Analgesic Effect of Paracetamol, Paracetamol + Codeine, Ibuprofen and Their Combination - Full Text View

Sponsor:	Ullevaal University Hospital
Collaborator:	University of Oslo
Information provided by:	Ullevaal University Hospital
ClinicalTrials.gov Identifier:	NCT00921700

Purpose

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.

Condition	Intervention	Phase
Pain, Postoperative	Drug: Ibuprofen + Paracetamol Drug: Ibuprofen + Paracetamol + Codeine Drug: Paracetamol + Codeine Drug: Placebo	Phase IV

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

Resource links provided by NLM:

Drug Information available for: Lactose Ibuprofen Codeine phosphate Codeine Acetaminophen CT 2584

U.S. FDA Resources

Further study details as provided by Ullevaal University Hospital:

Primary Outcome Measures:

Sum pain intensity SPI (0-10 Numerical Rating Scale) [ Time Frame: 6 hours ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

Sum pain intensity difference score (PID) [ Time Frame: 6 hours ] [ Designated as safety issue: No ]
Overall assessment of efficacy (4-point Verbal Rating Scale) [ Time Frame: 6 hours ] [ Designated as safety issue: No ]
Adverse effects AE (Specific reporting of AE - type, duration and severity) [ Time Frame: 6 hours ] [ Designated as safety issue: Yes ]

Estimated Enrollment:	200
Study Start Date:	June 2009
Estimated Study Completion Date:	June 2011
Estimated Primary Completion Date:	June 2011 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: Ibuprofen + Paracetamol Single oral dose of ibuprofen 400 mg + paracetamol (acetaminophen) 1000 mg	Drug: Ibuprofen + Paracetamol Single oral dose of ibuprofen 400 mg combined with paracetamol (acetaminophen) 1000 mg in gelatine capsules Other Names: Ibuprofen ATC code: M01A E01 Paracetamol (Acetaminophen) ATC code: N02B E01
Experimental: Ibuprofen + Paracetamol + Codeine Single oral dose of ibuprofen 400 mg + paracetamol (acetaminophen) 1000 mg + codeine 60 mg	Drug: Ibuprofen + Paracetamol + Codeine Single oral dose of ibuprofen 400 mg combined with paracetamol (acetaminophen) 1000 mg and codeine 60 mg in gelatine capsules Other Names: Ibuprofen ATC code: M01A E01 Paracetamol (Acetaminophen) ATC code: N02B E01 Codeine ATC code: R05D A04
Active Comparator: Paracetamol + Codeine Single oral dose of paracetamol (acetaminophen) 1000 mg + codeine 60 mg	Drug: Paracetamol + Codeine Single oral dose of paracetamol (acetaminophen) 1000 mg combined with codeine 60 mg in gelatine capsules Other Names: Paracetamol (Acetaminophen) ATC code: N02B E01 Codeine ATC code: R05D A04
Placebo Comparator: Placebo Single oral dose of lactose as placebo	Drug: Placebo Single oral dose of lactose as placebo in gelatine capsules Other Names: Placebo Lactose CAS No: 63-42-3

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

Ages Eligible for Study:	18 Years to 30 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

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.

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00921700

Contacts

Contact: Lasse A Skoglund, DDS, DSci	004722844672	lasses@odont.uio.no
Contact: Per Skjelbred, DDS, MD, PhD	004722118484	p.skjelbred@ulleval.no

Locations

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

Sponsors and Collaborators

Ullevaal University Hospital

University of Oslo

Investigators

Study Director:	Lasse A Skoglund, DDS, DSci	University of Oslo
Principal Investigator:	Gaute Lyngstad, DDS	University of Oslo

More Information

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.

Responsible Party:	Professor Lasse A. Skoglund, DDS, DSci, University of Oslo
ClinicalTrials.gov Identifier:	NCT00921700 History of Changes
Other Study ID Numbers:	PARIBU-022, EUDRACT No. 2007-001778-10
Study First Received:	June 15, 2009
Last Updated:	March 2, 2010
Health Authority:	Norway: The National Committees for Research Ethics in Norway; Norway: Norwegian Medicines Agency; Norway: Norwegian Social Science Data Services

Keywords provided by Ullevaal University Hospital:

Paracetamol
Acetaminophen
Ibuprofen

Pain
Postoperative pain
third molar

Additional relevant MeSH terms:

Pain, Postoperative
Postoperative Complications
Pathologic Processes
Pain
Signs and Symptoms
Acetaminophen
Ibuprofen
Analgesics
Codeine
Antipyretics
Physiological Effects of Drugs
Pharmacologic Actions
Analgesics, Non-Narcotic
Sensory System Agents

Peripheral Nervous System Agents
Central Nervous System Agents
Therapeutic Uses
Analgesics, Opioid
Central Nervous System Depressants
Antitussive Agents
Respiratory System Agents
Narcotics
Anti-Inflammatory Agents, Non-Steroidal
Anti-Inflammatory Agents
Antirheumatic Agents
Cyclooxygenase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on February 09, 2012