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Home , Addiction medicine, Analgesic, Butorphanol, Medetomidine, Mexiletine, Pain management

Pain Management in Patients with Substance-Use Disorders

By Valerie , Pharm.D., FAPhA, BCPS

Reviewed by Beth A. Sproule, Pharm.D.; Jeffrey T. Sherer, Pharm.D., MPH, BCPS; and Patricia H. Powell, Pharm.D., BCPS

Learning Objectives regarding with illicit substances or prescribed . Finally, there are issues 1. Construct a therapeutic plan to overcome barri- ers to effective in a patient with related to the comorbidities of the patient with addic- . tion (e.g., psychiatric disorders or physical concerns 2. Distinguish high-risk patients from low-risk patients related to the addiction) that should influence product regarding use of to manage pain. selection. 3. Design a treatment plan for the management of acute pain in a patient with addiction. Epidemiology 4. Design a pharmacotherapy plan for a patient with Pain is the second most common cause of work- coexisting addiction and chronic noncancer pain. place absenteeism. The prevalence of may 5. Design a pain management plan that encompasses be much higher among patients with substance use dis- recommended nonpharmacologic components for orders than among the general population. In the 2006 a patient with a history of . National Survey on Drug Use and Health, past-year alco- hol addiction or abuse occurred in 10.3% of men and 5.1% of women. In the same survey, 12.3% of men and Introduction 6.3% of women were reported as having a substance-use Pain, which is one of the most common reasons disorder (abuse or addiction) during the past year. Men patients seek medical care, is often undertreated. are more likely to use illicit ; they also have a higher Addiction and pain are interrelated, with each condi- incidence and prevalence of drug-use disorders, depend- tion influencing the treatment of the other. Patients ing on the specific substance and age of use. with addiction have special clinical considerations and are at increased risk of receiving inadequate pain man- Nomenclature agement. There are three broad categories of clinical Terminology in this area of is often misused. considerations specific to this patient population. First, The American Pain Society, the American Academy of there are issues related to the addiction itself, such as Pain Medicine, and the American Society of Addiction abuse of opioids, altered pain perception, and adherence Medicine have issued a consensus statement to to pain drug /. Next, there are issues define certain terms.Addiction is a primary, chronic,

Baseline Review Resources The goal of PSAP is to provide only the most recent (past 3–5 years) information or topics. Chapters do not provide an overall review. Suggested resources for background information on this topic include: • Klipa D, Russeau JC. Pain and its management. In: Koda-Kimble MA, Young LY, Alldredge BK, Corelli RL, Guglielmo BJ, Kradjan WA, et al, eds. Applied Therapeutics: The Clinical Use of Drugs. Philadelphia: Lippincott Williams & Wilkins, 2009:8-1–8-36. • Recovery Network. Available at usaprn.org. Accessed December 7, 2010. • Flannery B, Newlin D. use disorders and their treatment. In: Smith HS, Passik SD, eds. Pain and Chemical Dependency. New York: Oxford University Press, 2008;131–6.

PSAP-VII • Chronic Illnesses 171 Pain Management dependence is a separate and distinct issue from the Abbreviations in This Chapter compulsive, consequential, drug-taking behaviors of NSAID Nonsteroidal anti-inflammatory addiction. Physical dependence is a state of adaptation drug manifested by a –specific withdrawal syn- PCA Patient-controlled analgesia drome that can be produced by abrupt cessation, rapid REMS Risk Evaluation and Mitigation dose reduction, decreased concentration, and/or Strategy administration of an antagonist. Physical dependency is SOAPP-R Screener and Assessment a neurologic condition. Tolerance is a state of adaptation for Patients with Pain – Revised in which exposure to a drug induces changes that result TENS Transcutaneous electrical nerve in a decrease of the drug’s effects over time. stimulation Addiction is a psychiatric condition associated with neurobiologic changes and behavioral manifestations. People with addiction often have both tolerance and neurobiologic with genetic, psychosocial, and physical dependency, but not all patients who are toler- environmental factors influencing its development and ant or physically dependent are addicted. Box 1-1 lists manifestations. It is characterized by behavior that diagnostic criteria for from the includes one or more of the following: impaired control DSM-IV-TR . over drug use, compulsive use, continued use despite Pseudoaddiction is a term used to describe aberrant harm, and craving. Although many expert groups and drug-seeking behaviors in patients with undertreated journals in the field commonly accept and use this term, pain. In pseudoaddiction, the behaviors resolve with a text revision of Diagnostic and Statistical Manual of adequate pain relief. For clarity, the term addiction is Mental Disorders, fourth edition (DSM-IV-TR), uses a used in this chapter. different term,substance dependence, to describe addic- tion. This term is confusing to patients and providers because of its similarity to the term physical dependence. Pain Physical dependence is an expected response to is the process of communication the chronic administration of many classes of drugs, between a site of tissue damage and the central ner- including opioids, steroids, and β-blockers. Physical vous system. The four steps in the process are as follows:

Box 1-1. DSM-IV-TR Diagnostic Criteria for Substance Dependence: Addiction A maladaptive pattern of substance use, leading to clinically significant impairment or distress, as manifested by three (or more) of the following, occurring any time in the same 12-month period: 1. Tolerance as defined by either of the following: a. A need for markedly increased amounts of the substance to achieve intoxication or desired effect b. A markedly diminished effect with continued use of the same amount of the substance 2. Withdrawal as manifested by either of the following: a. The characteristic withdrawal syndrome for the substance (refer to criteria A and B of the criteria sets for withdrawal from the specific substances) b. The same (or a closely related) substance is taken to relieve or avoid withdrawal symptoms 3. Substance often taken in larger amounts or for a longer period than was intended 4. A persistent desire or unsuccessful efforts to cut back on or control substance use 5. Much time spent on activities necessary to obtain the substance (e.g., visiting many doctors, driving long distances), use the substance (e.g., chain-smoking), or recover from the effects of the substance 6. Important social, occupational, or recreational activities given up or reduced because of substance use 7. Substance use continued despite knowledge of a persistent or recurrent physical or psychological problem that is likely to have been caused or exacerbated by the substance (e.g., current use despite recognition of cocaine-induced , continued drinking despite recognition that an ulcer was made worse by alcohol consumption) Information from American Psychiatric Association Task Force on DSM-IV. Diagnostic and Statistical Manual of Mental Disorders, Text Revision (DSM-IV-TR), 4th ed. Washington, DC: APA Press, 2000.

Pain Management 172 PSAP-VII • Chronic Illnesses transduction ( convert stimulus energy into Screening and Barriers electrical nerve impulses), transmission (nerve impulses Identification of High-Risk Patients travel from periphery to spinal cord and brain), percep- The risk of developing addiction in the course of treat- tion (brain and spinal cord appreciate nerve impulses), ing acute pain is very small in the general population. and modulation (descending input from brain influ- Some studies of long-term opioid therapy in patients ences spinal cord nociception). is with chronic pain suggest the risk of addiction or select caused by the abnormal processing of nerve impulses in aberrant behaviors related to opioid misuse is minimal the periphery or central . (about 3%); however, no patient may be free from the risk of addiction. Additional precautions are required Addiction when patients identified as being at high risk of develop- Addiction is a pathophysiologic brain adaptation to ing substance abuse disorders are prescribed opioids. A the repeated use of psychoactive drugs over time. The universal precautions approach to managing pain is rec- common element in the action of these drugs is their ommended to minimize addiction risks. impact on brain reward pathways. The reward pathways It is difficult to ascertain which patients are at highest mediate response to natural rewards necessary to sus- risk of developing addiction to opioids. Several studies tain life such as food and sex. Drugs of abuse activate of high-risk predictors have been reported in the liter- these reward pathways at an intensity above that of natu- ature with conflicting results. The strongest high-risk ral rewards. With time, this repeated intense stimulation predictor consistently reported is a personal history of causes adaptations that lead to two major consequences. alcohol and illicit drug abuse. Other predictors, stud- First, the diminished response to natural rewards leads ied less often but established as positive predictors, are to a need to use the drug to feel “normal.” Second, the a family history of drug and illicit drug abuse, a history emotional memories associated with drug use remain of childhood sexual abuse, a history of convictions for during months to years of abstinence. Drug-associated driving under the influence or drug-related offenses, environmental cues or stressful events can trigger inten- lost or stolen prescriptions, and the use of supplemental sive craving and relapse, in part by activating the brain’s sources to obtain opioids. It is also important to recog- reward pathways through the presence of these memories. nize symptoms during the course of therapy that may indicate emerging addiction. Interface Between Addiction and Pain Several clinical tools have been developed to assist Physiologic states common in patients with addic- in identifying high risk in patients being considered for tion can affect nociceptive input, processing, and/or or currently receiving long-term opioid therapy. The modulation. Chronic use of addictive drugs may affect Current Opioid Misuse Measure is a tool that assesses the processing of pain stimuli through sympathetic a patient’s relative frequency of a thought or behavior in stimulation, hypothalamic-pituitary-adrenal axis dys- the past 30 days. The Screener and Opioid Assessment regulation, and opioid tolerance. Addictive disease for Patients with Pain – Revised (SOAPP-R) is a appears to augment the experience of pain, and evidence tool designed to predict future misuse based on past suggests that people with have decreased pain behavior or thoughts; this tool is only appropriate for tolerance. The presence of both conditions can result in patients under consideration for long-term opioid ther- a reorganization of baseline perceptual pathways in the apy. Clinicians can use the SOAPP-R and the Current brain that results in increased pain perception. Opioid Misuse Measure in tandem to identify high-risk Personality traits of patients with addiction, such patients who require more intensive monitoring at dif- as an external locus of control and a tendency to per- ferent stages of chronic long-term opioid therapy. ceive circumstances as worse than they are or to expect Potentially aberrant symptoms can occur at times in the worst to happen, have been associated with poorer a patient on chronic opioid therapy. However, persis- outcomes in patients with pain. Intoxication and with- tent or frequent symptoms are of concern. Alert signs drawal both activate the sympathetic nervous system, include persistent or increasing sedation, which augments the patient’s pain perception. This acti- decreasing functional level despite adequate pain relief, vation of the sympathetic nervous system also results in or increased psychiatric symptoms such as anxiety, increased muscle tension, irritability, and anxiety, fur- depression, or . Attempts to obtain early refills, ther contributing to discomfort. use opioids from illicit sources, or go “doctor shopping” Withdrawal is associated with a negative affective for additional prescriptions indicate either addiction or state caused by dopamine depletion in the brain that pseudoaddiction. Preoccupation with opioid use is a exacerbates discomfort in patients with addiction. In core feature of addiction. This preoccupation may result addition, these patients often experience interpersonal in patients who are nonadherent to lifestyle and other conflicts and loss of social support that are detrimental nonopioid pain relief modalities and who believe that to adequate pain management. nothing but opioids will relieve their pain.

PSAP-VII • Chronic Illnesses 173 Pain Management Barriers to Care effects of therapy, maximize nonpharmacologic treat- Issues that decrease either patient or provider ment approaches, improve quality of life, and educate access to therapy may compromise the quality of about self-care of pain. Patients with opioid addictions care in patients with both pain and addiction. The have an additional set of goals because of the complexity Controlled Substances Act gives the Drug Enforcement of their clinical circumstance (Box 1-2). Administration authority to regulate controlled pre- It is important for any patient with chronic pain and scription drugs. In addition, new Risk Evaluation and the clinician to understand that the complete absence of Mitigation Strategy (REMS) programs are in develop- pain may not be a realistic goal, but a decrease in pain to ment for opioids. The goal of opioid REMS programs facilitate increased functioning is likely to be attainable. is to promote the appropriate use of opioids; these Patients should set personal goals for therapy based on programs are likely to include mandatory their activities of daily living (e.g., participating in fam- education and increased documentation. Many pain ily events, attending church, maintaining a job). The management health care providers are concerned that patient whose only goal is to be pain free may consider the restrictions associated with REMS programs for treatment a failure if that state is not achieved and there- opioids will decrease access to care for patients with fore be more likely to self-medicate. Self- pain. can lead to a full-blown relapse of addiction and a con- State regulations allow for opioid prescription mon- sequent lack of adherence to the global treatment plan. itoring programs. Many of these programs are also Therapeutic success can be compromised by many accompanied by restrictions on prescribing. Prescribing errors on the part of patients and practitioners. Setting patterns can be reviewed by regulatory and other unrealistic goals and giving insufficient time for an authorities. These programs have led to debate regard- intervention to work are common errors. A practitioner ing what is and is not legitimate medical practice. Fear can err by imposing overly tight restrictions on opioids, of sanctions by state medical boards can be a barrier resulting in inadequate pain relief that in turn leads to to prescribing opioids when needed. The drug-seeking behaviors by the patient, which leads to Federation of State Medical Boards developed model further restrictions in pain drugs. This vicious cycle can guidelines that describe professional standards for prevent therapeutic success. appropriate opioid prescribing. These standards have been adopted by many state medical boards. Another barrier to care is physician attitudes of dis- Pain Management trust toward patients with pain, particularly the patient Opioids with a history of substance use. This barrier leads to Opioids are the drugs of choice in managing severe less-than-optimal pain treatment. If the patient is pain, including acute postsurgical or trauma-induced pain undertreated and consequently exhibits signs of pseu- and . Their role in the management of chronic doaddiction, assessment and management of pain noncancer pain is not clearly defined. Physicians have become even more difficult. It is critical for all parties to expressed several concerns regarding opioid prescribing, openly acknowledge the history of substance abuse. The including abuse, addiction, adverse first step in forming a plan to address the patient’s pain effects, tolerance, and drug interactions. Conflicting lit- is to obtain accurate knowledge of the patient’s current erature is available on the long-term benefits of opioids and past substance use. for treatment of chronic noncancer pain. Findings from Other methods for overcoming the patient-physician a recent controlled study of primary care patients over lack of trust barrier include being attentive to withdrawal concerns, relapse triggers, and comorbid conditions, and increasing patient assessment and monitoring. It is helpful to establish a therapeutic relationship not only Box 1-2. Pain Management Goals of Therapy for with the patient but also with his/her family. Family Patients with Opioid Addiction members can potentially help the patient avoid fail- Prevent withdrawal ure by monitoring adherence to the drug therapy and Treat symptoms nonpharmacologic components of the treatment plan, Provide effective analgesia holding the patient accountable for his/her actions, and Prevent relapse to addiction being a source of information for the practitioner. Effective treatment of opioid addiction (maintenance opioid therapy) Treatment Goals Treatment of psychiatric disorders such as anxiety Therapy goals for pain management in the general Information from Mehta V, Langford RM. Acute pain management patient population are as follows: minimize physio- for opioid dependent patients. Anaesthesia 2006;61:269–276. logic adverse effects of unrelieved pain, avoid adverse

Pain Management 174 PSAP-VII • Chronic Illnesses 6 years suggest that low-dose (20–40 mg of at the time of a short-term pain episode. Alcohol with- morphine or equivalent daily) improve quality of life in drawal may produce signs that are interpreted as patients with pain compared with patients not receiving increased pain levels (e.g., tachycardia), whereas opioid opioid therapy. In contrast, a large epidemiologic study withdrawal produces additional pain and anxiety. from outside the United States reported decreased qual- There are special considerations regarding the ity of life in patients with pain who were on long-term adverse effects of opioid use in opioid-dependent opioid therapy. patients. Respiratory depression is less common in A was conducted in the devel- these patients than in the general population because opment of Canadian guidelines on the use of opioids tolerance of this effect occurs sooner than does toler- for chronic noncancer pain. Strong and weak opioids ance of the therapeutic effects. Respiratory depression were more effective for pain than regardless can be seen when doses of long-acting agents such as of the type of pain (neuropathic or nociceptive), and and are titrated or when opioid they worked better for treating pain than for improving agents are rotated. Respiratory support should be used function. Opioids have small to moderate benefits for instead of to manage respiratory depression, if nociceptive pain of musculoskeletal origin (e.g., osteo- possible, because of the risk of precipitating withdrawal arthritis, low , ), and patients usually with naloxone use. respond to moderate doses. Opioids have small to mod- Risks associated with opioid use should be discussed erate benefits in neuropathic pain as well, but patients with the patient before initiating therapy. The patient is with this type of pain often require high-dose opioids likely to focus on the risk of withdrawal and/or relapse and concomitant therapy with tricyclic much more than other adverse effects that may be of or . Because of a lack of evidence, opi- greater concern in the general patient population. oids were not recommended for or tension or for functional gastrointestinal problems Opioid Selection Considerations such as irritable bowel disease. has evidence Both global concepts (e.g., ) and of a small benefit in patients with . More individual patient factors are important when selecting evidence is needed to facilitate our understanding of opioids for managing pain in patients with addiction. which types of patients with chronic pain would achieve Recent research provides evidence that a patient’s ther- the best outcomes with opioid therapy. apeutic and adverse response to a specific opioid is One clear benefit of opioid use in short-term pain influenced by . Patient-specific dif- management is the rapid onset of relief. One of the dis- ferences in m and other subtypes can influence advantages of use for long-term pain management is a patient’s therapeutic and reward response to a certain the inevitable development of tolerance and the conse- opioid. quent negative perception by the patient and providers Meperidine and propoxyphene are recognized as that the patient’s drug use is escalating. The expense poor choices in the general population, and the same is to our health care system associated with treatment true in patients with addictions. Mixed -antag- and complications of addiction is well documented. onist agents (, , ) Expenditures necessary for adequate pain management may reverse analgesia and precipitate withdrawal in opi- in these patients help prevent the cost to the system oid-dependent patients. These patients are most often associated with relapse. tolerant to the m receptor effects, so the ceiling effect of the mixed agonist-antagonist agents precludes their use. Opioid Use Considerations in Patients and tramadol are partial m ago- with Substance-Use Disorders nists that have clinical utility in patients with addiction. Use of opioids for acute pain is unlikely to have a long- Tramadol is not free of addiction potential, and it is a term effect on the course of a patient’s addiction unless drug of choice for many patients in substance abuse the patient is in remission at the time of opioid use; opi- treatment centers. It effectively has an ceil- oids may trigger relapse in these patients. Relapse has ing because of its potential for causing seizures at also been attributed to inadequate pain relief, so opioid doses above 400 mg/day. Tramadol, like other opi- use in these patients may be necessary along with appro- oids, has been associated with seratonergic syndrome. priate monitoring. Buprenorphine can be used as an analgesic when dosed Reward is attenuated to some degree in most patients at 6-hour to 8-hour intervals, but it may exhibit a ceil- in the presence of pain regardless of the patient’s prior ing effect that limits its use in patients with the most or current use or abuse of opioids. has severe pain. Practitioners presenting at conferences been documented in opioid-dependent populations specific to the issue of substance dependence in health and is manifested by increased pain caused (instead care professionals report using buprenorphine to treat of relieved) by high-dose opioid therapy. Withdrawal pain in patients with addiction. Pure opioid should be prevented in patients who are not in remission remain the best choice of therapy for many patients with

PSAP-VII • Chronic Illnesses 175 Pain Management pain despite the presence of addiction. There are some withdrawal in addition to opioids for pain management. important considerations when selecting a pure agonist Although patient-controlled analgesia (PCA) devices agent. Chronic pain should not be managed solely with involve self-administration and as-needed dosing by short-acting opioids in patients with substance-use dis- the patient, they are useful for pain relief in this popu- orders; a wearing-off effect may occur near the end of lation. A PCA pump provides small incremental doses the dosing interval, resulting in withdrawal symptoms that help maintain a more stable serum concentration and increased pain perception. Onset of action should than intravenous bolus administration. If a patient has also be considered. Rapid onset of action is a critical a high tolerance level, a continuous infusion of opioids property identified to contribute to potential for abuse. or a long-acting oral opioid may be required in addition If the controlled-release properties of an opioid product to the PCA. If the patient is in remission and therefore are altered, the patient receives a rapid peak concentra- has no potential for withdrawal, use of intraspinal anes- tion. Controlled-release forms of opioids, when taken thesia may be the best choice. If the patient is not in as intended, provide less fluctuation in serum concen- remission, intraspinal opioids may be an option as long trations. Scheduled dosing obviates the need for the as a baseline systemic dose of an opioid is maintained to patient to make a decision to take the opioid in response avoid withdrawal. to perceived pain. An important opioid selection consideration in patients An important concept in pain management in the with chronic pain is the drug’s half-life. Levorphanol and general population is the provision of both a long-acting methadone have long half-lives and N-methyl-d-aspartic agent on a scheduled basis and a short-acting agent on an acid activity that may help lessen the as-needed basis for breakthrough pain. This approach development of tolerance. Methadone has a wide-ranging can be problematic in patients with addiction because half-life and must be titrated carefully to avoid excessive administration of the drug is associated with pain relief accumulation and oversedation. Methadone has many and reinforces the behavior of taking additional doses of drug interactions that can result in QT prolongation. opioids. Two alternative approaches in the patient with addiction can be used to avoid this . The Nonsteroidal Anti-inflammatory Drugs first is to schedule doses of a short-acting agent at times Nonsteroidal anti-inflammatory drugs (NSAIDs) are of the day when the patient is most likely to experience primarily useful for somatic pain of mild to moderate breakthrough pain. The second is to premedicate with intensity and are usually not effective for neuropathic the short-acting product 30 minutes before an activity pain. These agents can be useful adjuncts to low-potency that is known to increase pain. One strategy for mini- opioids in the management of severe pain. Nonsteroidal mizing problems associated with the use of short-acting anti-inflammatory drugs have dual mechanisms for agents is to have a family member or friend dispense the pain relief and act both in the periphery and in the cen- drug per dose or per day. Scheduled dosing decreases tral nervous system with effects independent of their the perception of the person administering the drug anti-inflammatory properties. The adverse effects of that the patient is drug seeking. Use of short-acting NSAIDs are of concern in patients with addictions who agents may be minimized in some patients through the have comorbid complications secondary to abuse. use of nondrug interventions and activity pacing. Short- Antiplatelet and gastrointestinal effects of NSAIDs acting agents for unpredictable breakthrough pain may are significant dangers to patients with hepatic disease. be necessary in some patients. Patients with are prone to excessive bleed- Important acute pain opioid selection considerations ing and have a high incidence of gastric varices and/or include pharmacokinetics and administration route. ulceration. Choline trisalicylate has less Intravenous access may be an issue in patients with a antiplatelet effect than other NSAIDs. Proton pump history of injectable drug abuse. Peak concentrations inhibitors should be used with NSAIDs to protect of the opioid relative to the patient’s tolerance level pro- patients from gastrointestinal adverse effects. This ther- vide an important determinant of the level of reward apy is preferable to using a -2 selective caused by a given opioid dosage form. Intravenous NSAID because of potential cardiovascular risks asso- administration provides a rapid onset of effects and high ciated with these agents. Lithium serum concentrations serum drug concentrations when given as intermittent in patients with concomitant bipolar disease and addic- boluses, enhancing the rewarding effects of the drug. tion will be affected by an NSAID-induced decrease in Intravenous administration of opioids is less rewarding renal clearance. when administered as a continuous infusion. can be avoided by administer- Antidepressants ing a baseline dose of opioid that corresponds to the Tricyclic antidepressants are useful in the manage- patient’s usual opioid use in addition to opioids required ment of most neuropathic pain. Evidence suggests to address the pain. Another option in a hospitalized that tricyclics modulate pain pathways and enhance patient is the administration of methadone to prevent the effect of opioids at their receptors. Patients with

Pain Management 176 PSAP-VII • Chronic Illnesses addictions are often impulsive and gravitate toward is often effective for the management of immediate gratification; they should be counseled that neuropathic pain and can be dosed starting at 100 mg it usually takes several weeks before the full effect of the at bedtime, with 100-mg to 300-mg increases in dose drug therapy is realized. They should also be aware that every 3–5 days with a maximal dosage of 3600 mg/day. tolerance of many of the initial unpleasant anticholiner- Patients with addiction commonly suffer from insom- gic adverse effects of the drugs may develop. nia that causes a decreased level of alertness and ability The mixed reuptake agents venla- to concentrate during the day. The daytime somnolent faxine and are effective for neuropathic pain effects of gabapentin may be more pronounced in these and are associated with fewer falls, fewer anticholiner- patients during the first 2 weeks of therapy until toler- gic effects, and no cardiac conduction disturbances. ance develops. Recent clinical trials have shown that Recent trials with duloxetine showed its effectiveness in gabapentin in dosages of 900–1200 mg/day is effective diabetic at dosages of 60 mg once when used preoperatively to reduce the opioid require- or twice daily as well as in fibromyalgia with or without ment postoperatively and reduce opioid adverse effects. concomitant depression. In the presence of concurrent A recent trial provided evidence for use depression and neuropathic or nonspecific pain, dulox- of this agent in the management of diabetic neuropa- etine and are first-line choices on the basis thy. When used to manage various types of neuropathic of recent trials. Duloxetine should be avoided in patients pain, pregabalin should be dosed initially at 50 mg three with hepatic disease. Clinicians should be aware that times/day and increased to 100 mg three times/day for 7 duloxetine has been associated with seratonergic syn- days. Dosages up to 600 mg/day may be required, with an drome. Venlafaxine should be used with caution in average dosage of 450 mg/day in fibromyalgia. , patients with . weight gain, , edema, and are the adverse effects of note for pregabalin. Anticonvulsants Clonazepam has also shown efficacy as a treatment Many antiepileptic drugs are effective in treating for neuropathic pain. It is not a first-line choice because neuropathic pain, even though their exact mechanisms of concerns about use leading to craving of action are not fully understood. Anticonvulsants and relapse. It is also associated with and is a have a slow onset of pain relief, and the patient may not poor choice for the patient with concurrent depression. fully appreciate the full effects for several weeks after therapy initiation. The efficacy of agents may be very different from their effectiveness because of infusion inhibits spontaneous C fiber pronounced adverse effects. activity associated with . Lidocaine can be can be administered as a 1-g loading dose infused at a dose of 5 mg/kg over 30 minutes, resulting for acute pain, and the average maintenance dosage for in pain relief that may last for several days. Repeat infu- acute or chronic pain is 300 mg/day. The efficacy of car- sions may not achieve an equal response. bamazepine for chronic pain is superior to phenytoin, is effective at high doses for treatment of neuropathic and dosing can be initiated at 100 mg/day and increased pain. Prescribers should initiate therapy with 150 mg/ in increments of 100 mg every 3–7 days to minimize the day and increase the dosage by 150-mg increments dizziness often associated with both phenytoin and car- every 3–5 days up to a dosage of 300 mg three times/ bamazepine therapy. Both anticonvulsants share the day. Adverse effects include sedation, dizziness, , of somnolence, which may lessen over and tremor. Hematologic reactions are rare, making this time as the patient acclimates to anticonvulsant therapy. a useful option in patients with blood dyscrasias. Failure to tolerate the effects of anticonvul- Mexiletine has an onset of pain relief much more sants in the early stages of therapy is a common reason rapid than that of anticonvulsant and for treatment failure. Patients who are not in remission agents. Although clinical trials have shown mexiletine from addiction are often nonadherent to drug therapy to be effective, adverse effects limited patient accep- or the necessary laboratory monitoring associated with tance. In a study using survival analysis to determine these narrow drugs. Rates of human factors that predicted continued therapy with mexi- immunodeficiency virus (HIV) are higher among letine, the median time to discontinuation of mexiletine patients with substance-use disorders than among the was only 53 days. Characteristics predictive of continu- general population, and the potential adverse impact of ing mexiletine therapy long term were male sex, younger and phenytoin on blood counts make age, and a positive response to lidocaine infusion. These them unfavorable choices for these patients. Patients findings illuminate the difference between the clinical on methadone maintenance therapy are very sensitive efficacy, as reflected by conventional end points such to small changes in the serum concentration of metha- as changes in pain score, and the clinical utility of a done, so they should avoid the use of phenytoin because drug with limited patient . Mexiletine is an of its drug profile. acceptable agent to use in an effort to explore nonopioid

PSAP-VII • Chronic Illnesses 177 Pain Management options in patients with addiction who have not ade- were participating in a home program. Efficacy quately responded to first-line neuropathic pain agents and patient satisfaction were similar in both groups. or who have blood dyscrasias. Lumbar facet injections achieve short- and long-term pain relief in select patients with neck or back pain. The Topical Agents long-term benefit of epidural injections is Topical agents can be useful in patients with moderate at best according to a position statement by substance abuse disorders as an adjunct to other ther- the American Academy of . apeutic modalities that provide incomplete relief of Procedures that provide sympathetic blockade (e.g., predominantly peripheral pain. Use of topical agents targeted injections) can provide relief for may help avoid the need to initiate opioid therapy. pain involving the sympathetic nervous system and Topical and were compared in a the viscera. Abnormal sympathetic activity may be a randomized, double-blind, placebo-controlled trial for source of complex regional pain syndrome. Bupivacaine efficacy in neuropathic pain. The primary outcome mea- is superior to local temperature modula- sure was change in daily average pain intensity using an tion in patients with complex regional pain syndrome. 11-point pain rating scale. Secondary outcomes mea- Bupivacaine blocks achieve complete or partial pain sures included the McGill Pain Questionnaire, patient relief in 76% of patients, with a shorter duration of relief satisfaction, and measures of and hyperalge- associated with a longer duration of complex pain syn- sia. Each therapy and the combination of both agents drome. The evidence does not yet support the use of achieved a good response. sympathetic blockade as the standard of care. On the Lidocaine 5% patches were as effective as basis of recent trials, spinal cord stimulation may be an for carpal tunnel pain and were preferred by patients. alternative in patients with addictions and unrelieved Lidocaine patches can be useful for a variety of neuro- back pain or pectoris pain. Spinal cord stimula- pathic pain types and have few adverse effects (primarily tion requires surgical intervention to implant a device to local irritation). Patches should be worn for 12 hours/ deliver electrical stimulation; thus, it should not be con- day. and eutectic mixture of local anesthetics sidered a first-line therapy. and lidocaine are effective in some patients provides pain relief in patients with with neuropathic pain, especially those with pain in pain induced by dystonia or muscle . Adverse small areas. The use of both agents together (administer effects include local reactions or unacceptable weakness eutectic mixture of local anesthetics prilocaine and lido- of muscle groups that can result in gait disturbances. caine first) may be an alternative in patients who find Injections, which usually do not last longer than 3 the burning sensation associated with capsaicin intol- months, must be repeated, and the long-term effects of erable. Topical agents are listed as potentially effective repeat injections are unknown. alternatives in current guidelines but are not among the recommended first- or second- Lifestyle and Physical tier agents. In a recent trial of patients with , heat application was most effective when combined with Muscle Relaxants exercise. Cold application may reduce local inflamma- , , and are spas- tion and muscle spasm and may be more effective than molytic agents used for muscle spasm because of neural heat in acute pain. Transcutaneous electrical nerve . , , , stimulation (TENS) is a nondrug option for patients and have effects through with addiction and joint, neck, or other acute pain, but depression, not a true antispas- it is less effective for back pain. In a placebo-controlled modic action. The literature lacks sufficient evidence to trial of 200 patients with chronic back pain, those ran- support using these agents in pain management, and domized to TENS showed improvements in pain and most should be avoided in patients with addictions neck strength. The TENS therapy should be used in because of their potential for abuse. conjunction with . Exercise is beneficial in many types of chronic pain Interventional Injections/Blockade to decrease pain and increase functionality. Patients Mechanical and procedural options offer alternatives should be encouraged to set functional goals because to opioid use pain management in patients with sub- exercise may initially result in increased pain. stance-use disorders. These options may avoid adverse can be applied by needling, heat, pres- effects or suboptimal efficacy associated with daily oral sure, or electrical stimulation. Acupuncture modulates therapy. Trigger point injections have been used for nerve fiber firing and stimulates release of . myofascial pain. Botulinum toxin A and bupivacaine Recent studies support the use of acupuncture in osteo- were compared in a double-blind randomized crossover arthritis and fibromyalgia. There is more evidence to trial of patients with myofascial pain syndrome who support the use of acupuncture for somatic pain than

Pain Management 178 PSAP-VII • Chronic Illnesses for neuropathic pain. Acupuncture is a safe and viable cross tolerance can result in ineffective analgesia and/ treatment option for patients with addiction. or withdrawal effects. Methadone is not an ideal agent for acute pain management because of its wide-ranging half-life and potential for causing delayed respiratory Management of Acute Pain in the depression during dosage titration. Maintenance of the Patient with Opioid Addiction usual methadone dose in combination with a different Few randomized, controlled trials of acute pain in agent to manage acute pain offers the advantage of keep- patients with opioid addiction have been performed, so ing the two issues (prevention of withdrawal and pain the evidence comes primarily from case reports, retro- management) separate and distinct. spective studies, and expert opinion. Clinically, it can be If the exact usual dose of methadone cannot be con- helpful to classify patients with opioid addiction expe- firmed with the patient’s methadone maintenance riencing pain as follows: (1) patients with an active , it is advisable to divide the total daily dose addiction who are currently using and/or pre- reported by the patient into three or four increments so scription opioids (includes patients who are prescribed he/she can be monitored for adverse effects after each opioids for chronic pain and have an active addiction); dose. Intravenous methadone dosing should be done (2) patients who are currently in remission from addic- with caution because of the poor predictability of the tion and who are receiving opioid substitution therapy oral of the drug. The usual oral daily dose with methadone or buprenorphine; and (3) patients should be cut in half when administered intravenously. who are currently in remission but not receiving opioid Subcutaneous doses of methadone should be one-half substitution therapy. Another group requiring special to two-thirds the daily oral dose of methadone. Recent literature suggests that patients on metha- consideration when needing short-term treatment with done maintenance therapy require substantially more opioids is patients with chronic pain who require main- analgesia after cesarean delivery than control tenance opioid therapy and who are therefore physically patients. In one retrospective trial, patients on metha- dependent as expected, but who do not have an addiction. done maintenance therapy required 70% more Because this chapter focuses on patients with substance- to manage pain than controls on the basis of use disorders, this last group is not considered here. equivalents administered during a 72-hour period Understanding the concepts of pain intolerance, opi- postpartum. oid tolerance, and withdrawal prevention is essential to A different strategy is preferred if the patient is main- deliver effective analgesia in patients with substance- tained on buprenorphine therapy. Buprenorphine binds use disorders who are currently opioid-dependent strongly to m and k receptors and may prevent additional (groups 1 and 2 above). Opioid-dependent patients have from being effective. If the acute pain episode a measurable degree of pain intolerance and increased is anticipated (e.g., surgical pain), buprenorphine should sensitivity during cold pressor and thermal testing. be discontinued for several days before the episode and These changes may lead to increased opioid require- supplemented with methadone to prevent withdrawal. ments for effective pain relief. In addition, the issue of If the pain is unanticipated (e.g., from trauma) and it opioid tolerance must be considered. Patients on long- is not possible to discontinue the buprenorphine, use term opioid therapy commonly require higher doses of of an intravenous form of an opioid that binds strongly opioids to achieve analgesia. Cross-tolerance to opioids to m receptors, such as , is preferred (see Figure varies widely among patients. This variability necessi- 1-1) is an analog of fentanyl that is 10–15 tates extreme caution when substituting one opioid for times more potent than fentanyl. Higher doses of opi- another to gain better pain control or compensate for oids are often necessary to overcome the buprenorphine baseline opioid use during a short-term pain episode. occupation of receptors, so very close monitoring of Prevention of withdrawal is best accomplished if the the patient is required. If a patient is on very low-dose patient receives an amount equivalent to his/her daily buprenorphine, it may be possible to increase the daily opioid dose plus additional opioids to provide effective buprenorphine dose and split administration into four analgesia. Clinicians must gain the patient’s trust to get doses to achieve an analgesic effect. When buprenor- an accurate history of the dose and type of opioids he/ phine/naloxone is discontinued to manage anticipated she habitually consumes. pain with a full opioid agonist, the clinician should carefully change the patient back to buprenorphine/nal- Patients on Opioid Replacement Therapy oxone to prevent precipitating opioid withdrawal. Patients on methadone maintenance therapy should receive their usual daily dose of methadone plus a dif- Peri- and Postoperative Considerations ferent opioid agent for management of the acute pain. It Opioid-dependent patients scheduled for is best to avoid conversion of methadone to an equian- should be instructed to take their usual dose of oral opi- algesic dose of a different opioid because variations in oid (including methadone) on the morning of surgery

PSAP-VII • Chronic Illnesses 179 Pain Management Establish relationship of trust with the patient to facilitate open communication about opioid use

Buprenorphine Quantify daily baseline Methadone opioid consumption

Administer methadone Administer usual to meet baseline opioid methadone dose requirements Maximize use of adjunctive agents such as NSAIDs, acetaminophen

IV fentanyl by PCA pump Opioid of choice by OR long-acting opioid PCA pump OR long- scheduled plus acting opioid scheduled short-acting opioid Increase recovery-related activities and short-acting opioid supplemental doses such as attending meetings, meeting supplemental doses scheduled for times of with sponsor, participating in faith scheduled for times of anticipated increased pain community anticipated increased pain

Figure 1-1. Treatment algorithm for management of acute pain in patients on opioid replacement therapy. IV = intravenous; NSAIDs = nonsteroidal anti-inflammatory drugs; PCA = patient-controlled analgesia. Information from Savage SR, Horvath BA. Opioid therapy of pain. In: Ries RK, Fiellin DA, Miller LSC, Saitz R. Principles of . Philadelphia: Lippincott Williams & Wilkins, 2009:1329–51. with a sip of water. If the patient did not take an opioid at because withdrawal symptoms will develop owing baseline, a roughly equivalent loading dose of morphine to the lack of systemic opioids. One case report doc- or can be administered preoperatively umented use of epidural sufentanil that successfully as an oral elixir or intravenously, either at the induction managed pain and prevented withdrawal symptoms in of or during the operation. If the patient is a methadone-dependent patient with cancer. wearing a fentanyl patch, it should be kept on during If the patient receives long-term opioid therapy in surgery. If it is removed sooner than 12 hours before implantable devices (intrathecal or epidural), main- surgery completion, an intravenous fentanyl infusion tain their use during the perioperative period except for is indicated. A new patch should be applied intraoper- intrathecal devices containing baclofen. Baclofen’s cen- atively, but bridging with an agent having a more rapid tral effects and peripheral relaxant action onset of action will be necessary because of the slow may enhance neuromuscular blockade and contribute to onset of transdermal fentanyl. The fentanyl infusion hypotension or unacceptable levels of sedation. rate can be tapered during the patch’s onset of action. Although it is acceptable to use systemic opioids for Nonopioid Alternatives for Perioperative Analgesia analgesia in opioid-dependent patients, local anesthet- Limited data exist on the use of ics offer an alternative. Doses of local agents as an analgesic alternative or adjunct to opioids. If should be reduced in patients with hepatic dysfunction more evidence reveals that dexmedetomidine is effec- or hypoalbuminemia. Multimodal analgesia is accept- tive in these roles, use of this agent may be particularly able and may be required to achieve pain control. advantageous in the perioperative pain management Postoperative analgesia by epidural routes alone is of patients with alcohol addiction. Dexmedetomidine usually not advisable in patients dependent on opioids is an α2-agonist approved for use in

Pain Management 180 PSAP-VII • Chronic Illnesses sedation. It is 10 times more potent than and tool supportive of accountability and therefore recov- has a half-life of about 2.3 hours. Dexmedetomidine is ery. If there is concern that the patient may be diverting effective in the management of postoperative pain and the prescribed agent to purchase an alternative drug of alcohol withdrawal syndrome. There are case reports of choice, an opioid challenge test can be performed in patients with alcohol addiction in whom dexmedetomi- a closely supervised setting. The patient should have dine was used to maintain analgesia after induction with intravenous access established, and a supply of opioid an opioid agent. No opioids were administered intraop- antagonist should be available. The patient should then eratively or postoperatively, and the patients remained receive his/her usual dose and be observed carefully calm and comfortable. throughout the onset and peak effect. Use of dexmedetomidine permits limiting the use of A recent study at a Veterans Affairs medical center opioids and benzodiazepines, both of which have been showed that with appropriate support, many patients reported in case reports to stimulate alcohol craving with continuing substance use or aberrant behaviors can in recovering alcoholics. The analgesic effects of dex- successfully manage their pain. In this study, patients have been reported as a secondary end attended consultations with clinical pharmacists, signed point in trials and, in one small trial, were evaluated as “second-chance” agreements, and were subject to many the primary end point. This compared dex- of the other support measures previously mentioned. medetomidine with morphine in 34 surgical patients. Forty-five percent of the patients in the study were able Infusion of dexmedetomidine during the intraopera- to remain in the pain management program with their tive period reduced the need for morphine by 66% and behavior controlled to an acceptable level. was associated with a slower heart rate during recovery. Patient contracts are advisable for any patient with a This beneficial effect did not extend to the 24 hours after history of substance abuse who is initiating opioid ther- the patient’s transfer to the floor, however, so the overall apy. The contract should clearly specify expectations opioid-sparing effect of this agent is questionable. of the patient and the provider, including reasons for which opioid therapy will be discontinued. Contracts commonly stipulate a greater intensity and frequency Patient Education and of monitoring than is standard for patients at lower risk Support Systems of aberrant drug behaviors. Family members should become educated about both addiction and pain and A primary goal of pain management in patients with can be enlisted to provide monitoring, support, and dis- addiction is to control pain while avoiding withdrawal pensing of drugs. and relapse. Additional measures are required in this For patients with addiction experiencing pain who are patient population to support this goal. Selection of treat- pharmacists, recovery networks can provide ment modality may be influenced by the risks associated monitoring and accountability, and most such networks with opioid therapy. More invasive and/or expensive have formal arrangements with the local state board of options can be used earlier in therapy to minimize opioid . Other health care professionals (e.g., physi- use. Earlier use of long-acting opioids is preferable, even cians and nurses) also have respective recovery groups though they may be more expensive, because the use of with connections to the local licensing board that can short-acting opioids has a greater propensity to stimulate provide support and accountability. It is important for craving and relapse. The patient’s goal of avoiding relapse the pharmacist with a substance abuse disorder to be can also be supported by limiting the quantities of opi- known to the local pharmacist recovery network and/or oids dispensed to the patient at a single time. Increasing board of pharmacy, both for the benefit of the pharmacist recovery-related activities can be a considerable source with the addiction and for public safety. If the pharma- of support for many patients. This might take the form cist is known only to an employee assistance program, of meeting more often with a 12-step program sponsor a change in job will result in not receiving the support or group, becoming more active in a faith community, or he/she requires, and the public will not be protected. If increasing daily readings and journaling. a pharmacist with an addiction and concomitant pain The frequency of monitoring should be increased shows aberrant drug behaviors, the most appropriate compared with pain patients who do not suffer from place to report these behaviors is to the state board of addiction. Increased monitoring of tests such as urine pharmacy through a pharmacist recovery network, if one drug screens to detect illicit substances can be help- is available, or directly to the board of pharmacy, if no ful in providing accountability to support the patient’s pharmacist recovery network exists. goal of maintaining recovery. Some evidence suggests that patient populations who undergo routine urine drug screens as part of an overall adherence monitor- Quality Improvement ing program have a reduced prevalence of illicit drug use It is important for pain patients to understand that a during long-term opioid therapy. Pill counts are another pain-free state is an unrealistic therapeutic end point.

PSAP-VII • Chronic Illnesses 181 Pain Management Realistic outcomes for patients with chronic pain 2. Pain Management Without Psychological Dependence: include substantial pain reduction, increase in func- A Guide for Healthcare Providers. Substance Abuse in tional ability, increased quality of life, and decreased Brief Fact Sheet. 2006. Volume 4. Issue 1. Substance psychological complications of chronic pain. Patients Abuse and Services Administration. U.S. Department of Health and Human Services. should be assessed for signs of functional impairment Available at http://kap.samhsa.gov/products/brochures/ such as inability to participate in household chores or to text/saib_0401.htm. Accessed December 7, 2010. leave the house to participate in activities and increased This fact sheet provides a brief overview of several time spent reclining or remaining in nightclothes. Use critical concepts regarding pain management and the of the Sheehan Scale can help quantify func- interface with substance dependence. It includes many tional impairment and document response to treatment. references and a resource list that guides the reader to further information on a variety of related issues such as regulatory and substance abuse treatment informa- Conclusion tion. Nonopioid therapy options and important opioid Pain management in patients with substance use dis- therapy considerations are discussed, as are barriers to prescribing opioids for pain and strategies to reduce orders is a complex, challenging, and common clinical the risk of psychological dependence on opioids. Signs scenario. Clinicians must be attentive to all the con- of inappropriate opioid use by patients are listed, along siderations common to any patient with pain, as well with suggestions for actions to take if a pattern of these as to the special considerations of this patient popula- signs develops. The fact sheet also provides practical tion. Patients and prescribers often have attitudes and information on counseling patients suspected of having fears that are barriers to quality care and increase the substance-use problems. chance of suboptimal therapy. Open communication 3. Barry D, Beitel M, Joshi D, Schottenfeld R. Pain and and increased monitoring are important components of substance-related pain-reduction behaviors among caring for patients with substance use disorders. opioid dependent individuals seeking methadone main- tenance treatment. Am J Addict 2009;18:117–21. Annotated Bibliography These research findings could have implications for planning pain management services in conjunction with 1. Meyer M, Wagner K, Benvenuto A, Plante D, Howard methadone maintenance programs. Some 293 subjects D. Intrapartum and postpartum analgesia for women applying for enrollment in methadone maintenance maintained on methadone during pregnancy. Obstet programs were asked to complete an anonymous survey Gynecol 2007;110:261–6. as part of the screening process at the initial appoint- Opioid-dependent patients on methadone mainte- ment. Subjects were told the survey answers would not nance therapy require higher doses of analgesia after affect their methadone treatment at the clinic. The brief cesarean section than control patients. This study evalu- survey assessed the prevalence of pain types (recent vs. ated whether analgesic requirements can be expected to lifetime history of chronic pain), characteristics of pain be higher in patients on methadone maintenance ther- (intensity, frequency), substance-related pain reduc- apy during the intrapartum and postpartum periods. tion behaviors, and demographics. On the basis of Sixty-eight patients treated with methadone for opiate answers to the pain-related items, subjects were classi- dependency during pregnancy were matched retro- fied into two pain groups: (1) no recent pain (in the past spectively to control women. Thirty-five of the patients 7 days) or (2) recent pain (only in the past 7 days). The maintained on methadone had vaginal deliveries, and recent pain group was subdivided into the two groups: (1) moderate pain intensity with lifetime history of 33 underwent a cesarean section. The primary outcome chronic pain; or (2) moderate pain intensity without was cumulative opiate use expressed as oxycodone lifetime history of chronic pain. Of the study subjects, equivalents, and secondary outcomes were self- 88% reported recent pain. This illustrates the need for assessed pain scores and intrapartum analgesia. This practitioners to understand appropriate management of study found a statistically significant difference in pain short-term pain in patients on opioid replacement ther- scores between the patients maintained on methadone apy. The results are consistent with studies examining maintenance therapy and the patients in the control pain in patients currently enrolled in methadone main- group during both vaginal and cesarean delivery. This tenance therapy. Eighty-three percent of those who difference did not result in greater opioid use intrapar- reported recent pain characterized their pain as moder- tum in the methadone group, but it did result in a 70% ate to severe based on a 5-point scale. Sixty-six percent increase in opioid use (80.1 mg ± 48.4 vs. 47.2 mg ± of subjects who reported recent pain of at least mod- 19.1; p<0.001) in the postpartum period among women erate intensity reported a lifetime history of chronic on methadone maintenance therapy who delivered by pain. Subjects who reported recent pain of moderate cesarean section. These findings suggest that greater intensity reported no marked difference in substance- than normal doses of opioids are necessary for effective related pain reduction behavior (i.e., using more than management of cesarean section–induced acute pain in the prescribed amount of opioids) among the group patients on methadone maintenance therapy. with lifetime pain and the group without lifetime pain.

Pain Management 182 PSAP-VII • Chronic Illnesses Many subjects reported greater use of benzodiazepines of opioid therapy plus or minus adjunctive drugs. (7) than prescribed or use of benzodiazepines that were not Reassess pain score and level of function. (8) Regularly prescribed at all. Clinicians working with pain patients assess the four A’s of pain medicine (analgesia, activity, on methadone maintenance therapy should be aware adverse effects, and aberrant behavior), and document that benzodiazepines may be used for self-management a fifth A (affect). (9) Periodically review pain diagnosis of pain. Patients should receive education about the and comorbid conditions, including addictive disorders. overdose and sedation dangers of concomitant unmoni- (10) Provide documentation. Patients can be stratified tored medical use of benzodiazepines and methadone. into three risk categories to determine which patients’ pain can be managed in a primary care setting. Group 4. Ives TJ, Chelminski PR, Hammett-Stabler CA, Malone I (primary care patients) have no substance-use disor- RM, Perhac JS, Potisek NM, et al. Predictors of opi- der or history of it and a noncontributory family history. oid misuse in patients with chronic pain: a prospective Group II (primary care patients with specialist support) cohort study. BMC Health Serv Res 2006;6:46. may have a history of a treated substance-use disorder This study of 196 patients with chronic, noncancer or a significant family history of problematic drug use. pain treated with opioids helps delineate patients for They may also have a past or current psychiatric disor- whom the risk-benefit ratio of opioid use is less favor- der. Group III (specialty pain management) patients are able based on the risk of opioid misuse. Opioid misuse the most complex because of an active substance-use was defined as abnormal drug screens (absence of pre- disorder or a major untreated psychopathology. scribed opioids, presence of controlled substances not prescribed by research prescribers, or presence of stim- 6. Apolone G, Corli O, Negri E, Mangano S, Montanari M, ulants such as cocaine or ), evidence of Geco MT, et al. Effects of transdermal buprenorphine “doctor shopping,” opioid diversion, or prescription on reported outcomes in cancer patients: results from forgery. Patients were recruited from within an aca- the Cancer Pain Outcome Research study (CPOR) demic practice. Patients signed a study group. Clin J Pain 2009;25:671–82. medication agreement on enrollment that facilitated This study evaluated the efficacy of transdermal data collection through review of clinical history, med- buprenorphine in patients with cancer. This was a mul- ications, outside medical records, and communication ticenter, open-label, prospective, nonrandomized study with and providers in addition to urine with 1801 subjects. The primary outcome of the study toxicology screens. The mean patient age was 55 years, was pain intensity as measured by the 11-point rating and most subjects were white men. Predictors of mis- scale of the Brief Pain Inventory. Thirty-four percent use identified on multivariate analysis included younger of subjects on transdermal buprenorphine reported at age, past cocaine abuse, driving under the influence or least a 2-point improvement in “worst pain” scores, 20% other drug-related conviction, and past . reported improvement in pain relief, and 40% reported There was no evidence of a correlation between pain improved satisfaction with pain management. This scores and misuse. Race, income, education, depression study is limited by its observational design, but it does score, disability score, and literacy were also unassoci- suggest that further, better-designed comparative stud- ated with misuse. One limitation of this study was the ies of transdermal buprenorphine are warranted. It also failure to assess a correlation between family history suggests that this delivery method is likely to be received and risk of misuse. This study suggests that patients well by patients. Transdermal buprenorphine could with a history of alcohol or cocaine abuse or related become an important therapeutic tool for pain man- convictions should be carefully monitored for signs of agement in patients with any type of addiction whose misuse when opioids are prescribed. pain does not exceed buprenorphine’s ability to treat. A transdermal buprenorphine formulation was approved 5. Gourlay DL, Heit HA, Almahrezi A. Universal pre- in the United States in 2010 for use in chronic pain at a cautions in pain medicine: a rational approach to the dose not to exceed 20 mcg/hour. Buprenorphine sub- treatment of chronic pain. Pain Med 2005;6:107–12. lingual formulation is typically dosed at 8–16 mg/day This article describes the components of universal as an opioid replacement therapy. precautions as the term applies to pain management. The authors provide a scheme for classifying 7. Chou R, Fanciullo G, Fine P, Adler J, Ballantyne J, patients into risk categories and recommendations for Davies P, et al. Clinical guidelines for the use of chronic management and referral. A summary of the 10 steps of opioid therapy in chronic noncancer pain. J Pain universal precautions in pain medicine are as follows. 2009;10:113–30. (1) Make a diagnosis (address comorbid conditions). These guidelines were issued jointly by the American (2) Perform a psychological assessment including risk Pain Society and the American Academy of Pain of addictive disorders (urine drug screening should be Medicine based on a systematic evidence review of considered). (3) Gain informed consent. (4) Prepare data from adult patients on long-term opioid therapy. a treatment agreement (patient contract is important The guidelines were developed in recognition of the to set boundaries and to make early identification and legitimate medical need for opioids in some patients intervention around aberrant behavior possible). (5) with chronic noncancer pain but also in recognition Perform a pre- and postintervention assessment of pain of the growing incidence of prescription opioid mis- level and function. (6) Perform an appropriate trial use and mortality associated with opioid use. These

PSAP-VII • Chronic Illnesses 183 Pain Management guidelines recommend that patients be assessed before and those without. Patients with mental health or sub- a trial of long-term opioid therapy for the potential risk- stance abuse disorders have often been excluded from benefit ratio based on screening tools such as the opioid trials, so little evidence exists about the relative SOAPP-R and for pain management. risk versus benefit of using opioids in this patient popu- Clinicians are advised to obtain informed consent from lation. Data were collected from two sources: Arkansas the patient before initiating long-term opioid therapy. Medicaid enrollees and a national commercially insured The guidelines advocate the use of a patient contract. group of patients. Patients were included on the basis of Specific monitoring recommendations are offered on ICD (International Classification of ) codes the basis of the patient’s risk stratification. The recom- for back pain, neck pain, joint pain, , or HIV/ mendations range from monitoring once every 3–6 AIDS (acquired immunodeficiency syndrome); age (at months for low-risk patients to monitoring weekly for least 18 years old); and enrollment in the insurance pro- patients at very high risk. Monitoring tools such as gram (enrolled for at least 9 months). Exclusion criteria random urine drug screens, prescription monitoring included patients with a cancer diagnosis, home program data, pill counts, caregiver interviews, and residents, and patients. Chronic opioid therapy instruments designed to detect aberrant drug-related was defined as receiving greater than a 90-day supply behavior are advocated. The use of chronic opioid ther- of opioids during the calendar year. Rates of opioid use, apy in patients with a history of substance abuse is considered appropriate in some circumstances, with doses, and types of opioids prescribed were evaluated. additional monitoring and consultative services from In both the Medicaid and commercially insured popu- an addiction medicine specialist if possible. Guidelines lations, there was a statistically significant difference in are offered for and discontinuation. the chronic use of opioids for noncancer pain between Evidence was not presented regarding specific dis- patients with and without mental health and substance ease states for which chronic opioid therapy would be abuse disorders. Patients with mental health disorders appropriate. showed greater chronicity of use and a greater increase in use during a 5-year period of the study. Limitations 8. Trescot AM, Helm S, Hansen H, Benyamin R, Glaser of this study include the reliance on administrative SE, Adlaka R, et al. Opioids in the management of diagnosis with no clinical assessment of patients, the chronic non-cancer pain: an update of American exclusion of opioids bought over the Internet or pur- Society of the Interventional Pain Physicians’ (ASIPP) chased illegally, and indistinguishability of methadone guidelines. Pain Physician 2008;11:S5–S62. used for maintenance therapy from methadone used for These guidelines were issued to address inconsisten- pain management. This study illustrates that a patient cies in philosophy among different groups regarding population most at risk of addiction is also receiving the opioid use in chronic noncancer pain, to improve pain greatest amount of opioids. management, and to decrease the incidence of abuse and . An extensive review of the litera- 10. Alford DP, Compton P, Samet JH. Acute pain ture resulted in recommendations graded using the U.S. management for patients receiving maintenance meth- Preventive Services Task Force criteria. The guidelines adone or buprenorphine therapy. Ann Intern Med include a broad range of information including terminol- 2006;144:127–34. ogy, , documentation recommendations, This article provides a concise review of common and adherence monitoring. The best evidence for effec- misconceptions of health care providers that result tiveness of long-term opioids in reducing pain and in undertreatment of acute pain in patients receiv- improving functional status for 6 months or longer is for ing opioid-replacement therapy. The article discusses transdermal fentanyl and sustained-release morphine. the pharmacokinetic and pharmacodynamic factors Transdermal fentanyl patches are not appropriate as ini- involved in the lack of analgesia patients receive from tial therapy in opioid-naïve individuals. In patients with substance-use disorders, sustained-release morphine is opioid replacement therapy alone, including the con- a better choice than fentanyl because of concerns about cepts of tolerance and opioid-induced hyperalgesia. The tampering and the potency of fentanyl. The weakest evi- authors compare the risk of relapse from use of opioids dence for long-term use of opioids is for methadone and for analgesia in patients on opioid-replacement ther- . A sample patient contract is included in apy with the risk of relapse associated with unrelieved the guidelines, as is information about urine drug tests. pain. The authors address concerns regarding the addi- tive effects of opioid analgesics and opioid-replacement therapy. The article includes a discussion of the desire to 9. Edlund MJ, Martin BC, Devries A, Fan MY, Brennan B, avoid manipulation by drug-seeking patients. General Sullivan MD. Trends in use of opioids for chronic non- recommendations for the provision of pain manage- cancer pain among individuals with mental health and ment in patients on opioid replacement therapy are substance use disorders: the TROUP study. Clin J Pain provided, as well as information specific to each of the 2010;26:1–8. two most commonly used opioid-replacement agents This study compared the use of prescription opioids (methadone and buprenorphine). for chronic noncancer pain in two patient populations, those with mental health and substance abuse disorders

Pain Management 184 PSAP-VII • Chronic Illnesses Self-Assessment Questions

1. A 32-year-old woman is admitted to the for C. Methadone 100 mg intravenously on the day surgical repair of a broken femur from a motor vehi- of surgery plus oxycodone/acetaminophen cle crash. In the operating room she received 2 mg 10/650-mg dose every 4 hours postoperatively. of morphine by mouth. Six hours later she rates her D. Fentanyl patch 100-mcg dose placed the day of pain as 9/10 and complains of nausea and inability surgery. to take drugs intravenously. Her medical history is significant for heroin use for 10 years before attain- 4. A 32-year-old woman suffers chronic pain from ing remission from substance dependence. Her only sustained in an industrial accident 6 months home medication is methadone 100 mg by mouth ago. She has a 15-year history of marijuana use and daily as part of a methadone maintenance program. reports current use on weekends. 800 mg Which one of the following is the most appropri- orally every 6 hours failed to control her pain. Her ate choice to treat this patient’s pain? is concerned about prescrib- A. Methadone 90 mg subcutaneously daily plus ing long-term opioids for her because of her history 30 mg intramuscularly now. of illicit substance use. Which one of the follow- B. Methadone 120 mg subcutaneously daily plus ing is most likely to minimize the addiction risk morphine 5 mg intravenously every 4 hours. associated with chronic therapy in this C. Methadone 50 mg intravenously daily plus patient? morphine patient-controlled analgesia (PCA). A. Make a patient contract between the physician D. Methadone 90 mg intravenously daily plus and the patient. morphine 2.5 mg intravenously every 4 hours. B. Establish a relationship with her family members. 2. A 52-year-old man presents to the pain clinic with C. Limit prescribed to tramadol and a history of degenerative disc disease and a current propoxyphene. pain score of 8/10 secondary to a recent occupa- D. Use low-dose, low-potency narcotics. tional back injury. He has been receiving morphine 15 mg orally twice daily for 5 years. He is mar- 5. A 32-year-old woman has been maintained on daily ried, and his mother had an alcohol addiction. He buprenorphine and naloxone as opioid replacement reports occasional use of marijuana but no other therapy for 2 years. She has an appointment for illicit drugs. Which one of the following is most sinus surgery next week. She has been in remission predictive of this patient’s risk of displaying with no history of use during aberrant drug behaviors in response to opioid the past 2 years. Which one of the following is pain management? the most appropriate strategy to manage this A. Duration of morphine use. patient’s anticipated surgical pain? B. Pain intensity of 8/10. A. Buprenorphine and naloxone orally on the C. Current use of marijuana. day of surgery plus morphine intravenously D. Family history of substance abuse. postoperatively. B. Methadone orally daily for 7 days before and 3. A 26-year-old woman who has been on metha- including the day of surgery, plus sustained- done maintenance therapy during her pregnancy release morphine postoperatively. presents to the hospital for a scheduled cesarean C. Buprenorphine and naloxone orally on section. She does not plan to breastfeed her baby. the day of surgery plus methadone orally Her home medications include methadone 100 mg postoperatively. orally daily. Which one of the following would D. Methadone orally on the day of surgery plus best address this patient’s anticipated postpar- buprenorphine orally postoperatively. tum pain? A. Methadone 100 mg orally on the day of 6. A 52-year-old man who suffered from active alco- surgery plus oxycodone/acetaminophen hol dependence for 15 years entered remission 6 10/650 mg every 6 hours postoperatively. months ago. His medical history includes diabetes, B. Buprenorphine 8 mg on the day of surgery plus refractory hypertension, heart failure, gastric vari- oxycodone/acetaminophen 7.5/650-mg dose ces, ascites, and cirrhosis. He presents with pain in every 4 hours postoperatively. both feet that he describes as “like stepping on pins

PSAP-VII • Chronic Illnesses 185 Pain Management and needles” and that occurs on a daily basis. He that her pain is much better now, and she uses the has unsuccessfully tried to relieve the pain at home hydrocodone prescribed for her only occasionally. with acetaminophen and warm water soaks. Which Which one of the following is the best assess- one of the following is the best initial therapy for ment of this patient’s clinical circumstance? this patient’s pain? A. She is an addict who has reverted to the use of A. Duloxetine. street drugs primarily. B. Pregabalin. B. Her drug-seeking behaviors of early refills, C. Venlafaxine. use of illicit drugs, and obtaining opioid D. Gabapentin. prescriptions from several providers prove she is an addict. 7. A 42-year-old woman is hospitalized secondary to C. Her behavior is typical of pseudoaddiction injuries sustained in a motor vehicle crash 6 hours because the undesirable behaviors decreased ago. She has taken methadone 80 mg/day orally as her pain decreased. as opioid replacement therapy for 1 year after a D. She was tolerant of opioids after 10-year history of heroin use. Her medical history hospitalization but has returned to is otherwise nonsignificant, and she takes no other her baseline response to opioids and, home medications. Which one of the following is consequently, requires less now to control her the most appropriate strategy for managing this pain. patient’s acute pain? A. Methadone 80 mg orally on the day of surgery 9. A 53-year-old man with a 15-year history of opioid plus methadone orally every 8 hours. addiction was admitted to the intensive care unit 2 B. Methadone 40 mg intravenously on the day weeks ago for extensive injuries received in a motor of surgery plus morphine 10 mg orally every 4 vehicle crash. He reported daily use of opioids hours postoperatively. before this hospitalization, and required high-dose C. Morphine sustained release in an opioids during his complicated hospital stay. He is dose to methadone 80 mg orally being discharged today to an addiction treatment on the day of surgery plus immediate-release program. He is expected to suffer chronic pain as morphine orally postoperatively. a result of his injuries. Which one of the follow- D. Methadone 80 mg orally on the day of surgery ing is the best recommendation to manage this plus morphine intravenously by PCA pump patient’s pain after discharge from the acute care postoperatively. hospital? A. Morphine 30 mg sustained release twice daily 8. A 27-year-old woman sustained several broken plus morphine immediate release 30 minutes in a motor vehicle crash that required sur- before activities associated with increased gical intervention in February. She was prescribed pain. hydrocodone 5 mg plus acetaminophen 500 mg B. Methadone 80 mg orally at bedtime plus three times/day as needed on hospital discharge. morphine immediate release every 3 hours as She presented to her usual pharmacy three times needed. in March requesting early refills, and her profile C. Fentanyl 75-mcg patch every 72 hours plus revealed she had narcotics from different prescrib- morphine immediate release every 4 hours as ers filled in March, also. When questioned, the needed. patient said that she had not been truthful with D. Methadone 70 mg orally daily plus the prescribers about the amount of narcotics she hydrocodone 7.5 mg and acetaminophen every already had and that she had taken narcotics pur- 6 hours. chased on the street. She stated her pain keeps her awake at night, making it hard to concentrate 10. A 33-year-old woman has chronic leg pain from during the day with only the original narcotic she a crush injury sustained in a motor vehicle acci- was prescribed. She presents to the pharmacy again dent years ago. She was maintained on methadone in May to pick up a narcotic refill, and a review of 30 mg three times/day at a pain clinic for 5 years. her profile reveals that she has not filled a narcotic At that time, her average pain intensity was 2/10. prescription in several weeks, even though she sub- She had no history of seeking early refills or addi- mitted a prescription in April that was never picked tional prescriptions from different physicians. She up. A quick check with other pharmacies in the moved to a new city and established care with a small town confirms that she has not filled nar- physician, who is concerned about cotic prescriptions elsewhere. The patient reports prescribing “too much narcotics.” This physician

Pain Management 186 PSAP-VII • Chronic Illnesses changed her regimen to 7.5 mg of hydrocodone and to change opioids or increase the dose, saying he is 500 mg of acetaminophen twice daily. She sought afraid of the potential to “switch” his drug of choice early refills on her hydrocodone prescription in 3 of from alcohol to opioids if the dose is increased or the last 4 months, claiming that she had lost the bot- has a lesser analgesic effect with a different agent. tle or someone stole her it from her. Telephone calls Which one of the following is best to add to this to area pharmacies reveal that she has filled many patient’s current regimen? hydrocodone prescriptions from several local phy- A. Transcutaneous electrical stimulation. sicians. When confronted with this information, B. Trigger point injections. she becomes tearful and states that she finds it hard C. Botulinum toxin injections. to sleep at night or go to work when her pain is so D. Spinal cord stimulation. intense. She rates her pain level while receiving the new analgesic regimen as 9/10. In addition to dis- 13. A 51-year-old woman has , cir- continuing her current medications, which one rhosis, gastric varices, chronic disease, and of the following is the best choice for treating chronic neck pain. She self-assesses her pain as this patient’s pain? 6/10. She has tried unsuccessfully to treat her neck A. Tramadol. pain with over-the-counter naproxen sodium, heat- B. Oxycodone/acetaminophen. ing pads, and glucosamine/chondroitin. Which C. Methadone. one of the following is the best recommendation D. Nonsteroidal anti-inflammatory drug. to manage this patient’s chronic pain? A. Ibuprofen 800 mg orally three times/day. 11. A 55-year-old man has just relocated with his fam- B. Tramadol 100 mg orally every 6 hours/day. ily to a new state. He presents to a family medicine C. Cyclobenzaprine 10 mg orally every 8 hours clinic to establish care with a new primary care daily. provider. He is seeking management of gastroesoph- D. Morphine sustained release 15 mg orally every ageal reflux disease, hypertension, and chronic back 12 hours. pain. He has a 30-year history of alcohol and opi- oid abuse. He is concerned about the physician’s 14. A 42-year-old woman presents to a family medi- willingness to address all of his problems or accept cine clinic complaining of tingling and burning him as a patient if the physician is aware of his sub- in her lower extremities. Her medical history stance abuse history. The physician is concerned includes diabetes, hypertension, opioid addiction, about not contributing to drug-seeking behaviors and heart failure. Her current drugs include lisino- and the liability involved with prescribing narcot- pril, , , insulin, and methadone. ics. Which one of the following is the best initial Which one of the following is the best option for step in constructing a therapeutic plan to over- come barriers to this patient’s care? initial management of this patient’s pain? A. Engage in frank, nonjudgmental, two-way A. Pregabalin 50 mg orally three times/day. dialogue regarding substance use. B. Phenytoin 100 mg orally three times/day. B. Document current substance use. C. Carbamazepine 100 mg orally daily. C. Assess risk factors predictive of aberrant drug D. Duloxetine 60 mg orally daily. behaviors. D. Establish a relationship with the patient’s 15. A 45-year-old pharmacist suffers from degenerative family. joint disease. He says that he used cocaine in the remote past and had two driving while intoxicated 12. A 42-year-old man suffers from and convictions about 10 years ago. His family history chronic low back pain. His alcohol addiction has is positive for alcoholism. He has occasionally used been in remission for 7 years. His job as a postal prescribed opioids appropriately for acute pain. His carrier in a dense urban environment requires him chronic pain has not responded to acupuncture, to walk 5–6 miles each day while carrying heavy herbal remedies, or nonsteroidal anti-inflammatory loads. He has been maintained on morphine sus- drugs. Which one of the following would best tained release 30 mg two times/day for several minimize addiction risk if added to this patient’s years; this resulted in a pain level of 3/10 and abil- treatment plan? ity to continue performing his job. His pain has A. Use of a patient contract. been increasing during the past several months. He B. Use of less-potent opioid agents. currently assesses the level at 6/10, which makes it C. Involvement in a 12-step support group. difficult for him to perform his job. He is reluctant D. Enrollment in a pharmacist recovery network.

PSAP-VII • Chronic Illnesses 187 Pain Management 16. Your co-worker, a 27-year-old pharmacist, has suf- of this woman’s diabetic neuropathy has been mod- fered chronic pain since a motor vehicle crash 3 erately successful, resulting in an assessed level years ago. She wears a fentanyl patch, and her pain is of pain of 5/10. This pain level is unacceptable to well controlled. Recently, she was observed stealing her because it interfers with her ability to stand on several hundred hydrocodone tablets. When con- her feet to do her job. Which one of the follow- fronted, she explained that hydrocodone gives her ing agents would be best to add to her therapy to the energy she requires to complete the demand of improve control of this patient’s pain? working 12-hour days in a high-volume retail phar- A. Capsaicin cream. macy. To best address the interests of both the B. Duloxetine. pharmacist and patient safety, which one of the C. Tramadol. following should you first inform of her hydro- D. Mexelitine. codone hoarding behavior? A. Fentanyl patch prescriber. 20. A 39-year-old man has peripheral neuropathy, alco- B. State board of pharmacy. hol addiction, , gastroesophageal reflux C. Drug Enforcement Agency. disease, anxiety, depression, , and throm- D. Pharmacy’s employee assistance program. bocytopenia. He underwent a trial of gabapentin for neuropathic pain, but discontinued it after 10 17. A 63-year-old man presents to the family medicine days when he “couldn’t feel any difference” and “felt clinic complaining of burning and tingling in his zonked out all the time.” During a recent hospital- extremities, inability to sleep at night, and a feeling ization, he experienced pronounced pain relief from of hopelessness. He also reports a 20-pound weight intravenous lidocaine. Which one of the following gain over the past 6 months, and lack of ability to would be best to try next to manage this patient’s concentrate. His medical history includes chronic neuropathic pain? obstructive pulmonary disease, gastroesophageal A. Carbamazepine. reflux disease, and alcoholism (heavy consump- B. Amitriptyline. tion for 20 years; in recovery for 15 years). Which C. Pregabalin. one of the following is the best choice for initial D. Mexiletine. management of this patient’s pain? A. Tramadol. B. Duloxetine. C. Clonazepam. D. Pregabalin.

18. A 59-year-old woman presents to her primary care practitioner complaining of a burning sensation in her feet. Her medical history includes type 2 diabe- tes mellitus, hypertension, , depression, and anxiety. All of her conditions are well controlled with her current treatment regi- mens. She has a remote history of opioid abuse. Her current drugs include , lisinopril, hydro- chlorothiazide, and citalopram. Which one of the following is the best choice for initial pain man- agement in this patient? A. Amitriptyline. B. Venlafaxine. C. Tramadol. D. Lidocaine 5% patch.

19. A 46-year-old woman suffers from diabetic neurop- athy, depression, anxiety, and alcohol dependence. She is an alcoholic and has been in remission for 5 years. Her home drugs include , amitrip- tyline, and . Amitriptyline monotherapy

Pain Management 188 PSAP-VII • Chronic Illnesses