Scientists Discover a Safer Way to Use Opioids for Chronic Pain—Without the Deadly Side Effects

Scientists at the University of South Florida have discovered a revolutionary approach to opioid pain relief that could eliminate the deadly breathing problems that cause most overdose deaths. Their research reveals that certain experimental compounds can amplify the pain-relieving effects of morphine and fentanyl without making the dangerous respiratory suppression worse.

The breakthrough centers on mu opioid receptors—proteins found on nerve cells that reduce pain signals when activated by opioids like morphine. While these receptors provide pain relief, they also trigger the life-threatening side effects that contribute to the opioid crisis. In 2024, opioids were involved in 68 percent of overdose deaths, with fentanyl and other synthetic opioids accounting for 88 percent of those fatalities.

How Does This New Approach Work?

The research team discovered that the earliest step in opioid signaling can actually move in reverse—something scientists didn't know was possible. When opioids bind to receptors, they normally trigger a forward chain reaction that leads to both pain relief and dangerous side effects. But some compounds appear to favor pushing this process backward instead.

"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 the University of South Florida Health Morsani College of Medicine.

The researchers studied two experimental chemicals that strongly favor this reverse cycle. When given at doses that wouldn't normally work on their own, these compounds enhanced morphine and fentanyl-induced pain relief while not making the breathing suppression effects worse.

What Makes These Compounds Different?

The experimental compounds work by changing how opioid receptors behave at the molecular level. Here's what makes them unique:

• Reverse Signaling: They favor pushing the receptor's signaling process backward rather than forward, which appears to separate pain relief from breathing suppression
• Enhancement Effect: At non-effective doses, they can boost the pain-relieving power of existing opioids like morphine and fentanyl
• Selective Action: They amplify pain relief without intensifying the dangerous respiratory depression that causes overdose deaths

"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.

Are These Ready for Patients Yet?

The newly studied molecules are not considered drug candidates and won't be available to patients anytime soon. At higher doses, they still suppress breathing and haven't been tested for toxicity or other opioid-related side effects. However, they provide valuable guidance for designing safer pain medications in the future.

The research builds on Dr. Bohn's laboratory's previous work with a compound called SR-17018. Unlike traditional opioids, SR-17018 doesn't cause breathing suppression or tolerance. It activates the same opioid receptor targeted by morphine and fentanyl, but attaches in a different way that leaves the receptor available for the body's own natural pain-relieving chemicals.

"Our overarching research aims to understand how opioids work so that we can ultimately provide safer options for chronic pain and develop therapies for opioid use disorders," Dr. Bohn said. The team plans to use these new findings to improve upon SR-17018 and develop even better compounds.

This research could also influence drug development beyond pain management. Other receptors, including the serotonin 1A receptor—an important target for treating depression and psychosis—may also be activated in a reverse direction, opening new possibilities for psychiatric medications.