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”

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.

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.

Intervention(s) in this Clinical Trial

• Drug: Ibuprofen + Paracetamol
  • Single oral dose of ibuprofen 400 mg combined with paracetamol (acetaminophen) 1000 mg in gelatine capsules
• Drug: Ibuprofen + Paracetamol + Codeine
  • Single oral dose of ibuprofen 400 mg combined with paracetamol (acetaminophen) 1000 mg and codeine 60 mg in gelatine capsules
• Drug: Paracetamol + Codeine
  • Single oral dose of paracetamol (acetaminophen) 1000 mg combined with codeine 60 mg in gelatine capsules
• Drug: Placebo
  • Single oral dose of lactose as placebo in gelatine capsules

Arms, Groups and Cohorts in this Clinical Trial

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

Primary Measures

• Sum pain intensity SPI (0-10 Numerical Rating Scale)
  • Time Frame: 6 hours
    Safety Issue?: No

Secondary Measures

• Sum pain intensity difference score (PID)
  • Time Frame: 6 hours
    Safety Issue?: No
• Overall assessment of efficacy (4-point Verbal Rating Scale)
  • Time Frame: 6 hours
    Safety Issue?: No
• Adverse effects AE (Specific reporting of AE - type, duration and severity)
  • Time Frame: 6 hours
    Safety Issue?: Yes

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.

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: 30 Years

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Investigator: Ullevaal University Hospital Other

Overall Clinical Trial Officials and Contacts

Lasse A Skoglund, DDS, DSci Study Director University of Oslo  

Overall Contact: Lasse A Skoglund, DDS, DSci 004722844672 lasses@odont.uio.no

Information obtained from ClinicalTrials.gov on February 09, 2012

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00921700

Study ID Number: PARIBU-022

ClinicalTrials.gov Identifier: NCT00921700

Health Authority: Norway: The National Committees for Research Ethics in Norway