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