Objectives: Interindividual variability in analgesic responsiveness often results in therapy failure (TF) or adverse drug reactions (ADR) and poses a major challenge in chronic pain management, as it is influenced by multiple factors. This exploratory study investigated whether pharmacogenetic (PGx) testing could identify drug-gene-interactions (DGIs) explaining variability in drug response. Additionally, we explored whether genetic predispositions in CYP2D6 and COMT , indicating increased pain sensitivity, are linked to TF. Methods: We analyzed data from chronic pain patients who underwent pharmacogenotyping due to suspected TF or ADR. PGx panel testing was carried out by a commercial provider. Additional genotyping of COMT rs6269, rs4633, and rs4818 was performed using PCR, RFLP, and Sanger sequencing. Results: PGx panel testing confirmed at least one relevant genetic variant in 45% of the suspected DGIs. Notably, 41% involved the pharmacogenes CYP2D6 , CYP2C19 , and CYP2C9 . Subgroup analyses revealed that patients carrying the COMT high pain sensitivity (HPS) allele, COMT high pain phenotype, or CYP2D6 intermediate metabolizer (IM) phenotype were significantly more likely to experience TF. Logistic regression confirmed both phenotypes as significant predictors of TF. Discussion: Our findings support the relevance of CYP2D6 , CYP2C19 , and CYP2C9 as key pharmacogenes for PGx testing in chronic pain management. The results suggest that a genetic predisposition in CYP2D6 and COMT , associated with increased pain sensitivity, may contribute to insufficient analgesia and subsequent TF. These insights indicate the potential value of incorporating CYP2D6 and COMT as pain-modulating genetic markers into the broader framework of PGx testing.
Bollinger et al. (Mon,) studied this question.