A preliminary randomized, double-blind, placebo-controlled study of the safety and efficacy of ondansetron in the treatment of cocaine dependence.

Department of Psychiatric Medicine, University of Virginia, P.O. Box 800623, Charlottesville, VA 22908-0623, USA.
Drug and Alcohol Dependence (Impact Factor: 3.28). 11/2006; 84(3):256-63. DOI: 10.1016/j.drugalcdep.2006.02.011
Source: PubMed

ABSTRACT Prior studies have demonstrated inefficacy among dopamine receptor antagonists for treating cocaine dependence. An alternative approach would be to investigate the ability of indirect inhibitors of cortico-mesolimbic dopamine release, such as the 5-HT(3) receptor antagonist ondansetron, to reduce cocaine's reinforcing effects. We hypothesized that ondansetron might be more efficacious than placebo at reducing cocaine intake and promoting abstinence in cocaine-dependent individuals. In a pilot randomized, double-blind, 10-week controlled trial, 63 treatment-seeking, cocaine-dependent men and women received ondansetron (0.25 mg, 1.0 mg, or 4.0 mg twice daily) or placebo. Up to three times per week, participants were assessed on several measures of cocaine use, including urine benzoylecgonine. Cognitive behavioral therapy was administered weekly. Ondansetron was well tolerated, causing no serious adverse events. The ondansetron 4.0 mg group had the lowest dropout rate among all treatment groups and a greater rate of improvement in percentage of participants with a cocaine-free week compared with the placebo group (p = 0.02), whereas the ondansetron 1.0 mg group had a lower rate of improvement in percentage of weekly mean non-use days than did placebo recipients (p = 0.04). These results suggest the possibility of a non-linear dose-response function, with evidence supporting efficacy for the 4.0 mg group.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Introduction: There are no FDA-approved pharmacotherapies for treating cocaine addiction; thus, developing drugs to treat cocaine dependence is an unmet critical need. Fortunately, there are a number of drugs that are currently in Phase II clinical trial/s. This is due in part to the advances from in vivo imaging in humans which provided a roadmap of the neurochemistry of the cocaine-dependent brain. Most drugs currently in Phase II clinical trials attempt to modulate the disturbed neurochemistry in cocaine dependents to resemble those of healthy individuals. These predominantly modulate dopamine, serotonin, glutamate, GABA or noradrenaline signalling. Areas covered: This review summarizes the therapeutic potential of each drug as evidenced by clinical and preclinical studies. It also discusses their utility in terms of bioavailability and half-life. Expert opinion: Amphetamine salts and topiramate clearly stand out in terms of their potential efficacy in treating cocaine addiction. The efficacy of topiramate was closely associated with regular cognitive-behavioural therapy (CBT), which highlights the importance of a combined effort to promote abstinence and enhance retention via CBT. Cognitive/psychological screening appears necessary for a more symptom-based approach with more reasonable outcomes other than abstinence (e.g., improved quality of life) in treating cocaine addiction.
    Expert Opinion on Investigational Drugs 04/2014; 23(8). DOI:10.1517/13543784.2014.915312 · 5.43 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Since cocaine and psychostimulant dependence are related to increased dopamine release, antipsychotics have been tried to reduce their reinforcing properties. A meta-analysis was undertaken to assess the efficacy and tolerability of antipsychotics in cocaine- or stimulant-dependent patients. We searched PubMed, Cochrane Library databases, and PsycINFO from database inception until June 24, 2013, using the following keywords: (randomized OR random OR randomly) AND (placebo) AND (methylphenidate OR cocaine OR methamphetamine OR amphetamine OR 3,4-methylenedioxymethamphetamine) AND (dependence OR abuse) AND (antipsychotic OR neuroleptic OR 34 specific antipsychotic names). Included were randomized, placebo-controlled trials of antipsychotics lasting at least 2 weeks in patients with primary cocaine or psychostimulant dependence. Of 363 hits, we removed 316 duplicates, 20 references based on abstract/title, and 13 ineligible full-text articles, retaining 14 trials for this meta-analysis. Two authors independently extracted the data. Coprimary outcomes included degree of substance use and lack of abstinence. Risk ratio (RR), 95% CI, and standardized mean difference were calculated. Ten studies in patients with primary cocaine dependence (risperidone = 5, olanzapine = 3, reserpine = 2; n = 562) and 4 in those with amphetamine/methamphetamine dependence (aripiprazole = 4; n = 179) were meta-analyzed (14 studies, total n = 741). When study results were pooled together, antipsychotics did not differ from placebo in regard to cocaine use days and lack of cocaine or amphetamine/methamphetamine abstinence, severity of addiction, cocaine or amphetamine/methamphetamine craving, Clinical Global Impressions-Severity of Illness (CGI-S) scores, depression, anxiety, compliance, all-cause discontinuation, and several side effects. However, antipsychotics caused more intolerability-related discontinuation than placebo (P = .0009). Individually, aripiprazole was superior to placebo in regard to CGI-S (P = .001), while olanzapine was inferior to placebo in regard to cocaine craving (P = .03) and risperidone was inferior to placebo in regard to depression (P = .002). Antipsychotics had no advantages over placebo in regard to cocaine use and cocaine or psychostimulant abstinence or craving, while causing more intolerability-related discontinuations.
    The Journal of Clinical Psychiatry 12/2013; 74(12):e1169-80. DOI:10.4088/JCP.13r08525 · 5.14 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Ondansetron is the drug of choice to prevent nausea in women undergoing cesarean surgery and can be used to prevent neonatal abstinence syndrome (NAS). Pharmacokinetics of ondansetron has not been characterized in pregnant women or in newborns. A nonlinear mixed-effects modeling approach was used to analyze plasma samples obtained from 20 non-pregnant and 40 pregnant women following single administration of 4 or 8 mg ondansetron, from umbilical cord blood at delivery, and from neonates after birth. The analysis indicates that: ondansetron disposition is not affected by pregnancy (p>0.05), but influenced by dose (p<0.05), and is characterized by rapid transplacental transfer and longer elimination half-life in neonates compared to their mother. A dosing regimen for prevention of NAS was designed based on the model. The regimen involves IV administration of 4 mg to the mothers shortly before cord clamping, or oral administration of 0.07 mg/kg (or equivalently 0.04 mg/kg IV) to neonates. This article is protected by copyright. All rights reserved.
    Clinical Pharmacology &#38 Therapeutics 11/2014; 97(2). DOI:10.1002/cpt.5 · 7.39 Impact Factor