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

• Sum Pain Intensity Difference Score (SPID) [ Time Frame: 3 hours ] [ Designated as safety issue: No ]
• Sum Pain Intensity Score (SPI) [ Time Frame: 6 hours ] [ Designated as safety issue: No ]
• Sum Pain Intensity Difference Score (SPID) [ Time Frame: 6 hours ] [ Designated as safety issue: No ]
• Maximum Pain Intensity Difference Score (MAXPID) [ Time Frame: Unknown, calculated variable ] [ Designated as safety issue: No ]
• Time to Maximum Pain Intensity Difference Score [ Time Frame: Unknown, calculated variable ] [ Designated as safety issue: No ]
• Self-reported Occurrence of Adverse Effects [ Time Frame: 3 hours ] [ Designated as safety issue: Yes ]
• Self-reported Occurrence of Adverse Effects [ Time Frame: 6 hours ] [ Designated as safety issue: Yes ]

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.

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.

• Drug: Placebo
  Lactose as powder in gelatine capsules, single dose
  Other Name: Lactose
• Drug: Ibuprofen 400 mg
  Ibuprofen 400 mg as powder in gelatine capsules, single dose
  Other Name: M01A E01 Ibuprofen
• Drug: Ibuprofen 600 mg
  Ibuprofen 600 mg as powder in gelatine capsules, single dose
  Other Name: M01A E01 Ibuprofen
• Drug: Ibuprofen 800 mg
  Ibuprofen 800 mg as powder in gelatine capsules, single dose
  Other Name: M01A E01 Ibuprofen
• Drug: Paracetamol (acetaminophen) 500 mg
  Paracetamol (acetaminophen) 500 mg as powder in gelatine capsules, single dose
  Other Name: N02B E01 Paracetamol (acetaminophen)
• Drug: Paracetamol (acetaminophen) 1000 mg
  Paracetamol (acetaminophen) 1000 mg as powder in gelatine capsules, single dose
  Other Name: N02B E01 Paracetamol (acetaminophen)
• Drug: Paracetamol (acetaminophen) 1000 mg + codeine 60 mg
  Paracetamol (acetaminophen) 1000 mg + codeine 60 mg as powder in gelatine capsules, single dose
  Other Name: N02B E01 Paracetamol (acetaminophen) + R05D A04 codeine

• Placebo Comparator: Placebo
  Single dose placebo capsule
  Intervention: Drug: Placebo
• Active Comparator: Ibuprofen 400 mg
  Single dose ibuprofen 400 mg capsule
  Intervention: Drug: Ibuprofen 400 mg
• Active Comparator: Ibuprofen 600 mg
  Single dose ibuprofen 600 mg capsule
  Intervention: Drug: Ibuprofen 600 mg
• Active Comparator: Ibuprofen 800 mg
  Single dose ibuprofen 800 mg capsule
  Intervention: Drug: Ibuprofen 800 mg
• Active Comparator: Paracetamol 500 mg
  Paracetamol 500 mg (acetaminophen) capsule
  Intervention: Drug: Paracetamol (acetaminophen) 500 mg
• Active Comparator: Paracetamol 1000 mg
  Single dose paracetamol 1000 mg (acetaminophen) capsule
  Intervention: Drug: Paracetamol (acetaminophen) 1000 mg
• Active Comparator: Paracetamol 1000 mg + codeine 60 mg
  Single dose paracetamol (acetaminophen) 1000 mg + codeine 60 mg capsule
  Intervention: Drug: Paracetamol (acetaminophen) 1000 mg + codeine 60 mg

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.