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Levacetylmethadol

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Levacetylmethadol

Levacetylmethadol
Systematic (IUPAC) name
(3S,6S)-(6-dimethylamino-4,4-diphenyl-heptan-3-yl) acetate
Clinical data
Legal status
Routes Oral
Pharmacokinetic data
Protein binding ~80%
Metabolism CYP3A4
Half-life 2.6 days
Identifiers
CAS number  YesY
43033-72-3 (hydrochloride)
ATC code N07
PubChem
DrugBank
ChemSpider  N
UNII  N
KEGG  YesY
ChEMBL  N
Chemical data
Formula C23H31NO2 
Mol. mass 353.498 g/mol
 N   

Levacetylmethadol (INN), levomethadyl acetate (USAN), OrLAAM (trade name) or levo-α-acetylmethadol (LAAM)[1] is a synthetic opioid similar in structure to methadone. It has a long duration of action due to its active metabolites. It was approved in 1993 by the U.S. Food and Drug Administration for use in the treatment of opioid dependence. In 2001, Orlaam was removed from the European market due to reports of life-threatening ventricular rhythm disorders.[2] In 2003, Roxane Laboratories, Inc. discontinued Orlaam in the US.[3]

Indications

LAAM is indicated as a second-line treatment for the treatment and management of opioid dependence if patients fail to respond to drugs like methadone or buprenorphine. Before August 1993, LAAM was classified as a schedule I drug in the United States. LAAM is not approved for use in Australia and Canada. At present, it is a Schedule II Narcotic controlled substance in the United States with a DEA ACSCN of 9648 and a national aggregate annual manufacturing quota of 4 grammes as of 2013.

Chemistry and pharmacology

Levacetylmethadyl acts as a mu-opioid receptor agonist. It also acts as a potent, noncompetitive α3β4 neuronal nicotinic acetylcholine receptor antagonist.[4]

Levomethadyl acetate is the levo isomer of α-methadyl acetate. The dextro isomer, alphacetylmethadol, is more potent but shorter acting. The levo isomer is also less toxic with an LD50 in mice of 110 mg/kg s.c. and 172.8 mg/kg orally as opposed to LD50s of 61 mg/kg s.c. and 118.3 mg/kg orally for dl-α-methadyl acetate. It has a melting point of 215 °C and a molecular weight of 353.50. β-methadyl acetate also exists, however it is more toxic and less active than α-methadyl acetate and has no current medical use.

Levomethadyl acetate undergoes extensive first-pass metabolism to the active demethylated metabolite nor-LAAM, which is further demethylated to a second active metabolite, dinor-LAAM. These metabolites are more potent than the parent drug.

Dosing

LAAM is used as an oral solution of levomethadyl acetate hydrochloride at a concentration of 10 mg/mL in bottles of 120 and 500 mL under the brand name Orlaam. The first dose of LAAM for patients who have not started treatment with methadone is 20–40 mg. The first dose for patients who have been receiving methadone will be a little higher than the amount of methadone that was being taken every day, but not more than 120 mg. Afterwards, the dosage may be adjusted as needed. Unlike methadone, which requires daily administration, LAAM is administered two to three times a week.

See also

References

  1. ^ US Patent 2565592
  2. ^ EMEA public statement on levoacethylmethadol, link is broken
  3. ^ U. S. FDA: Drug Shortages
  4. ^ "Blockade of Rat α3β4 Nicotinic Receptor Function by Methadone, Its Metabolites, and Structural Analogs — JPET". 

External links

  • LAAM Drug Information
  • RxList Monograph for Orlaam
  • DrugBank: Levomethadyl Acetate
  • http://cat.inist.fr/?aModele=afficheN&cpsidt=2706063
  • http://cat.inist.fr/?aModele=afficheN&cpsidt=2390242


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