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: The PANSAID Randomized Clinical Trial
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, 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
Abstract
Importance: Multimodal postoperative analgesia is widely used but lacks evidence of benefit.
Objective: Investigate beneficial and harmful effects of 4 nonopioid analgesics regimens.
Design, setting, and participants: 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.
Interventions: 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.
Main outcomes and measures: 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, 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).
Results: 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; 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 relevance: 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.
Trial registration: ClinicalTrials.gov Identifier: NCT02571361.
Conflict of interest statement
Conflict of Interest Disclosures: Dr Thybo reported grants from the following: the Danish Society of Anaesthesiology and Intensive Care Medicine (DASAIM), Sophus Johansens Fund, Region Zealand Health Scientific Research Foundation, the local research foundation at Næstved-Slagelse-Ringsted Hospitals, the A.P. Møller Foundation for the Advancement of Medical Science, Aase og Ejnar Danielsens Fund, and the Grosserer Christian Andersen og Hustru Ingeborg Andersen, f. Schmidts legat (fund) during the conduct of the study; and was employed as a doctoral student while he was primary investigator of this trial. Dr Overgaard reported grants from Biomet Denmark, Biomet Inc, DePuy and Protesekompagniet, and Zimmer; serving as an investigator for Sanofi-Aventis Denmark A/S; and serving on an advisory board for Eli Lilly and Multipharma International Ltd outside the submitted work. No other disclosures were reported.
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Source: PubMed