A clinical genetic method to identify mechanisms by which pain causes depression and anxiety

Mitchell B. Max, Tianxia Wu, Steven J. Atlas, Robert R. Edwards, Jennifer Haythornthwaite, Antonella F. Bollettino, Heather S. Hipp, Colin D. McKnight, Inge A. Osman, Erin N. Crawford, Maryland Pao, Jemiel Nejim, Albert Kingman, Daniel C. Aisen, Michele A. Scully, Robert B. Keller, David Goldman, Inna Belfer

Research output: Contribution to journalArticle

Abstract

Background: Pain patients are often depressed and anxious, and benefit less from psychotropic drugs than pain-free patients. We hypothesize that this partial resistance is due to the unique neurochemical contribution to mood by afferent pain projections through the spino-parabrachial-hypothalamic-amygdalar systems and their projections to other mood-mediating systems. New psychotropic drugs for pain patients might target molecules in such brain systems. We propose a method to prioritize molecular targets by studying polymorphic genes in cohorts of patients undergoing surgical procedures associated with a variable pain relief response. We seek molecules that show a significant statistical interaction between (1) the amount of surgical pain relief, and (2) the alleles of the gene, on depression and anxiety during the first postoperative year. Results: We collected DNA from 280 patients with sciatica due to a lumbar disc herniation, 162 treated surgically and 118 non-surgically, who had been followed for 10 years in the Maine Lumbar Spine Study, a large, prospective, observational study. In patients whose pain was reduced >25% by surgery, symptoms of depression and anxiety, assessed with the SF-36 Mental Health Scale, improved briskly at the first postoperative measurement. In patients with little or no surgical pain reduction, mood scores stayed about the same on average. There was large inter-individual variability at each level of residual pain. Polymorphisms in three pre-specified pain-mood candidate genes, catechol-O-methyl transferase (COMT), serotonin transporter, and brain-derived neurotrophic factor (BDNF) were not associated with late postoperative mood or with a pain-gene interaction on mood. Although the sample size did not provide enough power to persuasively search through a larger number of genes, an exploratory survey of 25 other genes provides illustrations of pain-gene interactions on postoperative mood - the mu opioid receptor for short-term effects of acute sciatica on mood, and the galanin-2 receptor for effects of unrelieved post-discectomy pain on mood one year after surgery. Conclusion: Genomic analysis of longitudinal studies of pain, depression, and anxiety in patients undergoing pain-relieving surgery may help to identify molecules through which pain alters mood. Detection of alleles with modest-sized effects will require larger cohorts.

Original languageEnglish (US)
Article number14
JournalMolecular Pain
Volume2
DOIs
StatePublished - Apr 19 2006

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Anxiety
Depression
Pain
Genes
Sciatica
Psychotropic Drugs
Receptor, Galanin, Type 2
Alleles
Guaiacol
Diskectomy
Serotonin Plasma Membrane Transport Proteins
mu Opioid Receptor
Brain-Derived Neurotrophic Factor
Transferases
Sample Size
Observational Studies
Longitudinal Studies
Mental Health
Spine
Prospective Studies

ASJC Scopus subject areas

  • Anesthesiology and Pain Medicine
  • Molecular Medicine
  • Cellular and Molecular Neuroscience

Cite this

A clinical genetic method to identify mechanisms by which pain causes depression and anxiety. / Max, Mitchell B.; Wu, Tianxia; Atlas, Steven J.; Edwards, Robert R.; Haythornthwaite, Jennifer; Bollettino, Antonella F.; Hipp, Heather S.; McKnight, Colin D.; Osman, Inge A.; Crawford, Erin N.; Pao, Maryland; Nejim, Jemiel; Kingman, Albert; Aisen, Daniel C.; Scully, Michele A.; Keller, Robert B.; Goldman, David; Belfer, Inna.

In: Molecular Pain, Vol. 2, 14, 19.04.2006.

Research output: Contribution to journalArticle

Max, MB, Wu, T, Atlas, SJ, Edwards, RR, Haythornthwaite, J, Bollettino, AF, Hipp, HS, McKnight, CD, Osman, IA, Crawford, EN, Pao, M, Nejim, J, Kingman, A, Aisen, DC, Scully, MA, Keller, RB, Goldman, D & Belfer, I 2006, 'A clinical genetic method to identify mechanisms by which pain causes depression and anxiety', Molecular Pain, vol. 2, 14. https://doi.org/10.1186/1744-8069-2-14
Max, Mitchell B. ; Wu, Tianxia ; Atlas, Steven J. ; Edwards, Robert R. ; Haythornthwaite, Jennifer ; Bollettino, Antonella F. ; Hipp, Heather S. ; McKnight, Colin D. ; Osman, Inge A. ; Crawford, Erin N. ; Pao, Maryland ; Nejim, Jemiel ; Kingman, Albert ; Aisen, Daniel C. ; Scully, Michele A. ; Keller, Robert B. ; Goldman, David ; Belfer, Inna. / A clinical genetic method to identify mechanisms by which pain causes depression and anxiety. In: Molecular Pain. 2006 ; Vol. 2.
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AU - Max, Mitchell B.

AU - Wu, Tianxia

AU - Atlas, Steven J.

AU - Edwards, Robert R.

AU - Haythornthwaite, Jennifer

AU - Bollettino, Antonella F.

AU - Hipp, Heather S.

AU - McKnight, Colin D.

AU - Osman, Inge A.

AU - Crawford, Erin N.

AU - Pao, Maryland

AU - Nejim, Jemiel

AU - Kingman, Albert

AU - Aisen, Daniel C.

AU - Scully, Michele A.

AU - Keller, Robert B.

AU - Goldman, David

AU - Belfer, Inna

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N2 - Background: Pain patients are often depressed and anxious, and benefit less from psychotropic drugs than pain-free patients. We hypothesize that this partial resistance is due to the unique neurochemical contribution to mood by afferent pain projections through the spino-parabrachial-hypothalamic-amygdalar systems and their projections to other mood-mediating systems. New psychotropic drugs for pain patients might target molecules in such brain systems. We propose a method to prioritize molecular targets by studying polymorphic genes in cohorts of patients undergoing surgical procedures associated with a variable pain relief response. We seek molecules that show a significant statistical interaction between (1) the amount of surgical pain relief, and (2) the alleles of the gene, on depression and anxiety during the first postoperative year. Results: We collected DNA from 280 patients with sciatica due to a lumbar disc herniation, 162 treated surgically and 118 non-surgically, who had been followed for 10 years in the Maine Lumbar Spine Study, a large, prospective, observational study. In patients whose pain was reduced >25% by surgery, symptoms of depression and anxiety, assessed with the SF-36 Mental Health Scale, improved briskly at the first postoperative measurement. In patients with little or no surgical pain reduction, mood scores stayed about the same on average. There was large inter-individual variability at each level of residual pain. Polymorphisms in three pre-specified pain-mood candidate genes, catechol-O-methyl transferase (COMT), serotonin transporter, and brain-derived neurotrophic factor (BDNF) were not associated with late postoperative mood or with a pain-gene interaction on mood. Although the sample size did not provide enough power to persuasively search through a larger number of genes, an exploratory survey of 25 other genes provides illustrations of pain-gene interactions on postoperative mood - the mu opioid receptor for short-term effects of acute sciatica on mood, and the galanin-2 receptor for effects of unrelieved post-discectomy pain on mood one year after surgery. Conclusion: Genomic analysis of longitudinal studies of pain, depression, and anxiety in patients undergoing pain-relieving surgery may help to identify molecules through which pain alters mood. Detection of alleles with modest-sized effects will require larger cohorts.

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