Contribution of dihydrocodeine and dihydromorphine to analgesia following dihydrocodeine administration in man: a PK-PD modelling analysis.

AIMS: It is not clear whether the analgesic effect following dihydrocodeine (DHC) administration is due to either DHC itself or its metabolite, dihydromorphine (DHM). We examined the relative contribution of DHC and DHM to analgesia following DHC administration in a group of healthy volunteers using a PK-PD link modelling approach. METHODS: A single oral dose of DHC (90 mg) was administered to 10 healthy volunteers in a randomised, double-blind, placebo-controlled study. A computerized cold pressor test (CPT) was used to measure analgesia. On each study day, the volunteers performed the CPT before study medication and at 1.25, 2.75, 4.25 and 5.75 h postdose. Blood samples were taken at 0.25 h (predose) and then at half hourly intervals for 5.75 h postdose. PK-PD link modelling was used to describe the relationships between DHC, DHM and analgesic effect. RESULTS: Mean pain AUCs following DHC administration were significantly different to those following placebo administration (P = 0.001). Mean pain AUC changes were 91 score x s(-1) for DHC and -17 score x s(-1) for placebo (95% CI = +/- 36.5 for both treatments). The assumption of a simple linear relationship between DHC concentration and effect provided a significantly better fit than the model containing DHM as the active moiety (AIC = 4.431 vs 4.668, respectively). The more complex models did not improve the likelihood of model fits significantly. CONCLUSIONS: The findings suggest that the analgesic effect following DHC ingestion is mainly attributed to the parent drug rather than its DHM metabolite. It can thus be inferred that polymorphic differences in DHC metabolism to DHM have little or no effect on the analgesic affect.

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 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.

Antiprogestins inhibit the binding of opioids to mu-opioid receptors in nervous membrane preparations.

The present study showed that the glucocorticoid/progesterone antagonists, 17 beta-hydroxy-1 1 beta-(4-dimethylamino-phenyl-1)-17-(prop-1-ynyl)estra-4,9-dien+ ++-3-one (RU486) and 17 beta-hydroxy-11 beta-(4-dimethylamino-phenyl-1)-17-(propan-3-ol)estra-4,9-dien-3-o ne (ZK 98299), inhibit the binding of labeled dihydromorphine to mu-opioid receptors present on membrane preparations derived from rat and mouse brain, as well as from human neuroblastoma cells. The inhibitory effect of RU486 was dose-dependent and linked to a decrease of the affinity of labeled dihydromorphine to the mu-opioid receptors. Kinetic experiments have shown that RU486 induces a decrease of the association rate constant (k + 1) of dihydromorphine. RU486 also proved able to dissociate the dihydromorphine-mu-opioid receptor complex, although at a rate slower than that exhibited by unlabeled dihydromorphine. Finally, the addition of NaCl (100 mM) to the incubation buffer induced a 50% decrease of the inhibitory effect of RU486. A 6-day treatment of neuroblastoma cells with RU486 eliminated the inhibitory effect morphine exerts on the intracellular accumulation of cyclic AMP induced by prostaglandin E1. These results indicate that RU-486 may interact with brain mu-opioid receptors in vitro, by decreasing the affinity of opioid ligands.

Simultaneous determination of dihydrocodeine and dihydromorphine in serum by gas chromatography-tandem mass spectrometry.

A sensitive and specific method was developed for the determination of dihydrocodeine and its metabolite dihydromorphine in human serum using codeine and morphine as internal standards. Measurement is performed with GC-tandem MS after one simple extraction step and derivatization to the pentafluoropropionic esters. Sensitivity of the method is excellent and allows for the reproducible quantification of dihydrocodeine and dihydromorphine with limits of quantification of 2 ng/ml and 40 pg/ml serum, respectively. The method is therefore well suited for investigation of the pharmacokinetics and the metabolism of dihydrocodeine.