Analgesic Effect of Ibuprofen, Paracetamol (Acetaminophen), and Paracetamol (Acetaminophen) Plus Codeine on Acute Pain

Study Overview
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Brief Summary
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The purpose of this placebo controlled clinical trial is to evaluate the dose response relationship of ibuprofen in doses from 400 mg to 800 mg and paracetamol (acetaminophen)in doses from 500 mg to 1000 mg compared with paracetamol (acetaminophen)1000 mg plus codeine 60 mg on acute postoperative pain after surgical removal of impacted third molars.

Detailed Description
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Acetaminophen (paracetamol) and related aspirin-like drugs have traditionally been used for pain control of minor to moderate postoperative pain. Gradually traditional non-steroidal anti-inflammatory drugs (NSAIDs) have become more popular as analgesics due to assumed superior therapeutic effects and aggressive marketing campaigns orchestrated by the pharmaceutical industry. Ibuprofen is a widely used analgesic both in non-prescription and prescription doses. A dose-response relationship for low ibuprofen doses is shown. Evidence of a progressing dose response relationship for moderate (i.e. 400 mg) to higher doses is scarce. A possible analgesic ceiling effect has been suggested for doses above 400 mg, although a correlation between given ibuprofen doses above 400 mg and patient serum levels is shown. However, it may be questioned if the plasma concentration of ibuprofen is an important determinator of analgesic drug efficacy. A higher dose is more likely to influence the duration of analgesic effect rather than the peak analgesic effect. There are few clinical trials investigating the dose-response relationship of increasing ibuprofen doses and paracetamol doses. To our knowledge no published study has investigated the dose-response relationship of ibuprofen and paracetamol in the same trial with a negative (i.e. placebo) and a positive (i.e. best standard analgesic treatment) control group.

Official Title
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Analgesic Effect of Ibuprofen 400, 600 and 800 mg, Paracetamol 500 and 1000 mg, and Paracetamol 1000 mg Plus 60 mg Codeine: Single-dose, Randomized, Placebo-controlled and Double-blind Study on Acute Pain After Third Molar Surgery

Conditions
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Surgery

Intervention / Treatment
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* Drug: Placebo
* Drug: Ibuprofen 400 mg
* Drug: Ibuprofen 600 mg
* Drug: Ibuprofen 800 mg
* Drug: Paracetamol (acetaminophen) 500 mg
* Drug: Paracetamol (acetaminophen) 1000 mg
* Drug: Paracetamol (acetaminophen) 1000 mg + codeine 60 mg


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients of both sexes referred for surgical removal of impacted third molars, due to symptoms or after being advised to do so by their dentist. Persons of both sexes (ASA type I). Females who are not pregnant or plan conception. Persons who have not used analgesics for 3 days prior to the day of surgery. Persons without known active ulcus or gastrointestinal bleeding. Persons without any known hypersensitivity for NSAIDs. Persons under no other continuous drug treatment than contraceptives. Caucasian origin. Persons with at least moderate postoperative pain as defined by subjective score on a verbal rating scale after surgical removal of third molars. Exclusion Criteria: 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. Smoking before taking the test-drug or during the observation period.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 30 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Single dose placebo capsule | Drug: Placebo<br>* Lactose as powder in gelatine capsules, single dose<br>* Other names: Lactose;|
| Active Comparator: Ibuprofen 400 mg<br>Single dose ibuprofen 400 mg capsule | Drug: Ibuprofen 400 mg<br>* Ibuprofen 400 mg as powder in gelatine capsules, single dose<br>* Other names: M01A E01 Ibuprofen;|
| Active Comparator: Ibuprofen 600 mg<br>Single dose ibuprofen 600 mg capsule | Drug: Ibuprofen 600 mg<br>* Ibuprofen 600 mg as powder in gelatine capsules, single dose<br>* Other names: M01A E01 Ibuprofen;|
| Active Comparator: Ibuprofen 800 mg<br>Single dose ibuprofen 800 mg capsule | Drug: Ibuprofen 800 mg<br>* Ibuprofen 800 mg as powder in gelatine capsules, single dose<br>* Other names: M01A E01 Ibuprofen;|
| Active Comparator: Paracetamol 500 mg<br>Paracetamol 500 mg (acetaminophen) capsule | Drug: Paracetamol (acetaminophen) 500 mg<br>* Paracetamol (acetaminophen) 500 mg as powder in gelatine capsules, single dose<br>* Other names: N02B E01 Paracetamol (acetaminophen);|
| Active Comparator: Paracetamol 1000 mg<br>Single dose paracetamol 1000 mg (acetaminophen) capsule | Drug: Paracetamol (acetaminophen) 1000 mg<br>* Paracetamol (acetaminophen) 1000 mg as powder in gelatine capsules, single dose<br>* Other names: N02B E01 Paracetamol (acetaminophen);|
| Active Comparator: Paracetamol 1000 mg + codeine 60 mg<br>Single dose paracetamol (acetaminophen) 1000 mg + codeine 60 mg capsule | Drug: Paracetamol (acetaminophen) 1000 mg + codeine 60 mg<br>* Paracetamol (acetaminophen) 1000 mg + codeine 60 mg as powder in gelatine capsules, single dose<br>* Other names: N02B E01 Paracetamol (acetaminophen) + R05D A04 codeine;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Sum Pain Intensity Score(SPI) |  | 3 hour observation period | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Sum Pain Intensity Difference Score (SPID) |  | 3 hours | 
| Sum Pain Intensity Score (SPI) |  | 6 hours | 
| Sum Pain Intensity Difference Score (SPID) |  | 6 hours | 
| Maximum Pain Intensity Difference Score (MAXPID) |  | Unknown, calculated variable | 
| Time to Maximum Pain Intensity Difference Score |  | Unknown, calculated variable | 
| Self-reported Occurrence of Adverse Effects |  | 3 hours | 
| Self-reported Occurrence of Adverse Effects |  | 6 hours | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pain, Analgesics, Molar, Third, Acetaminophen, Paracetamol, Ibuprofen, Codeine, Placebo