Poulsen L, Brøsen K, Arendt-Nielsen L, Gram L F, Elbaek K, Sindrup S H
Department of Clinical Pharmacology, Odense University, Denmark.
Eur J Clin Pharmacol. 1996;51(3-4):289-95. doi: 10.1007/s002280050200.
Codeine O-demethylation to morphine is catalysed by the genetic polymorphic sparteine oxygenase (CYP2D6). The objective of the present study was to assess the analgesic effect of codeine on different types of experimental pain in relation to sparteine phenotype.
Fourteen extensive (EMs) and 14 poor metabolizers (PMs) of sparteine completed a randomized, double-blind, three-way, cross-over study with a single oral dose of codeine (75 or 100 mg) against morphine (20 or 30 mg) and placebo. Pain tests performed before and 1, 2, 3, and 4 h after medication included the cold pressor test and pain thresholds for heat and pressure stimulation. Adverse effects were rated by a structured interview.
After morphine, morphine and morphine-6-glucuronide were present in equal amounts in plasma of PMs and EMs. After codeine, neither morphine nor morphine-6-glucuronide could be detected in 13 of the 14 PMs, whereas at least one of the compounds could be detected in all EMs. Peak pain and discomfort rated on a VAS scale during the cold pressor test were significantly reduced by morphine in both EMs and PMs, with a median peak change of 8.5 and 7.0 mm, respectively, for peak pain, and 11.5 and 15.5 mm, respectively, for discomfort. Codeine only reduced these pain measures significantly in EMs, with a median peak change of 5.5 mm for peak pain and 10.5 mm for discomfort. Pain detection and tolerance thresholds to heat and pressure were not consistently altered by either morphine or codeine. In PMs, adverse effects were significantly more pronounced on morphine than on codeine and only showed a slight difference between codeine and placebo. In EMs, there was no difference between codeine and morphine and more pronounced adverse effects on both drugs as compared to placebo.
This study confirms that codeine O-demethylation depends on CYP2D6; it shows that the 6-glucuronidation of morphine is independent of CYP2D6; it supports the theory that the analgesic effect of codeine depends on its O-demethylation; and it indicates that this is probably also the case for the adverse effects. The results lend no support to the suggestion of a non-opioid analgesic effect of codeine.
可待因O - 去甲基化生成吗啡是由基因多态性的司巴丁氧化酶（CYP2D6）催化的。本研究的目的是评估可待因对不同类型实验性疼痛的镇痛作用与司巴丁表型的关系。
14名司巴丁代谢广泛者（EMs）和14名代谢不良者（PMs）完成了一项随机、双盲、三因素交叉研究，单次口服可待因（75或100毫克），与吗啡（20或30毫克）和安慰剂进行对比。用药前及用药后1、2、3和4小时进行的疼痛测试包括冷加压试验以及热和压力刺激的疼痛阈值。通过结构化访谈对不良反应进行评分。
服用吗啡后，PMs和EMs血浆中吗啡和吗啡 - 6 - 葡萄糖醛酸的含量相等。服用可待因后，14名PMs中有13名检测不到吗啡和吗啡 - 6 - 葡萄糖醛酸，而所有EMs中至少能检测到其中一种化合物。在冷加压试验期间，用视觉模拟量表（VAS）评定的峰值疼痛和不适在EMs和PMs中均被吗啡显著降低，峰值疼痛的中位峰值变化分别为8.5和7.0毫米，不适的中位峰值变化分别为11.5和15.5毫米。可待因仅在EMs中显著降低了这些疼痛指标，峰值疼痛的中位峰值变化为5.5毫米，不适为10.5毫米。吗啡或可待因均未持续改变热和压力的疼痛检测及耐受阈值。在PMs中，吗啡的不良反应比可待因明显更显著，且可待因与安慰剂之间仅显示出轻微差异。在EMs中，可待因和吗啡之间无差异，与安慰剂相比，两种药物的不良反应更明显。
本研究证实可待因O - 去甲基化依赖于CYP2D6；表明吗啡的6 - 葡萄糖醛酸化独立于CYP2D6；支持可待因的镇痛作用取决于其O - 去甲基化的理论；并表明不良反应可能也是如此。结果不支持可待因具有非阿片类镇痛作用的观点。
