By Pat Anson, PNN Editor

Illicit fentanyl has been public health enemy #1 in the United States since 2016, when the DEA first declared there was a "fentanyl crisis" and warned that overdose deaths would increase due to the growing trade in street drugs laced with the potent synthetic opioid. That prediction sadly came true, as illicit fentanyl is now involved in about 71,000 U.S. overdose deaths a year. 

A team of scientists says it can reverse that trend by using sodium to make fentanyl far less dangerous, yet still effective in treating pain. 

“In its current form, fentanyl is like a weapon of mass destruction,” says Vsevolod Katritch, PhD, a computational biologist at the USC Michelson Center for Convergent Bioscience. “Our new collaborative work suggests that we could redesign the drug in such a way that we convert this frequent overdose killer to a much more benign but still effective analgesic.”

Katritch and colleagues at Washington University in St. Louis and Stanford University have published a study in the journal Nature demonstrating that chemically linking sodium to fentanyl can alter the way fentanyl binds to opioid receptors in the brain. In tests on laboratory mice, the modified drug was still an effective pain reliever, but didn’t have as many risky side effects. 

“We are desperately looking for ways to maintain the analgesic effects of opioids, while avoiding dangerous side effects such as addiction and respiratory distress that too often lead to death. Our research is still in its early stages, but we’re excited about its potential for leading to safer pain-relieving drugs,” Susruta Majumdar, PhD, an associate professor of anesthesiology at Washington University, said in a statement.,.

In modifying fentanyl with sodium, researchers developed a variation of the drug that still binds to mu-opioid receptors -- known as G-protein coupled receptors -- but also engages with a sodium ion binding site. That alters the pathway through which fentanyl reduces pain, making it possible for the drug to maintain most of its analgesic effects while also reducing the risk of respiratory depression leading to an overdose.

“The idea that the sodium ion, something we find in table salt, could modulate the activity of G-protein coupled receptors, such as these opioid receptors, is not new, but our group appears to be the first to successfully alter the chemistry of fentanyl so that it interacts with the sodium site on the receptor,” says Majumdar, who believes the same technique can be used in other medications, including other opioids, to make them safer.  

“Almost one-third of all drugs currently on the market — from blood pressure drugs to diabetes drugs to analgesics like fentanyl — bind to various G-protein coupled receptors, so it may be possible to make many drugs more effective, and to limit their side effects, by altering how they bind with such receptors.”

Researchers say further study is needed to prove that their altered version of fentanyl will work in humans, but they believe they've found a way to potentially improve its safety and those of other painkillers.

The research appears promising and may someday benefit pain patients, but it overlooks a simple fact: most of the fentanyl that is killing people is illicitly produced. And the clandestine labs, drug cartels, pill pressers and drug dealers responsible for the vast majority of overdoses will have no interest in adding sodium to their counterfeit pills and other fentanyl-laced drugs to make them safer.

The Nature study also perpetuates some longstanding myths about the overdose crisis, calling fentanyl and other prescription opioids a "major public health concern due to their adverse side effects."

But as pain management expert Dr. Lynn Webster pointed out in a 2019 PNN column, calling fentanyl a "weapon of mass destruction" is a bit of an overreach. Fentanyl has been legally used for decades -- safely and effectively -- as a surgical analgesic, and in transdermal patches and lozenges intended for patients with severe pain from cancer and other intractable pain conditions.

"Each of these new uses of fentanyl exposed millions of Americans to the drug without evidence of an inordinate degree of harm if it was used as directed," Webster wrote. "The opioid crisis is now largely driven by nonpharmaceutical fentanyl and fentanyl analogs, not prescription fentanyl."

Few pain patients who use fentanyl as directed become addicted or overdose, although many do become dependent on the drug to continue working, perform simple household chores, maintain personal hygiene, and have some quality of life. Modifying prescription fentanyl with sodium to make it safer might benefit some of those patients, but it will likely have no effect on the fentanyl crisis or prevent many overdoses.