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

Br J Anaesth. 2017 Jan;118(1):22-31. doi: 10.1093/bja/aew391.


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 24 h, respectively. For AOM used alone, morphine consumption reduction was greatest with α-2 agonists, NSAIDs, and COX-2 inhibitors. When considering the risk of nausea, NSAIDs, corticosteroids and α-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 (α-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.

Keywords: analgesics; balanced analgesia; postoperative pain; surgery; systematic review.

Publication types

  • Meta-Analysis
  • Review
  • Systematic Review

MeSH terms

  • Adult
  • Analgesics, Non-Narcotic / adverse effects
  • Analgesics, Non-Narcotic / therapeutic use*
  • Anti-Inflammatory Agents, Non-Steroidal / therapeutic use
  • Humans
  • Nefopam / therapeutic use
  • Pain, Postoperative / drug therapy*


  • Analgesics, Non-Narcotic
  • Anti-Inflammatory Agents, Non-Steroidal
  • Nefopam