alexa
Reach Us +44-2476101207
Is it Time to Consider Use of Levo-methadone (R-(-)-Methadone) to Replace Racemic Methadone? | OMICS International
ISSN: 2329-6631
Journal of Developing Drugs
Make the best use of Scientific Research and information from our 700+ peer reviewed, Open Access Journals that operates with the help of 50,000+ Editorial Board Members and esteemed reviewers and 1000+ Scientific associations in Medical, Clinical, Pharmaceutical, Engineering, Technology and Management Fields.
Meet Inspiring Speakers and Experts at our 3000+ Global Conferenceseries Events with over 600+ Conferences, 1200+ Symposiums and 1200+ Workshops on
Medical, Pharma, Engineering, Science, Technology and Business

Is it Time to Consider Use of Levo-methadone (R-(-)-Methadone) to Replace Racemic Methadone?

Philip Lisberg and Feodor Scheinmann*

FSR Ltd., c/o Chittendens Accountants, 456 Chester Road, Manchester M16 9HD, UK

*Corresponding Author:
Feodor Scheinmann
Formerly Founding Director and CEO of Salford Ultrafine Chemicals and Research Ltd
Reader in Organic Chemistry at University of Salford
visiting Professor at Universities of Manchester
Liverpool and Zurich, UK
E-mail: [email protected]

Received Date: July 25, 2013; Accepted Date: August 14, 2013; Published Date: August 20, 2013

Citation: Lisberg P, Scheinmann F (2013) Is it Time to Consider Use of Levomethadone (R-(-)-Methadone) to Replace Racemic Methadone? J Develop Drugs 2:109. doi: 10.4172/2329-6631.1000109

Copyright: © 2013 Lisberg P, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Visit for more related articles at Journal of Developing Drugs

Racemic methadone, a mixture of its two enantiomeric optically active forms, R-(-)-Methadone and S-(+)-Methadone (also known as levo-methadone and dextro-methadone), was first synthesized in Germany before the outbreak of World War II.

Racemic methadone is now generic and was admitted in 2005 to W.H.O.’s Essential Medicines List [1] and issued in over 70 countries around the world:

1. in the management of chronic pain, and

2. as the gold standard substitution therapy for illicit opioid misuse.

History of Racemic Methadone and its Optical Isomers

By 1945, researchers at Hoechst had isolated levo-methadone (a difficult and costly process), discovering it had a far greater analgesic activity over the racemic form [2]. By the late 1940s, USA-based Eli Lilly (who bought the methadone patent as war reparations for the peppercorn sum of $1) confirmed the analgesic superiority of levomethadone [3,4]. To date, levo-methadone has never been developed commercially in the U.S.A.

However, events took a different turn in Germany where in 1965 Hoechst discontinued its production of racemic methadone, replacing it with levo-methadone (L-polamidon). In 1992, racemic methadone was re-approved in Germany to fall in line with international standards of MMT (methadone maintenance therapy). To this day in Germany, both racemic methadone and levo-methadone are available. Surprisingly levo-methadone has command of about 25% of the methadone market there in spite of it being up to 3 times more expensive to purchase [5].

The F.D.A. has issued a “Black Box Warning” regarding the use of racemic methadone where life threatening side effects such as cardiac arrhythmias and potassium channel blockage are attributed to S-(+)- methadone [6]. Toxicity problems may also arise from metabolism by Cytochrome P450 enzymes (CYP3A4 and CYP2B6) in the presence of benzodiazapines, tranquilizers and alcohol [7].

Meanwhile in the absence of levo-methadone in most countries, the worldwide manufacture of racemic methadone continues to increase reaching 43.9 tons in 2010 with almost half being used in the U.S.A [8].

Comment

In the U.S.A. there are over 5,000 deaths every year attributed to racemic methadone [9]. Over a million patients are currently being treated with racemic methadone for both pain management and MMT (Methadone Maintenance Treatment). More choice in medication may benefit patients by switching to levo-methadone once market authorization has been obtained. As levo-methadone is used only in German-speaking countries (Germany, Austria & Switzerland), some studies evaluating racemic methadone and levo-methadone safety and efficacy have been published in German [10-12].

Reasons for Switching to Safer Levo-methadone

The preference for stereochemical control and the use of one stereo isomer at a given biological target follows from authoritative recommendations:

a) In 1992, the F.D.A. recommended that the biological active isomer should be used instead of the racemate where possible in medication [13]. To encourage such new drug development in 2007 FDCA s.505 (u) was introduced granting chiral switches five years of market exclusivity [14].

b) Use of levo-methadone instead of racemic methadone allows for half the dose for equipotency in treatment of pain and methadone maintenance therapy [15,16].

c) Studies of chiral isolates of methadone on the cardiac potassium channel IKr and stereoselective block by S-(+)-methadone have been reported [17-19]. Thus, levo-methadone has a greater safety profile.

Although levo-methadone has been licensed for use in Germany, it is not available in the U.S.A. even though senior clinicians have expressed their interest in carrying out further trials to firmly establish the selectivity of the chiral isolates for greater safety and efficacy in the treatment of pain and drug addiction, now that a cost effective method of preparation is available and ready for scale-up for A.P.I manufacture.

Scientific and Commercial Considerations

The resolution of racemic methadone to provide levo-methadone by classical methods is done at the end of the synthesis, or at the penultimate stage, whereby more than half of the material by weight is lost. This extra stage makes levo-methadone more expensive for an equipotent dose and is wasteful on equipment and reagent resources.

This waste can be eliminated by an asymmetric synthesis with a cheap chiral starting material and proving that chirality is not lost during the total synthesis to provide levo-methadone. This has been done and is the subject of a publication [20] and U.S. patent [21].

The prime objective must be to prescribe what is best for the patient and the literature cited indicates that levo-methadone is a safer drug for MMT and treating somatic pain. The asymmetric synthesis makes better use of the existing equipment and reagents and is more cost effective than classical resolution for synthesizing levomethadone. Progress in medication, and more choice for professionals in prescribing, justify making changes [22].

Conclusion

Since the article revealing the chiral cardiotoxicity of racemic methadone was published, an increasing number of health professionals worldwide have demanded a better assessment of the risks and chiral R-(-)-methadone prescription [23,24].

Is it now time for the regulatory (FDA in USA and MHRA in the UK) and health authorities to decide what is best for the patient and review the data and subsequent work which shows that it is safe to switch from racemic methadone to levo-methadone [25] and to provide fast track assessment of additional work that may be required for market authorization?

Hopefully this will soon provide medical practitioners more choice of medication in treating somatic pain and for MMT.

References

Select your language of interest to view the total content in your interested language
Post your comment

Share This Article

Article Usage

  • Total views: 14779
  • [From(publication date):
    October-2013 - Dec 17, 2018]
  • Breakdown by view type
  • HTML page views : 10871
  • PDF downloads : 3908
 

Post your comment

captcha   Reload  Can't read the image? click here to refresh

Peer Reviewed Journals
 
Make the best use of Scientific Research and information from our 700 + peer reviewed, Open Access Journals
International Conferences 2018-19
 
Meet Inspiring Speakers and Experts at our 3000+ Global Annual Meetings

Contact Us

Agri and Aquaculture Journals

Dr. Krish

[email protected]

+1-702-714-7001Extn: 9040

Biochemistry Journals

Datta A

[email protected]

1-702-714-7001Extn: 9037

Business & Management Journals

Ronald

[email protected]

1-702-714-7001Extn: 9042

Chemistry Journals

Gabriel Shaw

[email protected]

1-702-714-7001Extn: 9040

Clinical Journals

Datta A

[email protected]

1-702-714-7001Extn: 9037

Engineering Journals

James Franklin

[email protected]

1-702-714-7001Extn: 9042

Food & Nutrition Journals

Katie Wilson

[email protected]

1-702-714-7001Extn: 9042

General Science

Andrea Jason

[email protected]

1-702-714-7001Extn: 9043

Genetics & Molecular Biology Journals

Anna Melissa

[email protected]

1-702-714-7001Extn: 9006

Immunology & Microbiology Journals

David Gorantl

[email protected]

1-702-714-7001Extn: 9014

Materials Science Journals

Rachle Green

[email protected]

1-702-714-7001Extn: 9039

Nursing & Health Care Journals

Stephanie Skinner

[email protected]

1-702-714-7001Extn: 9039

Medical Journals

Nimmi Anna

[email protected]

1-702-714-7001Extn: 9038

Neuroscience & Psychology Journals

Nathan T

[email protected]

1-702-714-7001Extn: 9041

Pharmaceutical Sciences Journals

Ann Jose

[email protected]

1-702-714-7001Extn: 9007

Social & Political Science Journals

Steve Harry

streamtajm

[email protected]

1-702-714-7001Extn: 9042

 
© 2008- 2018 OMICS International - Open Access Publisher. Best viewed in Mozilla Firefox | Google Chrome | Above IE 7.0 version