Individual variability in clinical effect and tolerability of opioid analgesics – Importance of drug interactions and pharmacogenetics

Abstract

Abstract Background As pain is often a comorbid condition, many patients use opioid analgesics in combination with several other drugs. This implies a generally increased risk of drug interactions, which along with inherent pharmacogenetic variability and other factors may cause differences in therapeutic response of opioids. Aim To provide an overview of interactions and pharmacogenetic variability of relevance for individual differences in effect and tolerability of opioid analgesics, which physicians and other healthcare professionals should be aware of in clinical practice. Methods The article was based on unsystematic searches in PubMed to identify literature highlighting the clinical impact of drug interactions and pharmacogenetics as sources of variable response of opioid analgesics. Results Cytochrome P450 (CYP)-mediated metabolism is an important process for both clinically relevant interactions and pharmacogenetic variability of several opioids. Concomitant use of CYP inhibitors (e.g. paroxetine, fluoxetine and bupropion) or inducers (e.g. carbamazepine, phenobarbital and phenytoin) could counteract the clinical effect or trigger side effects of analgesics in the same manner as genetically determined differences in CYP2D6-mediated metabolism of many opioids. Moreover, combination treatment with drugs that inhibit or induce P-glycoprotein (ABCB1), a blood-brain barrier efflux transporter, may alter the amount (‘dose’) of opioids distributed to the brain. At the pharmacodynamic level, it is crucial to be aware of the potential risk of interaction causing serotonergic syndrome when combining opioids and serotonergic drugs, in particular antidepressants inhibiting serotonin reuptake (SSRIs and SNRIs). Regarding pharmacogenetics at the receptor level of pain treatment, the knowledge is currently scarce, but an allelic variant of the μ1 opioid receptor (OPRM1) gene has been associated with higher dosage requirement to achieve analgesia. Conclusions and implications Drug interactions and pharmacogenetic differences may lead to therapeutic failure or serious side effects of opioid analgesics. Many interactions involve combinations with antidepressants and antiepileptics, which are highly relevant drugs in patients suffering from pain. To prevent unfavourable drug interactions it is important that clinicians pay close attention and use electronic drug interaction checkers when treatments are initiated or discontinued. For the management of issues related to pharmacogenetic differences, blood-based CYP genotyping is available as routine test at many laboratories, and provide a valuable tool for proper choice of drugs and doses for treatment of pain and other diseases.