Genetic polymorphism and drug interactions: their importance in the treatment of pain

Objectives: To evaluate the impact of certain genetic polymorphisms on variable responses to analgesics. Sources: Systematic review, by means of a structured computerized search in the Medline database (1966-2004). Key words: pharmacogenetics, polymorphism, cytochrome P450 (CYP), glycoprotein P (P-gp), pain, antalgics, opiates, morphine, codeine, tramadol, non-steroidal anti-inflammatory drugs (NSAID). Articles in English and French were selected. References in relevant articles were also retrieved. Main findings: Most analgesics are metabolized by CYP isoenzymes subject to genetic polymorphism. NSAIDs are metabolized by CYP2C9; opioids described as weak (codeine, tramadol), antidepressants and dextromethorphan are metabolized by CYP2D6 and some potent opioids (buprenorphine, methadone or fentanyl) by CYP3A4/5. After the usual doses have been administered, drug toxicity or, on the contrary, therapeutic ineffectiveness may occur, depending on polymorphism and the substance. Drug interactions mimicking genetic defects because of the existence of CYP inhibitors and inducers, also contribute to the variable response to analgesics. Some opioids are substrates of P-gp, a transmembrane transporter also subject to genetic polymorphism. However, P-gp could only play a minor modulating role in man on the central effects of morphine, methadone and fentanyl. Conclusion: In the near future, pharmacogenetics should enable us to optimize therapeutics by individualizing our approach to analgesic drugs and making numerous analgesics safer and more effective. The clinical usefulness of these individualized approaches will have to be demonstrated by appropriate pharmaco-economic studies and analyses.