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The molecular epidemiology of pain: a new discipline for drug discovery

Nature Reviews Drug Discovery volume 7, pages 647–658 (2008)Cite this article

Abstract

Recent candidate gene studies have identified and replicated the first associations between several common polymorphisms and pain severity in humans. Moreover, human studies in twins suggest high heritability for responses to experimental pain stimuli. Human genome-wide association studies of pain phenotypes might identify novel analgesic targets, help to prioritize research among current targets, and increase the likelihood of success for analgesic candidates emerging from animal studies. However, clinical research in pain has largely focused on small neurophysiology-based studies, so expansion of epidemiological understanding will be essential to the success of genetic or proteomic dissection of complex pain disorders. This Perspective outlines how methods of molecular epidemiology, proved effective in the study of other diseases, can enhance the returns from human genomic studies and expedite the development of new drugs to prevent or treat pain.

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Figure 1: Association of COMT haplotypes with experimental pain sensitivity and with rate of metabolism of catecholamines.
Figure 2: Association of GCH1 haplotypes with human chronic spinal nerve root pain, experimental pain and synthesis of biopterin.
Figure 3: Required number of cases and controls for whole-genome association study.
Figure 4: Models of back pain and headache pain progression.
Figure 5: Neural pathways of pain.

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Acknowledgements

We thank D. Goldman and his colleagues in the Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism (NIAAA), for generous mentorship, training and collaboration. A. Kingman, S. Diehl, M. Devor, J. Mogil, W. Lariviere and Z. Seltzer for advice and encouragement. Also, I. Belfer, T. Wu, S. Atlas, C. Woolf, M. Costigan, W. Maixner, L. Diatchenko, R. Fillingim and the many other collaborators in the studies described above. M.B.M.'s contribution to the scientific reports cited in this work was funded by a National Institute of Dental of Craniofacial Research intramural grant ZO1 DE00366, NIAAA Intramural Grant Z01 AA000301, and the Comprehensive Neuroscience Program Grant USUHS G192BR-C4.

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  1. Departments of Anesthesiology and Medicine, Mitchell B. Max is at the Center for Pain Research, University of Pittsburgh, A-1305 Scaife Hall, 3550 Terrace St, Pittsburgh, Pennsylvania 15261, USA.,

    Mitchell B. Max

  2. Walter F. Stewart is at the Center for Health Research, Geisinger Health System, 100 N Academy Ave, Danville, Pennsylvania 17822, USA.,

    Walter F. Stewart

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Correspondence to Mitchell B. Max.

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M.B.M. is co-inventor on a patent for the use of KCNS1 and GCH1 genotypes as a diagnostic test, which has been licensed by Solace Pharmaceuticals. The genes and company are mentioned in the article. No income is received or projected in the near or medium future.

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A historical explanation for the relative neglect of pain epidemiology, genetics and visceral pain (PDF 120 kb)

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Max, M., Stewart, W. The molecular epidemiology of pain: a new discipline for drug discovery. Nat Rev Drug Discov 7, 647–658 (2008). https://doi.org/10.1038/nrd2595

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