Effect of Combination of Paracetamol (Acetaminophen) and Ibuprofen vs Either Alone on Patient-Controlled Morphine Consumption in the First 24 Hours After Total Hip Arthroplasty
Authors: 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, Ole Mathiesen
Journal: JAMA (2019)

<h3>Importance</h3> Multimodal postoperative analgesia is widely used but lacks evidence of benefit. <h3>Objective</h3> Investigate beneficial and harmful effects of 4 nonopioid analgesics regimens. <h3>Design, Setting, and Participants</h3> Randomized, 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. <h3>Interventions</h3> Participants 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. <h3>Main Outcomes and Measures</h3> Two co–primary outcomes: 24-hour morphine consumption using patient-controlled analgesia in pairwise comparisons between the 4 groups (multiplicity-adjusted thresholds for statistical significance,<i>P</i> &lt; .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,<i>P</i> &lt; .025). <h3>Results</h3> Among 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;<i>P</i> &lt; .001); for the PCM-alone group vs HS–PCM + IBU, 8 mg (99.6% CI, −1 to 14;<i>P</i> = .001); and for the PCM + IBU group vs IBU alone, 6 mg (99.6% CI, −2 to 16;<i>P</i> = .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];<i>P</i> = .005) or for the PCM-alone group vs IBU alone (10 mg [99.6% CI, −2 to 16];<i>P</i> = .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];<i>P</i> = .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;<i>P</i> = .18). <h3>Conclusions and Relevance</h3> Among 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. <h3>Trial Registration</h3> ClinicalTrials.gov Identifier:NCT02571361