Pharmacogenetics of Pain: The Future of Personalized Medicine

  • Lynn R. Webster


Physicians who treat chronic pain using opioids recognize that patients vary considerably in their responses to medications and painful stimuli. An increasing body of scientific literature supports the observation that the success or failure of opioid pharmacotherapy for pain may be rooted in individual genetic variations (Argoff, Clin J Pain 26(Suppl 10):S16–S20, 2010; Stamer and Stüber, Curr Opin Anaesthesiol 20(5):478–484, 2007a; Kim et al., Pain 109(3):488–496, 2004). Given the advances, genetic research appears to lay a foundation for future pain therapy informed by an appreciation of each person’s unique genome. In essence, applied pharmacogenetics – the intersection of pharmaceuticals and genetics – heralds personalized medicine. However, pain and opioid responses are polygenic and complex. Research indicates many gene-gene and gene x environment interactions with influence on pain and analgesia response (Mogil et al., Nat Neurosci 14(12):1569–1573, 2011; Khalil et al., Biol Res Nurs 19(2):170–179, 2017). Variability in therapeutic responses might result from the interaction of multiple genes from different biologic pathways (Miller et al., Curr Allergy Asthma Rep 13(5):443–452, 2013). The genome determines a person’s potential response to a pain stimulus or analgesic; however, it is social and environmental experiences that will influence the final expression (Buskila and Sarzi-Puttini, Arthritis Res Ther 8(5):218, 2006). Environmental factors contribute to pain because pain is a multifactorial experience, largely influenced by affective input from anticipatory and emotional areas of the brain. The precise size of the contribution of genetics and environment to pain sensitivity is uncertain and is influenced by the type of pain stimulus (Nielsen et al., Pain 136(1–2):21–29, 2008). The field of pharmacogenetics is constantly evolving. The process of isolating candidate genes that contribute to such specific responses as pain sensitivity and speed of drug metabolism is painstaking. Studies also suggest that gender and ethnic differences in pain sensitivity have a genetic contribution, expressed through genetic determinations of cognitive, limbic, and affective neural networks (Kim et al., Pain 109(3):488–496, 2004). However, additional studies found ethnic variations in pain response to be insignificant when controlling for potentially confounding variables, including pain-coping mechanisms (Edwards et al., Pain Med 6(1):88–98, 2005). Failure to replicate some findings underlines the difficulty of determining which genetic markers promise clinical utility. Even well-supported innovations and insights from the research laboratory do not yet translate to clinical practice in most instances. Patients who suffer from intractable pain and the physicians who treat them are still locked in a clinical environment where conventional treatments for chronic pain tend to work only for some patients and then sporadically and imperfectly. As advances in research continue and the cost of genome sequencing drops, the association between genetic profiles and pain profiles should grow clearer. The aim of this chapter is to provide the reader with an overview of the potential clinical implications of understanding the unique genetic pain processing of the individual and how pharmacogenetic therapy might inform personalized medical care.



Dr. Webster acknowledges the contribution of medical writer Beth Dove of Dove Medical Communications, LLC, Salt Lake City, Utah, in the preparation of this manuscript.


  1. Akkuş, S., Delibaş, N., & Tamer, M. N. (2000). Do sex hormones play a role in fibromyalgia? Rheumatology (Oxford, England), 39(10), 1161–1163.CrossRefGoogle Scholar
  2. Aklillu, E., Persson, I., Bertilsson, L., et al. (1996). Frequent distribution of ultrarapid metabolizers of debrisoquine in an Ethiopian population carrying duplicated and multiduplicated functional CYP2D6 alleles. The Journal of Pharmacology and Experimental Therapeutics, 278, 441–446.PubMedGoogle Scholar
  3. Argoff, C. E. (2010). Clinical implications of opioid pharmacogenetics. The Clinical Journal of Pain, 26(Suppl 10), S16–S20.CrossRefGoogle Scholar
  4. Belfer, I., Wu, T., Kingman, A., et al. (2004). Candidate gene studies of human pain mechanisms: Methods for optimizing choice of polymorphisms and sample size. Anesthesiology, 100(6), 1562–1572.CrossRefGoogle Scholar
  5. Buskila, D., & Sarzi-Puttini, P. (2006). Biology and therapy of fibromyalgia. Genetic aspects of fibromyalgia syndrome. Arthritis Research & Therapy, 8(5), 218.CrossRefGoogle Scholar
  6. Campbell, C. M., France, C. R., Robinson, M. E., Logan, H. L., Geffken, G. R., & Fillingim, R. B. (2008). Ethnic differences in diffuse noxious inhibitory controls. The Journal of Pain, 9(8), 759–766.CrossRefGoogle Scholar
  7. Cepeda, M. S., & Carr, D. B. (2003). Women experience more pain and require more morphine than men to achieve a similar degree of analgesia. Anesthesia and Analgesia, 97(5), 1464–1468.CrossRefGoogle Scholar
  8. Chou, R., Fanciullo, G. J., Fine, P. G., American Pain Society-American Academy of Pain Medicine Opioids Guidelines Panel, et al. (2009). Clinical guidelines for the use of chronic opioid therapy in chronic noncancer pain. The Journal of Pain, 10(2), 113–130.CrossRefGoogle Scholar
  9. Chou, W. Y., Wang, C. H., Liu, P. H., et al. (2006a). Human opioid receptor A118G polymorphism affects intravenous patient-controlled analgesia morphine consumption after total abdominal hysterectomy. Anesthesiology, 105(2), 334–337.CrossRefGoogle Scholar
  10. Chou, W. Y., Yang, L. C., Lu, H. F., et al. (2006b). Association of mu-opioid receptor gene polymorphism (A118G) with variations in morphine consumption for analgesia after total knee arthroplasty. Acta Anaesthesiologica Scandinavica, 50(7), 787–792.CrossRefGoogle Scholar
  11. Diatchenko, L., Slade, G. D., & Nackley, A. G. (2005). Genetic basis for individual variations in pain perception and the development of a chronic pain condition. Human Molecular Genetics, 14(1), 135–143.CrossRefGoogle Scholar
  12. Diatchenko, L. R. (2016, March 3). Experimental therapeutics and metabolism program seminar series. Invited presentation: Translational studies in the genomic era: Expansion of mu-opioid receptor gene locus. Research Institute of the McGill University Health Centre.Google Scholar
  13. Edwards, R. R., Moric, M., Husfeldt, B., Buvanendran, A., & Ivankovich, O. (2005). Ethnic similarities and differences in the chronic pain experience: A comparison of African American, Hispanic, and white patients. Pain Medicine, 6(1), 88–98.CrossRefGoogle Scholar
  14. EGAPP Working Group Recommendations. CDC’s Office of Public Health Genomics, Evaluation of Genomic Applications in Practice and Prevention (EGAPP). Available at: Accessed October 6, 2010.
  15. Evans, W. E., Relling, M. V., Rahman, A., McLeod, H. L., Scott, E. P., & Lin, J. S. (1993). Genetic basis for a lower prevalence of deficient CYP2D6 oxidative drug metabolism phenotypes in black Americans. The Journal of Clinical Investigation, 91(5), 2150–2154.CrossRefGoogle Scholar
  16. Fillingim, R. B., King, C. D., Ribeiro-Dasilva, M. C., Rahim-Williams, B., & Riley, J. L., III. (2009). Sex, gender, and pain: A review of recent clinical and experimental findings. The Journal of Pain, 10(5), 447–485 Review.CrossRefGoogle Scholar
  17. Fishbain, D. A., Fishbain, D., Lewis, J., et al. (2004). Genetic testing for enzymes of drug metabolism: Does it have clinical utility for pain medicine at the present time? A structured review. Pain Medicine, 5, 81–93.CrossRefGoogle Scholar
  18. Gear, R. W., Miaskowski, C., Gordon, N. C., et al. (1996). Kappa-opioids produce significantly greater analgesia in women than in men. Nature Medicine, 2(11), 1248–1250.CrossRefGoogle Scholar
  19. GeneReviews. (2010). Bethesda, MD: National Center for Biotechnology Information, National Library of Medicine. Available at: Accessed October 6, 2010.
  20. Genetic Testing Registry. (2010). Bethesda, MD: Office of Science Policy, National Library of Medicine. Available at: Accessed October 5, 2010.
  21. Hamburg, M. A., & Collins, F. S. (2010). The path to personalized medicine. The New England Journal of Medicine, 363(4), 301–304.CrossRefGoogle Scholar
  22. Holliday, K. L., Nicholl, B. I., Macfarlane, G. J., Thomson, W., Davies, K. A., & McBeth, J. (2009). Do genetic predictors of pain sensitivity associate with persistent widespread pain? Molecular Pain, 5, 56.CrossRefGoogle Scholar
  23. Hwang, I. C., Park, J. Y., Myung, S. K., Ahn, H. Y., Fukuda, K., & Liao, Q. (2014). OPRM1 A118G gene variant and postoperative opioid requirement: A systematic review and meta-analysis. Anesthesiology, 121(4), 825–834.CrossRefGoogle Scholar
  24. Ingelman-Sundberg, M. (2005). Genetic polymorphisms of cytochrome P450 2D6 (CYP2D6): Clinical consequences, evolutionary aspects and functional diversity. The Pharmacogenomics Journal, 5(1), 6–13.CrossRefGoogle Scholar
  25. Khalil, H., Sereika, S. M., Dai, F., et al. (2017). OPRM1 and COMT gene-gene interaction is associated with postoperative pain and opioid consumption after orthopedic trauma. Biological Research for Nursing, 19(2), 170–179.CrossRefGoogle Scholar
  26. Kim, H., Neubert, J. K., San Miguel, A., et al. (2004). Genetic influence on variability in human acute experimental pain sensitivity associated with gender, ethnicity and psychological temperament. Pain, 109(3), 488–496.CrossRefGoogle Scholar
  27. Klepstad, P., Fladvad, T., Skorpen, F., On behalf of the European Palliative Care Research Collaborative (EPCRC) and the European Association for Palliative Care Research Network, et al. (2011). Influence from genetic variability on opioid use for cancer pain: A European genetic association study of 2294 cancer pain patients. Pain, 152(5), 1139–1145.CrossRefGoogle Scholar
  28. Lacroix-Fralish, M. L., Ledoux, J. B., & Mogil, J. S. (2007). The pain genes database: An interactive web browser of pain-related transgenic knockout studies. Pain, 1–2, 3.e1–3.e4.CrossRefGoogle Scholar
  29. Le Maitre, C. L., Freemont, A. J., & Hoyland, J. A. (2005). The role of interleukin-1 in the pathogenesis of human intervertebral disc degeneration. Arthritis Research & Therapy, 7(4), R732–R745.CrossRefGoogle Scholar
  30. Le Maitre, C. L., Hoyland, J. A., & Freemont, A. J. (2007). Interleukin-1 receptor antagonist delivered directly and by gene therapy inhibits matrix degradation in the intact degenerate human intervertebral disc: An in situ zymographic and gene therapy study. Arthritis Research & Therapy, 9(4), R83.CrossRefGoogle Scholar
  31. Martin, V. T. (2009). Ovarian hormones and pain response: A review of clinical and basic science studies. Gender Medicine, 6(Suppl 2), 168–192.CrossRefGoogle Scholar
  32. Mercadante, S., & Bruera, E. (2006). Opioid switching: A systematic and critical review. Cancer Treatment Reviews, 32, 304–315.CrossRefGoogle Scholar
  33. Miller, G. (2010). Genetics of opioid prescribing: Many questions, few answers. Pain Medicine News, 8(2). Available at: article_id=14613. Accessed September 29, 2010.
  34. Miller, S. M., & Ortega, V. E. (2013). Pharmacogenetics and the development of personalized approaches for combination therapy in asthma. Current Allergy and Asthma Reports, 13(5), 443–452.CrossRefGoogle Scholar
  35. Mobascher, A., Brinkmeyer, J., Thiele, H., et al. (2010). The val158met polymorphism of human catechol-O-methyltransferase (COMT) affects anterior cingulate cortex activation in response to painful laser stimulation. Molecular Pain, 6, 32.CrossRefGoogle Scholar
  36. Mogil, J. S., Wilson, S. G., Chesler, E. J., et al. (2003). The melanocortin-1 receptor gene mediates female-specific mechanisms of analgesia in mice and humans. Proceedings of the National Academy of Sciences of the United States of America, 100(8), 4867–4872.CrossRefGoogle Scholar
  37. Mogil, J. S., Sorge, R. E., LaCroix-Fralish, M. L., et al. (2011). Pain sensitivity and vasopressin analgesia are mediated by a gene-sex-environment interaction. Nature Neuroscience, 14(12), 1569–1573.CrossRefGoogle Scholar
  38. Nackley, A. G., Tan, K. S., Fecho, K., Flood, P., Diatchenko, L., & Maixner, W. (2007). Catechol-O-methyltransferase inhibition increases pain sensitivity through activation of both beta2- and beta3-adrenergic receptors. Pain, 128(3), 199–208.CrossRefGoogle Scholar
  39. Nicholl, B. I., Holliday, K. L., Macfarlane, G. J., European Male Ageing Study Group, et al. (2010). No evidence for a role of the catechol-O-methyltransferase pain sensitivity haplotypes in chronic widespread pain. Annals of the Rheumatic Diseases, 69(11), 2009–2012.CrossRefGoogle Scholar
  40. Nielsen, C. S., Stubhaug, A., Price, D. D., Vassend, O., Czajkowski, N., & Harris, J. R. (2008). Individual differences in pain sensitivity: Genetic and environmental contributions. Pain, 136(1–2), 21–29.CrossRefGoogle Scholar
  41. Olsen, M. B., Jacobsen, L. M., Schistad, E. I., et al. (2012). Pain intensity the first year after lumbar disc herniation is associated with the A118G polymorphism in the opioid receptor mu 1 gene: Evidence of a sex and genotype interaction. The Journal of Neuroscience, 32(29), 9831.CrossRefGoogle Scholar
  42. Online Mendelian Inheritance in Man (OMIM). (2010). Bethesda, MD: National Center for Biotechnology Information, National Library of Medicine. Available at: Accessed October 6, 2010.
  43. Pasternak, G. W. (2001). Incomplete cross tolerance and multiple mu opioid peptide receptors. Trends in Pharmacological Sciences, 22(2), 67–70 Review.CrossRefGoogle Scholar
  44. Phillips, K. A., Veenstra, D. L., Oren, E., et al. (2001). Potential role of pharmacogenomics in reducing adverse drug reactions: A systematic review. JAMA, 286(18), 2270–2279.CrossRefGoogle Scholar
  45. Reimann, F., Cox, J. J., Belfer, I., et al. (2010). Pain perception is altered by a nucleotide polymorphism in SCN9A. Proceedings of the National Academy of Sciences of the United States of America, 107(11), 5148–5153.CrossRefGoogle Scholar
  46. Ribeiro-Dasilva, M. C., Peres Line, S. R., Santos, M. C., dos, L. G., Arthuri, M. T., Hou, W., Fillingim, R. B., et al. (2009). Estrogen receptor-alpha polymorphisms and predisposition to TMJ disorder. The Journal of Pain, 10(5), 527–533.CrossRefGoogle Scholar
  47. Roizenblatt, M., Rosa Neto, N. S., Tufik, S., & Roizenblatt, S. (2012). Pain-related diseases and sleep disorders. Brazilian Journal of Medical and Biological Research, 45(9), 792–798.CrossRefGoogle Scholar
  48. Ronald, G., Lafrenière, M. Z., Cader, J.-F. P., et al. (2010). A dominant-negative mutation in the TRESK potassium channel is linked to familial migraine with aura. Nature Medicine, 16, 1157–1160.CrossRefGoogle Scholar
  49. Seltzer, Z., & Diehl, S. R. (2017). Genetic biomarkers of orofacial pain disorders. In J.-P. Goulet & A. M. Velly (Eds.), Orofacial pain biomarkers (pp. 107–118). Berlin, Heidelberg: Springer Berlin Heidelberg. Scholar
  50. Solovieva, S., Leino-Arjas, P., Saarela, J., Luoma, K., Raininko, R., & Riihimäki, H. (2004). Possible association of interleukin 1 gene locus polymorphisms with low back pain. Pain, 109(1–2), 8–19.CrossRefGoogle Scholar
  51. Stamer, U. M., & Stüber, F. (2007a). Genetic factors in pain and its treatment. Current Opinion in Anaesthesiology, 20(5), 478–484.CrossRefGoogle Scholar
  52. Stamer, U. M., & Stüber, F. (2007b). The pharmacogenetics of analgesia. Expert Opinion on Pharmacotherapy, 8(14), 2235–2245.CrossRefGoogle Scholar
  53. Takahashi, P. Y., Ryu, E., Pathak, J., et al. (2017). Increased risk of hospitalization for ultrarapid metabolizers of cytochrome P450 2D6. Pharmacogenomics and Personalized Medicine, 10, 39–47.CrossRefGoogle Scholar
  54. Webster, L. R., & Belfer, I. (2016). Pharmacogenetics and personalized medicine in pain management. Clinics in Laboratory Medicine, 36(3), 493–506.CrossRefGoogle Scholar
  55. Young, E. E., Lariviere, W. R., & Belfer, I. (2012). Genetic basis of pain variability: Recent advances. Journal of Medical Genetics, 49(1), 1–9.CrossRefGoogle Scholar
  56. Zhang, W., Chang, Y. Z., Kan, Q. C., et al. (2010). Association of human micro-opioid receptor gene polymorphism A118G with fentanyl analgesia consumption in Chinese gynaecological patients. Anaesthesia, 65(2), 130–135.CrossRefGoogle Scholar
  57. Zhou, S. F. (2009). Polymorphism of human cytochrome P450 2D6 and its clinical significance: Part I. Clinical Pharmacokinectics, 48(11), 689–723.CrossRefGoogle Scholar
  58. Zorina-Lichtenwalter, K., Meloto, C. B., Khoury, S., & Diatchenko, L. (2016). Genetic predictors of human chronic pain conditions. Neuroscience, 338, 36–62.CrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Lynn R. Webster
    • 1
  1. 1.PRA Health SciencesSalt Lake CityUSA

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