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Systematic Review and Meta-Analysis of Genetic Risk of Developing Chronic Postsurgical Pain.

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.

SUBMITTER: Chidambaran V

PROVIDER: S-EPMC6874752 | biostudies-literature | 2020 Jan - Feb

REPOSITORIES: biostudies-literature

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Project description:IntroductionDetermining the prevalence of chronic postsurgical pain (CPSP) after video-assisted thoracoscopic surgery (VATS) and identifying CPSP predictors should improve the prognosis of patients undergoing VATS. Although several studies have investigated predictors of CPSP after VATS, there were significant dissimilarities in the findings due to the confounding of predictors.MethodsPubMed, Cochrane, MEDLINE, Web of Science, Chinese Biomedical Literature, and China National Knowledge Infrastructure databases were comprehensively searched using the Medical Subject Headings terms "pain, postoperative," "thoracic surgery, video-assisted," and all related free terms from inception until March 27, 2022. The Stata metaprop package was used to comprehensively analyze the incidence of CPSP following VATS. Furthermore, the pooled odds ratios (OR) or the standardized mean differences (SMD) and their corresponding 95% confidence intervals (95% CI) were calculated, and qualitative analyses were performed for predictors that could not be assessed quantitatively to evaluate the effects of the included risk factors on the occurrence of CPSP. Unadjusted odds ratios were utilized to consider the impact of non-significant estimates if the original study did not report them.ResultsOf the 4302 studies, 183 were considered eligible, and 17 were finally included in this study. The overall incidence of CPSP after VATS was 35.3% (95% CI 27.1-43.5%). The qualitative synthesis results revealed that female sex, age, and acute postoperative pain were definite predictors of CPSP after VATS. The number of ports, operation time, duration of drainage, and insufficient analgesia were also considered predictors. Consistent, quantitative synthesis results also showed that the aforementioned predictors were closely related to the occurrence of CPSP after VATS. Only by quantitative analysis, postoperative chemotherapy and an educational level less than junior school were also risk factors for CPSP. Other predictors displayed no evidence or unclear evidence of association with CPSP after VATS.ConclusionThis study preliminarily determined the incidence of CPSP after VATS based on the existing literature. Female sex, age, and acute pain were identified as risk factors for CPSP after VATS, and other potential risk factors were also identified and analyzed. However, as a result of the inclusion of retrospective studies and inevitable limitations in this systematic review and meta-analysis, the results of this study still need to be verified by large-scale prospective clinical studies.Trial registrationCRD42022323179.

Project description:Chronic postsurgical pain (CPSP) is a debilitating chronic pain condition that has a substantial effect on quality of life. CPSP shows considerable clinical overlap with different chronic peripheral pain syndromes, suggesting a shared aetiology. This study aims to assess the genetic overlap between different chronic pain syndromes and CPSP, providing relevant biological context for potential chronic pain markers of CPSP. To analyse the genetic overlap between CPSP and chronic peripheral pain syndromes, recent GWAS studies were combined for polygenic risk scores (PRS) analysis, using a cohort of CPSP patients as starting point. Biological contextualisation of genetic marker, overlap between CPSP and chronic pain syndromes, was assessed through Gene Ontology (GO), using Pathway Scoring Algorithm (PASCAL) and REVIGO. PRS analyses suggest a significant genetic overlap between CPSP and 3 chronic pain disorders: chronic widespread pain (CWP, p value threshold = 0.003, R2 0.06, p = 0.003), rheumatoid arthritis (RA, p value threshold = 0.0177, R2 = 0.04, p = 0.017) and possibly sciatica (p value threshold = 0.00025, R2 = 0.03, p = 0.045). Whereas no significant genetic overlap was found with cluster headache and migraine, the outcome for osteoarthritis (OA) was inconsistent between the cohorts. This is likely related to cohort composition, as repeated random reallocation of patients' nullified CPSP/OA outcome variation between the discovery and replication cohorts. GO analyses suggested an aetiological involvement of genetic markers that control neurological signalling (specifically sodium channels) and inflammatory response. The current study reaffirms the impact of sample size, cohort composition and open data accessibility on the unbiased identification of genetic overlap across disorders. In conclusion, this study is the first to report genetic overlap between regulatory processes implicated in CPSP and chronic peripheral pain syndromes. Interaction between neurological signalling and inflammatory response may explain the genetic overlap between CPSP, CWP and RA. Enhanced understanding of mechanisms underlying chronification of pain will aid the development of new therapeutic strategies for CPSP with sodium channel biochemistry as a potential candidate.

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Systematic Review and Meta-Analysis of Genetic Risk of Developing Chronic Postsurgical Pain.

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