The influence of pharmacogenetics on opioid analgesia: studies with codeine and oxycodone in the Sprague-Dawley/Dark Agouti rat model.

In the Sprague-Dawley (SD) rat, the O-demethylation of codeine to morphine is catalyzed by cytochrome P4502D1 (CYP2D1), which is absent in the female Dark Agouti (DA) rat. Oxycodone is similar in structure to codeine but, in contrast, has an analgesic potency in humans similar to morphine. The aim of the study was to test whether the DA rat and the SD rat pretreated with the CYP2D1 inhibitor quinine showed attenuation in analgesia to codeine and oxycodone. With the use of the tail flick model, dose-response curves were constructed to codeine, morphine, oxycodone and oxymorphone (the O-demethylated metabolite of oxycodone) in both rat strains. Codeine did not induce analgesia in the DA rat and there was a 60% reduction in codeine analgesia in the SD rat pretreated with quinine in comparison to the untreated SD rat. In the DA rat, the ED50 to oxycodone was increased 10-fold but there was a significant (P = .0001) prolongation in the duration of analgesia in comparison to that in the untreated SD rat. In the quinine-pretreated SD rat, there was no reduction in oxycodone analgesia but the duration of analgesia was also prolonged. It was concluded that 1) codeine-mediated analgesia requires the formation of morphine through the functional activity of CYP2D1 and 2) oxycodone-mediated analgesia may only be partly dependent on CYP2D1.