Original Investigation |

Topiramate for the Treatment of Cocaine Addiction:  A Randomized Clinical Trial

Bankole A. Johnson, DSc, MD1,2; Nassima Ait-Daoud, MD1; Xin-Qun Wang, MS3; J. Kim Penberthy, PhD1; Martin A. Javors, PhD4; Chamindi Seneviratne, MD1; Lei Liu, PhD5
[+] Author Affiliations
1Department of Psychiatry and Neurobehavioral Sciences, University of Virginia, Charlottesville
2now with Department of Psychiatry, University of Maryland School of Medicine, Baltimore
3Department of Public Health Sciences, University of Virginia, Charlottesville
4Department of Psychiatry, The University of Texas Health Science Center at San Antonio, San Antonio
5Department of Preventive Medicine and Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Northwestern University, Chicago, Illinois
JAMA Psychiatry. 2013;70(12):1338-1346. doi:10.1001/jamapsychiatry.2013.2295.
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Importance  No medication has been established as an efficacious treatment for cocaine dependence. We hypothesized that dual modulation of the mesocorticolimbic dopamine system by topiramate—a glutamate receptor antagonist and γ-aminobutyric acid receptor agonist—would result in efficacious treatment for cocaine dependence compared with placebo.

Objective  To determine the efficacy of topiramate vs placebo as a treatment for cocaine dependence.

Design, Setting, and Participants  Double-blind, randomized, placebo-controlled, 12-week trial of 142 cocaine-dependent adults in clinical research facilities at the University of Virginia between November 22, 2005, and July 25, 2011.

Interventions  Topiramate (n = 71) or placebo (n = 71) in escalating doses from 50 mg/d to the target maintenance dose of 300 mg/d in weeks 6 to 12, combined with weekly cognitive-behavioral treatment.

Main Outcomes and Measures  For the efficacy period, weeks 6 to 12, the primary outcome was the weekly difference from baseline in the proportion of cocaine nonuse days; the secondary outcome was urinary cocaine-free weeks, and exploratory outcomes included craving and self- and observer-rated global functioning on the Clinical Global Impression scales.

Results  Using an intent-to-treat analysis, topiramate was more efficacious than placebo at increasing the weekly proportion of cocaine nonuse days, irrespective of whether missing data were not or were imputed conservatively to the baseline value (13.3% vs 5.3%, 95% CI for the estimated mean difference, 1.4%-14.6%, P = .02 or 8.9% vs 3.7%, 95% CI for the estimated mean difference, 0.2%-10.1%, P = .04, respectively). Topiramate also was associated, significantly more than placebo, with increasing the likelihood of urinary cocaine-free weeks (16.6% vs 5.8%; odds ratio, 3.21; 95% CI, 1.24-8.32; P = .02), as well as decreasing craving and improving observer-rated global functioning (all P < .05).

Conclusions and Relevance  Topiramate is more efficacious than placebo at increasing the mean weekly proportion of cocaine nonuse days and associated measures of clinical improvement among cocaine-dependent individuals.

Trial Registration  clinicaltrials.gov Identifier: NCT00249691

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Figure 1.
Trial Profile

Disposition of the participants during the trial.

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Figure 2.
Weekly Mean Proportion of Cocaine Nonuse Days From Baseline Through Study Week 12

Each symbol represents the mean proportion of cocaine nonuse days for each study week, and the error bars indicate standard error (SEM). Weekly mean proportion of cocaine nonuse days was analyzed (A) without imputing missing data and (B) imputing missing data using baseline values. Mean (SEM) values for the weekly proportion of cocaine nonuse days at baseline (ie, mean cocaine use during the 2-week baseline period) for the 2 groups receiving topiramate and placebo were 0.5775 (0.0294) and 0.5665 (0.0302), respectively. Participants were allocated to treatment groups at the end of the 2-week baseline period. Study medication was provided at week 0 and, therefore, week 1 contains those individuals who had received 1 or more weeks of double-blind treatment.

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