April 8, 2019

By Kris Schanilec

Scientists at the National Institute on Drug Abuse (NIDA) and their collaborators report that methadone may produce less euphoria than other opioids, suggesting it may hold less risk for abuse or misuse.

In a study led by Sergi Ferré, MD, PhD, and Annabelle Belcher, PhD, published in the Journal of Clinical Investigation, researchers conducted experiments using cells in culture, as well as an animal model, to assess the effects of different opioids on the brain. They found that methadone was much less potent than morphine and fentanyl in activating receptors that drive feelings of euphoria.

In the experiments, the scientists examined the response of opioid receptors in cells in the ventral tegmental area (VTA) of the brain. The VTA is a key area involved in the brain’s “reward circuit.” The researchers found that opioid receptors located in the VTA link with receptors for another neurotransmitter called galanin to form complexes; and that these complexes are less responsive to methadone than to the other opioids.

The researchers also looked at patient data from the RLS Opioid Registry and from a clinical trial for opioid use disorder (opioid addiction). In both studies, significantly fewer patients said they experienced a “high” from taking methadone compared with the other opioids – confirming results of the lab experiments.

“Our work provides very important support for the use of methadone in RLS. These results provide a substantial basis for arguments for its continued availability and use as an opioid treatment with little addictive potential,” says Dr. Ferré, who is a member of the RLS Foundation Scientific and Medical Advisory Board.

“The results also open a new path to address the discovery of opioids with lower risk of addiction, which already include methadone. Our ongoing studies will identify the mechanism by which methadone does not activate the opioid-galanin receptor complexes, which light up the reward circuitry, to use this as the basis for future drug development. This is the Holy Grail in the search for effective opioids for the treatment of pain and RLS – we want to emulate that,” Dr. Ferré says.

Opioid therapy is used to treat RLS when all other options have failed. At low total daily doses, opioids are effective for controlling RLS symptoms in most patients. Methadone and oxycontin are specifically used for RLS because they are longer-acting, so a single dose can control symptoms across a span of many hours.

The NIDA findings present a new way for clinicians to distinguish among opioids, according to co-author John Winkelman, MD, PhD. “This study suggests that methadone may be distinctive in that it doesn’t activate the euphoric, or rewarding, centers in the brain, and therefore lessens the risk of misuse or abuse. From this perspective, methadone in low doses is not as worrisome as other opioids. However, it is still an opioid and needs to be used only in select patients and carefully in those individuals,” says Dr. Winkelman.

RLS patients who may feel stigmatized for taking methadone can find reassurance in these new findings, according to RLS Foundation Executive Director Karla Dzienkowski, “This gives the RLS patient community validation for this treatment, and hope for the future.”

In this video by NIDA, Dr. Ferre and Dr. Belcher discuss what they have learned about methadone, a drug used to manage opioid addiction that does not have euphoric effects as strong as other opioids: