Analgesic Effect of Different Combinations of Dexketoprofen Trometamol With Tramadol Hydrochloride in a Model of Moderate to Severe Pain

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the analgesic efficacy of Dexketoprofen Trometamol and Tramadol Hydrochloride given in combinations and the analgesic efficacy of each single component in comparison to placebo on moderate to severe pain following impacted third mandibular molar tooth extraction. Ibuprofen will be used as an active control to validate the pain model.

Detailed Description
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The aim of this study is to develop a combination of Dexketoprofen Trometamol (DKP.TRIS) and Tramadol Hydrochloride (TRAM.HCl) for the treatment of acute moderate to severe pain, based on the rationale that more than one drug is necessary in most patients suffering of acute and chronic pain, particularly of moderate to severe intensity. DKP.TRIS and TRAM.HCl have different mechanisms of action, therefore their combination is expect to result in an additive or synergistic analgesia, thus allowing a decrease in the required doses of the individual agents, and consequently a reduced risk of adverse events In this study, patients who present moderate to severe pain after impacted third mandibular molar tooth extraction will be randomised to a total of 10 treatment arms including 4 combinations of DKP.TRIS + TRAM.HCl, the four corresponding single treatments, placebo and ibuprofen. Treatment administration will be followed by a 24-hour pain and analgesic effect assessment.

Official Title
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Double-blind, Randomised, Placebo and Active Controlled, Parallel Group Study to Evaluate the Analgesic Effect of a Single Oral Administration of Four Different Combination Doses of DKP.TRIS With TRAM.HCL in Comparison With the Single Agents, on Moderate to Severe Pain Following Impacted Third Mandibular Molar Tooth Extraction

Conditions
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Pain

Intervention / Treatment
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* Drug: Dexketoprofen Trometamol
* Drug: Dexketoprofen Trometamol
* Drug: Tramadol Hydrochloride
* Drug: Tramadol Hydrochloride
* Drug: Ibuprofen
* Drug: Placebo
* Drug: Dexketoprofen Trometamol + Tramadol Hydrochloride
* Drug: Dexketoprofen Trometamol + Tramadol Hydrochloride
* Drug: Dexketoprofen Trometamol + Tramadol Hydrochloride
* Drug: Dexketoprofen Trometamol + Tramadol Hydrochloride


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients meeting ALL the following criteria will be eligible for entry into the study: Male or female patients aged 18 to 70 years old. Females participating in the study must be either: of non-childbearing potential, or willing to use a highly effective contraceptive method. Scheduled for outpatient surgical extraction -under local anaesthesia- of third mandibular molar teeth, with at least one of which is fully or partially impacted in the mandible requiring bone manipulation. Normal physical examination or without clinically relevant abnormalities. At randomisation (after surgery): No intake of analgesics (including prescription and over the counter drugs) within 24h prior to the surgery. No complication during the surgery, duration of surgery < 1 hour and not requiring re-anaesthesia. Patients experiencing pain of moderate or higher intensity in the first four hours after the end of surgery. Exclusion Criteria: History of allergy or hypersensitivity to NSAIDs, opioids or acetyl salicylic acid. History of asthma, bronchospasm, acute rhinitis, nasal polyps, urticaria or angioneurotic oedema. History of peptic ulcer, gastrointestinal disorders by NSAIDs, gastrointestinal bleeding or other active bleedings.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br> | Drug: Placebo<br>* Placebo, oral film-coated table, once<br>|
| Active Comparator: Ibuprofen<br> | Drug: Ibuprofen<br>* Ibuprofen 400 mg, oral film-coated table, once<br>|
| Active Comparator: TRAM.HCl high dose<br> | Drug: Tramadol Hydrochloride<br>* Tramadol Hydrochloride high dose, oral film-coated table, once<br>|
| Active Comparator: TRAM.HCl low dose<br> | Drug: Tramadol Hydrochloride<br>* Tramadol Hydrochloride low dose, oral film-coated table, once<br>|
| Active Comparator: DKP-TRIS high dose<br> | Drug: Dexketoprofen Trometamol<br>* Dexketoprofen Trometamol high dose, oral film-coated table, once<br>|
| Active Comparator: DKP-TRIS low dose<br> | Drug: Dexketoprofen Trometamol<br>* Dexketoprofen Trometamol low dose, oral film-coated table, once<br>|
| Experimental: DKP-TRIS low dose - TRAM.HCl low dose<br> | Drug: Dexketoprofen Trometamol + Tramadol Hydrochloride<br>* DKP-TRIS low dose - TRAM.HCl low dose, oral film-coated table, once<br>|
| Experimental: DKP-TRIS low dose - TRAM.HCl high dose<br> | Drug: Dexketoprofen Trometamol + Tramadol Hydrochloride<br>* DKP-TRIS low dose - TRAM.HCl high dose, oral film-coated table, once<br>|
| Experimental: DKP-TRIS high dose - TRAM.HCl low dose<br> | Drug: Dexketoprofen Trometamol + Tramadol Hydrochloride<br>* DKP-TRIS high dose - TRAM.HCl low dose, oral film-coated tablet, once<br>|
| Experimental: DKP-TRIS high dose - TRAM.HCl high dose<br> | Drug: Dexketoprofen Trometamol + Tramadol Hydrochloride<br>* DKP-TRIS high dose - TRAM.HCl high dose, oral film-coated tablet, once<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Patients Achieving at Least 50 % of the Theoretical Maximum Total Pain Relief Score at 6 Hours Post-dosing. | Pain relief is measured by a verbal rating scale (ranging from 0=none to 4=complete). Theoretical maximum TOTPAR at 6 hours is calculated by summing up the maximum score of analgesia which the patient can attribute at defined time points along 6 hour (maxTOTPAR6h= 24). Unit of measure is % | 6 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Patients Achieving at Least 50 % of the Theoretical Maximum Total Pain Relief Score at 4, 8 and 12 Hours Post-dosing. | Pain relief is measured by a verbal rating scale (ranging from 0=none to 4=complete). Theoretical maximum TOTPAR at 6 hours is calculated by summing up the maximum score of analgesia which the patient can attribute at defined time points along 4, 8 and 12 hours(maxTOTPAR4h= 16, maxTOTPAR8h= 32 and maxTOTPAR12h= 48, respectively) Unit of measure is % | 4, 8 and 12 hours | 
| Percentage of Patients Using Rescue Medication at 6 Hours | Percentage of patients using rescue medication at 6 hours post-dosing. | Baseline to 6 hours | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Moderate to severe pain, Postoperative pain, Analgesics, Dexketoprofen, Tramadol