Genetic Testing for Opioid Pain Management: A Primer

Deepti Agarwal, Mercy A Udoji, Andrea Trescot, Deepti Agarwal, Mercy A Udoji, Andrea Trescot

Abstract

Patients see their primary care physicians (PCPs) for a variety of medical conditions, chronic pain being one of the most common. An increased use of prescription medications (especially opioids) has led to an increase in adverse drug reactions and has heightened our awareness of the variability in response to medications. Opioids and other pain adjuvants are widely used, and drug-drug interactions involving these analgesics can be problematic and potentially lethal. Pharmacogenetics has improved our understanding of drug efficacy and response, opened doors to individual tailoring of medical management, and created a series of ethical and economic considerations. Since it is a relatively new field, genetic testing has not been fully integrated into the primary care setting. The purpose of this paper is to review the metabolism of commonly prescribed opioids, discuss the economic and ethical issues, and provide PCPs with an understanding of how to incorporate genetic testing into routine use to improve clinical practice and patient management.

Keywords: Adverse drug reactions; Chronic pain; Drug interactions; Opiates; Opioid metabolism; Opioids; Pharmacogenetic testing.

References

    1. Hardt J, Jacobsen C, Goldberg J, Nickel R, Buchwald D. Prevalence of chronic pain in a representative sample in the United States. Pain Med. 2008;9:803–812. doi: 10.1111/j.1526-4637.2008.00425.x.
    1. Furlan AD, Reardon R, Weppler C. Opioids for chronic noncancer pain: a new Canadian practice guideline. Can Med Assoc J. 2010;182:923–930. doi: 10.1503/cmaj.100187.
    1. Kapur BM, Lala PK, Shaw JL. Pharmacogenetics of chronic pain management. Clin Biochem. 2014;47(13–14):1169–1187. doi: 10.1016/j.clinbiochem.2014.05.065.
    1. Steimer W, Müller B, Leucht S, Kissling W. Pharmacogenetics: a new diagnostic tool in the management of antidepressive drug therapy. Clin Chim Acta. 2001;308(1–2):33–41. doi: 10.1016/S0009-8981(01)00423-5.
    1. Stamer UM, Stuber F. Genetic factors in pain and its treatment. Curr Opin Anaesthesiol. 2007;20:478–484. doi: 10.1097/ACO.0b013e3282ef6b2c.
    1. CDC/NCHS National Ambulatory Medical Care Survey: 2010 Summary Tables Atlanta, GA: Centers for Disease Control and Prevention . Accessed 12/15/16.
    1. Mills R, Voora D, Peyser B, Haga S. Delivering pharmacogenetic testing in a primary care setting. Pharmgenom Pers Med. 2013;6:105–112.
    1. Trescot AM, Faynboym S. A review of the role of genetic testing in pain medicine. Pain Physician. 2014;17:425–445.
    1. Trescot AM. Genetics and implications in perioperative analgesia. Best Pract Res Clin Anaesthesiol. 2014;28(2):1153–1166. doi: 10.1016/j.bpa.2014.03.004.
    1. Yang Z, Arheart KL, Morris R, et al. CYP2D6 poor metabolizer genotype and smoking predict severe postoperative pain in female patients on arrival to the recovery room. Pain Med. 2012;13:604–609. doi: 10.1111/j.1526-4637.2012.01296.x.
    1. Kadiev E, Patel V, Rad P, et al. Role of pharmacogenetics in variable response to drugs: focus on opioids. Expert Opin Drug Metab Toxicol. 2008;41(1):77–91. doi: 10.1517/17425255.4.1.77.
    1. Reynolds KK, Ramey-Hartung B, Jortani SA. The value of CYP2D6 and OPRM1 pharmacogenetic testing for opioid therapy. Clin Lab Med. 2008;28(4):581–98. doi: 10.1016/j.cll.2008.10.003.
    1. Reyes-Gibby CC, Shete S, Rakvag T, et al. Exploring joint effects of genes and the clinical efficacy of morphine for cancer pain: OPRM1 and COMT gene. Pain. 2007;130:25–30. doi: 10.1016/j.pain.2006.10.023.
    1. Klepstad P. Genetic variability and opioid efficacy. Curr Anaesth Crit Care. 2007;18:149–156. doi: 10.1016/j.cacc.2007.06.001.
    1. Samer CF, Daali Y, Wagner M, et al. Genetic polymorphisms and drug interactions modulating CYP2D6 and CYP3A activities have a major effect on oxycodone analgesic efficacy and safety. Br J Pharmacol. 2010;160:919–930. doi: 10.1111/j.1476-5381.2010.00709.x.
    1. Crist RC, Berrettini WH. Pharmacogenetics of OPRM1. Pharmacol Biochem Behav. 2014;123:25–33. doi: 10.1016/j.pbb.2013.10.018.
    1. Trescot AM. Genetic testing in pain medicine. Pain Med News. 2013:1–8.
    1. Kirchcheiner J, Schmidt H, Tzvetkov M, Keulen JT, Lotsch J, Roots I, Brockmoller J. Pharmacokinetics of codeine and its metabolite morphine in ultra rapid metabolizers due to CYP2D6 duplication. Pharmacogenom J. 2007;7:257–65. doi: 10.1038/sj.tpj.6500406.
    1. Kaplan HL, Busto UE, Baylon GJ, Cheung SW, Otton SV, Somer G, Sellers EM. Inhibition of cytochrome P450 2D6 metabolism of hydrocodone to hydromorphone does not importantly affect abuse liability. J Pharm Exp Ther. 1997;281(1):103–8.
    1. Grond S, Sablotzki A. Clinical pharmacology of tramadol. Clin Pharmacokinet. 2004;43(13):879–923. doi: 10.2165/00003088-200443130-00004.
    1. Paar WD, Poche S, Gerloff J, Dengler HJ. Polymorphic CYP2D6 mediates O-demethylation of the opioid analgesic tramadol. Eur J Clin Pharmacol. 1997;53:235–239. doi: 10.1007/s002280050368.
    1. Trescot AM, Datta S, Lee M, Hansen H. Opioid pharmacology. Pain Physician. 2008;11(Opioid Special Issue):S133–S153.
    1. Barakat NH, Atayee RS, Best BM, Pesce AJ. Relationship between the concentration of hydrocodone and its conversion to hydromorphone in chronic pain patients using urinary excretion data. J Anal Toxicol. 2012;36(4):257–264. doi: 10.1093/jat/bks019.
    1. VanderVaart S, Berger H, Sistonen J, Madadi P, Matok I, Gijsen VM, et al. CYP2D6 polymorphisms and codeine analgesia in postpartum pain management: a pilot study. Ther Drug Monit. 2011;33(4):425–432. doi: 10.1097/FTD.0b013e3182272b10.
    1. Liukas A, Hagelberg NM, Kuusniemi K, Neuvonen PJ, Olkkola KT. Inhibition of cytochrome P450 3A by clarithromycin uniformly affects the pharmacokinetics and pharmacodynamics of oxycodone in young and elderly volunteers. J Clin Psychopharmacol. 2011;31(3):302–308. doi: 10.1097/JCP.0b013e3182189892.
    1. Iribarne C, Berthou F, Baird S, Dreano Y, Picart D, Bail JP, et al. Involvement of cytochrome P450 3A4 enzyme in the N-demethylation of methadone in human liver microsomes. Chem Res Toxicol. 1996;9(2):365–373. doi: 10.1021/tx950116m.
    1. Totah RA, Sheffels P, Roberts T, Whittington D, Thummel K, Kharasch ED. Role of CYP2B6 in stereoselective human methadone metabolism. Anesthesiology. 2008;108(3):363–374. doi: 10.1097/ALN.0b013e3181642938.
    1. Levran O, Peles E, Hamon S, Randesi M, Adelson M, Kreek MJ. CYP2B6 SNPs are associated with methadone dose required for effective treatment of opioid addiction. Addict Biol. 2011;18(4):709–716. doi: 10.1111/j.1369-1600.2011.00349.x.
    1. Kirchheiner J, Nickchen K, Bauer M, Wong ML, Licinio J, Roots I, et al. Pharmacogenetics of antidepressants and antipsychotics: the contribution of allelic variations to the phenotype of drug response. Mol Psychiatry. 2004;9(5):442–473. doi: 10.1038/sj.mp.4001494.
    1. Hesse LM, Venkatakrishnan K, Court MH, von Moltke LL, Duan SX, Shader RI, et al. CYP2B6 mediates the in vitro hydroxylation of bupropion: potential drug interactions with other antidepressants. Drug Metab Dispos. 2000;28(10):1176–1183.
    1. Zanger UM, Klein K. Pharmacogenetics of cytochrome P450 2B6 (CYP2B6): advances on polymorphisms, mechanisms, and clinical relevance. Front Genet. 2013;4:24. doi: 10.3389/fgene.2013.00024.
    1. Hesse LM, von Moltke LL, Shader RI, Greenblatt DJ. Ritonavir, efavirenz, and nelfinavir inhibit CYP2B6 activity in vitro: potential drug interactions with bupropion. Drug Metab Dispos. 2001;29(2):100–102.
    1. Basile VS, Ozdemir V, Masellis M, Walker ML, Meltzer HY, Lieberman JA, et al. A functional polymorphism of the cytochrome P450 1A2 (CYP1A2) gene: association with tardive dyskinesia in schizophrenia. Mol Psychiatry. 2000;5(4):410–417. doi: 10.1038/sj.mp.4000736.
    1. Kalow W, Tang BK. Use of caffeine metabolite ratios to explore CYP1A2 and xanthine oxidase activities. Clin Pharmacol Ther. 1991;50(5 Pt 1):508–519. doi: 10.1038/clpt.1991.176.
    1. Anderson GD, Chan LN. Pharmacokinetic drug interactions with tobacco, cannabinoids and smoking cessation products. Clin Pharmacokinet. 2016;55(11):1353–1368. doi: 10.1007/s40262-016-0400-9.
    1. Rodenburg EM, Eijgelsheim M, Geleijnse JM, Amin N, van Duijn CM, Hofman A, et al. CYP1A2 and coffee intake and the modifying effect of sex, age, and smoking. Am J Clin Nutr. 2012;96(1):182–187. doi: 10.3945/ajcn.111.027102.
    1. Jalil NJ, Bannur Z, Derahman A, Maskon O, Darinah N, Hamidi H, et al. The Implication of the Polymorphisms of COX-1, UGT1A6, and CYP2C9 among Cardiovascular Disease (CVD) Patients Treated with Aspirin. J Pharm Pharm Sci Publ Can Soc Pharm Sci (Société canadienne des sciences pharmaceutiques). 2015;18(3):474–483.
    1. Xia MM, Wang L, Pan PP, Wang HY, Chen MC, Chen Y, et al. The role of CYP2C9 genetic polymorphisms in the oxidative metabolism of diclofenac in vitro. Pharmazie. 2014;69(12):898–903.
    1. Garcia-Martin E, Martinez C, Ladero JM, Gamito FJ, Agundez JA. High frequency of mutations related to impaired CYP2C9 metabolism in a Caucasian population. Eur J Clin Pharmacol. 2001;57(1):47–49. doi: 10.1007/s002280100264.
    1. Scordo MG, Aklillu E, Yasar U, Dahl ML, Spina E, Ingelman-Sundberg M. Genetic polymorphism of cytochrome P450 2C9 in a Caucasian and a black African population. Br J Clin Pharmacol. 2001;52(4):447–450. doi: 10.1046/j.0306-5251.2001.01460.x.
    1. Kim YM, Yoo SH, Kang RY, Kim MJ, Bae YY, Lee YK, et al. Identifying drugs needing pharmacogenetic monitoring in a Korean hospital. Am J Health Syst Pharm AJHP. 2007;64(2):166–175. doi: 10.2146/ajhp050490.
    1. Klieber M, Oberacher H, Hofstaetter S, Beer B, Neururer M, Amann A, et al. CYP2C19 phenoconversion by routinely prescribed proton pump inhibitors omeprazole and esomeprazole: clinical implications for personalized medicine. J Pharmacol Exp Ther. 2015;354(3):426–430. doi: 10.1124/jpet.115.225680.
    1. Sim SC, Risinger C, Dahl ML, Aklillu E, Christensen M, Bertilsson L, et al. A common novel CYP2C19 gene variant causes ultrarapid drug metabolism relevant for the drug response to proton pump inhibitors and antidepressants. Clin Pharmacol Ther. 2006;79(1):103–113. doi: 10.1016/j.clpt.2005.10.002.
    1. Smith HS. The metabolism of opioid agents and the clinical impact of their active metabolites. Clin J Pain. 2011;27(9):824–838. doi: 10.1097/AJP.0b013e31821d8ac1.
    1. Crist RC, Berrettini WH. Pharmacogenetics of OPRM1. Pharmacol Biochem Behav. 2014;123:25–33. doi: 10.1016/j.pbb.2013.10.018.
    1. Guillot CR, Fanning JR, Liang T, Berman ME. COMT associations with disordered gambling and drinking measures. Journal of gambling studies/co-sponsored by the National Council on Problem Gambling and Institute for the Study of Gambling and Commercial Gaming. 2014.
    1. Agarin T, Trescot AM, Agarin A, Lesanics D, Decastro C. Reducing opioid analgesic deaths in America: what health providers can do. Pain Physician. 2015;18(3):E307–E322.
    1. 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(4):559–566. doi: 10.1038/sj.clpt.6100385.
    1. Laugesen S, Enggaard TP, Pedersen RS, Sindrup SH, Brosen K. Paroxetine, a cytochrome P450 2D6 inhibitor, diminishes the stereoselective O-demethylation and reduces the hypoalgesic effect of tramadol. Clin Pharmacol Ther. 2005;77(4):312–323. doi: 10.1016/j.clpt.2004.11.002.
    1. Skinner MH, Kuan HY, Pan A, et al. Duloxetine is both an inhibitor and a substrate of cytochrome P450 2D6 in healthy volunteers. Clin Pharmacol Ther. 2003;73(3):170–177. doi: 10.1067/mcp.2003.28.
    1. Verbeurgt P, Mamiya T, Oesterheld J. How common are drug and gene interactions? Prevalence in a sample of 1143 patients with CYP2C9, CYP2C19 and CYP2D6 genotyping. Pharmacogenomics. 2014;15(5):655–665. doi: 10.2217/pgs.14.6.
    1. Madadi P, Amstutz U, Rieder M, et al. Clinical practice guideline: CYP2D6 genotyping for safe and efficacious codeine therapy. J Popul Therap Clin Pharm (Journal de la therapeutique des populations et de la pharamcologie clinique). 2013;20(3):e369–e396.
    1. Madadi P, Ciszkowski C, Gaedigk A, et al. Genetic transmission of cytochrome P450 2D6 (CYP2D6) ultrarapid metabolism: implications for breastfeeding women taking codeine. Curr Drug Saf. 2011;6(1):36–39. doi: 10.2174/157488611794479991.
    1. Lipton P. Pharmacogenetics: the ethical issues. Pharmacogenom J. 2003;3:14–16. doi: 10.1038/sj.tpj.6500159.
    1. Barash, CI. Ethical Issues in Pharmacogenetics. Action Bioscience. April 2013. . Accessed 12/15/16.
    1. Genetic Alliance; The New York-Mid-Atlantic Consortium for Genetic and Newborn Screening Services. Understanding Genetics: a New York, Mid-Atlantic Guide for Patients and Health Professionals. Washington (DC): Genetic Alliance; 2009 Jul 8. APPENDIX Q, National Coalition for Health Professional Education in Genetics (NCHPEG): Principles of Genetics for Health Professionals. Available from: . Accessed 12/15/16.
    1. Weber W. Pharmacogenetics. Oxford: Oxford Press; 1997.
    1. Sharma M, Kantorovich S, Lee C, Anand N, Blanchard J, Fung ET, et al. An observational study of the impact of genetic testing for pain perception in the clinical management of chronic non-cancer pain. J Psychiatr Res. 2017;89:65–72. doi: 10.1016/j.jpsychires.2017.01.015.
    1. Zittel S, Lohmann K, Bauer P, Klein C, Munchau A. Munchausen syndrome by genetics: next-generation challenges for clinicians. Neurology. 2017;88(10):1000–1001. doi: 10.1212/WNL.0000000000003695.
    1. Vogenberg FR, Barash CI, Pursel M. Personalized medicine Part 3: Challenges facing health care plans in implementing coverage for policies for pharmacogenomic and genetic testing. 2010; 35(12):670–75.
    1. Lehmann-Che J, Poirot B, Boyer JC, Evrard A. Cancer genomics guide clinical practice in personalized medicine. Therapie. 2017
    1. Kaufman AL, Spitz J, Jacobs M, Sorrentino M, Yuen S, Danahey K, Saner D, Klein TE, Altman RB, Ratain MJ, O'Donnell PH. Evidence for clinical implementation of pharmacogenomics in cardiac drugs. Mayo Clin Proc. 2015;90(6):716–29. doi: 10.1016/j.mayocp.2015.03.016.
    1. Wu AC, Fuhlbrigge AL. Economic evaluation of pharmacogenetic tests. Clin Pharmacol Ther. 2008;84(2):272–274. doi: 10.1038/clpt.2008.127.
    1. Elliott LS, Henderson JC, Neradilek MB, Moyer NA, Ashcraft KC, Thirumaran RK. Clinical impact of pharmacogenic profiling with a clinical decision support tool in polypharmacy home health patients: A prospective pilot randomized controlled trial. PLoS One. 2017;12(2):a0170905. doi: 10.1371/journal.pone.0170905.
    1. Tollman P, Guy P, Altshuler J, et al. A Revolution in R&D. How genomics and genetics are transforming the biopharmaceutical industry. Boston: Boston Consulting Group; 2001.
    1. Lesko LJ, Zineh I, Huang SM. What is clinical utility and why should we care? Clin Pharmacol Ther. 2010;88(6):729–733. doi: 10.1038/clpt.2010.229.
    1. Moeller KE, Lee KC, Kissak JC. Urine drug screening: practical guide for clinicians. Mayo Clin Proc. 2008;83:66–76. doi: 10.4065/83.1.66.
    1. Drummer OH. Drug testing in oral fluid. Clin Biochem Rev. 2006;27(3):147–159.
    1. McMichael GL, Gibson CS, O’Callaghan ME, et al. DNA from buccal swabs suitable for high-throughput SNP multiplex analysis. J Biomol Tech. 2009;20(5):232–235.
    1. Belmonte I, Barrecheguren M, Esquinas C, Rodriguez E, Miravitlles M, Rodriguez-Frias F. Genetic diagnosis of alpha1-antitrypsin deficiency using DNA from buccal swab and serum samples. Clin Chem Lab Med. 2017.

Source: PubMed

Sponsors and Collaborators

Medical Conditions

Drug Interventions

3
Subscribe