阿片类药物镇痛效果影响因素的研究进展
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摘要
阿片类药物是目前应用最广泛的镇痛药,其镇痛效果在个体之间存在广泛差异,造成这些差异的因素有很多,其中遗传因素占有重要的地位,药物代谢酶、转运蛋白、受体和药物作用靶点的基因多态性特别是基因的单核苷酸多态性(SNP)是引起阿片类药物效应和副作用个体差异的重要原因。此外,还包括年龄、性别、肝病肾病、肥胖等因素对其镇痛效果也会产生一定的影响,本文对关于这些影响因素的研究进行综述,从而指导临床阿片类药物的用药。
Opioids are the most widely used analgesic drugs at present, and their analgesic effects wary widely among individuals. There are many factors that can cause these differences, among which genetic factors play an important role. Drug metabolism enzymes, transporters, receptors, and genetic polymorphisms of drug targets in particular gene single nucleotide polymorphisms(SNPs) are also important causes of individual differences in opioid drug effects and side effects. In addition, age, gender, liver disease, kidney disease, obesity and other factors may also have a certain impact on the analgesic effects. This article reviews the research on these influencing factors to guide the clinical use of opioiods.
Opioids are the most widely used analgesic drugs at present, and their analgesic effects wary widely among individuals. There are many factors that can cause these differences, among which genetic factors play an important role. Drug metabolism enzymes, transporters, receptors, and genetic polymorphisms of drug targets in particular gene single nucleotide polymorphisms(SNPs) are also important causes of individual differences in opioid drug effects and side effects. In addition, age, gender, liver disease, kidney disease, obesity and other factors may also have a certain impact on the analgesic effects. This article reviews the research on these influencing factors to guide the clinical use of opioiods.
引文
[1] MERCADANTE S,PORZIO G,GEBBIA V.New opioids[J].J Clin Oncol,2014,32(16):1671-1676.DOI:10.1200/JCO.2013.51.8662.
[2] MERCADANTE S.Why are our patients still suffering pain?[J].Nat Clin Pract Oncol,2007,4(3):138-139.
[3] MITRA S,CARLYLE D,KODUMUDI G,et al.New advances in acute postoperative pain management[J].Curr Pain Headache Rep,2018,22(5):35.DOI:10.1007/s11916-018-0690-8.
[4] LOVIC-SAPOLA J,SMITH C E,BRANDT C P.Postoperative pain control[J].Surg Clin North Am,2015,95(2):301-318.DOI:10.1016/j.suc.2014.10.002.
[5] ANGST M S,PHILLIPS N G,DROVER D R,et al.Pain sensitivity and opioid analgesia:a pharmacogenomic twin study[J].Pain,2012,153(7):1397-1409.DOI:10.1016/j.pain.2012.02.022.
[6] 姚伟锋,黑子清.基于基因多态性的阿片类药物个体化应用提高围术期麻醉质量与安全[J].麻醉安全与质控,2017,1(4):208-211.DOI:10.3969/j.issn.2096-2681.2017.04.012.
[7] YUAN J J,HOU J K,ZHANG W,et al.CYP3A4 * 1G genetic polymorphism influences metabolism of fentanyl in human liver microsomes in Chinese patients[J].Pharmacology,2015,96(1-2):55-60.DOI:10.1159/000433441.
[8] YAN Q,SU Y,GAO L,et al.Impact of CYP3A4*1G Polymorphism on Fentanyl Analgesia Assessed by Analgesia Nociception Index in Chinese Patients Undergoing Hysteroscopy[J].Chin Med J (Engl),2018,131(22):2693-2698.DOI:10.4103/0366-6999.243934.
[9] ZHANG H,CHEN M,WANG X,et al.Patients with CYP3A4*1G genetic polymorphism consumed significantly lower amount of sufentanil in general anesthesia during lung resection[J].Medicine (Baltimore),2017,96(4):e6013.DOI:10.1097/MD.0000000000006013.
[10] LV J,LIU F,FENG N,et al.CYP3A4 gene polymorphism is correlated with individual consumption of sufentanil[J].Acta Anaesthesiol Scand,2018,62(10):1367-1373.DOI:10.1111/aas.13178.
[11] DAGOSTINO C,ALLEGRI M,NAPOLIONI V,et al.CYP2D6 genotype can help to predict effectiveness and safety during opioid treatment for chronic low back pain:results from a retrospective study in an Italian cohort[J].Pharmgenomics Pers Med,2018,11:179-191.DOI:10.2147/PGPM.S181334.
[12] TOCE M S,KIM H,CHUNG S,et al.Prolonged central apnoea after intravenous morphine administration in a 12-year-old male with a UGT1A1 loss-of-function polymorphism[J].Br J Clin Pharmacol,2019,85(1):258-262.DOI:10.1111/bcp.13779.
[13] ZHANG F,TONG J,HU J,et al.COMT gene haplotypes are closely associated with postoperative fentanyl dose in patients[J].Anesth Analg,2015,120(4):933-940.DOI:10.1213/ANE.0000000000000563.
[14] NIGAM S K.What do drug transporters really do?[J].Nat Rev Drug Discov,2015,14(1):29-44.DOI:10.1038/nrd4461.
[15] DZAMBAZOVSKA-TRAJKOVSKA V,NOJKOV J,KARTALOV A,et al.Association of single-nucleotide polymorhism C3435T in the ABCB1 gene with opioid sensitivity in treatment of postoperative pain[J].Pril (Makedon Akad Nauk Umet Odd Med Nauki),2016,37(2-3):73-80.DOI:10.1515/prilozi-2016-0019.
[16] CANDIOTTI K,YANG Z,XUE L,et al.Single-nucleotide polymorphism C3435T in the ABCB1 gene is associated with opioid consumption in postoperative pain[J].Pain Med,2013,14(12):1977-1984.DOI:10.1111/pme.12226.
[17] 吴成凤,申文,陈立平,等.ABCB1基因C3435T多态性对手术患者术后阿片类药物使用量及镇痛效果影响的Meta分析[J].中国药房,2018,29(18):2537-2544.DOI:10.6039/j.issn.1001-0408.2018.18.21.
[18] 朱敏,潘志强,张璐,等.ABCB1基因多态性与癌痛感知及癌痛病人阿片需求量的关联性分析[J].中国疼痛医学杂志,2017,23(6):426-433.DOI:10.3969/j.issn.1006-9852.2017.06.006.
[19] HAJJ A,PEOC’H K,LAPLANCHE J L,et al.Genotyping test with clinical factors:better management of acute postoperative pain?[J].Int J Mol Sci,2015,16(3):6298-6311.DOI:10.3390/ijms16036298.
[20] CRIST R C,BERRETTINI W H.Pharmacogenetics of OPRM1[J].Pharmacol Biochem Behav,2014,123:25-33.DOI:10.1016/j.pbb.2013.10.018.
[21] REN Z Y,XU X Q,BAO Y P,et al.The impact of genetic variation on sensitivity to opioid analgesics in patients with postoperative pain:a systematic review and meta-analysis[J].Pain Physician,2015,18(2):131-152.
[22] HAJJ A,HALEPIAN L,OSTA N E,et al.OPRM1 c.118A>G Polymorphism and duration of morphine treatment associated with morphine doses and quality-of-life in palliative cancer pain settings[J].Int J Mol Sci,2017,18(4):669.DOI:10.3390/ijms18040669.
[23] 李颖,吴飞雪,孙立,等.OPRM1 A118G多态性对我国汉族癌痛患者阿片类药物使用剂量的影响[J].中国药房,2016,27(20):2737-2739.DOI:10.6039/j.issn.1001-0408.2016.20.01.
[24] NAPLES J G,GELLAD W F,HANLON J T.The role of opioid analgesics in geriatric pain management[J].Clin Geriatr Med,2016,32(4):725-735.DOI:10.1016/j.cger.2016.06.006.
[25] MCLACHLAN A J,BATH S,NAGANATHAN V,et al.Clinical pharmacology of analgesic medicines in older people:impact of frailty and cognitive impairment[J].Br J Clin Pharmacol,2011,71(3):351-364.DOI:10.1111/j.1365-2125.2010.03847.x.
[26] ZIESENITZ V C,VAUGHNS J D,KOCH G,et al.Correction to:Pharmacokinetics of Fentanyl and Its Derivatives in Children:A Comprehensive Review[J].Clin Pharmacokinet,2018,57(3):393-417.DOI:10.1007/s40262-017-0609-2.
[27] KILHAM H A,GRANT M,MHEREKUMOMBE M.Morphine and children:an Australian perspective[J].J Paediatr Child Health,2015,51(5):482-485.DOI:10.1111/jpc.12875.
[28] AVERITT D L,EIDSON L N,DOYLE H H,et al.Neuronal and glial factors contributing to sex differences in opioid modulation of pain[J].Neuropsychopharmacology,2019,44(1):155-165.DOI:10.1038/s41386-018-0127-4.
[29] KEST B,SARTON E,DAHAN A.Gender differences in opioid-mediated analgesia:animal and human studies[J].Anesthesiology,2000,93(2):539-547.DOI:10.1097/00000542-200008000-00034.
[30] LOYD D R,MURPHY A Z.The role of the periaqueductal gray in the modulation of pain in males and females:are the anatomy and physiology really that different?[J].Neural Plast,2009,2009:462879.DOI:10.1155/2009/462879.
[31] SANDE T A,LAIRD B J,FALLON M T.The use of opioids in cancer patients with renal impairment-a systematic review[J].Support Care Cancer,2017,25(2):661-675.DOI:10.1007/s00520-016-3447-0.
[32] KING S,FORBES K,HANKS G W,et al.A systematic review of the use of opioid medication for those with moderate to severe cancer pain and renal impairment:a European Palliative Care Research Collaborative opioid guidelines project[J].Palliat Med,2011,25(5):525-552.DOI:10.1177/0269216311406313.
[33] HAN P Y,DUFFULL S B,KIRKPATRICK C M,et al.Dosing in obesity:a simple solution to a big problem[J].Clin Pharmacol Ther,2007,82(5):505-508.DOI:10.1038/sj.clpt.6100381.
[34] VAUGHNS J D,ZIESENITZ V C,WILLIAMS E F,et al.Use of Fentanyl in Adolescents with Clinically Severe Obesity Undergoing Bariatric Surgery:A Pilot Study[J].Paediatr Drugs,2017,19(3):251-257.DOI:10.1007/s40272-017-0216-6.
[35] GRODOFSKY S R,SINHA A C.The association of gender and body mass index with postoperative pain scores when undergoing ankle fracture surgery[J].J Anaesthesiol Clin Pharmacol,2014,30(2):248-252.DOI:10.4103/0970-9185.130041.
[36] 陈志勇,吴丹,朱姝,等.以瘦体重给药在肥胖患者无痛人流术中的应用[J].临床麻醉学杂志,2016,32(8):808-809.
[37] HAGHIGHI A,MELKA M G,BERNARD M,et al.Opioid receptor mu 1 gene,fat intake and obesity in adolescence[J].Mol Psychiatry,2014,19(1):63-68.DOI:10.1038/mp.2012.179.
[38] HUSSAIN Z,CURTAIN C,MIRKAZEMI C,et al.Peri-operative medication dosing in adult obese elective surgical patients:a systematic review of clinical studies[J].Clin Drug Investig,2018,38(8):673-693.DOI:10.1007/s40261-018-0662-0.
[2] MERCADANTE S.Why are our patients still suffering pain?[J].Nat Clin Pract Oncol,2007,4(3):138-139.
[3] MITRA S,CARLYLE D,KODUMUDI G,et al.New advances in acute postoperative pain management[J].Curr Pain Headache Rep,2018,22(5):35.DOI:10.1007/s11916-018-0690-8.
[4] LOVIC-SAPOLA J,SMITH C E,BRANDT C P.Postoperative pain control[J].Surg Clin North Am,2015,95(2):301-318.DOI:10.1016/j.suc.2014.10.002.
[5] ANGST M S,PHILLIPS N G,DROVER D R,et al.Pain sensitivity and opioid analgesia:a pharmacogenomic twin study[J].Pain,2012,153(7):1397-1409.DOI:10.1016/j.pain.2012.02.022.
[6] 姚伟锋,黑子清.基于基因多态性的阿片类药物个体化应用提高围术期麻醉质量与安全[J].麻醉安全与质控,2017,1(4):208-211.DOI:10.3969/j.issn.2096-2681.2017.04.012.
[7] YUAN J J,HOU J K,ZHANG W,et al.CYP3A4 * 1G genetic polymorphism influences metabolism of fentanyl in human liver microsomes in Chinese patients[J].Pharmacology,2015,96(1-2):55-60.DOI:10.1159/000433441.
[8] YAN Q,SU Y,GAO L,et al.Impact of CYP3A4*1G Polymorphism on Fentanyl Analgesia Assessed by Analgesia Nociception Index in Chinese Patients Undergoing Hysteroscopy[J].Chin Med J (Engl),2018,131(22):2693-2698.DOI:10.4103/0366-6999.243934.
[9] ZHANG H,CHEN M,WANG X,et al.Patients with CYP3A4*1G genetic polymorphism consumed significantly lower amount of sufentanil in general anesthesia during lung resection[J].Medicine (Baltimore),2017,96(4):e6013.DOI:10.1097/MD.0000000000006013.
[10] LV J,LIU F,FENG N,et al.CYP3A4 gene polymorphism is correlated with individual consumption of sufentanil[J].Acta Anaesthesiol Scand,2018,62(10):1367-1373.DOI:10.1111/aas.13178.
[11] DAGOSTINO C,ALLEGRI M,NAPOLIONI V,et al.CYP2D6 genotype can help to predict effectiveness and safety during opioid treatment for chronic low back pain:results from a retrospective study in an Italian cohort[J].Pharmgenomics Pers Med,2018,11:179-191.DOI:10.2147/PGPM.S181334.
[12] TOCE M S,KIM H,CHUNG S,et al.Prolonged central apnoea after intravenous morphine administration in a 12-year-old male with a UGT1A1 loss-of-function polymorphism[J].Br J Clin Pharmacol,2019,85(1):258-262.DOI:10.1111/bcp.13779.
[13] ZHANG F,TONG J,HU J,et al.COMT gene haplotypes are closely associated with postoperative fentanyl dose in patients[J].Anesth Analg,2015,120(4):933-940.DOI:10.1213/ANE.0000000000000563.
[14] NIGAM S K.What do drug transporters really do?[J].Nat Rev Drug Discov,2015,14(1):29-44.DOI:10.1038/nrd4461.
[15] DZAMBAZOVSKA-TRAJKOVSKA V,NOJKOV J,KARTALOV A,et al.Association of single-nucleotide polymorhism C3435T in the ABCB1 gene with opioid sensitivity in treatment of postoperative pain[J].Pril (Makedon Akad Nauk Umet Odd Med Nauki),2016,37(2-3):73-80.DOI:10.1515/prilozi-2016-0019.
[16] CANDIOTTI K,YANG Z,XUE L,et al.Single-nucleotide polymorphism C3435T in the ABCB1 gene is associated with opioid consumption in postoperative pain[J].Pain Med,2013,14(12):1977-1984.DOI:10.1111/pme.12226.
[17] 吴成凤,申文,陈立平,等.ABCB1基因C3435T多态性对手术患者术后阿片类药物使用量及镇痛效果影响的Meta分析[J].中国药房,2018,29(18):2537-2544.DOI:10.6039/j.issn.1001-0408.2018.18.21.
[18] 朱敏,潘志强,张璐,等.ABCB1基因多态性与癌痛感知及癌痛病人阿片需求量的关联性分析[J].中国疼痛医学杂志,2017,23(6):426-433.DOI:10.3969/j.issn.1006-9852.2017.06.006.
[19] HAJJ A,PEOC’H K,LAPLANCHE J L,et al.Genotyping test with clinical factors:better management of acute postoperative pain?[J].Int J Mol Sci,2015,16(3):6298-6311.DOI:10.3390/ijms16036298.
[20] CRIST R C,BERRETTINI W H.Pharmacogenetics of OPRM1[J].Pharmacol Biochem Behav,2014,123:25-33.DOI:10.1016/j.pbb.2013.10.018.
[21] REN Z Y,XU X Q,BAO Y P,et al.The impact of genetic variation on sensitivity to opioid analgesics in patients with postoperative pain:a systematic review and meta-analysis[J].Pain Physician,2015,18(2):131-152.
[22] HAJJ A,HALEPIAN L,OSTA N E,et al.OPRM1 c.118A>G Polymorphism and duration of morphine treatment associated with morphine doses and quality-of-life in palliative cancer pain settings[J].Int J Mol Sci,2017,18(4):669.DOI:10.3390/ijms18040669.
[23] 李颖,吴飞雪,孙立,等.OPRM1 A118G多态性对我国汉族癌痛患者阿片类药物使用剂量的影响[J].中国药房,2016,27(20):2737-2739.DOI:10.6039/j.issn.1001-0408.2016.20.01.
[24] NAPLES J G,GELLAD W F,HANLON J T.The role of opioid analgesics in geriatric pain management[J].Clin Geriatr Med,2016,32(4):725-735.DOI:10.1016/j.cger.2016.06.006.
[25] MCLACHLAN A J,BATH S,NAGANATHAN V,et al.Clinical pharmacology of analgesic medicines in older people:impact of frailty and cognitive impairment[J].Br J Clin Pharmacol,2011,71(3):351-364.DOI:10.1111/j.1365-2125.2010.03847.x.
[26] ZIESENITZ V C,VAUGHNS J D,KOCH G,et al.Correction to:Pharmacokinetics of Fentanyl and Its Derivatives in Children:A Comprehensive Review[J].Clin Pharmacokinet,2018,57(3):393-417.DOI:10.1007/s40262-017-0609-2.
[27] KILHAM H A,GRANT M,MHEREKUMOMBE M.Morphine and children:an Australian perspective[J].J Paediatr Child Health,2015,51(5):482-485.DOI:10.1111/jpc.12875.
[28] AVERITT D L,EIDSON L N,DOYLE H H,et al.Neuronal and glial factors contributing to sex differences in opioid modulation of pain[J].Neuropsychopharmacology,2019,44(1):155-165.DOI:10.1038/s41386-018-0127-4.
[29] KEST B,SARTON E,DAHAN A.Gender differences in opioid-mediated analgesia:animal and human studies[J].Anesthesiology,2000,93(2):539-547.DOI:10.1097/00000542-200008000-00034.
[30] LOYD D R,MURPHY A Z.The role of the periaqueductal gray in the modulation of pain in males and females:are the anatomy and physiology really that different?[J].Neural Plast,2009,2009:462879.DOI:10.1155/2009/462879.
[31] SANDE T A,LAIRD B J,FALLON M T.The use of opioids in cancer patients with renal impairment-a systematic review[J].Support Care Cancer,2017,25(2):661-675.DOI:10.1007/s00520-016-3447-0.
[32] KING S,FORBES K,HANKS G W,et al.A systematic review of the use of opioid medication for those with moderate to severe cancer pain and renal impairment:a European Palliative Care Research Collaborative opioid guidelines project[J].Palliat Med,2011,25(5):525-552.DOI:10.1177/0269216311406313.
[33] HAN P Y,DUFFULL S B,KIRKPATRICK C M,et al.Dosing in obesity:a simple solution to a big problem[J].Clin Pharmacol Ther,2007,82(5):505-508.DOI:10.1038/sj.clpt.6100381.
[34] VAUGHNS J D,ZIESENITZ V C,WILLIAMS E F,et al.Use of Fentanyl in Adolescents with Clinically Severe Obesity Undergoing Bariatric Surgery:A Pilot Study[J].Paediatr Drugs,2017,19(3):251-257.DOI:10.1007/s40272-017-0216-6.
[35] GRODOFSKY S R,SINHA A C.The association of gender and body mass index with postoperative pain scores when undergoing ankle fracture surgery[J].J Anaesthesiol Clin Pharmacol,2014,30(2):248-252.DOI:10.4103/0970-9185.130041.
[36] 陈志勇,吴丹,朱姝,等.以瘦体重给药在肥胖患者无痛人流术中的应用[J].临床麻醉学杂志,2016,32(8):808-809.
[37] HAGHIGHI A,MELKA M G,BERNARD M,et al.Opioid receptor mu 1 gene,fat intake and obesity in adolescence[J].Mol Psychiatry,2014,19(1):63-68.DOI:10.1038/mp.2012.179.
[38] HUSSAIN Z,CURTAIN C,MIRKAZEMI C,et al.Peri-operative medication dosing in adult obese elective surgical patients:a systematic review of clinical studies[J].Clin Drug Investig,2018,38(8):673-693.DOI:10.1007/s40261-018-0662-0.
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