Pharmacogenetics of Pain: The Future of Personalized Medicine

Abstract

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.