Psychophysiological responses to pain identify reproducible human clusters

Adam D. Farmer*, Steven J. Coen, Michiko Kano, Peter A. Paine, Mustafa Shwahdi, Jafar Jafari, Jessin Kishor, Sian F. Worthen, Holly E. Rossiter, Veena Kumari, Steven C.R. Williams, Michael Brammer, Vincent P. Giampietro, Joanne Droney, Julia Riley, Paul L. Furlong, Charles H. Knowles, Stafford L. Lightman, Qasim Aziz

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


Pain is a ubiquitous yet highly variable experience. The psychophysiological and genetic factors responsible for this variability remain unresolved. We hypothesised the existence of distinct human pain clusters (PCs) composed of distinct psychophysiological and genetic profiles coupled with differences in the perception and the brain processing of pain. We studied 120 healthy subjects in whom the baseline personality and anxiety traits and the serotonin transporter-linked polymorphic region (5-HTTLPR) genotype were measured. Real-time autonomic nervous system parameters and serum cortisol were measured at baseline and after standardised visceral and somatic pain stimuli. Brain processing reactions to visceral pain were studied in 29 subjects using functional magnetic resonance imaging (fMRI). The reproducibility of the psychophysiological responses to pain was assessed at 1 year. In group analysis, visceral and somatic pain caused an expected increase in sympathetic and cortisol responses and activated the pain matrix according to fMRI studies. However, using cluster analysis, we found 2 reproducible PCs: at baseline, PC1 had higher neuroticism/anxiety scores (P ≤ 0.01); greater sympathetic tone (P < 0.05); and higher cortisol levels (P ≤ 0.001). During pain, less stimulus was tolerated (P ≤ 0.01), and there was an increase in parasympathetic tone (P ≤ 0.05). The 5-HTTLPR short allele was over-represented (P ≤ 0.005). PC2 had the converse profile at baseline and during pain. Brain activity differed (P ≤ 0.001); greater activity occurred in the left frontal cortex in PC1, whereas PC2 showed greater activity in the right medial/frontal cortex and right anterior insula. In health, 2 distinct reproducible PCs exist in humans. In the future, PC characterization may help to identify subjects at risk for developing chronic pain and may reduce variability in brain imaging studies. © 2013 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

Original languageEnglish
Pages (from-to)2266-2276
Number of pages11
Issue number11
Early online date25 May 2013
Publication statusPublished - Nov 2013

Bibliographical note

NOTICE: this is the author’s version of a work that was accepted for publication in Pain. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in Farmer, AD, Coen, SJ, Kano, M, Paine, PA, Shwahdi, M, Jafari, J, Kishor, J, Worthen, SF, Rossiter, HE, Kumari, V, Williams, SCR, Brammer, M, Giampietro, VP, Droney, J, Riley, J, Furlong, PL, Knowles, CH, Lightman, SL & Aziz, Q, 'Psychophysiological responses to pain identify reproducible human clusters' Pain. Vol. 154, No. 11 (2014) DOI 10.1016/j.pain.2013.05.016

Funding: Medical Research Council [MGAB1A1R]


  • autonomic nervous system
  • hypothalamic-pituitary- adrenal axis
  • personality traits
  • serotonin transporter genotype
  • somatic pain
  • visceral pain


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