细胞色素 2D6 基因型是否影响门诊手术后可待因的镇痛疗效？987 例成年人的前瞻性试验。

Does cytochrome 2D6 genotype affect the analgesic efficacy of codeine after ambulatory surgery? Prospective trial in 987 adults.

机构信息

Department of Anaesthesiology, Intensive Care and Pain Medicine, University of Helsinki and Perioperative and Intensive Care, Helsinki University Hospital, Helsinki, Finland.

Gastroenterological surgery, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.

出版信息

Acta Anaesthesiol Scand. 2025 Jan;69(1):e14549. doi: 10.1111/aas.14549.

DOI:10.1111/aas.14549

Abstract

BACKGROUND

Paracetamol-codeine combination tablet is widely used in pain management after day surgery. For safety reasons, its use has decreased in recent years. Codeine is a prodrug metabolised in the liver by the cytochrome P450 2D6 (CYP2D6) enzyme to morphine that produces the analgesic effect of codeine. CYP2D6 is highly polymorphic, and based on genotypes, individuals can be divided into four categories: poor-, intermediate-, normal- and ultrarapid metabolisers. Differences in morphine and its metabolite concentrations have been described between different CYP2D6 genotypes following codeine administration. The aim of the study was to investigate the possible effect of CYP2D6 genotype on codeine efficacy and adverse effects in a large cohort of adult patients undergoing ambulatory surgery.

METHODS

A total of 987 patients scheduled for ambulatory surgery were included in the analyses. Operation types or anaesthesia methods were not limited in the study protocol. All study patients received a fixed dose of paracetamol (1000 mg) and codeine (60 mg) orally for premedication. A blood sample was drawn to identify the genotype of CYP2D6. At home, the first-line analgesic was paracetamol-codeine combination of 1-2 tablets at 1-3 times per day. Data on the efficacy and side effects of codeine were collected on the day of surgery and the following two postoperative days.

RESULTS

Of the studied patients, 37 (3.7%) were poor CYP2D6 metabolisers, 264 (27%) were intermediate, 623 (63%) were normal and 63 (6.4%) were ultrarapid metabolisers. Activity scores ranged from 0 to 4. CYP2D6 genotype was not associated in a statistically significant manner with postoperative pain, opioid consumption or the adverse effects of codeine, except for constipation at home. Poor CYP2D6 metabolisers reported significantly less severe constipation compared with normal metabolisers (p = .009, OR 0.40, 95% Cl 0.20-0.80).

CONCLUSION

CYP2D6 genotype appears to be of minor importance for the analgesic efficacy of oral paracetamol-codeine combination therapy after ambulatory surgery in adult patients undergoing similar types of surgery as in the present study but it may affect the risk of constipation.

摘要

背景

扑热息痛-可待因复方片广泛用于日间手术后的疼痛管理。出于安全原因，近年来其使用有所减少。可待因是一种前体药物，在肝脏中由细胞色素 P450 2D6（CYP2D6）酶代谢为吗啡，从而产生可待因的镇痛作用。CYP2D6 高度多态性，根据基因型，个体可分为四类：弱代谢型、中间代谢型、正常代谢型和超快代谢型。在给予可待因后，不同 CYP2D6 基因型之间的吗啡及其代谢物浓度存在差异。本研究的目的是在接受日间手术的大量成年患者中研究 CYP2D6 基因型对可待因疗效和不良反应的可能影响。

方法

共有 987 例接受日间手术的患者纳入分析。研究方案中未限制手术类型或麻醉方法。所有研究患者均接受扑热息痛（1000mg）和可待因（60mg）的固定剂量口服进行术前用药。采集血样以确定 CYP2D6 基因型。在家中，一线镇痛药是扑热息痛-可待因复方 1-2 片，每日 1-3 次。在手术当天和随后的两天术后收集可待因的疗效和不良反应数据。

结果

在所研究的患者中，37 例（3.7%）为弱 CYP2D6 代谢者，264 例（27%）为中间代谢者，623 例（63%）为正常代谢者，63 例（6.4%）为超快代谢者。活性评分范围为 0 至 4。CYP2D6 基因型与术后疼痛、阿片类药物消耗或可待因的不良反应无显著相关性，除了在家中的便秘。与正常代谢者相比，弱 CYP2D6 代谢者报告的便秘严重程度明显较轻（p=0.009，OR 0.40，95%CI 0.20-0.80）。