The visceral and somatic antinociceptive effects of dihydrocodeine and its metabolite, dihydromorphine. A cross-over study with extensive and quinidine-induced poor metabolizers.
OBJECTIVE
Dihydrocodeine is metabolized to dihydromorphine via the isoenzyme cytochrome P450 2D6, whose activity is determined by genetic polymorphism. 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 and visceral pain thresholds in extensive and quinidine-induced poor metabolizers.


METHODS
Eleven healthy subjects participated in a double-blind, randomized, placebo-controlled, four-way cross-over study comparing the effects of single doses of placebo and slow-release dihydrocodeine 60 mg with and without premedication with quinidine sulphate 50 mg on electrical, heat and rectal distension pain tolerance thresholds. Plasma concentrations and urinary excretion of dihydrocodeine and dihydromorphine were measured.


RESULTS
In quinidine-induced poor metabolizers 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 from 0.91% to 0.28% of the dihydrocodeine dose (P < 0.001). Dihydrocodeine significantly raised the heat pain tolerance thresholds (at 3.3 h and 5 h postdosing, 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 thresholds, but decreased the effect of dihydrocodeine on defaecatory urge thresholds (at 1.5 h, 3.3 h and 10 h postdosing, P < 0.05).


CONCLUSIONS
In quinidine-induced poor metabolizers significant reduction in dihydromorphine metabolite production did not result in diminished analgesic effects of a single dose of dihydrocodeine. The metabolism of dihydrocodeine to dihydromorphine may therefore not be of clinical importance for analgesia. This conclusion must however, be confirmed with repeated dosing in patients with pain.
Wilder-Smith
C H
CH
Nociception Research Group and Institute of Clinical Pharmacology, University of Berne, Switzerland.
Hufschmid
E
E
Thormann
W
W
D000328:Adult; D000701:Analgesics, Opioid / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D003061:Codeine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D018592:Cross-Over Studies; D004090:Dihydromorphine / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D004311:Double-Blind Method; D004558:Electric Stimulation; D006801:Humans; D008297:Male; D010147:Pain Measurement; D017288:Pain Threshold / Q000187:drug effects; D011802:Quinidine / Q000494:pharmacology; D012879:Skin Physiological Phenomena / Q000187:drug effects
D000701:Analgesics, Opioid; D004090:Dihydromorphine; D011802:Quinidine; C014481:dihydrocodeine; D003061:Codeine