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首页> 外文期刊>Pain. >Same incidence of adverse drug events after codeine administration irrespective of the genetically determined differences in morphine formation.
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Same incidence of adverse drug events after codeine administration irrespective of the genetically determined differences in morphine formation.

机译：可待因给药后不良药物事件的发生率相同，而与吗啡形成的遗传确定差异无关。

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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 phenotypes. These findings have implications for the clinical use of codeine. Since side effects occurred in both EM and PM subjects, the use of codeine as an analgesic will expose 7% to 10% of patients who are PMs to the side effects of the drug without providing any beneficial analgesic effects.
机译：弱阿片类可待因的镇痛作用和不良事件被认为是由其代谢物吗啡介导的。细胞色素P-450酶CYP2D6催化吗啡的形成表现出遗传多态性。人群中存在两种不同的表型，即广泛型（EMs）和弱代谢型（PMs）。白人人群中PM的患病率为7％至10％。由于PM不表达功能性CYP2D6，因此它们代谢作为该酶底物的药物的能力严重受损。如果可待因的镇痛作用和不良事件是由其代谢物吗啡介导的，则预期与表型相关的差异很大，并且由于仅形成微量吗啡的PM可以作为模型来检验是否镇痛的假说可待因的不良反应由母体药物或其代谢物吗啡介导。因此，我们在冷安慰剂试验中在9个EM和9 PM中研究了170 mg可待因（p.o.）与20 mg吗啡（p.o.）和安慰剂在9个EM和9 PM中的镇痛效果。使用视觉模拟量表（VAS）评估副作用的持续时间和强度。测定血清和尿液中可待因和吗啡的浓度。与安慰剂相比，20 mg吗啡在表型，EMs和PMs上均导致疼痛耐受性显着增加（16.2 +/- 27.4 vs. -0.66 +/- 27.4 s x h，n = 18）。但是，在服用可待因后，仅在EM中观察到镇痛作用，而在PM中则没有观察到镇痛作用（EMs：54.9 +/- 42.2 vs. 1.7 +/- 4.2 sxh，P <0.01; PMs：9.6 +/- 10.9 vs. 3.3 + / -23.7 sxh，不重要）。与安慰剂相比，在吗啡和可待因中，吗啡和可待因的不良事件明显更为明显。与可待因的镇痛作用的表型相关差异相反，但是，在表型之间未观察到不良事件的差异。在药代动力学研究中，可待因给药后可观察到两种表型在吗啡形成上的显着差异。而PMs（Cmax：44 +/- 13 nmol / l：AUC：199 +/- 45 nmol x h / l）和EMs（Cmax：48 +/- 17 nmol / l）中的吗啡血浆浓度相似;吗啡给药后AUC：210 +/- 65 nmol xh / l），在170 mg可待因后，仅在EM中观察到与吗啡应用后可比的吗啡血浆浓度（Cmax：38 +/- 16 nmol / l; AUC：173） +/- 90 nmol xh / l）。在PM中，血浆中仅检测到吗啡痕迹（Cmax：2 +/- 1 nmol / l; AUC：10 +/- 7 nmol x h / l）。可待因剂量转化为吗啡及其代谢产物的百分比在EM中为3.9％，在PM中为0.17％。可待因镇痛的个体差异与吗啡形成的遗传决定的差异有关，这清楚地表明该代谢产物是可待因镇痛作用的原因。与止痛作用相反，不良反应的发生频率和强度在两种表型之间没有显着差异。这些发现对可待因的临床使用具有影响。由于在EM和PM受试者中均发生了副作用，因此将可待因用作镇痛药会使7％的PM患者暴露于该药的副作用，而没有提供任何有益的镇痛作用。

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