Introduction: Opioids are the most commonly used analgesic drugs for acute and chronic severe pain and are metabolized in the liver via cytochrome P450 (CYP) enzymes and UDP-glucuronosyltransferases (UGTs). Methods: A narrative review of the literature was conducted by searching the PubMed database up to December 2025, with English as the only language restriction. Relevant studies were identified using the keywords “opioids,” “pharmacogenetic,” “cytochrome mutations,” and “interactions.” Results: Polymorphisms in CYP2D6 and CYP3A4 genes can affect the pharmacokinetics, clinical effect, and safety of opioids. Furthermore, enzyme induction and inhibition by concomitant drugs or compounds (herbal products or food) are sources of variability factors in drug response that may be predictable. Conclusions: This review article summarizes current evidence on the role of pharmacogenetics and opioid-related interactions, offering a framework to better understand interindividual variability in opioid response and to inform future multimodal approaches.

Introduction: Opioids are the most commonly used analgesic drugs for acute and chronic severe pain metabolized in the liver via cytochrome P450 (CYP) and UDP-glucuronosyltransferase (UGT). Methods: A narrative review of the literature was conducted by searching MEDLINE and PubMed databases up to October 2025, using the English language as the only restriction. Relevant studies were identified using the keywords “opioids,” “pharmacogenetic,” “cytochrome mutations,” and “interactions.” Results: Polymorphisms in the CYP2D6 and CYP3A4 genes can affect the pharmacokinetics, clinical effect, and safety of opioids. Furthermore, enzyme induction and inhibition using concomitant drugs or compounds (herbal or food) are variability factors in drug response that may be predictable. Conclusion: This review article provides an overview of the role of pharmacogenetics and opioid interactions as a rationale for multimodal approaches aimed at optimizing treatment in clinical practice, in particular opioids should be tailored to each clinical indication and patients should be stratified to receive the appropriate dose.