Highlights
- •Systematic literature review revealed genetic associations with chronic post-surgical pain (CPSP) for variants of 26 genes involved in different nociceptive pathways
- •6 variants of 5 genes (COMT, OPRM1, GCH1, KCNS1, TNFA) were included in a meta-analysis
- •At rs734784 (A>G) of KCNS1, presence of G allele was found to marginally increase risk of CPSP
- •Meta-analysis limitations included study heterogeneity in surgical populations, methodology and outcomes
Abstract
Chronic postsurgical pain (CPSP) is a significant detriment to postsurgical recovery
and a risk factor for prolonged opioid use. Emerging evidence suggests the estimated
heritability for chronic pain is 45% and that genetic factors partially explain individual
susceptibility to CPSP. The aim of this study was to systematically review, assess
quality, and summarize the studies in humans that have investigated genetic factors
associated with CPSP. We also conducted a meta-analysis to derive a single effect
size for evaluable genetic associations with CPSP. Our comprehensive literature search
included review of 21 full-text articles evaluating variants of 69 genes for association
with CPSP. We found significant gene variant associations reported for variants/haplotypes
of 26 genes involved in neurotransmission, pain signaling, immune responses and neuroactive
ligand–receptor interaction, with CPSP. Six variants of 5 genes (COMT: rs4680 and rs6269, OPRM1: rs1799971, GCH1: rs3783641, KCNS1: rs734784 and TNFA: rs1800629), were evaluated by more than one study and were included in the meta-analysis.
At rs734784 (A>G) of KCNS1, presence of G allele marginally increased risk of CPSP (Additive genetic model;
Odds ratio: 1.511; 95% CI 1–2.284; P value: .050), while the other variants did not withstand meta-analyses criteria.
Our findings demonstrate the role of genetic factors with different functions in CPSP,
and also emphasize that single genetic factors have small effect sizes in explaining
complex conditions like CPSP. Heterogeneity in surgical cohorts, population structure,
and outcome definitions, as well as small number of available studies evaluating same
variants, limit the meta-analysis. There is a need for large-scale, homogenous, replication
studies to validate candidate genes, and understand the underlying biological networks
underpinning CPSP.
Perspective
Our systematic review comprehensively describes 21 studies evaluating genetic association
with CPSP, and limitations thereof. A meta-analysis of 6 variants (5 genes) found
marginally increased risk for CPSP associated with rs734784 A>G of the potassium voltage-gated
channel gene (KCNS1). Understanding genetic predisposition for CPSP will enable prediction and personalized
management.
Key words
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References
- Hypothesis-driven candidate gene association studies: Practical design and analytical considerations.Am J Epidemiol. 2009; 170: 986-993
- Candidate genes versus genome-wide associations: Which are better for detecting genetic susceptibility to infectious disease?.Proc Biol Sci. 2011; 278: 1183-1188
- Pain sensitivity and opioid analgesia: A pharmacogenomic twin study.Pain. 2012; 153: 1397-1409
- Association of functional variations in COMT and GCH1 genes with postherniotomy pain and related impairment.Pain. 2015; 156: 273-279
- Effect of the A118G polymorphism on binding affinity, potency and agonist-mediated endocytosis, desensitization, and resensitization of the human mu-opioid receptor.J Neurochem. 2004; 89: 553-560
- Opioid genetics: The key to personalized pain control?.Clin Genet. 2012; 82: 301-310
- Epigenetics and the transition from acute to chronic pain.Pain Med. 2012; 13: 1474-1490
- Catechol-o-methyltransferase polymorphisms predict opioid consumption in postoperative pain.Anesthesia and analgesia. 2014; 119: 1194-1200
- The transition of acute postoperative pain to chronic pain: An integrative overview of research on mechanisms.J Pain. 2017; 18 (359 e351-359 e338)
- Predicting the pain continuum after adolescent idiopathic scoliosis surgery: A prospective cohort study.Eur J Pain. 2017; 21: 1252-1265
- Association of OPRM1 A118G variant with risk of morphine-induced respiratory depression following spine fusion in adolescents.Pharmacogenomics J. 2015; 15: 255-262
- Enrichment of genomic pathways based on differential DNA methylation associated with chronic postsurgical pain and anxiety in children: A prospective, pilot study.J Pain. 2019; 20: 71-785
- DNA methylation at the mu-1 opioid receptor gene (OPRM1) promoter predicts preoperative, acute, and chronic postsurgical pain after spine fusion.Pharmgenomics Pers Med. 2017; 10: 157-168
- Genetics of chronic post-surgical pain: A crucial step toward personal pain medicine.Can J Anaesth. 2015; 62: 294-303
- Neuropathic pain: Mechanisms and their clinical implications.BMJ. 2014; 348: f7656
- Chronic postoperative pain: Recent findings in understanding and management.F1000Res. 2017; 6: 1054
- Multiple chronic pain states are associated with a common amino acid-changing allele in KCNS1.Brain. 2010; 133: 2519-2527
- OPRM1 receptor as new biomarker to help the prediction of post mastectomy pain and recurrence in breast cancer.Minerva Anestesiol. 2015; 81: 894-900
- Catechol-O-methyltransferase gene polymorphisms are associated with multiple pain-evoking stimuli.Pain. 2006; 125: 216-224
- Genetic basis for individual variations in pain perception and the development of a chronic pain condition.Hum Mol Genet. 2005; 14: 135-143
- The DQB1 *03:02 HLA haplotype is associated with increased risk of chronic pain after inguinal hernia surgery and lumbar disc herniation.Pain. 2013; 154: 427-433
- Temporomandibular joint pain: Relationship to internal derangement type, osteoarthrosis, and synovial fluid mediator level of tumor necrosis factor-alpha.Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2000; 90: 442-449
- euCPSP: European observational study on chronic post-surgical pain.Eur J Anaesthesiol. 2011; 28: 461-462
- Influence of TNF-alpha-308 G/A gene polymorphism on temporomandibular disorder.Am J Orthodon Dentofac Orthop. 2016; 149: 692-698
- The Economic Costs of Pain in the United States.National Academies Press (US), Washington D.C.2011
- Biopsychosocial influence on exercise-induced injury: Genetic and psychological combinations are predictive of shoulder pain phenotypes.J Pain. 2014; 15: 68-80
- Biopsychosocial influence on shoulder pain: Influence of genetic and psychological combinations on twelve-month postoperative pain and disability outcomes.Arthritis Care Res (Hoboken). 2016; 68: 1671-1680
- Brennan Persistent Postsurgical Pain: Pathogenic Mechanisms and Preventive Strategies.IASP Press, Washington D.C.2014
- Pain following the repair of an abdominal hernia.Surg Today. 2010; 40: 8-21
- Analgesic requirements after major abdominal surgery are associated with OPRM1 gene polymorphism genotype and haplotype.Pharmacogenomics. 2008; 9: 1605-1616
- Multivariate prognostic modeling of persistent pain following lumbar discectomy.Pain Phys. 2012; 15: 421-434
- Persistent pain after mastectomy with reconstruction.J Clin Anesth. 2011; 23: 482-488
- Heritability of chronic pain in 2195 extended families.Eur J Pain. 2012; 16: 1053-1063
- Genetic polymorphisms and their association with the prevalence and severity of chronic postsurgical pain: A systematic review.Br J Anaesth. 2016; 117: 708-719
- A common single nucleotide polymorphism A118G of the mu opioid receptor alters its N-glycosylation and protein stability.Biochem J. 2012; 441: 379-386
- STREGA: A 'How-To' guide for reporting genetic associations.Hum Genet. 2009; 125: 117-118
- Chronic pain and its impact on quality of life in adolescents and their families.J Pediatr Psychol. 2001; 26: 145-153
- OPRM1 A118G gene variant and postoperative opioid requirement: A systematic review and meta-analysis.Anesthesiology. 2014; 121: 825-834
- Assessment of cumulative evidence on genetic associations: Interim guidelines.Int J Epidemiol. 2008; 37: 120-132
- Chronic postsurgical pain: Is there a possible genetic link?.Br J Pain. 2017; 1: 11
- Genetic susceptibility to postherniotomy pain. The influence of polymorphisms in the Mu opioid receptor, TNF-alpha, GRIK3, GCH1, BDNF and CACNA2D2 genes.Scand J Pain. 2016; 12: 1-6
- Depression and functional disability in chronic pediatric pain.Clin J Pain. 2001; 17: 341-349
- One man's risk factor is another man's outcome: Difference in risk factor profiles for chronic postsurgical pain maintenance vs transition.Pain. 2012; 153: 505-506
- Transition from acute to chronic postsurgical pain: Risk factors and protective factors.Expert Rev Neurother. 2009; 9: 723-744
- OPRM1 and COMT gene-gene interaction is associated with postoperative pain and opioid consumption after orthopedic trauma.Biol Res Nurs. 2017; 19: 170-179
- Genetic contributions to clinical pain and analgesia: Avoiding pitfalls in genetic research.J Pain. 2009; 10: 663-693
- Genetic contributions to clinical pain and analgesia: Avoiding pitfalls in genetic research.J Pain. 2009; 10: 663-693
- Chronic pain after lower abdominal surgery: Do catechol-O-methyl transferase/opioid receptor mu-1 polymorphisms contribute?.Mol Pain. 2013; 9: 19
- Variations in potassium channel genes are associated with distinct trajectories of persistent breast pain after breast cancer surgery.Pain. 2015; 156: 371-380
- Association of serotonin-1A and -2A receptor promoter polymorphisms with depressive symptoms, functional recovery, and pain in patients 6 months after lumbar disc surgery.Pain. 2013; 154: 377-384
- The influence of genotype polymorphism on morphine analgesic effect for postoperative pain in children.Korean J Pain. 2016; 29: 34-39
- STrengthening the REporting of Genetic Association studies (STREGA) – an extension of the STROBE statement.Eur J Clin Invest. 2009; 39: 247-266
- Strengthening the reporting of genetic association studies (STREGA): An extension of the STROBE Statement.Hum Genet. 2009; 125: 131-151
- Up-regulation of cathepsin G in the development of chronic postsurgical pain: An experimental and clinical genetic study.Anesthesiology. 2015; 123: 838-850
- Chronic post-surgical pain: 10 years on.Br J Anaesth. 2008; 101: 77-86
- The genetic mediation of individual differences in sensitivity to pain and its inhibition.Proc Natl Acad Sci U S A. 1999; 96: 7744-7751
- Preferred reporting items for systematic reviews and meta-analyses: The PRISMA Statement.Open Med. 2009; 3: e123-e130
- Genetic and clinical factors associated with chronic postsurgical pain after hernia repair, hysterectomy, and thoracotomy: A two-year multicenter cohort study.Anesthesiology. 2015; 122: 1123-1141
- Genetic and clinical factors associated with chronic postsurgical pain after hernia repair, hysterectomy, and thoracotomy: A two-year multicenter cohort study.Anesthesiology. 2015; 122: 1123-1141
- Susceptibility to chronic pain following nerve injury is genetically affected by CACNG2.Genome Res. 2010; 20: 1180-1190
- Heritability of responses to painful stimuli in women: A classical twin study.Brain. 2007; 130: 3041-3049
- Genetic-epigenetic interaction modulates mu-opioid receptor regulation.Hum Mol Genet. 2012; 21: 4751-4760
- Economic and humanistic burden of post-trauma and post-surgical neuropathic pain among adults in the United States.J Pain Res. 2013; 6: 459-469
- Prevalence and predictors of chronic postsurgical pain in children: A systematic review and meta-analysis.J Pain. 2017; 18: 605-614
- Human Mu opioid receptor (OPRM1 A118G) polymorphism is associated with brain mu-opioid receptor binding potential in smokers.Proc Natl Acad Sci U S A. 2011; 108: 9268-9273
- Modification of delayed rectifier potassium currents by the Kv9.1 potassium channel subunit.Hear Res. 2000; 147: 21-30
- Influence of variation in the catechol-O-methyltransferase gene on the clinical outcome after lumbar spine surgery for one-level symptomatic disc disease: A report on 176 cases.Acta Neurochir (Wien). 2014; 156: 245-252
- Pharmacogenomics of opioids and perioperative pain management.Pharmacogenomics. 2012; 13: 1719-1740
- Genetics of pain perception, COMT and postoperative pain management in children.Pharmacogenomics. 2014; 15: 277-284
- Genetic and environmental determinants of postthoracotomy pain syndrome.Curr Opin Anaesthesiol. 2008; 21: 8-11
- The influence of ATP-binding cassette sub-family B member -1 (ABCB1) genetic polymorphisms on acute and chronic pain after intrathecal morphine for caesarean section: A prospective cohort study.Int J Obstet Anesth. 2010; 19: 254-260
- Assessing the quality of published genetic association studies in meta-analyses: The quality of genetic studies (Q-Genie) tool.BMC Genet. 2015; 16: 50
- Genetically determined P2X7 receptor pore formation regulates variability in chronic pain sensitivity.Nat Med. 2012; 18: 595-599
- Associations between cytokine gene variations and severe persistent breast pain in women following breast cancer surgery.J Pain. 2014; 15: 169-180
- Associations between genetic and epigenetic variations in cytokine genes and mild persistent breast pain in women following breast cancer surgery.Cytokine. 2017; 99: 203-213
- Big data: Astronomical or genomical?.PLoS Biol. 2015; 13e1002195
- A Language and Environment for Statistical Computing.R Foundation for Statistical Computing, Vienna, Austria2018
- Reduced hyperalgesia in homozygous carriers of a GTP cyclohydrolase 1 haplotype.Eur J Pain. 2008; 12: 1069-1077
- GTP cyclohydrolase and tetrahydrobiopterin regulate pain sensitivity and persistence.Nat Med. 2006; 12: 1269-1277
- Predictive factors of chronic post-surgical pain at 6 months following knee replacement: Influence of postoperative pain trajectory and genetics.Pain Phys. 2016; 19: E729-E741
- Sensory neuron downregulation of the Kv9.1 potassium channel subunit mediates neuropathic pain following nerve injury.J Neurosci. 2012; 32: 17502-17513
- Systematic reviews and meta-analyses.J Can Acad Child Adolesc Psychiatr. 2011; 20: 57-59
- Systematic review and meta-analysis of genetic risk factors for neuropathic pain.Pain. 2018; 159: 825-848
- Conducting meta-analyses in R with the metafor package.J Stat Softw. 2010; 36: 1-48
- The heterogeneity statistic I(2) can be biased in small meta-analyses.BMC Med Res Methodol. 2015; 15: 35
- Meta-analysis of the relevance of the OPRM1 118A>G genetic variant for pain treatment.Pain. 2009; 146: 270-275
- Genome-wide association scan of neuropathic pain symptoms post total joint replacement highlights a variant in the protein-kinase C gene.Eur J Hum Genet: EJHG. 2017; 25: 446-451
- The psychology of chronic post-surgical pain: New frontiers in risk factor identification, prevention and management.Br J Pain. 2017; 11: 169-177
- I. Defining persistent post-surgical pain: Is an update required?.Br J Anaesth. 2014; 113: 1-4
- The nicotinic alpha6 subunit gene determines variability in chronic pain sensitivity via cross-inhibition of P2X2/3 receptors.Sci Transl Med. 2015; 7: 287ra272
- Genetic basis of pain variability: Recent advances.J Med Genet. 2012; 49: 1-9
- COMT val158met genotype affects mu-opioid neurotransmitter responses to a pain stressor.Science. 2003; 299: 1240-1243
Article info
Publication history
Published online: May 23, 2019
Footnotes
Disclosures: None of the authors have any conflicts of interest to disclose. This project was supported through the Eunice Kennedy Shriver National Institute of Child Health & Human Development, National Institutes of Health with the grant no. 5K23HD082782 (PI: Chidambaran).
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© 2019 by United States Association for the Study of Pain, Inc.
