In the new study from the Center for Substance Abuse Research, Temple and NIH/NIDA researchers administered the troriluzole, a prodrug of FDA-approved riluzole, to rats and found that it significantly alleviated multiple adverse effects associated with long-term opioid exposure. The next step for this research could be a clinical trial at Temple University Hospital in patients with opioid use disorder.

One of the biggest challenges when it comes to combatting the opioid crisis is the physical and psychological dependence that develops among opioid users. It is a debilitating, physiological battle, making it all the more likely for users to ultimately relapse. 

For researchers working to combat addiction, this represents the enduring struggle. But that is why new research out of Temple University’s Lewis Katz School of Medicine and the Center for Substance Abuse Research (CSAR) has the potential to be so impactful. It all starts with a drug known as troriluzole (TRLZ), prodrug of the FDA-approved drug riluzole, which is a dual glutamate release inhibitor/transport activator. 

Recently published in the British Journal of Pharmacology, the scholarly journal article “Troriluzole attenuates opioid intake, reinforcing efficacy, seeking behaviours, physical dependence and antinociceptive tolerance in rats” outlines how TRLZ could potentially be a game changer when it comes to treating opioid use disorder. Conducted in a preclinical model, the study found that troriluzole administration reduced the physical dependence, reinforcing effects and relapse-like behaviors caused by chronic opioid exposure. The compound also lessened morphine-derived analgesic tolerance and respiratory depression. 

“For us, this is exciting because what we found is that TRLZ has the potential to really alleviate multiple adverse effects associated with long-term opioid use,” said Scott Rawls, professor of pharmacology at the Katz School who co-authored the study and is senior author on the publication. “TRLZ is a prodrug of riluzole, which is approved by the FDA for ALS. TRLZ, based on preclinical work conducted in our lab with methamphetamine, is also being currently tested in patients with methamphetamine use disorder in a National Institutes of Health (NIH)-funded clinical trial at University of Kentucky, so we are now feeling optimistic about the potential for TRLZ to combat addiction caused by stimulants and opioids.” 

Rawls also serves as a professor at CSAR and a professor in the Department of Neural Sciences. Saadet Inan, an associate scientist with CSAR, and Sonita Wiah, a research technician and laboratory manager, also served as two of Rawls’ collaborators in the research, along with Allen Reitz, CEO of Fox Chase Therapeutics Discovery, Inc. who discovered TRLZ and has partnered with pharmaceutical company Biohaven for further clinical development. 

In compiling the study, Rawls and his co-authors utilized a self-administration model with rats that had previously been trained to take opioids. With this model, the subjects routinely press a lever to make it clear that they want more of the opioid drug, but that changed once TRLZ was introduced into the process. 

“Opioid intake dropped significantly with TRLZ treatment,” Rawls said. “The compound also reduced motivation to seek the drug and, perhaps most importantly, prevented relapse behaviors after a period of opioid abstinence. That’s really the biggest challenge in treating addiction, preventing relapse. And that’s why these findings are so exciting.” 

The studies directed toward TRLZ have already garnered funding from the National Institute on Drug Abuse (NIDA). In addition to the NIH-funded clinical trial at University of Kentucky involving TRLZ and methamphetamine use disorder, there are also plans to explore a clinical trial at Temple University Hospital involving opioids. 

“From my perspective, this study really helps illustrate the important work happening within CSAR,” Rawls said. “Addiction is a very real problem, and it’s difficult to treat. I think the great thing about TRLZ is that it seems to have effectiveness against different classes of addictive drugs, which means it could potentially treat patients who are engaging in polydrug misuse and taking multiple drugs. For us, as researchers, this is just the beginning, but we are optimistic about what we can find moving forward.” 

Other researchers who contributed to the study include Ewa Galaj and George Adamson from Colgate University, Guo-Hua Bi and Zheng-Xiong Xi from the National Institute on Drug Abuse Intramural Research Program in Baltimore.