Methadone, is a racemic mixture of stereoisomers R (opiate active) and S (opiate inactive). The R stereoisomer has 25 fold activity on the mu receptor compared with the S isomer. There is significant variability in metabolism of this drug with the S isomer inhibiting some of the metabolism of the R isomer. There are many hepatic enzymes that demethylate the drug (principle mode of metabolism) and a large number of drugs that inhibit some of the pathways of metabolism. The enantiomers therefore have different half lives. In cancer patients, the active enantiomer (R) has a half life of 53 hours while the S isomer has a half life of 31 hours. This makes methadone titration particularly tricky given that steady state may not be reached for 7 days (3 half lives). Therefore titration of the drug should only occur every 7 days. The daily oral morphine to methadone ratio in cancer and hospice patients averaged 5, but varied from 1.3 to 11. (Ther Drug Monit. 2006 Jun;28(3):359-66) Therefore conversion charts are useless when referring to methadone since there is significant variability in clearance of the drug and analgesia that appears to be unrelated to plasma levels of the drug.
It is a pure mu agonist with modest NMDA receptor inhibitor properties...
Therefore other mu receptor breakthrough meds may be used in conjunction with methadone.
Tips: use extreme caution in prescribing this medication to the elderly (dramatically reduce doses and frequency of the drug). Do not use methadone in patients with any hepatic dysfunction or who are at risk for development of sudden hepatic dysfunction (eg alcoholics, those taking hepatotoxic drugs). Avoid using the drug in those with a prolonged QT interval (it is a good idea to obtain an ECG prior to prescribing methadone).
Don't give this drug to stupid people (cannot follow dosing directions), those that have accelerated the dosage of other narcotics without the physicians prior approval), HIV patients on certain anti-medications at home, or Anna Nicole Smith look alikes...
