1. 2017;20;569-596Optimization of Postoperative Intravenous Patient-Controlled Analgesia with Opioid-Dexmedetomidine Combinations: An Updated Meta-Analysis with Trial Sequential Analysis of Randomized Controlled Trials
   Systematic Review
   Ke Peng, MD, Juan Zhang, MD, Xiao-wen Meng, PhD, Hua-yue Liu, MD, and Fu-hai Ji, MD.

BACKGROUND: It is still a challenge to optimize postoperative pain management. The effects of adding dexmedetomidine (DEX) to opioid-based postoperative intravenous patient-controlled analgesia (PCA) are not fully understood.

OBJECTIVES: The aim of this study is to assess the efficacy and safety of opioid-DEX combinations for postoperative PCA, and a trial sequential analysis (TSA) is utilized to evaluate the robustness of the current evidence.

STUDY DESIGN: A systematic review and meta-analysis.

SETTING: Randomized controlled trials that compared opioid-DEX combinations with opioid-only for PCA in adult surgical patients.

METHODS: MEDLINE, EMBASE, and CENTRAL databases were searched for relevant articles. The main outcomes analyzed were postoperative pain intensity, opioid requirement, and opioid-related adverse events. The random-effects model was used to estimate mean differences (MDs) or relative risks (RRs) with 95% confidence intervals (CIs). A TSA was performed to test whether the evidence was reliable and significant. The quality of evidence for the main outcomes was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology.

RESULTS: Eighteen studies involving 1,284 patients were included. The meta-analysis indicated that 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 traditional boundary and the trial sequential monitoring boundary for benefit. DEX had no effect on the incidence of hypotension or bradycardia, which was also confirmed by the TSA. The GRADE level of evidence was high for postoperative nausea, moderate for pain intensity at rest at 24 hours postoperatively, morphine-equivalent requirement during 0 – 24 hours postoperatively, and postoperative vomiting, pruritus, and bradycardia, and low for postoperative hypotension.

LIMITATIONS: The risk of introducing potentially significant heterogeneity exists, and this study did not evaluate the effects of DEX combined with opioids on long-term outcomes including chronic pain and patients’ satisfaction after hospital discharge.

CONCLUSIONS: Postoperative PCA strategies with opioid-DEX combinations decreased postoperative pain, opioid requirement, and opioid-related adverse events. DEX is a useful adjuvant to opioid-based PCA.

KEY WORDS: Dexmedetomidine, pain, postoperative analgesia, opioid, patient-controlled