O-Desmethyltramadol

O-Desmethyltramadol (M1) is an opioid analgesic which is made in the body from tramadol.

(+)-O-Desmethyltramadol is the most important metabolite of tramadol produced in the liver after tramadol is consumed. This metabolite is considerably more potent as a μ opioid agonist than the parent compound, and indeed is so much more potent that tramadol can to some extent be regarded as a prodrug for O-desmethyltramadol in the same way that codeine is a prodrug for morphine.

Tramadol is demethylated by the liver enzyme CYP2D6 in the same way as codeine, and so similarly to the variation in effects seen with codeine, individuals who have a less active form of CYP2D6 ("poor metabolisers") will tend to get reduced analgesic effects from tramadol.

The two enantiomers of O-desmethyltramadol show quite distinct pharmacological profiles; both (+) and (-)-O-desmethyltramadol are inactive as serotonin reuptake inhibitors, but (-)-O-desmethyltramadol retains activity as a dopamine and noradrenaline reuptake inhibitor and so the mix of metabolites produced contributes significantly to the complex pharmacological profile of tramadol.

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