Non-opioid analgesics in adults after major surgery: systematic review with network meta-analysis of randomized trials

Background. Morphine, and analgesics other than morphine (AOM), are commonly used to treat postoperative pain after major surgery. However, which AOM provides the best efficacy-safety profile remains unclear. Methods. Randomized trials of any AOM alone or any combination of AOM compared with placebo or another AOM in adults undergoing major surgery and receiving morphine patient-controlled analgesia were included in a network meta-analysis. The outcomes were morphine consumption, pain, incidence of nausea, vomiting at 24 h and severe adverse effects. Results. 135 trials (13,287 patients) assessing 14 AOM alone or in combination were included. For all outcomes, comparisons with placebo were over-represented. Few trials assessed combinations of two AOM and none the combination of three or more. Network meta-analysis found morphine consumption reduction was greatest with the combination of two AOM (acetaminophen + nefopam, acetaminophen + NSAID, and tramadol + metamizol): -23.9 (95% CI -40;-7.7), -22.8 (-31.5;-14) and -19.8 (35.4;-4.2) mg per 24h, respectively. For AOM used alone, morphine consumption reduction was greatest with alpha-2 agonists, NSAIDs, and COX-2 inhibitors. When considering the risk of nausea, NSAIDs, corticosteroids and a-2 agonists used alone were the most efficacious (OR 0.7 [95% CI: 0.6-0.8], 0.36 [0.18-0.79], 0.41 [0.15-.64], respectively). The paucity of severe adverse effects data did not allow assessment of efficacy-safety balance. Conclusions. A combination of aetaminophen with either an NSAID or nefopam was superior to most AOM used alone, in reducing morphine consumption. Efficacy was best with three AOM used alone (a-2 agonists, NSAIDs and COX-2 inhibitors) and least with tramadol and acetaminophen. There is insufficient trial data reporting adverse events. Clinical trial registration. PROSPERO: CRD42013003912.