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Original Release: 2003; Revised 2007 and 2010; Updated: June 2013 Expiration: Dec 31, 2014

Effective pain management presents a significant challenge for physicians, other healthcare
professionals and their patients. Pain is one of the most common reasons for patients to seek
medical attention and one of the most prevalent medical complaints in the US; 1,2 9 out of 10
Americans aged 18 or older suffer pain at least once a month, and 42% experience it every day.3
In America, more than 116 million Americans are burdened with chronic pain alone.4
Consequently, physicians and other practitioners need education to assist in developing the skills
needed to evaluate and manage patients with pain.

Educational Objectives
Compare and contrast pharmacologic and nonpharmacologic options for the management
of pain.
Review recommended approaches for risk stratification and appropriate monitoring of
patients who might receive opioid analgesics.
Recognize and manage the side effects of nonopioid and opioid analgesics.
Utilize a rational approach to the selection, administration, and titration of analgesics used
in pain management.
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To obtain AMA PRA Category 1 Credit for this module you will
need to review the CME Information front matter, read the module
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certificate. Follow these steps to obtain your CME credit and
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2. Read the module content
3. Complete the online self-assessment and evaluation. A
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claim credit.

care physicians and those physicians who care for patients

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experiencing pain.

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Communications. The June 2013 revision of this activity is

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CME Principal Faculty

Russell K. Portenoy, MD, Contributing Author, Planning
Chairman, Department of Pain Medicine
and Palliative Care, Beth Israel Medical Center
New York, NY
Professor of Neurology and Anesthesiology
Albert Einstein College of Medicine
Bronx, NY
Arthur G. Lipman, PharmD, FASHP, Clinical Content
University Professor, Department of Pharmacotherapy,
College of Pharmacy
Adjunct Professor, Department of Anesthesiology, School
of Medicine
Director of Clinical Pharmacology, Pain Management
Center, University Health Care
University of Utah Health Sciences Center
Editor, Journal of Pain & Palliative Care Pharmacotherapy
Charles E. Argoff, MD, Reviewer
Professor of Neurology
Albany Medical College
Director, Comprehensive Pain Center
Albany Medical Center
Albany, NY
Jonathan S Berek, MD, MMS, Clinical Content Reviewer
Professor and Chair
Department of Obstetrics & Gynecology
Stanford University School of Medicine
Director, Stanford Women's Cancer Center
Stanford Cancer Institute
Stanford, CA
Reed Thompson, MD , FACS, Clinical Content Reviewer
Associate Professor, Donald W. Reynolds Department of
University of Arkansas for Medical Sciences
Little Rock , AR
Karen Knox, PhD, RN, ARNP, MSN, MPH, ACNS-BC
Advanced Practice Registered Nurse, Clinical Content
Associate Professor, College of Nursing
Allen College
Waterloo, IA

Martin Grabois, MD, Reviewer

President, American Academy of Pain Medicine,
Baylor College of Medicine
Department of Physical Medicine and Rehabilitation
Houston, Texas
Bill McCarberg, MD, Reviewer
Adjunct Assistant Clinical Professor, University of
San Diego, CA
Founder, Chronic Pain Management Program, Southern
California Permanente Medical Group
Escondido, CA
Cheryl L. Lambing, MD, Reviewer
Assistant Clinical Professor
University of California , Los Angeles
Medical Director for Professional and Community
Education and Outreach
Ventura County Health Care Agency
Ventura, CA
Bruce Ferrell, MD, Director, Reviewer
UCLA Adult Palliative Care Services
University of California, Los Angeles
Los Angeles, CA
Seddon R. Savage, MD, MS, Reviewer
Pain Consultant, Manchester VAMC
Adjunct Associate Professor of Anesthesiology,
Department of Anesthesiology, Geisel School of Medicine
at Dartmouth College
Hanover, NH
Planning Committee
Rita LePard, CME Program Committee
American Medical Association
Barry D. Dickinson, PhD
Secretary, Council on Science & Public Health
American Medical Association
Janet Williams
Senior Policy Analyst
American Medical Association

Vitaly Gordin, MD, Reviewer

Director for Pain Division, Department of Anesthesiology
Penn State Hershey Medical Center
Hershey, PA

Disclosure Policy

In order to assure the highest quality of certified CME programming, and to comply with the
ACCME Standards for Commercial Support, the AMA requires that all faculty, planning committee
and AMA CME Program Committee members disclose relevant financial relationships with any
commercial or proprietary entity producing health care goods or services relevant to the content
being planned or presented. The following disclosures are provided:
CME Advisory Board
Dr. Argoff:

Dr. Berek:
Dr. Ferrell:
Dr. Gordin:
Dr. Grabois:
Dr. Knox :
Dr. McCarberg
Dr. Lambing:
Dr. Lipman:
Dr. Portenoy:

Dr. Savage:
Dr. Thompson:

Consultant, Speakers Bureau, Grant support: Endo, Forest, Lilly, Neurogenex, Pfizer,
Consultant: Insys Pharmaceuticals, Gruenthal Pharmaceuticals, King, Sanofi-Aventis,
Nuvo Research, Jazz, Shinogi, Iroko, Zogeniz,
Consultant, Speakers Bureau: Ameritox, Covidien, Depomed, Millenium, Quest
Speakers Bureau: Horizon
Nothing relevant to disclose
Nothing relevant to disclose
Nothing relevant to disclose
Consultant: Pfizer
Nothing relevant to disclose
Consultant: Endo, Insys Pharmaceuticals, Neurogenex, Pfizer, Purdue Pharma, QRx
Pharma, Salix, Sucampo, Teva
Nothing relevant to disclose
Nothing relevant to disclose
Grant support: Boston Scientific, Covidien Mallinckrodt, Endo, Medtronic, ProStrakan,
Purdue Pharma, Salix, St. Jude
Speakers Bureau: Grupo Ferrer
Nothing relevant to disclose
Nothing relevant to disclose

AMA Staff
Dr. Dickinson: Nothing relevant to disclose
Ms. LePard:
Nothing relevant to disclose
Ms. Williams:
Nothing relevant to disclose
AMA CME Program Committee members have no relevant relationships to disclose

Disclosure of Off-Label Uses

The content of this CME publication may contain discussion of off-label uses of some of the agents
mentioned. Please consult the product prescribing information for full disclosure of labeled uses.

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CME Needs Assessment

Pain is one of the most common reasons for patients to seek medical attention and one of the
most prevalent medical complaints in the US. According to the 2011 Institute of Medicine
Report-Relieving Pain In America, approximately 116 million Americans are burdened with
chronic pain.4 Three in five of those 65 years or older said that they experienced pain that lasted a
year or more; more than 60% of U.S. nursing home residents report pain, most commonly
attributable to arthritis, and 17% have substantial daily pain.2,4 More than one-quarter of adults
said they had experienced low back pain, and 15% of adults experienced migraine or severe
headache in the past three months. For the millions of Americans who experience persistent pain,
the impact on function and quality of life can be profound. 2-5 Pain is associated with high
utilization of health care and the societal costs related to treatment are compounded by the loss
in productivity associated with persistent pain.6 Lost productive time from common pain
conditions among workers costs an estimated $61.2 billion per year and most of this is related to
reduced performance while at work.7 The annual economic cost associated with chronic pain
most likely exceeds $560 billion.4
Opioid medications are prescribed commonly for acute pain and pain associated with advanced
illness, and although the use of these drugs to help manage chronic non-cancer pain continues to
be limited, their use for the latter indication has increased substantially during the past two
decades. In parallel with this increase in medical use has been a deeply concerning rise in
prescription drug abuse and unintentional overdose. Drug overdose deaths in the United States
exceed 38,000 annually with prescription drugs involved in more than 55% of such deaths.
Prescription opioid drugs were involved in nearly 75% of the 22,000 plus prescription drug
overdose deaths reported in 2010.8 Consequently, federal actions such as FDA-mandated risk
mitigation strategies for long-acting opioids, federal support for requiring mandatory education for
DEA registration, and state-based initiatives designed to more tightly regulate opioid use have
emerged. Physicians and other clinicians need current, state-of-the-art education to assist them
in developing the necessary skills to manage patients with persistent pain, including the skills
needed to use opioid drugs safely and effectively. This CME program reviews the assessment
and management of pain and persistent pain syndromes that are commonly seen in primary care.
1. Watkins EA, Wollan PC, Melton LJ 3rd, Yawn BP. A population in pain: report from the Olmsted County
health study. Pain Med. 2008;9:166-174.
3. Blay SL, Andreoli SB, Gastal FL. Chronic painful physical conditions, disturbed sleep and psychiatric
morbidity: results from an elderly survey. Ann Clin Psychiatry. 2007;19:169-174.
4. Institute of Medicine. Relieving Pain in America: A Blueprint for Transforming Prevention, Care,
Education, and Research. 2011. Washington, DC. The National Academies Press.
5. Sawyer P, Lillis JP, Bodner EV, Allman RM. Substantial daily pain among nursing home residents. J Am
Med Directors Assoc. 2007;8:158-165.
6. Von Korff M, Lin EH, Fenton JJ, Saunders K. Frequency and priority of pain patients health care use. Clin
J Pain. 2007;23:400-408.
7. Stewart, WF, Ricci, JA, Chee, E, Morganstein D, & Lipton R. (2003). Lost productive time and cost due to
common pain conditions in the US workforce. JAMA. 2003; 290(18);2443-2454.
8. Jones CM, Mack KA, Paulozzi LJ. Pharmaceutical overdose deaths, United States, 2010.

The goals of pain management vary from patient to patient. When pain is acute, the overriding
goal is to reduce pain intensity as quickly as possible, often in association with amelioration of its
underlying cause. In those with persistent pain related to a serious medical illness, such as
cancer, the goal of comfort may become linked to other concerns, such as the relief of other
symptoms and management of diverse problems undermining physical, psychosocial and
spiritual well being. In common types of persistent musculoskeletal pain, the goal of functional
restoration may be given equal importance to the goal of pain management.
Although the importance of concurrent goalsidentifying and potentially treating the underlying
cause of the pain, and providing therapies to address related and comorbid problemsis clear,
these imperatives should not distract attention from the importance of pain control. The
effectiveness of any strategy usually is enhanced if undertaken when pain is at a tolerable level.

Analgesics Strategies
Effective pain management, particularly in the context of persistent pain, requires the skillful
application of one or more specific therapies, implemented safely and adjusted based on
repeated outcome assessment over time. In some cases, a single modality, such as an analgesic
drug or an injection is appropriate. In other cases, particularly those characterized by persistent
pain associated with a high level of disability or a poor response to analgesic trials in the past, the
best approach is a multimodality strategy (see Module 7). A subset of patients who are good
candidates for a multimodality strategy presumably would be optimally managed through referral
to a interdisciplinary team of pain specialists.
Analgesic treatments can be broadly grouped into seven categories. Clinicians should carefully
consider the broad range of options in these categories when developing the plan of care for a
patient with pain. (Table: Categories of Analgesic Strategies)

Table: Categories of Analgesic Strategies

Type of Analgesic




Complementary and

Nonopioid drugs
Opioid drugs
Adjuvant analgesics
Physical and occupational therapy
Modalities (heat, cold, ultrasound, electrical stimulation)
Cognitive-behavioral therapy
Specific treatments (e.g., biofeedback)
Other types of psychotherapy
Trancutaneous electrical nerve stimulation, peripheral
nerve stimulation, spinal cord stimulation, transcranial
direct current or magnetic stimulation
Injection therapy (e.g., spinal injections, or trigger point or
joint injections)
Neural blockade (e.g., stellate ganglion block and other
regional anesthesia techniques, neurolytic procedures)
Implant therapies (spinal cord stimulator, peripheral nerve
stimulation, neuraxial analgesia via pump)
Neurectomy, nerve decompression, cordotomy
Acupuncture, massage, chiropractic, nutraceuticals/
botanicals, energy therapies, non-Western systems
(traditional Chinese medicine)

Nonpharmacologic Strategies
Although systemic pharmacotherapy is the mainstay approach in the treatment of acute and
many types of persistent pain, optimal pain management includes diverse nonpharmacologic
therapies. These include an array of non-invasive strategies and a number of invasive
approaches. Many patients also appear to benefit from complementary and alternative medicine
(CAM) approaches, and some of the latter therapies, such as acupuncture and massage, have
sufficient evidence of safety and potential effectiveness to be recommended by clinicians.
Interventional Approaches
The invasive analgesic therapies are known generically as interventional approaches. 1,2 These
include varied injection therapies, many types of neural blockade, and implant therapies. Patients
suffering from focal or regional pain that is likely to be relieved with injection and patients failing to
achieve adequate analgesia without intolerable adverse effects from acceptable non-invasive
therapies represent the major indications for referral for interventional therapies.
Injection Therapies
The injection therapies comprise a diverse array of approaches that differ in technical complexity
and objectives. The simplest approachestrigger point injections into tender muscles or their
connections and joint injectionsusually are within the purview of the primary care physician.
Other injections target specific structures, such as the spinal epidural space, the small joints that
connect vertebral bodies or scars that may entrap neuromas. In some cases, the technical skills
required to inject these sites is relatively minor and the primary care physician can provide the
treatment. In other cases, referral to an interventionally-trained pain specialist is necessary. For
further discussion on interventional approaches see Module 12.
Cognitive-Behavioral Therapy and Other Psychological Approaches
Psychological traits or experiences, environmental factors, and varied types of psychopathology
affect an individuals response to pain and suffering. Psychological approaches almost always
should be considered when developing a plan of care for chronic pain. Many types of
psychoeducational and psychotherapeutic strategies may be used to provide support, enhance
coping and adaptation, reduce catastrophization, encourage the appropriate use of health care,
and help to ameliorate pain and sustain functioning. The most common types used in practice are
subsumed under the broad framework of cognitive-behavioral therapy (CBT). CBT employs a
combination of cognitive therapy (composed primarily of education) in conjunction with behavioral
therapy. The integration of these two approaches is aimed at reducing or extinguishing the
influence of the factors that reinforce or maintain patients maladaptive behaviors, beliefs, and
patterns of thought. Included are strategies that can be taught to the patient and may lessen pain
intensity, improve coping, increase function and reduce overall disability. These strategies include
education about pain and its impact; cognitive strategies to reduce catastrophization and
helplessness; training in cognitive therapies such as biofeedback, relaxation and imagery; and
specific behavioral interventions such as graduated exercise, pacing and time management and
sleep hygiene training.
A CBT strategy at its most comprehensive requires a multidisciplinary approach performed by
experts.3 Certain aspects of the strategy, such as training in biofeedback, can be obtained
separately by referral to specific practitioners. Others, like education about pain and disability and
use of an activity diary to encourage exercise, can be performed by the individual physician.4
CBT is most appropriate for patients who have pain-associated disability or distress, and express
a willingness to work on psychological components of care. Studies demonstrate that the addition
of CBT can reduce pain and disability for certain chronic pain conditions, especially low back pain
and fibromyalgia.5-8 These approaches appear to be less effective in patients suffering from
persistent neuropathic pain.9

Other types of specific psychological modalities should be similarly considered when patients
have pain associated with a premorbid or comorbid psychiatric disorder. This is particularly
important if the pain has been persistent, or may be transitioning from an acute phase to a
chronic phase. Among the most important premorbid disorders to recognize are personality
disorders, an affective disorder such as generalized anxiety or recurrent depression, or a
substance use disorder including significant drug abuse or the possibility of alcoholism or another
addiction. A comprehensive evaluation of the patient that identifies these problems may allow
early referral for diagnosis and primary treatment of the psychiatric problem concurrent with
therapy for pain. Similarly, patients who have pain and reveal psychological or emotional
disturbances that may reflect comorbid psychiatric pathology, such as a new affective disorder or
an emerging substance use disorder, should be considered for referral to a mental health
professional. One systematic review found that psychological therapies can help people with
chronic pain reduce negative mood (depression and anxiety), disability, and in some cases
pain, but guidance is still required on the best content, duration, intensity, and format of
Rehabilitation and Physical Medicine Approaches
Rehabilitation involves the restoration of lost function and includes physical rehabilitation as well
as occupational, vocational, social, and other forms of rehabilitation. Specific treatment usually
considered under the purview of physical medicine or rehabilitation may be prescribed as part of
a CBT program, or separately. Some patients with acute pains, particularly musculoskeletal pain,
should be given specific instructions for exercise, or referral to a physical therapist, as a first-line
approach to pain therapy with functional restoration. For example, most patients with acute low
back pain should be told to rest for no more than a few days, and then begin gentle exercise,
which has been shown to be as effective as other therapies in resolving the acute pain.11 In
populations with persistent pain, these strategies are especially appropriate when pain is not
related to a serious medical disorder and is associated with impairment in physical functioning
and deconditioning, or more global disability.
Although physicians commonly recommend exercises to patients, a significant need for
conditioning or restoration of function should suggest referral to a trained professional. In some
cases, the best approach is referral to a physician who specializes in physical medicine and
rehabilitation, who can provide a detailed recommendation to a physical therapist or occupational
therapist, a recommendation to a rehabilitation program, or other therapies. In other cases, direct
referral to a physical therapist may be appropriate, particularly if the targets of therapeutic
exercise appear obvious. Therapeutic exercise may focus on general conditioning, gait training,
stretching, specific exercises involving the painful part of the body, specific spinal stabilization
exercises and training, and attention to ergonomics and body mechanics.
In addition to physical therapy and occupational therapy, the category of rehabilitative strategies
for pain usually includes more comprehensive programs and specific modalities. Programs that
may be available through hospitals, free-standing facilities, government services or corporate
entities include vocational assessment and training, job retraining programs, work hardening
programs, and rehabilitation-oriented pain management programs.
In contrast to the broader, function-oriented interventions, physical modalities are used
specifically as an adjunct to other therapies to lessen pain. These modalities include heat, cold,
electricity, vibration, and ultrasound. In transcutaneous electrical nerve stimulation (TENS), a well
known neurostimulatiion therapy, cutaneous stimulation is delivered through a contact pad by an
electrical pulse generator. TENS was developed based on the gate control theory of pain, which
hypothesized that a pain modulating system in the dorsal horn of the spinal cord can be activated
by stimulation of large-diameter non-nociceptive primary afferent neurons (so-called A beta
fibers) and thereby inhibit pain transmission from the periphery to the brain. This theory has
morphed into a broader construct with the identification of dozens of endogenous pain modulating
systems, which function at every level in the periphery and CNS and have numerous and
complex mechanisms. Mechanisms activated by A beta stimulation have been characterized and
provide a rationale for TENS and other neurostimulation therapies. Although there have been

many controlled studies of TENS, systematic analyses have concluded that evidence is
insufficient to permit firm characterizations about its effectiveness for the treatment of either acute
or chronic pain.12,13 Nonetheless, the safety of the approach, combined with favorable anecdotal
experiences, leads many experts to continue recommending a trial of TENS in the clinical setting
for patients with focal or regional chronic pain.

Pharmacologic Strategies
Analgesic drug therapy involves the administration of nonopioid and opioid analgesics, and a
diverse group of drugs often called the adjuvant analgesics. The latter drugs were originally
conceptualized as a group of agents that have indications other than pain but may be analgesic in
specific circumstances. Historically, they were considered to be useful adjuvants when combined
with other analgesics. During the past decades, however, research has characterized the
analgesic potential of many drugs and led to the use of some, such as selected antidepressants
and antiepileptic drugs, as primary therapies for pain. Accordingly, the term adjuvant analgesic
is actually a misnomer applied generically to a large and diverse group of drugs that vary in
evidence and utility as analgesics.

Principles of Pain Control and Analgesic Therapy

Perform a comprehensive evaluation and develop an individualized plan

of care by considering a range of analgesic interventions and concurrent
therapies targeting the pain itself, pain-related functional impairments and
disability, and both medical and psychiatric comorbidities
Identify and treat the source of pain, if possible and appropriate
Do not use placebo
Select the simplest, least invasive, and most cost-effective approaches,
and understand that favorable outcomes often can be achieved by
effectively delivering one or two therapies
Appreciate that some patients, particularly those with chronic pain and
disability, will do best if offered a multimodality strategy that incorporates
pharmacologic and nonpharmacologic therapies
Use analgesic drugs cautiously, based on case-by-case analysis of risk
and benefit
Obtain the input of consultants if there is uncertainty about the value of
specific drug therapies, such as opioids, or the potential for other specific
pain-relieving interventions

There is no one systematic approach to the use of drugs for pain control. Many disease-specific
or syndrome-specific guidelines have been published, some of which are based on good
evidence and some of which have become widely accepted. For example, in 1986, the World
Health Organization (WHO) developed a 3-step conceptual model (Figure: World Health
Organization Analgesic Ladder) to guide the management of cancer pain, which suggests that
the overall severity of the pain should be used to guide the selection of an analgesic (e.g.,
NSAID, so-called weak opioid, and so-called strong opioid for mild, moderate and severe pain,
respectively).14 This broad recommendation has been useful over the years as a tool for
developing policies and education, and for structuring more specific guidelines for cancer pain
management.15-17 As a guideline, it is generally accepted as applying to patients with active
cancer and patients with advanced illnesses of other types, such HIV/AIDS. It should not be
applied to all chronic pain. The current view and application of the WHO ladder to treating cancer
pain has been modified in recent years, at least in the Unites States, with a better understanding
of the disadvantages that can accompany the clinical use of codeine, and the lack of
pharmacologic basis for classifying the combination of pure opioid agonists such as hydrocodone

or oxycodone with acetaminophen or ibuprofen as a weak opioid. To the contrary, hydrocodone

and oxycodone are potent opioid analgesics (see Module 11)
Another example is provided by an evidence-based guideline for the treatment of neuropathic
pain, which was developed by an international panel of experts. 18 In contrast to the WHO model,
which indicates that an opioid is a first-line approach for all patients with persistent moderate to
severe pain, this guideline suggests that opioids might be used transiently in an effort to get
control over very severe pain, but are not first-line for long-term management. Rather, tricyclic
antidepressants, dual reuptake inhibitors of serotonin and norepinephrine, gabapentinoids (which
block calcium channels), and topical lidocaine play this role; opioid analgesics and tramadol or
taptentadol are considered after these and other reasonable approaches have proved
unsuccessful or in other specific clinical circumstances (see Modules 7 and 9). In a similar way,
evidence-based guidelines for the management of osteoarthritis recommends acetaminophen
and NSAIDs as the first-line drugs though the latter may present higher risks in the elderly and
patients with higher risk of cardiovascular disease, nephrotoxicity, and gastrointestinal toxicity
(see Modules 5 and 8).19-22

World Health Organization (WHO) Analgesic Ladder

Adapted with permission from Gabriel SE. Cancer Pain Relief: with a Guide to Opioid Availability. 2nd ed.
Geneva: World Health Organization; 1996.

Pharmacologic Strategies: Nonopioid Analgesics

Acetaminophen, aspirin and other salicylates, and NSAIDs (Table: Nonopioid Analgesics)
provide effective relief of many types of acute and persistent pain, including somatic pain from
metastatic bone cancer or arthritis, as well as trauma-related pain, and dental and postoperative

pain. Prescribed alone, these agents can relieve many types of mild to moderate pain.
Alternatively, for moderate to severe pain, they can be used in combination with opioid drugs to
enhance pain relief. These agents differ from opioid analgesics in several ways: (1) they have a
ceiling effect to analgesia; (2) they do not produce tolerance or physical dependence and are not
associated with abuse or addiction; (3) they are antipyretic and all except acetaminophen are
anti-inflammatory; and (4) their primary mechanism of action is inhibition of prostaglandin

Nonopioid Analgesics & Prostaglandin Inhibition

Some classes of drugs, most notably the NSAIDs, owe their principal therapeutic (and adverse)
effects to blockade of the formation of prostaglandins. 24 Prostaglandins are necessary for many
physiological processes and both local and systemic response to injury. These compounds
contribute to pain and inflammation, febrile responses, hemostasis, thrombosis, gastrointestinal
secretion, renal function, joint metabolism, smooth muscle tone, parturition, and other processes.
Membrane lipids, principally arachidonic acid, supply the substrate for the synthesis of
prostaglandins, leukotrienes, and related compounds. Prostaglandins are generated by the
actions of an enzyme complex that includes cyclooxygenase (COX), which catalyzes the
oxygenation of arachidonic acid and is the target for the majority of pharmacologic inhibitors. Two
major isoforms of this enzyme complex exist and are commonly referred to as COX-1 and
COX-2. The oxygenation of arachidonic acid leads to the unstable intermediate prostaglandin H2
(PGH2), which is ultimately converted to the various prostaglandins, thromboxane, and
prostacyclin in cells and tissues. The conversion of arachidonic acid to PGH2 involves free radical
generation and hydroperoxide intermediates which alter the oxidation state of the COX enzyme.
COX-1 is the primary constitutive form of cyclooxygenase found in most normal cells and tissues.
A splice variant of COX-1 (termed COX-3 by some investigators) exists in low concentrations in
the central nervous system.25 COX-2 is constitutively expressed in kidney and brain and is
induced in endothelial cells by shear laminar forces, in the brain by pyrogens and at other sites by
factors associated with inflammation, including cytokines, growth factors, and endotoxin. In
mature platelets, the dominant end-product is thromboxane A2 (TxA2) formed by COX-1, which
contributes to vasoconstriction and platelet aggregation. Prostaglandin I2 (PGI 2, or prostacyclin),
formed primarily by COX-2 in endothelial cells, opposes and modulates the effects of TxA 2 on
vascular tone and platelet function in vivo.
The non-inducible COX-1 isozyme functions to produce prostaglandins involved in homeostasis
(gastric cytoprotection, renal function). The inhibition of COX-2 is thought to mediate, at least in
part, the antipyretic, analgesic, and anti-inflammatory action of NSAIDs. The therapeutic effects of
the NSAIDs are presumably largely mediated by their inhibition of COX-2; the simultaneous
inhibition of COX-1 results in certain unwanted side effects, particularly those that lead to gastric
NSAIDs include aspirin, which irreversibly acetylates COX 1 & 2, and several other classes of
organic acids which compete with arachidonic acid at the active site of cyclooxygenase. Most
available NSAIDs inhibit both COX-1 and COX-2, but the selectivity at COX-1 and COX-2, (i.e.,
the balance between these actions), varies by drug. In recent years, drugs that are relatively
highly selective for COX-2 have been labeled COX-2 selective NSAIDs and distinguished from
the larger group of drugs labeled as non-selective COX-1/COX-2 inhibitors. The COX-2 selective
drugs have relatively less risk of gastrointestinal (GI) toxicities.
All NSAIDs have the ability to promote prothrombotic effects, increasing the risk of adverse
cardiovascular toxicity. This ability is primarily related to COX-2 inhibition. Because all NSAIDs
inhibit COX-2, all such drugs possess this risk (see Module 5). Presumably, the risk is relatively
higher among those drugs that are COX-2 selective. Concern about cardiovascular toxicity has
led to the withdrawal from the market of rofecoxib and contributed to the withdrawal of valdecoxib,
both of which were labeled selective COX-2 inhibitors. The only labeled COX-2 inhibitor now

marketed in the U.S. is celecoxib (Celebrex). The U.S. Food and Drug Administration requires a
boxed warning for all NSAIDs reminding clinicians of both cardiovascular and gastrointestinal risk.
Acetaminophen inhibits COX in a cell-specific manner, including the central nervous system. It is
relatively inactive as an anti-inflammatory agent, but is an effective antipyretic and analgesic
agent. In contrast to the NSAIDs, acetaminophen does not cause gastric ulceration or inhibit
platelet aggregation. Acetaminophen does not act as a competitive COX inhibitor, but rather
appears to interfere with the oxidative state of COX, an action that itself is reversed or prevented
by the tissue peroxide tone and which explains acetaminophens relative lack of antiinflammatory effects.25-27

Clinical Use: Aspirin

Aspirin (acetylsalicylic acid) is as effective as other nonopioid analgesics in relieving pain. Today,
the use of aspirin is largely limited to low dose cardioprotection for patients at risk of MI or stroke.
It is uniquely effective for this indication because aspirin irreversibly inhibits platelet aggregation,
thus providing reliable protection against unwanted clotting. Aspirin is contraindicated in children
under the age of 12 who have viral illness (particularly varicella) due to the risk of Reyes
syndrome. Some patients exhibit hypersensitivity to aspirin and in a cross-sensitive manner other
Aspirin competes with some other NSAIDs for the binding site of the COX enzyme. If aspirin is
given soon after a dose of ibuprofen or naproxen, it is possible that it will not be able to effectively
acetylate enough COX in platelets to have favorable anti-aggregation effects. For this reason, it is
prudent to inform patients to take low dose aspirin at least several hours before a dose of one of
these other NSAIDs.

Clinical Uses: Acetaminophen

Acetaminophen is similar to aspirin in its analgesic and antipyretic potency. Like NSAIDS,
acetaminophen exhibits a ceiling effect beyond which larger doses do not provide greater pain
relief. The combination of acetaminophen and NSAIDs is unlikely to provide greater analgesia
than either drug alone. However, unlike aspirin, acetaminophen lacks antiplatelet activity, exhibits
little or no anti-inflammatory effect and does not damage the gastric mucosa. Acetaminophen is
commonly used to treat mild-to-moderate pain and is the recommended first-line analgesic
therapy for the treatment of osteoarthritic pain.17 Acetaminophen is available in various OTC
combinations with other compounds, including aspirin, caffeine, antihistamines, and
decongestants and combined with a variety of opioids in prescription drug products (e.g., Vicodin,
Tylox, Percocet, Roxicet, Roxilox). Intravenous acetaminophen is now available in the United
States. It has been studied in both children and adults and offers an option for parenteral
treatment in the postoperative and other settings where patients are unable to take oral

Adverse Effects of Acetaminophen

Acetaminophen is a well-tolerated drug and is considered relatively nontoxic in therapeutic doses.
However, acetaminophen is the leading cause of acute liver failure in the United States, with
nearly half of acetaminophen-related cases being associated with unintentional overdose. 29 It is
estimated that acetaminophen overuse is associated with approximately 56,000 emergency
department visits, 26,000 hospitalizations, and more than 450 deaths annually. A hepatotoxic
metabolite generated by oxidative metabolism of acetaminophen by cytochrome P450 in the liver
mediates this.
Although the conventional safe maximum daily dose of acetaminophen for chronic use has been
considered to be 4000 mg/day from all sources in patients who have no serious liver disease or
history of heavy alcohol use, the amount that is potentially hepatotoxic may be significantly less in
those with risk factors for hepatic damage. Significant liver disease or heavy drinking should be
considered relative contraindications to the use of acetaminophen. In order to reduce the potential
for unintentional overdose and liver toxicity, the FDA has advocated adoption of a lower

usual maximum dose (3000 mg per day) and has asked manufacturers of prescription
combination products to limit the amount of acetaminophen to 325 mg. Patients should be
warned about the risk of unintentional overdose and told to avoid consumption of acetaminophen
from various sources unless they clearly understand the recommended limits from all sources.
Although it does not affect platelet activity, acetaminophen has been reported to potentiate anticoagulation when administered to patients taking warfarin.30 Chronic excessive use of
acetaminophen may impair renal function, although markedly less than NSAIDs.

Acetaminophen Considerations

Dosage limits have been considered to be 4000 mg/ day but the
FDA is now recommending 3,000 mg/day

Use cautiously in patients who have chronic alcoholism and liver

disease, or who consume more that 2-3 alcoholic drinks per day

May increase effects of warfarin

Clinical Uses: NSAIDS

All NSAIDs share the ability to inhibit the synthesis of prostaglandins through their inhibition of
COX enzymes in peripheral tissues and in the central nervous system. NSAIDs are widely used
to treat common musculoskeletal and inflammatory pain problems, dental pain, and mild-to
moderate cancer pain. Most NSAIDs are relatively nonselective, inhibiting both COX-1 and 2
enzymes in a ratio that varies from drug to drug. The coxib class of NSAIDs includes drugs that
are more selective inhibitors of the COX-2 enzyme (celecoxib). Analgesic effects between the two
classes of inhibitors are comparable.
NSAIDs are predominantly administered orally. There is little difference in the effectiveness of
NSAIDs among different patient populations, but there are very large interindividual and
intraindividual differences in the effectiveness and side effects produced by the various drugs.
The failure of one NSAID does not predict failure of all NSAIDs. Combination therapy with two
NSAIDs provides no known benefit because NSAID toxicity is additive. Recently, intravenous
ibuprofen was introduced in the U.S. Although further study will be needed to clarify the benefits
and risks associated with the use of this agent, including the postoperative period, it has a better
safety profile than ketorolac and offers an alternative when the latter drug would be considered.

Clinical Uses: Adverse Effects of NSAIDs

The relationship between the risk of serious GI side effects and the use of nonselective NSAIDs
is well-established.31,32 Because COX-1 is constitutive in the stomach and is involved in the
production of gastroprotective prostaglandins, COX-1 inhibition is the primary factor in
gastrointestinal (GI) adverse effects associated with NSAIDs. Gastric prostaglandins inhibit acid
secretion, and promote mucus secretion, local blood flow and epithelial cell integrity.
The gastrointestinal toxicity from use of NSAIDs can range from distress related to epigastric
pain, pyrosis, bloating or nausea, to frank ulceration, potentially with significant hemorrhage that
can lead to death. COX-2 selective inhibitors have a lower risk of gastroduodenopathy and may
be preferred in populations at increased risk of GI toxicity, including the elderly. 32-38 However,
protection from gastrointestinal toxicity is not complete with celecoxib and other NSAID-related
toxicities are comparable.37
While nonselective NSAIDs increase the risk of GI erosion or bleeding more than the COX-2
selective agents, some may be less likely than others to produce GI toxicity. Ibuprofen is the most
well established and others that are sometimes considered include diclofenac, meloxicam,

nabumetone, and nonacetylated salicylates (e.g.,choline magnesium trisalicylate,

A variety of factors predispose to the development of GI toxicity, most importantly high dose and
prolonged use, advanced age, prior peptic ulcer disease or NSAID-induced gastroduodenopathy,
concurrent corticosteroid, aspirin or clopidrogel use, and certain comorbidities (e.g. rheumatoid
arthritis).40 Infection with Helicobacter pylori is an additive risk factor.41 Concurrent therapy with a
proton pump inhibitor (PPI), misoprostol, or in some studies, an H 2 blocker, reduces the GI risk. In
patients with an increased risk of GI complications, the use of a nonselective NSAID with a PPI
may not be as effective as the use of a COX-2 selective inhibitor alone.41 When NSAID therapy is
absolutely necessary in patients at relatively higher GI risk, 32 most experts recommend adding a
All NSAIDs, including both the nonselective and selective COX-2 inhibitors, may cause renal
toxicity. This is because the COX-2 enzyme is present in renal tissue and may be important in
maintaining renal perfusion, particularly under dehydrating conditions or in the face of
vasoconstrictor influences. NSAIDs decrease renal blood flow and glomerular filtration rate in
patients with congestive heart failure, liver disease (ascites), chronic renal disease, or
hypovolemia. NSAIDs also promote salt and water retention by reducing prostaglandin-induced
inhibition of chloride reabsorption and the action of antidiuretic hormone. The latter effect may
cause edema in some patients, reduce the effectiveness of antihypertensive regimens, or
promote hyperkalemia.These effects on the kidney can lead to a variety of negative outcomes,
including acute or chronic renal insufficiency, proteinuria, fluid overload with edema, and
exacerbation of existing cardiovascular disease.
All NSAIDSincluding nonprescription productshave prothrombotic effects that could increase
risk of stroke, transient ischemic attack, symptomatic coronary artery disease, myocardial
infarction (MI) or symptomatic peripheral vascular disease. 42 The use of NSAIDs is associated
with persistently increased coronary risk regardless of time elapsed after a first-time MI.43 NSAIDs
also can exacerbate hypertension, which in turn increases the risks associated with these
outcomes, as well as congestive heart failure.44 Blood pressure should be monitored in patients
who receive these drugs.
The existing data indicate that the prothrombotic effect of NSAIDs is associated with COX-2
inhibition, whether this occurs with a selective COX-2 inhibitor or a nonselective inhibitor.37 Thus,
some risk exists with all NSAIDs, providing a rationale for the boxed warning carried by all
NSAIDs in the U.S. Whether COX-2 inhibitors as a class carry a substantially higher risk is not
certain. Some of these drugs do appear to have relatively high risk, and it was this consideration
that led to the withdrawal of rofecoxiib from the US market by its manufacturer. Although the
overall risk of these adverse events is relatively low, the potential for toxicity should be
considered before any of these drugs are prescribed on a chronic basis. It is reasonable to
assume that the risk of cardiovascular toxicity starts when dosing begins and increases with the
cumulative time on the drug. Presumably, patients with pre-existing atherosclerotic disease would
be at increased risk, but the extent and clinical implications are as yet uncertain. Drug-selective
differences in cardiovascular risk may exist among nonselective COX inhibitors and most experts
believe that naproxen is the safest NSAID from the cardiovascular perspective (see Module 5).
It also is uncertain whether co-administration of low-dose aspirin or other antiplatelet agents
protects against adverse cardiovascular events. Co-administration of aspirin with celecoxib
eliminates the latter drugs advantage in terms of GI toxicity.
Other side effects associated with the NSAIDs include rashes, hypersensitivity and
bronchospasm in patients with asthma and nasal polyps, blood dyscrasias (which are rare but
can be fatal), liver abnormalities, and CNS effects, such as headache, drowsiness, and dizziness.
Celecoxib is contraindicated in patients with sulfonamide allergy or sensitivity.

Drug-Drug Interactions
As a class, most NSAIDs bind tightly to plasma proteins, and thus, drug-drug interactions can
occur when there is competition for binding sites. Because many patients with persistent pain are
elderly and receiving other drug therapy, the potential for drug interactions is significant. The most
common drug interactions of NSAIDs and other medications are listed in the Table, Potential
Drug Interactions with NSAID Analgesics.45 As described previously, recent studies also have
demonstrated an important pharmacodynamic action between specific NSAIDs, including
ibuprofen and naproxen, and aspirin.45 Specifically, these and probably other NSAIDs, have the
potential to block aspirins effect on platelets. As a result, there is a theoretical concern that
regular NSAID use may compromise the therapeutic effects of low-dose aspirin on the prevention
of cerebrovascular and heart disease. The extent of this risk, in terms of cardiovascular events, is
not known and drug-specific effects are uncertain.46 Because these data are limited, the proper
advice to give patients is not clear. The role of naproxen, for example, is especially uncertain, as
the data suggesting a lower risk of NSAID-induced cardiovascular toxicity would appear to conflict
with data suggesting inhibition of the aspirin protective effect. Accordingly, the most prudent
approach at this time would be to consider aspirin prophylaxis as another relative contraindication
to the long-term use of a NSAID, to perhaps avoid ibuprofen (the best studied and clearest
offender) if aspirin-treated patients would benefit from an NSAID, and encourage patients to take
their daily dose of aspirin several hours before their daily dose of the NSAID on the assumption
that the interaction would have the least impact with this timing.
Given these toxicities, the decision to undertake NSAID therapy must first consider the overall
risk: benefit ratio. The inclination to prescribe is generally higher with inflammatory pain or bone
pain. Concern about risk should be relatively high in patients with factors that predispose to GI
toxicity or cardiovascular toxicity, or who have renal insufficiency or a bleeding diathesis. If the
decision is made to use an NSAID, it is reasonable to consider a COX-2 selective drug in those
predisposed to GI toxicity, or to consider co-administration of a gastroprotective agent,
specifically a proton pump inhibitor or misoprostol. In those predisposed to atherothrombotic
cardiovascular toxicity, it may be reasonable to consider naproxen. In all cases, it is reasonable to
consider choosing NSAIDs with relatively good safety profiles, such as celecoxib, naproxen or
naproxen sodium, or ibuprofen, ketoprofen, diclofenac, etodolac, nabumetone, meloxicam, or one
of the nonacetylated salicylates, and to use the lowest effective dose for the shortest duration of

Table: Nonopioid Analgesics

Drug Name

Usual Adult Dose

Max. Adult Dose

Acetaminophen (Anacin Aspirin Free,

Genepap, Genebs, Tylenol, and others)

325 to 650mg PO q 4-6 hrs

Consider 3000 mg as maximum

dose for most patients. Reduce
maximum dose 50% to 75% in
patients with hepatic
insufficiency; history of alcohol

Intravenous (Ofirmev)

aspirin (Bayer, Ecotrin, Genecote,
Norwich Aspirin)
choline magnesium trisalicylate*
(Tricosol, Trilisate)
diflunisal* ( Dolobid, Diflunisal
magnesium salicylate* (Doans
Caplets, Keygesic-10, Momentum,
salsalate (Argesic SA, Disalcid,
Salflex, Salsitab, Mono Gesic)
sodium salicylate*

1000 mg every 6 hours or 650 mg every

4 hours to a maximum of 4000 mg per
day in adults >50 kg. Minimum dosing
interval of 4 hours
650-975 mg PO q 4-6 hrs

4000 mg

1000-1500 mg PO q 12 hrs

3000 mg

1000 mg PO initial dose followed by

500 mg q 12 hrs
650 mg PO q 4-6 hrs

1500 mg

1000-1500 mg PO q 12 hrs

3000 mg

325-650 mg PO q 3-4 hrs


Other NSAIDs
sulindac* (Clinoril)
diclofenac potassium* (Cataflam)
etodolac* (Lodine, Etodolac ExtendedRelease)
fenoprofen calcium* (Nalfon)
ibuprofen* (Advil, Genpril, Haltran,
Ibu-Tab, IBU, Menadol, Motrin)
ibuprofen i.v. (Caldolor)
indomethacin* (Indocin)
ketoprofen* (Actron, Ketoprofen
Capsules, Orudis, Orudis KT, Oruvail)
ketorolac tromethamine*

meclofenamate sodium* (Meclomen)

mefenamic acid* (Ponstel)
meloxicam* (Mobic)
nabumetone* (Relafen)
naproxen* (Naprosyn, EC-Naprosyn)
naproxen sodium* (Anaprox, Aleve,
celecoxib* (Celebrex)

200 mg PO q 12 hrs, after satisfactory

response is achieved, dose may be
decreased accordingly
50 mg PO q 8 hr
200-400 mg PO q 6-8 hr

400 mg

200-600 mg PO q 6 hrs
400-800 mg PO q 6-8 hrs

2400 mg
3200 mg

400-800 mg IV over 30 min q 6 hrs

25-50 mg PO q 8 hrs
25-50 mg PO q 6-8 hrs

3200 mg
150 mg
300 mg

Pts.<65 yrs of age: 30-60 mg IM initially

followed by 15-30 mg q 6 hrs.
Oral dose following IM dosage: 10 mg q
6-8 hrs.
IV Dosage: 30 mg IV q 6 hrs
Pts.>65 yrs of age: 15 mg IV/IM q 6 hrs

Pts.<65 yrs of age: 120 mg

50-100 mg PO 4-6 hrs

500 mg PO initially followed by 250 mg
PO q 6 hr
7.5 mg PO initially once daily may
increase by 7.5 mg
1000 mg PO initially once daily may increase BID to 1500-2000 mg
500 mg PO initially followed by 250 mg
PO q 6-8 hrs
550 mg PO initially, followed by 275 mg
PO q 6-8 hrs
100-200 mg PO q 12 hr

150 mg
1200 mg

Pts>65 yrs of age:60 mg

400 mg
1250 mg
15 mg
2000 mg
1250 mg the first day, then 1000
1375 mg the first day, then 1100
400 mg

Modified from Institute for Clinical Improvements, October 2002. *Available by nonproprietary name.

Table: Potential Drug Interactions with NSAID Analgesics

Drug Combination


Oral anticoagulants
with all NSAIDs

Increased oral warfarin activity

Increased risk of bleeding (especially GI)

Lithium with all NSAIDs

Increased steady state lithium

Lithium toxicity

Antihypertensive agents
(beta-blockers, ACE inhibitors, vasodilators, diuretics) with several NSAIDs

Antihypertensive effect antagonized

Hyperkalemia may occur with potassiumsparing diuretics and ACE inhibitors

Digoxin with NSAIDs

Renal clearance inhibited

Monitor prothrombin time and for
occult blood in stool and urine
Avoid concurrent use of aspirin
Monitor lithium concentrations
Interactions less likely with aspirin
than naproxen sodium or
Monitor blood pressure and
cardiac function
Monitor potassium concentration
Low-dose aspirin (e.g., 75 mg/day)
may not interact with ACE inhibitor
Monitor digoxin concentrations
Adjust dose as necessary

Diuretics may increase the risk of developing renal failure


Valproate with aspirin

Phenytoin with ibuprofen and high-dose


Oxidation of valproate inhibited

Up to 30% reduction in clearance
Possible valproate toxicity
Increased phenytoin levels: phenytoin is
displaced from serum protein binding
sites, if phenytoin metabolism is saturated
or folate concentrations are low

Methotrexate with all NSAIDs

Reduced renal clearance

Increased plasma methotrexate

Antacids (in high doses) with salicylates,

Salicylate concentrations possibly

reduced by 25%
Aluminum hydroxide decreases naproxen
sodium absorption
Reduced clearance of naproxen sodium
Potential salicylate toxicity Potentially
reduced naproxen sodium effect


Aluminum hydroxide and naproxen

Probenecid with naproxen sodium
H2-blocking agents with salicylates,
naproxen sodium
Corticosteroids with aspirin; salicylates
(high doses
Insulin with salicylates
Sulfonylureas with salicylates (moderate
to high-dose)

Possible decreased salicylate effect due

to increased clearance
Possible decreased hypoglycemic effect
with large salicylate doses
Hypoglycemic activity increased

Cephalosporins with aspirin

Aminoglycoside antibiotic s and NSAIDs

Possible increased bleeding risk

Inhibits aminoglycoside renal clearance

Cyclosporine and NSAIDs

Possible increased nephrotoxicity

Avoid aspirin with valproate

Naproxen sodium is an alternative
Monitor unbound phenytoin
concentrations and adjust dose, if
Ensure patient has sufficient folate
Avoid NSAIDs with high-dose
Monitor concentrations with
concurrent therapy
Monitor clinical status
Determine if salicylate dose needs
to be increased
Monitor for adverse effects
Monitor salicylate concentration
Monitor clinical status
Monitor salicylate concentration
when changing corticosteroid dose
Monitor blood glucose
Avoid concurrent use
Monitor blood glucose
when changing salicylate dose
Avoid concurrent use
Monitor antibiotic concentrations
and adjust dose as needed
Monitor renal function

Source: American Hospital Formulary Service. Drug Information. American Society of HealthSystem Pharmacists. 2011. Bethesda, MD.

Pharmacologic Strategies: Opioid Analgesics

Opioids produce analgesia by acting on both central and peripheral mu, kappa and delta opioid
receptors to inhibit the transmission and perception of nociceptive input. Opioids can be classified
by their action (full agonist, partial agonist, mixed agonist-antagonist, antagonist) at various opioid
receptors. Most of the opioids used in clinical practice are full mu receptor agonists (Table:
Opioid Analgesic Classification by Receptor Activity). Partial agonists (e.g.,
buprenorphine) have lower intrinsic activity at the mu opioid receptor and the mixed agonistantagonists (e.g., butorphanol, nalbuphine) have different effects at the various opioid receptors.
The partial agonists and mixed agonist-antagonists have a ceiling effect for analgesia.


Reduced absorption of other NSAIDs also but not to the same extent
Probenecid reduces the renal clearance of certain other NSAIDs as well


Agonist drugs may be further divided into immediate-release short-acting preparations and longacting drugs, based on their time-action properties.13 For example, morphine is a short-acting
opioid and, as such, requires frequent dosing to maintain analgesia. Extended-release oral (e.g.,
morphine, oxycodone, oxymorphone, hydromorphone,) and transdermal (e.g., fentanyl,
buprenorphine) formulations, and oral opioids with long half-lives (e.g., methadone, levorphanol)
are alternatives to short-acting opioids. They typically are used when around-the-clock dosing is
required and in patients who are opioid tolerant.
Long-acting preparations are not indicated for the management of acute or intermittent pain, postoperative pain, or in patients who require opioid analgesics for only a short period of time. Some
extended release/long-acting opioids (ER/LA) are labeled for use only in opioid tolerant patients
and others are not recommended as initial opioid therapy. A few ER/LA products carry FDAapproved product labeling indicating they could be used in opioid naive patients starting with the
lowest dose recommended for initial dose titration (Table Long Acting/Extended Release
Opioids). However, most pain experts avoid initial use of these products in such patients.


Table. Long Acting/Extended Release Opioids


Dosage Form

3 days

Specific Drug Interactions or

Concomitant use of CYP3A4
inhibitors may [fentanyl] to harmful
levels. Peak concentrations occur
within 20 to 72 hours of treatment
with greatest risk of respiratory

5,10,20 mcg/hr
(10 and 20 mcg
dosage forms for
use in opioid
tolerant patients
5 and 10 mg
tablets. Initial
dose in opioid
patients 2.5 to 10

7 days

Prolongs QTc interval. Class IA and

III antiarrhythmics may increase
arrhythmia risk. CYP3A4 inhibitors
may [Bup] and inducers may .
Potential hepatotoxicity and
application site skin reactions
CYP inducers shown to decrease
[methadone]. Some CYP3A5
inhibitors increase [methadone].
Anti-retroviral agents have mixed
effects on disposition kinetics of
methadone. Cardiac toxicity with high
doses or with CYP3Ar4 inhibitors.
Peak respiratory depression occurs
later and persists longer than
analgesic effects.

Morphine sulfate ER

20 mg caps

24 hrs

Initial dose in opioid non-tolerant patients is 30

mg. Max daily dose = 1600 mg due to risk of renal
toxicity with excipient fumaric acid. Titrate using a
minimum of 3 day intervals.

MS Contin

15,30, 60, 100,

200 mg tabs

8-12 hrs

Kadian (MS ER)

0,100, and 200
mg caps

12-24 hrs

Swallow tablets whole (do not chew, crush, or

dissolve). Titrate using a minimum of 2-day
intervals. 100 mg and 200 mg strengths for use in
opiod tolerant patients only.
Titrate using a minimum of 2 day intervals. Beads
can be sprinkled on applesauce just before

Oromorph (MS SR)

15,30,60,100 mg

8-12 hrs

12-24 hrs

Oxycodone CR

100 mg caps
with amounts
of naltrexone
(0.8 to 4 mg)
60,80 mg tabs

Oxymorphone ER

30,40 mg tabs

12 hrs

Hydromorphone ER

8,12,16 mg tabs

24 hrs

Tapentadol ER

and 250 mg

12 hrs




Embeda (MS ER
with naltrexone

8-12 hrs

12 hrs

P-Glycoprotein (PGP) inhibitors e.g.

quinidine) may double systemic
exposure. Alcohol may increase rate
of morphine release

Other Key Instructions

For use only in opioid tolerant patients. Use
product specific information for dose conversion
from prior opioid. Apply to intact, non-irritated or
irradiated skin on a flat surface. Rotate site of
application. Avoid exposure to heat. Avoid
secondary exposure to unwashed/unclothed
application site.
Apply to hairless or near hairless skin site. Rotate
application site; do not use same site within 3
weeks. Temperature dependent increase in
release kinetics. In opioid nave patients or in
those with hepatic impairment, initial dose must
be 5 mcg/hr.
Complex pharmacokinetics. High inter-patient
variability in disposition kinetics an analgesic
potency. Long half-life so accumulates with
repeated doses. Equianalgesic tables
underestimate potency and when used in
converting opioidtolerant patients may result in
overdosage. Follow instructions in package

Beads can be sprinkled on applesauce just before

swallowing. Contains naltrexone to prevent
tampering. Initial dose 20 mg when used as first
opioid. 100 mg dose for opioid tolerant patient
only. Titrate using a minimum of 3 day intervals.

Metabolized by CYP3A (primary) and

2D6 followed by glucuronidation.
33%-50% of normal dose in patient
with hepatic impairment. 50% of
usual dose in patients with creatinine
Cl <60 ml/mn. CYP3A4 inhibitors
may oxycodone exposure; inducers
may systemic exposure.
Alcohol increases rate of release.
Use lowest dose (5 mg q12h) in
patients with mild hepatic
impairment, creatinine Cl <50 ml/min,
and in patients >65 yrs.
75% dose reduction in patients with
moderate hepatic impairment
50% dose reduction in patient with
moderate renal impairment
75% dose reduction in those with
severe renal impairment. Do not use
in patients with sulfa allergy
Alcohol increases rate of absorption.
Dose once daily in patients with

Swallow tablet whole (do not chew, crush, or

dissolve). Oral bioavailability 60 to 87%; steady
state within 24 to 36 hours. Titrate using a
minimum of 1-2 day intervals. Single dose >40 mg
or total daily dose >80 mg are for use in opioidtolerant patients only.

Swallow tablets whole (do not chew, crush, or

dissolve). Can be used in opioid naive patients at
5 mg q 12h. Titrate using a minimum of 2 day
intervals. Contraindicated in moderate/severe
hepatic impairment.
Swallow tablet whole (do not chew, crush or
dissolve). Plasma levels rise for the first 6 to 8
hours after first dose; steady state achieved within
3 to 4 days. Use the conversion ratios in individual
product information. Titrate using 3 to 4 day
intervals. For use in opioid tolerant patient only.
Swallow tablet whole (do not chew, crush, or
dissolve). Use 50- mg q12 h in no1n-8opioid tolerant

tabs. Maximujm
daily dose = 500

moderate hepatic impairment with a

maximum of 100 mg. Avoid use in
patients with severe hepatic or renal

patients. Max daily dose = 500 mg. Lifethreatening serotonin syndrome can occur with
use of SSRIs, SNRIs, TCAs, MAOIs, and triptans.
No data on conversion from other opioids.

Each product has specific features that govern safe use including dosing instructions, titration
intervals, drug interactions or other concerns. The ER/LA opioids are now associated with anFDA
class-wide risk evaluation and mitigations strategies (REMS) program, which stresses voluntary
education about risks.

Table: Opioid Analgesics Classification by Receptor Activity

Opioid type
Pure agonists


No clinically relevant ceiling effect to analgesia; as dose
is raised, analgesic effects increase until analgesia is
achieved or dose-limiting side effects supervene.
Codeine, hydrocodone, oxycodone combination
products are most widely prescribed and used for
short-term and long-term management of
moderate to severe pain. Codeine not preferred
because of variation in metabolic conversion to
active metabolite. Dosing of combination products
limited by safety of the nonopioid constituent.
Single entity formulations, particularly long-acting
versions, are mainstay of therapy for long-term
moderate to severe cancer pain.
Meperidine is generally not used due to potential effects
of toxic metabolites.
Methadone must be used with caution; only clinicians
who are knowledgeable about the risks posed by long
and variable half-life, unpredictable potency, respiratory
depression, and potential for QTc prolongation should
use this drug without guidance.


Partial agonists
Mixed agonist-antagonists

Agonist-antagonists include -agonists with lower

intrinsic efficacy (partial agonists) and drugs that have
agonist effects at one receptor and antagonist effects at
another (mixed agonist-antagonists). Most developed to
be less attractive to those with addiction.
All these drugs have a ceiling effect for analgesia.
All have the potential to cause acute withdrawal if
administered to patients with physical dependency
to agonist opioids.
Some, most notably pentazocine and butorphanol, have
relatively high risk of psychotomimetic side effects.
Buprenorphine is available as a long-acting formulation
in a transdermal patch and is a useful analgesic.

Importantly, long acting and extended-release products are the opioid analgesics that have been
most commonly implicated in unintentional overdoses, poisonings, and deaths in recent years.
Tramadol and tapentadol are centrally-acting analgesics that activate the mu opioid receptor and
also inhibit the neuronal reuptake of monoamines. Tramadol is unscheduled and considered for

moderate to moderately severe pain. Tapentadol is a schedule II substance considered for

moderate to severe pain. Dose escalation to treat persistent severe pain may be precluded by
dose-related toxicity; tramadol doses greater than 400 mg/d are associated with an increased risk
of seizures. Daily dosage of tapentadol is limited to <600 mg.
Tramadol and tapentadol should not be considered to be identical agents. In terms of
mechanism, tramadol increases the concentration of both norepinephrine and serotonin at
synapses; tapentadol blocks the reuptake of norepinephrine only. 47 Although both are opioid
agonists, as noted above tapentadol is a schedule II controlled substance because of concerns
about risk for abuse, whereas tramadol is unscheduled (although some states place tramadol in
Schedule IV). Tramadol is metabolized by CYP2D6 to form the active metabolite, O-desmethyl
tramadol (M1). Formation of M1 is dependent on CYP2D6 and as such is subject to inhibition and
polymorphism, which may affect the therapeutic response. Tramadol is also metabolized by
CYP3A4. Administration of CYP3A4 inhibitors, such as ketoconazole and erythromycin with
tramadol may affect the metabolism of tramadol leading to altered tramadol exposure.
Concomitant administration of CYP2D6 and/or CYP3A4 inhibitors, such as quinidine, fluoxetine,
paroxetine and amitriptyline (CYP2D6 inhibitors), and ketoconazole and erythromycin (CYP3A4
inhibitors), may reduce metabolic clearance of tramadol, increasing the risk for serious adverse
events including seizures and serotonin syndrome. Neither tramadol nor tapentadol should be
administered in conjunction with a monoamine oxidase inhibitor. Concomitant use with selective
serotonin reuptake inhibitors, selective norepinephrine/serotonin reuptake inhibitors, or triptan
derivatives used for migraine headaches increases the risk of serotonin syndrome with both
drugs. Concomitant use of reuptake inhibitors increase the seizure risk with tramadol.
For the management of common moderate to severe pain in opioid-nave patients who can use
oral medications, such as those with acute trauma or those who have undergone ambulatory
surgery, the usual opioids are one of a group of immediate-release, short-acting full agonist drugs
conventionally selected for pain of this type. 13 These drugs include codeine, hydrocodone and
oxycodone, which in this context (patients who are relatively opioid-nave), usually are selected in
a formulation combined with acetaminophen, aspirin or ibuprofen. As previously noted, the daily
dosage of such combination products is limited by the nonopioid constituent. Tramadol is another
Full mu agonists that are administered as a single entity oral or transdermal formulations,
including morphine, hydromorphone, oxycodone, oxymorphone, methadone, levorphanol, and
fentanyl, do not exhibit a ceiling effect with increasing dose or carry the limitation in dosing
imposed by the nonopioid constituent. In practice, the ceiling for these single entity drugs is
determined by the occurrence of opioid-related side effects as the dose is increased. One
exception is the sustained-release formulation of morphine sulfate that contains the excipient,
fumaric acid (Avinza); the daily dose of this drug is limited to 1600 mg based on the risk of renal
toxicity from the excipient. ER/LA products are not indicated for the management of acute
Codeine is a commonly used mu agonist in outpatients, but may be a poor choice as an
analgesic. Some experts believe that codeine is more likely to produce constipation than other
opioids, particularly at higher doses. Perhaps more important, codeine is a pro-drug which must
be converted to morphine in the body. The 2D6 isozyme of the hepatic CYP450 complex
(CYP2D6) is responsible for this conversion. The efficiency of this isozyme varies widely in the
population and 5-10% of Caucasians are slow metabolizers, potentially unable to convert enough
morphine from codeine to produce analgesia. Conversely, the risk of morphine toxicity is higher in
ultrarapid metabolizers.48 Guidance has been developed for codeine dosing based on
interpretation of CYP2D6 genotype test results. 49 The concern about variation in effects related to
the function of the 2D6 isozyme is obviated if another opioid is used.
Meperidine (Demerol, others) is a mu agonist that is metabolized to a neurotoxic metabolite
(normeperidine), which is associated with tremulousness, delirium and seizures. Normeperidine

has a far longer half-life than meperidine and can accumulate during repeated doses. The
concentration of the metabolite compared to the parent compound is relatively greater in the
elderly and in those with renal impairment, two populations that are at particular risk from
normeperidine toxicity. Meperidine is not favored by pain experts in the U.S. and it generally
should not be used for more than a few days.
The use of transmucosal immediate-release fentanyl products (TIRF) is limited to the
management of breakthrough pain in adults with cancer who are routinely taking other opioid pain
medicines around-the-clock for pain. Breakthrough pain is pain that comes on suddenly for short
periods of time and is not alleviated by a patients normal pain management plan. TIRF products
are intended for use only in patients who are opioid tolerant based on the concurrent regular use
of another opioid medication. The FDA definition of patients considered opioid tolerant are those
who are taking at least 60 mg oral morphine daily, 25 mcg transdermal fentanyl/hr, 30 mg oral
oxycodone or 8 mg oral oxymorphone daily, or an equianalgesic dose of another opioid for one
week. All TIRF products are subject to a class-wide REMS program (Table Transmucosal
Immediate Release Fentanyl Products).

Choice of Opioid and Route of Administration

Opioids can be administered by a wide variety of routes, including oral, sublingual, intravenous,
subcutaneous, rectal, parenteral, transdermal, transmucosal, intrathecal, and epidural. One of the
longstanding myths regarding opioid therapy is that intravenous administration is more effective
than oral administration. In practice, the same analgesic effect can be achieved with any route,
and both the oral or transdermal routes are easy, effective, and relatively inexpensive.
Intravenous administration is indicated for postoperative pain relief or other circumstances when
GI absorption is restricted, patients cannot swallow, or rapid (or closely tailored) effects are
desirable. Patient-controlled analgesia is one of the most effective means of providing parenteral
analgesia. Neuraxial administration is reserved for a small subset of patients and is delivered
intrathecally or epidurally. The benefits and risks of the various administration routes are listed in
the Table: Benefits/Risks of Various Routes of Administration.

Table - Transmucosal Immediate Release Fentanyl Products

Brand name



Sublingual tablet


Fentanyl citrate oral

transmucosal lozenge


Fentanyl citrate buccal



Fentanyl nasal spray


Fentanyl buccal soluble


Dosage and Administration

Individually titrate Abstral to a dose that provides adequate analgesia with
tolerable side effects. Titration from an initial dose of 100 mcg is the safest
approach. See package insert for dosage titration instructions.
Titration from an initial dose of 200 mcg is the safest approach. The Actiq
unit should be consumed over 15 minutes. Patients should be prescribed
an initial titration supply of six 200 mcg Actiq units, thus limiting the
number of units in the home during titration. Patients should use up all
units before increasing to a higher dose to prevent confusion and possible
overdose. See package insert for dosage titration instructions.
Fentora is not bioequivalent with other fentanyl products. Do not convert
patients on a mcg per mcg basis from other fentanyl products. There are
no conversion directions available for patients on any other fentanyl
products other than Actiq. (Note: This includes oral, transdermal, or
parenteral formulations of fentanyl.) Titration from an initial dose of
100 mcg is the safest approach, with the only exception being patients
already using Actiq. For patients being converted from Actiq, prescribers
must use the Initial Dosing Recommendations for Patients on Actiq in the
package insert. Patients must be instructed to stop the use of Actiq and
dispose of it.
Titration from an initial intranasal dose of 100 mcg is the safest approach.
Lazanda is not equivalent with any other fentanyl product. product.
Patients must wait at least 2 hours before treating another episode of
breakthrough cancer pain with Lazanda. See package insert for dosage
titration instructions.
Individually titrate Onsolis to a dose that provides adequate analgesia with
tolerable side effects. Titration from an initial dose of 200 mcg is the safest
approach. Onsolis is not equivalent on a mcg per mcg basis with any other
fentanyl product. See package insert titration instructions.


Opioids are absorbed from the GI tract after oral or rectal administration. Orally-administered
opioids are subject to the first-pass metabolism in the liver; thus, larger doses would be required
compared to parenteral routes to produce the same analgesia. Most immediate-release oral
opioids require 20 to 40 minutes for onset of action, with peak analgesia reached within 45 to 60
minutes. Intravenous administration yields peak analgesia in a range of almost immediately to as
long as 20 minutes depending on the characteristics of the specific drug. Intramuscular
administration is not generally recommended due to its multiple disadvantages: painful
administration, unpredictable absorption, and complications involving tissue fibrosis and
abscesses. Subcutaneous (SC) administration, which has kinetics similar to the IM route, is not
associated with these problems and is preferred.

Risk Assessment
Opioid medications are the mainstay therapies for acute severe pain and moderate to severe
persistent pain due to active cancer or other advanced illnesses. During the last few decades,
growing numbers of patients with other types of persistent pain also have been offered long-term
opioid therapy (see Module 7). Increased access to these drugs has been paralleled by a large
increase in adverse consequences, including drug abuse, addiction, diversion and
The statistics demonstrate a serious public health concern: During the past decade, the number
of patients seeking substance abuse treatment for the primary abuse of prescription pain relievers
has increased six-fold. Drug overdoses deaths in the United States also have increased steadily
and now exceed 38,000 annually.50 Prescription drugs are involved in more than 57% of such
deaths (~22,000) with opioids involved in 75% of the prescription drug overdose deaths reported
in 2010 or about 43% of drug overdose deaths overall.50
The estimated number of emergency department (ED) visits related to the nonmedical use of
opioid analgesics increased 79% from 201,280 in 2006 to 359,921 in 2010, according to the most
recent data from the Drug Abuse Warning Network (DAWN). 51 The greatest increases were seen
in buprenorphine, hydromorphone, and oxycodone-related ED visits. With respect to the broader
public health impact, the proportion of individuals 12 and older who are using prescription pain
relievers in a nonmedical fashion is substantially larger. 52 For each ED visit, 15 others use
prescription pain relievers nonmedically some time in their lifetime. These trends have continued
to increase for prescription opioids except for methadone which has shown a decrease in
unintentional overdoses since 2007.53
Among patients on chronic opioid therapy, the relative risk of an overdose increases with the
average daily dose and use of multiple prescribers .54-56 Demographic variables (e.g., Caucasian,
male sex, age 30-54, state and residence in a non-metro county, lower income) and personal
characteristics (e.g., history of nonmedical use or substance abuse, other mental health
diagnosis, route of administration) also are markers for overdose risk.54-58
The medical community must be a partner in a multi-pronged effort to reduce the adverse
consequences related to prescription drug abuse. Numerous federal and state actions have
begun, such as the FDA REMS for long-acting opioids, state-based initiatives designed to more
tightly regulate opioid use, and federal support for requiring mandatory education for DEA
registration. Given the likelihood that part of the problem relates to poor patient selection for
treatment, inappropriate drug selection or dosing, inadequate monitoring, or failure to address
clinical problems when they occur, clinician education is essential.
The assessment of risks related to prescription drug abuse, addiction, diversion and unintentional
overdose must be considered whenever opioid drugs are considered for use. Clinicians must
have a working knowledge of these outcomes, an understanding of medically-relevant definitions,
and basic skills in the elements of risk assessment and management that constitute a universal
precautions approach. Risk assessment and management must be viewed as a necessary part

of all opioid prescribing. At the same time, clinicians must not conclude that opioids should be
avoided even when there is a generally accepted indication (e.g., acute pain or chronic pain
related to active cancer or other serious illness) or never used when there is a more controversial
indication (selected patients with so-called chronic non-cancer pain).
The goal from the clinical perspective is a balanced approach by which clinicians neither reject
the use of opioids nor use them without due regard for the risks associated with abuse, addiction,
diversion and unintentional overdose.


Table: Benefits/Risk of Various Routes of Administration




Oral (PO)

Requires functioning GI tract

Rectal (PR)

Insertion of suppository or solution

Intramuscular (IM)

Injection into large muscle

Intravenous (IV)

Single, repetitive bolus or patientcontrolled analgesia

Subcutaneous (SC)

Infusion via butterfly needle

Transdermal (TD)

Absorbed through skin, gradual release

into systemic circulation

Oral transmucosal (OT)

Includes buccal/ sublingual fentanyl

incorporated into a sweet matrix on a

Epidural analgesia (EA)

Indwelling catheter is tunneled under

the skin or surgically implanted

Intrathecal analgesia (IA)

An indwelling intrathecal catheter is

placed for long-term analgesia

Patient controlled analgesia


Patient controls dosage up to a

maximum, usually with IV or epidural

Convenient, noninvasive, flexible, less

Slow onset of action, requires patient
Useful for patients who cannot take
medications by mouth
Absorption may be unpredictable
Not recommended due to painful
injections, wide
fluctuations in drug levels, rapid decline in
effect compared
with oral administration
Most effective for immediate analgesia,
permits rapid titration
Continuous IV infusion provides steadier
drug blood
levels, maximizing pain relief and minimizing
side effects
Produces steady blood levels, obviates
need for GI function
Costs less than IV administration
Slower onset and offset, lower peak effects
than IV administration
Convenient, noninvasive
Provides prolonged, relatively stable
Delayed onset of action with first dose
Easy, requires little staff supervision,
avoids significant liver first-pass effect
Some absorption via oral mucosa, some
via GI tract
Higher drug levels and better bioavailability
For acute postoperative pain and
persistent pain
Permits concomitant use of other drugs,
e.g., local anesthetics, clonidine, and
Provides analgesia at lower doses than
Requires invasive procedure
For acute pain and persistent pain of all
Single bolus more common for acute pain
Provides analgesia at lower doses than
systemic or epidural administration
Permits concomitant use of other drugs,
e.g., local anesthetics, clonidine, and
Infection risk
Requires invasive procedure and an
implant for long-term infusion
Allows patient to manage dynamic
changes in pain

Modified with permission from Berry PH, Chapman CR, Covington EC, et al. Pain: Current Understanding of Assessment,
Management, and Treatments. Reston, VA: National Pharmaceutical Council and the Joint Commission for Accreditation of Healthcare
Organizations; December, 2001.


Positioning Opioid Therapy

As previously noted, opioid analgesics are conventionally considered the first-line therapy for
severe acute pain and moderate to severe persistent pain due to active cancer or advanced
illnesses of other types, such HIV/AIDS. The role of long-term opioid therapy for common types of
persistent pain, such as back pain or other musculoskeletal pains, continues to be controversial
(see Module 7). Chronic pain is a heterogenous set of conditions and it is important that pain
care be tailored to the individual patient. Some patients with chronic pain and good coping and
functioning may be best managed with one or more treatments specifically intended to enhance
comfort. Others, whose pain may be associated with functional impairment, mood disorder, or
global disability, may do best if multimodality care is provided by an interdisciplinary care team.
For pain that is complicated by negative effects on function or mood, a treatment strategy the
targets both pain and disability, that empowers the patient to use self-care and techniques to
improve coping and adaptation, usually offers the best foundation for treatment. In these cases,
medications and procedures must be used judiciously. Unless the patient has a serious illness,
opioids are not conventionally considered first-line treatment. However, opioids may be an
appropriate intervention to try when other treatments are not effective or pose relatively greater
Long-term opioid therapy should always be initiated as a trial, even if treatment with a
short-acting opioid drug has been ongoing. If the therapeutic intent is to evaluate opioid
therapy as a long-term treatment strategy, the patient should be educated about the approach
usually a switch to a long-acting drug with dose titration and side effect management,
accompanied by careful observation of benefits on pain and function, side effects, and
adherenceand the goals. He or she should understand clearly that the therapy will be stopped if
benefits are not demonstrated or adverse consequences occur, including any nonadherence.
Opioids can be continued when they serve the goals of treatment for reduced pain and enhanced
function and quality of life, but discontinued when they are ineffective or risk harm to the patient
or the public health (see Module 7).
Pain Assessment
Pain is usually considered persistent if it continues more than 3 to 6 months or if it meets one of
the following criteria: 1) persisting for at least one month beyond the usual course of an acute
illness or the time required for an injury to heal, 2) associated with a chronic pathologic process,
or 3) recurring at relatively short intervals (days, weeks, or several months). The management of
persistent pain depends on a comprehensive assessment. Competent initial assessment and
reassessment is particularly essential when the pain is complicated by disability, and when the
treatment strategies considered have the potential for risk or monitoring over the long-term, such
as opioid therapy. The complexity of the assessment may increase if the pain has not responded
well to prior treatments, or occurs in a biomedical or psychosocial context that complicates the
understanding of the pain or poses challenges in management. 59 Cultural factors also may
complicate the clinical understanding of the pain.
Pain assessment should be individualized, and documented so that all involved in the patients
care have a clear understanding of the pain problem. One key competency is assessment based
on detailed evaluation of the patients self-report, combined with other information. As a result of
the pain assessment, the clinician should understand the nature of the pain in terms of its
etiology, pathophysiology and syndrome, its impact on many domains of life; and relevant premorbid conditions and comorbidities that will influence treatment decisions. This understanding
requires detailed questions about the pain characteristics, an assessment of the impact of the
pain in multiple domains, and an evaluation of related concerns and comorbidities. Based on this
information, the findings on a physical examination and review of records and existing laboratory
and imaging data, a working diagnosis can be developed that includes an understanding of the
pains etiology, pathophysiology and syndrome. From this formulation, a plan of care can be
developed that may include the need for additional evaluation and an initial set of therapies to
address the pain and other concerns. See Module 1 for further discussion on Pain

The assessment of all patients with pain should include a personal and family history of
substance use, including tobacco, alcohol, prescription drugs and illicit drugs. This understanding
is a key foundation of the universal precautions approach to risk assessment and management
described previously.
For patients with pain due to serious illness and a small minority of other patients, long-term
opioid therapy is considered, trialed and continues. The following section outlines the general
principles of opioid use, and provides further details about the approach to risk assessment and
risk stratification, and structuring therapy when chronic opioid therapy is undertaken. For further
information on issues related to the use of opioids in patients with persistent pain see
Module 7.

Principles of Opioid Use for Pain Management

The broad guidelines for pain management apply to all patients, including those with a substance
abuse history.59 The use of a universal precautions approach to risk assessment and
management,60 a comprehensive patient evaluation, and development of a patient centered
treatment plan coupled with periodic review and compliance monitoring inform the overall
management strategy (see Table).
The Ten Steps of Universal Precautions in Pain Medicine60
1. Make a diagnosis with appropriate differential
2. Psychological assessment includes risk of addiction disorders
3. Informed consent
4. Treatment agreement
5. Pre- and post-intervention assessment of pain level and function
6. Appropriate trial of opioid therapy +/- adjunctive medication
7. Reassessment of pain score and level of function
8. Regularly assess the four As of pain medicine
9. Periodically review pain diagnosis and comorbid conditions
10. Documentation

If the patient has a disorder for which opioid therapy is widely considered the mainstay approach,
such as advanced cancer or HIV/AIDS, healthcare providers should follow established guidelines
for pharmacologic management.61,62 The universal precautions approach still applies, with risk
stratification and the use of specific interventions (required consultations, monitoring with urine or
saliva drug screening, use of one pharmacy, pill counts and other approaches) applied as
appropriate to the clinical situation to ensure that monitoring of drug-related behavior is
appropriate and the patient is assisted in controlling drug use (see discussion on Structuring
Risk Assessment and Stratification
The population of prescription opioid users is heterogeneous. Among patients with well
characterized chronic pain syndromes, there are those who are responsive to the medication and
adherent, others who are so-called chemical copers, and some who develop problems with
substance use disorders or addiction. Nonmedical users also are heterogeneous. Some are selftreating pain or a psychiatric disorder, others are using drugs in a recreational pattern, and some
develop an addictive pattern of use characterized by a loss of control, craving, a compulsion to
use, or the continued use of the drug despite harm. Because the extant data do not allow certain
prediction of future nonadherence, all patients who are being considered for treatment with an
opioid or other potentially abusable drug should be stratified for risk, and should treatment be

undertaken, the type of controls built into the treatment plan should be commensurate with this
Studies have evaluated numerous factors as potential predictors of problematic drug-related
behavior, including abuse and addiction. The most consistent are a prior or current history of
alcohol or drug abuse, a family history of alcohol or drug abuse, and a history of major psychiatric
disorder.63 The presence of one or more of these factors should indicate that the patient may be
at relatively high risk of problematic drug use, an important consideration in the decision to
proceed with therapy, and if this is done, in the decisions that must be made about the degree of
structure and control that should be incorporated (see Structuring Therapy).
Conceptually, patients can be divided or triaged into two (low and high) or three (low, medium
and high) risk groups (see Table-Risk Assessment and Stratification in Clinical Practice).
Those with a low risk usually can be managed by primary care physicians using the basic
elements of a universal precautions approach. Those at moderate risk require more controls
incorporated into the prescribing and monitoring approach; when managed by a primary care
physician, some of these patients may benefit from consultation with appropriate specialist
support. Those patients at high risk of opioid abuseshould they be judged candidates for opioid
treatmentrequire a careful approach to prescribing and monitoring, and should be considered
for referral to a specialist in addiction medicine, or in some cases, pain medicine. Additional
screening tools can help identify patients at risk for misuse.

Table. Risk Assessment and Stratification in Clinical Practice


Characteristics that Suggest Stratum*

Recent history of nonadherence to medication regimens including controlled
drugs, particularly more serious nonadherence such as multiple prescribers,
repeated dose escalation, etc.
Recent history of alcohol or drug abuse
History of addiction
History of a serious psychiatric disorder other than addiction
Recent history of nonadherence to medication regimens
History in the past (e.g., >1 year ago) of alcohol or drug abuse, but no history of
addiction, and no family history of alcohol or drug abuse
No serious psychiatric disorder
History of chaotic home or social situation, or frequent exposure to drug abuse
History of adherence to prior medications
No personal or family history of alcohol or drug abuse
No serious psychiatric disorder
*Some experts consider the existing daily dose in morphine equivalents in stratifying risk

Screening Tools for Identifying Patients at Risk

Several clinical tools are available that hold promise to identify patients who are at risk for misuse
or abuse of prescribed opioids.63-65
The Screener and Opioid Assessment for Patients with Pain (SOAPP) is a brief paper and
pencil tool to facilitate assessment and planning for chronic pain patients being considered for
long-term opioid treatment.64 This 14-item, self administered form captures the primary
determinants of aberrant drug-related behavior. It has been validated over a 6-month period in
chronic pain patients, appears to have adequate sensitivity and selectivity, but may not be
representative of all patient groups. A score of 7 identifies 91% of patients who are high risk.64 A
revised version (SOAPP-R) containing 24 questions also is available.65
One of the briefest measures available for use in risk stratification, the Opioid Risk Tool (ORT)
consists of five yes-or-no self-report items that are designed to predict the probability of a patient
displaying aberrant behavior when prescribed opioids for chronic pain. 63 Each positive response

is given a score, and then the scores are summed, with scores in the 03 range associated with
low risk, 47 with moderate risk, and 8 and over with high risk. Although the ORT is useful due to
its brevity and ease of scoring, the validation is limited. Its face validity is reassuring, but also
raises concern about the potential for deception. Other tools also are available (e.g., COMM,
DIRE) to monitor for misuse and aberrant behaviors (see below).

Supplementation of Screening Efforts with Laboratory Tests

Biofluid (typically urine or saliva) measurement of drug concentrations can provide objective
evidence to help identify and assess patients who are receiving opioid drugs. Many commercial
laboratories now provide specific pain panels, which include most of the prescribed opioids. The
appropriate use of these results depends on interpretation. When findings are inconsistent with
therapy (e.g., a prescribed drug is missing, or either a non-prescribed drug or an illicit drug is
present), a careful evaluation is needed. The limits of the tests, potential for cross-reacting
agents, effect of time on the results and other factors must be appreciated. If there are questions
about the interpretation of a finding, the clinical toxicologist at the laboratory should be called to
resolve them. A change in the care plan and documentation in the medical record usually should
follow a discussion with the patient about the finding and its interpretation.
Prescription Drug Monitoring Programs
State-based prescription drug monitoring programs (PDMPs) represent another important
resource for information on patient drug-related behaviors. Most are designed to capture data
on prescriptions for either scheduled II-IV or II-V drugs; a few monitor only for schedule II drugs.
Patient activity reports will generally provide information on the drug dispensed, date, dose and
quantity, prescriber name and DEA#, and the pharmacy name and location. Current PDMPs vary
in the controlled substances they monitor and their overriding administrative authority. Most
commonly, the state board of pharmacy operates the PDMP. Otherwise, a public health,
professional, substance abuse, consumer protection, or law enforcement agency operates the
Program. Some PDMPs operate proactively, routinely analyzing prescription data (trend analysis)
to identify individuals, physicians, or pharmacies with unusual patterns of use. Most are passive,
however, and are being utilized only for specific requests or searches that satisfy specific criteria.
Reporting requirements, including the time for fulfillment of requests, are variable.
The data contained in PDMP reports potentially serves a multitude of functions. These include
assisting in patient risk assessment, facilitating the identification of individuals who engage
multiple prescribers (doctor shopping), detecting signals of substance use disorders or
addiction, fostering appropriate intervention and treatment of such individuals, and providing data
on use and abuse trends to inform educational and public health initiatives.
The number of states that share PDMP information is increasing with the assistance of integrated
software platforms that enable this practice. Although challenges are inherent in conducting high
quality research on PDMP effectiveness, a 2012 review of published data concluded that PDMPs
reduce doctor shopping, change prescribing behavior, and reduce prescription drug abuse. A
more recent study suggests that states with operational PDMPs have experienced less
substantial increases in various measures of prescription drug abuse that have been trending
upward for the last decade.68 While PDMP reports provide a wealth of useful information, they do
not directly inform on patterns of consumption for individual prescriptions, the amount of a
prescription that may have been consumed versus hoarding, and the route of administration that
may have been used.

Structuring Therapy--Monitoring and Maintenance Strategies

The population with persistent pain is extremely diverse and the strategies used to administer and
monitor opioid therapy should be individualized based on the pain assessment, the risk of
adverse effects, and the perceived likelihood of problematic drug-related behavior. It is critical

that clinicians structure care to reduce risks and monitor all patients carefully. Some patients
need no special monitoring (low risk). Others (moderate to high risk) need more extensive
structure to assist them in adhering to the pain management therapy and to increase the
likelihood that any problems are identified promptly. The latter structure may include frequent
visits, prescription of small amounts of opioids, use of an opioid agreement (describing
expectations and consequences of problematic behavior), occasional biofluid drug screening,
requiring consultations or co-therapy with mental health care providers, and other similar
strategies (See Table. Tailor Monitoring to Patients Risk of Opioid Misuse, Abuse or
Diversion). Clinicians who cannot establish structured approaches should not independently
treat patients who require such an approach.
Monitoring Outcomes
During a trial of long-acting therapy, and thereafter should treatment be continued, safe and
effective management requires a patient-centered treatment plan and ongoing assessment of a
range of critical outcomes. These outcomes include: 1) analgesia (goal: continuing satisfactory
relief of pain, 2) side effects (goal: tolerable and manageable, and producing a degree of burden
clearly outweighed by the benefit of therapy, 3) physical and psychosocial functioning (goal:
stable or improved function in one or more meaningful domains), and 4) therapeutic adherence
(goal: lack of aberrant drug-related behaviors) (see the 4 As). Functional outcomes often are
more objective and verifiable, and in patients with pain associated with disability, functional
improvement can be designated as a therapeutic goal as important, or more important, than relief
of pain.
It is critically important to monitor these outcomes systematically, and to change therapy if an
indication to do so arises. These outcomes should be documented in the medical record
repeatedly over time, whether or not patients have relatively increased risk for aberrant drugrelated behavior.59 In monitoring the latter behaviors, there is an expectation that the occurrence
of any problem should be documented and followed by an evaluation to appropriately interpret its
naturefor example, addiction vs. some other psychiatric disorder vs. bothand management
should be pursued based on this interpretation, the seriousness of the behavior, and the skills of
the clinician.59
The 4 As
A useful mnemonic has been applied to the four key outcomes of long-term opioid therapy: the
Analgesia. The effectiveness of the opioid for its primary indication, pain, should be assessed at
regular intervals.
Adverse effects. Opioids carry a substantial side effect liability and therapy should not be
continued if the burden posed by side effects is excessive.
Activities. Physical and psychosocial functioning must be assessed and documented during
opioid therapy. During successful therapy, patients maintain their level of function or improve;
therapy is unsuccessful if function declines. Use of an activity monitoring form can be instructive.
Aberrant drug-related behavior. Therapeutic adherence is essential for safe care. Problematic
behaviors may be characterized as misuse, abuse, or addiction, or possibly indicate diversion;
these behaviors occur on a continuum and must be carefully assessed in order to clarify their
seriousness and resolve the differential diagnosis. Relatively mild problems, such as the
occasional use of an extra dose (particularly if not cautioned against this), must be contrasted
with serious events which are more indicative of addiction, such as repeated requests for early
refills, acquisition of prescription opioids from multiple sources, or the concurrent use of illicit
drugs (Table - Aberrant Drug-Related Behaviors That May Occur During Long-Term Opioid
Therapy). Aberrant drug behaviors can be relatively less or more suggestive of addiction in
association with long-term opioid therapy. Once aberrant behavior is identified, an assessment is

needed to interpret it appropriately.59 There are recognized risk factors for the development of
aberrant behaviors (Table- Patient Risk Factors for Aberrant Behaviors/Harm).
As mentioned above, validated instruments may be useful in screening patients or monitoring
drug-related behavior during therapy. The Current Opioid Misuse Measure (COMM) assists in
identifying whether a patient, currently on long-term opioid therapy, may be exhibiting aberrant
behaviors associated with misuse of opioid medications. 69 In contrast, the previously described
Screener and Opioid Assessment for Patients with Pain (SOAPP) is intended to predict which
patients being considered for long-term opioid therapy, may exhibit aberrant medication
behaviors in the future. Since the COMM examines concurrent misuse, it is more suited for
helping clinicians monitor patients' aberrant medication-related behaviors over the course of
treatment. Another screening tool, the Diagnosis, Intractability, Risk, Efficacy (DIRE) score, was
designed to predict analgesia and adherence during long-term opioid treatment, but also may be
useful during ongoing treatment.70 Each category (diagnosis, intractability, efficacy, and risk
[psychological, chemical health, reliability, and social support]) is rated from 1 to 3, with higher
scores indicating a greater possibility of successful opioid therapy. The tool requires a good
history and a good relationship with the patient, and requires less than 2 minutes to complete.
The Addiction Behavior Checklist (ABC) also may be useful in evaluating adverse behaviors and
inappropriate opioid use in chronic pain. 71 See Module 4 for more discussion on the use of these
screening instruments.
In addition to the use of these instruments, data obtained from state-based PDMP reports and the
use of biofluid drug testing are important monitoring activities. Medication reconciliation, pill
counts, and consultation with family members are additional approaches that can be part of the
evaluation of patient behavior.
Table. Suggested Strategies in Tailoring Monitoring to Patients Assessed Risk of Opioid
Misuse, Abuse or Diversion
Sole Prescriber
Frequency of

Lowest Level of
Very Low Risk
Q 6 months

Moderate Level of
Significant Risk
Q 2 weeks to
Q 2 weeks after
med change
Q 3 months if
stable after 6
months if NO
family or friend
to attend
Commonly used

Opioid Pain


30 day supply

14-30 day supply

Consider no PRN dosing
Consider pill counts

Biofluid Drug

Commonly used
approach is

Common practice is
initial visit plus randomly

Highest Level of Monitoring:

Very High Risk
Q week to start X 4 wks
Q week after med
Q 2 weeks thereafter
for 3 months then
monthly if no aberrant
3rd party must attend

Commonly used

7-14 day supply

No PRN dosing
Consider Pill counts
Consider 3rd party control of
Common practice is initial visit
plus on a quarterly or monthly


initial visit plus

randomly on an
annual basis
thereafter, and
after the
occurrence of
any aberrant
Only if indicated

on a semiannual or
quarterly basis
thereafter, and after the
occurrence of any
aberrant behavior

thereafter, and after the

occurrence of any aberrant

Consider behavioral
health/Pain evaluation

Strongly consider behavioral

health evaluation and/or referral
for evaluation by a pain
specialist, and referral to a
specialist in addiction medicine
if any aberrant behavior occurs

Others as needed

*Monitoring measures should be modified based upon the condition of the patient.
Patients who are very ill or declining rapidly will not need the same level of assessment and monitoring as
patients with a longer life expectancy.


Patient Risk Factors for Aberrant Behaviors

Age <45 years
Male sex
Family history of
prescription drug or
alcohol abuse
Cigarette smoking
Physical illnesses
Pain severity

Substance use disorder
Preadolescent sexual
abuse (in women)
Major psychiatric disorder
(e.g., personality disorder,
anxiety or depressive
disorder, bipolar disorder)

Prior legal problems
History of motor vehicle
Poor family support
Involvement in a
problematic subculture

Aberrant Drug-Related Behaviors That May Occur During Long-Term Opioid

Highly Aberrant, More Likely to Reflect Addiction
Illicit or potentially illicit behaviors
Selling prescription drugs
Forging prescriptions
Stealing or borrowing drugs from others
Obtaining prescription drugs from nonmedical sources
Injecting or inhaling (snorting, smoking) oral formulations
Concurrently abusing alcohol or illicit drugs
Non-adherence behaviors
Having multiple dose escalations or other nonadherence with therapy,
despite warnings
Repeatedly losing prescriptions
Repeatedly seeking prescriptions from other clinicians or from emergency
department staff
Deterioration in function at work, in the family, or socially
Less Aberrant Non-adherence Behaviors
Repeatedly resisting changes in therapy, despite clear evidence of
adverse physical or psychological effects from the drug
Aggressive complaining about the need for more drug
Drug hoarding during periods of reduced symptoms
Requesting specific drugs
Openly acquiring similar drugs from other medical sources
Having unsanctioned dose escalation or other nonadherence with therapy
on 1 or 2 occasions
Using the drug, without approval, to treat another symptom
*In some cases, one or more of these behaviors may be interpreted as indicators of the key
characteristics of addiction. For example, use despite harm may be reflected in decreased physical or
psychosocial functioning, loss of job or motor vehicle infractions; loss of control may be indicated by
repeated appearances at clinic without an appointment, frequent visits to emergency room, or family
reports of overuse or intoxication; compulsive use may be reflected in nonsanctioned dose escalation or
reports of lost or stolen prescriptions; and craving or preoccupation with opioids may be suggested
by the failure to comply with nondrug pain therapies and persistent focus on symptoms and not


Individualization of the dose through the process of gradual dose titration is the key principle in
attaining a favorable balance between analgesia and side effects. Full mu opioid agonists, such
as morphine, have a fairly linear dose response curve and upward dose titration can be done until
either satisfactory analgesia is reported or the patient experiences an intolerable and
unmanageable side effect. The latter scenario is known as poor responsiveness and should be
considered specific for the particular opioid and route of administration.29
Clinically, the potency and effectiveness of mu receptor agonists can vary unpredictably among
patients, with some patients achieving excellent relief with one agent, while other patients require
a different drug. Side effects such as nausea and vomiting also differ among individuals. If side
effects become problematic during dose titration, it is reasonable to consider a change in the
Part of the explanation may lie in the fact that the mu opioid receptor gene generates a variety of
different mu opioid receptor subtypes in the form of splice variants with different response
characteristics, the pattern of which varies among individuals. 74-76 Thus, the most effective drug
for one patient may not be the best one for another individual. The presence of incomplete cross
tolerance among mu opioids is another example of differences among the drugs. Patients highly
tolerant to one mu opioid may regain their sensitivity when switched to another mu opioid, an
observation which has led to the practice of opioid rotation.
Morphine sulfate is regarded as the prototype opioid drug, and the potency of other members of
the class are typically compared to a 10-mg parenteral dose of morphine (Table: Equianalgesic
Dosing of Opioid Analgesics). Although the variation in potency is very large (e.g., microgram
quantities of fentanyl yield effects comparable to many milligrams of morphine), clinicians are
able to select appropriate starting doses in the patient who is relatively opioid-nave by consulting
the package insert. In the patient who is already taking an opioid, a change in the opioida
technique called opioid rotationcan begin with a starting dose by cautiously applying the
information in the equianalgesic dose table. The data in the table is only a guide, however, and
cannot be used without adjustments, nor do they guarantee safety. A variety of factors alters the
ratios, including variation in bioavailability when a route other than the intravenous route is used,
and often more important, shifts in relative potency between drugs that occur as tolerance
develops during long-term therapy. It must be understood that the data that have been codified in
the equianalgesic dose table reflect studies that were done on populations with limited opioid
exposure, and that differences in cross-tolerance to analgesia and other effects may greatly
influence the effects produced when drugs are changed during long-term treatment.
When comparing intravenous morphine and hydromorphone, for example, the equianalgesic table
relies on early studies showing that 10 mg of the former provides roughly the same analgesia
as 1.5 mg of the latter. This reflects a potency difference in a population with little opioid
exposure. During chronic therapy with one or the other drug, however, the relative potency
can shift, necessitating caution when changing drugs in the clinical setting. It is important that the
clinician always consult the equianalgesic dose table prior to switching opioid drugs or routes of
administration, and very importantly, use these values only as a broad guide. A protocol for opioid
rotation that incorporates judicious reduction in the calculated equianalgesic dose to maintain
safety should be followed.72


Table:# Equianalgesic Dosing of Opioid Analgesics

Dose (mg)


Parenteral Dose
SC, IM, IV(mg)

An equianalgesic table can be used to switch drugs or routes of administration.

Adapted from The Education for Physicians on End-of-Life Care (EPEC)
Curriculum. Chicago: Robert Wood Johnson Foundation, 1999; Foley KM. The
treatment of cancer pain. N Engl J Med. 1985;313:84-95; and, 2011 Update to
Demystifying Opioid Conversion Calculations: A Guide for Effective Dosing.
*Although the PO:IM morphine ratio was 6:1 in a single dose study, other
observations indicate a ratio of 2-3:1 with repeated administration (Portenoy
RK: Lancet 2011:377:2236-2247.

In short, the use of an equianalgesic table to help guide switching is based on the best available
science but has inherent limitations based on the populations and types of pain evaluated,
duration of treatment, formulations that have been studied, and the directionality of the switch.
Therefore, all equivalents should be considered approximations only and can be affected by
interpatient variability, type of pain (i.e., acute vs chronic), chronicity of treatment, tolerance, and
incomplete cross tolerance. An alternate approach that obviates the need to consult
equianalgesic table has recently been offered (please see Module 7 for further discussion). In
any event, patients should be monitored for efficacy and adverse reactions and the dose adjusted
Fentanyl. Although the parenteral morphine:fentanyl ratio in the Table is shown as 10:0.1 (or a
100:1 ratio), in clinical practice the ratio has been described as anywhere between 15 and
112.5:1; many clinicians use an equivalency of 4 mg/hr IV morphine equivalent to 100 mcg/hr
parenteral or transdermal fentanyl. Transdermal fentanyl 25 mcg/hr used for chronic pain is
roughly equivalent to 50 mg oral morphine/day, however, when converting from morphine
equivalents per day to transdermal fentanyl, the fentanyl dose in adjusted in 25 mcg/hr
increments over approximately a 90 mg morphine range. These conversions are in the package

Table. Oral Morphine to Fentanyl Conversion

24 hr Oral Morphine (mg)
To Fentanyl Dose (mcg/hr)
Source: FDA-approved product labeling
Methadone. Methadone is a drug with unique pharmacology. It is available as a racemic mixture
of the l-isomer (which is a mu agonist) and d-isomer (which is an antagonist of the n-methyl-daspartate (NMDA) receptor. The d-isomer may yield independent analgesic effects and reverse
opioid tolerance, and may be responsible for a greater that expected potency when methadone
replaces another prescribed opioid. Methadone is far more difficult to prescribe safely for pain
than other opioids. The challenges inherent in safe methadone prescribing relate to its long and

variable half-life, complex metabolism and risk of drug-drug interactions, potential to prolong the
QTc interval, and relative potency ratios with other opioids that change with the dose and duration
of treatment at the time of a switch to methadone therapy. The analgesic effects of methadone
persist for up to 4 to 6 hours, therefore it usually must be administered three times daily. For
patients who are opioid-nave or have very limited prior opioid exposure, methadone can be
initiated at doses of 2.5-5 mg tid, with the smaller and less frequent doses reserved for those with
chronic illness or more than 70 years of age. Patients should be warned that initial pain relief
may be inadequate and not to take extra methadone. A short-acting opioid can be used initially
for augmentation and breakthrough pain. See Module 7 for further discussion on methadone.
For those patients receiving higher opioid doses, there are a number of strategies that can be
used to safely change to methadone. One approach starts with the calculated equianalgesic dose
and then reduces the starting dose of methadone by 75-90% depending on the size of the dose,
the medical frailty of the patient and the severity of the pain. Another approach calculates the
starting dose of methadone in ranges determined by the dose of the prior drug, and then adds a
safety factor. A table of conversions from oral morphine illustrates this (see below).

Table. Oral Morphine to Oral Methadone Conversion for

Chronic Administrationa
Total Daily Baseline Oral
Morphine Dose (MED)
<100 mg
100-300 mg
300-600 mg
600 mg-1000 mg
>1000 mg
Methadone package insert

Estimated Daily Oral

Methadone Requirement
as % of Total Daily MED

After estimating the equianalgesic dose, a safety factor is introduced by identifying an automatic
does reduction of 25%-50% with the larger reduction intended for patients receiving relatively
high doses, non-Caucasian race, or is elderly or medically frail.
For individuals on very high opioid doses (e.g., 1,000 mg morphine equivalents/ day or higher)
great caution should be exercised in converting to methadone. Based on clinical experience,
some experts advocate never starting a dose above 40 mg per day; others suggest that a higher
starting dose can be done but strongly consider doing so in a monitored setting.
Dose Titration
Initial oral dosing regimens typically utilize a short-acting, immediate-release preparation and the
dose is titrated upward to determine the optimal dosage. Dose titration for immediate release
preparations should be accomplished by increasing the dose as a percentage of the total daily
dose. An increase of 25% to 50% usually is safe. Thus, a patient with inadequate pain relief with
30 mg morphine can receive 45 mg, while a patient on a dosage of 300 mg may require an
increase to 450 mg with careful monitoring of the patient for side effects. Frequent reassessment
is invaluable in ensuring appropriate and adequate dosing.
Patients prescribed short-acting drugs may require multiple doses throughout the day, which can
be inconvenient and reduce adherence. If pain is constant or recurs frequently, opioids should be
administered on a time-contingent (regularly scheduled) basis and this is usually best
accomplished with a long-acting opioid. Once the total dose of an immediate-release formulation
is determined, the regimen can be converted to a modified-release opioid formulation or


Modified-release preparations of morphine increase the drugs duration from 2 to 4 hours (for
short-acting agents) to 8 to 12 hour for some formulations and 24 hours for others. Modifiedrelease oral formulations are also available for oxycodone, oxymorphone, hydromorphone, and
tapentadol (oral), and modified-release transdermal formulations are available for fentanyl and
buprenorphine. When patients are switched to one of these drugs, they should be warned that
initial pain relief may be inadequate; a short-acting opioid can be used initially for augmentation
and breakthrough pain.
The occurrence of tolerance to analgesic effects of opioid drugs can occur, and is a common
worry of clinicians and patients alike. Tolerance to analgesic effects and tolerance to other
effects, such as respiratory depression and constipation, occur at different rates and to varying
extents. Only tolerance to analgesia poses an issue clinically. Observational data based on case
series or open-label extension studies support the view that some patients can be maintained on
low to moderate doses for several months to years; 77-80 others require periodic dose changes that
can be accommodated by the clinician and patient. Randomized clinical trial data have not
adequately characterized the long-term outcomes of opioid therapy in heterogeneous populations
with chronic pain. Epidemiological evaluations based on administrative and clinical data derived
from large population-based studies have tended to suggest a lack of efficacy or functional
improvement with long term use (see Module 7 for further discussion on the evidence related
to long term opioid therapy). These data do not exclude the potential for significant benefit in a
subset of patients managed in careful practice settings. Large epidemiologic studies also include
patients who have dose escalated and are not doing well, and perhaps reflect a pattern of opioid
use for a wider range of diagnoses. 54,56,57,81-84 The extant data suggest that some patients reach a
low stable dose, others escalate their dose but eventually stabilize, but many others never seem
to stabilize. Importantly, benefits do not seem to last and functional improvement is not apparent
in most of those who dose escalate.86 Regardless, many patients who are started on chronic
opioid therapy eventually discontinue either because of adverse effects or inadequate pain relief
(see Module 7).
Another concern that relates to opioid titration is the potential for opioid-induced hyperalgesia, a
state of nociceptive sensitization caused by exposure to opioids. The phenomenon, which has
been well characterized in animal models, would be clinically manifest by the occurrence in
patients treated with opioids of greater sensitivity to noxious stimuli or more clinical pain.87,88
Although there are observations that suggest that this occurs in patients (see Module 7), it is
difficult to distinguish it from tolerance or other explanations for increasing pain, including disease
progression and anxiety. A recent controlled clinical trial demonstrated that tolerance occurred
after a month of chronic opioid treatment in patients with back pain, but hyperalgesia could not be
Breakthrough pain is common in populations with cancer pain and non-cancer pain.90,91 The coadministration of an immediate-release, short-acting rescue dose is now the standard approach
when treating persistent pain in the cancer population. In the population with opioid-treated
noncancer pain, the rescue dose is used commonly, but should not be considered the standard of
care; patients should be carefully assessed to determine whether the potential benefits of this
additional opioid outweigh any risks. A typical rescue dose consists of 5% to 15% of the patients
24-hour dose of medication or the equivalent dose of a different drug, as calculated from
analgesic conversion charts (Table: Equianalgesic Dosing of Opioid Analgesics). The only
exception to this is provided by oral transmucosal immediate release fentanyl products which
should be initiated at low doses in all patients, and then titrated upward as needed. This is a key
element of the FDA REMS program for the transmucosal immediate-release formulations.

Opioid Analgesics: Adverse Reactions

Side effects are common during opioid therapy and should be anticipated and treated (see Table:
Strategies to Minimize Opioid Side Effects). Constipation is the most common side effect of
opioids during chronic use, and is a consequence of both central nervous system effects and

binding to mu2 opioid receptors in the GI tract. Unfortunately, this often continues as a significant
problem as patients either fail to develop tolerance or experience concomitant causes. A
prophylactic bowel regimen should be considered in patients who are predisposed to this side
effect, such as the elderly, sedentary patients, patients with poor oral intake, and patients treated
with other constipating drugs. Peristaltic stimulants, such as senna concentrate or bisacodyl are
routinely recommended, unless use of these agents is contraindicated. Numerous other laxative
options exist, including commonly-used osmotic agents such as lactulose or polyethylene glycol.
Methylnaltrexone, an injectable opioid antagonist that does not cross the blood-brain barrier, is
FDA-approved for refractory opioid-induced constipation. Occasional patients are offered oral
naloxone, which has very poor oral bioavailability and also has been used to treat opioid-induced

Strategies to Minimize Opioid Side Effects

Preventive measures
Slow titration of doses
Verifying that symptoms are an opioid side effect
Changing the dosing regimen or route of administration
Using a nonopioid or adjuvant analgesic for an opioid sparing effect
Adding a drug to counteract the side effect
Constipation prophylaxis

Nausea and vomiting, which may be related to direct drug effect in the brainstem, to
gastroparesis, or to sensitization of the labyrinthine-vestibular system, is a problem for a
substantial minority of patients at the start of therapy. Some patients, however, report persistent
nausea during chronic therapy. Although nausea often resolves spontaneously, some patients
may require an antiemetic. If the nausea appears to be mediated by activation of a
chemoreceptor trigger zone in the medulla, centrally-acting antiemetics, such as
prochlorperazine, are the most effective. Patients with nausea associated with vertigo or
aggravated by motion, may be helped with an antivertiginous drug (e.g., cyclizine, scopolamine,
meclizine). If the nausea is most prominent after eating and is associated with early satiety or
post-prandial distension, a trial of metaclopramide is reasonable given its dual central effects on
dopamine receptors and gastrokinetic properties.

Major Adverse Reactions of Opioids

Nausea and vomiting
Mental clouding
Sleep-disordered breathing
Respiratory depression

Opioid-induced sedation and mental clouding occur in a dose-dependent fashion and are most
common when treatment is initiated. The risk of respiratory depression also is greatest when
dosing is initiated in the patient who is relatively opioid-nave. Sedation and other cognitive effects
typically wane over time.
However, some patients experience persistent sedation or cognitive impairment. If this occurs, a
change in therapy is indicated. In the medically ill, co-administration of a psychostimulant, such
as dextroamphetamine, methylphenidate hydrochloride, or modafinil, often is tried. The use of
psychostimulants may be associated with side effects, however, and must be carefully monitored.
Respiratory depression during opioid therapy occurs rarely if appropriate doses are administered
and monitoring is appropriate. The risk is greatest when opioid-naive patients are first exposed to
relatively large doses of these drugs or doses are escalated too rapidly, especially with
methadone. The initiation of therapy and dose titration should be undertaken with particular
caution in patients with serious pulmonary dysfunction. Tolerance to the respiratory effect of

opioids typically occurs with chronic therapy, but presumably, tolerance is incomplete and
residual respiratory depressant effects are demonstrable by a shift in the CO 2-response curve but
not clinically.
This phenomenon would explain the response to naloxone that usually is seen when an opioidtreated patient develops compromised respirations as a result of a new cardiopulmonary event,
such as pulmonary embolism or respiratory infection. Clinicians should be aware that respiratory
depression is dose-related and does not occur if a patient has demonstrated an ability to tolerate
a dose at a steady-state level. If a patient who is stable develops late respiratory depression, a
new cardiopulmonary insult should be sought even if there is a response to naloxone. Moreover,
opioid-induced respiratory depression does not occur with tachypnea or dyspnea; these findings
also indicate a high likelihood of a new cardiopulmonary insult, again even if there is a response
to naloxone. Concomitant use of benzodiazepines increases the risk of respiratory
depression in patients receiving opioid analgesics..
Other potential consequences of long-term opioid therapy include neuroendocrine effects
(hypogonadism potentially causing fatigue, mood change, sexual dysfunction, osteoporosis,
infertility, and amenorrhea) and urinary retention. Some opioids can cause histamine release
producing sweating, flushing, pruritus, and urticaria; true anaphylactic reactions are extremely
rare. Some patients also may experience problems with dental hygeine and oral health due to
opioid-induced xerostomia. Opioid-related dysimmune effects have been reported but have
uncertain clinical relevance.
Although liver dysfunction usually must be severe to affect opioid pharmacokinetics, the potential
for pharmacodynamic changes suggests that they should be used cautiously in patients with
hepatic disease. Opioids have the potential to interact with a variety of medications, primarily
other CNS depressants with which additive effects occur. Increased sedation is a frequent
interaction that has been reported with alcohol, benzodiazepines, butyrophenones,
phenothiazines, sedative-hypnotics, tricyclic antidepressants, and anticonvulsants. Drug
interactions and relevant notations regarding specific hepatic cytochrome P450 isozymes are
summarized in the table (Table: Important Opioid Drug Interactions).

Table: Important Opioid Drug Interactions


Interacting drug(s)
First generation antihistamines

Increased sedation

Benzodiazepines, antipsychotics, barbiturates,

tricyclic antidepressants, alcohol

Increased sedation, potentiation of

opioid-induced respiratory
Earlier peak plasma concentration,
increased sedation
Inhibition of conversion to active
metabolite by CYP2D6, decreased
Also metabolized in part by
Reduce systemic clearance;
increased plasma levels.

Controlled-release opioids


Codeine, tramadol

Quinidine, fluoxetine, paroxetine, duloxetine,

bupropion, sertraline, terbinafine

Oxycodone, hydrocodone
Fentanyl, methadone

Clarithromycin, ketoconazole, itraconazole,

indinavir, nelfinavir, ritonavir, grapefruit juice, and
other CYP3A4 inhibitors
Carbamazepine, oxcarbazepine, barbiturates,
phenytoin, rifampin, nevirapine, efavirennz, St.
Johns wort, and other CYP3A4 inducers

Oxycodone, tramadol,
Fentanyl, meperidine, tramadol

Increased systemic clearance,

reducing plasma levels, reducing
efficacy or precipitating withdrawal
Also metabolized in part by

Monoamine oxidase inhibitors during previous 14

Excitatory response (includes


Meperidine, morphine


seizures, arrhythmia, and

Inhibition of opioid metabolism,
increased opioid effects
Inhibition of desipramine
metabolism, toxicity possible
Prolongation of QT interval


Class I or III antiarrhythmics, calcium channel

blockers, certain antipsychotics and tricyclic


SSRIs, tricyclic antidepressants, MAO inhibitors


Increased risk of seizures or

serotonin syndrome


MAO inhibitors

Increased risk of serotonin


Source: Jackson KC, Lipman AG. Opioid Analgesics. In: Tallison CD, Satterwaite JR, Tollison JW, eds. Practical Pain Management. 3rd ed.
Philadelphia: Lippincott Williams & Wilkins; 2001; 216-231.

Safe and effective use of opioid analgesics requires proper patient selection and risk assessment
including the use of universal precautions, development of a patient-centered treatment plan,
periodic review using the 4 As, and reassessment of underlying disease if symptoms or response
to treatment changes. Ongoing monitoring for compliance and evaluation of drug-related behavior
is essential. Opioid analgesics are but one component of a comprehensive treatment plan. When
contemplating use in patients with persistent pain, opioids should only be prescribed on a trial
basis. Each visit requires reassessment of continuing need and safety. Opioid therapy is
modifiable through dose titration, rotation and conversion, or discontinuation based on individual
variability and response.

Adjuvant Analgesics
Adjuvant analgesics (Table: Examples of Adjuvant Analgesic Use) were historically defined as
drugs that are used primarily for treating conditions other than pain, but may be analgesic in
selected circumstances.92 They now include some drugs (selected antidepressants and
antiepileptic drugs) that are primarily approved for specific types of pain). Adjuvant analgesics
include agents useful in all types of pain (such as antidepressants), analgesics for neuropathic
pain (such as the antidepressants, and selected antiepileptic drugs (AEDs), and analgesics
typically used for musculoskeletal pain (such as so-called muscle relaxants).
Antidepressants have been used for decades as primary analgesics. They may be considered
multipurpose analgesics, appropriate for a trial in any persistent pain condition. The tricyclic
antidepressants have been well studied and are most likely to be effective. Their side effect
liability is higher than newer drugs. The selective serotonin and norepinephrine reuptake
inhibitors (SNRIs) appear to be more effective analgesics than the selective serotonin reuptake
inhibitors (SSRIs). Duloxetine and minalcipran have FDA-approved labeling for treatment of
specific pain syndromes, including diabetic painful neuropathy and fibromyalgia. Drugs that are
predominantly noradrenergic, such as bupropion, also may be analgesic.
The secondary amine tricyclic antidepressants, such as desipramine and nortriptyline, have a
relatively favorable side effect profile and are generally preferred when an antidepressant of this
type is tried for pain. These drugs are well absorbed from the GI tract and have long half-lives,
making single daily doses effective. A low starting dose (e.g., 25 mg in adults and 10 mg in the
elderly) should be gradually titrated upward. The usual effective dose range is 50-150 mg per
day. Side effects include dry mouth, urinary retention, constipation, sedation, and orthostatic
hypotension. The most serious side effects are cardiac rhythm disturbances, and patients should
be carefully evaluated for cardiac abnormalities prior to initiating therapy. One of the SNRIs

should be considered if the tricyclic is not tolerated or the risk of adverse effects is judged to be
too high for a trial.
Antiepileptic agents are commonly used to treat neuropathic pain. 32 Gabapentin and pregabalin
are currently the most commonly prescribed drugs for this indication. Gabapentin has FDAapproved labeling for the treatment of postherpetic neuralgia (PHN) and pregabalin is FDA
approved for diabetic painful polyneuropathy (DPN), PHN, spinal cord injury pain, and
fibromyalgia. Pregabalin has more stable pharmacokinetics than gabapentin and should be more
simple to use. Other antiepileptics, such as phenytoin, carbamazepine, clonazepam and sodium
divalproex, and newer drugs, such as lamotrigine, topiramate, tiagabine, lacosamide, and
oxcarbazepine, also are used as analgesics for refractory neuropathic pain. All of these drugs
should be dosed and monitored in a manner similar to their use in seizure prevention. Although
all can cause sedation and mental clouding, other side effects vary and clinicians should become
familiar with their guidelines for use before adopting them in the treatment of persistent
neuropathic pain. Lidocaine (5%) and capsaicin (8%) patches are FDA-approved for PHN.
Many other drugs categorized broadly under the so-called adjuvant analgesics may be
considered for trials in patients with refractory neuropathic pain. These drugs, most of which are
approved for indications other than pain, include numerous agents in many classes, a large
number of which may be tried for neuropathic pain (see Table: Examples of Adjuvant
Analgesic Use). In addition to the analgesic antidepressants, gabapentinoids, other antiepileptic
Table: Examples of Adjuvant Analgesic Use
Multiple types of pain syndromes
Corticosteroids (dexamethasone, prednisone )
Tricyclic antidepressants*
Selective serotonin and norepinephrine reuptake
inhibitor (SSRI/SNRIs) antidepressants*
Alpha-2-adrenergic agonists
Topical therapies
lidocaine patch (5%)
capsaicin patch (8%)
doxepin or another compounded tricyclic
Gabapentinoids (gabapentin, pregabalin)
Other anticonvulsants
sodium divalproex
NMDA receptor antagonists
Oral sodium channel blockers
GABA Agonists


Complex regional pain syndrome

or suspected sympathetically
maintained pain
Bone pain from cancer

Bisphosphonates (e.g.,pamidronate)

*Multipurpose drugs but used in neuropathic pain.

Adapted from Portenoy RK, Lesage P. Management of cancer pain. Lancet.1999;

drugs and topical treatment noted previously, this category includes 1) alpha-2 adrenergic
agonists such as tizanidine and clonidine, 2) sodium channel blockers such as mexiletine (and
the novel lacosamide, which is a sodium channel modulator approved for the treatment of
epilepsy), 3) other GABA agonists such as baclofen, 4) N-methyl-D-aspartate antagonists such
as memantine, and 5) cannabinoids such as tetrahydrocannabinol and nabilone. See Module 9
for further information on the use of adjuvant analgesics.

Based on the comprehensive assessment, one or more than one treatment strategy should be
selected. Often, the goals of therapy are both pain relief and functional restoration. If
pharmacotherapy is used, clinicians should have an understanding of the approaches used to
optimize treatment with NSAIDs, adjuvant analgesics, and opioids.

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