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Pre-emptive Analgesia for the Prevention of Chronic Postsurgical Pain: A Systematic Review and Meta-analysis with Trial Sequential Analysis

Endale Gebreegziabher Gebremedhn, Worku Mekonnen Sefefe

Background: Chronic Postsurgical Pain (CPSP) remains a continuing challenge in the healthcare systems worldwide due to limited treatment options. Pre-emptive analgesia is reported to be effective for the prevention of postoperative pain. However, there is limited evidence regarding the effectiveness of pre-emptive analgesia on the prevention of CPSP. A comprehensive systematic review and meta-analysis of clinical studies were performed to determine its effectiveness in the prevention of CPSP.
Methods: Relevant articles were searched from EMBASE, PubMed, Medline and Google scholar databases. The main outcome was chronic pain at 3 months and beyond after surgery. The random model was used to estimate the relative Risk Reduction (RR) using the 95% confidence interval. We assessed the routes of administration of analgesics (surgical types categorized under it), time of pre-emptive analgesia administration, pre-emptive vs. prolonged blockade and postoperative follow-up times.
Results: Thirty (27 randomized controlled trials and 3 non-RCT) studies with a total of 2,137 participants were reviewed. Pre-emptive analgesia prevented CPSP in the majority of studies (n=22/30, 73.3%). Pre-emptive analgesia significantly reduced CPSP in comparison to the post-incisional and placebo groups with the Relative Risk (RR) of 0.46 (P=0.0009, 95% CI=0.29-0.73) and 0.54 (P<0.001; 95% CI=0.42-0.68) respectively. Pre-emptive analgesics administered between<1 hr and 48-72 hrs before skin incision in different groups reduced CPSP with the RR of. 62 (P=0.001; 95% CI=0.46-0.83) and 0.42 (P=0.002; 95% CI=0.24-0.73) respectively. Surprisingly, no difference was observed between the pre-emptive and prolonged blockade (pre-emptive plus intraoperative and postoperative analgesia) groups. Subgroup analyses of intravenous route studies showed significant reduction of CPSP at 3 months with RR 0.33 (P=0.03; 95% CI=0.12-0.92), but not at 6 months follow-up. Additionally, oral route studies revealed a reduction of CPSP at 6 months with the RR of 0.44 (P<0.0001, 95% CI=0.29-0.66). Moreover, the overall analysis of epidural studies at 6 months showed a significant reduction of chronic pain with the RR of 0.56 (P=0.007, 95%CI=0.37-0.85). No difference was observed between the pre-emptive analgesia and placebo groups from the trial sequential analyses.
Conclusion: Pre-emptive analgesia reduced CPSP in the majority of studies at 3 months and beyond after surgery. However, pre-emptive analgesia did not show any benefit on the reduction of CPSP in a large number of studies, which could attribute to the heterogeneities in the studies reviewed. A prospective clinical trial studies should be conducted in a large cohort of patients in relation to preoperative risk factors for pain, pre-emptive analgesia, type and extent of surgery, and postoperative follow-up times to strengthen the current findings.