Inhibition of cytochrome P450 2D6 modifies codeine abuse liability

Oral codeine preparations, widely used for analgesia and cough suppression, are abused by some individuals for their mood-altering properties. The enz ymatic O-demethylation of codeine is catalyzed by cytochrome P450 2D6 (CYP2 D6), leading to the production of metabolites (morphine, morphine-6-glucuro nide) that are pharmacologically more potent than codeine. A placebo-contro lled, single-blind study was conducted to characterize the subjective effec ts of codeine associated with abuse liability and to determine the importan ce of metabolic O-demethylation to codeine abuse liability. Twelve non-drug -dependent subjects received oral administration of placebo and codeine 60, 120, and 180 mg, and a favorite dose CFD) was determined for each subject. The FD was readministered after pretreatment with placebo, 50 mg of quinid ine (a specific, selective CYP2D6 inhibitor) once, or 50 mg of quinidine gi ven four times a day for 4 days. Single-dose quinidine pretreatment signifi cantly decreased the recovery of O-demethylated metabolites in plasma (p < 0.01) and resulted in a decrease in the positive (e.g., "high," p < 0.05) a nd negative (e.g., nausea, p < 0.05) subjective effects of codeine in both the FD120 and FD180 groups. Short-term quinidine pretreatment inhibited cod eine O-demethyiation more than did single-dose quinidine pretreatment (p < 0.01), and it decreased positive codeine effects in the FD120 group (N = 7) , but unexpectedly not in the FD180 group (N = 5). These results suggest th at the O-demethylated metabolites contribute substantially to the subjectiv e effects and abuse liability of codeine.