A novel approach to treating opioid use disorder

An FDA-approved drug called exendin-4 decreased voluntary oxycodone taking and drug-seeking behavior during withdrawal in rats without reducing the relief the opioid provided.

Opioid use disorder and overdose deaths are a major public health crisis in the United States, costing close to $80 billion annually. While medication-assisted treatments exist, they’re often inadequate and result in a high rate of relapse following detoxification.

closeup of prescription pill container on its side with white oblong pills spilling out.

Preclinical research recently published in the journal Neuropsychopharmacology from the University of Pennsylvania School of Nursing and Penn’s Perelman School of Medicine found that systemic use of an FDA-approved drug called exendin-4 decreased how frequently rats intravenously self-administered oxycodone and how much of the opioid they sought during withdrawal. 

Beyond that, at doses that decreased oxycodone taking, exendin-4 did not produce adverse effects or block the pain relief from the drug. 

Exendin-4 is a drug that mimics glucagon-like peptide 1 (GLP-1), a naturally occurring hormone in the body. Exendin-4 binds to and activates GLP-1 receptors, proteins expressed throughout the body, including in the pancreas and brain. Activation of GLP-1 receptors produces many positive effects in humans, like reducing food intake and lowering blood glucose levels, which is why drugs like exendin-4 that activate GLP-1 receptors are effective treatments for diabetes and obesity.

Previous work from the lab of Penn’s Heath D. Schmidt, senior researcher on the paper, found success using GLP-1 receptor agonists to fight cocaine addiction in rats. But until now, no studies had examined how effective GLP-1 receptor agonists might be in combating opioid abuse. This research, led by Penn Nursing postdoctoral fellow Yafang Zhang, highlights a potentially new role for the GLP-1 receptor system in the fight against the opioid crisis.  

“Central GLP-1 receptors could serve as targets for novel medications aimed at treating opioid use disorder,” Zhang explains. And, she adds, they may do so without interfering with the pain relief provided by opioids. In other words, these medications could possibly serve as adjunct treatments for patients with chronic pain, limiting opioid abuse potential but preserving opioid-induced analgesic responses.

More research is required to fully understand the role of GLP-1 receptor agonists in treating opioid use disorder and pain, like determining whether tolerance to repeated treatments might develop.  

Funding for this research came from the National Institutes of Health (Grant R01 DA037897) and from Penn’s Center for Undergraduate Research & Fellowships and the Office of Nursing Research at Penn Nursing.

Heath D. Schmidt is a neuropharmacologist and director of the Laboratory of Neuropsychopharmacology at the University of Pennsylvania School of Nursing. He is also an assistant professor of psychiatry at Penn’s Perelman School of Medicine and part of the Center for Neurobiology and Behavior.

Yafang Zhang is a postdoctoral fellow in the Laboratory of Neuropsychopharmacology at the University of Pennsylvania School of Nursing