Levomethadone
{{Short description|Synthetic opioid}}
{{cs1 config|name-list-style=vanc|display-authors=6}}
{{Drugbox
| IUPAC_name = (6R)-6-(dimethylamino)-4,4-diphenyl-3-heptanone
| image = Levomethadone structure.svg
| width = 200px
| image2 = Levomethadone-xtal-1974-ball-and-stick.png
| width2 = 225px
| Drugs.com = {{Drugs.com|international|levomethadone}}
| pregnancy_category =
| legal_DE = Anlage III
| legal_US = Schedule II
| legal_UK = Class A
| legal_UN = Narcotic Schedule I
| routes_of_administration = By mouth, IV, IM, SC, IT
| CAS_number = 125-58-6
| CAS_supplemental =
{{CAS|5967-73-7}} (HCl)
| ATC_prefix = N07
| ATC_suffix = BC05
| PubChem = 22267
| ChemSpiderID = 20904
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = 6Y75Z4E8NS
| KEGG = D08121
| ChEMBL = 159659
| ChEBI = 136003
| synonyms = Levamethadone; l-Methadone; 6R-Methadone; (–)-Methadone; R-(–)-Methadone; D-(–)-Methadone
| metabolism =
| elimination_half-life = ~18 hours
| excretion =
| C=21 | H=27 | N=1 | O=1
| SMILES = O=C(C(c1ccccc1)(c2ccccc2)C[C@H](N(C)C)C)CC
| StdInChI = 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
| StdInChIKey = USSIQXCVUWKGNF-QGZVFWFLSA-N
| solubility = 48.48
| melting_point = 99.5
}}
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.{{cite book | vauthors = Macdonald F | title = Dictionary of Pharmacological Agents | url = https://books.google.com/books?id=A0THacd46ZsC&pg=PA1294 | access-date = 17 May 2012 | year = 1997 | publisher = CRC Press | isbn = 978-0-412-46630-4 | page = 1294}}{{cite book | title = Index Nominum 2000: International Drug Directory | url = https://books.google.com/books?id=5GpcTQD_L2oC&pg=PA605 | access-date = 17 May 2012 | year = 2000 | publisher = Taylor & Francis US | isbn = 978-3-88763-075-1 | page = 605}} In addition to being used as a pharmaceutical drug itself, levomethadone is the main therapeutic component of methadone.
Levomethadone is used for narcotic maintenance in place of, or in some cases alongside as an alternative, to racemic methadone,{{cite journal | vauthors = Judson BA, Horns WH, Goldstein A | title = Side effects of levomethadone and racemic methadone in a maintenance program | journal = Clinical Pharmacology and Therapeutics | volume = 20 | issue = 4 | pages = 445–449 | date = October 1976 | pmid = 788990 | doi = 10.1002/cpt1976204445 }} owing to concern about the cardiotoxic and QT-prolonging action of racemic methadone being primarily caused by the dextrorotatory enantiomer, dextromethadone.{{cite journal | vauthors = Eap CB, Crettol S, Rougier JS, Schläpfer J, Sintra Grilo L, Déglon JJ, Besson J, Croquette-Krokar M, Carrupt PA, Abriel H | title = Stereoselective Block of hERG Channel by (S)-Methadone and QT Interval Prolongation in CYP2B6 Slow Metabolizers | journal = Clinical Pharmacology and Therapeutics | volume = 81 | issue = 5 | pages = 719–728 | date = May 2007 | pmid = 17329992 | doi = 10.1038/sj.clpt.6100120 }}
Pharmacology
=Pharmacodynamics=
Levomethadone has approximately 50x the potency of the S-(+)-enantiomer as well as greater μ-opioid receptor selectivity.{{cite book | vauthors = Förch R, Schönherr H, Tobias A, Jenkins A | title = Surface Design: Applications in Bioscience and Nanotechnology | url = https://books.google.com/books?id=J0fhTBYVJioC&pg=PA193 | access-date = 17 May 2012 | date = 11 August 2009 | publisher = Wiley-VCH | isbn = 978-3-527-40789-7 | page = 193}} Accordingly, it is about twice as potent as methadone by weight and its effects are virtually identical in comparison.{{cite book | vauthors = Bruera E, Yennurajalingam S | title = Oxford American Handbook of Hospice and Palliative Medicine | url = https://books.google.com/books?id=I1laHM-HP1QC&pg=PA43 | access-date = 17 May 2012 | date = 16 August 2011 | publisher = Oxford University Press | isbn = 978-0-19-538015-6 | page = 43}}{{cite journal | vauthors = Verthein U, Ullmann R, Lachmann A, Düring A, Koch B, Meyer-Thompson HG, Schmidt R, Reimer J, Haasen C | title = The effects of racemic D,L-methadone and L-methadone in substituted patients--a randomized controlled study | journal = Drug and Alcohol Dependence | volume = 80 | issue = 2 | pages = 267–271 | date = November 2005 | pmid = 15916866 | doi = 10.1016/j.drugalcdep.2005.04.007 }} 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{{cite book | vauthors = Strain EC, Stitzer ML | title = The Treatment of Opioid Dependence | url = https://books.google.com/books?id=entNMgTdeJ4C&pg=PA63 | access-date = 19 May 2012 | date = 4 November 2005 | publisher = JHU Press | isbn = 978-0-8018-8303-3 | page = 63}} and as a potent noncompetitive antagonist of the α3β4 nicotinic acetylcholine (nACh) receptor.{{cite journal | vauthors = Xiao Y, Smith RD, Caruso FS, Kellar KJ | title = Blockade of rat alpha3beta4 nicotinic receptor function by methadone, its metabolites, and structural analogs | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 299 | issue = 1 | pages = 366–371 | date = October 2001 | doi = 10.1016/S0022-3565(24)29338-1 | pmid = 11561100 }}
{{Methadone at opioid receptors, monoamine transporters, and the NMDA receptor|floatleft=yes}}
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Chemistry
The separation of the stereoisomers is one of the easier in organic chemistry and is described in the original patent.{{cite journal | vauthors = Brooks WH, Guida WC, Daniel KG | title = The significance of chirality in drug design and development | journal = Current Topics in Medicinal Chemistry | volume = 11 | issue = 7 | pages = 760–770 | date = 2011 | pmid = 21291399 | pmc = 5765859 | doi = 10.2174/156802611795165098 }} 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."{{cite web | title = Synthesis of Methadone | url = https://www.erowid.org/archive/rhodium/chemistry/methadone.html | work = Erowid }}
There is now an asymmetric synthesis{{cite journal |vauthors=Hull JD, Scheinmann F, Turner NJ | title = Synthesis of optically active methadones, LAAM and bufuralol by lipase-catalysed acylations | journal = Tetrahedron: Asymmetry | volume = 14 | issue = 5 | pages = 567–576 |date=March 2003 | doi = 10.1016/S0957-4166(03)00019-3 }} available to prepare both levomethadone (R-(−)-methadone) and dextromethadone (S-(+)-methadone).{{cite patent | country = US | number = 6143933 | inventor = Scheinmann F, Hull JD, Turner NJ | assign1 = Salford Ultrafine Chemicals | title = Process for the preparation of optically active methadones in high enantiomeric purity | gdate = 7 November 2000 | postscript = . }}
Society and culture
=Generic names=
Levomethadone is the generic name of the drug and its {{abbrlink|INN|International Nonproprietary Name}}.
=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.{{cite web | title = Levomethadone | url = https://www.drugs.com/international/levomethadone.html | archive-url = https://web.archive.org/web/20160303203540/https://www.drugs.com/international/levomethadone.html | archive-date = 3 March 2016 | work = Drugs.com }}
=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.{{cite web | title = Conversion Factors for Controlled Substances | url = http://www.deadiversion.usdoj.gov/quotas/conv_factor/index.html | work = Diversion Control Division | publisher = Drug Enforcement Administration, United States Department of Justice | access-date = 2014-08-21 | archive-date = 2016-03-02 | archive-url = https://web.archive.org/web/20160302162948/http://deadiversion.usdoj.gov/quotas/conv_factor/index.html | url-status = dead }} It is similarly controlled under the German Betäubungsmittelgesetz and similar laws in practically every other country.{{cite journal | vauthors = Rosner B, Neicun J, Yang JC, Roman-Urrestarazu A | title = Opioid prescription patterns in Germany and the global opioid epidemic: Systematic review of available evidence | journal = PLOS ONE | volume = 14 | issue = 8 | pages = e0221153 | date = 2019-08-28 | pmid = 31461466 | pmc = 6713321 | doi = 10.1371/journal.pone.0221153 | bibcode = 2019PLoSO..1421153R | veditors = Cheungpasitporn W | doi-access = free }}{{cite book | vauthors = Robertson K, Solberg U |title=Reviewing Current Practice in Drug-substitution Treatment in the European Union |date=2000 |publisher=European Monitoring Centre for Drugs and Drug Addiction |isbn=978-92-9168-104-4 |url=https://www.emcdda.europa.eu/system/files/publications/111/Insight3_64348.pdf }}{{pn|date=February 2025}}
References
{{Reflist}}
{{Analgesics}}
{{Dependence treatment}}
{{Antitussives}}
{{Navboxes
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Category:Dimethylamino compounds
Category:Glycine receptor antagonists
Category:Mu-opioid receptor agonists
Category:Nicotinic antagonists