O-Desmethyltramadol

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O-Desmethyltramadol
O-desmethyltramadol racemate2DCSD3.svg
Systematic (IUPAC) name
3-(2-((dimethylamino)methyl)-1-hydroxycyclohexyl)phenol
Clinical data
Routes of
administration		 Converted Metabolite
Pharmacokinetic data
Metabolism CYP2D6[1]
Biological half-life ~ 9 h
Identifiers
CAS Number 80456-81-1 YesY
PubChem CID: 130829
ChemSpider 115703 YesY
UNII 2WA8F50C3F YesY
ChEMBL CHEMBL1400 N
Chemical data
Formula C15H23NO2
Molecular mass 249.349 g/mol
  • OC2(c1cc(O)ccc1)CCCCC2CN(C)C
  • InChI=1S/C15H23NO2/c1-16(2)11-13-6-3-4-9-15(13,18)12-7-5-8-14(17)10-12/h5,7-8,10,13,17-18H,3-4,6,9,11H2,1-2H3 YesY
  • Key:UWJUQVWARXYRCG-UHFFFAOYSA-N YesY
 NYesY (what is this?)  (verify)

O-Desmethyltramadol (O-DSMT) is an opioid analgesic and the main active metabolite of tramadol.[2] (+)-O-DSMT[lower-alpha 1] is the most important metabolite of tramadol produced in the liver after tramadol is consumed. Tramadol is demethylated by the liver enzyme CYP2D6[3] 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.[citation needed] 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.

Pharmacology

O-DSMT is considerably more potent as a μ opioid agonist compared to tramadol.[4] Additionally, unlike tramadol, it is a high-affinity ligand of the δ- and κ-opioid receptors.[5]

The two enantiomers of O-DSMT show quite distinct pharmacological profiles;[6] both (+) and (−)-O-DSMT are inactive as serotonin reuptake inhibitors,[7] but (−)-O-DSMT retains activity as a norepinephrine reuptake inhibitor,[8] 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.

Recreational use

O-DSMT 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-DSMT was reportedly linked to at least 9 accidental deaths from overdose during 2010–2011.[9][10][11]

The metabolic conversion of tramadol to O-DSMT 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-DSMT 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.

Metabolites

O-DSMT is metabolized in the liver into the active metabolite N,O-didesmethyltramadol via CYP3A4 & CYP2B6. The inactive tramadol metabolite N-desmethyltramadol is metabolized into the active metabolite N,O-didesmethyltramadol by CYP2D6.

See also

Note list

  1. ↑ N.B. that the "O" is capitalized and italicized and refers to the oxygen atom in this instance. A small case letter "o" that is likewise italicized and a prefix, in chemistry, usually indicates a substitution in the "ortho" or second position placeholder of the benzene; which would be the next place free of a heteroatom (non-hydrogen) after the juncture taken by the phenyl connector on the benzene.

References

  1. ↑ Tramadol Pharmacokinetics, PharmGKB
  2. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  3. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  4. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  5. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  6. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  7. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  8. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  9. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  10. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  11. ↑ Lua error in package.lua at line 80: module 'strict' not found.


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