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

doi:10.1001/jama.2018.22039

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

^*Corresponding author for this work

Department of Clinical Medicine

36 Citations (Scopus)

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.

Original language	English
Journal	JAMA - Journal of the American Medical Association
Volume	321
Issue number	6
Pages (from-to)	562-571
Number of pages	10
ISSN	0098-7484
DOIs	https://doi.org/10.1001/jama.2018.22039
Publication status	Published - 2019

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Thybo, K. H., Hägi-Pedersen, D., Dahl, J. B., Wetterslev, J., Nersesjan, M., Jakobsen, J. C., Pedersen, N. A., Overgaard, S., Schrøder, H. M., Schmidt, H., Bjørck, J. G., Skovmand, K., Frederiksen, R., Buus-Nielsen, M., Sørensen, C. V., Kruuse, L. S., Lindholm, P., & Mathiesen, O. (2019). 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. JAMA - Journal of the American Medical Association, 321(6), 562-571. https://doi.org/10.1001/jama.2018.22039

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. / Thybo, Kasper Højgaard; Hägi-Pedersen, Daniel; Dahl, Jørgen Berg et al.
In: JAMA - Journal of the American Medical Association, Vol. 321, No. 6, 2019, p. 562-571.

Research output: Contribution to journal › Journal article › Research › peer-review

Thybo, KH, Hägi-Pedersen, D, Dahl, JB, Wetterslev, J, Nersesjan, M, Jakobsen, JC, Pedersen, NA, Overgaard, S, Schrøder, HM, Schmidt, H, Bjørck, JG, Skovmand, K, Frederiksen, R, Buus-Nielsen, M, Sørensen, CV, Kruuse, LS, Lindholm, P & Mathiesen, O 2019, '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', JAMA - Journal of the American Medical Association, vol. 321, no. 6, pp. 562-571. https://doi.org/10.1001/jama.2018.22039

Thybo KH, Hägi-Pedersen D, Dahl JB, Wetterslev J, Nersesjan M, Jakobsen JC et al. 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. JAMA - Journal of the American Medical Association. 2019;321(6):562-571. doi: 10.1001/jama.2018.22039

Thybo, Kasper Højgaard ; Hägi-Pedersen, Daniel ; Dahl, Jørgen Berg et al. / 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. In: JAMA - Journal of the American Medical Association. 2019 ; Vol. 321, No. 6. pp. 562-571.

@article{e40ce198022549039c9234b8d63cf52f,

title = "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",

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.",

author = "Thybo, {Kasper H{\o}jgaard} and Daniel H{\"a}gi-Pedersen and Dahl, {J{\o}rgen Berg} and J{\o}rn Wetterslev and Mariam Nersesjan and Jakobsen, {Janus Christian} and Pedersen, {Niels Anker} and S{\o}ren Overgaard and Schr{\o}der, {Henrik M.} and Harald Schmidt and Bj{\o}rck, {Jan Gottfrid} and Kamilla Skovmand and Rune Frederiksen and Morten Buus-Nielsen and S{\o}rensen, {Charlotte Voss} and Kruuse, {Laura Smedegaard} and Peter Lindholm and Ole Mathiesen",

year = "2019",

doi = "10.1001/jama.2018.22039",

language = "English",

volume = "321",

pages = "562--571",

journal = "JAMA - Journal of the American Medical Association",

issn = "0098-7484",

publisher = "American Medical Association",

number = "6",

}

TY - JOUR

T1 - 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

T2 - The PANSAID Randomized Clinical Trial

AU - Thybo, Kasper Højgaard

AU - Hägi-Pedersen, Daniel

AU - Dahl, Jørgen Berg

AU - Wetterslev, Jørn

AU - Nersesjan, Mariam

AU - Jakobsen, Janus Christian

AU - Pedersen, Niels Anker

AU - Overgaard, Søren

AU - Schrøder, Henrik M.

AU - Schmidt, Harald

AU - Bjørck, Jan Gottfrid

AU - Skovmand, Kamilla

AU - Frederiksen, Rune

AU - Buus-Nielsen, Morten

AU - Sørensen, Charlotte Voss

AU - Kruuse, Laura Smedegaard

AU - Lindholm, Peter

AU - Mathiesen, Ole

PY - 2019

Y1 - 2019

N2 - 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.

AB - 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.

U2 - 10.1001/jama.2018.22039

DO - 10.1001/jama.2018.22039

M3 - Journal article

C2 - 30747964

AN - SCOPUS:85061314999

SN - 0098-7484

VL - 321

SP - 562

EP - 571

JO - JAMA - Journal of the American Medical Association

JF - JAMA - Journal of the American Medical Association

IS - 6

ER -