Odesmethyltramadol

O-desmethyltramadol, commonly referred to as M1, is an active metabolite of the analgesic tramadol. It is produced in the liver from tramadol primarily by the enzyme CYP2D6, with additional, less major pathways contributing. As an active metabolite, M1 contributes to the overall analgesic effect of tramadol, alongside tramadol’s own pharmacologic actions.

Pharmacologically, M1 exhibits a higher affinity for the μ-opioid receptor than parent tramadol and generally is considered more potent at producing opioid-mediated analgesia. The extent of its contribution to clinical pain relief depends on individual metabolism, since CYP2D6 activity varies widely among people. Tramadol’s analgesia also derives from its inhibition of serotonin and norepinephrine reuptake, a mechanism largely independent of M1.

Pharmacokinetically, M1 formation is influenced by genetic polymorphisms of CYP2D6, leading to substantial interindividual variability in response. Poor metabolizers may generate little M1 and experience reduced opioid analgesia, while ultrarapid metabolizers can accumulate higher M1 levels, increasing both analgesic effect and risk of opioid-related adverse events. M1 is cleared mainly through hepatic conjugation to glucuronides and subsequent renal excretion; elimination can be prolonged in hepatic or renal impairment.

clinically, M1 is not administered as a separate drug but is a key component of tramadol’s effect profile. Regulatory status varies by jurisdiction. Risks associated with M1 reflect those of opioids in general, including potential for dependence, tolerance, respiratory depression, and sedation; interactions with other serotonergic or central nervous system–active drugs can raise the risk of adverse effects such as sedation or, in some cases, serotonin syndrome.