Abstract
The μ1 opioid receptor (OPRM1) genetic variant A118G results in decreased μ-receptor binding potential in the brain and increases morphine requirement. We hypothesized that OPRM1 A118G polymorphism will affect morphine-induced respiratory depression (MIRD) risk in children receiving morphine. A prospective genotype-blinded study was conducted in 88 healthy adolescents (11–18 years; 67% female, 85% Caucasian) who underwent spine fusion for scoliosis. They were followed for 48 h postoperatively for MIRD, pain scores, morphine consumption and use of analgesic adjuvants. Patients were genotyped for OPRM1 A118G variant—76% were wild type (AA) and 24% heterozygous/homozygous for variant (AG/GG). Multivariable logistic regression showed that the risk of MIRD in patients with AA genotype was significantly higher (odds ratio 5.6, 95% CI: 1.4–37.2, P=0.030). Presence of G allele was associated with higher pain scores (effect size 0.73, P=0.045). This novel association is an important step toward predicting MIRD susceptibility and personalizing morphine use.
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References
Overdyk FJ, Carter R, Maddox RR, Callura J, Herrin AE, Henriquez C . Continuous oximetry/capnometry monitoring reveals frequent desaturation and bradypnea during patient-controlled analgesia. Anesth Analg 2007; 105: 412–418.
Voepel-Lewis T, Marinkovic A, Kostrzewa A, Tait AR, Malviya S . The prevalence of and risk factors for adverse events in children receiving patient-controlled analgesia by proxy or patient-controlled analgesia after surgery. Anesth Analg 2008; 107: 70–75.
Sadhasivam S, Boat A, Mahmoud M . Comparison of patient-controlled analgesia with and without dexmedetomidine following spine surgery in children. J Clin Anesth 2009; 21: 493–501.
Fecho K, Jackson F, Smith F, Overdyk FJ . In-hospital resuscitation: opioids and other factors influencing survival. Therapeut Clin Risk Manag 2009; 5: 961–968.
Overdyk FJ . Postoperative opioids remain a serious patient safety threat. Anesthesiology 2010; 113: 259–260.
Lotsch J, Dudziak R, Freynhagen R, Marschner J, Geisslinger G . Fatal respiratory depression after multiple intravenous morphine injections. Clin Pharmacokinet 2006; 45: 1051–1060.
Brennan F, Carr DB, Cousins M . Pain management: a fundamental human right. Anesth Analg 2007; 105: 205–221.
Liu SS, Wu CL . Effect of postoperative analgesia on major postoperative complications: a systematic update of the evidence. Anesth Analg 2007; 104: 689–702.
Duarte LT, Fernandes Mdo C, Costa VV, Saraiva RA . The incidence of postoperative respiratory depression in patients undergoing intravenous or epidural analgesia with opioids. Br J Anestesiol 2009; 59: 409–420.
Bouwmeester NJ, Anderson BJ, Tibboel D, Holford NH . Developmental pharmacokinetics of morphine and its metabolites in neonates, infants and young children. Br J Anaesth 2004; 92: 208–217.
Sadhasivam S, Chidambaran V, Ngamprasertwong P, Esslinger HR, Prows C, Zhang X et al. Race and unequal burden of perioperative pain and opioid related adverse effects in children. Pediatrics 2012; 129: 832–838.
Angst MS, Lazzeroni LC, Phillips NG, Drover DR, Tingle M, Ray A et al. Aversive and reinforcing opioid effects: a pharmacogenomic twin study. Anesthesiology 2012; 117: 22–37.
Angst MS, Phillips NG, Drover DR, Tingle M, Ray A, Swan GE et al. Pain sensitivity and opioid analgesia: a pharmacogenomic twin study. Pain 2012; 153: 1397–1409.
Dahan A, Aarts L, Smith TW . Incidence, reversal, and prevention of opioid-induced respiratory depression. Anesthesiology 2010; 112: 226–238.
Dahan A, Sarton E, Teppema L, Olievier C, Nieuwenhuijs D, Matthes HW et al. Anesthetic potency and influence of morphine and sevoflurane on respiration in mu-opioid receptor knockout mice. Anesthesiology 2001; 94: 824–832.
Huang P, Chen C, Mague SD, Blendy JA, Liu-Chen LY . A common single nucleotide polymorphism A118G of the mu opioid receptor alters its N-glycosylation and protein stability. Biochem J 2012; 441: 379–386.
Chou WY, Wang CH, Liu PH, Liu CC, Tseng CC, Jawan B . Human opioid receptor A118G polymorphism affects intravenous patient-controlled analgesia morphine consumption after total abdominal hysterectomy. Anesthesiology 2006; 105: 334–337.
Chou WY, Yang LC, Lu HF, Ko JY, Wang CH, Lin SH et al. Association of mu-opioid receptor gene polymorphism (A118G) with variations in morphine consumption for analgesia after total knee arthroplasty. Acta Anaesthesiol Scand 2006; 50: 787–792.
Sia AT, Lim Y, Lim EC, Goh RW, Law HY, Landau R et al. A118G single nucleotide polymorphism of human mu-opioid receptor gene influences pain perception and patient-controlled intravenous morphine consumption after intrathecal morphine for postcesarean analgesia. Anesthesiology 2008; 109: 520–526.
Tan EC, Lim EC, Teo YY, Lim Y, Law HY, Sia AT . Ethnicity and OPRM variant independently predict pain perception and patient-controlled analgesia usage for post-operative pain. Mol Pain 2009; 5: 32.
Walter C, Lotsch J . Meta-analysis of the relevance of the OPRM1 118A>G genetic variant for pain treatment. Pain 2009; 146: 270–275.
Sadhasivam S, Ganesh A, Robison A, Kaye R, Watcha MF . Validation of the bispectral index monitor for measuring the depth of sedation in children. Anesth Analg 2006; 102: 383–388.
Voepel-Lewis T, Burke CN, Jeffreys N, Malviya S, Tait AR . Do 0-10 numeric rating scores translate into clinically meaningful pain measures for children? Anesth Analg 2011; 112: 415–421.
Gauderman W, Morrison J QUANTO 1.1: A computer program for power and sample size calculations for genetic-epidemiology studies. Available at http://biostats.usc.edu/Quanto.html; Accessed on September 2014.
Campa D, Gioia A, Tomei A, Poli P, Barale R . Association of ABCB1/MDR1 and OPRM1 gene polymorphisms with morphine pain relief. Clin Pharmacol Ther 2008; 83: 559–566.
Mura E, Govoni S, Racchi M, Carossa V, Ranzani GN, Allegri M et al. Consequences of the 118A>G polymorphism in the OPRM1 gene: translation from bench to bedside? J Pain Res 2013; 6: 331–353.
Oertel BG, Schmidt R, Schneider A, Geisslinger G, Lotsch J . The mu-opioid receptor gene polymorphism 118A>G depletes alfentanil-induced analgesia and protects against respiratory depression in homozygous carriers. Pharmacogenet Genom 2006; 16: 625–636.
Romberg RR, Olofsen E, Bijl H, Taschner PE, Teppema LJ, Sarton EY et al. Polymorphism of mu-opioid receptor gene (OPRM1:c.118A>G) does not protect against opioid-induced respiratory depression despite reduced analgesic response. Anesthesiology 2005; 102: 522–530.
Hayashida M, Nagashima M, Satoh Y, Katoh R, Tagami M, Ide S et al. Analgesic requirements after major abdominal surgery are associated with OPRM1 gene polymorphism genotype and haplotype. Pharmacogenomics 2008; 9: 1605–1616.
Huehne K, Leis S, Muenster T, Wehrfritz A, Winter S, Maihofner C et al. High post surgical opioid requirements in Crohn's disease are not due to a general change in pain sensitivity. Eur J Pain 2009; 13: 1036–1042.
Kroslak T, Laforge KS, Gianotti RJ, Ho A, Nielsen DA, Kreek MJ . The single nucleotide polymorphism A118G alters functional properties of the human mu opioid receptor. J Neurochem 2007; 103: 77–87.
Connor M, Osborne PB, Christie MJ . Mu-opioid receptor desensitization: is morphine different? Br J Pharmacol 2004; 143: 685–696.
Dang VC, Christie MJ . Mechanisms of rapid opioid receptor desensitization, resensitization and tolerance in brain neurons. Br J Pharmacol 2012; 165: 1704–1716.
Kim KS, Lee KW, Im JY, Yoo JY, Kim SW, Lee JK et al. Adenylyl cyclase type 5 (AC5) is an essential mediator of morphine action. Proc Natl Acad Sci USA 2006; 103: 3908–3913.
Martini L, Whistler JL . The role of mu opioid receptor desensitization and endocytosis in morphine tolerance and dependence. Curr Opin Neurobiol 2007; 17: 556–564.
Johnson AD, Zhang Y, Papp AC, Pinsonneault JK, Lim JE, Saffen D et al. Polymorphisms affecting gene transcription and mRNA processing in pharmacogenetic candidate genes: detection through allelic expression imbalance in human target tissues. Pharmacogenet Genom 2008; 18: 781–791.
Oertel BG, Doehring A, Roskam B, Kettner M, Hackmann N, Ferreiros N et al. Genetic-epigenetic interaction modulates mu-opioid receptor regulation. Hum Mol Genet 2012; 21: 4751–4760.
Beyer A, Koch T, Schroder H, Schulz S, Hollt V . Effect of the A118G polymorphism on binding affinity, potency and agonist-mediated endocytosis, desensitization, and resensitization of the human mu-opioid receptor. J Neurochem 2004; 89: 553–560.
Oertel BG, Kettner M, Scholich K, Renne C, Roskam B, Geisslinger G et al. A common human micro-opioid receptor genetic variant diminishes the receptor signaling efficacy in brain regions processing the sensory information of pain. J Biol Chem 2009; 284: 6530–6535.
Zhang Y, Wang D, Johnson AD, Papp AC, Sadee W . Allelic expression imbalance of human mu opioid receptor (OPRM1) caused by variant A118G. J Biol Chem 2005; 280: 32618–32624.
Ray R, Ruparel K, Newberg A, Wileyto EP, Loughead JW, Divgi C et al. Human Mu Opioid Receptor (OPRM1 A118G) polymorphism is associated with brain mu-opioid receptor binding potential in smokers. Proc Natl Acad Sci USA 2011; 108: 9268–9273.
Bond C, LaForge KS, Tian M, Melia D, Zhang S, Borg L et al. Single-nucleotide polymorphism in the human mu opioid receptor gene alters beta-endorphin binding and activity: possible implications for opiate addiction. Proc Natl Acad Sci USA 1998; 95: 9608–9613.
Yildiz K, Tercan E, Dogru K, Ozkan U, Boyaci A . Comparison of patient-controlled analgesia with and without a background infusion after appendicectomy in children. Paediatr Anaesth 2003; 13: 427–431.
Gordon DB, Pellino TA . Incidence and characteristics of naloxone use in postoperative pain management: a critical examination of naloxone use as a potential quality measure. Pain Manag Nurs 2005; 6: 30–36.
Sinatra RS, Jahr JS, Reynolds LW, Viscusi ER, Groudine SB, Payen-Champenois C . Efficacy and safety of single and repeated administration of 1 gram intravenous acetaminophen injection (paracetamol) for pain management after major orthopedic surgery. Anesthesiology 2005; 102: 822–831.
Hiller A, Helenius I, Nurmi E, Neuvonen PJ, Kaukonen M, Hartikainen T et al. Acetaminophen improves analgesia but does not reduce opioid requirement after major spine surgery in children and adolescents. Spine 2012; 37: E1225–E1231.
Angst MS, Koppert W, Pahl I, Clark DJ, Schmelz M . Short-term infusion of the mu-opioid agonist remifentanil in humans causes hyperalgesia during withdrawal. Pain 2003; 106: 49–57.
dbSNP: the NCBI database of genetic variation. http://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=1799971database on the Internet. 2001 [cited December 5th 2013]. Available from http://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=1799971.
Lotsch J, Zimmermann M, Darimont J, Marx C, Dudziak R, Skarke C et al. Does the A118G polymorphism at the mu-opioid receptor gene protect against morphine-6-glucuronide toxicity? Anesthesiology 2002; 97: 814–819.
Landau R, Kern C, Columb MO, Smiley RM, Blouin JL . Genetic variability of the mu-opioid receptor influences intrathecal fentanyl analgesia requirements in laboring women. Pain 2008; 139: 5–14.
Song Z, Du B, Wang K, Shi X . Effects of OPRM1 A118G polymorphism on epidural analgesia with fentanyl during labor: a meta-analysis. Genetic Testing and Molecular Biomarkers 2013; 17: 743–749.
Sprouse-Blum AS, Smith G, Sugai D, Parsa FD . Understanding endorphins and their importance in pain management. Hawaii Med J 2010; 69: 70–71.
Acknowledgements
The project described was supported by the National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health, through Grant 8 UL1 TR000077 through the T1 Junior Faculty Award and Clinical Research Feasibility Funds (PI: Chidambaran). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. It was also supported by the APSF / ASA Safety Scientist Career Development Award by the Anesthesia Patient Safety Foundation (PI: Chidambaran). We acknowledge the contributions of the Clinical Analytic support team at Cincinnati Children’s Hospital for their assistance with medical record data retrieval.
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Chidambaran, V., Mavi, J., Esslinger, H. et al. Association of OPRM1 A118G variant with risk of morphine-induced respiratory depression following spine fusion in adolescents. Pharmacogenomics J 15, 255–262 (2015). https://doi.org/10.1038/tpj.2014.59
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DOI: https://doi.org/10.1038/tpj.2014.59
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