Levacetylmethadol ( INN), levomethadyl acetate ( USAN), OrLAAM (trade name) or levo-α-acetylmethadol (LAAM) is a synthetic

opioid Opioids are a class of Drug, drugs that derive from, or mimic, natural substances found in the Papaver somniferum, opium poppy plant. Opioids work on opioid receptors in the brain and other organs to produce a variety of morphine-like effects, ...

similar in structure to

methadone Methadone, sold under the brand names Dolophine and Methadose among others, is a synthetic opioid used medically to treat chronic pain and opioid use disorder. Prescribed for daily use, the medicine relieves cravings and opioid withdrawal sym ...

. It has a long duration of action due to its active

metabolites In biochemistry, a metabolite is an intermediate or end product of metabolism. The term is usually used for small molecules. Metabolites have various functions, including fuel, structure, signaling, stimulatory and inhibitory effects on enzymes, c ...

Medical uses

LAAM is indicated as a second-line treatment for the treatment and management of

opioid dependence Opioid use disorder (OUD) is a substance use disorder characterized by cravings for opioids, continued use despite physical and/or psychological deterioration, increased tolerance with use, and withdrawal symptoms after discontinuing opioids. ...

if patients fail to respond to drugs like

or buprenorphine. LAAM is used as an

oral The word oral may refer to: Relating to the mouth * Relating to the mouth, the first portion of the alimentary canal that primarily receives food and liquid **Oral administration of medicines ** Oral examination (also known as an oral exam or ora ...

solution Solution may refer to: * Solution (chemistry), a mixture where one substance is dissolved in another * Solution (equation), in mathematics ** Numerical solution, in numerical analysis, approximate solutions within specified error bounds * Solu ...

of LAAM 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

is 20–40 mg. The first dose for patients who have been receiving

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.

Pharmacology

Pharmacodynamics

LAAM acts as a

μ-opioid receptor The μ-opioid receptors (MOR) are a class of opioid receptors with a high affinity for enkephalins and beta-endorphin, but a low affinity for dynorphins. They are also referred to as μ(''mu'')-opioid peptide (MOP) receptors. The prototypical ...

agonist An agonist is a chemical that activates a Receptor (biochemistry), receptor to produce a biological response. Receptors are Cell (biology), cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an R ...

.
It also acts as a potent, noncompetitive α₃β₄ neuronal

nicotinic acetylcholine receptor Nicotinic acetylcholine receptors, or nAChRs, are Receptor (biochemistry), receptor polypeptides that respond to the neurotransmitter acetylcholine. Nicotinic receptors also respond to drugs such as the agonist nicotine. They are found in the c ...

antagonist An antagonist is a character in a story who is presented as the main enemy or rival of the protagonist and is often depicted as a villain.

Pharmacokinetics

LAAM undergoes extensive

first-pass metabolism The first pass effect (also known as first-pass metabolism or presystemic metabolism) is a phenomenon of drug metabolism at a specific location in the body which leads to a reduction in the concentration of the active drug before it reaches the ...

to the active demethylated metabolite nor-LAAM, which is further demethylated to a second active metabolite, dinor-LAAM. These

are more potent than the parent drug.

Chemistry

LAAM, or levomethadyl acetate, is the ''levo'' isomer of acetylmethadol, or α-methadyl acetate. The ''dextro'' isomer, ''d''- alphacetylmethadol (''d''-α-acetylmethadol), is more potent but shorter acting. The ''levo'' isomer is also less toxic with an in mice of 110 mg/kg s.c. and 172.8 mg/kg orally as opposed to s of 61 mg/kg s.c. and 118.3 mg/kg orally for ''dl''-α-methadyl acetate. It has a

melting point The melting point (or, rarely, liquefaction point) of a substance is the temperature at which it changes state of matter, state from solid to liquid. At the melting point the solid and liquid phase (matter), phase exist in Thermodynamic equilib ...

of 215 °C and a

molecular weight A molecule is a group of two or more atoms that are held together by Force, attractive forces known as chemical bonds; depending on context, the term may or may not include ions that satisfy this criterion. In quantum physics, organic chemi ...

of 353.50. β-methadyl acetate also exists, but is more

toxic Toxicity is the degree to which a chemical substance or a particular mixture of substances can damage an organism. Toxicity can refer to the effect on a whole organism, such as an animal, bacterium, or plant, as well as the effect on a subst ...

and less active than α-methadyl acetate and has no current medical use.

History

LAAM was approved in 1993 by the U.S. Food and Drug Administration for use in the treatment of

. In 2001, LAAM was removed from the European market due to reports of life-threatening ventricular rhythm disorders. In 2003, Roxane Laboratories, Inc. discontinued Orlaam in the US.

Society and culture

Legal status

Before August 1993, LAAM was classified as a schedule I drug in the United States. LAAM is not approved for use in

Australia Australia, officially the Commonwealth of Australia, is a country comprising mainland Australia, the mainland of the Australia (continent), Australian continent, the island of Tasmania and list of islands of Australia, numerous smaller isl ...

and

Canada Canada is a country in North America. Its Provinces and territories of Canada, ten provinces and three territories extend from the Atlantic Ocean to the Pacific Ocean and northward into the Arctic Ocean, making it the world's List of coun ...

. 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 4grams as of 2013.

References

External links

* * * {{Opioid receptor modulators Acetate esters Enantiopure drugs Dimethylamino compounds HERG blocker Mu-opioid receptor agonists Nicotinic antagonists Synthetic opioids