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

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Abstract

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 highs 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.

Introduction

Clinical and empirical evidence are accumulating to indicate that persons maintained on the long-acting opioid agonist, methadone, for the treatment of opiate addiction demonstrate characteristic pain responses, such that their sensitivity for experimental pain is lower than that of matched normal controls (Martin and Inglis, 1965, Ho and Dole, 1979, Compton et al., 1998). Central pain and opiate addiction systems are inherently related at the substrate of the μ-opioid receptor (Compton and Gebhart, 1998). Binding of these receptors by opioid agonists results in activation of both analgesic and reward pathways (Reisine and Pasternak, 1996, Gardner, 1997, Wise, 1998), with chronic administration resulting in the interrelated neuroadaptations of analgesic tolerance and physical dependence (O'Brien, 1996, Reisine and Pasternak, 1996).

Mayer and colleagues (Mao et al., 1995a, Mao et al., 1995b, Mayer et al., 1995a, Mayer et al., 1995b) provide good evidence that the second-messenger mediated changes that accompany the development of morphine tolerance and physical dependence in pain-free animals concomitantly induce a neuropathic-like hyperalgesic state, leading some experts to question if what appears to be analgesic tolerance is actually an organismic expression of an opioid-induced increased sensitivity to pain (Colpaert, 1996, Laulin et al., 1999). Certain drug-free former opiate addicts have been shown to tolerate pain better than methadone-maintained former addicts (Compton, 1994), and to the same degree as controls (Liebmann et al., 1994, Liebmann et al., 1997, Liebmann et al., 1998), further supporting the notion of an opioid-induced hyperalgesia in this population.

In both the preclinical model of chronic opioid-induced hyperalgesia and its hypothesized clinical counterpart in methadone-maintained patients, full μ-opioid agonists, morphine or methadone, have been administered. It is increasingly understood that opioids with different levels of intrinsic activity (i.e. high vs. low efficacy) have differential ligand-receptor binding effects with respect to receptor phosphorylation and desensitization, and G-protein activation (Emmerson et al., 1996, Yu et al., 1997), processes believed to contribute to the development of opioid tolerance and physical dependence. If pain intolerance in the methadone-maintained patient population is a byproduct of opioid tolerance and physical dependence, long-acting opioid maintenance agents with differing levels of intrinsic efficacy might be expected to have differential effects on concomitant pain responses.

For example, buprenorphine, currently under evaluation as an opioid addiction pharmacotherapy, is a partial agonist at the μ-receptor (Reisine and Pasternak, 1996) with a lower level of intrinsic activity than the full agonists morphine (Martin et al., 1976, Picker et al., 1993, Morgan et al., 1999a) and methadone (Paronis and Holtzman, 1992, Morgan and Picker, 1998). It induces analgesic tolerance with slower onset than morphine (Cowan et al., 1977), and produces uniquely low levels of physical dependence in animals and men (Cowan et al., 1977, Jasinski et al., 1978). To further explore the phenomenon of opioid-induced hyperalgesia with respect to the intrinsic efficacy of long-acting opioid maintenance agent, experimental pain responses are described in well-characterized groups of former opiate addicts maintained on either methadone (MM) or buprenorphine (BM), in comparison to matched drug-naive controls.

Section snippets

Method

A three-group quasi-experimental design with matching was used. Withdrawal latencies for cold-pressor (CP) pain (the average of three measurements taken on separate occasions) were compared between 18 MM, 18 BM and 18 control subjects. Participants were selected to match on age, race and gender, variables known to affect CP withdrawal latency (Walsh et al., 1989).

Results

As can be seen from the Table 1, groups were successfully matched on age, race and gender. For the MM group, average daily methadone dose and levels of concurrent illicit drug use reflect national averages (Center for Substance Abuse Treatment, 1993). Mean methadone (range 12–100 mg/d PO) and buprenorphine (range 8–12 mg/d SL) doses are comparable to those demonstrated to be equally effective in substituting for heroin (Johnson et al., 1992, Kosten et al., 1993 Strain et al., 1994), indicating

Discussion

Repeated intermittent morphine dosing in pain-free animals, which causes analgesic tolerance and physical dependence, has been demonstrated to concomitantly induce a neuropathic-like hyperalgesia (Mao et al., 1995a, Mao et al., 1995b, Mayer et al., 1995a, Mayer et al., 1995b). It was hypothesized that, if the pain intolerance noted in methadone-maintained ex-addicts reflects this phenomenon, then different intrinsic activities of opioid maintenance agent might induce differing degrees of

Acknowledgements

Supported by NIDA grant 1R03DA09866. The authors gratefully acknowledge the expert data collection and management contributions of Mr. Conrad Sisson and the clinical support of Mr. Al Hasson.

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