Low- versus high-dose intraoperative opioids: A systematic review with meta-analyses and trial sequential analyses.

Background: Opioid-induced hyperalgesia is a state of nociceptive sensitisation secondary to opioid administration. The objective of this meta-analysis was to test the hypothesis that high-dose intraoperative opioids contribute to increased post-operative pain and hyperalgesia when compared with a low-dose regimen in patients under general anaesthesia.

Methods: We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement guidelines and rated the certainty of evidence with the Grading of Recommendations, Assessment, Development and Evaluation system. Only trials investigating pain outcomes and comparing two different dosages of the same intraoperative opioid in patients under general anaesthesia were included. The primary outcome was pain score (analogue scale, 0-10) at 24 post-operative hours. Secondary outcomes included pain score and cumulative intravenous morphine equivalents (mg) consumed at 2 post-operative hours, together with mechanical pain threshold (g·mm ).

Results: Twenty-seven randomised controlled trials, including 1630 patients, were identified. Pain score at rest at 24 post-operative hours was increased in the high-dose group (mean difference [95% CI]: -0.2 [-0.4, -0.1]; trial sequential analysis-adjusted CI: -0.4, -0.02; low certainty of evidence). Similarly, at 2 post-operative hours, both pain score (mean difference [95% CI]: -0.4 [-0.6, -0.2]; low certainty of evidence) and cumulative intravenous morphine equivalents consumed (mean difference [95% CI]: -1.6 mg [-2.6, -0.7]; low certainty of evidence) were significantly higher in the high-dose group. Finally, the threshold for mechanical pain was significantly lower in the high-dose group (mean difference to pressure [95% CI]: 3.8 g·mm [1.8, 5.8]; low certainty of evidence).

Conclusions: There is low certainty of evidence that high-dose intraoperative opioid administration increases pain scores in the post-operative period, when compared with a low-dose regimen.