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

NCT ID: NCT00921700

Last Updated: 2016-03-30

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE4
• Total Enrollment: 200 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2009-06-30
• Study Completion Date: 2015-04-30

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.

Conditions

Pain, Postoperative

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Ibuprofen + Paracetamol

Single oral dose of ibuprofen 400 mg + paracetamol (acetaminophen) 1000 mg

Group Type: EXPERIMENTAL

Ibuprofen + Paracetamol

Intervention Type: DRUG

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 + paracetamol (acetaminophen) 1000 mg + codeine 60 mg

Group Type: EXPERIMENTAL

Ibuprofen + Paracetamol + Codeine

Intervention Type: DRUG

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 + codeine 60 mg

Group Type: ACTIVE_COMPARATOR

Paracetamol + Codeine

Intervention Type: DRUG

Single oral dose of paracetamol (acetaminophen) 1000 mg combined with codeine 60 mg in gelatine capsules

Placebo

Single oral dose of lactose as placebo

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Single oral dose of lactose as placebo in gelatine capsules

Interventions

Ibuprofen + Paracetamol

Single oral dose of ibuprofen 400 mg combined with paracetamol (acetaminophen) 1000 mg in gelatine capsules

Intervention Type: DRUG

Ibuprofen + Paracetamol + Codeine

Single oral dose of ibuprofen 400 mg combined with paracetamol (acetaminophen) 1000 mg and codeine 60 mg in gelatine capsules

Intervention Type: DRUG

Paracetamol + Codeine

Single oral dose of paracetamol (acetaminophen) 1000 mg combined with codeine 60 mg in gelatine capsules

Intervention Type: DRUG

Placebo

Single oral dose of lactose as placebo in gelatine capsules

Intervention Type: DRUG

Other Intervention Names

Ibuprofen; ATC code: M01A E01; Paracetamol (Acetaminophen); ATC code: N02B E01; Ibuprofen; ATC code: M01A E01; Paracetamol (Acetaminophen); ATC code: N02B E01; Codeine; ATC code: R05D A04; Paracetamol (Acetaminophen); ATC code: N02B E01; Codeine; ATC code: R05D A04; Lactose; CAS No: 63-42-3

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.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 30 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

University of Oslo

OTHER

Sponsor Role: collaborator

Ullevaal University Hospital

OTHER

Sponsor Role: lead

Responsible Party

Lasse Ansgar Skoglund

Professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Lasse A Skoglund, DDS, DSci

Role: STUDY_DIRECTOR

University of Oslo

Gaute Lyngstad, DDS

Role: PRINCIPAL_INVESTIGATOR

University of Oslo

Locations

Ullevaal University Hospital

Oslo, , Norway

Countries

Norway

References

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.

Reference Type: BACKGROUND

PMID: 8252318 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 8322582 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 10613619 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 11878655 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 11878654 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 1745622 (View on PubMed)

Lyngstad G, Skjelbred P, Swanson DM, Skoglund LA. Analgesic effect of oral paracetamol 1000 mg/ibuprofen 400 mg, paracetamol 1000 mg/codeine 60 mg, paracetamol 1000 mg/ibuprofen 400 mg/codeine 60 mg, or placebo on acute postoperative pain: a single-dose, randomized, and double-blind study. Eur J Clin Pharmacol. 2023 Aug;79(8):1131-1141. doi: 10.1007/s00228-023-03525-0. Epub 2023 Jun 22.

Reference Type: DERIVED

PMID: 37349498 (View on PubMed)

Other Identifiers

EUDRACT No. 2007-001778-10

Identifier Type: -

Identifier Source: secondary_id

PARIBU-022

Identifier Type: -

Identifier Source: org_study_id