Clinical Study On The Effect Of Genetic Polymorphism On Opioid Drugs

Every year,there are a large number of patients needing to accept general anesthesia and analgesic treatment,opioid drugs are increasingly needed in pain treatment.In the course of clinical diagnosis and treatment practice,it was found that there were obvious individual differences in the clinical efficacy of opioid drugs.With the development of the human genome project in depth,some genetic locus of acting recptors,metabolic enzymes and transporters that related to opioid drugs have been found.At the same time,with the great development of pharmacogenomics,the genetic mechanism of individual differences in the clinical efficacy of opioid drugs have been gradually revealed.The detection of drug-related genetic polymorphism is benefit for formulatiing scheme on clinical medication plan,reducing the incidence of adverse reactions during the medication and improving the efficacy of medication.The studies on the mechanism of individual differences in efficacy of opioid drugs have been mainly focused on morphine and fentanyl.Sufentanil now is one of the most widely used analgesic,but there were relatively few studies on the effect of genetic polymorphisms on sufentanil and the conclusions were different.Further studies will be needed to clarify the mechanism of individual differences in sufentanil.We will explore the effects of single genetic polymorphism or multiple genetic interactions on the efficacy of sufentanil by analyzing the polymorphisms of sufentanil-related genes to provide clinical data for safe 、 efficient and accurate use of opioid drugs in clinical work.PARTⅠ: Effect of OPRM1A118 G Genetic Polymorphism on Postoperative Patient-Controlled Analgesia with Sufentanil in Laryngocarcinoma PatientsObjective: To investigate the effect of OPRM1A118 G genetic polymorphism on the postoperative patient-controlled analgesia with sufentanil in laryngocarcinoma patients and provide reference and data for rational formulation of individual medication scheme on PCIA with sufentanil.Methods: The participates were male patients undergoing selective laryngocarcinoma radical surgery with general anesthesia.The OPRM1A118 G genetic polymorphism was detected by blood sampling after vein puncture.According to the genotype of OPRM1A118 G,the patients were divided into three groups : wild homozygote group(A/A),heterozygote group(A/G)and mutation homozygote group(G/G).General anesthesia was induced with propofol,sufentanil and rocuronium.Inhaled sevoflurane and remifentanil was continuously infused which was used for maintenance of anesthesia.Patients recovered after operation were sent to PACU for VAS score and then received PCIA treatment.The analgesic solution of PCA contained sufentanil 100 ug and tropisetron 5 mg in 100 ml of normal saline was programmed to give a 0.4 ml bolus dose with a 15 min lock out time and background infusion at a rate of 1.0 ml/h.The primary outcomes were sufentanil consumption,PCIA additional times and VAS score at 24 and 48 hours after operation,the secondary outcomes were the LOS score and the incidence of adverse reactions such as PONV and Vertigo.Results: From September 1,2016 to February 28,2018,127 patients were enrolled,and 120 participants completed the trial.1)54 participants were A/A genotype,48 were A/G genotype,18 were G/G genotype,and the frequency of OPRM1A118 G allele G was 35%.The distribution of allele in this sample conformed to Hardy-Weinberg equilibrium;2)There were statistically significant differences in sufentanil consumption,PCIA additional times and VAS score among the three groups at 24 and 48 hours after operation (P<0.05),G/G group was higher than A/G group and A/A group,but there was no significant difference between A/A group and A/G group(P > 0.05);3)There was no significant difference in LOS sedation score among the three groups(P > 0.05);There was no significant difference in the incidence of PONV and Vertigo(P > 0.05).No other adverse reactions occurred.Conclusions: OPRM1A118 G genetic polymorphism is a genetic factor affecting the efficacy of PCIA with sufentanil.For mutation homozygote as G/G genotype,the background dose and additional dose of sufentanil in PCIA should be increased appropriately,It is suggested that preoperative genetic screening is helpful to formulate reasonable individual treatment plans of sufentanil for patients.PARTⅡ: Effects of CYP3A4*1G and ABCBB1-C3435 T Genetic Polymorphisms Alone or Interacted with Each Other on Blood Concentration of Sufentanil during Operation and Postoperative Patient-Controlled Analgesia with Sufentanil in Laryngocarcinoma PatientsObjective: To investigate the CYP3A4*1G and ABCBB1-C3435 T genetic polymorphisms alone or interacted with each other on blood concentration of sufentanil during operation and individual differences in efficacy of postoperative patient-controlled analgesia with sufentanil in laryngocarcinoma patients,and provide reference and data for rational formulation for individual medication scheme on anesthesia induction,intraoperative addition and PCIA treatment with sufentanil.Methods: The participates were male patients undergoing selective laryngocarcinoma radical surgery with general anesthesia.The CYP3A4*1G and ABCBB1-C3435 T genetic polymorphisms were detected by blood sampling after venepuncture.According to the genotypes of CYP3A4*1G and ABCBB1-C3435 T,the patients were divided into wild homozygote group(A/A and C/C),heterozygote group(A/*1G and C/T)and mutation homozygote group(*1G/*1G and T/T).General anesthesia was induced with target-controlled pump injection of propofol,sufentanil 1 ug/kg by constant venous infusion in 5 min and intravenous injection of cis-atracurium besylate.Inhaled sevoflurane and remifentanil was continuously infused which was used for maintenance of anesthesia.The arterial blood concentration of sufentanil was measured before induction and at 1、3、5、7、10、15、30、60、90、120 min after administration of sufentanil.Patients recovered after operation were sent to PACU for VAS score and then received PCIA treatment.The analgesic solution of PCA contained sufentanil 100 ug and tropisetron 5 mg in 100 ml of normal saline was programmed to give a 0.4 ml bolus dose with a 15 min lock out time and background infusion at a rate of 1.0 ml/h.The primary outcomes were sufentanil consumption,PCIA additional times and VAS score at 24 and 48 hours after operation,Blood Concentration-Time curve of sufentanil;the secondary outcomes were the LOS score and the incidence of adverse reactions such as PONV and Vertigo.Results: From March 1,2018 to January 30,2019,57 patients were enrolled,and 50 participants completed the trial.1)The frequency of CYP3A4*1G allele *1G was 27%;The frequency of ABCB1-C3435 T allele T was 40%;2)For single genetic polymorphism,there were significant differences in sufentanil consumption and PCIA additional times at 24 and 48 hours after operation(P<0.05),*1G/*1G or T/T group was lower than the other two groups;The VAS score of T/T group was lower than that of C/C and C/T group at 48 hours after operation(P<0.05);For different genomic combinations,there were significant differences in sufentanil consumption,PCIA additional times and VAS score at 24 and 48 hours after operation(P<0.05),*1G/*1G and T/T+(A/A 、 A/*1G)groups were lower than the other groups;3)For single genetic polymorphism,the sufentanil blood concentration of *1G/*1G and T/T groups increased during 7 ~ 120 min after administration(P<0.05);For different genomic combinations,the blood concentration of *1G/*1G and T/T+(A/A 、 A/*1G)groups increased significantly during 10~120 min after administration(P<0.05);4)There was no significant difference in LOS sedation score and Vertigo(P > 0.05);The incidence of PONV of A/*1G and C/T was higher than the other two groups(P<0.05);No other adverse reactions occurred.Conclusions: CYP3A4*1G and ABCBB1-C3435 T genetic polymorphisms alone or interacted with each other could influence the blood concentration of sufentanil during operation and the efficacy of PCIA with sufentanil in patients with laryngeal cancer.Mutant homozygous *1G/*1G and T/T could increase the blood concentration of sufentanil,enhance analgesic efficacy,and may have a superimposed effect.