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

Condition(s) targeted: Pain, Postoperative

Intervention: Ibuprofen + Paracetamol (Drug); Ibuprofen + Paracetamol + Codeine (Drug); Paracetamol + Codeine (Drug); Placebo (Drug)

Phase: Phase 4

Status: Recruiting

Sponsored by: Ullevaal University Hospital

Official(s) and/or principal investigator(s):
Lasse A Skoglund, DDS, DSci, Study Director, Affiliation: University of Oslo
Gaute Lyngstad, DDS, Principal Investigator, Affiliation: University of Oslo

Overall contact:
Lasse A Skoglund, DDS, DSci, Phone: 004722844672, Email: lasses@odont.uio.no

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.

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 design: Allocation: Randomized, Endpoint Classification: Pharmacodynamics Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Primary outcome: Sum pain intensity SPI (0-10 Numerical Rating Scale)

Secondary outcome:

Sum pain intensity difference score (PID)

Overall assessment of efficacy (4-point Verbal Rating Scale)

Adverse effects AE (Specific reporting of AE - type, duration and severity)

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.

Minimum age: 18 Years. Maximum age: 30 Years. Gender(s): Both.

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.

Lasse A Skoglund, DDS, DSci, Phone: 004722844672, Email: lasses@odont.uio.no

Ullevaal University Hospital, Oslo NO-0407, Norway; Recruiting
Lasse A Skoglund, DDS, DSci, Phone: 004722844672, Email: lasses@odont.uio.no
Gaute Lyngstad, DDS, Phone: 004722844673, Email: gautelyn@odont.uio.no
Gaute Lyngstad, DDS, Principal Investigator
Lasse A Skoglund, DDS, DSci, Sub-Investigator

Related publications:

Seideman P. Additive effect of combined naproxen and paracetamol in rheumatoid arthritis. Br J Rheumatol. 1993 Dec;32(12):1077-82.

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.

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.

Rømsing J, Møiniche 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. Review.

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. Review.

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.

Starting date: June 2009
Last updated: March 2, 2010