Opioid Analgesics for Pain Management · PDF fileOpioid Analgesics for Pain Management: Critical Thinking to Balance Benefits & Risk Release date: June 2007 Expiration date: June 2009

Opioid Analgesics for Pain Management:Critical Thinking to Balance Benefits & Risk

Release date: June 2007

Expiration date: June 2009

Target audience: Primary care physicians

This program is sponsored by the University of Nebraska Medical Center, Center for Continuing Education.

Supported by an unrestricted educational grantfrom Endo Pharmaceuticals.

Faculty

Bill H. McCarberg, MD (Chair) Perry G. Fine, MD Steven D. Passik, PhD

Kaiser Permanente University of Utah Memorial Sloan-Kettering Cancer CenterEscondido, CA Salt Lake City, UT New York, NY

Gavril Pasternak, MD, PhD Raymond S. Sinatra, MD, PhD

Memorial Sloan-Kettering Cancer Center Yale University School of MedicineNew York, NY New Haven, CT

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 MedicalEducation 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 AMAPRA 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 Speaker’s 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 Speaker’s 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 Speaker’s Bureau for Adolor Corporation, Cephalon, Endo Pharmaceuticals, EpiCept, J&J, LimerickNeurosciences, 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 whenpossible.(B)

B. There is evidence of types II, III, or IV, andfindings are generally consistent.

www.guideline.gov/summary/summary.aspx?doc_id=3691

Opioid analgesic drugs may help relieve moderate to severe pain,especially nociceptive pain. Opioids for episodic (noncontinuous) painshould be prescribed as needed, rather than around the clock. Long-actingor sustained-release analgesic preparations should be used for continuouspain. Breakthrough pain should be identified and treated by the use offast-onset, short-acting preparations.(IA)

Level I: Evidence from at least one properlyrandomized, controlled trial.A. Good evidence to support the use of arecommendation; clinicians “should do this all thetime.”


Patients taking analgesic medications should be monitored closely.Patients should be reevaluated frequently for drug efficacy and sideeffects during initiation, titration, or any change in dose of analgesicmedications.(IA)

Level I: Evidence from at least one properlyrandomized, controlled trial.A. Good evidence to support the use of a recom-mendation; clinicians “should do this all the time.”


The clinician should watch for signs of opioid use for inappropriateindications (eg, anxiety, depression, grief, loss). Requests for early refillsshould include evaluation of tolerance, progressive disease, inappropriatebehavior, or drug diversion by others.(IIIA)

Level III: Evidence from respected authorities, basedon clinical experience, descriptive studies, or reportsof expert committees.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 beprevented. Assessment of bowel function should be part of the initialassessment and of every follow-up visit for all patients receivinganalgesics. A prophylactic bowel regimen should be initiated with thecommencement of persistent opioid therapy.(IA)



Fixed-dose combinations of opioid with acetaminophen or NSAIDs maybe useful for mild to moderate pain. The maximum recommended doseshould not be exceeded, to minimize acetaminophen or NSAID toxicity. Ifa maximum safe (nontoxic) dose is reached without sufficient pain reliefbecause of limits imposed by the maximum safe acetaminophen or NSAIDdose, switching to noncombination preparations is recommended.(IA)



C R I T I C A L T H I N K I N G TO B A L A N C E B E N E F I T S & R I S K 1

IntroductionChronic pain in America remains a prevalent, challenging, andexpensive problem.1 A recent national telephone survey foundthat more than half of Americans live with chronic or recurrentpain.2 However, while 63% of Americans report having soughtmedical help for pain, fewer than half report that they have “alot” of control over their pain, and fewer than one third hadcomplete or a great deal of pain relief.2;3 The impact of pain issubstantial, with 4 in 10 Americans reporting that paininterferes with their enjoyment of life, mood, sleep, andactivities.2 In addition to affecting quality of life (QOL), pain alsointerferes with ability to work. The American Productivity Auditof more than 28,000 US workers found that lost productivetime resulting from pain conditions costs employers $61.2billion each year.4

It is not surprising that pain is among the most commonreasons for office visits, and that nonsteroidal anti-inflammatorydrugs (NSAIDs), opioids, and nonopioid analgesics are amongthe most frequently prescribed therapeutic classes.5 Whentreating patients whose pain is not adequately managed withnonopioids, it is important that primary care physicians (PCPs)have sufficient knowledge of the pharmacology of opioids inorder to prescribe them in a fashion that maximizes benefitsand minimizes risk to patients.

Principles of Prescribing

Opioid AnalgesicsWhen opioids are indicated for pain conditions not effectivelymanaged by nonopioids, selecting an agent requires dueconsideration of a number of factors. The selection is based onthe severity and pattern of pain; the patient’s age, medicalcomorbidities, and prior opioid exposure and experience(including efficacy and adverse effects); drug-specificdifferences; available formulations; cost; and personalexperience.6 The availability of long-acting opioids has increasedfocus on the role of dosing intervals as a consideration in opioidtherapy.7 Most short-acting opioids require a dosing interval of 4 to 6 hours; however, these may be favored initially becausethey are easier to titrate than long-acting opioids.

Although there is no evidence for the efficacy of one mu-opioidagonist over another in populations, individual patients maydisplay a much better response to one drug over another, whichis why consideration should be given to agents that the patienthas found helpful in the past. A number of explanations for thisinterindividual response to opioids have been proposed.

Multiple ReceptorsThe 3 major opioid receptor families are mu, kappa, and delta.8

The primary site of action of most clinically used opioid

ContentsIntroduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .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

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 AG E M E N T2

analgesics is the mu-opioid receptor,9;10 which is expressed at aspinal level in the dorsal horn and in multiple regions withinthe brain.10 The interindividual variability in response to mu-opioid analgesics can be explained in part by multiple mu-opioid receptors—splice variants—with different mechanismsof action and different distributions within a cell, regionallywithin the nervous system (brain and spinal cord), and in theperipheral nervous system.8;9;11

PharmacogeneticsThe observed interindividual variability in response to opioidsmay be due in part to genetic polymorphisms.10 Studies haveidentified significant differences in the genotype of patients whorequired switching to alternative opioids compared with patientswho responded to morphine.10 Response to an opioid dependson a number of factors, including drug absorption, distribution,metabolism, and elimination.10 Therefore a patient’s response toa particular opioid is potentially influenced by genetic variation inthe alleles of several candidate genes.10;12 An example is thevariable response to codeine in individuals with a polymorphismof the cytochrome P450 (CYP450) 2D6 gene, which preventsmetabolism of the prodrug codeine to the active drugmorphine.7;10 Up to 10% of people will have a poor analgesicresponse to codeine because they lack normal CYP2D6activity.13 Morphine, although active alone, is also metabolized to a very active metabolite, morphine-6-glucuronide (MG6),chiefly through conjugation by uridine diphosphate glucuronyltransferase (UGT) enzymes.13;14 It has not yet been determined if polymorphisms in genes controlling the metabolism ofmorphine explain interindividual variability in response tomorphine, but this may be related to patient characteristics such as age and renal and hepatic function.10;15;16 In manypatients with renal failure, accumulation of the pharmacologicallyactive morphine metabolite MG6 may cause toxicity.15;17

Drug InteractionsMost opioids are metabolized through the liver microsomalCYP450 system, which is responsible for the metabolism of awide variety of drugs.7 Codeine, hydrocodone, methadone,oxycodone, and tramadol are chiefly metabolized throughoxidative reactions by CYP2D6, while fentanyl, meperidine,and buprenorphine are metabolized by CYP3A4.7 Concomitanttreatment with drugs that inhibit or induce CYP450 enzymescan alter the levels of these opioids and their metabolites;this may change their analgesic or side-effect profile andcause possible opioid overdose or acute withdrawal.7;13;14

Morphine, hydromorphone, and oxymorphone are metabolizedchiefly through conjugation reactions with UGT enzymes.13;14

Because they are not oxidatively metabolized by CYP450enzymes, inhibition/induction or genetic polymorphisms ofCYP450 enzymes should have little to no effect on themetabolism and clearance of these drugs.14

Short-Acting OpioidsShort-acting opioids are available as single-entity agents or incombination with a nonopioid with a complementarymechanism of action (NSAIDs or acetaminophen). If pain ispresent for only a few brief periods during the day, patientsmay take an as-needed dose of a short-acting mu opioid.18 Forpersistent pain, a long-acting agent is recommended to controlbaseline pain around the clock and avoid breakthrough pain(BTP). But in most cases, a short-acting opioid is used to

initiate and titrate around-the-clock therapy and, if necessary,as-needed dosing can be added to regular dosing in order tocontrol or avoid BTP.

When initiating an opioid trial in an opioid-naïve patient, thedose should be individualized to the patient by starting at thelowest likely effective dose, which should be increasedincrementally, with both the size of the increment and theinterval between increments influenced by the degree of painrelief, functional improvements, and side effects experiencedby the patient.7;11;18 Starting doses for common oral short-actingopioids to treat moderate to severe pain in opioid-naïve adultsare shown in TABLE 1.6 A dose increment of 30% to 50% issafe and usually large enough to observe a meaningfulchange in analgesia.7 If pain is severe and the patient is notpredisposed to opioid toxicity, a higher increment—up to100% of the existing dose—may be considered.7 Inambulatory care, an additional consideration with regard todose titration is the availability of an individual at home withthe patient who is a reliable observer for potential adverseeffects. An alternative approach in patients who receiveadditional as-needed opioids for BTP is to sum the amount ofsupplemental drug used per day during the previous few daysand convert it into the fixed-schedule administration.7

There is no predictable maximal therapeutic dose (“ceilingeffect”) for analgesia with single-entity opioid agonists, butdose-limiting adverse effects can occur.11;18 In contrast, thedoses of opioids marketed in combination with a nonopioidare limited by the maximum dose of the nonopioid (eg,acetaminophen dose limit: 4 g per day in patients withoutcompromised liver function or without a history of alcoholism).18

If significant adverse events occur before adequate analgesiais achieved, the dose may be reduced and the events shouldbe treated. After a stable dose is achieved with a short-actingopioid, it may be converted to a long-acting opioid, for example,if there is a desire for a simplified regimen to optimizeadherence, among other possible reasons.

Long-Acting OpioidsLong-acting opioids administered around the clock to treatpersistent baseline pain can be given along with additional as-needed doses of short-acting opioids for exacerbations of pain(ie, BTP), to permit activity such as physical therapy, and for

TABLE 1 Commonly Used Oral Short-Acting Opioids

Starting oral dose* in opioid-naïve Name adults with moderate to severe pain

lower range: higher range: unmonitored outpatients monitored setting

Codeine 30-60 mg q3-4h

Hydrocodone 5-10 mg q3-4h

Hydromorphone 4-8 mg q3-4h

Morphine 15-30 mg q3-4h

Oxycodone 10-30 mg q4h

Oxymorphone †10-20 mg q4-6h

Tramadol 50-100 mg q6h

*Reduce initial dose by up to 50% in frail, older patients and titrate upward basedon therapeutic response and undesirable side effects; †If deemed necessary toinitiate therapy at a lower dose, patients may be started with 5 mg oxymorphone.Adapted from: American Pain Society. Guideline for the Management of CancerPain in Adults and Children. Clinical Practice Guideline No. 3. Glenview, IL:American Pain Society; 2005.


incident pain.11;18;19 Although many PCPs have not adopted thepractice of using long-acting opioids for indications other thancancer pain, there are significant benefits from using these agentsfor long-term pain, including improved control of baseline painand the need for smaller quantities of pills. The most commonlyused long-acting opioids are sustained-release (SR) preparationsof short-acting opioids. Some SR opioids can be initiated in opioid-naïve patients, although not all have been systematically evaluatedas an initial agent, and most experts would recommend startinga short-acting agent before using a long-acting agent (TABLE 2).Once initiated, the long-acting opioid dose can also be titratedby incorporating the as-needed short-acting doses into the dailylong-acting dose. Patients should be advised to swallow SR oralopioid formulations whole, and not to break, crush, or chewtablets in order to prevent the rapid release of potentiallydangerous opioid levels (refer to prescribing information forindividual agents). Some formulations also have warningsregarding use with alcohol that can cause “dumping” of theopioid content all at once, rather than in a sustained fashion.

Managing Adverse EffectsTreatment of opioid-induced side effects is integral to opioid painmanagement. A number of adverse effects are associated withthe use of opioid analgesics. The most common are opioid-induced bowel dysfunction (constipation), sedation, nausea andvomiting, pruritus, sweating, dry mouth, and weakness.11;18;20;21

Other adverse effects include respiratory depression, urinaryretention, confusion, hallucinations, nightmares, myoclonus,dizziness, dysphoria, and the very rare hypersensitivity reactionof anaphylaxis. With the exception of bowel dysfunction,tolerance often develops rapidly to some of the common opioid-related side effects, such as nausea and vomiting. Therefore,

routine prophylactic administration of an antiemetic agent is nottypically indicated, except in patients with a history of severeopioid-induced nausea.7;11;19 Opioid-induced bowel dysfunctionshould be anticipated and treated prophylactically with astimulating laxative to increase bowel motility, with or withoutstool softeners as indicated by stool consistency.11;18;19

Nonpharmacologic approaches for all patients include:7

■ Increase fluid intake as tolerated.■ Increase dietary fiber as tolerated (unless patient is severely

debilitated or bowel obstruction is suspected).■ Encourage mobility and ambulation if appropriate.■ Ensure comfort and privacy for defecation.■ Encourage bowel movements at the same time each day.■ Rule out or treat impaction.

TABLE 3 shows examples of the pharmacologic managementof common opioid-induced adverse effects.7 In some patientswho poorly tolerate one opioid, it may be necessary to changeto a different opioid.18

Incomplete Cross-TolerancePatients often exhibit limited cross-tolerance when one opioidis substituted for another, which might reflect their differingselectivities for the mu-opioid receptor subtypes (mu-opioidreceptor splice variants).22;23 Clinicians have long made use ofthe incomplete cross-tolerance among mu-opioid analgesics byusing the concept of opioid rotation, in which highly tolerantpatients are rotated to a different drug to regain analgesicsensitivity.8;22 Incomplete cross-tolerance among opioids affectsthe conversion from one opioid to another.9 When switchingbetween opioids in an opioid-tolerant patient, it is recommendedto calculate the equianalgesic dose based on the predicted

TABLE 2 Long-Acting Opioids

Opioid Administration Starting dose* in opioid-naïve patients Notes

Fentanyl

Duragesic® q72h For use only in opioid-tolerant patients —

Methadone: Use not recommended without significant expertise. Repeated administration at short intervals may lead toaccumulation in plasma and delayed adverse effects because the prolonged half-life is greater than the duration of analgesia.

Morphine

Avinza® q24h 30 mg q24h; adjust in increments not 60, 90, and 120 mg capsules aregreater than 30 mg every 4 days for use only in opioid-tolerant patients

Kadian® q12 or q24h No systematic evaluation† Patients who do not have a proven toleranceto opioids should initially receive only the 20 mg strength, and the dosage usuallyshould be increased at a rate not greaterthan 20 mg q48h

MS Contin® q12h No systematic evaluation† 200 mg tablets for use only inopioid-tolerant patients

Oramorph SR® q12h No systematic evaluation† —

Oxycodone

OxyContin® q12h 10 mg q12h; except for the increase from 80 and 160 mg tablets for use only10 mg to 20 mg q12h, the total daily in opioid-tolerant patients oxycodone dose usually can be increased by 25% to 50% of the current dose ateach increase

Oxymorphone

Opana ER® q12h 5 mg q12h; it is recommended that the —dose be individually titrated, preferably atincrements of 5-10 mg q12h every 3-7 days

*Individualize dose for each patient; †Not approved for initiation of therapy—advisable to begin treatment with immediate-release opioid.


equivalent dose in conversion tables, which were determined by relative potency studies in opioid-naïve patients, and then cutthe calculated dose by at least 50% in order to account forincomplete cross-tolerance.9;22 Using this method, shortfalls inefficacy for the sake of safety can be compensated for in theshort term by using immediate-release (IR) opioid (“rescue”)doses, with corrections in around-the-clock dosing determinedafter steady state is achieved with the new drug, which requires3- to 5-times the half-life of the drug.

Patient Selection for Long-Term Opioid TherapyMost patients with pain do not need opioids, but such therapymay be required to effectively control moderate to severepain.24;25 However, recent reports suggest that certainpopulations receiving long-term opioid therapy are particularlyat risk for poor outcomes.26;27 It is certainly true that poorpatient selection for opioid therapy, opioid monotherapy in theabsence of comprehensive management, and inadequatefollow-up of patients can be detrimental to patients. At thesame time, most PCPs have some experience of treatingpatients for whom opioid therapy is appropriate and effective,with good long-term outcomes. Because the potential long-term benefits of chronic opioid therapy can be contentious,careful patient selection, comprehensive management, andappropriate follow-up are crucial.

Opioids alone are not the optimal therapy, but when used inconjunction with nonopioid analgesics, such as an NSAID oradjuvant, and psychologic and physical approaches, they canhelp to maximize patient outcomes.18;28 For certain populations,such as chronic low back pain and headache patients, andthose with a personal or family history of substance abuse,some PCPs may decline to prescribe opioids or defer initiating

opioid therapy until specialist evaluation and support isobtained. When opioid treatment is warranted, a treatment planshould state objectives that will be used to determinetreatment success, such as pain relief, improved physical andpsychosocial function, manageable side effects, and drug-takingthat follows the rules of appropriate behavior.

Assessing PainSelecting patients for long-term opioid analgesic therapyrequires a comprehensive assessment of pain, includingobtaining, evaluating, and documenting a thorough medicalhistory and physical examination, as well as patient and diseasecharacteristics.7;25;29 Because pain is inherently subjective, patientself-report is the “gold standard” for assessment.7 Painassessment should focus on the type and quality of pain,source, intensity, location, duration/time course, associatedfactors that exacerbate or relieve pain, pain affect, and effects onlifestyle and functional status.7;29 Numerous tools are available tomeasure pain intensity, such as the numerical rating scale, theverbal rating scale, visual analog scales, and the faces of painscale.29 These tools are simple to use and sensitive enough todetect changes that occur during pain treatment.

As well as the nociceptive input, pain can also be composed ofpsychologic and emotional overlays, such as anxiety, depression,and fear. Analgesics such as opioids, however, are only effectivein reducing pain intensity, and will not address other aspects ofpatients’ pain experiences. If the PCP suspects these conditionsare present, it is important to assess and address these domainsat the same time as the nociceptive pain. This may be necessaryat the initial visit, or there may be no indications of a problemuntil a subsequent visit or, for example, after an early refillrequest. Several short, accurate, and easy-to-use instruments todetect depression are available (eg, Beck Depression Inventory,

TABLE 3 Pharmacologic Interventions for Opioid Adverse Effects

Adverse effects Examples of pharmacologic interventions

Opioid-induced bowel dysfunction*

Intermittent use (q2-3d) of osmotic laxative Magnesium hydroxide, magnesium citrate, sodium phosphateTrial of daily softening agent alone Sodium docusateIntermittent use (q2-3d) of contact cathartic Senna, bisacodylDaily use of cathartic preparation (± softening agent) Senna, bisacodylDaily use of lactulose or sorbitalDaily use of polyethylene glycolNausea and vomiting

Neuroleptics Prochlorperazine, chlorpromazine, haloperidolAnticholinergic drugs ScopolamineAntihistamines Promethazine, meclizine, diphenhydramine, dimenhydrinate,

hydroxyzine, trimethobenzamideProkinetic drugs MetoclopramideCorticosteroids DexamethasoneBenzodiazepines LorazepamCannabinoids Dronabinol5-HT3 receptor antagonists Ondansetron, granisetron, dolasetronSomnolence and cognitive impairment

Psychostimulants Methylphenidate, dextroamphetamine, modafinilMyoclonus†

Low-dose benzodiazepines ClonazepamAnticonvulsantsBaclofenPruritus

Antihistamines Diphenhydramine, hydroxyzineSedative hypnotics LorazepamSelective serotonin reuptake inhibitors Paroxetine

*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.


Zung Self-Depression Scale).30 Brief instruments, includingasking the patient 2 questions about the presence of depressedmood and anhedonia (“Over the past 2 weeks, have you feltdown, depressed, or hopeless?” and “Over the past 2 weeks,have you felt little interest or pleasure in doing things?”), appearto perform as well as longer instruments.30

Information about medical and surgical conditions, history ofchronic pain, and previous pain treatments is also important.7

Identifying the etiology, syndrome, or pathophysiology of pain can help guide the selection of treatment and suggest the prognosis.7

Assessing RiskThe potential for misuse, abuse, and addiction should beaddressed when considering long-term opioid analgesictreatment. Assessing risk is not intended to deny high-riskpatients treatment for their pain, but rather to match thedegree of clinical monitoring and controls to the degree of riskin order to achieve better clinical outcomes and minimizemisuse. There are many ways to assess risk, including apsychiatric interview and the use of one or more of anincreasing number of screening tools (eg, Opioid Risk Tool[ORT], Screener and Opioid Assessment for Patients with Pain[SOAPP], DIRE score).31-33 Such tools should be used byclinicians, for example, when considering initiating opioidanalgesic therapy for a chronic pain problem or for a patientbeing treated with opioids for an acute pain problem that isbecoming chronic and long-term opioid therapy is an option. A patient who displays an aberrant drug-related behavior thatraises concern (eg, requests an early opioid refill) or does notseem to be doing well requires attention, such as asking him or her to come in to complete a screening tool for addiction,social problems, or other psychologic distress, rather thanautomatically writing a refill.

Informed ConsentIt is an ethical and often regulatory duty to describe in under-standable terms the risks and benefits of the use of long-termopioid analgesic therapy with the patient or persons designatedby the patient.25 The physician can consider the use of a writtenagreement outlining the treatment plan, expectations, and theresponsibilities of the patient and physician.25;34 Althoughphysicians often feel uncomfortable asking patients to sign anagreement, a signed plan of care is particularly important if thepatient is at high risk for medication abuse, and may be requiredin some states.25;34 It is also important to outline the proceduresor actions that will be taken should problems arise and thepatient does not adhere to the terms of the agreement.34 Asample opioid treatment agreement is available at theAmerican Academy of Pain Medicine Website: www.painmed.org/productpub/statements/pdfs/controlled_substances_sample_agrmt.pdf. Clinicians should take care to follow theguidelines in the written agreements that they utilize or theyrisk exposing themselves to potential liability.34 They shouldadapt an agreement so that the language provides flexibilityfor them to make clinical decisions when managing patients(eg,“Early refills will generally not be given”).

Individualized TherapyClinical treatment of pain with opioids requires individualizationof therapy, due to variability in efficacy, side effects, toleranceprofiles, and risk of drug abuse among patients.8;9;12;35 Somepatients may respond far better to one mu opioid than to

another with respect to both analgesia and side effects.8;9;15

For example, patients unable to tolerate morphine due tosevere nausea/vomiting may be able to take another muagonist without a problem.8;10 Patients also vary in their sensitivityto a specific opioid, with some needing higher or lower dosesto achieve optimal analgesia.9 At present, it cannot bepredicted which patients are likely to achieve adequateanalgesia or develop intolerable adverse effects from a givenopioid, and in clinical practice, therapy often needs to beswitched from one opioid to another to identify the mosteffective.9;10 The availability of a wide variety of opioids allowsclinicians to better match the drug to the patient.35 Increasedoptions become available when novel opioid analgesicmolecules are developed and when existing drugs arereformulated into different delivery systems (eg, transdermaldelivery system, SR oral tablet) or have a different mode ofadministration (eg, patient-controlled analgesia, computer-assisted delivery).35

Periodic ReviewPatients should be monitored regularly to assess their responseto therapy, to identify and manage side effects, and to identifyand manage aberrant drug-related behavior. The frequency offollow-up should be as often as clinically necessary and incompliance with state regulations, where present. Continuationor modification of controlled substances for pain managementtherapy depends on the evaluation of progress towardtreatment objectives. The “Four A’s” of pain medicine will helpto direct therapy and support the pharmacologic options taken(TABLE 4 ).36;37 The “Four A’s” serve as a mnemonic device toremind clinicians that a successful outcome in pain therapyinvolves more than lowering pain scores. Equally importantoutcomes include stabilization or improvement in psychosocialfunctioning and sleep, tolerable side effects, optimization ofphysical functioning, and absence of aberrant behaviors.38

Urine drug testing can be an important tool to assist inmonitoring adherence to a treatment plan when managingpatients receiving opioid therapy.39;40 Controversies existregarding their clinical value, partly because many currentmethods are designed for, or adapted from, forensic or work-place deterrent-based testing for illicit drug use.40;41 As a result,they are not necessarily optimized for clinical applications wherea number of licit prescription drugs must also be included.40

However, when used with an appropriate level of understanding,urine drug testing can improve a physician’s ability to managetherapy with opioids and identify substance misuse.39;40

As more PCPs prescribe opioid analgesics for the management of chronic moderate to severe pain, the questions of how tomonitor adherence to the therapeutic regimen and when torefer a patient for additional evaluation and treatment in order toachieve treatment objectives have become important issues.25;42

TABLE 4 The “Four A’s” of Pain Medicine36;37

Analgesia (meaningful pain relief)

Activities of daily living (stabilization & improvement in psychosocialfunction & specifically identified functional [physical activity] goals)

Adverse effects (side effects)

Aberrant drug-related behaviors (adherence to plan of care &addiction-related outcomes)


In general, referral to a pain specialist or pain center isappropriate when the clinician has exceeded his or her expertise in any specific area of opioid-related painmanagement. Reasons may include the dose of opioidsprescribed, the patient’s inability to adhere to the prescribedregimen, an inability to achieve adequate pain control despiteincreasing the dose or switching to different opioids,unresolved troublesome side effects, or unresolved issues ofsubstance misuse.42 Special attention should be given topatients who are at high risk for medication misuse, abuse, or diversion, and especially those with a known history of drug addiction.

Differentiating Aberrant Drug-Related BehaviorsNo behavior is absolutely predictive of addictive disease, andthese behaviors exist along a continuum, with certain behaviorsbeing less problematic and others being more so (TABLE 5).43

There are multiple explanations in the differential diagnosis ofaberrant drug-related behaviors, with criminal intent anddiversion being only one possibility.38;44 Other explanations fornonadherent behavior include untreated pain, psychologicdistress, and addiction.45 It is important that clinicians candistinguish between physical dependence, addiction, andtolerance (TABLE 6), so that they do not incorrectly assumethat a patient is addicted.

Aberrant behaviors are not to be ignored, but do not meanthat prescribing should be immediately discontinued.Clinicians should proceed with caution, set limits, bethoughtful, and react therapeutically.45 The syndrome of drug-seeking behaviors that arises when a patient cannot obtainadequate relief with the prescribed dose of analgesic andseeks alternate sources or increased doses of analgesic isreferred to as pseudoaddiction.43;46;47 This may be the result ofincreasing pain due to disease progression, development of a

new condition, or inadequate instruction or dose provision bythe clinician.

Psychiatric factors, such as anxiety or depression, apersonality disorder, or changes in cognitive state, such asmild encephalopathy due to the treatment regimen of medicalcomorbidities or underlying psychiatric problems, may beresponsible for the behaviors identified.43;48 The pain patientwho escalates his or her opioid dose to self-medicate untreatedanxiety, depression, or insomnia bears resemblance to addictionwith regard to how the drug and drug procurement becomesa central part of the patient’s life.38 Such patients who usechemicals to cope with adverse life situations (also known as“chemical copers”) need structure, psychiatric input, and drugtreatments that decentralize the pain medication to theircoping and prevent maladaptive opioid analgesic use.

Changing Course: Discontinuing Opioid Therapy(“Exit Strategy”)Long-term opioid therapy may need to be discontinued for anumber of reasons, including when opioids are no longereffective for pain or to improve function, when unacceptableside effects or toxicity occur, or when patients violate theopioid treatment agreement or display certain aberrant drug-related behaviors.50 When it is necessary to discontinuetreatment, withdrawal symptoms can usually be avoided by useof a slow opioid tapering schedule (reducing the dose by 10%to 20% each day or more slowly if symptoms occur).18 Anxiety,tachycardia, sweating, and other autonomic symptoms thatpersist may be lessened by slowing the taper or using clonidineat an oral dose of 0.1 to 0.2 mg/day. The use of buprenorphinefor both pain and opioid dependence in the primary care officeis increasingly common, but requires certification under theDrug Addiction Treatment Act of 2000.51

TABLE 5 Examples of Aberrant Drug-Related Behaviors43

Less indicative of addiction More indicative of addiction

Drug hoarding during periods of reduced symptoms Prescription forgery

Acquisition of similar drugs from other medical sources Concurrent abuse of related illicit drugs

Aggressive complaining about the need for higher doses Recurrent prescription losses

Unapproved use of the drug to treat another symptom Selling prescription drugs

Unsanctioned dose escalation 1 or 2 times Multiple unsanctioned dose escalations

Reporting psychic effects not intended by the clinician Stealing or borrowing another patient’s drugs

Requesting specific drugs Obtaining prescription drugs from nonmedical sources

TABLE 6 Definitions of Addiction, Physical Dependence, Tolerance, and Pseudoaddiction47;49

Addiction: A primary, chronic, neurobiologic disease, with genetic, psychosocial, and environmental factors influencing its developmentand 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 byabrupt 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 drug’seffects over time.

Pseudoaddiction: An iatrogenic syndrome of behaviors developing in direct consequence of inadequate pain management. The naturalhistory of pseudoaddiction is a progression through 3 characteristic phases including: (1) inadequate prescription of analgesics to meetthe primary pain stimulus; (2) escalation of analgesic demands by the patient associated with behavioral changes to convince others ofthe pain’s severity; and (3) a crisis of mistrust between the patient and the health care team.


Case StudiesThe following case studies illustrate the application of the principles of prescribing opioids for pain management, ranging from asimple acute case through to more complex patients with chronic pain and psychologic dysfunction. Although there is no question thatphysicians should seek consultation when needed, such a requirement is not necessary for every case, especially if the practitioner isknowledgeable about pain management.52 PCPs have varying levels of comfort, knowledge, and experience in the treatment of chronicpain, 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.

The Case of Mr K: A 25-Year-Old Man With Acute Ankle SprainMr K, a 25-year-old male patient of yours for 6 years, presents in significant pain with a traumatic acute ankle sprain that occurred whileplaying recreational tennis 2 days ago. Since the injury, he has been taking NSAIDs regularly, rested and kept the foot elevated whenpossible, and used ice to reduce the swelling. He has missed 2 days of work as an architect and is anxious to return as soon as possible.

History■ No prior history of ankle pain or any chronic musculoskeletal problems, apart

from a broken wrist several years ago.■ He is otherwise healthy and is taking no medication other than the NSAID.

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.■ Findings suggest a second-degree sprain.

What Next? ■ Continue ice and elevation, but add gradual motion and motility with use of an

ankle support. Achilles tendon stretching should begin 48 to 72 hours after ankleinjury since tissues contract after trauma with immobility.

■ Hydrocodone/acetaminophen 5 mg/500 mg 20 tablets, q4-6h.

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.

The Case of Mrs T: A 60-Year-Old Woman With Osteoarthritis of the KneesMrs T is a 60-year-old woman with osteoarthritis (OA) who has been your patient for many years. She has progressivelyincreasing pain in her knees, rated at 7/10 with activity, for which she currently takes around-the-clock naproxen andacetaminophen. She has been at the maximum acetaminophen and NSAID doses for 7 months, and although initially alleviatingher symptoms, this regimen no longer controls her pain with activity, and she feels restricted in what she is able to do.

Past Medical History■ Mrs T had an acute myocardial infarction (MI) 2 years ago, following which she

experienced major depression, which was treated to remission with fluoxetine.■ Hysterectomy 3 years ago.■ A 5-year history of OA of the knee. You previously recommended weight reduction and

physical exercise, which she complied with (losing 5 Ibs), but she is finding it difficult tocomplete her exercise regimen (45 minutes cardio and strength training, 4 times a week).

■ Knee injections by an orthopedic specialist provided only short-term relief.■ No allergies.

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.

You opt for a short course of a short-acting (ie, IR) opioid to treat his moderate to severe pain not controlled by the NSAID alone, so that he can increase his activity and beginrehabilitation.53 Options include hydrocodone,oxycodone, and tramadol. Mr K related thathydrocodone relieved his pain following a wristfracture several years ago.

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 comprehensivemedical 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.■ She is fully cooperative with the history and physical examination. ■ Pain with limited range of motion (ROM) in both knees.

What Next? ■ Discontinue naproxen.■ Initiate IR tramadol at 25 mg/day qAM, titrate in 25 mg increments as separate

doses every 3 days to reach 100 mg/day (25 mg q6h), and increase by 50 mgevery 3 days to reach 200 mg/day (50 mg q6h).

One Week Later■ Pain control is good, but to provide a more convenient regimen you switch Mrs T

to SR tramadol, 200 mg q24h.

Interim Phone Call■ Pain control and function are good.■ Mrs T is experiencing tremors and has become hypertensive.■ Initiate SR oxymorphone 5 mg q12h, with instructions to increase the dose to

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

oxymorphone.■ Prescribe a stimulating laxative to prevent constipation.

Interim Phone Call■ Pain was well controlled with oxymorphone 10 mg q12h—she used 1 IR

oxymorphone 5 mg tablet about an hour prior to going to the gym 4 days a week,and occasionally if her pain was exacerbated (2 to 3 times a week).

■ Bowel function is normal.

Two Months Later■ Mrs T is doing well on her current regimen (SR oxymorphone 10 mg q12h with

IR oxymorphone 5 mg [30 tablets/month]). She is not experiencing adverse effects and is able to work and to exercise.

■ Continue her regimen and schedule a follow-up appointment for 2 months.

The Case of Mrs J: An 82-Year-Old Woman With OsteoarthritisPain from OA has been present in Mrs J’s hips, knees, ankles, and shoulders for more than 10 years, for which occasional useof NSAIDs (ibuprofen, naproxen) had been sufficient. However, her pain intensity with activity is now 6/10, and she experiencesincreasing dyspepsia with NSAID use.

Past Medical History■ Osteoporosis with degenerative disk disease (no vertebral fractures).■ Type 2 diabetes mellitus managed with diet alone.■ Hysterectomy for fibroids.■ Mild dementia from Alzheimer’s disease.

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.”


Any continuous NSAID use poses some degreeof gastrointestinal (GI), cardiovascular, and renalrisks. Mrs T is an elderly woman with a personaland family history of MI.

You ask her about her prior experience withopioids for pain—morphine prescribed for herpost-hysterectomy was not effective and causeda great deal of nausea and vomiting for the 5 daysthat she had taken it. You select tramadol to addto her current acetaminophen regimen.

This patient is a good candidate for long-acting,around-the-clock analgesia for chronic OA; optionsinclude transdermal fentanyl and SR morphine,oxycodone, oxymorphone, and tramadol. BecauseIR tramadol is providing good pain relief, youconvert her regimen to ER tramadol.

Tremor and hypertension are common sideeffects of tramadol. To avoid these side effects,you switch to another SR opioid.

This case represents shared decision-making over a number of years with an elderly patient who has progressive disease and hercaregiver daughter.


■ Her sister died of uterine cancer.■ Her brother had coronary artery bypass graft surgery at age 57 years and died

of a cerebrovascular accident at age 68 years.

Psychosocial History■ Mrs J graduated from teacher’s college and taught until motherhood.■ Her husband died suddenly 8 years ago of an acute MI and she lives alone on a

fixed income from Supplemental Security Income (SSI) and her husband’s annuity; basic living expenses are covered, but not much is left over.

■ One daughter lives close by and is supportive, and 2 children live out of state. ■ Relies on Medicare supplemental insurance (co-pay: $25 for brand drugs, $10 for generics).■ She does not use alcohol.■ She has no living will or written advanced directives.

Review of Systems■ Progressive short-term memory loss, occasional confusion, and increasing difficulty

with routine tasks.■ No chest pain, dyspnea at rest, melena, or hemoptysis.■ Sleep, mood, and bowel/bladder function unremarkable.

Physical Examination■ Well groomed, in no obvious distress.■ Alert and oriented to time, place, person, and objects, but unable to subtract

“serial 7s” and could not recall 3 objects. ■ No visual or hearing changes, normal gait and balance.■ No cardiac, peripheral vascular, or pulmonary problems. ■ Kyphosis of the spine, but no localized tenderness or tender points. ■ Limited ROM in the spine and joints, but no erythema or swelling.

Description of Pain■ Dull and constant, with sharp exacerbations in the low back, knees, and hips with

walking, bending, or prolonged standing.■ No radicular complaints, burning, paresthesias, loss of grip strength, or loss of

bowel or bladder control. Findings are suggestive of nociceptive pain due to moderate to advanced OA without a neuropathic component.

What Next? ■ Discontinue NSAIDs. ■ Initiate acetaminophen 1 g q6h. ■ Recommend “arthroswim” through the Arthritis Foundation Aquatic Program.

Interim Phone Call■ Pain is 1-2/10 at rest and “tolerable” (3-4/10) with activity.■ Mrs J is reluctant to travel to her YMCA for arthroswim. Warm baths feel good

and help her sleep. You suggest that she exercise when pain and stiffness areminimal (eg, after a warm bath or application of superficial moist heat).59

Two Months Later■ Pain has increased to 8/10 with activity and she has difficulty sleeping:

“I can’t get comfortable.” ■ She is experiencing difficulties with self-care and mood disturbance:

“I don’t care about anything anymore.” ■ Initiate 200 mg celecoxib q24h.

Two Weeks Later■ Pain is improved, with no apparent adverse events, but still keeps her less active

than she would like. ■ Her daughter reports that Mrs J’s mood, sleep, energy, self-care, and general

appearance seem better, but she cringes with activity and pain is “intolerable”when walking.

What Next? ■ Discontinue celecoxib and initiate tramadol 25 mg qAM, increased by 25 mg every

3 days to 100 mg/day (25 mg q6h) and by 50 mg every 3 days to 200 mg/day (50 mg q6h).

■ Convert IR tramadol to SR tramadol 200 mg q24h.

Rather than increase the celecoxib dose to 200 mgbid (because of GI, renal, and cardiovascularrisk), you select opioid therapy. Opioids arerecommended when moderate to severe OA painnot controlled by other treatments affects thepatient’s QOL.29 You select single-entity tramadol,a weak mu-opioid agonist and inhibitor ofserotonin and norepinephrine reuptake, to add toher current acetaminophen as the combinationproduct is more expensive.18

Select celecoxib because of a history of GIintolerance with nonselective NSAIDs.

Acetaminophen carries a lower risk of GIcomplications than NSAIDs.54-56 It should beconsidered early in the management of OA painbecause of its safety profile at daily doses notexceeding 4 g (avoid in patients with chronicalcohol abuse and use with caution in patientswith liver disease). Recent data suggests elevatedalanine aminotransferase levels in healthy adultsreceiving 4 g daily, but the transient elevationsusually resolve with continued acetaminophentreatment, and are not accompanied by signs ofliver injury.57;58

Consider a physical activity program for all olderpatients that includes exercises to reducestiffness and improve flexibility, ROM, strength,and endurance.54

Chronic pain can have a tremendous psychologicimpact and can lead to both physiologic andemotional decline.

Although more expensive, the long-acting agenttaken once daily will simplify dosing.


One Year Later■ She is experiencing exacerbation and progression of her OA. Pain is minimal at

rest, but is “real bad” in the low back, hips, and lower extremities after walking 50 feet: “My legs feel like rubber…like they’re someone else’s.”

■ Good tissue perfusion and pulses; no focal neurologic signs, atrophy, or tender points.

■ She sleeps well, but feels stiff in the morning.■ Exerts all her time and energy performing basic ADLs. ■ Blood pressure remains high normal.■ She has developed neurogenic claudication secondary to probable spinal stenosis. ■ The daughter reports more confusion, occasional disorientation, and forgetfulness

about medicine. She is worried about Mrs J’s ability to care for herself.

What Next? ■ Review goals of therapy with Mrs J and her daughter.■ A series of epidural injections were not beneficial.■ Discuss surgery, but the daughter wants to manage the patient medically.■ Discontinue tramadol; initiate SR morphine 15 mg q12h.■ Initiate a prophylactic bowel regimen with a senna stimulant and stool softener.54

Encourage adequate diet and fluid intake, regular toileting habits, and physicalactivity.54 Advise her to avoid bulking agents, which should be used with caution in patients who are immobile and with questionable hydration.54 Remind the daughter to check on adherence to the bowel regimen.

Several Months Later■ Incident pain is worsening and unremitting after any amount of standing or walking. ■ Pain in the low back is 5-6/10, nonradiating at rest but referred down her legs

with activity. Mrs J believes that morphine has “stopped working” and makesher “feel bad.”

■ The daughter notices some twitching in her hands.■ No problems with bowel/bladder function or changes in muscle strength. ■ Discontinue SR morphine, initiate SR oxycodone 20 mg q12h.■ Oxycodone IR 5 mg prior to activities that incite breakthrough pain (BTP).

One Year Later ■ Mrs J did well for the first few months of SR opioid therapy with IR medications,

rating her pain as 3/10 on average, but has gradually required increased doses tomaintain pain control and function (currently SR oxycodone 20 mg q8h).

■ She is forgetting doses and the resulting pain interferes with self-care. Her daughter worries that Mrs J will take too little oxycodone and suffer or take too much and overdose.

■ Mrs J is losing memory and struggles with simple tasks. While there is still cognitive capacity for decision-making, you discuss advance directives and review goals of therapy, her living situation, and what to expect as Alzheimer’s disease progresses. You emphasize the importance of pain evaluation and control because of the adverse effects on neuropsychologic and physical function.

■ Discontinue SR oxycodone and initiate transdermal fentanyl 25 µg q72h. After 3 weeks increase dose to a 50 µg fentanyl patch (using 12 µg patches for dose titration).

■ Instruct the daughter to evaluate her mother’s verbal and behavioral responses to activity and supplement/“pre-treat” with oxycodone IR as needed. She leaves one 10 mg oxycodone/325 mg acetaminophen tablet available to her mother and checks on her throughout the day to replace it, if necessary.

Long-Term OutcomeSeveral months later, Mrs J moves in with her daughter. Home hospice care is initiated when she progresses to end-stage Alzheimer’s disease. Pain control is maintained with transdermal fentanyl and oxycodone solution for BTP for her remaining 2 weeks.

The daughter wonders whether the confusion is dueto progressing dementia or opioid-related toxicity.However, while medications used to treat pain canresult in cognitive disruption, pain itself also affectscognitive function.60,61 Older adults with pain oftendemonstrate more neuropsychologic impairment andphysical disability compared with pain-free olderadults, but long-term opioid therapy has been shownto improve neuropsychologic performance.61-65

Now that the pain is not responding to tramadol,you suggest continuous opioid therapy with a fullmu agonist. Experience in chronic pain supportsthe use of long-acting opioids for continuous painto improve patient adherence and minimize sideeffects as well as drug level peaks and troughs.54,29

Drug co-pay is straining Mrs J’s budget. Althoughmethadone costs less than other long-acting opioids,it should be used with caution due to risk of drugaccumulation and adverse events prior to achievingsteady state. Long-acting opioid options aremorphine, oxycodone, oxymorphone, and fentanyl.Both patient and daughter are reluctant to consider“narcotics.” It is important to understand an olderperson’s attitude toward opioids, because this cannegatively impact adherence to therapy.60 Patientsand families should be asked about concerns andeducated to alleviate them. After counseling Mrs Jand her daughter regarding continuous opioidtherapy, they agree to a trial of SR morphine, witha follow-up visit scheduled for 2 weeks later toassess therapeutic and adverse effects.

Mrs J has likely become tolerant to morphine and/or her disease is slowly progressing. You decide toexploit the incomplete cross-tolerance among mu-opioid analgesics by rotating to an alternative SRopioid to regain analgesic sensitivity.8 You select SRoxycodone, 20 mg q12h, from the available choices.

Add oxycodone IR 5 mg prior to activities thatpredictably incite BTP—transitory exacerbationsof otherwise stable, persistent pain.60 BTP is well-recognized in cancer, affecting 40% to 80% ofpatients. It is less studied with various types ofchronic noncancer pain, and additional research isneeded to evaluate whether the clinical impactand therapeutic challenges posed by BTP in thisheterogeneous population are comparable to thecancer population.66 However, BTP is prevalent inchronic pain patients and should be addressed asit is shown to add to morbidity in cancer patients,including decreased functioning and increasedanxiety and depression.60,66

Pain assessment of older persons can bechallenging given the multiple comorbidities thatare often present.60 In addition to the generalissues that affect the pain assessment of peopleof any age, specific concerns are:60

• Myths that pain is “natural” for older adults andthat pain perception will decrease with time,and therefore no further therapy is indicated.

• Exaggerated fears about the possibility ofaddiction to opioids.

• Increased stoicism prevents some olderpatients from reporting pain.

• Sensory and cognitive impairments with progressive dementia.

Transdermal fentanyl simplifies the managementof Mrs J, who is forgetting to take medications.


The Case of Mr A: A 45-Year-Old Man With Low Back PainMr A is a 45-year-old male with pain in the low back radiating into the right buttock for many years. He is new to your practicerequesting a refill of hydrocodone/acetaminophen 5 mg/500 mg, which he began 7 months ago because he was experiencingincreasing dyspepsia with regular use of NSAIDs. His pain intensity with activity is 8/10, prohibiting him from working orparticipating in other activities; he is able but sometimes unwilling to perform ADLs.

Oral Medical History■ After a back injury at work 6 years ago, he went through extensive workup

including multiple courses of PT, physical medicine review, anesthetic procedures,and acupuncture.

■ MRIs have shown “3 bulging discs and a narrow canal.” ■ His medical history is otherwise remarkable only for hypertension.■ He has tried codeine/acetaminophen 60 mg/300 mg q6h, several NSAIDs,

lidocaine patch 5%, gabapentin 600 mg q8h, and amitriptyline 25 mg qhs, but claims they all stopped working or he was unable to tolerate them. His current medication regimen is atenolol 50 mg q24h and hydrocodone/acetaminophen 5 mg/500 mg 2 q6h.

Family and Psychosocial History■ His father had an MI at age 65 years and is still living. He is an alcoholic

who would return from the bar after work and beat the patient as a child. ■ His mother died of breast cancer 6 years ago. She was submissive to the

husband’s aggressive behavior and was withdrawn and anxious.■ Two children in their early 20s live locally—one has undergone drug

rehabilitation and the other uses no alcohol. ■ Mr A used marijuana frequently as a teenager. He currently smokes cigarettes,

drinks 2 beers a day, and occasionally the “hard stuff.” Alcohol and “Vicodin” help his “nerves.”

■ He lives with his wife, relying on a modest fixed income from SSI and herincome; his wife resents his lack of employment.

Review of Systems■ Blood pressure is 135/85.■ Sleep is “poor” and the patient states his mood is “okay,” but looks depressed.

Physical Examination■ The patient is not well groomed and has a ruddy complexion.■ He answers in short sentences and seems in a hurry to leave with his

hydrocodone prescription. ■ The exam is unremarkable except for mild tenderness to light touch over

the midline of the back from L3-S1 and mild tenderness in the right SI joint. Normal reflexes, strength, and sensations; no atrophy noted. Normal straight leg raise and normal but slow gait.

What Next? ■ Administer the Opioid Risk Tool (ORT): Mr A is at high risk for opioid abuse.■ Implement a written opioid treatment agreement outlining the conditions under

which you will prescribe opioid therapy. ■ Request his past medical records to verify his verbal report. ■ Prescribe hydrocodone/acetaminophen 5 mg/500 mg 2 q6h, 56 tablets

for 1 week.

Five Days Later■ Mr A calls for an early refill. Hydrocodone is not helping his pain, but along

with alcohol is the only thing that helps his anxiety and sleep.■ Medical records confirm his stated history. ■ Ask him to come in for evaluation. Review the treatment agreement and

the fact that he violated it, and obtain a urine sample.■ Your nurse arranges a referral to a psychiatrist in 2 weeks and a local pain

specialist in 12 weeks.■ Prescribe 2 transdermal fentanyl patches 25 µg q72h with a follow-up visit

in 6 days.

Mr A is at high risk for opioid abuse, but this doesnot necessarily invalidate his report of pain. He readilyprovided the contact details for his prior physicianand permission to request past medical records. Yougive him a limited supply of hydrocodone (1 week)while awaiting his records, but explain that therapyis not directed at just pain relief, but also to increasefunction and overall QOL, and that continuedtherapy is contingent on evidence of benefit. Youwant to establish a therapeutic relationship withthe patient who is at high risk for addiction, whichcan be started by frequent office visits.

Mr A’s family and psychosocial history are verysuggestive of addiction problems.

Opioids do not address psychologic or emotionalproblems. Patients who use drugs (± alcohol) tocope with adverse life situations need structure andpsychiatric input to prevent maladaptive opioid use.

A written agreement is advised when there areconcerns about appropriate use or adherence tothe plan of care.25,54 Among the provisions in theopioid agreement are permission for you to talkfreely with family members, pharmacists, or otherhealth care professionals; early refills will generallynot be given; he will not seek controlled substancesfrom another physician; one pharmacy will be usedto fill controlled substance prescriptions; he willsafeguard his medication; he will submit to urinedrug tests; and lost medications may not be replaced.

The visit takes longer than anticipated, but the extratime is needed with this patient to begin to build atherapeutic relationship.

Early refill requests should trigger evaluation fortolerance, progressive disease, aberrant behavior,or drug diversion.54 You request a urine samplefrom him to reinforce that you are serious aboutthe treatment agreement, but do not submit thissample for testing.

At this point you might want to refer the patient.There is a 3-month wait to see a local painphysician, but only 2 weeks for a psychiatricreferral. In the meantime, you do not prescribemore hydrocodone, which he has demonstrateddifficulty managing. This may be a good time totry a long-acting opioid, with fewer doses andmore steady blood levels. Options include fentanyl,morphine, oxycodone, oxymorphone, and tramadol.

You are concerned that Mr A is requesting acontrolled substance without your first reviewinghis previous medical records.


Interim Call■ Mr A’s wife is worried about the patient lying around the house doing nothing.■ You ask her to accompany Mr A on his visit that week.

Six Days Later■ Mr A keeps his appointment but complains that his pain is out of control

and that he needs more medication. The patches “don’t stay on.” ■ 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.

■ Prescribe SR morphine q24h 30 mg, 7 tablets.

Seven Days Later■ 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 disheveled—he states that he lost his morphine

the previous day. ■ His wife states that his function has not improved.■ Another urine sample is sent to the laboratory for testing.

The results 24 hours later reveal hydrocodone, marijuana, and morphine.

What Next?■ Explain that because opioids are clearly not improving his function

you will not continue to prescribe them, at least until his referral to the pain specialist in 10 weeks. Mr A is angry, but you reiterate that the opioid therapy is harmful to him.

■ 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.■ Further explain that you will see him every week to support him

through this time. He agrees to come to the office the following week, and continues to do so.

Twelve Weeks Later■ The pain physician tries an epidural steroid injection, with little success.

No other evaluation or treatments were offered.■ You refer the patient to a pain psychologist for weekly visits and

continue to see him every 2 weeks.

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 A’s wife.■ The patient achieves some relief from this regimen and continues to

work with the psychologist.

Family members can be a therapeutic ally whenmanaging a patient on opioid therapy. They can alsobe part of the problem, so it is important to obtaincollateral information from them. This includestalking with family members to determine theirconcerns and whether or not they are onboard withthe treatment plan, and documenting this discussion.

Many PCPs will want to refer the patient at thispoint, although it is still appropriate for physicianswho are confident and experienced in managingsuch patients to continue doing so.

It is a week until Mr A’s psychiatry referral. Thefentanyl may not be working for a number of reasonsand Mr A may be exhibiting pseudoaddiction. Youswitch to SR morphine, but do not provide anyshort-acting agents for BTP as you do not want toreinforce his maladaptive opioid use.

He appears to show signs of withdrawal. Youcounsel Mr A to refrain from use of illicit drugsand encourage him to participate in a substanceabuse program, which he is reluctant to do.

This is a difficult patient to manage. When apatient displays consistent aberrant drug-takingbehavior, it may be necessary to refuse toprescribe opioids—they are not appropriate for allpatients with pain. Consider prescribing themagain in comanagement with a pain specialist.

A pain psychologist can help patients to makechanges in their lifestyle and derive a sense ofacceptance, including the limitations of what canbe expected from analgesics.

The patient’s wife accompanied her husband tosome sessions with the psychologist and is eagerto see Mr A continue to improve his function.

ConclusionChronic pain is a common presenting complaint in manypractice settings and has substantial effects on patients’ QOLand ability to work. Opioid analgesics may be required torelieve moderate to severe pain and it is therefore importantfor physicians to identify when opioids might be useful, bycareful patient assessment, selection, and monitoring, and tounderstand the principles of prescribing opioids. At the sametime, it is just as essential that physicians are able to identifypatients for whom opioid analgesia may create more harmthan not using this treatment option. Physicians should beprepared to develop an “exit strategy” for such patientsalready being treated with opioids, and to formulate a plan tomanage and support these patients with other pharmacologicand nonpharmacologic modalities.

Estimated time to complete thisactivity: 1.5 hours

Release date: June 2007

Expiration date: June 2009

Instructions to obtain CME credit:■ Read the monograph.■ Visit www.unmc.edu/dept/cce/opioid_

criticalthinking.htm to complete the posttest and evaluation.

■ Pass the posttest and print your certificate.

C R I T I C A L T H I N K I N G TO B A L A N C E B E N E F I T S & R I S K

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