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

The primary objective of this randomized clinical trial is to evaluate if the implementation of **pharmacogenetics** in clinical practice can enhance the treatment of acute postoperative pain by increasing efficacy and reducing adverse reactions. This is clinically relevant as it aims to personalize pain management strategies, potentially leading to improved patient outcomes and reduced incidence of adverse drug reactions.

Secondary objectives include:

• To evaluate whether treatment adjusted according to **CYP2D6** phenotype can reduce adverse reactions to tramadol in acute postoperative pain.
• To compare the efficacy and safety of dexketoprofen and tramadol in the treatment of acute postoperative pain.
• 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**.
• To evaluate the relationship of tramadol, M1, and dexketoprofen plasma concentrations with response to treatment and the occurrence of adverse reactions.

The clinical trial involves a study population comprising both **male** and **female** participants, all of whom are over the age of 18. The participants are patients scheduled for outpatient surgical extraction of at least two impacted third molars, with at least one requiring bone removal, under local anesthesia. The trial does not include a vulnerable population. The sponsor has not provided information regarding the total number of participants. Participants were selected based on their scheduled surgical procedures and their consent to participate in the study. The trial aims to evaluate the role of **pharmacogenetics** in enhancing the treatment of acute postoperative pain, focusing on increasing efficacy and reducing adverse reactions. Lifestyle considerations such as diet, physical activity, or habits have not been specified by the sponsor.

The clinical trial is designed to evaluate the utility of **CYP2D6 genotyping** in improving the efficacy and safety of **tramadol** for the treatment of acute postoperative pain. This is a randomized, double-blind, controlled trial, categorized as a Phase IV and low-intervention study. The trial involves the use of already marketed drugs, including **tramadol hydrochloride**, **metamizole magnesium**, **paracetamol**, and **dexketoprofen trometamol**, administered orally in various pharmaceutical forms such as capsules and tablets. The trial is expected to run for approximately one year, with an estimated recruitment start date of April 30, 2022, and an estimated end date of April 30, 2023.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age (over 18 years) and the requirement for outpatient surgical extraction of impacted third molars. Following the screening, eligible participants will be randomized to receive the study medication. The trial includes follow-up visits to monitor the efficacy and safety of the treatment, as well as to collect data on any adverse reactions. The end-of-study visit will conclude the participant's involvement, during which final assessments will be conducted.

The expected length of participant involvement is up to three months, corresponding to the maximum treatment period. Conditions that may lead to early termination from the study are not anticipated, as the study is designed to align with standard clinical practice. The primary endpoint focuses on evaluating the improvement in treatment efficacy and reduction in adverse reactions through the implementation of pharmacogenetics. No secondary endpoints have been specified. The trial aims to provide insights into the potential benefits of integrating pharmacogenetic testing into routine clinical practice for managing acute postoperative pain.

The clinical trial involves the administration of several medications, each with specific characteristics and dosing regimens. **Metamizole magnesium** is provided in the form of hard capsules, marketed as Metamizol Normon 575 mg cápsulas duras EFG. The active substance, metamizole magnesium, is chemically derived and administered orally. The maximum daily dose is 2300 mg, with a total maximum dose of 6900 mg over a treatment period of up to 3 days. The medication is produced by Laboratorios Normon, S.A., and is not a pediatric formulation.

**Paracetamol** is administered in tablet form, known as Paracetamol Normon 500 mg comprimidos EFG. This chemical substance is also taken orally, with a maximum daily dose of 2 grams and a total maximum dose of 6 grams over a 3-day period. The tablets are manufactured by Laboratorios Normon, S.A., and are not intended for pediatric use.

**Dexketoprofen trometamol** is provided as film-coated tablets, marketed as Dexketoprofeno Normon 25 mg comprimidos recubiertos con película EFG. The active substance is chemically derived and administered orally. The maximum daily dose is 75 mg, with a total maximum dose of 225 mg over a treatment period of up to 3 days. This product is also manufactured by Laboratorios Normon, S.A., and is not a pediatric formulation.

**Tramadol hydrochloride** is available in two different dosages, both in the form of hard capsules. The first is Tramadol Normon 50 mg cápsulas duras EFG, with a maximum daily dose of 150 mg and a total maximum dose of 450 mg over 3 days. The second is Tramadol Normon 100 mg cápsulas duras, with a maximum daily dose of 300 mg and a total maximum dose of 900 mg over the same period. Both formulations are chemically derived, administered orally, and produced by Laboratorios Normon, S.A. Neither formulation is intended for pediatric use.

Throughout the trial, participant compliance with the dosing schedule will be monitored to ensure adherence to the prescribed regimen. The trial aims to evaluate the utility of CYP2D6 genotyping in improving the efficacy and safety of tramadol in treating acute postoperative pain, with the objective of enhancing treatment outcomes by integrating pharmacogenetics into clinical practice.

The efficacy of the clinical trial will be assessed by evaluating the utility of **CYP2D6 genotyping** in improving the treatment of acute postoperative pain with tramadol. The primary objective is to determine if the implementation of pharmacogenetics in clinical practice can enhance treatment efficacy and reduce adverse reactions. The trial involves patients undergoing outpatient surgical extraction of impacted third molars, with the study designed to align with standard clinical practice. The trial is categorized as a low-intervention, Phase IV study, utilizing already marketed drugs without imposing additional burdens on participants. The assessment of efficacy will focus on the improvement of pain management outcomes through personalized medicine approaches, specifically the use of genetic information to tailor tramadol treatment.