Analgesic Effect of Paracetamol, Paracetamol + Codeine, Ibuprofen and Their Combination

• ClinicalTrials.gov Identifier: NCT00921700
• Recruitment Status: Completed
• First Posted: June 16, 2009
• Last Update Posted: March 30, 2016
• Sponsor: Ullevaal University Hospital
• Collaborator: University of Oslo
• Information provided by (Responsible Party): Lasse Ansgar Skoglund, Oslo University Hospital

Tracking Information

• First Submitted Date: June 15, 2009
• First Posted Date: June 16, 2009
• Last Update Posted Date: March 30, 2016
• Study Start Date: June 2009
• Actual Primary Completion Date: November 2014 (Final data collection date for primary outcome measure)
• Current Primary Outcome Measures (submitted: June 15, 2009): Sum pain intensity SPI (0-10 Numerical Rating Scale) [ Time Frame: 6 hours ]
• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: June 15, 2009)

• Sum pain intensity difference score (PID) [ Time Frame: 6 hours ]
• Overall assessment of efficacy (4-point Verbal Rating Scale) [ Time Frame: 6 hours ]
• Adverse effects AE (Specific reporting of AE - type, duration and severity) [ Time Frame: 6 hours ]

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Analgesic Effect of Paracetamol, Paracetamol + Codeine, Ibuprofen and Their Combination
• Official Title: Analgesic Effect of Ibuprofen 400 mg/Paracetamol 1000 mg, Ibuprofen 400 mg/ Paracetamol 1000 mg/60 mg Codeine, and Paracetamol 1000 mg/Codeine 60 mg: A Single-dose, Randomized, Placebo-controlled and Double-blind Study
• Brief Summary: The purpose of this study is to determine whether the combination of paracetamol (acetaminophen) and other NSAIDs with or without weak opioids can give synergistic analgesic effect.

Detailed Description

Combining paracetamol and other NSAIDs could give a theoretical synergistic analgesic effect according to already known or assumed mechanisms of action. Synergism is defined as an additive or supra-additive effect not achieved by one of the drugs alone. Such synergism is shown in clinical studies between acetaminophen and naproxen in coxarthrosis and rheumatoid arthritis. Later, a significant additive effect of 100 mg diclofenac with 1 g acetaminophen was demonstrated in a dental pain model.

One review article conclude that acetaminophen and NSAIDs may be appropriate to combine, and the combination is superior to acetaminophen, but not to NSAIDs alone. This view is contested by another review article which concludes that paracetamol may enhance the analgesic effect when added to an NSAID. In both reviews the authors also state that the clinical trials are too few, with different drug formulations, and different pain models not allowing definite conclusions.

There seems to be a need for studies investigating the potential synergistic effects of paracetamol combined with another NSAID displaying similar pharmacokinetic characteristics. To the best of our knowledge no published study has investigated the analgesic effect of the combination of ibuprofen and paracetamol, ibuprofen and paracetamol + codeine versus placebo (i.e. negative control to adjust for possible analgesic placebo effects) and the best standard analgesic treatment (i.e. paracetamol + codeine) as a positive control group.

• Study Type: Interventional
• Study Phase: Phase 4
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Pain, Postoperative

Intervention

• Drug: Ibuprofen + Paracetamol
  Single oral dose of ibuprofen 400 mg combined with paracetamol (acetaminophen) 1000 mg in gelatine capsules
  Other Names:

  • Ibuprofen
  • ATC code: M01A E01
  • Paracetamol (Acetaminophen)
  • ATC code: N02B E01
• Drug: Ibuprofen + Paracetamol + Codeine
  Single oral dose of ibuprofen 400 mg combined with paracetamol (acetaminophen) 1000 mg and codeine 60 mg in gelatine capsules
  Other Names:

  • Ibuprofen
  • ATC code: M01A E01
  • Paracetamol (Acetaminophen)
  • ATC code: N02B E01
  • Codeine
  • ATC code: R05D A04
• Drug: Paracetamol + Codeine
  Single oral dose of paracetamol (acetaminophen) 1000 mg combined with codeine 60 mg in gelatine capsules
  Other Names:

  • Paracetamol (Acetaminophen)
  • ATC code: N02B E01
  • Codeine
  • ATC code: R05D A04
• Drug: Placebo
  Single oral dose of lactose as placebo in gelatine capsules
  Other Names:

  • Lactose
  • CAS No: 63-42-3

Study Arms

• Experimental: Ibuprofen + Paracetamol
  Single oral dose of ibuprofen 400 mg + paracetamol (acetaminophen) 1000 mg
  Intervention: Drug: Ibuprofen + Paracetamol
• Experimental: Ibuprofen + Paracetamol + Codeine
  Single oral dose of ibuprofen 400 mg + paracetamol (acetaminophen) 1000 mg + codeine 60 mg
  Intervention: Drug: Ibuprofen + Paracetamol + Codeine
• Active Comparator: Paracetamol + Codeine
  Single oral dose of paracetamol (acetaminophen) 1000 mg + codeine 60 mg
  Intervention: Drug: Paracetamol + Codeine
• Placebo Comparator: Placebo
  Single oral dose of lactose as placebo
  Intervention: Drug: Placebo

Publications *

• Seideman P. Additive effect of combined naproxen and paracetamol in rheumatoid arthritis. Br J Rheumatol. 1993 Dec;32(12):1077-82. doi: 10.1093/rheumatology/32.12.1077.
• Seideman P, Samuelson P, Neander G. Naproxen and paracetamol compared with naproxen only in coxarthrosis. Increased effect of the combination in 18 patients. Acta Orthop Scand. 1993 Jun;64(3):285-8. doi: 10.3109/17453679308993626.
• Breivik EK, Barkvoll P, Skovlund E. Combining diclofenac with acetaminophen or acetaminophen-codeine after oral surgery: a randomized, double-blind single-dose study. Clin Pharmacol Ther. 1999 Dec;66(6):625-35. doi: 10.1053/cp.1999.v66.103629001.
• Romsing J, Moiniche S, Dahl JB. Rectal and parenteral paracetamol, and paracetamol in combination with NSAIDs, for postoperative analgesia. Br J Anaesth. 2002 Feb;88(2):215-26. doi: 10.1093/bja/88.2.215.
• Hyllested M, Jones S, Pedersen JL, Kehlet H. Comparative effect of paracetamol, NSAIDs or their combination in postoperative pain management: a qualitative review. Br J Anaesth. 2002 Feb;88(2):199-214. doi: 10.1093/bja/88.2.199.
• Skoglund LA, Skjelbred P, Fyllingen G. Analgesic efficacy of acetaminophen 1000 mg, acetaminophen 2000 mg, and the combination of acetaminophen 1000 mg and codeine phosphate 60 mg versus placebo in acute postoperative pain. Pharmacotherapy. 1991;11(5):364-9.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: June 15, 2009): 200
• Original Estimated Enrollment: Same as current
• Actual Study Completion Date: April 2015
• Actual Primary Completion Date: November 2014 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Patients of ASA class I in need of surgical removal of impacted third molars and with at least moderate postoperative pain as defined by subjective score on a verbal rating scale after surgical removal of third molars.

Exclusion Criteria:

• Females stating not suspected or not verified pregnancy after being questioned by investigator.
• Patients who have used analgesics for 3 days prior to the day of surgery.
• Patients with known active gastrointestinal bleeding or ulcer.
• Patients with any known hypersensitivity to NSAIDs.
• Patients with other drug treatment than contraceptives.
• Patients smoking before taking the test-drug or during the observation period.
• Drug addicts or rehabilitated drug addicts.
• Patients with surgery time exceeding 60 minutes
• Peroperative complications such as profuse bleeding or perforation to the maxillary sinus requiring additional drug treatment during or after the surgical removal of the third molar.
• Postoperative complications such as extended bleeding, nausea and regurgitation during the observation period.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 30 Years (Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Norway

Administrative Information

• NCT Number: NCT00921700
• Other Study ID Numbers: PARIBU-022; EUDRACT No. 2007-001778-10
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Lasse Ansgar Skoglund, Oslo University Hospital
• Original Responsible Party: Professor Lasse A. Skoglund, DDS, DSci, University of Oslo
• Current Study Sponsor: Ullevaal University Hospital
• Original Study Sponsor: Same as current
• Collaborators: University of Oslo

Investigators

• Study Director: Lasse A Skoglund, DDS, DSci; University of Oslo
• Principal Investigator: Gaute Lyngstad, DDS; University of Oslo

• PRS Account: Oslo University Hospital
• Verification Date: March 2016