Peggy Compton

College on Problems of Drug Dependence taskforce on prescription opioid non-medical use and abuse: position statement

This position paper from the College on Problems of Drug Dependence addresses the issues related to non-medical use and abuse of prescription opioids. A central theme throughout is the need to strike a balance between risk management strategies to prevent and deter prescription opioid abuse and the need for physicians and patients to have appropriate access to opioid pharmaceuticals for the treatment of pain. The epidemiology of prescription opioid use and abuse is reviewed. Non-medical use and abuse of prescription opioids are on the rise in the United States, illicit use of several widely prescribed opioids has increased disproportionately more than illicit use, and the prevalence of prescription opioid abuse appears to be similar to that of heroin and cocaine abuse. There is a paucity of abuse liability testing of prescription opioids, and methods should be developed to fill critical gaps in our knowledge in this area. The role of regulatory agencies in preventing diversion of prescription opioids and identifying potential sources of diversion are discussed. More research is needed to identify those populations most at risk for abusing prescription opioids, and then to develop appropriately targeted prevention programs. Treatment options are discussed; these depend on whether or not an abuser is in pain. Prescription opioid abuse has harmful ramifications for the legitimate and appropriate use of opioids, including stigmatization, opiophobia, and undertreatment of pain. Recommended steps to take include further epidemiological research, laboratory testing of prescription opioids to determine abuse liability, and clinical trials to determine the efficacy of different approaches to the prevention and treatment of prescription opioid abuse.

Pain intolerance in opioid-maintained former opiate addicts: effect of long-acting maintenance agent.

Patients on methadone maintenance therapy are relatively intolerant of pain, a finding hypothesized to reflect a hyperalgesic state induced by chronic opioid administration. To explore if the intrinsic activity of the opioid maintenance agent might affect expression of hyperalgesia in this population, withdrawal latency for cold-pressor (CP) pain was compared between small groups of methadone-maintained (n = 18), buprenorphine-maintained (n = 18), and matched control (n = 18) subjects. The opioid-maintained groups had equal and significantly shorter withdrawal latencies than controls, however it is possible that high rates of continued illicit opioid use precluded finding differences between methadone and buprenorphine groups. Differential effects of maintenance agent were found for the few subjects without illicit opioid use, such that withdrawal latencies for methadone-maintained (n = 5) were less than for buprenorphine-maintained (n = 7) which were less than controls (n = 18). Diminished pain tolerance in patients receiving opioid maintenance treatment has significant clinical implications. More research is needed to determine if buprenorphine offers advantages over methadone in this regard.

Acute Pain Management for Patients Receiving Maintenance Methadone or Buprenorphine Therapy

The treatment of opioid dependence, both on heroin and prescription narcotics, with opioid agonist therapy (OAT) (that is, methadone or buprenorphine) is effective: It decreases opioid and other drug abuse, increases treatment retention, decreases criminal activity, improves individual functioning, and decreases HIV seroconversion (1-5). Because of the increasing use of these medications for prolonged periods in primary care, a practice called office-based opioid treatment, nonaddiction specialists will be treating more of these affected patients in clinical practice, including those with episodes of acute pain (6-11). Adequate treatment of acute painful conditions is an essential dimension of quality medical care (12-17). Inadequate treatment is common among a wide spectrum of patients (18-23). Nonopioid analgesics (for example, nonsteroidal anti-inflammatory drugs and acetaminophen) are recommended for treating acute pain; however, moderate to severe acute pain will often require opioid analgesics (24). Physicians may not prescribe effective opioid analgesia across all patient populations because of fears of cognitive, respiratory, and psychomotor side effects; iatrogenic drug addiction; and prescription drug diversion (25, 26). This tendency of health care professionals to undermedicate patients with opioid analgesics has been termed opiophobia (27). Such fears are exaggerated when treating patients with a known history of a substance use disorder. The provision of opioid analgesics to a patient with opioid dependence receiving OAT can be particularly challenging (28, 29). We highlight the issues associated with the management of acute pain in patients receiving OAT and describe theoretical and empirical findings that suggest unique requirements for opioid analgesia for such patients. In addition, we identify common misconceptions of health care providers that underlie inadequate pain management and provide practical recommendations for the analgesic management of acute pain in this special clinical population. To help illustrate these issues, we present the following clinical vignette from our experience. A 29-year-old woman reported severe right arm pain after fracturing her olecranon process. She had a history of injection heroin use and received methadone, 90 mg/d, in a methadone maintenance program. In the emergency department, she seemed uncomfortable and received one 2-mg dose of intramuscular morphine sulfate over 6 hours. While hospitalized, she continued to report severe pain despite receiving her daily methadone dose and intramuscular ketorolac. She was told that her usual methadone dose should help control her pain. She was labeled as drug-seeking because of her constant requests for additional pain medications. Pain and Opioid Dependence The clinical conditions of pain and opioid dependence are not unrelated phenomena (30-32). Forty-one years ago, Martin and Inglis (33) observed that opioid-addicted patients abuse opioids to treat an abnormally low tolerance for painful stimuli. Opioids, whether administered with analgesic or addictive intent, activate opiate receptors in the locus coeruleus and amygdala, which provide both analgesia and reward (34, 35). The presence of one condition seems to influence the expression of the other. Clinical examples of this include how the presence of acute pain seems to decrease the euphorogenic (pleasurable) qualities of the opioid (36) and how the presence of addictive disease seems to worsen the experience of pain. With respect to the latter, Savage and Schofferman (37) found a decade ago that persons with addiction and pain have a syndrome of pain facilitation. Their pain experience is worsened by subtle withdrawal syndromes, intoxication, withdrawal-related sympathetic nervous system arousal, sleep disturbances, and affective changes, all consequences of addictive disease (37). Supporting a negative effect of addiction on pain tolerance, patients who abuse stimulants and those who abuse opioids have been shown to be less tolerant of pain than their peers in remission (38, 39). The clinical approach is complicated by the confusing and often misunderstood terminology used in pain management and addiction medicine (40-43). As detailed in Table 1, physical dependence and tolerance are typical and predictable physiologic consequences of opioid exposure. These terms in and of themselves do not indicate maladaptive behaviors and do not meet the diagnostic criteria of substance dependence (41) outlined in the Diagnostic and Statistical Manual of Mental Disorders, 4th edition, text revision, without, for example, loss of control or continued use despite harm. Drug-seeking is another commonly ill-defined term that may indicate the presence of addiction but, as will be described, can also reflect pain reliefseeking because of unrelieved pain or anxiety about pain management (44). Table 1. Pain and Addiction Terminology Common Misconceptions Four common misconceptions of health providers result in the undertreatment of acute pain in patients receiving OAT: 1) The maintenance opioid agonist (methadone or buprenorphine) provides analgesia; 2) use of opioids for analgesia may result in addiction relapse; 3) the additive effects of opioid analgesics and OAT may cause respiratory and central nervous system (CNS) depression; and 4) the pain complaint may be a manipulation to obtain opioid medications, or drug-seeking, because of opioid addiction. Misconception 1: The Maintenance Opioid Agonist (Methadone or Buprenorphine) Provides Analgesia There are pharmacokinetic and pharmacodynamic explanations for why patients do not receive adequate analgesia from maintenance opioids prescribed for addiction treatment. Not only do the analgesic and addiction treatment profiles of these opioids differ, but the neuroplastic changes associated with long-term opioid exposure (that is, tolerance and hyperalgesia) may effectively diminish their analgesic effectiveness (45). Analgesic Properties of Maintenance Opioids Patients receiving maintenance therapy with opioids for addiction treatment do not derive sustained analgesia from it. Methadone and buprenorphine, potent analgesics, have a duration of action for analgesia (4 to 8 hours) that is substantially shorter than their suppression of opioid withdrawal (24 to 48 hours) (46-50). Because most patients receiving OAT are given a dose every 24 to 48 hours, the period of even partial pain relief with these medications is small. Opioid Tolerance Tolerance is one factor that explains why these patients derive little pain relief from maintenance opioids. Tolerance, the need for increasing doses of a medication to achieve its initial effects, develops with continuous opioid use but differentially affects specific opioid properties. For example, tolerance readily develops to the respiratory and CNS depressive effects of opioids but not to their constipating effects (51, 52). Analgesic tolerance develops for different medications within the opioid class, a phenomenon called cross-tolerance (53, 54). Doverty and colleagues (55) found that patients receiving maintenance methadone therapy were cross-tolerant to the analgesic effects of morphine and that pain relief, when obtained, did not last as long as expected. Therefore, cross-tolerance between the opioids used for maintenance therapy and other opioids used for analgesia may explain why patients receiving OAT often require higher and more frequent doses of opioid analgesics to achieve adequate pain control. Opioid-Induced Hyperalgesia An alternative explanation for the lack of analgesia derived from maintenance opioids may be the presence of opioid-induced hyperalgesia. This is the result of neuroplastic changes in pain perception that yield an increase in pain sensitivity. The outcome is that opioids have less potent analgesic effects (45, 56-58). Empirical evidence supports increased sensitivity to experimental pain in patients receiving OAT (33, 38, 55, 59-62), such that patients receiving maintenance methadone therapy tolerate cold-pressor pain only half as long as do matched controls (55, 59). Accumulating evidence suggests that maintenance with buprenorphine therapy has similar and statistically significant effects on pain tolerance, although to a lesser degree than methadone (63). The pain intolerance of patients receiving methadone and buprenorphine maintenance therapy can be conceptualized as a latent hyperalgesia secondary to long-term opioid exposure. The presence of hyperalgesia with ongoing opioid use has resulted in reexamination of the previously described phenomenon of opioid analgesic tolerance. Both hyperalgesia and opioid tolerance involve neuroplastic changes associated with excitatory amino acid (N-methyl-d-aspartate) and opioid receptors (64-70). The hyperalgesic processes precipitated by opioid administration serve to counteract opioid analgesia (56, 71-73); thus, it is possible that what seems to be opioid analgesic tolerance may in fact be an expression of an opioid-induced increased sensitivity to pain. Therefore, despite the benefits of OAT for the opioid-dependent person, the accompanying hyperalgesia (or analgesic tolerance) counteracts the analgesic effects of opioids and complicates pain management. At clinically effective doses for the treatment of opioid dependence, patients do not experience analgesia to experimental pain but demonstrate the hyperalgesic effects of OAT. Thus, from a theoretical and experimental basis, it is clear that the perception of pain is not decreased in OAT patients. Misconception 2: Use of Opioids for Analgesia May Result in Addiction Relapse A common concern of physicians is that the use of opioids for analgesia in patients receiving OAT May result in relapse to active drug use. However, there is no evidence that exposure to opioid analgesics in the presence of acute pain increases rates of relapse in such patients. A small retrospectiv

Pain Responses in Methadone-Maintained Opioid Abusers

Providing pain management for known opioid abusers is a challenging clinical task, in part because little is known about their pain experience and analgesic requirements. This study was designed to describe pain tolerance and analgesic response in a sample of opioid addicts stabilized in methadone-maintenance (MM) treatment (n = 60) in comparison to matched nondependent control subjects (n = 60). By using a placebo-controlled, two-way factorial design, tolerance to cold-pressor (CP) pain was examined, both before and after oral administration of therapeutic doses of common opioid (hydromorphone 2 mg) and nonsteroidal anti-inflammatory (ketorolac 10 mg) analgesic agents. Results showed that MM individuals were significantly less tolerant of CP pain than control subjects, replicating previous work. Analgesic effects were significant neither for medication nor group. These data indicate that MM opioid abusers represent a pain-intolerant subset of clinical patients. Their complaints of pain should be evaluated seriously and managed aggressively.

Methadone Safety: A Clinical Practice Guideline From the American Pain Society and College on Problems of Drug Dependence, in Collaboration With the Heart Rhythm Society

UNLABELLED Methadone is used for the treatment of opioid addiction and for treatment of chronic pain. The safety of methadone has been called into question by data indicating a large increase in the number of methadone-associated overdose deaths in recent years that has occurred in parallel with a dramatic rise in the use of methadone for chronic pain. The American Pain Society and the College on Problems of Drug Dependence, in collaboration with the Heart Rhythm Society, commissioned an interdisciplinary expert panel to develop a clinical practice guideline on safer prescribing of methadone for treatment of opioid addiction and chronic pain. As part of the guideline development process, the American Pain Society commissioned a systematic review of various aspects related to safety of methadone. After a review of the available evidence, the expert panel concluded that measures can be taken to promote safer use of methadone. Specific recommendations include the need to educate and counsel patients on methadone safety, use of electrocardiography to identify persons at greater risk for methadone-associated arrhythmia, use of alternative opioids in patients at high risk of complications related to corrected electrocardiographic QTc interval prolongation, careful dose initiation and titration of methadone, and diligent monitoring and follow-up. Although these guidelines are based on a systematic review, the panel identified numerous research gaps, most recommendations were based on low-quality evidence, and no recommendations were based on high-quality evidence. PERSPECTIVE This guideline, based on a systematic review of the evidence on methadone safety, provides recommendations developed by a multidisciplinary expert panel. Safe use of methadone requires clinical skills and knowledge in use of methadone to mitigate potential risks, including serious risks related to risk of overdose and cardiac arrhythmias.

Diagnosing Addictive Disease in Chronic Pain Patients

As opiate therapy is increasingly accepted for the management of chronic pain, the consultation-liaison psychiatrist is often challenged to diagnose and provide treatment recommendations for addictive disease in chronic pain patients. Reviewed are the defining characteristics of addiction within the context of chronic pain, and the interesting commonalities between addictive disease and chronic pain. Guidelines for assessment of addiction in patients with chronic pain are presented, as are suggestions for the management of these concurrent disorders. Underlying this review is a belief that opiates should not be withheld from persons with chronic pain, even in the presence of addictive disease.

Introduction of a self-report version of the Prescription Drug Use Questionnaire and relationship to medication agreement noncompliance.

The Prescription Drug Use Questionnaire (PDUQ) is one of several published tools developed to help clinicians better identify the presence of opioid abuse or dependence in patients with chronic pain. This paper introduces a patient version of the PDUQ (PDUQp), a 31-item questionnaire derived from the items of the original tool designed for self-administration, and describes evidence for its validity and reliability in a sample of patients with chronic nonmalignant pain and on opioid therapy. Further, this study examines instances of discontinuation from opioid medication treatment related to violation of the medication agreement in this population, and the relationship of these with problematic opioid misuse behaviors, PDUQ and PDUQp scores. A sample of 135 consecutive patients with chronic nonmalignant pain was recruited from a multidisciplinary Veterans Affairs chronic pain clinic, and prospectively followed over one year of opioid therapy. Using the PDUQ as a criterion measure, moderate to good concurrent and predictive validity data for the PDUQp are presented, as well as item-by-item comparison of the two formats. Reliability data indicate moderate test stability over time. Of those patients whose opioid treatment was discontinued due to medication agreement violation-related discontinuation (MAVRD) (n=38 or 28% of sample), 40% of these (n=11) were due to specific problematic opioid misuse behaviors. Based upon specificity and sensitivity analyses, a suggested cutoff PDUQp score for predicting MAVRD is provided. This study supports the PDUQp as a useful tool for assessing and predicting problematic opioid medication use in a chronic pain patient sample.

Association between human μ‐opioid receptor gene polymorphism, pain tolerance, and opioid addiction

Central to both pain responses and opioid addiction is activity at the μ‐opioid receptor. To explore the role of the μ‐opioid receptor gene (OPRM) in human pain tolerance and opioid addiction, we examined the relationships among OPRM genotype and experimental pain tolerance in opioid addicts in methadone treatment (n = 50) and healthy normal controls (n = 59). Pain phenotype (pain tolerant vs. pain intolerant) was operationalized as tolerance to a standardized noxious stimulus (either thermal or mechanical), and dichotomized based on distribution. One microsatellite and two single nucleotide polymorphisms, A118G and C17T, in exon 1 were typed to study the OPRM gene. Although the established relationship between the phenotypes of opioid addiction and pain intolerance was validated (P = 0.02), genotype differed neither between addict‐affected vs. control, nor pain tolerant vs. intolerant subjects. The variant A118G was absent in all individuals and the C17T polymorphism appeared in only three African‐American individuals (two addicts and one control). The absence of this polymorphism, the small sample size and the heterogeneous ethnic backgrounds of participants in the pilot study allow only tentative conclusions based on the results, thus the role of the opioid receptor in pain and opioid reward response remains uncertain.

Cocaine use and withdrawal : the effect on sleep and mood

Three recreational cocaine users (age, 26.7 years), after one adaptation night, spent 5 days and nights in the laboratory where their EEG, EOG, and submental EMG were recorded during all of their sleep. On the second afternoon and evening of the study, subjects used an estimated 1 to 2 g cocaine intranasally. They all slept between 2:00 A.M. and 9:00 A.M. that night. Blood samples were drawn each evening and morning. Absolute plasma cocaine levels and patterns of elimination were consistent with subjects report of dose and time of administration. Mood ratings were made repeatedly throughout the study. There was suppression of REM sleep during the use of cocaine followed by a rebound which is specific to REM sleep and is not seen in other stages of sleep. REM variables subsided to normal levels on the third recovery night following cocaine use.

Chronic pain, substance abuse and addiction ☆

Health care professionals face numerous challenges in assessing and treating chronic pain patients with a substance abuse history. Societal perspectives on morality and criminality, imprecise addiction terminology, litigation fears, and genuine concern for a patients relapse into or escalation of substance abuse result in unrelieved and under-relieved pain in precisely the population that--as increasing evidence indicates--is generally intolerant of pain. Before adequate pain relief can occur in chronic pain patients with current or past substance abuse issues, it is imperative that the clinician recognize addiction as a disease with known symptoms and treatments. Further, the clinician must realize the difference between true addiction and similar conditions, so the patients condition can be monitored and regulated properly. Although clinicians are often reluctant to medicate with opioids, it is always best to err on the side of adequate pain relief. Withholding opioids from chronic pain patients in order to avoid the onset or relapse of addiction is contrary to the growing body of evidence and results only in unnecessary pain for the patient. Chronic pain in patients with a history of addictive disease can be treated successfully with opiate analgesia; it just requires caution and careful monitoring of medication use. If addiction is treated as a known risk when providing opioid analgesia to a recovering addict, its development can be minimized while pain relief is provided.