A double-blind, placebo-controlled outpatient trial of pergolide for cocaine dependence

doi:10.1016/S0376-8716(99)00151-9

Drug and Alcohol Dependence

Volume 60, Issue 2, 1 August 2000, Pages 161-168

https://doi.org/10.1016/S0376-8716(99)00151-9 Get rights and content

Abstract

Results of preclinical studies suggest that pergolide, a mixed D₁/D₂ dopamine receptor agonist, may be useful in treating cocaine dependence. To empirically investigate this possibility, we conducted a 5-year, double-blind, placebo-controlled clinical trial of two doses of pergolide (0.05 and 0.25 mg bid) in subjects with cocaine dependence and combined cocaine/alcohol dependence. Data analysis was performed on an intent to treat population (N=358) and a per protocol population (N=108) with urine drug screens (UDS) used as the main outcome measure. There were no significant effects on UDS at either pergolide dose. Pergolide had no significant effect on alcohol use in the comorbid alcohol/cocaine dependence group. Pergolide does not appear to have clinical value in the treatment of cocaine dependence or in decreasing alcohol use in cocaine-dependent individuals at the presently studied doses.

Introduction

Although numerous agents have been studied for the treatment of cocaine dependence, the results of most controlled clinical trials have been disappointing. Early reports of dopamine agonists reducing cocaine craving in cocaine-dependent subjects appeared promising (Giannini et al., 1987, Tennant and Sagherian, 1987), but subsequent results of double-blind, placebo-controlled trials with amantadine (Handelsman et al., 1995), bromocriptine (Eliler et al., 1995, Handelsman et al., 1997), and bupropion (Margolin et al., 1997) did not demonstrate efficacy of these agents in decreasing cocaine use. On the other hand, a recent placebo-controlled trial of amantadine in cocaine-dependent individuals demonstrated efficacy as compared to placebo on several measures of clinical outcome (Shoptaw et al., 1999). In spite of the conflicting data, Gorelick et al. (1994) found that a third of physicians surveyed used dopamine agonists to treat cocaine dependence.

Pergolide is a mixed D₁/D₂ agonist with a long half-life (15–40 h) that is used in the treatment of Parkinson’s disease (Langtry and Clissold, 1990, Fuller and Clemens, 1991). Pergolide is 10–100 times more potent than bromocriptine and has been reported to have a more favorable side effect profile than bromocriptine (Martin et al., 1984). A preliminary open-label trial with pergolide in cocaine-dependent hospitalized patients reported less subjective craving for cocaine in individuals taking pergolide as compared to individuals treated without medications (Malcolm et al., 1991). A second open-label study comparing pergolide to bromocriptine in cocaine-dependent hospitalized patients showed significantly less craving for cocaine, fewer ‘against medical advice’ (AMA) discharges, and longer hospital stays compared to no medication treatment (Malcolm et al., 1994).

Preclinical evidence has accumulated to suggest that dopamine receptors influence acquisition of ethanol self-administration (Hodge et al., 1996), and in some animal models dopamine agonists have been shown to reduce alcohol consumption (Dyr et al., 1993, Mardones and Quintanilla, 1996), although in some studies increases in alcohol consumption have also been found (Nadal et al., 1996). Thus, it appears that pergolide may be a useful agent in the treatment of cocaine-dependent individuals with or without comorbid alcohol dependence because of its positive effects on cocaine use in open-label trials and possible effects on alcohol consumption. Pergolide is also better tolerated and has a longer long half-life relative to other dopamine agonists, which should enhance compliance.

To investigate the use of pergolide in the treatment of cocaine dependence, we conducted a 12-week double-blind, placebo-controlled trial comparing two doses of pergolide in cocaine-dependent subjects with and without alcohol dependence. In our setting, alcohol and cocaine dependence are frequently comorbid, so we wished to assess the efficacy and safety of pergolide in this particularly prevalent comorbid population.

Section snippets

Participants

Patients were eligible for this study if: (1) they were able to give informed consent, as approved by the University Institutional Review Board (IRB); (2) if they met the ‘Diagnostic and Statistical Manual of Mental Disorders’, Third Edition-Revised (DSM III-R) criteria for cocaine dependence with or without comorbid alcohol dependence as determined by the structured clinical interview for DSM III-R (SCID-III-R); and (3) endorsed crack cocaine as their primary drug of choice. Males and females

Description and disposition of the study participants

From the three recruitment sites a total of 1300 subjects were screened. Four hundred and sixty-four patients met inclusion criteria, gave written informed consent, and were randomized. Of these, 273 patients met criteria for cocaine dependence and 191 met criteria for cocaine/alcohol dependence. Patients were randomized as follows, placebo (N=153), low dose pergolide (N=155) and high dose pergolide (N=156). Table 1 summarizes retention by study week over the 12-week trial.

Based on the study

Discussion

Overall, analysis of both a total set of subjects randomized using an ITT population and a smaller PP population indicated no significant effects of high- or low-dose pergolide in decreasing cocaine use. Outcome was not affected by baseline psychological variables such as depression, anxiety, and cocaine craving. Groups also did not differ with respect to weekly hours of psychosocial treatment throughout the study.

Our results are consistent with findings of previous placebo-controlled trials in

Acknowledgements

This study was supported by NIDA (R01 DA08355).

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A double-blind, placebo-controlled outpatient trial of pergolide for cocaine dependence

Abstract

Introduction

Section snippets

Participants

Description and disposition of the study participants

Discussion

Acknowledgements

Alcohol

Life Sci.

Drug Alcohol Depend.

Alcohol

New methodologies for pharmacologic treatment trials for alcohol dependence

Alcohol. Clin. Exp. Res.

Double-blind comparison of bromocriptine and placebo in cocaine withdrawal

Am. J. Drug Alcohol Abuse

Bromocriptine therapy and cocaine withdrawal

J. Clin. Pharmacol.

Pharmacotherapy of cocaine dependence in the United States: comparing scientific evidence and clinical practice

Sub. Abuse

Bromocriptine for cocaine dependence: a controlled clinical trial

Am. J. Addict.

Effects of pergolide on intravenous cocaine self-administration in men and women

Psychopharmacology

Dopamine receptors in the medial prefrontal cortex influence ethanol- and sucrose-reinforced responding

Alcohol. Clin. Exp. Res.

Average partial association in three-way contingency tables

Int. Stat. Rev.

Pergolide: review of its pharmacological properties and therapeutic potential in Parkinson’s disease

Drugs

Pergolide mesylate treatment of cocaine withdrawal

J. Clin. Psychiatry