Analgesic Effect of Different Combinations of Dexketoprofen Trometamol With Tramadol Hydrochloride in a Model of Moderate to Severe Pain (DEX-TRA 02)

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

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.

Study Overview

• Status: Completed
• Conditions: Pain
• Intervention / Treatment: Drug: Placebo; Drug: Ibuprofen; Drug: Tramadol Hydrochloride; Drug: Tramadol Hydrochloride; Drug: Dexketoprofen Trometamol; Drug: Dexketoprofen Trometamol; Drug: Dexketoprofen Trometamol + Tramadol Hydrochloride; Drug: Dexketoprofen Trometamol + Tramadol Hydrochloride; Drug: Dexketoprofen Trometamol + Tramadol Hydrochloride; Drug: Dexketoprofen Trometamol + Tramadol Hydrochloride

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 745
• Phase: Phase 2

Contacts and Locations

Study Locations

• Germany
  • Mecklenburg-Vorpommern
    • Greifswald, Mecklenburg-Vorpommern, Germany, 17475
      • Klinik und Polickinik für Mund-Kiefer-Gesichtschirurgie/Plastische Operationen Greifswald
  • Schleswig-Holstein
    • Kiel, Schleswig-Holstein, Germany, 24105
      • Klinik für Mund-, Kiefer- und Gesichtschirurgie, Universitätsklinikum Schleswig Holstein, Campus Kiel
• Hungary
  • Budapest, Hungary, 1052
    • Dr Tóth Bagi Zoltán Fogászati Rendeloje
• Italy
  • Pisa, Italy, 56126
    • Centro di Farmacologia Clinica per la Sperimentazione dei Farmaci
  • Verona, Italy, 37134
    • Centro di Ricerche Cliniche di Verona Srl. Policlinico G.B.Rossi
• Poland
  • Mazowieckie
    • Warsaw, Mazowieckie, Poland, 00-852
      • Gabinet Stomatologiczny Andrzej Wojtowicz AW Clinic
    • Warszawa, Mazowieckie, Poland, 02-791
      • Dental Service spólka jawna
• Spain
  • Madrid, Spain, 28040
    • Universidad Complutense de Madrid
  • Sevilla, Spain, 41009
    • Departamento de Estomatología, Facultad de Odontología. Universidad de Sevilla
  • Valencia, Spain, 46014
    • Hospital General Universitario de Valencia
  • Valencia, Spain, 046010
    • Departament d'Estomatologia, Clínica Odontològica, Universidad de Valencia - Fundació Lluís Alcanyís
  • A Coruña
    • Santiago de Compostela, A Coruña, Spain, 15706
      • Hospital Médico Quirúrgico de Conxo
  • Barcelona
    • L'Hospitalet de Llobregat, Barcelona, Spain, 08907
      • Facultad de Odontología. Departamento de Cirugía Bucal y Maxilofacial, University of Barcelona - Bellvitge Institute for Biomedical Research (IDIBELL)
• United Kingdom
  • England
    • Birmingham, England, United Kingdom, B4 6 NN
      • The School of Dentistry, College of Medical and Dental Sciences, University of Birmingham
    • Manchester, England, United Kingdom, M15 6FH
      • University Dental School Manchester
  • Wales
    • Cardiff, Wales, United Kingdom, CF14 4 XY
      • University Dental Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

10

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Menarini Group
• Collaborators: PRA Health Sciences
• Investigators: Study Chair: Cosme Gay-Escoda, Professor, Department of Oral and Maxillofacial Surgery, School of Dentistry, University of Barcelona - Bellvitge Institute for Biomedical Research (IDIBELL) 08907 Hospitalet de Llobregat, Barcelona (Spain); Study Chair: R Andrew Moore, Professor, Pain Research & Nuffield Division of Anaesthesics, Department of Clinical Neurosciences, University of Oxford. The Churchill, Oxford OX3 7LJ (United Kingdom)

Publications and helpful links

General Publications

• Moore RA, Gay-Escoda C, Figueiredo R, Toth-Bagi Z, Dietrich T, Milleri S, Torres-Lagares D, Hill CM, Garcia-Garcia A, Coulthard P, Wojtowicz A, Matenko D, Penarrocha-Diago M, Cuadripani S, Piza-Vallespir B, Guerrero-Bayon C, Bertolotti M, Contini MP, Scartoni S, Nizzardo A, Capriati A, Maggi CA. Dexketoprofen/tramadol: randomised double-blind trial and confirmation of empirical theory of combination analgesics in acute pain. J Headache Pain. 2015;16:541. doi: 10.1186/s10194-015-0541-5. Epub 2015 Jun 27.

Study record dates

Study Major Dates

• Study Start: February 1, 2011
• Primary Completion (Actual): October 1, 2011
• Study Completion (Actual): October 1, 2011

Study Registration Dates

• First Submitted: February 28, 2011
• First Submitted That Met QC Criteria: March 1, 2011
• First Posted (Estimate): March 2, 2011

Study Record Updates

• Last Update Posted (Estimate): August 12, 2013
• Last Update Submitted That Met QC Criteria: July 31, 2013
• Last Verified: July 1, 2013

More Information

Terms related to this study

• Keywords: Postoperative pain; Analgesics; Tramadol; Dexketoprofen; Moderate to severe pain
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Cyclooxygenase Inhibitors; Analgesics, Opioid; Narcotics; Ibuprofen; Tramadol; Ketoprofen; Dexketoprofen trometamol
• Other Study ID Numbers: DEX-TRA 02; 2010-022798-32 (EudraCT Number)