Effects of the combination of metyrapone and oxazepam on cocaine craving and cocaine taking: a double-blind, randomized, placebo-controlled pilot study

Abstract

Although cocaine dependence affects an estimated 1.6 million people in the USA, there are currently no medications approved for the treatment of this disorder. Experiments performed in animal models have demonstrated that inhibitors of the stress response effectively reduce intravenous cocaine self-administration. This exploratory, double-blind, placebo-controlled study was designed to assess the safety and efficacy of combinations of the cortisol synthesis inhibitor metyrapone, and the benzodiazepine oxazepam, in 45 cocaine-dependent individuals. The subjects were randomized to a total daily dose of 500 mg metyrapone/20 mg oxazepam (low dose), a total daily dose of 1500 mg metyrapone/20 mg oxazepam (high dose), or placebo for 6 weeks of treatment. The outcome measures were a reduction in cocaine craving and associated cocaine use as determined by quantitative measurements of the cocaine metabolite benzoylecgonine (BE) in urine at all visits. Of the randomized subjects, 49% completed the study. The combination of metyrapone and oxazepam was well tolerated and tended to reduce cocaine craving and cocaine use, with significant reductions at several time points when controlling for baseline scores. These data suggest that further assessments of the ability of the metyrapone and oxazepam combination to support cocaine abstinence in cocaine-dependent subjects are warranted.

Combination pharmacotherapies for stimulant use disorder: a review of clinical findings and recommendations for future research

“…Four of these studies selected cocaine abstinence, verified by negative urine benzoylecgonine screens, as the primary outcome variable [51,54,55,56], whereas three studies tested the efficacy of combinations to alleviate symptoms of cocaine withdrawal and/or reduce cocaine craving [42,57,58]. In the earliest study testing a combination to promote cocaine abstinence, treatment seeking cocaine dependent subjects (N=199) were enrolled in a 10-week study in which they were assigned to placebo, amantadine (300 mg/day), propranolol (a beta blocker; 100 mg/day) or combined amantadine and propranolol [54].…”

“…In the most recent study, 45 cocaine dependent subjects were randomized to placebo, metyrapone (a cortisol inhibitor; 500 mg/day) combined with oxazepam (a positive GABA A modulator; 20 mg/day) or metyrapone (1500 mg/day) combined with oxazepam for 6 weeks [58]. Cocaine craving was not reduced significantly in any treatment group across the full trial.…”

Role of GABA-active neurosteroids in the efficacy of metyrapone against cocaine addiction

“…We have recently focused on metyrapone, both alone and in combination with oxazepam, as possible therapeutics for drug dependence [18,[29][30][31]33]. The experiments described herein demonstrate that metyrapone pretreatment resulted in a dose-dependent decrease in cocaine-reinforced responding.…”

“…Similarly, pharmacological modulators of HPA axis methamphetamine and nicotine-taking and nicotine-seeking behaviors in rats [18,29,30]. Furthermore, this MET/OX combination is effective in reducing craving and decreasing urinary cocaine metabolites in cocaine-dependent human subjects [31]. However, the mechanism(s) by which MET reduces cocaine's behavioral effects is unknown at this time, especially since the reductions in cocaine self-administration and cocaine use were not correlated with changes in plasma glucocorticoid hormones, suggesting that the suppression of adrenal glucocorticoid synthesis is not a prerequisite for metyrapone's behavioral effects [24,29,[31][32][33].…”

“…Furthermore, this MET/OX combination is effective in reducing craving and decreasing urinary cocaine metabolites in cocaine-dependent human subjects [31]. However, the mechanism(s) by which MET reduces cocaine's behavioral effects is unknown at this time, especially since the reductions in cocaine self-administration and cocaine use were not correlated with changes in plasma glucocorticoid hormones, suggesting that the suppression of adrenal glucocorticoid synthesis is not a prerequisite for metyrapone's behavioral effects [24,29,[31][32][33]. For example, MET, especially when combined with a sub-effective dose of oxazepam, decreases cocaine self-administration in rats without significantly reducing plasma corticosterone or altering the pharmacokinetics of these drugs [29].…”