OPRM1和CYP3A基因多态性对芬太尼镇痛效应的影响
摘要
【背景与目的】
芬太尼是我国常用的术后静脉镇痛药物,但临床发现芬太尼术后镇痛的需求量和不良反应存在明显的个体差异。研究提示遗传因素可能通过改变受体或代谢酶的表达等机制影响阿片类药物的药动学和药效学,进而导致其临床效应的个体差异。本研究旨在通过分析μ阿片受体(μopioid receptor,OPRM1)基因A118G、CYP3A4~*1G和CYP3A5~*3多态性和CYP3A酶活性,探讨妇科患者全麻术后静脉自控镇痛芬太尼需求量和不良反应个体差异的遗传因素,为临床芬太尼术后镇痛的个体化用药提供参考。
【材料与方法】
1.研究对象与分组
204例妇科择期全麻下腹式子宫全切术或子宫肌瘤剔除术患者,年龄20-50岁,体重指数在正常范围(1±20%),ASAⅠ或Ⅱ级,行术后静脉镇痛者。排除标准:有吸烟、酗酒史,糖尿病、严重心血管疾病、肾脏病、肝脏病史,慢性疼痛史、长期使用镇痛药物、术前1个月内服用过肝脏CYP3A酶诱导剂或抑制剂的患者。根据各基因型检测结果将患者分为野生型纯合子、突变型杂合子和突变型纯合子三组。
2.麻醉与镇痛
所有患者经医院伦理委员会同意并签署知情同意书后进入试验。不使用术前药,入室后使用电刺激仪进行测痛,重复测定3次痛阈和耐痛阈,各取其平均值。所有患者用统一的全身麻醉方法,静脉注射咪达唑仑、异丙酚、瑞芬太尼和琥珀酰胆碱麻醉诱导;麻醉维持:静脉输注瑞芬太尼和异丙酚,间断静脉注射阿曲库铵;手术结束时停用所有麻醉药,待患者神志清醒,自主呼吸恢复满意后拔除气管导管,行疼痛视觉模拟评分(visual analog scale,VAS)并记录,接6300型CADD-Legacy电子镇痛泵行芬太尼静脉病人自控镇痛(patient-controlledintravenous analgesia,PCIA)。观察并记录术后即刻和第1、2个24h内平均VAS评分、芬太尼消耗量以及术后镇痛不良反应的发生情况。
镇痛泵内药液配方:芬太尼1.0 mg、氟哌利多5 mg,加生理盐水至100 ml。PCIA设置:背景剂量0.5 ml/h、追加剂量2 ml/次、锁定时间5 min、芬太尼最大限量145μg/h。VAS评分≤3分定义为镇痛有效,若PCIA每小时最大剂量仍不能满足镇痛需要(VAS＞3分),则辅用其他镇痛药物并将该病例从试验中剔除。
3.基因多态性检测
抽取外周静脉血2 ml,采用酚-氯仿法提取基因组DNA;采用聚合酶链反应-限制性片段长度多态性分析(PCR-RFLP)技术,对OPRM1 A118G、CYP3A4~*1G和CYP3A5~*3多态性位点进行检测分析。通过PCR扩增产物直接测序验证基因型检测方法的可靠性。
4.酶活性检测
麻醉诱导静脉注射0.1 mg/kg咪达唑仑60 min时抽取外周静脉血5 ml,离心取上层血浆,液相色谱-质谱检测法测定血浆中咪达唑仑(MDZ)及其代谢产物1-羟基咪达唑仑(1′-OH MDZ)浓度。以1′-OH MDZ:MDZ作为CYP3A酶活性的指标。
5.统计学分析
数据采用SPSS13.0软件进行处理,计量资料以(?)±s表示,以x~2检验检测等位基因和基因型分布是否符合Hardy-Weinberg平衡;x~2检验或Fisher's精确概率检验检测不同种族间基因多态性分布的差异;多组间数据进行单因素方差分析(ANOVA),各组间比较采用LSD法。不同基因型间芬太尼消耗量的比较采用协方差分析以排除其它影响因素。计量资料变量之间的关系采用直线相关分析,突变等位基因与芬太尼消耗量之间的相关性采用等级相关分析。检验水准为α=0.05。
【结果】
1.一般情况
204例女性患者中,术前电刺激痛阈测定值为2.0±0.6 mA;术前耐痛阈测定值为5.1±2.0 mA。术后即刻VAS评分较高(5.7±1.4),随PCIA实施达到有效镇痛。术后第1个24 h平均VAS评分为2.2±0.8分,芬太尼消耗量为396.2±210.0μg;术后第2个24 h平均VAS评分为1.3±0.4,芬太尼消耗量为190.9±43.2μg。使用芬太尼镇痛时术后恶心呕吐的发生率为28.92%;瘙痒的发生率为0.49%;轻度镇静的发生率为1.47%;未见其他不良反应。
2.妇科患者中OPRM1 A118G、CYP3A4~*1G和CYP3A5~*3的等位基因频率
OPRM1 A118G、CYP3A4~*1G和CYP3A5~*3等位基因在妇科手术患者中的发生频率分别为32.0%、29.9%和69.4%,等位基因和基因型分布符合Hardy-Weinberg平衡(P＞0.05)。OPRM1 A118G等位基因的发生频率高于非裔美国人(1.6%～2.8%)和高加索人(10.5%～16.4%),低于日本人(48.5%)和印度人(47%)(P＜0.05),与已有中国健康人群中报道的发生频率(35.1%)相近(P＞0.05)。CYP3A4~*1G等位基因的发生频率与日本人(24.9%)相近(P＞0.05)。CYP3A5~*3等位基因的发生频率低于白种人群(91.7%),高于黑种人群(47.5%)(P＜0.05)。
3.OPRM1 A118G多态性对妇科患者术前痛阈、耐痛阈和芬太尼镇痛效应的影响
按OPRM1 A118G基因型分组后野生型纯合子(A/A)、突变型杂合子(A/G)和突变型纯合子(G/G)三组间一般情况比较差异无统计学意义(P＞0.05);术后即刻及24 h平均VAS评分差异无统计学意义(P＞0.05)。三组间痛阈差异无统计学意义(P＞0.05);耐痛阈差异有统计学意义(P＜0.05),A/A组(5.6±2.4 mA)高于A/G组(4.9±1.3 mA),A/G组高于G/G组(3.8±1.0 mA)。术后24 h芬太尼消耗量三组间差异有统计学意义(P＜0.05),G/G组(507.9±290.2μg)高于A/G组(412.0±189.8μg)和A/A组(363.6±198.8μg);术后24 h芬太尼消耗量与OPRM1 118G等位基因数量呈正相关(r=0.20,P＜0.05)。术前痛阈或耐痛阈与术后芬太尼消耗量之间无相关性(P＞0.05)。三组间术后镇痛不良反应发生率差异无统计学意义(P＞0.05)。
4.CYP3A4~*1G多态性对妇科患者CYP3A酶活性和术后芬太尼镇痛效应的影响
按CYP3A4~*1G基因型分组后野生型纯合子(CYP3A4~*1/~*1)、突变型杂合子(CYP3A4~*1/~*1G)和突变型纯合子(CYP3A4~*1G/~*1G)三组间一般情况比较差异无统计学意义(P＞0.05);术后即刻及24 h平均VAS评分差异无统计学意义(P＞0.05)。三组间术后24 h芬太尼消耗量差异有统计学意义(P＜0.05),CYP3A4~*1G/~*1G组(260.0±101.1μg)低于CYP3A4~*1/~*1G组(414.1±238.5μg)和CYP3A4~*1/~*1组(407.4±187.4μg);术后24 h芬太尼消耗量与CYP3A4~*1G等位基因数量呈负相关(r=0.14,P＜0.05)。CYP3A酶活性比较三组间差异有统计学意义(P＜0.05),CYP3A4~*1G/~*1G组CYP3A酶活性(0.34±0.15)低于CYP3A4~*1/~*1组(0.46±0.14)和CYP3A4~*1/~*1G组(0.46±0.12)。三组间术后镇痛不良反应发生率差异无统计学意义(P＞0.05)。
5.CYP3A5~*3多态性对妇科患者CYP3A酶活性和术后芬太尼镇痛效应的影响
按CYP3A5~*3基因型分组后野生型纯合子(CYP3A5~*1/~*1)、突变型杂合子(CYP3A5~*1/~*3)和突变型纯合子(CYP3A5~*3/~*3)三组间一般情况比较差异无统计学意义(P＞0.05);三组术后即刻及24 h平均VAS评分差异无统计学意义(P＞0.05)。三组间术后24 h芬太尼消耗量差异无统计学意义(P＞0.05);三组间CYP3A酶活性比较差异无统计学意义(P＞0.05);三组间术后镇痛不良反应发生率差异无统计学意义(P＞0.05)。
6.CYP3A4/CYP3A5单体型对妇科患者术后芬太尼镇痛效应的影响
CYP3A4/CYP3A5构成单体型时,根据是否携带CYP3A4~*1和CYP3A5~*3将患者分为四组,携带CYP3A4~*1和CYP3A5~*1/~*1组、携带CYP3A4~*1和CYP3A5~*3组、携带CYP3A4~*1G/~*1G和CYP3A5~*1/~*1组、携带CYP3A4~*1G/~*1G和CYP3A5~*3组。四组间一般情况比较差异无统计学意义(P＞0.05);术后24 h芬太尼消耗量四组间差异有统计学意义(P＜0.05),携带CYP3A5~*1/~*1和CYP3A4~*1组术后芬太尼消耗量高于其余各组;携带CYP3A5~*3和CYP3A4~*1G/~*1G组术后芬太尼消耗量降低;四组间术后镇痛芬太尼不良反应的发生率差异无统计学意义(P＞0.05)。
7.OPRM1 A118G和CYP3A4~*1G多态性对芬太尼镇痛效应的交互作用
根据是否携带OPRM1 118A和CYP3A4~*1等位基因将患者分为四组,携带OPRM1 118A和CYP3A4~*1G/~*1G组、携带OPRM1 118A和CYP3A4~*1组、携带OPRM1 118G/G和CYP3A4~*1G/~*1G组、携带OPRM1 118G/G和CYP3A4~*1组。四组间一般情况比较差异无统计学意义(P＞0.05);术后24 h芬太尼消耗量四组间差异有统计学意义(P＜0.05),携带OPRM1 118G/G和CYP3A4~*1者术后芬太尼消耗量高于其余各组;四组间术后镇痛芬太尼不良反应的发生率差异无统计学意义(P＞0.05)。
【结论】
1.OPRM1 A118G多态性与术前电刺激耐痛阈降低有关,且呈基因剂量依赖效应;术后24 h芬太尼消耗量与OPRM1 118G等位基因数量呈正相关;本课题首次研究了芬太尼静脉镇痛效应与OPRM1 A118G多态性的关系;
2.术后24 h芬太尼消耗量与CYP3A4~*1G等位基因数量呈负相关:CYP3A5~*3多态性对术后芬太尼消耗量无明显影响。CYP3A4/CYP3A5构成单体型时,携带CYP3A4~*1G/CYP3A5~*3者术后芬太尼消耗量降低。本研究首次证明了芬太尼静脉镇痛效应与CYP3A4~*1G多态性相关;
3.OPRM1 A118G和CYP3A4~*1G多态性间存在交互作用,携带OPRM1 118G/G和CYP3A4~*1者术后芬太尼消耗量显著增高。
Background and Objective
Fentanyl is a synthetic opioid widely used for analgesia.The analgesia effect of fentanyl varies in different individuals,which makes it difficult to know the appropriate dose for a particular patient.Recent advances in genetic research indicated that genetic polymorphisms may also contribute to the patient's variability in response to opioid treatment.This study was performed to observe the impact ofμ-opioid receptor gene A118G,CYP3A4~*1G and CYP3A5~*3 polymorphisms on fentanyl effect for intravenous analgesia.The present study provides an important foundation and theoretical evidence for the gene-directed rationalization and individualization of medication in the pain treatment.
Materials and Methods
1.Subjects
Total two hundred and four subjects,aged 20-50 yr,within±20%of ideal body weight,and having an American Society of Anesthesiologists(ASA) physical status ofⅠorⅡ,undergoing selective abdominal total hysterectomy or myomectomy with general anesthesia were included.Exclusion criteria included the following:known history of psychiatric disease,significant cardiovascular disease,hepatic or renal dysfunction,diabetes mellitus,alcohol or drug abuse,chronic analgesic use, pregnancy or nursing.Subjects who have consumed drugs known to inhibit or induce the expression of CYP3A enzymes in two weeks were also excluded.The study design was approved by Institutional Ethics Committee of Zhengzhou University.The subjects were divided into three groups according to the genotypes.
2.Anesthetic Technique and Analgesia
Preoperatively,the pain threshold and pain tolerance threshold were measured using electrical stimulation.To familiarize the subjects with the assessment method,a training session was given in the preoperative holding area.The pain threshold(PT) and pain tolerance threshold(PTT) for each patient was obtained by the mean of three successive measurements,with a time interval of 5 min.A standardized,general anesthesia technique was used for all subjects.General anesthesia was induced with 0.1mg/kg midazolam,0.5 mg/kg propofol,2μg/kg remifentanyl and 1 mg/kg succinylcholine.Atracurium 0.6 mg/kg was administered intravenously as an initial dosage immediately after tracheal intubation was confirmed and then 0.1-0.2 mg/kg was administered as repeated boluses.During the operation,remifentanyl(0.1-0.2μg/kg/min) and propofol(6-8 mg/kg/h) were used for maintenance of anesthesia. Intravenous fentanyl patient-controlled analgesia(PCA) was provided postoperatively for satisfactory analgesia.The degrees of pain during PCA treatment were assessed with visual analog scale(VAS).The fentanyl consumption and occurrence of any adverse effects in the first 24 h postoperatively were recorded.
The analgesic solution in the PCA pump(6300 CADD-Legacy,USA) contained 100 ml normal saline and 1 mg fentanyl,5 mg droperidol.The PCA pump was programmed to give a 2ml bolus of fentanyl solution with 5 min lockout time,0.5 ml/h background infusion and maximum 145μg per hour.
3.Genotyping assays
Venous blood samples(2 ml) were collected from all subjects in this study.DNA was extracted from leukocytes using a standard phenol/chloroform procedure. Genotyping of OPRM1 A118G and CYP3A4~*1G,CYP3A5~*3alleles was conducted by polymerase chain reaction-restriction fragment length polymorphism(PCR-RFLP).
4.Evaluation of CYP3A activity
CYP3A activity was measured by plasma 1'-hydroxymidazolam:midazolam (1'-OHMDZ:MDZ) ratio at 60 min after intravenous administration of 0.1 mg/kg midazolam for induction of anesthesia.Midazolam and 1'-hydroxymidazolam concentrations were determined using liquid chromatography-mass spectrometry method(LC-MS).
5.Statistical analysis
SPSS 13.0 software was used for statistical analyses.The allele frequencies were estimated from the observed numbers of each specific allele.Chi-square test was used to verify Hardy-Weinberg equilibrium.One-way analysis of variance was used to assess whether significant differences exist between the three genotypes.Data for the fentanyl consumption were compared among the genotype group using one-way analysis of variance with post hoc Bonferroni correction for multiple comparisons was performed before and after adjusted for age,weight and remifentanil consumption in the operation.The incidences of any adverse effects were analyzed using Chi-square test or Fisher exact test.Theαwas set at 0.05.
Results
1.General information
Among the 204 subjects,the preoperative pain threshold was 2.0±0.6 mA,and the pain tolerance threshold was 5.1±2.0 mA.The VAS pain score immediately after surgery was 5.7±1.4.At 24 h after surgery,it was 2.2±0.8.The fentanyl consumption was 396.2±210.0μg and 190.9±43.2μg in the postoperative first and second 24 h, respectively.The incidence of PONV within 24 h in our study was 28.92%.
2.Frequencies of OPRM1 A118G,CYP3A4~*1G and CYP3A5~*3 alleles
The frequencies of OPRM1 118G,CYP3A4~*1G and CYP3A5~*3 alleles in Chinese gynecologic patients were 0.320,0.299 and 0.694,respectively.The allele frequencies were in Hardy-Weinberg equilibrium(P＞0.05).
3.Association of OPRM1 A118G gene polymorphism with preoperative pain tolerance and fentanyl analgesic effect
There were no significant differences in general information among the three genotype groups(P＞0.05).PTT was statistical different between A/A(5.6±2.4 mA) and A/G(4.9±1.3 mA) groups,between A/G and G/G(3.8±1.0 mA) groups and between A/A and A/G groups(P＜0.05).However,PT did not show a significant difference among the three genotypes(P＞0.05).Subjects in G/G group(507.9±290.2μg) consumed significantly more fentanyl than subjects in A/A(363.6±198.8μg) and A/G(412.0±189.8μg) groups in the first 24 h postoperatively(P＜0.05).Fentanyl consumption increased in accordance with the number of OPRM1 118G alleles (P＜0.05 for linear trend).There was no significant difference in incidences of adverse events among the different genotype groups(P＞0.05).
4.Association of CYP3A4~*1G gene polymorphism with CYP3A activity and fentanyl analgesic effect
There were no significant differences in general information among the three genotype groups(P＞0.05).The subjects with the CYP3A4~*1G/~*1G genotype (260.0±101.1μg) need less fentanyl to achieve pain control than subjects carrying the CYP3A4~*1/~*1(407.4±187.4μg) and CYP3A4~*1/~*1G(414.1±238.5μg) genotypes (P＜0.05).Fentanyl consumption increased in accordance with the number of ~*1G alleles(P＜0.05 for linear trend).The activity of CYP3A in ~*1G/~*1G group(0.34±0.15) was lower than in ~*1/~*1(0.46±0.14) and ~*1/~*1G(0.46±0.12) groups(P＜0.05).There was no significant difference in incidences of adverse events among the different genotype groups(P＞0.05).
5.Association of CYP3A5~*3 gene polymorphism with CYP3A activity and fentanyl analgesic effect
There were no significant differences in general information among the three genotype groups(P＞0.05).There were no significant differences in postoperative fentanyl consumptions or in CYP3A activity among the three genotype groups (P＞0.05).There was no significant difference in incidences of adverse events among the different genotype groups(P＞0.05).
6.Effect of CYP3A4/CYP3A5 haplotype on fentanyl analgesic effect
For CYP3A4/CYP3A5 haplotype,the subjects possessing CYP3A4~*1G/CYP3A5~*3 haplotype(CYP3A4~*1G/~*1G and CYP3A5~*1/~*3 or CYP3A5~*1/~*3) need less fentanyl to achieve pain control than subjects possessing CYP3A4~*1/CYP3A5~*1 haplotype(CYP3A4~*1/~*1 and CYP3A5~*1/~*1)(P＜0.05).
7.Joint effects of OPRM1 A118G and CYP3A4~*1G gene polymorphisms on fentanyl analgesic effect
To explore the joint effects of genes and the clinical efficacy of fentanyl,we created four groups:(1) ~*1G/~*1G but not G/G;(2) neither G/G nor ~*1G/~*1G;(3) G/G and ~*1G/~*1G;(4) G/G but not ~*1G/~*1G.There was significant difference in fentanyl consumption among the four genotype groups.Carriers of the OPRM1 118G/G and the CYP3A4~*1 genotypes required the most fentanyl dose(P＜0.05).There was no significant difference in incidence of adverse events among the different genotype groups(P＞0.05).
Conclusions
1.The preoperative pain tolerance threshold is lower in OPRM1 118G homozygotes. The OPRM1 A118G polymorphism has a gene-dose-dependent effect on the pain tolerance threshold.Postoperative fentanyl consumption increase in accordance with the number of 118G alleles.This is the first report on the association of OPRM1 A118G polymorphism with the effect of fentanyl for intravenous analgesia.
2.Carrying CYP3A4~*1G decrease the activity of CYP3A4 and patient-controlled intravenous fentanyl consumption.CYP3A5~*3 polymorphism may have no significant impact on fentanyl analgesic effect.For CYP3A4/CYP3A5 haplotype, CYP3A4~*1G/CYP3A5~*3 decrease the consumption of fentanyl for intravenous analgesia.This is the first report on the association of CYP3A4~*1G polymorphism with the effect of fentanyl.
3.Carriers of the OPRM1 118G/G and the CYP3A4~*1 genotypes require the most fentanyl dose when explored for joint effects of OPRM1 and CYP3A4 genes.
芬太尼是我国常用的术后静脉镇痛药物,但临床发现芬太尼术后镇痛的需求量和不良反应存在明显的个体差异。研究提示遗传因素可能通过改变受体或代谢酶的表达等机制影响阿片类药物的药动学和药效学,进而导致其临床效应的个体差异。本研究旨在通过分析μ阿片受体(μopioid receptor,OPRM1)基因A118G、CYP3A4~*1G和CYP3A5~*3多态性和CYP3A酶活性,探讨妇科患者全麻术后静脉自控镇痛芬太尼需求量和不良反应个体差异的遗传因素,为临床芬太尼术后镇痛的个体化用药提供参考。
【材料与方法】
1.研究对象与分组
204例妇科择期全麻下腹式子宫全切术或子宫肌瘤剔除术患者,年龄20-50岁,体重指数在正常范围(1±20%),ASAⅠ或Ⅱ级,行术后静脉镇痛者。排除标准:有吸烟、酗酒史,糖尿病、严重心血管疾病、肾脏病、肝脏病史,慢性疼痛史、长期使用镇痛药物、术前1个月内服用过肝脏CYP3A酶诱导剂或抑制剂的患者。根据各基因型检测结果将患者分为野生型纯合子、突变型杂合子和突变型纯合子三组。
2.麻醉与镇痛
所有患者经医院伦理委员会同意并签署知情同意书后进入试验。不使用术前药,入室后使用电刺激仪进行测痛,重复测定3次痛阈和耐痛阈,各取其平均值。所有患者用统一的全身麻醉方法,静脉注射咪达唑仑、异丙酚、瑞芬太尼和琥珀酰胆碱麻醉诱导;麻醉维持:静脉输注瑞芬太尼和异丙酚,间断静脉注射阿曲库铵;手术结束时停用所有麻醉药,待患者神志清醒,自主呼吸恢复满意后拔除气管导管,行疼痛视觉模拟评分(visual analog scale,VAS)并记录,接6300型CADD-Legacy电子镇痛泵行芬太尼静脉病人自控镇痛(patient-controlledintravenous analgesia,PCIA)。观察并记录术后即刻和第1、2个24h内平均VAS评分、芬太尼消耗量以及术后镇痛不良反应的发生情况。
镇痛泵内药液配方:芬太尼1.0 mg、氟哌利多5 mg,加生理盐水至100 ml。PCIA设置:背景剂量0.5 ml/h、追加剂量2 ml/次、锁定时间5 min、芬太尼最大限量145μg/h。VAS评分≤3分定义为镇痛有效,若PCIA每小时最大剂量仍不能满足镇痛需要(VAS＞3分),则辅用其他镇痛药物并将该病例从试验中剔除。
3.基因多态性检测
抽取外周静脉血2 ml,采用酚-氯仿法提取基因组DNA;采用聚合酶链反应-限制性片段长度多态性分析(PCR-RFLP)技术,对OPRM1 A118G、CYP3A4~*1G和CYP3A5~*3多态性位点进行检测分析。通过PCR扩增产物直接测序验证基因型检测方法的可靠性。
4.酶活性检测
麻醉诱导静脉注射0.1 mg/kg咪达唑仑60 min时抽取外周静脉血5 ml,离心取上层血浆,液相色谱-质谱检测法测定血浆中咪达唑仑(MDZ)及其代谢产物1-羟基咪达唑仑(1′-OH MDZ)浓度。以1′-OH MDZ:MDZ作为CYP3A酶活性的指标。
5.统计学分析
数据采用SPSS13.0软件进行处理,计量资料以(?)±s表示,以x~2检验检测等位基因和基因型分布是否符合Hardy-Weinberg平衡;x~2检验或Fisher's精确概率检验检测不同种族间基因多态性分布的差异;多组间数据进行单因素方差分析(ANOVA),各组间比较采用LSD法。不同基因型间芬太尼消耗量的比较采用协方差分析以排除其它影响因素。计量资料变量之间的关系采用直线相关分析,突变等位基因与芬太尼消耗量之间的相关性采用等级相关分析。检验水准为α=0.05。
【结果】
1.一般情况
204例女性患者中,术前电刺激痛阈测定值为2.0±0.6 mA;术前耐痛阈测定值为5.1±2.0 mA。术后即刻VAS评分较高(5.7±1.4),随PCIA实施达到有效镇痛。术后第1个24 h平均VAS评分为2.2±0.8分,芬太尼消耗量为396.2±210.0μg;术后第2个24 h平均VAS评分为1.3±0.4,芬太尼消耗量为190.9±43.2μg。使用芬太尼镇痛时术后恶心呕吐的发生率为28.92%;瘙痒的发生率为0.49%;轻度镇静的发生率为1.47%;未见其他不良反应。
2.妇科患者中OPRM1 A118G、CYP3A4~*1G和CYP3A5~*3的等位基因频率
OPRM1 A118G、CYP3A4~*1G和CYP3A5~*3等位基因在妇科手术患者中的发生频率分别为32.0%、29.9%和69.4%,等位基因和基因型分布符合Hardy-Weinberg平衡(P＞0.05)。OPRM1 A118G等位基因的发生频率高于非裔美国人(1.6%～2.8%)和高加索人(10.5%～16.4%),低于日本人(48.5%)和印度人(47%)(P＜0.05),与已有中国健康人群中报道的发生频率(35.1%)相近(P＞0.05)。CYP3A4~*1G等位基因的发生频率与日本人(24.9%)相近(P＞0.05)。CYP3A5~*3等位基因的发生频率低于白种人群(91.7%),高于黑种人群(47.5%)(P＜0.05)。
3.OPRM1 A118G多态性对妇科患者术前痛阈、耐痛阈和芬太尼镇痛效应的影响
按OPRM1 A118G基因型分组后野生型纯合子(A/A)、突变型杂合子(A/G)和突变型纯合子(G/G)三组间一般情况比较差异无统计学意义(P＞0.05);术后即刻及24 h平均VAS评分差异无统计学意义(P＞0.05)。三组间痛阈差异无统计学意义(P＞0.05);耐痛阈差异有统计学意义(P＜0.05),A/A组(5.6±2.4 mA)高于A/G组(4.9±1.3 mA),A/G组高于G/G组(3.8±1.0 mA)。术后24 h芬太尼消耗量三组间差异有统计学意义(P＜0.05),G/G组(507.9±290.2μg)高于A/G组(412.0±189.8μg)和A/A组(363.6±198.8μg);术后24 h芬太尼消耗量与OPRM1 118G等位基因数量呈正相关(r=0.20,P＜0.05)。术前痛阈或耐痛阈与术后芬太尼消耗量之间无相关性(P＞0.05)。三组间术后镇痛不良反应发生率差异无统计学意义(P＞0.05)。
4.CYP3A4~*1G多态性对妇科患者CYP3A酶活性和术后芬太尼镇痛效应的影响
按CYP3A4~*1G基因型分组后野生型纯合子(CYP3A4~*1/~*1)、突变型杂合子(CYP3A4~*1/~*1G)和突变型纯合子(CYP3A4~*1G/~*1G)三组间一般情况比较差异无统计学意义(P＞0.05);术后即刻及24 h平均VAS评分差异无统计学意义(P＞0.05)。三组间术后24 h芬太尼消耗量差异有统计学意义(P＜0.05),CYP3A4~*1G/~*1G组(260.0±101.1μg)低于CYP3A4~*1/~*1G组(414.1±238.5μg)和CYP3A4~*1/~*1组(407.4±187.4μg);术后24 h芬太尼消耗量与CYP3A4~*1G等位基因数量呈负相关(r=0.14,P＜0.05)。CYP3A酶活性比较三组间差异有统计学意义(P＜0.05),CYP3A4~*1G/~*1G组CYP3A酶活性(0.34±0.15)低于CYP3A4~*1/~*1组(0.46±0.14)和CYP3A4~*1/~*1G组(0.46±0.12)。三组间术后镇痛不良反应发生率差异无统计学意义(P＞0.05)。
5.CYP3A5~*3多态性对妇科患者CYP3A酶活性和术后芬太尼镇痛效应的影响
按CYP3A5~*3基因型分组后野生型纯合子(CYP3A5~*1/~*1)、突变型杂合子(CYP3A5~*1/~*3)和突变型纯合子(CYP3A5~*3/~*3)三组间一般情况比较差异无统计学意义(P＞0.05);三组术后即刻及24 h平均VAS评分差异无统计学意义(P＞0.05)。三组间术后24 h芬太尼消耗量差异无统计学意义(P＞0.05);三组间CYP3A酶活性比较差异无统计学意义(P＞0.05);三组间术后镇痛不良反应发生率差异无统计学意义(P＞0.05)。
6.CYP3A4/CYP3A5单体型对妇科患者术后芬太尼镇痛效应的影响
CYP3A4/CYP3A5构成单体型时,根据是否携带CYP3A4~*1和CYP3A5~*3将患者分为四组,携带CYP3A4~*1和CYP3A5~*1/~*1组、携带CYP3A4~*1和CYP3A5~*3组、携带CYP3A4~*1G/~*1G和CYP3A5~*1/~*1组、携带CYP3A4~*1G/~*1G和CYP3A5~*3组。四组间一般情况比较差异无统计学意义(P＞0.05);术后24 h芬太尼消耗量四组间差异有统计学意义(P＜0.05),携带CYP3A5~*1/~*1和CYP3A4~*1组术后芬太尼消耗量高于其余各组;携带CYP3A5~*3和CYP3A4~*1G/~*1G组术后芬太尼消耗量降低;四组间术后镇痛芬太尼不良反应的发生率差异无统计学意义(P＞0.05)。
7.OPRM1 A118G和CYP3A4~*1G多态性对芬太尼镇痛效应的交互作用
根据是否携带OPRM1 118A和CYP3A4~*1等位基因将患者分为四组,携带OPRM1 118A和CYP3A4~*1G/~*1G组、携带OPRM1 118A和CYP3A4~*1组、携带OPRM1 118G/G和CYP3A4~*1G/~*1G组、携带OPRM1 118G/G和CYP3A4~*1组。四组间一般情况比较差异无统计学意义(P＞0.05);术后24 h芬太尼消耗量四组间差异有统计学意义(P＜0.05),携带OPRM1 118G/G和CYP3A4~*1者术后芬太尼消耗量高于其余各组;四组间术后镇痛芬太尼不良反应的发生率差异无统计学意义(P＞0.05)。
【结论】
1.OPRM1 A118G多态性与术前电刺激耐痛阈降低有关,且呈基因剂量依赖效应;术后24 h芬太尼消耗量与OPRM1 118G等位基因数量呈正相关;本课题首次研究了芬太尼静脉镇痛效应与OPRM1 A118G多态性的关系;
2.术后24 h芬太尼消耗量与CYP3A4~*1G等位基因数量呈负相关:CYP3A5~*3多态性对术后芬太尼消耗量无明显影响。CYP3A4/CYP3A5构成单体型时,携带CYP3A4~*1G/CYP3A5~*3者术后芬太尼消耗量降低。本研究首次证明了芬太尼静脉镇痛效应与CYP3A4~*1G多态性相关;
3.OPRM1 A118G和CYP3A4~*1G多态性间存在交互作用,携带OPRM1 118G/G和CYP3A4~*1者术后芬太尼消耗量显著增高。
Background and Objective
Fentanyl is a synthetic opioid widely used for analgesia.The analgesia effect of fentanyl varies in different individuals,which makes it difficult to know the appropriate dose for a particular patient.Recent advances in genetic research indicated that genetic polymorphisms may also contribute to the patient's variability in response to opioid treatment.This study was performed to observe the impact ofμ-opioid receptor gene A118G,CYP3A4~*1G and CYP3A5~*3 polymorphisms on fentanyl effect for intravenous analgesia.The present study provides an important foundation and theoretical evidence for the gene-directed rationalization and individualization of medication in the pain treatment.
Materials and Methods
1.Subjects
Total two hundred and four subjects,aged 20-50 yr,within±20%of ideal body weight,and having an American Society of Anesthesiologists(ASA) physical status ofⅠorⅡ,undergoing selective abdominal total hysterectomy or myomectomy with general anesthesia were included.Exclusion criteria included the following:known history of psychiatric disease,significant cardiovascular disease,hepatic or renal dysfunction,diabetes mellitus,alcohol or drug abuse,chronic analgesic use, pregnancy or nursing.Subjects who have consumed drugs known to inhibit or induce the expression of CYP3A enzymes in two weeks were also excluded.The study design was approved by Institutional Ethics Committee of Zhengzhou University.The subjects were divided into three groups according to the genotypes.
2.Anesthetic Technique and Analgesia
Preoperatively,the pain threshold and pain tolerance threshold were measured using electrical stimulation.To familiarize the subjects with the assessment method,a training session was given in the preoperative holding area.The pain threshold(PT) and pain tolerance threshold(PTT) for each patient was obtained by the mean of three successive measurements,with a time interval of 5 min.A standardized,general anesthesia technique was used for all subjects.General anesthesia was induced with 0.1mg/kg midazolam,0.5 mg/kg propofol,2μg/kg remifentanyl and 1 mg/kg succinylcholine.Atracurium 0.6 mg/kg was administered intravenously as an initial dosage immediately after tracheal intubation was confirmed and then 0.1-0.2 mg/kg was administered as repeated boluses.During the operation,remifentanyl(0.1-0.2μg/kg/min) and propofol(6-8 mg/kg/h) were used for maintenance of anesthesia. Intravenous fentanyl patient-controlled analgesia(PCA) was provided postoperatively for satisfactory analgesia.The degrees of pain during PCA treatment were assessed with visual analog scale(VAS).The fentanyl consumption and occurrence of any adverse effects in the first 24 h postoperatively were recorded.
The analgesic solution in the PCA pump(6300 CADD-Legacy,USA) contained 100 ml normal saline and 1 mg fentanyl,5 mg droperidol.The PCA pump was programmed to give a 2ml bolus of fentanyl solution with 5 min lockout time,0.5 ml/h background infusion and maximum 145μg per hour.
3.Genotyping assays
Venous blood samples(2 ml) were collected from all subjects in this study.DNA was extracted from leukocytes using a standard phenol/chloroform procedure. Genotyping of OPRM1 A118G and CYP3A4~*1G,CYP3A5~*3alleles was conducted by polymerase chain reaction-restriction fragment length polymorphism(PCR-RFLP).
4.Evaluation of CYP3A activity
CYP3A activity was measured by plasma 1'-hydroxymidazolam:midazolam (1'-OHMDZ:MDZ) ratio at 60 min after intravenous administration of 0.1 mg/kg midazolam for induction of anesthesia.Midazolam and 1'-hydroxymidazolam concentrations were determined using liquid chromatography-mass spectrometry method(LC-MS).
5.Statistical analysis
SPSS 13.0 software was used for statistical analyses.The allele frequencies were estimated from the observed numbers of each specific allele.Chi-square test was used to verify Hardy-Weinberg equilibrium.One-way analysis of variance was used to assess whether significant differences exist between the three genotypes.Data for the fentanyl consumption were compared among the genotype group using one-way analysis of variance with post hoc Bonferroni correction for multiple comparisons was performed before and after adjusted for age,weight and remifentanil consumption in the operation.The incidences of any adverse effects were analyzed using Chi-square test or Fisher exact test.Theαwas set at 0.05.
Results
1.General information
Among the 204 subjects,the preoperative pain threshold was 2.0±0.6 mA,and the pain tolerance threshold was 5.1±2.0 mA.The VAS pain score immediately after surgery was 5.7±1.4.At 24 h after surgery,it was 2.2±0.8.The fentanyl consumption was 396.2±210.0μg and 190.9±43.2μg in the postoperative first and second 24 h, respectively.The incidence of PONV within 24 h in our study was 28.92%.
2.Frequencies of OPRM1 A118G,CYP3A4~*1G and CYP3A5~*3 alleles
The frequencies of OPRM1 118G,CYP3A4~*1G and CYP3A5~*3 alleles in Chinese gynecologic patients were 0.320,0.299 and 0.694,respectively.The allele frequencies were in Hardy-Weinberg equilibrium(P＞0.05).
3.Association of OPRM1 A118G gene polymorphism with preoperative pain tolerance and fentanyl analgesic effect
There were no significant differences in general information among the three genotype groups(P＞0.05).PTT was statistical different between A/A(5.6±2.4 mA) and A/G(4.9±1.3 mA) groups,between A/G and G/G(3.8±1.0 mA) groups and between A/A and A/G groups(P＜0.05).However,PT did not show a significant difference among the three genotypes(P＞0.05).Subjects in G/G group(507.9±290.2μg) consumed significantly more fentanyl than subjects in A/A(363.6±198.8μg) and A/G(412.0±189.8μg) groups in the first 24 h postoperatively(P＜0.05).Fentanyl consumption increased in accordance with the number of OPRM1 118G alleles (P＜0.05 for linear trend).There was no significant difference in incidences of adverse events among the different genotype groups(P＞0.05).
4.Association of CYP3A4~*1G gene polymorphism with CYP3A activity and fentanyl analgesic effect
There were no significant differences in general information among the three genotype groups(P＞0.05).The subjects with the CYP3A4~*1G/~*1G genotype (260.0±101.1μg) need less fentanyl to achieve pain control than subjects carrying the CYP3A4~*1/~*1(407.4±187.4μg) and CYP3A4~*1/~*1G(414.1±238.5μg) genotypes (P＜0.05).Fentanyl consumption increased in accordance with the number of ~*1G alleles(P＜0.05 for linear trend).The activity of CYP3A in ~*1G/~*1G group(0.34±0.15) was lower than in ~*1/~*1(0.46±0.14) and ~*1/~*1G(0.46±0.12) groups(P＜0.05).There was no significant difference in incidences of adverse events among the different genotype groups(P＞0.05).
5.Association of CYP3A5~*3 gene polymorphism with CYP3A activity and fentanyl analgesic effect
There were no significant differences in general information among the three genotype groups(P＞0.05).There were no significant differences in postoperative fentanyl consumptions or in CYP3A activity among the three genotype groups (P＞0.05).There was no significant difference in incidences of adverse events among the different genotype groups(P＞0.05).
6.Effect of CYP3A4/CYP3A5 haplotype on fentanyl analgesic effect
For CYP3A4/CYP3A5 haplotype,the subjects possessing CYP3A4~*1G/CYP3A5~*3 haplotype(CYP3A4~*1G/~*1G and CYP3A5~*1/~*3 or CYP3A5~*1/~*3) need less fentanyl to achieve pain control than subjects possessing CYP3A4~*1/CYP3A5~*1 haplotype(CYP3A4~*1/~*1 and CYP3A5~*1/~*1)(P＜0.05).
7.Joint effects of OPRM1 A118G and CYP3A4~*1G gene polymorphisms on fentanyl analgesic effect
To explore the joint effects of genes and the clinical efficacy of fentanyl,we created four groups:(1) ~*1G/~*1G but not G/G;(2) neither G/G nor ~*1G/~*1G;(3) G/G and ~*1G/~*1G;(4) G/G but not ~*1G/~*1G.There was significant difference in fentanyl consumption among the four genotype groups.Carriers of the OPRM1 118G/G and the CYP3A4~*1 genotypes required the most fentanyl dose(P＜0.05).There was no significant difference in incidence of adverse events among the different genotype groups(P＞0.05).
Conclusions
1.The preoperative pain tolerance threshold is lower in OPRM1 118G homozygotes. The OPRM1 A118G polymorphism has a gene-dose-dependent effect on the pain tolerance threshold.Postoperative fentanyl consumption increase in accordance with the number of 118G alleles.This is the first report on the association of OPRM1 A118G polymorphism with the effect of fentanyl for intravenous analgesia.
2.Carrying CYP3A4~*1G decrease the activity of CYP3A4 and patient-controlled intravenous fentanyl consumption.CYP3A5~*3 polymorphism may have no significant impact on fentanyl analgesic effect.For CYP3A4/CYP3A5 haplotype, CYP3A4~*1G/CYP3A5~*3 decrease the consumption of fentanyl for intravenous analgesia.This is the first report on the association of CYP3A4~*1G polymorphism with the effect of fentanyl.
3.Carriers of the OPRM1 118G/G and the CYP3A4~*1 genotypes require the most fentanyl dose when explored for joint effects of OPRM1 and CYP3A4 genes.
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