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: 3.42). 11/2006; 84(3):256-63. DOI: 10.1016/j.drugalcdep.2006.02.011
Source: PubMed


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.

9 Reads
  • Source
    • "The vast majority of these studies have reported no supportive evidence for efficacy, although a few studies of robust stimulant compounds, such as d-amphetamine (Grabowski et al., 2001, 2004b; Shearer et al., 2003) and methamphetamine (Mooney et al., 2009) have produced statistically significant signals of efficacy. While preclinical studies suggest a critical role for the serotonergic actions of cocaine (Walsh and Cunningham, 1997), randomized clinical trials of serotonergic agents in primary cocaine dependent individuals, including fluoxetine (Batki et al., 1996; Grabowski et al., 1995; Schmitz et al., 2001; Winstanley et al., 2011), tryptophan (Jones et al., 2004), ritanserin (Johnson et al., 1997), ondansetron (Johnson et al., 2006) and others have largely failed to demonstrate effi- cacy. There is preclinical evidence suggesting that targeting the noradrenergic action of cocaine may be a rational approach (Sofuoglu and Sewell, 2009; Weinshenker and Schroeder, 2007). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Background: Cocaine abuse continues to be a significant public health problem associated with morbidity and mortality. To date, no pharmacotherapeutic approach has proven effective for treating cocaine use disorders. Preclinical and clinical evidence suggests that noradrenergic activity may play a role in mediating some effects of cocaine and may be a rational target for treatment. Methods: This double blind, placebo-controlled randomized, parallel group, 12-week outpatient clinical trial enrolled cocaine dependent individuals seeking treatment to examine the potential efficacy of the selective norepinephrine reuptake inhibitor, atomoxetine (80 mg/day; p.o.; n = 25), compared to placebo (n = 25). Subjects were initially stratified on cocaine use (< 15 days or ≥ 15 days of the last 30), age and race using urn randomization. Attendance, medication adherence and study compliance were reinforced with contingency management, and weekly counseling was offered. An array of measures (vital signs, laboratory chemistries, cognitive and psychomotor tests, cocaine craving and urine samples for drug testing) was collected throughout the study and at follow-up. Results: Survival analysis revealed no differences in study retention between the two groups, with approximately 56% of subjects completing the 12-week study (Cox analysis χ(2) = .72; p = .40; Hazard Ratio 1.48 [95% CI 0.62-3.39]). GEE analysis of the proportion of urine samples positive for benzoylecgonine, a cocaine metabolite, revealed no differences between the atomoxetine and placebo groups (χ(2) = 0.2, p = .66; OR = 0.89 [95% CI 0.41-1.74]). Atomoxetine was generally well tolerated in this population. Conclusions: These data provide no support for the utility of atomoxetine in the treatment of cocaine dependence.
    Drug and alcohol dependence 11/2012; 130(1-3). DOI:10.1016/j.drugalcdep.2012.10.024 · 3.42 Impact Factor
  • Source
    • "Although research has indicated that the longer individuals stay in treatment, the better outcomes they will demonstrate, attrition continues to be a major problem, particularly during the first few weeks of treatment. During this period, dropout rates of 50% or higher are not uncommon (e.g., Johnson et al., 2006; Levin, Evans, Brooks, & Garawi, 2007; Schmitz, Stotts, Rhoades, & Grabowski, 2001; Stark). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Participant retention is one of the more challenging issues in the treatment of substance use disorders. Using data from the National Institute on Drug Abuse Clinical Trials Network's Women and Trauma Study (recruitment in 2004-2005), we examine prominent factors associated with early attrition among women with cooccurring substance use disorders and posttraumatic stress disorder (N = 340). Early treatment attrition is associated with a history of youth partner violence, perceived need for psychological treatment, and abuse of alcohol, opioids, and stimulants. Logistical barriers (e.g., transportation, having children) were not significantly associated with early attrition. Findings provide insight into characteristics of women who might need additional supports to engage in treatment.
    Journal of Social Work Practice in the Addictions 01/2012; 12(4):348. DOI:10.1080/1533256X.2012.728104
  • Source
    • "In a pilot randomized, double-blind, 10-week controlled trial, 63 treatment-seeking, cocaine-dependent subjects received ondansetron (0.25mg, 1.0mg, or 4.0mg twice daily) or placebo. The ondansetron 4.0mg group had the lowest dropout rate among all treatment groups and a greater rate of improvement in terms of percentage of participants with a cocaine-free week compared with the placebo group [149]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Cocaine dependence is characterized by compulsive drug seeking and high vulnerability to relapse. Overall, cocaine remains one of the most used illicit drugs in the world. Given the difficulty of achieving sustained recovery, pharmacotherapy of cocaine addiction remains one of the most important clinical challenges. Recent advances in neurobiology, brain imaging and clinical trials suggest that certain medications show promise in the treatment of cocaine addiction. The pharmacotherapeutic approaches for cocaine dependence include medications able to target specific subtypes of dopamine receptors, affect different neurotransmitter systems (i.e. noradrenergic, serotonergic, cholinergic, glutamatergic, GABAergic and opioidergic pathways), and modulate neurological processes. The systematic reviews concerning the pharmacological treatment of cocaine dependence appear to indicate controversial findings and inconclusive results. The aim of future studies should be to identify the effective medications matching the specific needs of patients with specific characteristics, abandoning the strategies extended to the entire population of cocaine dependent patients. In the present review we summarize the current pharmacotherapeutic approaches to the treatment of cocaine dependence with a focus on the new patents.
    05/2011; 6(2):146-60. DOI:10.2174/157488911795933893
Show more