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

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ClinicalTrials.gov Identifier: NCT00921700

Recruitment Status : Completed

First Posted : June 16, 2009

Last Update Posted : March 30, 2016

Sponsor:

Collaborator:

University of Oslo

Information provided by (Responsible Party):

Lasse Ansgar Skoglund, Oslo University Hospital

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Pain, Postoperative	Drug: Ibuprofen + Paracetamol Drug: Ibuprofen + Paracetamol + Codeine Drug: Paracetamol + Codeine Drug: Placebo	Phase 4

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.

Study Design


Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	200 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	Quadruple (Participant, Care Provider, 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
Study Start Date :	June 2009
Actual Primary Completion Date :	November 2014
Actual Study Completion Date :	April 2015

Resource links provided by the National Library of Medicine

Drug Information available for: Codeine Ibuprofen Ibuprofen sodium Ibuprofen lysine

U.S. FDA Resources

Arms and Interventions

Arm	Intervention/treatment
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: Lactose CAS No: 63-42-3

Outcome Measures

Primary Outcome Measures :

Sum pain intensity SPI (0-10 Numerical Rating Scale) [ Time Frame: 6 hours ]

Secondary Outcome Measures :

Sum pain intensity difference score (PID) [ Time Frame: 6 hours ]
Overall assessment of efficacy (4-point Verbal Rating Scale) [ Time Frame: 6 hours ]
Adverse effects AE (Specific reporting of AE - type, duration and severity) [ Time Frame: 6 hours ]

Eligibility Criteria

Information from the National Library of Medicine

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Ages Eligible for Study:	18 Years to 30 Years (Adult)
Sexes Eligible for Study:	All
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00921700

Locations


Norway
Ullevaal University Hospital
Oslo, Norway, NO-0407

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:	Lasse Ansgar Skoglund, Professor, Oslo University Hospital
ClinicalTrials.gov Identifier:	NCT00921700 History of Changes
Other Study ID Numbers:	PARIBU-022 EUDRACT No. 2007-001778-10
First Posted:	June 16, 2009 Key Record Dates
Last Update Posted:	March 30, 2016
Last Verified:	March 2016

Keywords provided by Lasse Ansgar Skoglund, Oslo University Hospital:


Paracetamol Acetaminophen Ibuprofen	Pain Postoperative pain third molar

Additional relevant MeSH terms:


Pain, Postoperative Pain Neurologic Manifestations Nervous System Diseases Postoperative Complications Pathologic Processes Signs and Symptoms Acetaminophen Ibuprofen Analgesics Codeine Analgesics, Non-Narcotic Sensory System Agents Peripheral Nervous System Agents	Physiological Effects of Drugs Antipyretics Anti-Inflammatory Agents, Non-Steroidal Anti-Inflammatory Agents Antirheumatic Agents Cyclooxygenase Inhibitors Enzyme Inhibitors Molecular Mechanisms of Pharmacological Action Analgesics, Opioid Narcotics Central Nervous System Depressants Antitussive Agents Respiratory System Agents

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