Desmetramadol

Pharmacology

Pharmacodynamics

(+)-Desmetramadol is a G-protein biased μ-opioid receptor full agonist. It shows comparatively far lower affinity for the δ- and κ-opioid receptors. 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), they increase the potential for drug interactions compared to other opioids, and may also contribute to side effects. Desmetramadol is also an antagonist of the serotonin 5-HT2C receptor, at pharmacologically relevant concentrations, via competitive inhibition. This suggests that the apparent anti-depressant properties of tramadol may be at least partially mediated by desmetramadol, thus prolonging the duration of therapeutic benefit. Inhibition of the 5-HT2C receptor is a suggested factor in the mechanism of anti-depressant effects of agomelatine and maprotiline. The potential selectivity and favorable side effect profile of desmetramadol compared to tramadol, makes it more suitable for use as antidepressant, although clinical development appears to have stopped. Upon inhibition of the receptor, downstream signaling causes dopamine and norepinephrine release, and the receptor is thought to significantly regulate mood, anxiety, feeding, and reproductive behavior. 5-HT2C receptors regulate dopamine release in the striatum, prefrontal cortex, nucleus accumbens, hippocampus, hypothalamus, and amygdala, among others. Research indicates that some suicide victims have an abnormally high number of 5-HT2C receptors in the prefrontal cortex. There is some mixed evidence that agomelatine, a 5-HT2C antagonist, is an effective antidepressant. Antagonism of 5-HT2C receptors by agomelatine results in an increase of dopamine and norepinephrine activity in the frontal cortex.

Pharmacokinetics

Metabolites

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.

Society and culture

Recreational use

A herbal remedy called Krypton was found to contain kratom leaf powder and desmetramadol. Krypton was reportedly linked to at least 9 accidental opioid overdose deaths in Sweden during 2010–2011.

Legality

United States

Desmetramadol is not a scheduled substance in the United States.

United Kingdom

Desmetramadol was made a Class B drug in the United Kingdom on 26 Feb 2013.

References

References

1. [http://www.pharmgkb.org/pathway/PA165946349 Tramadol Pharmacokinetics], PharmGKB
2. (September 1993). "Effects of the central analgesic tramadol and its main metabolite, O-desmethyltramadol, on rat locus coeruleus neurones". British Journal of Pharmacology.
3. (November 2003). "A rapid and simple CYP2D6 genotyping assay--case study with the analgetic tramadol". Metabolism.
4. Erowid, DrugsData. org. (n.d.). Drugsdata.org: Test results - “O-DSMT” (Desmetramadol). https://drugsdata.org/results.php?search_field=all&s=o-dsmt
5. (2019). "Desmetramadol Is Identified as a G-Protein Biased µ Opioid Receptor Agonist". Frontiers in Pharmacology.
6. (September 2000). "Anticonvulsant and proconvulsant effects of tramadol, its enantiomers and its M1 metabolite in the rat kindling model of epilepsy". British Journal of Pharmacology.
7. (October 2000). "Modeling of the in vivo antinociceptive interaction between an opioid agonist, (+)-O-desmethyltramadol, and a monoamine reuptake inhibitor, (-)-O-desmethyltramadol, in rats". The Journal of Pharmacology and Experimental Therapeutics.
8. (September 1997). "Actions of tramadol, its enantiomers and principal metabolite, O-desmethyltramadol, on serotonin (5-HT) efflux and uptake in the rat dorsal raphe nucleus". British Journal of Anaesthesia.
9. (March 1993). "Effects of the central analgesic tramadol on the uptake and release of noradrenaline and dopamine in vitro". British Journal of Pharmacology.
10. (2006). "The tramadol metabolite, O-desmethyl tramadol, inhibits 5-hydroxytryptamine type 2C receptors expressed in Xenopus Oocytes". Pharmacology.
11. (July 2007). "Serotonin 5-HT(2C) receptors regulate anxiety-like behavior". Genes, Brain and Behavior.
12. (May 2001). "RNA editing of the human serotonin 5-HT2C receptor. alterations in suicide and implications for serotonergic pharmacotherapy". Neuropsychopharmacology.
13. (June 2010). "Agomelatine: The evidence for its place in the treatment of depression". Core Evidence.
14. "Figure 7. Tramadol and desmetramadol metabolism catalyzed by CYPs in vitro".
15. (May 2011). "Kratom alkaloids and O-desmethyltramadol in urine of a "Krypton" herbal mixture consumer". Forensic Science International.
16. (2010). "[Krypton--new, deadly Internet drug. Since October 2009 have nine young persons died in Sweden]". Läkartidningen.
17. (May 2011). "Unintentional fatal intoxications with mitragynine and O-desmethyltramadol from the herbal blend Krypton". Journal of Analytical Toxicology.
18. (31 January 2013). "The Misuse of Drugs (Designation) (Amendment) (England, Wales and Scotland) Order 2013". UK Home Office.