A team of researchers from Scripps Research in Florida has developed a new class of painkillers that work like morphine and other opioids but without the harmful side effects that have led to opiate overdoses and fatalities.

Biochemist Laura Bohn, PhD, and colleagues describe a compound called SR-17018, which activates the same pain-relieving receptor as opioid drugs like morphine, oxycodone, and fentanyl; however, it binds to opioid receptors in a different way than those drugs, leaving the opioid receptor open and available to the body’s own natural pain-relieving substances, apparently augmenting pain relief.

The group revealed that the chemical worked particularly well in animal trials of chemotherapy-induced neuropathic pain in research published earlier this year, the experts write.

The authors of the new paper have made significant progress in understanding why these medications appear to be so dissimilar.

“We demonstrate that these compounds bind to a different site on the receptor than a typical opioid. Because of that, they seem to leave the receptor on and yet still receptive to endogenous opioids,” said Bohn, who chairs the Scripps Research Department of Molecular Medicine in Jupiter, Florida.

“In neuropathy pain, we show they are far superior to morphine and oxycodone; moreover, SR-17018 does not decrease breathing.”

Additionally, the authors described a similar compound that, due to its increased strength, induces respiratory suppression, albeit at doses greater than those required to treat pain. Notably for safety, when administered at dosages sufficient to suppress respiration, this compound, SR-14968, demonstrated responsiveness to the overdose rescue medicine naloxone.

Perhaps most importantly for people suffering from severe chronic pain, SR-17018 demonstrated the ability to provide prolonged pain relief over time without developing tolerance, a problem associated with decreased efficacy over time, requiring increased doses and increasing the risk of overdose.

According to the paper’s first author, Edward L. Stahl, the novel compounds are referred to as “biased agonists” because they activate the mu opioid receptor in a way that favors one of its signaling pathways, the one associated with pain relief, over another associated with reduced breathing.

“The compound SR-17018 is the first biased agonist of the mu opioid receptor that does not lead to tolerance with chronic use,” said Stahl, a senior staff scientist in the Bohn lab. “This is a desirable feature for potential use in the context of chronic, severe pain.”

The novel compounds were designed to circumvent the “beta-arrestin” signaling cascade that results in opioids’ dangerous and undesirable characteristics, such as respiratory depression, which is a cause of overdose, and constipation, he adds.

Opioid drugs continue to be the first line of defense against extreme pain, whether caused by surgery, a sudden injury, or nerve damage. However, as opioid addiction and overdose deaths continue to rise in the United States, the need for better approaches to treat acute pain has become more pressing, according to Bohn.

Bohn and her colleagues have established the viability of disentangling opioids’ pain-relieving capabilities from their harmful side effects over the course of more than two decades of research. Not only has her study advanced our understanding of how opioid receptors control different physiological reactions, but it has also steered the field toward possibly safer methods of relieving severe pain.

Bohn’s research group has created a number of compounds that, in mouse studies, inhibit beta-arrestin signaling activation. Additional opioid-related issues, such as dependence or addiction, continue to pose difficulties. The fact that SR-17018 does not develop tolerance with prolonged use is a positive development, according to Bohn. Additionally, she notes how quickly it wears off.

“The compound showed a nice, slow tapering. That, in itself, may help curb some of the dependence problems. A drug like morphine provides a quick rush then a quick clear, and you need the rush again.”

The team is now refining and testing the substances in order to eventually test them in a clinical setting.

“Severe and chronic pain associated with surgery, nerve damage, and trauma require strong pain relief,” Bohn said.

“Safer solutions are needed. We believe these new compounds are a big step in the right direction.”

Source: 10.1073/pnas.2102178118

Image Credit: iStock

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