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

Research output: Contribution to journalJournal articleResearchpeer-review

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 languageEnglish
JournalJAMA - Journal of the American Medical Association
Volume321
Issue number6
Pages (from-to)562-571
ISSN0098-7484
DOIs
Publication statusPublished - 12. Feb 2019

Fingerprint

Ibuprofen
Acetaminophen
Morphine
Hip
Randomized Controlled Trials
Placebos
Patient-Controlled Analgesia
Outcome Assessment (Health Care)

Keywords

  • Acetaminophen/administration & dosage
  • Administration, Oral
  • Aged
  • Analgesics, Non-Narcotic/administration & dosage
  • Analgesics, Opioid/administration & dosage
  • Arthroplasty, Replacement, Hip/adverse effects
  • Double-Blind Method
  • Drug Therapy, Combination
  • Female
  • Humans
  • Ibuprofen/administration & dosage
  • Male
  • Middle Aged
  • Morphine/administration & dosage
  • Pain Measurement
  • Pain, Postoperative/drug therapy

Cite this

Thybo, Kasper Højgaard ; Hägi-Pedersen, Daniel ; Dahl, Jørgen Berg ; Wetterslev, Jørn ; Nersesjan, Mariam ; Jakobsen, Janus Christian ; Pedersen, Niels Anker ; Overgaard, Søren ; Schrøder, Henrik M. ; Schmidt, Harald ; Bjørck, Jan Gottfrid ; Skovmand, Kamilla ; Frederiksen, Rune ; Buus-Nielsen, Morten ; Sørensen, Charlotte Voss ; Kruuse, Laura Smedegaard ; Lindholm, Peter ; Mathiesen, Ole. / 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{67f3a37aa9c942bb9acd774bc52c267d,
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.",
keywords = "Acetaminophen/administration & dosage, Administration, Oral, Aged, Analgesics, Non-Narcotic/administration & dosage, Analgesics, Opioid/administration & dosage, Arthroplasty, Replacement, Hip/adverse effects, Double-Blind Method, Drug Therapy, Combination, Female, Humans, Ibuprofen/administration & dosage, Male, Middle Aged, Morphine/administration & dosage, Pain Measurement, Pain, Postoperative/drug therapy",
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",
month = "2",
day = "12",
doi = "10.1001/jama.2018.22039",
language = "English",
volume = "321",
pages = "562--571",
journal = "J A M A: The Journal of the American Medical Association",
issn = "0098-7484",
publisher = "American Medical Association",
number = "6",

}

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; Wetterslev, Jørn; Nersesjan, Mariam; Jakobsen, Janus Christian; Pedersen, Niels Anker; Overgaard, Søren; Schrøder, Henrik M.; Schmidt, Harald; Bjørck, Jan Gottfrid; Skovmand, Kamilla; Frederiksen, Rune; Buus-Nielsen, Morten; Sørensen, Charlotte Voss; Kruuse, Laura Smedegaard; Lindholm, Peter; Mathiesen, Ole.

In: JAMA - Journal of the American Medical Association, Vol. 321, No. 6, 12.02.2019, p. 562-571.

Research output: Contribution to journalJournal articleResearchpeer-review

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 - 2019/2/12

Y1 - 2019/2/12

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.

KW - Acetaminophen/administration & dosage

KW - Administration, Oral

KW - Aged

KW - Analgesics, Non-Narcotic/administration & dosage

KW - Analgesics, Opioid/administration & dosage

KW - Arthroplasty, Replacement, Hip/adverse effects

KW - Double-Blind Method

KW - Drug Therapy, Combination

KW - Female

KW - Humans

KW - Ibuprofen/administration & dosage

KW - Male

KW - Middle Aged

KW - Morphine/administration & dosage

KW - Pain Measurement

KW - Pain, Postoperative/drug therapy

U2 - 10.1001/jama.2018.22039

DO - 10.1001/jama.2018.22039

M3 - Journal article

C2 - 30747964

AN - SCOPUS:85061314999

VL - 321

SP - 562

EP - 571

JO - J A M A: The Journal of the American Medical Association

JF - J A M A: The Journal of the American Medical Association

SN - 0098-7484

IS - 6

ER -