d-Methadone For Neuropathic Pain

Today's post from dddmag.com (see link below) looks at d-methadone, a relative of methadone, which is being developed to treat neuropathic pain without the potential side effects associated with methadone and other opioids. Methadone has a bad rap! It's associated with drug addicts weaning off yet stronger drugs, yet is used very successfully with many people with neuropathic pain that doesn't respond to other drugs. Those people may get relief from their pain but have to suffer the unjustified stigma that methadone brings with it. Still in the development phase, d-methadone will achieve the same results without the side effects and that has to be very good news indeed. Unfortunately, parts of this report/article may well appear to be double-dutch to many readers due to the complexity of the science but you will get the gist. d-methadone may end up being a huge breakthrough in efficient treatment of nerve pain.
 

d-Methadone: A Novel Approach for Neuropathic Pain
 Eliseo Salinas, MD, MSc, President and Chief Scientific Officer, Relmada Therapeutics Thu, 03/12/2015
 
At a time when opioid abuse and addiction are making headlines, a new molecule is being studied to treat neuropathic pain without such negative effects. A relative of methadone, a widely known synthetic opioid medication, d-Methadone represents half of methadone’s chemical structure with profoundly different activity on the mu opioid receptor, considered a “gateway for addiction.”

A Gold Standard Treatment

Methadone is a widely known synthetic opioid medication that has been used for decades. It is used to reduce withdrawal symptoms in people addicted to heroin or other narcotic drugs without causing the "high" associated with the drug addiction. Methadone is also used as a pain reliever.

Like many narcotics, methadone suffers from poor safety and tolerability. Some of the adverse effects of methadone include sedation, constipation, dizziness, sleepiness, respiratory depression, and nausea/vomiting. Two enantiomers of a generic amino acid that is chiral Methadone is a chiral compound, meaning that it is comprised of two molecules (optical isomers) with identical composition, but which are arranged in a non-superposable mirror image (see image).

Usually one of the optical isomers of synthetic opioids accounts for most of the pharmacologic activity and the addictiveness of the racemic compound. The other isomer generally exhibits less activity and less addictiveness.

Methadone is an outstanding example of a compound in which greatly different activity and addictiveness occur in the optical isomers. Both the l-optical and d-optical isomers of racemic methadone are noncompetitive inhibitors of N-methyl-D-aspartate (NMDA), a glutamate receptor and ion channel protein found in nerve cells. In view of the fact that upregulation of NMDA plays an important role in neuropathic pain, inhibition of the receptor may provide strong pain relief in neuropathic pain states.

Where the l-optical and d-optical isomers of racemic methadone differ is their effect on the mu opioid receptor. While the l-optical isomer is a potent analgesic with addictiveness greater than or equal to morphine, the d-optical isomer is a weak opioid with potentially low addictiveness. This means d-methadone could be an effective agent to treat neuropathic pain through inhibition of NMDA without the poor safety and tolerability associated with activating the mu opioid receptor.

Early Studies

Leveraging research from Cornell University, d-Methadone is being developed as a novel drug with the potential to treat neuropathic pain. The first Phase 1 study in healthy subjects was initiated in late 2014 to evaluate single ascending doses of d-methadone. The goal of this study is to determine the maximum single dose of d-methadone that can be taken without evidence of the typical opioid effects. The second planned Phase 1 study will evaluate multiple ascending doses. Results from both studies will guide a planned Phase 2 study to assess the effect of d-methadone in patients with neuropathic pain.

While early in clinical development, published clinical studies with low doses of another NMDA inhibitor called ketamine (a psychoactive ‘party drug’ better known as Special K) have produced strong pain relief in neuropathic pain states and serve as proof of concept for d-methadone. Severe side effects limit the use of ketamine, such as hallucinations, memory defects, panic attacks, and nausea/vomiting. In contrast, d-methadone appears to be well tolerated.

Neuropathic pain is defined as a disorder of the sensorimotor system and is distinctly different from nociceptive pain, which is a consequence of trauma, injury, or inflammation. The term neuropathic pain is used to describe a wide range of pain syndromes, including painful diabetic neuropathy, postherpetic neuralgia, and trigeminal neuralgia. According to the Neuropathy Association, neuropathic pain is estimated to affect more than 20 million people in the United States alone.

The main classes of drugs used to treat these neuropathic pain conditions are anticonvulsants, antidepressants, opioids, and topical treatments. However, despite the availability of multiple pain medications only about 50 percent of patients respond to treatment with currently available therapy options, and they present the risk of numerous side effects that reduce their tolerability. Accordingly, the treatment of neuropathic pain represents a large unmet medical need.

Eliseo Salinas, MD, MSc joined Relmada Therapeutics in February 2014. Dr. Salinas has more than 20 years of experience developing therapeutic products for CNS disorders in many key jurisdictions worldwide, including the United States, Canada, the European Union, and Japan. Under Dr. Salinas’ leadership, 15 programs obtained regulatory approval in the United States and other major international markets. Prior to joining Relmada, Dr. Salinas was Executive Vice President and Head of Research and Development at StemCells, Inc. Dr. Salinas has also held high-level positions at Elan Pharmaceuticals, Adolor Corporation, and Shire plc. Dr. Salinas earned his medical degree from the University of Buenos Aires, Argentina, performed a residency in psychiatry in Paris at the Clinique des Maladies Mentales et de l'Encéphale, and obtained a master's degree in pharmacology from the Université Pierre et Marie Curie, Académie de Paris, France.

http://www.dddmag.com/articles/2015/03/d-methadone-novel-approach-neuropathic-pain