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

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.

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.