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