Optimization of Postoperative Intravenous Patient-Controlled Analgesia with OpioidDexmedetomidine Combinations: An Updated Meta-Analysis with Trial Sequential Analysis of Randomized Controlled Trials

Background: It is still a challenge to optimize postoperative pain management. The effects ofadding dexmedetomidine (DEX) to opioid-based postoperative intravenous patient-controlledanalgesia (PCA) are not fully understood.Objectives: The aim of this study is to assess the efficacy and safety of opioid-DEX combinationsfor postoperative PCA, and a trial sequential analysis (TSA) is utilized to evaluate the robustness ofthe current evidence.Study Design: A systematic review and meta-analysis.Setting: Randomized controlled trials that compared opioid-DEX combinations with opioid-onlyfor PCA in adult surgical patients.Methods: MEDLINE, EMBASE, and CENTRAL databases were searched for relevant articles. Themain outcomes analyzed were postoperative pain intensity, opioid requirement, and opioid-relatedadverse events. The random-effects model was used to estimate mean differences (MDs) or relativerisks (RRs) with 95% confidence intervals (CIs). A TSA was performed to test whether the evidencewas reliable and significant. The quality of evidence for the main outcomes was assessed using theGrading of Recommendations Assessment, Development and Evaluation (GRADE) methodology.Results: Eighteen studies involving 1,284 patients were included. The meta-analysis indicatedthat opioid-DEX combinations were associated with lower postoperative pain intensity (at rest: MD[24 hours] = -0.48, 95% CI [-0.75, -0.21], P = 0.0005), lower morphine-equivalent requirement(MD [0 – 24 hours] = -12.16 mg [-16.12, -8.21], P < 0.00001), and lower adverse events (nausea:RR = 0.66 [0.52, 0.83]; vomiting: RR = 0.65 [0.49, 0.87]; and pruritus: RR = 0.57 [0.40, 0.81]).For the above results, the TSA revealed that the cumulative Z-curve exceeded both the traditionalboundary and the trial sequential monitoring boundary for benefit. DEX had no effect on theincidence of hypotension or bradycardia, which was also confirmed by the TSA. The GRADElevel of evidence was high for postoperative nausea, moderate for pain intensity at rest at 24hours postoperatively, morphine-equivalent requirement during 0 – 24 hours postoperatively, andpostoperative vomiting, pruritus, and bradycardia, and low for postoperative hypotension.Limitations: The risk of introducing potentially significant heterogeneity exists, and this studydid not evaluate the effects of DEX combined with opioids on long-term outcomes includingchronic pain and patients’ satisfaction after hospital discharge.Conclusions: Postoperative PCA strategies with opioid-DEX combinations decreasedpostoperative pain, opioid requirement, and opioid-related adverse events. DEX is a useful adjuvantto opioid-based PCA.Key words: Dexmedetomidine, pain, postoperative analgesia, opioid, patient-controlled