CYP3A4、CYP3A5、COMT及OPRM1基因多态性对术后芬太尼镇痛剂量的影响

Correlation between CYP3A4/CYP3A5/COMT/OPRM1 gene polymorphisms and postoperative fentanyl requirements

目的探讨代谢酶相关基因(CYP3A4*1G、CYP3A5*3、COMT Val158Met)和药物作用靶点基因(OPRM1 rs563649)的多态性与芬太尼术后镇痛剂量个体差异的相关性。方法选择2018年10月至2020年3月复旦大学附属中山医院收治的择期全麻下行腹腔镜辅助结肠癌根治术患者91例,抽取患者外周静脉血,通过Sanger测序技术检测CYP3A4*1G、CYP3A5*3、OPRM1 rs563649及COMT Val158Met各基因多态性,随访患者术后芬太尼镇痛剂量和视觉模拟评分(VAS)分值,分析基因多态性与腹腔镜术后芬太尼镇痛用量的关系。结果CYP3A4*1G、CYP3A5*3、OPRM1 rs563649及COMT Val158Met各位点在结肠癌患者中突变频率分别为31.87%、65.93%、9.40%、26.92%。携带CYP3A4*1G/*1G突变纯合子基因型的患者术后第1天、第2天芬太尼消耗量减少(P<0.05)。CYP3A5*3、OPRM1 rs563649及COMT Val158Met各基因型的芬太尼术后消耗量差异无统计学意义。CYP3A4*1G、CYP3A5*3、OPRM1 rs563649及COMT Val158Met各基因型恶心、呕吐、镇静等不良反应发生率差异无统计学意义。结论在术后疼痛评分差异无统计学意义的情况下,携带CYP3A4*1G/*1G突变型纯合子的患者镇痛芬太尼需求量较野生纯合子和突变杂合子减少,可为个体化镇痛提供参考。

Objective To explore the correlation between the individual difference in postoperative dosage of fentanyl and polymorphisms of several genes related to metabolic enzymes(CYP3A4*1G,CYP3A5*3,COMT Val158Met)and opioid receptor(OPRM1 rs563649).Methods A total of 91 patients receiving fentanyl anesthesia undergoing laparoscopic radical resection of colon tumors at Zhongshan Hospital,Fudan University from October 2018 to March 2020 were investigated in the present study.Peripheral venous blood samples were collected before surgery,and the Sanger method was used for gene sequencing of CYP3A4*1G,CYP3A5*3,OPRM1 rs563649 and COMT Val158Met.The postoperative analgesic requirement of fentanyl and VAS score were recorded after the operation.The gene polymorphisms were analyzed to investigate whether these factors contributed to postoperative opioid doses.Results The mutation frequencies of CYP3A4*1G,CYP3A5*3,OPRM1 rs563649 and COMT Val158Met alleles in colon cancer patients were 31.87%,65.93%,9.40%,and 26.92%,respectively.Patients with CYP3A4*1G/*1G mutation homozygous genotypes needed less fentanyl to achieve pain control on the first and second postoperative days(P<0.05).There were no significant differences in fentanyl consumption between the different genotypes of CYP3A5*3,OPRM1 rs563649,and COMT Val158Met alleles.There was no significant difference in the incidences of adverse reactions such as nausea,vomiting,and sedation among CYP3A4*1G,CYP3A5*3,OPRM1 rs563649,and COMT Val158Met genotypes.Conclusions In the absence of significant differences in postoperative pain scores,postoperative fentanyl requirements are reduced in patients with CYP3A4*1G/*1G mutant homozygotes.This finding may provide valuable information for personalized pain treatment.