Evidence for morphine-independent central nervous opioid effects after administration of codeine: Contribution of other codeine metabolites

Objective: Our objective was to investigate whether codeine or one of its metabolites contributes substantially to central nervous effects independent from the cytochrome P450 (CYP) 2D6-mediated O-demethylation to morphine. Methods: After oral administration of codeine, plasma concentrations of codeine and its metabolites, as well as pupil size as a measure of central nervous effects, were measured in 11 healthy volunteers representing poor, intermediate, extensive, and ultrarapid metabolizers for CYP2D6. Subsequently, the observed plasma morphine concentrations were mimicked by use of computerized morphine infusion, and the miotic effects were compared with those observed after codeine administration. The contribution of codeine, codeine-6-glucuronide, norcodeine, morphine, morphine-6-glucuronide, and normorphine to the miotic effects was analyzed by means of pharmacokinetic-pharmacodynamic modeling. Results: The areas under the curve of the miotic effects after codeine were 1.7 +/- 2 times greater than after morphine (P < 0.01). This contrasted to similar or even lower morphine concentrations after codeine than after morphine (area under the curve ratio, 0.5 +/- 0.4; P = .21). A pharmacokinetic-pharmacodynamic fit of the miotic effects by use of morphine as the only active moiety was most significantly (P < .0001) improved when codeine-6-glucuronide as a second active moiety was added. Conclusion: CYP2D6-dependent formation of morphine does not explain exclusively the central nervous effects of codeine. Codeine-6-glucuronide is the most likely additional active moiety.