What is known about the interaction between quinidine and codeine?

Fråga: What is known about the interaction between quinidine and codeine?

Sammanfattning: Coadministration of quinidine and codeine lead to no analgesic effect of codeine. Morphine is the metabolite of codeine responsible for the analgesic effect of codeine. Quinidine inhibits the formation of morphine from codeine by inhibiting CYP2D6.

Svar: The analgesic effect of codeine is mediated by morphine, a metabolite formed by O-demethylation of codeine. The O-demethylation is dependent of the cytochrome P-450 2D6 (CYP2D6) enzyme. Poor metabolisers on CYP2D6 lack the enzyme and have no clinically relevant analgesic effect of codeine (1). Quinidine is a potent inhibitor of CYP2D6 and interacts with codeine (2).

Four studies investigating the interaction between quinidine and codeine in healthy volunteers have been found (3,4,5,6).

In a doubleblind, randomised crossover study, eight healthy volunteers recived placebo or quinidine 50 mg and placebo or codeine 100 mg. Seven were extensive metabolisers on CYP2D6 and one was a poor metaboliser. In the poor metaboliser almost no morphine (Cmax 0.6 nmol/l) was detected in plasma after administration of placebo and 100 mg codeine and no increase in pain threshold, measured by using electrical stimulations, was seen. In the extensive metabolisers mean Cmax of morphine reached 17.9 nmol/l when placebo and codeine was administered. The combination of quinidine and codeine to extensive metabolisers gave a mean Cmax of plasma morphine of 1.5 nmol/l. Codeine mediated analgesia disappeared after quinidine pretreatment (3).

Sixteen extensive metabolisers, in a doubleblind, randomised, four-way, crossover study, received placebo/placebo, quinidine 200 mg/placebo, placebo/codeine 100 mg or quinidine 200mg/codeine 100 mg. Morphine was detected in all subjects recieveing placebo/codeine. No morphine could be detected in subjects recieveing codeine after pretreatment with quinidine. Pretreatment with quinidine significantly reduced pin-prick pain threshold compared to placebo/codeine. Pain tolerance threshold was significantly increased in subjects receiveing placebo/codeine or quinidine/codeine compared to placebo, however the threshold in subjects recieveing quinidine/codeine was not higher than in patients receiving quinidine/placebo (4).

In another double blind crossover study including sixteen healthy volunteers, 10 extensive metabolisers and six poor metabolisers, recieved placebo/quinidine 100 mg, placebo/codeine 120 mg or quinidine 100 mg/codeine 120 mg. Morphine and morphine metabolites were detected in plasma from extensive metabolisers after codeine treatment. No morphine was detected in poor metabolisers and in extensive metabolisers after quinidine pretreatment. Respiratory, psychomotor and pupillary effects of codeine were greater in extensive metabolisers receiving codeine than in poor metabolisers and in extensive metabolisers pretreated with quinidine (5).

In yet another randomised double blind cross over study the effect of codeine was measured in nine Caucasian- and eight Chinese healthy extensive metabolisers. The subjects received codeine 120 mg and placebo or quinidine 100 mg. The level of plasma morphine after codeine administration did not differ between Caucasian and Chinese subjects although codeine clearence was significantly greater in Caucasians than in the Chinese. No morphine or morphine metabolites were found in plasma when the subjects had been pretreated with quinidine (6). Drugline no 20317 (year 2003) FASS 2003 interaktionskapitel Desmeules J, Gascon MP, Dayer P, Magistris M. Impact of environmental and genetic factors on codeine analgesia. Eur J Clin Pharmacol 1991;41:23-6. Sindrup SH, Arendt-Nielsen L, Brosen K, Bjerring P, Angelo HR, et al. The effect of quinidine on the analgesic effect of codeine. Eur J Clin Pharmacol 1992;42:587-92. CaracoY, Sheller J, Wood AJ. Pharmacogenetic determination of the effects of codeine and prediction of drug interactions. J Pharmacol Exp Ther 1996;278(3):1165-74. CaracoY, Sheller J, Wood AJ. Impact of ethnic origin and quinidine coadministration on codeine´s disposition and pharmacodynamic effects. J Pharmacol Exp Ther 1999;290(1):413-22.