Non-steroidal anti-inflammatory drugs and CYP2C9 - Impacts of genetics and phenoconversion on the risk of adverse effects.

Chronic pain affects over a quarter of Canadians and remains a leading cause of outpatient visits. It is prevalent in both adults and children, often persisting into adulthood, and imposes a significant economic burden exceeding $40 billion annually. Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used for pain management as a safer alternative to opioids. However, the safety and efficacy of NSAIDs are influenced by genetic factors, particularly cytochrome P450 (CYP) polymorphisms, which affect drug metabolism. The CYP2C9 enzyme metabolizes several NSAIDs, and genetic variations can lead to altered drug clearance, increasing the risk of adverse effects such as gastrointestinal bleeding. Pharmacogenomic (PGx) testing, including CYP2C9 genotyping, provides insights into individual drug response, aiding personalized pain management. Guidelines from the Clinical Pharmacogenetics Implementation Consortium (CPIC) recommend NSAID dose adjustments based on CYP2C9 genotype. Additionally, drug-gene interactions, drug-drug interactions, and phenoconversion further complicate the metabolism of NSAIDs. Phenoconversion, wherein drug-induced or disease-related changes alter an individual's metabolic phenotype independent of their genotype, can significantly impact the metabolism of NSAIDs and therapeutic outcomes, highlighting the need for dynamic clinical assessments. Integrating PGx testing into clinical practice can enhance the safety and efficacy of NSAIDs, reducing adverse effects and optimizing pain treatment. Further research is needed to explore additional genetic and environmental factors, including phenoconversion mechanisms, which influence responses to NSAIDs, paving the way for precision medicine in pain management.