¹Department of Anesthesiology, Næstved Hospital, Næstved, Denmark
²Department of Anesthesiology, Bispebjerg and Frederiksberg Hospitals, Copenhagen, Denmark
³Copenhagen Trial Unit, Centre for Clinical Intervention Research Department, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
⁴Department of Anesthesiology, Zealand University Hospital, Køge, Denmark
⁵Department of Cardiology, Holbæk Hospital, Holbæk, Denmark
⁶Department of Anesthesia, Gildhoj Private Hospital, Brondby, Denmark
⁷Orthopedic Research Unit, Department of Orthopedic Surgery and Traumatology, Odense University Hospital, Odense, Denmark
⁸Department of Clinical Research, University of Southern Denmark, Odense, Denmark
⁹Department of Orthopedic Surgery, Næstved Hospital, Næstved, Denmark
¹⁰Department of Orthopedics, Nykøbing Falster Hospital, Nykøbing, Denmark
¹¹Department of Anesthesiology, Nykøbing Falster Hospital, Nykøbing, Denmark
¹²Department of Anesthesiology, Holbæk Sygehus, Holbæk, Denmark
¹³Department of Orthopedic Surgery, Zealand University Hospital, Køge, Denmark
¹⁴Department of Anesthesiology and Intensive Care, Odense University Hospital, Odense, Denmark
¹⁵Centre of Anaesthesiological Research, Department of Anesthesiology, Zealand University Hospital, Køge, Denmark
¹⁶Department of Clinical Medicine, Faculty of Health and Medical Sciences, Copenhagen University, Copenhagen, Denmark

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Key Points

Question Does paracetamol (acetaminophen) combined with ibuprofen reduce postoperative morphine usage relative to the use of each drug alone in patients undergoing total hip arthroplasty (THA), and does ibuprofen increase the incidence of serious adverse events (SAEs)?

Findings In this randomized clinical trial that included 556 patients who underwent THA, morphine usage in the first 24 hours was statistically significantly lower for the combination of paracetamol 1000 mg and ibuprofen 400 mg than for either alone; however, the combined medications did not meet the prespecified threshold for clinically important postoperative morphine reduction (10 mg) compared with ibuprofen alone. The percentage of patients with SAEs for those in any of the ibuprofen groups vs paracetamol alone was 15% vs 11%, which was not statistically significant.

Meaning Although the combined use of paracetamol and ibuprofen reduced immediate postoperative morphine consumption compared with paracetamol alone in patients undergoing THA, ibuprofen alone resulted in comparable pain control without increasing SAEs, suggesting that ibuprofen alone may be a reasonable option.

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

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Article Information

Corresponding Author: Kasper Højgaard Thybo, MD, Department of Anesthesiology, Næstved Hospital, Ringstedgade 61, 4700 Næstved, Denmark (khty@regionsjealland.dk).

Accepted for Publication: December 26, 2018.

Author Contributions: Dr Thybo had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Drs Thybo and Hägi-Pedersen contributed equally to this article. Dr Mathiesen was senior author.

Concept and design: Thybo, Hägi-Pedersen, Dahl, Wetterslev, Mathiesen.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Thybo, Hägi-Pedersen, Dahl, Wetterslev, Skovmand, Mathiesen.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Thybo, Wetterslev, Jakobsen.

Obtained funding: Thybo, Dahl.

Administrative, technical, or material support: Thybo, Jakobsen, Overgaard, Schrøder, Bjørck, Skovmand, Frederiksen, Buus-Nielsen, Sørensen, Kruuse, Lindholm.

Supervision: Thybo, Hägi-Pedersen, Dahl, Pedersen, Overgaard, Bjørck, Skovmand, Lindholm, Mathiesen.

Other - Recruitment of participants and collection of data: Nersesjan.

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.

Funding/Support: Funding was provided by DASAIM, Sophus Johansens Fond, 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 Fond, and the Grosserer Christian Andersen og Hustru Ingeborg Andersen, f. Schmidts legat (fund).

Role of the Funder/Sponsor: None of the funders had a role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Additional Contributions: We wish to thank patients, relatives, and clinical and research staff at all trial sites. We give thanks to monitors for their excellent cooperation, in particular Birgitte Grøn, PhD, and Pernille Ask Aabo, MScPharm, at the Good Clinical Practice (GCP) unit at Copenhagen University Hospital, and Henriette Kunch Bendixen, MScPharm, at the GCP unit at Odense University Hospital. We also wish to thank Janus Engstrøm, BSc, at Copenhagen trial unit for creating and maintaining the trial database and creating the randomization list and allocation system. Finally, we wish to thank the Pharmacy of the Capital Region, Herlev for masking the trial medicine. Neither Grøn, Aabo, Bendixen, nor Engstrøm received personal compensation for their role in the trial.

Compensation for the Role in the Trial: The Copenhagen Trial Unit was paid for randomization and the electronic case report form. The GCP unit was compensated for monitoring the trial according to Danish law.

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Effect of Combination of Paracetamol (Acetaminophen) and Ibuprofen vs Either Alone on Patient-Controlled Morphine Consumption in the First 24 Hours After Total Hip ArthroplastyThe PANSAID Randomized Clinical Trial

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