| Background:Opioid analgesics is widely used in the treatment of acute and chronic pain. In patient controlled intravenous analgesia(PCIA), there are significant individual differences in morphine and fentanyl requirements and their adverse reactions. Polymorphism is an important factor in opioid consumption. Fentanyl plays a major role in the central nervous system by μ-opioid receptors, which exerts its biological effects clinical and encoded by the μ opioid receptor gene(OPRM1). However, there are many single nucleotide polymorphism(SNP) in OPRM1 gene. In addition, fentanyl plays a main biological role in the liver by the cytochrome P450(CYP) 3A4, which encoded by CYP3A4 gene polymorphisms and can cause pharmacokinetic or pharmacodynamic significant individual differences. Therefore, it is necessary to investigate polymorphism on usage of fentanyl in patient controlled analgesia. Objectives:1.To evaluate the effect of patient controlled intravenous analgesia(PCIA) in non-small cell lung cancer patients after thoracotomy.2.To investigate the effect of the μ-opioid receptor gene(OPRM1) A118 G polymorphism on the fentanyl requirement for patient controlled intravenous analgesia(PCIA) in non-small cell lung cancer patients after thoracotomy.3.To investigate the effect of cytochrome P450 3A4(CYP3A4)*18B polymorphisms and the interaction of the μ opioid receptor gene(OPRM1) A118 G and CYP3A4*18B polymorphisms on fentanyl requirement for patient controlled intravenous analgesia(PCIA) in non-small cell lung cancer patients after thoracotomy. Methods:1. From Jan 2014 to Mar 2015, 40 patients of non-small cell lung cancer were recruited in this study and divided into two groups, patient controlled intravenous analgesia(PCIA) group and control group with 20 patients in each group. The patients in the PCIA group were connected to intravenous self-control analgesia pump which contains 2 μg/ml of sufentanil and 8 mg of ondansetron diluting to 100 ml of 0.9% saline after surgery. Initial loading dose was 2 ml, background dose was 2 ml/h, single PCIA dose was 0.5 ml and locking time 15 min. 10 mg of morphine was intramuscular injected if necessary. Patients in the control group use intramuscular injection of morphine 10 mg single. The visual analogue score(VAS) of the two groups were recorded in the time point of 2 h, 4 h, 8 h, 12 h, 24 h. The morphine consumption of the two groups were also compared.2. From Mar 2014 to Jun 2015, a total of 174 patients with non-small cell lung cancer in our hospital undertaken thoracotomy were selected. After the establishment of intravenous access 2ml peripheral blood collected, placed in EDTA anticoagulant tubes placed 4oC refrigerator. Used within one month to extract DNA from the white blood cells. Polymerase chain reaction(PCR) technology and ABI 3130 Genetic Analyzer were used to detected DNA sequences in OPRM1 A118 G genotype. The patients were divided to AA group(wild type homozygote), AG group(heterozygous genotype) and GG group(homozygous mutant genotype). Anesthesia was induced with 0.05mg/kg midazolam, 4μg/kg fentanyl, 2mg/kg propofol and 0.2mg/kg of cisatracurium,anesthesia was maintained by 2% sevoflurane, according to the need for additional cisatracurium. The total amount of fentanyl was 12μg/kg. After surgery, the operation time and incision length were recorded. Patient-controlled intravenous analgesia pump was used which contains 30ug/kg fentanyl and 8mg ondansetron with 0.9% saline diluted to 200 ml. Without initial loading dose, background dose was 2 ml/h, single PCIA dose was 2 ml and locking time 15 min. The patient’s VAS score and the total amount of fentanyl were recorded within postoperative 24 hours and 48 hours. Incidence of nausea, vomiting, dizziness and other adverse reactions was recorded within 48 hours.3. From May 2014 to Aug 2015, a total of 139 patients with non-small cell lung cancer in our hospital undertaken thoracotomy were selected. After the establishment of intravenous access 2ml peripheral blood collected, placed in EDTA anticoagulant tubes placed 4oC refrigerator. Used within one month to extract DNA from the white blood cells. PCR technology and ABI 3130 Genetic Analyzer were used to detected DNA sequences in OPRM1 A118 G and CYP3A4*18B genotype. The patients in accordance with OPRM1 A118 G allele divided into AA, AG and GG group. The patients in accordance with different CYP3A4 *18B allele into *1/*1 group(wild type homozygote), *1/*18B group(heterozygote) and *18B/*18B group(homozygous mutant). In order to analyze the interaction between the two genes, divided into seven groups: AA+*1/*1 group, AA+*1/*18B group, AG+*1/*1 group, AG+*1/*18B group, GG +*1/*1 group, GG+*1/*18B group and *18B/*18B group. Anesthesia method, postoperative analgesia and the data record were the same to second part. Results:1. Patients in PCIA group after surgery, 2 hours, 4 hours, 8 hours, 12 hours, 24 hours visual analog pain score(VAS) were obviously lower than those in control group(P<0.05). And the incidence of nausea and vomiting and respiratory depression of patients in PCIA group was obviously lower than control group(P<0.05). Consumption of postoperative morphine in PCIA group was obviously less than control group(P< 0.05).2. Fentanyl doses were 7.2-14.7 μg/kg and 14.4-27.9μg/kg, 24 hours and 48 hours after surgery. Fentanyl doses in GG genotype patients in postoperative 24 hours and 48 hours were significantly higher than AA genotype(P< 0.05). Incidence of postoperative nausea, vomiting and dizziness had no significant difference between the three groups.3. Fentanyl doses in GG genotype patients in postoperative 24 hours and 48 hours were significantly higher than AA genotype(P< 0.05). In postoperative 48 hours, the amount of fentanyl of *18B/*18B group was significantly lower than *1/*1 group(P <0.05). GG + *1/*1 group were significantly higher than AA +*1/*1 group, AA +*1/*18B group, AG +*1/*1 group, AG +*1/*18B group, and *18B/*18B group(P <0.05); AA +*1/*18B group, AG +*1/*18B group was significantly lower than AA +*1/*1 group, AG +*1/*1 group, GG +*1/*1 group, GG +*1/*18B group(P <0.05); The fentanyl dosage of *18B/*18B group was significantly lower than the other six groups(P <0.05). Conclusions:1. Patient controlled intravenous analgesia can significant decrease the VAS score without increasing the toxicity in non-small cell lung cancer patients after thoracotomy.2. OPRM1 A118 G polymorphisms play a role in PCIA fentanyl dose in patients with non-small cell lung cancer after thoracotomy. 24 h and 48 h after surgery, GG genotype patients’ fentanyl dosage was significantly higher than AA genotype.3. OPRM1 A118 G genotype, CYP3A4 *18B genotype and their combination may affect fentanyl dose in patient-controlled intravenous analgesia of patients with non-small cell lung cancer after thoracotomy.In patients with CYP3A4 *18B/*18B polymorphism, doses of fentanyl was significantly less. |
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