A preliminary randomized, double-blind, placebo-controlled study of the safety and efficacy of ondansetron in the treatment of cocaine dependence
Introduction
Cocaine dependence and its psychiatric, social, and economic sequelae constitute a major public health problem in the US (Mendelson and Mello, 1996). While behavioral and psychosocial interventions have remained the mainstay of treatment, high relapse rates are typical (Di Ciano and Everitt, 2002), and medical treatments directed at treating the underlying pathophysiology of cocaine-taking offer the promise of greater efficacy. Yet, despite almost two decades of scientific effort, no medication has been approved by the Food and Drug Administration for the treatment of cocaine dependence.
Cortico-mesolimbic dopamine (DA) neurons mediate the reinforcing effects of cocaine that are associated with its abuse liability (Weiss and Porrino, 2002). Nevertheless, the obvious approach of using direct DA receptor antagonists in the treatment of cocaine dependence has not been fruitful (Kreek et al., 2002). While the reasons for this inefficacy are not well understood, it is plausible that central monoaminergic pathways exhibit high adaptability and compensatory mechanisms (Hemby et al., 1997), thereby reversing any early treatment effects or therapeutic gains of direct DA antagonists. In any case, poor compliance with direct DA receptor antagonists, due to their propensity to induce unpleasant adverse events (e.g., extrapyramidal symptoms) by non-selectively altering baseline DA function, limits their practical utility as treatment for cocaine dependence. Hence, an alternative scientific approach is needed. Logically, such an approach should include examination of the efficacy of indirect inhibitors of cortico-mesolimbic function, rather than direct DA antagonists, in the treatment of cocaine dependence.
Serotonin-3 (5-HT3) receptors co-localized with gamma-amino-butyric acid interneurons are indirect inhibitors of cortico-mesolimbic DA release (Bloom and Morales, 1998). It is, therefore, of scientific interest that 5-HT3 receptor antagonists such as ondansetron, presumably by attenuating the suprabasal release of cortico-mesolimbic DA, have been shown to reduce the reinforcing effects of a variety of abused drugs including alcohol and amphetamines (Costall et al., 1987, Di Chiara and Imperato, 1988, McBride and Li, 1998, Sellers et al., 1992). Direct study of the anti-reinforcing effects of 5-HT3 antagonists on cocaine-taking has, however, yielded some equivocal results. While 5-HT3 antagonists reduce cocaine-induced extracellular DA release (Kankaanpaa et al., 1996, McNeish et al., 1993) and locomotion (Kankaanpaa et al., 1996, McNeish et al., 1993, Reith, 1990, Svingos and Hitzemann, 1992), they do not appear to attenuate cocaine-induced self-administration (Kankaanpaa et al., 1996, Lane et al., 1992, McNeish et al., 1993, Peltier and Schenk, 1991, Reith, 1990, Svingos and Hitzemann, 1992). Nevertheless, 5-HT3 antagonists have been reported to reduce conditioned place preference for cocaine (Suzuki et al., 1992) cf. (Cervo et al., 1996), diminish the development of behavioral tolerance and sensitization to cocaine following a period of acute withdrawal (King et al., 1998) by down-regulation of 5-HT3 receptors in the nucleus accumbens (King et al., 1999), and decrease discomfort or post-cessation anxiety following psychostimulant withdrawal (Costall et al., 1990a, Costall et al., 1990b). In humans, the 5-HT3 antagonist, ondansetron, also has been shown to inhibit right orbitofrontal cortex increases in neuronal activation and cerebral blood flow in recently withdrawn cocaine addicts (Adinoff, 2004). It is, therefore, reasonable to propose that when considered with the preclinical data (King et al., 2000), ondansetron might aid the restoration of normative DA function during the period of recent withdrawal from cocaine use, and thus decrease the potential for relapse to drug-taking. Taken together, these data suggest that 5-HT3 antagonists such as ondansetron might impair the maintenance of preference for cocaine and reduce the likelihood of relapse to cocaine following cessation of its use.
As a proof-of-concept test of this hypothesis, we conducted a pilot randomized, double-blind, 10-week controlled, dose-ranging trial to determine whether ondansetron (0.25 mg, 1.0 mg, or 4.0 mg twice daily) would be more efficacious than placebo at reducing cocaine intake and promoting abstinence among cocaine-dependent individuals.
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Participants
We enrolled 63 men and women with a primary diagnosis of cocaine dependence according to the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV) (American Psychiatric Association, 1994). During a 2-week baseline period, enrolled participants also had to provide up to six urine samples (three per week); at least one out of a minimum of four samples had to test positive for the major cocaine metabolite, benzoylecgonine (BE). We included individuals with secondary
Participants
Table 1 shows the participants’ demographic and alcohol and cocaine use characteristics at baseline, by ondansetron treatment group. No significant demographic characteristics differed between groups. The ondansetron 4.0 mg group did, however, appear to include participants with the most severe psychopathology related to alcohol and cocaine consumption. Briefly, the participants were mostly male (n = 55; 87%), Hispanic (n = 28; 44%), and employed full-time (n = 36; 57%), and had on average a
Discussion
Our results showed that ondansetron 4.0 mg twice daily was associated with a significantly greater rate of improvement in the percentage of participants with a cocaine-free week compared with placebo. This finding is made more notable by the fact that the ondansetron 4.0 mg group included the participants with the most severe patterns of cocaine use and psychopathology. Indeed, the effect size of the ondansetron 4.0 mg treatment response (data not shown) appears to be similar to the order of
Acknowledgments
We are grateful to the National Institute on Drug Abuse for its support through contract N01-DA-9-8101. We also thank Robert H. Cormier, Jr. for his assistance with manuscript preparation.
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