Scientists Discover a Safer Way to Use Opioids for Pain Relief—Without the Dangerous Side Effects

Researchers at the University of South Florida have discovered a breakthrough approach to opioid pain relief that could dramatically reduce the risk of overdose deaths. Their findings show that certain experimental compounds can enhance the pain-relieving effects of morphine and fentanyl without making the dangerous breathing suppression worse—a discovery that could reshape how we treat chronic back pain, sciatica, and other severe pain conditions.

The research, published in Nature, focuses on mu opioid receptors—the proteins on nerve cells that reduce pain signals when activated by opioids like morphine. While these receptors provide powerful pain relief for conditions like herniated disc pain and spinal stenosis, they also trigger the breathing suppression that contributes to the 68 percent of overdose deaths involving opioids in 2024.

How Do These New Compounds Work Differently?

The breakthrough centers on a previously unknown way that opioid receptors can function. "We've found that the first step of the chain reaction is reversible, and that some drugs can favor a reverse reaction over the forward reaction," said Dr. Laura M. Bohn, senior associate dean for Basic and Translational Research at USF Health.

When traditional opioids bind to receptors, they trigger a sequence of events inside cells that leads to both pain relief and dangerous side effects. The researchers discovered that this earliest step can actually move in reverse, and some compounds strongly favor this backward reaction instead of pushing the process forward.

What Makes This Discovery So Promising for Pain Patients?

The experimental compounds studied offer several key advantages over current pain medications:

• Enhanced Pain Relief: When administered at doses that don't work alone, these compounds can boost the pain-relieving effects of morphine and fentanyl
• Reduced Breathing Risks: The compounds amplify pain relief without intensifying the respiratory suppression that causes overdose deaths
• Longer-Lasting Effects: The research suggests these approaches could lead to pain medications that work better and last longer than current options

"We've studied two new chemicals that strongly favor the reverse cycle and, when administered at non-effective doses, can enhance morphine and fentanyl-induced pain relief while not enhancing the respiratory suppression effects," Dr. Bohn explained.

The research builds on Dr. Bohn's laboratory's earlier work with a compound called SR-17018, which doesn't cause breathing suppression or tolerance. Unlike traditional opioids, SR-17018 activates the same receptor targeted by morphine and fentanyl but attaches differently, leaving the receptor available for the body's natural pain-relieving chemicals.

When Might These Safer Pain Medications Become Available?

While the discovery represents a major scientific breakthrough, the newly studied molecules are not ready for patient use. At higher doses, they still suppress breathing and haven't undergone testing for toxicity or other opioid-related side effects. However, they provide valuable guidance for future drug design.

"They do provide the framework for building new drugs," Dr. Bohn said. The research team plans to use these new findings to improve upon SR-17018 and develop even safer pain medications.

The implications extend beyond opioids. Dr. Edward Stahl, assistant professor of Molecular Pharmacology and Physiology and corresponding author on the study, noted that this research "significantly improves scientific understanding of how receptors function." Other receptors, including the serotonin 1A receptor involved in depression and psychosis, may also be activated in this reverse direction.

For the millions of Americans suffering from chronic back pain, lumbar pain, and degenerative disc conditions, this research offers hope for future treatments that could provide powerful relief without the life-threatening risks that have made the opioid crisis such a devastating public health emergency.