Recent literature suggests that the withdrawal of
remifentanil (RF) infusion can be associated with
hyperalgesia in clinical and nonclinical settings. We performed a systematic review and a meta-analysis of randomized controlled trials with cross-over design, to assess the effect of discontinuing RF infusion on
pain intensity and areas of
hyperalgesia and
allodynia in healthy volunteers. Nine studies were included. The intervention treatment consisted in RF infusion that was compared with placebo (
saline solution). The primary outcome was
pain intensity assessment at 30 ± 15 minutes after RF or placebo discontinuation, assessed by any
pain scale and using any quantitative sensory testing. Moreover, postwithdrawal
pain scores were compared with baseline scores in each treatment. Secondary outcomes included the areas (% of basal values) of
hyperalgesia and
allodynia. Subjects during RF treatment reported higher
pain scores after discontinuation than during treatment with placebo [standardized mean difference (SMD): 0.50, 95% confidence interval (CI): 0.03-0.97; P = 0.04, I2 = 71%]. A significant decrease in
pain scores, compared with baseline values, was found in the placebo treatment (SMD: -0.87, 95% CI: -1.61 to -0.13; P = 0.02, I2 = 87%), but not in the RF treatment (SMD: -0.28, 95% CI: -1.18 to 0.62; P = 0.54, I2 = 91%). The area of
hyperalgesia was larger after RF withdrawal (SMD: 0.55; 95% CI: 0.27-0.84; P = 0.001; I2 = 0%). The area of
allodynia did not vary between treatments. These findings suggest that the withdrawal of RF induces a mild but nonclinically relevant degree of
hyperalgesia in HVs, likely linked to a reduced pain threshold.