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Accreditation
This activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for
Continuing Medical Education through the joint sponsorship of the University of Nebraska Medical Center, Center for Continuing Education
and PharmaCom Group.
The University of Nebraska Medical Center, Center for Continuing Education is accredited by the Accreditation Council for Continuing Medical
Education to provide continuing medical education for physicians.
The University of Nebraska Medical Center, Center for Continuing Education designates this educational activity for a maximum of 1.5 AMA
PRA Category 1 CreditsTM. Each physician should only claim credit commensurate with the extent of their participation in the activity.
Estimated time to complete this activity: 1.5 hours.
To complete the posttest and evaluation, visit www.unmc.edu/dept/cce/opioid_criticalthinking.htm (see page 12).
Please call 402.559.4152 or toll-free 877.832.6924 with any questions.
Disclosures
Dr Fine is on the Advisory Board for Cephalon, Endo Pharmaceuticals, Lilly, and Merck; and is a Speaker for Cephalon.
Dr McCarberg is on the Speakers Bureau for Endo Pharmaceuticals, Forest, Lilly, Merck, Pfizer, PriCara, and Purdue Pharma L.P.
Dr Passik is a Consultant for Alpharma, Cephalon, Endo Pharmaceuticals, and Ligand/King; receives Grants from Cephalon and Lilly;
and is on the Speakers Bureau for Cephalon and Ligand/King.
Dr Sinatra is a Consultant for Endo Pharmaceuticals, Upjohn-McNeil, and Merck and Company.
Dr Pasternak is on the Advisory Board and Speakers Bureau for Adolor Corporation, Cephalon, Endo Pharmaceuticals, EpiCept, J&J, Limerick
Neurosciences, Ortho-McNeil, and Sarentis.
Learning Objectives
At the conclusion of this activity, the participant will be able to:
1. Discuss factors affecting the selection of an opioid analgesic for individual patients.
2. Select appropriate patients for long-term opioid therapy.
3. Differentiate aberrant drug-related behaviors.
Practice Recommendations
Recommendations Evidence Source
Self-report should be the primary source of pain assessment when B. There is evidence of types II, III, or IV, and www.guideline.gov/s
possible.(B) findings are generally consistent. ummary/summary.as
px?doc_id=3691
Opioid analgesic drugs may help relieve moderate to severe pain, Level I: Evidence from at least one properly www.guideline.gov/s
especially nociceptive pain. Opioids for episodic (noncontinuous) pain randomized, controlled trial. ummary/summary.as
should be prescribed as needed, rather than around the clock. Long-acting A. Good evidence to support the use of a px?doc_id=3365
or sustained-release analgesic preparations should be used for continuous recommendation; clinicians should do this all the
pain. Breakthrough pain should be identified and treated by the use of time.
fast-onset, short-acting preparations.(IA)
Patients taking analgesic medications should be monitored closely. Level I: Evidence from at least one properly www.guideline.gov/s
Patients should be reevaluated frequently for drug efficacy and side randomized, controlled trial. ummary/summary.as
effects during initiation, titration, or any change in dose of analgesic A. Good evidence to support the use of a recom- px?doc_id=3365
medications.(IA) mendation; clinicians should do this all the time.
The clinician should watch for signs of opioid use for inappropriate Level III: Evidence from respected authorities, based www.guideline.gov/s
indications (eg, anxiety, depression, grief, loss). Requests for early refills on clinical experience, descriptive studies, or reports ummary/summary.as
should include evaluation of tolerance, progressive disease, inappropriate of expert committees. px?doc_id=3365
behavior, or drug diversion by others.(IIIA) A. Good evidence to support the use of a recom-
mendation; clinicians should do this all the time.
Constipation and opioid-related gastrointestinal symptoms should be Level I: Evidence from at least one properly www.guideline.gov/s
prevented. Assessment of bowel function should be part of the initial randomized, controlled trial. ummary/summary.as
assessment and of every follow-up visit for all patients receiving A. Good evidence to support the use of a px?doc_id=3365
analgesics. A prophylactic bowel regimen should be initiated with the recommendation; clinicians should do this all the
commencement of persistent opioid therapy.(IA) time.
Fixed-dose combinations of opioid with acetaminophen or NSAIDs may Level I: Evidence from at least one properly www.guideline.gov/s
be useful for mild to moderate pain. The maximum recommended dose randomized, controlled trial. ummary/summary.as
should not be exceeded, to minimize acetaminophen or NSAID toxicity. If A. Good evidence to support the use of a px?doc_id=3365
a maximum safe (nontoxic) dose is reached without sufficient pain relief recommendation; clinicians should do this all the
because of limits imposed by the maximum safe acetaminophen or NSAID time.
dose, switching to noncombination preparations is recommended.(IA)
C R I T I C A L T H I N K I N G TO BA L A N C E B E N E F I T S & R I S K 1
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1
Principles of Prescribing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1
Opioid Analgesics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1
Multiple Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1
Pharmacogenetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2
Drug Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2
Short-Acting Opioids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2
Long-Acting Opioids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2
Managing Adverse Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .3
Incomplete Cross-Tolerance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .3
Patient Selection for Long-Term Opioid Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .4
Assessing Pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .4
Assessing Risk . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .5
Informed Consent . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .5
Individualized Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .5
Periodic Review . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .5
Differentiating Aberrant Drug-Related Behaviors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .6
Changing Course: Discontinuing Opioid Therapy (Exit Strategy) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .6
Case Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .7
The Case of Mr K: A 25-Year-Old Man With Acute Ankle Sprain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .7
The Case of Mrs T: A 60-Year-Old Woman With Osteoarthritis of the Knees . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .7
The Case of Mrs J: An 82-Year-Old Woman With Osteoarthritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .8
The Case of Mr A: A 45-Year-Old Man With Low Back Pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .11
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .12
It is not surprising that pain is among the most common Although there is no evidence for the efficacy of one mu-opioid
reasons for office visits, and that nonsteroidal anti-inflammatory agonist over another in populations, individual patients may
drugs (NSAIDs), opioids, and nonopioid analgesics are among display a much better response to one drug over another, which
the most frequently prescribed therapeutic classes.5 When is why consideration should be given to agents that the patient
treating patients whose pain is not adequately managed with has found helpful in the past. A number of explanations for this
nonopioids, it is important that primary care physicians (PCPs) interindividual response to opioids have been proposed.
have sufficient knowledge of the pharmacology of opioids in Multiple Receptors
order to prescribe them in a fashion that maximizes benefits The 3 major opioid receptor families are mu, kappa, and delta.8
and minimizes risk to patients. The primary site of action of most clinically used opioid
2 O P I O I D A N A L G E S I C S F O R PA I N M A N A G E M E N T
analgesics is the mu-opioid receptor,9;10 which is expressed at a initiate and titrate around-the-clock therapy and, if necessary,
spinal level in the dorsal horn and in multiple regions within as-needed dosing can be added to regular dosing in order to
the brain.10 The interindividual variability in response to mu- control or avoid BTP.
opioid analgesics can be explained in part by multiple mu-
When initiating an opioid trial in an opioid-nave patient, the
opioid receptorssplice variantswith different mechanisms
dose should be individualized to the patient by starting at the
of action and different distributions within a cell, regionally
lowest likely effective dose, which should be increased
within the nervous system (brain and spinal cord), and in the
incrementally, with both the size of the increment and the
peripheral nervous system.8;9;11
interval between increments influenced by the degree of pain
Pharmacogenetics relief, functional improvements, and side effects experienced
The observed interindividual variability in response to opioids by the patient.7;11;18 Starting doses for common oral short-acting
may be due in part to genetic polymorphisms.10 Studies have opioids to treat moderate to severe pain in opioid-nave adults
identified significant differences in the genotype of patients who are shown in TABLE 1.6 A dose increment of 30% to 50% is
required switching to alternative opioids compared with patients safe and usually large enough to observe a meaningful
who responded to morphine.10 Response to an opioid depends change in analgesia.7 If pain is severe and the patient is not
on a number of factors, including drug absorption, distribution, predisposed to opioid toxicity, a higher incrementup to
metabolism, and elimination.10 Therefore a patients response to 100% of the existing dosemay be considered.7 In
a particular opioid is potentially influenced by genetic variation in ambulatory care, an additional consideration with regard to
the alleles of several candidate genes.10;12 An example is the dose titration is the availability of an individual at home with
variable response to codeine in individuals with a polymorphism the patient who is a reliable observer for potential adverse
of the cytochrome P450 (CYP450) 2D6 gene, which prevents effects. An alternative approach in patients who receive
metabolism of the prodrug codeine to the active drug additional as-needed opioids for BTP is to sum the amount of
morphine.7;10 Up to 10% of people will have a poor analgesic supplemental drug used per day during the previous few days
response to codeine because they lack normal CYP2D6 and convert it into the fixed-schedule administration.7
activity.13 Morphine, although active alone, is also metabolized
There is no predictable maximal therapeutic dose (ceiling
to a very active metabolite, morphine-6-glucuronide (MG6),
effect) for analgesia with single-entity opioid agonists, but
chiefly through conjugation by uridine diphosphate glucuronyl
dose-limiting adverse effects can occur.11;18 In contrast, the
transferase (UGT) enzymes.13;14 It has not yet been determined
doses of opioids marketed in combination with a nonopioid
if polymorphisms in genes controlling the metabolism of
are limited by the maximum dose of the nonopioid (eg,
morphine explain interindividual variability in response to
acetaminophen dose limit: 4 g per day in patients without
morphine, but this may be related to patient characteristics
compromised liver function or without a history of alcoholism).18
such as age and renal and hepatic function.10;15;16 In many
If significant adverse events occur before adequate analgesia
patients with renal failure, accumulation of the pharmacologically
is achieved, the dose may be reduced and the events should
active morphine metabolite MG6 may cause toxicity.15;17
be treated. After a stable dose is achieved with a short-acting
Drug Interactions opioid, it may be converted to a long-acting opioid, for example,
Most opioids are metabolized through the liver microsomal if there is a desire for a simplified regimen to optimize
CYP450 system, which is responsible for the metabolism of a adherence, among other possible reasons.
wide variety of drugs.7 Codeine, hydrocodone, methadone,
Long-Acting Opioids
oxycodone, and tramadol are chiefly metabolized through
Long-acting opioids administered around the clock to treat
oxidative reactions by CYP2D6, while fentanyl, meperidine,
persistent baseline pain can be given along with additional as-
and buprenorphine are metabolized by CYP3A4.7 Concomitant
needed doses of short-acting opioids for exacerbations of pain
treatment with drugs that inhibit or induce CYP450 enzymes
(ie, BTP), to permit activity such as physical therapy, and for
can alter the levels of these opioids and their metabolites;
this may change their analgesic or side-effect profile and
cause possible opioid overdose or acute withdrawal.7;13;14
TA B L E 1 Commonly Used Oral Short-Acting Opioids
Morphine, hydromorphone, and oxymorphone are metabolized
Starting oral dose* in opioid-nave
chiefly through conjugation reactions with UGT enzymes.13;14 Name adults with moderate to severe pain
Because they are not oxidatively metabolized by CYP450 lower range: higher range:
unmonitored outpatients monitored setting
enzymes, inhibition/induction or genetic polymorphisms of
Codeine 30-60 mg q3-4h
CYP450 enzymes should have little to no effect on the
Hydrocodone 5-10 mg q3-4h
metabolism and clearance of these drugs.14
Hydromorphone 4-8 mg q3-4h
Short-Acting Opioids
Morphine 15-30 mg q3-4h
Short-acting opioids are available as single-entity agents or in
combination with a nonopioid with a complementary Oxycodone 10-30 mg q4h
Oxymorphone 10-20 mg q4-6h
mechanism of action (NSAIDs or acetaminophen). If pain is
present for only a few brief periods during the day, patients Tramadol 50-100 mg q6h
may take an as-needed dose of a short-acting mu opioid.18 For *Reduce initial dose by up to 50% in frail, older patients and titrate upward based
persistent pain, a long-acting agent is recommended to control on therapeutic response and undesirable side effects; If deemed necessary to
initiate therapy at a lower dose, patients may be started with 5 mg oxymorphone.
baseline pain around the clock and avoid breakthrough pain Adapted from: American Pain Society. Guideline for the Management of Cancer
Pain in Adults and Children. Clinical Practice Guideline No. 3. Glenview, IL:
(BTP). But in most cases, a short-acting opioid is used to American Pain Society; 2005.
C R I T I C A L T H I N K I N G TO BA L A N C E B E N E F I T S & R I S K 3
incident pain.11;18;19 Although many PCPs have not adopted the routine prophylactic administration of an antiemetic agent is not
practice of using long-acting opioids for indications other than typically indicated, except in patients with a history of severe
cancer pain, there are significant benefits from using these agents opioid-induced nausea.7;11;19 Opioid-induced bowel dysfunction
for long-term pain, including improved control of baseline pain should be anticipated and treated prophylactically with a
and the need for smaller quantities of pills. The most commonly stimulating laxative to increase bowel motility, with or without
used long-acting opioids are sustained-release (SR) preparations stool softeners as indicated by stool consistency.11;18;19
of short-acting opioids. Some SR opioids can be initiated in opioid-
Nonpharmacologic approaches for all patients include:7
nave patients, although not all have been systematically evaluated
Increase fluid intake as tolerated.
as an initial agent, and most experts would recommend starting
Increase dietary fiber as tolerated (unless patient is severely
a short-acting agent before using a long-acting agent (TABLE 2).
debilitated or bowel obstruction is suspected).
Once initiated, the long-acting opioid dose can also be titrated
Encourage mobility and ambulation if appropriate.
by incorporating the as-needed short-acting doses into the daily
Ensure comfort and privacy for defecation.
long-acting dose. Patients should be advised to swallow SR oral
Encourage bowel movements at the same time each day.
opioid formulations whole, and not to break, crush, or chew
Rule out or treat impaction.
tablets in order to prevent the rapid release of potentially
dangerous opioid levels (refer to prescribing information for TABLE 3 shows examples of the pharmacologic management
individual agents). Some formulations also have warnings of common opioid-induced adverse effects.7 In some patients
regarding use with alcohol that can cause dumping of the who poorly tolerate one opioid, it may be necessary to change
opioid content all at once, rather than in a sustained fashion. to a different opioid.18
Managing Adverse Effects Incomplete Cross-Tolerance
Treatment of opioid-induced side effects is integral to opioid pain Patients often exhibit limited cross-tolerance when one opioid
management. A number of adverse effects are associated with is substituted for another, which might reflect their differing
the use of opioid analgesics. The most common are opioid- selectivities for the mu-opioid receptor subtypes (mu-opioid
induced bowel dysfunction (constipation), sedation, nausea and receptor splice variants).22;23 Clinicians have long made use of
vomiting, pruritus, sweating, dry mouth, and weakness.11;18;20;21 the incomplete cross-tolerance among mu-opioid analgesics by
Other adverse effects include respiratory depression, urinary using the concept of opioid rotation, in which highly tolerant
retention, confusion, hallucinations, nightmares, myoclonus, patients are rotated to a different drug to regain analgesic
dizziness, dysphoria, and the very rare hypersensitivity reaction sensitivity.8;22 Incomplete cross-tolerance among opioids affects
of anaphylaxis. With the exception of bowel dysfunction, the conversion from one opioid to another.9 When switching
tolerance often develops rapidly to some of the common opioid- between opioids in an opioid-tolerant patient, it is recommended
related side effects, such as nausea and vomiting. Therefore, to calculate the equianalgesic dose based on the predicted
TA B L E 2 Long-Acting Opioids
*Individualize dose for each patient; Not approved for initiation of therapyadvisable to begin treatment with immediate-release opioid.
4 O P I O I D A N A L G E S I C S F O R PA I N M A N A G E M E N T
equivalent dose in conversion tables, which were determined opioid therapy until specialist evaluation and support is
by relative potency studies in opioid-nave patients, and then cut obtained. When opioid treatment is warranted, a treatment plan
the calculated dose by at least 50% in order to account for should state objectives that will be used to determine
incomplete cross-tolerance.9;22 Using this method, shortfalls in treatment success, such as pain relief, improved physical and
efficacy for the sake of safety can be compensated for in the psychosocial function, manageable side effects, and drug-taking
short term by using immediate-release (IR) opioid (rescue) that follows the rules of appropriate behavior.
doses, with corrections in around-the-clock dosing determined Assessing Pain
after steady state is achieved with the new drug, which requires Selecting patients for long-term opioid analgesic therapy
3- to 5-times the half-life of the drug. requires a comprehensive assessment of pain, including
obtaining, evaluating, and documenting a thorough medical
Patient Selection for Long-Term Opioid Therapy history and physical examination, as well as patient and disease
Most patients with pain do not need opioids, but such therapy characteristics.7;25;29 Because pain is inherently subjective, patient
may be required to effectively control moderate to severe self-report is the gold standard for assessment.7 Pain
pain.24;25 However, recent reports suggest that certain assessment should focus on the type and quality of pain,
populations receiving long-term opioid therapy are particularly source, intensity, location, duration/time course, associated
at risk for poor outcomes.26;27 It is certainly true that poor factors that exacerbate or relieve pain, pain affect, and effects on
patient selection for opioid therapy, opioid monotherapy in the lifestyle and functional status.7;29 Numerous tools are available to
absence of comprehensive management, and inadequate measure pain intensity, such as the numerical rating scale, the
follow-up of patients can be detrimental to patients. At the verbal rating scale, visual analog scales, and the faces of pain
same time, most PCPs have some experience of treating scale.29 These tools are simple to use and sensitive enough to
patients for whom opioid therapy is appropriate and effective, detect changes that occur during pain treatment.
with good long-term outcomes. Because the potential long-
As well as the nociceptive input, pain can also be composed of
term benefits of chronic opioid therapy can be contentious,
psychologic and emotional overlays, such as anxiety, depression,
careful patient selection, comprehensive management, and
and fear. Analgesics such as opioids, however, are only effective
appropriate follow-up are crucial.
in reducing pain intensity, and will not address other aspects of
Opioids alone are not the optimal therapy, but when used in patients pain experiences. If the PCP suspects these conditions
conjunction with nonopioid analgesics, such as an NSAID or are present, it is important to assess and address these domains
adjuvant, and psychologic and physical approaches, they can at the same time as the nociceptive pain. This may be necessary
help to maximize patient outcomes.18;28 For certain populations, at the initial visit, or there may be no indications of a problem
such as chronic low back pain and headache patients, and until a subsequent visit or, for example, after an early refill
those with a personal or family history of substance abuse, request. Several short, accurate, and easy-to-use instruments to
some PCPs may decline to prescribe opioids or defer initiating detect depression are available (eg, Beck Depression Inventory,
*Adjust dose and dosing schedule of selected therapy to optimize effects. Switch or combine conventional approaches if initial therapy is inadequate;
Decrease opioid dose. Adapted from: Fine PG, Portenoy RK. A clinical guide to opioid analgesia. McGraw-Hill, 2004.
C R I T I C A L T H I N K I N G TO BA L A N C E B E N E F I T S & R I S K 5
Zung Self-Depression Scale).30 Brief instruments, including another with respect to both analgesia and side effects.8;9;15
asking the patient 2 questions about the presence of depressed For example, patients unable to tolerate morphine due to
mood and anhedonia (Over the past 2 weeks, have you felt severe nausea/vomiting may be able to take another mu
down, depressed, or hopeless? and Over the past 2 weeks, agonist without a problem.8;10 Patients also vary in their sensitivity
have you felt little interest or pleasure in doing things?), appear to a specific opioid, with some needing higher or lower doses
to perform as well as longer instruments.30 to achieve optimal analgesia.9 At present, it cannot be
predicted which patients are likely to achieve adequate
Information about medical and surgical conditions, history of
analgesia or develop intolerable adverse effects from a given
chronic pain, and previous pain treatments is also important.7
opioid, and in clinical practice, therapy often needs to be
Identifying the etiology, syndrome, or pathophysiology of
switched from one opioid to another to identify the most
pain can help guide the selection of treatment and suggest
effective.9;10 The availability of a wide variety of opioids allows
the prognosis.7
clinicians to better match the drug to the patient.35 Increased
Assessing Risk options become available when novel opioid analgesic
The potential for misuse, abuse, and addiction should be molecules are developed and when existing drugs are
addressed when considering long-term opioid analgesic reformulated into different delivery systems (eg, transdermal
treatment. Assessing risk is not intended to deny high-risk delivery system, SR oral tablet) or have a different mode of
patients treatment for their pain, but rather to match the administration (eg, patient-controlled analgesia, computer-
degree of clinical monitoring and controls to the degree of risk assisted delivery).35
in order to achieve better clinical outcomes and minimize
Periodic Review
misuse. There are many ways to assess risk, including a
Patients should be monitored regularly to assess their response
psychiatric interview and the use of one or more of an
to therapy, to identify and manage side effects, and to identify
increasing number of screening tools (eg, Opioid Risk Tool
and manage aberrant drug-related behavior. The frequency of
[ORT], Screener and Opioid Assessment for Patients with Pain
follow-up should be as often as clinically necessary and in
[SOAPP], DIRE score).31-33 Such tools should be used by
compliance with state regulations, where present. Continuation
clinicians, for example, when considering initiating opioid
or modification of controlled substances for pain management
analgesic therapy for a chronic pain problem or for a patient
therapy depends on the evaluation of progress toward
being treated with opioids for an acute pain problem that is
treatment objectives. The Four As of pain medicine will help
becoming chronic and long-term opioid therapy is an option.
to direct therapy and support the pharmacologic options taken
A patient who displays an aberrant drug-related behavior that
(TA B L E 4 ).36;37 The Four As serve as a mnemonic device to
raises concern (eg, requests an early opioid refill) or does not
remind clinicians that a successful outcome in pain therapy
seem to be doing well requires attention, such as asking him
involves more than lowering pain scores. Equally important
or her to come in to complete a screening tool for addiction,
outcomes include stabilization or improvement in psychosocial
social problems, or other psychologic distress, rather than
functioning and sleep, tolerable side effects, optimization of
automatically writing a refill.
physical functioning, and absence of aberrant behaviors.38
Informed Consent
It is an ethical and often regulatory duty to describe in under- Urine drug testing can be an important tool to assist in
standable terms the risks and benefits of the use of long-term monitoring adherence to a treatment plan when managing
opioid analgesic therapy with the patient or persons designated patients receiving opioid therapy.39;40 Controversies exist
by the patient.25 The physician can consider the use of a written regarding their clinical value, partly because many current
agreement outlining the treatment plan, expectations, and the methods are designed for, or adapted from, forensic or work-
responsibilities of the patient and physician.25;34 Although place deterrent-based testing for illicit drug use.40;41 As a result,
physicians often feel uncomfortable asking patients to sign an they are not necessarily optimized for clinical applications where
agreement, a signed plan of care is particularly important if the a number of licit prescription drugs must also be included.40
patient is at high risk for medication abuse, and may be required However, when used with an appropriate level of understanding,
in some states.25;34 It is also important to outline the procedures urine drug testing can improve a physicians ability to manage
or actions that will be taken should problems arise and the therapy with opioids and identify substance misuse.39;40
patient does not adhere to the terms of the agreement.34 A As more PCPs prescribe opioid analgesics for the management
sample opioid treatment agreement is available at the of chronic moderate to severe pain, the questions of how to
American Academy of Pain Medicine Website: www.painmed. monitor adherence to the therapeutic regimen and when to
org/productpub/statements/pdfs/controlled_substances_sample refer a patient for additional evaluation and treatment in order to
_agrmt.pdf. Clinicians should take care to follow the achieve treatment objectives have become important issues.25;42
guidelines in the written agreements that they utilize or they
risk exposing themselves to potential liability.34 They should
adapt an agreement so that the language provides flexibility TA B L E 4 The Four As of Pain Medicine36;37
for them to make clinical decisions when managing patients
Analgesia (meaningful pain relief)
(eg,Early refills will generally not be given).
Activities of daily living (stabilization & improvement in psychosocial
Individualized Therapy function & specifically identified functional [physical activity] goals)
Clinical treatment of pain with opioids requires individualization
Adverse effects (side effects)
of therapy, due to variability in efficacy, side effects, tolerance
profiles, and risk of drug abuse among patients.8;9;12;35 Some Aberrant drug-related behaviors (adherence to plan of care &
patients may respond far better to one mu opioid than to addiction-related outcomes)
6 O P I O I D A N A L G E S I C S F O R PA I N M A N A G E M E N T
In general, referral to a pain specialist or pain center is new condition, or inadequate instruction or dose provision by
appropriate when the clinician has exceeded his or her the clinician.
expertise in any specific area of opioid-related pain
Psychiatric factors, such as anxiety or depression, a
management. Reasons may include the dose of opioids
personality disorder, or changes in cognitive state, such as
prescribed, the patients inability to adhere to the prescribed
mild encephalopathy due to the treatment regimen of medical
regimen, an inability to achieve adequate pain control despite
comorbidities or underlying psychiatric problems, may be
increasing the dose or switching to different opioids,
responsible for the behaviors identified.43;48 The pain patient
unresolved troublesome side effects, or unresolved issues of
who escalates his or her opioid dose to self-medicate untreated
substance misuse.42 Special attention should be given to
anxiety, depression, or insomnia bears resemblance to addiction
patients who are at high risk for medication misuse, abuse,
with regard to how the drug and drug procurement becomes
or diversion, and especially those with a known history of
a central part of the patients life.38 Such patients who use
drug addiction.
chemicals to cope with adverse life situations (also known as
Differentiating Aberrant Drug-Related Behaviors chemical copers) need structure, psychiatric input, and drug
No behavior is absolutely predictive of addictive disease, and treatments that decentralize the pain medication to their
these behaviors exist along a continuum, with certain behaviors coping and prevent maladaptive opioid analgesic use.
being less problematic and others being more so (TABLE 5).43
There are multiple explanations in the differential diagnosis of
Changing Course: Discontinuing Opioid Therapy
aberrant drug-related behaviors, with criminal intent and (Exit Strategy)
diversion being only one possibility.38;44 Other explanations for Long-term opioid therapy may need to be discontinued for a
nonadherent behavior include untreated pain, psychologic number of reasons, including when opioids are no longer
distress, and addiction.45 It is important that clinicians can effective for pain or to improve function, when unacceptable
distinguish between physical dependence, addiction, and side effects or toxicity occur, or when patients violate the
tolerance (TABLE 6), so that they do not incorrectly assume opioid treatment agreement or display certain aberrant drug-
that a patient is addicted. related behaviors.50 When it is necessary to discontinue
Aberrant behaviors are not to be ignored, but do not mean treatment, withdrawal symptoms can usually be avoided by use
that prescribing should be immediately discontinued. of a slow opioid tapering schedule (reducing the dose by 10%
Clinicians should proceed with caution, set limits, be to 20% each day or more slowly if symptoms occur).18 Anxiety,
thoughtful, and react therapeutically.45 The syndrome of drug- tachycardia, sweating, and other autonomic symptoms that
seeking behaviors that arises when a patient cannot obtain persist may be lessened by slowing the taper or using clonidine
adequate relief with the prescribed dose of analgesic and at an oral dose of 0.1 to 0.2 mg/day. The use of buprenorphine
seeks alternate sources or increased doses of analgesic is for both pain and opioid dependence in the primary care office
referred to as pseudoaddiction.43;46;47 This may be the result of is increasingly common, but requires certification under the
increasing pain due to disease progression, development of a Drug Addiction Treatment Act of 2000.51
Addiction: A primary, chronic, neurobiologic disease, with genetic, psychosocial, and environmental factors influencing its development
and manifestations. It is characterized by behaviors that include one or more of the following: impaired control over drug use,
compulsive use, continued use despite harm, and craving.
Physical dependence: A state of adaptation that is manifested by a drug-class-specific withdrawal syndrome that can be produced by
abrupt cessation, rapid dose reduction, decreasing blood level of the drug, and/or administration of an antagonist.
Tolerance: A state of adaptation in which exposure to a drug induces changes that result in a diminution of one or more of the drugs
effects over time.
Pseudoaddiction: An iatrogenic syndrome of behaviors developing in direct consequence of inadequate pain management. The natural
history of pseudoaddiction is a progression through 3 characteristic phases including: (1) inadequate prescription of analgesics to meet
the primary pain stimulus; (2) escalation of analgesic demands by the patient associated with behavioral changes to convince others of
the pains severity; and (3) a crisis of mistrust between the patient and the health care team.
C R I T I C A L T H I N K I N G TO BA L A N C E B E N E F I T S & R I S K 7
Case Studies
The following case studies illustrate the application of the principles of prescribing opioids for pain management, ranging from a
simple acute case through to more complex patients with chronic pain and psychologic dysfunction. Although there is no question that
physicians should seek consultation when needed, such a requirement is not necessary for every case, especially if the practitioner is
knowledgeable about pain management.52 PCPs have varying levels of comfort, knowledge, and experience in the treatment of chronic
pain, which will affect the threshold for obtaining consultation or referral for each patient. Furthermore, the availability of pain specialists,
pain management programs, and addiction disease specialists varies widely depending on practice location and resources.
Physical Examination
Well-developed, thin male in apparent discomfort.
Localized pain that is increased upon ankle inversion.
Able to bear weight with attendant pain rated at 7-8/10.
Swelling is present.
You opt for a short course of a short-acting
Findings suggest a second-degree sprain.
(ie, IR) opioid to treat his moderate to severe
What Next? pain not controlled by the NSAID alone, so that
he can increase his activity and begin
Continue ice and elevation, but add gradual motion and motility with use of an
rehabilitation.53 Options include hydrocodone,
ankle support. Achilles tendon stretching should begin 48 to 72 hours after ankle oxycodone, and tramadol. Mr K related that
injury since tissues contract after trauma with immobility. hydrocodone relieved his pain following a wrist
Hydrocodone/acetaminophen 5 mg/500 mg 20 tablets, q4-6h. fracture several years ago.
Outcome:
Mr K presents at the follow-up visit in 2 weeks able to walk with care without
opioid analgesia, with only mild pain.
Two hydrocodone/acetaminophen 5 mg/500 mg tablets are left.
He has returned to his employment as an architect, with temporary
modifications to minimize his need to walk.
Advise him to continue a progressive physical therapy (PT) program, and caution
him that full strength may not return for a number of months.
Medication Use
Naproxen and acetaminophen.
Glucosamine sulfate and chondroitin sulfate supplements.
Timolol maleate 10 mg q12h.
ASA 81 mg + multivitamin q24h.
Family History
Her father died of an MI at age 63 years and her mother died of old age.
She has no siblings.
8 O P I O I D A N A L G E S I C S F O R PA I N M A N A G E M E N T
Psychosocial History
Mrs T works part-time (2 days per week) as a bookkeeper. Her husband is
retired, but their investment income is comfortable; they have comprehensive
medical insurance.
One son lives out of state.
She does not use alcohol.
She is unwilling to consider evaluation for joint replacement.
Physical Examination
Mrs T is a pleasantly interactive, slightly overweight female in no acute distress. Any continuous NSAID use poses some degree
of gastrointestinal (GI), cardiovascular, and renal
She is fully cooperative with the history and physical examination.
risks. Mrs T is an elderly woman with a personal
Pain with limited range of motion (ROM) in both knees. and family history of MI.
What Next? You ask her about her prior experience with
Discontinue naproxen. opioids for painmorphine prescribed for her
Initiate IR tramadol at 25 mg/day qAM, titrate in 25 mg increments as separate post-hysterectomy was not effective and caused
a great deal of nausea and vomiting for the 5 days
doses every 3 days to reach 100 mg/day (25 mg q6h), and increase by 50 mg
that she had taken it. You select tramadol to add
every 3 days to reach 200 mg/day (50 mg q6h). to her current acetaminophen regimen.
One Week Later
Pain control is good, but to provide a more convenient regimen you switch Mrs T
to SR tramadol, 200 mg q24h. This patient is a good candidate for long-acting,
around-the-clock analgesia for chronic OA; options
Interim Phone Call include transdermal fentanyl and SR morphine,
Pain control and function are good. oxycodone, oxymorphone, and tramadol. Because
Mrs T is experiencing tremors and has become hypertensive. IR tramadol is providing good pain relief, you
Initiate SR oxymorphone 5 mg q12h, with instructions to increase the dose to convert her regimen to ER tramadol.
10 mg q12h after 3 days if pain is not adequately controlled.
Prescribe IR oxymorphone 5 mg to use as needed prior to exercising.
Ask her to call the office in 5 days to review her need for supplemental Tremor and hypertension are common side
oxymorphone. effects of tramadol. To avoid these side effects,
Prescribe a stimulating laxative to prevent constipation. you switch to another SR opioid.
Medication Use
NSAIDs.
Glucosamine sulfate and chondroitin sulfate supplements.
Alendronate.
Donepezil 5 mg q24h.
ASA 81 mg + multivitamin q24h.
Family History
Both parents died of old age. Her mother was in considerable pain, all bent over
for many years. Her father used a cane and had trouble walking from arthritis.
C R I T I C A L T H I N K I N G TO BA L A N C E B E N E F I T S & R I S K 9
Physical Examination
Well groomed, in no obvious distress.
Alert and oriented to time, place, person, and objects, but unable to subtract Acetaminophen carries a lower risk of GI
serial 7s and could not recall 3 objects. complications than NSAIDs.54-56 It should be
No visual or hearing changes, normal gait and balance. considered early in the management of OA pain
No cardiac, peripheral vascular, or pulmonary problems. because of its safety profile at daily doses not
exceeding 4 g (avoid in patients with chronic
Kyphosis of the spine, but no localized tenderness or tender points. alcohol abuse and use with caution in patients
Limited ROM in the spine and joints, but no erythema or swelling. with liver disease). Recent data suggests elevated
alanine aminotransferase levels in healthy adults
Description of Pain
receiving 4 g daily, but the transient elevations
Dull and constant, with sharp exacerbations in the low back, knees, and hips with usually resolve with continued acetaminophen
walking, bending, or prolonged standing. treatment, and are not accompanied by signs of
No radicular complaints, burning, paresthesias, loss of grip strength, or loss of liver injury.57;58
bowel or bladder control. Findings are suggestive of nociceptive pain due to
moderate to advanced OA without a neuropathic component.
Consider a physical activity program for all older
What Next?
patients that includes exercises to reduce
Discontinue NSAIDs. stiffness and improve flexibility, ROM, strength,
Initiate acetaminophen 1 g q6h. and endurance.54
Recommend arthroswim through the Arthritis Foundation Aquatic Program.
Interim Call
Family members can be a therapeutic ally when
Mr As wife is worried about the patient lying around the house doing nothing. managing a patient on opioid therapy. They can also
You ask her to accompany Mr A on his visit that week. be part of the problem, so it is important to obtain
collateral information from them. This includes
Six Days Later talking with family members to determine their
Mr A keeps his appointment but complains that his pain is out of control concerns and whether or not they are onboard with
and that he needs more medication. The patches dont stay on. the treatment plan, and documenting this discussion.
His wife reiterates that he lies around all day, is not bathing, and it appears
to be because his pain is uncontrolled. She is eager for her husband to
improve his function. Many PCPs will want to refer the patient at this
Prescribe SR morphine q24h 30 mg, 7 tablets. point, although it is still appropriate for physicians
who are confident and experienced in managing
Seven Days Later such patients to continue doing so.
The psychiatrist diagnoses Mr A as depressed and initiates fluoxetine.
He is unable to make a determination about his pain or addiction.
Mr A comes in looking disheveledhe states that he lost his morphine It is a week until Mr As psychiatry referral. The
the previous day. fentanyl may not be working for a number of reasons
His wife states that his function has not improved. and Mr A may be exhibiting pseudoaddiction. You
switch to SR morphine, but do not provide any
Another urine sample is sent to the laboratory for testing.
short-acting agents for BTP as you do not want to
The results 24 hours later reveal hydrocodone, marijuana, and morphine. reinforce his maladaptive opioid use.
What Next?
Explain that because opioids are clearly not improving his function
He appears to show signs of withdrawal. You
you will not continue to prescribe them, at least until his referral
counsel Mr A to refrain from use of illicit drugs
to the pain specialist in 10 weeks. Mr A is angry, but you reiterate and encourage him to participate in a substance
that the opioid therapy is harmful to him. abuse program, which he is reluctant to do.
Refer Mr A to a substance abuse specialist and prescribe clonidine to
treat withdrawal.
You arrange for Mr A to attend a weekly physical rehabilitation program. This is a difficult patient to manage. When a
Further explain that you will see him every week to support him patient displays consistent aberrant drug-taking
through this time. He agrees to come to the office the following week, behavior, it may be necessary to refuse to
prescribe opioidsthey are not appropriate for all
and continues to do so.
patients with pain. Consider prescribing them
Twelve Weeks Later again in comanagement with a pain specialist.
The pain physician tries an epidural steroid injection, with little success.
No other evaluation or treatments were offered. A pain psychologist can help patients to make
You refer the patient to a pain psychologist for weekly visits and changes in their lifestyle and derive a sense of
continue to see him every 2 weeks. acceptance, including the limitations of what can
be expected from analgesics.
Outcome
The pain psychologist recommends you initiate a regimen of SR morphine
q24h 30 mg, 7 tablets weekly, to be doled out daily by Mr As wife. The patients wife accompanied her husband to
The patient achieves some relief from this regimen and continues to some sessions with the psychologist and is eager
to see Mr A continue to improve his function.
work with the psychologist.
Conclusion
Chronic pain is a common presenting complaint in many
practice settings and has substantial effects on patients QOL Estimated time to complete this
and ability to work. Opioid analgesics may be required to activity: 1.5 hours
relieve moderate to severe pain and it is therefore important
for physicians to identify when opioids might be useful, by
Release date: June 2007
careful patient assessment, selection, and monitoring, and to Expiration date: June 2009
understand the principles of prescribing opioids. At the same
Instructions to obtain CME credit:
time, it is just as essential that physicians are able to identify Read the monograph.
patients for whom opioid analgesia may create more harm Visit www.unmc.edu/dept/cce/opioid_
than not using this treatment option. Physicians should be criticalthinking.htm to complete the
prepared to develop an exit strategy for such patients posttest and evaluation.
already being treated with opioids, and to formulate a plan to Pass the posttest and print your certificate.
manage and support these patients with other pharmacologic
and nonpharmacologic modalities.
C R I T I C A L T H I N K I N G TO BA L A N C E B E N E F I T S & R I S K
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