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Opioid overdoses can be deadly because the drug can signal the brain to stop a person’s breathing.

Brian Snyder/REUTERS

Redesigning opioids may not prevent their fatal side effect

The dark side of opioids’ ability to deaden pain is the risk that they might kill their user. The same brain receptors that blunt pain when drugs such as morphine or oxycodone bind to them can also signal breathing to slow down. It’s this respiratory suppression that causes most overdose deaths.

So scientists have hoped to design opioids that are “biased” toward activating painkilling signals while leaving respiratory signaling alone. Several companies have cropped up to develop and test biased opioids. But two new studies in mice contest a key hypothesis underlying these efforts—that a signaling protein called beta-arrestin2 is fundamental to opioids’ effect on breathing.

“It seems like the premise was wrong,” says Gaspard Montandon, a neuroscientist and respiratory physiologist at the University of Toronto. He and others doubt that the good and bad effects of opioids can be disentangled.

Hopes first arose in the late 1990s and early 2000s, as neuroscientist Laura Bohn, biochemist Robert Lefkowitz, and colleagues at Duke University explored the cascades of signals triggered when a drug binds to muopioid receptors on a neuron. This binding changes the receptor’s structure and its interactions with two types of proteins inside the cell—signaling molecules known as G-proteins, and beta-arrestins, which, among other effects, inhibit G-protein signaling.

It’s still not clear how the resulting signal cascades influence cells or brain circuits. But the researchers reported in 1999 that mice engineered to lack the gene for beta-arrestin2 got stronger and longer lasting pain relief from morphine. And in 2005, Bohn and her colleagues at Ohio State University found that two morphine-induced side effects, constipation and slowed breathing, were dramatically reduced in these “knockout” mice. The findings suggested that a drug able to nudge the mu-opioid receptors toward G-protein signaling and away from beta-arrestin2 signaling would prompt more pain relief with fewer risks.

Accentuate the positive

Researchers have long hoped that opioids that favor G-protein signaling would be safer (below, right), but studies of mice genetically engineered to mimic the effects of that bias have raised doubts.

N mu-opioid receptor Extracellular Intracellular Cell membrane G-proteinsignaling G-proteinsignaling beta-arrestin2pathway beta-arrestin2pathway Morphine SR-17018 Biased opioids Classical opioids Powerfulpain relief Powerfulpain relief Respiratory depressionand constipation Less respiratory depressionand constipation Cl Cl Cl O H HO HO H H N HN N O

A hunt for biased opioids ensued. A commercial front-runner was Trevena, which tested its intravenous drug candidate oliceridine for postsurgical pain. But at high doses, the compound failed to show significantly better respiratory safety than morphine. In 2018, the U.S. Food and Drug Administration rejected oliceridine. Trevena resubmitted its application with additional data this month.

But some researchers question the mouse studies that inspired the hunt. Last year in Nature Communications, a group including pharmacologists Andrea Kliewer and Stefan Schulz at Friedrich Schiller University of Jena described experiments with mice carrying mutations in the mu-opioid receptor gene that prevented the receptor from interacting with beta-arrestin2. When given morphine, these animals had constipation and suppressed breathing that was sometimes more severe than in mice without a mutation.

Since then, the Jena team and labs in Bristol, U.K., and Sydney have tried to replicate the 2005 finding directly using beta-arrestin2 knockout mice. All three labs observed opioid-induced constipation and breathing side effects similar to those in mice that could produce beta-arrestin2. The idea that G-protein–biased opioids would be safer was “too easy,” Kliewer says.

The results, published 12 February in the British Journal of Pharmacology, are “quite convincing,” says Charles Chavkin, a pharmacologist at the University of Washington, Seattle. Opioid side effects are unlikely to rely solely on beta-arrestin2, he says.

Perhaps the simplest explanation for the conflicting 2005 and 2020 results is that the mice were genetically different. Mice in the initial studies were a mix of multiple strains; further crossing and inbreeding may have changed the way they respond to opioids. “I have every bit of confidence in the early data,” says Bohn, now at Scripps Research. “There’s no way for us to go back and have that same mix of animal that we had 20 years ago.”

Bohn says her original findings were “oversold and oversimplified” by commercial interests. “G doesn’t stand for good and beta doesn’t stand for bad,” she says. Betaarrestin2 knockout mice were an important starting point, she says, but they’re an imperfect model of drug response, in part because they may have somehow compensated to survive without this key protein. Her group is now creating new biased opioids and comparing them with traditional opioids in animal studies that measure breathing suppression and other negative effects such as the development of tolerance and dependence.

“I believe both sets of data, because both groups are careful,” says Bryan Roth, a molecular pharmacologist at the University of North Carolina, Chapel Hill, who helped develop a biased opioid known as PZM21 and holds stock in a company that licensed it. Resolving the role of beta-arrestin2 will require more strongly biased opioids, he says. “If the [biased opioid] hypothesis is true, it would be tremendously beneficial for the human race,” he says. “It’s a hypothesis that should be tested.”