Same incidence of adverse drug events after codeine administration irrespective of the genetically determined differences in morphine formation

Abstract

The analgesic effect and adverse events of the weak opioid codeine is assumed to be mediated by its metabolite morphine. The cytochrome P-450 enzyme CYP2D6 catalysing the formation of morphine exhibits a genetic polymorphism. Two distinct phenotypes, the extensive (EMs) and poor metabolisers (PMs), are present in the population. The prevalence of PMs in the Caucasian population is 7% to 10%. Since PMs do not express functional CYP2D6, they have a severely impaired capacity to metabolise drugs which are substrates of this enzyme. Provided the analgesic effect and the adverse events of codeine are mediated by its metabolite morphine, large phenotype-related differences are to be expected and PMs, as they form only trace amounts of morphine, can serve as a model to test the hypothesis whether the analgesia and adverse events of codeine are mediated by the parent drug or its metabolite morphine. Therefore we have studied in a randomised placebo-controlled double-blind trial the analgesic effect of 170 mg codeine (p.o.) compared to 20 mg morphine (p.o.) and placebo in 9 EMs and 9 PMs using the cold pressor test. The duration and intensity of the side effects were assessed using visual analogue scales (VAS). Codeine and morphine concentrations were measured in serum and urine. Compared to placebo, 20 mg morphine caused a significant increase in pain tolerance in both phenotypes, EMs and PMs (16.2+/-27.4 vs. -0.66+/-27.4 s x h, n=18). However, following administration of codeine, analgesia was only observed in EMs but not in PMs (EMs: 54.9+/-42.2 vs. 1.7+/-4.2 s x h, P < 0.01; PMs: 9.6+/-10.9 vs. 3.3+/-23.7 s x h, not significant). Adverse events were significantly more pronounced after morphine and codeine compared to placebo in both EMs and PMs. In contrast to the phenotype-related differences in the analgesic effect of codeine, however, no difference in adverse events between the phenotypes could be observed. In the pharmacokinetic studies, significant differences between the two phenotypes in the formation of morphine after codeine administration could be observed. Whereas morphine plasma concentrations were similar in PMs (Cmax: 44+/-13 nmol/l: AUC: 199+/-45 nmol x h/l) and EMs (Cmax: 48+/-17 nmol/l); AUC: 210+/-65 nmol x h/l) after morphine administration, following 170 mg codeine, morphine plasma concentrations comparable to those after morphine application were only observed in EMs (Cmax: 38+/-16 nmol/l; AUC: 173+/-90 nmol x h/l). In PMs only traces of morphine could be detected in plasma (Cmax: 2+/-1 nmol/l; AUC: 10+/-7 nmol x h/l). The percentage of the codeine dose converted to morphine and its metabolites was 3.9% in EMs and 0.17% in PMs. The interindividual variability in analgesia of codeine which is related to genetically determined differences in the formation of morphine clearly indicate that this metabolite is responsible for the analgesic effect of codeine. In contrast to the analgesic effect, frequency and intensity of the adverse events did not present significant differences between the two phenoty...

Affinities of Dihydrocodeine and its Metabolites to Opioid Receptors

“…Thus, the pharmacological effects of dihydrocodeine may be lower in poor metabolizers and more pronounced in ultrarapid metabolizers. Corresponding results have been reported for the effects of codeine depending on the formation of its metabolite morphine via CYP2D6 (Poulsen et al 1996;Eckhardt et al 1998) but these are not unequivocal (Vree et al 2000). Results concerning dihydrocodeine were also contradictory (Fromm et al 1995;Jurna et al 1997;Wilder-Smith et al 1998).…”

National Patterns of Codeine Prescriptions for Children in the Emergency Department

“…However, children who are poor metabolizers (up to one-third of the population) 2 convert very little codeine, leading to inadequate symptom relief. 3 More concerning, ultra-rapid metabolizers convert 5 to 30 times more than is typical, which can lead to fatal toxicity. 1 Case reports describe over a dozen fatalities associated with standard doses of codeine in ultra-rapid metabolizers, 4 and the ethnic subpopulation prevalence of this phenotype ranges from 2% to 40%.…”

Pharmacokinetics of codeine and its metabolite morphine in ultra-rapid metabolizers due to CYP2D6 duplication

“…A study on analgesic effects in nine PMs and nine EMs reported analgesic effects only in EMs but the same incidence of adverse drug effects in both groups. 36 Opioid effects also depend on biotransformation within the brain, and, thus, concentrations of codeine, norcodeine and C6G in the brain might differ from those observed in plasma. Recently, a functional variant of CYP2D7 leading to expression of this pseudogene in brain and to brain metabolism of codeine to morphine has been described in four of eight individuals of whom brain autopsies were obtained.…”