Clinical Information

Methadone, a long-acting synthetic opioid analgesic, is an agonist at the mu receptor. It has several actions qualitatively similar to those of morphine, primarily involving the central nervous system and organs composed of smooth muscles. Analgesia, sedation, and detoxification or maintenance in opioid addiction can be achieved with therapeutic use of methadone hydrochloride. Methadone acts by binding to the mu-opioid receptor but also has some affinity for the N-methyl-D-aspartate receptor (NMDA) ionotropic glutamate receptor.

Methadone undergoes extensive biotransformation in the liver. Methadone is metabolized by cytochrome P450 (CYP) 3A4, CYP2B6, CYP2C19, and CYP2D6 enzymes. It is also a substrate for the P-glycoprotein efflux protein. The major inactive metabolite is a result of N-demethylation and cyclization, and forms 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidene (EDDP).

Substantial interindividual and intraindividual variabilities in metabolism and elimination have been noted. The half-life of methadone is highly variable and typically ranges from 7 to 59 hours; however, longer half-lives have been reported.