Pharmacogenetics of Pain

Abstract

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 interindividual 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 transporters, 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.

Key Concepts:

  • Pain severity ratings and analgesic dosing requirements differ considerably between individuals with apparently similar pain states.

  • Factors contributing to interindividual variability in human pain sensitivity include genetic factors, environmental factors and their interaction.

  • More than 350 candidate pain genes have been identified as potentially contributing to heritable differences in pain sensitivity.

  • The findings of genetic association studies using a candidate gene approach have failed to replicate or have been only partially replicated by independent investigators.

  • Future research aimed at elucidating genetic influences on pain phenotypes and analgesic responsiveness need to utilise strategies other than the candidate gene approach.

Keywords: pain; analgesia; genetics; single nucleotide polymorphism (SNP); genetic association studies

Figure 1.

Schematic diagram illustrating the considerable interindividual variability in pain sensitivity ratings is underpinned by genetic and environmental factors, as well as their interactions. Adapted with permission from Muralidharan and Smith . © Springer.

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Further Reading

Altman RB , Flockhart D and Goldstein DB (2012) Principles of Pharmacogenetics and Pharmacogenomics. New York: Cambridge University press.

Hirschhorn JN , Lohmueller K , Byrne E and Hirschhorn K (2002) A comprehensive review of genetic association studies. Genetics in Medicine 4(2): 45–61.

Lötsch J (2011) Genetic variability of pain perception and treatment – Clinical pharmacological implications. European Journal of Clinical Pharmacology 67(6): 541–551.

Lötsch J (2012) Pharmacogenetics of pain medication. In: Maitland‐Van Der Zee A‐H and Daly AK (eds) Pharmacogenetics and Individualized Therapy. Hoboken: John Wiley & Sons, Inc.

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Smith, Maree T, and Muralidharan, Arjun(Dec 2013) Pharmacogenetics of Pain. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0025152]