Fenotipos metabólicos de CYP2D6 relacionados a efectos adversos y falla terapéutica en pacientes colombianos tratados con tramadol

Abstract

Introduction: Tramadol is a medication commonly used in clinical practice for the management of moderate to severe pain; This is a prodrug that needs to be metabolized by CYP2D6, to generate its active metabolite O-Desmethyltramadol, which acts on miu receptors and thus fulfills much of its analgesic action. This drug has been implicated in various adverse effects and therapeutic failure despite adequate dosage and avoiding drug interaction; therefore, it is important to investigate the metabolic phenotypes produced by CYP2D6 polymorphisms in order to establish whether this has a relevant role in the response to medication and which individuals are at risk of presenting a side effect or inadequate effectiveness when using this drug. Methodology: Based on a database from the CIGGUR (Center for Research in Genetics and Genomics of the Universidad del Rosario) as a secondary source of information, a cross-sectional study was proposed in Colombian patients of legal age who have been managed with Tramadol for moderate or severe pain; which determined the proportion of each of the CYP2D6 drug metabolizer phenotype subgroups based on the interpretation of the functional estimate of the genotype by the Clinical Pharmacogenetics Implementation Consortium method (slow PM, normal EM, and ultrarapid UM); Also, by using a stratified bivariate analysis, it was proposed to estimate the relationship between CYP2D6 abnormal metabolizer phenotypes (corresponding to ultra-rapid and slow metabolic profiles), sociodemographic, clinical and pharmacological characteristics with the presence of adverse effects and therapeutic failure in the participants. Results: In the present study with 121 participants, it was found that the sample had 10 different CYP2D6 genotypes, which when interpreted, 83% of the patients had a normal CYP2D6 metabolic phenotype, 6.6% an ultrarapid metabolizer phenotype. and 4.1 a poor metabolizer phenotype; 52.3% of the total presented some adverse effect to the medication and 15.7% therapeutic failure. When exploring the relationship of the independent variables with the occurrence of adverse factors to tramadol, it was found that the variables related in a statistically significant way were chronic pain (PR= 1.57 CI95% 1.12-2.19), single dose of Tramadol (PR=1.54 CI95% 1.11-2.12) and when stratified by confounding variables, showed a relationship between female gender and the enteral route to the administration of the medication. On the other hand, when relating the independent variables with the occurrence of therapeutic failure, we found that the variables age over 60 years (PR= 3.12 CI95% 1.37-7.12), male gender (PR: 4.11 95% CI 1.58-10.7), chronic pain (PR= 2.61 95% CI 1.11-6.15) and when stratified by confounding variables, it showed a relationship between the route of enteral administration. Conclusion: This study is one of the few studies that seeks to demonstrate the relationship between multiple clinical, sociodemographic and pharmacogenetic variables with the occurrence of adverse effects and therapeutic failure in the use of Tramadol; The results of the research show that the variables related to the occurrence of adverse events are: temporality of the pain, being chronic pain, having received a single dose of Tramadol, being female, and having received the medication enterally; On the other hand, the variables related to the occurrence of therapeutic failure were: being a patient over 60 years of age, being male, temporality of pain being chronic pain, and having received enteral medication. It was not possible to demonstrate a relationship between abnormal CYP2D6 metabolic phenotypes and the occurrence of therapeutic failure and adverse event to the use of Tramadol due to the limitations of the study itself.