Rmethadone

R-methadone, or the R-enantiomer of methadone, is one of the two mirror-image forms of the synthetic opioid methadone. Methadone is typically administered as a racemate, a 50:50 mixture of the R- and S-enantiomers, and the two enantiomers have distinct pharmacological profiles. In practice, the clinical effects of methadone are largely driven by the R-enantiomer, while the S-enantiomer contributes other pharmacological actions.

Pharmacology and mechanism: R-methadone acts as a potent mu-opioid receptor agonist, producing analgesia and helping to suppress withdrawal symptoms in opioid use disorder. The S-enantiomer has less mu-opioid activity but may interact with other targets, such as NMDA receptors, contributing to a broader pharmacological profile when the racemate is used.

Pharmacokinetics: Both enantiomers are extensively metabolized in the liver by cytochrome P450 enzymes, including CYP3A4 and CYP2B6, with potential involvement of other isoforms. The enantiomers can have different clearance rates, contributing to the overall long, variable half-life of methadone and to complex drug interactions. The major active metabolite is EDDP (2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine).

Clinical use and indications: R-methadone is not typically marketed or prescribed separately; methadone for pain or opioid use disorder is usually given as the racemate. Research into the individual enantiomers has explored potential differences in efficacy and safety, but standard medical practice generally uses racemic methadone.

Safety: As with other opioids, R-methadone carries risks of respiratory depression, sedation, and overdose. Methadone can prolong the QT interval, increasing the risk of torsades de pointes, especially with high doses or concurrent QT-prolonging medications.

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