A pilot trial of topiramate for the treatment of cocaine dependence

Department of Psychiatry, University of Pennsylvania School of Medicine, 3900 Chestnut Street, Philadelphia, PA 19104, USA.
Drug and Alcohol Dependence (Impact Factor: 3.42). 10/2004; 75(3):233-40. DOI: 10.1016/j.drugalcdep.2004.03.008
Source: PubMed

ABSTRACT Both GABAergic and glutamatergic neurons appear to be important modulators of the brain reward system and medications that affect GABA and glutamatergic neurotransmission may reduce the rewarding properties of cocaine and reduce cocaine craving. Topiramate, an anticonvulsant, raises cerebral GABA levels, facilitates GABAergic neurotransmission and inhibits glutametergic activity at AMPA/kainite receptors. Thus, it may be useful for treating cocaine dependence.
The efficacy of topiramate for cocaine dependence was tested in a 13-week, double-blind, placebo-controlled pilot trial (n = 40). Topiramate was titrated gradually over 8 weeks to a dose of 200 mg daily. The primary outcome measure was cocaine abstinence verified by twice weekly urine benzoylecgonine tests (UBT).
Eighty-two percent of subjects completed the trial. Analysis of the UBT using a GEE model showed that after week 8, when the dose titration was completed, topiramate-treated subjects were more likely to be abstinent from cocaine compared to placebo-treated subjects (Z = 2.67, P = 0.01). Topiramate-treated subjects were also more likely to attain 3 weeks of continuous abstinence from cocaine (chi2 = 3.9, d.f. = 1, P = 0.05).
Topiramate may be effective for the treatment of cocaine dependence.

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    • "Study eligibility criteria were as follows: (a) cocaine and opioid dependence (based on an evaluation with the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders , fourth edition [DSM–IV] [SCID]) and seeking treatment; (b) age between 18 and 55 years; (c) eligible to receive methadone maintenance treatment; (d) no allergy to sulfonamide medications or topiramate; (e) no chronic disorders with risk of acidosis; (f) no history of nephrolithiases or unexplained hematuria; (g) not on Highly Active Antiretroviral Therapy; (h) no glaucoma, family history of glaucoma, intraocular pressure Ͼ20 mm Hg, or onesided blindness (i) no seizure disorder or use of antiepileptic medications; (j) no current benzodiazepine dependence; (k) no serious psychiatric illness (psychosis, dementia); and (l) no pregnancy , lactation, or refusal to use an effective contraceptive method. Computerized randomization to placebo and topiramate groups was stratified on (a) gender, (b) age (Յ40 years old, Y/N), (c) cocaine withdrawal severity (Cocaine Selective Severity Assessment [CSSA] Յ20, Y/N; Kampman et al., 2004), and (d) current alcohol dependence. A detailed description of participant screening and randomization can be found in Umbricht et al. (2014). "
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    ABSTRACT: Topiramate is being investigated as a potential pharmacotherapy for the treatment of addictive disorders. However, its cognitive side effects raise concerns about its use, especially in populations with cognitive impairment, such as persons with chronic substance use disorders. This study investigated topiramate's cognitive effects in individuals dually dependent on cocaine and opioids as part of a double-blind, randomized, controlled trial of topiramate for cocaine dependence treatment. After 5 weeks of stabilization on daily oral methadone (M = 96 mg), participants were randomized to topiramate (n = 18) or placebo (n = 22). Cognitive testing took place at 2 time points: study weeks 4 through 5 to assess baseline performance and 10 to 13 weeks later to assess performance during stable dosing (300 mg topiramate or placebo). All participants were maintained on methadone at both testing times, and testing occurred 2 hours after the daily methadone plus topiramate/placebo administration. The topiramate and placebo groups did not differ on sex, level of education, premorbid intelligence, methadone dose, or illicit drug use. Topiramate slowed psychomotor and information processing speed, worsened divided attention, reduced n-back working memory accuracy, and increased the false alarm rate in recognition memory. Topiramate had no effects on visual processing, other measures of psychomotor function, risk-taking, self-control, Sternberg working memory, free recall, and metamemory. These findings indicate that topiramate may cause cognitive impairment in this population. This effect may limit its acceptability and use as a treatment in individuals with chronic opioid and cocaine use disorders, among whom preexisting cognitive impairments are common. (PsycINFO Database Record (c) 2014 APA, all rights reserved).
    Psychology of Addictive Behaviors 11/2014; DOI:10.1037/adb0000027 · 2.09 Impact Factor
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    • "Compared to other psychostimulants like cocaine, there is less research involving MA abuse in monkey models. For some compounds, clinical studies have reported opposite effects on cocaine and MA (Kampman et al. 2004; Johnson et al. 2007; see Winchell et al. 2012) which further warrants the evaluation of potential psychostimulant treatment drugs in animals self-administering cocaine and MA (see also Martelle et al. 2014). Thus, an additional goal of these studies was to extend this evaluation of PG619 and buspirone from cocaine to MA. "
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    ABSTRACT: The dopamine (DA) D2 and D3 receptors have been associated with cocaine abuse. A recent study with the D3 receptor (D3R) partial agonist PG619 found that it attenuated cocaine-induced reinstatement and the D2-like receptor antagonist buspirone has shown positive outcomes in two studies of cocaine abuse in monkeys. However, a recent clinical trial indicated that buspirone did not improve abstinence in treatment-seeking cocaine abusers. The objective of the study was to examine PG619 and buspirone under a food-drug choice paradigm in order to better model the clinical findings. In addition, we extended the characterization of both compounds to include methamphetamine (MA) self-administration (SA). Six adult male rhesus monkeys were trained to respond under a concurrent food (1.0-g pellets) and drug (0.01-0.3 mg/kg/injection cocaine or MA) choice paradigm in which complete SA dose-response curves were determined each session (N = 3/group). Monkeys received 5 days of treatment with either PG619 (0.1-3.0 mg/kg, i.v.) or buspirone (0.01-1.0 mg/kg, i.m.). In a follow-up study, the SA doses were reduced (0.003-0.1 mg/kg/injection) to increase reinforcement frequency and buspirone was retested. PG619 did not affect cocaine or MA choice, while buspirone increased low-dose cocaine choice. Changing the SA doses increased the number of reinforcers received each session, but buspirone did not decrease drug choice. Consistent with clinical findings, these results do not support the use of buspirone for psychostimulant abuse and suggest that food-drug choice paradigms may have greater predictive validity than the use of other schedules of reinforcement.
    Psychopharmacology 10/2014; 232(7). DOI:10.1007/s00213-014-3760-6 · 3.88 Impact Factor
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    • "Un essai monocentrique randomisé, contrôlé versus placebo, en double insu, pendant 13 semaines (40 sujets fumeurs de crack) [29] n'a pas rapporté de différence significative entre les deux groupes à la fin de l'étude. Cependant, le risque de consommer de la cocaïne dans le groupe recevant du topiramate était significativement plus faible que dans le groupe recevant le placebo (comparaison des Odds Ratio z = 2,67, p = 0,01) sur la période où le topiramate était à posologie maximale, de la neuvième à la treizième semaine. "
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    ABSTRACT: Background Drug treatments used in substance use disorders are not effective in all patients. Objective To assess the effectiveness of topiramate use in the treatment of substance use disorders. Information sources Medline database from January 1966 to December 2013, Cochrane database and Selection of studies We used keywords topiramate, addiction, substance abuse, alcohol, tobacco, nicotine, cocaine, methamphetamine, opiate, heroin, benzodiazepine, cannabis, bulimia nervosa, binge eating disorder, gambling. All clinical trials were included. Animal trials, laboratory tests, reviews, answers to writers, case-reports, case series and publications unrelated to the topic were excluded. Twenty-eight articles investigating the efficacy of topiramate in substance use were included. Results In alcohol-related disorder, several trials and a meta-analysis showed a reduction of days of consumption. In a single-center trial on tobacco-related disorder, topiramate was not found effective in reducing the carbon monoxide expired. In cocaine-related disorder, one single-center trial showed a reduction of days of consumption and two single-center trials have found a trend in favour of topiramate. In alcohol and cocaine co-dependency, a single-center trial found a trend in favour of topiramate. In methamphetamine-related disorder, a multicenter trial found a trend in favour of topiramate. In bulimia nervosa, two single-center trials showed a reduction in binge eating and compensatory behaviours. In binge eating disorder, several trials showed a reduction of binge eating and weight. In gambling, one single-center trial did not show any significant results. There were no randomized controlled trials found in opioid-related disorder, benzodiazepines-related disorder, and cannabis-related disorder. Limitations Definition of abstinence and methods to assess the efficacy of topiramate differed between trials. The methodological quality of included trials was variable, especially with no double-blind procedure in eight trials. Conclusion Topiramate showed interest mainly in alcoholism, binge eating disorder and bulimia nervosa. No definitive conclusions can be reached for other substance use disorders such as nicotine dependence, cocaine dependence, amphetamine dependence or cannabis dependence and for gambling.
    La Presse Médicale 09/2014; 43(9). DOI:10.1016/j.lpm.2014.02.030 · 1.08 Impact Factor
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