[Genetic polymorphism and drug interactions: their importance in the treatment of pain].
OBJECTIVE
To evaluate the impact of certain genetic polymorphisms on variable responses to analgesics


METHODS
Systematic review, by means of a structured computerized search in the Medline database (1966-2004). Articles in English and French were selected. References in relevant articles were also retrieved.


RESULTS
Most analgesics are metabolized by CYP isoenzymes subject to genetic polymorphism. NSAIDs are metabolized by CYP2C9; opioids described as "weak" (codeine, tramadol), anti-depressants 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.


CONCLUSIONS
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 pharmacoeconomic studies and analyses.
Samer
Caroline F
CF
Service de pharmacologie et toxicologie cliniques et Centre multidisciplinaire d'étude et de traitement de la douleur, Hôpitaux Universitaires de Genève, Genève, Suisse. Caroline.Samer@hcuge.ch
Piguet
Valérie
V
Dayer
Pierre
P
Desmeules
Jules A
JA
D000700:Analgesics / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000378:metabolism; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004347:Drug Interactions / Q000235:genetics*; D006801:Humans; D010146:Pain / Q000188:drug therapy*; D010641:Phenotype; D011110:Polymorphism, Genetic
D000700:Analgesics; D000894:Anti-Inflammatory Agents, Non-Steroidal; D003577:Cytochrome P-450 Enzyme System; C104464:CYP3A protein, human; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human