely attributable to anxiety include
physical symptoms such as tremor, sweating, tachycardia, hyper-
ventilation, and restlessness. Psychological symptoms of anxiety
include worry, rumination, and fear.134,135 In the palliative care
setting, it may not be easy to distinguish the somatic causes of
anxiety from the psychological ones.135 The common causes of
anxiety symptoms in palliative care are outlined in Box 46.6.
BOX 46.6  COMMON CAUSES OF ANXIETY
SYMPTOMS IN PALLIATIVE CARE
Situational
• Recent diagnosis of serious illness
• Impending surgery or chemotherapy
• Impending diagnostic imaging
• Perceived risk for receiving bad news
• Fear of death/existential anxiety
Psychiatric disorders
• Delirium
• Depressive disorders
• Panic disorder
• Posttraumatic stress disorder
• Phobias
• Generalized anxiety disorder
For patients with pervasive worry and autonomic hyperreactiv-
ity, pharmacotherapy may be indicated. The categories of medi-
cations used to treat anxiety are listed in Box 46.7. The essential
medicines recommended by the International Association for
Hospice and Palliative Care for treatment of anxiety in palliative
care are diazepam, lorazepam, and midazolam.61 Unfortunately,
there is an overall lack of evidence on the role of benzodiazepines
and most other anxiolytics including antidepressants in palliative
care patients.82,136–138 Benzodiazepines are the most commonly
prescribed agents, and they are effective first-line agents. These
medications may cause significant sedation or trigger delirium in
patients who are on other psychoactive medications (including
opioids) or who are particularly frail. These drugs should be used
cautiously and, when feasible, should be discontinued. The short-
acting benzodiazepines lorazepam and alprazolam are used most
frequently. For patients with coexisting delirium, risperidone,
quetiapine, or other neuroleptic agents are useful for the manage-
ment of symptoms. Antihistamines and other sedative hypnotic
agents can also provide useful anxiolysis, particularly at night
when insomnia is an issue. Finally, most psychotherapies shown
as effective for reducing depression are also useful for ameliorat-
ing anxiety in cancer patients.88

Symptom-related
BOX 46.7  DRUG THERAPY OF ANXIETY
• Pain Benzodiazepines
• Dyspnea
• Palpitations
• Alprazolam
• Nausea
• Diazepam
• Lorazepam
Metabolic disturbances • Clonazepam
• Midazolam
• Hypercalcemia
• Hypoglycemia Antidepressant agents
• Carcinoid syndrome
• Pulmonary embolus
• SSRI and newer antidepressants
• Paraneoplastic syndrome
Neuroleptic agents
Drug-associated
• Haloperidol
• Akathisia due to antipsychotics or antiemetics
• Atypical antipsychotics
(dopamine-2 antagonists)
• Steroids
Other drug therapies
• Bronchodilators
• Psychostimulants
• Buspirone
• Thyroid replacement
• β blockers (for autonomic symptom relief)
• Allergic reactions
• Sedative hypnotics (for relief of insomnia)
• Substances or withdrawal from substances
• Antihistamines
450
KEY LEARNING POINTS
• Depression and anxiety are common in patients
with serious illness.
• Despite a body of research that spans several
decades and includes hundreds of clinical trials,
one can make no strong recommendations about
the effectiveness of antidepressants or psycho-
logical interventions at improving depression or
anxiety outcomes for patients with cancer and
other serious chronic illnesses.
• Simple, direct questions to explore issues about
mood, anxiety, or desire for death are important
and appreciated by patients.
• An awareness of the potential for drug interac-
tions with antidepressants and some other drugs
commonly used in palliative care is important.
• Patients with serious chronic illnesses would
benefit from multidisciplinary care that includes
access to specialists in behavioral health when
needed.
Conclusion
Depression and anxiety are the most common psychological
and/or psychiatric issues experienced by patients with serious
physical disease including cancer. The best estimate is that major
depression has a point prevalence of 10–20% in cancer patients,
irrespective of cancer stage. This prevalence is similar to that
seen in patients with other chronic medical illnesses. The esti-
mated prevalence of clinical anxiety is within a ranger 15–30%.
Appropriate management of depression and anxiety is essential
for maintaining optimal medical care, as these distress can lead
to serious and far-reaching negative consequences in patients
with serious physical disease. These psychological and/or psy-
chiatric problems can reduce patients’ quantity and quality of
life and cause severe suffering and suicide, as even though both
psychotherapies and pharmacotherapies are useful treatments
for depression and anxiety among these patients, one can make
no strong recommendations about the effectiveness of antide-
pressants or psychological interventions at improving depression
or anxiety outcomes for patients with cancer and other serious
chronic illnesses. Patients with serious chronic illnesses would
benefit from multidisciplinary collaborative care.
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94. Lloyd-Williams M, Dennis M, Taylor F, Baker I. Is asking patients in
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95. Akechi T, Okuyama T, Sugawara Y, Shima Y, Furukawa TA, Uchitomi
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102. Cankurtaran ES, Ozalp E, Soygur H, Akbiyik DI, Turhan L, Alkis N.
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103. Lydiatt WM, Denman D, McNeilly DP, Puumula SE, Burke WJ. A ran-
domized, placebo-controlled trial of citalopram for the prevention of
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104. Rayner L, Price A, Hotopf M, Higginson IJ. The development of evi-
dence-based European guidelines on the management of depression in
palliative cancer care. Eur J Cancer 2011;47(5):702–712.
105. Shimizu K, Akechi T, Shimamoto M, Okamura M, Nakano T,
Murakami T, et al. Can psychiatric intervention improve major
depression in very near end-of-life cancer patients? Palliat Support
Care 2007;5(1):3–9.
106. Chochinov HM, Kristjanson LJ, Breitbart W, McClement S, Hack TF,
Hassard T, et al. Effect of dignity therapy on distress and end-of-life
experience in terminally ill patients: a randomised controlled trial.
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107. Breitbart W, Poppito S, Rosenfeld B, Vickers AJ, Li Y, Abbey J, et al.
Pilot randomized controlled trial of individual meaning-centered
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108. Breitbart W, Rosenfeld B, Pessin H, Applebaum A, Kulikowski J,
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Psychiatric evaluation of death-hastening requests. Lessons from dial-
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117. Meyer HA, Sinnott C, Seed PT. Depressive symptoms in advanced can-
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118. Devine EC, Westlake SK. The effects of psychoeducational care pro-
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124. Ross L, Boesen EH, Dalton SO, Johansen C. Mind and cancer: does psy-
chosocial intervention improve survival and psychological well-being?
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125. Akechi T, Okuyama T, Onishi J, Morita T, Furukawa TA. Psychotherapy
for depression among incurable cancer patients. Cochrane Database
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126. Okuyama T, Akechi T, Mackenzie L, Furukawa TA. Psychotherapy
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127. Spencer R, Nilsson M, Wright A, Pirl W, Prigerson H. Anxiety disor-
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128. Stark DP, House A. Anxiety in cancer patients. Br J Cancer
2000;83(10):1261–1267.
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129. Akechi T, Okuyama T, Sugawara Y, Nakano T, Shima Y, Uchitomi Y.
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130. Okamura H, Watanabe T, Narabayashi M, Katsumata N, Ando M,
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131. Akechi T, Okamura H, Nishiwaki Y, Uchitomi Y. Psychiatric dis-
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132. Andersen BL, DeRubeis RJ, Berman BS, Gruman J, Champion
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133. DieTrill M. Anxiety and sleep disorders in cancer patients. EJC sup-
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47
DELIRIUM

Yesne Alici and William S. Breitbart

Contents
Introduction........................................................................................................................................................................................................................455
Delirium in palliative care settings................................................................................................................................................................................ 456
Prevalence of delirium................................................................................................................................................................................................ 456
Pathophysiology of delirium..................................................................................................................................................................................... 456
Diagnosing delirium................................................................................................................................................................................................... 456
Delirium screening and diagnostic tools................................................................................................................................................................ 457
Subtypes of delirium................................................................................................................................................................................................... 457
Differential diagnosis of delirium............................................................................................................................................................................ 458
Management of delirium in palliative care settings............................................................................................................................................. 458
Assessment of etiologies of delirium..................................................................................................................................................................459
Nonpharmacological interventions....................................................................................................................................................................459
Pharmacological interventions in delirium...................................................................................................................................................... 460
Prevention of delirium............................................................................................................................................................................................... 463
Controversies in the management of terminal delirium..................................................................................................................................... 463
Prognostic implications of delirium in the terminally ill.................................................................................................................................... 464
Conclusion.......................................................................................................................................................................................................................... 464
References........................................................................................................................................................................................................................... 464

Introduction on acyclovir for central nervous system herpes who is experienc-

A variety of psychiatric or mental syndromes can be seen in
patients with advanced disease. These syndromes could fall under
one of the following1:
• Delirium, dementia (major neurocognitive disorder), and
other neurocognitive disorders
• Depressive disorder due to another medical condition
• Bipolar and related disorder due to another medical
condition
• Anxiety disorder due to another medical condition
• Psychotic disorder due to another medical condition
• Substance-related disorders
• Catatonic disorder due to another medical condition
• Personality change due to another medical condition
While virtually all of these mental syndromes can be seen in the
patient with advanced disease, the most common are delirium,
other neurocognitive disorders, and depressive and anxiety dis-
orders due to another medical condition. Neurocognitive disor-
ders are unfortunately all too common in patients with advanced
illness. For cognitively intact or minimally impaired patients, the
more prominent symptoms tend to consist of anxiety, mood dis-
turbance, delusions, hallucinations, or personality change. For
instance, the patient with mood disturbance meeting criteria for
major depression who is severely hypothyroid or on high-dose
corticosteroids is most accurately diagnosed as having a depres-
sive disorder due to hypothyroidism or corticosteroid-induced
depressive disorder, respectively (particularly if medical factors
are judged to be the primary etiology related to the mood dis-
turbance). Similarly, the patient with hyponatremia or patient
ing visual hallucinations but has a normal level of alertness and
attention span with minimal cognitive deficits is more accurately
diagnosed as having a psychotic disorder due to another medical
condition or a substance-induced psychotic disorder, respectively.
Delirium is a common and often serious neuropsychiatric com-
plication in palliative care settings that is characterized by concur-
rent disturbances in the level of alertness, awareness, attention,
thinking, perception, memory, psychomotor behavior, mood, and
sleep–wake cycle. Disorientation, fluctuation, and waxing and
waning of these symptoms, as well as an acute or abrupt onset of
such disturbances are other critical features of delirium. It is a sign
of significant physiological disturbance, usually involving multiple
causes, including infections, organ failure, and medication adverse
effects. Delirium, in contrast with dementia, is conceptualized
as a reversible process. Reversibility of the process of delirium is
possible even in the patient with advanced illness; however, it may
not be reversible in the last 24–48 hours of life and this influences
the outcomes of its management.2 This is most likely due to the
fact that irreversible processes, such as multiple organ failure, are
occurring in the final hours of life. Delirium occurring in these last
days of life is often referred to as terminal restlessness or terminal
agitation in the palliative care literature.
Delirium is associated with significant morbidity and mortal-
ity. Increased health-care costs, prolonged hospital stays, and
long-term cognitive decline are well-recognized outcomes of
delirium. 3–5 It is a harbinger of impending death in terminally
ill patients, causing significant distress for patients, family mem-
bers, and staff.5–9 In a study of the “Delirium Experience” of ter-
minally ill cancer patients, Breitbart and colleagues found that
54% of patients recalled their delirium experience after recovery
from delirium.6 Factors predicting delirium recall included the

455
456
degree of short-term memory impairment, delirium severity, and
the presence of perceptual disturbances (the more severe fac-
tors, the less likely recall). The most significant factor predicting
distress for patients was the presence of hallucinations and delu-
sions. Patients with hypoactive delirium were just as distressed
as patients with hyperactive delirium. Predictors of spouse dis-
tress included the patients’ Karnofsky Performance Status (the
lower the Karnofsky status, the worse the spouse distress), and
predictors of nurse distress included delirium severity and per-
ceptual disturbances. A survey of 300 bereaved Japanese fami-
lies showed that two-thirds of the families found delirium in the
family members to be highly distressing.7 Symptoms that caused
the most distress included agitation and cognitive impairment.
In a study of 99 patients with advanced cancer who had recov-
ered from delirium, 74% remembered their delirium episode.8
Patients who recalled their delirium episode reported a higher
level of distress than patients with no recall. Family caregivers
of those patients reported higher levels of distress compared to
nurses and physicians caring for patients with delirium.8 Another
study on caregivers has shown that the family members of deliri-
ous terminally ill patients were 12 times more likely to develop an
anxiety disorder than caregivers of nondelirious patients.9 These
findings highlight the importance of not only treating the causes
and controlling the symptoms of delirium, but also educating the
caregivers about the medical nature of delirium and the potential
treatment options to reduce caregiver distress.
Delirium can interfere dramatically with the recognition and
control of other physical and psychological symptoms such as
pain in later stages of illness.5 Uncontrolled pain can cause agi-
tation. Patients with delirium use a significantly greater num-
ber of “breakthrough” doses of opioids at night compared with
patients without delirium due to sleep–wake cycle reversal.11 On
the other hand, agitation due to delirium may be misinterpreted
as uncontrolled pain, resulting in inappropriate escalation of opi-
oids, potentially worsening delirium.12 A retrospective study of
284 hospice patients sought to identify factors that contribute to
impairment of communication capacity in terminally ill cancer
patients.13 The study demonstrated that communication capac-
ity was frequently impaired in terminally ill cancer patients and
the degree of impairment was significantly associated with higher
doses of opioids. Patients with delirium were also found to have
difficulty in communicating their needs, emphasizing the impor-
tance of further investigations to explore new strategies for main-
taining communication capacity in this population.13
Unfortunately, delirium is often underrecognized or misdiag-
nosed and inappropriately treated or untreated in terminally ill
patients.5 The diversity of the signs and symptoms of delirium
and the fluctuating clinical course primarily leads to under-
recognition and mistreatment of delirium. Practitioners caring
for patients with life-threatening illnesses must be able to diag-
nose delirium accurately, undertake appropriate assessment of
the etiologies, and be familiar with the risks and benefits of the
pharmacological and nonpharmacological interventions cur-
rently available in managing delirium among the terminally ill.
Improved recognition of delirium with delirium assessment tools
validated in palliative care settings and the terminally ill is the
first step toward better management of delirium. Implementation
of delirium assessment strategies to routine care should become
the standard of care to rule out this disabling condition in pallia-
tive care settings.10
This chapter provides an overview of the prevalence as
well as the main clinical features of delirium, including its
Textbook of Palliative Medicine and Supportive Care
subtypes, differential diagnosis, and assessment of etiologies.
Pharmacological and nonpharmacological interventions and
controversies common to the management of delirium in pallia-
tive care settings are also summarized.
Delirium in palliative care settings
Prevalence of delirium
Delirium is one of the most common mental disorders encoun-
tered in general hospital practice. Delirium is highly prevalent in
cancer and AIDS patients with advanced disease, particularly in
the terminally ill patients in the last weeks of life, with prevalence
rates ranging from 20 to 88%.5,14–19 The wide range of prevalence
reports in the literature is due to the diverse and complex nature
of delirium and heterogeneity of sample populations, settings of
care, and the assessment scales used.5
Prospective studies conducted in inpatient palliative care set-
tings have found a delirium occurrence rate of 20–42% upon
admission, and an incident delirium developing during admission
in 32–62% of patients.14,15,17–19 Approximately, 25–50% of medi-
cally hospitalized cancer patients and about 85% of terminally ill
cancer patients develop delirium.5,20
Pathophysiology of delirium
The study of the pathophysiology of delirium is vital to our
understanding of the phenomenology, prognosis, treatment,
and prevention of delirium.21,22 As reflected by its diverse phe-
nomenology, delirium is a dysfunction of multiple regions of
the brain, a global cerebral dysfunction characterized by con-
current disturbances in level of alertness, awareness, atten-
tion, perception, cognition, psychomotor behavior, mood, and
sleep–wake cycle.21 Various hypotheses have been put forth as
contributing to the pathophysiology of delirium, including but
not limited to neuronal aging, neuroinflammation, oxidative
stress, neuroendocrine, circadian rhythm dysregulation, and
neurotransmitter hypotheses, none of them being mutually
exclusive.22 Variable contribution of these hypotheses may lead
to the development of various cognitive and behavioral dysfunc-
tions characteristic of delirium. As detailed in a comprehensive
review by Maldonado, 22 delirium is a neurobehavioral syndrome
caused by the transient disruption of normal neuronal activity,
mediated by alterations in the neurotransmitters and dysfunc-
tion of neuronal networks, secondary to systemic disturbances.
Many neurotransmitter systems, such as the serotonergic, nor-
adrenergic, opioidergic, glutamatergic, and histaminergic sys-
tems, may contribute to delirium as a syndrome.22 Literature on
the pathophysiology of delirium has continued to expand in the
past decade, yet remains limited.
Diagnosing delirium
The diagnostic “gold standard” is the clinician’s assessment
using the Diagnostic and Statistical Manual of Mental Disorders
(DSM)-5 criteria for delirium.1 According to DSM-5, the essen-
tial features of delirium are: disrupted attention (e.g., difficulty
directing, focusing, sustaining, or shifting attention) and aware-
ness (i.e., reduced orientation to the environment); a change from
baseline that develops over hours to days and fluctuates within
a day; additional cognitive problems (e.g., in memory, orienta-
tion, language, visuospatial ability, or perception); the condition
is not better explained by another neurocognitive disorder and
is not associated with a state of severely reduced arousal such as
coma; history, physical exam, or lab findings suggest the patient’s
Delirium
mental state is a direct physiological result of another medical
condition, substance intoxication or withdrawal, exposure to a
toxin, or multiple etiological factors.1
The clinical features of delirium are quite numerous and
include a variety of neuropsychiatric symptoms that are also com-
mon to other psychiatric disorders such as depression, dementia,
and psychosis.5,23 Main features of delirium include prodromal
symptoms (e.g., restlessness, anxiety, sleep disturbances, and irri-
tability); rapidly fluctuating course; abrupt onset of symptoms,
reduced attention span (easily distractible); altered level of alert-
ness; increased or decreased psychomotor activity; disturbance
of sleep–wake cycle; affective symptoms (e.g., emotional lability,
sadness, anger, and euphoria); altered perceptions (e.g., misper-
ceptions, illusions, delusions, and hallucinations); disorganized
thinking and incoherent speech; disorientation to time, place, or
person; and memory impairment (cannot register new material) or
impairment in other cognitive domains (e.g., dysnomia, sensorim-
otor aphasia, dysgraphia, constructional apraxia, and executive
dysfunction) (Table 47.1). The DSM-5 criteria for delirium does
not address the prodromal or affective symptoms (i.e., depressed
mood) of delirium, which might be more prominent in patients
with delirium in palliative care settings and also associated with
worse outcomes.5 Neurological examination abnormalities may
include motor abnormalities (e.g., tremor, asterixis, myoclonus,
and reflex and tone changes) and/or signs of frontal release (i.e.,
grasp, palmomental, glabellar tap, and snout reflexes).5
Cognitive impairment was found to be the most common
symptom noted in phenomenology studies with disorienta-
tion occurring in 78–100%, attention deficits in 62–100%,
memory deficits in 62–90%, and diffuse cognitive deficits in
77% of patients.24 Disturbance of consciousness was recorded
in 65–100% of patients with delirium. In addition, disorganized
thinking was found in 95%, language abnormalities in 47–93%,
and sleep–wake cycle disturbances in 49–96% of patients.24 A
phenomenology study by Meagher and colleagues has found the
sleep–wake cycle abnormalities (97%) and inattention (97%) to be
the most frequent symptoms in patients with delirium; disorien-
tation was found to be the least common symptom.25
The clinical presentation of delirium may vary based on the age
of the patients. A phenomenology study of different age groups
has shown that childhood delirium presents more likely with
severe perceptual disturbances, severe delusions, severe lability
of mood, and agitation when compared with delirium in adult
TABLE 47.1  Clinical Features of Delirium
Disturbance in the level of awareness
Attentional disturbances
Rapidly fluctuating clinical course and abrupt onset of symptoms
Disorientation
Cognitive disturbances (i.e., memory impairment, executive dysfunction,
apraxia, agnosia, visuospatial dysfunction, and language disturbances)
Increased or decreased psychomotor activity
Disturbance of sleep–wake cycle
Mood symptoms (depression, mood lability)
Perceptual disturbances (hallucinations or illusions) or delusions
Disorganized thought process
Incoherent speech
Neurological findings (may include asterixis, myoclonus, tremor, frontal
release signs, changes in muscle tone)
Source: Adapted from Breitbart W, Alici Y. JAMA 2008;300:2898.
457
and geriatric patient populations.26 More severe cognitive symp-
toms were observed in geriatric patients with delirium.26
It is important to emphasize that clinicians should assess for
subsyndromal delirium (i.e., delirium that does not meet the full
DSM-5 criteria for a diagnosis of delirium) or prodromal signs of
delirium to timely recognize and treat this disabling condition in
palliative care settings.27
Delirium screening and diagnostic tools
The diagnostic gold standard for delirium is the clinician’s assess-
ment utilizing the DSM-5 criteria as outlined earlier.28–34 A num-
ber of scales or instruments have been developed that can aid
the clinician in rapidly screening for neurocognitive disorders
(dementia or delirium), establishing a diagnosis of delirium, and
assessing delirium severity. A detailed review of these assessment
tools is available elsewhere.28 Several examples of delirium assess-
ment tools currently used in palliative care settings include the
Memorial Delirium Assessment Scale (MDAS),29,30 the Delirium
Rating Scale-Revised 98, 31 and the Confusion Assessment
Method (CAM). 32,33 Of these, the MDAS and the CAM have been
validated in palliative care settings. 30,33 Each of these scales has
good reliability and validity.28–34
Subtypes of delirium
Three clinical subtypes of delirium, based on psychomotor
behavior and the level of alertness, have been described. 35,36
These subtypes include the “hyperactive” subtype, the “hypoac-
tive” subtype, and a “mixed” subtype with alternating features of
hyperactive and hypoactive delirium.5,18,35–41
In the palliative care setting, hypoactive delirium is most com-
mon and is frequently misdiagnosed as depression or severe
fatigue.5 Despite the frequency of hypoactive delirium, hypoac-
tive delirium has been found to be underdetected when com-
pared with the detection rates of hyperactive or mixed subtypes
of delirium in palliative care settings. 37
Research suggests that the hyperactive form is most often
characterized by hallucinations, delusions, hypervigilance, and
psychomotor agitation, while the hypoactive form is character-
ized by psychomotor retardation, lethargy, sedation, and reduced
awareness of surroundings.5 Delirium phenomenology studies
suggest that cognitive performance is similar across motor sub-
types of delirium. A study of 100 consecutive cases of DSM-IV-TR
delirium across motor subtypes (33 patients with hypoactive,
18 with hyperactive, 26 with mixed, and 23 patients with no
motor alteration were included) in a palliative care unit showed
that patients with mixed motoric subtype had more severe delir-
ium, with highest scores for DRS-R-98 sleep–wake cycle distur-
bance, hallucinations, delusions, and language abnormalities. 38
Cognitive performance did not differ across hyperactive, mixed,
and hypoactive motor groups. Authors concluded that motor
variants in delirium have similar cognitive profiles, but mixed
cases differ in the expression of several noncognitive features. A
phenomenology study showed that although perceptual distur-
bances and delusions were more prevalent in hyperactive (70.2
and 78.7%, respectively) than in hypoactive delirium (50.9 and
43.4%, respectively), the prevalence of perceptual disturbances
and delusions in hypoactive delirium was much higher than pre-
viously reported, deserving clinical attention and intervention. 39
The mean prevalence of hypoactive delirium was reported to
be 48% (ranging from 15 to 71%) in comparison to hyperactive
delirium that occurred in 13–46% of patients in the palliative care
settings.5,36,40 In a hospice setting, 29% of 100 acute admissions
458
were found to have delirium; 86% of these had the hypoactive sub-
type.18 The prototypically agitated delirious patient most famil-
iar to clinicians may actually constitute less than half of patients
with delirium in the terminally ill.
There is evidence suggesting that specific delirium subtypes may
be related to specific etiologies of delirium and may have unique
pathophysiologies, differential responses to treatment, and prog-
nosis.5,18,41–44 Hypoactive delirium has been shown to be associ-
ated with higher rates of mortality than hyperactive delirium.18,41
Hypoactive delirium has been found to occur with hypoxia, meta-
bolic disturbances, and anticholinergic medications. Hyperactive
delirium has been correlated with alcohol and drug withdrawal,
drug intoxication, or medication adverse effects.5,18,41 A random-
ized controlled trial (RCT) of haloperidol and chlorpromazine
found that both drugs were equally effective in hypoactive and
hyperactive subtypes of delirium, whereas an open-label trial of
olanzapine found poorer treatment response with hypoactive
delirium.42,43 A case-matched study comparing the efficacy of halo-
peridol and aripiprazole in the treatment of delirium has shown no
significant differences in treatment results between the two medi-
cations for patients with hypoactive or hyperactive delirium.44
Differential diagnosis of delirium
Many of the clinical features and symptoms of delirium can also
be associated with other psychiatric disorders such as depres-
sion, mania, psychosis, and dementia. Delirium, particularly the
“hypoactive” subtype, is often initially misdiagnosed as depres-
sion. Symptoms of major depression, including altered level of
psychomotor activity (hypoactivity), insomnia, reduced ability
to concentrate, depressed mood, and even suicidal ideation, can
overlap with symptoms of delirium, making an accurate diagnosis
more difficult. In distinguishing delirium from depression, par-
ticularly in the context of advanced disease, an evaluation of the
onset and temporal sequencing of depressive and cognitive symp-
toms is particularly helpful. Importantly, the degree of cognitive
impairment in delirium is much more severe and pervasive than
in depression, with a more abrupt temporal onset. Moreover, in
delirium the characteristic disturbance in the level of alertness is
present, while it is usually not a feature of depression. Similarly, a
manic episode may share some features of delirium, particularly a
“hyperactive” or “mixed” subtype of delirium. Again, the tempo-
ral onset and course of symptoms, the presence of a disturbance
in the level of alertness as well as of cognition, and the identifica-
tion of a presumed medical etiology or medications for delirium
are helpful in differentiating these disorders. Past psychiatric
history or family history of mood disorders is usually evident in
patients with depression or a manic episode. Symptoms such as
severe anxiety and autonomic hyperactivity can lead the clini-
cian to an erroneous diagnosis of panic disorder. Delirium that
is characterized by vivid hallucinations and delusions must be
distinguished from a variety of psychotic disorders. In delirium,
such psychotic symptoms occur in the context of a disturbance
in the level of alertness and impaired attention span, as well as
memory impairment and disorientation, which is not the case in
other psychotic disorders. Delusions in delirium tend to be poorly
organized and of abrupt onset, and hallucinations are predomi-
nantly visual or tactile rather than auditory as is typical of schizo-
phrenia. Finally, the development of these psychotic symptoms in
the context of advanced medical illness makes delirium a more
likely diagnosis. It is important to note that not all patients with
agitation have delirium. Patients with uncontrolled pain, medica-
tion-induced akathisia, and panic attacks may also present with
Textbook of Palliative Medicine and Supportive Care
agitation. The diagnosis of delirium is reserved for patients who
meet the diagnostic criteria for delirium.
The most challenging differential diagnostic issue is whether
the patient has delirium, or dementia, or a delirium superimposed
upon a preexisting dementia. Both delirium and dementia are cog-
nitive impairment disorders and share common clinical features
such as impaired memory, thinking, judgment, aphasia, apraxia,
agnosia, executive dysfunction, and disorientation. Delusions and
hallucinations can be seen in patients with dementia. The patient
with dementia is alert and does not have a disturbance in the
level of alertness that is characteristic of delirium. The temporal
onset of symptoms in dementia is more subacute and chronically
progressive. It is the abrupt onset, fluctuating course, and distur-
bances of consciousness that differentiate delirium from demen-
tia. It is also important to note that delirium represents an acute
change from the patient’s baseline cognitive functioning, even
if the patient has dementia or other cognitive disturbances at
baseline. Delirium superimposed on an underlying dementia can
be encountered such as in the case of an older patient, an AIDS
patient, or a patient with a paraneoplastic syndrome. Reversibility
of the delirium is possible even in the patient with advanced illness
as opposed to dementia. However, as noted previously, delirium
may not be reversible in the last 24–48 hours of life. Clinically,
a number of scales or instruments aid clinicians in the diagnosis
of delirium, dementia, or delirium superimposed on dementia.28,34
Boettger and colleagues reviewed the treatment and phenomeno-
logical characteristics of 100 cancer patients with delirium super-
imposed on dementia (DD) in contrast to patients with delirium
in the absence of dementia (ND).45,46 Patients in the DD (n = 18)
group, compared to the ND group (n = 82), had significantly
greater levels of disturbance of consciousness and impairments in
all cognitive domains (i.e., orientation, short-term memory, and
concentration). There were no significant differences between the
DD and ND groups in terms of the presence or severity of hallu-
cinations, delusions, psychomotor behavior, and sleep–wake cycle
disturbances. The MDAS scores at baseline were significantly
higher in DD group (21.1) compared to ND group (17.6). Over the
course of treatment, MDAS scores were significantly higher in DD
group with 11.7 compared with 7.0 in ND group. After 3 days of
management, delirium resolution rates were significantly lower
in DD group with 18.2% compared to 53.9% in ND group, and at
7 days, delirium resolution rates were 50 and 83%, respectively.
Researchers concluded that when delirium is superimposed on
dementia, it may present with more severe cognitive symptoms,
may respond poorly to treatment, and may resolve at a lower rate
when compared to nondemented patients with delirium.45,46
Management of delirium in palliative care settings
The standard approach to the management of delirium includes
a search for underlying causes, correction of those factors, and
management of the symptoms of delirium (utilizing both phar-
macological and nonpharmacological interventions).10 Treatment
of the symptoms of delirium should be initiated before, or in con-
cert with, a diagnostic assessment of the etiologies to minimize
distress to patients, staff, and family members. In the terminally
ill patient who develops delirium in the last days of life (“terminal”
delirium), the management of delirium is unique, presenting a
number of dilemmas, and the dying process may significantly
alter the desired clinical outcome. The desired and often achiev-
able outcome is a patient who is awake, alert, calm, comfortable,
cognitively intact, not psychotic, not in pain, and communicating
coherently with family and staff.
Delirium
Assessment of etiologies of delirium
The underlying etiologies of delirium are multiple (Table 47.2).
In the medical setting, the diagnostic workup typically includes
an assessment of potentially reversible causes, for example, dehy-
dration or medication, as well as those that are potentially irre-
versible, for example, sepsis or major organ failure. The clinician
should obtain a detailed history of the patient’s baseline mental
status from the family and staff and verify the current fluctuat-
ing mental status. Predisposing delirium risk factors should be
reviewed in detail, including old age, physical frailty, multiple
medical comorbidities, dementia, admission to the hospital with
infection or dehydration, visual impairment, deafness, polyphar-
macy, renal impairment, and malnutrition. 3 Physical examination
should seek evidence of infection, dehydration, fecal impaction,
urinary retention, or organ (e.g., liver, pulmonary, and renal) fail-
ure.5 Medication adverse effects should be reviewed as a possible
cause. It is important to inquire about alcohol or other substance
use disorders to be able to recognize and treat alcohol or other
substance-induced withdrawal delirium. Opioids, corticoste-
roids, benzodiazepines, and anticholinergics are commonly asso-
ciated with delirium particularly in the elderly and the terminally
ill.5,47 In palliative care settings, medications used for symptom
control (e.g., antihistamines, opioids, tricyclic antidepressants,
and corticosteroids) have been shown to significantly increase
the overall burden of anticholinergic adverse effects, increasing
the risk for delirium.47,48 Laboratory tests can identify metabolic
abnormalities (e.g., hypercalcemia, hyponatremia, hypoglyce-
mia), hypoxia, or disseminated intravascular coagulation. In
some instances, an electroencephalogram (to rule out seizures),
brain imaging studies (to rule out brain metastases, intracranial
bleeding, or ischemia), and lumbar puncture (to rule out lepto-
meningeal carcinomatosis or meningitis) may be appropriate.5
When confronted with delirium in the terminally ill or dying
patient, a differential diagnosis should always be formulated as to
the likely etiology or etiologies including underlying medical con-
ditions, such as infections, electrolyte disturbances, organ failure,
uncontrolled pain, and medication adverse effects. However, the
clinician must take an individualized and judicious approach to
such testing, consistent with the goals of care. There is an ongoing
debate as to the appropriate extent of diagnostic evaluation that
should be pursued in a dying patient with a terminal delirium. Most
palliative care clinicians would undertake diagnostic studies only
when a clinically suspected etiology can be identified easily, with
TABLE 47.2 Causes of Delirium in Patients with Advanced
Disease
Direct central nervous system causes
Primary brain tumors
Metastatic spreads to brain
Seizures (including nonepileptiform status epilepticus)
Indirect causes
Metabolic encephalopathy due to major organ failure
Electrolyte imbalance
Treatment side effects from chemotherapeutic agents,
corticosteroids, radiation therapy, opioids, anticholinergics,
antiemetics, antivirals, and other medications and therapeutic
modalities
Infections
Hematological abnormalities
Nutritional deficiencies
Paraneoplastic syndromes
459
a minimal use of invasive procedures, and treated effectively with
simple interventions that carry minimal burden or risk of causing
further distress. A survey of 270 physicians from 4 disciplines (pal-
liative care, medical oncology, geriatrics, and geriatric psychiatry)
found that about 85% of specialists would order basic blood tests
when confronted with delirium in patients with advanced can-
cer; more than 40% of specialists reported that they would not do
any investigation in patients with terminal delirium.49 Diagnostic
workup in pursuit of an etiology for delirium may be limited by
either practical constraints such as the setting (home, hospice) or
the focus on patient comfort so that unpleasant or painful diag-
nostics may be avoided. However, most often the etiology of ter-
minal delirium is multifactorial or may not be determined. When
a distinct cause is found for delirium in the terminally ill, it is
often irreversible or difficult to treat. Studies, however, in patients
with earlier stages of advanced cancer have demonstrated the
potential utility of a thorough diagnostic assessment. When such
diagnostic information is available, specific therapy may be able
to reverse delirium. In a study of patients with advanced cancer
admitted to hospice, the overall delirium reversibility rate was
only 20% and the 30-day mortality rate was 83%.50 Reversibility
of delirium was highly dependent on the etiology: hypercalcemia
was reversible in 38%; medications in 37%; infection in 12%; and
hepatic failure, hypoxia, disseminated intravascular coagulation,
and dehydration each in less than 10% of patients. Leonard and
colleagues found 27% recovery rate from delirium among patients
in palliative care. Patients with irreversible delirium experienced
greater disturbances of sleep and cognition. Mean (SD) time until
death was 39.7 (69.8) days for 33 patients with reversible delirium
versus 16.8 (10.0) days for 88 patients with irreversible delirium.2
In a prospective study of delirium in patients in a palliative care
unit, investigators reported that the etiology of delirium was mul-
tifactorial in a majority of cases.51 Even though delirium occurred
in 88% of dying patients in the last week of life, delirium was
reversible in approximately 50% of episodes. Causes of delirium
that were most associated with reversibility included dehydration
and psychoactive or opioid medications. Major organ failure and
hypoxic encephalopathies were less likely to be reversed in termi-
nal delirium.51
In light of the several studies on the reversibility of delirium,
the prognosis of patients who develop delirium is defined by the
interaction of the patients’ baseline physiologic susceptibility to
delirium (e.g., predisposing factors), the precipitating etiologies,
and any response to treatment. If a patient’s susceptibility or
resilience is modifiable, then targeted interventions may reduce
the risk of delirium upon exposure to a precipitant and enhance
the capacity to respond to treatment. Conversely, if a patient’s
vulnerability is high and resistant to modification, then exposure
to precipitants enhances the likelihood of developing delirium
and may diminish the probability of a complete restoration of
cognitive function.
Nonpharmacological interventions
In addition to seeking out and potentially correcting underlying
causes of delirium, nonpharmacological and supportive therapies
are important. Nonpharmacological and supportive therapies
play an essential role in the treatment of patients with delirium,
especially in patients with terminal delirium. In fact, in the dying
patient, they may be the only steps that can be taken. Fluid and
electrolyte balance, nutrition, measures to help reduce anxiety
and disorientation, and interactions with and education of family
460
TABLE 47.3  Summary of Nonpharmacological Interventions
Used in the Prevention and Treatment of Delirium
Reducing polypharmacy
Control of pain
Sleep hygiene (e.g., minimize noise and interventions at bedtime)
Monitor for dehydration and fluid-electrolyte disturbances
Monitor nutrition
Monitor for sensory deficits, provide visual and hearing aids
Encourage early mobilization
Minimize the use of immobilizing catheters, IV lines, and physical restraints
Monitor bowel and bladder functioning
Reorient the patient frequently
Place an orientation board, clock, or familiar objects in patient rooms
Encourage cognitively stimulating activities
Source: Adapted from Breitbart W, Alici Y. JAMA 2008;300: 2898.
members may be useful. Measures to help reduce anxiety and dis-
orientation (i.e., structure and familiarity) include a quiet, well-lit
room with familiar objects, a visible clock or calendar, and the
presence of family.
In nonpalliative care settings, there is evidence that non-
pharmacological interventions result in faster improvement in
delirium and slower deterioration in cognition. However, these
interventions were not found to have any beneficial effects on
mortality or health-related quality of life when compared with
usual care.52–57 Nonpharmacological interventions used in these
studies include oxygen delivery, fluid and electrolyte adminis-
tration, ensuring bowel and bladder function, nutrition, mobi-
lization, pain treatment, frequent orientation, use of visual and
hearing aids, and environmental modifications to enhance a
sense of familiarity (Table 47.3).52–57 Low implementation rates
of all the components of the interventions were identified as the
main limiting factor in the interpretation of the study results in
a majority of nonpharmacological intervention trials.58 Physical
restraints should be avoided in patients who are at risk for devel-
oping delirium and for those with delirium. Physical restraints
have been identified as an independent risk factor for the persis-
tence of delirium at discharge.59 Evidence suggests that restraint-
free management of patients should be the standard of care for
prevention and treatment of delirium.60 One-to-one observation
may be necessary while maintaining the safety of the patient
without the use of any restraints.
Pharmacological interventions in delirium
Symptomatic treatment with psychotropic medications is often
essential to control the symptoms of delirium.10 Since publica-
tion of the American Psychiatric Association (APA) guidelines
for treatment of delirium in 1999, a number of systematic reviews
and guidelines have been released based on evidence-based man-
agement of delirium. The guidelines highlight the importance
of multicomponent nonpharmacological prevention strategies,
education of health-care professionals, medical evaluation of
delirium etiology, optimizing pain management, and avoiding
high-risk medications. The guidelines include avoidance of drug
treatment for hypoactive delirium and avoidance of benzodiaz-
epines for treatment of delirium, except in cases of alcohol or
benzodiazepine withdrawal.
In palliative care settings, the evidence is supportive of short-
term low-dose use of antipsychotics in the control of symp-
toms of delirium with close monitoring for possible side effects,
Textbook of Palliative Medicine and Supportive Care
especially in older patients with multiple medical comorbidities
(Tables 47.4).10 It is also recommended that nonpharmacological
interventions in the routine care of patients at risk for delirium
and patients with delirium be implemented, based on the evi-
dence from the medically ill older persons.10 Following is a brief
description of each medication class with a review of the evidence
of their use in the treatment of delirium in palliative care settings.
Antipsychotics
Antipsychotics, formerly known as neuroleptics, are a group of
medications primarily indicated for schizophrenia, bipolar dis-
order, and other mood disorders. The mechanisms by which
these drugs ameliorate disturbances of thought and affect in psy-
chotic states are not fully understood, but presumably, they act
by blocking the postsynaptic mesolimbic dopamine receptors.
Typical (conventional or first-generation) and atypical (second-
generation) antipsychotics differ in their effects on the different
dopamine and serotonin receptor subtypes. Typical antipsychot-
ics are traditionally known to be associated with a higher inci-
dence of extrapyramidal side effects (EPS) due to their effects
on the striatal dopamine 2 (D2) receptors. On the other hand,
atypical antipsychotics (i.e., risperidone, olanzapine, quetiapine,
ziprasidone, and aripiprazole) have been associated with weight
gain, and metabolic syndrome, but significantly less risk for EPS.
APA provided guidance for the use of antipsychotics in the treat-
ment of delirium in 1999. Since then antipsychotic use has been
studied in many settings and different patient populations in the
past two decades.42–44,61–65
Treatment with antipsychotic agents is the norm in the every-
day management of symptoms of delirium across settings and
different patient populations.10 Last decade has seen the biggest
surge in the number of treatment trials on delirium. Several
recent studies did not show benefit of antipsychotics in decreas-
ing the duration or severity of delirium. A 2016 systematic review
examined antipsychotic drugs including oral risperidone, oral
olanzapine, oral quetiapine, intramuscular ziprasidone, and oral,
intravenous, and intramuscular haloperidol61 and concluded that
the current evidence does not support the use of antipsychotics for
treatment (or prevention) of delirium in hospitalized older adults.
There was no significant decrease in delirium incidence among 19
studies and no change in delirium duration, severity, hospital or
intensive care length of stay, or reduction in mortality. Potential
harm was demonstrated in two studies in which more patients
required institutionalization after treatment with antipsychotics.
In a more recent systematic review of antipsychotics in treatment
of delirium, among 16 RCTs and 10 observational studies, there
was no difference in sedation status, delirium duration, hospital
length of stay, or mortality between haloperidol and atypical anti-
psychotics versus placebo.62 There was no difference in delirium
severity and cognitive functioning for haloperidol versus second-
generation antipsychotics. Significant heterogeneity was present
among the studies in terms of dose, administration route of anti-
psychotics, outcomes, and measurement instruments. There was
insufficient or no evidence regarding multiple clinically impor-
tant outcomes. In an RCT63 of atypical antipsychotic drugs in
palliative care settings, participants receiving oral risperidone
or haloperidol had higher delirium symptom scores and were
more likely to require breakthrough treatment compared with
participants receiving placebo. This study was largely publicized
due to the finding that participants in the placebo group had bet-
ter overall survival compared to those in the haloperidol group.
Interestingly, survival was not one of the primary study outcomes
Delirium 461

TABLE 47.4  Antipsychotic Medications Used in the Treatment of Delirium

Routes of
Medication Dose Range Administration Side Effects Comments
Haloperidol 0.5–2 mg every 2–12 h PO, IV, IM, SC Extrapyramidal adverse effects Remains the gold standard therapy for
can occur at higher doses. delirium. May add lorazepam (0.5–1
Monitor QT interval on mg every 2–4 h) for agitated patients.
electrocardiogram (EKG). Double-blinded controlled trials
support efficacy in the treatment of
delirium. A pilot placebo-controlled
trial suggests lack of efficacy when
compared to placebo
Chlorpromazine 12.5–50 mg every 4–6 h PO, IV, IM, SC, PR More sedating and May be preferred in agitated patients
anticholinergic compared with due to its sedative effect. Double-
haloperidol. Monitor blood blind controlled trials support efficacy
pressure for hypotension. in the treatment of delirium.
More suitable for use in intensive No placebo-controlled trials
care unit settings for closer
blood pressure monitoring
Olanzapine 2.5–5 mg every 12–24 h PO, IM Sedation is the main dose- Older age, preexisting dementia, and
limiting adverse effect in hypoactive subtype of delirium have
short-term use been associated with poor response.
Double-blind comparison trials with
haloperidol and risperidone support
efficacy in the treatment of delirium.
A pilot placebo-controlled prevention
trial suggested worsening in delirium
severity. A placebo-controlled study is
supportive of efficacy in reducing
delirium severity and duration
Risperidone 0.25–1 mg every 12–24 h PO Extrapyramidal adverse effects Double-blind comparison trials
can occur with doses >6 mg/ support efficacy in the treatment of
day. Orthostatic hypotension delirium. No placebo-controlled trials.
Quetiapine 12.5–100 mg every 12–24 h PO Sedation, orthostatic Sedating effects may be helpful in
hypotension patients with sleep–wake cycle
disturbance. Pilot placebo-controlled
trials suggest efficacy in the treatment
of delirium. However, studies allowed
for the concomitant use of
haloperidol, which makes the results
difficult to interpret
Ziprasidone 10–40 mg every 12–24 h PO, IM Monitor QT interval on EKG Placebo-controlled, double blind trial
suggests lack of efficacy in the
treatment of delirium
Aripiprazole 5–30 mg every 24 hours PO, IM Monitor for akathisia Evidence is limited. A prospective
open-label trial suggests comparable
efficacy to haloperidol. No placebo-
controlled trials
Source: Adapted from Breitbart W, Alici Y. J Clin Oncol 2012 April 10;30(11):1206.

and the patients in the haloperidol arm were medically sicker with
greater opioid use and more severe delirium. A Cochrane review
on drug therapy for delirium in the terminally ill64 concluded that
there was no high-quality evidence to support or refute the use
of drug therapy for delirium symptoms in terminally ill adults.
As noted eloquently in a debate article by Meagher et al.,65 evi-
dence-based concerns must be applied to all interventions, both
pharmacological and nonpharmacological, with equal vigilance.
Nonpharmacological interventions can be effective in prevention
of delirium in certain settings and may be a helpful tool in treat-
ment of delirium; on the other hand, interventions such as early
mobilization or cognitive remediation may be more agitating to
patients with severe delirium rather than being beneficial.
Management of delirium in palliative care settings is nuanced.
The judicious, most specifically short-term and low-dose, use
of antipsychotics continues to be the mainstay of treatment of
symptoms of delirium (e.g., severe agitation, delusions, and hallu-
cinations interfering with care) in the palliative care settings with
the understanding that antipsychotics are not expected to cure
the underlying etiologies or prolong survival, but are expected to
allow for patients to safely and successfully be managed. In light
of the recent research on use of antipsychotics, it is important
462 Textbook of Palliative Medicine and Supportive Care

to emphasize that in hypoactive delirium, or delirium of all sub-
types that is of mild to moderate severity, antipsychotics are best
avoided or only used if the benefits of medications clearly out-
weigh the risks associated with their use.
Haloperidol is considered to be the preferred antipsychotic in
the treatment of delirium in patients with advanced disease due to
its efficacy and tolerability (e.g., few anticholinergic effects, lack of
active metabolites, and availability in different routes of adminis-
tration).5 In general, doses of haloperidol need not exceed 20 mg in
a 24-hour period; however, some clinicians advocate higher doses
(up to 250 mg/24 hour of haloperidol intravenously) in selected
cases.66 Typically 0.5–1.0 mg haloperidol (PO, intravenous [IV],
intramuscular [IM], subcutaneous [SC]) is administered, with
repeat doses every 45–60 minutes titrated against target symp-
toms of agitation, paranoia, and fear.23 An IV route can facilitate
rapid onset of medication effects. If IV access is unavailable, IM
or SC routes of administration could be used with switch to the
oral route when possible. The majority of delirious patients can
be managed with oral haloperidol. Haloperidol is administered by
the SC route by many palliative care practitioners.5 It is impor-
tant to note that the Food and Drug Administration (FDA) has
issued a warning about the risk of QTc prolongation and torsades
de pointes on electrocardiogram with IV haloperidol; therefore,
monitoring QTc intervals closely among medically ill patients
on IV haloperidol has become the standard clinical practice.67
A common strategy in the management of symptoms related to
delirium is to add parenteral lorazepam to a regimen of haloperi-
dol.5 Lorazepam (0.5–1.0 mg every 1–2 hours PO or IV) along with
haloperidol may be more effective in rapidly sedating the agitated
delirious patient and may minimize EPS associated with haloperi-
dol especially in palliative care settings.68 An alternative strategy is
to switch from haloperidol to a more sedating antipsychotic such
as chlorpromazine, especially in the intensive care unit setting
where close blood pressure monitoring is feasible. It is important
to monitor for anticholinergic and hypotensive adverse effects of
chlorpromazine, particularly in elderly patients.5
Atypical antipsychotic agents (i.e., risperidone, olanzapine,
quetiapine, ziprasidone, and aripiprazole) are increasingly used
in the treatment of delirium in palliative care settings due to
decreased risk of extrapyramidal adverse effects. In the light
of existing literature, risperidone may be used in the treatment
of delirium, starting at doses ranging from 0.125 to 1 mg and
titrated up as necessary with particular attention to the risks
of EPS, orthostatic hypotension, and sedation at higher doses.
Olanzapine can be started between 2.5 and 5 mg nightly and
titrated up with sedation being the major limiting factor, which
may be favorable in the treatment of hyperactive delirium. The
current literature on the use of quetiapine suggests a starting
dose of 25–50 mg and a titration up to 100–200 mg a day (usually
at twice daily divided doses). Sedation and orthostatic hypoten-
sion are the main dose-limiting factors. Findings to date and our
clinical experience suggest a starting dose of 2 to 5 mg daily for
aripiprazole, with a maximum dose of 15 mg daily.
Important considerations in starting treatment with any anti-
psychotic for delirium should include EPS risk, sedation, anticho-
linergic side effects, cardiac arrhythmias, and possible drug–drug
interactions (Table 47.5). Most importantly, the FDA has issued a
“black box” warning of increased risk of death associated with the
use of typical and atypical antipsychotics in elderly patients with
dementia-related psychoses.69 Caution is advised when using anti-
psychotic medications, especially in elderly patients with dementia,
due to the FDA warnings described earlier. Therefore, the use of
nonpharmacological interventions is critical to reduce the need to
use antipsychotic medications whenever possible. It is also impor-
tant to recognize that antipsychotics have complex mechanisms
of action, mostly affecting multiple neurotransmitter systems that
can lead to unwanted side effects. Therefore, the benefits of initiat-
ing antipsychotic treatment for delirium should be weighed against
risks associated with its use. As mentioned previously, in palliative
care settings, the evidence is most clearly supportive of the short-
term low-dose use of antipsychotics for the control of the symp-
toms of delirium, with close monitoring for possible side effects,
especially in older patients with multiple medical comorbidities.10
Delirium in pediatric settings is similarly managed through
treatment of underlying medical etiologies and minimizing iat-
rogenic triggers.70 However, if the delirium persists and the child
has agitated behaviors that are distressing or interfering with the
medical care plan, pharmacologic therapies may be considered.
Most experts recommend use of the atypical antipsychotics, such
as quetiapine.70
Psychostimulants
The use of psychostimulants in the treatment of hypoactive sub-
type of delirium has been suggested.71,72 However, studies with psy-
chostimulants in treating delirium symptoms are limited.71,72 The
risks of precipitating agitation and exacerbating psychotic symp-
toms should be carefully evaluated when psychostimulants are
considered in the treatment of delirium in palliative care settings.10

TABLE 47.5 Recommendations on Monitoring Patients with Delirium for Antipsychotic Side Effects in Palliative Care
Settingsa
EKGb: Baseline and with every dose increase [consider daily monitoring if on high doses (e.g., haloperidol > 5–10 mg daily), patients with underlying
unstable cardiac disease, patients with electrolyte disturbances, patients on other QT-prolonging medications,11 medically frail, older patients;
patients with unstable cardiac diseases or those on IV antipsychotics may require continuous monitoring in consultation with cardiology]
Fasting blood glucose: Baseline and weekly
Body mass index: Baseline and weekly
EPS (including parkinsonism, dystonia, akathisia, neuroleptic malignant syndrome): Baseline and daily
Blood pressure, pulse: Baseline and at least daily (continuous monitoring may be required in medically unstable patients; orthostatic measurements
should be considered with antipsychotics with alpha-1 antagonist effects such as chlorpromazine, risperidone, and quetiapine)
Source: Adapted from Breitbart W, Alici Y. J Clin Oncol 2012 April 10;30(11):1206.
a Recommendations are based on the Consensus Development Conference on antipsychotic drugs and obesity and diabetes.

b The risk of QT prolongation is directly correlated with higher antipsychotic doses, with parenteral formulations (e.g., IV haloperidol) of antipsychotics, and with certain

medications (e.g., ziprasidone, thioridazine). In individual patients, an absolute QTc interval of > 500 ms or an increase of 60 ms (or more than 20%) from baseline is regarded
as indicating an increased risk of torsades des pointes. Discontinuation of the antipsychotic and a consultation with cardiology should be considered, especially if there is
continued need for the use of antipsychotics.
Delirium
Cholinesterase inhibitors
Impaired cholinergic function has been implicated as one of the
final common pathways in the neuropathogenesis of delirium.22
Despite case reports of beneficial effects of donepezil and riv-
astigmine, current evidence does not support use of cholinester-
ase inhibitors in the treatment of delirium.10
Alpha-2 agonists
Dexmedetomidine, an alpha-2 agonist, mostly studied for use
postoperatively and in critical care settings, has been compared to
standard sedatives such as midazolam and propofol, and to opioids
and placebo in RCTs. A systematic review and meta-analysis with
incidence of delirium and delirium resolution as the primary out-
comes, showed that the administration of dexmedetomidine was
associated with significantly lower overall incidence and duration
of delirium when compared to placebo, propofol, midazolam, and
opioids. The main side effects were increased risk of bradycardia
and hypotension.73 It is important to emphasize that dexmedeto-
midine is used in postsurgical and critical care settings and pri-
marily for mechanically ventilated patients. Evidence for its use in
palliative care settings remains to be studied.
Other agents
While antipsychotics are most effective in diminishing agita-
tion, clearing the sensorium and improving cognition are not
always possible in delirium, which complicates the last days of
life. Approximately 30% of dying patients with delirium do not
have their symptoms adequately controlled with antipsychotic
medications.74–76 Processes causing delirium may be ongoing
and irreversible during the active dying phase. In such cases,
a reasonable choice is the use of sedative agents such as benzo-
diazepines (e.g., midazolam and lorazepam), propofol, or opi-
oids to achieve a state of quiet sedation.74–78 Delirium has, in
fact, been identified as the main indication for the use of pal-
liative sedation in up to 82% of cases in symptom control stud-
ies among the terminally ill.74–81 Clinicians are often concerned
that the use of sedating medications may hasten death via respi-
ratory depression, hypotension, or even starvation. However,
studies have shown that the use of opioids and psychotropic
agents in hospice and palliative care settings is associated with
longer rather than shorter survival.79-81
Prevention of delirium
Several researchers have studied both pharmacological and non-
pharmacological interventions in the prevention of delirium
among older patient populations, particularly in surgical set-
tings. The applicability of these interventions to the prevention of
delirium in palliative care settings has not been widely studied.82
In a 2016 Cochrane review that examined prophylactic anti-
psychotics compared with control for preventing delirium in hos-
pitalized non-ICU medical and surgical adult patients 16 years
or older, there was no clear benefit of antipsychotics as a group.83
There is some evidence suggesting that both melatonin84 and
ramelteon85 may be effective in reducing incidence of delirium in
older patients admitted to acute care settings. Based on the cur-
rent literature, no recommendations can be made regarding the
use of medications in the prevention of delirium among palliative
care patients.
Prevention of delirium with nonpharmacological multicom-
ponent approaches has been shown to be effective and has
gained widespread acceptance as the most effective strategy
for delirium. 86 In a meta-analysis of 14 interventional studies
463
based on the Hospital Elder Life Program, multicomponent
approaches significantly reduced the risk of incident delirium
by 53%, and the risk of falls by 62%, among hospitalized, non-
ICU patients who were 65 years and older.82 In oncology set-
tings and in the terminally ill, the effect of these interventions
on delirium incidence has been more limited. In a study of 1516
patients with terminal cancer, Gagnon et al. 87 were not able to
reduce incidence of delirium with a multicomponent interven-
tion including early assessment of patient risk factors, active
engagement of physicians in planning for delirium, and educa-
tion of family members.
Controversies in the management
of terminal delirium
Several aspects of the use of antipsychotics and other pharmaco-
logical agents in the management of delirium in the dying patient
remain controversial in some circles. A study by Agar and col-
leagues49 showed that physicians from different disciplines man-
age terminal delirium differently. According to a survey of 270
physicians from different disciplines, medical oncologists were
found to be more likely to manage terminal delirium with ben-
zodiazepines or benzodiazepine and antipsychotic combinations.
On the other hand, palliative care physicians were more likely
to use antipsychotics to manage delirium symptoms, including
hypoactive subtype of delirium.
Some have argued that pharmacological interventions with
antipsychotics or benzodiazepines are inappropriate in the dying
patient. Delirium is viewed by some as a natural part of the dying
process that should not be altered. In particular, there are clini-
cians who care for the dying who view hallucinations and delu-
sions, which involve dead relatives communicating with or in fact
welcoming dying patients to heaven, as an important element in
the transition from life to death. Clearly, there are many patients
who experience hallucinations and delusions during delirium
that are pleasant and in fact comforting, and many clinicians
question the appropriateness of intervening pharmacologically
in such instances. Another concern that is often raised is that
these patients are so close to death that aggressive treatment is
unnecessary. Parenteral antipsychotics or sedatives may be mis-
takenly avoided because of exaggerated fears that they might has-
ten death through hypotension or respiratory depression. Many
are unnecessarily pessimistic about the possible results of neuro-
leptic treatment for delirium. They argue that since the underly-
ing pathophysiological process often continues unabated (such as
hepatic or renal failure), no improvement can be expected in the
patient’s mental status. There is concern that antipsychotics or
sedatives may worsen delirium by making the patient more con-
fused or sedated.
Clinical experience in managing delirium in dying patients
suggests that the use of antipsychotics in the management of agi-
tation, paranoia, hallucinations, and altered sensorium is safe,
effective, and often quite appropriate.5 Management of delirium
on a case-by-case basis seems wisest. The agitated delirious dying
patient should probably be given antipsychotics to help restore
calm. A “wait-and-see” approach, prior to using antipsychotics,
may be appropriate with some patients who have a lethargic or
somnolent presentation of delirium or those who have frankly
pleasant or comforting hallucinations. Such a “wait-and-see”
approach must, however, be tempered by the knowledge that a
lethargic or “hypoactive” delirium may very quickly and unex-
pectedly become an agitated or “hyperactive” delirium that can
threaten the serenity and safety of the patient, family, and staff.
464
Similarly, hallucinations and delusions during a delirium that are
pleasant and comforting can quickly become menacing and terri-
fying. It is important to remember that by their nature, the symp-
toms of delirium are unstable and fluctuate over time.
Finally, perhaps the most challenging of clinical problems is
management of the dying patient with a “terminal” delirium that
is unresponsive to standard antipsychotic interventions, whose
symptoms can only be controlled by sedation to the point of a sig-
nificantly decreased level of consciousness. Before undertaking
interventions, such as midazolam or propofol infusions, where
the best achievable goal is a calm and comfortable but sedated
and unresponsive patient, the clinician must first take several
steps. The clinician must have a discussion with the family (and
the patient if there are lucid moments when the patient appears
to have capacity), eliciting their concerns and wishes for the type
of care that can best honor their desire to provide comfort and
symptom control during the dying process. The clinician should
describe the optimal achievable goals of therapy as they cur-
rently exist. Family members should be informed that the goal
of sedation is to provide comfort and symptom control, not to
hasten death. They should also be told to anticipate that sedation
may result in a premature sense of loss and that they may feel
their loved one is in some sort of limbo state, not yet dead, but
yet no longer alive in the vital sense. The distress and confusion
that family members can experience during such a period can be
ameliorated by including the family in the decision-making and
emphasizing the shared goals of care. Sedation in such patients
is not always complete or irreversible; some patients have peri-
ods of wakefulness despite sedation, and many clinicians will
periodically lighten sedation to reassess the patient’s condition.
Ultimately, the clinician must always keep in mind the goals of
care and communicate these goals to the staff, patients, and fam-
ily members. The clinician must weigh each of the issues outlined
earlier in making decisions on how to best manage the dying
patient who presents with delirium that preserves and respects
the dignity and values of that individual and family.
Prognostic implications of delirium
in the terminally ill
It is important to emphasize the prognostic value of delirium in
terminally ill patients. Delirium is a relatively reliable predictor
of approaching death in the coming days to weeks.58 The death
rates among hospitalized elderly patients with delirium over the
3-month post-discharge period range from 22 to 76%, the wide
range most likely reflecting the variability in underlying general
medical conditions contributing to delirium in elderly patients.59
In the palliative care setting, several studies provide support
that delirium reliably predicts impending death in patients with
advanced cancer.88,89
Given prognostic significance of delirium, recognizing an epi-
sode of delirium in the late phases of palliative care is critically
important in treatment planning and in advising family members
on what to expect.
Conclusion
Palliative care clinicians commonly encounter delirium as a
major complication of terminal illness. Proper assessment, diag-
nosis, and management of delirium are essential in improving the
quality of life and minimizing morbidity in palliative care set-
tings for patients, families, and health-care professionals.
Textbook of Palliative Medicine and Supportive Care
KEY LEARNING POINTS
• Delirium occurs in up to 85% of patients prior to
death.
• Hypoactive subtype of delirium is as common
and as distressing as the hyperactive subtype of
delirium.
• There are typically three or more etiologies for
delirium in the palliative care setting.
• In the terminally ill, delirium is reversible in only
50% of cases compared with more than 80% of
cases in patients with earlier stage disease.
• The management of delirium involves the concur-
rent search for and treatment of the underlying
etiology while actively controlling the symptoms
of delirium.
• Delirium often is a harbinger of impending
death. Issues of end-of-life care treatment prefer-
ences are ideally dealt with prior to the onset of
delirium.
• Delirium is associated with high levels of dis-
tress in patients, family members, and nurses.
Education of family members and nurses in the
palliative care setting is important.
• Current evidence is supportive of the short-term
use of antipsychotics in the treatment of symp-
toms of delirium (i.e., agitation, sleep–wake cycle
disturbances, delusions, hallucinations) with
close monitoring for possible side effects espe-
cially in elderly patients with multiple medical
comorbidities. The choice of antipsychotic medi-
cation for the treatment of delirium should be
based on the clinical presentation of the patient
and the side effect profile of each antipsychotic
drug, as none of the antipsychotics were found to
be superior to others in comparison trials.
• It is strongly recommended to implement non-
pharmacological interventions in the routine
care of patients who are either at risk for delirium
or have established delirium, based on the evi-
dence from nonpalliative care settings.
• Sedation may be necessary in up to 30% of patients
with delirium unresponsive to antipsychotics.
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48
SLEEP DISTURBANCES IN ADVANCED CANCER PATIENTS

Delmer A. Montoya and Sriram Yennurajalingam

Contents
Introduction....................................................................................................................................................................................................................... 467
Pathophysiology of sleep disorders in cancer patients.............................................................................................................................................. 469
Normal sleep architecture......................................................................................................................................................................................... 469
Mechanisms of cancer-related sleep disturbances................................................................................................................................................470
Assessment of sleep disorders.........................................................................................................................................................................................471
Treatment of sleep disturbances.....................................................................................................................................................................................472
Nonpharmacological interventions..........................................................................................................................................................................472
Pharmacological interventions..................................................................................................................................................................................473
Multimodal intervention for treatment of sleep disturbances in advanced cancer........................................................................................474
Conclusion...........................................................................................................................................................................................................................474
References............................................................................................................................................................................................................................474

Introduction for another key component. Other symptoms that commonly

Sleep disturbances (SDs) can be defined as any symptom or con-
dition that interferes with normal sleep.1 They are very common
in patients with advanced cancer,2 with a prevalence reported
between 24 and 95% in this population. 3 However, this problem
is usually neglected in treatment strategies for advanced cancer,
as many studies have focused on patients with early-stage dis-
ease and survivors.4 SDs in the cancer population can present as
a temporary symptom associated with the cancer or as part of
depression or anxiety disorders, and physicians often assume that
the SDs will resolve when the underlying problem is treated.4–6
The sleep disorders are a group of pathologic conditions that
have been defined based on clinical presentation and diagnos-
tic criteria.7 There is a classification system published by the
American Academy of Sleep Medicine (AASM; see Table 48.1)
that standardizes the diagnosis of sleep disorders and is especially
useful in the research setting.8 This system recognizes six major
sleep disorder categories: insomnia, sleep-related breathing dis-
orders, hypersomnia, circadian rhythm sleep disorders, parasom-
nias, and sleep-related movement disorders. Of those disorder
categories, the most common in advanced cancer patients, com-
pared with the general population, is insomnia, which accounts
for 35% of the diagnoses in these patients.9,10
Insomnia is a complex complaint that can be defined as a diffi-
culty initiating sleep, trouble staying asleep, with prolonged noc-
turnal awakenings, early morning awakening with inability to
resume sleep, or impairment of daytime functioning. Insomnia
can appear as an isolated disorder or as a symptom that accompa-
nies a different disorder.
The Diagnostic and Statistical Manual of Mental disorders,
fifth edition (DSM-5) and the International Classification of Sleep
Disorders, third edition (ICSD-3) insomnia’s diagnostic criteria
are similar because of collaborative efforts between the American
Psychiatric Association and the AASM classification task forces.
The DSM-IV distinction into primary and secondary insomnia
is removed in DSM-5. Daytime distress or impairment in work,
family, academic, and other vital areas of functioning account
accompany insomnia include mood disturbance and irritabil-
ity, anergia, and, especially in children, behavior problems such
as hyperactivity, impulsivity, or aggression. ICSD-3 and DSM-5
both distinguish between short-term and chronic insomnia, with
the latter continuing for 3 months or longer.75
The prevalence of sleep disorders in cancer patients is about
twice that of the general population. Screening tests used for
sleep disorder are heavily weighted toward diagnosing insomnia;
therefore, it is not surprising that the most common SDs found
by Sela et al. in palliative cancer patients were difficulty falling
asleep (40%), difficulty staying asleep (63%), and not feeling rested
in the morning (72%).1 Adjustment insomnia (acute insomnia)
and insomnia due to medical conditions (comorbid insomnia) are
the most common new-onset SD subtypes. The general criteria
for insomnia in adults are presented in Table 48.2.12
The prevalence of SDs varies depending upon the type of can-
cer. For example, breast cancer patients have a high frequency
of insomnia and fatigue, whereas lung cancer patients have the
highest prevalence of SDs in general, owing to coughing, diffi-
culty in breathing, and nocturia that lead to frequent awakenings
that disrupt the patient’s sleep pattern. Proper diagnostic criteria
and classification schemes have not been used when studying the
frequency of sleep disorders in individuals with cancer, making
it somewhat difficult to establish the incidence and prevalence of
conditions other than insomnia.2
Some studies have suggested that a disrupted sleep–wake
cycle is associated with a shorter survival rate in patients with
advanced cancer,76,77 but these cross-sectional findings need to be
interpreted cautiously, as a poorer prognosis could also lead to
worse rest–activity rhythms.
In this chapter, we will describe normal sleep architecture
and discuss the mechanisms of cancer-related SD. We will then
turn to assessment and diagnosis of SD, through subjective self-
reports and more objective medical tests such as polysomnog-
raphy (PSG). We will conclude by summarizing the treatments
available, ranging from nonpharmacological methods to SD
medications.

467
468 Textbook of Palliative Medicine and Supportive Care

TABLE 48.1  International Classification of Disorders

1. Insomnia
a. Adjustment insomnia (acute insomnia)
b. Psychophysiological insomnia
c. Paradoxical insomnia
d. Idiopathic insomnia
e. Insomnia due to mental disorder
f. Inadequate sleep hygiene
g. Behavioral insomnia of childhood
h. Insomnia due to drug or substance
i. Insomnia due to medical condition
j. Insomnia not due to substance or known physiological condition, unspecified (nonorganic insomnia, not otherwise specified (NOS))
k. Physiological (organic) insomnia, unspecified
2. Sleep-related breathing disorders
a. Central sleep apnea syndromes
i. Primary central sleep apnea
ii. Central sleep apnea due to Cheyne–Stokes breathing pattern
iii. Central sleep apnea due to high-altitude periodic breathing
iv. Central sleep apnea due to medical condition, not Cheyne–Stokes
v. Central sleep apnea due to drug or substance
vi. Primary sleep apnea of infancy
b. Obstructive sleep apnoa (OSA) syndromes
i. OSA, adult
ii. OSA, pediatric
c. Sleep-related hypoventilation/hypoxemic syndromes
i. Sleep-related nonobstructive alveolar hypoventilation, idiopathic
ii. Congenital central alveolar hypoventilation syndrome
d. Sleep-related hypoventilation/hypoxemia due to medical conditions
i. Sleep-related hypoventilation/hypoxemia due to pulmonary parenchymal or vascular pathology
ii. Sleep-related hypoventilation/hypoxemia due to lower airway obstruction
iii. Sleep-related hypoventilation/hypoxemia due to neuromuscular and chest wall disorders
e. Other sleep apnea/sleep-related breathing disorders
3. Hypersomnia of central origin not due to a circadian rhythm disorder or other cause of disturbed nocturnal sleep
a. Narcolepsy with cataplexy
b. Narcolepsy without cataplexy
c. Narcolepsy due to medical conditions
d. Narcolepsy unspecified
e. Recurrent hypersomnia
i. Kleine–Levin syndrome
ii. Menstrual-related hypersomnia
f. Idiopathic hypersomnia with long sleep time
g. Idiopathic hypersomnia without long sleep time
h. Behaviorally induced insufficient sleep syndrome
i. Hypersomnia due to medical conditions
j. Hypersomnia due to drug or substance
k. Hypersomnia not due to substance or known physiological condition (nonorganic hypersomnia, NOS)
l. Physiological (organic) hypersomnia, unspecified (organic hypersomnia, NOS)
4. Circadian rhythm sleep disorder
a. Circadian rhythm disorder, delayed sleep-phase type (delayed sleep-phase disorder)
b. Circadian rhythm disorder, advanced sleep-phase type (advanced sleep-phase disorder)
c. Circadian rhythm disorder, irregular sleep–wake type (irregular sleep–wake rhythm)
d. Circadian rhythm disorder, free-running type (nonentrained type)
e. Circadian rhythm disorder, jet lag type (jet lag disorder)
f. Circadian rhythm disorder, shift work type (shift work disorder)
g. Circadian rhythm disorder, due to medical conditions
h. Other circadian rhythm disorder (circadian rhythm disorder, NOS)
i. Other circadian rhythm disorder due to drug or substance
Sleep Disturbances in Advanced Cancer Patients 469

TABLE 48.1  International Classification of Disorders (Continued)

5. Parasomnia
a. Disorders of arousal from non-rapid eye movement (NREM) sleep
i. Confusional arousals
ii. Sleepwalking
iii. Sleep terrors
b. Parasomnias usually associated with REM sleep
i. REM sleep behavior disorder
ii. Recurrent isolated sleep paralysis
iii. Nightmare disorder
c. Other parasomnias
i. Sleep-related dissociative disorders
ii. Sleep enuresis
iii. Sleep-related groaning (catathrenia)
iv. Exploding head syndrome
v. Sleep-related hallucinations
vi. Sleep-related eating disorder
vii. Parasomnia, unspecified
viii Parasomnias due to drug or substance
ix. Parasomnias due to medical conditions
6. Sleep-related movement disorder
a. Restless legs syndrome
b. Periodic limb movement disorder
c. Sleep-related leg cramps
d. Sleep-related bruxism
e. Sleep-related rhythmic movement disorder
f. Sleep-related movement disorder, unspecified
g. Sleep-related movement disorder due to drug or substance
h. Sleep-related movement disorder due to medical conditions
7. Isolated symptoms, apparently normal variants and unresolved issues
a. Long sleepers
b. Short sleepers
c. Snoring
d. Sleep talking
e. Sleep starts (hypnic jerks)
f. Benign sleep myoclonus of infancy
g. Hypnagogic foot tremor and alternating leg muscle activation during sleep
h. Propriospinal myoclonus at sleep onset
i. Excessive fragmentary myoclonus
8. Other sleep disorders
a. Other physiological (organic) sleep disorder
b. Other sleep disorder not due to substance or known sleep disorder
c. Environmental sleep disorder
Sources: Adapted from American Academy of Sleep Medicine. International Classification of Sleep Disorders: Diagnostic and Coding Manual, 2nd edn. Westchester, IL:
American Academy of Sleep Medicine, 2005; Freedom T. Classification of sleep disorders. Disease-a-Month 2011;57: 323.

Pathophysiology of sleep of voluntary muscle paralysis with evidence of electroencepha-

disorders in cancer patients
Normal sleep architecture
The normal sleep physiology has been divided into two distinct
physiologic types: rapid eye movement (REM) and non-rapid eye
movement (NREM) sleep. The latter is subdivided in stages num-
bered from N1 to N3. The last stage is known as slow-wave sleep
based on the electroencephalography. Perhaps the most impor-
tant difference between NREM and REM sleep is the presence
lographic activity in the latter. During REM sleep, people expe-
rience dreams and significant autonomic variability.13 Sleepers
experience complete paralysis of voluntary skeletal muscles,
which is mediated through changes in the brain stem that causes
activation of descending inhibitory pathways on the brain stem
and spinal cord.14
During a normal sleep night, individuals progress between dif-
ferent sleep stages, from light (stage 1) to deep or slow-wave sleep,
returning to more light stages and to REM sleep in between.
470 Textbook of Palliative Medicine and Supportive Care

TABLE 48.2  General Criteria for Insomnia in Adults

1. Difficulty initiating sleep, difficulty maintaining sleep, or waking up too early or sleep that is chronically nonrestorative or poor in quality
2. Sleep difficulty occurring despite adequate opportunities and circumstances for sleep
3. Patient reports at least one of the following forms of daytime impairment related to the nighttime sleep difficulty:
• Fatigue or malaise
• Attention, concentration, or memory impairment—social or vocational dysfunction
• Mood disturbance or irritability
• Daytime sleepiness
• Motivation, energy, or initiative reduction
• Proneness for errors or accidents at work or while driving
• Tension, headache, or gastrointestinal symptoms in response to sleep loss
• Concerns or worries about sleep
Source: Adapted from American Academy of Sleep Medicine. International Classification of Sleep Disorders: Diagnostic and Coding Manual, 2nd edn. Westchester, IL:
American Academy of Sleep Medicine, 2005.

A normal night sleep consists of several of these fluctuations
(between 4 and 6). The distinction between the physiological
stages of sleep is important because certain pathologies present
exclusively during certain stages (parasomnias) or are exacer-
bated during specific phases (such as sleep-disordered breathing
during REM sleep).15,16
Mechanisms of cancer-related sleep disturbances
Just as many aspects of sleep physiology are still not understood,
the precise mechanism by which cancer leads to SDs also remains
unknown. Several models have been developed to explain sleep–
wake disorders in the context of cancer. All these models appear
to coincide in the multifactorial nature of the disorder and the
hypothesis that physiological, psychological, and behavioral phe-
nomena play an important role in the development of deviations
from normal sleep and pathologic changes.17 The most commonly
cited hypothesis in patients with cancer is based on the Speilman
three-factor model: (1) predisposing factors that increase the indi-
vidual’s vulnerability to insomnia (gender, age, and a family his-
tory of insomnia); (2) precipitating factors that trigger the onset
of insomnia (disease-specific biological factors, cancer-related
emotional factors, functional loss, treatment, pain, and delirium);
and (3) perpetuating factors that maintain insomnia over time
(maladaptive sleep behaviors and misconceptions about sleep).
The most important contributors for each category of factors are
summarized in Table 48.3.10
This model assumes that predisposing factors are rarely modifi-
able and that many cancer patients may have preestablished sleep
disorders, thus making the determination of true risk factors dif-
ficult, especially since some populations have been studied pref-
erentially (e.g., breast cancer patients). The cancer-specific-related
risk factors for SDs may be subdivided into disease-specific,
treatment-related, or associated phenomenon. Patients with can-
cer share demographic and age risk factors for SDs with the normal
population. The single most important unmodifiable risk factor
for sleep–wake disturbances is age, especially since cancer tends
to be diagnosed in older patients. The cancer-specific factors may
be subdivided into disease-specific, treatment-related, or associ-
ated phenomena.12 These cancer-specific factors have been divided
into pathophysiological changes induced by the disease, symptoms
that may interfere with normal sleep initiation or maintenance,
and changes in lifestyle that could contribute to disturbances in
the sleep–wake cycle.
Cancer can affect the patient’s sleep by contributing to symp-
toms that are known to cause sleep–wake disruption. Changes
in sleep architecture have been described with decrease in

TABLE 48.3  Key Etiologic Factors of Insomnia in Cancer Patients

Predisposing Factors Precipitating Factors Perpetuating Factors
• Psychiatric disorders • Pain • Poor sleep habits (excessive time spent in bed, napping,
irregular sleep schedules)
• Medical illness
• Female sex • Mutilating surgery
• Advancing age • Hospitalization
• Hyperarousability • Radiation therapy •
• Family history of • Bone marrow transplantation • Dysfunctional reactions to sleep (anxiety associated
insomnia with the act of sleeping)
• Personal history of • Medications (antiemetic drugs, hormonal therapy,
insomnia chemotherapy)
• Misconceptions about
the causes of insomnia
• • Unrealistic sleep requirements
• • Delirium •
• Misattributions of daytime impairments
Source: Adapted from Savard J, Morin CM. J Clin Oncol 2001February 1;19: 895.
Sleep Disturbances in Advanced Cancer Patients
slow-wave sleep and REM sleep and corresponding increases in
stages N1 and N2 sleep.18 Symptoms such as urinary disturbances
can cause patients to awaken frequently, disturbing their sleep
cycles. Several agents used to treat malignancies also can lead to
symptoms such as neuropathy or pain that can further disrupt
the sleep–wake cycle.
Pain has been proposed as an important factor leading to
insomnia, although there have been very few trials to support
this widely accepted association.2,19 Likewise, inadequate pain
management can lead to significant changes in insomnia occur-
rence and severity. In a study of symptom assessment, Meuser
et al. showed that adequate pain control may actually be asso-
ciated with a decrease in the incidence of insomnia.20 Another
important aspect of pain in cancer patients is that it is frequently
treated with opioids, which can cause changes in the normal sleep
physiology and lead to respiratory depression with exacerbation
of other sleep disorders.21
Mood and anxiety disorders, which appear to interfere signifi-
cantly with normal sleep, are the most common psychiatric diag-
noses in cancer patients and have been demonstrated to cause
disruption of the sleep architecture, as in depression.22–24 In con-
trast, anxiety can lead to increased arousal with patients experi-
encing difficulty falling asleep. Despite the extensive association
between affective problems and anxiety with SDs, there is very
little evidence that this association is exclusive to the cancer popu-
lation, suggesting that the symptoms may precede the cancer diag-
nosis.25,26 Severe emotional distress, not uncommon in this group
of patients, may further alter the patient’s ability to maintain sleep.
There is growing interest in the potential role of cytokines
in the development of specific symptoms in cancer patients.
Elevated levels of proinflammatory cytokines have been found in
patients with cancer.27 Cytokines exert their effect in the brain
through different pathways including the liberation of prosta-
glandin E2 thus elevating the body temperature and stimulating
the hypothalamic–pituitary–adrenal axis that in turn may lead
to changes in the sleep–wake cycle. As symptoms experienced by
this population may resemble those suffered by individuals with
infections, cytokines have been studied as potential mediators
of most chemotherapy and cancer-related symptoms.28,29 Some
cancer patients receiving interleukin-2 and tumor necrosis fac-
tor alpha (TNF-α) as treatment for their underlying malignancy
develop systemic signs of inflammation and the appearance of
symptoms such as fever, fatigue, anorexia, and insomnia.2
Further experimental data from animal models suggest
the important role of these cytokines in sleep. For example,
interleukin-1 and TNF-α increased intracellular calcium con-
centrations in gamma amino butyric acid (GABA)-producing
cultured rat hypothalamic neurons. 30 In addition, studies done
in rats have shown that the administration of interleukin-1 or
TNF-α can induce and increase slow-wave sleep when admin-
istered topically to the somatosensory cortex under the dura. 31
It also appears that the effects of the cytokines on sleep may
be modulated through the serotonin system, since the dorsal
raphe, the main serotoninergic system in the brain, has recep-
tors for interleukin-1 and exposure to cytokines increases
NREM sleep in rats. 32 In addition, most of the effects of inter-
leukin-1 on sleep are lost with disruption of the serotoniner-
gic system in the brain. 33,34 Finally, other animal models have
demonstrated that the infusion of interleukin-1 to the preop-
tic nucleus of the hypothalamus can change the firing rates
of active neurons, further substantiating the potential role of
these cytokines in sleep. 35
471
Interleukin-6, another cytokine that may be involved in the
regulation of sleep, is important in the modulation of response to
interleukin-1 among other functions. Interleukin-6 shows a nor-
mal diurnal variation in levels that mirror changes in the sleep–
wake cycle36 and can also increase slow-wave sleep and reduce
REM sleep in humans. 37 Interestingly, clinical studies using the
TNF-α receptor antagonist etanercept have shown a decrease in
plasma interleukin-6 levels as well as daytime sleepiness in sleep
apnea patients. 38 There are clinical studies showing that interleu-
kin-6 levels may correlate with the amount of sleep and that sleep
deprivation may change the normal temporal pattern of circadian
interleukin-6 secretion. 39
Thus, growing evidence supports the role of cytokines as sleep
modulatory substances. Most of the data come from animal
experiments, but some clinical data are slowly appearing. One
important aspect from a therapeutic standpoint is the modula-
tion potential of these protein levels as a treatment for SD.
Assessment of sleep disorders
The most important aspect during assessment of SD in cancer
patients is characterizing the sleep difficulty and identifying the
causes, exacerbating factors, and comorbidities that trigger the
SD. Taking into consideration that cancer patients occasionally
do not report SD to their physicians, a thorough history is essen-
tial to identify the factors that contribute to SD. The patients
should be able to provide this information, and their partners
should be asked to contribute to the sleep history to rule out other
sleep disorders such as restless legs syndrome or obstructive sleep
apnea (OSA).40,41
Several screening and evaluation tests are available for detect-
ing and diagnosing SD. The first group of the tests relies on self-
reports about sleep latency, quality, satisfaction, and awakenings.
This information is usually gathered with sleep quality question-
naires, sleep history questionnaires, sleep diaries, and daytime
sleepiness questionnaires.13 The Pittsburgh Sleep Quality Index
(PSQI), the standard for self-reported sleep data, is a frequently
used tool in clinical research. The PSQI measures the quality and
patterns of sleep and differentiates “poor” from “good” sleep by
measuring subjective sleep quality, sleep latency, sleep duration,
habitual sleep efficiency, SD, use of sleeping medication, and day-
time dysfunction.42 The Edmonton Symptom Assessment Scale
(ESAS) evaluates the prevalence and severity of 10 self-reported
symptoms commonly experienced by cancer patients over the
previous 24 hours: pain, fatigue, nausea, depression, anxiety,
drowsiness, dyspnea, loss of appetite, sense of well-being, and
sleep. The severity of each symptom is rated on a numerical scale
of 0–10, where 0 means that the symptom is absent, and 10 indi-
cates the worst possible severity.43 The cutoff point of the pres-
ence of ESAS sleep symptom is 3 out of 10 for the screening of
SD. This cutoff has a sensitivity of 86% and a specificity of 53%. 3
Another way to document SDs and monitor the effect of inter-
ventions is with sleep diaries, which are more objective than
patient or partner recall. Several sleep diary models collect vari-
ous kinds of data, but in general, the patient records daily infor-
mation on time of initiation of sleep, total sleep time, and number
of awakenings. Daytime sleepiness and sleep-related habits are
recorded as well.44 The daytime sleepiness inventories are aimed
at finding the repercussions of impaired sleep on the patient’s
daytime functioning.
Because of the subjective nature of the self-reported instru-
ments, it is often recommended that researchers and physicians
472
also use objective measures of SD. The standard for detection
of specific sleep and wake states is PSG.45 PSG records several
bioelectrical signals such as electroencephalogram (EEG), heart
rate, respiratory rate, upper airway flow, presence of snoring,
EMG, and leg movement to characterize the sleep architecture
and detect SD. Another frequently used test in the diagnosis of
SD is actigraphy which uses an accelerometer to monitor activ-
ity throughout the day. With the use of computer algorithms,
actigraphy calculates sleep time, latency, and awakenings. Unlike
subjective measures, which can differ significantly from the poly-
somnogram, actigraphy correlates well with polysomnographic
data.46 Both PSG and actigraphy complement the self-reported
SD. These tests help us gather more objective information about
stages of sleep in hospital settings or sleep–wake patterns of
patients in their own homes.47
Laboratory investigations may be considered when associ-
ated medical conditions are causing SD. For example, ferritin
measurement can help diagnose restless legs syndrome, and
a physical examination of the head and neck can help iden-
tify OSA as a cause of daytime tiredness and fatigue secondary
to SD. The STOP-Bang (snoring, tired, observed, blood pres-
sure–BMI, age, neck circumference, gender) questionnaire
was developed as a screening tool for OSA in surgical patients
and preoperative clinics. This questionnaire is short and easy
to apply and has sensitivity between 93 and 100% for moder-
ate-to-severe OSA.48
Treatment of sleep disturbances
SD has a negative effect on quality of life in patients suffer-
ing from advanced cancer and other diseases, emphasizing the
need to treat this condition.49 Management of the underlying
pathology is paramount in order to lessen the somatic, psycho-
logical, and social effects of SD experienced by cancer patients.
Symptoms such as fatigue, impaired daytime functioning, and
mood disturbances are commonly reported by advanced cancer
patients and could be secondary to SD.10 Therefore, the develop-
ment of interventions aimed at improving SD can help alleviate
these symptoms and increase patients’ coping capacity.10 A mul-
timodal approach with pharmacological and nonpharmacologi-
cal interventions has been used to treat SD in advanced cancer
patients, but data on the effectiveness of these measures in this
specific population are limited.50 Although there are no prospec-
tive studies that inform an evidence-based approach, for many
patients a combined approach is most helpful.
TABLE 48.4  Commonly Recommended Sleep Hygiene Measures
1. Maintain a regular bed and wake time schedule including weekends.
2. Establish a regular, relaxing bedtime routine such as soaking in a hot bath and then reading a book or listening to soothing music.
3. Create a sleep-conducive environment that is dark, quiet, comfortable, and cool.
4. Sleep on a comfortable mattress and pillows.
5. Use your bedroom only for sleep and sex.
6. Finish eating at least 2–3 hours before your regular bedtime.
7. Exercise regularly. It is best to complete your workout at least a few hours before bedtime.
8. Avoid caffeine (e.g., coffee, tea, soft drinks, chocolate etc.) close to bedtime. It can keep you awake.
9. Avoid nicotine (e.g., cigarettes, tobacco products). When used close to bedtime, it can lead to poor sleep.
10. Avoid alcohol close to bedtime.
Sources: Adapted from National Sleep Foundation. Healthy Sleep Tips. http://www.sleepfoundation.org/article/sleep-topics/healthy-sleep-tips. (Accessed May 23, 2012);
American Academy of Sleep Medicine. International Classification of Sleep Disorders: Diagnostic and Coding Manual, 2nd edn. Westchester, IL: American Academy
of Sleep Medicine, 2005.
Textbook of Palliative Medicine and Supportive Care
Nonpharmacological interventions
The AASM strongly recommends educating patients about sleep
hygiene measures51 (see Table 48.4). These interventions alone
have not been demonstrated to be effective against insomnia but
are easy to implement and have a high possibility of improving
sleep when combined with other therapeutic interventions such
as cognitive behavioral treatment (CBT). Awareness of good sleep
hygiene may also help the patient identify abnormal behavior that
can interfere with restful sleep.
Several nonpharmacological therapies to treat insomnia have
been tried in the general population. The most commonly evalu-
ated modalities include behavioral and CBTs. CBT is a supportive
counseling intervention aimed at eliminating factors associated
with chronic insomnia, reducing the severity of perpetuating fac-
tors below the insomnia threshold, and deactivating the hyper-
arousal.12 Importantly, two meta-analyses revealed that some of
these interventions might have efficacy against insomnia.10 Not
all measures of sleep quality have responded equally well to CBT.
The largest therapeutic effects have been obtained for sleep-onset
latency, sleep quality ratings, and duration of awakenings. The
National Institutes of Health State-of-the-Science Conference
on Insomnia concluded that CBT is as effective as hypnotic
medications are for the short-term management of insomnia.2
CBT’s effects are also longer lasting than those of pharmacologi-
cal agents, and in general, CBT may have other benefits for the
patient’s quality of life. The American Academy of Sleep Medicine’s
Practice Parameters, published in 2006, recommended behavioral
and psychological interventions as a standard for the treatment of
chronic comorbid insomnia.12 Other techniques that have proven
beneficial include stimulus control, relaxation, sleep restriction,
and multicomponent therapy that are part of CBT.
Several studies have evaluated the effectiveness of CBT for
the treatment of insomnia in the cancer population. A recent
review reports that four randomized controlled trials and nine
quasi-experimental studies have shown that in general, CBT is
an effective intervention that leads to improvement of several
sleep outcome measures including sleep quality using the PSQI.12
These studies have been performed in different cancer popula-
tions, including patients undergoing active treatment and sur-
vivors. Among other interventions, supportive expressive group
therapy showed an increase in the wake-latency time in breast
cancer patients.52 Objective measures, such as actigraphy, and
subjective measures, such as sleep diaries and questionnaires,
showed improvement with CBT in a randomized controlled
crossover study done by Fiorentino et al.53
Sleep Disturbances in Advanced Cancer Patients
Complementary interventions that have been tested include
progressive muscle relaxation, which decreased sleep latency in
patients with multiple cancers; hypnosis interventions, which
decreased hot flashes in breast cancer patients; and bright light
therapy, which may improve SD and fatigue in breast cancer
patients during chemotherapy.2,12 Exercise interventions such as
stretching, concentrating, and strengthening affect the circadian
phase (evening exercise produced substantial phase advances
for evening exercises). Regular exercise for a sustained period of
time may help to improve sleep latency and quality.47 Exercise
may prove beneficial for cancer patients, but further studies are
required before these interventions can be widely recommended.12
Although not all studies found benefit from combining specific
interventions, layering different approaches appears to be helpful
to at least some patients, and they are all low-risk interventions.
Pharmacological interventions
The approach to SD should take into account the patient’s over-
all clinical condition. Patients receiving palliative care but who
maintain a relatively better prognosis and have minimal comor-
bid conditions will likely tolerate pharmacological treatments
for insomnia similar to medically healthy individuals. However,
patients approaching end of life or who are more debilitated may
be more susceptible to the side effects of pharmacological treat-
ment due to drug–drug interactions or the presence of end organ
impairment.71
Pharmacotherapy is the most common SD intervention in the
general population and cancer patients. Table 48.5 summarizes
the most commonly used hypnotic agents in the cancer popu-
lation. The newer, short-acting benzodiazepines have a more
selective hypnotic effect with less residual side effects than the
long-acting benzodiazepines. Benzodiazepines interact with the
GABA-A receptor, increasing the conductance to chloride and
TABLE 48.5  Commonly Used Hypnotic Medications
Activity
Ultrashort acting Zaleplon
Short-onset brief duration Triazolam
Alprazolam
Short-onset, intermediate duration of action Zolpidem
Zopiclone
Eszopiclone
Intermediate onset, duration Lorazepam
Temazepam
Longer latency to onset, prolonged activity Clonazepam
Chlordiazepoxide
Diazepam
Longer latency to onset, prolonged activity Amitriptyline
(off-label for insomnia) Imipramine
Doxepin
Trazodone
Mirtazapine
Variable activity (off-label for insomnia) Haloperidol
Risperidone
Olanzapine
Quetiapine
Source: Adapted from Delgado-Guay M, Yennurajalingam S. Oxford American Handbook of Hospice and Palliative Medicine, Yennurajalingam S, Bruera E (eds.). New York:
Oxford University Press, 2011, pp. 115–126.
473
therefore hyperpolarizing the neurons.54 In general, benzodiaz-
epines cause central nervous system depression, with amnestic
and hypnotic effects, and have been shown to decrease sleep
latency and duration in short-term studies in the general popula-
tion.55,56 However, objective data from polysomnographic studies
show that self-reported measures may overestimate the effect on
sleep latency.57 There are many different benzodiazepines with
variable half-lives depending on their metabolism. This becomes
important when using long half-life medications, since residual
effects with impairment of daytime functioning may occur, espe-
cially in the elderly, leading to an increased risk of falls and hip
fractures.58 Another important concern in elderly cancer patients
is the potential of benzodiazepines to cause delirium, cognitive
impairment, and respiratory depression when combined with
opioids.59–62 These adverse interactions have been described with
methadone even at a low dose.63 In addition, very little informa-
tion is available on the long-term efficacy of these agents, and the
well-known pharmacological effects, such as the patient’s toler-
ance and dependence on these agents, may make them undesir-
able for long-term use.64
Antidepressant medications with sedative properties, such
as trazodone, amitriptyline, and doxepin, can be beneficial for
depressed patients with SD.10 Since selective serotonin reuptake
inhibitors (SSRIs) have very low sedative effects, the use of SSRIs
is limited to depression-related insomnia. Venlafaxine can be
used to treat both hot flashes and SD in breast cancer patients;
however, no beneficial effects for sleep have been reported. SSRI
and serotonin norepinephrine reuptake inhibitors (SNRIs) can
produce SD as well owing to their pharmacological action over
the 5-HT2 and 5-HT3 receptors.65
Side effects associated with antidepressants, such as ortho-
stasis (mostly with trazodone), anticholinergic activity, nausea,
and constipation, should be considered before prescribing these
Initial Dose (mg) considerations
5–10 Little to no anxiolytic effect; costly
0.125 Rapid sleep induction; limited effect on sleep maintenance
0.5–1
5–10 No clear advantage over benzodiazepines; costly; minimal
5–7.5 anxiolytic effect
3
0.5–4 Adequate effect on sleep induction and maintenance; risk
7.5–15 of daytime drowsiness
0.5–2 Slow sleep induction with increased risk of accumulation
50–100 of metabolites; high risk of daytime sedation
5–10
25–100 Increased risk of daytime sedation, confusion, constipation,
25–100 and cardiac conduction abnormalities
25–100
25–100
15–30
0.5–5 Used in sleep disturbance related to psychosis or delirium
0.5–1
5–10
25
474
medications to cancer patients.65 Tricyclic antidepressants can
decrease sleep latency, reduce awakenings, and increase sleep
quality, but they also can cause concerning side effects, such as
daytime sedation, an anticholinergic effect, and cardiovascular
problems, especially in older patients.65–67
Mirtazapine is a good option for managing multiple distressing
symptoms in cancer patients. A noradrenergic and specific sero-
tonergic antidepressant with antagonistic effects on 5-HT2 and
5-HT3 receptors, mirtazapine can improve nausea, vomiting, and
insomnia. An advantageous side effect associated with mirtazap-
ine is weight gain because this agent increases appetite and thus
improves anorexia in cancer patients. Benzodiazepines should
not be used with mirtazapine because of the risk of sedation.68
Diphenhydramine is an over-the-counter antihistamine with
sedating properties. However, the side effects, primarily related
to the anticholinergic action (e.g., dry mouth, decreased cognitive
function, delirium etc.), the rapid development of tolerance, and
the lack of safety data in palliative care patients should discourage
their widespread use, particularly in the palliative care context.74
Melatonin, a naturally existing hormone produced in the pineal
gland, regulates circadian rhythm by regulating the suprachias-
matic nucleus of the hypothalamus through G-protein-coupled
receptors (MT1–MT3). The use of melatonin in the treatment of
sleep disorders is still controversial. Data from several meta-
analyses suggest that melatonin’s effects are limited to delayed
sleep-phase syndrome.69 One of the suggested reasons for melato-
nin’s failure to achieve results against insomnia in clinical trials is
the lack of consistency in the melatonin presentations, which has
led to the development of specific melatonin (MT1–MT2) ago-
nists that have received Food and Drug Administration approval
for the treatment of insomnia. An example is Ramelteon, a selec-
tive melatonin receptor agonist that can potentially be helpful in
patients with sleep onset problems or sleep phase disruption. In
contrast to benzodiazepines and benzodiazepine receptor ago-
nists, it is non-habit forming and does not appear to have the side
effects associated with other hypnotics.73 Ramelteon does, how-
ever, have important drug–drug interactions that should be care-
fully considered, especially in palliative care patients who may
be on a number of different agents. It is metabolized primarily
through the CYP450 1A2 pathway, thus it should not be coad-
ministered with other potent inhibitors of this pathway, such as
ciprofloxacin and fluvoxamine.
Because of the lack of conclusive data for melatonin use in the
cancer population, the routine use of this supplement or its ago-
nists cannot be recommended, 50 even though melatonin appears
to be very safe with few side effects.
Multimodal intervention for treatment of
sleep disturbances in advanced cancer
In patients with advanced cancer, due to the multidimensional
nature of sleep disturbances including sleep quality disturbance,
it is unlikely that sleep disturbance can be effectively treated
using a single intervention. A multimodal approach of combi-
nation of pharmacological and nonpharmacological treatments
simultaneously should be considered on the basis of a predomi-
nant pathophysiologic mechanism for a given patient.
We recently completed a study (five to obtain feasibility data
and effect sizes for various known treatments, including bright
light therapy, melatonin, methylphenidate, their placebos, and
combinations thereof to improve sleep quality, as measured
by change in PSQI scores from baseline to day 15 and day 30
[NCT01628029]). We described these treatment combinations
Textbook of Palliative Medicine and Supportive Care
as multimodal therapy. For the conduct of the study, we only
included cancer patients with sleep quality disturbance (PSQI
≥ 5). Using a double-blind randomized factorial study design,
patients were randomized into one of the eight arms of the study,
which included combinations of interventions or their corre-
sponding placebo treatments for 2 weeks. All patients received
three sessions of standardized psychoeducation intervention
based on the principles of CBT to control for insomnia counsel-
ing. We found that 84% (54 of 64) of randomized patients com-
pleted the study. There were no differences in the demographics
and baseline sleep quality scores between groups, and there were
no significant differences in adverse events by groups (p = 0.80).
The adherence rates for bright light therapy, melatonin, methyl-
phenidate, and CBT were 93, 100, 100, and 100%, respectively.
The effect size for change in PSQI scores for bright light therapy
(N = 29) was 0.46, p = 0.017; for melatonin (N = 26) was 0.24, p =
0.20; and for methylphenidate (N = 26) was 0.06, p = 0.46. Based
on these results, we concluded that the use of multimodal therapy
interventions to treat sleep quality disturbance was feasible. Most
importantly, bright light therapy+ melatonin+ CBT showed the
most promising effect size (0.64) in improvement in sleep quality.
In addition, we found that most of the patients wanted an oppor-
tunity to receive the active treatment, i.e., bright light therapy+
melatonin+ CBT, after the randomized phase. However, further
studies are needed to validate these findings.
Conclusion
SDs have a negative effect on quality of life in the advanced can-
cer patients. Fatigue, impaired daytime functioning, and mood
disturbances are commonly reported in this population and
could be secondary to SDs. Both subjective and objective screen-
ing tools are available for evaluation of SD in the cancer popula-
tion. Interventions that are aimed at improving SDs help alleviate
these symptoms and increase the copying capacity. Management
of these symptoms usually requires a multimodality approach
with the use of nonpharmacological and pharmacological mea-
sures to obtain long-lasting results.
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49
COUNSELING IN PALLIATIVE CARE

Sophie A. McGilvray and David W. Kissane

Contents
What issues present for counseling?..............................................................................................................................................................................477
What diagnoses potentially underpin these concerns?..............................................................................................................................................478
Indications for counseling................................................................................................................................................................................................478
Models of counseling.........................................................................................................................................................................................................479
Psychoeducational interventions..............................................................................................................................................................................479
Supportive psychotherapy..........................................................................................................................................................................................479
Grief therapy.................................................................................................................................................................................................................479
Existential psychotherapy.......................................................................................................................................................................................... 480
Cognitive behavioral therapy.....................................................................................................................................................................................481
Mindfulness-based interventions.............................................................................................................................................................................481
Psychodynamic psychotherapy, including Managing Cancer and Living Meaningfully (CALM) therapy...............................................481
Life narrative, biography, and dignity-conserving therapies...............................................................................................................................481
Meaning-centered psychotherapy........................................................................................................................................................................... 482
Systemic therapies....................................................................................................................................................................................................... 482
Therapist and process issues........................................................................................................................................................................................... 482
Effectiveness of counseling and limitations................................................................................................................................................................. 482
References........................................................................................................................................................................................................................... 483

Psychotherapeutic interventions and support may be offered not
only to the individual palliative care patient, but also to their fam-
ilies and caregivers. Although the incidence of distress found in
studies varies, approximately 15–40% of palliative care patients
will develop significant symptoms of anxiety, demoralization or
depression, with rates rising higher at the end of life.1,2 Similar
rates are found among caregivers.3 Systematic reviews have shown
the benefit of psychological treatments, especially for patients
and families at high risk.4,5 The approach to counseling will vary
according to needs and clinical indications. Services may be deliv-
ered individually, some will be more effective when targeting the
couple, and meeting with the immediate or extended caregiving
family is both helpful and cost-effective. Self-help or profession-
ally led groups are beneficial in promoting support, while focused
family therapy and multifamily groups present other options.
In this chapter, the indications for counseling, varied models of
intervention, issues for therapists, and process challenges in the
delivery of the counseling will be reviewed alongside the evidence
for effectiveness of outcome.
What issues present for counseling?
Patients present often with a concern or worry, sometimes with
a symptom and rarely with a labeled disorder. The concern
may be phrased as a question, buried in a bewildered maze of
thoughts and feelings or projected as a problem onto another
family member. Whatever the presentation—whether emo-
tional, attitudinal, behavioral, or conative—each request for
help challenges the clinician to recognize what is relevant and
organize this meaningfully. Understanding the person with
their gamut of life’s experiences and influences, successes and
failures, accomplishments and omissions, shame and secrets,
and health or illness is at the heart of being able to respond to
the whole person as a unique individual within their culture,
family, and social world.6
Clinicians respond to such complexity with organizational
schemata that structure the phenomena into recognizable pat-
terns and hierarchies. Training, skill, and experience are crucial
here if order is to emerge from potential chaos and be chan-
neled constructively toward improved coping and beneficial
outcome. Nevertheless, health professionals need to suspend
any preconceptions and listen intently, lest the real needs of the
patient are ignored with an inherent inability to heal, even if
the disease is being treated. During the final weeks and days of
life, matters existential, relational, and spiritual come to the fore
and may be more important ultimately than physical symptom
management.7
How do clinicians organize patients’ concerns to aid compre-
hension and plan consequent intervention? While listening to
the narrative of illness, themes are identified and clustered into
groups. Common themes include: (1) loss, (2) emotional response,
(3) meaning, and (4) coping. Loss is myriad in its presentations
during the course of illness, and unless normalized as universal
yet forever challenging, grief may not be well supported. When
loss corresponds with expectations consonant with the life cycle,
acceptance results readily; when illness is out of step with this
natural order, distress, resentment, and profound grief develop
easily. Identifying relevant emotions and any meaning attributed
to illness is pertinent. Concepts of the inevitability of change or
transitions associated with aging prove helpful, while adaptation
as a response invokes some form of coping to optimize outcome
and sustain quality of life.
The biopsychosocial and existential/spiritual model is one
framework for organizing common issues that present for

477
478 Textbook of Palliative Medicine and Supportive Care

TABLE 49.1  Biopsychosocial and Spiritual Orientation to Common Issues that may Arise in Counseling during Palliative Care
Biological
Specific somatic symptoms,
e.g., pain, fatigue,
insomnia
Reduced physical function,
e.g., frailty, impairment,
disability
Altered bodily appearance,
e.g., disfigurement
Treatment processes, e.g.,
radiation, chemotherapy
Psychological
Emotional responses, e.g., sadness, grief,
anger, fear, low morale
Adaptation, e.g., courage, acceptance,
avoidance, rejection
Sense of self, e.g., self-esteem, shame,
stigma, loss of worth
Decision-making, e.g., quality of life and
treatment adherence
Powerlessness, e.g., hopelessness,
trapped, suicidality
Social Spiritual
Instrumental care, e.g., nursing, Meaning of illness, e.g., dying,
pharmacy punishment, spiritual doubt
Occupational and physical therapies, Dignity of person, e.g., respect,
e.g., respite, aides valuing accomplishments
Relational, e.g., marital, family, sexual, Freedom and control, e.g., choice,
intimacy mastery, being a burden
Financial and supportive, e.g., burden, Rituals, e.g., prayer, connection
withdrawal with the sacred

counseling during palliative care. Its value lies in its integra-
tion of the somatic with psychological, social, and spiritual
concerns. Table 49.1 illustrates typical issues without seeking
to be exhaustive in its coverage of potential themes.
What diagnoses potentially
underpin these concerns?
Sometimes therapists offer counseling about specific issues or
focused requests like “what do I say to my children?” In these cir-
cumstances, direct exploration of options and role play will assist
readily. Generally, however, the process of making a clinical diag-
nosis is pivotal to considering all of the therapeutic options avail-
able to ease distress and promote healing. The beauty of diagnosis is
that it should trigger a comprehensive treatment plan, one based on
experience, clinical wisdom, and, indeed, evidence of effectiveness.
In this sense, no counseling should occur in palliative care without
a competent, thorough clinical assessment leading to a thoughtful
management plan. The clinician is thus always the professional.
Moreover, just as each physical symptom should lead to an
assessment, examination, differential diagnosis, and continued
reevaluation of response to treatment, so too should each emo-
tional theme generate its differential and continued exploration.
Thus, is the sadness an expression of grief or depression? Is the
fear grounded in reality or is it excessive because of coping style?
Does a pattern of low self-esteem increase embarrassment or
sense of stigma? Does the loss of meaning constitute demoral-
ization or depression?8 Is concern about being a burden driven
by altruism, independence, or shame at loss of control? Before
considering what the applicable model of intervention is, these
golden rules are vital: always take a careful history; examine the
mental state; understand what has predisposed to, precipitated,
or perpetuated such distress; and formulate why this person is ill
in this manner and at this time.
Table 49.2 overviews the common clinical diagnoses that are
suitable for counseling. In terms of psychiatric nosological sys-
tems, these fall into grief reactions, situational or adjustment
disorders, anxiety and depression, existential concerns, and rela-
tional and V-code categories. Diagnostic and Statistical Manual
of Mental Disorders, fifth edition, with more emphasis on the
dimensional severity on any disorder, has not changed the basic
diagnoses. Other common diagnoses such as delirium, dementia,
psychoses, and a range of other organic states are not suitable for
psychotherapy primarily, pharmacotherapy being the mainstay
of treatment. For a number of conditions including anxiety and
depressive disorders, combinations of psychotropic and psycho-
therapeutic treatment are indicated.
Indications for counseling
Distress, formal psychiatric disorder, concern about coping, and
lack of sufficient social supports are the common indications for
counseling. Sometimes it can be as simple as unmet information
needs, but in general, we try to distinguish those who can be sup-
ported by all members of the multidisciplinary care team from
those who warrant referral for specialist counseling. The latter
involves particularly clinicians trained in social work, psychol-
ogy, or psychiatry.
Risk factors for poorer coping include:
1. Factors in the person: Past history of depression or psychi-
atric disorder, cumulative life events, and high levels of
perceived stress or poor coping.
2. Factors in the illness: Onset at a young age; delay in diag-
nosis; recent diagnosis with rapid disease progression;
long, intensive treatments or complications of treat-
ment; specific cancers—pancreatic, neuroendocrine,
lymphomas.

TABLE 49.2  Common Psychiatric Diagnoses that Lead to Counseling Therapies

Category Examples
Adjustment disorder Coping with intense grief, social withdrawal
Anxiety disorder Panic attacks, nightmares, insomnia
Depressive disorder Anhedonia, unhappiness, lost interest
Demoralization disorder Loss of meaning, loss of hope, suicidality
Relational disorder Marital and family dysfunction, personality disorders, sexual dysfunction
Existential disorder Spiritual despair, concern about being a burden, need to be in control, profound aloneness
Organic psychiatric disorder Delirium, medication side effects, alcohol and substance abuse, or withdrawal
Counseling in Palliative Care
3. Factors in the environment: Poor social supports, family
dysfunction, socioeconomic deprivation, potential to leave
young children behind.
Whenever one or more of these factors are present, consider-
ation of the benefits of supportive counseling proves worthwhile.9
Once an established psychiatric disorder exists, referral should
be axiomatic.
Because of the large research literature showing that psychiat-
ric disorders are often missed,10 usually through normalization of
grief, many institutions utilize a model of screening for distress11
to assist recognition of those in greater need of psychosocial
care. A randomized controlled trial of computer-assisted screen-
ing and referral for intervention has demonstrated an ability to
reduce depressive disorders in oncology patients.12 Many services
today use a triage mechanism to refer patients with milder levels
of distress to social workers and those with more severe distress
to psychologists or psychiatrists.
Models of counseling
A number of schools of psychotherapy exist, many developed
originally for specific clinical circumstances, but generally these
are applied eclectically by counselors so that aspects of these dif-
ferent models are combined to suit the clinical predicament of
the patient or family. Table 49.3 summarizes the common models
of psychotherapy. The following case example will illustrate how
each psychotherapeutic model can be used.
David and Alison had been married for 22 years and had
three teenage children. Shortly after the eldest started
university, Alison, who was aged 45, was diagnosed with
metastatic ovarian cancer involving the peritoneum, with
extensive intra-abdominal lymphadenopathy. Alison was
working as a registered mental health nurse, while raising
three children with David. These were her two great pas-
sions in life, family and service to the community. However,
as the cancer progressed, Alison was increasingly fatigued
and unable to engage in family life with the same energy and
vigor of earlier years. She had significant abdominal pain
and a recurrent bowel obstruction, which resulted in recur-
ring hospitalization. Alison began to feel burdensome to
her family, who would drop everything to be at her bedside.
She felt guilt for taking her children away from their stud-
ies, and her husband from his work as an engineer, which
TABLE 49.3  Models of Psychotherapy
Targets of Therapy Categories of Therapy
Individual Psychoeducational
Supportive expressive
Grief therapy
Mindfulness therapy
Couple Existential psychotherapy
Cognitive behavioral therapy
Group Interpersonal psychotherapy
Psychodynamic therapies
Family Narrative and dignity therapies
Meaning-centered therapies
CALM therapy
Community Systemic therapies
479
was essential income since she had stopped working. Alison
was afraid that her children would remember her as a frail
sick woman, and not as the vibrant, capable mother that she
had always been. She was concerned that her care placed too
great a demand on her family.
Psychoeducational interventions
Whether delivered individually to groups, or to families, the provi-
sion of information about the illness and its treatment is founda-
tional and a counseling component of all clinical encounters. In
their meta-analysis of 116 studies, Devine and Westlake13 proved
that psychoeducational models have a large effect size, which
should not be surprising, as the outcome measure in such studies
is simply the acquisition of new knowledge. Studies of unmet needs
have nevertheless identified information provision as a major con-
cern of patients. The efficacy of psychoeducation improves when
delivered by individuals with medical or nursing expertise.14
In Alison’s case, nursing education covered pain and other
symptom management, the nature of her cancer and its
treatment, the anticipated process of dying, and how David
could optimize his role and coordinate care with other
members of Alison’s family.
Supportive psychotherapy
Supporting a patient and family through cancer is best done by
listening to the story of illness and its treatment, providing emo-
tional support, exploring the meaning of the diagnosis and prog-
nosis, conveying understanding, and building trust. The counselor
employs a range of therapeutic techniques including questions that
seek clarification and invite sharing of emotions; comments that
affirm, reassure, encourage, or explain; and suggestions that guide,
promote acceptance, and optimize support. This approach is the
most generic form of counseling and its techniques are found in
all other models of psychotherapy. Although cited in group work,
the following goals are also pursued in individual supportive ther-
apy: building bonds, expressing emotions about the illness and its
impact on relationships, detoxifying death and dying, redefining
life priorities, mobilizing supports, and improving coping and
communication.15–17 Evidence for its effectiveness in advanced
cancer is strongest for supportive-expressive group therapy (SEGT)
where randomized controlled trials have demonstrated its ability
to reduce emotional distress, anxiety, and depression.18
The unfairness of Alison’s illness occurring out of step with
her expected life cycle was acknowledged, her grief at the
many losses normalized, her courage praised and the fam-
ily’s commitment to each other affirmed. Helping Alison
and David to share their feelings and consider how best
to support one another led to recognition of their greater
closeness that this tragedy had brought. Accompaniment
and commitment were key principles in sustaining conti-
nuity of care for them.
Grief therapy
Loss is found universally in the illness experience and with it
comes grief. Thus, the model of counseling developed for the
bereaved serves well also as a response to the cumulative experi-
ence of loss during any journey with advanced disease. The tasks
involved include promoting the sharing of emotion, normalizing
the sadness, educating about the pattern of distress (waves of
480 Textbook of Palliative Medicine and Supportive Care

emotionality) and time course of mourning, interpreting any dis-
placement of anger, and encouraging adaptive coping responses.
Care needs to be taken to avoid premature grief, as time spent
grieving distracts from a focus on the living. Such counseling
techniques should be applied by all clinicians working in pallia-
tive medicine.
Counseling the bereaved also becomes an important dimen-
sion of comprehensive palliative care, those at high risk being
identified through recognition of (1) personal vulnerability,
such as past history of psychiatric disorder; (2) relational prob-
lems like dependence or ambivalence; (3) a death experienced
as in some way shocking, unexpected, or traumatic; and (4) the
presence of family dysfunction or perception of being unsup-
ported or disenfranchised. Group work is especially helpful for
the isolated.
Existential psychotherapy
Based on the challenges that arise from the very givens of our
humanity, existential psychotherapy addresses concepts of self-
awareness, freedom and autonomous choice, fundamental alone-
ness and our human need for relatedness, the meaning of life, and
the inevitable reality of death.19 Existential distress is a dominant
experience for patients diagnosed with cancer as it forces indi-
viduals to confront their mortality.20
The common sources of existential distress are summarized in
Table 49.4 with suitable models of counseling for specific chal-
lenges. The counselor helps to define the particular existential
challenge that each patient perceives and invites consideration
of realistic ways of responding. Built upon processes of con-
frontation, reaction formation, and inviting choice about those
aspects of life that should be most valued, and informed by the

TABLE 49.4  Adaptive and Maladaptive Responses to Existential Challenges and Relevant Counseling
Form of
Nature of Existential
Existential Features of Successful Distress Common Symptoms Related Psychiatric Suitable Model of
Challenge Adaptation Problematic Experienced Disorders Therapy
1. Death Courageous awareness Death anxiety Fear of the process of dying or Anxiety disorders, panic Psychoeducational,
of and acceptance of the state of being dead; panic at disorder, agoraphobia, cognitive behavioral
death; saying goodbye somatic symptoms; distress at generalized anxiety therapy, existential
uncertainty disorder, acute stress psychotherapy,
disorder, adjustment psychodynamic
disorder with anxious mood therapy
2. Loss Sad at reality of loss Complicated Intense tearfulness, grief, and Depressive disorders Supportive
yet resigned to the grief waves of emotionality, distress psychotherapy, grief
occurrence of illness therapy, interpersonal
psychotherapy
3. Aloneness Accompanied and Profound Isolated, alienated, and sense of Dysfunctional family, Interpersonal
supported by family loneliness complete aloneness in life absence of social support, psychotherapy,
and friends relationship problems family-focused
therapy, supportive
group therapy
4. Freedom Acceptance of frailty Loss of control Angst at loss of control; Phobic disorders, obsessive Supportive
and reduced obsessional mastery; indecisive, compulsive disorders, psychotherapy,
independence nonadherent to treatments; substance abuse disorders interpersonal
fear of dependency psychotherapy,
psychodynamic therapy
5. Meaning Sense of fulfillment Demoralization Pointlessness, hopelessness, Demoralization syndrome, Interpersonal
futility, loss of role, desire to die adjustment or depressive psychotherapy,
disorders with narrative and
demoralization dignity-conserving
therapies, meaning-
centered therapies,
existential therapy
6. Dignity Sense of worth despite Worthlessness Shame, horror, body image Adjustment disorders Narrative and
disfigurement or concerns, fear of being a dignity-conserving
handicap burden therapies, supportive
psychotherapy, grief
therapy
7. Mystery Reverence for the Spiritual doubt Guilt, loss of faith, loss of Adjustment, anxiety and Meaning-centered
unknowable and and despair connection with the depressive disorders therapy, life narrative
sacred transcendent therapies, spiritual
ritual
Counseling in Palliative Care
narrative story of their life, patients are helped to live authen-
tic and purposeful lives with a particular focus on living in the
present moment.21,22 Recent end-of-life models of therapy (dig-
nity- and meaning-centered) have developed from existential
psychotherapy.
In Alison’s case, questions were asked about the mean-
ing of her relationship with David and her children. They
explored the values they held in their life together as part-
ners and parents. They focused on realistic priorities and
family goals. David expressed the significant meaning he
derived in being able to care for Alison after years where
she had “taken care of” him. Open acknowledgment of
the potential for death helped identify the preciousness of
each moment. Grief was checked to the extent that it risked
spoiling continued living. The random nature of Alison’s
illness, which they had once felt to be so unfair, was con-
trasted with their spiritual wonder about life’s mysteries.
Cognitive behavioral therapy
Cognitive behavioral therapy (CBT) involves teaching the patient
to make connections between emotional events or triggers, asso-
ciated automatic thoughts or beliefs, and resultant feelings or
behaviors. This model has been developed specifically for the
cancer setting where thoughts are evaluated for how helpful or
realistic they are.23 Cognitive reframing and disputing of nega-
tive automatic thoughts is used, taking a metacognitive stance
when thoughts are not helpful.24 Existential themes are explored
in parallel, examining guilt about prior lifestyle choices; checking
feelings of burden, hopelessness, or helplessness; and counter-
ing perceptions of loss of control, anxiety about disfigurement,
perceived rejection by friends, and fear of the dying process.
Attention can be given to effective communication, problem-
solving, and activity scheduling to optimize living.25
Mind reading and negative predictions were identified as
some of the cognitive distortions being used and alterna-
tive explanations were suggested to Alison. As well, she
was urged to clarify this with David, who was distressed
to learn that she was feeling this way. David explained that
being present for Alison and attentive to her needs was a
privilege that enabled him to feel purposeful in a situation
where he otherwise felt powerless. He reiterated to her that
he was committed to their life together in sickness and in
health, and that the grace he witnessed in her acceptance
of each day, made him love and respect her more than ever.
Mindfulness-based interventions
Additional interventions teach mindfulness and build on older
processes of relaxation training through progressive muscu-
lar relaxation, guided imagery, hypnosis, and meditation.26
Mindfulness has not only been developed to reduce stress, but
also combined with cognitively oriented techniques to foster
inner calm and sense of well-being.27 Massage therapy is also
popular in community-based palliative care.
Psychodynamic psychotherapy, including Managing
Cancer and Living Meaningfully (CALM) therapy
Patterns of prior coping and relationship difficulties may be
revealed in the threat of loss, and recognition of such patterns in
earlier life may increase understanding and aid resolution of con-
flicts.28 Making sense of transference and countertransference
481
reactions are useful processes to optimally support the dying
patient with cancer. Projected feelings of helplessness may develop
in therapists treating patients facing the terminal phase of illness.
Understanding this as a countertransference response increases
the therapist’s insight into what the patient is experiencing,
guiding what the focus of therapeutic work might therefore be.
Defenses such as denial and regression may, in fact, be adaptive
and promote functioning, while death awareness can also coexist
with a strong will to live in the patients with advanced cancer.
Such defenses may serve to alleviate distress such as fear or help-
lessness, assuming they do not result in disruption of appropriate
medical treatment or fulfillment of goals, including the organiza-
tion of one’s final affairs.
Derived from relational theory, attachment theory, and exis-
tential therapy, a brief 3- to 6-session individual psychotherapy,
managing Cancer And Living Meaningfully (CALM), has been
found to provide substantial benefit for patients with advanced
cancer prior to end of life.29 Therapeutic elements of CALM
include the supportive relationship, authenticity, modulation of
affect, encouragement of reflective functioning, renegotiation of
attachment security, joint creation of meaning, shifting frame
and flexibility, and facing the limits and boundaries related to
mortality, interpretation, and ultimately, termination. 30
In reminiscing about her childhood, Alison recalled how
her mother was frequently unwell with rheumatoid arthri-
tis, which resulted in significant pain flares and retreat. Her
father, who worked in shipping, was a heavy drinker and
went missing whenever Alison’s mother was unwell. As a
result, Alison had to take care of her siblings and her mother.
She felt abandoned by both parents and observed her father
abandoning her mother in illness. Alison was afraid of being
unwell lest this drive David away. When Alison asked her
therapist if the sessions were too upsetting, comparison was
drawn between her fears of being a burden to the therapist
and to David, akin to how she feared her absent parents in
her childhood. It dawned on Alison that her fear of David
retreating from her care was based on her old pattern of
relating and not something coming from David.
Life narrative, biography, and
dignity-conserving therapies
The narrative account of the person’s life aims to generate an
understanding of the patient’s reaction to illness from the per-
spective of their overall philosophy and approach to life. The ther-
apist uses the coherent developmental story to promote a sense of
accomplishment, fostering celebration and sense of fulfillment,
while highlighting key roles, relationships, and any apparent
meaning in the patients’ life. A shared consensus is sought about
all that has been accomplished.
Chochinov developed a model of dignity-conserving care for
patients approaching death. Efforts to improve their self-worth
and promote respect are at its core. A key goal is to promote hope,
autonomy, and sense of control, while also addressing the spiri-
tual concerns. Dignity therapy invites the patient to give a narra-
tive account on tape of important aspects of their life that they
would most want remembered. This biography is transcribed,
edited, and given to the patient, as well as being a legacy for their
family. Key questions include: how they want their families to
remember them?; vital roles they have played within their fam-
ily, job, and community; accomplishments they are most proud
of; hopes and dreams for relatives and friends; words of advice to
482
pass along to others; things they want to say to family that have
not been said before or that they want to say again; and words that
might provide comfort to their family and friends. Although dig-
nity therapy was not found to be better than client-centered care
or standard palliative care in reducing overall distress, patients
reported that it was helpful.31 Community volunteers have taken
up this model as biographers, leaving the narrative as a legacy
that families deeply appreciate.
Meaning-centered psychotherapy
Individual and group meaning-centered psychotherapies (IMCT
and MCGT) have been developed that promote a sense of mean-
ing and purpose, 32,33 adopting many principles from Viktor
Frankl’s “logotherapy.” Patients are active members in their own
treatment, sharing experiences that have helped promote a sense
of meaning, peace, and purpose. Exercises are assigned as home-
work and reviewed at subsequent meetings. Sense of personal
responsibility, attitudes, creative and experiential values, and the
meaning they bring to life are explored.
Alison identified the immense fulfillment and joy that
David had brought into her life as a partner and co-parent,
which she ascribed as her greatest achievement in life.
She was grateful for the life they had built together, which
had given her a sense of purpose and meaning. Alison
expressed her sadness that she would not grow old with
David, but told him that she hoped he would find some-
one after her death that he could build the next stage of his
life with. David told Alison that he would continue to talk
about her with the children, continue parenting them as
they had done, and that he would tell future grandchildren
about her so that her legacy lived on.
Systemic therapies
Whether focused on the marital, parental, or sibling systems,
the family of origin, or current nuclear family, the mutual and
reciprocal influence of one party upon another can be an impor-
tant consideration therapeutically. Furthermore, insight into
recurring patterns across generations helps families to vary
these “scripts” and choose a new direction in their relationships.
Family-focused grief therapy (FFGT) is one preventive model
that targets at-risk families during palliative care and continues
with the bereaved post death, aiming to optimize family func-
tioning so that complicated grief and prolonged grief disorder are
prevented. 34 Communication is enhanced in families who have
struggled to talk about an approaching death. FFGT has much
to offer families at risk in palliative care, its brief and focused
approach delivering cost-effectiveness alongside continuity of
care into bereavement.
Similarly, when couples struggle to communicate and support
one another, couple sessions can do much to open up communi-
cation and foster compassion and intimacy. 35
Alison and David were brought together with their siblings
and their parents, the broader family rallying to support
the couple and their children. Open communication about
the cancer and its treatment ensured their grief was shared,
hope fostered, and respite organized to protect David from
exhaustion. As teamwork grew, each family’s sense of cel-
ebration of Alison’s life became apparent, and support was
sustained for David and their children throughout the sub-
sequent period of bereavement.
Textbook of Palliative Medicine and Supportive Care
Therapist and process issues
On the one hand, all members of the multidisciplinary team make
a contribution to psychosocial support. But when it comes to
developing skill and expertise in the specific models of counsel-
ing described in this chapter, formal training is needed. Research
confirms that patients respond better to brief interventions pro-
vided by well-trained and skilled therapists.
The core elements of counseling comprise the relationship
that is established, the explanatory model of intervention used,
the procedure for promoting change, and the healing that in turn
induces further benefit. A number of therapeutic factors are com-
mon to all models of intervention. Developing a strong working
relationship, often termed a therapeutic alliance, with the patient
and their caregivers is foundational. Other key factors include
engaging in active listening, allowing patients to ventilate their
feelings about their experience, validating their concerns, provid-
ing support, and building trust and respect. Exploration of prior
losses, especially deaths in the family, and how members coped
with their related grief is illuminating.
For much of this counseling in palliative care, a delicate bal-
ance is needed between promoting hope and supporting grief,
these two themes often evolving in parallel. The counselor pro-
vides a secure relationship, whose structure creates an experience
in which “holding” and “containment” of distress are achieved.
The therapist’s warmth, empathy, and unconditional regard help
create this holding frame. Nevertheless, an emphasis still exists
on appropriate restriction of therapist self-disclosure, here and
now feelings being sensitively shared, while greater caution is
exercised over one’s personal life. Disclosure of a gay orientation
may be helpful to homosexual patients, but disclosure of personal
cancer or illness experiences is generally unwise, the focus of the
therapy being truly directed toward the patient.
In the setting of medical illness, most counseling needs to
be brief and focused for pragmatic reasons. Clinical judgments
determine what is worthy of constructive focus and what should
be wisely left as a long-term or irremediable pattern of behavior.
Personality disorders would not be addressed at the individual
therapy level, and entrenched family conflict might be respected
as ultimately a difference of opinion best resolved by accepting
distance between relatives. Selection of a model of therapy is
usually eclectic and based on clinical experience, combining ele-
ments from several models in response to the prevailing symp-
toms or predicaments that the patient presents.
Flexibility in number, frequency, and duration of sessions,
location of appointments, and modality of treatment used are
necessary parts of working with the palliative care population.
Telephone support may substitute for direct patient care. Physical
symptoms, side effects of treatments, and stage of illness all sig-
nificantly impact on delivery of services and a change in medical
status may necessitate a shift in therapeutic focus. An open flexible
approach is best maintained throughout the course of treatment.
The potential for psychopharmacological treatment is always con-
sidered alongside any counseling and its need monitored.
Effectiveness of counseling and limitations
Several meta-analyses have examined the effectiveness of psycho-
logical interventions for the treatment of anxiety and depression
in patients with cancer.4,5 The overall evidence for benefit is mod-
est. 36 Research limitations were felt to include challenges related
to issues of recruitment and attrition, data analyses, follow-up
Counseling in Palliative Care
KEY LEARNING POINTS
• High rates of distress exist among patients, care-
givers, and family members during palliative care.
• Counseling interventions have proven efficacy
in relieving distress, anxiety, depression and in
enhancing coping.
• The training and experience of the thera-
pist strongly influences the effectiveness of
interventions.
• Outcome is progressively improved by longer
interventions.
• Group interventions are at least as efficacious
as individual therapies; family group counseling
may be more cost-effective when applicable.
• While psychoeducational, supportive, and grief
therapies are the mainstay of psychotherapeutic
approaches, interpersonal, narrative, and mean-
ing-centered models also offer promise in ame-
liorating existential distress.
assessments, confounding factors, and operationalization of
outcomes.
Group therapy is at least as effective as individual counseling,
while length of treatment and experience of therapist are perti-
nent influences on outcome. These findings challenge palliative
care services to hire appropriately skilled counselors.
Finally, a caveat is needed about the risks of counseling. Just
as pharmacotherapy can induce side effects, sometimes with del-
eterious consequences, similarly counseling can also cause harm.
Research suggests that about 10% of counseling interventions gen-
erate untoward effects, such as worsening anxiety, depression, or
marital and family conflict. This limitation calls for skill and expe-
rience derived from formal training in the models of intervention
and in one of the basic psychosocial disciplines, so that therapists
can identify any deterioration and introduce corrective strategies.
When counseling is delivered by trained and experienced profes-
sionals, it has much to offer in ameliorating distress and suffering.
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Oncol 2016;34:1921–1927.
35. Zaider TI, Kissane DW. Couples therapy in advanced cancer: Using
intimacy and meaning to reduce existential distress. In: Watson
M, Kissane DW, eds. Handbook of Psychotherapy in Cancer Care.
Chichester, U.K.: Wiley-Blackwell, 2011, pp. 161–173.
36. Okuyama T, Akechi T, Mackenzie L, Furukawa TA. Psychotherapy for
depression among advanced, incurable cancer patients: a systematic
review and meta-analysis. Cancer Treat Rev 2017;56:16–27.
50
HOPE IN END-OF-LIFE CARE

Cheryl L. Nekolaichuk

The biggest pain to go through in the end…

is the gradual drop-away of visitors.
Hope my friends keep their promises.
Promises about sitting with me
and being with me when that time comes.
A palliative care patient (May 29, 2012)

Contents
Introduction....................................................................................................................................................................................................................... 485
Therapeutic value of hope in illness.............................................................................................................................................................................. 485
Nature of hope in palliative care.................................................................................................................................................................................... 486
Universality................................................................................................................................................................................................................... 486
Dimensionality............................................................................................................................................................................................................. 486
Intangibility.................................................................................................................................................................................................................. 486
Temporality.................................................................................................................................................................................................................. 486
Predictability................................................................................................................................................................................................................ 487
Value based................................................................................................................................................................................................................... 487
Reality based................................................................................................................................................................................................................. 487
Assessment of hope.......................................................................................................................................................................................................... 487
Hope-enhancing strategies and interventions............................................................................................................................................................ 488
Summary............................................................................................................................................................................................................................. 489
References........................................................................................................................................................................................................................... 489

Introduction and spiritual—with hope as a central existential phenomenon

The progressive, unpredictable nature of a terminal illness—
marked by debilitating symptoms, body image distortions, and
multiple losses—propels patients and their families onto a path-
way of uncertainty, fear, and, for some, despair. Traditional roles
may be reversed or erased, as patients feel marginalized from
society. External messages of “There is no cure” become internal
messages of “There is no hope,” as they wrestle with their own
mortality. In a study involving advanced cancer patients, 48% of
participants reported at least some sense of hopelessness.1
Despite these substantive challenges, patients at the end of life
strive to maintain hope within their caring circles. In interviews
with 120 terminally ill cancer patients, 99% of respondents rated
having a sense of hope as a very important existential concern.2
Based on a review of research studies, Lin and Bauer-Wu3 identi-
fied living with meaning and hope as one of six essential themes of
psychosocial spiritual well-being in patients with advanced can-
cer. In a qualitative study focusing on information needs, patients
with advanced cancer identified the provision of hope and need
for hopeful messages as one of the two most important concerns
regarding information content.4
Health-care professionals equally emphasize the importance
of hope in the delivery of palliative care. Numerous position
papers and literature reviews highlight the need for intentionally
incorporating hope within end-of-life care.5–11 Janssens et al.12 have
further embedded the concept within a philosophy of care for pal-
liative care, consisting of three realms—medical, psychosocial,
within the spiritual realm.
Despite these overwhelming endorsements, the systematic
integration of hope within routine clinical practice remains
relatively underdeveloped. Beginning with an overview of the
therapeutic value of hope, this chapter will address the follow-
ing questions for intentionally integrating hope within end-of-
life care:
• What is the nature of hope in palliative care?
• How can we enhance our approaches for assessing hope in
people who are terminally ill?
• What types of hope-enhancing strategies and interventions
would be most appropriate for this unique population?
Therapeutic value of hope in illness
The therapeutic value of hope in chronic and life-threatening ill-
nesses is well documented. Hope has been positively linked to
effective coping,13–15 enhanced quality of life,16–18 spiritual well-
being,19 and healing;20–22 inversely associated with depression23
and weakly associated with symptom burden.23 In contrast,
hopelessness may be associated with low levels of perceived emo-
tional support,24,25 depression,25,26 suicidal intent,27 desire for has-
tened death,28 and pain.28,29 Studies in terminally ill patients have
revealed that hopelessness is a strong predictor of poorer health-
related quality of life, 30 desire for hastened death, 31,32 will to live, 33
and suicidal intent. 34

485
486
Although these findings are significant, some caution is war-
ranted in making cross-study comparisons. Study samples were
quite diverse and were not entirely limited to the terminal illness
phase, including patients with human immunodeficiency virus
(HIV)/acquired immune deficiency syndrome (AIDS)19,24,25 and
cancer,13,16,31,32,34 depressed patients,21,22,26,27 patients with long-
term disabilites,14,20 and older patients.17 The use of different mea-
sures to assess hope or hopelessness across studies further limits
meaningful comparisons. Future research studies, focusing on
relationships between hope, symptom expression, and positive
health indicators, such as quality of life, well-being, and cop-
ing, need to specifically target the terminally ill, using consistent
measurement approaches appropriate for this population.
Nature of hope in palliative care
What does hope mean to you as a health-care provider?
What does hope mean to the patients for whom you provide care?
In health care, the concept of hope has been closely linked
with treatments and cures. 35–37 When hope for a cure is no longer
viable, health-care professionals and patients may give up hope.
Although the situation may be hopeless, there is always hope for
the individual. 38 A key challenge is to understand the nature of
hope in palliative care.
A diversity of conceptual frameworks exist in the literature,
with no consensus for a universal definition of hope. A critique of
the hope literature revealed seven themes associated with these
differing perspectives39 (see Figure 50.1), accompanied by the fol-
lowing assumptions:
• Universality: Hope is both a universal and an intensely per-
sonal experience.
• Dimensionality: Hope is a complex concept, ranging from
unidimensional to multidimensional aspects of a person’s
experience.
• Intangibility: Hope has both tangible and intangible com-
ponents, some of which may never be elucidated.
• Temporality: Hope appears to imply some sense of tem-
porality, although this may not necessarily be limited to a
future orientation. It is also possible that some components
of hope may not be bound by time.
FIGURE 50.1  Thematic analysis of the concept of hope.
Textbook of Palliative Medicine and Supportive Care
• Predictability: The experience of hope may have both pre-
dictable and unpredictable components.
• Value based: The value of hope appears to be embedded in
personal experience.
• Reality based: Hope appears to be connected with some
sense of realism, although the viewpoints of reality remain
unclear.
These seven themes provide a cohesive framework for under-
standing the nature of hope in palliative care. Subsequent text
provides a brief description of each of these themes, with cor-
responding reflective questions for interacting with patients in
clinical practice.
Universality
Although hope is a universal human experience, it is also intensely
unique. A number of qualitative studies, focusing on the termi-
nally ill patient’s experience of hope, have been conducted in
diverse settings, such as palliative home care,40–45 inpatients,45–50
outpatient clinics, 37,40,46,50–53 and nonmedical settings. 38,54–56
Samples varied, including patients with cancer,40–42,45,46,48,50 HIV/
AIDS, 38,54–56 amyotrophic lateral sclerosis (ALS), 57 end-stage
renal disease, 51 chronic obstructive lung disease,45 and heart fail-
ure.45 In contrast, one study involved interviewing nurses about
their perceptions of hope in palliative care patients with cancer.52
Another study integrated the triadic perspectives of patients,
their “loved ones,” and physicians in a tertiary specialized cancer
center.58 This theme gives rise to the following reflective question
for use in the clinical setting: What is this person’s unique experi-
ence or personal story of hope?
Dimensionality
A diversity of conceptual frameworks for hope has emerged,
ranging from unidimensional to multidimensional models. Of
the many diverse frameworks, Dufault and Martocchio’s model, 59
qualitatively derived from a sample of older cancer and terminally
ill patients, provides a useful initial framework for understanding
hope in the terminally ill patients. Dufault and Martocchio pro-
posed a multidimensional framework for hope, consisting of six
dimensions: cognitive, affective, behavioral, affiliative, contex-
tual, and temporal. Each of these dimensions may be impacted in
different ways when a person is facing a terminal illness, resulting
in the question, How has the challenge of facing a life-threatening
illness impacted each of these dimensions for this person?
Intangibility
The experience of hope may have both tangible and intangible
components. Dufault and Martocchio59 described these two types
of hope as particularized and generalized hopes. Particularized
hopes are hopes that are directed toward specific goals. For ter-
minally ill patients, specific hopes may change over time,60,61 for
example, shifting from hope for a cure to hope for symptom relief,
a special time with family, or a peaceful death. In contrast, gen-
eralized hopes represent an intangible inner experience of hope
that is not connected to any specific goal. This invisible part of
hope may be difficult to articulate and is often experienced at a
deep, spiritual level, leading to two questions for reflection: What
specific hopes does this person have? What is this person’s general
orientation to hope?
Temporality
Although most definitions for hope include a future orienta-
tion, this may not always be appropriate for the terminally ill.5
Hope In End-of-life Care
For some people, with strong faith beliefs, hope may be tied to a
future beyond this life. For others, the experience of hope may
be interwoven with past, present, and future experiences5,59,62,63;
may be lived in the present16; or may transcend time. 59,64 It might
be helpful to deemphasize the future component of hope, while
reflecting on the question, How has this person’s hope(s) changed
over time?
Predictability
The uncertainty of advancing disease raises fears in most patients
who are terminally ill. Although frameworks do differ, some
models have included uncertainty as an inherent part of the hope
experience.52,65 Exploring personal fears, as well as focusing on
predictable aspects of an individual’s life, helps buffer the uncer-
tainties of progressive illness: What is in this person’s control?
What is not in this person’s control?
Value based
Few could argue with the potential therapeutic benefits that hope
offers to the dying. Not everyone, however, may value hope posi-
tively, particularly if they have been previously disappointed by
hope. For example, patients who direct all their hopes toward
finding a cure are often devastated when they are told that their
condition is incurable. The challenge is to be able to help patients
develop a broad hoping repertoire, including hopes beyond a cure,5
using the following reflective questions as a guide: To what extent
does this person value hope? Is this a positive or negative experience?
How, if at all, can this person develop a broader hoping repertoire?
Reality based
Often, people may concurrently hold two opposing hopes, such
as hope for a cure and hope for a peaceful death. 39,66 This may
be troubling for some professional caregivers and family mem-
bers, who might view this as unrealistic or unhealthy denial. In
contrast, Jevne and Nekolaichuk67 describe this phenomenon as a
normal way for patients to prioritize their hopes:
It is important to listen to the descriptive words that they
[patients] attach to their hopes, acknowledging the range
(and depth) of their hopes. One elderly patient who was
forced to stop traveling due to a progression of his disease
described his hope to travel as a “forlorn” hope. Another pal-
liative patient who expressed a hope for peace in the world
described that particular hope as a “big” hope. Yet another
patient who hung onto a hope for a cure, despite being told
that her cancer was incurable, suggested that it “may not be
TABLE 50.1  A Hope Assessment Framework for Terminally Ill Patients
Theme Questions for the Health-Care Professional
Personal spirit What is meaningful in this person’s life?
What is this person’s relationship with time?
How might past, present, and future experiences
influence this person’s experience of hope?
Risk What is this person’s tolerance for uncertainty?
How can I enhance this person’s hope, beyond a hope for
a cure?
Authentic caring Who authentically cares about this person?
How can I provide truthful information to this person,
yet still remain hopeful?
Source: Adapted from Nekolaichuk CL, Bruera E. J Palliat Care 1998;14:36.
487
a very realistic” hope, but that “miracles do happen.” For a
patient who believed in life after death, her hope to be united
with God was her “ultimate” hope. (p. 195)
Professional caregivers need to normalize these apparently polar-
izing views, balancing the provision of honest truthful information
with the maintenance of hope.66,68,69 In an interpretive synthesis
of 31 articles focusing on health-care professionals’ views on hope
of palliative care patients, Olsman et al.69 revealed three distinct
perspectives: (a) hope as an expectation of being truthful (realis-
tic), (b) hope as a coping mechanism (functional), and (c) hope as
meaningful (narrative). The integration of all three perspectives
can help health-care professionals work with polarizing viewpoints
and improve their communication with patients, guided by the fol-
lowing question: How can health-care professionals provide honest
truthful information while still maintaining a person’s hope?
Assessment of hope
How can you tell how hopeful a person is?
What do you need to know to understand a person’s experience
of hope?
Although a variety of hope assessment approaches have been
developed in clinical practice,66 few have been developed specifi-
cally for palliative care.5,10,70 Given the frailty of this population,
assessments need to be relatively brief, psychometrically sound in
terms of quantitative measures, and closely linked with the devel-
opment of hope-enhancing strategies and interventions. In some
cases, the assessment itself may be a therapeutic intervention. The
Herth Hope Index71 is a well-validated measure that has been used
extensively in the palliative care population. Although psychomet-
ric findings are generally favorable across different cultures, in one
validation study involving Swedish palliative patients, the authors
cautioned against its use in Swedish clinical palliative settings, due
to linguistic, conceptual, and cultural translation difficulties.72
Given the complexity of the hope experience, quantita-
tive measures need to be combined with qualitative assess-
ments. Olsman and colleagues73 developed a qualitative Hope
Communication Tool (HCT), focusing on four concepts: hope,
further exploration of hope, hopelessness/despair, and support,
which they pilot tested with 14 health-care professionals. They
concluded that the HCT is feasible for use in clinical practice, but
requires further evaluation. Another example of a qualitative hope
assessment framework for palliative care appears in Table 50.1.5
Questions for the Patient
What gives you meaning in your life?
How has your hope changed over time?
Tell me about a time in your past that has influenced your hope
in some way
How have you handled times of uncertainty in the past? What
are you most afraid of?
Without taking away your hope for a cure, what else might
keep you going in the event that a cure is not possible?
Who in your world cares about you?
Whom do you care about?
488 Textbook of Palliative Medicine and Supportive Care

This framework is based on an empirically derived model of hope,
consisting of three dimensions: personal spirit, risk, and authen-
tic caring.74 Personal spirit is a predominant personal dimen-
sion, represented by a core theme of meaning. Risk, a situational
dimension, is primarily represented by an underlying theme of
uncertainty. Authentic caring, a relational dimension, is charac-
terized by the complementary themes of credibility and caring.
Thus, a person’s experience of hope may be associated with find-
ing meaning in life, taking risks in spite of uncertainty, and devel-
oping caring, credible relationships.
Hope-enhancing strategies and interventions
How do you enhance hope for someone who appears to have
given up?
How do you serve as a model of hope for your patients?
There are many descriptions of hope-enhancing strategies and
interventions for the terminally ill patients, based on literature
reviews,75 research studies,8,60,76–80 theoretical perspectives,81 and
clinical experience.82–84 In a systematic review of nursing litera-
ture, Holt85 identified 14 hope intervention themes, the 6 most
common being positive relationships, patient self-worth, patient
control, goal setting, use of distraction, and family support.
Despite the interest in this area, there are very few hope-focused
intervention studies, specifically targeted for the terminally ill
population. Duggleby and colleagues have developed a Living
with Hope Program (LWHP), which they evaluated in senior pal-
liative home care patients.86 Using a mixed-method concurrent
nested experimental design, patients in the LWHP arm had sig-
nificantly higher hope (p = 0.005) and quality of life (p = 0.027)
than those in the standard care comparison group. In a subse-
quent qualitative study with 13 patients with advanced cancer–
caregiver dyads, Duggleby et al.87 identified four psychosocial
processes by which the LWHP fosters positive hope outcomes:
(a) reminiscing, (b) leaving a legacy, (c) positive appraisal, and (d)
motivational processes. They have also pilot tested a parallel pro-
gram for caregivers of family members with advanced cancer.88
Using a quasi-experimental design, Herth89 demonstrated the
effectiveness of an eight-session hope-enhancing nursing inter-
vention program in a convenience sample of patients with first
recurrence of cancer. Patients in the treatment arm had signifi-
cantly higher levels of hope and quality of life immediately after
and at 3-, 6-, and 9-month post treatment than the comparison
group. A follow-up evaluation of this intervention program was
also conducted with the treatment group.90 Preliminary find-
ings of the development of an interactive art installation (i.e.,
“Hope Tree”) in a hospice setting provide support for the use of
the creative arts as an expression and promotion of hope among
patients, family members, and hospice staff.91 However, further
research with larger and more diverse sample sizes, as well as dif-
ferent palliative care settings, is needed.
In contrast to targeted hope interventions, other studies
involving advanced cancer patients have included hope or hope-
lessness as an outcome of specific therapeutic interventions, such
as meaning-centered therapy,92 dignity therapy,93,94 forgiveness
therapy,95 or life review,96 with mixed results. Further, DeMartini
and colleagues97 explored the relationship between patients’
hopes and advanced cancer treatment. A range of treatment
hopes were identified, consisting of eight hope categories: quality
of life, life extension, tumor stabilization, remission, milestone,
unqualified cure, control not otherwise specified, and cure tem-
pered by realism.
Others have demonstrated the effectiveness of hope-specific
interventions in nonpalliative populations, such as homeless vet-
erans98 and patients newly diagnosed with cancer.99 Based on a
quasi-experimental design, Tollett and Thomas98 studied the effect
of rational thought on levels of hope in a sample of 40 homeless
veterans. Rustøen et al.99 conducted a quasi-experimental study to
evaluate the effect of an eight-session hope-focused nursing inter-
vention on hope and quality of life in patients newly diagnosed
with cancer. In both of these studies, hope was significantly higher
after the intervention than in the comparison groups.
In a systematic review of interventions for the treatment of
holistic suffering in cancer, Best and colleagues100 provided
further support for three of the hope-focused interventions:
Duggleby et al.’s LWHP,86 Herth’s hope-enhancing nursing inter-
vention program for cancer recurrence, 89 and Rustøen et al.’s
hope-focused nursing intervention for patients newly diagnosed
with cancer.99 They concluded that these interventions showed
promise in enhancing hope in patients at different stages of the
cancer trajectory, including end of life, as well as impacting exis-
tential well-being. They also suggested, however, that further
research is warranted to determine the extent to which the effec-
tiveness of these interventions is sustained over time.
An example of an integrated hope intervention framework for
cancer patients appears in Table 50.2. This framework was derived
from a thematic analysis of the literature, patient interviews, and
clinical experiences. It consists of seven hope-enhancing themes:
caring, communication, commitment, coping, creating, com-
munity, and celebrating. Within each theme, specific strategies
for enhancing hope are proposed, some of which may be explicit
while others may be implicit (see Jevne and Nekolaichuk67 for
detailed descriptions of additional strategies). Although this

TABLE 50.2  The Seven Cs: A Hope Intervention Framework

Theme Questions for the Patient
Caring Tell me about a time in your life when you experienced a moment of caring
Communication Tell me about what it is like to be ill. How has your hope changed since you have become ill?
Commitment What would be one small thing that you might do on a regular basis to help strengthen your hope?
Coping What has helped you through difficult times in the past?
Creating If you were to create a “hope kit,” what things would you put in it?
Community How is hope experienced in your community (culture)?
Celebrating If you were to plan a celebration of hope, what might you do?
Source: Adapted from Jevne RF, Nekolaichuk CL. Threat and hope in coping with cancer for health care professionals. In: Jacoby R, Keinan
G, eds. Between Stress and Hope: From a Disease-Centered to a Health-Centered Perspective. Westport, CT: Praeger Publishers,
2003, pp. 187–212.
Hope In End-of-life Care
KEY LEARNING POINTS
• Patients, health-care providers, and health
researchers have all acknowledged the important
role of hope in terminal illness.
• Hope is an inherent part of being human.
Although it is a universal human experience, it
is also an intensely personal one. It is important
to understand what hope means to each person
suffering from a terminal illness.
• Hope assessments and interventions are closely
intertwined. Assessment is a continuous process
and may be a type of intervention. Interventions
are closely linked to the types of assessments that
are conducted.
• Although many assessment and intervention
approaches for hope have been proposed, few
have been developed for and validated in the ter-
minally ill.
• Systematic approaches for hope assessment and
intervention need to be developed and integrated
into routine clinical practice in end-of-life care.
framework was developed for cancer patients, many of these
strategies could be applied to the terminally ill patients. Further
research is needed to extend its use in this population.
The use of explicit hope-enhancing interventions needs to be
integrated with implicit approaches, in which hope is modeled
by the professional caregiver’s hopeful presence and orientation.67
To better understand patients’ experiences of hope and develop
appropriate interventions, professional caregivers need to have
an awareness of their own perceptions and experiences of hope,
which can impact their interactions with patients and families.
A number of qualitative studies have focused on professional
caregivers’ experiences of hope in palliative care, including reg-
istered nurses,101–103 physicians,103,104 and interdisciplinary team
members.102,103 In a qualitative study of 14 community palliative
care nurses, participants identified a main concern of “keeping
their hope when faced with work life challenges and contrast-
ing viewpoints (p. 281),” when their hopes varied from others.101
In another study focusing on palliative care professionals’ hope
experiences, Olsman and colleagues103 identified four metaphors
of hope—grip (safety), source (strength), tune (harmony), and
vision (positive perspective)—which could be used to improve
communication in palliative care. The importance of therapeutic
presence is further supported by a study focusing on the develop-
ment of an empirical model of therapeutic effectiveness, based
on the perceptions of 78 psychosocial oncology clinicians.105
Although not specific to palliative care, many of the elements of
this model of communication could be adapted for supporting
patients and family members at end of life.
Summary
You have to have hope.
There isn’t anything if you haven’t got hope…
Even if it’s a small percentage. You have to have it.
A palliative care patient
How might we create a space for hope in end-of-life care?
489
This chapter highlighted three specific challenges for inten-
tionally integrating hope within clinical practice:
• The need to understand the nature of hope at end of life
• The need to develop brief, psychometrically sound measures
and complementary qualitative assessment frameworks
• The need to develop and evaluate specific hope-enhancing
interventions for the terminally ill
The concept of hope is a dynamic, yet enduring element of pallia-
tive care. The lack of well-developed assessment approaches and
effective hope-enhancing interventions, targeted specifically for
the terminally ill, has impeded progress in this area. Through col-
laborative efforts involving patients, family members, clinicians,
and researchers, appropriate hope assessment frameworks and
hope-focused interventions need to be developed that eventually
may become part of routine end-of-life care.
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51
DEHYDRATION AND REHYDRATION

Robin L. Fainsinger

Contents
Introduction�����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������493
Scenario 1����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������493
Scenario 2����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������493
Scenario 1����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������493
Scenario 2����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������494
What is dehydration?�������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������494
Hydration controversy�����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������495
Hydration research�����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������496
Biochemical findings and hydration status������������������������������������������������������������������������������������������������������������������������������������������������������������496
Biochemical findings/hydration status and clinical symptoms�������������������������������������������������������������������������������������������������������������������������496
Ethical, social, and cultural considerations������������������������������������������������������������������������������������������������������������������������������������������������������������������497
Alternative hydration techniques����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������498
Nasogastric tubes and gastrostomy�������������������������������������������������������������������������������������������������������������������������������������������������������������������������498
Hypodermoclysis���������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������498
Proctoclysis�������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������498
Conclusion��������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������498
References���������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������499

Introduction intake. The family’s access to transportation that would enable

There are many facets to the often-complicated and controversial
topic of dehydration and rehydration of palliative care popula-
tions. The ongoing divergent opinion is well illustrated by the fol-
lowing statements:
them to travel to the nearest hospital 10 km away is limited. Her
extended family nurses her at home, and after a few days, she is
able to resume a reasonable oral intake, her strength improves,
and she resumes her role with household maintenance and care
of her grandchildren.

Research is limited but suggests that artificial hydration in Scenario 2

imminently dying patients influences neither survival nor A 70-year-old woman living in a wealthy country with univer-
symptom control.1 sal health care develops increasing abdominal discomfort. She
The best available evidence suggests that hydration of has been active and in good health, although she notes that she
advanced cancer patients plays an important role in main- has lost approximately 3 kg of weight over the last few months.
taining cognitive function and is therefore an important Extensive diagnostic imaging and subsequent liver biopsy con-
factor in the prevention and reversal of delirium in this firm pancreatic cancer with liver metastases. She develops severe
population.2 nausea and vomiting and presents to the emergency department
of her local hospital with clinical evidence of dehydration. She
Superimposed on these conflicting medical comments are other is rehydrated with intravenous fluids and admitted for investi-
complex issues: gation. No evidence of bowel obstruction is found on diagnostic
imaging. The patient improves, resumes a reasonable oral intake,
Terminal dehydration is a controversial topic, weighted and is discharged home.
heavily with historic symbolism, and strong religious, soci-
etal, and cultural conflicts. 3 Scenario 1
Over the course of the next few weeks, the woman again develops
Some of these issues can be illustrated with the following increasing abdominal pain, poor appetite and loss of weight, and
examples. intermittent nausea and vomiting. She is fortunate that a mobile
health clinic has now started to visit her isolated community on
Scenario 1 a monthly basis. The nurse practitioner doing the examination
A 70-year-old woman living in an isolated rural community in notes that the patient looks cachectic and has an enlarged, tender
southern Africa develops increasing abdominal discomfort. She liver. She suspects that the patient is dying from an unknown gas-
has been active and in good health, although she has lost approxi- trointestinal primary with extensive intra-abdominal metastatic
mately 3 kg of weight over the last 2 months. She develops severe disease. The family and patient are provided with an explanation
nausea and vomiting and inability to maintain an adequate oral of the suspected diagnosis and prognosis. The clinic is able to

493
494 Textbook of Palliative Medicine and Supportive Care

provide a free prescription of morphine liquid and an explanation

of dietary supplements they could use to prevent constipation.
The nurse practitioner is aware of the options for hydration sup-
plementation such as intravenous, hypodermoclysis, and rectal
hydration. However, for a variety of reasons, including economic
and the increased burden this would place on the family caregiv-
ers, all of these options are rejected. Instead, the family is given
suggestions to assist the patient to continue to drink as long as
this is comfortable for her, as well as some suggestions to provide
mouth care. The nurse practitioner wishes the patient and family FIGURE 51.1  Types of fluid deficit.
well and indicates that they should return for a follow-up visit
when the mobile clinic is back in their community. The nonverbal
communication in the room indicates that all of them understand is predominantly intracellular and associated with hypernatre-
that the nurse practitioner does not really expect to see them for mia. Volume depletion implies a deficit in the intravascular fluid
a follow-up visit. volume and can be isotonic, hyponatremic, or hypernatremic
(Figure 51.1).
Scenario 2 A variety of factors can be associated with fluid deficits
Over the next few weeks, increasing abdominal pain requires
(Table 51.1). Any of these etiologies for fluid deficit can occur at
escalating morphine doses to achieve good control. The patient
any stage of a palliative care illness and multiple possible mecha-
expresses a preference to remain at home as she deteriorates.
nisms can occur simultaneously.
However, the patient and her husband indicate to the family
The assessment of risk or presence of fluid deficits is based
physician that their religious beliefs are that everything pos-
on a variety of factors that can be determined by history, physi-
sible should be done to maintain life for as long as possible.
cal examination, and laboratory findings. The history is of
Intermittent nausea and vomiting result in the oral morphine
obvious value in determining the possible risk factors listed in
being changed to the subcutaneous route, and increasing abdom-
Table 51.1. There are sometimes practical difficulties in estimat-
inal pain requires increasing the morphine dose to 100 mg sub-
ing the accuracy of fluid intake estimates and potential fluid loss
cutaneously per day. The family physician discusses the option of
through urine and fecal incontinence. Symptoms of fluid defi-
parenteral hydration. Hypodermoclysis at 1 L overnight is insti-
cit can include behavior and cognitive changes, fatigue, thirst,
tuted. A daughter and son now arrive to assist and support their
nausea, and dry mouth. The classic signs of fluid deficit include
father in caring for their mother. The son has worked as a hospice
dry mouth, reduced skin turgor, postural hypotension, tachycar-
nurse and questions the value of ongoing hydration at this point.
dia, reduced jugular venous pressure, sunken eyes, and reduced
The daughter is a nephrologist who believes that hydration is nec-
sweating. However, all of these problems need to be interpreted
essary to maintain normal renal function and avoid the accumu-
with caution as they can be associated with other causes present
lation of morphine metabolites that may cause side effects. The
in aging, cachexia, advanced cancer, and side effects due to com-
patient and her husband have had extensive discussions over the
monly used medications.
years with their family physician who has a good understanding
Laboratory evaluation can provide some helpful information
of how their spirituality affects their decision-making. Although
in evaluating fluid deficits but will obviously depend on the set-
respecting their children’s opinions, the couple relies heavily on
ting of care and whether such investigations are acceptable to the
their family physician to provide information and direction on
patient, family, and health-care team. The common findings pres-
appropriate management.
ent in volume-depleted patients include elevated levels of urea,
These scenarios highlight some of the complexity that sur-
creatinine, plasma proteins, hematocrit, and sodium. It is worth
rounds this widely debated and controversial topic. At the
noting that in a systematic review attempted to clarify the physi-
center of the discussion, irrespective of the setting and circum-
cal diagnosis of hypovolemia in adults, 5 the authors concluded
stances, is the desire to keep patients as comfortable as pos-
that in patients with vomiting, diarrhea, or decreased oral intake,
sible while avoiding unnecessary management or procedures.
few findings, with the exception of serum electrolytes, urea, and
However, there is no doubt that the definition of “unneces-
creatinine values, have proven value.
sary” will have great international variation. Clinicians with
the responsibility to make these decisions will need to sort
through expressions of opinion, information on pathophysi-
TABLE 51.1  Factors Associated with Fluid
ology and biochemical changes, research looking at a variety
Deficits
of outcomes, differing family and cultural expectations, and
consensus statements. This diverse information then has to Decreased Intake Increased Fluid Loss
be individually applied to the specific trajectory and circum- Asthenia Bowel resection
stances of patients and their families.
Anorexia Diarrhea
Coma Diuretics
What is dehydration? Delirium Diabetes mellitus/
insipidus
As has been pointed out in past reviews, use of the term dehy- Dementia Fistulas
dration in considering this issue is often inaccurate.2,4 Fluid defi- Depression Fever/sweating
cit is the state of water loss with or without electrolytes, which
Dysphagia Hypercalcemia
includes the subtypes of volume depletion and dehydration.
Nausea Vomiting
Dehydration should be understood as total body water deficit that
Dehydration and Rehydration 495

Hydration controversy
There is no controversy that palliative care populations should
be encouraged to maintain an adequate oral intake to prevent
fluid deficit. However, there are many literature reports illustrat-
ing opposing viewpoints on the use of supplemental parenteral
hydration. These have been considered from both clinical and
ethical viewpoints.6–16 Historical reviews on this topic have refer-
enced a similar collection of clinical anecdotes and opinions. The
arguments for and against hydrating palliative care populations
are summarized in Box 51.1.11,12
It would appear that the arguments for initiating or maintain-
ing parenteral hydration in palliative care populations originate
from the standard medical approach to fluid deficits. Thus, it
would be reasonable to expect that most patients dying in hos-
pitals will have an intravenous line unless they have undergone
rapid deterioration or unanticipated demise. This was originally
demonstrated by a Canadian report17 where 73 of 106 cancer
patients dying in a tertiary care hospital were noted to have intra-
venous fluids administered. A retrospective study on the use of
artificial hydration in an acute care hospital in England1 noted
that of 111 patients, 65% were hydrated during the last week of life
and 46% were being hydrated at the time of death. The mean rate
of parenteral hydration was 2000 mL/day. The results suggested
that artificial hydration is no longer necessarily considered rou-
tine hospital practice for dying patients in this setting.
In order to clarify the routine practice of physicians involved in
end-of-life care in Edmonton, Canada, the routine management
of parenteral hydration for patients dying in a palliative care unit
and acute care hospital while receiving or not receiving consult
advice from the palliative care program was reported.18 A retro-
spective chart review of 50 consecutive patients dying at each of
the three sites was included. The majority of patients (66–98%) at
all sites received hydration during the last week of life. However,
the volume of hydration was noted to be significantly lower in the
palliative care unit site.
A survey questionnaire of Japanese physicians attempted to
clarify attitudes toward terminal dehydration. Results revealed
that physicians with more positive attitudes toward intravenous
hydration were less involved in end-of-life care and more likely to
regard fluid as a necessary physiological requirement, consider
it a minimum standard of care, and believe that this was ben-
eficial for palliating symptoms.19 A Canadian study distributed a
questionnaire to 18 palliative care physicians in major Canadian
centers in an attempt to clarify the routine practice of physicians
involved in end-of-life care.20 Results demonstrated a wide range
of practice. Physicians estimated that they ordered parenteral
hydration in a median of 6–10% of patients (range 0–100%). The
routes of parenteral hydration were intravenous hydration, with
a median of 30% (range 0–100%), and hypodermoclysis, with a
median of 70% (range 0–100%). The estimated average volume
range per 24 hours was between 200 and 2400 mL. A survey of
238 palliative care physicians in Latin America reported that 60%
prescribed parenteral hydration to 40–100% of their patients in
the last weeks of life. These results differ from traditional hospice
philosophy, and the report concludes that clinical perceptions of
benefit drive practice to prescribe or withhold parenteral hydra-
tion based on individualized treatment decisions.21
It is easy to imagine the problems inflicted on advanced pal-
liative care populations by a policy of maintaining intravenous
hydration with volumes in excess of 3 L/day. Under this circum-
stance, complications such as increased respiratory and gastro-
intestinal symptom distress can be anticipated. The literature
reports against parenteral hydration would suggest that some
health-care professionals looking after palliative care popula-
tions have reacted to overuse of intravenous fluids and concluded
that no parenteral hydration is the preferred approach. This has
been reinforced by anecdotal literature reports noting that many

BOX 51.1  HYDRATION IN PALLIATIVE CARE

Arguments against parenteral hydration:

• Symptom distress is not experienced by comatose patients.

• Dying is prolonged by parenteral fluids.
• There is less urine and thus less problem with incontinence and catheter use.
• Decreased gastrointestinal fluid associated with dehydration results in less nausea and vomiting.
• Decreased respiratory secretions will result in less cough and pulmonary edema.
• The severity of edema and ascites is decreased.
• Dehydration can act as a natural anesthetic for the central nervous system.
• Parenteral hydration is uncomfortable and limits patient mobility.

For parenteral hydration:

• Parenteral hydration assists in making dying patients more comfortable.

• There is no evidence that parenteral hydration prolongs life.
• Fluid deficits can cause restlessness, confusion, and neuromuscular irritability.
• Oral hydration is provided to dying patients complaining of thirst, and therefore, parenteral hydration should be an
option.
• Emphasis on the poor quality of life of palliative care populations detracts from efforts to improve comfort and life
quality.
• Parenteral hydration is considered a minimum standard of care.
• Withholding parenteral fluid from palliative care populations may result in withholding therapies to other compro-
mised patient groups.
496
palliative care patients appear to die comfortably without paren-
teral hydration. Nevertheless, a review of the literature indicates
that these reports are mostly based on unsubstantiated data.12
There are other issues worth considering11,12,22–25:
• Fluid deficit as a cause of confusion and restlessness in
non-terminally ill patients is well recognized. The prob-
lems of delirium and agitation have been well reported in
palliative care populations.2
• Reduced intravascular volume and glomerular filtration
rate caused by fluid deficits are well accepted as a cause of
prerenal failure.2,4 Opioid metabolite accumulation in the
presence of renal failure, resulting in confusion, myoclo-
nus, and seizures, has been well documented.
Reports with regard to agitated delirium and terminal restless-
ness have frequently appeared in the palliative care literature.
Discussion of these problems has generally been centered on the
need for pharmacological management, which often includes
sedation.26–28 Ventafridda et al.29 reported 9% of patients requir-
ing sedation for agitated delirium in a study of unendurable symp-
toms experienced by patients with cancer during their last days of
life. This prompted a report by our group30 that agitated delirium
was the most frequent problem requiring sedation in the last
week of life in 10% of our patients. A later report noted that the
severity of agitated delirium requiring sedation had decreased to
3% in our palliative care unit. 31 We speculated that this resulted
due to a change in our practice to include more frequent use of
hypodermoclysis for hydration, switching opioids earlier when
toxicity developed, and the use of less sedating treatments such as
haloperidol for delirium, decreasing the prevalence and difficulty
of managing agitated delirium in this setting. 32
Reports in the palliative care literature have noted a range of
options for the pharmacological management of symptoms asso-
ciated with agitated delirium, including the use of intravenous
propofol. 33–35 A retrospective chart review of 76 consecutive
patients dying at St. Luke’s Hospice in Cape Town, South Africa,
found that 29% of patients required sedation for agitated delir-
ium. Although none of these patients were treated with paren-
teral hydration, patients requiring sedation were noted to require
significantly higher doses of opioids during a longer admission. 36
Further reports on the use of sedation have suggested that
agitated delirium appears to be less problematic in a number of
different settings in Edmonton, 37 where parenteral hydration is
more common practice,18 compared with requirements for seda-
tion in a number of other international settings. 38 As a result, it
has been suggested that dehydration could be a reversible compo-
nent of agitated delirium, which may be ignored by an approach
that focuses on a sedative pharmacological solution to this appar-
ently common and certainly distressing situation. 39 Thus, it may
be illogical for a patient to receive medications for agitated delir-
ium, myoclonus, and seizures, if in some circumstances these
problems could be prevented or corrected by the use of parenteral
hydration.
Hydration research
Research into the use of hydration in palliative care settings has
focused on three dimensions40:
• The association between biochemical findings and hydra-
tion status
Textbook of Palliative Medicine and Supportive Care
TABLE 51.2  Comparison of Biochemical Findings in Patients
Taking Oral Fluids (Sips) 47 and those Receiving
Hypodermoclysis48
Fainsinger et al.48 Ellershaw et al.47
Normal
Mean Range Mean Normal Range
Urea (mmol/L) 8.8 3.2–8.2 15.5 2.5–6.5
Creatinine 101 62–133 177 60–120 (μmol/L)
• The association between biochemical findings and clinical
symptoms
• The association between hydration status and clinical
symptoms
Biochemical findings and hydration status
There is no controversy that dehydration is a cause of renal fail-
ure.41–43 However, while parenteral hydration is accepted stan-
dard management in many settings, the impact of fluid deficit
and rehydration on the renal function and electrolyte balance of
palliative care populations is still questioned.10,44–47
Ellershaw et al.48 undertook a biochemical investigation in 82
patients with advanced cancer. The patients were taking oral sips
of fluid and were no longer able to tolerate oral medication. Our
group49 reported biochemical investigation of 100 consecutive
patients, 69 of whom received hypodermoclysis at an average vol-
ume of 1203 ± 505 mL/day. A comparison of these two reports50
has been published (Table 51.2). Morita et al.51 published further
results on the biochemistry of terminally ill cancer patients and
concluded that relatively small amounts of parenteral hydra-
tion may result in less abnormal biochemistry, particularly with
regard to renal function.
Biochemical findings/hydration status
and clinical symptoms
Much of the early literature on this issue was based on anec-
dotal opposing viewpoints and case reports.52,53 However, sub-
sequent reports attempted to study this issue more carefully.
Burge46 reported a cross-sectional survey studying the quantita-
tive assessment of the dehydration experience in patients with
advanced cancer. The study concluded that parenteral hydration
on the basis of fluid intake and laboratory measures were not
helpful if the aim was to reduce thirst. McCann et al.54 stud-
ied 48 consecutive patients with regard to symptom prevalence
and management of hunger and thirst in terminally ill patients
not receiving parenteral hydration. Symptoms of hunger, thirst,
and dry mouth were apparently well managed with oral sips and
mouth care.
Ellershaw et al.48 investigated the relationship between symp-
toms and dehydration in 82 patients not provided with parenteral
hydration. No significant association was demonstrated between
the level of hydration and respiratory tract secretions, thirst,
and dry mouth. However, they did acknowledge that the effect
of renal failure and possible consequences of agitation and con-
fusion were not assessed. Musgrave et al.55 studied the effect of
intravenous fluids on a group of patients with advanced cancer
dying in a hospital oncology unit. No relationship was demon-
strated between level of thirst, intravenous fluids, and biochemi-
cal parameters. A subsequent study56 also failed to demonstrate
any relation between intravenous fluids, fluid balance, and the
prevalence of crepitations, ascites, and leg edema. A retrospective
Dehydration and Rehydration
chart review of 117 and 162 patients admitted to a palliative care
unit in 1988–1989 and 1991–1992 assessed the impact of a change
in practice with regard to management of dehydration and cogni-
tive impairment.57 The authors concluded that the data suggested
that routine cognitive assessment, opioid rotation, and hydration
may reduce the frequency of agitated confusion in terminally
ill cancer patients. Although hydration may have had a role, it
was not possible to determine the relative contribution. A par-
tial replication of this study considered the role of hydration and
an incomplete opioid substitution on the prevalence of agitated
delirium.58 No significant decrease in the occurrence of agitated
delirium was noted.
Ashby et al.59 measured plasma concentrations of morphine and
metabolites in 36 hospice patients. They concluded that morphine
metabolites may be a causal aggravating factor in nausea and vomit-
ing and cognitive impairment in palliative care patients with signifi-
cant renal impairment. Lawlor et al.60 completed prospective serial
assessments of 113 patients with advanced cancer in a delirium
study. Univariate analysis demonstrated reversibility associated
with psychoactive medications and dehydration. They concluded
that although delirium is multifactorial, hydration using hypoder-
moclysis may be one of the potential useful measures to consider.
Bruera et al. published the first randomized, controlled, dou-
ble-blind study of parenteral hydration in terminally ill cancer
patients. This was a multicenter study where patients with clinical
and biochemical evidence of dehydration and history of an oral
intake of less than 1 L of fluid per day were randomly assigned
to receive 1000 mL (treatment group) or 100 mL (placebo group)
of normal saline over 4 hours for 2 days. The outcome measures
were patient- and investigator-rated symptoms of fatigue, seda-
tion, myoclonus, hallucinations, and a global sense of well-being.
A significant improvement in sedation and myoclonus scores
was noted in the hydration treatment group.61 A follow-up study
using similar methodology and 6 hospices in the Houston area
included 129 patients randomly assigned to hydration or placebo
and found no significant differences. The authors concluded that
in this population, hydration of 1000 mL/day does not improve
symptoms, quality of life, or survival compared with placebo.
They did comment that further research in other patient popu-
lations such as delirium associated with dehydration and opioid
toxicity should be explored in future studies.62
Fritzon et al.A completed an observational study of symptoms
and parenteral fluid administered in the last week of life and sug-
gested an association with higher volumes and increased docu-
mentation of dyspnea.
A review by Burge63 concluded that there is little clinical evi-
dence to guide patients, families, and clinicians in treatment
decisions regarding fluid intake during the terminal phase of
life. A subsequent systematic review by Viola et al.64 summarized
existing evidence regarding fluid status effects and fluid therapy.
Six studies were selected for inclusion and the authors concluded
that given the study limitations, it was impossible to draw firm
conclusions regarding clinical care. A Cochrane review (updated
in 2014) concluded that there was insufficient quality research
for practice recommendations in the use of alternative hydration
assistance for palliative care patients.65
Ethical, social, and cultural considerations
There are other important issues to consider with regard to the
use of parenteral hydration.66 Patient and family attitudes, level
of comfort with the situation, and education and health-care
497
workers’ attitudes, level of education, and biases in presentation
all influence the decision-making process.
Unfortunately, artificial nutrition and hydration are often
considered as the same issue in ethical and clinical discussion
papers. This causes unnecessary confusion, as the arguments and
rationale for providing nutritional calories via artificial means as
opposed to hydration should be considered independently.
Morita et al.67 studied patients’ and family members’ per-
ceptions about rehydration to identify factors contributing to
decision-making. The survey included 121 Japanese hospice
patients with insufficient oral intake. Patient performance status,
fluid retention symptoms, denial, physician recommendations,
patients’ and family members’ beliefs with regard to hydration
effect on patient distress, and family anxiety about withholding
rehydration were significantly associated with decision-making.
The main determinants for rehydration were the patient perfor-
mance status, fluid retention symptoms, denial, and care receiv-
er’s beliefs about the effects of rehydration on patient distress.
A Canadian study68 identified issues of importance to family
caregivers with regard to administering parenteral hydration to
patients with advanced cancer. Factors influencing caregivers
included symptom distress issues, ethical and emotional consid-
erations, information exchanged between health professionals
and families, and culture. Perceived benefits of artificial hydra-
tion were central to the ethical, emotional, and cultural con-
siderations involved in caregivers’ decision-making. An article
presenting the values of the Jewish faith with regard to terminal
dehydration69 illustrates the difficulty of applying cultural and
ethnic research and opinion. Letters in response varied from
describing this as an “excellent article” 70 to “extremely offensive
in its references to Jewish people.” 71
Malia et al. noted that artificial hydration in palliative care is
a controversial practice in the United Kingdom and applied Q
methodology to identify issues of most concern to patients in
influencing decisions. The importance of considering the differ-
ent views patients bring to their decision-making and the need to
involve them in making unbiased informed treatment choices are
nicely demonstrated in this novel research study.72 Cohen et al.
used phenomenological interviews with patients and caregivers
in home hospice care in the United States to understand how they
viewed parenteral hydration. Findings differed from traditional
hospice beliefs in that this was described by some participants as
enhancing comfort, dignity, and quality of life.73
Gent et al. (B) completed a literature review on attitudes and
knowledge of patients, families, health-care personnels and the
general public toward assisted hydration in dying patients and
identified three core themes: symbolic value; beliefs and miscon-
ceptions; and cultural, ethical, and legal ideas.
It has been proposed that terminal dehydration or voluntary
cessation of drinking may provide an alternative to physician-
assisted suicide. Miller and Meier74 suggested that terminal dehy-
dration accompanied by standard palliative care management
offers patients a way to escape agonizing, incurable conditions
that they consider to be worse than death, without requiring
transformation of the law and medical ethics. Quill et al.75 sug-
gested that voluntary cessation of “eating and drinking are clini-
cal options that may be acceptable to a patient and physician and
do not require fundamental changes in the law.”
Craig76 argued passionately that a blanket policy of no hydra-
tion, as initially endorsed in a national guideline end-of-life
care pathway in the United Kingdom, was ethically indefen-
sible. Her primary concern was that the value of hydration is
498
underestimated and could increase deaths associated with pal-
liative sedation. Craig77 has devoted a book to this issue, in which
she stated, “My personal role in the hydration debate has been
to highlight the ethical, legal and medical dangers of a regime of
sedation without hydration in the dying and draw attention to the
plight of dissenting relatives.”
Alternative hydration techniques
There is universal agreement that the best and most convenient
route to correct fluid deficits is increasing or improving oral
intake. However, when this is impossible or inadequate, there are
some circumstances where parenteral hydration may be of ben-
efit. It is often not well understood that we are not necessarily
all seeing patients in the same trajectory of illness. Clinical cir-
cumstances evolve78 and a physically independent and cognitively
intact patient at an early stage of a palliative illness is likely to be
viewed very differently to the same patient a number of months
later who is now cognitively impaired and physically dependent.
However, if a decision is made to use parenteral hydration, there
are considerations with regard to the type of fluid, volume, and
route of administration. There is no doubt that intravenous
hydration is the route of choice in acute care institutions. It has
obvious disadvantages such as difficulty finding venous access,
pain, infection, limitations to mobility, and displaced lines, par-
ticularly with confused patients. Nevertheless, it should be noted
that a report from an Italian palliative care program stated that
82% of palliative care patients will have an intravenous line and
receive a range of 1–1.5 L of fluid per day.79 In addition, they stated
that although hypodermoclysis has been suggested as an alterna-
tive, experience suggests that it is not less stressful for palliative
care patients and that the intravenous route is preferred.
Nasogastric tubes and gastrostomy
Nasogastric tubes are generally uncomfortable for patients and
prolonged use, particularly in palliative care populations, and
should be avoided where possible.80,81 Percutaneous gastros-
tomies are commonly used with head and neck or esophageal
cancer patients with increasing dysphagia who may benefit from
nutrition as well as hydration.82 As patients deteriorate, there is
a need to review the goals of care with regard to enteral nutri-
tion. However, difficulty with discontinuing management and
ease of access can result in ongoing enteral nutrition and hydra-
tion in circumstances where this might not otherwise have been
instituted.
Hypodermoclysis
The safety of hypodermoclysis has been well documented and
reported in noncancer patients.83,84 There have also been studies
in palliative care patients demonstrating the ease of administra-
tion and minimal toxicity.49,85,86
The procedure is simple and associated with minimal pain.
A butterfly needle is inserted subcutaneously and attached to a
fluid line that can run via gravity or an infusion pump. It requires
minimal training for insertion and surveillance, and family care-
givers can be trained to supervise this management in the home
with minimal burden, equipment, or technical support (C*).
There is evidence of increasing acceptance of hypodermoclysis in
the acute care setting.18 It is generally recommended that solu-
tions with some electrolytes are used, as nonelectrolyte solutions
have been reported to draw fluid into the interstitial space.11,12,87
Initial recommendation suggested rates of infusion limited to a
Textbook of Palliative Medicine and Supportive Care
maximum of 100–120 mL/hour; however, patients can tolerate
boluses up to 500 mL/hour.88
The use of hypodermoclysis has been assisted by adding hyal-
uronidase to promote absorption in a dose ranging from 150 to 750
units/L. Initially, smaller volumes of hyaluronidase were demon-
strated to be just as effective.88 However, a shortage of hyaluroni-
dase led to clinical experience and anecdotal reports suggesting
good absorption of hypodermoclysis without hyaluronidase. This
resulted in a report of 24 consecutive patients receiving hypoder-
moclysis without hyaluronidase.89 Hydration was maintained for
a mean 12 ± 9 days, with an infusion varying in range between 20
and 300 mL/hour. Three patients were demonstrated to tolerate
twice daily boluses of 500 mL over 1 hour. The average infusion
site duration was 3.3 ± 3.6 days. These results and the increasing
difficulty obtaining hyaluronidase have resulted in the ongoing
clinical observation that most patients tolerate hypodermocly-
sis without requiring the addition of hyaluronidase. This is now
standard practice in our setting with rates up to 80 mL/hour
well tolerated by most patients. However, recombinant human
hyaluronidase use has been reported in clinical studies and may
have a future role in improving the absorption of subcutaneously
administered fluids.90
Proctoclysis
As noted, intravenous hydration can be uncomfortable, expen-
sive, and difficult to maintain in the home, while even hypoder-
moclysis can be expensive and too complicated in some settings.
The potential advantage of the rectal administration of fluid,
particularly in resource-limited developing countries, prompted
a trial of rectal hydration in terminally ill cancer patients.91
Proctoclysis was offered to 17 adult patients with a fluid deficit
where resources were inadequate for the use of hypodermocly-
sis. Tap water was used and the rectal infusion was increased
from 100 mL to a maximum of 400 mL/hour, unless fluid leak-
age occurred before the maximum volume was achieved. The
mean daily volume, hourly rate, and duration were reported as
1035 ± 150 mL/day, 224 ± 58 mL/hour, and 14 ± 8 days, respec-
tively. Rectal hydration was noted to be well tolerated with mini-
mal side effects in the majority of patients. A follow-up report92
included 78 advanced cancer patients receiving rectal hydration.
Volumes infused, patient tolerance, and side effects were similar
to the earlier report, confirming that this is a safe, effective, and
low-cost technique for rehydration in terminally ill palliative care
populations.
Conclusion
Reconsider the varying circumstances and sociocultural circum-
stances of the two patients described in the introduction to this
chapter. Discussion of management of these two patients, the
manner in which information should be presented to them, liter-
ature interpretation as reviewed earlier, and the biases of health-
care providers and the circumstances in which we work will have
significant implications on how we consider the issue of fluid
deficit and rehydration. We can perhaps achieve consensus that
dehydration is a cause of renal failure and that hypodermoclysis
is a safe and effective way of providing rehydration. There may
be agreement that rehydration of palliative care populations may
result in better biochemical parameters for some patients. There
is certainly much evidence to recommend that if terminally ill
patients are not rehydrated, medications such as opioids should
be gradually decreased to avoid accumulation and unnecessary
Dehydration and Rehydration
KEY LEARNING POINTS
• Hydration in palliative care is a controversial
topic with divergent opinions.
• Fluid deficits can cause confusion and renal
failure.
• Hydration research is inconclusive in guiding
clinical care.
• Hypodermoclysis is an excellent alternative for
rehydration in palliative care populations.
• Diverse clinical and sociocultural circumstances
need to be considered.
• Evidence recommends that if terminally ill
patients are not rehydrated, medications should
be decreased to avoid accumulation and side
effects.
• Rehydration may be helpful in some individual
situations.
• Patient and family preferences need to be under-
stood and incorporated into the treatment plan.
side effects. There is likely to be consensus that the major clini-
cal issue is to consider whether rehydration will cause benefit or
harm to palliative care patients unable to sustain adequate oral
intake.
The need to consider individual circumstances and predictions
of life expectancy in evaluating the potential benefits of rehydra-
tion is a recurring theme.2,11,93 Although starting from different
perspectives, there is some consensus10,39,64 that:
• Available data are inadequate for final conclusions on this
issue.
• Careful individual assessment of the relevance of fluid defi-
cit to each clinical situation is essential.
• Further carefully designed research trials are requi
red. 61,62
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2003;6:557–563.
59. Ashby M, Fleming B, Wood M, et al. Plasma morphine and glucuronide
(M3G & M6G), concentrations in hospice in-patients. J Pain Symptom
Manage 1997;14:157–167.
60. Lawlor PG, Gagnon B, Mancini IL, et al. Occurrence, causes, and out-
come of delirium in patients with advanced cancer. Arch Intern Med
2000;160:786–794.
61. Bruera E, Sala R, Rico MA, et al. Effects of parenteral hydration
in terminally ill cancer patients: a preliminary study. J Clin Oncol
2005;23(10):2366–2371.
62. Bruera E, Hui D, Dalal S, et al. Parenteral hydration in patients with
advanced cancer: a multicenter, double blind, placebo controlled ran-
domized trail. J Clin Oncol 2013;31(1):111–118.
63. Burge FI. Dehydration and provision of fluids in palliative care. What
is the evidence? Can Fam Physician 1996;42:2383–2388.
64. Viola RA, Wells GA, Peterson J. The effects of fluid status and fluid
therapy on the dying: a systematic review. J Pallia Care 1997;13:41–52.
65. Good P, Richard R, Syrmis W, et al. Medically assisted hydration
for adult palliative care patients. Cochrane Database of Syst Rev
2014;4:CD006273.
66. Baumrucker S. Science, hospice, and terminal dehydration. Am J Hosp
Palliat Care 1999;16:502–503.
67. Morita T, Tsunoda J, Inoue S, et al. Perceptions and decision making on
rehydration of terminally ill cancer patients and family members. Am J
Hosp Palliat Care 1999;16:509–516.
68. Parkash R, Burge F. The family’s perspective on issues of hydration in
terminal care. J Palliat Care 1997;13:23–27.
69. Bodell J, Weng MA. The Jewish patient in terminal dehydration: a hos-
pice ethical dilemma. Am J Hosp Palliat Care 2000;17:185–188.
70. Schur TG. Life and afterlife in Jewish tradition. Am J Hosp Palliat Care
2000;17:296–297.
71. Rothstein JM. Out of context? Am J Hosp Palliat Care 2000;17:297.
72. Malia C, Bennett MI. What influences patients’ decisions on artificial
hydration at the end of life? A Q-methodology study. J Pain Symptom
Manage 2011;42(2):192–201.
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73. Cohen MZ, Torres-Vigil I, Burbach BE, et al. The meaning of
parenteral hydration to family caregivers and patients with
advanced cancer receiving hospice care. J Pain Symptom Manage
2012;43:855–865.
74. Miller FG, Meier DE. Voluntary death: a comparison of termi-
nal dehydration and physician-assisted suicide. Ann Intern Med
1998;128:559–562.
75. Quill TE, Meier DE, Block SD, et al. The debate over physician-
assisted suicide: empirical data and conversant views. Ann Intern Med
1998;128:552–558.
76. Craig G. Palliative care in overdrive: patients in danger. Am J Hosp
Palliat Care 2008;25(2):155–160.
77. Craig G. Challenging Medical Ethics 1: No Water—No Life: Hydration
in the Dying. Cheshire, UK: Fairway Folio (Christian Publishing
Services), 2004.
78. Fainsinger R. Dehydration. In: MacDonald N. ed. Palliative Medicine:
A Case-Based Manual. New York: Oxford University Press, 1998. pp.
91–99.
79. Mercadante S, Villari P, Ferrera P. A model of acute symptom control
unit: Pain relief and palliative unit of La Maddalena Cancer Centre.
Support Care Cancer 2003;11:114–119.
80. Fainsinger RL, Spachynski K, Hanson J, et al. Symptom control in ter-
minally ill patients with malignant bowel obstruction. J Pain Symptom
Manage 1994;9:12–18.
81. Ripamonti C, Mercadante S, Groff L, et al. Role of octreotide, scopol-
amine butylbromide and hydration in symptom control of patients
with inoperable bowel obstruction and nasogastric tubes: A prospec-
tive randomized trial. J Pain Symptom Manage 2000;19:23–24.
82. Steiner N, Bruera E. Methods of hydration in palliative care patients. J
Palliat Care 1998;14:6–13.
83. Constans T, Dutertre J, Froge E. Hypodermoclysis in dehydrated
elderly patients: local effects with and without hyaluronidase. J Palliat
Care 1991;7:10–12.
84. Molloy DJ, Cunje A. Hypodermoclysis and the care of old adults. An old
solution for new problems? Can Fam Physician 1992;38:2038–2043.
85. Hays H. Hypodermoclysis for symptom control in terminal cancer.
Can Fam Physician 1985;31:1253–1256.
86. Bruera E, Legris M, Keuhn N, Miller MJ. Hypodermoclysis for the
administration of fluids and narcotic analgesics in patients with
advanced cancer. J Pain Symptom Manage 1990;5:218–220.
87. Turner T, Cassano A. Subcutaneous dextrose for rehydration of
elderly patients: an evidence based review. BioMed Central Geriatr
2004;4:2.
88. Bruera E, de Stoutz ND, Fainsinger RL, et al. Comparison of two
different concentrations of hyaluronidase in patients receiving
one hour infusions of hypodermoclysis. J Pain Symptom Manage
1995;10:505–509.
89. Centeno C, Bruera E. Subcutaneous hydration with no hyaluroni-
dase in patients with advanced cancer. J Pain Symptom Manage
1999;17:305–306.
90. Pirrello R, Ting Chen C, Thomas SH. Initial experiences with sub-
cutaneous recombinant human hyaluronidase. J Palliat Med
2007;10(4):861–864.
91. Bruera E, Schoeller T, Pruvost M. Proctoclysis for hydration of termi-
nal cancer patients. Lancet 1994;344:1699.
92. Bruera E, Pruvost M, Schoeller T. Proctoclysis for hydration of termi-
nally ill cancer patients. J Pain Symptom Manage 1998;15:216–219.
93. Dalal S, Del Fabbro E, Bruera E. Is there a role for hydration at the end-
of-life? Curr Opin Support Palliat Care 2009;3:72–78.
A. Fritzson A, Tavelin B, Axelsson B. Association between parenteral flu-
ids and symptoms in hospital end-of-life care: an observational study
of 280 patients. BMJ Support Palliat Care 2015;5:160–168.
B. Gen, MJ, Fradsham S, Whyte GM, et al. What influences attitudes
towards clinically assisted dehydration in the care of dying patients? A
review of the literature. BMJ Support Palliat Care 2015;5:223–231.
C. Vidal M, Hui D, Williams J, et al. A prospective study of hypodermoc-
lysis performed by caregivers in the home setting. J Pain Symptom
Manage 2016;52:570–574
52
FEVER, SWEATS, AND HOT FLASHES

Ahsan Azhar and Shalini Dalal

Contents
Introduction�����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������501
Fever�������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������501
Pathophysiology of fever��������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������501
Etiology of fever (Box 52.1)���������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������502
Infections����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������502
Paraneoplastic fever����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������502
Transfusion-associated fever������������������������������������������������������������������������������������������������������������������������������������������������������������������������������503
Drug fever���������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������503
Evaluation of fever�������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������503
Interventions for fever������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������503
Goals of care�����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������503
Nonspecific interventions������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������504
Primary interventions directed at the etiology of fever���������������������������������������������������������������������������������������������������������������������������������504
Fever versus hyperthermia����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������505
Sweats����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������506
Hot flashes��������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������507
Pathophysiology����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������507
Assessment and treatment of hot flashes���������������������������������������������������������������������������������������������������������������������������������������������������������������507
Hormone replacement therapy��������������������������������������������������������������������������������������������������������������������������������������������������������������������������508
Nonhormonal agents��������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������508
Other nonhormonal agents���������������������������������������������������������������������������������������������������������������������������������������������������������������������������������509
Complementary and alternative medicine approaches���������������������������������������������������������������������������������������������������������������������������������509
References���������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������509

Introduction acute phase reactants, and activation of immune systems.” 7 More

Fever, sweats, and hot flashes are commonly encountered in the ter-
minally ill and cancer patients. These may sometimes be associated
with considerable morbidity and mortality. Although infection
remains the most common etiology of fever in patients, irrespec-
tive of whether they are receiving chemotherapy or not, fever
is commonly seen in patients in the absence of infection as well.
Fever is also one of the most common symptoms experienced by
elderly people at the end of life.1,2 Similarly, hot flashes are reported
by the majority of menopausal women and, in some women, can be
a major source of distress.3,4 Less well recognized is the impact of
hot flashes on individuals with cancer, particularly women with a
history of breast cancer and men with prostate cancer. In women
with a history of breast cancer, approximately two-thirds experi-
ence hot flashes.5,6 Optimal management of fevers, chills, sweats,
and hot flashes is therefore of vital consideration in symptom man-
agement. As detailed in this chapter, it is contingent on meticulous
patient assessment, on ascertaining the likely etiology, if possible,
and on the implementation of appropriate treatment interventions
befitting the patient-determined goals of care.
Fever
Fever, as defined in Stedman’s Medical Dictionary, is a “complex
physiologic response to disease mediated by pyrogenic cytokines
and characterized by a rise in core temperature, generation of
commonly, fever is defined as the elevation of core body tempera-
ture above normal. Normal average adult core body temperature
is 37°C (98.6°F) and displays a circadian rhythm with body tem-
peratures being the lowest in the predawn hours, at 36.1°C (97°F)
or lower, and rising to 37.4°C (99.3°F) or higher in the afternoon.
In oncology practice, a single reading of temperature of more
than 38.3°C (101°F) or three readings (each taken at least an hour
apart) of temperatures more than 38°C (100.4°F) is considered
significant.
Pathophysiology of fever
Much like other fundamental aspects of human biology, core body
temperature is closely regulated by intricate control mechanisms,
involving a complex interplay of autonomic, endocrine, and behav-
ioral responses. Integral to this process is the hypothalamus, which
functions much like a thermostat, balancing heat production with
heat loss. Fever is considered a hallmark of immune system activa-
tion, resulting in a regulated rise in body temperature. The regu-
lation of this phenomenon is accomplished by the actions of two
types of endogenous immunoregulatory proteins called cytokines,
some functioning as pyrogens and others as antipyretics. This is
described later and illustrated in Figure 52.1.
A number of exogenous substances, often referred to as exog-
enous pyrogens, have been found to be capable of evoking fever
in animal models.8 Of these, lipopolysaccharide (LPS), a cell wall
product derived from Gram-negative bacteria, has been the most

501
502
FIGURE 52.1  Pathophysiology of fever. IL, interleukin; TNF,
tumor necrosis factor; IFN, interferon; PGE, prostaglandin E;
NSAID, nonsteroidal anti-inflammatory drug.
extensively studied. Exogenous pyrogens induce the produc-
tion of proinflammatory cytokines, such as interleukin (IL)-1b
and IL-6 (Castleman’s disease, pheochromocytoma, and renal
cell carcinoma), interferon α (INFα), and tumor necrosis factor
(TNF), like in Hodgkin’s disease, which act as humoral mediators
influencing brain structures involved in resetting the hypotha-
lamic set-point.9 Cytokines are thought to exert their effect on the
brain via direct and indirect mechanisms.10–13
Peripherally produced cytokines reach the central nervous sys-
tem (CNS) directly by crossing the leaky areas in the blood–brain
barrier via circumventricular vascular organs, which are net-
works of enlarged capillaries surrounding the hypothalamic reg-
ulatory centers.14,15 In disease states such as bacterial infections,
the blood–brain barrier can be compromised further, leading to
an influx of cytokines from the periphery. This can account for
several of the neurological manifestations associated with sick-
ness behavior, including fever.16,17 Cytokines are also produced
locally within the CNS,11 and may account for the hyperpyrexia of
CNS hemorrhage. Among the cytokines measurable in the blood
plasma during LPS-induced fever, circulating levels of IL-6 have
shown the best correlation with fever.18,19
Although not fully understood, it is proposed that cyto-
kines stimulate the central production of the inducible enzyme
Textbook of Palliative Medicine and Supportive Care
cyclooxygenase (COX)-2, and subsequently stimulate the produc-
tion of prostaglandins of the E series.20,21 These prostaglandins
activate thermoregulatory neurons of the anterior hypothalamic
area to elevate body temperature.22 Peripherally produced cyto-
kines can also communicate with the brain indirectly in sev-
eral ways, including the stimulation of terminal fibers of the
autonomic nervous system.23,24 Norepinephrine is the principal
neurotransmitter, although several others such as acetylcholine,
endorphins, enkephalins, substance P, somatostatin, and vasoac-
tive intestinal polypeptide (VIP) have also been implicated.25
Etiology of fever (Box 52.1)
Infections
Nearly two-thirds cases of fever in patients with prolonged neu-
tropenia may be attributed to infections, 26 a major cause of mor-
bidity in patients with cancer. Fever in a cancer patient should
be considered indicative of infection unless proven otherwise,
with appropriate assessments being instituted in a timely fash-
ion. Febrile neutropenic patients (absolute neutrophil count ≤
500/mm 3) represent an absolute emergency. In patients with
advanced Alzheimer’s disease, physical consequences of the
progression of dementia predispose them to infection and fever,
especially to aspiration pneumonia, urinary tract infections, 27−30
and decubiti.
Paraneoplastic fever
Fever may be a common presentation for some malignancies and
their progression may parallel the occurrence of fevers. Although
Hodgkin’s disease has classically been associated with Pel–
Epstein fevers (recurring periods of fever lasting for 3–10 days
at a time), several other malignancies are also associated with
paraneoplastic fevers and include acute leukemias, lymphomas,
renal cell carcinomas, bone sarcomas, adrenal carcinomas, and
pheochromocytomas. Solid tumors such as breast, lung, and
colon cancer are less often associated with paraneoplastic fevers.
However, the presence of liver metastasis from these tumors may
result in fever. In addition, any solid tumor causing obstruction
can result in fever.
Malignancy is often found during the workup of patients
presenting with fever of unknown origin. While earlier reports
found an incidence of 20%, a later study reported malignancy
as the cause of fever in 15% of patients. 31 In patients with cancer
presenting with fever of unknown origin, paraneoplastic fever
was found to be the most common etiology. 32 Although the exact
mechanism of tumor-associated fever is unclear, it is thought to
involve inflammatory cytokines such as TNFα, IL-1, and IL-6,
BOX 52.1  ETIOLOGY OF FEVER
IN CANCER PATIENTS
• Blood transfusion reaction
• CNS metastasis
• Drug-associated etiologies (e.g., cytotoxic agents,
antibiotics, IFN)
• Infections
• Radiation-induced fevers (e.g., radiation pneumonitis)
• Thrombosis
• Tumor (paraneoplastic fever)
Fever, Sweats, and Hot Flashes
which are produced either by host macrophages in response to
the tumor or by the tumor itself. 33,34
Transfusion-associated fever
Febrile and allergic nonhemolytic transfusion reactions
(NHTRs) are the most common adverse effects of blood trans-
fusions. 35,36 These reactions are generally not life threatening,
but they are expensive in their management, evaluation, and
associated blood product wastage. The true incidence of febrile
NHTRs (FNHTRs) is not well established in patients with can-
cer. In a large retrospective study, the incidence of side effects
following transfusion of 100,000 units of packed red blood
cells to more than 25,000 cancer patients over a 4-year period
was found to be at 0.3% (of these, 51.3% were FNHTRs, 36.7%
were allergic urticarial reactions, and 17% were hemolytic reac-
tions). 37 This is comparable to other studies where the incidence
has ranged from 0.2 to 0.7%. 38,39
The occurrence of fever is usually caused by the presence of
antibodies to antigens on the donor’s white blood cells. Its pre-
vention by using leukodepleted blood components was demon-
strated more than two decades ago.40−42 Some studies have shown
a correlation with storage time of platelets and the release of cyto-
kines as another reason for the occurrence of FNHTRs.43−45
Infection may also be a source of fever in patients receiving
blood transfusions.46−48 The prevalence of bacteria is estimated
to be about 0.04−2%, depending on the type of components, the
number and age of the evaluated components, and the detection
methods used. It is estimated that 1 in each 1000/2000 units of
platelet concentrates (obtained from whole blood or apheresis) is
contaminated with bacteria.49−52 The incidence of bacterial con-
tamination in red cell concentrates is much lower and almost
zero for fresh frozen plasma and cryoprecipitate.
Drug fever
Drug-associated fever is usually a diagnosis of exclusion, except
for some drugs such as biological response modifiers, ampho-
tericin B, and bleomycin, where the occurrence of fever may be
predictable. Other drugs commonly implicated as a cause of fever
include antibiotics, cardiovascular drugs, anticonvulsants, cyto-
toxic agents, and growth factors. In one retrospective study of 148
episodes of drug fever, antimicrobials were found to be the most
common offending agents (31%).53 Cytotoxic agents accounted for
11 episodes (7.4%).
In a retrospective chart review of 50 patients who had received
at least 100 mg of amphotericin B for at least 3 days, the inci-
dence of fever and chills was 34 and 56%, with rates of 2.6 and 3.5
mean episodes per patient per treatment course, respectively.54
INF therapy is associated with acute “flu-like” syndrome consist-
ing of fever, chills, fatigue, myalgias, arthralgia, and headaches,
with some variation according to type of IFN, route of admin-
istration, schedule, dose, and age of patient.55 The administra-
tion of growth factors is also associated with fever, being more
common following granulocyte macrophage colony-stimulating
factor (GM-CSF) administration than granulocyte colony-stim-
ulating factor (G-CSF) administration. Bleomycin-associated
fever occurs in 20−50% of patients and is more common when it
is administered intravenously. Fever is also associated with other
cytotoxic agents such as cisplatin, streptozocin, 5-fluorouracil,
and therapy with monoclonal antibodies.56−59 In addition to anti-
biotics, common drugs in palliative care setting which can mimic
rise in body temperature include antipsychotics (neuroleptic
503
malignant syndrome [NMS]) and antidepressants (serotonin
syndrome).60 See fever versus hyperthermia in the following.
Withdrawal from opioids can also present in similar manner.
Evaluation of fever
Assessment of fever requires a careful study of history, medica-
tion review, and a thorough physical examination to include all
major body systems. Patients should undergo meticulous evalua-
tion of the skin and all body orifices, including mouth, ears, nose,
throat, urethra, vagina, rectum, venipuncture sites, biopsy site,
skin folds (i.e., breast, axilla, abdomen, and groin), and interdigi-
tal spaces. In nearly two-thirds of neutropenic patients, the initial
evaluation may not identify a focus of infection. 33 This may relate
in part to the high frequency of empirical treatment with broad-
spectrum antibiotics, which may make it harder to determine
the site of infection. Careful physical examinations should be
repeated at least daily in patients with neutropenia, even after the
initiation of empirical antibiotics. It must be remembered that
immunocompromised patients may be vulnerable to more than
one infection and that different organisms may emerge during a
single febrile episode.
Interventions for fever
Goals of care
The presence of fever may be associated with potential metabolic
consequences including dehydration, increased oxygen con-
sumption, and metabolic rate,61,62 which may be especially pro-
nounced in debilitated terminally ill patients. If prolonged, fevers
may be associated with increased nutritional demands and debil-
itating fatigue. Although fever may be beneficial for enhancing
host defense,63,64 other factors such as the patient’s comfort and
physiological responses also deserve consideration. Suppression
of fever may help alleviate uncomfortable, constitutional symp-
toms of fatigue, myalgias, diaphoresis, and chills. In addition to
constitutional symptoms, focal findings related to the etiology
of fever may also contribute to symptom burden. For example,
abscess formation is often associated with pain, while uncom-
fortable dyspnea and cough can be related to pneumonia. The
specific interventions used for fever management are determined
by the underlying etiology, together with patient-determined
goals of care. Workup of fever can lead to unnecessary and pro-
longed hospitalization as well as additional costs for patients near
the end of their life, resulting in significant suffering.65 Patients
with advanced cancer may opt not to treat the underlying etiol-
ogy of fever and seek only nonspecific palliative measures. For
patients who can communicate, it may be beneficial to be cer-
tain that if the fever is uncomfortable, and whether curing the
fever is more uncomfortable than the fever itself for the patient.
Although empiric, there is no compelling reason to think that
treatment of fever actually reduces suffering for dying, unrespon-
sive patients.66 Individuals seeking comfort-oriented care exclu-
sively may decline parenteral antibiotic treatment of pneumonia
to avoid hospitalization and remain at home. For others, treating
the underlying etiology of fever with more aggressive interven-
tions, such as surgical drainage of a painful abscess, will offer
symptom palliation and potentially contribute to improvement
in quality of life and even life prolongation. Aggressive treat-
ment of infection does not improve survival rates among persons
with severe dementia and has been associated with accelerated
progression of the severity of dementia.67 Antibiotics and other
aggressive measures are often associated with numerous deleteri-
ous outcomes, including renal failure and ototoxicity, allergic or
504
drug reactions, rash, diarrhea, blood dyscrasias, antibiotic resis-
tance, use of intravenous lines and mechanical restraints, pro-
longed time to death, and increased costs.68,69
Nonspecific interventions
During febrile episodes, increasing fluid intake, removing excess
clothing and linens, tepid water bathing or sponging, and use
of antipyretics may offer relief. In the very sick, administration
of fluids intravenously or subcutaneously may be warranted.
Other comfort measures include the application of lubricant to
dried lips and keeping mucous membranes moist with ice chips.
Convective cooling via increasing air circulation by fans or using
an airflow blanket may be effective in reducing temperatures and
improving patient comfort.70 Ensure that clothes and bed linens
are dry and changed as needed. Again, patient preferences must
always be given priority. Noisy and labor-intensive measures that
may distract family and other caregivers from more meaningful
interactions at the death-bed should be avoided. Education and
reassurance is of paramount importance in such situations.66
Antipyretic agents such as acetaminophen, aspirin, or nonste-
roidal anti-inflammatory drugs (NSAIDS) act by lowering the
elevated thermal set-point by the inhibition of enzyme COX.
Although these agents are commonly administered to hospital-
ized patients to enhance patient comfort,71 no studies have been
done in the cancer population with fever, and carefully controlled
efficacy studies have not quantified the degree to which the anti-
pyretics therapy enhances the comfort of febrile patients in other
populations. Although theoretically, patients with pulmonary and
cardiovascular disorders may benefit from antipyretic therapy by
minimizing the impact of increased metabolic demands, the risk
versus benefit of this approach has not been determined. Similarly,
antipyretic therapy has not been demonstrated to prevent febrile
seizures in children.72 Several studies have confirmed that increas-
ing the dose of acetaminophen from moderate dosage (10 mg/kg
every 4 hours, maximum 5 doses/day) to relatively higher dosage
(15−20 mg/kg every 4 hours, maximum 5 doses/day) in children
failed to reduce the rate of recurrence of febrile seizures.73
Fever control may be enhanced by combining physical meth-
ods with antipyretics. In children, a randomized placebo-con-
trolled trial of sponging with ice water, isopropyl alcohol, or
tepid water (with or without acetaminophen) demonstrated
that all combinations enhanced fever control, but comfort was
greatest in children receiving placebo or sponging, followed by
those who received acetaminophen combined with tepid water
sponging.74 Discomfort was found to be greatest when sponging
with ice water or isopropyl alcohol with or without concomitant
administration. Like acetaminophen, aspirin may be effective in
reducing fever, but should be used with caution in patients with
or at risk of thrombocytopenia due to its antiplatelet effects. In
children, aspirin use is contraindicated due to the risk of Reye
syndrome with fever related to certain viral etiologies, including
varicella and influenza.75 NSAIDs should also be used cautiously
in the cancer population, as they inhibit platelet function and
may also cause gastrointestinal hemorrhage and adversely affect
renal function.
Primary interventions directed at the etiology of fever
Infections
Patients should be instructed to seek medical help if a fever
develops when the neutrophil count is low or declining. In febrile
Textbook of Palliative Medicine and Supportive Care
neutropenic patients, broad-spectrum antibiotics should be ini-
tiated immediately even before culture results are available,76 as
mortality rate is 70% for patients not receiving antibiotics within
48 hours.77 Initial antibiotic use is guided by the knowledge of
the treating institution’s antimicrobial spectrum and antibiotic
resistance pattern, as well as the suspected cause. Although there
is general consensus that empirical therapy is appropriate, there
is no consensus as to which antibiotics or combinations of antibi-
otics should be used. The Infectious Diseases Society of America
(IDSA) Fever and Neutropenia Guidelines Panel recommends
empirical antibiotics based on the patient’s clinical condition and
risk for complications, and determination of the need of vanco-
mycin in the initial regimen.78 These four protocols are depicted
in Table 52.1.
Treatment regimens are further modified by the duration of
fever and individual patient risk factors such as the presence of
central lines or other artificial devices, history of steroid use, and
history of injection drug use. After a specific pathogen is isolated,
antibiotic therapy is then changed to provide optimal therapeutic
response. The single most important determinant of successful
discontinuation of antibiotics is the neutrophil count. If infec-
tion is not identified after 3 days of treatment, if the neutrophil
count is >500 cells/mm3 for 2 consecutive days, and if the patient
is afebrile for >48 hours, antibiotic therapy may be discontinued.
For neutropenic hosts with persistent or recurrent fevers after
1 week of broad-spectrum antibiotic therapy, the addition of an
antifungal agent is recommended, as continued granulocytope-
nia is usually associated with the development of nonbacterial
opportunistic infections, particularly candidiasis and aspergil-
losis.79 Acyclovir is the drug of choice in the treatment of her-
pes simplex or varicella zoster viral infection. Ganciclovir has
activity against cytomegalovirus (CMV). Both agents can be used
prophylactically in the management of patients at high risk for
these infections. Foscarnet is useful in the treatment of CMV and
acyclovir-resistant herpes simplex virus.
Various investigators have developed models predicting risk
groups of febrile neutropenia, with implications for management
strategies. Therapeutic options under evaluation include early
hospital discharge, home intravenous antibiotic therapy, and oral
antibiotic regimens. Due to rapid changes in the field, the reader
is directed to specialized sources for specific management rec-
ommendations of febrile neutropenia.
Paraneoplastic fever
The best management for paraneoplastic fevers is the treatment of
the underlying neoplasm with definitive antineoplastic therapy. If
not possible, NSAIDs have been considered as the mainstay of
treatment,66 with naproxen being the most extensively studied.
However, indomethacin and diclofenac have also been found to be
effective.80 Several studies have suggested that neoplastic fevers
are more responsive to NSAIDs than infectious fevers, leading to
advocacy of the “naproxen test” to differentiate between neoplas-
tic and nonneoplastic fevers.65,81,82 However, this approach has
not been validated.83 Thalidomide, an immunomodulatory agent,
has been shown to have modulatory and/or suppressive effects on
several cytokines such as TNFα, IL-1, and IL-6,84,85 all involved in
paraneoplastic fever and which, theoretically, may have a role in
the treatment of cancer patients with fever and sweats.86 Despite
reports of its antipyretic and antidiaphoretic activity,87,88 this
agent has not been formally tested in clinical studies with can-
cer patients for fever or sweat control. Strategies, using the IL-1
Fever, Sweats, and Hot Flashes 505

TABLE 52.1 Empiric Antibiotic Regimens for Unexplained Neutropenic Fever in the Cancer
Population
Regimen Route
1 Oral
2 Intravenous
3 Intravenous
4 Intravenous
Source: Data from Milner LV. Butcher K. Transfusion 1978 July–August;18(4): 493.
Antibiotic Selection
Ciprofloxacin plus
amoxicillin-clavulanate
Choose one: cefepime,
ceftazidime, imipenem, or
meropenem
Aminoglycoside plus
antipseudomonal penicillin
or ceftazidime or
carbapenem
Vancomycin plus antibiotics
from regimens 2 or 3 above
Comments
• For use in select adult patients
• Patients mostly in remission and at low risk for
serious life-threatening infections
• Can be used on an outpatient basis if ready access
to care, no signs of focal infection and no signs or
symptoms suggestive of systemic infection other
than fever
• Mono drug choice is as effective as multiple drug
combinations for uncomplicated neutropenic
patients
• Monitor closely for poor response, emergence of
secondary infection(s) and drug resistance
• Advantages include potential synergistic effects
against some Gram-negative bacilli
• Potential minimal emergence of drug-resistant
strains during treatment
• Restrict to
• Institutions with high prevalence of infections
with penicillin-resistant Gram-positive
bacteria
• Suspected catheter-related cellulitis or
bacteremia
• Gram-positive bacteremia
• Evidence of septic shock

receptor antagonist model, have been explored in paraneoplastic
fever aimed at blocking IL-6 signaling pathways.13
Transfusion-associated fever
Many institutions have moved toward leukoreduced trans-
fusions in an effort to decrease incidence of FNHTRs, and
several countries have even restricted the manufacture and
transfusion of blood products to prestorage leukodepleted
blood components only. A retrospective analysis conducted
at Johns Hopkins Hospital examined the frequency of trans-
fusion reactions associated with the transfusion of red blood
cells (RBCs), between July 1994 and December 2001. 89 The
study directly compared two time periods before and after the
initiative toward leukoreduction. In the initial period (July–
December 1994) before the initiative to move toward leuko-
reduction, 96% of RBC inventory was non-leukoreduced. In
the study period after leukoreduction (July–December 2001)
99.5% of RBC inventory was leukoreduced. When comparing
these two time periods, the incidence of FNHTRs decreased
from 0.37 to 0.19% (p = 0.0008). The trend over the entire
7.5-year study period confirmed the decrease in FNHTRs as the
percentage of leukoreduced RBCs increased. The incidence of
allergic NHTRs remained unchanged. The decreased incidence
of FNHTRs with leukoreduction has been found in other stud-
ies as well.90−93 Common clinical practice prior to blood prod-
uct transfusions includes premedication with acetaminophen/
diphenhydramine with or without steroids. The use of eryth-
ropoietin for cancer-related anemia may decrease the need of
blood transfusions and may be used for cancer-related anemia.
The risks versus benefits, including cost, of such prophylactic
treatments to avoid or delay transfusions needs to be carefully
reviewed as they are not devoid of side effects, including reduc-
tion in survival.94−97
Drug fever
Drug-associated fever responds to cessation of the offending
agent, when possible. Response to fever and related symptoms,
with biological response modifier administration, is type-, route-,
dose-, and schedule-dependent. These factors may sometimes
be altered for fever control without compromising with effi-
cacy. Liposomal amphotericin B is as effective as conventional
amphotericin B for empirical antifungal therapy in patients with
fever and neutropenia, but is associated with decreased toxicity,
including occurrence of fever and chills.98 Caspofungin has also
shown promising responses.79 Fever may also be attenuated by
the use of acetaminophen, NSAIDs, with or without steroid, pre-
medication. It is common clinical practice to administer meperi-
dine to attenuate severe chills associated with a febrile reaction,
although empirical data confirming its efficacy are not available.
Index of suspicion should be kept higher when using multiple
antidepressants or antipsychotics and while rotating or suddenly
stopping opioids or any drugs of abuse when patient gets admit-
ted (withdrawal).
Fever versus hyperthermia
Although in the vast majority of patients, an elevated body
temperature usually represents a fever, there are instances
where elevated temperatures could be secondary to hyper-
thermia. These include heat stroke syndromes, certain meta-
bolic diseases (hyperthyroidism), and drugs that interfere with
506 Textbook of Palliative Medicine and Supportive Care

thermoregulation. With fever, thermoregulatory mechanisms cool fluid, gastric lavage or enemas with ice water, and even
remain intact, but the hypothalamic thermal set-point is raised extracorporeal circulation. No matter what technique is used,
by exposure to endogenous pyrogens,99 leading to behavioral and the body temperature must always be monitored closely to
physiological responses to elevate body temperature. In contrast, avoid hypothermia.
during hyperthermia, the setting of the thermoregulatory center
remains unchanged66 at normothermic levels, while body tem- Sweats
perature increases in an uncontrolled fashion and overrides the
ability to lose heat. Hyperthermia thus results from overwhelm- In patients with advanced disease or those receiving palliative
ing of the peripheral heat-dissipating mechanisms by disease, care, the prevalence of sweating (hyperhidrosis) ranges from 14
drugs, or from excessive heat, be it external or internal.100 to 28%, is frequently nocturnal (nocturnal diaphoresis or night
Atropine may increase endogenous heat production by sweats), and is moderate to severe in intensity.108−111 Although
interfering with thermoregulation: It blocks sweating and night sweats have been defined as drenching sweats that require
vasodilation, thereby raising core temperature. Hyperthermia the patient to change bedclothes, this definition may not describe
also occurs with NMS, an idiosyncratic reaction to drugs that the majority of patients who complain of the symptom. Sweating
block the dopamine receptor. Haloperidol and chlorproma- is a feature unique to humans (and apes) in which skin loses heat
zine, which are conventional antipsychotic agents, can be the through evaporation and it helps in regulating body tempera-
common offenders.101,102 Atypical antipsychotic medications, tures when exposed to hot environment. Patients with inherited
including clozapine, risperidone, olanzapine, and quetiapine, disorder of anhidrotic ectodermal hypoplasia as well as infants
have also been associated with NMS.103,104 There are also case and frail elderly fail to sweat sufficiently to maintain cooler body
reports of other medications causing NMS, including venla- temperatures.111 In the literature, night sweats have also been
faxine, promethazine, and metoclopramide.105,106 NMS typi- associated with a variety of medical problems including malig-
cally occurs within several days of the initiation of treatment, nancies (e.g., lymphomas), some infections including tubercu-
while dosages and serum concentration of these medications losis, autoimmune diseases, and drugs. Common malignancies
are usually within the therapeutic range. The probability of associated with night sweats include lymphomas, leukemia, renal
developing NMS is directly related to the antidopaminergic
potency of the neuroleptic agent. In addition, specific poly-
morphisms of the dopamine D2 receptor may predispose some
patients to NMS.107 Use of multiple antidepressants can pres- BOX 52.2  ETIOLOGY OF NIGHT SWEATS
ent with serotonin syndrome. 60 Great care should be taken
not to predispose a patient to withdrawal of opioids or sudden Malignancy
stoppage of a drug of abuse, especially immediately after the
patient gets admitted. • Castleman’s disease
It is important to make the distinction between fever and • Leukemia
hyperthermia, since management approaches to these distinct • Lymphoma
syndromes differ. There is no rapid way to differentiate elevated • Renal cell carcinoma
core temperature due to fever from hyperthermia, and a diagnosis
of hyperthermia is often made because of a preceding history of Infections
heat exposure or use of certain drugs that interfere with normal
thermoregulation. On physical examination, the skin is hot but • Endocarditis
dry in heat stroke syndromes and in patients taking drugs that • Fungal infections
block sweating. • Human immunodeficiency virus
Antipyretic agents act by lowering the elevated thermal set- • Infectious mononucleosis
point and are used in the treatment of fever, but are ineffec- • Lung abscess
tive in hyperthermia, where the thermal set-point is normal. In • Mycobacterium avium complex
hyperthermia, drugs that interfere with vasoconstriction, such as • Tuberculosis
phenothiazines and those that block muscle contractions or shiv-
ering, are useful. However, these are not true antipyretics as they Others
can reduce body temperature independently of hypothalamic
control. Shivering may be suppressed with intravenous benzodi- • Anxiety
azepines such as diazepam or lorazepam. Chlorpromazine intra- • Chronic fatigue syndrome
venously (25–50 mg) may also be used for this purpose if NMS is • Diabetes insipidus
not suspected. • Gastroesophageal reflux disease
In patients diagnosed with hyperthermia, physical cool- • Granulomatous disease
ing should be started immediately with techniques such as • Obstructive sleep apnea
removing bedclothes, sponging the patient with tepid water, • Rheumatologic diseases
and using bed fans. More rapid reductions in body tempera-
ture can be achieved by sponging the patient with alcohol Endocrine
or by using hypothermic mattresses or ice packs. Immersion
in ice water is the most effective means of physical cooling, • Acromegaly
but it should be reserved for true hyperthermic emergencies, • Diabetes insipidus
such as heat stroke. In true emergencies, treatment may also
include the intravenous or intraperitoneal administration of
Fever, Sweats, and Hot Flashes
• Diabetes mellitus (nocturnal hypoglycemia)
• Endocrine tumors (pheochromocytoma, carci-
noid tumor)
• Hyperthyroidism (thyrotoxicosis)
• Orchiectomy
• Perimenopausal and postmenopausal women
Drugs
• Antihypertensives
• Antipyretics: salicylates, acetaminophen
• Drugs of abuse: alcohol, heroin
• Leuprolide
• Niacin
• Opioids: morphine, diamorphine, methadone,
butorphanol
• Phenothiazines
• Selective estrogen receptor modulator drugs
(SERMs): tamoxifen and raloxifene
• Selective serotonin receptor inhibitors
cell carcinoma, and Castleman’s disease. The classic presenta-
tion of tuberculosis includes fever, weight loss, and night sweats.
AIDS-related infections might also cause night sweats, including
Mycobacterium avium complex (MAC) infection and CMV syn-
dromes. The differential diagnosis for night sweats is broad, and
Box 52.2 lists some of these conditions.
Patients presenting with night sweats warrant a detailed
evaluation including history and physical examination aimed at
revealing associated symptoms to help narrow down the broad
differential diagnosis and guide further workup. Compensatory
hyperhidrosis can usually occur in normal sweat-producing skin
areas in response to anhidrosis in other areas of skin. The preva-
lence of sweats and their impact on quality of life in the cancer
population is not well established and requires further descrip-
tion. Clinically, hot flashes are often seen in association with
sweats. By far this is the most common cause of sweats encoun-
tered in clinical medicine, experienced by the majority of peri-
menopausal and postmenopausal women, and hence, this topic is
being covered in detail later.
Hot flashes
Hot flashes, experienced by three-quarters of menopausal women,
are described as a sudden onset of an uncomfortable sensation of
intense heat, accompanied by skin flushing, warmth, and sweat-
ing, usually of the chest and face.4 Hot flashes typically last for
2–4 minutes and are often accompanied by palpitations and anxi-
ety, and may be triggered by emotional stress, anxiety, alcohol,
and certain foods.112 Factors associated with a greater risk of hot
flashes are listed in Box 52.3.113–116 Approximately two-thirds of
women with history of breast cancer experience hot flashes.5 In
postmenopausal women with a history of breast cancer, predic-
tors of hot flash severity include higher body mass index, a high
school education or less, younger age at diagnosis, and tamoxifen
use (SERM).117,118 For patients starting tamoxifen, hot flashes typi-
cally increase in the first 2–3 months, followed by a plateau and
then gradual dissipation.119
In men treated with androgen ablation for locally advanced
or metastatic prostate cancer, 50–88% experience hot
507
BOX 52.3  FACTORS ASSOCIATED
WITH HOT FLASHES
Abrupt menopause
• Chemotherapy
• Drugs
• Radiation
• Surgery
Cancer type
• Breast
• Prostate
Early menopause
Ethnicity
• African women
• Western women
Lack of exercise
High body mass index
Low education
Low estrogen levels
Low socioeconomic status
Smokers
flashes.120,121 Patients with other cancers are also affected with
hot flashes; however, data on this is limited. The rapid meno-
pause associated with cancer treatments does not allow for
a gradual adjustment of falling estrogen levels, and this may
explain why hot flashes resulting from cancer treatment tend
to be more profound.
Pathophysiology
The prevailing hypothesis relates the development of hot flashes
to lowering of estrogen levels leading to complex neuroendocrine
mechanisms, including alterations in the level of hypothalamic
neurotransmitters, which resets the thermostat to a lower level
with a narrower range, as compared with those who do not expe-
rience hot flashes.122,123 A small rise in core body temperature has
been found to occur 15 minutes prior to hot flashes in 60% of hot
flash episodes.124 This subtle elevation in core body temperature
stimulates mechanisms of heat dissipation, resulting in cutane-
ous vasodilation and sweating, the two central components of the
hot flash syndrome.
Two most recognized neurotransmitters involved in hypo-
thalamic thermoregulatory processes are norepinephrine and
serotonin. Catecholestrogens (estrogenic metabolites) abundant
in the hypothalamus stimulate the production of β-endorphins.
Both catecholestrogens and endorphins inhibit the production
of hypothalamic norepinephrine. Loss of this negative feedback
in low estrogenic states results in rise of norepinephrine levels
and an upregulation of certain hypothalamic serotonin receptors
responsible for resetting of the thermostat.125 Norepinephrine is
believed to be responsible for the rise in core temperature prior
to onset of hot flashes.124 In men, it is uncertain if low testoster-
one levels or decline in estrogen levels or both are responsible for
development of the hot flash syndrome.
508
BOX 52.4  TREATMENT INTERVENTIONS FOR
HOT FLASHES IN PATIENTS WITH CANCER
Hormonal agents
• Androgens
• Estrogens
• Progestational agents
Nonhormonal agents
• α-Adrenergic agents
• Antidepressants
• β-Blockers
• Gabapentin
• Veralipride
• Vitamin E
Complementary and alternative medicine (CAM)
approaches
• Herbal medications
• Acupuncture
• Behavioral interventions
Assessment and treatment of hot flashes
Hot flashes should be routinely assessed as a component of sys-
tematic symptom surveys, and if present, a careful assessment of
hot flash frequency, intensity, duration, potential triggers, and
impact on quality of life is advised in order to construct an indi-
vidualized treatment plan. Patient self-report diaries with hot
flash frequency, intensity, possible trigger factors, and associ-
ated distress can be helpful to clinicians to formulate treatment
recommendations.126 Hot flash score is determined by multi-
plying the daily frequency of hot flashes by their average sever-
ity. Box 52.4 lists the possible options for management of hot
flashes.
Hormone replacement therapy
Estrogen
Estrogen replacement is effective for treatment of hot flashes in
80–90% of patients, regardless of underlying etiology.127,128,129,130
However, some women have absolute or relative contraindica-
tions to hormone replacement therapy (HRT), and others are
reluctant to take hormones due to perceived risks and side
effects. The Women’s Health Initiative Study evaluated the risks
and benefits of estrogen plus progestin therapy in healthy post-
menopausal women.131 The estrogen plus progestin arm was
stopped prematurely in women with an intact uterus at a mean
follow-up of 5.2 years due to detection of a 1.26 times increased
breast cancer risk (95% CI 1.00–1.59). Observed benefits of HRT
on hip fractures and colon cancer risk were far outweighed
by increased risks of venous thromboembolic disease, breast
cancer, stroke, and coronary artery disease. Another popula-
tion-based, case-control study of 975 postmenopausal women
diagnosed with breast cancer supports an increased risk of
breast cancer with combined HRT.132 In this cohort, HRT use
Textbook of Palliative Medicine and Supportive Care
was associated with an increased risk of breast cancer, including
lobular, ductal, and estrogen and progesterone receptor positive
tumors.
Progestational agents
Progestational agents have comparable efficacy to estrogens for
hot flash reduction. Agents studied include megestrol acetate and
transdermal progesterone, and the long-acting intramuscular
preparation, depo-medroxyprogesterone acetate (DMPA).133,134,135
Despite benefit of amelioration of hot flashes, there is ongo-
ing debate about safety of progesterone in patients with breast,
uterine, or prostate cancer. In men with prostate cancer, several
investigators have reported a decline in prostate-specific antigen
levels after withdrawal of megestrol acetate, raising concerns that
its use may be harmful in this population.136–138 Risk associated
with progestin use in women with a history of breast cancer is
unknown at this time, as is its effect on the outcome of tamoxifen
treatment. Some data have suggested that progestational agents
may increase epithelial cell proliferation, an undesirable effect
in breast cancer.139,140 There is also some evidence of antitumor
activity in breast cancer.141
Tibolone
Tibolone, a synthetic steroid compound with combined estro-
genic, progestogenic, and androgenic properties, has been
reported to reduce hot flashes.142,143 One study of postmenopausal
women receiving tamoxifen after surgery for breast cancer found
a significant reduction in the severity of hot flashes with tibo-
lone compared with placebo (rated as 0.4 vs. 0.2, respectively, p =
0.031) but no change in the daily number of hot flashes with either
tibolone or placebo (p = 0.219).144 Tibolone is not available in the
United States.
Nonhormonal agents
Nonhormonal agents are gaining popularity as therapy for hot
flash reduction due to the heightened concerns about the risks of
using HRT. These include pharmacotherapies as well as comple-
mentary and alternative medicinal approaches.
Antidepressants
Several large placebo-controlled, randomized trials have
shown the beneficial effects of antidepressants from the selec-
tive serotonin reuptake inhibitors (SSRIs) and selective sero-
tonin and norepinephrine reuptake inhibitors (SSNRIs) class
in hot flash management. In the Mayo Clinic study, breast
cancer survivors and menopausal women experiencing hot
flashes were assigned to receive one of three different dose
levels of venlafaxine (37.5, 75, and 150 mg daily), or placebo for
4 weeks.145 A dose-related diminution in average hot flashes
scores from baseline was noted (27% in the placebo subjects
vs. 37, 61, and 61% for the three venlafaxine groups, respec-
tively). Similar beneficial results have been found in studies
with paroxetine and fluoxetine.146,147 Preliminary studies with
other newer antidepressants, including citalopram and mir-
tazapine, have also shown good results in standard starting
doses.148,149
Of note, many of the SSRIs can inhibit the cytochrome P450
enzyme system involved in the hepatic metabolism of tamoxi-
fen, a drug commonly used in the treatment of breast cancer.
In a prospective study, coadministration of paroxetine with
tamoxifen was shown to result in decreased concentrations
Fever, Sweats, and Hot Flashes
of 4-hydroxy-N-desmethyl-tamoxifen, an active tamoxifen
metabolite (also known as endoxifen).150 Women with the wild-
type CYP2D6 genotype demonstrated greater decreases in
endoxifen levels than those with a variant genotype (p = 0.03).
Given the widespread use of SSRIs for the treatment of mood
disorders and hot flashes, the interactions of SSRIs with tamox-
ifen merit further study.
Other nonhormonal agents
Several other agents have been found to be useful in hot flash
management. In a placebo-controlled, randomized study
of 59 postmenopausal women, gabapentin was more effec-
tive than placebo in reducing hot flash frequency (45 vs. 29%,
respectively) and hot flash composite score (54 vs. 31%, respec-
tively).151,152 Gabapentin appears to decrease hot flashes in men
to similar degree as in women.153 Clonidine, a central acting
α2-adrenergic receptor agonist, has been shown to have mod-
est benefits in hot flash reduction in several studies in healthy
postmenopausal women, breast cancer survivors on tamoxifen,
and men with prostate cancer, but with significant dose-related
side effects,154,155 especially dry mouth, constipation, and sleep-
ing problems. The North Central Cancer Treatment Group
(NCCTG), in a randomized, placebo-controlled crossover trial
of vitamin E in women with a history of breast cancer, found a
minor decrease with treatment, with a mean reduction of one
flash/day, without adverse effects.156 This reduction is unlikely
to be of meaningful clinical benefit. Bellergal, a combination of
belladonna and phenobarbital, was widely used in the past for
hot flash management. Although several reports favor its use
over placebo,157 this therapy cannot be recommended in view
of the risk of phenobarbital dependence and dose-dependent
anticholinergic side effects of belladonna, including dry mouth,
constipation, blurry vision, and dizziness.
Complementary and alternative
medicine approaches
Eighty percent of women in the 45–60-year age groups have
reported the use of nonprescription therapies for the manage-
ment of menopausal symptoms.158 Often perceived to be safer
than HRT, CAM may provide users with a sense of personal con-
trol over their healthcare.
Soy phytoestrogens are weak estrogens found in plant foods,
and while dietary supplementation with natural soy products
appears to be a benign intervention, long-term effects are not
known. Two randomized, placebo-controlled studies show
no clinical benefit of soy over placebo for hot flash manage-
ment.159,160 Breast cancer risk in the general population and risk
of recurrence in breast cancer survivors has not yet been clari-
fied, nor has its effect on hormonally mediated antitumor thera-
pies, such as tamoxifen and the aromatase inhibitors. Black
cohosh (Cimicifuga racemosa) is approved in Germany for the
treatment of hot flashes. The anecdotal clinical and observa-
tional experience suggests black cohosh may be 25–30% more
effective than placebo for menopausal symptoms, including hot
flashes.161 In a randomized, double-blind, placebo-controlled
study on breast cancer survivors in the United States, however,
efficacy of black cohosh was not significantly different from
placebo.162 The high prevalence of tamoxifen use in study par-
ticipants may have confounded study results. Red clover, which
contains isoflavones (phytoestrogens) and dong quai (Angelica
509
KEY LEARNING POINTS
• Fever, chills, and hot flashes are frequently
encountered in palliative care patients.
• Fever in patients with cancer should be consid-
ered indicative of infection, unless proven other-
wise. Neutropenic fever is a medical emergency.
• Fever may be associated with potential metabolic
consequences including dehydration and fatigue,
which may be especially pronounced in debili-
tated terminally ill patients.
• Paraneoplastic and drug fevers should be consid-
ered in the differential diagnosis of fever.
• Cytokines are implicated in the etiology of fever
secondary to infections and paraneoplastic
fevers.
• Both fever and hyperthermia result in the eleva-
tion of core body temperatures but differ in their
pathophysiology and management. Many pal-
liative care patients are on drugs that have the
potential to cause hyperthermia.
• Patients should be assessed for night sweats and
hot flashes.
• Hot flashes are widely prevalent in some cancers
(breast, prostate) and postmenopausal women
and may be associated with significant distress.
• Many nonhormonal therapies are available for
consideration for hot flash management.
sinensis, “female ginseng”), have not been found to be beneficial
in the management of hot flashes.
Acupuncture has been suggested as a remedy for hot flashes. In
a randomized controlled study, Wyon et al. compared the efficacy
of electro-acupuncture with oral estradiol treatment and superfi-
cial needle insertion on hot flash reduction in 45 postmenopausal
women.163 They found that electro-acupuncture decreased the
number of hot flashes significantly over time, but not to the same
extent as the estrogen treatment. No significant difference in
effect was found between electro-acupuncture and the superficial
needle insertion. In a small pilot study of prostate cancer patients
who underwent castration therapy, a substantial decrease (70%
reduction) in hot flash symptoms was noted at 10 weeks, with a
sustained reduction of 50% at 3 months.164 Further studies are
warranted to determine efficacy and potential mechanisms of
action of acupuncture as a modality of therapy for the treatment
of hot flashes.
Behavioral methods may play a role in hot flash management.
Studied methods include relaxation response training165 and
paced respirations.166 These may be used as primary alternatives
for patients who do not want to take medications or as an adjunct
for individuals who achieve suboptimal relief with other inter-
ventions. The beneficial effects may be related to the decreased
adrenergic tone mediated by relaxation techniques. Exercise
would similarly be beneficial.167,168
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Acupuncture treatment of vasomotor symptoms in men with prostatic
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53
PRURITUS

Michael Tang, Katie Taylor, and Andrew Thorns

Contents
Introduction�����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������515
Classification and pathogenesis of pruritus�����������������������������������������������������������������������������������������������������������������������������������������������������������������515
Neural pathways����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������515
Central and peripheral mediators����������������������������������������������������������������������������������������������������������������������������������������������������������������������������516
Scratch���������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������516
Complications of pruritus�����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������516
Assessment of the pruritic patient���������������������������������������������������������������������������������������������������������������������������������������������������������������������������������516
Measuring itch�������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������516
Causes of pruritus in advanced disease������������������������������������������������������������������������������������������������������������������������������������������������������������������������516
Management of pruritus��������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������517
General management techniques����������������������������������������������������������������������������������������������������������������������������������������������������������������������������517
Topical agents��������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������517
Systemic agents������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������517
Specific management strategies�������������������������������������������������������������������������������������������������������������������������������������������������������������������������������518
Cancer-specific pruritus��������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������518
Opioid-induced pruritus��������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������518
Cholestasis��������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������519
Chronic renal failure���������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������520
HIV/AIDS���������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������520
Central lesions and multiple sclerosis���������������������������������������������������������������������������������������������������������������������������������������������������������������520
Summary�����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������521
References���������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������521

Introduction Neural pathways

Pruritus is defined as “an unpleasant sensation that provokes the
desire to scratch.” It has a prevalence of 27% in common tumor
sites,1 and in cholestasis, up to 80% of patients may complain of
itch.2 Severe cases cause distress and can be difficult to treat. This
chapter will summarize the pathogenesis, causes, and effects of
pruritus and will discuss possible treatment options.
Classification and pathogenesis
of pruritus
The pathogenesis of itch is complex and has not been fully elu-
cidated. Both central and peripheral mechanisms are involved,
and a number of mediators are being studied to generate future
treatment options. The duration of symptoms can also be used
to classify pruritus with an acute pruritus indicating a duration
of less than 6 weeks or chronic pruritus indicating a duration of
longer than 6 weeks.EE The International Forum for the Study of
Itch (IFSI) has proposed a system which classifies pruritus into
three groups: pruritus on diseased skin, pruritus on skin without
disease, and pruritus presenting with secondary scratch lesions.EE
There are also six categories proposed which include the follow-
ing: dermatologic, systemic, neurologic, psychogenic, mixed, and
other.EE The category defined as “other” denotes an undetermined
origin.EE
The neurons responsible for the sensation of itch are a subset of
the large population of polymodal C-nociceptors. They are situ-
ated close to the dermal–epidermal junction and comprise about
20% of the C-fiber population in the skin.
The sensation of itch is closely linked to that of pain, and for
many years, it was thought that both were transmitted identi-
cally. Both are unpleasant sensory experiences; however, pain
sensation results in a reflex withdrawal, whereas itch results in
a scratch reflex. C fibers that are associated with itch are ana-
tomically identical to those that mediate pain, but there are some
important functional differences. The itch C fibers are insensitive
to mechanical stimuli and are more sensitive to histamine than
those responsible for the sensation of pain.4 Conduction is 50%
slower than for those fibers transmitting pain, and the receptor
field is three times larger and more superficial than that associ-
ated with pain.5
The neural impulse passes via the C fibers to the ipsilateral
dorsal root ganglia, and from there to the opposite anterolateral
spinothalamic tract, onto the posterolateral ventral thalamic
nucleus and through the internal capsule to the somatosensory
cortex of the postcentral gyrus. There is a substantial coactivation
of the motor areas of the brain which supports the clinical obser-
vation that itch is linked to scratching. There does not appear to
be a distinct “itch center.”6

515
516
The sensation of itch can originate at several points on the
neural pathway. Activation of the C fibers in the skin/mucous
membranes will trigger itch. This type of pruritus is mediated by
histamine and therefore generally responsive to treatment with
H1 antihistamines. In the chronic setting, this response dimin-
ishes, presumably secondary to desensitization at a central level.
Itch can originate at any point along the afferent pathway. This
may occur with neural damage locally (e.g., postherpetic neu-
ralgia) or centrally (e.g., a space-occupying lesion).7,8 This neuro-
pathic itch is not usually H1 antihistamine responsive. Pruritus
may also result from the accumulation of toxins (endogenous or
exogenous) in the spinal cord or brain. This type of pruritus is
histamine independent. The sensation of itch can be magnified
by psychological factors such as stress or anxiety or reduced by
training and distraction. It appears that the central inhibitory cir-
cuits can be altered, thereby affecting the threshold for detecting
pruritogenic stimuli.
Central and peripheral mediators
There are many substances known to be involved in the media-
tion of itch. Histamine is perhaps the best known of these. It is
released from mast cells in response to pruritogenic stimuli and
acts on the H1 receptors of the C fibers in the skin, causing the
characteristic wheal and flare reaction specific to histamine-
mediated pruritus. Prostaglandins E2 and H2 potentiate pruritus
via other mediators including histamine,9 and, in the case of pros-
taglandin E2, directly also.10 Substance P is synthesized in the cell
bodies of C fibers and can directly induce itch as well as modulate
the sensation. The release of substance P can be stimulated by
tryptase from activated mast cells and neutrophils, and this may
increase itch. Other neuropeptides, vasoactive intestinal polypep-
tide (VIP), and calcitonin gene-related protein (CGRP) are found
in the free nerve endings and have been implicated in the media-
tion of itch. An intradermal injection of acetylcholine causes itch
in atopic subjects, but pain in nonatopic subjects,11 which may
explain why some atopic subjects experience itch when sweating.
Opioids are thought to mediate itch at several points in the
pathway. Peripherally, opioids cause mast cell degranulation and
histamine release, but it is at a spinal level that the role of opioids
appears most interesting. They modulate secondary transmission
of the itch sensation by stimulating inhibitory signals to afferent
neurons. Centrally, opioids have been shown to trigger itch in
the laboratory setting by direct action on the floor of the fourth
ventricle.
Serotonin induces itch by two mechanisms: indirectly by
release of histamine from dermal mast cells, and centrally via a
mechanism, which may involve opioid neurotransmitters. Both
opioid and serotonin receptors appear to alter the central inhibi-
tory circuits, and therefore adjust the itch threshold.
More detailed reviews on the basic mechanisms of itch are
available.•12
Scratch
Scratch is the natural response to itch. In evolutional terms, it is
likely to have originated when most pruritogens were parasites or
insects and served to remove the superficial layers of skin which
harbor these.•13 Itch is linked to the motor response of scratch-
ing via a spinal reflex and can be inhibited by cortical centers.
Scratching stimulates A fibers adjacent to those conducting
itch and the A fibers in turn synapse with inhibitory interneu-
rons, subsequently causing inhibition of C fibers and a reduced
Textbook of Palliative Medicine and Supportive Care
sensation of itch. Scratching provides relief for several minutes;
it has been postulated that this occurs due to temporary disrup-
tion of the circuits in the relay synapses of the spinal cord which
otherwise reinforce the itch sensation.
Complications of pruritus
The commonest complication is excoriation that can result in
secondary infection. The effects of lack of sleep, social unaccept-
ability, and interference with daily functioning should not be
overlooked. One study found depressive symptoms in one-third
of patients with generalized pruritus.14 The power of suggestion
can result in itch and learned behavior can quickly develop. The
resultant itch-scratch cycle can be hard to break.
Assessment of the pruritic patient
Routine assessment involves careful history and examination,
particularly noting whether the itch is generalized or localized,
and with careful attention to drug history, exacerbating fac-
tors, and previous medical history. Examination should involve
a detailed description of the site and nature of any skin lesions
and ideally photographic records. A general first-line evaluation
may include complete blood count with differential, which can
help evaluate for malignancies, anemias or elevations in eosino-
phil counts, erythrocyte sedimentation rate, creatinine/blood
urea nitrogen to evaluate for renal dysfunction, and liver profiles
to evaluate for liver dysfunction if clinically indicated. Biopsy of
any suspicious lesions should be discussed with a dermatologist
or dermo-oncologist prior to proceeding.
Measuring itch
The subjective nature of this symptom makes it notoriously dif-
ficult to quantify. Two validated questionnaires have been devel-
oped which attempt to assess the qualitative, temporal, and
spatial characteristics of itch, based on the long and short forms
of the McGill Pain Questionnaire.6 Monitoring systems have
been developed which provide quantitative data independent of
hand/arm movement, and these provide the most reliable assess-
ment method to date.15
Causes of pruritus in advanced disease
Table 53.1 summarizes the causes of pruritus that may be rel-
evant in patients with advanced disease. These can be divided
into general causes of pruritus and those specifically related to
disease. In either case, pruritus may be localized or generalized.
Senile itch is defined as a chronic itch with no determined
etiology in a person aged 65 years or older.FF The majority have
xerosis and skin atrophy; in others the cause is unknown. It is
best treated with general measures (see the following text) and
the application of emollient creams. Pruritus can be iatrogenic,
and the following drugs are common culprits: opioids, aspirin,
etretinate, amphetamines, and drugs that can cause cholestasis
such as erythromycin, hormonal treatment, and phenothiazines.
Iron deficiency with or without anemia can cause pruritus16
and responds to iron replacement. Pruritus occurs in up to 11%
of patients with thyrotoxicosis, particularly long-term untreated
Grave’s disease and less commonly in hypothyroidism.
Other common causes of pruritus are discussed in the man-
agement section.
Pruritus 517

TABLE 53.1  Causes of Pruritus Patients should be advised to gently rub the skin rather than
scratching it, and to keep nails short and wear cotton gloves at
Localized Generalized
night to limit the damage to the skin. Sweating may exacerbate
Dry skin (xerosis) Primary skin diseases itch; the general measures described earlier may help reduce
Infestation, e.g., scabies Metabolic disorders: hypothyroidism sweating; otherwise, an antimuscarinic agent may be required.
Insect bites and hyperthyroidism, carcinoid Exposure to ultraviolet (UV) B light may help in cholestatic-,
syndrome: diabetes mellitus and uremic-, and acquired-immune–deficiency-syndrome (AIDS)-
insipidus related pruritus. Although the nontoxic nature of this treatment
Candida Renal disorders: renal failure with makes it an attractive alternative, it may not be a suitable treat-
uremia ment for a very sick patient. The antipruritic effect is thought to
Eczema Liver disorders: cholestasis be due to a reduction in the vitamin A content of the skin, inhibi-
Contact dermatitis Infection: HIV, syphilis tion of the release of histamine, and inhibition of dermal mast cell
Bullous pemphigoid Hematological disorders: proliferation.17,18
polycythemia vera, iron deficiency Sedatives such as benzodiazepines do not relieve itch but may
anemia help improve associated anxiety and insomnia.19 Behavioral
Dermatitis herpetiformis Neurological disorders:
treatments and hypnotherapy may help ease associated psycho-
cerebrovascular accident multiple
logical issues and break the cycle of itching and scratching.20
Urticaria
sclerosis, brain abscess/tumors,
Transcutaneous electronic nerve stimulation (TENS) and acu-
drug-induced (see text), senile
puncture have been successful in case reports.21,22
pruritus, aquagenic, and Topical agents
psychogenic Topical agents generally provide some relief but may be incon-
Cancer-specific pruritus venient to apply in generalized pruritus, and are probably best
Melanomatosis Chronic lymphocytic leukemia reserved for localized symptoms. A number of topical agents
Mycosis fungoides Hodgkin’s and non-Hodgkin’s have been suggested such as: zinc oxide, calamine, glycerin, and
lymphoma salicylates, but their mechanisms are not understood and their
Carcinoma in situ: vulval, anal Mycosis fungoides effectiveness is unproved. One double-blind, controlled trial of
Paraneoplastic syndrome: Cutaneous T cell lymphoma crotamiton (Eurax®) showed it to be ineffective.23 Polidocanol
prostatic, rectal/colonic, Multiple myeloma bath oil has been shown to reduce itch in uremia, 24 and 3%
cervical carcinomas; polidocanol/5% urea cream has been shown to reduce itch in
glioblastoma psoriasis.25
Metastatic infiltration of skin Paraneoplastic syndrome: breast, Corticosteroid creams may help localized areas of inflamed
colonic, lung, stomach carcinomas skin but are not generally indicated for chronic use.26 Local
and others anesthetic creams can be helpful but may cause skin sensitiza-
tion. Lidocaine is the least likely to have this effect, but systemic
absorption prevents its use over large areas or for prolonged peri-
Management of pruritus ods. Another anesthetic cream, parmoxine 1% lotion, used twice
a day to a localized area in patients with uremic pruritus was
Removal of causative agents (e.g., drugs) and appropriate inves- shown superior to placebo in a small randomized control trial.R
tigation and treatment of underlying disease are essential first- Topical counterirritants such as menthol 0.25–2% or camphor
line measures in the treatment of pruritus. Management can be 1–3% may be useful.
divided into general and pharmaceutical measures suitable for Capsaicin 0.025% acts by depleting substance P in C fibers on
all causes, and pharmacological measures that are more cause- repeated application thus reducing pain and itch. It needs to be
specific. With any intervention for pruritus, a strong placebo applied four times a day and has shown benefit in uremic pru-
response is common. ritus.27 Application can cause an initial burning sensation that
Evidence for the use of different systemic agents in the treat- prohibits widespread application and decreases compliance; for
ment of pruritus is limited. In the context of advanced disease, these reasons, it is best reserved for localized pruritus.
there are few useful trials, and the use of many agents remains Strontium nitrate cream is an effective antipruritic which may
historical or originates from case reports. This is not to say that act by selectively blocking C fiber transmission.28 Tacrolimus
these agents are not helpful, just that the evidence either confirm- 0.03% ointment has shown some effect in localized pruritus
ing or refuting their use is, thus far, unavailable. in renal impairment,29 as has topical gamma linolenic acid. 30
General management techniques Doxepin, a tricyclic antidepressant with potent antihistaminic
These measures are widely accepted as essential, although the action now produced in a topical form, has been shown to be
evidence for their efficacy is largely anecdotal. Exacerbating fac- effective in atopic dermatitis and chronic urticaria. The topical
tors such as heat, dehydration, anxiety, and boredom should be form has been shown to be less effective than the systemic form. 31
avoided. Particular attention should be paid to measures that Its place in other causes of pruritus has not been established.
keep the skin well hydrated and avoid sweating. Patients should Topical diphenhydramine preparations have been shown to have
wear light clothes, use fans to maintain a passage of air, take tepid a toxicity associated with them that has been described in litera-
baths or shower avoiding hot water, and use emulsifying oint- ture due to inconsistent absorption patterns. S
ment or aqueous cream instead of soap. Skin hydration should Systemic agents
be maintained with regular use of emollients. Alcohol and spicy Choice of systemic agents remains based on limited evidence and
foods may worsen the itch. theories of action. While the number of placebo-controlled trials
518
has increased clarifying some treatment choices, there are little
comparative data to indicate one treatment’s effectiveness over
another.
Antihistamines are active at either the H1 or H2 receptor. H1
receptor antagonists are often used as the first choice for any form
of generalized pruritus; however, there is little evidence for their
use other than in urticaria or allergy. The more sedative agents,
such as chlorphenamine, are believed to be more effective either
because of a more potent central action or because the sedation
itself helps to improve the insomnia caused by the itch. H2 anti-
histamines, such as cimetidine, have been shown to be beneficial
in the pruritus associated with lymphoproliferative disorders (see
the following text). Doxepin, which acts at H1 and H2 receptors, is
effective in atopic dermatitis, as discussed earlier.
The 5-hydroxytryptamine 3 (5-HT3) receptor antagonists
showed initial promising results in relieving itch from a num-
ber of causes. 32,33 However, there are some subsequent studies in
which the initial promising results have not been replicated. 34–37
The serotonin selective reuptake inhibitor (SSRI) paroxetine
is helpful in paraneoplastic pruritus, but the effect may only be
temporary, lasting about 6 weeks, 38 and may also be associated
with initial nausea and vomiting. Paroxetine and fluvoxamine
(also an SSRI) have shown a beneficial effect in chronic pruritus
of unknown origin. 39 Another SSRI, sertraline, has some effects
in cholestatic pruritus.40 Mirtazapine is a norepinephrine and
specific serotonin antidepressant, and its actions include block-
ing H1, 5-HT2, and 5-HT3 receptors. It has been shown to be a
helpful antipruritic agent in cholestasis, uremia, and lymphoma.41
Opioid antagonists and kappa-receptor agonists are receiving
increasing attention. In some case reports, naltrexone, an opioid
receptor antagonist, was shown to reduce pruritus in patients
with non-Hodgkin’s lymphoma and mycosis fungoides.KK,LL
Butorphanol was shown to also help reduce pruritus in one
patient with non-Hodgkin’s lymphoma.MM,NN
Gabapentinoids, such as gabapentin and pregabalin, appear
effective in uremic pruritus along with pruritus due to hemato-
logic diseases and paraneoplastic syndromes.GG,HH The mecha-
nism of action is thought to be due to central inhibition of the
perception of pruritus along with inhibition of serotonergic path-
ways and supraspinal neurons.II,JJ.
Specific management strategies
Cancer-specific pruritus
Pruritus can be associated with almost any malignancy, com-
plicating the disease in different ways: for example, as a conse-
quence of direct tumor growth, secondary to cholestasis, or as a
complication of treatment.42
Pruritus is commonly associated with hematological malig-
nancies. Pruritus occurs in about 50% of patients with polycythe-
mia rubra vera, in almost 100% of patients with cutaneous T-cell
lymphoma, and in 30% of patients with Hodgkin’s disease being
more common in the nodular sclerosing subtype with mediastinal
mass.43 Its presence may precede overt disease by up to 5 years.44
In pruritus secondary to polycythemia vera, the use of disease-
modifying therapy often reduces pruritus and should be consid-
ered first45; aspirin, paroxetine, and cimetidine have been shown
to be helpful.46,47,48
In Hodgkin’s disease, cimetidine49 and topical 5% sodium cro-
moglycate50 have been reported as helpful. Corticosteroids have
been used historically and are felt to be effective, but evidence
is lacking. Although cimetidine is an H2 receptor antagonist, its
action is not thought to have a direct antihistaminic effect as it
Textbook of Palliative Medicine and Supportive Care
has little effect on itching caused by histamine, but it is thought
to be related to its inhibitory action on CYP2D6 liver enzymes
that are involved in the synthesis of endogenous opioids and pos-
sibly other pruritogens.51
Mycosis fungoides often presents in the early stages with
pruritic dermatitis that may precede cutaneous lesions by up to
10 years.52 Tumor-modifying treatments are effective in reduc-
ing pruritus, and mycosis fungoides cells are very radiosensi-
tive. Neurokinin-1 receptor antagonists have also been shown
to provide relief in pruritus in patients with cutaneous T-cell
lymphoma.Z,AA Although the exact mechanism is not well under-
stood, thalidomide, which is an immunomodulatory agent, has
been shown to improve refractory pruritus in those with cutane-
ous T-cell lymphoma and Hodgkin’s lymphoma.BB,CC,DD
Other options suggested in lymphoma are mirtazepine41 or
kappa opioid agonists.54
In solid tumors, generalized pruritus may be part of a paraneo-
plastic syndrome in association with lung, colon, breast, stomach,
and prostate primary sites. Localized pruritus can result from
gliomas and carcinomas of the cervix, anus and rectum, sigmoid
colon, vulva, and prostate, which may manifest with pruritus in
the related anatomical areas sometimes as the presenting symp-
tom. Itch in Hodgkin’s disease may appear some years before the
tumor is identifiable. However, research has shown that patients
with generalized pruritus followed up for 6 years did not have a
higher overall incidence of malignancy and that follow-up screen-
ing was not warranted.55
Paroxetine, an SSRI antidepressant, has been shown to relieve
itch in a case series of advanced cancer patients with paraneoplas-
tic itch and in a randomized controlled trial for severe nonderma-
tological pruritus. Its action is probably due to downregulation of
5-HT3 receptors, but side effects (nausea, vomiting, and sedation)
may limit its use. 38,56
A small study showed that gabapentin was effective and safe in
the treatment of interleukin (IL)-2-induced pruritus for patients
undergoing this therapy for metastatic renal cell carcinoma and
malignant melanoma.57
Opioid-induced pruritus
Opioids provide good pain control for the majority of patients,
and are used frequently in advanced disease. Itch is a well-recog-
nized side effect of opioids although the exact etiology is currently
unknown. Pruritus occurs in about 1% of patients on opioids
delivered subcutaneously, orally, or intravenously, and up to 90%
of patients receiving neuroaxial opioids. Experience suggests that
pruritus tends to be generalized in patients on nonspinal opioids;
although in children, it is more common in the facial area, par-
ticularly the nose. In neuroaxial delivery, the pruritus spreads
upward from the level of injection, is commonly maximal in the
face, and may be limited to the nose.58
Postulated mechanisms include a direct central effect, 59
including serotonin release60 and a peripheral effect.61 With
regards to the peripheral effect, opioids seem to have two ways in
which they exert their effect: through a direct vasodilator effect
on vessels and through histamine release.OO,PP,QQ There is data to
suggest that certain opioids may have a histamine-independent
mechanism of action and only involve μ-receptors including fen-
tanyl, oxymorphone, and tramadol.OO,PP,QQ Another postulated
mechanism involves a more indirect role in that the activation
of μ-receptors reduces pain signaling and therefore can increase
pruritic signaling.D,E Although it is suggested that itch is more
Pruritus
common with the naturally occurring opioids, the effect is not
limited to one class of drug with previous reports of itch with
morphine,62,63 fentanyl,64 and oxycodone.65
Opioid antagonists are useful in reducing pruritus but may
reverse the analgesic effect,66 making them an unhelpful choice
of treatment for most patients with advanced disease. In addition
to this, only 2 of 13 studies that were included in a meta-analysis
involving naloxone for the treatment of opioid-induced pruritus,
among other side effects of opioids, included patients with cancer
pain.U There is evidence that using an agonist-antagonist drug,
such as nalbuphine or pentazocine,67 can reduce pruritus with-
out compromising analgesic effect.68 Methylnaltrexone, a selec-
tive peripheral opioid receptor antagonist, decreases several side
effects of opioids including pruritus.69,70,71 Opioid rotation, in par-
ticular changing to hydromorphone, may be a more practical and
effective solution.63
Ondansetron, among other 5-HT3 receptor antagonists, may
also be useful in opioid-induced itch mainly via the neuroaxial
route72 at traditional antiemetic doses.V–Y
Mirtazepine and gabapentin used prophylactically before neu-
roaxial opioids appear to decrease the frequency of itch.73,74
Antihistamines may be only of partial benefit given that the
mechanism of action for many opioids for causing a peripherally
induced pruritus involves more than just histamine release.OO,PP,QQ
Cholestasis
Cholestasis may occur in the general population as a result of gall-
stones, drugs, or intrahepatic disease, as well as obstruction from
primary or secondary tumors involving the biliary tree. Pruritus
is a common sequela of cholestasis, starting on the palmar and
planter surfaces and becoming more generalized. Accumulation
of bile salts has long been suspected as an etiological factor, and
although it may have a role to play, the evidence for a central
mechanism related to increased opioidergic tone and activation of
itch centers in the brain is gathering pace. 3 Bile salts also may play
a role in peripheral causes of pruritus as they have been shown
to cause mast cell degranulation in vitro.A A second mechanism
that has been reported involves the increased level of endogenous
opioids in patients with cholestasis.B,C Treatment of cholestatic
pruritus with the opioid antagonists naltrexone, naloxone, and
nalmefene follows this body of evidence and is successful.75,76,77,78
It is interesting to note that opioid withdrawal effects were noted
even in opioid-naive patients with cholestatic pruritus; this may
be an effect of high levels of endogenous opioids. Pain may also
FIGURE 53.1  Management of cholestatic pruritus.
519
be a complication of using opioid antagonists for symptom con-
trol.79 These side effects may be avoided by titrating an infusion
of naloxone to establish an effective dose before switching to an
oral form.80
The most effective method of relieving pruritus secondary to
cholestasis is to relieve the obstruction. This may be possible by
treating the underlying disease with surgery or chemotherapy or
high-dose dexamethasone, though the initial treatment of choice
is a biliary stent, even in the terminally ill.
Cholestyramine binds bile salts in the gut and has tradition-
ally been used for the treatment of cholestatic pruritus, although
evidence for benefit is limited to one small, open-label study com-
pleted more than 40 years ago.81 As a result of this mechanism of
action, it is ineffective in complete biliary obstruction. Although
often quoted as the first step in management ladders, its use is
limited in palliative care, because it is unpalatable and relatively
large quantities must be consumed for effect, although it is helpful
to mix it with fruit juice. Charcoal has been used along the same
therapeutic line, with similar success and similar acceptability
problems. Rifampicin has been shown to reduce pruritus in cho-
lestasis.82 The mechanism is not clear, but it is thought to interrupt
the enterohepatic circulation of bile acids and therefore reduce the
impact of bile acids on the metabolic processes of the liver. The
presence of severe idiosyncratic side effects in one study requires
liver transaminases to be monitored and may limit its use.83
Sertraline showed benefit in a small randomized double-blind
study.40 Gabapentin showed no benefit in cholestatic pruritus
in a double-blind placebo-controlled trial.84 Antihistamines are
unlikely to be helpful. Treatment with 5-HT3 antagonists was
supported by early evidence, but recent robust trials have found
little or no benefit. 32,34,35,85
The 17-α alkyl androgens have also been used historically with
some effect. The action is not fully understood, but the 17-α alkyl
androgens are directly toxic to hepatocytes and may limit the
capacity of the liver’s enkephalin production.86 Care should be
taken when considering long-term use of 17-α alkyl androgens
in patients with years to live as they have the potential to cause
masculinization in women and occasional serious liver impair-
ment. Their use in practice has been largely superseded by opioid
antagonists and other agents. Other experimental options have
also been explored including: albumin dialysis with molecular
absorbent recirculating system,F UV B phototherapy,G partial
biliary diversion,H and plasmapheresis.I Please see Figure 53.1 for
suggested management strategy.
520
Chronic renal failure
Renal failure may occur as a primary disorder or secondary to
a cancer. It is chronic renal failure that is likely to be associated
with pruritus. Pruritus may be generalized or limited to the back
and the forearm at the site of the arteriovenous shunt.88 There
have been several risk factors associated to pruritus in patients
with chronic renal failure and they include the following: inad-
equate dialysis,J hyperparathyroidism,K high calcium/phospho-
rus product,L and elevated serum magnesium and aluminum
concentrations.M,N The pathogenesis of pruritus in this setting
has not been fully defined but is thought to be multifactorial.
The skin of these patients is atrophic and dry,89 cytokine produc-
tion in the skin and IL-1 may cause the release of pruritogens.
Mast cells are more numerous in patients with pruritic uremia.90
Although plasma histamine levels have been shown to be highly
increased in this group of patients, antihistamines per se are inef-
fectual in improving the pruritus.91
Pruritus is reportedly more common in uremic patients receiv-
ing dialysis than those who are not, although a recent report of
symptoms in patients with stage 5 chronic kidney disease man-
aged without dialysis revealed that more than 80% reported itch
in the month before death.92 High-permeability hemodialysis has
been shown to be more effective in relieving itch than conven-
tional hemodialysis.93
Literature involving the management of uremic pruritus is
limited. Initial therapy typically involves optimizing dialysis,O
treatment of hyperparathyroidism,P and regular use of emollients
and topical agents.Q Pruritus is local in 70% of patients, and for
these patients, capsaicin cream can be effective and practical.26
For generalized pruritus resistant to the above measures, there
appears to be a role for the antiepileptic drugs gabapentin and
pregabalin in uremic patients receiving hemodialysis.94,95,96 The
doses studied are similar to those commonly used to treat neu-
ropathic pain.
The efficacy of opioid antagonists is under dispute: opioid
antagonists have been found to be effective by some researchers,97
and not by others. 33 A novel kappa-receptor agonist, nalfurafine
FIGURE 53.2  Suggested management strategy of uremic pruritus based on current literature regarding common management
practices.O,RR,SS,TT,UU,V V
Textbook of Palliative Medicine and Supportive Care
hydrochloride, improved both itch and sleep disturbance in end-
stage renal failure.98,99
Ondansetron has been used to treat uremic pruritus, but the
evidence for success is conflicting. 36,100
There is some good evidence of thalidomide having an antipru-
ritic effect in uremia.101 Postulated mechanisms for its antipru-
ritic effect include reduction of tumor necrosis factor synthesis
by monocytes, anti-inflammatory action, and interference with
cytokine production. It has also been shown to be effective in the
pruritus of various primary skin conditions, senile pruritus, and
primary biliary cirrhosis.102 UV B phototherapy is established
therapy for uremic itch. Its use in palliative care may be limited
by the delay of 1–2 months before having an effect.18
Other treatments that are being studied for the uremic patients
having dialysis include oral cromolyn sodium103 and topical 1%
pramoxine.104 Please see Figure 53.2 for a suggested management
strategy.
HIV/AIDS
There are many causes of pruritus in HIV-positive patients,106 and
itch can be the first symptom of disease even in the absence of
apparent skin lesions. Pruritus in HIV may be related to cyto-
kine-induced prostaglandin-2 synthesis, and increased plasma
cytokine levels are not uncommon in patients with HIV.107,108
Localized pruritus may occur with peripheral neuropathy.6 There
is a subset of HIV patients who may also experience refractory
pruritus that is thought to be due to overactivation of humoral
immunity. These patients often have recurrent urticarial pap-
ules and infrequent pustules with hypereosinophilia.T Treatment
should relate to the specific cause, but in the absence of an obvi-
ous cause, indometacin (25 mg) three times daily may be helpful. 3
Exposure to UV B light has been shown to be effective.109
Central lesions and multiple sclerosis
Historically, pruritus in this group of patients has been treated
effectively with antiepileptic drugs such as carbamazepine.
Pruritus
Gabapentin may be a better-tolerated choice and does not
interfere with other medications by inducing liver enzymes.110
Nonsteroidal anti-inflammatory drugs such as ibuprofen may
also be helpful.111
Summary
Pruritus can be a troublesome symptom in patients with advanced
disease and may have a substantial effect on quality of life despite
the apparent trivial nature of the symptom relative to a life-lim-
iting diagnosis. Careful history and examination may reveal an
easily reversible cause; where this is not the case, symptomatic
intervention may be helpful. First and foremost, management
should include patient education and lifestyle changes to recog-
nize and avoid triggering factors, and to include important gen-
eral measures for maximal skin hydration in daily routine. Besides
these measures, investigation and treatment of the underlying
cause, where possible, is helpful. Topical or systemic medication,
appropriate to the cause, should be used when required. The rela-
tively limited etiological understanding of pruritus has hindered
logical management, but there is now a more comprehensive body
of evidence slowly but surely being created. Development of fur-
ther useful interventions depends on continued investigation of
the complex mechanisms by which pruritus is created, and more
detailed evaluation of currently available interventions.
KEY LEARNING POINTS
• Pruritus may be directly related to advanced dis-
ease (e.g., cancer, multiple sclerosis), indirectly
related (e.g., cholestasis, uremia), or associated
with the treatment of advanced disease.
• Pruritus may significantly impact sleep, social
acceptance, and daily functioning, and has been
shown to be associated with depression.
• Initial management should include patient edu-
cation and lifestyle changes to encourage identifi-
cation and avoidance of triggering factors.
• The use of emollients to keep the skin continually
hydrated cannot be overemphasized and must
continue on a long-term basis. In addition, a large
number of other topical agents are available and
there is a reasonable evidence base supporting
their use.
• Diagnosis of the underlying cause of pruritus is
important and treatment of underlying disease,
in many cases, resolves the pruritus.
• If topical measures and lifestyle changes are not
adequate, systemic treatment may be necessary
and this chapter provides some evidence-based
suggestions for first-, second-, and third-line
treatments based on etiology.
• The historical use of histamine antagonists in the
treatment of all pruritus has now been modified
by the growing evidence base in this area, and
these drugs are now only recommended for use
in the treatment of urticaria, allergy, and lympho-
proliferative pruritus.
521
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54
INFECTIONS IN PALLIATIVE CARE

Rudolph M. Navari

Contents
Introduction�����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������525
Incidence and type of infections������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������525
Evaluation of fever������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������526
Treatment with antimicrobials���������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������527
Symptom control���������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������528
Patient survival������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������528
Guidelines for antibiotic use�������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������528
References���������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������529

Introduction judicious use of antimicrobials in such settings. It will also sug-

Patients receiving palliative care are at high risk for infections
as a result of their underlying disease, poor nutritional state,
and/or a direct suppression of the hematological system due to
chemotherapy or radiation treatments, viral infections, or use
of corticosteroids.1 An infectious complication may occur due
to an alteration in the phagocytic, cellular, or humoral immu-
nity; an alteration or breach of skin or mucosal defense bar-
riers; indwelling catheters; or a splenectomy. A high index of
suspicion, an awareness of the possibility of unusual infectious
agents, consideration of the empirical institution of antimicro-
bials, and constant surveillance of the hematological status of
the patients are necessary to optimally manage infections in
this patient population.
In addition to the high risk of infections, patients in pallia-
tive care also experience a high incidence of and a wide variety
of infections.1–5 Several retrospective studies have shown that
a large number of patients receiving hospice or palliative care
are treated with antibiotics for suspected or documented infec-
tions.6–13 The benefits and burdens of the use of antimicrobials
in this patient population are topics of much discussion. 3,5,10,14
Prospective studies have suggested that symptom control may
be the main objective of the decision to use antimicrobials to
treat clinically suspected or documented infections in patients
receiving palliative or hospice care.2,3,5,15,16 The use of symptom
control as the main determinant of whether to use antimicrobials
in any given clinical situation is markedly affected, however, by
the uncertainty of predicting which patients will achieve symp-
tom relief and which patients will experience only the additional
burdens of treatment. Determining whether fever is due to infec-
tion, tumor, or other causes, and deciding which symptoms from
suspected infections might respond to various antimicrobial
interventions can be difficult clinical judgments, particularly in
a patient population that has multiple active medical problems
and where the goal of treatment is symptom control. These are
crucial issues in patients receiving palliative care, in that studies
have shown that incurably ill patients often receive nonpalliative
interventions at the end of life.1,17
This chapter will discuss the incidence and the type of infec-
tions seen in various palliative care clinical settings and the
gest the use of symptom control as a major criterion for treat-
ment. The chapter concludes by suggesting guidelines for the
approach to infections in palliative care.
Incidence and type of infections
Patients who are receiving palliative care or hospice care have a
high frequency of infections due to the underlying disease, the
use of indwelling urinary catheters and vascular access devices,
and the generally poor functional status of the patients charac-
terized by impaired cognition and immobility. There have been a
number of reports on the use of antimicrobials in patients receiv-
ing hospice and palliative care.1–3,5–7,9,15,16
In a recent review of infections in palliative care, Macedo
et al.1 suggested that patients and family should be involved in
the discussion regarding how to best treat their infections. They
suggested that symptomatic control was the main indication for
the use of antimicrobials such as the antimicrobial treatment of
urinary tract infections. Antimicrobials improve symptoms in
a large majority of patients with urinary tract infections but are
much less successful in respiratory and skin infections; however,
bacteremia is very poorly controlled by these. They emphasized
that in all situations, the decision on starting an antimicrobial
therapy should depend on the predictable prognosis of survival
and the course of the illness, as the expected survival time of the
patient should be long enough to finish the course and profit from
the antibiotics.
Vallard et al.2 described the use of anticancer and non-anti-
cancer treatments in cancer patients in palliative care units. Data
from 1,091 cancer patients hospitalized in palliative care units
were prospectively collected in 2010–2011, through a multicenter,
observational cohort. The median overall survival after admit-
tance in the palliative care units was 15 days. Specific antican-
cer treatments were systematically stopped in the first 24 hours
in palliative care units, but 25.7% of patients were treated with
antibiotics and oral or systemic antifungal drugs were prescribed
in 21% of the patients. Infection symptoms independently pre-
dicted continuous prescription of antimicrobials. These prescrip-
tions remained commonplace in terminally ill palliative cancer
patients, although their benefit was questionable. Antibiotic and

525
526
antifungal agents were continuously prescribed until death with
questionable therapeutic benefit.
Vitetta et al.6 performed a retrospective chart review on the
prevalence of infections in 102 patients (92% with terminal malig-
nant illness) who died after admission to a tertiary care inpatient
palliative care unit. Thirty-seven patients were diagnosed with
42 infections. The urinary tract, respiratory tract, blood, skin
and subcutaneous tissues, and eyes were the most common sites
of infection. Escherichia coli was the most common infectious
organism. Of the 37 patients, 35 were treated with antibiotics and
symptom improvement was noted in half of the treated patients;
2 of 37 patients were not treated with antibiotics due to survival
limited to the day of admission.
Dagli et al.7 reported on 113 patients in a palliative care unit
during 2016–2017 in a retrospective study which showed that
nosocomial infections were observed in 74.3% of patients and
92.0% were treated with antibiotics. The mean duration of antibi-
otic use was 23.1 days; the use of antibiotics increased the length
of stay, increased the costs, and was not related to mortality. The
authors suggested that antibiotic use for aggressive treatment of
infections in palliative care is not consistent with the philosophy
of palliative care.
Oneschuk et al.9 retrospectively examined the frequency and
types of antibiotics prescribed in the last week of life in three pal-
liative care settings: acute care hospital, tertiary palliative care
unit, and hospice inpatient unit. Of the 50 patients in each set-
ting, 29 (58%) in the acute care hospital, 26 (52%) in the palliative
care unit, and 11 (22%) in the inpatient hospice unit received anti-
biotics in the last week of life. The types of infection, the specific
organisms, and symptom response were not reported. Clayton
et al.15 prospectively studied all patients receiving parenteral
antibiotics in a palliative care unit. Of the 913 consecutive admis-
sions over a 13-month period, 41 patients received 43 courses of
parenteral antibiotics. The most common sites of infection were
urinary tract (37%), lower respiratory tract (26%), and soft tis-
sue/skin (16%). The predominant organisms were not reported,
and the use of antibiotics was considered “helpful” in 27 of the
43 antibiotics courses (62%).
In a retrospective review of 138 patients in a palliative care
unit, Al-Shaqi et al.13 reported that 63% of patients were receiving
antimicrobials during the last week of life. In another retrospec-
tive review, Chun et al.12 reported that 70 of 131 patients receiv-
ing palliative care consultation were treated with antimicrobials.
Fifty-four of the 70 patients received empiric therapy, primarily
for presumed respiratory and urinary tract infections. The effec-
tiveness of the control of symptoms with antimicrobials was not
reported in either of these reports.
Lam et al.11 retrospectively reviewed 87 patients enrolled in a
palliative care service over a period of 6 months. Of 120 episodes
of infection in 70 patients, 117 were treated with antimicrobials.
The most frequent sites of infection were chest (52.5%), urinary
tract (29.2%), and skin/wound (5%), and dyspnea was associated
with a poor prognosis in patients with advanced cancer.
White et al. 3 studied 255 patients with advanced cancer at the
time they entered a community-based outpatient hospice and
palliative care program. Antimicrobial options were discussed
with patients at the time of the initiation of hospice care. Seventy-
nine percent of patients chose no use of antimicrobials or symp-
tomatic use only. The use and effectiveness of antimicrobials was
prospectively documented during the palliative care period. One
hundred and seventeen patients had a total of 129 infections
with the most common sites being urinary tract, respiratory
Textbook of Palliative Medicine and Supportive Care
tract, mouth/pharynx, and skin/subcutaneous tissues. The
most common organisms in this patient population were E. coli,
Staphylococcus aureus, Enterococcus spp., and Klebsiella pneu-
moniae. Seventy-seven patients received antimicrobials, and the
use of antimicrobials controlled the symptoms in the majority of
the urinary tract infections, but these were less effective in con-
trolling symptoms of the other sites of infection. Survival was not
affected by the patients’ choice of whether to use antimicrobials,
the prevalence of infections, or the actual use of antimicrobials.
Oh et al.10 retrospectively reviewed 141 terminal-stage cancer
patients who were hospitalized for symptom control. One hun-
dred and nineteen patients received antibiotics for a clinically
suspected infection. Symptomatic improvement in infection-
related symptoms was achieved in 18 patients (15.1%) with no
improvement in 66 patients (55.4%).
Reinbolt et al.5 prospectively followed 623 outpatient hospice
patients with advanced cancer who were treated with antimicro-
bials for a clinically suspected infection. A complete or partial
response of infection-related symptoms was observed in 79% of
265 patients with urinary tract infections, 43% of 221 patients
with respiratory tract infections, 46% of 63 patients with oral
cavity infections, 41% of 59 patients with skin or subcutaneous
infections, and 0 of 25 patients with bacteremia. There was no
difference in survival of patients with a diagnosed infection com-
pared to those without an infection and no difference in survival
of patients who received antimicrobials compared to those who
did not receive antimicrobials.
Thai et al.18 reported on 441 hospitalized advanced can-
cer patients referred to a palliative care consult service over a
12-month period. Sixteen percent had an episode of sepsis and
23.4% had organ-related infections; 89.7% of these received anti-
biotics. Sepsis and/or organ-related infection reduced overall sur-
vival, but a favorable antibiotic response was associated with an
increase in survival.
These studies, carried out in a wide variety of palliative care set-
tings, have suggested that 20–65% of patients receiving palliative
care have at least one or more infections which are considered for
antimicrobial treatment. The most common clinical conditions
are urinary tract infections, upper and lower respiratory tract
infections, skin and subcutaneous tissues infections, and a fewer
number of patients also suffer bacteremia. The most common
organisms responsible for infection are E. coli, Staphylococcus
spp., Enterococcus, and K. pneumoniae. Most patients are treated
with antimicrobials when an infection is suspected, with varying
responses.
Evaluation of fever
In patients with advanced cancer, fever is common and it may or
may not have an infectious etiology. It must be noted that fever
may be the only manifestation of an infection in an immunocom-
promised patient, and there is no pattern of fever that can be used
to definitively rule out an infectious etiology. Fever may also be
modified by the use of specific medications such as corticoste-
roids or nonsteroidal anti-inflammatory agents.
In patients with advanced or terminal cancer, fever must be
evaluated in terms of the underlying disease, the specific risk
for a local or systemic infection, the urgency for empirical anti-
microbial therapy, the presence or absence of neutropenia, and
any signs or symptoms which may suggest a site of infection.
Attention should be directed to the most common sites of infec-
tion such as the oral cavity, lungs, perirectal area, urinary tract,
Infections in Palliative Care
skin, and soft tissues. In most patients with fever and neutrope-
nia, the initial evaluation does not identify a site of infection.
Depending on the status of the patient at the time of the fever,
an initial evaluation may include, in addition to the history and
physical examination, a hematological profile, cultures of nose
and throat tissue, urine, blood, stool, and cerebrospinal fluid, and
radiological evaluation of the chest and sinuses. Whether or not
antimicrobials are initiated at the time of the initial fever, patients
should be carefully reevaluated at least every 24 hours. It must
be remembered that in patients with profound and prolonged
neutropenia, multiple sites of infection and multiple infectious
organisms may be present.
The approach to fever in patients receiving palliative care
should be similar to that outlined above, with symptom control
as the primary goal that should be accomplished through a mini-
mum of interventions. Chen et al.8 retrospectively studied 535
admissions to a hospice and palliative care unit and identified 93
fever episodes, of which 79 episodes were treated with antibiotics.
Although the use of antibiotics appeared to decrease fever-related
discomfort, it was not clear that quality of life was improved.
Treatment with antimicrobials
Studies suggest that antimicrobials are initiated in the over-
whelming majority (70–90%) of patients receiving palliative care
when they have fever or a suspected or documented infection.1,8
The response rate to antibiotics appears to vary with symptom
improvement in the majority of urinary tract infections, but there
was symptom improvement in less than half of patients with
infections of other organ systems.1–3,5,10,16
The decision-making process for the use of antimicrobials in
patients receiving palliative care is highly complex. In most situ-
ations, the approach should be individualized for each patient
based on the desires of the patient, the goal to control symptoms,
and quality–of-life issues. Issues to be considered include the
potential benefit of the use of antimicrobials compared to the
potential toxicities that may result from the extent of the investi-
gation of a suspected infection, the number of diagnostic tests to
be employed, and the means to be employed to treat a suspected
or documented infection. It may be appropriate to treat a fever
with an antipyretic alone in a patient whose death is imminent
rather than proceed with an extensive laboratory workup and
TABLE 54.1  Management of Common Infections in Patients Receiving Palliative Care
Infection Signs/symptoms
Urinary tract Dysuria, fever, frequency, pain
Oral Fever, mucositis, odynophagia, pain
Respiratory tract Cough, dyspnea, fever, sputum
production
Skin/subcutaneous Fever, pain, skin rash/discoloration
Bacteremia Fever, disorientation, hypotension,
tachycardia
a The decision to use any diagnostic intervention should be evaluated in terms of potential benefit to the patient in symptom control versus the potential toxicities of the
diagnostic interventions.
527
the initiation of antimicrobials. Alternatively, the pain resulting
from a urinary tract infection or a symptomatic, localized skin or
soft-tissue infection may be treated more successfully with both
antibiotics and pain medications. For patients receiving hospice
care at home or in an institution, such as a hospital palliative care
unit or a chronic care facility, consideration should be given to
initiating oral or parenteral antibiotics based on only clinical
indications without the use of laboratory or imaging criteria.
Mobilization of the patients for diagnostic interventions may lead
to significant discomfort.
Table 54.1 suggests an approach to the management of com-
mon infections in patients receiving palliative care. Patients
with uncomplicated urinary tract infections or cystitis can be
effectively and inexpensively treated with a 3-day course of oral
trimethoprim-sulfamethoxazole or a fluoroquinolone.19 Acute
uncomplicated pyelonephritis can often be managed with a 7-day
course of an oral fluoroquinolone.20 For community-acquired
bacterial pneumonia, an oral macrolide (erythromycin, azithro-
mycin, or clarithromycin), doxycycline, or a fluoroquinolone with
good anti-pneumococcal activity (levofloxacin, gatifloxacin, or
moxifloxacin) is recommended.21 An antipneumococcal fluoro-
quinolone may be added to cover Legionella, Mycoplasma, and
Chlamydia. For the management of skin- and soft-tissue infec-
tions, a first- or second-generation cephalosporin or a macrolide
is recommended.22 Vancomycin may be added if there is minimal
or no response.
Issues that patients, families, and physicians consider when
making decisions concerning the use of a respirator, cardiac
resuscitation, dialysis, etc. should, in general, also apply to the
use of antimicrobials. Antimicrobial use in patients receiving
palliative care may be a part of symptomatic care, may or may
not result in prolongation of life, and/or may be associated with
symptom-producing interventions such as laboratory testing,
venous access, and direct antimicrobial toxicities. The goal of
antimicrobial therapy in palliative care is symptom control, in
contrast to the goal of decreased morbidity and mortality in acute
medical or surgical situations.
White et al. 3 reported that when antimicrobial options were
discussed with 255 advanced cancer patients at the time of
admission to a hospice program, 79.2% chose either no anti-
microbials or symptomatic use only. In a survey of patients
concerning the use of antibiotics in a palliative care unit,
Antimicrobial(s) Diagnostica
Oral trimethoprim sulfamethoxazole Urine analysis, culture and
or fluoroquinolones sensitivity
Fluconazole, nystatin Mouth swab for culture and
sensitivity, endoscopy
Oral macrolides (erythromycin, Sputum culture, chest X-ray,
azithromycin, clarithromycin), bronchoscopy
doxycycline, fluoroquinolones
(levofloxacin, gatifloxacin,
moxifloxacin)
Cephalexin, macrolides Skin culture and sensitivity, blood
cultures
Cefotaxime or ceftriaxone Blood cultures
528
Stiel et al.4 reported that 286 (63.8%) of 448 patients received
antibiotic therapy. Eighty-eight patients had ongoing treatment
withdrawn for various reasons, and the outcome of treatment was
rated poor in 20%. The initiation of therapy was often decided by
physicians only, whereas withdrawing therapy demanded more
involvement of other team members. The involvement of patients
and family members is essential in the decision to use antibiotics
in patients receiving palliative care.
Symptom control
There has been much discussion in the literature about the
use of symptom control as criterion for use of antimicrobi-
als in patients receiving palliative care. However, there have
been only a few studies to evaluate the effects of antimicro-
bials on the symptoms associated with infections in patients
with advanced cancer. Bruera 23 reported a marked improve-
ment in pain with the use of antimicrobials for seven patients
with infected, ulcerated head and neck neoplasms. Green et
al. 24 described improved symptom control with the use of anti-
biotics in two patients with advanced cancer. One patient had
severe respiratory distress from pneumonia and one patient
had sepsis-induced delirium.
In a retrospective study of 102 patients admitted to a tertiary-
care palliative care unit, Vitetta et al.6 reported on antibiotic-
induced symptom control in 36 patients. Antibiotic-associated
positive symptom response was seen in 8 of 17 patients with uri-
nary tract infections, 3 of 9 patients with respiratory tract infec-
tions, 1 of 5 patients with subcutaneous skin infections, and 1 of 5
patients with bacteremia. Clayton et al.15 reported that the use of
parenteral antibiotics was “helpful” (overall condition improved
or symptoms and/or signs of infection improved) in 27 of 43 infec-
tions in 41 patients in an inpatient palliative care unit. Antibiotic
response was seen in 14 of 16 patients with urinary tract infec-
tions, 6 of 11 patients with lower respiratory tract infections, 2
of 2 patients with purulent terminal respiratory secretions, 5 of
7 patients with soft-tissue/wound infections, and 0 of 7 patients
with other suspected infections. The types of infections and the
response rates followed a similar pattern to that found in the
study by Vitetta et al.6, with a somewhat higher response rate
possibly due to the use of parenteral rather than oral antibiotics.
Mirhosseini et al.16 prospectively evaluated the effect of anti-
biotic treatment on infection-related symptoms in patients with
advanced cancer using a questionnaire given to the patients. In
26 patients on a tertiary palliative care unit with 31 episodes of
infection, patients reported a statistically significant improve-
ment only in dysuria. Physician assessment revealed a statistically
significant improvement only in cough.
In a prospective study of antibiotic choices by patients with
advanced cancer receiving outpatient hospice care by White et
al. 3, antibiotic-associated positive symptom response was seen in
25 of 30 patients with urinary tract infections, 10 of 26 patients
with respiratory tract infections, 4 of 9 patients with mouth/pha-
ryngeal infections, 4 of 9 patients with subcutaneous skin infec-
tions, and 0 of 3 patients with bacteremia.
In a large prospective study of 1,731 advanced cancer patients
receiving outpatient hospice care, a complete or partial response
of infection-related symptoms was observed in 79% of 265
patients with urinary tract infections, 43% of 221 patients with
respiratory tract infections, 46% of 63 patients with oral cavity
infections, 41% of 59 patients with skin or subcutaneous infec-
tions, and 0 of 25 patients with bacteremia.5
Textbook of Palliative Medicine and Supportive Care
The types of infections and the responses recorded appear sim-
ilar in the above studies, despite major differences in the types
of palliative care settings. In these studies, it appeared that the
majority of the organisms cultured were sensitive to the antimi-
crobials used, suggesting that the lack of symptom response in
some patients may have been due to comorbid conditions such as
an immunocompromised state, malnutrition, the failure of host
barriers, decreased level of consciousness or immobility, or the
presence of a neoplasm in the symptomatic organ. Regardless of
the reason for the lack of symptom response, it is essential that
treating clinicians use symptom control as the major criterion for
antibiotic use and be aware of the limitations of the use of anti-
microbials in this patient population in a palliative care modality.
Patient survival
Although symptomatic care, and not survival, is the main issue
in palliative and hospice care, survival may be an issue for some
patients, families, and health-care professionals. Survival was not
affected by the patients’ choice of whether to use antimicrobials,
the prevalence of infections, or the actual use of antimicrobials in
the study by White et al. 3 Similarly, in the large study by Reinbolt
et al., 5 survival was not affected by the presence of infection or
the use of antimicrobials.
Antimicrobial use did not affect survival in patients severely
affected with Alzheimer’s disease who were treated for fever.25 In
a retrospective study of inpatient hospice patients, a high early
mortality followed antibiotic administration.14 However, Vitetta
et al.6 and Chen et al.8 showed that terminally ill hospice patients
with documented infections treated with antibiotics had a lon-
ger median survival. A favorable antibiotic response did increase
survival in hospitalized advanced cancer patients with sepsis or
organ-related infection.18
The effect of the use of antimicrobials on survival is impor-
tant information for patients entering hospice care. This infor-
mation might strongly influence their choice of whether to use
antimicrobials.
Guidelines for antibiotic use
Based on the data generated in the current and previous stud-
ies, we suggest the following guidelines for the use of antimi-
crobials in patients with advanced cancer receiving hospice/
palliative care:
• On entry into hospice/palliative care, discussions should be
held with the patient and family members on their wishes
regarding the treatment of infections, just as is done for
cardiopulmonary resuscitation, use of a respirator, blood
transfusions, etc.
• Strong consideration should be given to symptom con-
trol as the major indication for the use of antimicrobials
for the treatment of infections. In a previous study, 3 79%
of patients chose either no antimicrobials or symptomatic
use only.
• Prospective studies3,5,16 and retrospective studies6,10 sug-
gest that antimicrobial treatment of urinary tract infec-
tions improves symptoms in majority of patients, but
antimicrobial treatment of respiratory tract infections,
mucositis, and skin infections is much less successful in
symptom control. Sepsis/bacteremia is poorly controlled
by antimicrobials in this patient population. 3,5,16
Infections in Palliative Care
KEY LEARNING POINTS
• Patients in palliative care settings experience
high incidence of infections.
• The most common sites of infection in patients
receiving palliative care are the urinary tract,
respiratory tract, skin and subcutaneous tissues,
mouth, and blood. The most common pathogens
are E. coli, Staphylococcus spp., Enterococcus, and
K. pneumoniae.
• Although the use of antimicrobials improves
symptoms in the majority of patients with uri-
nary tract infections, symptom control is less
successful with antimicrobial use in infections of
the respiratory tract, mouth/pharynx, skin/sub-
cutaneous tissue, or blood.
• Physicians should be aware of the limitations of
the use of antimicrobials in patients receiving
palliative care.
• Strong consideration should be given to the use
of symptom control as the major indication for
the use of antimicrobials for the treatment of
infections.
• Antimicrobial use has not been shown to signifi-
cantly affect patients’ survival and this informa-
tion is very valuable to physicians, patients, and
caregivers when making decisions about the use
of antimicrobials.
• Each patient’s specific situation and condition in
the palliative care setting must be evaluated in
the decision to employ antimicrobials for a sus-
pected or documented infection.
• Overall survival appears to be unaffected by antimicrobial
use;3,5 there may be some survival benefit in patients with
sepsis or organ-related infections, if the infection is sensi-
tive to the employed antimicrobial.18
• Patients and families should be informed of the effects of
antimicrobials on symptom control of various infections
and on overall survival.
• Each patient’s specific situation and condition must be
evaluated in the decision to employ antimicrobials for a
suspected or documented infection.
References
1. Macedo F, Nunes C, Ladeira K, et al. Antimicrobial therapy in pallia-
tive care: an overview. Support Care Cancer 2018;26:1361–1367.
2. Vallard A, Morisson S, Tinquaut F, et al. Drug management in end-
of-life hospitalized palliative care cancer patients: the RHESO cohort
study. Oncology 2019. DOI: 10.1159/000500783.
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3. White PH, Kuhlenschmidt HL, Vancura BG, Navari RM. Antimicrobial
use in patients with advanced cancer receiving hospice care. J Pain
Symptom Manage 2003;25:438–443.
4. Stiel S, Krumm N, Pestinger M, et al. Antibiotics in palliative medi-
cine – results from a prospective epidemiological investigation from
the HOPE survey. Support Care Cancer 2012;20:325–333.
5. Reinbolt RE, Shenk AM, White PH, Navari RM. Symptomatic treat-
ment of infections in patients with advanced cancer receiving hospice
care. J Pain Symptom Manage 2005;30:175–182.
6. Vitetta L, Kenner D, Sali A. Bacterial infections in terminally ill hos-
pice patients. J Pain Symptom Manage 2000;20:326–334.
7. Dagli O, Tasdemir E, Ulutasdemir N. Palliative care infec-
tions and antibiotic cost: a vicious circle. Aging Male 2019. DOI:
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8. Chen L, Chou Y, Hsu P, et al. Antibiotic prescription for fever episodes
in hospice patients. Support Care Cancer 2002;10:538–541.
9. Oneschuk D, Fainsinger R, Demoissac D. Antibiotic use in the last
week of life in three different palliative care settings. J Palliat Care
2002;18:25–28.
10. Oh DY, Kim JH, Kim DW, et al. Antibiotic use during the last days of
life in cancer patients. Eur J Cancer Care 2006;15:74–79.
11. Lam PT, Chan KS, Tse CY, Leung MW. Retrospective analysis of anti-
biotic use and survival in advanced cancer patients with infections. J
Pain Symptom Manage 2005;30:536–543.
12. Chun ED, Rodgers PE, Vitale CA, et al. Antimicrobial use among
patients receiving palliative care consultation. Am J Hospice Palliat
Med 2010;27:262–265.
13. Al-Shaqi MA, Alami AH, Al-Zahrani AS, et al. The pattern of antimi-
crobial use for palliative care in-patients during the last week of life.
Am J Hospice Palliat Med 2012;29:60–63.
14. Brabin E, Allsopp L. How effective are parenteral antibiotics in hospice
patients? Eur J Palliat Care 2008;15:115–117.
15. Clayton J, Fardell B, Hutton-Potts J, et al. Parenteral antibiotics in a
palliative care unit: prospective analysis of current practice. Palliat
Med 2003;17:44–48.
16. Mirhosseini M, Oneschuk D, Hunter B, et al. The role of antibiotics
in the management of infection-related symptoms in advanced cancer
patients. J Palliat Care 2006;22:69–74.
17. Ahronheim JC, Morrison S, Baskin SA, et al. Treatment of the dying in
the acute care hospital. Arch Intern Med 1996;156:2094–2100.
18. Thai V, Lau F, Wolch G, et al. Impact of infections on the survival
of hospitalized advanced cancer patients. J Pain Symptom Manage
2012;43:549–557.
19. Nicolle LE, Bradley SF, Colgan R, et al. Infectious Disease Society of
America guidelines for the diagnosis and treatment of asymptomatic
bacteriuria in adults. Clin Inf Dis 2005;40:643–654.
20. Hooton TM, Bradley SF, Cardena DD, et al. Diagnosis, prevention, and
treatment of catheter-associated urinary tract infections in adults.
Clin Inf Dis 2010;50:625–663.
21. Mandell LA, Wundernik RC, Anzueto A, et al. Infectious Disease
Society of America/American Thoracic Society Consensus Guidelines
on the management of community-acquired pneumonia in adults. Clin
Inf Dis 2007;44:S27–S72.
22. Stevens DL, Bisno AL, Chambers HF, et al. Practice guidelines for the
diagnosis and management of skin and soft-tissue infections. Clin Inf
Dis 2005;41:1373–1406.
23. Bruera E. Intractable pain in patients with advanced head and
neck tumors: a possible role of local infection. Cancer Treat Rep
1986;70:691–692.
24. Green K, Webster H, Watanabe S, Fainsinger R. Case report: manage-
ment of nosocomial respiratory tract infections in terminally ill cancer
patients. J Palliat Care 1994;10:31–34.
25. Fabiszewski KJ, Volicer B, Volicer L. Effect of antibiotic treatment
on outcome of fevers in institutionalized Alzheimer patients. JAMA
1990;263:3168–3172.
55
PEDIATRIC PALLIATIVE WOUND CARE:
THE UNIQUE ANATOMY AND PHYSIOLOGY OF NEONATAL SKIN

Ann Marie Nie and Joyce M. Black

Contents
Reducing pressure injury�������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������531
Use of prophylactic dressings�����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������532
Reducing pressure injury from medical devices���������������������������������������������������������������������������������������������������������������������������������������������������������533
Extracorporeal membrane oxygenation�����������������������������������������������������������������������������������������������������������������������������������������������������������������������533
Reducing medical adhesive-related skin injury����������������������������������������������������������������������������������������������������������������������������������������������������������533
Reducing extravasation injury����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������533
Pediatric traumatic wounds��������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������534
Surgical site infection�������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������535
Wounds commonly seen at end of life��������������������������������������������������������������������������������������������������������������������������������������������������������������������������535
Extruding cancers��������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������535
Dressings�����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������535
Symptom management����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������535
Conclusion��������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������536
References���������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������536

Preterm neonates have an increased vulnerability of skin inju-
ries and intolerance to external sources of skin injury due to
the nature of the underdeveloped skin structures. The stratum
corneum is thin in preterm neonates, having only 2–3 layers of
cells, compared with 10–20 layers of cells in full-term infants
and adults. In neonates less than 24 weeks of gestational age,
there may be virtually no stratum corneum. Stratum corneum
is thought to mature by 30–32 weeks of gestational age. In
preterm neonates, the papillary dermis underlying the dermo-
epidermal junction is edematous; collagen fibrils are smaller
than those of the full-term newborn or adult; and there are
fewer anchoring points with wide spaces between them. The
weak adherence of epidermis to dermis increases risk for skin
injury.1
The undeveloped stratum corneum is also less able to con-
trol evaporative heat and transepidermal water loss (TEWL).
The resulting dehydrated skin lacks the protective moisture and
becomes more predisposed to skin injuries. Less collagen and
fewer elastic fibers in the dermis can result in edema. Like adults,
edema affects skin turgor or elasticity and reduces blood flow,
resulting in ischemic injury.2–4
The mature skin’s acid mantle (pH 4.5–6) serves as a protection
against some microorganisms. Skin barrier function is altered
when the pH shifts from acidic to neutral, resulting in increase
in the total number of bacteria on skin surface or conditions
such as inflammatory dermatoses (“diaper dermatitis”). Prior to
birth and for the first few weeks of life, the skin is more alkaline.
Several mechanisms may play a role in alkaline skin pH at birth—
the most relevant could be the exposure to the alkaline amni-
otic fluid during the preborn life. This alkaline skin influences
the growth of skin bacterial flora, increasing the risk for dermal
inflammation.2–4
Anatomical variations increase the risk for pressure injury in
children. Pediatric cartilage, muscle, and fat-tissue structures are
softer than those of adults, making newborns and young children
more susceptible to deformation-type pressure injuries of the
nasal structures (Figure 55.1). In addition, children are at risk for
pressure injury on body areas that differ from adults, such as the
occiput (Figure 55.2) because the head of a child is proportion-
ally larger and lacks adipose tissue. Older children develop pres-
sure injuries in locations such as the sacrum, heels, and coccyx
(Figure 55.3A and Figure 55.3B).
The clinical implications that stem from the variances in anat-
omy and physiology increase the risk of skin injury in young chil-
dren. Injury can occur from exposure to pressure, shear, burns,
and chemicals. In addition, immature skin has a high permeabil-
ity to topical agents. Topical products can cause toxicity due to
systemic absorption.
Reducing pressure injury
Pressure injuries unfortunately do occur in children. One of
the largest sample of data (N = 39,984) was published from the
National Database of Nursing Quality Indicators and reported
that 30.2% of hospitalized children were considered at risk for
pressure injury.5 The incidence of pressure injuries was 1.14%.6
Bundled prevention programs have been shown to reduce pres-
sure injury incidence in children.7–9 The skin care bundles often
include using an appropriate support surface, frequent turning
and repositioning, moisture and incontinence management,

531
532
FIGURE 55.1  Continuous positive airway pressure exerting
pressure on the columella.
appropriate nutrition, and nursing staff education. Nurse support
was provided by skin champions on the units and advanced prac-
tice nurses.
Support surfaces need to envelop the patient to redistribute
the pressure and provide a low-friction interface to reduce shear.
However, manufacturers do not recommend the use of low air-
loss support surfaces in children weighing < 70 Kg as the lower
weight is not enough to allow for envelopment into the surface.
The clinician also needs to consider frequent movements, risk for
misplaced tubes and lines, and physical growth during the hospi-
tal stay. The most common pressure redistribution products and
research behind these products are geared toward the adult pop-
ulation. These products and their supporting research are limited
for the pediatric group. Computer simulation indicates that air
cell-based mattresses protect against increased soft-tissue defor-
mation around a misplaced tube compared to a foam mattress for
the newborn intensive care unit and pediatric intensive care unit
populations.10
FIGURE 55.2  Occipital pressure injury.
Textbook of Palliative Medicine and Supportive Care
FIGURE 55.3A  Coccygeal pressure injury in a teen; these
pressure injuries occur in sites common to adults.
Critically ill children are at risk for immobility pressure
injury and should be positioned using fluidized positioners.
These can be used to cradle the whole body, support back
of the head, elevate heels off the bed, and for assistance in
lateral positioning of the coccyx. These positioners retain
their shape after molding to the child or device. The preterm
infant is held in a position that mimics how the body would
have been in the womb, assisting development and preventing
pressure injury.
Use of prophylactic dressings
The occiput is the most common pressure injury site in children.
Its location is not surprising, because younger child’s head is
larger and heavier than the head of older child or adult. Children
at risk for occipital pressure injury are often sedated and intu-
bated (which may limit the ability of the head to be turned) on
complex therapies or vasopressive medications.11 Fluidized posi-
tioners float the occiput when the head cannot be easily turned.
Caution is needed to protect the ears from pressure when the
head is turned to the side.
FIGURE 55.3B  Coccygeal pressure injury following debridement.
Pediatric Palliative Wound Care: The Unique Anatomy and Physiology of Neonatal Skin
Reducing pressure injury
from medical devices
In 2003, Curley and colleagues published the first prospec-
tive data on medical device ulcers in children between the ages
of 21 days and 8 years. The overall incidence of ulceration was
27%, with 8% of children ulcerating due to medical devices. The
oxygen saturation probe, nasal continuous positive airway pres-
sure (CPAP) mask, bilevel positive airway pressure mask, trache-
ostomy and endotracheal tubes were the most common devices
(74%) responsible for ulceration.12 Medical devices remain the
most common cause for pressure injuries in neonates and chil-
dren. The causes of the injury vary from poorly fitted devices, not
having sizes for all ages, to overly tight securement of the device.
Logically, different devices create different sources of pressure.
The tracheostomy pressure stems from the trach plate, phalange,
and the securement straps. In endotracheal tubes, the tube itself
can cause a pressure injury on the lip, mouth, and/or columella.
The securement device can injure the face or head (depending on
how it is secured).
Injury extends beyond pressure injury to the skin and soft–tis-
sue injury; tight fitting nasal prongs can lead to nasal vestibular
stenosis or columellar necrosis.13 Over time, this process can lead
to ulceration, bacterial colonization, and then secondary healing
with granulation tissue formation leading to disruption of nasal
patency.
Protecting the premature infant from pressure damage is
imperative. Frequent skin assessments, focused examinations
of the face, using the correct prong size, providing adequate
humidification, and using skin barriers and silicone foams
are methods to assist in prevention. Proper positioning of the
oxygen delivery device can reduce pressure on the soft tissue.
Endotracheal tubes should be moved in the mouth on each shift
if not more often; tracheostomy ties should be padded. Pressure
from the phalange can be reduced with foam dressings.14 Soft
silicone dressing have been used under trach plates and pha-
lange for pressure injury prevention. These dressing are also
used to protect the columella and philtrum from pressure from
CPAP masks and nasal prongs.15
Electroencephalogram (EEG) electrodes create a unique risk
for injury. The wounds created resemble medical device pres-
sure injury because they are the shape of the electrode. Mietzsch
examined the problem of EEG electrode wounds in critically
ill neonates and found that silver/silver chloride-plated elec-
trodes, when exposed to external heat sources, can cause burns,
resembling pressure injury.16 Furthermore, the securement
device often increases the pressure of the leads on the scalp. The
Neurodiagnostic Society recommends that if a dressing is used
to assist in securing the leads, then stretchable, breathable gauze
should be used that can easily fit two fingers under the dressing.17
Extracorporeal membrane oxygenation
Indications for the use of extracorporeal membrane oxygenation
(ECMO) in the critically ill child is an expanding field. As experi-
ence grows with ECMO, patients who were previously considered
absolute contraindications are now being considered relative con-
traindications.18,19 Due to the risk of decannulation, many profes-
sionals limit the movement of the patient on ECMO, which leads
to pressure injury of the occiput, buttocks, and heels, depending
on the age of the patient and body size. Preventive foam dress-
ings should be applied to the high-risk areas and the head should
533
be cradled in a positioner that supports the cannulas in the large
vessels in the neck. The duration of ECMO has also increased;
the average run time in neonates with congenital heart disease is
259 hours.18 Given the high rate of morbidity with EMCO in older
patients, including muscle weakness, pressure ulcers and other
events, there is a more concentrated effort to reduce sedation and
move the patient both in bed and out of bed.20
Reducing medical adhesive-
related skin injury
The fragility of the skin and the increased pressure injury risk is
even more concerning when the skin is damaged. Medical adhe-
sive-related skin injury (MARSI) is chemical or mechanical injury
to the skin from dressings or tape.21 MARSI is a prevalent prob-
lem in pediatrics, with a rate of 37.15% (range 23.53–54.17%).22 In
fact, 10–15% of neonates leave the intensive care unit with scars.22
In addition, products that promote adhesion (e.g., tincture of
benzoin) may result in increased epidermal stripping because of
the very strong bond between a product and the skin. In babies,
transparent film has a stronger bond to the epidermis than the
bond of epidermis to the dermis.22 Not only is skin injury an issue,
the removal of adhesive materials, can increase TEWL levels in
the neonate. The open skin can compound the toxicity of agents
or further exacerbate skin damage.21
Hydrocolloids, polyurethane foams, and transparent films are
also adhesive and injure the skin. Great care should be taken by cli-
nicians when removing these products or applying products with
known strong adhesive properties (e.g., cloth tape, transparent
films). Gentle dressings or adhesives (e.g., tapes) with silicone are
generally recommended. Routine use of petroleum-based prod-
ucts or products with zinc oxide are preferred and recommended
for dermatitis as well as “crusting” techniques using stoma pow-
der in combination with a skin ointment barrier. Caustic effluent
from a percutaneous endoscopic gastrostomy tube may require
the use of a foam dressing for protection and absorption.
Reducing extravasation injury
Extravasation injury is damage to surrounding skin and soft tis-
sue from the leakage of vesicant fluid from a vein. These injuries
are most common in neonates and children due to the fragility
and small caliber of veins. Children are at high risk of infiltra-
tion and extravasation of intravenous (IV) fluids and medications
because of limited ability to communicate early signs of pain,
movement of arms and legs, and fragility of veins. Infiltration is
reported to occur in 5.5 cases per 1,000 patient days; extravasa-
tion is slightly less common at 4.4 cases per 1,000 patient days.23
Skin damage caused by vesicant fluid collection leads to vessel
obstruction and possible ischemia.24 Skin damage can be blister-
ing of skin or extensive with compartment syndrome with skin
necrosis (see Box 55.1). With deeper structure involvement, sur-
gical debridement and grafting is needed. The severity of extrava-
sation injury can be described in stages (see Figure 55.4).
Treatment of extravasation lacks empirical evidence. Saline
flush of the site and hyaluronidase injections into the extrava-
sation site are common treatment. This enzyme breaks down
the hyaluronic acid bond between tissue cells. The extravasated
medication can then disperse into larger area of capillary beds,
thereby reducing edema and decreasing the risk of damage to the
tissue and skin. The medication is normally given within 1 hour
534
BOX 55.1  EXTRAVASATION SEVERITY SCALE
Stage 1: painful IV site, no edema or redness at the
site; flushes without difficulty
Stage 2: painful IV site, slight edema, redness, no
blanching, brisk capillary refill below infiltration
site, good pulses below infiltration site
Stage 3: painful IV site, marked edema, blanching,
cool to touch, brisk capillary refill below infiltra-
tion site, good pulses below infiltration site
Stage 4: painful IV site, very marked edema, blanch-
ing, cool to touch, capillary refill of more than
4 seconds, decreased or absent pulses, skin
breakdown or necrosis
of the injury in 4–5 injections around the site of damage. There
is not standard time frame for administration.25 Treatment of the
wounded skin is dependent on the severity of the damage. Moist
wound healing should be followed for treatment options.
Due to the risk for significant injury, prevention is the key. While
it is standard nursing procedure to assess a peripheral IV site every
hour, this can be challenging when a parent or caregiver requests
that a child not be disturbed during the night hours. To prevent
these types of injuries, the hourly assessment should be adhered
to. Parents should be made aware of the need to prevent harm and
offered assurance that care will be taken so as to not wake the child.
FIGURE 55.4  Eleven month old with intravenous site extrava-
sation with compartment syndrome.
Textbook of Palliative Medicine and Supportive Care
Pediatric traumatic wounds
Traumatic injury is the leading cause of mortality and morbid-
ity in children. Serious wounds in children include burns, frac-
tures, abdominal and head trauma. Not all traumatic wounds
require surgical management (e.g., splenic and liver trauma)26;
however, penetrating injuries (e.g., gunshot, stab) are becoming
increasingly common and often require exploratory surgery. The
resulting wound is often left open to reduce the risk of abdominal
compartment syndrome27 (see Figure 55.5).
Burns are also common forms of injury among children.
Tragically, almost one-quarter of burn injuries occur in chil-
dren.28 In a study of 2,273 pediatric burn patients, scald burns
were the most common (71.1%, n = 1,617), with 53% attributable
to hot liquids related to cooking, including coffee or tea. In the
teenage group, flame burns were the dominant cause (53.8%; see
Figure 55.6). Mortality of burn injury was 0.9%.28 Some of these
burn cases are due to child abuse; estimates indicate that as high
as 40% of all burns in children are due to abuse by the parents
or caregiver. 30 The traditional classification of burns (first, sec-
ond, third degree) has been replaced by a classification system
that reflects the need for surgical therapy. Burns are currently
grouped as superficial, superficial partial-thickness, deep partial-
thickness, full-thickness, and fourth-degree burns (See Box 55.2).
Initial care of the burn patient includes preventing hypovole-
mic shock, reducing pain, and determining the extent of the
burn. Total body surface area (TBSA) calculation is important
to guide resuscitation, prognosis, and disposition. The larger the
TBSA burn, the higher the rate of death, infection, and need for
multiple operations to close the wounds. Sepsis is generally pre-
ventable with prompt resuscitation and early excision of burned
tissues. Prophylactic oral or topical antibiotics are not indicated.
Nutritional support is crucial due to the hypermetabolic state. 31
Debridement of loose tissue and blisters can be performed sim-
ply with use of a topical anesthetic solution. Silver sulfadiazine
(SSD) remains the traditional treatment for burn topical care
despite dwindling outcomes. A systematic review of the litera-
ture to assess nonsilver versus SSD in pediatric burns reported
that wounds treated with nonsilver dressings healed more rap-
idly, required less dressing changes, and had shorter length of
stay than those using SSD for treatment. The nonsilver dressings
FIGURE 55.5  Traumatic abdominal wound.
Pediatric Palliative Wound Care: The Unique Anatomy and Physiology of Neonatal Skin
FIGURE 55.6  Partial-thickness burn in a 9 week old from a
heating pad.
caused less pain and SSD did not prove to be a better preven-
tion measure for infection. Dressings that showed better efficacy
include hydrogels, silicone nonadherence dressing, and silicone
dressings with impregnated silver. 32
Surgical site infection
Risk factors for surgical site infection have been well studied in
adult patients; however, similar work in pediatric population is
not as well studied. Surgical site infection occurs in 0.25–6%
of children following cardiothoracic surgery. A case-matched
review found no identifiable risk factors for infection following
open heart surgery. In contrast, a systemic review found that
timing and type of preoperative antibiotics, use of implanted
products for repair, delayed recovery and more complex spinal
problems (such as a combination of neurological and orthopedic)
were more likely to develop infections. 33,34
Wounds commonly seen at end of life
Extruding cancers
There are several forms of soft-tissue cancers in children. While
there has been a dramatic improvement in survival of children
and adolescents suffering with these tumors, not all are curable.
BOX 55.2  BURN CLASSIFICATION
Superficial: epidermis involvement
Partial thickness: epidermis and varying degrees of
dermis involvement
Superficial partial thickness and indeterminate-
thicknessDeep partial thickness– deeper dermis
involvement
Full thickness: dermis involvement
Fourth degree: subcutaneous tissue with involve-
ment of fascia, muscle, tendon, and bone
535
FIGURE 55.7  A 7.5 month old with extruding angiosarcoma.
Rhabdomyosarcoma, a tumor of striated muscle, is the most
common soft-tissue sarcoma in children aged 0–14 years and
accounts for 50% of tumors in this age group. Ewing’s sarcoma
family of tumors includes bone and soft-tissue tumors that are
often characterized by a specific translocation between chromo-
some 11 and 22. Soft-tissue sarcoma is estimated to be about 8%
of cancers diagnosed in adolescents. 35 Angiosarcoma is a rare
tumor of blood vessels and little is known about its pathogenesis
(See Figure 55.7). When these tumors extrude through the skin,
wound care is needed to reduce the distress from the tumor.
Dressings
The ideal dressing should protect the wound from exposure to the
environment, thereby reducing the risk of infection and irrita-
tion, provide a humidified and warm local wound environment to
promote healing, absorb drainage from the wound bed and trans-
locate it to the surface of the dressing. In addition, cultural and
religious preferences should be observed. Some cultures and reli-
gions forbid the use of animal products (most commonly bovine
and porcine sources), and therefore dressings which contain ani-
mal product should be avoided. Hydrocolloid dressings can con-
tain porcine-derived gelatin. 36 Removal of a dressing should be
as pain free as possible. Silicone lined layer foam dressings are
preferred due to the absorptive capacity and pain-free removal. 37
If the child is mentally able to provide input, the clinician
should do his/her best to meet the psychosocial needs of the child,
including finding a dressing capable of being hidden by clothing
and one that the child will tolerate and leave alone. When wound
healing is not the goal, the dressings should be highly absorp-
tive to reduce the number of dressing changes. Furthermore,
there should be no need to “look at the wound” daily because, in
theory, no change will be made in the care based on the wound’s
condition.
Symptom management
The most common symptoms from the wound and its drainage
include odor, pain, and wet clothing from drainage. Drainage
from the inflammation in the wound is best controlled with
highly absorptive dressings, such as foams and alginates. There
should be no effort to examine the wound, except to change
dressings when they are saturated. Dressings with a 5- to 7-day
wear time should be used. 38
536
Odor is from the invasion of the wound with bacteria; frank
infection may be present. Depending on the timing of infection
and condition of the patient, some patients and families will
want it treated, others will not. Sharp debridement to debulk
the necrotic tissue and reduce the odor is important to offer as
an option. The debridement should not extend to bleeding tis-
sues, because bleeding is more difficult to control and, of course,
leads to great concern by the patient. If bleeding is encountered,
use pressure to control it. For wounds that will not be debrided,
ground metronidazole placed directly into the wound bed will
reduce the number of anaerobic organisms and the odor from
them. The odor from frank necrosis (gangrene) is very difficult to
control, so it is best to stay ahead of necrotic tissue. Maggots can
also be used to debride the wound; the benefit of maggots is that
they quickly digest necrotic material but do not enter the viable
wound tissue, so bleeding is not a concern. Maggots can be dis-
tasteful but can be placed into polymer bags, so they do not have
to be seen. Some patients will report a tingling from the mag-
gots, but often do not find it bothersome. Medical honey dress-
ings have been used in children’s wounds, with good acceptance
by the patient and care provider. The honey is a debriding agent
through its hypertonic state and an antiseptic. 39 Many studies
have been done on patients with wounds using medical-grade
(Manuka) honey with positive results. A full review is beyond the
scope of this chapter.40
Pain in the wound should be aggressively managed. Follow the
preferences of the patient and family to achieve comfort. Pressure
injuries do occur at end of life; they likely develop from a combi-
nation of efforts to allow the family time to be with the patient
rather than provide bedside care and a reduction in perfusion of
tissue. Adults and elders are said to have “skin failure” or “termi-
nal ulcers”; this terminology does not appear in pediatric cases.
Conclusion
Adult-based wound care practices provide a rudimentary foun-
dation for neonatal and pediatric wound care but do not negate
the need for developmentally specific evidence-based guidelines.
Most of the currently available guidelines and information are
based on adult research. However, given the wide variation in
percutaneous toxicity potential and developmental and integu-
mentary maturity spanning from the very-low-birth-weight pre-
mature infant through adolescence, clinicians desperately need
age-appropriate, safe, and effective products, educational tools,
and research-based guidelines so as to deliver safe and effective
wound care practice.
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56
MOUTH CARE

Flavio Fusco

Contents
Introduction and prevalence...........................................................................................................................................................................................539
Infections.............................................................................................................................................................................................................................539
Fungal infections..........................................................................................................................................................................................................539
Treatment of oral fungal infections............................................................................................................................................................................... 540
Viral infections............................................................................................................................................................................................................. 540
Treatment of oral viral infections.................................................................................................................................................................................. 540
Xerostomia......................................................................................................................................................................................................................... 540
Management of xerostomia............................................................................................................................................................................................ 541
Chemotherapy-/radiation-induced stomatitis............................................................................................................................................................ 541
Management of chemotherapy-/radiation-induced stomatitis............................................................................................................................... 542
Altered taste sensations................................................................................................................................................................................................... 542
Management of altered taste sensations...................................................................................................................................................................... 542
Oral lesions in HIV/AIDS patients................................................................................................................................................................................ 543
Management of oral lesions in patients with HIV/AIDS.......................................................................................................................................... 543
Osteonecrosis of the jaw.................................................................................................................................................................................................. 543
Management of osteonecrosis of the jaws................................................................................................................................................................... 543
Oral health in frail elderly with dementia.................................................................................................................................................................... 544
References........................................................................................................................................................................................................................... 544

Introduction and prevalence Infections

In a palliative care patient, oral cavity represents a true “target
organ.” The mouth plays a fundamental role in many aspects of
life: nutrition; hydration; phonation; speech articulation pro-
cesses; relational and communication activities; and emotional,
affective, and sexual relations.1 Several studies have shown that
oral complications and abnormalities of the oral microflora can
be found in significant numbers of terminally ill cancer patients,
affecting their quality of life. A total of 77 of 99 patients recruited
from 2 Norway palliative care units reported dry mouth, 67%
reported mouth pain, and problems with food intake were
referred by 56%.2
Sweeney and Bagg 3 studied the prevalence of oral signs and
symptoms among a group of 70 terminally ill cancer patients:
68 patients (97%) complained of oral dryness during the day,
and 59 patients (84%) complained of oral dryness at night. Oral
soreness was reported by 22 patients (31%). Forty-six patients
(66%) had difficulty talking, and 36 (51%) reported diffi-
culty eating. Oral mucosal abnormalities were detected in 45
patients (65%), most commonly erythema (20%), coated tongue
(20%), atrophic glossitis (17%), angular cheilitis (11%), and
pseudomembranous candidiasis (9%). This problem reaches a
dramatic evidence in frail population living in poor-resourced
settings: a study of 95 children referred for palliative care in
Malawi showed that 51% of them had mouth sores and 40% had
oral candidiasis.4
This chapter describes the major and more frequent oral prob-
lems experienced by patients with advanced cancer followed in
palliative care programs. Aspects of their management will also
be discussed.
Fungal and viral infections frequently develop in patients with
advanced cancer.
Fungal infections
The most common oral infection is oral candidiasis: high levels of
Candida have been reported among terminally ill patients, with
correspondingly high levels of mucosal disease. 5,6 Debilitated
patients, such as those receiving antibiotics, steroids, and cyto-
toxic therapies, are particularly susceptible to oral candidiasis.
Other general factors, such as diabetes mellitus, or predisposing
local factors (e.g., poor denture hygiene, presence of xerostomia)
are also important in the pathogenesis of oral candidiasis.
There are more than 150 species of Candida, but only 10–15 of
them are regarded as important pathogens for humans. Candida
albicans is one of these candidal species, which is found in the
oral cavity and responsible for most oral candidal infections.
The pseudomembranous form (thrush) is a classic clinical fea-
ture, characterized by creamy white, curd-like patches on the
tongue and other oral mucosal surfaces. The patches can be
removed by scraping and leave a raw, bleeding, and painful sur-
face. Beside the classic lesion, other manifestations include:
• Acute atrophic candidiasis or “antibiotic-related stomati-
tis”: This is a nonspecific atrophy of the tongue, associated
with burning sensation, dysphagia, and mouth pain.
• Chronic atrophic candidiasis (erythematous candidiasis)
or “denture sore mouth”: This is a chronic inflammatory
reaction and epithelial thinning under the dental plates.
Dysgeusia is usually present.

539
540
• Angular cheilitis: This is an inflammatory reaction at the
corners of the mouth (not due exclusively to Candida but
to mixed infection with Staphylococcus aureus or, less
frequently, beta-hemolytic Streptococci). Bleeding may be
sometimes present.
• Candida leukoplakia (hyperplasic candidiasis): In this, the
lesions are firm, adherent plaques involving the cheek, lips,
and tongue. Symptoms are usually absent.
The diagnosis can be made by the clinical appearance of the
lesion, by scraping (using either a potassium hydroxide smear or
a Gram stain to show masses of hyphae, pseudohyphae, and yeast
forms). Other simple methods are swabs, imprint cultures, or cul-
ture of oral rinses.
Treatment of oral fungal infections
Specific antifungal treatment may be provided either topically
and systemically.
Nystatin in the form of suspension (100,000 units/mL, 4–6 mL
every 6 h), pastilles, or tablets (100,000 units) is a traditional
local treatment. Duration of treatment is usually 10–14 days, but
some patients need to continue the treatment for at least 2 weeks
after clinical resolution. Miconazole gel is useful for the man-
agement of angular cheilitis; it has a weak activity against gram-
positive cocci as well as yeasts.7 Clotrimazole lozenges (10 mg
5 times a day) are effective and well tolerated in the treatment of
oropharyngeal candidiasis forms.8 Ketoconazole is available in a
number of oral and topical forms. The slow therapeutic response,
variable absorption, and frequent adverse effects (anorexia, nau-
sea, vomiting, and liver toxicity) all make it a poor choice in
patients with advanced cancer. Fluconazole is a triazole with
established therapeutic efficacy in candidal infections. It is both
an oral and parenteral fungistatic agent that inhibits ergosterol
synthesis in yeasts. Fluconazole, 50–100 mg once daily, is one of
the most effective treatments of oropharyngeal candidiasis; daily
doses of 100–200 mg are recommended for esophageal candidi-
asis. Extensive clinical studies have demonstrated fluconazole’s
remarkable efficacy, favorable pharmacokinetics, and reassuring
safety profile, all of which have contributed to its widespread
use.9,10 Itraconazole, structural similar to ketoconazole, has a
broader spectrum of action, and it is available in parenteral and
oral formulations. To obtain the highest plasma concentration,
the tablet is given with food and acidic drinks, whereas the solu-
tion is taken in the fasted state.
The most common triazoles-related adverse effects are dose-
related nausea, abdominal discomfort, and diarrhea, but symp-
toms rarely necessitate stopping therapy.11
Ketoconazole and itraconazole may seriously interact with
some of the substrates of CYP3A4. In a double-blind, randomized,
three-phase crossover study, Varhe et al.12 reported that ketocon-
azole and itraconazole seriously affect the pharmacokinetics of
triazolam and increase the intensity and duration of its effects
with potentially hazardous consequences. Azoles have also been
implicated in fatal interactions with antihistamines (polymor-
phic ventricular tachycardia). Caution should be used when flu-
conazole and methadone are administrated concurrently.13,14
Several studies have showed an emerging high prevalence of
non-C. albicans yeasts and azole resistance in the oral flora of
patients with advanced cancer: Bagg et al.15 examined the oral
mycological flora of 207 patients receiving palliative care. A total
of 194 yeasts were isolated, of which 95 (49%) were C. albicans.
Textbook of Palliative Medicine and Supportive Care
There was a high prevalence of C. glabrata (47 isolates), of which
34 (72%) were resistant to both fluconazole and itraconazole.
Other non-C. albicans species, such as C. parapsilosis, C. kruseii,
and, more recently, C. dubliniensis, are less susceptible than C.
albicans to fluconazole.16
In the last years, the echinocandins (caspofungin, micafungin,
and anidulafungin) have shown fungicidal activity against most
Candida spp., including strains that are fluconazole-resistant.17
Posaconazole, a new oral broad-spectrum triazole agent, is active
against many species resistant to fluconazole and itraconazole.
It is administered as oral suspension, with a favorable toxicity
profile, and appears to be a promising addition in the antifungal
armamentarium.18
Viral infections
Herpes simplex virus (HSV-1) is the commonest cause of viral
infection of the oral mucosa. Herpes viruses are characterized
by their ability to establish and maintain latent infections, which
can get reactivated. Several stimuli, such as radiotherapy or che-
motherapy, can trigger the reactivation of herpes viruses.
Small vesicles usually appear on the pharyngeal and oral
mucosa; these rapidly ulcerate and increase in number, often
involving the soft palate, buccal mucosa, tongue, and floor of the
mouth. Anorexia, fever, mouth pain, and dysphagia may be pres-
ent. The disease generally runs its course over 10–14 days.
Treatment of oral viral infections
Acyclovir triphosphate is available as a topical 5% ointment, an
intravenous form, and an oral form. In the immunocompro-
mised patients, acyclovir is useful as both treatment and sup-
pression of recurrent mucocutaneous HSV lesions.19 Penciclovir,
a novel acyclic nucleoside analogue, has demonstrated efficacy
against HSV types 1 and 2 and seems to have a pharmacological
advantage due to a prolonged half-life of its active form in HSV-
infected cells.20,21
Al-Waili22 carried out an interesting, small, prospective, ran-
domized trial that compared topical application of honey with
acyclovir cream in patients with recurrent episodes of labial
and genital herpes simplex lesions. For labial herpes, the mean
duration of attacks, occurrence of crust, healing time, and pain
duration were significantly lower when treated with honey when
compared with acyclovir treatment (p < 0.05).
Xerostomia
Xerostomia, defined as the subjective feeling of oral dryness, is
one of the five most common symptoms affecting patients with
advanced cancer, with a reported prevalence between 30% and
97%.1,23,24 Indeed, despite the high prevalence of this distressing
symptom—which may contribute to mouth pain and oral infec-
tions—there has been relatively little research into this “orphan
topic in supportive care.”25
There are many general causes of xerostomia (Box 56.1), but
drug therapies are probably the most important, via a number of
different mechanisms: the direct effects include interference with
the nerve supply to the salivary glands (e.g., antidepressants), or
with the productive capacity of salivary glands (e.g., diuretics,
opioids). The indirect effects include imbalance with the normal
stimuli to the secretion of saliva.26
The effects of xerostomia on patient’s symptoms are numerous:
the absence of protective effect of saliva on the oral mucosa is a
Mouth Care
BOX 56.1  MAIN CAUSES OF XEROSTOMIA
IN PATIENTS WITH ADVANCED CANCER
Related to Cancer Itself
• Head and neck cancer
• Obstruction/compression/destruction of the sal-
ivary glands
Related to Dehydration
• Anorexia, poor fluid intake
• Diarrhea, vomiting
• Hemorrhage
• Fever
• Oxygen supply
Related to Treatment
• Radiotherapy
• Oral and jaw surgery
• Drug therapy: Anticholinergics, antihistamines;
antihypertensive/diuretics; opioid analgesics;
nonsteroidal anti-inflammatory drugs (NSAIDs);
corticosteroids; proton pump inhibitors
Related to Concurrent Disorders
• Sjögren syndrome
• Diabetes (mellitus and insipidus)
• Sarcoidosis
• Thyroid dysfunctions
• Anxiety/depression states
facilitating factor of exogenous bacterial colonization and infec-
tions and the loss of lubrification makes swallowing and chewing
difficult and painful. Another feature of xerostomia is taste alter-
ation with a subsequent loss of appetite. The sensation of burning,
soreness, and dryness sensations may have a considerable effect
on speech, with subsequent fall in mood state and relational abili-
ties. Saliva also plays an important role in preventing the loss of
tooth substance by its antimicrobial, buffering, and cleansing
activities: thus, dental caries and dental erosions are often seen in
terminally ill patients. 3,24
Management of xerostomia
The primary management of xerostomia involves treatment of
underlying cause. A recent, cross-sectional study of 135 patients
with advanced progressive diseases underlined the importance
to take a detailed assessment, highlighting the functional impact
on day-to-day activities such as talking, dysphagia, and sleep.27
Discontinuation or substitution of regimens of xerostomic drugs
may sometimes be possible. Patients with ill-fitting dentures can
be advised to see their dentist: relining of dentures can improve
their fit and function and help to lessen oral pain and dryness
caused by the lack of support for dentures. Dentate patients
should receive preventive or dietary advice, as well as treatment
of any caries present.
541
Current therapy for chronic xerostomia involves the use of sali-
vary substitutes or salivary stimulants. Pilocarpine is a muscarinic
agonist, although it does have some effect on the beta-adrenergic
receptors in the salivary and sweat glands. There have been a
number of double-blind, randomized controlled studies that have
shown that pilocarpine is an effective treatment for radiation and
drug-induced xerostomia. Davies et al.,28 in a multicenter, cross-
over study, compared a mucin-based artificial saliva with oral for-
mulation of pilocarpine hydrochloride in 70 patients with advanced
disease and xerostomia. The pilocarpine formulation was found to
be more effective than artificial saliva, but it was found to be asso-
ciated with more side effects, such as sweating, lacrimation, and
dizziness. Extreme caution in the use of pilocarpine is important
due to reported side effects of glaucoma, cardiac disturbances, and
sweating. For this reason, other studies explored the possibility to
use other saliva stimulants. Davies29 carried out a prospective, ran-
domized, open, crossover study comparing a mucin-based artificial
saliva with a low-tack, sugar-free chewing gum in the management
of xerostomia in 43 patients with advanced cancer. Chewing gum
is a saliva stimulant. It produces an increase in salivary flow due to
a combination of stimulation of chemo- and mechanoreceptors. In
this study, both artificial saliva and chewing gum were effective in
the management of xerostomia, but 61% of the patients preferred
the chewing gum to the artificial saliva. The use of chewing gum
may be limited by the presence of jaw and oral discomfort, head-
ache, and swallowing difficulties.
A variety of saliva substitutes are now commercially available.
The substitutes contain different synthetic polymers as thick-
ening agents, for example, carboxymethylcellulose, polyacrylic
acid, and xanthan gum, but conflicting results have been repor
ted.1,3,24,30 Recent developments—still in the experimental stage—
include bioactive salivary substitutes and mouthwashes contain-
ing antimicrobial peptides to protect the oral tissues against
microbial colonization and to suppress and to cure mucosal and
gingival inflammation. 30
A randomized, controlled trial of standard fractionated radia-
tion with or without amifostine 200 mg/m2, before each fraction
of radiation, was conducted in 315 patients with head and neck
(H&N) cancer. Amifostine administration was associated with
a reduced incidence of grade ≥ 2 xerostomia over 2 years of fol-
low-up (p = 0.002), an increase in the proportion of patients with
meaningful (>0.1 g) unstimulated saliva production at 24 months
(p = 0.011), and reduced mouth dryness scores on a patient benefit
questionnaire at 24 months (p < 0.001). 31
A recent, systematic review was carried out by a task force
of the Multinational Association of Supportive Care in Cancer
(MASCC) and International Society of Oral Oncology (ISOO)
to assess the literature for management strategies and economic
impact of salivary gland hypofunction and xerostomia induced
by cancer therapies and to determine the quality of evidence-
based management recommendations. There was evidence that
salivary gland hypofunction and xerostomia induced by cancer
therapies can be prevented or symptoms be minimized with
intensity-modulated radiation therapy (RT), amifostine, musca-
rinic agonist stimulation, oral mucosal lubricants, acupuncture,
and submandibular gland transfer. 32
Chemotherapy-/radiation-induced stomatitis
The oral mucosa is frequently damaged during chemotherapy/
radiotherapy in patients with cancer, leading to a high incidence
of oral and esophageal mucositis. Patients with mucositis often
542
experience considerable pain and discomfort. The incidence of
oral mucositis (OM) ranges from 15% to 40% in patients receiv-
ing stomatotoxic chemotherapy or radiotherapy, raising to 80% in
patients with H&N cancer. 33
Raber-Durlacher et al. 34 reported a retrospective analysis of the
incidence and the severity of chemotherapy-associated OM in
150 patients with various solid tumors. Eighty-seven episodes of
mucositis occurred in 47 (31%) patients. Twenty-six patients each
experienced only 1 episode, whereas 21 patients had up to 8 epi-
sodes of mucositis. Multivariate analysis identified the adminis-
tration of paclitaxel, doxorubicin, or etoposide as an independent
risk factor (adjusted rate ratio 8.06, 7.35, and 6.70, respectively),
whereas low body mass was associated with a slightly increased
risk (adjusted rate ratio 0.92).
Other anticancer drugs, such as alkylating agents, vinca alka-
loids, antimetabolites, and antitumor antibiotics, are especially
liable to cause stomatitis, and it is important to carefully consider
their use in patients with advanced cancer. 35
Both chemotherapy and radiotherapy interfere with cellular
mitosis and reduce the regenerative property of the oral mucosa.
A poor nutritional status further interferes with mucosal regen-
eration; oral infections can exacerbate the mucositis and may lead
to systemic infections. If the patient develops both severe mucosi-
tis and thrombocytopenia, oral bleeding may occur and this may
be difficult to treat.
Direct stomatotoxicity usually is seen 5–7 days after the start
of chemotherapy or radiotherapy; in non-immunocompromised
patient, oral lesion heals within 2–3 weeks. The most common
sites include the buccal, labial, and soft palate mucosa, as well as
the floor of the mouth and the ventral surface of the tongue. 35
In recent years, development of biological targeted therapies
and immune checkpoints inhibitors has redefined the treatment
of many cancers but has brought a new spectrum of toxicities,
including stomatitis, migratory glossitis, hyperkeratotic lesions,
lichenoid reactions, and osteonecrosis of the jaw. These oral
adverse events also appear to be less symptomatic than chemo-
therapy-induced mucositis but may require dose adjustments.
Oral lesions can be clinically quite specific, and systematic exam-
ination of the oral mucosa is recommended as part of the moni-
toring regimen of patients treated with these drugs. Physicians
should be aware of these induced mucosal changes; early recogni-
tion and appropriate management are essential in order to pre-
serve better patients’ quality of life. 36
Management of chemotherapy-/
radiation-induced stomatitis
A recent systematic review of basic oral care for the management
of OM in cancer patients was conducted by the Mucositis Study
Group of the MASCC/ISOO to update the clinical practice guide-
lines for the use of basic oral care interventions for the prevention
and/or treatment of OM in cancer patients. The panel suggests that
the implementation of multi-agent combination oral care protocols
is beneficial for the prevention of OM during chemotherapy, H&N
RT, and hematopoietic stem-cell transplantation (Level of Evidence
III). The panel suggests that chlorhexidine not be used to prevent
OM in patients undergoing H&N RT (Level of Evidence III).37
A Cochrane Review was conducted in 2006 to evaluate the
effectiveness of prophylactic agents for OM in patients receiving
treatment, compared to other interventions, placebo, or no treat-
ment. It included 5217 randomized patients. Of the 29 interven-
tions included in trials, 10 showed some evidence of benefit. Only
Textbook of Palliative Medicine and Supportive Care
amifostine, antibiotic paste or pastille, hydrolytic enzymes, and
ice cubes showed a significant difference when compared with
placebo or no treatment in more than one trial. Benzydamine,
calcium phosphate, honey, oral care protocols, povidone, and zinc
sulfate showed some benefit in only one trial. 38 Topical anesthet-
ics, mixtures (also called cocktails), and mucosal coating agents
have been used despite the lack of experimental evidence sup-
porting their efficacy.
In the last 5 years, palifermin, a recombinant humanized kera-
tinocyte growth factor, has demonstrated an ability to decrease
the incidence and duration of mucositis in randomized, placebo-
controlled studies and in systematic reviews. The drug seems to
be generally well tolerated, but most patients experienced thick-
ening of oral mucosa, flushing, and dysgeusia. 39,40
Biswal et al.41 carried out the first prospective, randomized
trial to evaluate the effect of pure natural honey with radiation-
induced mucositis. Forty patients undergoing radiotherapy to the
head and neck region received topical application of the honey
along with radiotherapy or radiotherapy alone. A significant
reduction in the symptomatic grade 3–4 mucositis (radiation/
toxicity oncology grading system) was found in the honey group
in respect to controls (p = 0.0005). Another recent Egyptian study
tried to evaluate the effect of topical application of honey and a
mixture of honey, olive oil-propolis extract, and beeswax (HOPE)
in the treatment of OM in 90 pediatric patients with acute lym-
phoblastic leukemia and OM grades 2 and 3. Generally, in both
grades of mucositis, honey produced faster healing than either
HOPE or controls (p < 0.05).42
The potential analgesic effect of topical morphine, prepared
with taste supplements, in treating persistent mucosal pain
in palliative care patients, has been explored in two studies. In
one study, mouth rinses with morphine were superior to topi-
cal lidocaine in treating pain due to chemotherapy-associated
mucositis.43 In another, randomized, double-blind study, an oral
application of 2/1000 morphine solution in patients suffering from
radiotherapy- and/or chemotherapy-induced OM showed a pain
alleviation 1 h after mouthwash. Duration of pain relief was 123.7
(standard deviation ±98.2) minutes for morphine mouthwash.44
Altered taste sensations
A reduction (hypogeusia), distortion (dysgeusia), or absence
(ageusia) of normal taste sensation is common in patients with
cancer and can be the result of the disease itself and/or its treat-
ment (drug therapy, chemotherapy, radiotherapy). Between 25%
and 50% of patients with cancer are reported to experience taste
changes. A recent longitudinal, observational study showed that
the prevalence of taste alterations in patients receiving chemo-
therapy was alarmingly high (69.9%). Patients receiving irinotecan
courses reported significantly more taste alterations than patients
in other treatment groups.45 Taste alterations often start at the
beginning of chemotherapy and may persist for weeks or even
months beyond its termination.46 Typically, patients appeared to
have difficulty in differentiating sour and bitter tastes, which are
affected more than salty and sweet tastes. Women appeared to
report greater changes in taste than men.1,47,48 Zinc deficiency has
been linked with abnormalities in taste sensation.
Management of altered taste sensations
Nonpharmacological treatment includes mouth care, dental
hygiene improvement, the withdrawal of drugs that can induce
Mouth Care
the symptoms, and dietary advice. The urea content in the diet can
be reduced by eating white meats and eggs. This masks the bitter
taste of food. Food should be eaten cold or at room temperature.
Ripamonti et al.,49 in a randomized, double-blind, placebo-con-
trolled trial, described the beneficial effects of oral zinc sulfate tablets
(45 mg 3 times a day) in 18 patients with cancer receiving external
radiotherapy (ERT) to the head and neck region. One month after
ERT was terminated, the patients receiving zinc sulfate had a quicker
recovery of taste acuity than those receiving placebo.
A recent, randomized, double-blind, placebo-controlled,
pilot trial described the impact of delta-9-tetrahydrocannabinol
(THC) on taste and smell (chemosensory) perception in 46 adults
with advanced cancer. Compared with placebo, THC-treated
patients reported improved (p = 0.026) and enhanced (p < 0.001)
chemosensory perception and food “tasted better” (p = 0.04).50
Oral lesions in HIV/AIDS patients
Oral candidiasis, hairy leukoplakia, Kaposi sarcoma, necrotiz-
ing ulcerative gingivitis, linear gingival erythema, necrotizing
ulcerative periodontitis, and oral non-Hodgkin lymphoma are
strongly associated with human immunodeficiency virus (HIV)
infection and may be present in up to 80% of people with acquired
immune deficiency syndrome (AIDS).51 These lesions parallel the
decline in number of CD4 cells and an increase in viral load.
Cross-sectional studies have associated low CD4 lymphocyte
count with the presence of oral Kaposi sarcoma, non-Hodgkin
lymphoma, and necrotizing ulcerative periodontitis. 52
Highly active antiretroviral therapy (HAART) has altered the
prevalence and incidence of oral mucosal lesions of HIV infec-
tion. Although oral candidiasis appears to be the infection more
significantly decreased after the introduction of HAART, recent
reports show a variation in the prevalence of oral mucosal lesions
in different population groups. A cross-sectional estimation of
the prevalence of oral mucosal lesions was carried out in 101 HIV-
infected ethnic Chinese in Hong Kong. The prevalence of oral
mucosal lesions was more common in patients who were classi-
fied at baseline as Centers for Disease Control (CDC) C3 category
than CDC A2, A3, B2, and B3 (p < 0.05). An overall prevalence
of 1.98% was observed for oral Kaposi sarcoma.53 Another study,
aimed to determine the therapeutic effects of HAART on the
clinical presentations of HIV-related oral lesions in 142 Nigerian
adults recruited into the HAART program of an AIDS referral
center, showed that parotid gland enlargement, melanotic hyper-
pigmentation, and Kaposi sarcoma were more persistent and had
slower response to HAART.54
HAART may predispose to human papilloma virus infection
and potentially increase the risk of later oral squamous cell car-
cinoma.55,56 Regimens based on protease inhibitors may also have
adverse effects including oral problems such as paresthesia, taste
disturbances, and xerostomia and may interact with a number of
drugs used in oral health care.57
Management of oral lesions in
patients with HIV/AIDS
The greater majority of HIV/AIDS-affected people reside today
in the developing world and do not have affordable access to
HAART and/or conventional antifungal therapy (clotrimazole,
fluconazole, and itraconazole). For this reason, some less expen-
sive and more readily available alternatives are being tested: in
Malawi, gentian violet was found to be as effective as nystatine
543
for the management of oral candidiasis; topical chlorhexidine, in
a pilot study, also showed promise in the prevention of oral can-
didiasis in HIV-infected children; the essential oral oil solution of
Melaleuca alternifolia (tea tree oil) has been successfully used to
treat fluconazole-refractory oropharyngeal candidiasis in AIDS
patients.51,58,59 In poor-resourced limited settings, thalidomide
may be a cheap palliative therapy for mucocutaneous pediatric
Kaposi sarcoma.51
Osteonecrosis of the jaw
Osteonecrosis of the jaw has been shown to be associated with
the use of pamidronate and zoledronic acid, two bisphosphonates
that inhibit bone resorption and thus bone renewal by suppress-
ing the recruitment and activity of osteoclasts. People at risk
include those with multiple myeloma and cancer metastatic to
bone who are receiving intravenous bisphosphonates. The risk of
developing complication appears to increase with the time of use
of the medication.60,51
The predilection for mandibular molar and premolar regions
and the infectious conditions that often precede the onset of
osteonecrosis support recent pathogenesis theories stating that
local inflammation and associated pH changes may trigger the
release and activation of nitrogen-containing bisphosphonates,
ultimately resulting in necrosis.62
Bamias et al.63 studied the incidence, characteristics, and risk
factors for the development of osteonecrosis of the jaw among 252
patients with advanced cancer. The incidence increased with time
to exposure from 1.5% among patients treated for 4–12 months
to 7.7% in those treated for 37–48 months. The cumulative haz-
ard was significantly higher with zoledronic acid compared with
pamidronate alone or pamidronate and zoledronic acid sequen-
tially (p < 0.001). In addition, some authors have reported a few
cases of osteonecrosis of the jaw in patients taking oral doses of
alendronate to treat osteoporosis or osteopenia.64,65
Comorbid factors may play a role, such as the presence of dia-
betes mellitus, the degree of immunosuppression, and the use of
other medications (chemotherapeutic agents, corticosteroids).
Other drug-related risk factors include the use of antiangiogenic
agents such as thalidomide and bortezomib in patients with mul-
tiple myeloma.66 Local comorbid factors include oral health sta-
tus, presence of infection, and the history of radiation therapy.
A survey conducted by the International Myeloma Foundation,
in 1203 patients receiving intravenous bisphosphonate therapy
for the treatment of myeloma or breast cancer, showed that 81%
of the patients with myeloma and 69% of the patients with breast
cancer who developed osteonecrosis had underlying dental dis-
ease, such as infection, or had a dental extraction, as compared
with 33% of the patients who did not develop osteonecrosis.61
The most common initial complaint is the sudden presence
of intraoral discomfort and the presence of roughness that may
traumatize the oral soft tissues surrounding the area of necrotic
bone. The classic clinical features are a growing, painful, and
unilateral swelling with jaw pain and difficulty in chewing and
brushing teeth.67 The mandible and maxilla, with or without oro-
antral fistulae, are the main areas affected by osteonecrosis.
Management of osteonecrosis of the jaws
The treatment in patients receiving oral or intravenous bisphos-
phonate therapy is principally preventive in nature.60 Ruggiero et
al.,64 in a case series of 63 patients, reported that despite several
544
BOX 56.2  BISPHOSPHONATE-
ASSOCIATED OSTEONECROSIS OF THE
JAW: PREVENTIVE MEASURES
• Clinical dental examination: Comprehensive
extraoral and intraoral examination; full-mouth
radiographic series plus panoramic radiograph;
evaluation of third molars
• Removal of abscessed and nonrestorable teeth
• Restore periodontal health status (pocket elimi-
nation, plaque reduction)
• Caries control, elimination of defective
restorations
• Oral hygiene and self-care education
• Functional rehabilitation of salvageable dentition
(endodontic therapy)
• Properly fitting dentures
• Scheduled periodic follow-up visits
treatment modalities, such as minor debridement, major surgical
sequestrectomies, partial or complete maxillectomies, and hyper-
baric oxygen therapies, no healing occurred in any of the patients
treated. For this reason, preventive measures prior to the initia-
tion of intravenous bisphosphonate therapy are of paramount
importance, with the dentist and oncologist working collabora-
tively. In an observational, longitudinal, noncontrolled study of
43 consecutive patients treated with zoledronate who underwent
tooth extractions, the removal of the alveolar bone after the tooth
extractions (alveolectomy) and correct antimicrobial prophylaxis
(antibiotics and mouthwash) could reduce the risk of occurrence
of osteonecrosis.62
Box 56.2 summarizes the potential preventive measures in
osteonecrosis of the jaw.
There is no scientific evidence to support the discontinuation
of bisphosphonate therapy to promote healing of necrotic osse-
ous tissues in the oral cavity.60
Systemic antibiotic therapy to control secondary infection and
pain may be beneficial and should be administered whenever active
infection is present. Antibiotics that have been found useful for
osteonecrosis include penicillin or amoxicillin and, in the presence
of penicillin-related allergy, clindamycin or erytromycin ethylsuc-
cinate. A 0.12% chlorohexidine antiseptic mouthwash, or minocy-
cline hydrochloride, can be useful for periodontal pockets.69,70
Oral health in frail elderly with dementia
Caring for patients with advanced dementia will be a most
important challenge in the next future of palliatrive care with an
expected 115 million people with dementia by 2050: almost half
of them experience daily pain. 37 Orofacial pain in this population
is common and may be caused by teeth or their supporting tis-
sues, the muscles and joints of the masticatory system, or other
non-odontogenic tissues but can be difficult to detect and is often
undertreated.71,72
A cross-sectional observational study was carried out in 2
UK hospitals to identify orofacial pain, in 101 participants with
dementia, admitted to acute medical wards using a specific tool,
the Orofacial Pain Scale in Non-Verbal Individuals (OPS-NVI)
Orofacial pain, assessed with the OPS-NVI, was present in 11.9%
Textbook of Palliative Medicine and Supportive Care
KEY LEARNING POINTS
• Oral disturbances are frequently experienced by
patients with advanced cancer.
• The most common problems are xerostomia,
fungal infections, therapy-related mucositis, and
taste disturbances.
• Azoles resistance may become a clinical problem
in the treatment of oral fungal infections.
• Improving dental and oral hygiene, good fluid
intake, ice chips, and dietary advice are the main-
stay of nonpharmacological prophylaxis and
treatment of xerostomia, mucositis, and taste
alterations in palliative care patients.
• Honey can be a cheaper and worldwide available
choice for treating herpes simplex lesions and
radiation-induced mucositis.
• In poor-resourced limited settings, mouth care
for people with AIDS is a basic clinical strategy.
• Bisphosphonate-related osteonecrosis of the jaw
is a challenging problem in palliative care: pre-
vention of the osteonecrosis is the best approach
to management of this complication.
• Mouth care in advanced dementia elderly people
is a challenge for palliative care teams in the next
future.
(95% confidence interval (CI) 5.9, 18.8) of participants at rest and
21.9% (95% CI 14.6, 31.3) while chewing. Brush frequency, indi-
cation of chewing quality, consistency of the food, presence of
extra-oral abnormalities, person who performed mouth care, and
oral hygiene in dentate participants were significant predictors
for the presence of orofacial pain. This study highlights that dry
mouth in patients with advanced disease can have a significant
negative impact on the day-today ability to talk, eat, and taste and
can interfere with nasal passages, lips, throat, swallowing, and
sleep.73
Unfortunately, current available evidence in literature on oro-
facial pain and mouth care in this frail population is insufficient
and has produced variable findings. This emphasizes the urgent
need for further research in this area.
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57
FISTULAS

Maurizio Lucchesi, Fabio Fulfaro, Raffaele Giusti, and Carla Ida Ripamonti

Contents
Fistulas................................................................................................................................................................................................................................. 547
General principles of treatment..................................................................................................................................................................................... 547
Gastrointestinal fistulas................................................................................................................................................................................................... 547
Esophageal fistulas...................................................................................................................................................................................................... 547
Gastric and duodenal fistulas................................................................................................................................................................................... 548
Pancreatic fistulas........................................................................................................................................................................................................ 548
Small bowel and colonic fistulas.............................................................................................................................................................................. 549
Head and neck fistulas..................................................................................................................................................................................................... 549
Bronchopleural fistulas.................................................................................................................................................................................................... 549
Genitourinary fistulas.......................................................................................................................................................................................................550
Conclusions.........................................................................................................................................................................................................................550
References............................................................................................................................................................................................................................550

Fistulas TABLE 57.2  Frequent Complications Induced by the Fistulas

Infection → sepsis
A fistula is an abnormal communication between two internal
organs (internal fistula) or between the skin and an internal Hydro-electrolytic losses
organ (external fistula).1 Fistulas may be classified according to Malnutrition
the amount of the output: low output (<200 mL/24 h period), Skin lesions
moderate output (200–500 mL/day), and high output (>500 Hemorrhages
mL/day).2 Fistulas may be single or multiple. 3 In oncological Delay in oncological treatments
patients, the most frequent causes of fistulas are related to can- Psychosocial problems
cer (local progression of the disease and/or local relapse) and/
or treatments (surgery, radiotherapy, chemotherapy, antiangio-
genic biological therapy, locoregional liver tumor ablation, pho- General principles of treatment
todynamics, endoscopy, and invasive diagnostic procedures) or
both4–16 (Table 57.1). Prior to planning a treatment, it is important to define the objec-
The onset of a fistula produces various complications: infec- tives to be achieved.
tion (sepsis), electrolyte imbalance, dehydration, malnutrition, In advanced cancer patients, treatment will be conservative,
cutaneous lesions, bleeding, delay in oncological treatments, and whereas for a patient with a longer survival expectancy, a more
psychosocial problems. invasive treatment may be performed. Table 57.3 shows the pos-
Sepsis is the most frequent cause of death in patients with fis- sible conservative20–22 and nonconservative treatments.23,24
tulas.17 Nutritional status as well as a condition of impaired tissue
vascularity may be predisposing factors18,19 (Table 57.2). Gastrointestinal fistulas
Gastrointestinal fistulas may be classified as external (entero-
cutaneous fistulas) and internal (communication between hol-
TABLE 57.1  Causes of Fistulas in Cancer Patients low organs), or according to the anatomical site of onset such
Causes correlated to treatments Surgery as esophageal, gastric and duodenal, pancreatic, enteric, and
Radiotherapy colonic.18
Chemotherapy
Photodynamics
Esophageal fistulas
Esophageal fistulas may be classified as esophagorespiratory
Endoscopy
(particularly esophagotrachealis) and esophagocardiovascular.
Invasive diagnostic procedure
As far as the first ones are concerned, most of them are due to
Causes correlated to cancer Tumoral local progression
esophageal carcinoma (75%) and lung cancer (16%).25,26
locoregional relapse of the disease
Literature cites some rare cases due to Hodgkin’s disease.27
Mixed causes (correlated to
The patient’s symptoms may be dysphagia, coughing, aspira-
treatments and to cancer)
tion, suffocation, and fever.

547
548
TABLE 57.3  General Management of Fistulas
Conservative treatment
• Skin care and local disinfection
• Pouching of secretions (particularly gastric and pancreatic)
• Control of odor, delicate fistula areas, and use of antibiotics against
anaerobic bacteria (metronidazole)
• Control of local itching and pain
• Control of infections (specific antibiotic treatment, care in the use of
corticosteroids, Radiotherapy RT, and chemotherapy)
• Control of nutrition and electrolytes (particularly in high-output
fistulas) and eventual TPN and antisecretory treatments
(scopolamine, octreotide)
• Treatment of site-related symptoms (antiemetic, antispastic,
antihemorrhagic, antisecretory, use of vasopressin for urinary
incontinence, use of urinary catheters)
• Control of psychological conditions (distortion of body image,
isolation, social discomfort)
Nonconservative treatment
• Surgical resection of fistula
• Surgical repair with corrective procedures or with myocutaneous
flaps
• Colonic and/or urinary diversion
• Endoscopic treatments with metallic stents
Whenever the patient’s clinical condition allows it, surgery may
be performed28 with an eventual gastrostomy and/or jejunostomy
(including newly drainage tubeless bypass surgery approach), the
use of metallic stents,29–32 and/or palliative radiotherapy.
Regarding self-expandable metal stent, stricture of the upper
esophagus and shorter stent patency are independent predictors
of initial clinical failure. Moreover, initial clinical failure is an
independent predictor of shorter survival. 33
Chemotherapy is indicated particularly in the presence of lym-
phomas. Stents are used also for palliation of other symptoms or
issues, such as dysphagia. In these cases, plastic stent, conven-
tional stent, and fully covered self-expandable metal stents were
better treatments in terms of lower risk of fistula formation. 34
From a prognostic point of view, patients with esophago-respi-
ratory fistula are at high risk of developing lung abscesses, empy-
ema, and pneumonia ab ingestis.28
Esophagocardiovascular fistulas are very rare in cancer
patients and also include the aortoesophageal fistula, which is
mainly caused by the rupture of a thoracic aneurysm into the
esophagus, and the esophagocardiac fistula.4,28
Gastric and duodenal fistulas
More than 90% of gastric and duodenal fistulas are a consequence
of surgery in those areas. 35 Postoperative fistulas are frequently
due to an “anastomotic leak” and abscess formation. Cancers of
the transverse colon, stomach, and duodenum are more prone to
fistulization. Other rare causes are lymphomas and the placing of
pumps for chemotherapy infusion in the gastroduodenal artery.10
While external fistulas are easily diagnosed, internal fistulas that
can cause diarrhea and nutritional deficit are less detectable.
Generally, internal fistulas diagnosis occurs between the fifth
and tenth postoperative day. Main fistulas-related complications
are sepsis, abdominal abscess, wound infection, pneumonia, and
intra-abdominal bleeding. 36
Textbook of Palliative Medicine and Supportive Care
Most postoperative gastrointestinal fistulas heal spontane-
ously within 4–5 weeks. Factors associated with poor healing or
delayed healing include multiple fistulous tracts, malnutrition,
acute infection or sepsis, level of serum transferrin (unfavorable
<200 mg/dL), 37,38 cancer progression, and previous radiotherapy
carried out in the involved areas.17
Treatment of gastric and duodenal fistulas may be medical,
endoscopic, and/or surgical. Nutritional support39 and treatment
of infection40 are essential in the management of postoperative
fistula.
Conservative and/or endoscopic/percutaneous treatment is/are
the first choice. However, if the patient clinical condition wors-
ens, surgery becomes mandatory and duodenostomy appears to
be the most effective surgical procedure. 36 Endoscopically, some
authorities have reported obliteration of the fistula tract with
adhesive fibrin tissue.41 For patients with persistent fistulas and
a good performance status, three different surgical approaches
are described: (1) exclusion, (2) resection, and (3) “closure of the
leak.”35 The exclusion of a fistula is not the treatment of choice
and is reserved for the very ill patients. This procedure is carried
out with a resection of the diseased segment and an exterioriza-
tion of the end parts. In this way, an uncontrolled anastomotic
leak is converted into a controlled external fistula. However, pro-
cedure of choice is the resection of the anastomotic leak with the
formation of a new anastomosis. Major contraindications to this
procedure are ischemia or tension on the anastomosis. If resec-
tion of the anastomotic leak cannot be performed, then closure
of the leak with a serosal patch or roux-en-y anastomosis is the
preferred surgical alternative. 35
Pancreatic fistulas
Pancreatic fistulas are more frequently external and are usu-
ally complications due to upper abdominal invasive procedures
on the pancreas or surrounding area42 and occur in 6%–25% of
pancreaticoduodenectomies.43 Fistulas are more frequent dur-
ing the first postoperative week and present a high level of serum
amylase. Internal fistulas, which most commonly involve the
peritoneum, are rare. They are usually diagnosed by radiological
examination (fistulography, CAT scan), ultrasonography, and/or
by endoscopic retrograde cholangiopancreatography.44 IL-6 lev-
els in the 96-postoperative hours seem to be associated with the
development of pancreatic fistula.45
Postoperative external fistulas heal spontaneously in 80%
of cases with conservative treatment incorporating skin care,
drainage and collection of pancreatic secretion, control of infec-
tion, and parenteral nutrition (to reduce pancreatic secretion).44
Octreotide, in doses of 50–200 mcg tid, has been used in the con-
servative treatment to reduce GI secretion.46,47 Many authors sug-
gest the use of subcutaneous injection of octreotide at doses of
50–200 mcg tid according to output.48 However, some authors49,104
have expressed some concern about the use of octreotide in the
treatment of pancreatic fistula.
Surgical approaches are reserved for situations of conservative
management failure in patients with good performance status
and a favorable tumor anatomy.44 The placement of an endo-
scopic stent has proved effective in certain studies, but a longer
follow-up is necessary to evaluate possible long-term complica-
tions.44 A randomized trial has demonstrated the role of external
stent drainage to reduce postoperative pancreatic fistula after
pancreaticojejunostomy.50
The postoperative pancreatic fistulas-related mortality rate
has remained at approximately 1% over the past 25 years. Only
Fistulas
externally draining and transanastomotic stents were able to
decrease the postoperative pancreatic fistulas-related mortality
rate.51
Small bowel and colonic fistulas
Intestinal fistulas are classified as internal, external, or mixed;
the most common are external (enterocutaneous). 52 Most of them
are a consequence of postoperative complications following sur-
gery on GI cancers with diastasis of the anastomotic wound and
damage to the bowel and its vascularization.
The severity of enterocutaneous fistula depends on the site and
the amount of secretion: for example, a large volume of secretion
and small bowel fistulas can be associated with severe fluid and
electrolyte abnormalities and malabsorption. In a series of 25
cancer patients with enterocutaneous fistulas, the most frequent
site was the jejunum-ileum, and mortality was correlated to pre-
vious radiotherapy, the site, fistula output, and the presence of
hypoalbuminemia. In 63% of patients, the presence of a fistula
brought about the suspension of any ongoing anticancer treat-
ment. 52 A rare presentation of an enterocutaneous fistula may
be subcutaneous emphysema. 53 Enterocutaneous fistulas may
heal spontaneously with adequate supportive therapy including
total parenteral nutrition (TPN), prevention and treatment of
infective complications (in 70% of these cases). Several studies
supported the use of somatostatin analogues to reduce secretion
volume, but a recent meta-analysis suggests that somatostatin
could be better than analogues in relation to the number of fis-
tulas closed and time to closure. 21,54,55 The use of TPN allows an
adequate fluid intake, normalization of electrolytes as well as
catabolic blockage. Factors that negatively influence spontane-
ous closure of the fistula include the presence of cancer together
with sepsis, malnutrition, distal obstruction to the fistula, and
the epithelialization of the fistulous tract. 56 Surgery is indicated
whenever conservative treatment has not been effective and
when the patient’s condition allows it. 56 Preoperative adminis-
tration of oral arginine and glutamine could be valuable in the
postoperative recovery of patients with enterocutaneous fistulas
submitted to definitive surgery. 57
Colonic fistulas, although considered uncommon, can also
be classified as external, internal (colocutaneous), and mixed. 58
Among the internal fistulas, the most common are colovesi-
cal, followed by colovaginal and coloenteric. The most evident
sign of colocutaneous fistulas is the passage of air and feces
through an incision in the abdominal wall following surgery.
Other signs and symptoms are sepsis, fever, tachycardia, leuko-
cytosis, and pain due to abscess with local peritonitis. Patients
with an internal fistula complain of various symptoms accord-
ing to the viscera involved. Patients with colovesical fistulas fre-
quently complain of cystitis, high fever, shivering, and sweating
and, if the fistulous tract is wide, pneumaturia and fecaluria.
Patients with colovaginal fistulas suffer from an increase of vag-
inal secretion, sometimes associated with the passage of feces.
Patients with coloenteric fistulas suffer from abdominal pain
and abundant diarrhea. 59
The diagnosis of an internal colovesical fistula is obtained by
means of a cystoscopy, for colovaginal fistula by means of a fistu-
logram and/or a vaginogram, for coloenteric fistula by an abdom-
inal CAT scan with contrast.
Colocutaneous fistulas may be conservatively treated even if
the rate of healing is lower than in enteric ones, particularly in the
presence of a malignancy or a distal occlusion. Some patients may
require a surgical bowel diversion.
549
In the presence of a malignancy, a partial cystectomy per-
formed together with the sigmoid colon is indicated for colo-
vesical fistulas. Radiotherapy-induced fistulas may be complex
and often involve more than one organ, for example, the colon
or rectum respectively with the bladder, the vagina, the small
bowel, and the skin. These fistulas are more difficult to treat
because of the low rate of spontaneous healing and the high
rate of relapse.60 It is possible to treat coloenteric fistulas with
stents. 59
Head and neck fistulas
As regards the head and neck cancer patients, the most frequent
fistulas are pharyngocutaneous and they are the most common
complications resulting from total laryngectomy. It was observed
that 12%–16% of the patients undergoing laryngectomy develop
fistulas 11–14 days after surgery.61–63 Although spontaneous fis-
tula closure occurs in two-thirds of the cases, about 20% of the
patients have to undergo surgery with direct suture of pharyngeal
mucosa or reparative surgery by means of a deltopectoral flap or
a pectoralis major myocutaneous flap.64,65
Negative prognostic factors that give rise to fistulas can be
hemoglobin levels lower than 12.5 g/dL, concomitant heart
pathology, extension of surgery, the surgeon’s experience, tumor
size, and the use of catgut.61,66 A randomized study demonstrated
the efficacy of arginine-supplemented enteral nutrition in this
group of patients.67
Previous radiotherapy to the head and neck increases the
risk of developing fistulas by 10%–12% and the healing rate is
lower.68,69
In some groups of patients treated with radiotherapy, the per-
centage of fistulization increases up to 30% after total laryngec-
tomy with prolonged hospitalization.70,71
Some authors suggest using growth factors with the aim of
preventing infection and sepsis.72 The concomitant use of oxy-
gen therapy and radiotherapy favors neovascularization and pre-
vents fistulas from occurring. Another relatively frequent group
of fistulas are the esophagotracheal ones, already described in the
paragraph: esophageal fistulas.
Other rarer fistulas are the tracheocutaneous, which are often
correlated to a long-term tracheostomy, salivary fistulas,73 oroan-
tral fistulas,74 and chylous fistulas.75
Bronchopleural fistulas
Bronchopleural fistulas are often correlated to pneumonectomy
in treating lung cancer.76 The incidence is about 8%–10%.77
Significant risk factors involved in the development of fistulas
are preoperative infection, dx pneumonectomy, and the presence
of subcarenal metastatic lymph nodes, preoperative radiotherapy,
and diabetes.
Moreover, low preoperative serum level of albumine can serve
as a significant risk factor for postoperative bronchopleural fistu-
als in patients undergoing pulmonary resections.78
From a pathophysiological viewpoint, it is difficult to preserve
bronchial arteries in the dissection of the metastatic subcarenal
lymph nodes, which adhere to the bronchial tree.
The bronchial arteries ligature or the protrusion of the bron-
chial stump in the pleura reduces the blood flow to very low lev-
els, thus favoring fistula development.77 The most common signs
and symptoms are air in the pleural cavity, dyspnea, and front
chest pain.79
550
The diagnosis is usually carried out through a bronchoscopy,
although, recently, scintigraphic techniques with xenon-133 and
technetium-99 m have given good results.80
Surgery is the first-choice treatment, whenever possible.79,81
However, in the case of fistulas smaller than 3 mm, successful
results have been found by means of reparative endoscopy.81,82 A
thorough follow-up in the first 3 months after pneumonectomy is
indicated as a preventive measure.81,82
Genitourinary fistulas
The incidence of fistulas in the genitourinary tract is about 2% in
cancer patients.
The most frequent causes are surgery (hysterectomy, prosta-
tectomy, rectal resections, pelvic evisceration), 83,84 radiotherapy
on the pelvic organs, 85 and locoregional relapses. Signs and
symptoms are characterized by urinary incontinence, pain, and
itching at the fistula site, pneumaturia, sometimes fecaluria, GI
disorders, hemorrhage, and are often present with psychological
distress.86 For diagnostic aims, the following are often used: CAT,
MNR, cystoscopy, charcoaluria, and barium enema.87–89
As far as the anatomical site is concerned, the most frequent fis-
tulas in this group of patients are rectovaginal, enterovescical, vesci-
covaginal, ureterovaginal, urethrocutaneous, and rectoureteral.
The rarer are the vescicocutaneous, the intraperitoneal chylo,
and the vescicouterinos.90,91
The rectovaginal and enterovescical fistulas are often the con-
sequence of radiotherapy on the pelvis, with necrosis of the vagi-
nal and rectal walls or hysterectomies.89,92,93
Carcinomas of the rectum, uterine cervix, and vagina are those
most at risk of fistulaization due to the site and necessary treat-
ments.94 When the fistula is in the lower part of the rectum, fecal
incontinence due to involvement of anal sphincter may be pres-
ent. Surgical treatment consists of colon or urinary stomia.95
Profuse hemorrhages can be controlled by embolization.96
Vescicovaginal fistulas are often the outcome of hysterecto-
mies97 and the two orifices are 1 cm above the trigone for the
bladder and the anterior wall for the vagina.
These fistulas heal using a catheter from 12 to 20 days with a
closed drainage to prevent infection.98
Ureterovaginal fistulas are often the result of radical hyster-
ectomy via laparotomy. The risk of renal damage should always
be taken into consideration and the areas most at risk of fistulai-
zation are common iliac artery, uterine artery, and sacrouterine
ligament. The treatment of the fistulas in these areas is the use of
the ureteral catheter of Finney, when possible, or eventually an
ureteroneocystostomy may be indicated.99
Urethrocutaneous fistulas most frequently concern the pros-
tatic urethra as compared to the bulbar urethra.
The urethrocutaneous fistulas are the result of a perineal pros-
tatectomy, and there is almost always a concomitant prostatic
abscess. The cutaneous orifice is usually central and in a preanal
area. The urethral orifice is located above the urogenital dia-
phragm and may reach the bladder.100
The urethrorectal fistulas are often associated with carcinoma
of the rectum, prostate, and bladder with concomitant abscess.
The rectal orifice is suprasphincteric concealed behind a mucosal
fold or in the Morgagni cyst.
The urethral orifice is situated in the prostatic urethra.100
The vescicocutaneous fistulas, rarer, are often correlated to
lesions of the bladder fundus on the laparotomic wound. The cuta-
neous orifice is suprapubic. Contentive treatment is important in
Textbook of Palliative Medicine and Supportive Care
these fistulas.101,102 The use of some biological agents such as suni-
tinib may cause in rare cases fistulization.103
Conclusions
In cancer patients, fistulas are complications to be held in con-
sideration due to delays that can be caused in the treatment
of cancer as well as in the worsening of the patients’ clinical
and psychological conditions. Prior to planning a conservative
treatment versus an invasive one, it is mandatory to assess the
patient’s chances of survival as well as his/her quality of life.
Considerable effort should be made by caregivers in order to
manage all the different symptoms related to this complication
in cancer patients.
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vescicovaginal fistulae—A ten-year retrospective study. Scand J Urol
Nephrol 1999;33:100–103.
98. Nesrallah LJ, Srougi M, Gittes RF. The O’Conor technique: the
gold standard for supratrigonal vescicovaginal fistula repair. J Urol
1999;161:566–568.
99. Emmert C, Kohler U. Management of genital fistulas in patients with
cervical cancer. Arch Gynecol Obstetr 1996;259:19–24.
100. Harpster LE, Rommel FM, Sieber PR, et al. The incidence and manage-
ment of rectal injury associated with radical prostatectomy in a com-
munity based urology practice. J Urol 1995;154:1435–1438.
101 Turner-Warwick R. Urinary fistulae in the female. In: Walsh PC, Gittes
RF, Perlmutter AC, Stanley TA, eds. Campbell’s Urology, 5th edn.
Philadelphia, PA: W.B. Saunders, 1986, pp. 2718–2738.
102. Dangle PP, Wang WP, Pohar KS. Vesicoenteric, vesicovaginal, vesico-
cutaneous fistula—An unusual complication with intravesical mito-
mycin. Can J Urol 2008;15(5):4269–4272.
103. Watanabe K, Otsu S, Morinaga R, et al. Vesicocutaneous fistula for-
mation during treatment with sunitinib malate: case report. BMC
Gastroenterol 2010;1(10):128.
104. Garg PK, Sharma J, Jakhetiya A, et al. The role of prophylactic octreo-
tide following pancreaticoduodenectomy to prevent postoperative
pancreatic fistula: a meta-analysis of the randomized controlled trials.
Surg J 2018;4:e182C–e187.
58
ASSESSMENT AND MANAGEMENT OF LYMPHEDEMA

Ying Guo and Mark V. Schaverien

Contents
Lymphedema classification and incidence....................................................................................................................................................................553
Classification (Table 58.1)................................................................................................................................................................................................553
Primary lymphedema..................................................................................................................................................................................................553
Secondary lymphedema..............................................................................................................................................................................................553
Pathophysiology................................................................................................................................................................................................................ 554
Common complications...................................................................................................................................................................................................555
Diagnosis..............................................................................................................................................................................................................................555
History and physical examination (Box 58.2).........................................................................................................................................................555
Volume and skin condition measurements.............................................................................................................................................................556
Image studies.................................................................................................................................................................................................................557
Differential diagnosis.........................................................................................................................................................................................................557
Lipedema.......................................................................................................................................................................................................................557
Deep vein thrombosis and chronic venous disease...............................................................................................................................................557
Heart failure or renal failure......................................................................................................................................................................................557
Staging of lymphedema.....................................................................................................................................................................................................557
Prevention...........................................................................................................................................................................................................................557
Treatment............................................................................................................................................................................................................................557
Skin care.........................................................................................................................................................................................................................558
Manual lymphatic drainage........................................................................................................................................................................................558
Exercise..........................................................................................................................................................................................................................558
Compression bandage and compression garment.................................................................................................................................................558
Pneumatic compression..............................................................................................................................................................................................558
Surgery...........................................................................................................................................................................................................................558
Drug therapy.................................................................................................................................................................................................................559
Psychosocial support...................................................................................................................................................................................................559
Weight loss................................................................................................................................................................................................................... 560
References........................................................................................................................................................................................................................... 560

Lymphedema classification and incidence
Lymphedema is a chronic, progressive, incurable condition, esti-
mated to affect approximately 10 million Americans, and up to
250 million patients worldwide. Filariasis, a parasitic infestation, is
the most common cause. Lymphedema is an accumulation of lym-
phatic fluid in the interstitial tissue that causes swelling, most often
in the upper or lower extremity(ies), and occasionally in face, neck,
trunk, and external genitalia. Lymphedema negatively affects the
activities of daily living, vocational, psychosocial, sexual lives, and
quality of life of patients.1–5 In addition, it puts patients at increased
risk for life-threatening infections and malignancies.6
Classification (Table 58.1)
Primary lymphedema
Primary lymphedema is caused by a congenital abnormality or
dysfunction in the lymphatic system and can be further classified
according to age of onset. Primary lymphedema is rare, affect-
ing 1.15 per 100,000 people younger than 20 years of age.7 The
congenital form is detected at birth or in the first two years of
life and may either be sporadic or familial. Milroy disease and
Aagenaes syndrome are both congenital and hereditary forms of
lymphedema. The onset of lymphedema praecox is between the
ages of 2 and 35 years. The onset of lymphedema tarda occurs
after 35 years of age.
Alternatively, primary lymphedema can be classified according
to the abnormality found in the lymphatics. Thus, it may be due
to aplastia, hypoplastia, or hyperplastia of the lymphatic system.
While this is true for congenital lymphedema, cases of later-onset
primary lymphedema might be due to an acquired abnormality
where there is a predisposing abnormality of the lymphatic system.
Secondary lymphedema
Secondary lymphedema is edema due to a reduction in lymph
flow by an acquired cause. The causes of secondary lymphedema
include trauma, recurrent infection, and malignancy and its treat-
ment (surgery, radiation). In the developed world, the most com-
mon cause of secondary lymphedema is malignancy (including
that resulting from cancer treatment). Lymphedema is common
in the developing world secondary to infection with the parasitic
nematode Wuchereria bancrofti (otherwise known as filariasis),
making this the most common cause of lymphedema worldwide.8
Cancer-related lymphedema usually occurs at proximal limb

553
554
TABLE 58.1  Staging of Lymphedema
Elevation
Stage Edema Reverses Swelling Pitting
0 − NA − −
1 + + +
2 + Partially ± +
3 + − −
+, Present; −, absent.
segments (i.e., lymph nodes) due to infection, ligation, malig-
nancy, scar tissue, and radiation therapy.9 The pelvic and inguinal
nodes in the lower extremities and the axillary nodes of the upper
extremities are the primary sites of obstruction.
This chapter will be emphasizing secondary lymphedema
related to cancer and its treatment, which is frequently over-
looked.10–17 Recent studies have shown that the rate of lymph-
edema after sentinel node biopsy ranges from 2% to 8% and
ranges from 4.5% to 14% following axillary node dissection.18–23
The severity of breast cancer–related lymphedema, measured by
interlimb arm volume difference, is associated with educational
attainment (−4.89, p = 0.03), having more lymph nodes removed
(4.75, p = 0.01) and years since treatment (0.55, p < 0.001).24
The incidence of lower limb lymphedema secondary to gyne-
cological cancer was reported to be 13%–58%, with radiation as
a main risk factor.25–28 In patients with penile carcinomas, lymph
node metastasis is reported in up to 35%29 and following treat-
ment by groin node dissection, lymphedema developed in 50%–
100% of the patients.29,30 A small study reported that 8/26 patients
developed lymphedema after extended pelvic lymphadenectomy
followed by androgen deprivation therapy and radiotherapy. 31,32
Pathophysiology
Lymphedema occurs when lymphatic fluid load exceeds the lym-
phatic transport capacity, causing an abnormal amount of pro-
tein-rich fluid to collect in the tissues of the affected area. In most
cases, not only is the transport capacity impaired, but in patients
with venous insufficiency, the lymphatic load is also increased.
The lymphatic drainage system is separate from the general cir-
culatory system and is the conduit for returning tissue fluids to
the circulation. 33
The superficial lymphatic system begins with initial lymphat-
ics, which are formed from one-layer endothelial cells, overlap-
ping each other but not forming a continuous connection. Each
of the cells is attached to the surrounding tissue by anchoring
filaments. When there is a change in tissue pressure caused by
arterial pulsation, muscle contraction, or respiration, or when
the skin is lightly stretched, the anchoring filaments pull on the
cells of the initial lymphatics. Because of this, the gap between
the cells opens, and fluid drains into the vessels. 34 Initial lym-
phatics combine to form larger vessels called precollectors and
collectors, which in turn lead to the lymph nodes in the axillary
and inguinal regions. The collector vessels of the lymphatic sys-
tem contain smooth muscle and valves to regulate flow. 34 The
regional lymph nodes drain fluid from the ipsilateral limb and
torso quadrant. Deep lymph nodes are located along major arter-
ies for visceral drainage. Major somatic drainage areas are con-
nected via subcutaneous collateral channels, both anteriorly and
posteriorly. Lymph drains from the lower limbs into the lumbar
lymphatic trunk, which joins the intestinal lymphatic trunk and
Textbook of Palliative Medicine and Supportive Care
Skin Lesions (Fungal,
Fibrosis/Stemmer’s Sign Cyst, Fistula, Papillomas)
−
− −
−
+ +
cisterna chyli to form the thoracic duct. Lymph returns to the
blood circulation at the venous angles, which are formed by the
junctures of the internal jugular and subclavian veins. Most of
the lymph in the body drains via the thoracic duct, which enters
the circulation at the left venous angle. Only the right upper torso,
arm, face, and neck drain into circulation on the right side via
the right lymphatic duct, which empties into the right subclavian
vein. 33 An important function of the lymphatic system is the pre-
vention of infection. The lymphatic system is responsible for pick-
ing up excess interstitial water and protein as well as other cells,
including bacteria, which can enter the tissue through small cuts
or breaks in the skin. Bacteria and other antigens are transported
by the lymphatic system from the interstitium to lymphocytes in
the lymph nodes, where an immune response may be initiated.
Physiologically, most of the interstitial fluid generated daily (18 L)
arises from the blood capillaries. Fourteen-to-sixteen liters sub-
sequently return directly to the venous circulation. The remain-
ing 10%–20%, approximately 2 L/day, passes through lymphatic
transport.
Histologically, the reparative process in the traumatized lym-
phatic vessels after mastectomy demonstrates fibrosis and an
accompanying reduction in vessel diameter. With the subsequent
ligation or interruption of lymph channels and lymphadenec-
tomy, the body attempts a regenerative process with the forma-
tion of collateral circulation. The radiation treatment may lead
to fibrosis. Nonirradiated lymph nodes develop compensatory
dilated sinuses to handle lymph volume. This may anatomically
be associated with a lymph node hyperplasia. If the lymphatic
system fails locally, protein subsequently accumulates in the
interstitial space. If no intervention occurs at this point, fibro-
sclerosis will follow along with inflammation, scarring, and loss
of regional lymphatic integrity.
The frequency with which lymphedema occurs after cancer
therapy depends on multiple factors (Box 58.1):
1. The extent of lymphatic system damage. In a study by Kiel
in 1996, in the absence of lymph node dissection, the inci-
dence of edema after breast cancer treatment was 21%.
With 11–15 nodes removed, edema was present in 27%.
With greater than 15 lymph nodes removed, it was 44%.35
Lymphatics have excellent regenerative capabilities. Even
after radical lymph node excision for malignancy, lymph-
edema does not always happen. When it does occur, it is
often a late complication. The reasons for this late devel-
opment are uncertain, but gradual failure of distal lym-
phatics, which have to “pump” lymph at a greater pressure
through damaged proximal ducts, has been postulated. The
transected lymphatics will regenerate after node clearance
procedures. If combined with radiotherapy, however, the
risk of lymphedema is higher, as fibrous scarring reduces
regrowth of ducts.
Assessment and Management of Lymphedema
BOX 58.1  FACTORS AFFECTING DEVELOPMENT
OF CANCER-RELATED LYMPHEDEMA
Extent of lymphatic system damage
• Recurrence of tumor
• Lymph node dissection
• Radiation
Inherent compensatory ability of the lymphatic system
• Age
• Obesity
• Infection
• Heart failure
• Venous insufficiency
• Other factors that affect lymph load
2. The inherent compensatory ability of the lymphatic sys-
tem. Patient’s weight and age may affect the development of
lymphedema. Twenty-two percent of breast cancer patients
older than 55 were shown to have an increased lymph-
edema risk when compared to their younger counterparts
(14%). 35,36 Comorbidities, such as heart failure, renal insuf-
ficiency, and venous insufficiency, may contribute to the
onset and progression of lymphedema. Recurrent cellulitis
can further compromise the fluid return. Any situation that
causes an increase in lymphatic load can predispose patients
to development or worsening of lymphedema. The onset of
lymphedema may be provoked in a variety of common situ-
ations that occur on a daily basis: muscle fatigue resulting
from overuse; vasodilatation following exposure heat; local
trauma; vigorous massage; constriction or a “tourniquet
effect,” which causes swelling distal to that point; or sus-
tained dependency of the limb. Other situations that may
increase lymphatic load include airplane flights and higher
elevations; these situations involve decreased atmospheric
pressure and may result in increased filtration into the tis-
sue from the blood capillaries.
Common complications
1. Lymph fluid reflux: Over-distended lymph vessel causes
valvular insufficiency and retrograde flow, and patient
presents with blister-like formation on the surface of the
skin, called lymphatic cysts. Lymphatic cysts, usually
located in axillary, cubital, genital, and popliteal area, can
easily break open and lead to infection or fistula. Treatment
should include prevention of infection.
2. Muscular skeletal complications: Lymphedema can lead
to muscular skeletal pain and decreased range of motion.
Swelling and pain can interfere with mobility and affect the
sufferers’ perceptions of themselves.1
3. Infection: Bacterial and fungal infection are common in
stage 2 and 3 lymphedema. Clinical symptoms of cellulites
(erysipelas) are fever, erythema, warm, and tenderness.
Patients should be treated with either oral or intravenous
antibiotics. In general, an antibiotic needs to cover the
normal skin flora (i.e., gram-positive cocci) and have good
skin penetration. Therapy with an intravenous antibiotic is
555
considered when there is more significant local or systemic
infection. Some patients develop chronic infections that
may necessitate ongoing antibiotic therapy. Fungal infec-
tion causes skin itching, crusting, maceration between
the toes, and typical fungal nail changes. Systemic or local
antifungal treatment can be used. Recurrence of infection/
inflammation indicates reduced local immunity. 37 It is rea-
sonable to emphasize the importance of lymphedema limb
care. 38 Decongestive lymphatic therapy (DLT) is contrain-
dicated until infection subsides.
4. Hyperkeratosis: It presents as thickening of skin and wart-
like papillomas. Care must be taken to avoid skin break-
down and infection.
5. Malignancies: Lymphangiosarcoma is a rare late compli-
cation of lymphedema, 39 also described as Stewart Treves
syndrome.40 In patients with long-standing lymphedema
and cellulitis that does not respond to systemic antibiot-
ics, the physician should consider a skin biopsy. Treatment
is primary radiotherapy, with surgery reserved for patients
with discrete, nonmetastatic disease.
Diagnosis
History and physical examination (Box 58.2)
The history should include the full medical history, all anti-
cancer therapies, past surgeries, postoperative complications,
radiation treatment, the time interval from radiation or surgery
to the onset of symptoms, and intervening variables in the pres-
ence or severity of symptoms. The quality and behavior of the
edema (fluctuation with position, progression over time) and
associated symptoms should be assessed. History of trauma or
infection should be determined. In addition, information con-
cerning current medications may be important. Edema may not
be detectable clinically until the interstitial volume exceeds 30%
above normal. Lymphedema following axillary lymph node sur-
gery/radiation initially presents as mild edema in the hand or
forearm, often in the dorsal epicondylar region (Figure 58.1A
and B). Other complaints related to lymphedema are heaviness
BOX 58.2  FACTORS AFFECTING DEVELOPMENT
OF CANCER-RELATED LYMPHEDEMA
History
• Medical history (anticancer therapies, past oper-
ations, postoperative complications, radiation
treatment)
• Edema (onset, fluctuation, progression)
• Associated symptoms
• Infection and trauma
• Function
• Social history
• Psychological impact
Physical examination
• Edema: skin texture, color, infection, scar; volume
• Neurological examination
• Range of motion
• Functional assessment
556 Textbook of Palliative Medicine and Supportive Care

Volume and skin condition measurements

The initial assessment of lymphedema and follow-up on the
response to treatment should include the measurement of vol-
ume and assessment of skin condition.42 The most commonly
used assessment tool involves measuring the contralateral limb
circumference at several points along the limb. However, when
the disease affects both sides, this type of comparison may not
be accurate.43 Multiple transverse tapes in a device are placed
at 4-cm intervals, can be used to measure circumferences with
accuracy, and it is a simple convenient method.44 Volume can be
calculated from surface measurements.45 The truncal swelling
can be measured by skinfold calipers.
Water displacement volumetry (plethysmography), although
no longer commonly used, measures limb volume and is more
accurate than calculating the leg volume from circumferential
measurements with a tape measure, but it is time-consuming and
difficult with hygiene.42
The optoelectronic perometer is a validated, reliable, easy-to-
use tool for the limb volume measurement46 (Figure 58.2) but can
be expensive.
Bioelectrical impedance has been used successfully for the
evaluation of swelling in patients with postmastectomy lymph-
edema47 and lower extremity lymphedema.48 This method can
detect subclinical lymphedema, therefore a good tool for screen-
ing, it is easy to use.
Ultrasound can be used to detect fibrotic changes, but stan-
dard has not been established.

FIGURE 58.1  Right upper extremity lymphedema.

or fullness related to the weight of the limb, skin feeling tight,

decreased flexibility in the hand, wrist, or ankle, difficulty fit-
ting into clothing in one specific area, or ring/wristwatch/
bracelet tightness. Associated clinical features of lower limb
lymphedema include tightness of or inability to wear shoes,
itching of the legs or toes, burning sensation in the legs, sleep
disturbances, and loss of hair. Ambulation is affected because of
the limb size and weight, causing an inability to wear clothing.
Activities of daily living, hobby, work, and psychological impact
on patient need to be assessed as well.
On examination, the affected limb is swollen with enhanced
skin creases, hyperkeratosis, and papillomatosis. Lymphedema
is traditionally described as non-pitting, but in early cases, pit-
ting may be present. Stemmer’s sign—inability to pinch the skin
at the base of the second toe due to the thickened skin folds—is
a useful clinical sign.41 Cutaneous fungal or bacterial infections
are not unusual in patients with lymphatic obstruction. Skin folds
should be frequently inspected for ulcers and infections. A neu-
rologic examination for possible nerve entrapment and plexus
involvement, and range-of-motion of different joints also, need
to be assessed. In established cases of lymphedema, the clini-
cal features are diagnostic with no requirement for diagnostic FIGURE 58.2  Using optoelectronic perometer to measure
investigations. upper extremity volume.
Assessment and Management of Lymphedema
Image studies
Lymphoscintigraphy permits imaging of peripheral lymphatic
vessels and provides insight into lymph flow dynamics and lymph
node drainage. It has limitation with visualization of lymphatic
vessels. The procedure involves intradermal injection of a radio-
active tracer in the web space in upper or lower extremities and
does not adversely affect the lymphatic vascular endothelium.
Radioactive tracers are injected subcutaneously in the web space
of the upper or lower extremities; imaging is then performed
after 30–60 min to visualize the lymphatic vessels and nodes,
lymph node uptake speed, and also measure the rate of lymph
transport.49 Patients with a provisional diagnosis of peripheral
lymphatic dysfunction or idiopathic edema should undergo diag-
nostic lymphoscintigraphy to verify diagnostic accuracy, pinpoint
the specific abnormality, and help guide subsequent therapy.50
High-resolution MR lymphangiography can enhance the visual-
ization of lymphatic vessels in patients with lymphedema, and it
has been used for surgical planning.51
Near-infrared fluorescence with indocyanine green (ICG) is
been used in the recent years as a new technique for lymphedema
prevention and treatment, with reported high sensitivity and
specificity, especially in surgival planning.52
Magnetic resonance imaging and computed tomography com-
plement lymphoscintigraphy in monitoring the progression of
lymphedema. Ultrasonography has proved useful in the setting
of filariasis and differential diagnosis of venous obstruction.
Dual X-ray absorptiometry (DEXA) or biphotonic absorptiom-
etry is useful in assessing the chemical component of limb swell-
ing (percentage of fat, water, and lean mass).53
Differential diagnosis
Lipedema
The clinical features of lipedema (also known as lipomatosis
of the leg) include early age of onset, female exclusivity, and
positive family history in some patients. 54,55 The clinical signs
include elastic symmetrical enlargement of both legs with spar-
ing of the feet.
Deep vein thrombosis and chronic venous disease
Deep vein thrombosis (DVT) results in obstruction to venous
flow. The clinical picture is thus one of a swollen, warm, tender
extremity. The resulting edema is pitting in nature and is usu-
ally much softer than in established lymphedema. Often, there
are underlying risk factors, such as recent surgery or immobil-
ity, malignancy, a preceding long flight, or thrombophilia. The
diagnosis is confirmed with duplex ultrasound or venography.
Treatment is with anticoagulation. Chronic venous stasis results
in hyperpigmentation, and varicose veins, and in severe cases,
venous ulceration may be more difficult to differentiate from
lymphedema. Untreated venous insufficiency can progress into
a combined venous/lymphatic disorder, which is treated in the
same way as lymphedema.
Heart failure or renal failure
These conditions need proper medical management. 56
Staging of lymphedema
Generally, the staging of lymphedema is based on the three-stage
International Society of Lymphology scale. However, there are an
increasing number of individuals, who recognize stage 0. At this
557
TABLE 58.2  Severity of Lymphedema Based on Limb Volume
Differences
Severity of Lymphedema Volume Increase (%)
Minimal <20
Moderate 20–40
Severe >40
stage, swelling is not evident, despite alteration in lymph trans-
port (i.e., preclinical). In stage I, there is an early accumulation
of a high protein-laden fluid (versus venous edema) that subsides
with limb elevation. Pitting of the extremity may be present. In
stage II, limb elevation alone rarely reduces tissue swelling, the
patient may or may not have pitting, and skin fibrosis may occur.
Stage III is characterized by lymphostatic elephantiasis. Pitting is
absent, and the trophic skin is characteristically acanthotic with
warty overgrowth.41 The severity of unilateral lymphedema in
each stage can be further assessed by limb volume differences;
minimal (<20% increase in limb volume), moderate (20%–40%
increase), or severe (more than 40% increase) (Table 58.2).
The clinician should also assess how the lymphedema affects
patients’ function, symptoms, and quality-of-life issues (psycho-
social, social, emotional, physical disabilities).
Prevention
Primary prevention can be done with modification of can-
cer treatment, such as surgery, radiation, and chemotherapy.
Secondary prevention can be done with patient education, weight
control and life-style changes, regular screening with early detec-
tion, early self-detection, prompt treatment, psychosocial sup-
port, and exercise.
Treatment
As with most chronic problems, the responsibility for manag-
ing lymphedema falls on the patient. Education about the etiol-
ogy of lymphedema and principles for management are the first
and most important part of patient care. The management of this
condition involves decongesting the reduced lymphatic pathways;
encouraging the development of collateral drainage routes and
stimulating the function of remaining patent routes, the lymph-
edema control will be long lasting.
The International Society of Lymphology Executive Committee
in 2013 revised a consensus document that offered an integrated
view of the management of lymphedema. 57 The controversy about
the efficacy and application of treatment approaches in different
situations still exists.
The most commonly used method is called DLT, also known
as complete decongestive therapy (CDT), which involves a two-
stage treatment program.58 In the first phase, intensive every
other day physical therapy visits are recommended for a course
of 4–6 weeks, although daily treatment is more effective; these
treatments usually include applying and teaching patient manual
lymphatic drainage (MLD), multilayer bandaging, care of the
skin, and exercises to promote lymph drainage. MLD is a light
massage technique used to mobilize lymphatic and reestablish
pathways for lymph flow.59 The multilayer bandaging consists of
applying multilayered padding materials and short-stretch (also
called low-stretch) bandages repeatedly. The goals of this phase
are to reduce the size of the limb and improve the texture and
558
the health of the skin. In a study by Ko et al.,60 299 patients with
both upper and lower extremity lymphedema underwent CDT
for 15.9 days. Lymphedema reduction averaged 59.1% after upper
extremity CDT and 67.7% in lower extremity treatment. When
followed up at 9 months, improvement had been maintained in
86% of patients. These individuals maintained at least 90% of the
initial reduction. Incidence of infection also decreased by approx-
imately 50%.60 Various outcomes from different studies were due
to the skill of the treating therapist, and patient compliance, exer-
cise protocols, duration of the DLT, or number of treatments per
week, etc.
DLT may be used palliatively in lymphedema as the result of
tumor-obstructing lymphatics. This treatment is usually con-
ducted in conjunction with chemoradiation. In the past, contro-
versy existed as to whether massage and mechanical compression
would promote metastasis. In practice, disease is already present
and the goal simply is palliation of morbid swelling.49,60–62
In the second phase of treatment, patients are usually recom-
mended to wear strong compression hosiery (20–50 mmHg of
pressure) to maintain the reduction in swelling, carry out regu-
lar daily exercise, and perform regular MLD, where possible. The
goal of the second phase is to preserve and optimize the improve-
ments gained in the first phase. The role of weight control and
regular exercises in the management of lymphedema is thought
to be important. With the continuation of compression, even
fibrosis can partially resolve.
Relative contraindications to DLT include significant conges-
tive heart failure, acute DVT, acute or untreated infection or
inflammation of the affected limb, and active malignancy.
Skin care
Skin care should include routine skin inspection (for ingrown
toenails, cuticle integrity, abrasions, bruising, ulcerations, and
impaired circulation), use of skin emollients, and avoidance of
extremes in heat and cold including sun exposures. In the clini-
cian’s office or hospital setting, blood pressure measurements,
venipuncture, or injections should not be undertaken on the
affected side. Recent study showed that acupuncture appears safe
in lymphedema related to breast cancer surgery.63,64
The patient is counseled on avoiding trauma to the affected
region from clothing (brassiere, purse straps). In early pitting
stage, many patients benefit from elevating the limb at or above
relative heart level overnight. An opinion regarding exercise has
changed significantly; recent research showed that slowly pro-
gressive exercise is not associated with the development or exac-
erbation of breast cancer–related lymphedema and can be safely
pursued with proper supervision.65
Manual lymphatic drainage
MLD is a therapeutic technique used to increase lymph flow. It
consists of movement of the therapist’s hands over the patient’s
skin and subcutaneous tissue. The pressure applied is very gentle,
and the movements are slow to correspond with the slow lym-
phatic pulsations. The massage sequence begins at the center of
the body and moves to the periphery and from unaffected side to
affected side. The rationale for this is that the lymph nodes must
be emptied before they can receive more lymph from the periph-
ery. Each maneuver is performed in a distal to proximal direction.
Patients and family members or friends can be included in the
training of gentle form of self-massage. So far the jury is still out
on this topic. Several studies have suggested that MLD provides
no additional benefit.66,67 But Cochrane review in 2015 indicated
Textbook of Palliative Medicine and Supportive Care
MLD may be more beneficial to mild-to-moderate breast cancer–
related lymphedema.68 A more recent review also showed that
MLD in addition to standard therapy was superior to standard
treatment in limb volume reduction.69
Exercise
When combined with nonelastic compression bandage, it is
hypothesized that the contraction of muscle against the nonelas-
tic bandage, provides increased subcutaneous tissue pressure,
and thus encourages movement of interstitial fluid into the lym-
phatic system.70 Studies have shown that exercise, combined with
compression therapy, is more effective than compression alone in
reduction of lymphedema limb volume reduction.71
Compression bandage and compression garment
Wrapping the limb with low-stretch bandages in conjunction
with padding and foam provides the ideal type of compression in
lymphedema patients. It allows a low resting pressure and a high
working pressure during muscle contraction to facilitate lym-
phatic flow. The bandage accommodates the change of volume
overtime and provides “custom-made” compression. However,
the disadvantages include that this technique is difficult to
apply, requires training, and is cumbersome. One study showed
that compression bandage use prior to compression garment
is more effective than compression garment alone.72 Once the
extremity reaches its smallest obtainable size, a customized low-
stretch elastic compression garment can be fitted and used dur-
ing normal activities. Compression garments provide gradient
pressure, ranging from 20 to 60 mmHg. Replacement is needed
every 6 months. Proper fitting is necessary to avoid a tourniquet
effect.73,74 Hornsby investigated the use of hosiery comparing to
control and concluded that the results suggest that wearing a
compression sleeve is beneficial. Both groups had high dropout
rate.75 Recent study showed that a precast adjustable compression
system and the multilayered compression bandages had similar
efficacy in reducing of lymphedema volume and symptoms.76
Contraindications to its use include concurrent presence of
arterial disease, allergy, ulceration, or a painful postphlebitic
syndrome.
Pneumatic compression
Controversy exists regarding the use of pneumatic compression
pumps. Some schools that support the utilization of pumps gener-
ally suggest using relatively low pressures (40 mmHg77 maximum
distal pressure) as part of a comprehensive program.78,79 Pressures
greater than 50–60 mmHg may cause injury to lymphatic ves-
sels. The extremity is placed into a long inflatable sleeve that is
connected to a pump that inflates the sleeve to a predetermined
pressure. External compression therapy is applied with a sequen-
tial gradient “pump.” Between pump uses, the extremity should
be wrapped with compression bandage or have compression gar-
ments applied to reduce recurrence of lymph in the extremity. It
may take months to obtain a demonstrable reduction in the size
of the extremity.80 There is low-level evidence of moderate quality
showing significant outcomes achieved with the use of sequential
pneumatic compression programs.77
Surgery
A growing body of evidence supports the effectiveness of mod-
ern surgical techniques in ameliorating the long-term disabil-
ity and functional impairment inflicted by lymphedema on the
lives of those affected and reducing the risk of future episodes
of cellulitis.81–85 These procedures can be broadly categorized as
Assessment and Management of Lymphedema 559

physiological or debulking. Physiological procedures, including Psychosocial support

lymphovenous bypass (LVB) and vascularized lymph node trans- For a patient with lymphedema, physical and emotional chal-
plant (VLNT) procedures, aim to restore lymphatic fluid drain- lenges are profound. In a study by Tobin et al., patients with arm
age within the affected area.86,87 The operations are effective at edema experienced greater functional impairment, and increased
decreasing the symptoms of lymphedema, reducing the risk of difficulty adjusting to their illness, home life, and personal/famil-
future infections, and decreasing the amount of time spend daily ial relationships.1 The openly exposed lymphedematous limb is a
for lymphedema care; selected patients may be able to discontinue constant reminder to the patient and the community at large, the
their compression garments. The LVB procedure is indicated in occurrence of a cancer, and that the patient is physically different
early stage lymphedema and involves identification of obstructed
lymphatic vessels and targeted bypass of these into neighbor-
ing venules. Using a fluorescent lymphography imaging system,
intradermal injection of ICG into the webspaces of the affected KEY LEARNING POINTS
extremity allows the lymphatic vessels to be mapped, and discrete
Definition: Lymphatic fluid exceeds the lymphatic trans-
lymphatic vessels distal to areas of dermal backflow are targeted
port capacity.
for supermicrosurgical anastomosis to adjacent small venules.88
Immediate bypass of the lymphatic vessels severed at the time of
Classification:
axillary or inguinal lymphadenectomy into adjacent veins within
the surgical field (LYMPHA technique) has demonstrated efficacy
• Primary
at reducing the risk of subsequent lymphedema development and
• Secondary: Caused by filariasis, cancer, and its
is an area of ongoing investigation for lymphedema prevention.89
treatment, other
The VLNT procedure is indicated in advanced presentation
lymphedema and involves microvascular anastomosis of functional
Staging: 0, 1, 2, 3
lymph nodes into an extremity, either to an anatomical (orthotopic)
or non-anatomical (heterotopic) location, to restore physiological
Grading: Mild, moderate, severe
lymphatic function. Orthotopic VLNT to the axilla has the addi-
tional advantage of allowing for radical scar release and decompres-
Diagnosis:
sion of the subclavian vein, which may decrease the lymphatic load
with subsequent improvement of the lymphedema. VLN flaps may be • History: medical and surgical history, edema and
harvested from the superficial inguinal, supraclavicular, submental, associated symptoms, function, psychosocial effect
or lateral thoracic regional lymph node basins.90 For patients wish- • Physical examination:
ing to avoid any risk of iatrogenic donor extremity lymphedema or • Volume (circumference, water displacement vol-
visible donor site scars, intraabdominal LN flap options are increas- umetry, optoelectronic pedometer, bioelectrical
ingly being performed, including the omental (gastroepiploic) flap, impedance, skinfold calipers)
which may be harvested laparoscopically.91 In patients undergoing • Skin (texture, color, tonometry)
postmastectomy breast reconstruction, VLNT may be performed by
transferring a deep inferior epigastric artery perforator flap with a Image study:
chimeric groin lymph node flap.92
Once established, the chronic lymphedema phenotype is char- • Lymphosctinigraphy
acterized by hypertrophy of fibroadipose soft tissues, which can • Indocyanine green (ICG) lymphography
only be removed directed by suction-assisted lipectomy (SAL) or • Magnetic resonance imaging and computed
excisional procedures to restore function and appearance and tomography
reduce the risk of future infections.93 Traditional excisional sur- • Ultrasonography (differential diagnosis of deep
geries that result in unacceptable scarring and morbidity have venous thrombosis)
been replaced except in severe cases by minimally invasive SAL.94 • DEXA or biphotonic absorptiometry
SAL debulking provides only minimal physiological improve-
ment of the lymphatic system and therefore patients need to Treatment:
wear compression garments lifelong to prevent recurrence. For
patients with large volume advanced fibrotic disease, SAL is inef- • Goal
fective and excisional techniques are required. These include • Development of collateral drainage routes, stim-
staged direct excision (modified Homan’s procedure), and, in ulating the function of remaining patent routes
extreme cases, excision and skin grafting (Charles procedure). • Decrease volume and improve skin condition,
prevent complications
Drug therapy • Methods
No pharmacologic therapy is recommended for the treatment • Skin care
of lymphedema. Coumarin (5,6-benzo-[(alpha)]-pyrone or • Manual lymphatic drainage
1,2-benzopyrone) and related drugs have no significant effect • Exercise
on lymphedema volume or symptom.95 It appears that at pres- • Compression bandaging/compression garment
ent, there is no drug that will reduce chronic lymphedema and • Pneumatic compression
allow the reduction to be maintained.95,96 Antibiotics should be • Surgery and drug therapy
administered when patients develop cellulitis in the affected • Psychosocial support
limb. Patients with recurrent episodes of cellulitis may benefit • Weight loss
from prophylactic antibiotics.
560
from the norm. As a result, the patient may lose an interest in their
dress or general appearance. This loss of self-esteem may also
contribute to difficulties with interpersonal relationships, social
activities, and intimacy.97 Efforts may be made to strengthen the
women’s coping skills, eventually in a multidisciplinary approach
by palliative and rehabilitation professionals.
Weight loss
Obesity is a risk factor for developing cancer-related lymph-
edema, it can also exacerbate existing lymphedema, and there-
fore, weight reduction has been recommended in lymphedema
management. A randomized study had showed the effectiveness
of weight reduction.98
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59
HYPERCALCEMIA

Kimberson Tanco and Saima Rashid

Contents
Introduction........................................................................................................................................................................................................................563
Epidemiology......................................................................................................................................................................................................................563
Pathophysiology.................................................................................................................................................................................................................563
Differential diagnosis........................................................................................................................................................................................................ 564
Clinical manifestation...................................................................................................................................................................................................... 564
Laboratory evaluation...................................................................................................................................................................................................... 564
Treatment........................................................................................................................................................................................................................... 565
Hydration...................................................................................................................................................................................................................... 565
Bisphosphonates.......................................................................................................................................................................................................... 565
Nitrogen-containing bisphosphonates.............................................................................................................................................................. 565
Non-nitrogen-containing bisphosphonates..................................................................................................................................................... 565
Calcitonin..................................................................................................................................................................................................................... 565
Corticosteroids............................................................................................................................................................................................................ 566
Gallium nitrate............................................................................................................................................................................................................. 566
RANKL inhibitors....................................................................................................................................................................................................... 566
Other treatments......................................................................................................................................................................................................... 566
References........................................................................................................................................................................................................................... 566

Introduction absorption from the GI tract, (2) decreased excretion from the kid-
neys, and (3) enhanced calcium resorption from bone. However,
Hypercalcemia is a common metabolic complication of malig- it is a common misconception that bone metastasis is required to
nancy and has been termed hypercalcemia of malignancy cause hypercalcemia. 5 There are two mechanisms of HCM:
(HCM), tumor-induced hypercalcemia, and humoral HCM.
Hypercalcemia is a metabolic emergency and the most common • Secretion of parathyroid hormone-related protein (PTHrP),
paraneoplastic syndrome. Signs and symptoms of hypercalce- which stimulates osteoclastic bone resorption and calcium
mia may be subtle and can be missed unless there is a high index reabsorption through the kidneys
of suspicion.1 Treating hypercalcemia can provide significant • Lytic bone metastases through cytokines released by
patient palliation.2,3 tumor cells18

Epidemiology PTHrP is a 16-kDa peptide, is larger than parathyroid hormone

The two most common causes of hypercalcemia are primary
hyperparathyroidism and malignancy.4 Hypercalcemia occurs in
up to 30% of cancer patients, and more frequently in advanced
stages.5–9 HCM is more common in certain types of cancers,
particularly primary solid tumors of the lung, breast, head and
neck, kidney, and ovary. It also occurs preferentially in certain
histologies, such as squamous cell cancer of the lung compared to
adenocarcinomas or small cell lung cancer. However, hypercalce-
mia should not be discounted in other cancers, such as prostate,
colon, cervix, and uterus.1,10–14 Certain hematological malignan-
cies can also present with hypercalcemia, including multiple
myeloma.15–17
Pathophysiology
The regulation of calcium levels within the body theoretically is
centered on three key organ systems – gastrointestinal (GI) tract,
kidneys, and bone. Hypercalcemia results from a combination of
any of three main mechanisms, particularly (1) increased calcium
(PTH), and shares a 61% sequence homology with PTH in the first
13 amino acids at the N-terminal. 5,19,20 It has four times the bio-
activity of PTH and binds competitively to the PTH receptor.21
PTHrP is the predominant cause of hypercalcemia in patients
with cancer. At least 80% of patients with solid tumors and hyper-
calcemia have increased serum concentrations of PTHrP. In addi-
tion to its humoral effects, PTHrP can also induce local osteolysis
around bone metastases, and it appears to be important in the
progression of bone metastases in patients with breast carci-
noma.22–25 Other humoral factors secreted by solid and hemato-
logic tumors that are associated with hypercalcemia include IL-1,
IL-6, TNF-α, G-CSF, macrophage inflammatory protein-1α, and
tumor-induced 1,25(OH)2D3. Cytokines may cause bone resorp-
tion and hypercalcemia through stimulation of osteoclast precur-
sors to differentiate into mature osteoclasts.
The increased calcium level from PTHrP-related secretion and
osteolysis diminishes the efficiency of renal elimination of excess
calcium. In addition, decreased intravascular volume, secondary
to hypercalcemia-induced nausea and anorexia, results in sodium
and calcium resorption through the proximal tubule.

563
564
Differential diagnosis
Primary hyperparathyroidism and HCM account for greater than
90% of cases.26–28 Primary hyperparathyroidism accounts for the
majority of cases among the general population. The patients
usually are relatively well, presenting with vague or little symp-
toms. In contrast to primary hyperparathyroidism, HCM usually
occurs suddenly and results in higher calcium levels. Patients
with HCM are more symptomatic than individuals with primary
hyperparathyroidism and carry a poor prognosis with a median
survival of approximately 6 weeks.16,22
A potential overlooked and confounding cause of hypercal-
cemia is vitamin D intoxication. There has recently been an
increase in support of vitamin D intake for a variety of medical
reasons and is commonly procured over the counter. One char-
acteristic of vitamin D intoxication is the presence of elevated
levels of both 25(OH)D and 1,25(OH)2D along with suppressed
levels of PTH.29
Clinical manifestation
The signs and symptoms of hypercalcemia may be subtle and
require a high index of suspicion to make the appropriate diag-
nosis (Table 59.1). The severity of symptoms depends on the level
of serum calcium and, more importantly, the rate of increase in
serum calcium level.29,30 Mild hypercalcemia may present with
nonspecific symptoms, like fatigue, lethargy, and vague-general-
ized discomforts, or may be asymptomatic. On the other hand,
sudden, rapid, severe elevations of calcium levels can present with
acute multi-organ effects, including neurocognitive dysfunctions
such as delirium and coma.29
A wide range of multi-organ system changes can result.
Neurological symptoms range from subtle mental status changes
such as changes in concentration, memory, mood and irritabil-
ity to sedation, stupor, delirium, and coma.31,32 High symptom
expression, including pain, fatigue, insomnia, and drowsiness,
can result in cases of delirium and there should be a low tolerance
in testing for hypercalcemia, as it is readily treated and results in
symptom control. 33
Anorexia, nausea, vomiting, and constipation result from
decreased smooth muscle contractility, delayed gastric emp-
tying, and slowed intestinal motility. Other GI effects include
acute pancreatitis and peptic ulcers, which occur with long-
standing hypercalcemia. The resulting volume contraction from
decreased oral intake secondary to nausea and vomiting can
lead to hypotension, tachycardia, mucosal dryness, and altered
skin turgor. Furthermore, glomerular filtration decreases and
contributes to renal insufficiency. Polyuria and compensatory
polydipsia also result from the impaired ability of the dis-
tal nephrons to concentrate urine. 34 Nephrolithiasis may also
TABLE 59.1  Clinical Manifestations
Neurological Concentration changes, memory loss, mood
changes, irritability, sedation, delirium, stupor,
coma
Gastrointestinal Anorexia, nausea, vomiting, constipation, acute
pancreatitis, peptic ulcers
Renal Polyuria, polydipsia, nephrolithiasis, dehydration,
decreased glomerular filtration, renal insufficiency
Cardiac Shortened QT, wide T, prolonged PR, bradycardia,
hypotension, arrhythmia
Textbook of Palliative Medicine and Supportive Care
develop. However, this is less common with HCM since the
hypercalcemic state develops rapidly.
Cardiac effects, if they develop, may be the terminal event.
Shortened QT intervals, wide T wave, prolonged PR intervals,
bradycardia, and arrhythmia result from altered cardiac electri-
cal impulses secondary to the increase in calcium ions.
Due to the relatively rapid elevation in serum calcium in malig-
nancy, the commonly formed mnemonic of “bones, stones, moans
and groans” are rarely seen. These symptoms are more frequently
associated with chronic elevation in serum calcium.
Laboratory evaluation
Getting serum calcium levels is the initial step in diagnosing
suspected hypercalcemia. Measurement of serum-ionized cal-
cium should be preferred over total serum calcium levels because
hypoalbuminemia may be associated with low total calcium, but
with normal concentration of ionized calcium. 35 If total serum
calcium levels are requested, this should be taken with serum
albumin levels. Calcium exists in three forms in plasma: bound
to albumin and other proteins (∼40%), chelated to serum anions
(∼13%), and as free ionized calcium (∼47%). 36,37 Free ionized cal-
cium is the active component of total calcium. A common error
is using the uncorrected total serum calcium level, instead of
using the corrected or ionized calcium level. Alterations in pH
may affect the calcium ion binding to albumin. Decreases in pH
may result in increase in ionized calcium while pH increases may
demonstrate the opposite effect. 38
Calculations for corrected total serum calcium level adjusted
for serum albumin levels are as follows:
• In imperial units: corrected calcium (mg/dL) = serum cal-
cium + 0.8 mg/dL (4 g/dL − serum albumin)
• In SI units: corrected calcium (mmol/L) = serum calcium +
0.2 mmol/L (40 g/L − serum albumin)
Based on the corrected total serum calcium level, hypercalcemia
can be classified as mild (10.5–11.9 mg/dL), moderate (12–13.9
mg/dL), and severe (≥14 mg/dL).7,29
Other routine laboratory tests have become standard in cancer
patients and most cases of HCM are found during the asymptom-
atic phase. The laboratory evaluation for HCM includes serum
electrolytes, phosphorus, creatinine, alkaline phosphatase, albu-
min, PTH, PTHrP, 25(OH)D, and 1,25(OH)2D3. Measuring cre-
atinine clearance and serum electrolytes are recommended to
monitor renal function, which may affect serum PTH levels. The
milk-alkali syndrome may increase serum bicarbonate.
PTH-mediated hypercalcemia demonstrates elevated levels
of PTH and 1,25(OH)2D3, low-to-normal 25(OH)D levels, and
low phosphorus levels. On the other hand, PTHrP-mediated
hypercalcemia demonstrates elevated PTHrP levels, low-to-
normal 1,25(OH)2D3 levels, and low PTH and phosphorus levels.
Measurement of 25(OH)D and 1,25(OH)2D3 evaluate for exces-
sive vitamin D production or ingestion.29 Levels of 1,25(OH)2D3
are elevated in granulomatous disorders such as sarcoidosis and
lymphomas. 35 Furthermore, 1,25(OH)2D3-mediated hypercalce-
mia also demonstrates low PTH, PTHrP, and phosphorus levels
as well as low-to-normal 25(OH)D levels. This is contrary with
vitamin D intoxication where 25(OH)D levels are high and phos-
phorus levels range from normal to high.29
Measurement of 24-h urine calcium and creatinine clearance
is recommended when the etiology for hypercalcemia is not clear.
Hypercalcemia
This test can distinguish between primary hyperparathyroidism
from familial hypocalciuric hypercalcemia. Familial hypocalciu-
ric hypercalcemia is suspected when the urine calcium to cre-
atinine clearance is low. If so, genetic testing may follow.29,39 If
diagnosis is still unknown, other tests may be considered includ-
ing measuring serum and urine protein electrophoresis, vitamin
A levels, and a skeletal survey.29
Treatment
The magnitude of hypercalcemia and the rapidity of serum cal-
cium increase are two central factors that determine symptoms
and the urgency of therapy. Patients with mild hypercalcemia
often do not require immediate treatment and focus should be
placed on avoidance of aggravating factors. Moderate hypercal-
cemia in symptomatic patients will require immediate aggressive
therapy. Severe hypercalcemia will require immediate aggressive
therapy regardless of symptom burden.40 Therapeutic dosage of
medications is shown in Table 59.2.
Hydration
In cases of severe hypercalcemia, aggressive intravenous rehydra-
tion with isotonic saline and close monitoring of volume status
is the key initial step in treatment. This helps reverse the vicious
cycle of decreased intravascular volume, decreased glomerular
filtration, and impaired calcium excretion. Hydration is started at
a rate of 200–300 mL/h, which is then adjusted to 100–150 mL/h
until volume repletion.
Mild hypercalcemia can usually be corrected with outpatient
oral rehydration. Patients with asymptomatic or mildly symp-
tomatic moderate hypercalcemia may also not require aggressive
immediate treatment. Monitoring of other electrolytes like potas-
sium and magnesium should also be done as there are usually
concurrent electrolyte abnormalities present.41 Administration
of diuretics, such as furosemide, poses risks such as further vol-
ume depletion and electrolyte imbalances and is no longer rec-
ommended unless there is evidence of fluid overload.6,42
TABLE 59.2  Therapeutic Dosages*
• IV or SC hydration
• Isotonic saline ≥ 1–3 L/day
• Bisphosphonates
• Nitrogen-containing
– Pamidronate 60–90 mg IV over 2–24 h; wait at least 7 days
before considering re-treatment
– Ibandronate 2–6 mg IV over 1–2 h
– Zoledronate 4 mg IV; wait at least 7 days before considering
re-treatment
• Non-nitrogen-containing
– Clodronate 1500 mg IV or SC single dose or 300 mg IV daily,
not more than 7 days
• Calcitonin 4 units/kg SC/IM q12 hours; if response is unsatisfactory
after 24–48 h, increase to 8 units/kg q12 hours. If response continues
to be unsatisfactory after 48 h, increase to 8 units/kg q6 hours
• Corticosteroids
• Hydrocortisone 200–400 mg/day
• Dexamethasone 4–12 mg/day
• Prednisone 40–60 mg/day
• Gallium nitrate 100–200 mg/m2/day IV over 24 hours × 5 days
• Denosumab 120 mg SC every 4 weeks × 1 month, additional 120 mg
on days 8 and 15
*Dosages are based on patients with normal renal function
565
Bisphosphonates
The mainstay of treatment is bisphosphonates, which inhibit
osteoclastic bone resorption through osteoclastic apoptosis. Due
to poor bioavailability of the oral route, parenteral administra-
tion is indicated.43 It usually takes 2–6 days to achieve normal
calcium levels. There are two classes of bisphosphonates: nitrogen
and non-nitrogen containing.
Common adverse effects from bisphosphonates include hypo-
calcemia and transient renal insufficiency. Rare side effects
include renal failure, jaw osteonecrosis, and ocular reactions such
as iritis, episcleritis, scleritis, and conjunctivitis. Acute phase
reactions include transient fever, malaise, myalgias, bone pain
flare, and lymphocytopenia. The acute phase reactions may be
decreased with pre-medication with acetaminophen.
Nitrogen-containing bisphosphonates
Nitrogen-containing bisphosphonates are more potent agents
through inhibition of farnesyl diphosphate synthase, resulting
in blockage of protein isoprenylation, which is a vital process for
osteoclast structural integrity, resulting in apoptosis.5
Pamidronate was the first nitrogen-containing agent available
clinically and, thus, is also the most thoroughly investigated.44
A dose-response study found that higher doses of pamidronate,
60–90 mg, have been more effective in achieving normocalce-
mia.45,46 This trend has also been found with alendronate, where
higher dosages have shown better efficacy.47 Zoledronate has been
found to be more effective than pamidronate in achieving normo-
calcemia. However, more renal adverse effects have been reported
with zoledronate than pamidronate, especially with higher doses
and shorter infusion times.48–50 When renal function is a concern,
ibandronate is an alternative as it has less nephrotoxicity.
Non-nitrogen-containing bisphosphonates
Non-nitrogen-containing bisphosphonates inhibit ATP-
dependent intracellular enzymes by incorporating into nonhydro-
lyzable adenosine triphosphate, which also results in apoptosis.10
Etidronate was one of the earliest bisphosphonates used clini-
cally. However, due to its low potency and potential effect of
inhibiting normal bone mineralization, its use has been relatively
anecdotal in the treatment of hypercalcemia.51,52 Clodronate and
pamidronate have been found to have similar efficacy at recom-
mended dosages, with pamidronate having a longer duration of
effect.53,54 Clodronate, a second-generation bisphosphonate, has
utility in treating HCM, in that it can be administered subcutane-
ously, which is of particular advantage in palliative settings such
as home or hospice facility.55–57
Calcitonin
Calcitonin inhibits bone resorption and renal tubular calcium
reabsorption. Physiologically, this hormone is secreted from
parafollicular or C cells within the thyroid in response to elevated
serum calcium levels. 58 Subcutaneous injections have a rapid
onset of action, usually in 2–4 h, with a maximum reduction in
serum calcium of approximately 1–2 mg/dL.59 However, effect
diminishes after 48 h due to tachyphylaxis secondary to down-
regulation of osteoclastic calcitonin receptors.60 Calcitonin is
useful when combined with bisphosphonates, more so in urgent,
life-threatening situations because of its rapid effect while the
bisphosphonates have a slower onset of action. Adverse effects
include nausea, flushing, abdominal pain, and local irritation at
the injection site.
566
Corticosteroids
Corticosteroids are more effective in treating HCM secondary
to steroid-responsive tumors such as lymphoma or myeloma.46,61
A study by Binstock reported that glucocorticoids prolonged the
effective time of treatment with calcitonin by upregulating cell
surface calcitonin receptors and therefore may be an effective
adjunct to calcitonin administration.62
Gallium nitrate
Gallium nitrate accumulates in metabolically active regions
of bone where it inhibits osteoclast-mediated bone resorption.
It prevents acidification and cell-mediated dissolution of bone
material by inhibiting an adenosine triphosphatase–dependent pro-
ton pump in the ruffled membrane of the osteoclast.63 Gallium
also inhibits PTH secretion from parathyroid cells in vitro.64 It
has been found to be effective in both PTHrP-mediated and non-
PTHrP-mediated hypercalcemia.65–68 It has been shown to be at
least or more effective than pamidronate, etidronate, and calcito-
nin. 35,63,64 The main concerns with the use of gallium have been
nephrotoxicity, hypophosphatemia, nausea, and administration
time of 5 days.
RANKL inhibitors
Preliminary data from studies of agents that interfere with the
receptor activator of nuclear factor-kB ligand (RANKL) system,
which is the molecular pathway that leads to osteoclast recruit-
ment and differentiation, have shown reductions in bone resorp-
tion in studies in animals and women with osteoporosis. These
agents include recombinant osteoprotegerin and monoclonal
antibodies against RANKL, such as denosumab.7,60,69–71
Denosumab is a human monoclonal antibody that is admin-
istered subcutaneously every 4 weeks for prevention of skeletal-
related events (e.g., fracture, spinal cord compression) in patients
with cancer metastatic to bone. Its use in HCM is less well studied
but promising. The expense of denosumab may be prohibitive as
it is more costly than the bisphosphonates.
Other treatments
Results of trials of combining anti-PTH-related protein anti-
bodies with zoledronic acid have shown to be optimistic so far
in decreasing tumor-associated osteoclasts.72 An additional ben-
efit of increased adipose tissue and muscle weight has also been
seen.73 Tyrosine kinase inhibitors focusing on IL-6 have also been
shown in studies to be potential agents in inhibiting osteoclast
resorption and treating hypercalcemia.74,75 A report on a noncal-
cemic analogue of calcitriol (e.g., 22-oxacalcitriol) suggests its
potential to suppress PTHrP gene expression through binding to
the vitamin D receptor in HTLV-1 infected cells.76
There have been case reports describing the use of long-acting
octreotide in controlling hypercalcemia in patients with neuro-
endocrine tumor and breast cancer.77,78 Ultrasound-guided per-
cutaneous ethanol injection has been studied in patients with
parathyroid carcinoma for palliation, resulting in a transitory
decrease in PTH and calcium levels.79
In patients with HCM resulting from refractory parathyroid
carcinoma and secondary hyperparathyroidism, calcimemetics
(e.g., cinacalcet) are used in patents with refractory hypercalce-
mia. Calcimemetics attenuate calcium levels by decreasing PTH
secretion through increase in calcium-receptor sensitivity.80
Patients for whom hydration is not feasible due to concern for
volume overload particularly in the setting of renal insufficiency
or congestive heart failure, short-term dialysis may be required
Textbook of Palliative Medicine and Supportive Care
KEY LEARNING POINTS
• Hypercalcemia is a common, treatable complica-
tion of malignant disease.
• Secretion of PTHrP is the predominant cause of
hypercalcemia in HCM, even without overt bone
metastasis.
• Signs and symptoms may be subtle; a high index
of suspicion is required.
• The severity of symptoms depends on the rate of
increase in serum calcium levels more than the
absolute serum calcium levels.
• Treatment of HCM can result in improved overall
palliation.
• Rehydration is a key initial step in the manage-
ment of HCM.
• Intravenous bisphosphonates are the agents of
choice in the treatment of HCM with nitrogen-
containing bisphosphonates being the more
potent agents.
until normocalcemia is achieved. Hemodialysis can be consid-
ered in addition to hydration, calcitonin, and bisphosphonates if
a patient’s calcium is 18–20 mg/dL with neurological symptoms.
Calcium levels are augmented by using dialysis fluid with mini-
mal to no calcium.81
The treatments listed above are only temporizing measures.
The most effective long-term treatment is still treating the under-
lying cause, especially in the case of HCM, which is effective
antineoplastic intervention. Goals of care should be discussed
with the patient and family as hypercalcemia often occurs late
in the course of the cancer. Discontinuing medications that can
cause hypercalcemia, like thiazides and vitamin D, should not be
overlooked.
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Medicine 1980;93:269–272.
64. Cvitkovic F, Armand JP, Tubiana-Hulin M, et al. Randomized, double-
blind, phase II trial of gallium nitrate compared with pamidronate for
acute control of cancer-related hypercalcemia. The Cancer Journal
2006;12(1):47–53.
65. Ridefelt P, Gylfe E, Akerström G, et al. Effects of the antihypercalcemic
drugs gallium nitrate and pamidronate on hormone release of patho-
logic human parathyroid cells. Surgery 1995;117:56–61.
66. Warrell RP Jr, Bockman RS, Coonley CJ, et al. Gallium nitrate inhibits
calcium resorption from bone and is effective treatment for cancer-
related hypercalcemia. J Clin Invest 1984;73:1487–1490.
67. Warrell RP Jr, Israel R, Frisone M, et al. Gallium nitrate for acute treat-
ment of cancer-related hypercalcemia: a randomized, double-blind
comparison to calcitonin. Ann Intern Med 1988;108:669–674.
68. Warrell RP Jr, Murphy WK, Schulman P, et al. A randomized
double-blind study of gallium nitrate compared with etidronate
for acute control of cancer-related hypercalcemia. J Clin Oncol
1991;9:1467–1475.
69. Hu MI, Gucalp R, Insogna K, et al. Denosumab for treatment of hyper-
calcemia of malignancy in patients with solid tumors or hematological
malignancies refractory to IV bisphosphonates: a single-arm multi-
center study. In: 53rd American Society of Hematology Annual Meeting
and Exposition, 2011.
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70. Thosani S, Hu MI. Denosumab: a new agent in the management of
hypercalcemia of malignancy. Future Oncol 2015;11(21):2865–2871.
71. Camozzi V, Luisetto G, Basso SM, et al. Treatment of chronic hypercal-
cemia. Med Chem 2012;8(4):556–563.
72. Capparelli C, Kostenuik PJ, Morony S, et al. Osteoprotegerin prevents
and reverses hypercalcemia in a murine model of humoral hypercalce-
mia of malignancy. Cancer Res 2000;60(4):783–787.
73. Yamada T, Muguruma H, Yano S, et al. Intensification therapy with
anti-parathyroid hormone-related protein antibody plus zoledronic
acid for bone metastases of small cell lung cancer cells in severe com-
bined immunodeficient mice. Mol Cancer Ther 2009;8(1):119–126.
74. Iguchi H, Aramaki Y, Maruta S, et al. Effects of anti-parathyroid hor-
mone-related protein monoclonal antibody and osteroprotegerin on
PTHrP-producing tumor-induced cachexia in nude mice. J Bone Miner
Metab 2006;24(1):16–19.
75. Yoneda T, Lowe C, Lee CH, et al. Herbimycin A, a pp60c-src tyrosine
kinase inhibitor, inhibits osteoclastic bone resorption in vitro and
hypercalcemia in vivo. J Clin Invest 1993;91(6):2791–2795.
76. Moriyama K, Williams PJ, Niewolna M, et al. Herbimycin A, a tyro-
sine kinase inhibitor, impairs hypercalcemia associated with a human
squamous cancer producing interleukin-6 in nude mice. J Bone Miner
Res 1996;11(7):905–911.
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77. Inoue D, Matsumoto T, Ogata E, et al. 22-Oxacalcitriol, a noncal-
cemic analogue of calcitriol, suppresses both cell proliferation and
parathyroid hormone-related peptide gene expression in human
T cell lymphotrophic virus, type I-infected T cells. J Biol Chem
1993;268(22):16730–16736.
78. Mantzoros CS, Suva LJ, Moses AC, et al. Intractable hypercalcaemia
due to parathyroid hormone-related peptide secretion by a carcinoid
tumour. Clin Endocrinol 1997;46(3):373–375.
79. Shiba E, Inoue T, Akazawa K, Takai S. Somatostatin analogue treat-
ment for malignant hypercalcemia associated with advanced breast
cancer. Gan To Kagaku Ryoho 1996;23(3):343–347.
80. Collins MT, Skarulis MC, Bilezikian JP, et al. Treatment of hypercal-
cemia secondary to parathyroid carcinoma with a novel calcimimetic
agent. J Clin Endocrinol Metab 1998;83:1083–1088.
81. Koo WS, Jeon DS, Ahn SJ, et al. Calcium-free hemodialysis for the
management of hypercalcemia. Nephron 1996;72:424–428.
60
HEMORRHAGE

Timothy Fuller, Kencee Graves, and Jen-Yu Wei

Contents
Introduction........................................................................................................................................................................................................................569
Clinical presentation, underlying pathophysiology, and management of localized bleeding in patients with terminal illness..................570
Gastrointestinal bleeding............................................................................................................................................................................................570
Epistaxis.........................................................................................................................................................................................................................570
Hemoptysis....................................................................................................................................................................................................................570
Vaginal bleeding...........................................................................................................................................................................................................571
Hematuria......................................................................................................................................................................................................................571
Other causes..................................................................................................................................................................................................................571
Disseminated intravascular coagulation...................................................................................................................................................................... 572
Chronic DIC................................................................................................................................................................................................................. 572
Treatment of DIC........................................................................................................................................................................................................ 572
Platelet transfusion and fresh frozen plasma................................................................................................................................................... 572
Heparin.................................................................................................................................................................................................................... 572
Thrombocytopenia and hemorrhagic risk in patients with cancer......................................................................................................................... 572
General approach to hemorrhage (Table 60.2)............................................................................................................................................................573
Management of bleeding............................................................................................................................................................................................573
Local interventions (Table 60.3)..........................................................................................................................................................................574
Radiotherapy...........................................................................................................................................................................................................574
Embolization...........................................................................................................................................................................................................574
Surgery......................................................................................................................................................................................................................574
Systemic interventions..........................................................................................................................................................................................575
Endoscopy (Table 60.4).........................................................................................................................................................................................575
Transfusion of blood products............................................................................................................................................................................575
Palliative measures.................................................................................................................................................................................................575
Conclusion...........................................................................................................................................................................................................................576
References............................................................................................................................................................................................................................576

Introduction Bleeding at the end of life can manifest as hemoptysis, hema-

Patients in palliative care can experience a variety of bleeding
problems, yet there are scant data regarding the bleeding preva-
lence in palliative care patients as a whole. One prospective obser-
vational study examined 1,199 terminally ill patients who were
admitted to an inpatient palliative care unit for advanced cancer,
pulmonary, cardiac, or neurologic disease and found that 9.8%
developed clinically relevant bleeding over a 3-month period.1
However, it should be noted that 91% of the patients included in
the study were admitted for cancer as their primary palliative
diagnosis. Bleeding in advanced cancer has been well described
in the literature with approximately 10% of cancer patients expe-
riencing at least one episode and close to 30% in those with hema-
tologic malignancies.2 Nevertheless, hemorrhage and bleeding is
a common problem in many of the disease states common to the
field of palliative care. For instance, in patients with cirrhosis of
the liver, rates of bleeding have been reported to be between 5.5%
and 7.4%; and in end stage renal disease, rates of bleeding as high
as 50% have been reported. 3,4
turia, vaginal bleeding, rectal bleeding, hematemesis, melena, or
bleeding from the skin. A vast array of etiologies and factors con-
tribute to hemorrhage in these patients and the resultant bleeding
manifests on a spectrum from slow bleeds leading to gradual ane-
mia to catastrophic hemorrhage leading to exsanguination and
a precipitous death. Many of these patients may require admis-
sion to the palliative care unit for intense symptom management,
including transfusions and palliative sedation to manage anxiety
and related psychological issues. 5 It is crucial that palliative care
providers are prepared to alleviate the suffering that can occur in
terminal illness, as terminal hemorrhage can lead to significant
psychological distress for patients and families.
This chapter focuses on the causes and management of hem-
orrhage in patients with terminal illness. We first briefly sum-
marize the pathophysiology of hemorrhage in these patients and
then turn to specific bleeding problems. We then provide more
in-depth discussions of disseminated intravascular coagulation
(DIC) and thrombocytopenia and conclude with recommenda-
tions for the clinical approach to hemorrhage.

569
570
Clinical presentation, underlying
pathophysiology, and management
of localized bleeding in patients
with terminal illness
Clinically relevant bleeding may be anatomic, generalized, or
combined (Table 60.1). Bleeding may involve damage to local ves-
sels, invasion of vessels, mucositis, a systemic process such as DIC,
or abnormalities in platelet number and function. The underly-
ing causes of these abnormalities vary and include liver failure,
medications such as anticoagulants, chemotherapy, radiotherapy,
surgery, and the cancer itself.
Gastrointestinal bleeding
Symptomatic gastrointestinal hemorrhage may arise from
either the upper or lower gastrointestinal tract and can result
in hematemesis and melena or hematochezia. In some cases,
patients may also present with hypotension or orthostasis.
Gastrointestinal bleeding can occur in patients with end-stage
liver disease, peptic ulcer disease, hemorrhoids, malignancies,
and vascular abnormalities in the gastrointestinal system.
Rectal bleeding occurs in 10%–20% of patients with colorectal
cancer. The underlying tumor causing gastrointestinal hemor-
rhage may be a primary neoplasm arising within the gastroin-
testinal tract, most commonly from the stomach, large bowel,
or rectum, or may be the result of direct invasion of a locally
advanced tumor from adjacent structures such as the uterus.
Modest doses of radiation to the bleeding sites will often
control the bleeding effectively and durably.6,7 Surgery is the
treatment of choice in cases of neoplasm-related lower gastroin-
testinal tract bleeding but is rarely required. In addition to radio-
therapy, endoscopic interventions involving thermal coagulation,
cryotherapy, mechanical ligation techniques, and local injection
of vasoconstricting medications may be used.8,9 Interventional
angiography with transcatheter embolization to control bleeding
also has been effective for both upper and lower gastrointestinal
hemorrhage.10,11 Tranexamic acid may have a small benefit in
upper gastrointestinal bleeding, but no benefit in lower gastroin-
testinal bleeding.12,13
Epistaxis
Epistaxis is one of the most common causes for emergency admis-
sion to otolaryngology services second only to pharyngitis. There
is a bimodal age distribution with an early peak in childhood and
TABLE 60.1  Etiology of Bleeding in Patients with Terminal
Illness
Anatomical
• Local tumor invasion (tumor invasion into blood vessels)
• Tumor surface bleeding (skin wounds, internal bleeding)
• Mucositis (infection, drug-induced, radiation-induced,
chemotherapy-related, peptic acid-related, stress)
Generalized
• Platelet disorder (thrombocytopenia or platelet function defects)
• Bone marrow involvement by cancer (hematological malignancies)
• DIC
• Liver failure
• Medications (anticoagulants, aspirin, NSAIDs)
• Concomitant disease (cirrhosis, von Willebrand disease)
Combined
• Local and systemic factors
Textbook of Palliative Medicine and Supportive Care
again in patients aged 60–70 years.14 Although there exist little
data on prevalence within the palliative population, there is a 60%
lifetime prevalence in the general population.15 Despite this high
prevalence, management of epistaxis lacks a strong evidence base
in the literature and is driven primarily by expert opinion.14
On the initial assessment of a patient who presents with epi-
staxis, the clinician should first perform a primary survey and
obtain IV access. After determining that a patient’s airway,
breathing, and circulation are intact and there is no need for
immediate resuscitation, a more thorough assessment can be
made. Epistaxis may result from many different causes includ-
ing chemical irritants, tumors, digital trauma, and prolonged
nasal cannula use.16 Consider systemic factors such as renal
failure, alcoholism, or liver failure which may be contributing
and be sure to ask the patient about family history of heritable
coagulopathies, nonsteroidal anti-inflammatory drug (NSAID)
use, anticoagulant and antiplatelet medications, as well as che-
motherapies that may cause marrow suppression and resultant
thrombocytopenia.16
Prior to starting your exam, don the appropriate gown,
gloves, mask, and eye protection. Ask the patient to blow his
or her nose to expel any clots with the patient leaning forward
in the sniffing position. Use a nasal speculum to view the nares
and nasal septum for the source of the bleed. The majority (90%)
of epistaxis bleeding originates from the Kiesselbach plexus at
the anterior nasal septum and it is important to attempt to dif-
ferentiate this from a posterior bleed originating from the sphe-
nopalatine artery (not visible without the use of endoscopic or
surgical techniques).16
If an anterior source of the bleed has been visualized or if
the source is still uncertain, again have the patient clear any
clots from the nares, then apply a topical vasoconstrictor such
as oxymetazoline or phenylephrine using pledgets or spray.14,16
Next, apply direct pressure by pinching the nose over the car-
tilaginous portion (not over the nasal bone) for 10–15 min. If
two attempts at direct pressure are insufficient at stopping the
bleed, then an attempt at silver nitrate cautery or electrocautery
should be made with the latter only being performed by ENT.14,16
If cautery fails, hemostasis may be achieved by tamponade with
the use of nasal packing such as preformed nasal tampons or
sponges as well as anterior epistaxis balloons. If anterior nasal
packing does not result in hemostasis, it is likely that the bleed-
ing is originating from the posterior location and the spheno-
palatine artery. A posterior nasal pack should be placed with
caution when inflating the balloon so as not to cause septal
necrosis, ENT should be consulted, and the patient admitted
under their care.
Hemoptysis
Hemoptysis, the expectoration of blood or bloody mucus from
the lung parenchyma or airways, is a common symptom of bron-
chial carcinoma, often owing to tumor invasion of intrathoracic
vascular structures. Hemoptysis is present in approximately 50%
of cancer patients at presentation and may also accompany pul-
monary metastasis.17 Although rare, massive hemoptysis carries
a 50% mortality rate if not treated promptly.18 While rarely of
hemodynamic significance, hemoptysis is a distressing symptom
for the patient and an indication for local radiotherapy.19 In terms
of survival, there are no proven advantages in treating patients
with inoperable lung cancer who are asymptomatic. However,
some evidence suggests that tumors greater than 10 cm in diam-
eter, whether primary or metastasized, carry a significant risk of
Hemorrhage
hemorrhage, and it has been suggested that patients with such
lesions should receive prophylactic treatment for hemoptysis.20
Surgical resection may be considered for hemoptysis in patients
with good performance status, but in advanced cancer, nonsur-
gical approaches often remain the appropriate first-line treat-
ment.21 While not specific to cancer-related hemoptysis, there is
a growing body of evidence to suggest the use of both inhaled and
IV tranexamic acid in the treatment of hemoptysis may be benefi-
cial. One RCT conducted by Wand et al. demonstrated that TXA
reduced the amount of blood expectorated, eliminated the need
for additional intervention, reduced the length of hospital stay,
and reduced the rate of rebleeding when compared to placebo.22
In another RCT, Bellam and colleagues showed that the use of IV
TXA reduced the severity of hemoptysis and resulted in fewer
interventions when compared with normal saline.23
Other nonsurgical interventions include bronchial arterial
embolization and bronchial stenting, which have shown prom-
ising results in multiple case reports.24–27 In several small stud-
ies, bronchial arterial embolization achieved clinical success in
82%–96% of patients, with massive hemoptysis and cavitary lung
mass shown to predict shortened hemoptysis-free survival.28,29
Vaginal bleeding
Vaginal bleeding can result from a number of conditions, includ-
ing pregnancy and its associated complications, genitourinary
trauma, genitourinary infections, arteriovenous malformations,
coagulation disorders, medications, and gynecologic cancers. In
the palliative care population, vaginal bleeding is most likely to be
due to coagulation disorders, medications, or malignancy. Many
patients with post-menopausal abnormal uterine bleeding are
found to have gynecologic malignancy; however, vaginal bleed-
ing is rarely excessive and can usually be managed conservatively.
Occasionally, a patient with a uterine tumor may present with a
major hemorrhage requiring immediate resuscitation and vagi-
nal packing before the initiation of urgent treatment to stop the
hemorrhage.
Vaginal bleeding in advanced or metastatic cancer may be due
to recurrent or locally advanced tumors of the cervix or uterus.
Pain and vaginal bleeding are the most significant quality-of-life
issues for patients with gynecologic malignancy. 30 Endometrial
cancer typically spreads to nearby organs, including local infiltra-
tions of advanced cancers of the bladder and rectum or mucosal
deposits along the vaginal wall.
There are a number of options for management of vaginal
bleeding in advanced cancer, including radiotherapy, vaginal
packing with or without formaldehyde, tranexamic acid, or
interventional radiology. Most studies are in patients with cer-
vical cancer. Early in the course of illness, surgical resection in
gynecologic malignancy may be helpful. In patients with distant
metastases or those who prefer palliative therapy, other options
are available. Radiotherapy using either external-beam irradia-
tion or intracavity treatment has been shown to reduce vaginal
bleeding in patients with cervical cancer, ovarian cancer, and
endometrial cancer. 31–33 Progestin intrauterine device place-
ment may reduce vaginal bleeding in uterine cancer. 32 Uterine
or other pelvic arterial embolization may be feasible in select
cases. Uterine arterial embolization has been used relatively
frequently in cases of postpartum hemorrhage and sometimes
also in the management of cancer-related vaginal bleeding. 34
In advanced cervical cancer, there are no studies comparing
the efficacy of the methods listed above, though each has been
shown to be effective. 34
571
Hematuria
Hematuria is a frequent symptom and sign of underlying urologi-
cal disease. In patients with advanced cancer, hematuria may be
secondary to an underlying malignancy, a coagulation disorder,
or the result of interventions such as pelvic irradiation and cyclo-
phosphamide treatment. Hematuria usually manifests as the pas-
sage of brown or red urine or could involve the passage of large
clots, clot retention, or colic.
Retained clots require immediate intervention before specific
studies are initiated. Upon clinical confirmation of an obstructed
and palpable bladder, resulting from a clot, a complete evacua-
tion can be achieved by inserting a multi-eyed Robinson
catheter (24 F or 26 F) into the urethra. Once the catheter
has passed into the bladder, vigorous irrigation with water or
saline using a Toomey syringe will enable removal of all clots. 35
Irrigation of the bladder is uncomfortable and may require anal-
gesia. Unsuccessful initial placement of the catheter or continued
bleeding and recurrent obstruction of the irrigating catheter are
indications for endoscopic evaluation.
If bleeding is refractory to conservative measures, instillation
of 1%–2% alum (potassium or ammonium aluminum sulfate), 1%
silver nitrate, or formalin may be tried. The instillation of these
chemicals causes protein precipitation and the subsequent occlu-
sion of the bleeding vessels.2 However, caution is needed when
using alum irrigation in patients with renal insufficiency or blad-
der lesions that may allow alum to enter the vascular system,
and blood aluminum levels should be monitored in these cases.
Previously, instillation of formalin was also performed to achieve
hemostasis. Despite being effective, this practice has fallen out
of favor because of the concomitant risks of renal failure, blad-
der perforation, fibrosis as well as the need for general or regional
anesthesia required to control the pain of instillation.2
Another treatment option for cancer-related hematuria is
hypofractionated radiotherapy with various regimens ranging
from 3 to 8 Gy/fraction and reported rates of hemostasis between
50% and 92%.2 Bleeding as a result of radiation cystitis may
respond to hyperbaric oxygen, and in chronic cases, oral pento-
san polysulfate may be used. 35,36
Laser resection or vaporization is a viable option for bleed-
ing associated with superficial and invasive bladder lesions. A
more invasive treatment for the same issue as above is trans-
urethral resection, which may control bleeding more effectively.
Embolization or surgical ligation of hypogastric arteries may be
required in extreme cases. Cystectomy with urinary diversion
should only be considered in patients with good performance sta-
tus if all other options have failed or are not feasible. 37
Other causes
Bleeding is one of the most common complications associated
with left ventricular assist device (LVAD) therapy. 38 Patients
with advanced heart failure are often managed with LVAD des-
tination therapy or as a bridge to transplant, bleeding is poten-
tially an issue that may present at the end of life. Bleeding in the
LVAD patient is most likely due to acquired von Willebrand fac-
tor or anticoagulation required for LVAD function. Clinically,
this may present as upper or lower gastrointestinal bleeding,
often due to arteriovenous malformations. Intracranial hem-
orrhage may also occur, but is rarer, with reported incidence
of 0.03–0.08 hemorrhagic events per patient-year. Also, many
patients are treated with anticoagulant therapy for primary or
secondary prevention of stroke in atrial fibrillation or treatment
of thromboembolism. These medications increase the risk of
572
hemorrhage in patients and could worsen the severity of hemor-
rhage when it occurs.
Disseminated intravascular coagulation
DIC is systemic activation of coagulation, resulting in thrombo-
ses of both small and large vessels, often causing organ dysfunc-
tion. There is concurrent consumption of platelets and clotting
factors, which may cause profuse hemorrhage. DIC is always due
to an underlying condition such as sepsis, hematologic malig-
nancy, solid tumors, trauma, or obstetric complications.39
Common manifestations of acute DIC include small and mid-
size vessel thrombosis leading to dysfunction of the kidney, liver,
lungs, and central nervous system (CNS). Thrombosis and associ-
ated organ dysfunction is seen in 10%–15% of patients with can-
cer and up to 40% of patients with sepsis.39 Major hemorrhage is
seen in 5%–12% of patients and is more likely with a platelet count
of less than 50 × 109/L. 39 Bleeding is more common in trauma,
hematologic malignancies, liver disease, and vascular malforma-
tions; and thrombosis is more common in malignancy and post-
cardiopulmonary resuscitation.40
Petechiae and ecchymoses, in conjunction with blood oozing
from wound sites, intravenous lines, and mucosal surfaces, are
clinical signs of DIC. Such bleeding can be life-threatening if it
involves the gastrointestinal tract, lungs, or CNS. In patients who
develop DIC after surgical procedures, hemorrhage may develop
around indwelling lines, catheters, drains, and tracheostomies,
and blood may accumulate in serous cavities.
Malignancy often causes chronic DIC. It can also lead to acute
DIC, particularly in patients with acute promyelocytic leuke-
mia.41 While the presentation of DIC in patients with malig-
nancy is variable, it is often present at the time of diagnosis or
soon after the initiation of cytotoxic chemotherapy in patients
with this disorder.41 DIC can cause life-threatening bleeding in
these patients, more frequently when a concurrent infection is
present.41 Management of this condition, described in further
detail below, includes treatment of the underlying disease when
possible, treatment with blood products and inducing tumor cell
differentiation with all-trans-retinoic acid (ATRA).41
Chronic DIC
Chronic DIC develops when blood is continuously or intermit-
tently exposed to small amounts of tissue factor, and compen-
satory mechanisms in the liver and bone marrow are at least
partially able to replete coagulation proteins and platelets, respec-
tively. Under these conditions, the patient can be asymptomatic
or can have manifestations thrombosis, bleeding, or both.42
While there is no gold standard single test to make the diagnosis
of DIC, there are a number of scoring systems issued by national
thrombosis and hemostasis organizations. These scoring systems
are a combination of laboratory results such as prothrombin time
(PT), fibrinogen, and platelet count. 39 The laboratory values in
these studies vary in chronic DIC because a slower-than-normal
rate of the consumption of the coagulation factors may be off-
set by enhanced synthesis of these proteins. In such patients, the
diagnosis may be largely based on finding microangiopathy in the
peripheral blood smear and increased levels of fibrin degradation
products, in particular, D dimer.
Treatment of DIC
Treatment of the underlying disease (e.g., sepsis, malignancy)
is of central importance in controlling acute or chronic DIC.
Textbook of Palliative Medicine and Supportive Care
Hemodynamic support is essential, but many patients do not
require specific therapy for coagulopathy, because it is either
short term or not severe enough to pose a major risk for bleeding
or thrombosis. When in line with the patient’s goals of care, blood
component replacement therapy or heparin may be of value in
certain instances as described below. DIC associated with acute
promyelocytic leukemia responds more to treatment with ATRA
than to traditional chemotherapy alone, because ATRA exerts
anticoagulant and anti-fibrinolytic effects in addition to its effects
on acute promyelocytic leukemia progression.43
Platelet transfusion and fresh frozen plasma
Patients with DIC bleed because of thrombocytopenia and coag-
ulation factor deficiency. There is no evidence to support the
administration of platelets and coagulation factors in patients
who are not bleeding. However, treatment is justified in patients
who have serious bleeding, are at high risk for bleeding (e.g., after
surgery), or require invasive procedures.
Patients with marked thrombocytopenia (less than 20,000
platelets/μL) are at risk for bleeding, and those with moderate
thrombocytopenia (less than 50,000 platelets/μL) and serious
bleeding should be given platelet transfusions (1–2 units/10 kg/
day). Patients who are actively bleeding with a significantly ele-
vated PT, or activated partial thromboplastin time (>1.5 times
the normal value) or a fibrinogen concentration less than 1.5 g/dL
should receive fresh frozen plasma or cryoprecipitate, the latter
for fibrinogen replacement. It is preferable to keep the fibrinogen
level above 100 mg/dL. Prothrombin complex concentrate (PCC)
may be considered for actively bleeding patients when fresh fro-
zen plasma is not available. In patients electing for comfort, it is
important to consider the symptoms of volume overload that can
occur with blood product transfusion for correction of coagu-
lation abnormalities.43 Further study is needed to demonstrate
clear benefit in the use of anticoagulant factor concentrates (anti-
thrombin, activated protein C), though guidelines note that these
may be considered in patients with DIC.43
Heparin
Experimental studies have shown that heparin can partly inhibit
activation of coagulation in DIC, but there are no trials dem-
onstrating that use of heparin in these patients improved clini-
cally important outcomes. However, guidelines recommend use
of therapeutic low-molecular weight heparin for patients with
thrombotic predominance, and prophylactic dose of either low-
molecular weight or unfractionated heparin in patient with DIC
who are not bleeding.43
Thrombocytopenia and hemorrhagic
risk in patients with cancer
Gaydos et al. first documented the direct relationship between
the platelet count and bleeding episodes in patients with malig-
nant diseases in 1962 in patients with acute leukemia.44 In this
study, major bleeding rarely occurred when the platelet count
exceeded 20,000/μL; it gradually increased as the platelet count
ranged between 20,000 and 5,000/μL, and dramatically increased
when the platelet count fell below 5,000/μL.44
The incidence of hemorrhagic complications in patients with
solid tumors was first studied by Belt et al. in a cohort of 718
patients receiving myelosuppressive chemotherapeutic agents.45
Hemorrhage
In this study, 10.4% experienced one or more episodes of hemor-
rhage. Bleeding was due to tumor invasion in 33.3% and to DIC in
9.3%. It was unrelated to malignant neoplasms or drug treatment
in 8% and 49.3% had hemorrhages associated with drug-induced
thrombocytopenia. Additionally, the results of this study dem-
onstrated a quantitative relationship between the incidence of
hemorrhage and the platelet count. However, the incidence of
hemorrhage was low until the platelet count decreased below
10,000/μL, and fatal bleeding was unlikely to occur at platelet
counts above 5,000/μL.45
In 2015, Crighton et al. performed a systematic review to
compare a prophylactic platelet transfusion policy versus a ther-
apeutic-only platelet transfusion policy in cancer patients with
thrombocytopenia.46 In their review of 6 RCTs with 1,195 total
participants, they found evidence that a prophylactic transfusion
policy led to a decreased risk of bleeding when compared to a
therapeutic-only policy. However, there was insufficient evidence
to show differences in mortality or overall survival.46
More recently, Estcourt et al. conducted a systematic review
comparing three RCTs. Their results demonstrated that in patients
with hematological disorders who are thrombocytopenic second-
ary to HSCT or myelosuppressive chemotherapy, there was evi-
dence that a standard threshold for platelet infusion of (10 × 109/L)
is not associated with an increase in the risk of bleeding when com-
pared to a higher threshold (20 × 109/L or 30 × 109/L).47 There was
also evidence that the threshold level of (10 × 109/L) is associated
with fewer transfusions being given when compared to a higher
level (20 × 109/L or 30 × 109/L).47 While the authors recommend
this (10 × 109/L) threshold for transfusion of platelets, they also
acknowledge the need for higher quality evidence and ongoing
research in this area.47
The risk of bleeding in thrombocytopenia depends not only
on the platelet count but also on the underlying disease, the
use of drugs that interfere with platelet function, and compli-
cations such as fever, infection, or coagulation defects. Aspirin,
NSAIDs, and some antibiotics such as high-dose penicillin may
impair platelet function. As a consequence, it is not the absolute
platelet count but rather the number of functional platelets that
is important for the prevention of bleeding. Furthermore, there
is evidence to support the use of a prophylactic platelet transfu-
sion policy to lower the risk of bleeding in the cancer population
as well as evidence that transfusing at the lower threshold (10 ×
109/L) may reduce the number of transfusions with no increased
risk of bleeding.46,47
General approach to hemorrhage (Table 60.2)
A broad, open, and inquisitive frame of mind must be used when
treating hemorrhage episodes. The patient’s history and physical
examination should provide important baseline information. Key
laboratory tests must be quickly ordered and interpreted. Using
these data, one can quickly determine the etiology and severity of
the hemorrhagic disorder. This, in combination with reviewing the
patient’s goals of care, allows for development of a treatment plan
as well as insight into likelihood of bleeding cessation.
In the palliative setting, many factors must be considered with
regard to the management of bleeding. The clinician has to not
only considered the underlying cause and the clinical presenta-
tion, including the severity and nature of such an event, but also
taken into account other salient factors, such as the setting of
care, and the availability of various resources. The patient’s over-
all disease burden, predicted life expectancy, patient’s quality of
573
TABLE 60.2  Management of Hemorrhage
Identify patients at risk
• General risk factors (hematological cancers, large head and neck
cancers or centrally located lung cancers, liver disease, or clotting
derangements)
• Thorough history, physical, review of lab, and imaging data
Multidisciplinary team discussion and planning
• Preparation and planning
• Involve physicians, nurses, chaplain, social worker, pharmacists,
counselors
• Factors to consider include patient’s prognosis, performance status,
and patient’s perceived quality of life and preferences
Level of discussion depends on
• Diagnosis and prognosis based on all current patient data
• Bleeding risk
• Patient’s preference
• Available treatment modalities along with associated risks and
benefits
General measures
• Apply external pressure if bleeding is visible
• Have dark towels and basins at bedside
• Have equipment available for suctioning at bedside
• Provide psychological support
• Prepare emergency sedative medications that can be given
intravenously or subcutaneously quickly
Resuscitative measures
• Fluid resuscitation
• Transfusion of blood products
• Vasopressors if indicated
Specific measures
• Local hemostatic agents
• Radiotherapy
• Surgical interventions
• Interventional arterial embolization
• Systemic treatments (tranexamic acid, correction of clotting
derangements)
life, and the wishes of the patient and family are considered as
well. The patients and families facing the prospect or reality of
massive bleeding require extensive psychological support.
The choice of treatment modality must balance the risk of
aggressive management and its associated risks and side effects
against the withholding of specific treatments and forgoing their
potential benefits. Although the staff providing palliative care
can initiate many simple treatments, a definitive approach to
hemorrhage management requires an interdisciplinary approach
and sometimes the expertise of various specialists.
As an example of the need to set priorities, interventional
radiology or surgical ligation of the pelvic vessel in a patient
with vaginal bleeding would be less likely to be considered for a
home-bound, cachectic patient who has expressed the desire to
remain home in their final hours to days. On the other hand, had
the same patient presented soon after significant hemorrhaging
began, it would have been reasonable to consider the aforemen-
tioned treatments, particularly if specialists with the required
skills and equipment were available.
Management of bleeding
Management of bleeding needs to be individualized and depends
on the underlying cause, the likelihood of reversing or controlling
574
the underlying cause, and the burden-to-benefit ratio of the
treatment. If the patient’s goals of care, disease burden and life
expectancy warrant it; then the management of a bleeding epi-
sode consists of general resuscitative measures, such as volume
and fluid replacement, and specific measures to stop the bleeding
such as interventional or transfusion-related treatments. On the
other hand, palliative measures may be most appropriate in end-
stage patients.
Appropriate management involves a detailed assessment,
including a review of prior bleeding episodes, past illness, psy-
chosocial stressors (including level of family support), and medi-
cations such as NSAIDS or anticoagulants. Physical examination
should focus on whether the bleeding is focal or occurring at
multiple sites. Tests such as a hemogram or a clotting profile may
reveal a systemic disease, whereas endoscopic studies or angiog-
raphy may reveal the site of the bleeding.
Local interventions (Table 60.3)
Packing can be used with or without pressure to achieve hemo-
stasis when bleeding originates in the nose, vagina, or rectum.
Surgical swabs of various sizes may be used for this purpose. They
can be coated with chemicals that facilitate hemostasis, such as
cocaine in nasal packing. Non-adherent dressings should be used.
A variety of hemostatic agents and dressings, mostly designed
for surgical procedures, are beneficial for exterior topical use.
Thromboplastin, a natural blood-clotting agent obtained from
bovine plasma, is available as a powder for topical preparation.
Thrombin (factor II) is a blood-clotting agent in the human clot-
ting cascade. Previously derived from bovine plasma, it is now
produced as a recombinant human thrombin and is available as a
powder which can be reconstituted in water and applied topically
to achieve hemostasis.50
Absorbable gelatin is available as a sterile sponge-like dressing
or sterile powder that can be applied (dry or saturated with sterile
sodium solution). It is usually absorbed within 4–6 weeks. When
the gelatin is applied, fibrin is deposited in the interstices of the
foam, resulting in the swelling of the sponge, thereby forming a
large synthetic clot.51
Other bioabsorbable topical hemostatic agents include fibrin
sealants and oxidized cellulose.51 Fibrin sealants are derived
from human plasma and reproduce the final steps in the coagula-
tion pathway to form a clot. The inherent hemostatic activity of
absorbable collagen agents provokes a clotting cascade when the
bovine-derived mesh comes into contact with blood and forms
TABLE 60.3  Local Measures
Epinephrine May be used topically, but its liberal use is
discouraged
Prostaglandins E2 and F2 Used in intractable hemorrhagic cystitis
Silver nitrate Induces chemical cauterization and has
been used to control hemorrhages in the
bladder and epistaxis
Aluminum astringents An example is 1% alum, which can be
delivered by continuous irrigation of the
bladder
Sucralfate Controls cancer-related gastrointestinal
bleeding and cutaneous oozing
Tranexamic acid (TA) Controls bleeding when used locally or
systemically (topical, nebulizer, oral, or IV)
[22, 23, 48, 49]
Textbook of Palliative Medicine and Supportive Care
a clot. Other available hemostatic agents are oxidized cellulose
compounds and highly absorbent alginate dressings derived from
seaweed. Vasoconstricting or cauterizing agents are used to man-
age localized capillary-based bleeding.
Radiotherapy
External beam radiotherapy is used to relieve bleeding in a num-
ber of oncologic conditions. Radiation can decrease the hemop-
tysis caused by lung cancer in 60% of patients.52 In patients with
rectal cancer, radiation therapy was shown to improve bleeding in
86.7% of patients, with a mean duration of 5.4 months.6 Radiation
has also been shown to help with bleeding in gastric cancer, with
a retrospective cohort study showing that after two fractions,
73% of patients achieved hemostasis, with a rebleeding-free dura-
tion of 27 days.53 Radiotherapy should also be considered for
treating bleeding from cancerous lesions in the vagina, ovaries,
uterus, and bladder.2,54,55 Although radiotherapy can be useful in
controlling the bleeding in patients with head and neck cancers,
many patients have already received the maximal allowable doses
of radiotherapy by the time bleeding occurs and cannot receive
further radiation. Single or reduced fraction regimens appear to
be as effective as multiple fractions in controlling bleeding.
Embolization
Embolization may be useful in well-selected patients whose blood
vessels are accessible by catheter. The benefits of embolization
have been reported in patients with cancers involving the head
and neck, pelvis, lung, liver, and gastrointestinal tract.56–59
Embolization can be a helpful intervention in intractable bleed-
ing; however, patients must be willing to travel to and from an
intervention center and have a life expectancy where they will not
pass in transit for the procedure. Also, the patient must be able to
lie flat for the procedure and should ideally have good renal func-
tion, as contrast may be utilized. Complications of transcatheter
embolization can include bleeding or hematoma of the local site,
as well as vessel occlusion. Necrosis of the tumor may also occur,
which can result in pain or nausea and vomiting.2
Surgery
Surgery may be appropriate for select patients when benefits out-
weigh the burdens and risks, when it is in line with the patient’s
goals of care, and when conservative measures have failed.
Indications for surgery depend on the location and etiology of the
bleeding. As discussed in previous sections, surgical intervention
is beneficial in controlling bleeding related to lower GI neoplasms
or early cervical cancer. Additionally, surgery-controlled bleed-
ing was achieved in patients with head and neck cancers who
presented with acute or imminent carotid artery rupture and in
those with radiation proctitis in whom the bleeding was not con-
trolled by topically applied formalin.60,61
Surgical intervention by ligation of the sphenopaletine artery
is becoming more common in the treatment of epistaxis with
reported success rates between 70% and 100%. Furthermore,
there is evidence to suggest it reduces inpatient stay, improves
patient satisfaction, and reduces cost when compared to tradi-
tional nasal packing.14
Nevertheless, there are situations when surgical intervention is
generally not indicated. For instance, in the setting of hemoptysis,
surgery is not first line and is traditionally associated with high
rates of morbidity and mortality. There is, however, emerging
Hemorrhage
evidence suggesting that a certain subset of patients may benefit
from this procedure. Specifically, in a 2018 retrospective study,
those with benign lung disease who underwent elective, sub-
lobar resection using VATS procedure experienced fewer post-
operative complications.62
Systemic interventions
Vitamin K
Vitamin K (phytonadione, menadiol) may be useful in treating a
derangement in vitamin K-dependent coagulation factors, such
as factors II, VII, IX, and X, or for treating bleeding in patients
with advanced cancer that has been caused by excessive therapy
with warfarin. The preferable route of administration would be
oral or subcutaneous, but the intravenous route should be consid-
ered when rapid correction is required. The recommended doses
vary from 2.5 to 10 mg depending on the severity of bleeding.63
Vasopressin/Desmopressin
Vasopressin/Desmopressin is a hormone in the posterior pitu-
itary gland that causes splanchnic arteriolar constriction and
reduction in portal pressure when it is injected intravenously or
intra-arterially. It has been used in a controlled trial to manage
bleeding in select patients with upper gastrointestinal bleeding
related to a malignancy.64
Somatostatin analogues
Octreotide, an analogue of somatostatin, has been used in pallia-
tive care for reducing secretions in patients with a gastrointesti-
nal obstruction. It also reduces the splanchnic flow and pressure
by causing venous dilatation, thereby reducing portal pressure
and portal venous flow and may reduce bleeding.65
Antifibrinolytic agents
Tranexamic acid (TA) and epsilon-aminocaproic acid (EACA) are
synthetic antifibrinolytic agents that block the binding sites of
plasminogen, thereby inhibiting the conversion of plasminogen
into plasmin by the tissue plasminogen activator.66
TA and EACA can be administered orally and intravenously.
The most common adverse effects of TA and EACA are gastroin-
testinal in nature (nausea, vomiting, and diarrhea) and occur in
25% of cases.67 The adverse effects appear to be dose-dependent.
Thromboembolism is uncommon.66 TA has been studied for use
in gastrointestinal bleeding, with better results in upper gastroin-
testinal hemorrhage than lower. TA and EACA have been studied
in surgical use, but neither has been studied in the palliative care
population.13,66
Prothrombin complex concentrates
PCCs have been used in Europe for years to reverse the effect
of oral anticoagulant medications. These products have only
recently been approved in the United States and are effective in
reversing the effects of direct oral anticoagulants such as rivarox-
aban and apixaban, as well as reversal of warfarin.68,69 In patients
who are on an oral anticoagulant and have major bleeding, use
of a four-factor PCC may be an option if in line with the patient’s
goals of care and life expectancy.
Endoscopy (Table 60.4)
Endoscopy-based treatments have, for a long time, been used to
manage the bleeding from upper gastrointestinal varices, partic-
ularly after systemic therapies with agents such as vasopressin or
somatostatin analogues have failed.70,71
575
TABLE 60.4  Endoscopic Interventions and Their Role
Upper gastrointestinal Uses argon beam plasma coagulation to control
endoscopy bleeding in esophagogastric cancer
Cystoscopy Cystoscopic-assisted cautery by either heat or
laser probes; has been used in the treatment
of hematuria in bladder cancer patients
Bronchoscopy In case of hemoptysis, bronchoscopy allows for
stenting, ice-cold saline lavages, and/or the
use of balloon tamponade, laser
photocoagulation, or topical application of
thrombin or fibrinogen at the site of the
bleeding
Colonoscopy Techniques such as bipolar electrocoagulation,
heater probe, argon, and Nd:YAG lasers are
used to control bleeding in the lower
gastrointestinal tract
Transfusion of blood products
Transfusions of blood products should be undertaken on a selec-
tive basis. The American Association of Blood Banks proposes
a transfusion trigger at platelet count of 10 × 109 cells/L or less,
which is supported by the work of Estcort et al. but is still lacking
strong evidence.47 Lassauniere et al. proposed criteria for platelet
transfusions in patients with advanced hematological malignan-
cies.63 These criteria include continuous bleeding of the mouth or
gums, epistaxis, extensive and painful hematomas, severe head-
aches, or recent onset of disturbed vision, as well as continuous
bleeding through the gastrointestinal, gynecological, or urinary
systems.
Transfusions of fresh frozen plasma are indicated (1) in patients
who are bleeding and have specific deficiencies in certain coagu-
lation factors, (2) in patients in whom the effects of warfarin
urgently need to be reversed, (3) in patients who require urgent
invasive interventions such as thoracentesis or surgery, and (4)
with DIC, when appropriate. Transfusions of packed red cells are
indicated when anemia resulting from blood loss causes or aggra-
vates symptoms such as fatigue and dyspnea.
The continuation of platelet transfusion in patients with end-
stage thrombocytopenia poses an ethical dilemma. Even though
the ongoing transfusions may be futile, patients and their fami-
lies may perceive the cessation of transfusions as the withdrawal
of life-sustaining therapy. Sensitive and empathic discussions
among patients, their families, the attending physician, and the
health team are essential in order to explore their expectations,
fears, and concerns and to engage in advanced end-of-life plan-
ning while ensuring ongoing support and providing optimal
comfort care.
Palliative measures
General supportive measures should always be applied in cases
of massive hemorrhage. Apply external pressure if the source of
the bleeding is visible, administer oxygen or place patient in lat-
eral position if possible, and provide psychosocial support to the
patients and families. Other measures include using suction and
dark towels and basins to decrease the distress from visualiza-
tion of blood. The medical team should plan before the event by
having personal protective equipment such as face shields, dark
aprons, and towels readily available.
Hemorrhage can be extremely distressing, and many studies
have suggested having prefilled syringes of sedative medications
 576
(e.g., midazolam) readily available. The intent of the sedative
medication is to alleviate distress. Midazolam is found to be the
most commonly recommended drug in this setting in a system-
atic review on management of terminal hemorrhage by Harris
and Noble in 2009. 37 Midazolam is favored because it is rapid-
acting, safe, short-term, and provides some level of retrograde
amnesia and, therefore, is less likely to cause harm if the bleeding
is not terminal. 37 It is important to debrief and counsel staff and
families before and after the event. These measures can be done
in the home or in an inpatient setting.
Conclusion
Massive bleeding, which occurs in 6%–10% of patients in pal-
liative care settings, can be extremely distressing for both the
patients and caregivers.72 These episodes require an individu-
alized approach based on the specific needs of the patient and
family, which include the level of distress, the stage of disease,
and the expertise available. A multidisciplinary approach that
makes use of various modalities may be required. Treatments
range from simple hemostatic techniques to more invasive and
sophisticated modalities. Minimal management requires the
identification of patients at risk and preparatory measures to
empower caregivers to deal appropriately with massive bleeding
if it occurs.
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61
SPINAL CORD COMPRESSION

Maitry Patel, Adrian Cozma, Edward Chow, and Srinivas Raman

Contents
Introduction........................................................................................................................................................................................................................579
Pathophysiology.................................................................................................................................................................................................................579
Clinical presentation.........................................................................................................................................................................................................579
Spinal cord syndromes............................................................................................................................................................................................... 580
Diagnosis............................................................................................................................................................................................................................. 580
Management...................................................................................................................................................................................................................... 580
Medical management........................................................................................................................................................................................................581
Surgical treatment..............................................................................................................................................................................................................581
Spinal stability...............................................................................................................................................................................................................581
Degree of cord compression......................................................................................................................................................................................581
Radiosensitivity.............................................................................................................................................................................................................581
Patient prognosis..........................................................................................................................................................................................................582
Management with surgery..........................................................................................................................................................................................582
Radiotherapy.......................................................................................................................................................................................................................582
Radiation technique.....................................................................................................................................................................................................582
Radiation dose...............................................................................................................................................................................................................583
Radiation toxicities......................................................................................................................................................................................................583
Reirradiation.................................................................................................................................................................................................................583
Stereotactic body radiation therapy.........................................................................................................................................................................583
Outcome..............................................................................................................................................................................................................................583
References........................................................................................................................................................................................................................... 584

Introduction space; (2) destruction of vertebral bone, causing vertebral body

Common primary malignancies, such as breast, lung, and pros-
tate, frequently metastasize to the bones. Over 70% of all can-
cer patients develop symptoms from either their primary or
metastatic disease.1 Presence of bone metastases is a sign of dis-
seminated disease; and a commonly seen oncologic emergency
related to bone metastases is malignant spinal cord compression
(mSCC), which is defined as radiographic compression of spi-
nal cord or cauda equina.2–5 It is estimated that approximately
5%–10% of all cancer patients will develop mSCC and although
most patients have limited survival, up to one-third will survive
beyond 1 year.6–8 A Canadian population-based study described
that 2.5% of all cancer patients who died of their disease had
at least one admission for mSCC.9 Being a medical emergency,
mSCC requires urgent attention with timely diagnosis and man-
agement, to prevent permanent disability due to irreversible
injury.
Pathophysiology
The spinal cord extends from the foramen magnum to L1–L2 in
adults, and more inferiorly (L2–L4) in children. The dural sac
containing cerebrospinal fluid (CSF) surrounds the 31 nerve roots
and spinal cord, which include 8 cervical, 12 thoracic, 5 lumbar, 5
sacral, and 1 coccygeal levels.
There are four mechanisms by which mSCC occurs: (1) growth
and expansion of vertebral bone metastases into the epidural
collapse with displacement of bone fragments in the epidural
space; (3) paraspinal mass causing neural foramina extension;
and rarely (4) primary hematogenous seeding of malignant cells
in the epidural space. Extension into epidural space can cause
intramedullary edema of the white matter and then the gray
matter, which increases vascular permeability and pressure on
the small arterioles. As the capillary blood flow diminishes due
to disease progression, white matter ischemia occurs, causing
infarction and permanent cord damage, if left untreated.10
Clinical presentation
Approximately 60%–70% of mSCC to the spine occur in the tho-
racic spine, 20%–30% in the lumbosacral spine, and only about
10% in the cervical spine. Additionally, 17%–35% of patients will
have multiple sites of mSCC.11 About 30% of people with mSCC
will have metastases in more than one area of the spine. The most
common presentation of mSCC is back pain, and this symptom
usually precludes neurologic symptoms by 2–4 months. Back
pain, present in up to 95% of patients with mSCC, is more pro-
nounced at night or early morning when adrenal steroid secretion
is at its lowest.12,13
Other common findings are diffuse weakness in 61%–91% of
the patients, sensory deficits in 46%–90% of the patients, and
autonomic dysfunction in 40%–57% of patients with mSCC.14
Patients presenting with weakness are often non-ambulatory.
Patients complaining of sensory symptoms frequently describe

579
580
“band-like,” ascending, or “saddle” anesthesia/paresthesia symp-
toms, depending on location of the mSCC.
Physical exam findings will correspond to the location of the
tumor and may include severe spinal tenderness upon palpation,
upper motor neuron signs of spasticity, hyperactive reflexes, posi-
tive Babinski sign, and lower motor neuron signs of atrophy, flac-
cidity, and loss of reflexes. Valsalva maneuvers may exacerbate
radicular back pain associated with mSCC, but this can occur
with benign causes of mechanical back pain as well.
Spinal cord syndromes
Total transection of the cord causes interruption of the long
motor and sensory tracts with concomitant complete loss of vol-
untary motor and sensory function below the level of the tran-
section. Bowel and bladder dysfunction are commonly seen in
conjunction with weakness, and complete absence of reflex and
autonomic activity. Patients with anterior cord compression may
present with bilateral paraplegia, loss of pain and temperature
sensation, sphincter dysfunction (urinary retention), or weak-
ness. Contrarily, patients with posterior cord compression may
experience bilateral loss of proprioception and vibration, weak-
ness, ataxia, or bladder dysfunction.
Cauda equina syndrome (at the level of L1–L2 to S2) may
manifest as asymmetric radiculopathy, saddle anesthesia, blad-
der/bowel dysfunction (incontinence or retention), sensory loss,
reduced deep tendon reflexes, and paraplegia. Conus medullaris
syndrome may present very similarly to cuada equina syndrome
with the key difference being symmetric radiculopathy, hyperre-
flexia, and distal paresis of lower limbs. Very rarely, mSCC can
present itself as Brown-Séquard syndrome, in which patients may
suffer from ipsilateral upper motor neuron paralysis and loss of
proprioception, as well as contralateral loss of pain and tempera-
ture sensation.
Diagnosis
In patients with suspected mSCC, urgent magnetic resonance
imaging (MRI) of the entire spine within 24 h of presentation is
recommended to accurately identify the level and extent of the
disease, as well as other levels where asymptomatic lesions may
be present. Many of these lesions may be asymptomatic but could
warrant prophylactic treatment prior to the later development
of pain or irreversible symptoms like paralysis. Discrimination
between metastatic disease versus bacterial abscesses (mSCC
invades the disk space, where the latter does not), leptomeningeal
carcinomatosis (nodular or linear tumor deposits), intradural
extramedullary tumors (appearance and enhancement with con-
trast), and intramedullary metastases (that cause enlargement of
the cord) can easily be made with MRI.
In particular, sagittal T1 and/or STIR (short T1 inversion
recovery) sequences help detect metastases. Sagittal T2 supple-
mented with axial T1 or T2 weighted scans shows the degree of
spinal cord compression and the soft tissue component of the
mass. Imaging with and without contrast is particularly help-
ful for identifying metastases from other pathologies. While the
degree of intraosseous tumor is well delineated on non-contrast
sequences, IV gadolinium is routinely administered to define
the extent of epidural, foraminal, and paravertebral soft tissues
and to discern the presence of intramedullary or leptomeningeal
disease.
Axial T2-weighted images are used to assign the 6-point epi-
dural spinal cord compression (ESCC) score15 which can be used
Textbook of Palliative Medicine and Supportive Care
to quantify the extent of spinal cord or thecal cord compression,
and define management.
The following radiological parameters define ESCC score:
a. Grade 0: tumor is confined to bone;
b. Grade 1a: tumor with epidural extension without displace-
ment of thecal sac;
c. Grade 1b: tumor displacing the thecal sac, without spinal
cord abutment;
d. Grade 1c: deformation of the thecal sac with spinal cord
abutment, but without cord compression;
e. Grade 2: spinal cord compression with CSF visible around
the cord; and
f. Grade 3: circumferential epidural extension that causes
severe spinal cord compression with obliteration of the
CSF space.
High-grade ESCC refers to Grades 2 and 3, even if patients are
asymptomatic; and low grade refers to remaining patients, who
may have symptoms of nerve root compression but do not have
deficits attributable to mSCC.
MRI has high sensitivity (93%–100%) and high specificity
(90%–97%) in diagnosing mSCC, along with the benefit of it
being non-invasive.16,17 However, for patients with one or more
MRI contraindications (such as incompatible pacemaker, foreign
metallic body), a CT myelogram is recommended.16 CT myelog-
raphy is performed after injection of iodinated contrast into the
thecal sac, usually by image-guided lumbar puncture (IV contrast
is not used). Following contrast, CT imaging of cervical, thoracic,
and lumbar spine is performed with volumetric thin (<3 mm)
axial sections and multiplanar sagittal and coronal reformations.
There is comparable sensitivity and specificity of CT myelogra-
phy to MRI with contrast for diagnosis of mSCC.16
A biopsy may be indicated to confirm the diagnosis in non-sur-
gical patients with no or remote prior history of cancer, patients
with lack of oligo- or widespread metastatic disease, or if there
is a discordance between primary malignancy diagnosis and the
spinal lesion(s). A comprehensive history and physical exami-
nation (including neurologic assessment) are indicated for all
patients presenting with symptoms suggestive of mSCC.
Management
MSCC can significantly impact patients’ quality of life, and the
goal of treatment is symptom management, avoidance of com-
plications, and preservation or improvement of neurological
function. Patients with mSCC are heterogenous and personal-
ized treatment plan must be designed. A multidisciplinary team
(MDT) of radiologists, radiation oncologists, neurosurgeons,
medical oncologists, symptom control/palliative team, and/
or psychosocial care should be used to optimize the treatment
approach.
The Neurologic, Oncologic, Mechanical, Systemic (NOMS)
paradigm18 provides a useful framework for decision-making. The
extent of epidural extension in combination with tumor radio-
sensitivity allows clinicians to determine optimal radiotherapy
(RT) treatment plan and the need for surgical decompression.
Mechanical stability of the spine and the systemic disease con-
siderations further help determine the need and the feasibility of
surgical intervention.
General management involves administration of glucocorticoid
therapy, surgery for good prognosis patients who are medically
Spinal Cord Compression 581

and surgically operable, RT (upfront or in the post-operative set- TABLE 61.1  Spine Instability Neoplastic Score
ting), and pain management.19
Variable Score
Lesion Location:
Medical management Junctional (O–C2; C7–T2; T11–L1; L5–S1) 3
Corticosteroids must be promptly initiated as soon as mSCC is Mobile spine (C3–C6; L2–L4) 2
suspected. Glucocorticoids, such as dexamethasone, can pro- Semirigid spine (T3–T10) 1
vide pain relief (both neuropathic and inflammatory) by reduc- Rigid spine (S2–S5) 0
ing edema, preserve existing neurologic function, and serve as Mechanical Pain:
a bridge to definitive treatment.19 Typically, a loading dose of Yes 3
10 mg dexamethasone is administered intravenously (IV), fol- Occasional, but not mechanical 1
lowed by 4–6 mg IV q6 hours. Concurrent proton pump inhibitor No 0
should be prescribed for gastric prophylaxis. A few studies that Type of Bone Lesion:
have reviewed existed data20 and investigated the optimal dose Lytic 2
and duration of dexamethasone16 in this setting have found no Mixed (lytic and blastic) 1
significant difference in functional outcomes when comparing Blastic 0
high-dose dexamethasone (96 mg for 3 days, then tapered) ver- Radiographic Spinal Alignment:
sus moderate- or low-dose dexamethasone (10–16 mg for 3 days, Subluxation or translation present 4
then tapered). A systemic review of the aforementioned studies De novo deformity (kyphosis or scoliosis) 2
concluded that high-dose dexamethasone leads to higher risk of Normal 0
adverse effects, including perforated gastric ulcers, uncontrolled Vertebral Body Destruction:
hyperglycemia, hypomania, psychoses, and infection-related >50% collapse 3
death. Dexamethasone taper and duration thereof should be ini- <50% collapse 2
tiated based on severity of symptoms, clinical response, and deci- No collapse with >50% body involved 1
sion regarding definitive management. None of the above 0
Other important consideration for medical treatment in Involvement of Posterolateral Spinal Elements:
patients with mSCC is pain management, details of which are Bilateral 3
covered in detail in chapters (25-34). Most patients require opi- Unilateral 1
oids for pain relief, in conjunction with other analgesics, such as None of the above 0
steroidal or non-steroidal anti-inflammatories (e.g., naproxen, Total Score 0–18
ibuprofen), neuropathic agents (i.e., gabapentin, pregabalin), Stable 0–6
bisphosphonates, and acetaminophen. MDT management with Indeterminate (possibly unstable) 7–12
palliative care physicians and nurses is integral to provide opti- Unstable 13–18
mal pain control. Patients with mSCC are also at risk for consti-
pation due to opioid treatment, lack of mobility, and autonomic
dysfunction. Prophylactic combination of osmotic and stimulant
laxative is effective in most patients for constipation. Patients Instability Neoplastic Score (SINS) devised by the Spine Oncology
with mSCC are at especially increased risk of venous thrombo- Study Group in 2010 has 95.7% sensitivity and 79.5% specificity in
embolism (VTE) given that they may have limited or no mobility predicting spinal instability and can help clinicians make deci-
in addition to their cancer diagnosis and possibility of requiring sion for surgery.21 SINS assesses and scores six variables: location
surgical intervention. Although the value of prophylaxis against of lesion, presence of pain with recumbency, and/or movement
VTE has not been studied on a large scale in this population, con- of spine, bone lesion type, radiographic spine alignment, degree
sideration should be given to VTE prophylaxis in mSCC patient of vertebral body collapse, and posterolateral involvement. The
to manage known risks with administration of unfractionated scores for each variable are added, and a final score is derived.
heparin or low-molecular weight heparin. The scores range from 0 to 18. A score of 0–6 represents stability,
a score of 7–12 implies possibly impending instability, and a score
of 13–18 denotes instability. For a score more than 7, a surgical
Surgical treatment consultation is recommended.22
The definitive management of mSCC can be broadly categorized Degree of cord compression
into surgical and RT approaches. The decision to purse surgery Neurologic deficits identified on physical examination (such
is dependent on many factors including spinal stability, degree as abnormal reflexes, loss of motor control, loss of sensation,
of cord compression, neurologic deficits, radiosensitivity, patient inability to ambulate or unstable gait, etc.) in combination with
preferences, and patient prognosis. Although ideally each case high-grade compression shown on MRI (ESCC Grades 2–3) are
must be discussed in an MDT setting, the timelines to initiate typically considered indications for neurosurgical intervention.
treatment can be short and guidelines like the NOMS framework
can be used to prepare and organize appropriate treatments. Radiosensitivity
MSCC patients with radiosensitive tumors, such as lymphoma,
Spinal stability melanoma, germ cell tumors, and carcinomas arising from pros-
Spinal instability is a primary indication for surgical interven- tate, breast, and gastrointestinal, and gynecologic primaries,23
tion, independent of the ESCC score, or tumor radiosensitivity. can be treated successfully with RT unless there is spinal instabil-
Pain due to spinal instability will not be controlled with just ity, overlap with prior RT fields, or progression of tumor or symp-
medical management with or without the addition of RT. The Spine toms during radiation treatment. Highly radiosensitive histologic
582
types such as malignant lymphomas and seminomas respond
rapidly to glucocorticoids and RT. Carcinomas, with moderate
sensitivity, may take time to respond to a non-invasive treatment
approach. Thus, surgery could be considered if rapid decompres-
sion of the spinal cord is required. Tumors with low sensitivity to
RT such as melanoma, sarcoma, renal cell carcinoma, and pan-
creatic carcinomas (20) should be considered for upfront surgery
and post-operative RT to optimize local control.
Patient prognosis
Accurate prognoses are useful for both patients with mSCC and
clinicians treating patients presenting with mSCC in order to
weigh the potential benefits and risks of surgical intervention.
Clinicians are often inaccurate in estimating remaining lifespan
of cancer patients20 as prognosis is dependent not just on the pre-
senting oncologic emergency but the availability of further sys-
temic therapies thereafter, tumor factors, and patient preferences
regarding further interventions. As such estimating life expec-
tancy for patients with mSCC is also very difficult. To address
this, several prognostic scoring tools have been developed.
One such model, The Modified Bauer Score24 as per Table 61.2,
identifies three prognostic groups (0–1, 2, or 3–4 points) on the
foundation of four factors. One point is assigned for each positive
factor (minimum score of 0 and maximum score of 4).
The New England Spinal Metastasis Score25 constructs further
on the Modified Bauer Score by adding serum albumin levels
and patients’ ambulatory status, to help predict 1-year survival
following surgery for spinal metastases causing cord compres-
sion. Comparisons of various prognostic scoring systems24 do
not clearly indicate which scoring system is most robust.26 With
emergence of molecular genetics and biomarkers as predictors for
tumor response and survival, there may be role for modified scor-
ing tools to transpire; however, some or all of this information
may not be available in oncologic emergencies.20
Management with surgery
Decompressive surgery should be considered in all patients pre-
senting with mSCC who have spinal instability, high ESCC score,
and established radioresistant tumors. The primary surgical goal
is circumferential decompression of the spinal cord to preserve
neurologic function and restore mechanical stability. This, in
turn, will allow for pain control. Post-surgical ambulatory rates
have been noted as high as 90%, with surgical morbidity and mor-
tality ranging from 5% to 10%.27
Primary surgical options include laminectomy, corpectomy,
and separation surgery.28 Laminectomy, also known as decom-
pression surgery, entails removal of posterior arch of vertebrae
(lamina) to relieve pressure on the spinal cord and nerve root
canals. This procedure is usually indicated for patients who
TABLE 61.2  Modified Bauer Score
Positive Prognostic Factors Score
No visceral metastases 1 The external beam radiotherapy (EBRT) technique covers the
No lung cancer 1 width of the affected vertebral body and all areas of paravertebral
Primary tumor = breast, kidney, lymphoma, 1
multiple myeloma
One solitary skeletal metastasis 1
Total Points Median Overall Survival
0–1 4.8 months
2 18.2 months
3–4 28.4 months
Textbook of Palliative Medicine and Supportive Care
present with anterior extension of a posterior tumor. To date, the
only attempt at a randomized controlled trial29 failed to show any
significant differences in outcome between RT alone and lami-
nectomy and RT. Corpectomy is the removal of vertebral body
via thoracotomy or retroperitoneal approach; however, this pro-
cedure delays RT by at least 6 weeks to allow for spinal fusion.2
Separation surgery entails a posterolateral approach for debulk-
ing and instrumentation with the goal to create adequate separa-
tion between the neural elements and the tumor with adequate
margins for stereotactic radiosurgery (SRS) to achieve durable
tumor control. The combination of this approach with high-dose
hypofractionated or single-fraction SRS results in higher local
tumor control at 1 year compared to surgery alone in one retro-
spective study. 30
At the time of this publication, there is only one randomized
trial which evaluated RT alone versus surgery followed by RT.27
The study showed that 84% (42/50) of patients who underwent
surgery and RT were ambulatory when compared to RT alone
group, which only had 57% (29/51) patients who were ambu-
latory. Patients treated with surgery and RT also retained the
ability to ambulate significantly longer than did those with RT
alone (median 122 days vs. 13 days). Of the 32 patients who were
unable to walk at the time they entered the study, statistically
significant difference was noted in the surgery and RT group
patients who regained the ability to walk than patients in the RT
alone cohort (62% vs. 19%). Lastly, patients in surgery followed
by RT group required less corticosteroids and opioid analgesics.
However, this study was noted to have several limitations, 20 as
it took long time to accrue limited number of patients, indicat-
ing only selective patients were enrolled. Patients with spinal
instability were excluded, causing bias favoring the surgery arm.
The results were not reproducible in a subsequent matched pair
analysis31 which found no statistical difference in outcome of
patients with mSCC treated with RT alone when compared to
surgery plus RT, thus warranting the need for new randomized
trials. It is challenging to compare the two studies as radiore-
sistant tumors were excluded in the former study. Ultimately,
decision-making should be made on a case-by-case basis, ideally
in an MDT fashion.
Radiotherapy
RT can be considered in a primary setting for patients who are
not good surgical candidates, and also in post-operative setting.
Similar to surgery, the goal of RT is to reduce pain and prevent
further complications, such as development of pathologic frac-
ture, in addition to preservation of remaining function. Key con-
siderations for RT include dose fractionation and whether the
area has received prior radiation. The following paragraphs will
focus on introduction to RT in the setting mSCC.
Radiation technique
tumor extension, with typical extension of RT field being one ver-
tebral body above and one below the epidural metastasis as there
is uncertainty of microscopic disease extent once it has entered
the epidural space.
EBRT can be delivered using conventional field-based tech-
niques or more advanced techniques, which allow the delivery
of high doses of RT to the target while minimizing the dose to
the surrounding organs at risk. Conventional techniques such
Spinal Cord Compression
as single posterior-anterior (PA) field and two opposed anterior-
posterior (AP/PA) fields are used for delivery of palliative doses of
RT. AP/PA fields provide homogenous dose distribution and are
the preferred techniques for thoracic and lumbar spine, whereas
treatment to the cervical spine is delivered by opposed lateral
fields. The use of PA fields alone provides less ventral dose, cre-
ating a disadvantage. Field-based techniques are most common,
due to ease of planning and ability to start patient’s treatment
quickly. IMRT/VMAT is reserved for retreatment or for dose
escalation in the setting of stereotactic body radiation therapy
(SBRT), which is discussed below.
Radiation dose
Several randomized studies and matched pair-analyses have
investigated various RT dose fractionations (e.g., 8 Gy × 1, 4
Gy × 5, 3 Gy × 10, 2.5 Gy × 15, and 2 Gy × 20), mostly in patients
with survival <6 months, and have not shown any significant
difference in survival, motor function improvement, or post-
treatment ambulatory rates. 8,32–34 One of the more recent and
largest randomized trials investigated 8 Gy × 1 versus 4 Gy × 5
in 686 patients with mSCC from metastatic solid tumors. 35 The
median survival of all patients in the trial was 13.1 weeks and
the primary endpoint was ambulation at 8 weeks. The propor-
tion of patients who were ambulatory was similar but slightly
lower in the single fraction arm 69.3% versus 72.7% in the mul-
tifraction arm and did not meet the criterion for noninferiority
(11% difference).
Generally, an abbreviated RT course of 8 Gy × 1 is recom-
mended for patients with poor predicted survival (prognosis less
than 3 months) and longer fractionations may be used for other
patients. This recommendation is also supported by a systemic
review conducted by ASTRO staff in 201436 and a subsequent
meta-analysis in 201837 which observed no difference between
multi-fractionated and single-fractionated RT with respect to
motor response, sphincter dysfunction, or overall survival in the
setting of limited prognosis. The effective conclusion is that sin-
gle fraction RT focuses on patient convenience, improves access
to RT, and decreases financial burden on the limited resources,
while providing safe and effective treatment in patients with a
limited expectancy. Patients with life expectancy >3 months may
be considered for more protracted treatments with higher bio-
logically effective doses to optimize local control.
Radiation toxicities
Palliative RT plans can be designed on a relatively short notice
(less than 6 h) and patients requiring single fraction (8 Gy × 1)
can be treated on the same day as presentation and simulation
CT scan. As quality of life is an important goal for most patients
with metastatic malignancy, RT toxicities are taken into consid-
eration. Given most individuals with mSCC may have a short-life
expectancy and poor performance, acute/subacute toxicities can
adversely affect their remaining quality of life. While late effects
with palliative doses of RT have been rare, advances in systemic
therapies, including immunotherapy, may lead to patients living
longer and developing late side effects.
During or shortly after completion of RT, patients commonly
experience pain flare at the treated metastatic site. Incidence of
pain flare is 30%–40% and dexamethasone has been shown to
be a feasible prophylactic against pain flare. A recent double-
blind, randomized, placebo-controlled, phase 3 trial38 showed
dexamethasone-reduced RT-induced pain flare in the treatment
of painful bone metastases, such as mSCC. The study identified
583
that 29 of 148 patients in the dexamethasone group had pain flare
in days 0–5 and 46 of 150 patients had pain flare in the placebo
group. No difference in pain flare was identified between the two
groups on days 6–10. Other common acute side effects of RT are
fatigue, and location-specific toxicities such as esophagitis and
mucositis when treating cervical spine, nausea, and diarrhea
when treating thoracic or lumbar spine. Thus, treating selected
patients prophylactically with antiemetics and post-treatment
with mouthwash containing benzydamine hydrochloride may
be reasonable. 39 Late toxicity of RT-induced spinal cord injury
is very rare40 with palliative doses of RT being well below spinal
cord tolerance.41,42
Reirradiation
Reirradiation can be considered for patients who present with in-
field recurrences. Risk of RT induced myelopathy is very low if
there is duration of at least 6 months between two courses of RT
and the cumulative biologically effective dose to the spinal cord
is less than 120 Gy (2).43,44 The effect of reirradiation on motor
function in the former analysis was comparable with ambulatory
capacity before reirradiation. Thus, retreatment is possible within
limits of spinal cord tolerance, depending on the total dose to
spinal cord, fractionation regimen, and technique of RT delivery.
Stereotactic body radiation therapy
According to the Canadian Association of Radiation Oncology
task force, SBRT has been defined as the “precise delivery of
highly conformal and image-guided hypofractionated exter-
nal beam radiotherapy, delivered in a single or few fraction(s),
to an extracranial body target with doses at least biologically
equivalent to a radical course when given over a protracted
conventionally (1.8–3.0 Gy/fraction) fractionated schedule.”45
The main advantage of SBRT is that a short and convenient
treatment course can be used to deliver high-dose RT that
can provide durable treatment responses. SBRT delivers abla-
tive and often higher biologic-equivalent doses of RT than are
achievable with conventionally fractionated radiation, which
often translates into superior local tumor control compared
with conventional RT.46,47
The role of SBRT as primary treatment in mSCC has been
historically contraindicated. SBRT is not indicated for upfront
treatment of mSCC (ESCC Grades 2 and 3) given the target’s
proximity to the spinal cord which limits the delivery of a
therapeutic dose while meeting spinal cord constraints, and
time required for planning, which is not feasible in an emer-
gency setting. As per the NOMS framework, consideration can
be given to patients, who present mechanically stable spine but
radioresistant tumors such as renal cell carcinoma, to undergo
decompression surgery followed by post-operative SBRT.48
Patients with long life expectancy and oligometastatic disease
are considered to be good candidates for post-operative SBRT
to optimize long-term local tumor control. Typical SBRT dose
fractionations are 18–24 Gy × 1, 12 Gy × 2, 8–10 Gy × 3, or 6 Gy ×
5, and further details about the technique can be found in other
resources.49,50
Outcome
Pre-treatment neurologic function is the strongest predictor
of function post definitive treatment.51 Other determining fac-
tors are length of time during which deficits developed (sud-
denly vs. over weeks), tumor response to RT, and available of
584
post-treatment systemic therapies. Functional outcomes after
definitive treatment of mSCC can be reliably measured by assess-
ment of patients’ pain and performance status. Typically, the
0–10-point Numerical Rating Scale is used in a pre-treatment
setting and the same scale should be used as the outcome mea-
sure for pain intensity after treatment of spinal cord injury. 52 Pain
may be masked by use of dexamethasone and/or other analgesics;
however, reliable improvement is noted.35 Inpatient and outpa-
tient rehabilitation are important components of management
after primary treatment of mSCC in a post-treatment setting.53
A major component of rehabilitation is focus on improvement
of bladder and bowel function as neurogenic status is not only
uncomfortable and a health hazard but can also interfere with
patients’ sense of dignity. Bowel and bladder regimens can be for-
mulated with nursing staff, ensuring patient comfort, continence,
and convenience.
Rehabilitation program should be designed with an MDT team
of physical therapists (PT), occupational therapists (OT), rehab
nurses, social workers, psychosocial, and palliative teams.20 PTs
help patient progression from bed to ambulation, with emphasis on
facilitation of functional patterns of activity. OTs assist in improv-
ing patients’ independence in their activities of daily living, such
as bathing, eating, and grooming, with eventual goal of successful
reintegration into the community. Specialized oncology and rehab
nurses provide high-level care in prevention and caregiver educa-
tion regarding decubitus ulcers in severely immobilized patients.20
After discharge from hospital, patients should continue to
receive rehabilitation services at home, inpatient rehab facilities,
or nursing facilities. Goals regarding quality of life should be dis-
cussed with patients and family members. Patients with mSCC
also have psychosocial concerns that are practical (e.g., finances,
caregiver ability), emotional (e.g., coping with diagnosis), social
(e.g., family distress and burnout), and spiritual (e.g., prognosis,
isolation, grief) in nature. Early referral to psychosocial oncology
services has shown to be of significant. 54 Ongoing follow-up after
definitive treatment of mSCC should ideally be coordinated in a
multidisciplinary fashion, just as the decision-making process.
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static cancer: a randomised trial. Lancet (Lond, England) Aug 20–26
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62
CLINICAL FEATURES AND MANAGEMENT OF SUPERIOR VENA CAVA SYNDROME

Álvaro Sanz, María Luisa del Valle and Carlos Centeno

Contents
Introduction........................................................................................................................................................................................................................587
Etiology................................................................................................................................................................................................................................587
Clinical manifestations..................................................................................................................................................................................................... 588
Diagnosis............................................................................................................................................................................................................................. 588
Classification...................................................................................................................................................................................................................... 588
Treatment........................................................................................................................................................................................................................... 588
Medical management..................................................................................................................................................................................................590
Chemotherapy..............................................................................................................................................................................................................590
Radiation therapy.........................................................................................................................................................................................................590
Stent placement............................................................................................................................................................................................................591
Surgery...........................................................................................................................................................................................................................591
Overview of clinical management..................................................................................................................................................................................591
References............................................................................................................................................................................................................................591

Introduction bronchus and insert into right atrium. It is joined posteriorly by

the azygos vein as it loops over the right main-stem bronchus. It is
Superior vena cava syndrome (SVCS) results from the impair- a thin-walled vessel and the blood flows with relatively low intra-
ment of blood flow through the superior vena cava into the right vascular pressure (2–8 mmHg). 3,4 Thus, when the superior vena
atrium. Traditionally, SVCS has been explained as a medical cava is compressed, it slows or even interrupts local flow lead-
emergency. However, most cases are due to a subacute progres- ing to an increase in the intravenous pressure (to 20–40 mmHg).
sion of the disease and that the number of patients who die exclu- In this case, blood flow looks for a collateral vascular network to
sively from SCVS is low. the inferior vena cava or the azygos system. This collateral flow
dilates with the time and may accommodate to the needs of the
Etiology superior vena cava in a few weeks.
The severity of the syndrome depends on the rapidity of onset,
The spectrum of underlying conditions associated with SVCS has the relevance of the obstruction, and its location. 5 The more rapid
shifted from most cases caused by infectious diseases more than the onset, the more severe the symptoms, because the collateral
50 years ago to a preponderance of malignant disorders. Nowadays, veins do not have time to distend to accommodate the increased
one of every three SCVCs is due to thrombosis. It can be explained blood flow. If the obstruction is above the entry of the azygos vein,
because of the increased use of intravascular devices as intra-cava the syndrome is less pronounced because the azygos system—
catheters.1 The most common malignant cause of SVCS is non- that maintains anterograde flow—can readily distend to accom-
small cell lung cancer (NSCLC), followed by small cell lung carci- modate the shunted blood, allowing a reduction of the venous
noma (SCLC) (Table 62.1). Other malignant causes are lymphoma pressure in the head, arms, and upper torso. If the obstruction is
(the most common cause in patients less than 50 years old), germ- below the entry of the azygos vein, more florid and severe symp-
cell tumors, thymoma,2 and other tumors with direct mediastinal toms and signs are seen because blood pressure increases, and
progression (as mesothelioma or esophageal cancer) or those from the azygos flow becomes retrograde to return to the heart via the
any other origin that develop metastatic mediastinal lymph nodes. upper abdominal veins and the inferior vena cava.
Palliative care patients may suffer SVCS because of medias-
tinal tumors but from intravascular devices as well, as patients
with chronic renal failure that require maintained dialysis, or
advanced cancer patients with previously implanted intravascu- TABLE 62.1 Malignant Causes of Superior Vena Cava
lar devices to receive parenteral anticancer drugs as Port-a-Cath. Syndrome
SVCS results from the compression of the superior vena cava Nonsmall cell lung cancer 50%
by tumors arising in the mediastinum or in the right main or Small cell lung cancer 25%
upper lobe bronchus or by large-volume mediastinal nodes (most Lymphoma 10%
commonly right paratracheal lymph nodes). The superior vena Metastatic tumor <10%
cava carries blood to the hearth from the head, arms, and upper Germ-cell tumor <5%
torso. It is formed by the junction of the left and right brachio-
Thymoma <5%
cephalic veins in the mid-third of the mediastinum and extends
Other tumors <5%
caudally for 6–8 cm, coursing anterior to the right main-stem

587
588
Clinical manifestations
SVCS, as syndrome, is characterized by the concurrence of symp-
toms and signs that are coincident and causally related. The most
frequent manifestations that prompt suspicion include swelling of
the face, neck, upper trunk and extremities, cyanosis, coughing,
venous ingurgitation, hoarseness, and dyspnea (Table 62.2).6 Most
of them of are not SVCS specific: dyspnea, cough, or headache, for
instance, may be caused directly by the tumor that occludes the
superior vena cava. Severe complications include neurologic and
visual disturbances,7 dyspnea due to airflow obstruction, or even
hemodynamic compromise.
When the patient develops enough collateral circulation,
the symptoms and signs may stabilize or improve although
several stigmata as the presence of varicose veins may be
permanent.
Diagnosis
The first suspicion of SVCS usually came from the patient itself
or from proxies that refer a change in personal appearance with
facial, cervical, and supraclavicular swelling and sometimes ery-
thema or cyanosis. In severe cases, respiratory and neurologic
manifestations may appear. After the recognition of symptoms
and signs, the initial evaluation should include radiologic stud-
ies looking for mediastinal masses and/or thrombosis of the
superior vena cava. CT scan is the most recommended study to
diagnose SVCS because of its sensibility (>90%) and specificity
(>95%) in the diagnosis of SVCS. CT scan helps to evidence the
presence of masses, the patency of veins, the presence of thrombi,
and the anatomy of involved mediastinal nodes.8 Modern digital
technology allows to do a 3D reconstruction of the venous flow
combining CT scan and digital phlebography. It might also assist
in radiotherapy planning or act as a baseline for assessment of
response to treatment. MRI is an alternative in patients in whom
it is not possible to adequately perform a CT scan due to allergy
to iodinated contrasts. Nowadays, phlebography of superior vena
cava is almost limited to patients that will receive intravascular
therapy.
When there is radiological evidence of tumor in the mediasti-
num, a histological diagnosis should be obtained prior to initiat-
ing therapy.9–11 As most SVCSs are due to cancer and treatment
will depend on tumor histology,12 clinical recommendations
TABLE 62.2  Signs and Symptoms and in SVCS
Signs and Symptoms of Mild or Moderate SVCS
Swelling of the face and neck 80%
Distended neck veins 60%
Distended chest veins 55%
Swelling of the extremities 50%
Dyspnea 50%
Cough 50%
Signs and Symptoms of Severe SVCS
Syncope 10%
Headache 10%
Dizziness <10%
Confusion <5%
Visual symptoms <5%
Hoarseness/Stridor <5%
Textbook of Palliative Medicine and Supportive Care
highlight the need of histologic diagnosis before any specific
treatment is started.13 The protocol for biopsy is based on the
location of the tumor, the performance status of the patient, and
the clinical expertise. It may include bronchoscopy, biopsy of
superficial lymph nodes, or needle biopsy of a lung mass or medi-
astinal nodes using either CT or ultrasound guidance. In some
patients, more aggressive interventions such as mediastinoscopy,
mediastinotomy, video-assisted thoracoscopy, or thoracotomy
may be required. Complications of such procedures do not seem
to be increased because of the presence of SVCS.14 Any previous
vascular therapeutic intervention may influence the possibility
of interventions to reach histologic diagnosis as it may require
maintained anticoagulation.
SVCS secondary to venous thrombosis can be suspected when
there is evidence of an intravascular device, and there is a rapid
evolution even to complete superior vena cava obstruction. CT
scan may help to define the patency of flow, the presence of
thrombus, and its location.
Although prompt clinical attention is important, SVCS is rarely
a clinical emergency as it usually develops as a subacute process
with no sudden development of severe clinical manifestations,
giving time to clinical, radiological, and histological diagnosis.15
In fact, up to 75% of patients present symptoms and signs for over
a week before seeking medical attention.16 In addition, SVCS is
rarely lethal by itself; cancer patients with SVCS (even those with
advanced and refractory tumors) do not die because of this syn-
drome but from the extent of underlying disease. Only in excep-
tional cases, if tracheal obstruction or cerebral edema is present,
SVCS could be considered as a real oncological emergency requir-
ing immediate therapy. Anyway, oncologic treatment prior to
definitive diagnosis does not seem to be justified (Figure 62.1).17
Classification
Yale classification has been proposed to define the severity of
SVCS and to adapt the treatment.18 It is based in the fact that
sign and symptoms are usually associated with non-severe SCVS
(Table 62.3). Severe and life-threatening SVCS corresponded with
Grades 3, 4, and 5 (lethal) of this Yale classification. This scale
is adapted to Common Terminology Criteria for Adverse Events
in Oncology. Grade 1: mild; asymptomatic or mild symptoms;
intervention not indicated. Grade 2: moderate; minimal, local, or
non-invasive intervention indicated. Grade 3: severe or medically
significant but not immediately life-threatening. Grade 4: life-
threatening consequences; urgent intervention indicated. Grade
5: death related to the event.19 However, it has not been validated
prospectively so far.
The Kishi scoring system (Table 62.4) helps to identify severe
SVCS—with a score of at least five, corresponding to Grades 3
and 4 of Yale—where there is a consensus on the need of urgent
intravascular therapy.20
Treatment
Although we present SVCS in advanced or palliative care patients
as one specific chapter, it could present in patients with different
profile; it could have different causes (tumor, thrombi, or both),
different manifestations, and evolutions. For instance, it can be
some dissociation between severe radiologic appearance and mild-
to-moderate clinical manifestations. In these cases, the trend is
that decision-making be based more on the clinical manifesta-
tions than on radiology. On the other hand, several centers have
Clinical Features and Management of Superior Vena Cava Syndrome 589

FIGURE 62.1  Initial approach to patients with newly diagnosis of SCVS.

good experience in urgent radiologic interventions, but in other TABLE 62.4  Kishi Scoring System
places these options are not directly available. So, the final recom-
Manifestation (Signs/Symptoms) Score
mendation for any case should be not only clinically individual-
ized according to the conditions of the patient (Table 62.5) but Neurologic symptoms
supported on the experience and the medium where the patient Awareness disorders/coma 4
is treated. Visual disorders/headache/vertigo/memory disorders 3
An increasing proportion of episodes of SVCSs are induced by Mental disorders 2
the presence of thrombi on implantable venous systems. In these Malaise 1
cases, treatments are directed to solve the thrombus. In many Thoracic and pharyngo-laryngeal signs and symptoms
cases, anti-thrombotic drugs are not efficacious enough and the Orthopnea/laryngeal edema 3
patient requires that the device be removed.21
Stridor/dysphagia/dyspnea 2
Both radiological (95%) and clinical (85%) efficacy of endovas-
Cough/pleuresy 1
cular stents is impressive, as it uses to enhance diameter of the
Facial signs
vein in around one centimeter. It is related with an improvement
Lip edema/nasal obstruction/epistaxis 2
Facial edema 1
TABLE 62.3  Yale Scale for SVCS Vessel dilation
Grade Severity Manifestations Venous dilation: face/neck/arms 1

Grade 0 Asymptomatic Radiographic evidence of superior vena Mild ≤2; moderate 3–4; severe ≥5.
Note: Thoracic symptom and sign could be directly produced by the primary tumor
cava compromise without signs of
that induces the SVCS.
symptoms
Grade 1 Mild Edema and/or venous ingurgitation of
head and neck, cyanosis almost immediate of symptoms due to increased venous pressure,
Grade 2 Moderate Facial edema with mild compromise of
as headache; manifestations due to edema may last for a few days.
other organs: head and neck
However, these treatments require an adequate environment
movements, dysphagia, visual
and expertise.22 And even in this scenario, it is associated with
disturbances
a mortality of even 2%–3% due to migration of the stent into the
auricula, arrythmias, cardiac tamponade, bleeding, or rupture of
Grade 3 Severe Headache or dizziness secondary to
the vena cava that is superior of what is described by the SVCS
cerebral edema, mild-to-moderate
itself. Otherwise, in malignant SCVS, a good palliation may be
laryngeal edema, syncope after bending
achieved by the treatment specifically directed against the tumor
because of diminished cardiac reserve
as it may alleviate symptoms and prolong survival. Unless airway
Grade 4 Life-threatening Confusion or obtundation due to
obstruction or cerebral edema is present, delay of radiotherapy
cerebral edema, laryngeal edema with
and/or chemotherapy until the histological diagnosis does not
stridor, hemodynamic compromise with
relevantly modify the outcome (Figure 62.2).23 Clinically relevant
syncope, hypotension, or renal failure
SVCS can develop in more than 10% of patients with right-sided
Grade 5 Death
malignant intrathoracic tumors. In these patients, the treatment
590
TABLE 62.5 Variables that Influence the Treatment in
Patients with SVCS
Performance status and comorbidity
Prognosis of the patient
First presentation vs. relapse after therapy
Cause of the obstruction: external compression (tumoral/no tumoral) or
endovascular pathology (thrombosis)
Severity of symptoms and signs
Velocity of evolution
Severity of obstruction: percentage of the diameter of the vena cava
compromised and obstruction of other tributaries, as the azygous
Situation of the obstruction
Presence of collateral flow
Stage of disease
Expected short-term and medium-term evolution
Expectations of response or improvement with the different therapeutic
options
Evidence of response to therapy
Availability and expertise in the application of treatments
Possibility and availability of second chances and/or rescues therapies
Patient’s preferences
directed to relieve SVCS is commenced at the same time as che-
motherapy and/or radiotherapy. In patients with SVCS relapse
after the initial antitumor treatment, second-line therapy is
hardly successful.
Both clinical and radiological response assessment can be
done. Usually, signs and symptoms that appear initially are those
that improve more slowly. Anyway, the evolution of symptoms
and signs is not always parallel to the resolution of the obstruc-
tion of superior vena cava.24 Some patients may present clinical
improvement of SVCS even when vein patency is not equally
improved. Problems derived from vein blood pressure as neck
vein ingurgitation or even headache may disappear almost imme-
diately when vein flow is restarted. Facial, cervical, and brachial
blood flow may need hours or even days to improve. In patients
with persistent stop, collateral vessels dilate with time,25 and this
collateral flow may remain indefinitely as varicose veins in torso
even when SVCS resolves.
FIGURE 62.2  Treatment of malignant SVCS according to histologic diagnosis (CT: chemotherapy; RT: radiotherapy).
Textbook of Palliative Medicine and Supportive Care
Medical management
Supportive therapies are empiric and are not studied enough to
become evidence-based. They could be used in almost any SVCS
with clinical manifestations—Grade 1 or more in the Yale scale
(Table 62.4). Postural maneuvers seem to help to reduce edema,
since a raised head may help blood to flow better through the supe-
rior vena cava to the heart and are free of side effects.26 Corticoids
may reduce edema and prevent radiation-induced inflammation.
Anticoagulants are indicated—if there is not an evident risk of
bleeding—when there is evidence of thrombi and may prevent fur-
ther complications favored by flow obstruction in major vein in a
patient with active cancer and/or the presence of an intravascular
device. Oxygen may play a role only to alleviate dyspnea in respira-
tory insufficiency. Diuretics may reduce fluids, but they are not free
of side effects and their real impact is unclear.27
With catheter-associated thrombosis, usual practice is
directed to do thrombolysis and anticoagulation with catheter
withdrawal. Anyway, this recommendation should be individu-
alized since a few patients may require maintaining a catheter
that retains patency as collateral flow may progressively reduce
the initial impact of SVCS.
Chemotherapy
Response rates to chemotherapy in sensitive tumors approach
80%,28,29 and it is the treatment of choice in SVCS caused by
SCLC, lymphoma, and germ-cell tumors. In these cases, SCVS is
not an independent prognostic factor, and its presence does not
change the treatment approach. In tumors less chemo-sensitive, as
NSCLC, chemotherapy can relieve SVCS in 60% of the patients.30
Both in SCLC and NSCLC, recurrences of SVCS after response to
chemotherapy can be observed in 20% of patients.
Radiation therapy
When the obstruction of the superior vena cava is caused by a
tumor refractory to chemotherapy, radiation therapy remains
effective as symptomatic treatment.31,32 Overall, SVCS patients
respond to radiotherapy in 60% of NSCLC and 80% of SCLC.
The way to give this treatment will depend on histology, previous
therapy, extent of disease, prognosis, and performance status.33
Many fractionation schemes have been used, 34,35 with total doses
ranging from 6 to 8 Gy in a single fraction to 50 Gy in 25 fractions.
In patients with short life expectancy and poor performance sta-
tus, a short-term schedule would be recommended.
Clinical Features and Management of Superior Vena Cava Syndrome
In lung cancer, there appears to be no distinction between
radiotherapy and chemotherapy with regard the speed of pal-
liation. Patients with limited-stage SCLC or locally advanced
NSCLC may receive initially both therapies simultaneously.
Median time to response may range from few days to three weeks.
Stent placement
There are different endovascular therapies that could be used
to treat SCVS in advanced patients. 36 Chemical and mechani-
cal thrombolysis is limited to recent “soft” thrombi, in the
first 5 days from diagnosis. These techniques should be used
cautiously because it is associated to a relevant of bleeding risk.
Other options of endovascular treatments are angioplasty and
stent. 37 Angioplasty is used scarcely in this thin vein for the risk
of rupture and the high probability of relapse. Sometimes it could
be done in severe obstructions to allow the pass of a guide previ-
ously to the insertion of a stent.
There is a rapid increase in the use of intravascular expand-
able stent to treat the occlusion of superior vena cava. 38–40 This
procedure allows immediate restoration of the normal flow with
rapid resolution of symptoms.41,42 Radiographic response rates
with intraluminal stenting reach 95%, with clinical response in
85% of patients. 38,39,43 The proportion that relapses following stent
placement approaches 10%, frequently due to thrombus within
the stent, but this percentage depends of the length of follow-
up: with longer follow-up, even a 40% of re-stenosis is described.
Anyway, there is no agreement on the duration of anticoagulant
or antiaggregant therapy after stent placement to minimize the
probability of re-occlusion. Stenting should not be performed
on an intramural thrombus as it increases the risk of migration.
When SCVS obstruction affects both brachiocephalic veins, it is
required to unstop only one of them.
There is no agreement about the optimal timing of stenting.41
It is not recommended as a first choice for a majority of patients
when a response in the SVCS is expected when anticancer ther-
apy is started as stenting is associated with complications in a
10%–20% of patients, almost half of them severe, and a mor-
tality of 2%–3% due to migration of the stent into the auricula,
arrythmias, cardiac tamponade, bleeding, or rupture of the vena
cava,44 but this mortality is related both to stent and to the ade-
quate selections of cases: patients with poor performance status
and comorbidity have a higher risk of complications. Anyway,
in patients with tumors that are initially resistant or became to
treatment with moderate-to-severe symptoms and in the few
cases with severe and rapidly progressive SVCS, stent is the most
rapid option to solve SVCS.45
Surgery
There are just a few reports on palliative surgery for malignant
SVCS and none of them in palliative patients as the indications
are limited by the prognosis of patients and the risk of severe
complications.46
Overview of clinical management
In patients with good performance status, several variables must
be considered to select the best treatment. In tumors highly
sensitive to chemotherapy—as lymphoma, germ-cell tumors,
or SCLC—conventional systemic and local therapy produce a
quick response and improve survival and in many of them could
potentially curative. In these cancers, radiotherapy could be
included as part of the treatment to improve local control. In
591
KEY LEARNING POINTS
• The great majority of cases of SVCS in palliative
care are due to cancer; in these cases, a histologic
diagnosis should be established prior to initiating
therapy. The second cause is thrombosis second-
ary to intravascular devices.
• Most cases of SVCS trend to improve with time
as superior vane cava blood flows throughout col-
lateral veins. Emergency treatment is almost lim-
ited to a few cases of cerebral edema or tracheal
obstruction.
• SVCS by itself does not modify the prognosis of
cancer. The prognosis of SVCS is superimposable
con the prognosis of cancer.
• Anti-cancer therapies (chemotherapy and/or
radiotherapy) are the corner stone of initial treat-
ment of a majority of cancer-induced SVCS.
• Stent insertion provides rapid relief in patients
with severe life-threatening SVCS and in patients
who are or become refractory to anti-cancer
therapy.
patients with chemo-sensitive disease and poor performance
status and/or when cure is not possible chemotherapy, as exten-
sive-stage SCLC, chemotherapy remains as a primary palliative
resource.47
In other tumors where the benefit of chemotherapy is not so
impressive, as in NSCLC, systemic chemotherapy with or without
radiotherapy may produce relevant palliation of symptoms. There
are few data on targeted therapy or immunotherapy in these
cases. In patients with SVCS due to tumor chemo-resistance, pal-
liative radiotherapy is a good option for SCVS even in advanced
patients with limited prognosis. Stent insertion is a more aggres-
sive approach than single-fraction palliative radiotherapy and is
rarely recommended for patients with very poor survival expec-
tancy. There are no data supporting a schedule or timing for the
combination of treatments as radiotherapy and stents.
References
1. Wilson LD, Detterbeck FC, Yahalom J. Superior vena cava syndrome
with malignant causes. N Engl J Med 2007;356:1862–1869.
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4. Marini TJ, Chughtai K, Nuffer Z, et al. Blood finds a way: pictorial
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6. Landis BN, Bohanes P, Kohler R. Superior vena cava syndrome. CMAJ
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7. Betchtold RE, Wolfman NT, Karstaedt N, Choplin RH. Superior vena
caval obstruction: detection using CT. Radiology 1985;157:485–487.
8. Sheth S, Ebert MD, Fishman EK. Superior vena cava obstruction evalu-
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gencies. Cardiology 2017;138:147–158.
10. Khan UA, Shanholtz CB, McCurdy MT. Oncologic mechanical emer-
gencies. Hematol Oncol Clin N Am 2017;31:927–940.
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12. Bagheri S, Rahim M, Rezaeetalab F, et al. Malignant superior vena cava
syndrome: is this a medical emergency? Ann Thorac Cardiovasc Surg
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13. Porte H, Metois D, Finzi L, et al. Superior vena cava syndrome of
malignant origin: which surgical procedure for which diagnosis? Eur
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14. López-Riverol O, Camacho-Limas CP, Gerson-Cwilch R. Síndrome de
vena cava superior asociado a neoplasia. Consideraciones multidisci-
plinarias y tratamiento. Rev Hosp Jua Mex 2017;84:77–82.
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genic carcinoma: is this an oncologic emergency? Austral Radiol
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obstruction: is it a medical emergency? Am J Med 1981;70:1169–1174.
17. Kvale PA, Selecky PA, Prakash UB. Palliative care in lung cancer:
ACCP evidence-based clinical practice guidelines (2nd edition). Chest
2007;132:368S–403S.
18. Yu JB, Wilson LD, Detterbeck FC. Superior vena cava syndrome – a
proposed classification system and algorithm for management. J
Thorac Oncol 2008;3:811–814.
19. U.S. Department of Health and Human Services. Common
Terminology Criteria for Adverse Events (CTCAE). Version 5.0.
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20. Kishi K, Sonomura T, Mitsuzane K, et al. Self-expandable metallic
stent therapy for superior vena cava syndrome: clinical observations.
Radiology 1993;189:531–535.
21. Stockton PA, Ledson MJ, Walshaw MJ. Persistent superior vena cava
syndrome due to totally implantable venous access systems. J R Soc
Med 2001;94:584–585.
22. Ganeshan A, Quen Hon L, Warakaulle DR, et al. Superior vena
caval stenting for SVC obstruction: current status. Eur J Radiol
2009;71:343–349.
23. Chen JC, Bongard F, Klein SR. A contemporary perspective on superior
vena cava syndrome. Am J Surg 1990;160:207–211.
24. Ahmann FR. A reassessment of the clinical implications of the supe-
rior vena caval syndrome. J Clin Oncol 1984;2:961–969.
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sis, and treatment. Am J Crit Care 1992;1:54–64.
26. Rowell NP, Gleeson FV. Steroids, radiotherapy, chemotherapy and
stents for superior vena caval obstruction in carcinoma of the bron-
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29. Würschmidt F, Bünemann H, Heilman HP. Small cell lung cancer
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30. Tanigawa N, Sawada S, Mishima K, et al. Clinical outcome of stent-
ing in superior vena cava syndrome associated with malignant
tumors. Comparison with conventional treatment. Acta Radiol
1998;39:669–674.
31. Davenport D, Ferree C, Blake D, Raven M. Response of superior vena
cava syndrome to radiation therapy. Cancer 1976;38:1577–1580.
32. Rodríguez CI, Njo KH, Karim AB. Hypofractionated radiation ther-
apy in the treatment of superior vena cava syndrome. Lung Cancer
1993;10:221–228.
33. Levitt SH, Jones TK, Bogardus CR. Treatment of malignant superior
vena caval obstruction. a randomized study. Cancer 1969;24:447–451.
34. Chan RH, Dar AR, Yu E, et al. Superior vena cava obstruction in small-
cell lung cancer. Int J Radiat Oncol Biol Phys 1997;38:384–387.
35. Amstrong BA, Perez CA, Simpson JR, Hederman MA. Role of irradia-
tion in the management of superior vena cava syndrome. Int J Radiat
Oncol Biol Phys 1987;13:531–539.
36. Kalra M, Sen I, Gloviczki P. Endovenous and operative treatment of
superior vena cava syndrome. Surg Clin N Am 2018;98:321–335.
37. Rachapalli V, Boucher LM. Superior vena cava syndrome: role of the
interventionalist. Can Assoc Radiol J 2014;65:168–176.
38. Lanciego C, Pangua C, Chacón JI, et al. Endovascular stenting as the
first step in the overall management of malignant superior vena cava
syndrome. AJR 2009;193:549–558.
39. Hague J, Tippett R. Endovascular techniques in palliative care. Clin
Oncol (R Coll Radiol) 2010;22:771–780.
40. Urruticoechea A, Mesia R, Domínguez J, et al. Treatment of malig-
nant superior vena cava syndrome by endovascular stent inser-
tion. Experience on 52 patients with lung cancer. Lung Cancer
2004;43:209–214.
41. Nicholson AA, Teles DF, Arnold A, et al. Treatment of malignant supe-
rior vena cava obstruction: metal stents or radiation therapy. J Vasc
Intervent Radiol 1997;8:781–788.
42. Wilson E, Lynn A, Khan S. Radiological stenting provides effective
palliation in malignant central venous obstruction. Clin Oncol (R Coll
Radiol) 2000;12:331.
43. Watkinson AF, Yeow TN, Fraser C. Endovascular stenting to treat
obstruction of the superior vena cava. BMJ 2008;336:1434–1437.
44. Sobrinho G, Aguiar P. Stent placement for the treatment of malignant
superior vena cava syndrome—a single-center series of 56 patients.
Arch Bronconeumol 2014;50:135–140.
45. Kuo TT, Chen PL, Shih CC, et al. Endovascular stenting for end-stage
lung cancer patients with superior vena cava syndrome post first-line
treatments: a single-center experience and literature review. J Chin
Med Assoc 2017;80:482–486.
46. Spaggiari L, Magdeleinat P, Kondoc H, et al. Results of superior vena
cava resection for lung cancer: analysis of prognostic factors. Lung
Cancer 2004;44:339–346.
47. Bowcock SJ, Shee CD, Rassam SM, Harper PG. Chemotherapy for can-
cer patients who present late. BMJ 2004;328:1430–1432.
63
ACUTE PAIN AND MANAGEMENT

Mellar P. Davis

Contents
Introduction........................................................................................................................................................................................................................593
Acute pain pathways..........................................................................................................................................................................................................594
Cellular and molecular mechanisms of acute pain.....................................................................................................................................................594
Peripheral signals.........................................................................................................................................................................................................594
Central mechanisms to acute pain...........................................................................................................................................................................594
Recent neuroanatomical correlates with potential clinical importance.................................................................................................................595
Acute pain syndromes.......................................................................................................................................................................................................595
Assessing acute pain and pain responses................................................................................................................................................................596
Management of acute pain.........................................................................................................................................................................................596
Pharmacologic management of acute pain.............................................................................................................................................................596
Preventing acute postoperative pain........................................................................................................................................................................597
Patient-controlled analgesia for acute and postoperative pain...........................................................................................................................597
Managing acute postoperative pain in the opioid tolerant..................................................................................................................................598
Multimodality analgesia and innovations in managing acute postoperative pain..........................................................................................598
Bone and joint pain......................................................................................................................................................................................................599
Acute dosing strategies for acute pain in the emergency department..............................................................................................................599
Opioid dosing strategies for acute severe pain in cancer.................................................................................................................................... 600
Acute neuropathic pain...............................................................................................................................................................................................601
Breakthrough pain.......................................................................................................................................................................................................601
Acute pain management in organ failure......................................................................................................................................................... 602
Opioid-sparing strategies.................................................................................................................................................................................... 602
Different opioids and routes........................................................................................................................................................................................... 602
Tapentadol.................................................................................................................................................................................................................... 602
Buprenorphine....................................................................................................................................................................................................... 602
Fentanyl................................................................................................................................................................................................................... 602
Intranasal opioids for acute and breakthrough pain............................................................................................................................................ 603
Intranasal fentanyl................................................................................................................................................................................................. 603
Intranasal and sublingual sufentanil.................................................................................................................................................................. 603
Intranasal hydromorphone.................................................................................................................................................................................. 603
Nonopioid analgesics and adjuvants for acute pain............................................................................................................................................. 603
Classic NSAIDs...................................................................................................................................................................................................... 603
Meloxicam.............................................................................................................................................................................................................. 603
Ketorolac................................................................................................................................................................................................................. 603
Acetaminophen..................................................................................................................................................................................................... 604
Anticonvulsants................................................................................................................................................................................................................. 604
Gabapentin and pregabalin....................................................................................................................................................................................... 604
Ketamine....................................................................................................................................................................................................................... 604
Dexmedetomidine....................................................................................................................................................................................................... 605
Summary and discussion................................................................................................................................................................................................. 605
References........................................................................................................................................................................................................................... 605

Introduction attributable meaning to the pain. An extreme example of geneti-

Acute pain is a normal reaction to noxious stimuli that alerts
individuals to tissue damage and protects them from further tis-
sue damage. Individual pain experiences are controlled by several
genetically determined factors, neuroplasticity, and long-term
potentiation caused by afferent traffic which modulates the func-
tion of sensory system, psychologic state, and is influenced by
cally programmed pain involves absence of pain inherited in a
mutation of certain sodium channels.1–4 Loss of pain sensitivity
leads to progressive self-inflicted tissue damage while a gain of
pain sensitivity limits activity and reduces quality of life.
Historically, Henry Beecher provided some of the fundamen-
tals to acute pain concepts. His experience during World War II
suggested that acute pain was not proportional to tissue damage

593
594
and that the emotional experience of pain profoundly modulated
nociceptive input and ultimately the severity of pain.5 Second, he
found that over a range of conditions, 35% of patients improved
with placebo therapy.6 Such responses might be explained by clas-
sic conditioning response expectations (which leads to altered
endocannabinoid and opioid neurotransmission with anticipated
analgesia), psychoneuroimmunology, regression to the mean
(high intense pain over time tends to improve or regress to the
mean regardless of therapy), and shift response as patients adapt
to their pain.7–9 One of the lasting important findings of Henry
Beecher was that acute pain is widely variable as a human experi-
ence where it is a rather uniformly predicted in animals. This is
due to the differences in experimental designs. Animal studies
most frequently use nocifensive responses (spinal cord reactions
to pain) to measure pain, whereas human studies involve operant
conditioning models.
Acute pain pathways
Acute pain has several presentations: primary and secondary
hypersensitivity, allodynia (pain experienced with non-noxious
stimuli), and hyperalgesia (increased pain severity or duration
with noxious stimuli), which promotes guarding the affected
part, and shields damaged tissues from further injury.10 An area
of secondary hypersensitivity extends beyond the damaged area
due to central nervous system (CNS) facilitation through rostral
ventromedial medulla to spinal cord nociception input. Acute
visceral pain if severe will refer pain to somatic sites, due to
convergence of afferent input within the same dorsal horn seg-
ment.11 The somatosensory experience of pain evolves to an affect
response through activation of limbic nuclei, amygdala, and
nucleus accumbens and stores memory within the hippocam-
pus. In addition, pain inhibits pain. NK1 containing superficial
neurons send signals through the contralateral spinothalamic
tracts to the parabrachial nuclei within the brainstem which
sends signals downward to the periaqueductal gray and rostral
ventromedial medulla. The “off” cells within the rostral ventro-
medial nuclei send signals through the dorsal funiculus to com-
plete the cycle and “shut the gate” on further nociceptive traffic.
Supraspinal sites such as the anterior cingulate gyrus, dorsolat-
eral prefrontal cortex and amygdala, and nucleus accumbens also
send signals to the periaqueductal gray and rostral ventromedial
medulla to influence the pain experience.11–13
Cellular and molecular
mechanisms of acute pain
Peripheral signals
Transient receptor potential vanilloid (TRPV-1) receptors on
unmyelinated C-fibers and poorly myelinated type A-delta
fibers are transducers of noxious heat stimuli and activated by
capsaicin and temperatures greater than 43°C.11,14 These chan-
nels expressed on unmyelinated neurons with mu receptors are
upregulated in neuropathic and bone pain, while mu receptors
are downregulated in neuropathic pain. Secondary vanilloid
receptors (TRPV-2,3) are activated by heat intensities at which
TRPV-1 is silent (greater than 50°C) and may contribute to pain.
These channels are upregulated by inflammatory cytokines and
proalgesic mediators (protons, neurotrophins, and bradykinins)
and hence important mediators of acute inflammatory pain.
Sodium and calcium channels, in addition to TRPV channels, are
Textbook of Palliative Medicine and Supportive Care
also upregulated by neuropathic damage.15 TRPM-8 channels are
cold-sensitive channels responsive to methanol. These channels
are modulated by other channels including voltage-gated sodium
and potassium channels and also may contribute to the experi-
ence of acute pain.10,16–20
Because so many channels and receptors are involved in medi-
ating acute pain, it is unlikely that single analgesic targets will
significantly relieve acute pain in all patients.21–23
Mechanical transducers of pain include acid sense ion chan-
nels (ASICs), TRPV-2 and TRPV-4 channels.24–26 The ASIC
channels are found on unmyelinated fibers in bone marrow and
trabecular bone and are in part responsible for bone pain, which
frequently has an acid environment due to the accumulation of
protons and lactate. Certain potassium channels interact with an
ingredient in Szechuan peppercorns. These receptors are found in
abundance on C-fibers and A-delta fibers and play a role in acute
pain.27–29
Another transient receptor potential channel subunit family,
TRPA channels, are chemoreceptors that respond to chemother-
apy, 30 acrolein, teargas, automobile exhaust, and burning vegeta-
tion and are known to elicit acute pain.10
N- and T-type calcium channels on C-fibers are upregulated
by pathologic processes such as diabetes neuropathy. Gabapentin
targets subunits of the calcium channel (alpha 2-delta-1) and
reduces membrane expression of calcium channels and hence
reduces neuropathic and bone pain. 31,32 Gabapentin blocks neu-
roplasticity, synaptogenesis, and increases spinal noradrenaline
levels, suggesting that the early use of gabapentin is better than
starting gabapentin when pain is well established. 33 Ziconotide,
also an N-type calcium channel blocker, relieves cancer pain
when given intrathecally. 34
Inflammatory signaling molecules (substance P, calcitonin
gene related protein, bradykinin, protons, inflammatory cyto-
kines, prostaglandins, and proteases) sensitize certain channels,
namely, TRPV1, TRPA1, TRPV-2, TRPV-4, and ASIC, reducing
neuron membrane potentials to depolarization. 35–38
Central mechanisms to acute pain
Central sensitization, initiated by peripheral nociceptor and
resulting in spinal-bulbar-spinal facilitated neurotransmission,
enhances primary afferent neuron responsiveness through this
downward facilitation. The rostral ventromedial medulla area
is important to this process. This hypersensitivity can outlast
acute injury and continue independent of peripheral nerve input,
resulting in maladaptive pain. Low levels of stimulus (usually
non-noxious) maintain neuropathic pain as TPRV-1 channels
are upregulated and mu receptors downregulated. 35–38 Long-
term potentiation leads to “wind-up” as N-methyl-D-aspartate
(NMDA) receptors on wide dynamic range (WDR) neurons in
the deeper lamina (V) of the dorsal horn are activated, produc-
ing an expanded receptive field and secondary hyperalgesia. The
clinical effect of wind-up is not only secondary hyperalgesia but
allodynia within the injured.35–38 NMDA receptors increase intra-
cellular calcium that in turn activates kinases (protein kinase C
and calmodulin-dependent kinase II) to facilitate pain through
phosphorylation of ion channels and opioid receptors. A distinct
change in somatosensory processing through long-term poten-
tiation and increased membrane excitability can also arise from
loss of inhibitory GABA and glycinergic interneurons located in
lamina II. 39 Neuroplasticity involving in synapses and dendrites
will cause hypersensitization. Activation and proliferation of spi-
nal cord microglia occur in neuropathic injury and metastatic
Acute Pain and Management 595

bone disease.40 Activation occurs over minutes to hours with • Mesenteric venous thrombosis
acute pain. 39 As a result, there are no single defining molecular • Hepatic capsular invasion
mechanisms for central sensitization. • Peritoneal carcinomatosis
The development of central sensitization has important impli-
• Splenic infarct or rupture
cations. Certain short-acting opioids increase secondary hyper-
• Biliary or renal colic
algesia with acute injury while reducing pain arising from the
Thoracic Cancer
primary site.41–45 Certain adjuvant analgesics (lidocaine, cloni-
dine, ketamine, paracoxib, and acetaminophen) reduce secondary • Pulmonary artery invasion with infarct
hyperalgesia associated with acute pain or caused by short-acting • Bronchopleural fistula from cancer
opioids.43–45 Buprenorphine uniquely blocks secondary hyperal- • Esophageal rupture or fistula to bronchus or tracheal
gesia in contrast to fentanyl, which is primarily analgesic at the • Brachial neuropathy
site of injury.46 • Cardiac tamponade
The clinical implications of central sensitization are several- • Pleural effusion, implants, and chest wall invasion
fold. Certain pain phenotypes may not be as responsive to opioids Soft Tissue and Bone Cancer or Metastases
if the pain mechanism is largely due to central sensitization. Little • Muscle tumor or metastases
is known about the opioid responsiveness of referred visceral • Subcutaneous metastases
pain.47 If the central sensitization and long-term potentiation of • Neurogenic sarcomas or nerve root invasion
pain within the spinal cord are the main generators of pain, then
• Angiosarcoma or metastatic compression or blood vessels
interventional nerve blocks will be ineffective.48,49
• Cutaneous metastases, melanoma
• Vertebral and long bone metastases, fracture or collapse
Recent neuroanatomical correlates Central or Peripheral Nervous System
with potential clinical importance • Brain metastases
• Leptomeningeal metastases
Descending inhibition can be lost in pain processing disor-
ders such that normal sensations are experienced as pain. 50 • Intradural or spinal cord metastases
With acute pain there is release of interhemispheric inhibition Procedural Pain or Treatment-related Pain
through the corpus callosum such that the activation of the • Postoperative pain
motor (M1) cortex on one side activates the other side. This leads • Kyphoplasty
to somatosensory symptoms contralateral to the site of injury. 51 • Radiation induced mucositis, esophagitis, arachnoiditis, enteritis,
On the other hand, a transcollosal connections from the right cystitis, proctitis, skin desquamation
to the left dorsolateral prefrontal cortex increases acute pain • Chemotherapy endophebitis, extravasations, neuropathy
thresholds. 52–54 Transcranial direct current stimulation or mag- • Corticosteroid withdrawal arthralgias
netic stimulation of the left dorsolateral prefrontal cortex sig- • Gonadotropin hormone-related tumor flare
nificantly reduces acute pain. 55,56 In addition, stimulation of the • Hepatic artery embolization
M1 cortex using transcranial magnetic stimulation also reduces
• Portal vein embolization prior to partial hepatectomy
acute pain. 57–59 The prefrontal cortex provides “top-down” con-
• Embolization of renal bone or soft tissue metastases
trol over emotional processes through projections to striatal
• Thoracentesis and chemical pleurodesis
nuclei such as the amygdala. Activation of this pathway results
in relief of acute pain.60 The classic cannabinoid receptor CB1 • Pericardiocentesis
is highly expressed in the frontal-limbic connection relative to • Paracentesis
the somatosensory cortex. As a result, the phytocannabinoids, • Lumbar puncture headache
tetrahydrocannabinol, reduce the unpleasantness of pain rather • Bone marrow biopsy
than its intensity.61 • Venipuncture
• Wound dressing changes
Acute pain syndromes • Stent placement (gastrointestinal, genitourinary)
• Nephrostomy tube placement
Acute pain syndromes are variably classified. These syndromes • Transhepatic biliary drainage
may be the direct result of the cancer, its treatment, complica- Cancer Complications
tions, or underlying comorbidities. A partial list is provided in
• Pulmonary embolism
Table 63.1.
• Pneumonia with pleurisy
• Ascending cholangitis
TABLE 63.1  Acute Pain Syndromes • Venous thrombosis (superficial and deep)
Bone Metastases • Decubitus ulcer
• Joint destruction by tumor • Oral candidiasis, esophagitis, cystitis
• Pathologic fracture of long bone, vertebral body, pelvis • Shingles
Visceral Cancer • Clostridium enterocolitis
• Bowel obstruction • Pyelonephritis
• Bowel perforation with peritonitis • Superior vena cava syndrome
• Sacral, hypogastric, lumbar, or celiac plexus invasion • Malignant otitis media
• Budd-Chiari syndrome from tumor invasion into hepatic veins • Typhlitis
596
Assessing acute pain and pain responses
Acute pain by default is assessed like chronic pain parameters: by
location, quality, referral pattern, and palliative and exacerbat-
ing factors, intensity or severity, temporal pattern, and associated
symptoms.62–65 There is no evidence that directly links timing,
frequency, or choice of measure for assessment with timeliness,
choice, or safety of treatment in medical patients. There are cur-
rently no pain-relevant performance measures in place that can
support efforts to enhance pain care, and research on pain man-
agement in nonsurgical, nonmalignant acute pain is sparse.66
Severity can be measured by a numerical rating scale (NRS),
visual analog scale (VAS), categorical scale (CAT), and face scales
(for children less than 8 years of age). Meaningful changes in pain
severity can be due to active treatment, placebo responses, and/
or nonspecific effects such as recall bias. Nonspecific effects that
influence pain include the clinical setting, the natural history and
fluctuation of pain, altered mood, and the tendency for severe
pain to regress toward the mean or be averaged over time.67 There
is moderate variability in individual cut-off points for mild, mod-
erate, and severe pain.68 As a general rule, severity less than 4 is
mild, 5–7 moderate, and greater than 7 severe, on an 11-point
numerical scale. As outcomes to pain trials, responses are mea-
sured by a central tendency (which is either the change in mean or
median pain intensity).40 A clinically relevant outcome response is
the proportion of responders (responders’ analysis) based on clin-
ically meaningful changes in pain severity. A change in 2 points
on an 11-point NRS scale is clinically significant but assumes lin-
earity in scales while a change of 10 mm on a VAS is a perceptible
pain difference (PD).69 Linearity which is more of an assumption
been proven. Pain responses can also be determined by the need
for a second rescue dose of analgesic in trials. A 20% reduction in
pain intensity is determined to be minimally important clinically,
a 30% change was notable improvement, and a 50% reduction
substantial improvement.70 Cumulative responses by central ten-
dency analysis are obtained through measuring changes in pain
intensity over time. Differences in pain intensity over time (sum
of pain intensity difference) and PDs at separate times are used to
compare different treatments.71 Central tendency differences may
reflect a great response in a small number of individuals or little
response among the majority. In a responder analysis, the cumu-
lative proportion of responders over time provides clinicians with
the ability to determine the numbers needed to treat (NNT) in
order to obtain a meaningful reduction in pain severity in one
individual, which is more meaningful to clinicians than results
by the central tendency analysis.43 The NNT is the inverse of the
absolute risk reduction between groups. A 30% reduction in pain
intensity is considered a response in breakthrough pain trials, in
chronic neuropathic pain trials, and in nonopioid adjuvant tri-
als for neuropathic pain.72 None of the measures are intended to
diagnose the cause of pain and none are perfect across the spec-
trum of etiologies, pain types, comorbidities, and patient prefer-
ence. Multiple outcomes should be assessed during treatment:
analgesia, improved function, side effects, compliance, patient’s
satisfaction, lack of analgesic abuse, compliance, and affordabil-
ity. Since many suffer from breakthrough pain, assessment of rest
and dynamic (movement related) pain should be performed inde-
pendently. Rest pain should be assessed now and over the last 24
h or over the last week.73
Acute pain can detrimentally influence attention. Pain dimin-
ishes orienting and alerting attention but not executive atten-
tion.74 This is important to know if one is assessing cognitive
function in addition to acute pain. It is also important to assess
Textbook of Palliative Medicine and Supportive Care
symptom burden and symptom goals. Achieving personalized
symptom goals favorably influences global impression of clini-
cal improvement.75 This may be more important to individual
patients than the usual standard of a 2-point decrease in a NRS or
a 30% or 50% reduction in pain intensity.
Patients with uncontrolled pain are often anxious while
patients with uncontrolled chronic pain are often depressed.76
The presence of anxiety magnifies the expression of symptoms.77
It is a temptation to add a benzodiazepine to the opioid manage-
ment of acute pain in patients who are highly anxious. It would be
better to treat the acute pain and see if anxiety resolves.
One additional interesting scale should be considered in assess-
ing acute pain. This scale, used during therapy, is the “perceived
adequacy of analgesia” through deferred additional analgesics.
Rather than an arbitrary number or category, patients determine
their analgesia and comfort through deferring the need for more
analgesics. Compared to linear scales, the need for additional anal-
gesia is between “a perceived little change” and “much change” in
a minimal clinically important change in scale. Overall percent-
age reduction in pain intensity is better than linear changes in a
numerical scale when accounting for pain intensity.78
In a review of minimal clinically important changes in acute
pain scales that involved 37 randomized controlled trials and
8,479 patients, there were wide variations among studies.
Changes in a 100-mm VAS ranged from 13% to 85%. Both the
scale and trial design influenced minimal clinically important
differences in scales.79 Hence using standardized changes across
different scales in different trial designs may be quite imprecise.
Anchors for pain intensity scales are assumed to be the same
whether treating acute or chronic pain. However, patients with
chronic pain are more likely to make corrections of their pain
intensity considering anchors than those with acute pain (odds
ratio (OR), 7.2). This may reflect a shift response with experience
of chronic pain.80
Management of acute pain
Chronic pain is defined as pain present for more than 3 months
and is largely due to the fact that pain of that duration is unlikely
to spontaneously diminish and that tissue healing in most has
occurred.81 Acute pain can be anticipatory (procedural), acute
or associated with chronic pain (breakthrough pain), intermit-
tent without continuous pain, or unstable or changing pattern
and location most often associated with cancer complications.
Temporal pattern, location, radiating or referral pattern, severity,
underlying cause, and response to analgesia are more important
to clinical management than duration (less than 3 months vs.
greater than 3 months). Implementation of an acute pain services
improves pain and reduces side effects. Staff education and guide-
lines improve assessment, treatment, and pain relief.82
Pharmacologic management of acute pain
There is not one opioid superior to another, but certain opioids are
better for particular individuals.83 The development of parenteral
patient-controlled analgesia (PCA) predated the World Health
Organization analgesic ladder and provided clinical backdrop to
individualization of acute pain management. The fundamental
concept of PCA was developed because most individuals wanted
to participate in the management of their pain, which was abso-
lutely vital to individualized dosing. With the use of PCA, opioid
requirements were found to vary 8–10-fold between patients. In
1963, Roe and colleagues discovered that small intravenous (IV)
doses of morphine on a pro re nata (when necessary) basis for
acute pain severity were more effective than the conventional
Acute Pain and Management
approach of every 4-h, weight-based intramuscular morphine.84
Sechzer and colleagues confirmed that “on patient demand” dos-
ing was superior to every 4-h dosing.85 The initial protocol for
PCA required frequent assessments by nurses. In 1976, the first
commercially available PCA pump became available (Cardiff
Palliator).86 In general, PCA strategies provide marginally bet-
ter analgesia than conventional parenteral opioid dosing except
in wards with high nurse-to-patient ratios.87 One of the differ-
ences between acute and chronic pain management is that inter-
ventional approaches such as epidural or intrathecal analgesia are
used more frequently with chronic pain and at least for postop-
erative pain used as frequently as the primary pain management
strategy.88 In this way, acute pain management does not follow
the WHO analgesic ladder.
Optimizing opioid analgesia requires titration to individual
minimal effective drug concentrations, which differs between
individuals but is relatively constant for a single individual.
Opioids have diverse pharmacokinetic properties that influ-
ence dosing strategies for acute pain.89 There are delays between
peak blood concentrations and effective CNS opioid levels (hys-
teresis). Fentanyl is uniquely sequestered in the lung, which
delays CNS levels and differs from alfentanil that is not seques-
tered.90 Oxycodone and fentanyl are actively transported into
the CNS.91 Blood–brain barrier effluxes certain opioids from the
CNS; P-glycoprotein can be upregulated and cause opioid “tol-
erance” as seen in animal models.92 Certain medications block
active CNS transporters, potentially reducing CNS opioid lev-
els. Antidepressants, certain antiarrhythmics (mexiletine), and
ketamine block oxycodone uptake and potentially reduce opioid
analgesia.93 Verapamil blocks P-glycoprotein efflux and increases
CNS levels of P-glycoprotein-dependent opioids.94 Duration of
maximal CNS opioid concentrations differs between opioids (2
min for alfentanil and 96 min for morphine).89 Dosing strate-
gies for different opioids should be based on pharmacokinetics.
As such, morphine is more suitable than for an upgraded tradi-
tional approach to staff administer IV or subcutaneous doses and
should have a longer lock-out interval when used in PCA com-
pared with lipophilic opioids.89 Lipophilic opioids such as fen-
tanyl and alfentanil have a more rapid onset and shorter duration
of action at least initially than morphine and are more suitable
to IV PCA dosing strategies with short lock-out intervals and for
incident pain. Buccal, transmucosal, and intranasal lipophilic
opioids have a more rapid analgesic onset than immediate release
morphine for breakthrough pain and procedure-related acute
pain; fentanyl has been tailored as a rescue analgesic. Both trans-
mucosal and intranasal routes bypass hepatic first pass clear-
ance. Uniquely, fentanyl half-life increases over time as fat and
muscle storage sites become saturated. The frequent use of buccal
or intranasal fentanyl leads to delayed opioid toxicity as hepatic
clearance becomes rate limiting to fentanyl clearance rather than
redistribution.89 This is the reason for limiting the number of res-
cue doses per day. Children prefer a “needleless” pain manage-
ment strategy for procedures or acute pain and prefer intranasal
or buccal fentanyl to IV morphine.95
Preventing acute postoperative pain
Individuals with cancer are frequently faced with surgery either
to remove the primary or to treat complications related to their
cancer. Understanding perioperative acute pain management is
important to palliative specialists. Preventive analgesics reduce
postoperative pain and opioid requirements through perhaps
blunting or preventing central sensitization caused by acute
597
pain.96–101 Preemptive opioids without continuation through the
operation can lead to central sensitization.102,103 Analgesia should
begin preoperatively and continue through the operation to the
postoperative period of time and is preferred over preemptive
opioids prior to surgery alone. Postoperative tissue inflammation
upregulates opioid receptors, which improves postoperative opi-
oid responses. Surgery without significant tissue injury or dam-
age generally produces a proportional stimulus–pain response.
Pain recedes without central persistent sensitization. Extensive
tissue damage generates an afferent barrage through C and
A-delta fibers, which activate WDR neurons. Amplification of
nociceptive signals (through brain-derived neurotrophic factor
release) increases hypersensitivity through spinal-bulbar-spinal
facilitation of nociceptive circuits, causing allodynia and sec-
ondary hyperalgesia, and can lead to chronic pain that is poorly
controlled.104
The goals of preventive analgesia are to decrease acute pain,
prevent neuroplastic changes, which lead to chronic pain, and
reduce opioid requirements and opioid-related side effects.105
Associated with severe postoperative pain are the duration of sur-
gery, high intraoperative opioid doses, and general anesthetics.106
Nonopioid analgesics such as NSAIDs and adjuvant analgesics,
gabapentin, pregabalin, ketamine, lidocaine, bupivacaine, and
clonidine reduce postoperative pain and opioid requirements.107
Earlier reviews suggested little benefit to the use of adjuvants, but
recent reviews report significant benefits to pre- and periopera-
tive gabapentin, ketamine, NSAIDs, and local anesthetics applied
to the wound.104 The evidence for ketamine is weak.108,109
Adjuvants influence perioperative pain differently. In one
study, gabapentin reduced movement-related pain but not the
risk of chronic pain; venlafaxine reduced the risk of chronic post-
operative pain.110,111 Overall, when adjuvants are compared for
postoperative analgesic outcomes, there is little advantage of one
over the other.112 Clinical context will play a significant role in the
choice of adjuvant and nonopioid analgesics.
Combinations of adjuvant analgesics may improve acute proce-
dure and postoperative related pain. Gabapentin combined with
local anesthetics injected into the surgical wound improves anal-
gesia and reduces the risk of long-term chronic pain compared
with gabapentin alone.89,90 Combinations of gabapentin plus acet-
aminophen or an NSAID control acute postoperative pain better
than gabapentin or NSAIDs alone.113,114 Gabapentin, dexameth-
asone, ketamine, and acetaminophen reduce pain to a greater
extent than ketorolac plus acetaminophen.115 An oral local anes-
thetic (mexiletine) plus regional block reduces postoperative pain
longer than a regional block alone; the combination prevents late
onset dysesthesia.116 Aggressive early multimodality postopera-
tive pain management reduces pain intensity and reduces the risk
of chronic pain.115
Patient-controlled analgesia for
acute and postoperative pain
PCA strategies involve a loading dose, demand dose, lockout
interval, and background infusion rate (if opioid tolerant pre-
operatively). A 1- and 4-h limit on opioid doses is an additional
parameter but is rarely used.117 Subcutaneous PCA opioids are
as effective as IV opioids. In the opioid naïve, a background infu-
sion is generally not recommended. The addition of a background
infusion to a demand PCA in the opioid naïve does not improve
pain relief, sleep, or reduce the demand. Loading doses are given
in the postoperative acute care unit. Small but frequent doses
(morphine 1 mg or fentanyl 20–40 mcg) are titrated to reduce
598
pain severity to 4 or less on an NRS. Individuals are observed for
hemodynamic or respiratory compromise. A common morphine
dosing strategy for the opioid naïve is 1 mg bolus as a demand
dose with a 6–10-min lockout interval.117 Hydromorphone doses
are 0.2–0.4 mg with the same lockout interval and fentanyl 40
mcg with 10 min lockout intervals (6 doses/h). Tramadol demand
doses range between 10 and 20 mg with a 5–10-min lockout
interval. Demand doses and lockout intervals are adjusted to
response.117
Even with IV PCA in the postoperative setting, the incidence
of moderate pain is 35%, 10% will have severe pain.118 Opioid
adverse events are dose related. Nausea is greater with IV PCA
than with parenteral morphine or epidural analgesia. Sedation
occurs in 24% and is mostly mild. Pruritus occurs in 15%, nau-
sea in 25%, and vomiting in 20%.118 IV PCA analgesia is associ-
ated with a 1%–15% incidence of respiratory depression; despite
recommended lockout intervals, cell monitoring is important.
Hypotension occurs with less frequency (0.4%) than with epi-
dural analgesia (5.6%).119
In general, PCA opioid strategies lead to higher opioid con-
sumption, a greater incidence of pruritus but no difference in
other adverse events or hospital stay compared with regular par-
enteral intermittent opioid injections. Continuous opioid infu-
sions in the opioid naïve are associated with an increased risk of
respiratory depression. Transdermal opioids and oral sustained-
release opioids should not be used for acute pain management.
Neither should transmucosal and intranasal fentanyl be used in
the opioid be naïve. Routine addition of anti-emetics to PCA opi-
oids is unnecessary; nausea and vomiting should be managed as
it arises. Postoperative nausea and vomiting can be treated with
droperidol, metoclopramide, 5-HT-3 receptor antagonists, cor-
ticosteroids, or cyclizine.120 Opioid-related pruritus responds to
naloxone, naltrexone, nalbuphine, droperidol, and 5-HT-3 recep-
tor antagonists.121 PCA systems should include an anti-syphon
valve and, if used in nondedicated lines, anti-reflux valves.
Unfortunately, there are no standard doses or lockout intervals
and no randomized trials to guide clinicians in ordering PCAs.
Opioid-naïve patients with acute pain should be managed with
an “as needed” dosing strategy if PCA is used. Compared to clini-
cian-based as needed opioid administration, PCA administration
reduces opioid consumption on days 3 and 4 and reduces pain by
day 5. However, PCAs have a minor impact on overall analgesia
and opioid use. In one study, PCA used 65 versus 80 MEDD by day
5.122 The benefits of PCA depend upon the nurse-to-patient ratio
in the attentiveness of staff to the patient’s pain.
Managing acute postoperative
pain in the opioid tolerant
Opioid tolerant individuals require a distinctly different postop-
erative opioid dosing strategy than the opioid naïve. Poor pain
control and withdrawal symptoms are likely to occur if the same
dosing strategies are used as for the opioid naïve. On the pre-
operative day, patients should be instructed to take their usual
chronic opioid dose. A continuous IV opioid infusion or continu-
ous PCA with demand equivalent to the preoperative daily opi-
oid dose is maintained after recovery from anesthesia. This will
require conversion of the around-the-clock oral dose to paren-
teral equivalence.123 Regional analgesia will help control pain as
will epidural analgesia; however, at a minimum, these individuals
will need 50% of their preoperative chronic opioid dose to avoid
withdrawal since neither regional anesthesia nor epidural analge-
sia will prevent withdrawal.124 Demand doses to relieve pain are
Textbook of Palliative Medicine and Supportive Care
likely to be 2–4 times greater than those used for the opioid naïve.
For those on maintenance therapy, methadone or buprenorphine
should be continued postoperatively and a short acting potent
mu agonist such as morphine, hydromorphone, or fentanyl is
used for acute postoperative pain management.124 Alternatively,
the maintenance opioid dose can be divided and given for anal-
gesia. Postoperative pain control in the opioid tolerant may be
improved by the addition of low doses of ketamine (0.25–0.5 mg/
kg bolus and/or a 1–6-mcg/kg/min infusion).124 Other adjuvants
such as NSAIDs and gabapentinoids should be considered in the
perioperative period.
Multimodality analgesia and innovations
in managing acute postoperative pain
Single-dose extended-release epidural morphine lasts 48 h
without the need for an epidural pump. Sustained release epi-
dural morphine reduces perioperative pain associated with knee
arthroplasty and cesarean section and is associated with reduced
systemic opioid requirements and opioid side effects. However,
respiratory depression has been reported with doses of 15 mg or
greater.125,126 Naloxone was needed in 12% of individuals for pru-
ritus or respiratory depression.
Patient-controlled epidural analgesia (PCEA) uses fentanyl or
a combination of fentanyl with a local anesthetic such as bupiva-
caine or ropivacaine for pain control. Compared with continu-
ous epidural analgesia, PCEA side effects and overall analgesic
requirements are less. PCEA is superior to IV PCA in control-
ling pain in the postoperative setting.127 Thoracic epidural opioid
analgesia reduces postoperative complications related to aortic
aneurysm repair and thoracic surgery.128 The addition of a local
anesthetic reduces opioid-related side effects and the need for
rescue doses. The downside to the combination is an increased
incidence of hypotension, pruritus, motor block, and urinary
retention.127 Neuroaxis hydrophilic opioid boluses increase the
risk for delayed respiratory depression when compared with fen-
tanyl.129 Chlorhexidine dressings over the epidural entrance site
reduce bacterial colonization better than povidone-iodine.130
Patient-controlled regional anesthesia uses local anesthet-
ics alone or a combination of local anesthetic and opioid in a
regional infusion.131 Patient-controlled regional analgesia and
perineural patient-controlled regional anesthesia allow patients
to titrate the local anesthetic to comfort. Patient-controlled
regional analgesia results in equivalent to superior analgesia and
lowers systemic analgesic requirements compared with continu-
ous infusion regional analgesia.131 In a large review of more than
18,000 patients, PCEA and continuous regional analgesia pro-
duced superior analgesia to IV PCA.132 Intra-articular analgesia
using ropivacaine, morphine, and ketorolac as a form of regional
analgesia results in reduced systemic opioid requirements.131
The perioperative management of pain when patients are on
maintenance buprenorphine is controversy all. Some clinicians
have found no need to change patient’s buprenorphine doses
and continue buprenorphine through the perioperative period.
Patients are given short-acting potent opioids for acute pain and
appear to respond though they require higher doses.133–136 Regional
blocks, spinal analgesia, and adjuvant analgesics would be used in
addition to a potent short-acting opioid. Other physicians would
discontinue buprenorphine to improve perioperative pain con-
trol. This risks a relapse of addiction. Some would rotate patients
to methadone in order to prevent relapse. Discontinuation in the
perioperative period may make pain control more difficult in an
opioid tolerant individual. Short-acting potent opioids are used
Acute Pain and Management
in the perioperative period with buprenorphine. Another option
is to reduce the buprenorphine dose to less than or equal to 8 mg
daily and divide the dose to 2 mg every 6–8 h in hopes of pro-
viding postoperative analgesia. Immediate release potent opioids
would then be used for breakthrough pain as well as opioid spar-
ing adjuvant analgesics, regional blocks, or spinal analgesia.137
Sufentanil at a dose of 0.4 µm/kg has been compared to fen-
tanyl 4 µg/kg for postoperative pain control in the elderly.
Patients receiving sufentanil had a shorter extubation time and
better pain control, better cerebral oxygen saturation, and better
postoperative cognitive function.138
Bone and joint pain
Bone, joint disorders, and bone metastases are common causes
of acute pain. Bone metastases are the most common cause of
cancer incident pain.
Nociceptors in joints located in the capsule, ligaments,
menisci, periosteum, and subchondral bone are located on the
terminals of type IV (unmyelinated) or type III (myelinated with
unmyelinated free endings) afferent neurons. Movement gener-
ates shear stress on axon membranes that opens gated ion chan-
nels.139,140 Inflammation decreases firing thresholds and causes
peripheral sensitization, wind-up, and secondary hyperalgesia.
Synovial fluid volume which is normally 1–4 mL and maintained
at sub atmospheric pressures, with inflammation and subsequent
increased vascular permeability, increases to as much as 60 mL or
more with pressures up to +20 mmHg.139,140 The pressure stimu-
lates mechanical gated ion channels, causing burst firing from
afferent neurons. Joint and ligaments have a poor capacity to heal
as a result of inflamed joints and sustained or repeated trauma
becomes unstable and develops cartilage erosions, causing
osteoarthritis. Pain is experienced with passive joint movement
as mechanical gated ion channels are activated. Inflamed and
damaged joints release neuroexcitatory peptides (CGRP, SP, and
vasoactive intestinal peptide), causing joint pain sensitivity and
increased pain at rest as well as with movement. Immunocytes
and mast cells in synovium release prostaglandins, which in turn
upregulate sodium channels. Nociceptin at low concentrates
within the joint sensitizes afferents and at high doses paradoxi-
cally reduces sensitization.139,140 Voltage-gated calcium channels
on primary afferents are activated, causing hypersensitization.141
Gabapentin reduces knee joint pain and bone pain from cancer
by blocking alpha-2 delta-1 subunit on primary afferents.142 In
animal models, gabapentin also reduces secondary hyperalgesia
and referred allodynia by its central actions.143 Joint disorders in
animal models are also associated with neuropathic pain from
joint damage, which is responsive to amitriptyline.144 Referred
pain from the joint produces muscle soreness, and an extended
area of hyperalgesia proximal to the joint.145
NSAIDs are standard treatment for arthritis, which reduces
inflammatory pain and perhaps dampens central sensitization
through inhibiting cyclooxygenase, which is a second messenger
to NMDA receptors. Topical and systemic NSAIDs and intraar-
ticular corticosteroids block prostaglandin production and
reduce muscle soreness related to arthritis. Combining NSAIDs
with acetaminophen may be better than either drug alone.146
Osteolytic and osteoblastic metastases are associated with
osteoclast proliferation and bone remodeling. The acid envi-
ronment within the metastases and increased release of pro-
tons stimulates ASIC and TRPV1 channels on afferents.147
Stromal and tumor infiltration immunocytes increase lactate.
Bisphosphonates reduce cancer-related skeleton events and bone
599
pain.148 Bisphosphates bind to the matrix calcium and are taken
up by osteoclasts by endocytosis that causes osteoclast apopto-
sis. Long-term bisphosphonates, however, cause complications
in a minority due to inhibition of bone repair and remodeling.
Complications include fractures of the long bone and osteone-
crosis of the jaw.147
Salmon calcitonin reduces pain from osteoporotic fractures but
not from metastases.149 The mechanism of analgesia is not known.
It may be due to changes in descending serotonergic modification
on the sensory transmission mediated by C-fiber afferents.149
Tumors release into the stroma receptor activator nuclear fac-
tor kappa B ligand (RANKL), which binds to RANKL receptors
that regulates osteoclast activity. Denosumab, a fully humanized
monoclonal antibody to RANKL, reduces cancer-related bone
loss and skeletal events in breast and prostate cancer and myeloma
by blocking osteoclast activation.147 There are little data at present
to suggest that denosumab relieves pain. Complications related to
denosumab are similar to those of bisphosphonates.150,151
Tumor-infiltrating macrophages, neutrophils, T lymphocytes,
and fibroblasts and endothelial cells secrete a number of factors
that sensitize afferent neurons. These factors are bradykinins,
tumor necrosis factor, endothelin, epidermal growth factor,
transforming growth factor-alpha, inflammatory cytokines, and
nerve growth factor. Nerve growth factor binds to the receptor
TrKA, causing bone pain by upregulating multiple neurotrans-
mitters, sensitizing ion channels, and disinhibiting pronocicep-
tive receptors. Antinerve growth factor antibody therapy reduces
bone pain in animal models.147 Recent randomized trials have
found that tansumab reduces pain from severe osteoarthritis.152
Clinically, individuals with pain from bone metastases require
higher doses of morphine then individuals with inflammatory
pain.153 In mouse models, dose requirements to block cancer bone
pain are 10 times those needed to reduce inflammatory pain.154 A
characteristic neuropathic “signature” develops in the spinal cord
as a result of damage to sensory afferents in bone marrow, trabec-
ular bone, and cortical bone.154,155 Spinal cord microglia prolifer-
ates ipsilateral to the metastases, which is similar to neuropathic
pain.154 NSAIDs, opioids, and gabapentin modestly reduce met-
astatic bone pain.155 Loading dose ibandronate is reported to
relieve bone pain quickly without impairing renal function.156 In
a randomized trial, parenteral ibandronate reduced bone pain
more effectively than pamidronate.157 In the future, endothelin
receptor antagonists, anti-nerve growth factor, and osteoprote-
gerin (a RANKL blocker) may be found to be effective also.158
Acute dosing strategies for acute pain
in the emergency department
Three opioids have the most published evidence for managing
acute pain in the emergency department: morphine, hydromor-
phone, and fentanyl.159
In a randomized, double-blind placebo-controlled trial, IV
morphine 0.15 mg/kg was superior to 0.1 mg/kg in adults with
acute pain as determined by changes in severity at 60 min.160
Individuals in this study were opioid naïve. In a randomized,
double-blind trial, IV morphine 0.05 mg/kg was compared to
hydromorphone 0.0075 mg/kg. Response, defined as greater than
or equal to 50% reduction in intensity, was the same for both opi-
oids; however, only a minority of participants (45%) responded by
30 min.161 The authors felt that the dose and strategy were inad-
equate, and a titration strategy was needed.
Morphine 0.1 mg/kg bolus and 3 mg every 5 min were com-
pared with fentanyl 1 mcg/kg and 30 µg every 5 min as needed
600
for severe acute pain (determined by a VAS score greater than 60
mm).162 Morphine reduced pain severity to a similar extent as fen-
tanyl (from 83 to 40 mm and 77 to 35 mm at 30 min, respectively).
Patients rated analgesia good to excellent with equal frequency
(62% morphine and 76% fentanyl), and side effects were the same
for both opioids.
Morphine 5 mg has been compared with alfentanil 0.5 mg for
acute chest pain.163 Doses were repeated at 2 min intervals as
needed; a VAS scale for pain severity was obtained at 2, 4, 6, 10,
and 15 min as an outcome measure. Alfentanil resulted in quicker
pain relief, and no hemodynamic or respiratory side effects were
noted with either opioid.
Two studies reported using a “1 + 1” hydromorphone dosing
strategy. In the first study, opioid-naïve individuals less than
65 years of age with acute pain were treated with 1 and 1 mg of
hydromorphone was offered 15 min later if the answer was yes
to the question, “Do you want more pain medication?” Adequate
analgesia was obtained with the first dose in 77% and an addi-
tional 16% responded to the second dose. Eighty-six percent had a
2-point reduction in their NRS by 60 min. Median pain reduction
was 6 out of 10 on an NRS. None required naloxone, but 5% had
transient oxygen desaturation.164 In the second study, patients
were randomized between the “1 to 1” hydromorphone protocol
and a physician-derived dosing standard used in the emergency
department was the comparison strategy. Eligibility was the same
as in the first study. Patients were assessed at 15, 30, and 60 min;
pain intensity differences at 60 min were the primary outcome.
The “1 to 1” protocol was superior to the standard dosing regimen
with a 1.1-point difference between strategies on a 0–10 NRS,
which was statistically significant (95% confidence interval for
differences 0.3–1.9).
Fentanyl has been used at the scene of trauma using 0.050.1
mcg/kg every 15 min as needed. Patients had moderate-to-severe
pain on an NRS scale or a CAT. Fifty three of 67 had a good
response by narrative record review. One-hundred and twenty-
four doses were given (average two doses per patient). No patient
had oxygen saturations below 90%.165
Intranasal fentanyl is a “needleless” pain management strat-
egy. Several studies compared intranasal fentanyl with parenteral
morphine for acute pain from bone fractures. Doses were 1–2
mcg/kg (1.5 mcg/kg on average) and repeated if necessary, using
0.5 mcg/kg or 15 mcg repeated at 5–10 min intervals.166 Standard
vials of fentanyl (50 mcg/mL) were used for children and admin-
istered by the Tory Wolfe mucosal atomizer device (Salt Lake
City, UT, USA).95 Fentanyl doses were on average 60 mcg repeated
at 5 min prior to arrival at the emergency room. This dosing strat-
egy compared with IV morphine 2.5–5 mg at 5 min intervals as
needed provided excellent pain relief.167
In summary, a reasonable strategy to manage acute pain in the
emergency department is to start with 1 mg of parenteral hydro-
morphone, 5 mg of morphine, or 50–100 mcg of fentanyl and reas-
sess 15 min later. If pain is still severe, a second dose is offered.
Intranasal fentanyl using 1.5 mcg/kg at 5–10 min intervals for
children is a reasonable approach to controlling acute pain.
Opioid dosing strategies for acute
severe pain in cancer
Rapid titration of opioid by parenteral or oral route has been used
to treat acute cancer pain. Titration strategies involved boluses
at short intervals by clinician or PCA demand only.168 Morphine
and fentanyl are the two most common opioids used by clinicians
in managing acute cancer pain. Strategies included the following:
Textbook of Palliative Medicine and Supportive Care
(1) IV morphine 10–20 mg over 15 min every 30 min and double
the dose if no response after 60 min, (2) IV morphine 1.5 mg every
10 min, (3) IV morphine at 2 mg every 2 min, (4) IV morphine 1
mg every minute for 10 min followed by a 5-min rest, repeat ×2
as necessary up to a total of 30 mg of morphine, and (5) fentanyl
equivalents from morphine using a ratio of 100 to 1 (oral mor-
phine to parenteral fentanyl). Ten percent of the total daily mor-
phine dose was converted to fentanyl and used IV every 5 min.
A comparison between IV and subcutaneous (sc) opioid dosing
strategies has been reported.169 Dose intervals were 5 min for IV
and 30 min for sc opioids. Doses were dependent on total daily
morphine or equivalents. If the daily morphine dose was less than
120 mg, then the IV breakthrough dose was 2 mg and the sc dose
was 10 mg. If the oral daily morphine dose ranged between 121
and 360 mg/day, then the IV breakthrough dose was 3 mg and sc
dose 20 mg. If the oral daily morphine dose ranged between 361
and 600 mg/day, then the IV dose was 4 mg and the sc dose 30 mg.
If the daily oral morphine equivalents were greater than 600 mg,
then the IV dose was 5 mg and sc dose 40 mg. Adequate analgesia
was reached sooner with IV morphine (53 vs. 77 min) and at lower
doses (18.5 vs. 57.9 mg).
Clinician bedside parenteral rapid titration strategies produce
pain relief within 1 h. Evidence is however only from cohort stud-
ies and collected case reports, which involved both opioid-naïve
and opioid-tolerant individuals.168 The effective titrated dose was
every 4-h dose converted to oral equivalents in the opioid naïve.
In the opioid tolerant, the titrated dose should be added to the
chronic dose to maintain pain control.
PCA has been used without titration as a strategy to manage
acute pain. Fentanyl 50 mcg or morphine 1 mg with a 5-min lock-
out interval has been reported.168 Responses occurred within 6–24
h. The reason for the delay is the absence of opioid titration to effec-
tive pain control. Second, patients not familiar with the PCA device
often wait until severe pain to recur before activating the PCA.
Oral morphine dosing strategies involve (1) 10 mg of immedi-
ate release every 6 h increased to 33%–50% every 24 h for uncon-
trolled pain; (2) immediate release or sustained release starting
with 60 mg daily titrated daily to 90, 120, 180, and 270 mg; and
(3) immediate release titrated sequentially at 2–4-h intervals in
a step-dose strategy starting with 5 mg, then 10, 15, 20, 30, 40,
60, 80, 120, 160, and 200 mg. Pain relief occurs within 48 h if
titrated daily, 24 h if titrated at 4 h intervals, and 6 h if titrated at
2-h intervals.168
Optimal oral and parenteral dosing strategies for acute severe
cancer-related pain are not established with high-quality evi-
dence. Recommendations are based often based on expert opin-
ion. Parenteral opioid dosing at frequent intervals using small
doses titrated to response produces pain relief quickly usually
within 1 h, whereas PCA dosing without titration and oral dosing
strategies take longer to control pain.
The Merito Study, which was recently published, used an opioid
titration protocol, which leads to pain control relatively quickly.
The dosing strategy consisted of immediate release morphine 5
mg every 4 h around the clock and every 1 h as needed in the
opioid naïve and 10 mg every 4 h around the clock and every 1
h as needed for those on “weak” opioids. Seventy-nine percent
achieved pain control within 24 h and 50% within 8 h. Pain sever-
ity by NRS was initially 7.6 (mean) and decreased to 2.4 (mean)
within 3 days. Somnolence was seen in 24%, constipation in 22%,
vomiting in 13%, nausea in 10%, and confusion in 7%.170
A small study by Dr. Khojainova and colleagues added olanzap-
ine (2.5–7.5 mg daily) for patients in a pain crisis on opioids and
Acute Pain and Management
who were extremely anxious and/or had mild cognitive impair-
ment.171 Within 24 h, olanzapine had improved cognition and
anxiety and opioid requirements diminished.
Acute neuropathic pain
Acute postoperative neuropathic pain occurs in approximately
1% of individuals; half will have persistent pain at 12 months.172
Other causes for acute neuropathic pain include chemotherapy
(platinum-based, taxanes, vinca alkaloids, thalidomide), nerve root
or spinal cord compression, plexopathies from progressive cancers,
central poststroke pain syndromes, transverse myelitis, herpes zos-
ter infections, uncontrolled diabetes, and multiple sclerosis as well
as AIDS-associated neuropathy.172 Trauma to peripheral or CNS
is also a major cause of treatment-related acute neuropathic pain.
Amitriptyline used early in the course of an active zoster infec-
tion-reduced postherpetic neuralgia.173 Perioperative venlafaxine
reduced the risk of developing chronic postmastectomy pain.174
A single gabapentin dose of 900 mg reduces acute pain from
herpes zoster.175 Gabapentin also reduced acute pain from burn
injuries, which is often neuropathic.176 Gabapentin with mor-
phine reduced cancer-related neuropathic pain.177 Preemptive
venlafaxine reduces oxaliplatin acute neuropathic pain. Fifty mil-
ligrams prior to oxaliplatin and 37.5 mg twice daily after oxali-
platin for 10 days was used in 48 patients (27 males, median age:
67.6 years). Most had colorectal cancer (72.9%). Median number
of cycles administered at inclusion was 4.5 (mean cumulative
oxaliplatin dose: 684.6 mg). Complete pain relief was more fre-
quent in the venlafaxine arm: 31.3% versus 5.3% for placebo (P
= 0.03). Venlafaxine side effects were Grades 1–2 nausea (43.1%)
and asthenia (39.2%).178
Neuropathic injury is associated with upregulation of certain
sodium channels, and so it is rational to consider lidocaine either
topically or systemically. IV lidocaine reduced pain from partial
thickness burns. Alternatively, oral mexiletine may be considered
in the management of acute neuropathic injury.179 Current clini-
cal evidence is subject to the inherent weaknesses of case series
or reports.180 No information is available from the published ran-
domized control trials.
Neuropathic injury is associated with activation of NMDA
receptors and leads to long-term potentiation of pain. Ketamine
infusions have been used to reduce acute neuropathic pain unre-
sponsive to spinal bupivacaine and morphine.181–183 Oral ketamine
doses start with 100 mg daily and are titrated by 40 mg until
response though recent trials have failed to confirm benefits.184 A
combination of memantine plus a brachial plexus block reduced
postoperative phantom pain after acute traumatic upper extrem-
ity amputation. Memantine appears to be a reasonable option for
a patient who has failed or cannot tolerate other analgesics.185
IV salmon calcitonin has been used to treat acute neuropathic
pain after amputation, phantom limb pain, and complex regional
pain syndrome.186–188 It has been ineffective in complex regional
pain syndromes. An IV dose of 200 international units compared
to placebo significantly reduced phantom limb pain.
Breakthrough pain
At least half of the patients with chronic cancer pain experience
transient flares of pain (breakthrough pain). The median number
of breakthrough episodes is 3–6 per day depending on the series
and the average onset to maximum intensity is 3 min. Two-thirds
of pain flares are with activity (incident pain). Individuals with
breakthrough pain have more severe chronic pain, greater func-
tional impairment, anxiety, and depressed mood.189
601
Seventy-four percent of individuals with chronic nonmalig-
nant pain have breakthrough pain. The median number of epi-
sodes per day is similar to cancer patients. The time to maximum
intensity is 10 min and duration 30–60 min. Sixty-nine percent of
episodes are associated with activity.189
Time to maximum pain intensity is such that oral immediate
release morphine, hydromorphone, and oxycodone are unlikely
to be of great benefit. Innovations in breakthrough pain manage-
ment are therefore necessary to successfully reduce intensity of
pain in a timely manner. A recent review of the developments in
therapeutics for breakthrough pain has been published.190
Oral transmucosal fentanyl citrate (OTFC) was the first opioid
to be specifically licensed for breakthrough pain. High quality
randomized studies demonstrate dose proportional responses,
superiority over oral immediate release morphine but poor corre-
lations between the effective fentanyl rescue dose and the chronic
opioid dose.191 Responses are achieved within 10–15 min; the
time to onset of analgesia is close to that of IV morphine.192
Fentanyl buccal soluble film is a bilayer system that uses a bio-
degradable polymer over a fentanyl layer, which is designed to
prevent fentanyl from being dissolved in saliva and swallowed.193
The soluble film rapidly releases fentanyl, and pain relief occurs
within 15 min. The dose is empirically titrated to response since
there is also a poor correlation between the effective fentanyl res-
cue dose and the chronic opioid dose.194 In addition, because of
bioavailability differences between the fentanyl lozenge, buccal
film, and buccal tablet, conversion from OTFC to buccal fen-
tanyl is not recommended. Pain responses are the same regard-
less of the opioid used for chronic pain.195 Drug abuse and misuse
were rare in these studies largely due to screening prior to study
entrance.196 Individuals who are appropriate for OTFC, soluble
film, or buccal tablets must be opioid tolerant, defined as 60 mg
of daily morphine or equivalent (30 mg of oxycodone, 8 mg of
hydromorphone, or 25 mcg/h of transdermal fentanyl) per day
for 1 week.196 Serious adverse and fatal events associated with
transmucosal (and intranasal fentanyl) are related to improper
selection of patients (opioid-naïve individuals) and improper dos-
ing (intervals shorter than those recommended in randomized
trials). Doses should not be repeated sooner than 4 h. Patients
should be prescribed only one dose strength at a time.196
Dose ranges for breakthrough pain have been recommended.
If dosing ranges are used, fixed ranges at fixed intervals should
be used. The range should be limited with the upper dose limit
not more than 2–3 times the lower dose. One must consider
the clinical setting, patient pain characteristic, age, past experi-
ence, and response. As needed dosing in patients with chronic
pain and a history of drug abuse should be avoided. This usually
leads to dose escalation. Prescribing a particular dose for a par-
ticular dose intensity is not appropriate. Avoid duplications or
using multiple opioids and multiple routes. If multiple routes are
needed, specify the criteria for using the route. Intervals should
be based on patient characteristics and drug half-life. Finally, one
should be careful about drug-drug interactions.197
There is the question of whether one uses rapid-acting fentanyl
product or oral immediate release potent opioid for breakthrough
pain. As mentioned above, rapid-acting fentanyl products for
breakthrough pain should be used only in opioid tolerant indi-
viduals. A large cancer center published the experience of using
potent oral opioids for breakthrough pain. The median MEDD
for breakthrough pain was 30 mg, which was about 10% of the
total daily opioid dose. Eighty-nine percent responded. The
non-responders were younger, had greater pain intensity, were
602
anxious, or had dyspnea in addition to pain.198 In light of this
experience, rapid-acting fentanyl products should only be used if
the less expensive immediate release potent opioids are ineffec-
tive in controlling breakthrough pain.
Some patients do not want to take additional medications or
may simply tolerate transient episodes of pain. There was a recent
randomized trial in hospice using guided imagery and progres-
sive muscle relaxation for acute flares of pain. Pain severity by the
Edmonton Symptom Assessment Scale was used as the outcome
prior to and at 2 h after the episode. With the guided imagery
and muscle relaxation, the NRS score decreased 1.83 points as
opposed to 0.55 points (NRS 0–10 scale) in the control group. The
intervention also significantly reduced the distress and anxiety
associated with pain flares.199
Acute pain management in organ failure
There is a concern of delayed clearance of opioid analgesics in
organ failure. An as-needed dosing strategy is safer to use than
an around the clock dosing strategy for this reason. A relatively
safe approach to treating acute pain in renal failure has been pub-
lished. For patients with neuropathic pain, gabapentin 50–100
mg should be given at bedtime for seven nights then titrated
to a maximum dose of 300 mg at night as first-line therapy.
Carbamazepine 100 mg twice daily is a second-line therapy. The
doses can be titrated up to 1,200 mg/day. Carbamazepine does
stimulate CYP 3A4 and is subject to drug interactions. Another
second-line approach would be a tricyclic antidepressant such as
amitriptyline beginning with 10–25 mg at night or doxepin 10–25
mg at night. Acetaminophen up to 3 g daily can be added. The
first-line opioid is hydromorphone at 0.5 mg by mouth every 4–6
h or by parenteral administration at a dose of 0.2 mg every 4–6 h
and titrated to response. Second-line opioids include buprenor-
phine, fentanyl, or methadone.
For patients in renal failure and experiencing nociceptive pain,
acetaminophen up to 3 g/day as first-line therapy was suggested.
For patients with musculoskeletal pain, topical diclofenac 5% 3
times daily may be used. The first-line analgesic is hydromor-
phone at doses described previously. Second-line opioids are also
described in the previous paragraph.200
Opioid-sparing strategies
The opioid epidemic in United States has led to an increased
interest in opioid-sparing strategies. There have been multiple
proposed ways to reduce the dependence on opioids and maintain
analgesia. One way is to add acetaminophen though a recent trial
that added acetaminophen to IV hydromorphone did not demon-
strate an improvement in analgesia compared to hydromorphone
alone.201 The addition of a potent opioid like morphine and hydro-
morphone delays gastric emptying and reduces the bioavailability
of oral but not parenteral acetaminophen.202 Other opioid sparing
approaches include the addition of ketorolac or other NSAIDs, a
gabapentinoid (though this may increase the risk for respiratory
depression), ketamine, clonidine, dexmedetomidine, and IV lido-
caine.203 This is particularly important in patients at risk for respi-
ratory depression which includes patients with morbid obesity,
those with sleep disordered breathing or suffer from chronic lung
diseases. In patients with sleep disordered breathing, supplying
supplementary oxygen may delay the detection of hypoventila-
tion if the primary monitoring is by way of oxygen saturation. In
at risk individuals in end-tidal CO2 should be monitored rather
than oxygen saturation.203
Textbook of Palliative Medicine and Supportive Care
Different opioids and routes
Tapentadol
Tapentadol is an opioid agonist and a norepinephrine reuptake
inhibitor.204,205 Tapentadol binds to mu, kappa, and delta opi-
oid receptors. One hundred milligrams are equivalent to 20
mg of oxycodone and 30 mg of morphine (with some individual
patient differences). The type of pain influences equivalence.206
Tapentadol has been compared with morphine when treating
neuropathic pain. In another randomized trial following bunio-
nectomy, tapentadol 100 mg was equivalent to oxycodone 15 mg
and had less side effects (i.e., reduced constipation).207–209
Buprenorphine
Buprenorphine has not often been recommended as an opioid for
acute pain management. However, there may be some advantages
to using buprenorphine. There is a ceiling effect on respiratory
depression. Certainly, in the opioid maintenance population,
buprenorphine is associated with fewer deaths than methadone.
In comparison to fentanyl, buprenorphine appears to have bet-
ter utility.210–213 Utility defined as a wider separation between the
dose that results in analgesia and the dose that is associated with
respiratory depression over time.214 However, the risk of respira-
tory depression is amplified if a benzodiazepine is added or in
treating at risk populations such as those with advanced age,
advanced lung disease, or who have multiple comorbidities.214–216
Norbuprenorphine rather than buprenorphine causes respira-
tory depression. Norbuprenorphine is subject to P-glycoprotein
efflux and so there may be an increased risk of respiratory depres-
sion with a P-glycoprotein inhibitor.217,218 Respiratory depression
can be delayed occurring as late is 150–180 min after parenteral
administration even though analgesia may occur rapidly. The
time to maximum plasma concentrations after sublingual admin-
istration are as short as 20 min to as long as 3 h.219 Parenteral
injections can be given every 6–8 h without loss of analgesia
in-between due to the half-life of buprenorphine and this may
preclude the need for continuous infusions. Initial doses are 200–
400 mcg every 6–8 h. One of the drawbacks to buprenorphine is
that if respiratory depression does occur, high doses of naloxone
(2–4 mg bolus and 2–4 mg over 90 min) are needed to reverse
respiratory depression.
A recent systematic review of buprenorphine compared with
morphine for acute pain involved 9 studies and compared pain
intensity at less than 1 h, at 1 h, at 3 and 6 h after administra-
tion.220 There was no difference between opioids in the first hour.
Buprenorphine produced better analgesia at 3 and 6 h. There
was no difference in side effects including respiratory depression
nor were there differences in the need for rescue doses. A sec-
ond study compared buprenorphine to morphine and included
28 randomized controlled trials in 2,210 patients. Analgesia and
side effects compared with morphine were not different. There
was less pruritus with buprenorphine. Doses a buprenorphine
for acute pain were less than or equal to 2 mg sublingual. The
authors felt that buprenorphine was a useful alternative to mor-
phine when treating acute pain.221
Fentanyl
A recent study randomized patients to fentanyl to mcg/kg or 3
mcg/kg in the pre-hospital setting. Doses were divided such that
the initial doses were 1 µm/kg 0 and 1.5 µm/kg, respectively, with
the option of a new additional dose. There were greater numbers
Acute Pain and Management
of individuals who had “sufficient relief on” with the more lib-
eral dose within OR of 1.47 (44% vs. 37%). The relative reduction
in a numerical score was better, but not significantly better with
the liberal doses (OR 1.18, 95% confidence interval 0.95–1.48).222
Acute fentanyl administration has been associated with opioid-
induced hyperalgesia though the published experience is mixed
in regards to this issue.223
There are some concerns with high-dose acute fentanyl admin-
istration. In an animal study, fentanyl and the combination of
fentanyl plus diacetylmorphine (heroin) produced a rapid brain
hypoxia and subcutaneous hypoxia. The combination produced
a 10-fold greater affect than fentanyl alone and 5-fold greater
effect than diacetylmorphine. On the other hand, oxycodone in
low dose to moderate doses increased brain oxygen levels and
morphine in low doses increased brain oxygen levels. The neu-
rocirculatory responses to oxycodone and morphine oppose the
respiratory depression effects.224 This effect in animals reflexes
the increase deaths seen when heroin is combined with fentanyl.
Intranasal opioids for acute and breakthrough pain
Intranasal fentanyl
Drug absorption through the nasal cavity bypasses hepatic clear-
ance.225 The dose volume must be limited to 150 μL to avoid run-
off into nasopharynx. Intranasal fentanyl is 70% bioavailability.
To deliver 60 mcg (2 doses in a volume of 150 μL, one per nostril),
fentanyl is concentrated to 400 mcg/mL, the parenteral IV solu-
tion cannot be used in adults.226–229 A single dose of 50 mcg of
fentanyl produces rapid analgesia (within 5 min) in postoperative
gynecologic patients.230
Intranasal fentanyl has better bioavailability and shorter onset
to action (7 min) than transmucosal fentanyl.230 Fentanyl in pec-
tin and/or chitosan improves nasal absorption. A double-blind
randomized trial reported superiority of intranasal fentanyl spray
over placebo.231 In a selective patient population, fentanyl pectin
nasal spray was consistently effective in controlling breakthrough
pain.232 Titration is necessary to reach the effective dose as there
is a poor relationship to the around-the-clock opioid dose.233
In a double-blind, double-dummy crossover study, intranasal
compared with IV fentanyl for postoperative pain. Intranasal
fentanyl had a delayed time to maximum concentration (13 min)
compared with IV fentanyl (6 min). There was also a lower maxi-
mum concentration (1.2 vs. 2.0 ng/mL); analgesia was slightly
delayed. Duration of pain relief was dose dependent but not route
dependent.234
Intranasal fentanyl has been compared to IV fentanyl in indi-
viduals undergoing orthopedic, abdominal, and thyroid surger-
ies.235 Intranasal fentanyl doses were 25 mcg and IV PCA doses
17.5 mcg with a lockout interval of 6 min for both. Time to first
noticeable reduction in pain intensity was the same for both
(21–22 min). Pain intensity was reduced to the same extent (55 to
11 mm by VAS). A 50-mcg intranasal fentanyl dose reduced pain
within 5 min of administration.170
Intranasal and sublingual sufentanil
Intranasal sufentanil, in the form of nose drops or spray using the
parenteral solutions and a 10–20-mcg dose, is reported to be very
effective.236 Tmax ranges between 15 and 30 min.237 A dose of 0.05
mcg/kg (average dose to 3.5 mcg) reduced pain to less than 3 on an
NRS scale within 20 min in 80% of surgical patients.238 Sufentanil
in the emergency department using a dose of 0.4 µm/kg improved
pain control at 30 min which was superior to IV potent opioids
603
(response 72.2% vs. 51.4%) but at the cost of increased respiratory
depression (12.5% vs. 1.4% as determined by respiratory rate of
less than 10). Oxygen saturations and length of stay in the emer-
gency department were not different.239,240 Intranasal fentanyl
at a dose of 0.7 µm/kg has been compared to IV morphine at a
dose of 0.1 mg/kg in the emergency department. Responses at 10
min were not different. There are no serious adverse reactions or
need for rescue analgesics. There was no difference in patient’s
satisfaction.241
Sufentanil sublingual tablets 30 mcg have been developed to
manage acute pain in the medical supervised setting. The single
dose preparation limits errors. Repeat dosing can occur at 1:00
a.m. Pain reduction is usually observed in 15–30 min and the
duration of relief ranges from 2 to 24 h. There is a need for direct
comparison with other opioids including efficacy, utility, and cost
effectiveness.242
Intranasal hydromorphone
In a study of 35 children in acute pain, intranasal hydromorphone
at a dose of 0.03 mg/kg produced a 40% reduction in pain inten-
sity within 5–15 min. The duration of analgesia was greater than
1 h in 85% of patients.243
Nonopioid analgesics and adjuvants for acute pain
Classic NSAIDs
NSAIDs have been used for breakthrough pain. Flurbiprofen was
reported with some success.244 NSAIDs are used commonly for
postoperative pain management (47% in an Italian survey).245 The
five commonly used NSAIDs are ketorolac, diclofenac, ibupro-
fen, ketoprofen, and paracoxib.246 A novel diclofenac preparation
employs hydroxypropyl beta-cyclodextrin solvent, which concen-
trates diclofenac to a small volume. Half of patients responded
to 75 mg of IV diclofenac within 15 min, which was superior to
placebo.247 Diclofenac is superior to ketorolac in managing post-
operative pain when side effects were included as outcomes.248
Diclofenac not only blocks cyclooxygenase but inhibits substance
P release, blocks NMDA receptors, and ASIC, which may account
for the excellent responses.249
A new IV preparation of ibuprofen has been approved for use
during the first 24 h after surgery; doses are 800 mg every 6 h.
Parenteral ibuprofen reduced morphine requirements by 22% and
decreased pain at rest and with movement. Less nausea, vomit-
ing, and constipation were reported than with morphine alone.
The main side effect was dizziness that was dose dependent.189,250
Meloxicam
There are 7 postoperative acute pain trials using meloxicam
involving 1,426 patients.251 Patient has received fixed doses rang-
ing from 5 to 60 mg, most received greater than 2 doses (73%).
Almost all were aged less than 65 (93%). Bleeding was low in doses
that were less than 15 mg (2.5%) but increased with higher doses
(60 mg, 9.5%). Anemia was common relative to the compared her
(8% vs. 1.4%). There was not an increase in postoperative cardio-
vascular events reported in any of the trials.
Ketorolac
Ketorolac has been used in the emergency department for acute
pain and recently review.252 Doses ranged from 10 to 30 mg.
Patients had moderate-to-severe pain when placed on study (and
are asked ≥5). The pain reduction was similar regardless of dose
604
(10 mg, NRS 7 0.7–5.1; 15 mg NRS 7.5–5.0; 30 mg NRS 7.8–4.8).
Treatment emerging adverse effects were dizziness, nausea,
and headache. It does not appear that dose titration for pain in
patients not responding to 10 mg as a single dose will increase
pain control in most patients.
Acetaminophen
Acetaminophen, in animal models, is a cox-3 inhibitor and also
blocks NMDA receptors, nitric oxide release, and substance P
release.253 Parenteral acetaminophen is available either as the
parent drug or the prodrug propacetamol. Propacetamol is con-
verted to acetaminophen by circulating nonspecific esterases.254
IV acetaminophen was superior to placebo after cardiac sur-
gery.255 IV acetaminophen 1 g before and 4 and 16 h after breast
surgery reduced morphine requirements by 42% and was superior
to placebo. Acetaminophen improved postoperative ambulation
compared with metamizole.256 IV acetaminophen before surgery
and every 6 h after surgery for 24 h was equivalent to dipyrone and
reduced the risk of drug-related renal failure and peptic ulcers.
A comparison of acetaminophen to hydromorphone for acute
pain was recently published. The setting was the emergency
department.257 One group received 1 g of parenteral acetamino-
phen was compared to 1 mg of hydromorphone. Analgesia at 60
min was the main outcome. Two-hundred and twenty patients
participated in the study. Reductions in pain severity measured by
the NRS were greater with hydromorphone (5.3) compared with a
see the min if in (3.3). Almost two-thirds of patients treated with
hydromorphone declined a second dose (65%) compared with
44% of treated acetaminophen-treated patients. Side effects were
greater with hydromorphone including nausea (19% vs. 3%) and
vomiting (14% vs. 3%).
Anticonvulsants
Gabapentin and pregabalin
Preoperative gabapentin (doses of 300–1,200 mg) reduces post-
operative pain and morphine requirements by 30%. By meta-
regression analysis, benefits were not dose dependent. Both
rest- and activity-related pain improves. Opioid side effects are
less in part due to reduced morphine requirements. The NNT
for less nausea was 25, 6 for less vomiting, and 7 for less urinary
retention. Gabapentin side effects include sedation and dizziness,
with the number needed to harm of 35 for sedation and 12 for
dizziness.258–261 The same benefits and side effects are reported
with pregabalin.
Ketamine
Ketamine is a racemate of R and S enantiomers. In some European
countries, S-ketamine is available. Low-dose ketamine improves
postoperative analgesia and reduces morphine requirements.262
Low doses are considered to be less than 1 mg/kg IV bolus and IV
infusions are usually given less than 20 mcg/kg/min.263 Ketamine
has been used as bolus doses in the perioperative period, in con-
tinuous infusions, by PCA mixed with morphine, by mouth, and
as a transdermal patch.264–267 S-ketamine available in Europe is
also effective.268 Effective bolus doses of racemate ketamine range
from 0.15 to 0.25 mg/kg. Effective continuous infusion doses are
in the range of 1.5 mcg/kg/min. A demand PCA of morphine 1
mg and ketamine 5 mg given at 7 min lockout intervals has been
reported to be effective in managing postoperative pain.269,270
Transdermal ketamine, 25 mg over 24 h, is reported to be well
Textbook of Palliative Medicine and Supportive Care
absorbed.271 Transdermal delivery of ketamine was an useful
adjuvant to postoperative analgesia after epidural lidocaine block-
ade.271 Ketamine reduces nausea and vomiting in the postopera-
tive period, perhaps due to its opioid sparing effects. Ketamine,
unlike morphine, does not cause hypotension or respiratory
depression, which can be a problem for post-thoracotomy patient
and for those on high-dose morphine.272–274 Preemptive and IV
infusions of ketamine at the end of surgery (0.3 mg/kg bolus and
0.05 mg/kg/h during surgery) compared with preemptive gaba-
pentin 1,200 mg and placebo reduced postoperative morphine
requirements by 35%–42% and was superior to placebo. However,
incisional pain at 1, 3, and 6 months was better with gabapentin
compared with ketamine. 3
Ketamine infusions (0.1 mg/kg/h) have been compared with
morphine 0.1 mg/kg every 4 h as needed for acute musculo-
skeletal trauma. Ketamine resulted in better pain relief and less
drowsiness than intermittent morphine. None of the ketamine-
treated individuals required supplementary analgesia and were
easily mobilized for traction or splints.275
In a double-blind, randomized placebo-controlled trial involv-
ing individuals with severe acute pain (a VAS score of greater
than 60 mm on a 100-mm scale), IV morphine 0.1 mg/kg followed
by 3 mg every 5 min as needed with or without ketamine 0.2 mg/
kg over 10 min IV were compared. Morphine consumption was
less with the combination (0.149 vs. 0.202 mg/kg); the pain scores
were similar at 30 min (34 vs. 39 mm by VAS). Side effects with
ketamine are hallucinations, dizziness, diplopia, and dysphoria.276
In a retrospective review of the use of low-dose ketamine
(ranging from 0.1 to 0.6 mg/kg) in the emergency department,
pain severity was reduced by 54%. Most individuals (91%), how-
ever, received an opioid prior to or after ketamine. Eight of 35
individuals failed to respond to ketamine.277
A randomized control trial compared morphine (0.2 mg/kg)
with morphine (0.1 mg/kg) plus ketamine (0.2 mg/kg) prior to
hospitalization for acute trauma. Morphine doses needed for anal-
gesia were less with the combination (7 vs. 13.5 mg). Pain severity
by NRS improved with the combination to a greater extent than
to morphine alone (5.4 vs. 3.1). Blood pressure increased with
ketamine. Side effects occurred in a minority and did not differ
between groups.278
Small doses of ketamine in the opioid tolerant may produce
better pain control than escalation of opioid doses. This strategy
reduces the risk of oxygen desaturation, and less opioid is needed
to control pain.279 Rotations to methadone plus the addition of
100 mg of ketamine daily improved both rest and movement
related pain.280 In a cohort of patients receiving both intrathecal
opioids and high-dose systemic opioids for incident pain, the use
of intrathecal boluses of local anesthetics or sublingual ketamine
(25 mg) reduced pain within 10 min.281
Oral ketamine has been used at doses of 0.5 mg/kg twice to
three times daily. Responses in those with neuropathic pain
on oral opioids and/or antidepressants were seen within 24 h.
Sedation was experienced by a few, which resolved over a week or
2, despite continued ketamine.282
Retrospective reviews and small cohort studies have found ket-
amine effective in managing cancer pain.283,284 In a randomized,
double-blind, placebo-controlled trial, ketamine plus morphine
did not improve cancer pain compared with morphine alone.285
There is insufficient evidence to assess the benefits and harms of
ketamine as an adjuvant to opioids for the relief of cancer pain.286
Ketamine may be particularly helpful in opioid tolerant indi-
viduals during the postoperative. Initial recommended doses
Acute Pain and Management
should not exceed 0.35 mg/kg. Ketamine should be avoided in
individuals with poorly controlled cardiovascular disease, during
pregnancy, in patients with psychotic disorders or patients with
advanced cirrhosis. Also, ketamine should not be used in patients
with high intracranial or ocular pressures.287
Ketamine has been added to morphine for analgesia in trauma
patients with fractures. There was improvement in pain with
reduction in opioid requirements when ketamine was added.
Ketamine does increase the number of minor side effects when
combined with morphine or hydromorphone.287
Intranasal ketamine at a dose of 50 mcg or 1 mg/kg can be effec-
tive for perioperative pain and in the emergency department.288–292
Dexmedetomidine
Dexmedetomidine is a highly selective alpha-2 receptor ago-
nist that avidly binds to alpha-2A adrenergic receptors.293
Dexmedetomidine activates postsynaptic alpha-2 adrenergic
receptors, which hyperpolarize second-order afferent neurons,
thus inhibiting nociceptive. Dexmedetomidine inhibits adeny-
lyl cyclase, N-type calcium channels and promotes activation
of inward rectify potassium channels.293 Compared with cloni-
dine, dexmedetomidine is more selective and specific for alpha-2
adrenergic receptors.294 Side effects include hypotension, brady-
cardia, and sedation, which are a barrier to use the drug on gen-
eral medical wards.
Dexmedetomidine has been given preemptively at a bolus
dose between 1 and 0.5 mcg/kg and 0.4–0.5 mcg/kg/h infusion.
Postoperative opioid requirements and opioid side effects were
reduced, analgesia significantly improved. Mild bradycardia and
reduced blood pressure occurred but did not lead to dose reduction
or discontinuation for most individuals.295 Dexmedetomidine has
been combined with morphine in an IV PCA for postoperative
pain. Morphine 1 mg and dexmedetomidine 5 mcg with a lockout
interval of 5 min were compared to morphine alone. The com-
bination produced a 29% reduction in morphine requirements,
as well as reduction in postoperative nausea within the first 24 h
after surgery.296 Dexmedetomidine has been used for acute pain
in opioid-tolerant individuals admitted to the hospital in severe
pain. In a case series, 7 of 11 patients had substantial reductions
in opioid doses with dexmedetomidine.297 Dexmedetomidine,
using a loading dose of 0.9–1 mcg/kg over 1 h and an infusion
of 0.3–0.4 mcg/kg/h, improved pain control and reduced opioid
requirements postoperatively. The infusion can be safely done on
general medical wards.298 Dexmedetomidine reduces the risk of
drug-related delirium, preserves sleep architecture, ventilatory
drive, decreases sympathetic tone, and reduces postoperative
inflammatory responses.299–301
Summary and discussion
A recently published which summarize is nicely what we know
about pain.302 There are important take-home points regarding
acute pain. Ultimately, pain is a private mental event which is
expressed socially and through facial expressions and by way of
a common culturally collared language. Acute pain is meant for
self-preservation. However, untreated acute pain results in large
financial, personal, social, and familial adverse effects. In a subset
of patients with acute pain, pain will continue beyond the normal
time of tissue healing which by definition is chronic pain. Changes
from acute to chronic pain are the result of alterations in connec-
tivity within the brain. Predicting individuals who are at risk for
developing chronic pain and preventing the transformation of
605
acute to chronic pain is a major task for researchers and clinicians.
Moderate society has recategorized pain from a disease to a symp-
tom and as a result has largely focused on the underlying “cause”
of pain relegating pain to secondary important and less worthy
of research. Investment into treating pain is relatively small com-
pared to investments in treating “disease.” Acute and chronic
pain are difficult to treat and require a multidisciplinary approach
similar to treatment of diseases like cancer. Very few systematic
reviews of interventions show clinically meaningful reductions
in pain in the majority of patients treated and even fewer studies
have demonstrated any meaningful reduction in the transition of
acute to chronic pain. Even modern strategies such as PCA tech-
nologies reduce pain only by 10% over conventional therapies.
Intensity scales may not tell us what we need to know or what
we want to know. Intensity scales do not provide information
about the consequences of acute pain to the individual. The psy-
chosocial adverse effects are not reflected in intensity and may
be the most important outcome to pain management. We do
not know how to tailor evidence to the individual. We cannot
predict responses. “Ineffective” analgesics for whole groups of
patients assessed by a standard response measure may in fact be
quite effective in a subgroup of patients. We do not know how to
reduce harm which has become evident in the opioid epidemic.
The development of tamper resistant opioids is not a major step
forward in managing pain. There are many side effects to opioids
to which tamper-resistant opioids only address one potential
adverse effect and only partially. Guidelines are helpful only in
the initial choices of therapy. Thereafter individual attention to
responses and N-of-1 trials are the most reasonable approaches to
management until better strategies are established. Finally, pla-
cebo responses to acute pain are clinically meaningful to patients
and should not be ignored.
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299. Mantz J, Josserand J, Hamada S. Dexmedetomidine: new insights. Eur
J Anaesthesiol 2011;28(1):3–6.
300. Degos V, et al. Neuroprotective effects of dexmedetomidine against
glutamate agonist-induced neuronal cell death are related to increased
astrocyte brain-derived neurotrophic factor expression. Anesthesiology
2013;118(5):1123–1132.
301. Ng KT, Shubash CJ, Chong JS. The effect of dexmedetomidine on
delirium and agitation in patients in intensive care: systematic
review and meta-analysis with trial sequential analysis. Anaesthesia
2019;74(3):380–392.
302. Aldington D, Ecclestone C. Evidence-based pain management: build-
ing on the foundations of Cochrane systematic reviews. Am J Public
Health 2018;e1–e4.
64
SUICIDE

Daniel C. McFarland, Yesne Alici, and William S. Breitbart

Contents
Introduction........................................................................................................................................................................................................................613
Etiology of suicide in the medically ill...........................................................................................................................................................................613
Suicide and terminal illness.............................................................................................................................................................................................614
Assessment and management of the suicidal patient.................................................................................................................................................615
Desire for hastened death.................................................................................................................................................................................................616
Requests for assisted suicide or medical aid-in-dying................................................................................................................................................616
Interventions for despair at the end of life....................................................................................................................................................................617
Spiritual suffering.........................................................................................................................................................................................................617
Demoralization.............................................................................................................................................................................................................617
Loss of dignity...............................................................................................................................................................................................................618
Loss of meaning............................................................................................................................................................................................................619
Interventions for family members following a completed suicide...........................................................................................................................620
References............................................................................................................................................................................................................................621

Introduction symptoms, rather than diagnoses, as a way to understand suicide

Suicide is a tragic but often preventable response to the emo-
tional challenges of terminal physical illness. Although it is
often assumed that suicide is common in the chronically ill,
the fact remains that it is still relatively uncommon.1 Suicide
in terminal illness may represent a pathologic, and therefore
potentially treatable, coping response. The purpose of this
chapter is to examine the prevalence of suicide in pallia-
tive care settings, factors that contribute to it, and potential
interventions both to prevent it as well as to cope with the
trauma that completed suicides have on family and signifi-
cant others.
Etiology of suicide in the medically ill
Theories of suicide generally represent the convergence of the
past and present. For example, medical illness alone is unlikely
to precipitate a suicidal act. Multiple determinates act together
and are drawn from historical experience or genetic make-up and
current situational factors. Edwin Shneidman conceptualized
three dimensions interacting; perturbation (state of being per-
turbed or stirred up), pain (frustrated psychological needs leading
to psychological pain), and intensity (genetic and developmental
susceptibility).2 He coined the neologism “psyche-ache” as an
unbearable psychological pain—hurt, anguish, soreness, and ach-
ing. In his thinking, suicidal behavior resulted from unresolved
“psyche-ache” in almost all cases of suicide. The stress-diathesis
model of suicidal behavior focuses on present-day stressors on top
of a diathesis or tendency toward a given psychiatric condition or
behavior. 3 This coupling of present and past context is similarly
highlighted by the description of proximal and distal factors by
Moscicki in studying suicides of elderly patients.4 Interventions
are more likely to be successful if multiple risk factors are tar-
geted. It is helpful to focus on the risk and probability of suicide
within particular subgroups of patients experiencing psychiatric
in the medically or terminally ill.
Suicidal ideation is defined as thoughts of taking one’s own life.
For most patients, this may only occur as a fleeting consideration
they have during particularly distressing moments in their ill-
ness. These thoughts may serve as a “steam valve” for thoughts
and feelings that are often expressed by patients as “no matter
how bad things become, I always have a way out.” For others, it
may occur more frequency and result in a concrete plan of mea-
sures one will take to end their own life. When the latter occurs,
it is a psychiatric emergency that can require involuntary hos-
pitalization to protect the individual from self-injury. Because
terminally ill patients frequently experience these thoughts, it
is important for clinicians to feel comfortable assessing suicidal
ideation in their patients. Table 64.1 provides some suggestions
on asking patients about suicidal thoughts.
Some published reports have suggested that suicidal ideation is
relatively infrequent in illnesses such as cancer. However, suicidal
ideation is frequently not asked about and is certainly under-
reported. Suicidal ideation can vary in intensity from transient
thoughts to ruminative preoccupation. Chochinov et al. found
that 89 of 200 terminally ill patients (44.5%) reported fleeting
desire for death while 17 (8.5%) endorsed an enduring wish for
death.5 Suicidal ideation and history of suicidal behavior are
among the most salient short- and long-term risk factors for sui-
cide.6,7 While suicidal ideation is a typical prodrome (presuicidal
syndrome), actual suicide can occur without immediate warning.
That is, the actual occurrence of suicide does not always directly
proceed from a period of suicidal ideation.8 Major depression and
other mood disorders, highly prevalent in medically or terminally
ill populations, are closely associated with completed suicides. A
study conducted at St. Boniface Hospice in Winnipeg, Canada,
demonstrated that only 10 of 44 terminally ill cancer patients
were suicidal or desired an early death, and all 10 were suffering
from clinical depression.5 At Memorial Sloan-Kettering Cancer
Center (MSKCC), suicide risk evaluation accounted for 8.6% of

613
614
TABLE 64.1  Assessing Suicidal Ideation Severity
Suicidal ideation Many patients have passing thoughts of suicide, such
as “If my pain was bad enough, I might think about
suicide …” Have you had thoughts like that?
Have you found yourself thinking that you do not
want to live or that you would be better off dead?
Suicidal plan Have you stopped or wanted to stop taking care of
yourself?
Have you thought about how you would end your life?
Have you taken any steps toward planning suicide?
Suicidal intent Do you plan or intend to hurt yourself? What would
you do?
Do you think you would carry out these plans?
Is there anything that would prevent you from
committing suicide?
Source: Breitbart W. Cancer pain and suicide. In: Foley KM, Bonica JJ, Ventafridda
V (eds.), Advances in Pain Research and Therapy, 1990, New York: Raven
Press, vol. 16, pp. 399–412.
inpatient psychiatric consultations, usually requested by staff in
response to a patient verbalizing suicidal wishes.6 Among 185
cancer patients with pain studied at MSKCC, suicidal ideation
was found in 17% of the study population.6 The actual prevalence
of suicidal ideation is likely considerably higher than these fig-
ures suggest, in that patients often disclose these thoughts only
after a stable, ongoing physician−patient relationship has been
established. It has been our experience that once such a trusting
and safe relationship is formed, patients almost universally reveal
occasional persistent thoughts of suicide as a means of escaping
the threat of being overwhelmed by their illness.
Suicide and terminal illness
Terminally ill patients are at elevated risk of suicide when com-
pared to the general population. A study done by Hem and col-
leagues examining data from the Cancer Registry of Norway
revealed standardized mortality ratios of 1.55 for males and 1.35
for females.9 The study also found that risk was greatest in the
first months following diagnosis and was significantly increased
in male patients with respiratory cancers.9 While the first year
after a cancer diagnosis tends to be the time of greatest concern
for suicide completion, the relative risk is 12.6 (CI 8.6–17.8) dur-
ing the first week after diagnosis and is still significantly elevated
with a relative risk of 4.8 at 3 months after the diagnosis.10,11 A
study by Druss and Pincus examining the relationship between
suicide and medical illness found that cancer patients had a four-
fold increase in the likelihood of a suicide attempt.12 The type
of disease can make a difference as well. Some cancers, such
as bladder, kidney, and prostate, have persistently elevated risk
while some other cancers such as thyroid carcinoma carry a risk
of suicide similar to the general population.13–15 At the same time,
length of time since diagnosis and stage of disease at diagnosis are
also related to suicidality.16 Patients with more advanced disease
at diagnosis are at higher risk for suicide.16 These types of disease-
specific characteristics likely combine with other demographic
(e.g., elderly, white, unmarried, males) and clinical risk factors
(e.g., unremitting pain, physical deformity, reduced functional
status) for suicide to become a greater cumulative risk.17
A Swedish study of cancer-related suicides revealed that half
of all patients who committed suicide had previously conveyed
suicidal thoughts or plans to their relatives.12 In addition, many of
Textbook of Palliative Medicine and Supportive Care
TABLE 64.2 Advanced Illness Factors Associated with an
Increased Risk of Suicide
• Pain—aspects of suffering
• Advanced illness—poor prognosis
• Depression—hopelessness
• Anxiety-agitation and restlessness
• Delirium—disinhibition, poor impulse control, impaired judgment
• Loss of control—helplessness
• Preexisting psychopathology (e.g., psychiatric hospitalizations,
treatments etc.)
• Substance/alcohol use disorders (abuse or dependence)
• Personal or family history of suicide attempts
• Fatigue
• Lack of social support—social isolation
the completed cancer suicides had been preceded by an attempted
suicide.12 This is consistent with the statistics of suicide in general,
which shows that a previous suicide attempt greatly increases the
risk of completed suicide.18 A family history of suicide is also of
increasing relevance in assessing suicide risk.
Factors associated with increased risk of suicide in patients
with advanced physical disease are listed in Table 64.2. Patients
with advanced illness are at highest risk, perhaps because they are
most likely to have such complications such as pain, depression,
delirium, and physical disability. Psychiatric disorders including
substance use disorders are frequently present in hospitalized
patients who are suicidal. A review of consultation data from the
psychiatry service at MSKCC revealed that one-third of suicidal
cancer patients had a major depression, about 20% suffered from
delirium, and 50% were diagnosed as having an adjustment disor-
der with both anxious and depressed features at the time of evalu-
ation.19 Delirium and other cognitive disorders place terminally
ill patients at risk for suicidality by impairing impulse control and
judgment.
Physically ill patients complete suicide most frequently in the
advanced stages of disease.16,20 The incidence of significant cancer
pain increases with advancing disease. Uncontrolled pain in can-
cer patients is a dramatically important risk factor for suicide.21
Depression is a factor in 50%–75% of all suicides.19 Those suffer-
ing from depression are at 25 times greater risk of suicide than the
general population. The role depression plays in suicides among
the seriously medically ill is equally significant. Approximately
30%–40% of all patients with cancer experience depressive symp-
toms, with about 9.6% with a major depressive episode.22
Among those with advanced illness and progressively impaired
physical function, symptoms of severe depression rise to 77%.23
Depression also appears to be important in terms of patient
preferences for life-sustaining medical therapy. Ganzini and
colleagues reported that among older depressed patients, an
increase in desire for life-sustaining medical therapies followed
treatment of depression in those subjects who had been ini-
tially more severely depressed, more hopeless, and more likely
to overestimate the risks and to underestimate the benefits of
treatment.24 They concluded that whereas patients with mild-to-
moderate depression are unlikely to alter their decisions regard-
ing life-sustaining medical treatment in spite of treatment for
their depression, severely depressed patients—particularly those
who are hopeless—should be encouraged to engage in addressing
depression prior to making decisions about life sustain therapies
and advanced directives.
Suicide
Hopelessness is the key variable that links depression and sui-
cide in the general population. Further, hopelessness is a signifi-
cantly better predictor of completed suicide than is depression
alone. Chochinov and colleagues demonstrated that hopeless-
ness was correlated more highly with suicidal ideation in ter-
minally ill patients than was the level of depression.25 With the
typical cancer suicide being characterized by advanced illness
and poor prognosis, hopelessness is commonly experienced. In
Scandinavia, the highest incidence of suicide was found in cancer
patients who were offered no further treatment, and no further
contact with the healthcare system.26 Being left to face illness
alone creates a sense of isolation and abandonment that is critical
to the development of hopelessness.
Loss of control and a sense of helplessness in the face of one’s
illness are important factors in suicide vulnerability. Control
refers to both the helplessness induced by symptoms or deficits
due to the illness or its treatments, as well as the excessive need
on the part of some patients to be in control of all aspects of liv-
ing or dying. This need to control may be prominent in some
patients and cause distress with little provocation. Patients who
were accepting and adaptable were much less likely to com-
mit suicide than patients who exhibited a need to be in control
of even the most minute details of their care. However, it is not
uncommon for illness-related events to induce a great sense of
helplessness even in those who are not typically controlling indi-
viduals. Impairments or deficits induced by the patient’s illness
or its treatments often include loss of mobility, paraplegia, loss of
bowel and bladder function, amputation, aphonia, sensory loss,
and inability to eat or swallow. Most distressing to patients is the
sense that they are losing control of their minds, especially when
they are confused or sedated by medications. The risk of suicide is
increased in patients with such physical impairments, especially
when accompanied by psychological distress and disturbed inter-
personal relationships due to these deficit factors.
Fatigue, in the form of emotional, spiritual, financial, familial,
communal, and other resource exhaustion, increases the risk of
suicide in the seriously physically ill patient.27 Due to advance-
ments in treatment, illnesses such as cancer now often follow
more of a chronic course. Increased survival is accompanied
by an increased number of hospitalizations, complications, and
expenses. Symptom control thus becomes a prolonged process
with frequent advances and setbacks. The dying process also can
become extremely long and arduous for all concerned. It is not
uncommon for both family members and healthcare providers
to withdraw prematurely from the patient under these circum-
stances. A suicidal patient can thus feel even more isolated and
abandoned. The presence of a strong support system for the
patient that may act as an external control of suicidal behavior
reduces the risk of suicide significantly.
Assessment and management
of the suicidal patient
Assessment of suicide risk and applying appropriate interventions
are critical to preventing suicides. Early and comprehensive psy-
chiatric involvement with high-risk individuals can often avert
suicide. A careful evaluation includes a search for the meaning
of suicidal thoughts, as well as an exploration of the seriousness
of the risk. The clinician’s ability to establish rapport and elicit a
patient’s thoughts is essential as he or she assesses history, degree
of intent, and quality of internal and external controls. The cli-
nician should listen sympathetically, not appearing critical or
615
stating that such thoughts are inappropriate. Thoughts about sui-
cide should be validated such that the patients feel heard and the
listener understands their deliberation between the will to live or
die. Intervening to reduce suffering, restore connectedness, and
maintain safety defuses suicidal thinking.28 Allowing the patient
to have discussions about suicidal ideation often decreases the
risk of suicide. The myth that asking about suicidal thoughts “puts
the idea in their head” is one that should be dispelled. Patients
often reconsider and reject the idea of suicide when the physician
acknowledges the legitimacy of their option and the need to retain
a sense of control over aspects of their death. Once the setting has
been made secure, assessment of the relevant mental status and
adequacy of pain control can begin. Analgesics, antipsychotics,
or antidepressant drugs should be used when appropriate to treat
agitation, psychosis, major depression, or pain. Underlying causes
of delirium or pain should be addressed specifically when pos-
sible. Initiation of a crisis-intervention-oriented psychotherapeu-
tic approach, mobilizing as much of the patient’s support system
as possible, is important. A close family member or friend should
be involved in order to support the patient, provide information,
and assist in treatment planning. Psychiatric hospitalization can
sometimes be helpful but is usually not desirable in the termi-
nally ill patient. Thus, the medical hospital or home is the set-
ting in which management most often takes place. Whereas it
is appropriate to intervene when medical or psychiatric factors
are clearly the driving force in a cancer suicide, there are circum-
stances when usurping control from the patient and family with
overly aggressive intervention may be less helpful. This is most
evident in those with advanced illness where comfort and symp-
tom control are the primary concerns.
Normalization of the topic of suicide is important to be able to
get appropriate resources to patients in need. Often, a non-pro-
fessional is able to normalize these thoughts and feelings as well
as a professional. Preventing suicides has become a top priority
for hospitals and the Joint Commission has recently issued an ele-
ment of performance to prevent suicide, which became effective
in 2019.29 They state that prevention of suicide has not improved
in 10 years and remains the 10th leading cause of death in the
United States. To this end, suicide screening has become stan-
dard of care to meet joint commission hospital guideline stan-
dards. The Columbia Suicide Severity Rating Scale (C_SSRS) is a
suicide measure that can be used by non-mental health clinicians
and non-clinicians with high reliability. 30 It has been validated in
multiple settings and has numerous studies supporting its psycho-
metric validity. 31,32 Most screening instruments should encour-
age further assessment of any “non-zero” intent to die because of
the fluctuating nature of suicidal ideation and the mixed motives
involved in suicidal ideation. 33 A tool, such as the C-SSRS, enables
and empowers non-physician clinicians and even non-clinicians
to ask about suicide since suicide should be discussed whenever
the patient is endorsing depression or other psychological dis-
tress, hopelessness, has multiple untreated physical symptoms,
or a history of personal or familiar suicide attempts/completions,
for example. Screening and clinically responding to suicidal ide-
ation should really be no different in patients with life limiting
or terminal disease but will more likely indicate the presence of
another un-met need such as the treatment of pain, immobility,
or psychological distress that the medical team should be pre-
pared to address.
Ultimately, the palliative care clinician may not be able to pre-
vent all suicides in all terminally ill patients that he or she cares for.
The emphasis of intervention should be to aggressively attempt to
616 Textbook of Palliative Medicine and Supportive Care

TABLE 64.3  Questions to Ask Patients and Family When Assessing Suicide Risk
Acknowledge that these are common Most patients with cancer have passing thoughts about suicide, such as “I might do something if it gets
thoughts that can be discussed bad enough.” Have you ever had thoughts like that?
Have you had thoughts of not wanting to live?
Have you had those thoughts in the past few days? When was the last time you thought about suicide?
Assess level of risk Do you have thoughts about wanting to end your life? How?
Do you have a plan? Have you carried out any steps in your plan?
Do you have any strong social support?
Do you have pills stockpiled at home?
Do you own or have access to a weapon?
Obtain prior history of suicidal behaviors Have you ever had a psychiatric disorder, suffered from depression, or made a suicide attempt?
Is there a family history of suicide?
Identify substance abuse Have you ever had a problem with alcohol or drugs?
When was the last time you had X?
Have you ever had any relationship or legal problems due to substance use?
Identify bereavement and grief Have you lost anyone close to you recently?
How are you coping?
Identify medical predictors of risk Do you have pain that is not being relieved?
How long has the disease affected your life?
How is your memory and concentration?
Do you feel hopeless?
What do you plan for the future?
Source: Adapted from American Psychological Oncology Society. Quick Reference for Oncology Clinicians: The Psychiatric and Psychological Dimensions of Cancer Symptom
Management, Charlottesville, VA: IPOS Press, 2006.

prevent suicide that is driven by the desperation of uncontrolled
physical and psychological symptoms such as uncontrolled pain,
unrecognized delirium, and unrecognized and untreated depres-
sion. Prolonged suffering caused by poorly controlled symptoms
may lead to such desperation, and it is the appropriate role of the
palliative care team to provide effective management of physical
and psychological symptoms as an alternative to desire for death,
suicides, or requests for assisted suicide by their patient. Table 64.3
presents an overview of commonly used suicide assessment ques-
tions with terminally ill patients and their families.
Desire for hastened death
The desire for hastened death (DHD) is an issue that is commonly
encountered by the palliative care physician. It requires a pro-
found level of personal and professional development to respond
to the inherent challenges presented by DHD. 34 It may present
as a passive wish for death, the decision to forego aggressive
therapy that could alter survival outcomes, the decision to dis-
continue life-prolonging treatment, suicidal ideation, or a request
for physician-assisted suicide (PAS). Breitbart et al. found that
in a hospice setting, 17% of the 92 terminally ill patients evalu-
ated indicated a high DHD. 35 Chochinov et al. reported that
44.5% of the 200 terminally ill studied reported a fleeting desire
for death.5 A more persistent wish for hastened death occurred
in 8.5% of the sample.5 Because of its frequency, being able to
identify underlying factors contributing to a patient’s DHD is
key for care-providers. Breitbart et al. found that depression and
hopelessness were the strongest predictors of DHD among termi-
nally ill cancer patients. 35 Similarly, depression has been found
to act as a moderator in the relationship between hopelessness
and DHD. 36 They were also found to have significantly more
pain and less social support when compared to patients without
DHD. Similarly, in 2007, Rodin et al. found that DHD correlated
positively with hopelessness, depression, and physical distress. 37
Existential concerns such as loss of meaning and purpose, loss
of dignity, regret, awareness of incomplete life tasks, and anxi-
ety around what happens after death have been associated with a
DHD. Chochinov et al. found that terminally ill cancer patients
with a lowered sense of dignity were more likely to report a loss
of will to live.5 Terminally ill cancer patients who had low spiri-
tual wellbeing were more likely to endorse a DHD, hopelessness,
and suicidal ideation based on a study done by McClain and
colleagues. 38
In summary, common risk factors associated with a DHD
include depression or history of psychiatric illness, hopelessness,
physical distress (including pain and symptom burden), poor
social support, fear of being a burden to others as well as existen-
tial concerns such as loss of meaning and loss of dignity.
Requests for assisted suicide
or medical aid-in-dying
As mentioned in the preceding section, a DHD may present as
a request for PAS. This has become a highly controversial topic
in palliative medicine but one that is clearly in evolution. Since
the last edition of this textbook, several states across the United
States have legalized physician assisted suicide or medical aid-in-
dying (MAID) (Colorado, District of Columbia, Hawaii, Maine,
New Jersey, and Vermont) in addition to Oregon, Montana, and
Washington. Germany has been added to the list of countries
along with the United States (i.e., Netherlands and Switzerland)
to allow MAID for terminally ill patients. An article in The New
England Journal of Medicine examined attitudes for and against
PAS. 39 Those opposed to it argue that its legalization will alter the
fundamental role of the doctor as healer and may place certain
more vulnerable communities at risk of abuse, error, and coer-
cion. The International Association for Hospice and Palliative
Care put forth a position statement that in countries where
MAID and euthanasia are legal, there must be adequate and
Suicide
developed palliative and supportive care services but that pallia-
tive care units should not be responsible for overseeing or admin-
istering these practices.40 Similarly, the European Association
for Palliative Care put forth a white paper to ensure that these
practices adhere to the ethical practices of palliative care. They
provided clear definitions that highlighted for example that
euthanasia can never be involuntary by definition.41 However,
physician attitudes toward requests for MAID have become more
accepting in the last 16 years.42 Advocates argue that allowing
patients a legal and socially accepted way of controlling their own
death would avoid people having to plan in secrecy and endure
the difficult process alone. They also feel that safeguards, such
as a thorough informed consent process and the requirement
of an independent second opinion, would protect against most
risks. In Oregon of the United States, the Death with Dignity
Act (DWDA) was passed in 1997. From 1998 to 2017, a total of
1857 Oregonians have obtained DWDA prescriptions and 1179
(64%) have died from ingestion of the medication prescribed.43
Far more patients talk to their families and physicians regard-
ing the possibility of PAS compared to those terminally ill who
actually die using the Death with Dignity Act. This suggests that
even when legally permissible, few patients resort to assisted
suicide. Clinicians should allow patients to discuss their wishes
for hastened death and MAID in an open, frank manner. Being
empathic and nonjudgmental are essential to facilitating these
often difficult to discuss issues. Through such conversations,
one may be able to identify underlying reasons for such wishes,
such as hopelessness or depression and offer appropriate inter-
ventions. In a cross-sectional survey of 58 Oregonians who had
either requested aid in dying from a physician or contacted an aid
in dying advocacy group, Ganzini et al. found that 15 patients met
“caseness” criteria for depression, a diagnosis based on symptoms,
as opposed to a constellation of signs and symptoms.24 Three of
the 15 patients met criteria for depression, and all three of the
depressed participants died by legal ingestion within two months
of the research interview. The authors concluded that most termi-
nally ill Oregonians who receive aid in dying do not have depres-
sive disorders, but the current practice of the DWDA may fail to
protect some patients whose choices are influenced by depres-
sion.44 Breitbart et al. examined depression and DHD in patients
with advanced AIDS.45 Patients who were diagnosed with major
depressive disorder were placed on antidepressant treatment
and assessed weekly for symptoms of depression and DHD. The
results indicated that a patient’s DHD decreased dramatically in
patients who responded positively to antidepressant treatment.45
A prospective Dutch study of 138 terminally ill cancer patients
examined the association between depression and requests for
euthanasia. They found that of the 22% of patients, who requested
euthanasia, 23% were depressed at baseline and 44% of those
depressed requested euthanasia compared to 15% of the nonde-
pressed. The rate of request was 4.1 times greater than that of
patients without depression.46 Regardless of what one’s personal
beliefs are on PAS, being able to address treatable symptoms and
reduce suffering is at the core of palliative medicine. Clinicians
should pay particular attention to underlying depression, hope-
lessness, and physical distress when such requests are made. In
an article on PAS, Dr. Quill suggests that when a terminally ill
patient requests assistance in dying, the first step to take is to
make sure the person is getting the best possible palliative care.
He argues that when applied with skill and expertise, good pallia-
tive care can address most, but not always all, end-of-life suffer-
ing.47 Dr. Breitbart proposed an editorial on the same matter that
617
the solution to “suffering is the elimination of suffering not the
sufferer.” Suffering, he argues, can be ameliorated by “providing
excellent physical, psychological and existential, spiritual inter-
ventions in the care of the dying.”48 Table 64.4 provides an outline
of assessment of DHD and requests for MAID.
Interventions for despair at the end of life
In the past two decades, clinicians working with terminally ill
patients have developed psychotherapy techniques targeting fac-
tors that contribute to suffering at the end of life. In this section,
we will describe interventions that address some of these com-
mon factors including spiritual suffering, demoralization, loss of
dignity, and loss of meaning.
Spiritual suffering
For some patients, spiritual well-being is felt to be a crucial aspect
for coping with terminal illness. Often when faced with dying,
patients struggle with questions about their own mortality, the
meaning of life, and the existence of a higher power. Some may
turn to religion for such answers while others rely on other spiri-
tual beliefs. In their 2003 study examining spiritual well-being
in a population of terminally ill hospice patients, McClain and
colleagues found that terminally ill patients with a sense of spiri-
tual well-being had some protection against end-of-life despair. 38
This finding points to the importance of addressing spiritual con-
cerns in the terminally ill. By asking about their spiritual beliefs,
assessing the importance of spirituality in patients’ lives, explor-
ing whether they belong to a spiritual community, and offering
chaplaincy referrals, one may be able to address some of these
concerns.
Rousseau49 outlines an approach for the treatment of spiritual
suffering composed of the following steps:
1. Controlling physical symptoms
2. Providing a supportive presence
3. Encouraging life review to assist in recognizing purpose,
value, and meaning
4. Exploring guilt, remorse, forgiveness, reconciliation
5. Facilitating religious expression
6. Reframing goals
7. Encourage meditative practices, focus on healing rather
than cure
Rousseau has presented an approach to spiritual suffering,
which is an interesting blend of basic psychotherapeutic prin-
ciples. Psychotherapeutic techniques that are particularly adap-
tive to psychotherapy with the dying such as life narrative and
life review are also included. There is an emphasis on facilitating
religious expression and confession that in fact may be extremely
useful to many patients but is not applicable to all patients and
not necessarily an intervention that many clinicians feel com-
fortable providing. What Rousseau’s work suggests is that novel
psychotherapeutic interventions aimed at improving spiritual
well-being, sense of meaning, and diminishing hopelessness,
demoralization, and distress are critically necessary to be further
studied and disseminated for provision of best palliative care to
the terminally ill.
Demoralization
Kissane50 and colleagues have described a syndrome of demor-
alization in the terminally ill patient, which consists of a triad of
hopelessness, loss of meaning, and existential distress expressed
618
TABLE 64.4  Guidelines for the Assessment of Desire for Hastened Death and Requests for Medical Aid-in-Dying
Be alert to your own responses
Be open to hearing concerns and demonstrate presence
Assess contributing factors
Respond to specific issues
Conclude discussion
After discussion
Source: Adapted from Hudson PL, Schonfeild P, Kelly B, et al., Palliat. Med. 2006;20:703.
as a desire for death. They argue that this syndrome is distinct
from depression because unlike depression, it is not usually asso-
ciated with anhedonia. Demoralization is often seen in patients
with life-threatening illness, disability, bodily disfigurement, fear,
loss of dignity, social isolation, and feelings of being a burden.
Kissane and his group describe a treatment approach for demor-
alization syndrome, which is both multidisciplinary and multi-
modal. It consists of
• Ensuring continuity of care and active symptom
management
• Ensuring dignity in the dying process
• Utilizing various types of psychotherapy to help sustain
a sense of meaning, limit cognitive distortions and main-
tain family relationships (i.e., meaning-based, cognitive-
behavioral, interpersonal, and family psychotherapy
interventions)
• Using life review and narrative
• Paying attention to spiritual issues
• Using pharmacotherapy for comorbid anxiety, depression,
and delirium
Textbook of Palliative Medicine and Supportive Care
Demonstrate positive regard for the patient
Be aware of how your responses influence discussions
Monitor your attitude and responses
Seek supervision
Gently ask about emotional concerns
Be alert to verbal and nonverbal distress cues
Encourage expression of feelings
Actively listen without interrupting
Discuss desire for death using the patient’s words-obtain clarification as needed
Permit sadness, silence, and tears
Express empathy verbally and nonverbally
Acknowledge differences in response to illness
Prior psychiatric history
Prior suicide attempts
History of alcohol or substance abuse
Lack of social support
Feelings of burden
Family conflict
Need for additional assistance
Depression and anxiety
Existential concerns, loss of meaning and dignity
Cognitive impairment
Physical symptoms, especially severe pain
Acknowledge patient or family fears and concerns
Address modifiable contributing factors
Recommend interventions
Develop plan to manage more complicated
Issues
Summarize and review important points
Clarify patient perceptions
Provide opportunity for questions
Assist in facilitating discussion with others
Provide appropriate referrals
Document discussion in medical record
Communicate with members of the treatment team
The goal of this approach is to restore hope by valuing and affirm-
ing the story of their lives, their roles, accomplishments, and
sources of fulfillment.
Loss of dignity
Dignity is defined as the quality or state of being worthy, honored,
or esteemed. Dignity therapy, developed by Harvey Chochinov
and colleagues, is a therapeutic approach designed to decrease
suffering, enhance quality of life, and bolster a sense of dignity
for patient’s approaching death.51 Chochinov et al. examined
how dying patients understand and define the term “dignity,”
in order to develop a model of dignity in the terminally ill (see
Figure 64.1). A semistructured interview was designed to explore
how patients cope with their advanced cancer and to detail their
perceptions of dignity. Three major categories emerged from a
detailed qualitative analysis, including illness-related concerns
(concerns that derive from or are related to the illness itself, and
threaten to or actually do impinge on the patient’s sense of dig-
nity), dignity-conserving repertoire (internally held qualities or
personal approaches or techniques that patients use to bolster
or maintain their sense of dignity), and social dignity inventory
(social concerns or relationship dynamics that enhance or detract
Suicide 619

Illness-related concerns Repertoire of dignity conservation Social dignity inventory

Level of independence Dignity-conserving perspectives
• Cognitive acuity
• Functional capacity
Symptom distress
• Physical
• Psychological
• Medical uncertainty?
• Death anxiety
Privacy boundaries
Social support
• Continuity of self
Care tenor
• Role preservation
Burden to others
• Generativity/legacy
Aftermath concerns
• Maintenance of pride
• Hopefulness
• Autonomy/control
• Acceptance
• Resilience/fighting spirit

Dignity-conserving practices

• Living “in the moment”

• Maintaining normalcy
• Seeking spiritual comfort

FIGURE 64.1  Major dignity categories: themes and subthemes. (Adapted from Chochinov HM et al., Soc Sci Med 2002;54(3):433.)

from a patient’s sense of dignity). These broad categories and their
carefully defined themes and subthemes form the foundation for
an emerging model of dignity among the dying. The concept of
dignity and the notion of dignity-conserving care offer a way of
understanding how patients face advancing terminal illness and
present an approach that clinicians can use to explicitly target the
maintenance of dignity as a therapeutic objective and principle of
bedside care for patients nearing death. In the therapy, patients
are invited to discuss issues that matter most or that they would
most want remembered. Sessions are transcribed and edited,
with a final version that they can bequeath to a loved one. In 2005,
Chochinov and colleagues studied 100 terminally ill patients who
received dignity therapy: 91% reported feeling satisfied or highly
satisfied with the intervention, 86% found it helpful or very help-
ful, 76% found that it heightened their sense of dignity, 68% indi-
cated that it increased their sense of purpose, 67% reported that
it improved sense of meaning, and 47% indicated that dignity
therapy increased their will to live.52
Chochinov et al. reported their findings of the effect of dig-
nity therapy on distress and end-of-life experience in terminally
ill patients from a randomized controlled trial.53 Patients (aged
≥18 years) with a terminal prognosis (life expectancy ≤6 months)
who were receiving palliative care in a hospital or community
setting (hospice or home) in Canada, USA, and Australia were
randomly assigned to dignity therapy, client-centered care, or
standard palliative care. No significant differences were noted
in the distress levels before and after completion of the study in
the three groups. For the secondary outcomes, patients reported
that dignity therapy was significantly more likely than the other
two interventions to have been helpful, improve quality of life,
increase sense of dignity, change how their family saw and appre-
ciated them, and be helpful to their family. Dignity therapy was
significantly better than client-centered care in improving spiri-
tual well-being and was significantly better than standard pallia-
tive care in terms of lessening sadness or depression; significantly
more patients who had received dignity therapy reported that
the study group had been satisfactory, compared with those who
received standard palliative care. Although the ability of dignity
therapy to mitigate outright distress, such as depression, and
desire for death or suicidality, has yet to be proven, its benefits in
terms of self-reported end-of-life experiences support its clinical
application for patients nearing death. Dignity therapy is highly
applicable and adoptable to the palliative care setting.54,55 Further
evaluations are needed.
Loss of meaning
Interventions for hopelessness and loss of meaning and purpose
in the terminally ill are of particular importance when address-
ing the issues of desire for death and despair at the end of life.
Breitbart et al. have developed an intervention termed “mean-
ing-centered” psychotherapy for advanced cancer patients, an
intervention based on the concepts and principles of Viktor
Frankl’s writings and logotherapy. 56 Viktor Frankl, a holocaust
survivor and psychiatrist, described that the will to meaning is
an inherent drive to connect with something greater than one’s
own needs and through this, one finds meaning and self-tran-
scendence particularly at times of intense psychological and
physical suffering. Meaning-centered psychotherapy has aimed
at restoring a sense of meaning, peace, and purpose in patients
with advanced cancer. 57 Meaning-centered psychotherapy is
a manualized intervention that consists of eight, 60–90 min
weekly sessions. Each session includes didactics, discussion, and
experiential exercises focused around particular themes related
to meaning and advanced cancer. The session themes include:
Session 1: Concepts and sources of meaning
• Introductions to interventions and meaning
Session 2: Cancer and meaning
• Identity—Before and after cancer diagnosis
Session 3: Meaning and historical context of life
• Life as a living legacy (past)
Session 4: Storytelling, life project
• Life as a living legacy (present−future)
Session 5: Limitations and finiteness of life
• Encountering life’s limitations
Session 6: Responsibility, creativity, deeds
• Actively engaging in life (via creativity and responsibility)
Session 7: Experience, nature, art, humor
• Connecting with life (via love, beauty, and humor)
Session 8: Termination, goodbyes, hopes for the future
• Reflections and hopes for the future
In a 2010 study, Breitbart and colleagues found that when com-
pared to supportive group psychotherapy, patients involved in
620
meaning-centered group psychotherapy had significant benefits
in areas of spiritual well-being and enhancing a sense of mean-
ing.58 A later study examining individual meaning-centered psy-
chotherapy found that patients with advanced cancer had clear
short-term benefits for spiritual suffering and quality of life when
compared to therapeutic massage.59
Interventions for family members
following a completed suicide
When a terminally ill patient chooses to end his or her own life,
the treatment team must quickly turn its attention to address-
ing the needs of the patient’s family so as to reduce the chances
of complicated bereavement. In order to provide effective sup-
port, it is essential that the team is aware of the unique reactions
commonly found among suicide survivors. A number of studies
have compared the bereavement patterns of suicide survivors
and nonsuicide survivors.60 Findings from these studies indicate
that there are several distinguishing themes that arise in suicide
bereavement. Foremost among them is the desire for the survi-
vor to make meaning of the suicide, or to answer the question
“Why?” Van Dongen calls this process “agonizing questioning,”
given the impossibility of ascertaining the answer from the now
deceased.61,62 Second, survivors often express feelings of guilt,
blame, and responsibility for the death. Often they engage in a
struggle to retrace the days and months leading up to the suicide
in order to pick up clues that they “missed.” Another documented
theme is a heightened feeling of rejection or abandonment, which
is often accompanied by anger toward the deceased.”63 Finally,
perceived feelings of stigmatization, shame, and embarrassment
are well documented. These feelings may be warranted as there
is much evidence in the literature showing that suicide survivors
are in fact viewed more negatively by others in their social net-
work in comparison with other mourners.63 One study by Allen
et al. found that individuals bereaved by suicide were viewed as
more psychologically disturbed, less likable, more blameworthy,
and more in need of professional mental healthcare than those
bereaved by other causes.64 As a result, it is not surprising that
these individuals struggle with isolation and lack of social sup-
port at a time when it is needed most.
Although the aforementioned themes are likely to arise to
some extent in all suicide survivors, some may be more or less
likely when the suicide is completed by a terminally ill patient.
First, on the positive side, family members of a terminally ill sui-
cide completer may not struggle as restlessly with the meaning of
the suicide, particularly if their loved one was in a large amount of
physical pain or was somehow physically incapacitated. Second,
family members may not feel as much responsibility for the sui-
cide as there is a clear external factor, namely, the terminal illness,
to which one can assign blame. Finally, given that the suicide may
not be as unexpected among such a population, the family mem-
ber may have already started the anticipatory grieving process
and may not feel as rejected and abandoned as other survivors.
On the other hand, although suicide among the terminally ill may
be more socially accepted and thus less stigmatizing for the survi-
vor, this group may receive fewer offers of professional support in
comparison with other mourners. Additionally, guilt feelings may
be more common among this group of survivors as a consequence
of the simultaneous feeling of relief they may experience at the
end of a possibly long care-giving period.
Armed with an understanding of the key issues for suicide
survivors in general, and for survivors of a terminally ill patient’s
Textbook of Palliative Medicine and Supportive Care
suicide more specifically, the treatment team can now begin to
intervene on behalf of the family. First and foremost, the physi-
cian and mental health professional on the team should contact
the family immediately after hearing of the suicide. This will
KEY LEARNING POINTS
• Suicide is a tragic but often preventable response
to terminal illness.
• Terminally ill patients are at elevated risk of sui-
cide when compared to the general population.
This is likely due to the increased incidence of
distressing symptoms such as depression, physi-
cal disability, pain, and cognitive dysfunction. It
is far more common for patients to have thoughts
of suicide rather than actual intent of committing
suicide. For some patients, suicidal thoughts may
represent a personal sense of control over the
cancer.
• Assessment of suicide risk and appropriate inter-
vention is critical. Early and comprehensive psy-
chiatric involvement with high-risk individuals
can often avert suicide in the medical setting.
• Patients who present with a DHD should be
screened for common risk factors such as depres-
sion or history of psychiatric illness, hopelessness,
physical distress (including pain and symptom
burden), poor social support, fear of being a bur-
den to others as well as existential concerns such
as loss of meaning and loss of dignity. Studies
have shown that when these factors are treated,
patients show a decrease in DHD.
• PAS remains a controversial topic in palliative
care. If the issue should come up with a patient,
the physician should be empathic and nonjudg-
mental, allowing the patient to freely discuss
their thoughts. When approached by patients
for assistance in dying, the first step should be to
provide excellent palliative care.
• Analgesics, antipsychotics, or antidepressant
drugs should be used when appropriate to treat
any agitation, psychosis, major depression, or
pain that are contributing to the patient’s suicidal
ideation.
• Novel psychotherapeutic interventions aimed at
improving spiritual well-being, sense of meaning,
and diminishing hopelessness, demoralization,
and loss of dignity are being studied and dis-
seminated, which may prove effective in reducing
suicidal ideation and attempts. Interventions for
hopelessness and loss of meaning and purpose
in the terminally ill are of particular importance
when addressing the issues of desire for death and
despair at the end of life.
• In cases of completed suicide, clinicians need to
be sensitive to the needs of the patient’s family
and loved ones. These individuals may require
some form of intervention to assist them in cop-
ing. Such individuals may also be at a potentially
higher risk for suicide themselves.
Suicide
communicate that the treatment team does not criticize or blame
the family, and that they will not abandon the family just because
the patient has passed away. Similarly, attempts should be made to
attend the funeral memorial services. These acts will serve to dif-
fuse the family’s feelings of isolation and stigmatization. Second,
attempts should be made to connect the family member to a sup-
port group specifically designed for suicide survivors. Jordan49
argues that groups limited to suicide survivors seem more likely
to cohere quickly and to “avoid a replication of the empathic
failure that too often occurs for survivors in their larger social
networks.” Such groups should focus on areas such as facilitating
integration of the loss by understanding why and how the suicide
occurred, exploring the meaning of the loss for the survivor, and
providing space for the expression of all types of feelings, both
positive and negative.65 Effective support groups for suicide survi-
vors should also include a psychoeducational component, which
has been found to reduce survivor anxiety and bolster coping
strategies.65 Psychoeducational resources and materials should
also be designed to support and educate those in the survivor’s
support network so as to reduce their negatively held stereotypes
about this group of mourners. A third objective of the treatment
team should be to encourage the family to engage in a grieving rit-
ual for the survivor. Some cultures restrict the use of traditional
grieving rituals, which can leave the survivor with no closure.65
Developing their own unique ritual can be a liberating experience
for the family. Finally, survivors are at risk for increased suicidal-
ity of their own, although possibly less so when it is a terminally
ill patient that takes his or her own life. Nevertheless, the treat-
ment team should proactively assess the family member’s risk and
make an appropriate referral if warranted.
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65
CANCER: RADIOTHERAPY

Adrian Cozma, Maitry Patel, Edward Chow, Srinivas Raman

Contents
Introduction........................................................................................................................................................................................................................623
Bone metastases.................................................................................................................................................................................................................625
Brain metastases.................................................................................................................................................................................................................628
Lung cancer........................................................................................................................................................................................................................ 630
Pelvic disease.......................................................................................................................................................................................................................631
Head and neck cancer.......................................................................................................................................................................................................631
Esophageal cancer..............................................................................................................................................................................................................632
Skin cancer..........................................................................................................................................................................................................................632
Liver metastases.................................................................................................................................................................................................................633
References........................................................................................................................................................................................................................... 634

Introduction
Approximately half of all radiotherapy (RT) treatments are given
with palliative, as opposed to radical (curative), intent,1 and this
number is likely to further increase as patients continue to live
longer as a result of therapeutic advancements. The goal of pallia-
tive RT is to provide effective and durable symptom relief while
preserving function, integrity and minimizing treatment-related
toxicity. Ideally, this is achieved with the shortest, effective
course in order to minimize patients’ inconvenience and maxi-
mize health-care resources.
RT utilizes ionizing radiation to induce cellular DNA damage
and ultimately cell death within targeted tissues (Figure 65.1). RT
delivery is broadly classified as external-beam radiation therapy
(EBRT) or brachytherapy. EBRT, also known as conventional
RT, most commonly involves high-energy photons (X-rays or
gamma-rays) produced from a linear accelerator, or from a radio-
active cobalt source housed within the head of the treatment
machine. It is often further subcategorized based on the type
of technique used: three-dimensional conformal RT (3D-CRT),
intensity-modulated RT (IMRT), volumetric-modulated arc
therapy (VMAT), and stereotactic RT. Briefly, 3D-CRT utilizes
2–4 beams of equal intensity radiation that are conformed to the
tumor volume of interest. IMRT divides 6–7 beams into a mul-
titude of individual beamlets of varying intensity that are cali-
brated to deposit a high dose of radiation at the target and very
low dose to the surrounding normal tissue. VMAT delivers RT
in the form of arcs that are actively molded into various shapes
as the head of the machine travels around the patient, allowing
for modulation of beam shape and intensity. Stereotactic RT is
further divided into stereotactic radiosurgery (SRS) when used
for intracranial tumors and stereotactic body radiation therapy
(SBRT) or stereotactic ablative radiation therapy when treating
extracranial tumors. Although a form of EBRT, it is different from
the other modalities in that it utilizes ultrahigh radiation doses
per treatment for a fewer total number of treatments, in order
to deliver a biologically equivalent dose over a shorter period of
time. In doing so, it has more potent biologic effects as there is less
time between treatments for the tumor to regrow, at the potential
risk of substantially higher normal tissue toxicities should the inten-
sified dose be incorrectly targeted. State-of-the-art planning, patient
immobilization, respiratory motion management, quality assurance,
image guidance, and staff training are required for this approach.2
When treating superficial lesions, such as those in the skin, ortho-
voltage X-ray or electron-beam RT may be used. Maximal dose can
be delivered to superficial structures by using lower energy external
photon beams (orthovoltage) or by taking advantage of the depth–
dose profile of electron beams, which deliver most of their energy to
a target’s surface before slowly dropping off. RT can also utilize the
unique dose properties (Figure 65.2) of protons and carbon ions, but
these charged particles are not typically used for palliative indica-
tions, given the resources and expenses required for their use and
their uncertain benefit in the palliative setting.
Brachytherapy involves local delivery of radiation by placement
a radioactive source (e.g., iridium-192, iodine-125, and others) in
close proximity to the target of interest. This may involve perma-
nent seed implants or temporary activated catheters or needles,
which can be placed into (interstitial) or within (intracavitary)
a body surface, tissue, or cavity. An alternate form of brachy-
therapy involves using targeted radioactive isotopes that have an
affinity toward specific tissues, for example, bone or thyroid, and
are injected into the bloodstream with the intent of traveling to
the tissues of interest and depositing radiation locally. This chap-
ter will focus exclusively on external-beam RT, although brachy-
therapy has been introduced for completeness.
When a patient is seen in consultation for consideration of pal-
liative RT, the radiation oncologist extracts and takes into account
tumor factors, such as histology and location(s) of involvement,
previous treatments, and patient factors, such as symptom bur-
den, functional status, and life expectancy, to determine whether
and what type of treatment is most appropriate. It is particularly
important to know whether the previous RT has been delivered
as repeat treatment of the same area may or may not be possible
depending on the previous treatment parameters (dose and frac-
tionation), time since the previous RT, and the remaining radiation
tolerance of structures within the RT field. As RT is a local treat-
ment, the objective is to treat the tumor while minimizing dose
to surrounding normal tissue, and this is best achieved through

623
624
FIGURE 65.1  Radiation damaging nuclear DNA resulting in
cell death.
a planning session during which a patient receives updated imag-
ing. EBRT planning (simulation) involves localizing the tumor
clinically if the lesion is superficial or using one or a combination
of fluoroscopy, computed tomography (CT), magnetic resonance
imaging (MRI), and positron emission tomography (PET), if deep
seated. CT scans provide the fundamental density information
required by modern treatment planning software to calculate
the final dose distribution, but they can be superimposed (fused)
with MRI or PET images to provide additional detail for delinea-
tion of tumor boundaries. Various immobilization techniques are
also evaluated and trialed during this appointment to ensure that
each patient can maintain the same position between and during
FIGURE 65.2  Depth–dose curves of various particles used in
radiotherapy (from Ref. [B] under cc-wiki license).
Textbook of Palliative Medicine and Supportive Care
FIGURE 65.3  Volume definitions in radiotherapy (see fur-
ther Refs. [A,C]). GTV, gross tumor volume (detectable tumor
volume); CTV, clinical target volume (GTV plus volumes with
expected subclinical spread); PTV, planning target volume (CTV
plus safety margin for movements or deformations of CTV, tech-
nical uncertainties, etc.); TV, treatment volume (receiving the
prescribed dose); IV, irradiated volume (i.e., exposed to signifi-
cant doses with regard to normal tissue tolerance).
treatments, to reduce irradiation of normal tissues due to a geo-
metric miss. It is important to remember that the patient must be
able to lie still, unattended, on the simulator and treatment tables
(which are hard and narrow) for approximately 15 minutes at a
time. This may be difficult for patients who are delirious, orthop-
neic, or have uncontrolled pain. Next, radiation therapists and
radiation oncologists work to contour (identify and highlight)
organs at risk (OARs) and target (cancer) volumes (Figure 65.3):
gross tumor volume (GTV) is the tumor that is visible clinically
and with the use of imaging; clinical tumor volume (CTV) is
an adjacent area suspected to have submicroscopic disease; and
planning tumor volume (PTV), an additional area of uncertainty
surrounding the CTV target based on the reproductivity of the
patient’s positioning, mechanical accuracy of the equipment, and
possible set-up errors. The concept of the internal tumor volume
was recently introduced to account for a structure’s variation
in position, volume, and/or shape over time, e.g., a lung tumor’s
positional change during breathing. This is an expansion of the
CTV that is encompassed by the PTV. Finally, a proposed plan
meeting the clinical dose targets for the treatment area, while
not exceeding the OAR tolerance doses beyond which known
toxicities occur, is reviewed by Medical Physics for further opti-
mization of the calculated dose distributions. An approved plan
is then sent to the treatment units and the patient is ready to
receive their treatment from a linear accelerator or cobalt unit
(rarely) in a heavily shielded room.
RT prescriptions must describe the intended dose (absorbed
dose) and fractionation schedule (number of treatments). Dose is
a measure of the mean amount of energy (J) deposited by all types
of radiation (predominantly ionizing radiation) into an absorb-
ing tissue, per unit of mass (g or kg). The SI unit for absorbed
dose, however, is the gray (Gy) where 1 Gy = 1 J/kg and 1 Gy = 100
centigray (cGy)—prescriptions are typically written using either
notation.
Typically, RT is delivered consecutively, once (one fraction)
daily, 5 days a week (Monday through Friday) with weekend
treatment in instances of emergency or severe presentations,
Cancer: Radiotherapy
such as neurological compromise in the setting of severe spinal
cord compression. In conventional RT, small doses per fraction
delivered over many days is the preferred approach, as it takes
advantage of the observation that cancer cells have impaired
DNA repair as compared with normal tissue. Therefore, during
treatment, normal tissues can recover through repair and repop-
ulation, while DNA damage in malignant cells accumulates and
is fatal when the cell tries to divide. However, the differential
toxicity between cancer and normal tissue is not complete, and
normal tissues have a tolerance dose beyond which they are irre-
versibly damaged, hence the concept of OARs introduced earlier.
This tolerance dose is organ specific and, for example, is lower
for spinal cord and bowel, compared to muscle and bone. The
optimal dose of radiation is one that will produce the maximal
probability of tumor control with minimal complications. For
symptom palliation, a high total dose is not required; therefore,
palliative fractionation schedules can be shorter and use a higher
dose per fraction. This serves to minimize patient visits to the
cancer center and treatment-related side effects. Commonly used
palliative RT regimens include 8 Gy in a single fraction, 20 Gy
in 5 fractions (4 Gy per fraction), and 30 Gy in 10 fractions (3 Gy
per fraction). Table 65.1 illustrates potential applications of
palliative radiotherapy for various tumor sites and symptoms.
Treatment-related side effects are defined as acute (<90 days
after treatment start) or late (>90 days). As RT is a local treat-
ment, apart from fatigue, side effects depend on the area treated.
Acute toxicity is self-limiting and tends to resolve within 2 weeks
of treatment completion. Late toxicity is usually not a problem
in the palliative setting, given the low total RT doses used and
the limited life expectancy of patients with advanced cancer.
Nonetheless, the radiation tolerance of normal tissue such as the
spinal cord needs to be respected whenever possible, especially
when retreating, as patients are living longer and longer with
advancing treatments.
Bone metastases
Bone metastases are extremely common among patients with
advanced cancer, with postmortem studies reporting overall inci-
dences of up to 70%3 and over 90% in those with hematological
malignancies4 Unsurprisingly, they contribute a significant bur-
den of morbidity to patients’ quality of life and function. Primary
tumors of the breast and prostate are responsible for the major-
ity of skeletal metastases (up to 70%)5 with thyroid, lung, renal
cell, melanoma, bladder cancer, and hematological malignancies
accounting for the remainder. Their clinical presentation is vari-
able and highly dependent on the site of involvement, which has
most commonly shown to be the pelvis, spine, femur, ribs, and
the humerus.6
Skeletal metastases account for the most frequent presentation
of cancer pain4 often limiting instrumental and activities of daily
living, but patients may also experience sequelae of hypercalce-
mia, pathologic fracture, and/or altered strength or sensation.
We often characterize bone metastases based on their severity:
uncomplicated versus complicated, with the former encompassing
lesions that are unassociated with impending or existing patho-
logic fracture or neurologic comprising by spinal cord or cauda
equina compression. Although there is no established definition,
most radiation oncologists would also consider lesions with asso-
ciated soft tissue extension, those within weight-bearing bones at
high risk of fracture, previous surgical fixation, and select cases of
previous treatment, as being complicated, in practice.7
625
RT is an effective treatment modality and the current gold
standard for the palliation of painful uncomplicated and compli-
cated (with and without surgical stabilization) skeletal metasta-
ses in a single or limited number of sites, directly contributing to
pain relief and indirectly decreasing side effects from escalating
opioid consumption.6 It is also useful in preventing impending
pathologic fractures, promoting their healing when they occur,
improving mobility and function, and, in certain instances,
prolonging survival. For these reasons, palliation of skeletal
metastases accounts for approximately 40% of all palliative RT
treatments.1
The overall and complete pain response rates of palliative RT
for skeletal metastases have been reported as being approxi-
mately 60 and 25%, respectively, with a median time to pain relief
of 3 weeks and a median duration of pain relief of 12–24 weeks.8
Acute toxicities are mild, reported in 10–17% of patients, and late
toxicities are rare (4%).9 Toxicity is site specific, for example, RT
to the cervical or thoracolumbar spines can precipitate dysphagia
or nausea and vomiting, respectively, while pelvic radiation can
trigger diarrhea. Prophylactic ondansetron can be used to reduce
emesis when treating over the epigastrium, thoracolumbar spine,
or a large pelvic field.10 More recently, the phenomenon of pain
flare has been documented. Pain flare is defined as a 2-point
increase in the worst pain score (0–10) compared to baseline with
no decrease in analgesic intake, or a 25% increase in analgesic
intake with no decrease in the worst pain score within 10 days fol-
lowing RT at the index site. Hird et al.11 reported a 40% incidence
of pain flare among three Canadian Cancer Centres during and
within 10 days following palliative RT for painful skeletal metas-
tases, with some series reporting occurrences as high as 68%.11
It is believed that this phenomenon is driven by RT-triggered
inflammatory cytokine release, and early phase clinical trials
of corticosteroids have shown promise in attenuating the plane
flare response by leveraging their anti-inflammatory action. We
now have evidence from a Canadian, multicenter phase III trial
in which patients reported a 25% relative risk reduction in pain
flare incidence within the intention-to-treat analysis, when 8 mg
of dexamethasone was given at least 1 hour before the start of a
single (8 Gy) fraction of palliative RT and also for the 4 consecu-
tive days following, compared to placebo12 They also experienced
less nausea, improved appetite, and higher functional ability, with
overall excellent tolerability; 85% of study patients preferred cor-
ticosteroid prophylaxis to increasing their analgesic use when a
pain flare occurred.
Single-fraction RT is considered to be the standard of
care for palliating most uncomplicated skeletal metastases.
Although a multitude of dose and fractionation schedules
have been published, a recent updated systematic review
and meta-analysis of this literature showed similar response
rates and duration of pain relief for patients receiving single
(8 Gy) and multiple (20 Gy in 5, 30 Gy in 10, and 40 Gy in
20) fractions. 8 There were also no significant differences in
quality of life, analgesic use, or acute toxicities. This effect
extended across multifraction regiments, as a systematic
review and meta-analysis of this literature failed to show a
dose–response relationship and ultimately reported no differ-
ence in efficacy or toxicity in the pooled analysis.13 A lower
dose, single-fractionation regimen has also been investigated
in a large, multicenter trial in which patients with painful,
uncomplicated bone metastases were randomized to an 8 or 4
Gy treatment.14 A marked, consistent difference in pain relief
at each of the 4-, 8-, 12-, 24-, and 52-week time points was
626 Textbook of Palliative Medicine and Supportive Care

TABLE 65.1 Tumor Sites and Symptoms Amenable to receiving multiple fractions upfront may avoid the need for
Palliative Radiotherapy re-treatment and therefore, the choice of fractionation sched-
ule should be discussed with the patient.16
Anatomic Site Symptom
Approximately one-third of skeletal metastases are considered
Skeleton 1. Painful bone metastases to be complicated, occurring predominantly within the spine,
2. Spinal cord compression extremities, and pelvic bones and necessitating prophylactic
3. Status post vertebral body decompression surgical intervention and/or multifraction RT.17 Up-front surgi-
4. Status post fixation of long bone cal fixation is an important tool that should be considered for
Brain 1. Neurologic dysfunction patients with acceptable performance status and the long bone
2. Headaches lesions of which are predicted to carry a high risk of fracture using
3. Seizure
validated tools such as Mirels’ scoring system.18 Specifically risk
factures include metastases involving >50% cortical destruction
4. Status post resection of metastasis
of a long bone; femoral lesions >0.25 mm in the neck, subtrochan-
Lung 1. Cough
teric, intertrochanteric, or supracondylar regions; and diffuse
2. Shortness of breath
lytic lesions located in a weight-bearing bone, especially if pain-
3. Hemoptysis
ful.19 In these instances, up-front fixation is associated with bet-
4. Chest pain ter functional outcomes, increased survival, and a technically less
5. Post-obstructive pneumonia challenging procedure as opposed to waiting until after a patho-
6. Superior vena cava syndrome logic fracture has occurred.20 Multifraction RT (typically 20 Gy
Esophagus 1. Dysphagia in 5 fractions or 30 Gy in 10 fractions) should then be given to the
2. Pain surgical site approximately 2–4 weeks postoperatively as this has
Head and neck 1. Bleeding been shown to improve functional status, decrease pain, decrease
2. Pain failure rate of the prosthesis, reduce the risk of refracture, and
3. Dysphagia increase overall survival.21 The rationale of this postoperative RT
4. Shortness of breath is to reduce, destroy, and ultimately attempt to control any residual
5. Ulceration
macro- and microscopic disease and to promote remineralization
and bone healing in order to reduce the risk of subsequent frac-
Gynecologic 1. Pain
ture or loss of fixation.22 A similar approach is used for patients
2. Vaginal bleeding
who are surgical candidates and who are deemed to have spinal
3. Vaginal discharge instability secondary to their skeletal metastases, using validated
4. Obstruction spinal instability neoplastic score (SINS). Using the specific seg-
Genitourinary 1. Hematuria ment of the spine, the presence of mechanical pain, type of bone
2. Pain lesion, radiographic characterization of spinal alignment, and
3. Urinary outlet obstruction degree of vertebral body collapse, a SINS score can be calculated
Rectum 1. Pain where 0–6 is considered stable, 7–12 is indeterminate (possibly
2. Rectal bleeding impending) instability, and 13–18 denotes instability; >7 requires
3. Tenesmus surgical consultation.23 If indicated, prophylactic stabilization is
4. Rectal obstruction recommended, followed by multifraction RT. Most nonsurgical
Liver 1. Pain
candidates and patients whose Mirels’ and SINS scores are ≤7
and <13, respectively, should be treated with multifractional RT
2. Discomfort
alone.24–27 Spine metastases can also cause malignant spinal cord
3. Nausea
compression (msCC) by extension of the disease into the epi-
dural space or causing vertebral body collapse with displacement
of bone fragments in the epidural space. mSCC is an oncologic
reported, along with a higher re-treatment rate, in favor of emergency that requires prompt multidisciplinary management,
the single 8-Gy course. This is very encouraging data given and the readers are directed to Chapter 84, for a comprehensive
the significant convenience and cost-saving implications of discussion regarding this topic. Lastly, for skeletal metastases
single-fraction treatment in providing prompt and effective causing neuropathic pain, a dose of 20 Gy in 5 fractions appears
pain relief with minimal toxicity. Re-treatment, however, is an to be favorable to a single 8 Gy as outcomes were generally poorer
important consideration as 20% of single and 8% of multiple with the latter dose, but they were not statistically significantly
fraction courses will ultimately require additional RT corre- worse, and the quantitative differences were small.28 It, therefore,
sponding to a 2.6-fold higher rate. 8 Nonetheless, re-treatment may still be reasonable to employ a single-fractionation approach
offers effective palliation, with a pooled response rate of 58%. on a case-by-case basis, particularly in patients with poor perfor-
Generally, a 4-week interval is given before considering rera- mance status and/or those who prefer its increased convenience.
diation, to allow enough time to derive maximal benefit from Stereotactic body RT (SBRT) has recently emerged as an alter-
the initial treatment. Once a decision to treat is made, a sin- native to EBRT in the management of limited bone metastases,
gle (8 Gy) treatment has been shown to be non-inferior and owing to a number of potential advantages over conventional
less toxic compared to a multifraction (20 Gy in 5 fraction) treatment. Faster and more durable pain relief, improved local
regimen, in a recent multicenter, international phase III ran- control, higher efficacy (particularly for radioresistant histolo-
domized trial.15 Although a single 8-Gy fraction can be used gies), and better discrimination and avoidance of critical struc-
universally in the treatment of uncomplicated bone metas- tures have been reported in the literature.29,30 These must be
tases, for patients with longer life expectancies (>6 months), balanced with the increased cost, complexity, risk of late toxicity,
Cancer: Radiotherapy
and uncertainty regarding whether this treatment may alter the
natural course of the malignancy. A recent prospective random-
ized phase II non-inferiority trial comparing single-fraction SBRT
(12 Gy for ≥4 cm lesions or 16 Gy for <4 cm lesions) with standard
multi-fraction EBRT (30 Gy in 10 fractions) among 160 patients
with mostly non-spine bone lesions reported that single-fraction
SBRT resulted in a higher number of pain responders (complete
and partial response) at 2 weeks, 3 months, and 9 months. This
group also experienced higher local control rates at 1 and 2 years
and did not experience any additional toxicity or detriment to
their quality of life. 31 Most of our available evidence, however,
is derived from earlier work in the setting of spine metastases
where SBRT was used as a salvage treatment for patients who had
failed EBRT or were unable to receive standard of care (surgery
and/or EBRT). 32 More recently, however, it is being investigated
as up-front treatment in the RTOG 0631 phase III randomized
controlled trial that compares the efficacy of single-fraction pal-
liative spine EBRT (8 Gy/1) to spine SBRT (either 16 or 18 Gy/1).
Patients with an ECOG of 0–2 with up to three sites of disease
and up to two contiguous spinal levels, with a pain score of ≥5/10
on a numerical pain scale, were included while those with spi-
nal instability due to fracture, fractures with retropulsion, and/
or frank spinal cord compression were not. 33 The results were
recently presented in abstract form, and it was shown that there
was no difference in the primary endpoint, pain control, between
SBRT and EBRT at 3 months. 34 Further research is required to
clarify the most appropriate clinical selection criteria with which
to identify patients who will derive the most benefit from spine
SBRT treatment. The neurologic, oncologic, mechanical, and sys-
temic parameters35 and recursive partition analysis36 frameworks
were previously developed to provide guidance in this regard.
Spinal SBRT can be delivered as prescriptions of 16–24 Gy in a
single fraction, 24 Gy in 2 fractions, 21–27 Gy in 3 fractions, and
30–35 Gy in 5 fractions with no clearly established superiority
of one regimen over another.37 In general, the majority of avail-
able data regarding SBRT is heterogenous and predominantly
from phase I/II data. 38 A brief summary of this literature is that
the median survival of patients receiving spine SBRT was 30
months, the reported symptomatic improvement or control is
within the range of 80–90%, radiographic improvement or con-
trol at 1 year is 70–90%, and of the recurrences that occur, 50%
are within the epidural space and 17.9% are within the pedicles
and posterior elements of the spine. 39,40 These sites are typically
underdosed due to adjacent OAR constraints, particularly the
spinal cord. For patients with high-grade spinal cord compres-
sion, an accepted contraindication to up-front SBRT, posterolat-
eral surgical resection of the epidural tumor (without resection of
the vertebral body or residual paraspinal disease) with posterior
segment fixation, is recommended. 35 Following this “separation
surgery,” the surgical bed is treated with either high-dose single-
fraction SBRT (24 Gy) or hypo-fractionated SBRT (24–30 Gy/3
fractions). This is advantageous because postoperatively, the
residual disease is displaced away from the spinal cord, which
typically limits the amount of dose that can be delivered, allowing
higher doses of radiation to be used. Excellent and durable local
control rates have been achieved using this approach.41,42 This is
particularly attractive for patients with multiple medical comor-
bidities that may be unable to tolerate a more comprehensive
surgery, those with high-grade cord compression and/or radiore-
sistant tumor histologies. With higher doses delivered by spinal
SBRT, there is a greater risk for potentially serious complications
like vertebral fracture and radiation-induced myelopathy. 38 A
627
multi-institutional study investigating posttreatment vertebral
fractures reported an incidence of 14% (47% were new and 53%
were progressed prior fractures) with a median time to presen-
tation of 2.46 months and a higher risk for those receiving ≥20
Gy/1 fraction.43 The SINS score can be used to identify patients
at the highest risk of vertebral compression fracture post-SBRT,
and prophylactic cement augmentation may be required prior
to treatment.44 Relatively low rates of radiation myelopathy have
been reported in the SBRT literature; however, it is important to
remain prudent and to closely follow the American Association of
Physicists in Medicine recommendation to limit the dose for sin-
gle-fraction spine SBRT to <0.35 cc to a threshold dose of 10 Gy
(14 Gy point max); or for three-fraction SBRT, a threshold dose of
18 Gy (23.4 Gy point max); or for 5 fractions of SBRT a threshold
dose of 23 Gy (31 Gy point max).45
Patients with multiple sites of symptomatic bone involvement
whose distribution precludes treatment with conventional exter-
nal-beam RT could benefit from palliation with systemic radio-
nucleotides or hemi-body RT. Radium-223, strontium-89 (89Sr),
and samarium-153 lexidronam (153Sm) are commonly available
radiopharmaceuticals (radioactive bone-targeting molecules)
that have been studied and approved for the treatment of pain-
ful bone metastases. Radium-223 is a calcium ion mimetic that
binds to sites of increased bone turnover, particularly osteoblas-
tic and sclerotic metastases, and releases alpha-particle radiation
to induce double-stranded DNA breaks that are highly cyto-
toxic to nearby tumor cells.46 Alpha particles have a short range
(<100 μm), meaning that their toxic effects on adjacent tissue
and especially the bone marrow are minimized. A phase III, ran-
domized, double-blind, multi-institutional study comparing the
efficacy and safety of radium-223 versus placebo in patients with
castration-resistant prostate cancer bone metastases reported
a 30% reduction in the risk of death without significantly more
grade 3 or 4 toxic effects, resulting in early study termination.46
Patients also experienced significantly prolonged time to their
first symptomatic skeletal event (median 15.6 vs. 9.8 months). A
subsequent, prospective, health-related quality-of-life analysis
reported a significant improvement and slower decline over time
with treatment; 30% reduction in pain, in post hoc analyses.47
The initial phase II trial reported a clinically significant improve-
ment in pain response at 2 weeks with 71% patients benefiting
by 8 weeks for a mean duration of 44 days of pain relief.48 More
recent studies have reported pain responses of 41 and 52%.49,50
Radium-223 is well tolerated with no absolute contraindications,
although patients must be monitored for bone marrow suppres-
sion and resulting hematologic toxicity, dehydration (from com-
monly reported nausea, vomiting, and diarrhea), and potential
risk for developing new cancers due to the increased radiation
exposure.51 It has now been accepted as the standard of care for
the treatment of bone metastases among patients with castration-
resistant prostate cancer and no visceral metastases; a number
of clinical trials are underway exploring its application in other
metastatic solid tumors.52 Strontium-89 (89Sr) is also a calcium
analog, while samarium-153 lexidronam (153Sm) is absorbed by
hydroxyapatite and is converted to samarium oxide in an oxy-
gen-dependent process.53 Strontium has a half-life of 50.5 days
resulting in continuous, low-dose radiation versus samarium, the
half-life of which is only 1.9 days, delivering high doses over a
shorter period of time. Both are selectively absorbed into areas of
high bone turnover; however, they emit beta particles that have a
range of 0.2–3.0 mm and therefore a greater risk of toxicity, such
as myelosuppression.54 A randomized controlled trial among
628
patients with symptomatic bone metastases originating from
breast or prostate cancer reported similar efficacy, pain relief,
and risk of toxicity when it compared strontium-89 with samar-
ium-153 head-to-head;53 both reported poor outcomes among
mixed metastases of lytic and blastic lesions. Prospective studies
have shown that these radiopharmaceuticals result in the onset
of pain relief at 2–3 weeks with a mean duration of 3–6 months,
5–20% complete and 55–95% partial response rates. 55 Pain flare
rates of 10–40% were reported with an onset of myelosuppression
at 6–7 weeks and self-limiting resolution by 8–12 weeks post-
treatment. There are a number of important contraindications
for use, which include fracture, spinal cord compression, lesions
with extra-osseous component, renal failure, myelosuppression,
life expectancy <2 months, and recent chemotherapy adminis-
tration within the prior 1 month.54 A randomized controlled trial
comparing strontium-89 versus standard EBRT versus hemi-
body EBRT among 284 patients with painful metastatic prostate
bony lesions reported similar response rates in all arms, except
the radionucleotide group that experienced a decrease in the inci-
dence of new painful sites.56 The data suggests that in patients
who are unable to access radionucleotides due to limited avail-
ability, cost, or other contraindications, hemi-body EBRT can be
used with equal success in patients with multiple sites of painful,
blastic, bone metastases.55
Hemi- or half-body radiation (HBI) involves the delivery of
EBRT to either the upper half (base of skull to iliac crest) or lower
half (iliac crest to ankles) of the body in a single large RT field. 57
Single-fraction HBI has been shown to provide pain relief in
70–80% of patients.58 The onset of pain relief is quicker than with
local RT, occurring within 24–48 hours, suggesting that cells of
the inflammatory response pathway may be the initial target tis-
sue, since tumor cell activities are unlikely to be halted so quickly.
The dose delivered is typically a single fraction of 6 Gy to the
upper body (reduced dose due to potential for lung toxicity) and
8 Gy to the lower body.57 HBI is associated with acute gastroin-
testinal toxicity (nausea, vomiting, diarrhea), thought to be more
pronounced with the use of a single fraction. 59 Acute toxicity
usually requires intravenous fluids and premedication with anti-
emetics and corticosteroids, and, in some cases, an overnight stay
in hospital for observation. Reversible myelosuppression occurs;
therefore, sequential treatment of upper and lower body requires
a 4- to 6-week interval for counts to recover. This approach has
largely been replaced by radiopharmaceuticals in clinical prac-
tice, but it is still used on occasion.
Brain metastases
Brain metastases account for the most common and significant
neurologic complications of advanced cancer. Historically, they
have been reported to occur in up to 40% of patients, with tre-
mendous variability based on the primary site and dominant
histology.60 Cancers of the lung, breast, kidney, and skin (mela-
noma) account for up to 80% of all brain metastases.61 Their true
incidence and prevalence is likely much higher, and increasing,
with improving availability and sophistication of imaging tech-
niques and the development of more effective systemic treat-
ment options that prolong life and allow greater opportunity
for dissemination to the brain. The cerebellum is the most com-
mon site of spread, resulting in mass effect and hydrocephalus,
which may manifest as headaches, confusion, decreased level of
consciousness, nausea, vomiting, cranial nerve palsies, ataxia,
and lethargy.60 Symptoms of sensory and/or motor deficits are
Textbook of Palliative Medicine and Supportive Care
also frequently seen in cerebral metastases, and up to 30–40%
of patients may experience seizures. Ultimately, the clinical pre-
sentation can be quite variable depending on the location(s) of
the particular region of the brain involved; in approximately 10%
of cases, they may be entirely asymptomatic.62 Most patients
will have a shortened life span despite appropriate treatment,
with median population-based survival rates ranging from 3 to
12 months, depending on the cancer diagnosis.63
A variety of multidisciplinary treatment options involving sur-
gery, SRS, whole-brain radiation therapy (WBRT), systemic ther-
apy, and the best supportive care are employed to deliver the most
appropriate, individualized care. The exact approach depends on
the patients’ burden of intracranial disease (number, size, loca-
tion of metastasis, degree of mass effect and edema), prognosis,
functional status, extent of extracranial disease, and personal
preferences. A number of diagnosis-specific prognostic assess-
ment tools are available for lung, melanoma, renal cell, breast,
and gastrointestinal malignancies to provide assistance with joint
decision-making and counseling. Ultimately, the goals of treat-
ment include achieving durable control of intracranial disease
while minimizing the adverse effects of therapy, alleviating neu-
rologic symptoms, improving and maintaining quality of life, and
potentially extending survival.
Solitary metastases are best managed with surgical resection
and/or SRS. In the cases of diagnostic uncertainty, large lesions
(≥4 cm preoperative diameter) producing significant peritumoral
edema and mass effect, located in a surgically accessible area,
in the context of limited extracranial disease and an amenable
patient without absolute contraindications, resection should
be the recommended treatment choice. This approach helps to
exclude alternate diagnoses, which may be present in as many as
11% of cases despite appropriate investigations, and provides rapid
symptom relief. Patients proceeding with up-front surgical resec-
tion have been found to experience greater local control, overall
survival, quality of life, and duration of functional independence,
in two randomized clinical trials comparing surgical resection
followed by WBRT to WBRT alone.64,65 Further, subgroup analy-
ses of these studies have shown that patients with limited or
absent extracranial disease, longer time to development of brain
metastasis, and younger age tended to live longer. Those over
60 years of age and with active extracranial diseases lived less and
did not benefit from surgical management. Surgery is not without
risk, and common side effects of postoperative neurologic wors-
ening, infection, intracranial hemorrhage, perioperative stroke,
and permanent paresis have been reported in the literature.66
Overall, however, the procedure is considered to be safe with
most patients requiring less than 5 days of hospitalization and
is effective treatment with 90% of patients experiencing stable
or improved neurologic outcomes by 1-month postoperatively.67
Unfortunately, postoperative local recurrence is an important
consideration with rates of 50–60% of local failure at the surgical
site over the following 6–12 months, requiring adjunct treatment
with WBRT or SRS.68–70 The addition of postoperative WBRT
has been shown to reduce the risk of local and distant failure, by
approximately 36 and 52% in an earlier randomized controlled
trial, but it does not improve overall survival.70 Since the early
WBRT trials, there has been more recent evidence to support the
use of SRS as the preferred adjunct RT treatment. In a multicenter
trial randomizing patients to receive postoperative SRS or WBRT,
those assigned to the SRS group experienced higher performance
status, lower risk of cognitive deterioration, and similar median
overall survival, compared to WBRT.71 A second randomized,
Cancer: Radiotherapy
single-center trial showed similar improvements in local control,
but not overall survival when comparing postoperative SRS to
observation alone.69 In this trial, preoperative tumor diameter
>2.5 cm was the most important risk factor for local recurrence.
This is likely due to relative underdosing of these lesions by SRS
as a result of dose constraints imposed by surrounding healthy
brain tissue, which become increasingly important with larger
sized lesions from the perspective of inducing radiation necro-
sis.72 SRS may also be used as up-front in the cases of solitary
lesions that are not amenable or accessible to surgery, particu-
larly if they are small in size (<3 cm). Early multi-institutional
work investigating the application of SRS in this setting reported
local control rates of 85% with only 7% of patients experiencing
treatment-related complications (3% tumor hemorrhage, 3% peri-
tumoral edema, and 1% radiation necrosis).73 A significant sur-
vival advantage was also reported among patients with a single,
unresectable, brain metastasis allocated to the SRS group in the
RTOG 9508 randomized multicenter trial.74 More recently, it has
been shown that we can effectively treat lesions ≥3 cm by frac-
tionating a higher SRS dose prescription over consecutive days, as
opposed to a single treatment, as is typically used to treat smaller
lesions.75 Nonetheless, local and distant failures remain impor-
tant considerations when treating with SRS, and this will be dis-
cussed further in the following sections. Overall, there is no clear
evidence guiding the preferential selection of surgery or SRS as
the first-line treatment option for the treatment of solitary metas-
tases. A recent Cochrane Review attempted to compare the total-
ity of evidence from randomized controlled trials and concluded
that there is insufficient data available at this time to definitively
compare the effectiveness and safety of these two modalities.76
Therefore, in cases where patients are appropriate candidates for
either surgical resection or treatment with SRS, informed deci-
sion-making based on the patient’s preference should guide final
treatment plan selection; sometimes, both may be required such
as in cases where postoperative, fractionated SRS is delivered to
the surgical cavity.72
Up-front SRS alone has emerged as the standard of care in the
management of limited brain metastases. Randomized controlled
trials and large prospective observational studies have reported
excellent local control rates of 70% and higher, even while simul-
taneously treating up to 15 lesions.77 Interestingly, overall sur-
vival has not been found to depend on the number of sites treated
(comparing 2–4 vs. 5–10 tumors and 1–5 vs. 6–10 vs. 11–15 vs. >15
lesions).77–79 Even relatively radioresistant tumors such as renal
cell carcinoma80 and melanoma81 have reported similar rates of
local control following SRS. The treatment itself is well tolerated
with multiple studies reporting toxicity rates of <10%.82 Long-
term outcome and toxicity data were recently published from one
of the largest and first appropriately powered multi-institutional
observational studies investigating up-front SRS without WBRT,
and they have been highly encouraging.78 Specifically, a total of
1194 patients were followed for a median of 46.3 months, and
they experienced a median post-SRS survival of 12 months, with
91% passing away due to non-brain disease; 20% survived for >3
years following treatment. Approximately 12% experienced any
SRS-induced complication, of which less than 1.7% were of grade
4 or 5 toxicity. There were no significant declines in MMSE from
baseline at the 48-month follow-up, and none of these findings
differed based on the original tumor site or the initial number of
tumors (2–4 vs. 5–10). In general, patients are counseled about
the potential for acute toxicities related to fatigue, alopecia,
and transient peritumoral swelling (causing headaches, nausea,
629
presyncope, vertigo), which are typically managed with steroids.
Long-term toxicity includes the risk of radiation necrosis (higher
if previously radiated) and the development of neurologic deficits,
potentially death.83 Dose is an important factor in modulating the
risk of toxicity and also of relapse, with one study reporting >90%
local control rates when treating with ≥14 Gy as opposed to <50%
with <14 Gy; the median dose used was 18 Gy with a range of
10–21 Gy. Tumor volume was also highlighted as an important
consideration. This is not surprising given that SRS was designed
to deliver a very high dose of radiation to a discrete treatment
volume with rapid dose drop-off at its edges to spare adjacent nor-
mal tissue. Our current dosing regimen has been derived from
prior Radiation Therapy Oncology Group (RTOG) trials in which
lesions with a maximum dimension of <2.0 cm were treated with
a single fraction of 24 Gy, 2.1–3.0 cm with 18 Gy, and 3.1–4.0 cm
with 15 Gy. Fractionated SRS dosing may be used when treat-
ing larger (>3 cm) lesions or those near critical structures (e.g.,
brain stem, optic nerve, and chiasm), for example, a regimen of
30–42 Gy (median of 36 Gy) delivered over 6 fractions was shown
to have similar rates of local control and survival with decreased
toxicity compared to single-fraction dosing of 18–20 Gy.84 Despite
appropriate dosing, approximately 25–50% of patients will
develop new or recurrent brain metastases, particularly if they
have high-risk histologies (e.g., melanoma, triple-negative breast
cancer, poorly differentiated lung cancer), progressing systemic
disease and/or high intracranial tumor burden (>15 lesions).85
There have been a few randomized trials that have investigated
SRS alone versus SRS and WBRT in patients with limited brain
metastases (1–3 or 1–4). These trials have consistently shown that
while patients who received SRS treatment alone are at increased
risk of distant metastasis compared to those who received
SRS and WBRT, they have equivalent overall survival.68,86–89
Importantly, patients who received WBRT and SRS had worse
quality of life and neurocognitive outcomes. Therefore, SRS alone
has been adopted as the standard of care in patients with four
or less brain metastases. The use of SRS alone in patients with
more than 4 metastases is being investigated in several ongo-
ing trials (NCT02353000, NCT03550391, NCT01592968, and
NCT03775330).
While awaiting evidence regarding the optimal treatment of
multiple brain metastases, WBRT continues to be the preferred
treatment modality in many centers. Additional indications for
WBRT include leptomeningeal disease and multiple large lesions.
Multiple dose and fractionation schedules exist, and appropriate
treatment selection requires consideration of a patient’s overall
clinical status, severity of neurologic symptoms, extent of extra-
cranial disease, histology, and personal preferences. A dose of 20
Gy over 5 daily fractions would be preferable for patients with
a relatively poor prognosis, while a longer course of 30 Gy over
10 daily fractions or 40 Gy over 20 daily fractions may be more
appropriate to maximize local control in patients with better
prognoses. An extensive systematic review and meta-analysis of
randomized controlled trials applying various WBRT regimens
did not find a significant difference in overall survival, neuro-
logic function, or symptom control, compared to standard 30 Gy
in 10 fractions or 20 Gy in 5 fractions.90 Outcomes were simi-
lar between these two standard fractionation schedules, as well.
Of note, a regimen of 40 Gy in 20 fractions delivered twice daily
showed worse overall survival and poorer neurologic function
compared to 20 Gy in 5 once-daily fractions. The meta-analysis
also concluded that other adjunct treatments such as chemo-
therapy, radiosensitizers, and molecular-targeted agents used in
630
conjunction to WBRT were not beneficial based on the available
evidence. The acute side effects of treatment include fatigue, alo-
pecia, erythema of the scalp, tinnitus,91 and declines in learning
and memory function.88 Late effects for longer term survivors
include neurocognitive changes, somnolence syndrome, radia-
tion necrosis, migraine-like headache (SMART) syndrome,92 nor-
mal pressure hydrocephalus, increased cerebrovascular disease
risk,93 radiation-induced cataracts,94 xerophthalmia,95,96 optic
neuropathy,97 retinopathy,98 high-frequency hearing loss,91 endo-
crinopathies99,100 (hypothalamic, pituitary, hypothyroidism), and
secondary tumor formation. Prevention and/or amelioration of
treatment-induced neurocognitive impairment is an active area
of research with particular interest in hippocampal-sparing
approaches and supplementation with memantine, an NMDA
receptor antagonist, both of which have shown promise. The
results of a phase III clinical trial (NRG Oncology CC001) ran-
domizing patients with brain metastases to receive WBRT with
memantine or hippocampal-sparing WBRT with memantine
were recently published, showing that those in the latter group
experienced significantly less cognitive deterioration (execu-
tive function at 4 months, learning and memory at 6 months),
greater preservation of quality of life (less fatigue, less memory
difficulties, less interference of neurologic symptoms in daily
activities, fewer cognitive symptoms) with no difference in over-
all survival, intracranial progression free survival or toxicity.
The authors therefore concluded that in patients with good per-
formance status and no metastases in the hippocampal region,
hippocampal-sparing WBRT with memantine could be routinely
used to mitigate neurocognitive toxicity.101 Regarding oncologic
outcomes, prior WBRT studies have reported overall response
rates of 40–60% with a median occurrence of 1–8 months fol-
lowing treatment. Neurologic symptoms stabilized or improved
in 25–40% of patients over a median of 1–3 weeks, but more
than two-thirds of patients noticed an improvement at 4 weeks
post-WBRT.102
Patients with a very poor prognosis and/or performance status
may not benefit from aggressive RT. Although a number of earlier
trials36,103,104 suggested that WBRT improves survival by several
months, the Quality of Life after Treatment for Brain Metastases
(QUARTZ) study that randomized NSCLC patients to optimal
supportive care (including steroids) versus optimal supportive
care plus WBRT found that WBRT did not provide a clinically
significant benefit in this patient group, which had a median
survival of 9 weeks. While the validity of these results outside of
the NSCLC context is unclear, it highlights the idea that patients
whose survival and symptoms are driven by progression of their
extracranial disease are not likely to benefit from higher brain
metastasis control.
Lung cancer
Lung cancer is the leading cause of cancer-related mortality
among men and women around the world.105 Traditionally, the
disease has been classified into two primary groups: non–small
cell lung cancer (NSCLC; 80–90% of cases) and small-cell lung
cancer (SCLC; 10–20% of cases) owing to significant differences
in their treatment and prognosis.106 With few exceptions, SCLC
usually presents as a perihilar mass with early and extensive
lymph node metastases, leading to an aggressive clinical course.
Almost all patients with SCLC are treated with chemotherapy.
Patients with limited-stage disease may be treated with con-
current thoracic chemoradiation, whereas patients with more
Textbook of Palliative Medicine and Supportive Care
extensive disease may receive palliative RT to the chest, brain,
and other symptomatic areas. Among individuals with NSCLC,
more than 50% are diagnosed with locally advanced (stage III)
or metastatic (stage IV) disease, of which approximately 20–30%
will require palliative RT.107 Palliative EBRT has been shown to
improve symptom control and quality of life in up to two-thirds
and one-third of patients, respectively.107 The individual rates
vary with each symptom, for example: cough (50–60%), chest
pain (60–85%), dyspnea (40–60%), and atelectasis (20–25%).108
For patients with total atelectasis secondary to obstruction of the
main stem bronchus, receiving RT within 2 weeks of its develop-
ment resulted in higher rates of complete re-expansion (71 vs. 23%
after 2 weeks).109 Despite these optimistic outcomes, radiation
oncologists should wait for the onset of symptoms prior to initiat-
ing therapy. This recommendation is supported by a randomized
phase III trial that prospectively stratified patients, according to
the presence or absence of tumor-related symptoms, and reported
that non-symptomatic patients developed more symptoms and
symptomatic patients experienced improved symptom relief, fol-
lowing treatment.110 Another multicenter randomized controlled
trial also found that providing immediate palliative thoracic RT
did not improve symptom control, quality of life, or survival, as
compared to delaying it until symptoms required treatment.111
Once treatment is initiated, there are a multitude of dose pre-
scriptions available: 10 Gy/1 fraction, 16–17 Gy/2 fractions,
20 Gy/5 fractions, 30 Gy/10 fractions, 40 Gy/10 (split courses),
and 39–45 Gy/13–15 fractions, which have all been shown to
be effective for palliation in two recent systematic reviews and
meta-analyses of randomized controlled trials.112,113 In the analy-
sis by Fairchild et al.,112 however, the 2-year overall survival was
improved among patients receiving the higher dose schedule (of
35 Gy BED10 or more) at the expense of increased esophageal tox-
icity resulting in dysphagia. This effect was only seen within the
subgroup with an ECOG status of 0–2 and not among those with
an ECOG of 3–4. As a result, the American Society for Radiation
Oncology (ASTRO) clinical practice guidelines regarding pallia-
tive thoracic RT in NSCLC lung cancer recommend higher dose
regimens (e.g., 30 Gy/10) for patients with longer life expectancy
and better performance status (ECOG 0–2), as opposed to pro-
tracted schedules (e.g., 10 Gy/1, 16–17 Gy/2) that provide similar
symptomatic improvement with fewer treatments. These updated
guidelines have also introduced a strong recommendation for
concurrent administration of platinum-containing chemother-
apy with moderate-dose palliative thoracic RT only for patients
with stage III NSCLC who are unsuitable for curative therapy,
are candidates for chemotherapy, are ECOG 0–2, and have a life
expectancy of >3 months.106 The role of concurrent immunother-
apy is not yet known and remains under investigation.
Palliative RT has a particularly important role in the manage-
ment of NSCLC-related medical emergencies: superior vena cava
syndrome (SVCS) and hemoptysis. SVCS is a clinical diagnosis
that should be considered for patients with known right-sided
lung masses or pancoast tumors that present with symptoms
of cough, dyspnea, hoarseness, stridor, and/or signs of head and
neck or cerebral edema; it can be confirmed on CT.114 Emergent
treatment involves hemodynamic stabilization (if required), sup-
portive care (with steroids and diuretics), stent placement, and/or
potentially emergent RT/chemotherapy. If RT is needed, a hypo-
fractionated course of 30–40 Gy/3 fractions would appear to be
preferred over 20 Gy/5 fractions as it yielded symptomatic relief
in 70% of patients, in less than 2 weeks, compared to a response of
56% (P = .09). Hemoptysis can occur in approximately 20% of lung
Cancer: Radiotherapy
cancer patients, with 3% resulting in terminal massive hemopty-
sis.107 EBRT has been shown to be highly effective in select series,
within 24–48 hours, although no specific prescription has been
accepted to be superior (30–45 Gy/10–15 fractions, 8–10 Gy/1,
4–8 Gy/3–5).115
Another radiation technique, intraluminal endobronchial
brachytherapy (EBB) has been used in the treatment of NSCLC,
particularly in the cases of tumor recurrence where maximal
doses of external-beam RT had already been delivered. One com-
mon dose used is 30 Gy divided into 2 fractions over 2 weeks.116
Despite advancements in high dose–rate brachytherapy treat-
ment planning and delivery, this technique has increasingly been
replaced by interventional pulmonary procedures (e.g., argon
plasma coagulation, cryotherapy, laser phototherapy, radiofre-
quency, or direct tumor injection of chemotherapy).107 In a ran-
domized controlled trial comparing palliative EBB with EBRT,
there were no advantages for EBB in terms of survival and quality
of life.117 These results were further corroborated by an updated
systemic review on the topic in 2012.118 As such, EBB has not
been widely adopted, and its use is generally limited to specific
scenarios such as high-risk, re-treatment of endobronchial and
peribronchial disease.
Pelvic disease
Locally advanced and recurrent pelvic malignancies of genito-
urinary, gastrointestinal, or gynecological origin can precipitate
significant and disabling symptoms of hemorrhage, necrotic
vaginal discharge, nociceptive pelvic and/or neuropathic pain,
lower extremity edema, fistula formation, gastrointestinal tract
obstruction, and renal failure due to ureteric obstruction. Many
of these symptoms can be effectively palliated with the use of
1-to-3 fractions of 10 Gy given 4 weeks apart to the pelvis.119–121
RTOG 7905 examined combining 3 fractions with misonidazole
(a radiosensitizer) in patients with gynecologic, bowel, and pros-
tate cancers and found that the overall and complete response
rates to treatment were 62 and 38%, respectively.122 A dose–
response relationship was found, with repeat fractions giving
more effective symptom palliation.119,122 However, patients receiv-
ing 3 fractions experienced significantly higher rates (49%) of late
complications as compared to 0–10% among those given only 1
or 2 fractions.119,122 Therefore, given the high complication rates
observed with the RTOG 7905 regimen, an alternate RTOG 8502
approach was explored, which delivered 3.7 Gy twice a day for
2 days, with a rest interval of 2–4 weeks, repeated 3 times to a total
dose of 4.4 Gy.123 This prescription, also known as the “QUAD
SHOT,” was associated with a much lower risk of late toxicity (6%)
yet gave similar symptom palliation with approximately 50% of
patients having complete pain relief and 90% having complete
resolution of bleeding or obstruction.123,124 Therefore, among
patients with a predicted life expectancy greater than 9 months,
the RTOG 8502 (QUAD SHOT) prescription is preferred; alterna-
tively, the use of lower dose per fraction regimens or one-to-two
10-Gy fractions, delivered 4 weeks apart, may also be suitable.
Individuals with muscle-invasive bladder cancer are typically
smokers, older, and often have numerous medical comorbidities.
For patients unable to tolerate radical treatment, and for patients
with locally advanced incurable disease, palliative RT with the
goal of symptom relief can be given. A large randomized trial
comparing the efficacy and toxicity of two palliative RT schedules
(35 Gy in 10 fractions and 21 Gy in 3 fractions on alternate days
over 1 week)125 did not find a difference between the two arms,
631
with 68% overall improvement in bladder symptoms at 3 months,
median survival of 7.5 months, and late bowel toxicity rate of <1%.
Other groups have reported outcomes for the use of 5–6 weekly
fractions of 6 Gy with effective symptom palliation and limited
late bowel (2%) and bladder (11%) toxicity.126,127 Another trial
comparing 6.5 and 5.75 Gy prescriptions, delivered in 6 weekly
fractions, also showed a reduction in the incidence of late bowel
toxicity (from 15 to 0%).128 Of interest, the RT treatment volume
in these bladder cancer trials consisted of the bladder with a small
margin (usually 100 cm3), which was smaller than the volumes
treated in the RTOG trials (usually 225 cm3). This may partially
explain the higher bowel complication rates seen in the RTOG
trials. The use of modern CT-based radiation treatment planning
software to carefully target the tumor, while minimizing radia-
tion to the surrounding OARs, may further reduce treatment-
related toxicity and allow dose escalation.
Para-aortic adenopathy from pelvic primaries can result in
lower back pain that can be palliated with local RT. Recurrent
ovarian cancer is typically treated with chemotherapy; however,
RT offers very good symptom palliation with response rates of
70%, even in patients with platinum-resistant disease.129,130
Locally advanced and unresectable rectal cancer can cause
severe pelvic pain, bleeding, and bowel obstruction, and pal-
liative resection or diverting colostomy is often recommended.
Palliative chemoradiotherapy with concurrent 5-fluorouracil
(5-FU) has been shown to provide symptom relief in 94% of the
patient and produced a 1-year colostomy-free survival rate of
87%.131 This study recommended concurrent RT regimens of 36
Gy/12 across 3 weeks, 35 Gy/14 across 3 weeks, or 30 Gy/6 across
2 weeks. Despite a multitude of fractionation schedules available
with doses ranging from 15 to 70 Gy, there is no single prescrip-
tion that has been accepted as being universally superior.132
Locally advanced, hormone-refractory prostate cancer may
lead to pain, urinary obstruction, hematuria, and rectal symp-
toms. Hypo-fractionated RT of 20 Gy in 5 fractions has been
shown to provide excellent symptom relief with minimal side
effects. Nearly 90% of symptomatic patients treated with this
regimen noted partial or complete relief of their symptoms by
4 months after completing RT.133 In certain instances, however,
higher doses of palliative RT to the prostate can also confer an
overall survival benefit. The recently published STAMPEDE trial,
a phase III randomized controlled trial that compared men with
newly diagnosed metastatic prostate cancer who received pros-
tate RT at a dose of either 55 Gy/20 daily fractions or 36 Gy/6
weekly fractions, to those who did not, reported a 3-year survival
benefit among the subgroup who received RT and also had a low
metastatic burden (defined as an absence of four or more bone
metastases, with one or more outside of the vertebral bodies or
pelvis or visceral metastases or both).134 Therefore, delivery of
RT to the prostate in newly diagnosed metastatic prostate can-
cer with limited disease burden has now become the standard
of care, but the optimal dose schedule and technique of delivery
remain unclear.134
Head and neck cancer
Patients with local progression of head and neck cancer can
develop significant and devastating symptoms related, including
respiratory distress, pain, dysphagia, odynophagia, hoarseness,
otalgia, ulceration, and/or bleeding.135 These can be particu-
larly detrimental to a patient’s quality of life owing to the many
adjacent critical structures that may become effected over time.
632
Supportive care with multimodal analgesia, anticholinergic
blockade of secretions, airway support through tracheostomy
insertion, and provision of supplementary nutrition (potentially
via an additional gastrostomy tube) are essential first steps in
appropriate symptom management, which is associated with a
median survival of 3–5 months.136 Patients locally advanced head
and neck cancer receive high-dose RT, often in combination with
chemotherapy, with curative intent, whereas for patients with
recurrent or metastatic disease, systemic therapy is the mainstay
of treatment. However, due to the importance of local control as
stated earlier, radiation therapy is usually delivered at least once
during patients’ treatment trajectory.
A multitude of different palliative prescriptions have been pub-
lished in the literature, ranging from hypo-fractionated courses
of 24 Gy/3, 20–25 Gy/5, and 30–32 Gy/5–8 to standard regimens
of 30 Gy/10, 40 Gy/10, 40–50 Gy/16, and higher dose regimens
(50–72 Gy).137 The “QUAD SHOT” (RTOG 8502) regimen is also
a popular and effective choice for select head and neck patients.
A course of 24 Gy/3 delivered as weekly 8-Gy single fractions
may be optimal for those with limited life expectancy, given its
reported 82% symptom response rate, and the potential to halt
further treatment should the toxicity outweigh its benefit(s).138
Alternatively, a more conventional regimen of 30 Gy/10 fractions
has been reported to relieve symptoms by at least 50%, within
90% of study participants, and in a separate trial, it enabled 27%
of participants to receive additional RT up to a cumulative bio-
logically effective dose of 66 Gy.139,140 There is emerging data to
support the use of high-dose RT in metastatic head and neck
cancers such as nasopharyngeal carcinoma; however, final results
from prospective randomized trials are awaited.141 In the interim,
radiation dose in non-curative settings should be individualized
and determined by disease burden, symptoms, prognosis, perfor-
mance status, and availability of effective systemic therapies.
Esophageal cancer
More than half of patients with esophageal cancer present with
inoperable locally advanced or distant metastatic disease, and
many already have or develop cancer-related complications,
including dysphagia, odynophagia, cough, nausea, vomiting,
regurgitation, and retrosternal pain.142
Dysphagia is the most common and serious symptom due
to its significant impact on daily quality of life and potential
future treatment options available; therefore, its appropriate
management is very important.143 This requires careful consid-
eration and personalization of treatment with one or a combi-
nation of endoscopic interventions (e.g., esophageal dilatation,
stenting, absolute alcohol injection, intramural chemotherapy
injection, photodynamic therapy, argon plasma coagulation,
and cryospray ablation), intraluminal brachytherapy, EBRT,
chemotherapy, and rarely palliative surgery, to patient’s perfor-
mance and disease status.144 More realistically, surgical options
involving palliative esophagectomy or bypass are rarely utilized
due to their significant risk of complications (50–60%) and
30-day mortality (5–10%), despite providing effective palliation
in 71% of operative survivors.145 For patients with significant
symptoms requiring rapid relief, urgent gastroenterology con-
sultation for insertion of a self-expanding metal stent is the pre-
ferred approach.144 Alternatively, if less urgent intervention is
appropriate, a prior randomized controlled trial of 209 patients
reported that participants who received brachytherapy alone
(12 Gy/1) experienced lower dysphagia severity scores, a greater
Textbook of Palliative Medicine and Supportive Care
number of days with almost no dysphagia, and higher quality
of life were less likely to require retreatment for recurrent or
persistent dysphagia and reported fewer treatment complica-
tions in comparison to the those who received an endoscopi-
cally placed metal stent.146 The group who was stented, however,
experienced more rapid improvement within 30 days of their
procedure. Taken together, it appears prudent that patients with
more limited life expectancy (e.g., <3 months) be preferentially
treated with stenting as opposed to intraluminal brachytherapy
for those with a longer predicted life expectancy. Endoscopic
stenting alone has also been shown to be inferior to combined
treatment with stents containing radioactive iodine-125 seeds,
stents plus brachytherapy (24 Gy/3), and stents plus EBRT
(30 Gy/10) in terms of sustained dysphagia relief and overall
median survival with no differences in the complication rates
between groups.146–148 Patients unable to receive endoscopic
stenting were shown to derive similar benefits from brachy-
therapy (8 Gy/2) as with EBRT (30 Gy/10) with respect to
dysphagia, odynophagia, regurgitation, chest pain, and over-
all performance status, in a multicenter randomized trial of
219 patients.149 If more definitive treatment is indicated in
patients with a predicted life expectancy of >6 months, con-
current chemoradiotherapy with cisplatin and 5-FU can be uti-
lized.150 In a prospective, non-randomized trial of 120 patients,
the median time to symptomatic improvement of dysphagia was
2 weeks, 91% had an initial improvement of symptoms and 67%
maintained their improvements until death.151 A smaller, sin-
gle-center retrospective study reported a significantly improved
5-year survival with the use of concurrent chemoradiotherapy
(cisplatin + 5-FU + 50–60 Gy/25–30).152 In a more recent retro-
spective analysis of the use of concurrent chemoradiotherapy in
the palliation of dysphagia in stage IV esophageal cancer, 75%
of participants reported an improvement posttreatment with
a median time of 43 days until they no longer required nutri-
tion support, an overall response rate of 55% (95% experienced
disease control of their primary lesion and 30% achieved a
complete response), with a median progression free and over-
all survival of 139 and 308 days, respectively.153 In general, the
toxicities related to these treatments have been reported to be
well tolerated, when appropriate patient selection is followed.
Skin cancer
Primary skin malignancies are classified into two major catego-
ries: melanoma and nonmelanoma skin cancers [NMSC] (which
includes basal cell carcinoma [BCC], cutaneous squamous cell
carcinoma [cSCC], Kaposi’s sarcoma, Merkel cell carcinoma,
primary cutaneous B-cell lymphoma, carcinosarcoma, and der-
matofibrosarcoma).154 NMSC is the most common type of malig-
nancy worldwide, with 99% of cases being attributable to BCC
and cSCC, with BCC being 3–5 times more common of the two.
Less commonly, approximately 5% of patients with solid tumors
(predominantly breast cancer, lung cancer, and rarely adeno-
carcinoma of unknown origin, mucosal squamous carcinoma
of the head and neck) will develop cutaneous metastases.155 The
treatment of both primary and metastatic skin malignancies is
a multidisciplinary endeavor involving one or a combination of
surgical excision (including Mohs micrographic surgery), curet-
tage and electrodessication cryosurgery, photodynamic therapy,
laser therapy, radiation therapy, chemotherapy, immunotherapy,
hedgehog pathway inhibitors, and various topical agents. While
surgical resection of NMSC is the recommended treatment in
Cancer: Radiotherapy
most cases, RT is preferred for scenarios where surgery is contra-
indicated, or the lesion is located in a cosmetically sensitive area
(e.g., lower 1/2 of nose, eyelid, and ear). Adjuvant RT is the stan-
dard of care in the treatment of cutaneous malignancies that have
a high propensity for recurrence. Typically, superficial RT modal-
ities are applied in order to provide maximal dose to the skin
surface while sparing deeper tissue. These include orthovoltage,
which utilizes lower energy photon (X-ray) beams than standard
EBRT, electron-beam RT, which takes advantage of the reduced
penetrating potential of electrons, and interstitial brachytherapy.
Generally, anticipated side effects include changes in skin pig-
mentation, fibrosis, atrophy, alopecia, telangiectasias, possible
mucositis, gingivitis, tooth loss, or loss of salivary gland function.
More rarely, eyelid deformity, conjunctival scarring, cataract for-
mation, and soft tissue or bone necrosis may occur.156,157
Although the delivery of curative doses of RT, such as 60 Gy
in 30 fractions or 50 Gy in 20 fractions, has shown excellent
local control and recurrence rates, the focus of this section will
remain exclusively on palliative RT. A variety of dose fraction-
ation schedules exist and have been used historically for the pal-
liation of symptoms related to cutaneous malignancies, but few
have published their outcome data. A small retrospective analysis
of 28 patients with BCC or cSCC treated with standard-of-care
RT (orthovoltage, electrons, or megavoltage photons) using a dose
of 8 Gy per fraction delivered on days 0, 7, 21 determined that it
was a safe and effective regimen for the palliation of distressing
NMSC symptoms.158 Specifically, 61% of patients treated experi-
enced alleviation of their presenting symptoms of pain, bleeding,
odor, and/or discharge with no severe acute or late toxicities at
a median follow-up of 17-week posttreatment. From a practical
perspective, it enabled ulcerative lesions to dry out and allowed
dressing changes and nursing care to be easier among the study
participants, whom all had cognitive impairment and predomi-
nantly resided in a long-term care facility. Similar success has
been reported with the treatment of cutaneous metastases.159
More recently, it has been shown that the delivery of 36.75 Gy
over 7 weekly fractions did not result in a significant difference
in response or cosmetic outcome, when compared to 45 Gy in
15 weekday fractions in a study of 385 disabled elderly patients
with NMSC.160 Similarly, there is an emerging body of evidence
supporting the use of hypo-fractionated (<10-fraction) regimens
in the curative setting, blurring the line between palliative and
curative intent, for elderly patients that are unable to travel to
and from the hospital to complete a fractionated regimen.161 If
cosmesis is also a priority, a recent meta-analysis of the NMSC
literature recommended choosing between doses of 36.75 Gy/7
or 35 Gy/5 fractions as they resulted in favorable cosmesis in 80%
of patients treated.162
Melanoma is an aggressive cutaneous malignancy with a high
propensity for distant metastases. Patients may develop a vari-
ety of sequalae related to primary or metastatic involvement of
their skin, lymph nodes, soft tissues, axial or appendicular skel-
eton, and/or brain.163 This can result in pain, bleeding, compres-
sion of surrounding normal tissues, and compromised function.
Advanced melanoma usually requires multimodal treatment,
within which palliative RT can be utilized as an adjunct to sur-
gical excision, intralesional or targeted therapies, chemotherapy,
immunotherapy, or other systemic treatments. Although his-
torically it has been considered to be a relatively radioresistant
tumor, an early prospective RTOG 8305 randomized controlled
trial showed both complete and partial remission among select
study participants, with the use of two palliative RT regimens
633
(32 Gy/4, delivered weekly, and 50 Gy/20, delivered daily).164
Similar results of improved locoregional control with acceptable
levels of toxicity have been reported in another randomized trial
of participants with recurrent or metastatic malignant melanoma
who received 27 Gy/3 delivered weekly and 40 Gy/8 delivered
twice weekly.165 A retrospective review treating melanoma vis-
ceral metastases in the nasopharynx, lung, mediastinum, abdo-
men, and pelvis reported that these lesions experience a greater
locoregional response when they were treated with higher doses
per fraction (>5 Gy) compared to those using <4 Gy.165 This con-
firmed a number of earlier trials publishing this dose–response
relationship. Palliation of skeletal and intracranial sites of mela-
noma involvement follows the same principles introduced in the
sections previously: single-fraction (8 Gy) treatments for uncom-
plicated bony lesions and size-dependent SRS dosing (with or
without fractionation) for limited intracranial disease; WBRT or
best supportive care for more extensive involvement.
Liver metastases
The liver is a common site of primary and metastatic spread for
cancers of the lung, breast, and gastrointestinal tract.166 Patients
may present with a solitary site of metastasis or they may have
multifocal liver involvement with the possible extrahepatic
spread. A number of treatment options exist, including local
therapy with surgical resection, radiofrequency ablation, per-
cutaneous ethanol injection therapy, transarterial chemoem-
bolization, SBRT, and systemic therapy with targeted, immune
and/or chemotherapeutic agents. Systemic chemotherapy is
typically the standard of care for patients with advanced dis-
ease, but often it cannot be given due to severe hepatic dys-
function or the development of refractory hepatic lesions.167
Palliative RT, in the form of focal (SBRT) and whole-liver irra-
diation, has increasingly been used to treat liver metastases
in these patients. The application of SBRT has been shown to
provide excellent local control of both primary and metastatic
liver lesions, blurring its distinction as a form of palliative ther-
apy.168 Whole-liver RT (WLRT) is a well-studied and effective
method of palliating symptoms of hepatic pain, abdominal dis-
comfort, nausea, and night sweats, which may occur as a result
of progressed liver disease. Although it has not been shown to
improve survival, the pain relief rate is around 55–80%, and
it is a safe treatment modality that produces very low rates of
toxicity when delivered in doses of 2-Gy fractions up to a total
dose of 30–35 Gy.166 Its An earlier RTOG prospective, uncon-
trolled, non-randomized pilot study assessing the feasibility of
hepatic irradiation among 109 participants using doses rang-
ing from 21 to 30 Gy, delivered over 7–19 fractions, reported
that responses were seen for abdominal pain (55%), nausea and
vomiting (49%), fever and night sweats (45%), ascites (33%),
anorexia (28%), abdominal distension (27%), jaundice (27%),
and night sweats/fever (19%), with complete response rates for
individual symptoms ranging from 7 to 34%; 28% experienced
an improved performance status.
More recently, a prospective phase II trial of 41 patients with
HCC and liver metastases treated with a single 8-Gy fraction of
WLRT reported that 48% of participants had a clinically signifi-
cant improvement in their average pain at 1 month, with only one
patient experiencing grade 3 nausea at 1 week.169 Similar results
have also been observed in a prospective study of 52 patients
with unresectable hepatocellular carcinoma receiving a single
8-Gy fraction of WLRT; 50 and 55.6% of participants reported an
634
respectively, at 1 month following treatment.170 The median dura-
tion of response was 3 months in those who responded, compared
to 2 months for those that did not.
A phase III randomized controlled trial (NCT02511522) is cur-
rently underway, comparing the effectiveness of palliative WLRT
plus best supportive care (BSC) versus BSC alone in patients with
moderate–severe pain due to hepatocellular carcinoma or liver
metastases.
KEY LEARNING POINTS
• Palliative radiotherapy (RT) utilizes ionizing
radiation to induce cellular damage and produce
targeted cell death with the intention of pro-
viding effective and durable relief from cancer-
related symptoms.
• RT is predominantly delivered through external-
beam radiation using three-dimensional con
Textbook of Palliative Medicine and Supportive Care
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