THE VISCERAL AND SOMATIC ANTINOCICEPTIVE EFFECTS OF DIHYDROCODEINE AND ITS METABOLITE, DIHYDROMORPHINE - A CROSS-OVER STUDY WITH EXTENSIVE AND QUINIDINE-INDUCED POOR METABOLIZERS

Aims Dihydrocodeine is metabolized to dihydromorphine via the isoenzym e cytochrome P450 2D6, whose activity is determined by genetic polymor phism. The importance of the dihydromorphine metabolites for analgesia in poor metabolizers is unclear. The aim of this study was to assess the importance of the dihydromorphine metabolites of dihydrocodeine in analgesia by investigating the effects of dihydrocodeine on somatic a nd visceral pain thresholds in extensive and quinidine-induced poor me tabolizers. Methods Eleven healthy subjects participated in a double-b lind, randomized, placebo-controlled, four-way cross-over study compar ing the effects of single doses of placebo and slow-release dihydrocod eine 60 mg with and without premedication with quinidine sulphate 50 m g on electrical, heat and rectal distension pain tolerance thresholds. Plasma concentrations and urinary excretion of dihydrocodeine and dih ydromorphine were measured. Results In quinidine-induced poor metaboli zers the plasma concentrations of dihydromorphine were reduced between 3 and 4 fold from 1.5 h to 13.5 h after dosing (P<0.005) and urinary excretion of dihydromorphine in the first 12 h was decreased fi-om 0.9 1% to 0.28% of the dihydrocodeine dose (P<0.001). Dihydrocodeine signi ficantly raised the heat pain tolerance thresholds (at 3.3 h and 5 h p ostdosing, P<0.05) and the rectal distension defaecatory urge (at 3.3 h and 10 h postdosing, P<0.02) and pain tolerance thresholds (at 3.3 h and 5 h postdosing, P<0.05) compared with placebo. Premedication with quinidine did not change the effects of dihydrocodeine on pain thresh olds, but decreased the effect of dihydrocodeine on defaecatory urge t hresholds (at 1.5 h, 3.3 h and 10 h postdosing, P<0.05). Conclusions I n quinidine-induced poor metabolizers significant reduction in dihydro morphine metabolite production did not result in diminished analgesic effects of a single dose of dihydrocodeine. The metabolism of dihydroc odeine to dihydromorphine may therefore not be of clinical importance for analgesia. This conclusion must however, be confirmed with repeate d dosing in patients with pain.