Utility of CYP2D6 Genotyping to Improve the Efficacy and Safety of Tramadol (Tradol-PriME)

Randomized Clinical Trial to Evaluate the Utility of CYP2D6 Genotyping to Improve the Efficacy and Safety of Tramadol in the Treatment of Acute Postoperative Pain.

Randomized clinical trial to evaluate the utility of CYP2D6 genotyping to improve the efficacy and safety of tramadol in the treatment of acute postoperative pain.

Phase IV and low-intervention trial To evaluate if the implementation of pharmacogenetics in clinical practice can help to improve the treatment of acute pain, increasing efficacy and reducing adverse reactions.

The main evaluation variable: This is a simple study, which does not differ from standard clinical practice and therefore we do not expect early ending of the study.

Study Overview

• Status: Recruiting
• Conditions: Postoperative Pain; Pain, Acute; Post-surgical Pain
• Intervention / Treatment: Drug: The patients in experimental group will be genotyped before surgery and treatment will be prescribed according to the CYP2D6 phenotype

Detailed Description

Randomized clinical trial to evaluate the utility of CYP2D6 genotyping to improve the efficacy and safety of tramadol in the treatment of acute postoperative pain.

Phase IV and low-intervention trial The main objective is evaluate if the implementation of pharmacogenetics in clinical practice can help to improve the treatment of acute pain, increasing efficacy and reducing adverse reactions. Secondary objectives: 1. To evaluate whether treatment adjusted according to CYP2D6 phenotype can reduce adverse reactions to tramadol in acute postoperative pain. 2. To compare the efficacy and safety of dexketoprofen and tramadol in the treatment of acute postoperative pain. 3. To investigate the influence on analgesic response and the incidence of adverse reactions of polymorphisms of other genes involved in the pharmacokinetics and mechanism of action of dexketoprofen and tramadol, such as: CYP2C9, CYP2C8, CYP2C19, CYP3A4, CYP3A5, CYP2B6, CYP2E1, COMT, ABCB1, SLC22A1, OPRM1 and PTGS2. 4. To evaluate the relationship of tramadol, M1 and dexketoprofen plasma concentrations with response to treatment and the occurrence of adverse reactions.

Inclusion criteria: 1. Men or women over 18 years of age. 2. Patients scheduled for outpatient surgical extraction, under local anesthesia, of at least two impacted third molars, at least one of which will require bone removal. 3. Patients who agree to participate in the study and give written consent.

Exclusion criteria: 1. Patients under treatment with other drugs that can inhibit CYP2D6, or are contraindicated in combination with tramadol or dexketoprofen. 2. Patients on treatment with bisphosphonates. 3. Patients who are receiving analgesic treatment before the operation, 24 hours prior to the operation. This criterion will be evaluated at the intervention visit. 4. Patients suffering from other uncontrolled diseases. 5. Pregnant or breastfeeding women. 6. Patients with contraindications for treatment with tramadol or dexketoprofen.

• Study Type: Interventional
• Enrollment (Anticipated): 300
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Francisco Abad Santos, MD; Phone Number: +34915202593; Email: francisco.abad@salud.madrid.org
• Study Contact Backup: Name: Jesus Novalbos Reina, PhD; Phone Number: +34915202540; Email: jnovalbos@iis-princesa.org

Study Locations

• Spain
  • Alicante, Spain, 03550
    • Active, not recruiting
    • Hospital Universitario San Juan de Alicante
  • Burgos, Spain, 09006
    • Recruiting
    • Hospital General Universitario de Burgos y Clínica Colina
    • Contact: Cesar Colina Santamaría; Phone Number: +34 947 044 037; Email: cesar.colina@clinicacolina.com
    • Contact: Miriam Saiz Rodríguez, PhD; Email: msaiz@hubu.es
  • Madrid, Spain, 28006
    • Recruiting
    • Fundación para la Investigación Biomédica Hospital La Princesa
    • Contact: Jesús Novalbos Reina, PhD; Phone Number: +34 91 520 2540; Email: jnovalbos@iis-princesa.org
    • Contact: Francisco Abad Santos, MD; Phone Number: +34 91 520 2593; Email: francisco.abad@salud.madrid.org
  • Madrid, Spain, 28034
    • Active, not recruiting
    • Hospital Univesitario Ramón y Cajal
  • Madrid, Spain, 28040
    • Active, not recruiting
    • Hospital Universitario Clinico San Carlos
  • Madrid, Spain, 28040
    • Not yet recruiting
    • Hostpital Universitario Fundación Jiménez Díaz
    • Contact: Dolores Martinez Pérez, MD; Email: dmartinez@fjd.es
    • Contact: Lucía Llanos Jiménez, MD; Email: lucia.llanos@fjd.es
  • Madrid, Spain, 28046
    • Active, not recruiting
    • Hospital Universitaro La Paz
  • Madrid
    • Majadahonda, Madrid, Spain, 28220
      • Active, not recruiting
      • Hospital Universitario Puerta de Hierro

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Men or women over 18 years of age.
• Patients scheduled for outpatient surgical extraction, under local anesthesia, of at least two impacted third molars, at least one of which will require bone removal.
• Patients who agree to participate in the study and give written consent.

Exclusion Criteria:

• Patients under treatment with other drugs that can inhibit CYP2D6, or are contraindicated in combination with tramadol or dexketoprofen.
• Patients on treatment with bisphosphonates.
• Patients who are receiving analgesic treatment before the operation, 24 hours prior to the operation. This criterion will be evaluated at the intervention visit.
• Patients suffering from other uncontrolled diseases.
• Pregnant or breastfeeding women.
• Patients with contraindications for treatment with tramadol or dexketoprofen.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: Tramadol; Patients treated with Tramadol, 100 mg every 8 hours according to clinical practice for the treatment of postoperative pain.
No Intervention: Dexketoprofen; Patients treated with Dexketoprofen 25 mg every 8 hours according to clinical practice for the treatment of postoperative pain.
Experimental: Experimental Group; The patients in this group will be genotyped before surgery and treatment will be prescribed according to the CYP2D6 phenotype. Normal Metabolizers (NM): Tramadol 100 mg every 8 hour; Ultrarapid Metabolizers (UM): Tramadol 50 mg every 8 hours Intermediate and poor metabolizers (IM/PM): dexketoprofen 25 mg every 8 hours	Drug: The patients in experimental group will be genotyped before surgery and treatment will be prescribed according to the CYP2D6 phenotype; Treatment will be prescribed according to the CYP2D6 phenotype. Normal Metabolizers (NM): Tramadol 100 mg every 8 hour; Ultrarapid Metabolizers (UM): Tramadol 50 mg every 8 hours Intermediate and poor metabolizers (IM/PM): dexketoprofen 25 mg every 8 hours; Other Names: Tramadol 100 mg; Tramadol 50 mg; Dexketoprofen 25 mg

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Efficacy: analgesic effect (Pain assessment) 4 hours after treatment	To evaluate the analgesic effect (pain assessment) that will be evaluated throughout visual analogical scale (VAS) from 0 to 100.	4 hour after treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Efficacy at the end of treatment	Efficacy will also be evaluated based on the requirement of the study medication, if treatment has been completed during the three days (recommended in the study protocol), or on the contrary, three days of treatment have not been required due to pain remission; the requirement of rescue medication due to lack of efficacy of the prescribed treatments in the first 24 hours after the administration of the first dose. Time to rescue medication use will also be measured.	3 days after treatment administration (72 Hours)
Correlation between efficacy and the pharmacokinetic parameters (AUC)	The efficacy of the treatments will be analyzed and whether these correlate with the pharmacokinetic parameters (AUC) for each patient, calculated from the quantified plasma concentrations of tramadol and metabolite1 of tramadol (samples 2 hour and 4h) or dexketoprofen (samples 1h and 4h).	1 hours, 2 hours and 4 hours
Correlation between efficacy and pharmacogenetic profile (focus in CYP2D6)	The efficacy of the treatments will be analyzed with the pharmacogenetic profile of the patients, that is, if the pharmacokinetic profile, Tmax and AUC, correlates with the enzymatic activity rate for the CYP2D6 phenotype (Activity Score - AS) of poor metabolizer (AS-0), intermediate metabolizer (AS: between 0 and 1.25), normal metabolizer ( AS: between 1.25 and 2.25) or ultrarapid metabolizer (AS > 2.25)	Through study completion, an average of 1 year and 6 months
Safety evaluations	The safety evaluations will be carried out in accordance with the Good Clinical Practice Standards and current legislation. The safety of the treatments will be analyzed with the pharmacogenetic profile of the patients	Through study completion, an average of 1 year and 6 months

Collaborators and Investigators

• Sponsor: Fundación de Investigación Biomédica - Hospital Universitario de La Princesa
• Collaborators: Hospital Universitario Ramon y Cajal; Puerta de Hierro University Hospital; Hospital Universitario Fundación Jiménez Díaz; Hospital San Carlos, Madrid; Hospital Universitario La Paz; Hospital Universitario San Juan de Alicante; Hospital Universitario de Burgos

Study record dates

Study Major Dates

• Study Start (Actual): October 5, 2022
• Primary Completion (Anticipated): December 1, 2023
• Study Completion (Anticipated): December 1, 2023

Study Registration Dates

• First Submitted: October 10, 2022
• First Submitted That Met QC Criteria: December 11, 2022
• First Posted (Actual): December 20, 2022

Study Record Updates

• Last Update Posted (Actual): December 20, 2022
• Last Update Submitted That Met QC Criteria: December 11, 2022
• Last Verified: December 1, 2022

More Information

Terms related to this study

• Keywords: Pharmacogenetics; Therapeutic techniques in treatment of acute postoperative pain
• Additional Relevant MeSH Terms: Pathologic Processes; Postoperative Complications; Pain; Neurologic Manifestations; Pain, Postoperative; Acute Pain; Physiological Effects of Drugs; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Analgesics, Opioid; Narcotics; Tramadol; Dexketoprofen trometamol
• Other Study ID Numbers: 2022-500377-13-01

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No