Clinical trial NCT00921700: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Pain, Postoperative
Keywords: Paracetamol
Acetaminophen
Ibuprofen
Pain
Postoperative pain
third molar
Lead sponsor: Oslo University Hospital
Sponsor class: OTHER
Collaborators: name: University of Oslo
First posted: 2009-06-16
Enrollment: 200
Sex: ALL
Minimum age (years): 18
Maximum age (years): 30
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Sum pain intensity SPI (0-10 Numerical Rating Scale)
timeFrame: 6 hours
Secondary outcomes:
measure: Sum pain intensity difference score (PID)
timeFrame: 6 hours
measure: Overall assessment of efficacy (4-point Verbal Rating Scale)
timeFrame: 6 hours
measure: Adverse effects AE (Specific reporting of AE - type, duration and severity)
timeFrame: 6 hours
Other outcomes:
Locations:
city: Oslo
country: Norway
facility: Ullevaal University Hospital
Study officials:
affiliation: University of Oslo
name: Lasse A Skoglund, DDS, DSci
role: STUDY_DIRECTOR
affiliation: University of Oslo
name: Gaute Lyngstad, DDS
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.