|Systematic (IUPAC) name|
|Legal status||Unscheduled (US) Schedule IV (In some US states)|
|Half-life||~ 9 h|
|Mol. mass||249.349 g/mol|
|(what is this?)|
(+)-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.
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 noradrenaline reuptake inhibitor and so the mix of both the parent compound and metabolites produced 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.
O-Desmethyltramadol 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 O-desmethyltramadol was reportedly linked to at least 9 accidental deaths from overdose during 2010–2011.
The metabolic conversion of tramadol to O-desmethyltramadol 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.
Role in drug development
The opioid medication tapentadol was developed to mimic the actions of O-desmethyltramadol 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.
O-Desmethyltramadol is metabolized in the liver into the active metabolite N,O-didesmethyltramadol via CYP2D6. The inactive tramadol metabolite N-desmethyltramadol is also metabolized into the active metabolite N,O-didesmethyltramadol by the same enzyme.
- Tramadol Pharmacokinetics, PharmGKB
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- Arndt, T; Claussen, U; Güssregen, B; Schröfel, S; Stürzer, B; Werle, A; Wolf, G (2011). "Kratom alkaloids and O-desmethyltramadol in urine of a "Krypton" herbal mixture consumer". Forensic Science International 208 (1–3): 47–52. doi:10.1016/j.forsciint.2010.10.025. PMID 21112167.
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