Enadoline and butorphanol: Evaluation of kappa-agonists on cocaine pharmacodynamics and cocaine self-administration in humans

Preclinical studies have demonstrated that kappa -opioid agonists can atten uate the neurochemical and behavioral effects of cocaine that are related t o its reinforcing efficacy, suggesting that kappa -agonists may serve as ph armacotherapies for cocaine dependence. This 8-week inpatient study examine d the ability of enadoline, a selective and high-efficacy kappa -agonist, a nd butorphanol, a mixed agonist with intermediate efficacy at both mu- and kappa -receptors, to reduce the direct pharmacodynamic effects and self-adm inistration of intravenous cocaine in humans (n = 8). Acute doses of intram uscular enadoline (20, 40, and 80 mug/kg), butorphanol (1.5, 3, and 6 mg/70 kg) and placebo were examined separately as pretreatments during each of t hree test sessions with cocaine in a constrained random order. A cocaine do se-effect session (0, 20, and 40 mg cocaine i.v., 1 h apart) examined direc t pharmacodynamic interactions on subjective and physiological indices; sel f-administration sessions examined choice behavior for cocaine (40 mg i.v. for six trials) versus money 1) in the presence of a sample cocaine dose wi th money choices presented in ascending value, and 2) in the absence of a s ample dose with money choices presented in descending values. Enadoline (80 mug/70 kg) significantly (p < 0.05) reduced some of the positive subjectiv e effects of cocaine (e.g., ratings of "high"), while butorphanol failed to modify subjective responses. Both agents were safely tolerated in combinat ion with cocaine without adverse physiological responses. Cocaine self-admi nistration was significantly greater across all pretreatment conditions whe n the sample dose was given and ascending money choices were used. Enadolin e and butorphanol failed to modify cocaine self-administration. These data suggest that these K-agonists may be safely administered in the presence of cocaine but do not produce significant attenuation of cocaine's direct eff ects or self-administration under these acute dosing conditions.