Synthetic opioids, such as this fentanyl captured in a drug raid, have caused an alarming rise in overdose deaths.

CLIFF OWEN/AP PHOTO

Spurred by opioid epidemic, new pain drugs may lower the risk of overdose and addiction

BOSTON—As the opioid crisis continues to ravage U.S. communities, scientists and drug companies have intensified their efforts to develop safer and less addictive pain medications. Now, multiple research groups are claiming progress in devising novel opioids—or alternatives—that seem to offer pain relief with far less risk of addiction or of the opioid-induced respiratory depression that all too commonly leads to death.

Most of these studies, reported at a meeting here and in a paper released this week, have only been done in animals, so the experimental compounds face significant hurdles before they can become approved medications. Yet they are raising tentative hopes among researchers. "It's encouraging," says Laura Bohn, a biochemist at Scripps Research in Jupiter, Florida. "There has been a really big push to develop nonopioid pain relievers. But it has been really hard."

A record 72,000 people in the United States died last year from overdoses, up nearly 10% from 2016, according to an estimate this month by the Centers for Disease Control and Prevention. That rise was driven primarily by an increase in overdoses from highly potent synthetic opioids such as fentanyl and carfentanil. Another 2.1 million Americans are believed to regularly abuse opioids, including natural ones like morphine, semisynthetic compounds such as oxycodone, and the synthetics, and have signs of addiction, such as withdrawal symptoms, if they try to quit.

Opioids are powerful pain relievers because they bind to a key cell membrane protein, known as the µ-opioid receptor (MOR), on neurons in the brain and spinal cord. Once activated, the MOR triggers an intracellular "G protein" to initiate a molecular cascade that leads to pain relief. But traditional opioids also activate another intracellular protein, β-arrestin2, which produces respiratory depression and constipation, the most common opioid side effects for such drugs. Several "biased opioids," including one now under review by the Food and Drug Administration, offer pain relief while reducing β-arrestin2 activation, but it's not clear whether they are less addictive than conventional opioids.

At last week's meeting of the American Chemical Society here, Neel Anand, a senior director for medicinal chemistry at Nektar Therapeutics, a biotech firm in South San Francisco, California, described an approach that might help. Nektar's drug, called NKTR-181, is a version of oxycodone to which researchers have linked a molecular tail called polyethylene glycol, a common pharmaceutical strategy for extending the life span of medicines in the blood. Anand reported that in animal studies, NKTR-181 crosses the blood-brain barrier 70 times more slowly than oyxcodone. Instead of a sharp spike in both pain relief and euphoria, caused by an upsurge of the neurotransmitter dopamine in brain regions tied to addiction, NKTR-181 triggers a slower release of dopamine that produces flatter, more sustained pain relief and less euphoria. In clinical studies of more than 600 patients taking the compound, Nektar researchers found far fewer signs of addiction than in patients given oxycodone, as well as fewer side effects.

"It clearly works" as a painkiller, says Steven McKerrall, a medicinal chemist with Genentech in South San Francisco. "They've built [a timed release] into the drug itself." But McKerrall and others caution that opioid addicts have devised strategies to defeat other abuse-resistant formulations, for example, by crushing pills that have timed-release coatings. "Addicts will always find a way," Bohn says.

They might have a tougher time with a compound developed by Astraea Therapeutics, a biotech company in Mountain View, California, that hits two brain molecules at once. AT-121 stimulates not only MOR, but also a close cousin known as the nociceptin opioid receptor (NOR). When activated in the brain, NOR appears to counteract MOR. At the same time, it reinforces MOR's pain relieving activity elsewhere in the central nervous system, says Nurulain Zaveri, Astraea's founder and chief scientific officer. The drug isn't the first to target both receptors—another one is already in phase III trials for diabetic nerve pain, among other uses, but that compound targets other receptors as well, and animal studies suggest it may have addictive properties.

In this week's issue of Science Translational Medicine, Zaveri and academic colleagues in the United States and Japan report that rhesus monkeys given AT-121 experienced 100-fold greater pain relief than the same dose of morphine provided. Yet the drug did not trigger respiratory depression, addictivelike behaviors, or even tolerance, where more of a compound is needed over time to produce the same desirable effects such as pain relief. AT-121 even appears to counteract addiction to standard opioids, such as oxycodone, Zaveri says. Monkeys hooked on oxycodone and trained to self-administer the drug sharply reduced further drug seeking when given AT-121. "It looks very promising," Bohn says of the new compound.

Avoiding opioid receptors altogether is another appealing strategy for relieving pain with a reduced risk of addiction, says Roger Kroes, senior director for discovery science at Aptinyx, a biotech firm in Evanston, Illinois, who described one of his company's compounds at the meeting. Called NYX-2925, it activates the NMDA receptor, which helps strengthen neural synapses involved in learning and memory. Although acute pain doesn't involve a learned component, chronic pain is thought to bring about long-term neural changes orchestrated, in part, by NMDA receptors.

Many well-known drugs that block these receptors—among them ketamine and methadone—can relieve pain and can be less addictive than opioids. But these compounds hit other targets as well and have widespread side effects. NYX-2925, however, is more selective, data show. At the meeting, Kroes reported that in preclinical studies on mice and rats, the compound reduced pain and led to a remodeling of synapses involved in learning and memory, essentially rewiring neural circuitry away from being habituated to pain.

The results "were pretty exciting," says Ben Milgram, a medicinal chemist with Amgen in Cambridge, Massachusetts, who attended the meeting. Aptinyx is now testing NYX-2925 in two phase II clinical studies in people with diabetic nerve pain and fibromyalgia, a disease marked by widespread muscle and skeletal pain.

Drugs designed to deliver the benefits of opioids without the deadly risks can easily falter. At the meeting, researchers from Genentech, Merck & Co., and Amgen described compounds designed to tamp down yet another nonopioid receptor target, a protein called Nav1.7. Although all found their target and reduced pain in animals, they proved weaker on other scores; for example, some were poorly absorbed in the blood or blocked other Nav proteins, causing side effects. Still, with the opioid crisis taking an ever-larger toll, even preliminary good news is welcome.