Pharmacogenetics of Pain Maree T Smith, Centre for Integrated Preclinical Drug Development, University of Queensland, Brisbane, Queensland, Australia Arjun Muralidharan, Centre for Integrated Preclinical Drug Development, University of Queensland, Brisbane, Queensland, Australia Marked interindividual variability in pain severity ratings and the analgesic dosing requirements of patients with apparently similar pain states is underpinned by genetic and environmental factors, and their interactions. Over the past decade, rodent heritability studies, familial aggregation and twin studies in humans have provided insight into the genetic factors contributing to inter- individual variability in pain sensitivity. Concurrently, a large number of genetic association studies using the candidate gene paradigm have investigated the impact of single nucleotide polymorphisms in numerous genes encoding receptors, ion channels, enzymes and trans- porters, on pain sensitivity. Despite initial promise, most genetic association studies have either failed to replicate or have been only partially replicated by independent investigators; the underlying issues are addressed herein. Apart from deficiencies in study design and execution and inappropriate choice of statistical methods, subtle between-study differences in interacting environmental factors that affect pain phenotypes (epigenetics), are a likely explanation. Introduction According to the International Association for the Study of Pain, pain is ‘an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage’ (http:// www.iasp-pain.org). Acute pain following a surgical pro- cedure or due to traumatic injury has a protective role by producing guarding behaviour that promotes healing and gives a survival advantage. By contrast, chronic pain conditions such as fibromyalgia and many types of per- ipheral neuropathic pain are characterised by on-going pain either in the absence of apparent injury or long after an injury has healed. Such persistent pain states are regarded as maladaptive and ‘disease’ entities in their own right. See also: Pain and Analgesia The considerable interindividual variability in pain severity ratings self-reported by patients with apparently similar pain states is well known to clinicians (Young et al., 2012; Vuilleumier et al., 2012) as it manifests in marked interpatient variability in analgesic dosing regimens needed to produce satisfactory analgesia with tolerable side-effects. Significant interindividual variability in self- reported pain severity ratings is not confined to patients with clinical pain as this is mirrored in healthy human subjects exposed to standardised acute noxious nociceptive stimuli in a laboratory setting. Interestingly, healthy indi- viduals who reported high pain severity scores also exhib- ited more robust nociceptive stimulus-evoked cortical activation when assessed using functional magnetic reso- nance imaging, and vice versa (Ploner et al., 2010; Bro- dersen et al., 2012). Factors contributing to interindividual variability in self-reported pain severity ratings include the motivational-emotional response to nociceptive stimuli, as well as environmental and genetic factors and their inter- play (epigenetics) (Bain and Shaw, 2012; Doehring et al., 2013; Figure 1; Seo et al., 2013). Genetic factors may affect the regulation of neurotransmitters, receptors, enzymes and ion channels in nociceptive signalling pathways as well as those that underpin analgesic drug pharmacodynamics (Svetlik et al., 2013). Environmental factors include patient age, sex, disease comorbidities including hepatic and renal function, concurrent medications, as well as lifestyle vari- ables such as alcohol consumption and smoking (Smith and Muralidharan, 2010). In the following sections, research in rodents and humans aimed at identifying genetic factors potentially contributing to interpatient variability in pain severity ratings is reviewed. Pain Genetics: Insights from Mice Seminal work in the late 1990s using quantitative sensory trait analysis in 11 different mouse strains across 12 testing modalities demonstrated that there were pronounced between-strain differences in the levels of nociception/ hypersensitivity behaviours evoked by application of standardised acute noxious thermal, mechanical and che- mical stimuli and that these pain-related traits were Advanced article Article Contents . Introduction . Pain Genetics: Insights from Mice . Heritability Studies in Humans . Conclusion Online posting date: 9 th December 2013 eLS subject area: Genetics & Disease How to cite: Smith, Maree T; and Muralidharan, Arjun (December 2013) Pharmacogenetics of Pain. In: eLS. John Wiley & Sons, Ltd: Chichester. DOI: 10.1002/9780470015902.a0025152 eLS & 2013, John Wiley & Sons, Ltd. www.els.net 1