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

Pain, Postoperative Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00921700
• Other study ID #: PARIBU-022
• Secondary ID: EUDRACT No. 2007
• Status: Completed
• Phase: Phase 4
• First received: June 15, 2009
• Last updated: March 29, 2016
• Start date: June 2009
• Est. completion date: April 2015

Study information

• Verified date: March 2016
• Source: Oslo University Hospital
• Contact: n/a
• Is FDA regulated: No
• Health authority: Norway:National Committee for Medical and Health Research EthicsNorway: Norwegian Medicines AgencyNorway: Norwegian Social Science Data Services
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 200
• Est. completion date: April 2015
• Est. primary completion date: November 2014
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 30 Years

Eligibility

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.

Study Design

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

Related Conditions & MeSH terms

• Pain, Postoperative

Intervention

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

Locations

Country	Name	City	State
Norway	Ullevaal University Hospital	Oslo

Sponsors (2)

Lead Sponsor	Collaborator
Ullevaal University Hospital	University of Oslo

Country where clinical trial is conducted

Norway, 

References & Publications (6)

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. — View 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. Review. — View Citation

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. — View 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. — View Citation

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

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Sum pain intensity SPI (0-10 Numerical Rating Scale)		6 hours	No
Secondary	Sum pain intensity difference score (PID)		6 hours	No
Secondary	Overall assessment of efficacy (4-point Verbal Rating Scale)		6 hours	No
Secondary	Adverse effects AE (Specific reporting of AE - type, duration and severity)		6 hours	Yes