• Kasper Højgaard Thybo, Daniel Hägi-Pedersen, Jørgen Berg Dahl, Jørn Wetterslev, Mariam Nersesjan, Janus Christian Jakobsen, Niels Anker Pedersen, Søren Overgaard, Henrik M Schrøder, Harald Schmidt, Jan Gottfrid Bjørck, Kamilla Skovmand, Rune Frederiksen, Morten Buus-Nielsen, Charlotte Voss Sørensen, Laura Smedegaard Kruuse, Peter Lindholm, and Ole Mathiesen.
• Department of Anesthesiology, Næstved Hospital, Næstved, Denmark.
• JAMA. 2019 Feb 12; 321 (6): 562-571.

ImportanceMultimodal postoperative analgesia is widely used but lacks evidence of benefit.ObjectiveInvestigate beneficial and harmful effects of 4 nonopioid analgesics regimens.Design, Setting, And ParticipantsRandomized, blinded, placebo-controlled, 4-group trial in 6 Danish hospitals with 90-day follow-up that included 556 patients undergoing total hip arthroplasty (THA) from December 2015 to October 2017. Final date of follow-up was January 1, 2018.InterventionsParticipants were randomized to receive paracetamol (acetaminophen) 1000 mg plus ibuprofen 400 mg (n = 136; PCM + IBU), paracetamol 1000 mg plus matched placebo (n = 142; PCM), ibuprofen 400 mg plus matched placebo (n = 141; IBU), or half-strength paracetamol 500 mg plus ibuprofen 200 mg (n = 140; HS-PCM + IBU) orally every 6 hours for 24 hours postoperatively, starting 1 hour before surgery.Main Outcomes And MeasuresTwo co-primary outcomes: 24-hour morphine consumption using patient-controlled analgesia in pairwise comparisons between the 4 groups (multiplicity-adjusted thresholds for statistical significance, P < .0042; minimal clinically important difference, 10 mg), and proportion of patients with 1 or more serious adverse events (SAEs) within 90 days (multiplicity-adjusted thresholds for statistical significance, P < .025).ResultsAmong 559 randomized participants (mean age, 67 years; 277 [50%] women), 556 (99.5%) completed the trial and were included in the analysis. Median 24-hour morphine consumption was 20 mg (99.6% CI, 0-148) in the PCM + IBU group, 36 mg (99.6% CI, 0-166) for PCM alone, 26 mg (99.6% CI, 2-139) for IBU alone, and 28 mg (99.6% CI, 2-145) for HS-PCM + IBU. The median difference in morphine consumption between the PCM + IBU group vs PCM alone was 16 mg (99.6% CI, 6.5 to 24; P < .001); for the PCM-alone group vs HS-PCM + IBU, 8 mg (99.6% CI, -1 to 14; P = .001); and for the PCM + IBU group vs IBU alone, 6 mg (99.6% CI, -2 to 16; P = .002). The difference in morphine consumption was not statistically significant for the PCM + IBU group vs HS-PCM + IBU (8 mg [99.6% CI, -2 to 16]; P = .005) or for the PCM-alone group vs IBU alone (10 mg [99.6% CI, -2 to 16]; P = .004) after adjustment for multiple comparisons and 2 co-primary outcomes. There was no significant difference between the IBU-alone group vs HS-PCM + IBU (2 mg [99.6% CI, -10 to 7]; P = .81). The proportion of patients with SAEs in groups receiving IBU was 15%, and in the PCM-alone group, was 11%. The relative risk of SAE was 1.44 (97.5% CI, 0.79 to 2.64; P = .18).Conclusions And RelevanceAmong patients undergoing THA, paracetamol plus ibuprofen significantly reduced morphine consumption compared with paracetamol alone in the first 24 hours after surgery; there was no statistically significant increase in SAEs in the pooled groups receiving ibuprofen alone vs with paracetamol alone. However, the combination did not result in a clinically important improvement over ibuprofen alone, suggesting that ibuprofen alone may be a reasonable option for early postoperative oral analgesia.Trial RegistrationClinicalTrials.gov Identifier: NCT02571361.

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