Levomethadone

Levomethadone, sold under the brand name L-Polamidon among others, is a synthetic opioid analgesic and antitussive which is marketed in Europe and is used for pain management and in opioid maintenance therapy.^[1][2][3] In addition to being used as a pharmaceutical drug itself, levomethadone is the main therapeutic component of methadone.^[2]

Levomethadone

Clinical data
Other names	Levamethadone; l-Methadone; 6R-Methadone; (–)-Methadone; R-(–)-Methadone; D-(–)-Methadone
AHFS/Drugs.com	International Drug Names
Routes of administration	By mouth, IV, IM, SC, IT[1]
ATC code	N07BC05 (WHO)
Legal status
Legal status	DE: Anlage III (Special prescription form required) UK: Class A US: Schedule II UN: Narcotic Schedule I
Pharmacokinetic data
Bioavailability	High[1]
Protein binding	60–90%[1]
Elimination half-life	~18 hours[1]
Identifiers
IUPAC name (6R)-6-(dimethylamino)-4,4-diphenyl-3-heptanone
CAS Number	125-58-6 5967-73-7 (HCl)
PubChem CID	22267
ChemSpider	20904
UNII	6Y75Z4E8NS
KEGG	D08121
ChEBI	CHEBI:136003
ChEMBL	ChEMBL159659
CompTox Dashboard (EPA)	DTXSID701016376
ECHA InfoCard	100.120.592
Chemical and physical data
Formula	C21H27NO
Molar mass	309.453 g·mol−1
3D model (JSmol)	Interactive image
Melting point	99.5 °C (211.1 °F)
Solubility in water	48.48 mg/mL (20 °C)
SMILES O=C(C(c1ccccc1)(c2ccccc2)C[C@H](N(C)C)C)CC
InChI InChI=1S/C21H27NO/c1-5-20(23)21(16-17(2)22(3)4,18-12-8-6-9-13-18)19-14-10-7-11-15-19/h6-15,17H,5,16H2,1-4H3/t17-/m1/s1 Key:USSIQXCVUWKGNF-QGZVFWFLSA-N

Levomethadone is used for narcotic maintenance in place of, or in some cases alongside as an alternative, to racemic methadone,^[4] owing to concern about the cardiotoxic and QT-prolonging action of racemic methadone being primarily caused by the dextrorotatory enantiomer, dextromethadone.^[5][4]

Pharmacology

Pharmacodynamics

Levomethadone has approximately 50x the potency of the S-(+)-enantiomer as well as greater μ-opioid receptor selectivity.^[1][6] Accordingly, it is about twice as potent as methadone by weight and its effects are virtually identical in comparison.^[7][8] In addition to its activity at the opioid receptors, levomethadone has been found to act as a weak competitive antagonist of the N-methyl-D-aspartate (NMDA) receptor complex^[9] and as a potent noncompetitive antagonist of the α₃β₄ nicotinic acetylcholine (nACh) receptor.^[10]

• v
• t
• e

Receptor binding affinities of isomers of methadone^[11][12]

Compound	Affinities (KiTooltip Inhibitor constant, in nM)						Ratios
	MORTooltip μ-Opioid receptor	DORTooltip δ-Opioid receptor	KORTooltip κ-Opioid receptor	SERTTooltip Serotonin transporter	NETTooltip Norepinephrine transporter	NMDARTooltip N-Methyl-D-aspartate receptor	M:D:K	SERT:NET
Racemic methadone	1.7	435	405	1,400	259	2,500–8,300	1:256:238	1:5
Dextromethadone	19.7	960	1,370	992	12,700	2,600–7,400	1:49:70	1:13
Levomethadone	0.945	371	1,860	14.1	702	2,800–3,400	1:393:1968	1:50

Chemistry

The separation of the stereoisomers is one of the easier in organic chemistry and is described in the original patent.^[13] It involves "treatment of racemic methadone base with d-(+)-tartaric acid in an acetone/water mixture [which] precipitates almost solely the dextro-methadone levo-tartrate, and the more potent Levomethadone can easily be retrieved from the mother liquor in a high state of optical purity."^[14]

There is now an asymmetric synthesis^[15] available to prepare both levomethadone (R-(−)-methadone) and dextromethadone (S-(+)-methadone).^[16]

Society and culture

Generic names

Levomethadone is the generic name of the drug and its INNTooltip International Nonproprietary Name.^[3][2]

Brand names

Levomethadone has been sold under brand names including L-Polaflux, L-Polamidon, L-Polamivet, Levadone, Levo-Methasan, Levothyl, Mevodict, Levopidon and Vistadict, among others.^[17][3][2]

Legal status

Levomethadone is listed under the Single Convention On Narcotic Drugs 1961 and is a Schedule II Narcotic controlled substance in the US as an isomer of methadone (ACSCN 9250) and is not listed separately, nor is dextromethadone.^[18] It is similarly controlled under the German Betäubungsmittelgesetz and similar laws in practically every other country.^[19][20]