Perioperative Application Of Opioids And Genetic Analysis In Gastric Cancer/Colorectal Cancer Patients

ObjectiveSufentanil,the ?-opioid receptor agonist,is one of the most commonly used drugs in the control of perioperative pain.But its dose-related adverse responses and poor control of visceral pain affects its application in abdominal surgery.As the new generation of ?,?-opioid receptor agonists-oxycodone,there are few clinical studies about its superiority to other opioids in perioperative use in abdominal surgery.This study is to compare the efficacy and adverse responses of sufentanil and oxycodone in patients undergoing laparoscopic gastric cancer/colorectal cancer resections,combined with individuals' opioid-related genomics analysis,which could enable anesthesiologists to assess the differences of opioids' pharmacokinetics and pharmacodynamics and to accomplish a reference for individual treatments in gastrointestinal tumor patients.MethodsFifty-nine patients were enrolled,who received selective laparoscopic gastric cancer and colorectal cancer surgeries.The patients were randomly divided into oxycodone group(group O,n=30)and sufentanil group(group S,n=29)using reproducible random number generation method.Two ml of peripheral venous blood was extracted before the surgery and the single nucleotide polymorphisms(SNPS)of four alleles of ? opioid receptor gene: OPRM1 A118 G,cytochrome P450: CPY3A4*1G,CYP3A5*3 and CYP2D6*10 were detected by PCR-pyrosequencing.Anesthesia was induced with midazolam 0.05 mg/kg,propofol 1-2 mg/kg,and cisatracurium besilate 0.2 mg/kg intravenously.In addition Group S patients received intravenous sufentanil 0.3 ?g/kg,while group O patients received intravenous oxycodone 0.3 mg/kg.Anesthesia was maintained with intravenous and inhaled combined method.If the blood pressure or heart rate increased over 20% of the basal level,additional opioid drugs were added.In Group O patients were treated with oxycodone 0.1 mg/kg while in group S patients were treated with sufentanil 0.1 ?g/kg.Thirty minutes before the end of surgery,patients in group S and in group O were given sufentanil 0.1 ?g/kg and oxycodone 0.1 mg/kg,respectively.In the PACU,if the visual analogue scale(VAS)>4 patients were rescued with sufentanil 0.1 ?g/kg(group S),or oxycodone 0.1 mg/kg(group O).Hemodynamic index(T0-T12,induction of anesthesia-postoperative 48h),adverse responses and drug requirements were recorded.VAS score,sedation score(Ramsay score)and restless score(RS score)were also assessed(T6-T12,immediately after extubation-postoperative 48h).Results1.Drug effects:There was no significant difference about postoperative VAS score(T6-T12)between the two groups,P>0.05;There was no significant difference about analgesics rescue in PACU between the two groups,P>0.05,the Ramsay score in group O was higher than that in group S at T6(extubation immediately)and T7(5 min after extubation),P<0.05.2.Adverse responses:The incidence of induction period bucking in group O was significantly lower than that in group S,P=0.002.The incidence of postoperative agitation was significantly lower in group O than in group S,P=0.045;The RS score in group O was lower than that in group S at T7,P =0.035.There was no significant difference in postoperative nausea,vomiting and respiratory depression between the two groups,P>0.05.3.The mutation frequencies of OPRM1 A118 G,CYP3A4*1G,CYP3A5*3 and CYP2D6*10 in Chinese gastric cancer/colorectal cancer patients were 35.6%,23.7%,72.9% and 56.1%,respectively.The allele frequencies were in Hardy-Weinberg equilibrium,P>0.05.4.OPRM1 A118 G gene polymorphism was responsible for postoperative VAS score and drug requirements in group O.The VAS scores in GG group were higher than that in AA group and AG group at T6,T7,T8 and T9,P<0.05;The VAS scores in GG group and AG group were higher than that in AA group at T10 and T12,P<0.05;The number of analgesics rescue in GG group was higher than that in AA group and AG group,P=0.002.5.CYP3A4*1G gene polymorphism was responsible for postoperative VAS score,drug requirements and adverse responses in group S.The VAS score in AA group was lower than that in GG group and GA group at T7,T9 and T11,P<0.05;The total amount of intraoperative sufentanil in AA group was lower than that in GG and GA group,P<0.01;The incidence of respiratory depression in AA group was higher than that in GG and GA group,P=0.01.6.The analgesic efficacy of sufentanil and oxycodone was not associated with CYP3A5*3 and CYP2D6*10 gene polymorphisms: there were no significant differences about postoperative VAS scores,analgesics rescue,24-hour postoperative drug requirements and the incidence of adverse responses between different gene groups,P>0.05.Conclusion1.Compared with sufentanil,oxycodone can significantly reduce the incidence of bucking and postoperative agitation.Also,it can provide a better sedation for patients who received the gastric cancer/colorectal cancer surgery.2.The genetic polymorphism in patients with gastric cancer/colorectal cancer was responsible for the efficacy and adverse responses of opioids.In consideration of the higher VAS score and more analgesics rescue in the homozygous mutation GG type patients,we should focus on OPRM1 A118 G genotype when using oxycodone on them.In consideration of the lower VAS scores,less intraoperative sufentanil requirements and higher incidence of respiratory depression in the homozygous mutation AA type patients,we should focus on CYP3A4*1G genotype when using sufentanil on them.