O-Desmethyltramadol

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O-Desmethyltramadol
O-desmethyltramadol racemate2DCSD3.svg
Systematic (IUPAC) name
3-(2-((dimethylamino)methyl)-1-hydroxycyclohexyl)phenol
Clinical data
Legal status Unscheduled (US) Schedule IV (In some US states)
Routes Converted Metabolite
Pharmacokinetic data
Metabolism CYP2D6[1]
Half-life ~ 9 h
Identifiers
CAS number 73986-53-5 YesY
ATC code ?
PubChem CID 130829
ChemSpider 115703 YesY
ChEMBL CHEMBL1400 N
Chemical data
Formula C15H23NO2 
Mol. mass 249.349 g/mol
 N (what is this?)  (verify)

O-Desmethyltramadol (O-DSMT) is an opioid analgesic and the main active metabolite of tramadol.[2]

(+)-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.[3]

Tramadol is demethylated by the liver enzyme CYP2D6[4] 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]

The two enantiomers of O-desmethyltramadol show quite distinct pharmacological profiles;[5] both (+) and (−)-O-desmethyltramadol are inactive as serotonin reuptake inhibitors,[6] but (−)-O-desmethyltramadol retains activity as a noradrenaline reuptake inhibitor[7] 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.

Recreational use[edit]

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.[8][9][10]

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[edit]

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.

Metabolites[edit]

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.

See also[edit]

References[edit]

  1. ^ Tramadol Pharmacokinetics, PharmGKB
  2. ^ Sevcik, J; Nieber, K; Driessen, B; Illes, P (1993). "Effects of the central analgesic tramadol and its main metabolite, O-desmethyltramadol, on rat locus coeruleus neurones". British Journal of Pharmacology 110 (1): 169–76. PMC 2175982. PMID 8220877.  edit
  3. ^ Dayer, P; Desmeules, J; Collart, L (1997). "Pharmacology of tramadol". Drugs. 53 Suppl 2: 18–24. doi:10.2165/00003495-199700532-00006. PMID 9190321.  edit
  4. ^ Borlak, J; Hermann, R; Erb, K; Thum, T (2003). "A rapid and simple CYP2D6 genotyping assay--case study with the analgetic tramadol". Metabolism: clinical and experimental 52 (11): 1439–43. doi:10.1016/S0026-0495(03)00256-7. PMID 14624403.  edit
  5. ^ Garrido, MJ; Valle, M; Campanero, MA; Calvo, R; Trocóniz, IF (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 295 (1): 352–9. PMID 10992001.  edit
  6. ^ Bamigbade, T. A.; Davidson, C.; Langford, R. M.; Stamford, J. A. (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 79 (3): 352–356. doi:10.1093/bja/79.3.352. PMID 9389855.  edit
  7. ^ Driessen, B; Reimann, W; Giertz, H (1993). "Effects of the central analgesic tramadol on the uptake and release of noradrenaline and dopamine in vitro". British Journal of Pharmacology 108 (3): 806–11. PMC 1908052. PMID 8467366.  edit
  8. ^ 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. 
  9. ^ Bäckstrom, BG; Classon, G; Löwenhielm, P; Thelander, G (2010). "Krypton--new, deadly Internet drug. Since October 2009 have nine young persons died in Sweden". Lakartidningen 107 (50): 3196–7. PMID 21294331. 
  10. ^ Kronstrand, R; Roman, M; Thelander, G; Eriksson, A (2011). "Unintentional fatal intoxications with mitragynine and O-desmethyltramadol from the herbal blend Krypton". Journal of analytical toxicology 35 (4): 242–7. doi:10.1093/anatox/35.4.242. PMID 21513619.