Levomethadone Explained

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] 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,[3] owing to concern about the cardiotoxic and QT-prolonging action of racemic methadone being primarily caused by the dextrorotatory enantiomer, dextromethadone.[4] [3]

Pharmacology

Pharmacodynamics

Levomethadone has approximately 50x the potency of the S-(+)-enantiomer as well as greater μ-opioid receptor selectivity.[5] Accordingly, it is about twice as potent as methadone by weight and its effects are virtually identical in comparison.[6] [7] 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[8] and as a potent noncompetitive antagonist of the α3β4 nicotinic acetylcholine (nACh) receptor.[9]

Chemistry

The separation of the stereoisomers is one of the easier in organic chemistry and is described in the original patent.[10] 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."[11]

There is now an asymmetric synthesis[12] available to prepare both levomethadone (R-(−)-methadone) and dextromethadone (S-(+)-methadone).[13]

Society and culture

Generic names

Levomethadone is the generic name of the drug and its .

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.[14]

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.[15] It is similarly controlled under the German Betäubungsmittelgesetz and similar laws in practically every other country.[16] [17]

Notes and References

  1. Book: Macdonald F . Dictionary of Pharmacological Agents . 17 May 2012 . 1997 . CRC Press . 978-0-412-46630-4 . 1294.
  2. Book: Index Nominum 2000: International Drug Directory . 17 May 2012 . 2000 . Taylor & Francis US . 978-3-88763-075-1 . 605.
  3. Judson BA, Horns WH, Goldstein A . Side effects of levomethadone and racemic methadone in a maintenance program . Clinical Pharmacology and Therapeutics . 20 . 4 . 445–449 . October 1976 . 788990 . 10.1002/cpt1976204445 . 6051512 .
  4. Web site: Levomethadone - an overview ScienceDirect Topics. 2021-12-21. www.sciencedirect.com.
  5. Book: Förch R, Schönherr H, Tobias A, Jenkins A . Surface Design: Applications in Bioscience and Nanotechnology . 17 May 2012 . 11 August 2009 . Wiley-VCH . 978-3-527-40789-7 . 193.
  6. Book: Bruera E, Yennurajalingam S . Oxford American Handbook of Hospice and Palliative Medicine . 17 May 2012 . 16 August 2011 . Oxford University Press . 978-0-19-538015-6 . 43.
  7. Verthein U, Ullmann R, Lachmann A, Düring A, Koch B, Meyer-Thompson HG, Schmidt R, Reimer J, Haasen C . 6 . The effects of racemic D,L-methadone and L-methadone in substituted patients--a randomized controlled study . Drug and Alcohol Dependence . 80 . 2 . 267–271 . November 2005 . 15916866 . 10.1016/j.drugalcdep.2005.04.007 .
  8. Book: Strain EC, Stitzer ML . The Treatment of Opioid Dependence . 19 May 2012 . 4 November 2005 . JHU Press . 978-0-8018-8303-3 . 63.
  9. Xiao Y, Smith RD, Caruso FS, Kellar KJ . Blockade of rat alpha3beta4 nicotinic receptor function by methadone, its metabolites, and structural analogs . The Journal of Pharmacology and Experimental Therapeutics . 299 . 1 . 366–371 . October 2001 . 11561100 . 2012-05-19 . 2021-08-28 . https://web.archive.org/web/20210828170410/https://jpet.aspetjournals.org/content/299/1/366.long . dead .
  10. Brooks WH, Guida WC, Daniel KG . The significance of chirality in drug design and development . Current Topics in Medicinal Chemistry . 11 . 7 . 760–770 . 2011 . 21291399 . 5765859 . 10.2174/156802611795165098 .
  11. Web site: Synthesis of Methadone . Erowid .
  12. Hull JD, Scheinmann F, Turner NJ . Synthesis of optically active methadones, LAAM and bufuralol by lipase-catalysed acylations . Tetrahedron: Asymmetry . 14 . 5 . 567–576 . March 2003 . 10.1016/S0957-4166(03)00019-3 .
  13. US . 6143933 . Scheinmann F, Hull JD, Turner NJ . Salford Ultrafine Chemicals . Process for the preparation of optically active methadones in high enantiomeric purity . 7 November 2000 . . .
  14. Web site: Levomethadone . https://web.archive.org/web/20160303203540/https://www.drugs.com/international/levomethadone.html . 3 March 2016 . Drugs.com .
  15. Web site: Conversion Factors for Controlled Substances . Diversion Control Division . Drug Enforcement Administration, United States Department of Justice . 2014-08-21 . 2016-03-02 . https://web.archive.org/web/20160302162948/http://deadiversion.usdoj.gov/quotas/conv_factor/index.html . dead .
  16. Rosner B, Neicun J, Yang JC, Roman-Urrestarazu A . Opioid prescription patterns in Germany and the global opioid epidemic: Systematic review of available evidence . PLOS ONE . 14 . 8 . e0221153 . 2019-08-28 . 31461466 . 6713321 . 10.1371/journal.pone.0221153 . 2019PLoSO..1421153R . Cheungpasitporn W . free .
  17. Web site: Reviewing current practice in drug-substitution treatment in the European Union.

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