Inhibition of Cytochrome P450 2D6 Modifies Codeine Abuse Liability

Abstract

Oral codeine preparations, widely used for analgesia and cough suppression, are abused by some individuals for their mood-altering properties. The enzymatic O-demethylation of codeine is catalyzed by cytochrome P450 2D6 (CYP2D6), leading to the production of metabolites (morphine, morphine-6-glucuronide) that are pharmacologically more potent than codeine. A placebo-controlled, single-blind study was conducted to characterize the subjective effects of codeine associated with abuse liability and to determine the importance 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 (FD) was determined for each subject. The FD was readministered after pretreatment with placebo, 50 mg of quinidine (a specific, selective CYP2D6 inhibitor) once, or 50 mg of quinidine given four times a day for 4 days. Single-dose quinidine pretreatment significantly 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) and negative (e.g., nausea, p < 0.05) subjective effects of codeine in both the FD120 and FD180 groups. Short-term quinidine pretreatment inhibited codeine O-demethylation 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 that the O-demethylated metabolites contribute substantially to the subjective effects and abuse liability of codeine.

Genetic variability of drug-metabolizing enzymes: the dual impact on psychiatric therapy and regulation of brain function

“…72,73 In man, the concomitant administration of codeine and quinidine, a CYP2D6 inhibitor that does not cross the blood--brain barrier and therefore only affects hepatic function, still produces the central pharmacological effects of morphine, suggesting the existence of a brain-based metabolism of codeine to morphine. 74 Brain-specific drug metabolism has also been demonstrated for other CYP450 enzymes such as CYP2B6, which can be induced by nicotine. 75 Propofol is an anesthetic agent whose effect on sleeping times was increased by locally inhibiting its homolog CYP2B in the brain of rats.…”

Pharmacogenetics and Human Molecular Genetics of Opiate and Cocaine Addictions and Their Treatments

“…Some of these variants increase metabolism of these drugs into their more potent metabolites, whereas others decrease metabolism. The analgesic potency and abuse liability of opioid medications may, therefore, be influenced by variants in this gene (Sindrup et al, 1991(Sindrup et al, , 1993Kathiramalainathan et al, 2000). Tyndale et al (1997) reported that no subjects meeting DSM-IV criteria for oral opioid dependence had either of the defective mutant alleles CYP2D6*3 or CYP2D6*4 which reduce metabolism compared with control and multidrug-dependent individuals whose frequency for these alleles did not differ from that of previously reported Caucasian control populations.…”

“…Tyndale et al (1997) reported that no subjects meeting DSM-IV criteria for oral opioid dependence had either of the defective mutant alleles CYP2D6*3 or CYP2D6*4 which reduce metabolism compared with control and multidrug-dependent individuals whose frequency for these alleles did not differ from that of previously reported Caucasian control populations. Pharmacological inhibition of CYP2D6 with fluoxetine or quinidine, which significantly reduces the formation OPIATE AND COCAINE ADDICTION: GENETICS AND PHARMACOGENOMICS of morphine following codeine administration (Kathiramalainathan et al, 2000;Romach et al, 2000), however, failed to reduce daily codeine intake in a small cohort of codeine addicts (Fernandes et al, 2002). The effect of CYP2D6 alleles resulting in low versus ultrarapid metabolism has been investigated in methadone-maintained subjects.…”

Use of Slow-Release Oral Morphine for the Treatment of Opioid Dependence

“…Despite the benefi ts of once-daily, supervised maintenance treatment with slow-release morphine suggested by our study, consideration must be given to the possible impact of cytochrome P 450 induction, which leads to accelerated elimination of morphine [32] . The pharmacokinetics of opioids is known to be affected by pregnancy, as well as by the co-administration of certain other substances that interfere with cytochrome P 450 -induced metabolism [33,34] .…”