|Synonyms||O-Desmethyltramadol; O-DSMT; Omnitram|
|Metabolism||CYP3A4 and CYP2B6|
|Elimination half-life||6-8 hours|
|Chemical and physical data|
|Molar mass||249.349 g/mol|
|3D model (JSmol)|
Desmetramadol (INN), also known as O-desmethyltramadol (O-DSMT), is an opioid analgesic and the main active metabolite of tramadol. 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 metabolizers") will tend to get reduced analgesic effects from tramadol. This also results in a ceiling effect (dependent on CYP2D6 availability) which limits tramadol's range of therapeutic benefits to the treatment of moderate pain.
The two enantiomers of desmetramadol show quite distinct pharmacological profiles; both (+) and (−)-desmetramadol are inactive as serotonin reuptake inhibitors, but (−)-desmetramadol retains activity as a norepinephrine reuptake inhibitor, and so the mix of both the parent compound and metabolites contributes significantly to the complex pharmacological profile of tramadol. While the multiple receptor targets can be beneficial in the treatment of pain (especially complex pain syndromes such as neuropathic pain), it increases the potential for drug interactions compared to other opioids, and may also contribute to side effects.
Desmetramadol is metabolized in the liver into the active metabolite N,O-didesmethyltramadol via CYP3A4 and CYP2B6. The inactive tramadol metabolite N-desmethyltramadol is metabolized into the active metabolite N,O-didesmethyltramadol by CYP2D6.
Development of tapentadol
The opioid medication tapentadol was developed to mimic the actions of desmetramadol in order to create a weak-moderate analgesic which is not dependent on metabolic activation. Tapentadol, however, is generally considered to be a stronger analgesic than tramadol. This may be illusory due to the metabolism-dependent effects of tramadol.
Society and culture
Desmetramadol has recently been marketed as a currently legal substitute for illegal opioid drugs, either in powder form or mixed into various other preparations. One such blend sold under the brand Krypton and containing powdered kratom leaf (Mitragyna speciosa) laced with desmetramadol was reportedly linked to at least 9 accidental deaths from overdose during 2010–2011.
The metabolic conversion of tramadol to desmetramadol is highly dependent on individual metabolism, meaning that two users with an identical opioid tolerance can experience vastly different effects from the same dose. For this reason, tramadol is always initiated at the lowest possible dose in clinical settings and then titrated to the lowest effective dose. Recreational users tend to start with much higher doses without taking this into account, greatly increasing the risk of overdose.
- Tramadol Pharmacokinetics, PharmGKB
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