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Potential of Buprenorphine/Naltrexone in Treating Polydrug Addiction and Co-Occurring Psychiatric Disorders

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Potential of Buprenorphine/Naltrexone in Treating Polydrug Addiction and Co-Occurring Psychiatric Disorders nature publishing group DEVELOPMENT Potential of Buprenorphine/Naltrexone in Treating Polydrug Addiction and Co-occurring Psychiatric Disorders DJ McCann1 In recent years, we have seen regulatory approval being therefore, any potential cocaine addiction pharmacotherapy given for several new pharmacotherapies in the treatment under serious consideration for regulatory filing requires evalu- of drug addiction disorders. Within the United States, the ation in subjects with comorbid cocaine/alcohol dependence. most noteworthy development has been the approval of Correspondingly, alcohol dependence was not an exclusion cri- buprenorphine in the treatment of opioid dependence, and terion when the National Institute on Drug Abuse conducted its availability for prescribing in an office-based setting a recent 210-subject, multi-site, placebo-controlled study of has resulted in thousands of additional patients going into modafinil for the treatment of cocaine dependence. A post-hoc treatment. Although approved medications for the treatment longitudinal analysis of the resulting data revealed a significant of cocaine and methamphetamine dependence are still effect of modafinil in decreasing cocaine use in subjects who lacking, the National Institute on Drug Abuse has devoted were not dependent on alcohol but this effect was lacking in substantial effort toward meeting these clinical needs.1 Recent alcohol-dependent subjects; in fact, compared to placebo, studies of modafinil for the treatment of cocaine dependence there was a nonsignificant trend toward increased cocaine use have been especially encouraging. Looking to the future, the with modafinil treatment in alcohol-dependent patients (A.M. looming challenge is polydrug addiction, a situation that is Elkashef; presented at the 69th Annual Scientific Meeting of often complicated by co-occurring psychiatric disorders. As the College on Problems of Drug Dependence, 18 June 2007, we strive to address the needs of these complicated patients, Quebec City, Canada). Thus, it appears that modafinil may be studies of buprenorphine/naltrexone may hold the key to a effective for the treatment of cocaine dependence but not in major advance. patients with comorbid cocaine/alcohol dependence. The first indication that buprenorphine’s antiaddiction prop- THE CHALLENGE OF POLYDRUG ADDIctION erties extend beyond opioid dependence came from studies An example of the challenge posed by polydrug addiction focused on cocaine. Buprenorphine was shown to reduce intra- is provided by the apparent impact of alcohol dependence venous cocaine self-administration in rhesus monkeys6 and to on modafinil efficacy in treating cocaine dependence. In a significantly reduce cocaine use in opioid-dependent patients.7–9 double-blind, placebo-controlled trial in 62 cocaine-dependent The desire to translate this finding into an effective treatment for subjects,2 Dackis and co-workers demonstrated significant cocaine addicts who are not opioid-dependent poses a dilemma; reductions in cocaine use with modafinil treatment; however, would possible buprenorphine efficacy in treating cocaine alcohol-dependant subjects were excluded from participation dependence be worth the risk of converting patients to an opioid- in this study. Relevant to this exclusion, the symptoms of alco- dependent state? It has been noted that prolonged administra- hol withdrawal are thought to be mediated, at least in part, by tion of buprenorphine, by virtue of its partial agonist activity the ability of chronic alcohol to both enhance glutamate recep- at µ-opioid receptors, is associated with a comparatively mild tor sensitivity and inhibit γ-aminobutyric acid receptors.3 withdrawal syndrome.10 On the other hand, concerns regarding Modafinil acts to enhance glutamate transmission and inhibit physical dependence cannot be entirely dismissed. Fortunately, γ-aminobutyric acid transmission2,4; two effects which could there appears to be a simple solution to the dilemma. A recent exacerbate alcohol withdrawal. Unfortunately, alcoholism is open-label study by Gerra and co-workers11 suggests that seen in the majority of treatment-seeking cocaine users5 and, buprenorphine is effective in decreasing cocaine use even in 1Division of Pharmacotherapies and Medical Consequences of Drug Abuse, National Institute on Drug Abuse, National Institutes of Health, Bethesda, Maryland, USA. Correspondence: DJ McCann ([email protected]) Received 30 October 2007; accepted 17 December 2007; advance online publication 23 January 2008. doi:10.1038/sj.clpt.6100503 CLINICAL PHARMACOLOGY & THERAPEUTICS | VOLUME 83 NUMBER 4 | APRIL 2008 627 DEVELOPMENT the presence of naltrexone, the addition of which should alle- buprenorphine to act as an ORL-1 (opioid receptor-like1) recep- viate concerns regarding physical dependence. In this study tor agonist (Table 1). Although ORL-1 receptors share a high of 60 patients with a history of opiate-dependence, half of the degree of sequence homology with opiate receptors, they do patients were treated with naltrexone alone and half were treated not bind naloxone, naltrexone, or most traditional opioids with with both buprenorphine and naltrexone. During the first week high affinity; the agonist activity of buprenorphine at ORL-1 of treatment, urine tests for cocaine metabolites were positive receptors is virtually unique among opioids.16,17 Thus, in the with similar frequencies in patients receiving buprenorphine/ study by Gerra and co-workers,11 ORL-1 receptors would have naltrexone (40%) and naltrexone alone (37%); however, by the been activated in subjects receiving buprenorphine/naltrexone 12th week of treatment, only 9% of urine samples were positive but not in subjects receiving naltrexone alone. Compellingly, for cocaine metabolites in the buprenorphine/naltrexone group intracerebroventricular injections of the endogenous agonist for while 33% were positive in the group receiving naltrexone alone. ORL-1 receptors (nociceptin/orphanin FQ) have been shown It should be noted that the combination of buprenorphine and to block cocaine-conditioned place preference18 and to prevent naltrexone was previously studied by Rothman and co-workers 12 cocaine sensitization19 in rats. If a selective ORL-1 receptor ago- in 15 opioid-dependent subjects. Although the absence of a nist is ever advanced to clinical development, such a compound “naltrexone only” group in this earlier study precluded any will merit evaluation for the treatment of cocaine addiction. On firm conclusions, the results were encouraging. The findings of the other hand, increased receptor selectivity does not always Gerra and co-workers11 strongly suggest that buprenorphine has translate into improved clinical efficacy. The combined ORL-1 efficacy vs. cocaine dependence in the presence of naltrexone, and opioid receptor activities of the buprenorphine/naltrexone and their findings beg for follow-up studies in cocaine addicts combination may be highly desirable. who lack a history of opioid use. A three-armed study evaluating Before leaving behind the topic of buprenorphine/naltrexone buprenorphine/naltrexone, placebo/naltrexone, and placebo/ efficacy in the treatment of cocaine dependence, one additional placebo would be most informative. preclinical finding must be discussed. Mello and co-workers20 But why should the effects of buprenorphine/naltrexone differ have shown that the ability of buprenorphine to decrease cocaine from those of naltrexone alone? Gerra and co-workers,11 as well self-administration in rhesus monkeys is blocked by naltrexone. as Rothman and co-workers,12 proposed that buprenorphine/ This indicates, contrary to the suggestion of Gorelick,21 that the naltrexone acts as a functional κ-opioid receptor antagonist. partial agonist activity of buprenorphine at µ-opioid receptors There is growing preclinical evidence thatκ -opioid receptor may contribute to reductions in cocaine use when the medi- antagonism may be beneficial in treating cocaine addiction. For cation is administered in the absence of naltrexone.7–9 On the example, the selective κ-opioid antagonists nor-binaltorphimine other hand, the results of Mello and co-workers20 are not irrec- and JDTic have been shown to block stress-induced potentia- oncilable with the apparent ability of buprenorphine to decrease tion of cocaine-conditioned place preference in mice13 and to cocaine use in the presence of naltrexone11; the standard drug block stress-induced reinstatement of cocaine-seeking behavior self-administration model does not incorporate relapse triggers, in rats,14 respectively. Both buprenorphine and naltrexone are such as stress, that may be critically important in the detection antagonists at κ-opioid receptors; however, as shown in Table 1, of κ-opioid antagonist and/or ORL-1 agonist effects of relevance buprenorphine binds with higher affinity to κ- than µ-opioid to relapse prevention. The combination of buprenorphine and receptors while the opposite is true for naltrexone. It should naltrexone has not been evaluated in animal models of stress- be noted that the Ki values in Table 1 may understate the µ vs. induced relapse to cocaine-seeking behavior or for efficacy in κ preference of naltrexone; in guinea pig ileum bioassays, pA2 blocking a cocaine-conditioned place preference; however, based values of 9.19 and 8.11 were reported for naltrexone antagonism on the findings summarized above, positive findings would be of µ- and κ-opioid agonists, respectively.15 The smooth muscle predicted from
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