Elsevier

Drug and Alcohol Dependence

Volume 140, 1 July 2014, Pages 92-100
Drug and Alcohol Dependence

Full length article
Topiramate for cocaine dependence during methadone maintenance treatment: A randomized controlled trial

https://doi.org/10.1016/j.drugalcdep.2014.03.033Get rights and content

Abstract

Background

Dual dependence on opiate and cocaine occurs in about 60% of patients admitted to methadone maintenance and negatively impacts prognosis (Kosten et al. 2003. Drug Alcohol Depend. 70, 315). Topiramate (TOP) is an antiepileptic drug that may have utility in the treatment of cocaine dependence because it enhances the GABAergic system, antagonizes the glutamatergic system, and has been identified by NIDA as one of only a few medications providing a “positive signal” warranting further clinical investigation. (Vocci and Ling, 2005. Pharmacol. Ther. 108, 94).

Method

In this double-blind controlled clinical trial, cocaine dependent methadone maintenance patients (N = 171) were randomly assigned to one of four groups. Under a factorial design, participants received either TOP or placebo, and monetary voucher incentives that were either contingent (CM) or non-contingent (Non-CM) on drug abstinence. TOP participants were inducted onto TOP over 7 weeks, stabilized for 8 weeks at 300 mg daily then tapered over 3 weeks. Voucher incentives were supplied for 12 weeks, starting during the fourth week of TOP induction. Primary outcome measures were cocaine abstinence (Y/N) as measured by thrice weekly urinalysis and analyzed using Generalized Estimating Equations (GEE) and treatment retention. All analyses were intent to treat and included the 12-week evaluation phase of combined TOP/P treatment and voucher intervention period.

Results

There was no significant difference in cocaine abstinence between the TOP vs. P conditions nor between the CM vs. Non-CM conditions. There was no significant TOP/CM interaction. Retention was not significantly different between the groups.

Conclusion

Topiramate is not efficacious for increasing cocaine abstinence in methadone patients.

Introduction

Methadone is effective in the treatment of opioid dependence, but does not affect cocaine use, even at high doses (Castells et al., 2009). This is especially problematic in light of the fact that the majority of patients presenting for opioid maintenance treatment have concurrent cocaine dependence, which negatively impacts overall prognosis (Kosten et al., 2003). Nevertheless, effective adjunctive pharmacotherapies for cocaine dependence in this population are lacking. TOP has been identified as a strong candidate for this purpose (Vocci and Ling, 2005). In a key pilot study of relapse prevention in cocaine dependent men, TOP promoted abstinence at twice the rate of that achieved the placebo group (Kampman et al., 2004).

Topiramate [2,3:4,5-Bis-O-(1-methylethylidene)-β-D-fructopyranose sulfamate] was FDA approved in 1996 for the treatment of adult seizures. TOP increases GABA central levels and potentiates its action at the GABAA receptor (Braga et al., 2009). TOP is an AMPA receptor antagonist at the glycine site, a selective GluK1 inhibitor (Braga et al., 2009) and decreases presynaptic glutamate release (Alves et al., 2003).

GABA antagonism and glutamate potentiation have each been identified as having potential value in the treatment of cocaine dependence. GABA agonists reduce the dopamine response to cocaine, response to conditioned cues, and cocaine self-administration (Barrett et al., 2005, Weerts et al., 2005). The presynaptic GABA reuptake inhibitor tiagabine appeared to reduce cocaine use in methadone maintenance (Gonzales et al., 2007) and vigabatrin (an irreversible inhibitor of intrasynaptic GABA transaminase) increased cocaine abstinence in parolees (Brodie et al., 2009), though a later clinical trial showed no effect (Somoza et al., 2013). Prefrontal glutamatergic neurons innervating the nucleus accumbens play a critical role in cocaine reinforcement (McFarland et al., 2003, Kalivas, 2004). Glutamate inhibition blocks cocaine-induced reinstatement of cocaine seeking (Cornish and Kalivas, 2000, McFarland et al., 2003). Glutamate is involved in memory and neuroplasticity and a disruption of glutamate homeostasis could be at the core of compulsive drug taking (Kalivas et al., 2009). In preclinical studies, antagonists at AMPA-receptors (a glutamate receptor subtype) decreased cue-induced cocaine seeking (Bäcktröm and Hyytiä, 2006). Drugs with potential to restore glutamate homeostasis show promise as potential treatments for cocaine addiction (Moran et al., 2005, Peters et al., 2008, Kalivas, 2009). Given the potential of medications targeting independently the GABA and glutamate systems to help patients abstain from cocaine use, targeting these systems simultaneously with a medication such as TOP is of particular interest.

In addition to its potential for directly reducing cocaine use, TOP may have broad beneficial effects that further enhance its utility in the treatment of cocaine dependent methadone patients by addressing a variety of other symptoms and conditions common among poly-substance users. For example, TOP has produced promising results in treating other substance use disorders, reducing drinking in alcohol dependence (Johnson et al., 2003, Johnson et al., 2004, Johnson, 2005, Baltieri et al., 2008), reducing relapse to alcohol use after detoxification (Rubio et al., 2009), and promoting smoking cessation in men (Anthenelli et al., 2008). More broadly, TOP has been evaluated for the treatment of chronic pain (Khoromi et al., 2005), aggression (Nickel et al., 2004, Nickel et al., 2005a, Nickel et al., 2005b), compulsive disorders (Van Ameringen et al., 2006), and anxiety (Berlant, 2004, Khan and Liberzon, 2004).

The current study was designed to evaluate whether TOP would increase cocaine abstinence in cocaine dependent methadone patients. Participants were randomly assigned to one of four conditions in which they received TOP or placebo (P), and received vouchers contingent on providing cocaine negative urine samples (CM) or independently of their urine sample results (Non-CM). This design was planned as a means of comparing the effects of TOP against positive (CM) and negative (P) controls, as CM has been repeatedly demonstrated as successful in reducing cocaine use in methadone patients (Lussier et al., 2006, Prendergast et al., 2006). In all groups, voucher earnings were dependent on attendance and morning pills were consumed under observation. These procedures were designed to enhance attendance and TOP adherence across all participants. A secondary goal of the study was to evaluate the safety and acceptability of TOP in methadone patients, as there are no prior evaluations of TOP in this population.

Section snippets

Trial design and study flow

This randomized double-blind clinical trial featured a 2 × 2 factorial design. It was approved by the Johns Hopkins Medicine institutional review board and conducted from 2007 to 2011 at an outpatient methadone clinic on the Johns Hopkins Bayview Medical Campus, Baltimore, Maryland.

Fig. 1 shows the study timeline. Opioid and cocaine dependent adults who passed a telephone screening interview were scheduled for a full interview to determine eligibility. Participants were induced and stabilized on

Baseline demographic, treatment and drug use characteristics

Fig. 2 displays subject disposition through the end of the evaluation phase of the trial. No demographic differences were significant under a one factor analysis or for any post-hoc comparison between groups. Table 2 shows baseline demographic and drug use characteristics. A two-factor analysis showed that participants who received P were more likely to be alcohol dependent that those who received TOP (p = 0.03), but revealed no other significant differences. Of 250 participants admitted into the

Discussion

The results from this study show that topiramate was not different from placebo in reducing cocaine use in the treatment of dually cocaine and opioid dependent methadone patients. Although this finding is disappointing, it is not necessarily in conflict with the current evidence base for topiramate in the treatment of stimulant dependence. For example, a large double-blind randomized controlled trial of cocaine and alcohol dependent subjects who had achieved initial abstinence showed that 20%

Contributors

All authors have contributed equally to this manuscript.

Conflict of interest

No authors have any financial or other conflict of interest.

Acknowledgments

Preliminary results of this study were presented at the College on Drug Dependence in 2010 and 2012. The study was supported by grants from the National Institute on Drug Abuse (DA 021808) with additional funds from grant T32 DA07209 and grant K24 DA023186. Were are thankful to Paul Nuzzo for statistical analysis, and to the BPRU research staff, under the leadership of Mary Bailes and Connie Lowery, without whom this project would not have been possible.

Clinical Trial: NCT00685178.

Our gratitude

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