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. Weekly mean proportion of cocaine nonuse days was analyzed (A) without imputing missing data and (B) imputing missing data using baseline values. Each symbol represents the mean proportion of cocaine nonuse days for each study week, and the error bars indicate standard error (SEM). Participants were allocated to treatment groups at the end of the 2-week baseline period. 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.
Volunteers were recruited at the University of Virginia (Charlottesville and Richmond sites), where the trial was performed between November 22, 2005, and July 25, 2011. The University of Virginia’s institutional review board approved the research protocol, and all enrolled participants provided written informed consent.
We therefore hypothesized that topiramate, a fructopyranose derivative that enhances GABA function 27 - 30 and inhibits AMPA and kainate glutamate pathways, 31, 32 would modulate extracellular dopamine release in the mesocorticolimbic dopamine system and be 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. Importance No medication has been established as an efficacious treatment for cocaine dependence.
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.
02), as well as decreasing craving and improving observer-rated global functioning (all P <. 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 =. 05). 04, respectively). 02 or 8.9% vs 3.7%, 95% CI for the estimated mean difference, 0.2%-10.1%, P =. 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 =.
We managed the data according to the Food and Drug Administration guidelines of good clinical practice 50 (see the author material file for additional details of data quality).
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.
Objective To determine the efficacy of topiramate vs placebo as a treatment for cocaine dependence.
19, 20 Consistent with this hypothesis, a medication that decreases α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) and kainate glutamate receptor function could be an efficacious treatment for cocaine dependence. 25, 26. Chronic cocaine administration impairs GABA’s neuronal function relative to that of excitatory amino acids in the mesocorticolimbic dopamine system. 14, 15 Thus, a medication that augments GABA function could evince a therapeutic response in treating cocaine dependence. Thus, AMPA glutamate antagonists have been shown to decrease the locomotor effects of cocaine and other psychostimulants, 21, 22 reduce cue-induced reinstatement of cocaine taking, 23, 24 and decrease extracellular dopamine release in the mesocorticolimbic dopamine system. For instance, studies in animals show that medications potentiating the action of GABA in the central nervous system block cocaine-induced dopamine release, 13, 16, 17 raise brain stimulation reward thresholds, 18 diminish the development and expression of cocaine-associated cues, 16 and inhibit the acquisition and the expression of cocaine-induced conditioned place preference.
Of 266 volunteers screened, 124 (46.6%) were ineligible, and 142 were allocated at random to receive either topiramate or placebo. The disposition of the participants during the trial is presented in Figure 1. Of the 142 participants, 72.5% were male and 27.5% were female, and 28.9% were white, 70.4% were black, and 0.7% were Asian. Nevertheless, all 142 participants allocated to treatment were included in the intent-to-treat analysis. Thirteen of the 142 participants failed enrollment (8 and 5 in the topiramate and placebo groups, respectively)—that is, they were allocated at random to treatment but did not return to the clinic for the first double-blind visit.
Trial Registration clinicaltrials.gov Identifier: NCT.
The topiramate and placebo groups were well matched demographically ( Table 2 ). No statistically significant difference existed between them in the mean (SD) number of days of self-reported cocaine use during the 30 days before informed consent—13.3 (7.7) and 12.3 (7.9), respectively.
03) for having “reportedly no desire and no urge at all for cocaine in the last 24 hours.”. 048) for having “reportedly no desire at all for cocaine in the last 24 hours”; 0.572 vs 0.379 (OR, 2.19; 95% CI, 1.08-4.42; P =. 03) for having “reportedly no urge at all to use cocaine in the last 24 hours”; and 0.553 vs 0.364 (OR, 2.16; 95% CI, 1.08-4.34; P =. For the 2 craving subscales of the Cocaine Selective Severity Assessment scale, the estimated proportions of topiramate vs placebo were 0.573 vs 0.402 (OR, 2.00; 95% CI, 1.01-3.97; P =.
1. No medication has been established as an efficacious treatment for cocaine dependence, although there are 13.2 to 19.7 million cocaine users worldwide among adults aged 15 to 64 years (0.3%-0.4%).
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.
All exploratory outcomes were analyzed during the predetermined efficacy period from weeks 6 to 12.
During the 12-week double-blind treatment period, participants had to attend the clinic thrice weekly to provide information on self-reported cocaine use; have their urine tested for cocaine’s primary metabolite, benzoylecgonine; and report adverse events and concomitant medication use. In addition, health checks were performed at scheduled intervals, including urine pregnancy screens every fortnight to ensure that women were not pregnant. Weekly measurements of cocaine craving on the Brief Substance Craving Scale 40 and self- and observer-based assessments of global functioning with the Clinical Global Impression scales 41, 42 also were collected.
In a double-blind clinical trial of daily oral topiramate, 142 cocaine-dependent individuals aged 18 years or older, who were diagnosed according to the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders, 38 were allocated at random into 2 treatment groups: topiramate (n = 71) and placebo (n = 71).
41, 42. Global functioning was assessed on the Clinical Global Impression–Observer and Clinical Global Impression–Self scales. 41, 42 The Clinical Global Impression–Self scale, a self-administered assessment, asked the participant to rate the global severity of his or her cocaine dependence symptoms and the improvement of those symptoms since the beginning of the study. The severity of the participant’s cocaine dependence was rated according to 8 specific problem areas often associated with cocaine dependence. The global severity of, as well as global improvement in, cocaine dependence was rated. The Clinical Global Impression–Observer scale required the clinician or nurse practitioner to rate the global severity of the participant’s cocaine dependence symptoms and the improvement of those symptoms since the beginning of the study.
44. During the 12-week double-blind treatment phase, all participants received, as an adjunct to the medication, weekly cognitive-behavioral treatment, a manual-driven, psychosocial treatment shown to be effective at aiding cocaine abstinence 43 and study participation in pharmacotherapy trials.
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.
The Brief Substance Craving Scale used for this study was a modification of the State of Feelings and Cravings Questionnaire. These craving scales included (1) 2 well-validated subscales of the Cocaine Selective Severity Assessment scale (scores 0-7), which measure the highest intensity of craving and the frequency of the urge to use cocaine in the past 24 hours 49 and have been associated with predicting continued abstinence in treatment, 47 and (2) the Brief Substance Craving Scale (scores 1-5), a self-administered assessment that asks the participant to rate his or her craving for cocaine. 40. Because craving has multidimensional components, 47 we used 2 craving scales that had been well validated in previous pharmacotherapy trials for cocaine dependence 48 to broaden the dimensionality of its assessment.
8 Excitatory amino acids, including glutamate, are associated with the acquisition of place preference conditioning and other reinforcing effects of cocaine. 9 - 11 Furthermore, the enhancement of GABA pathways or the inhibition of corticofugal glutaminergic pathways in the mesocorticolimbic dopamine system can decrease extracellular dopamine release, 12, 13 the principal neurotransmitter that mediates cocaine reinforcement. An intact GABA efferent system from the nucleus accumbens, corpus striatum, and ventral pallidum to cortical structures 6, 7 is important for the expression of cocaine reinforcement. In animals, medications that antagonize the effects of excitatory amino acids or facilitate γ-aminobutyric acid (GABA) action in the mesocorticolimbic dopamine system can reduce cocaine’s reinforcing effects 2 - 5 that are associated with its abuse liability.
After randomization, double-blind treatment medication was provided twice daily (ie, morning and night) for 12 weeks (ie, weeks 1-12) using a double-dummy procedure that ensured that placebo and topiramate recipients received the same number of capsules. Study medication was randomized in a 1:1 ratio of daily oral topiramate or matched placebo. During weeks 6 to 12, the maximum achieved dose of topiramate or matching placebo was maintained. Randomization was stratified to balance participants between groups on age, sex, and frequency of cocaine use (>18 vs ≤18 days’ use in the past 30 days according to self-report, urine sample, or both) before randomization. Medication compliance was measured by pill count. At week 1, oral topiramate or the equivalent number of matching placebo capsules was initiated from 50 mg/d and escalated during the first 6 weeks until the ceiling dose of 300 mg/d or the participant’s maximum tolerated dose was achieved (see schedule in Table 1 ). If, however, a participant was intolerant of adverse events, the investigator could reduce the daily dose to obtain a minimum topiramate or matching placebo maintenance dose of 200 mg/d.
While alcohol-dependent individuals were included in this study, we excluded those with significant withdrawal symptoms that required medical detoxification (see the author material file for all inclusion and exclusion criteria and additional details of the study design). After providing written informed consent, participants were screened to determine eligibility based on diagnosis and health checks. This screening process included 2 weeks of baseline assessment to obtain an accurate recent history of self-reported cocaine use corroborated by urine drug screens. A diagnosis of cocaine dependence was established using the Structured Clinical Interview for DSM-IV Axis I Disorders. To be randomized into double-blind treatment, participants had to meet the criterion on recent history of cocaine use and eligibility criteria based on diagnosis and health checks. 39 All participants who met eligibility criteria for health checks and achieved the criterion on recent history of self-reported cocaine use were allocated at random to treatment. To meet the criterion on recent history of cocaine use, participants had to provide 1 or more cocaine-positive urine specimens (>300 ng/mL) during screening and 4 or more urine specimens during the 2-week baseline screening period.
We therefore conducted analyses for data with and without imputing missing data for dropouts. For the primary outcome variable, a mixed-effects linear regression model was used to assess the treatment effect, the time effect, and the interaction effect between them. Cohen’s effect size was computed for the primary outcome variable to provide the estimated magnitude of the treatment effect. To account for missing data during the present study, we conducted a sensitivity analysis whereby we imputed data for all dropouts as relapse to each participant’s baseline measure (ie, data on weekly mean proportion of cocaine nonuse days during the 2-week baseline screening period) to provide a conservative estimate for the difference in treatment effect between topiramate and placebo. 51 Effect sizes of 0.2, 0.5, and 0.8 represent small, medium, and large effects, respectively (see the author material file for complete details of the statistical analysis for all outcome measures, handling of missing data, and power analysis). The statistical model, which included random intercept and slope (for temporal trend), was adjusted for participants’ weekly mean proportion of cocaine nonuse days before randomization (ie, during the 2-week baseline screening period using the algorithm by Elkashef et al 45 ), age at onset of cocaine use, sex, race, and frequency of self-reported cocaine use in the 30 days before informed consent as covariates. All data were analyzed using the intent-to-treat principle, whereby all participants allocated at random to treatment were included in the statistical analyses.
Those who tested positive on any visit during a week or missed 1 or more visits in any study week were determined to be positive for benzoylecgonine. One urinary cocaine-free week was defined as when a participant provided 3 urine samples free of benzoylecgonine in 1 week. Because all missing urine samples were coded to the worst possible outcome (ie, as being positive for the cocaine metabolite), we not only accounted for the total amount of possible urine samples that could be collected (ie, there were no missing values) but also derived a conservative estimate of the amount of urinary cocaine-free weeks. Urine samples were collected thrice weekly for determining the benzoylecgonine level. The secondary outcome variable was urinary cocaine-free weeks during weeks 6 to 12.
To validate our hypothesis and impressions from previous studies in animals and humans, we conducted a randomized, double-blind trial to determine whether topiramate (up to 300 mg/d) would be more efficacious than placebo in treating cocaine dependence.
Medication compliance rate was the total dose (in milligrams) dispensed minus the total dose returned divided by the recommended dose, multiplied by 100. The mean (SD) compliance rate was 57.6% (11.4%) and 60.4% (9.3%) for the topiramate and placebo groups, respectively, with no significant difference between the groups.
Disposition of the participants during the trial.
02). 049). For the urinary cocaine-free weeks during weeks 6 to 12, those who received topiramate compared with placebo had a significantly greater likelihood of achieving urinary cocaine-free weeks (16.6% vs 5.8%; odds ratio, 3.21; 95% CI, 1.24-8.32; F = 5.77; P =. Interestingly, when the results were expanded as a sensitivity test to include study weeks 1 to 12, topiramate was still associated, significantly more than placebo, with an increasing likelihood of urinary cocaine-free weeks (13.5% vs 6.7%; OR, 2.17; 95% CI, 1.00-4.71; P =.
004) for having “reportedly no craving at all” in the intensity of craving on the worst day. For the craving subscales of the Brief Substance Craving Scale, the estimated proportions of topiramate vs placebo were 0.499 vs 0.300 (OR, 2.33; 95% CI, 1.15-4.71; P =. 02) for having “reportedly no craving at all” in terms of the intensity, frequency, and duration of craving in the past 24 hours and 0.501 vs 0.271 (OR, 2.70; 95% CI, 1.38-5.29; P =.
Figure 2 shows the effect of topiramate vs placebo during the entire trial period. 04). For the weekly mean proportion of cocaine nonuse days during weeks 6 to 12, there was a significant effect of topiramate vs placebo, irrespective of whether missing data were not (13.3% vs 5.3%; 95% CI, 1.4%-14.6%; effect size, 0.48; F = 5.66; P =. 02) or were imputed to the baseline value (8.9% vs 3.7%; 95% CI, 0.2%-10.1%; effect size, 0.35; F = 4.15; P =.
Finally, a recent laboratory study in humans by Johnson and colleagues 37 showed that topiramate (200 mg/d) reduced cocaine craving and decreased the monetary value of experimenter-administered high-dose cocaine (ie, 0.65 mg/kg intravenously), effects suggesting that topiramate can suppress cocaine’s reinforcing effects and abuse liability. 35 More directly, Kampman and colleagues 36 showed in a small (n = 40) placebo-controlled pilot study that topiramate reduced cocaine use after dose titration to 200 mg/d following 8 weeks of treatment. In humans, our hypothesis has been supported indirectly from our demonstration that topiramate is an efficacious treatment for alcohol dependence 33, 34 and can reduce relapse in abstinent methamphetamine addicts.
In their algorithm, they modified the rules from Preston et al 46 by combining self-reported use, urine benzoylecgonine, and the estimated concordance rate between them for each participant to determine whether he or she used cocaine for every study day (see author material file for details of the quantification of benzoylecgonine and the “Guidance Document for Scoring Use and Non-Use Days for Topiramate Trial of Cocaine Dependence,” the latter provided courtesy of Shou-Hua Li, PhD, at the National Institute on Drug Abuse). Urine samples were collected thrice weekly. The primary outcome variable was the weekly difference from baseline in the proportion of cocaine nonuse days, using the algorithm developed by Elkashef et al, 45 during weeks 6 to 12, the period from when the target topiramate dose or its matching placebo was achieved to the study’s end.
40, log-rank test) or number of missed visits (mean, 16.0 for topiramate recipients and 17.6 for placebo recipients; P =. Three participants did not return for the termination visit at week 12. Of these, 38 were topiramate recipients and 34 had received placebo, with no significant difference between the groups in time to dropout ( P =. 45, t test). At week 6, the retention rates were 77.8% for topiramate recipients and 74.2% for placebo recipients; this decreased to 63.5% and 53.0%, respectively, by the end of week 11. Figure 1 presents the reasons for dropout. Adjusting for the 13 who failed enrollment, 72 of the 129 participants who received 1 or more weeks of double-blind treatment completed the 12-week trial.