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Agonist replacement therapy for cocaine dependence: a translational review.

ABSTRACT: Cocaine use disorders are prevalent throughout the world. Agonist replacement therapy is among the most effective strategies for managing substance use disorders including nicotine and opioid dependence. This paper reviews the translational literature, including preclinical experiments, human laboratory studies and clinical trials, to determine whether agonist-replacement therapy is a viable strategy for managing cocaine dependence. Discussion is limited to transporter blockers (i.e., methylphenidate) and releasers (i.e., amphetamine analogs) that are available for use in humans in the hope of impacting clinical research and practice more quickly. The translational review suggests that agonist-replacement therapy, especially monoamine releasers, may be effective for managing cocaine dependence. Future directions for medications development are also discussed because the viability of agonist-replacement therapy for cocaine dependence may hinge on identifying novel compounds or formulations that have less abuse and diversion potential.

SUBMITTER: Rush CR

PROVIDER: S-EPMC3292908 | biostudies-literature | 2012 Feb

REPOSITORIES: biostudies-literature

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Agonist replacement therapy for cocaine dependence: a translational review.

Rush Craig R CR Stoops William W WW

Future medicinal chemistry 20120201 2

Cocaine use disorders are prevalent throughout the world. Agonist replacement therapy is among the most effective strategies for managing substance use disorders including nicotine and opioid dependence. This paper reviews the translational literature, including preclinical experiments, human laboratory studies and clinical trials, to determine whether agonist-replacement therapy is a viable strategy for managing cocaine dependence. Discussion is limited to transporter blockers (i.e., methylphen ...[more]

PMID: 22300101

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Project description:OBJECTIVE:To examine whether galantamine, a cognitive-enhancing medication that is both acetylcholinesterase inhibitor and agonist at nicotinic acetylcholine receptors, is effective at improving cocaine use outcomes and cognitive functioning, alone and in combination with computerized cognitive behavioral therapy (CBT). METHOD:A 12-week, randomized 2 × 2, factorial trial was conducted to evaluate galantamine versus placebo (double-blind) and computerized CBT plus standard methadone treatment versus standard methadone treatment alone in a community-based methadone maintenance program (September 2009-April 2015). One hundred twenty individuals diagnosed with DSM-IV cocaine use disorder were randomly assigned to the following conditions: (1) galantamine (8 mg/d) plus standard methadone maintenance treatment (treatment as usual [TAU]), (2) placebo plus TAU, (3) galantamine plus computerized CBT plus TAU, or (4) placebo plus computerized CBT plus TAU; medication administration was supervised at the time of daily methadone dosing. The primary cocaine use outcome was change in percent days of abstinence over time. Number of cocaine-negative urine toxicology screens submitted and cognitive function were secondary outcomes. RESULTS:Random effect regression analysis indicated significant reductions in frequency of cocaine use over time, with significant treatment-by-time effects for both galantamine over placebo (F = 5.3, P = .02, d = 0.34) and computerized CBT over standard methadone treatment (F = 4.2, P = .04, d = 0.30) but no evidence of significant benefit of the combination over either treatment alone. Pretreatment to posttreatment comparisons of multiple indices of cognitive functioning, including sustained attention, indicated no benefit of galantamine over placebo. CONCLUSIONS:Findings suggest benefits of galantamine and computerized CBT for reducing cocaine use in this sample. Although galantamine did not improve measures of cognitive function in this sample, multiple measures of cognitive function were associated with cocaine use outcomes, underlining the significance of cognitive function in cocaine treatment outcomes. TRIAL REGISTRATION:ClinicalTrials.gov identifier: NCT00809835.

Project description:BACKGROUND:Cocaine dependence is a severe disorder for which no medication has been approved. Like opioids for heroin dependence, replacement therapy with psychostimulants could be an effective therapy for treatment. OBJECTIVES:To assess the effects of psychostimulants for cocaine abuse and dependence. Specific outcomes include sustained cocaine abstinence and retention in treatment. We also studied the influence of type of drug and comorbid disorders on psychostimulant efficacy. SEARCH METHODS:This is an update of the review previously published in 2010. For this updated review, we searched the Cochrane Drugs and Alcohol Group Trials Register, CENTRAL, MEDLINE, Embase and PsycINFO up to 15 February 2016. We handsearched references of obtained articles and consulted experts in the field. SELECTION CRITERIA:We included randomised parallel group controlled clinical trials comparing the efficacy of a psychostimulant drug versus placebo. DATA COLLECTION AND ANALYSIS:We used standard methodological procedures expected by Cochrane. MAIN RESULTS:We included 26 studies involving 2366 participants. The included studies assessed nine drugs: bupropion, dexamphetamine, lisdexamfetamine, methylphenidate, modafinil, mazindol, methamphetamine, mixed amphetamine salts and selegiline. We did not consider any study to be at low risk of bias for all domains included in the Cochrane 'Risk of bias' tool. Attrition bias was the most frequently suspected potential source of bias of the included studies. We found very low quality evidence that psychostimulants improved sustained cocaine abstinence (risk ratio (RR) 1.36, 95% confidence interval (CI) 1.05 to 1.77, P = 0.02), but they did not reduce cocaine use (standardised mean difference (SMD) 0.16, 95% CI -0.02 to 0.33) among participants who continued to use it. Furthermore, we found moderate quality evidence that psychostimulants did not improve retention in treatment (RR 1.00, 95% CI 0.93 to 1.06). The proportion of adverse event-induced dropouts and cardiovascular adverse event-induced dropouts was similar for psychostimulants and placebo (RD 0.00, 95% CI -0.01 to 0.01; RD 0.00, 95% CI -0.02 to 0.01, respectively). When we included the type of drug as a moderating variable, the proportion of patients achieving sustained cocaine abstinence was higher with bupropion and dexamphetamine than with placebo. Psychostimulants also appeared to increase the proportion of patients achieving sustained cocaine and heroin abstinence amongst methadone-maintained, dual heroin-cocaine addicts. Retention to treatment was low, though, so our results may be compromised by attrition bias. We found no evidence of publication bias. AUTHORS' CONCLUSIONS:This review found mixed results. Psychostimulants improved cocaine abstinence compared to placebo in some analyses but did not improve treatment retention. Since treatment dropout was high, we cannot rule out the possibility that these results were influenced by attrition bias. Existing evidence does not clearly demonstrate the efficacy of any pharmacological treatment for cocaine dependence, but substitution treatment with psychostimulants appears promising and deserves further investigation.

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Agonist replacement therapy for cocaine dependence: a translational review.

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Agonist replacement therapy for cocaine dependence: a translational review.

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