Tramadol/Diclofenac Fixed-dose Combination Phase III Trial in Acute Pain After Third Molar Extraction

The purpose of this study was to demonstrate that the FDC of Tramadol and Diclofenac 50/50 has superior analgesic effect than the monotherapies and that the FDC of Tramadol and Diclofenac 25/25 has non-inferior analgesic effect than the monotherapies. There was an Enrollment Period, a blinded Treatment Period, and a Follow-up Period. Previously used analgesic medication was washed out for at least 24 hours before surgery. The Treatment Period starts on Day 1 with dental surgery and treatment allocation. Treatment was started within 4 hours after the end of surgery if the participant's pain intensity had reached at least 5 points on the 11-point numerical rating scale (NRS). Each participant received 3 doses of one of the four treatments within 24 hours. One fourth of the participants received the fixed-dose combination tablet at a low dose, one fourth at the higher dose, one fourth received 50 mg of the comparator tramadol alone, and one fourth 50 mg of the comparator diclofenac alone.

The first 2 doses of the investigational medicinal product (IMP) were taken at the site, the last dose in an out-patient setting. Participants returned to the site at 24 hours after the first dose. A Follow-up Period included a final visit at the site or a phone call on Day 14 to assess the participant's safety.

Inclusion criteria

• The participant has read the informed consent form, has understood the relevant aspects of the clinical study, and grants his/her authorization to participate by signing the informed consent form prior to the inclusion in the clinical study and the performance of any procedure.
• Male and female participants above 18 years up to 60 years.
• Female participants of childbearing potential must be practicing an acceptable method of birth control and must have a negative urine pregnancy test at enrollment with confirmation at the Allocation Visit.
• Participants are in good health, i.e., the medical record, vital signs, physical examination, and laboratory parameter assessments do not show any abnormal deviations impeding the participation in the clinical study.
• Participants requiring extraction of 3 or more third molars with 2 mandibular impacted third molars.
• Clinical and radiological diagnosis of impacted lower third molars.
• Class I and Class II molars according to Pell and Gregory's classification (Gay Escoda et al. 2004).
• Participants must be able to swallow the IMPs.

Exclusion criteria

at Enrollment:

• Findings in the medical record, vital signs, and/or physical examination demonstrating abnormal conditions of participant's general state of health preventing his/her participation in the clinical study according to the investigator's opinion.
• Participant unable to speak, read, or write in Spanish language.
• Clinical laboratory parameters exceed the pre-defined alert ranges (i.e., 1 standard deviation above or below the upper/lower limit of the normal ranges).
• Known hypersensitivity to the IMPs, the anesthetic to be used during surgery, or to the rescue medication (ibuprofen, ketorolac).
• Known alcohol or drug abuse in the last 6 months or any history of seizures. Alcohol abuse is defined as the consumption of more than 3 ounces (about 90 milliliters) of liquor or spirits or 18 ounces (about 530 milliliters) of beer per day, for 5 consecutive days during the 6-month period. Drug abuse is defined as the use of any recreational drug for 5 consecutive days during the 6 month period.
• Participants who take analgesic medication for chronic pain, monoamine oxidase inhibitors, tricyclic antidepressants, neuroleptics, or other drugs that reduce the seizure threshold within 4 weeks of enrollment.
• Pregnant or lactating women.
• Participants who received systemic corticosteroids or opioid analgesics less than 2 weeks before surgery.
• Participants with molars linked to the mandibular canal.
• Participants requiring immediate dental procedures other than third and fourth molars extraction,

Exclusion criteria

at the Allocation Visit:

• Participant received a long-acting non-steroidal anti-inflammatory drug within 24 hours or 5 times the elimination half-life of that drug prior to surgery, whatever the longer.
• Participant received any analgesic medication other than short-acting pre-operative or intra-operative anesthetic agents within 24 hours before taking IMPs.
• Participant received more than 300 mg of lidocaine in total.
• Participant received any analgesic medication other than the IMPs immediately after the oral surgical procedure was completed.
• Baseline pain intensity of the participant after oral surgical procedure remains below 5 points on the 11-point NRS.