Oliveto A, Poling J, Mancino MJ, Feldman Z, Cubells JF, Pruzinsky R et al. Randomized, double blind, placebo-controlled trial of disulfiram for the treatment of cocaine dependence in methadone-stabilized patients. Drug Alcohol Depend 113: 184-191

Psychiatry Dept, University of Arkansas for Medical Sciences, Slot 843, 4301 W Markham St, Little Rock, AR 72205, USA.
Drug and alcohol dependence (Impact Factor: 3.42). 01/2011; 113(2-3):184-91. DOI: 10.1016/j.drugalcdep.2010.07.022
Source: PubMed


This study examined the dose-related efficacy of disulfiram for treating cocaine dependence in methadone-stabilized cocaine dependent participants.
One hundred and sixty-one cocaine- and opioid-dependent volunteers were entered into a 14-week, double blind, randomized, placebo-controlled clinical trial at two sites.
Participants were stabilized on methadone during weeks 1-2 and received disulfiram at 0, 62.5, 125 or 250 mg/day during weeks 3-14. All participants also received weekly cognitive behavioral therapy. Thrice-weekly urine samples and weekly self-reported drug use assessments were obtained.
Baseline subject characteristics, retention and drug use did not differ across groups. Outcome analyses were performed on those who participated beyond week 2. Opioid-positive urine samples and self-reported opioid use did not differ by treatment group. The prevalence of alcohol use was low prior to and during the trial and did not differ by treatment group. Cocaine-positive urines increased over time in the 62.5 and 125 mg disulfiram groups and decreased over time in the 250 mg disulfiram and placebo groups (p < 0.0001). Self-reported cocaine use increased in the 125 mg disulfiram group relative to the other three treatment groups (p = 0.04).
Disulfiram may be contraindicated for cocaine dependence at doses <250 mg/day. Whether disulfiram at higher doses is efficacious in reducing cocaine use in dually cocaine and opioid dependent individuals needs to be determined.

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Available from: Michael J Mancino, Oct 07, 2015
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    • "We obtained additional data from the authors in four of these studies. Because we did not obtain a response from the fifth author [30], we were unable to include their trial. The final selection procedure thus allowed us to analyze 22 studies (Figure 1). "
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    ABSTRACT: Despite its success with compliant or supervised patients, disulfiram has been a controversial medication in the treatment of alcoholism. Often, study designs did not recognize a pivotal factor in disulfiram research, the importance of an open-label design. Our objectives are: (1) to analyze the efficacy and safety of disulfiram in RCTs in supporting abstinence and (2) to compare blind versus open-label studies, hypothesizing that blinded studies would show no difference between disulfiram and control groups because the threat would be evenly spread across all groups. We searched PubMed, EMBASE and the Cochrane Central Register for RCTs on disulfiram use with alcoholics in comparison to any alcoholic control group. The primary outcome was defined by the authors of each trial. Additional analyses included: blind vs. open-label, with or without supervision, cocaine study or not, and type of control. Overall, the 22 included studies showed a higher success rate of disulfiram compared to controls Hedges'g = .58 (95%CI = .35-.82). When comparing blind and open-label RCTs, only open-label trials showed a significant superiority over controls g = .70 (95%CI = .46-.93). RCTs with blind designs showed no efficacy of disulfiram compared to controls. Disulfiram was also more effective than the control condition when compared to naltrexone g = .77, 95%CI = .52-1.02, to acamprosate g = .76, 95%CI = .04-1.48, and to the no disulfiram groups g = .43, 95%CI = .17-.69. LIMITS INCLUDE: (1) a population of 89% male subjects and (2) a high but unavoidable heterogeneity of the studies with a substantial I-square in most subgroups of studies. Blinded studies were incapable of distinguishing a difference between treatment groups and thus are incompatible with disulfiram research. Based on results with open-label studies, disulfiram is a safe and efficacious treatment compared to other abstinence supportive pharmacological treatments or to no disulfiram in supervised studies for problems of alcohol abuse or dependence.
    PLoS ONE 02/2014; 9(2):e87366. DOI:10.1371/journal.pone.0087366 · 3.23 Impact Factor
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    • "Inhibition of dopamine b-hydroxylase (DBH), a catecholamine biosynthetic enzyme that is required for NE production, reduces transmission at all NE receptors simultaneously. Disulfiram (Antabuse), which inhibits DBH by copper chelation, has shown promise in the clinic as a treatment for cocaine dependence (Carroll et al, 2004; Gaval-Cruz and Weinshenker, 2009; Oliveto et al, 2011), although disulfiram's lack of specificity, hepatotoxicity, and low tolerability limit its widespread and effective use (Gaval-Cruz and Weinshenker, 2009; Schroeder et al, 2010). Nepicastat is direct, competitive inhibitor of DBH "
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    ABSTRACT: Although norepinephrine (NE) does not typically modulate cocaine self-administration under traditional schedules of reinforcement, it is required for different inducers of the reinstatement of cocaine-seeking behavior via activation of multiple adrenergic receptor subtypes. We predicted that blockade of NE synthesis would attenuate all known modalities of reinstatement, and showed previously that the selective dopamine β-hydroxylase (DBH) inhibitor, nepicastat, had no effect on either maintenance of operant cocaine self-administration maintained on a fixed-ratio 1 schedule or reinstatement of food seeking, but did abolish cocaine-primed reinstatement (Schroeder et al., 2010). In the present series of studies, we first evaluated the dose-dependent effect of nepicastat (5, 50, or 100 mg/kg) on novelty-induced locomotor activity, and found that it blunted exploration only at the highest dose. Next, we assessed the ability of nepicastat (50 mg/kg) to reduce breakpoint responding for cocaine on a progressive ratio schedule and reinstatement induced by drug-associated cues and stress. We found that nepicastat significantly lowered the breakpoint for cocaine, but not for regular chow or sucrose, and attenuated cue-, footshock-, and yohimbine-induced reinstatement. Combined, these results indicate that nepicastat can reduce the reinforcing properties of cocaine under a stringent schedule and can attenuate relapse-like behavior produced by cocaine, formerly cocaine-paired cues, and physiological and pharmacological stressors. Thus, nepicastat is one of those rare compounds that can reduce reinforced cocaine seeking as well as all three reinstatement modalities, while sparing exploratory behavior and natural reward seeking, making it a promising pharmacotherapy for cocaine addiction.Neuropsychopharmacology accepted article preview online, 3 January 2013; doi:10.1038/npp.2012.267.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 01/2013; 38(6). DOI:10.1038/npp.2012.267 · 7.05 Impact Factor
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    • "There is a recent report that acute disulfiram administration actually increases basal and cocaine-induced extracellular DA levels specifically in the PFC [50], which is inconsistent with previous DBH knockout data, DBH inhibitor data, and reduced cocaine-induced DA release in the PFC of cocaine-sensitized animals [30], [51], [52]. A lower dose of disulfiram (50 mg/kg) was used in that study, and recent evidence suggests that low doses of disulfiram increase, rather than decrease, cocaine use in humans [3]. It is also possible that the effects of DBH inhibitors on cocaine sensitization involve other neurotransmitter systems. "
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    ABSTRACT: The anti-alcoholism medication, disulfiram (Antabuse), decreases cocaine use in humans regardless of concurrent alcohol consumption and facilitates cocaine sensitization in rats, but the functional targets are unknown. Disulfiram inhibits dopamine β-hydroxylase (DBH), the enzyme that converts dopamine (DA) to norepinephrine (NE) in noradrenergic neurons. The goal of this study was to test the effects of chronic genetic or pharmacological DBH inhibition on behavioral responses to cocaine using DBH knockout (Dbh -/-) mice, disulfiram, and the selective DBH inhibitor, nepicastat. Locomotor activity was measured in control (Dbh +/-) and Dbh -/- mice during a 5 day regimen of saline+saline, disulfiram+saline, nepicastat+saline, saline+cocaine, disulfiram+cocaine, or nepicastat+cocaine. After a 10 day withdrawal period, all groups were administered cocaine, and locomotor activity and stereotypy were measured. Drug-naïve Dbh -/- mice were hypersensitive to cocaine-induced locomotion and resembled cocaine-sensitized Dbh +/- mice. Chronic disulfiram administration facilitated cocaine-induced locomotion in some mice and induced stereotypy in others during the development of sensitization, while cocaine-induced stereotypy was evident in all nepicastat-treated mice. Cocaine-induced stereotypy was profoundly increased in the disulfiram+cocaine, nepicastat+cocaine, and nepicastat+saline groups upon cocaine challenge after withdrawal in Dbh +/- mice. Disulfiram or nepicastat treatment had no effect on behavioral responses to cocaine in Dbh -/- mice. These results demonstrate that chronic DBH inhibition facilitates behavioral responses to cocaine, although different methods of inhibition (genetic vs. non-selective inhibitor vs. selective inhibitor) enhance qualitatively different cocaine-induced behaviors.
    PLoS ONE 11/2012; 7(11):e50583. DOI:10.1371/journal.pone.0050583 · 3.23 Impact Factor
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