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.

Keywords: Chronic postsurgical pain; genetics; meta-analysis; systematic review.

Figure 1:

PRISMA flow diagram represents the systematic literature search and assessment process used in this study.

Figure 2:

Pareto chart and clustered bar chart depicting the different cohorts evaluated by studies in the systematic review by surgery (top panel) and race/ethnicity (lower panel) respectively are presented. Surgical cohorts have been classified according to the surgical incision location or type. For example, abdominal surgeries include hernia, gynecologic, urogenital surgeries etc. excluding caesarian sections which are presented as a different surgical class; joint surgeries include surgeries on any joint including knee, shoulder and hip surgeries. The pareto chart plots the distribution of the data in descending order of frequency (the number of patients per category marked on the bar). The red line is the cumulative line on the secondary y-axis showing % of subjects per surgical type/total number of patients. The clustered bar chart shows the number of subjects per ethnicity/race overall in the cohort (number per category marked on the bar). The Caucasian cohort includes several European populations (including Danish, German, Irish, Swedish) and North American populations. Jewish population includes both Ashkenazi and non-Ashkenazi Jew cohorts studied. Although the Hispanic cohort presents the second largest racial group, they are represented in only one large study. NR: Not reported.

Figure 3:

Forest plots of studies reporting associations between polymorphisms and chronic post-surgical pain that were included in the meta-analysis are presented. Individual effect sizes of the studies included for the particular variant allele and fixed effect (FE) model odds ratios are presented with 95% confidence intervals (CI). For COMT rs4680 variant, 3 models were investigated (presented in table 3). Forest plot of dominant model (with least heterogeneity among them) is presented in this figure.