Efficacy and Safety of Ketamine or Esketamine versus Fentanyl-Class Opioids as Adjuncts to Propofol for Gastrointestinal Endoscopy: A Systematic Review and Meta-Analysis

OBJECTIVE: Propofol is widely used for gastrointestinal (GI) endoscopies but may cause respiratory depression and hemodynamic compromise when used alone. Adjuncts such as ketamine or esketamine and fentanyl-class opioids (fentanyl, alfentanil, and sufentanil) are used to optimize sedation, yet their comparative efficacy and safety remain uncertain. This meta-analysis evaluated ketamine or esketamine plus propofol (KP regimens) versus fentanyl/alfentanil/sufentanil plus propofol (FP regimens). METHODS: Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we systematically searched PubMed, Scopus, Cochrane Library, and Google Scholar from inception to February 2025 for randomized controlled trials (RCTs). Eligible studies included patients undergoing GI endoscopy (Population), receiving ketamine or esketamine with propofol (Intervention), compared with fentanyl-class opioids with propofol (Comparison), and reporting outcomes including propofol dose, comfort, adverse events, recovery time, or procedure time (Outcomes). Risk of bias was assessed with the Cochrane tool. Heterogeneity was evaluated using Cochran's Q test and the I2 statistic, and clinical heterogeneity was considered based on study design and population differences. Sensitivity analyses were conducted to test robustness of findings. RESULTS: Fifteen RCTs (1492 participants) were included. KP regimens significantly reduced total propofol use compared with FP (mean difference [MD] -0.42; 95% confidence interval [CI] -0.66 to -0.19; P = .0005), with greater benefit observed for esketamine (p for subgroup = 0.001). No significant differences were found in sedation (MD 0.01; 95% CI -0.40 to 0.43; P = .95) or pain scores (MD 0.24; 95% CI -0.18 to 0.65; P = .26). Safety outcomes were comparable across groups, with no significant differences in desaturation, nausea/vomiting, bradycardia, or tachycardia, except for hypotension, which was lower with KP (risk ratio [RR] 0.56; 95% CI 0.39 to 0.82; P = .003). Recovery and procedure times were similar between groups. CONCLUSIONS: Both KP and FP regimens are effective and safe for GI endoscopy. KP regimens reduce total propofol requirements and significantly lower the risk of hypotension, while showing comparable sedation quality, analgesia, and recovery profiles to FP. These findings suggest KP may offer safety and dosing advantages, though larger standardized trials are needed to confirm its clinical superiority.