Grassi MC, Cioce AM, Giudici FD, Antonilli L, Nencini P. Short-term efficacy of disulfiram or naltrexone in reducing positive urinalysis for both cocaine and cocaethylene in cocaine abusers: a pilot study. Pharmacol Res 55: 117-121

Department of Human Physiology and Pharmacology V. Erspamer, University of Rome La Sapienza, Piazzale Aldo Moro, 5, Rome 00185, Italy.
Pharmacological Research (Impact Factor: 4.41). 03/2007; 55(2):117-21. DOI: 10.1016/j.phrs.2006.11.005
Source: PubMed


Cocaine abusers frequently report taking the drug in association with alcohol. This combined intake leads to the synthesis of cocaethylene, an active metabolite with effects similar to those of cocaine, but more prolonged. Since pharmacological effects of cocaethylene may partially account for the habit of cocaine abusers to take the drug in combination with ethanol, a main therapeutic goal in these patients should be making body fluids negative for cocaethylene. This randomized controlled open study conducted on 12 subjects co-abusers of cocaine and alcohol, evaluates the efficacy of a 12-week pharmacological treatment with Disulfiram (DIS) 400mg daily or Naltrexone (NTX) 50mg daily associated with Cognitive Behaviour Therapy (CBT), as compared to CBT alone, in terms of: (i) stay in treatment; (ii) drug-free urinalyses for cocaine and cocaethylene; (iii) reduction of alcohol and cocaine craving. Data presented in this study are restricted to the first 4 weeks of treatment when all the enrolled subjects were still available for examination. In fact, of the 12 subjects enrolled in the study only 4 (33%) completed the 12-week treatment. Of these, three were in the CBT group and one in the NTX/CBT group. Results show that CBT treated subjects remained in treatment longer than those assigned to either DIS/CBT or NTX/CBT therapies. However, during the first 4 weeks of treatment, CBT-group urine tested positive almost always for both cocaine and cocaethylene. In contrast, both DIS/CBT and NTX/CBT treatments were associated to a statistically significant reduction, of positive urinalysis for both cocaine and cocaethylene, with respect to CBT alone. Moreover, across the first 4 weeks of treatment DIS/CBT and NTX/CBT treated subjects maintained lower scores at Visual Analogue Scales (VAS) for both cocaine and alcohol craving than subjects receiving CBT alone. This pilot study suggests that the transient efficacy of pharmacological treatments in maintaining subjects drug free, does not add to the capability of CBT to retain them in treatment.

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    • "The relevance of these findings to DBH inhibition as a potential pharmacotherapy for cocaine relapse prevention remains to be determined. Although several clinical trials with disulfiram showed a positive result for treatment of cocaine use (Carroll et al., 1998Carroll et al., , 2004George et al., 2000;Petrakis et al., 2000;Grassi et al., 2007), some subsequent studies have been less encouraging. For example, in one clinical trial, low doses of disulfiram treatment resulted in worse retention and increased cocaine-positive urine samples (Oliveto et al., 2011). "
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    ABSTRACT: Disulfiram has shown promise as a pharmacotherapy for cocaine dependence in clinical settings, though it has many targets and the behavioral and molecular mechanisms underlying its efficacy are unclear. One of many biochemical actions of disulfiram is inhibition of dopamine β-hydroxylase (DBH), the enzyme that converts dopamine (DA) to norepinephrine (NE) in noradrenergic neurons. Thus, disulfiram simultaneously reduces NE and elevates DA tissue levels in the brain. In rats, both disulfiram and the selective DBH inhibitor, nepicastat, block cocaine-primed reinstatement, a paradigm which is thought to model some aspects of drug relapse. This is consistent with some clinical results and supports the use of DBH inhibitors for the treatment of cocaine dependence. The present study was conducted to confirm and extend these results in nonhuman primates. Squirrel monkeys trained to self-administer cocaine under a second-order schedule were pretreated with disulfiram or nepicastat prior to cocaine-induced reinstatement sessions. Neither DBH inhibitor altered cocaine-induced reinstatement, even when dose and pretreatment time were varied systematically. Unexpectedly, nepicastat administered alone induced a modest reinstatement effect in squirrel monkeys, but not in rats. To investigate the neurochemical mechanisms underlyling the behavioral results, the effects of DBH inhibition on extracellular DA were analyzed in the nucleus accumbens (NAc) using in vivo microdialysis in squirrel monkeys. Both disulfiram and nepicastat attenuated cocaine-induced DA overflow in the NAc. Hence, the attenuation of cocaine-induced changes in DA neurochemistry in the NAc was not associated with altered cocaine-seeking behavior. Overall, the reported behavioral effects of DBH inhibition in rodent models of relapse did not extend to nonhuman primates under the conditions employed in the current studies.
    Preview · Article · May 2014 · Journal of Pharmacology and Experimental Therapeutics
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    • "Six studies had three arms. Four of these compared disulfiram to naltrexone and to one other condition: to no disulfiram [13], to acamprosate [22], [40], or to GHB [41]. The control arms in these studies were combined in order to calculate the overall efficacy and the following comparisons: blind versus open-label, supervision versus no supervision, and cocaine versus non cocaine. "
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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.
    Full-text · Article · Feb 2014 · PLoS ONE
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    • "Results from randomized clinical trials assessing therapeutic efficacy of disulfiram for cocaine dependence also appear complex. For instance, studies have found that disulfiram treatment decreases (Carroll et al., 1993; Higgins et al., 1993; Carroll et al., 2000; George et al., 2000; Grassi et al., 2007) or produces no change (Pettinati et al., 2008) in cocaine use. Patients in the study by Pettinati et al. were also dependent on alcohol, and only 1/3 took >80% of their disulfiram doses, which likely contributed to the lack of efficacy for disulfiram in this study. "
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    ABSTRACT: Much effort has been devoted to research focused on pharmacotherapies for cocaine dependence yet there are no FDA-approved medications for this brain disease. Preclinical models have been essential to defining the central and peripheral effects produced by cocaine. Recent evidence suggests that cocaine exerts its reinforcing effects by acting on multiple neurotransmitter systems within mesocorticolimibic circuitry. Imaging studies in cocaine-dependent individuals have identified deficiencies in dopaminergic signaling primarily localized to corticolimbic areas. In addition to dysregulated striatal dopamine, norepinephrine and glutamate are also altered in cocaine dependence. In this review, we present these brain abnormalities as therapeutic targets for the treatment of cocaine dependence. We then survey promising medications that exert their therapeutic effects by presumably ameliorating these brain deficiencies. Correcting neurochemical deficits in cocaine-dependent individuals improves memory and impulse control, and reduces drug craving that may decrease cocaine use. We hypothesize that using medications aimed at reversing known neurochemical imbalances is likely to be more productive than current approaches. This view is also consistent with treatment paradigms used in neuropsychiatry and general medicine.
    Full-text · Article · Jan 2012 · Pharmacology [?] Therapeutics
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