title: Non-opioid analgesics in adults after major surgery: systematic review with network meta-analysis of randomized trials.
abstract: 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.
  
  
  BACKGROUND
  PROSPERO: CRD42013003912.
authors.affiliation: Service d'Anesthésie Réanimation Chirurgicale, Hôpital Raymond Poincaré, Assistance Publique Hôpitaux de Paris, 104 boulevard Raymond Poincaré F-92380 Garches, France valeria.martinez@rpc.aphp.fr.|INSERM, U-987, Hôpital Ambroise Paré, Centre d'Evaluation et de Traitement de la Douleur, F-92100 France, Université Versailles Saint-Quentin, F-78035, France.
authors.forename: V
authors.initials: V
authors.lastname: Martinez
authors.affiliation: INSERM, UMR 1153, Centre of Research in Epidemiology and Statistics, Sorbonne Paris Cité-(CRESS), METHODS team, Paris, France.
authors.forename: H
authors.initials: H
authors.lastname: Beloeil
authors.affiliation: American hospital of Paris, 92 200 Neuilly-sur-Seine, Paris, France.
authors.forename: E
authors.initials: E
authors.lastname: Marret
authors.affiliation: Service d'Anesthésie Réanimation Chirurgicale, Hôpital Raymond Poincaré, Assistance Publique Hôpitaux de Paris, 104 boulevard Raymond Poincaré F-92380 Garches, France.|INSERM, U-987, Hôpital Ambroise Paré, Centre d'Evaluation et de Traitement de la Douleur, F-92100 France, Université Versailles Saint-Quentin, F-78035, France.
authors.forename: D
authors.initials: D
authors.lastname: Fletcher
authors.affiliation: INSERM, U-987, Hôpital Ambroise Paré, Centre d'Evaluation et de Traitement de la Douleur, F-92100 France, Université Versailles Saint-Quentin, F-78035, France.|CHU de Rennes, université Rennes 1, pôle anesthésie-réanimation-urgences-SAMU, Inserm UMR 991, 2, avenue H.-Le-Guillou, 35033 Rennes, France.|Assistance Publique-Hôpitaux de Paris, Centre d'Epidémiologie Clinique, Hôpital Hôtel-Dieu, 1 place du Parvis Notre-Dame, 75004 Paris.|Université Paris Descartes-Sorbonne Paris Cité, 12 Rue de l'École de Médecine, 75006 Paris, France.
authors.forename: P
authors.initials: P
authors.lastname: Ravaud
authors.affiliation: INSERM, U-987, Hôpital Ambroise Paré, Centre d'Evaluation et de Traitement de la Douleur, F-92100 France, Université Versailles Saint-Quentin, F-78035, France.|Department of Epidemiology, Mailman School of Public Health, Columbia University, New York City, USA.
authors.forename: L
authors.initials: L
authors.lastname: Trinquart
mesh_terms: D000328:Adult; D018712:Analgesics, Non-Narcotic / Q000009:adverse effects / Q000627:therapeutic use*; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use; D006801:Humans; D009340:Nefopam / Q000627:therapeutic use; D010149:Postoperative Pain / Q000188:drug therapy*
chemical_list: D018712:Analgesics, Non-Narcotic; D000894:Anti-Inflammatory Agents, Non-Steroidal; D009340:Nefopam
keywords: analgesics; balanced analgesia; postoperative pain; surgery; systematic review