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Potential of / in Treating Polydrug Addiction and Co-occurring Psychiatric Disorders

DJ McCann1

In recent years, we have seen regulatory approval being therefore, any potential 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 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 . 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

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the presence of naltrexone, the addition of which should alle- buprenorphine to act as an ORL-1 (-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 -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 , naltrexone, or most traditional 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 (/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 . 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- 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 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- 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 such studies. bioassay results correspond to almost a full log unit preference The mixed receptor activities of buprenorphine/naltrexone of naltrexone for µ- vs. κ-opioid receptors. It follows that in the appear especially well suited for the treatment of alcohol depen- study by Gerra et al.,11 the overall level of κ-opioid receptor dence. Because naltrexone is Food and Drug Administration– blockade may have been substantially greater when buprenor- approved for the treatment of alcoholism, we can assume that phine was combined with naltrexone. µ-opioid receptor antagonism will be beneficial. Beyond this, it Another possible explanation for the superiority of buprenor- is noteworthy that buprenorphine decreases alcohol drinking phine/naltrexone in decreasing cocaine use lies in the ability of in rats, and this effect is blocked by the selective ORL-1 recep- tor antagonist UFP-101.22 Consonant with the potential role Table 1 Buprenorphine and naltrexone receptor activity profiles of ORL-1 agonist activity in treating alcoholism, nociceptin/ K or IC (nM) orphanin FQ and/or the synthetic ORL-1 receptor agonist Ro i 50 64-6198 have been shown to: (i) block the reinforcing effects of µ-opioid -opioid ORL-1 κ ethanol in both conditioned place preference and self-admin- a Buprenorphine 1.5 0.8 8.4 istration studies; (ii) block the ability of ethanol to reinstate Naltrexone 0.2 0.4 5,200b ethanol-conditioned place preference; (iii) block the ability Unless otherwise noted, values are from Toll et al., 1998 (ref. 15). of conditioned cues to reinstate ethanol self-administration aWnendt et al., 1999 (ref. 16). bMeng et al., 1996 (ref. 17). behavior; and (iv) block the ability of stress to reinstate ethanol

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self-administration behavior.23–26 While many of these ORL-1 naltrexone. Related to the potential efficacy of buprenorphine/ agonist effects are similar to effects observed with naltrexone, naltrexone in treating disorders, it is noteworthy that the ability of nociceptin to block stress-induced reinstatement of selective ORL-1 receptor agonists33 and selective κ-opioid recep- ethanol self-administration behavior suggests there is a potential tor antagonists34 demonstrate favorable activity in animal mod- advantage exhibited by ORL-1 agonists over naltrexone, in that els of anxiety. Finally, buprenorphine may have the capacity for naltrexone is inactive in this model.27 It is also encouraging that antipsychotic activity,35 and the possibility that such activity may the selective κ-opioid receptor antagonist, nor-binaltorphimine, stem from κ-opioid receptor antagonism is suggested by a recent suppresses alcohol dependence-induced alcohol self-adminis- study of sensorimotor gating.36 tration in rats.28 Thus, by virtue of both its ORL-1 agonist and Clearly, effective treatment of co-occurring psychiatric dis- κ-opioid antagonist activities, there is reason to speculate that orders in drug-addicted patients is desirable per se and, to the the buprenorphine/naltrexone combination may prove more extent that such disorders engender further drug use, there may effective than naltrexone alone in treating alcoholism. be corresponding benefits in the treatment of drug addiction dis- From the above, it is clear that buprenorphine/naltrexone orders. A less obvious but equally important benefit may be seen has a strong theoretical rationale for efficacy in treating opioid, in treatment adherence. Simply put, if patients feel better (i.e., cocaine, and alcohol dependence, as well as the various combi- less depressed or anxious) and if they associate this improve- nations of these disorders but, what about the other drug addic- ment with their medication, they are more likely to continue tions? Preclinical studies of ORL-1 agonist/methamphetamine treatment. In this vein, it is interesting to note that compared interactions hint at potential efficacy in treating methamphet- to patients receiving naltrexone alone, a significantly larger amine dependence. For example, nociceptin has been shown percentage of patients receiving buprenorphine/­naltrexone to block methamphetamine-conditioned place preference.29 In completed 12 weeks of treatment in the study by Gerra and addition, the ability of the selective κ-opioid antagonist nor- co-workers.11 Almost certainly related to this finding, scores for binaltorphimine to block nicotine-induced elevations in cor- irritability, , tiredness and psychosomatic symptoms ticosterone30 may be relevant to smoking cessation. κ-opioid showed significantly greater improvement in the group that antagonist/methamphetamine interactions and ORL-1 agonist/ received buprenorphine/naltrexone. nicotine interactions have gone largely unexplored. Further pre- clinical studies in these areas appear warranted. Practical Considerations in Moving Forward The strong rationale for potential buprenorphine/naltrexone Co-Occurring Psychiatric Disorders efficacy in treating multiple drug addiction disorders, as well Beyond the challenge posed by polydrug addiction, physicians as co-occurring psychiatric disorders, argues for a thorough are often faced with co-occurring psychiatric disorders such as evaluation of the drug combination in clinical studies. In mov- anxiety and depression. These disorders may be antecedent to ing forward, practical considerations will direct our path. In initial drug use or a consequence of drug-induced changes in the clinical trials or practice, requiring patients to take both oral brain but, either way, they can serve to promote continued drug naltrexone and sublingual buprenorphine may be problematic. use and thwart the best efforts of drug addiction therapists. The Unfortunately, buprenorphine demonstrates poor oral bioavail- extent of the problem is apparent from a study of 89 treatment- ability and is not amenable to formulation with naltrexone as an seeking cocaine users5; 65% of these subjects exhibited some oral tablet. Likewise, naltrexone is not amenable to formulation type of non-substance use psychiatric disorder, with 29% suffer- with buprenorphine as a sublingual tablet; there is a physical ing from depressive disorders and 16% from anxiety disorders. limit to the amount of drug that can be added to such a tablet A more recent, broader epidemiological study31 observed a 48% and the potency of naltrexone appears insufficient. prevalence of depression and a 45% prevalence of anxiety disor- Currently, the best approach to evaluating buprenorphine/ ders in cocaine dependence. naltrexone in proof of concept clinical trials may be the use Fortuitously, buprenorphine/naltrexone may prove effective of buprenorphine sublingual tablets and the recently mar- in treating multiple psychiatric disorders. Until the mid-1950s, keted “extended-release injectable suspension” formulation of the use of and to treat depression was not uncom- naltrexone. This formulation of naltrexone requires just once mon (see ref. 10 for discussion). This practice virtually ceased monthly dosing for the treatment of alcoholism and it is likely due to addiction concerns and the development of alternative to have a similar duration of action in blocking the µ-opioid treatments; however, two recent open-label buprenorphine agonist effects of buprenorphine. In the near future, evaluation studies10,32 showed promising results in subjects with treat- and use of the buprenorphine/naltrexone combination may be ment-refractory depression. In both studies, subjects received facilitated by the availability of an orally active buprenorphine only buprenorphine and the possible role of µ-opioid receptor prodrug. Such a prodrug is currently under development as activation cannot be ruled out; however, the activity of selec- both a single-entity tablet and as a tablet combined with nal- tive κ-opioid receptor antagonists in preclinical trexone (C.B. O’Keeffe, personal communication). In the long screens14 suggests an alternative explanation. It is possible that term, chemists may discover a buprenorphine analog that acts buprenorphine’s κ-opioid antagonist properties were responsible as an antagonist or a much weaker partial agonist at µ-opioid for the observed clinical improvements. If so, the antidepres- receptors, yet retains the ORL-1 agonist and κ-opioid antagonist sant activity of buprenorphine should persist in the presence of activities of buprenorphine. Such a compound could incorporate

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