New, cleaner opioid offers hope for fewer side effects

Chronic pain is an enormous problem, affecting about 10 to 15 percent of the adult population.

Another enormous problem? Opioid painkiller addiction, which kills about 30,000 Americans annually.

Regulatory responses to that epidemic range from developing abuse-deterrent forms of opioid analgesics to tackling the concept of addiction as an illness rather than a crime. (See BioWorld Today, July 15, 2016.)

Now, scientific help stemming the tide may be on its way in the form of a new opioid receptor agonist that kills pain without the risk of killing the patient.

Despite their side effects, opioids remain pretty much the only game in town for patients with severe chronic pain.

Opioid painkillers, though – both morphine itself and codeine, oxycodone, oxycontin, hydrocodone and fentanyl – stimulate several different receptors. And those receptors can activate different second messenger systems to result in signaling through different pathways.

Previous work had suggested that the analgesic effects of opioids are mediated through the mu opioid receptor's activation of G protein-coupled receptors (GPCRs). Both the suppression of breathing, which is the greatest risk of opioids, and their addictive properties are mediated by other mechanisms.

And so the goal of the study, co-author Gregory Scherrer, assistant professor of anesthesiology, perioperative and pain medicine at Stanford University School of Medicine, told BioWorld Today, was to "develop new agonists [that] only engage events which are beneficial."

The team started with bioinformatics-based screening of several million compounds, and through a multistep process ultimately identified 23 compounds that stimulated the mu opioid receptor in ways that were different from opioids. Further winnowing and structure-guided optimization ultimately led to one compound, PZM21, which specifically stimulated the GPCR-coupled pathways that are downstream of opioid receptor activation.

In animal studies, PZM21 was as effective as morphine in terms of its analgesic effects. PZM21-induced analgesia, however, was longer lasting.

And the drug lacked morphine's most troubling side effects. PZM21 did not depress breathing in treated animals; constipation, another side effect that sounds less dramatic than respiratory problems but is also often dose-limiting, was also reduced compared to morphine.

The team also found that administering PZM21 to the animals did not have the consequences that are seen with addictive drugs in preclinical tests, namely increased motor activity and a preference for locations associated with the drug.

The researchers published their results in the Aug. 18, 2016, issue of Nature.

A unique aspect of PZM21 is that it specifically blocked so-called affective aspects of pain – basically, the fact that pain is an unpleasant experience – without affecting the reflexive pain that leads mice, and people, to snatch their paw away from a hot stimulus.

"Typical mu opioid receptor agonists strongly block reflexive behaviors," Scherrer said, which is not only clinically irrelevant, since "what painkillers need to do is to block the unpleasantness of pain," but can be counterproductive because blocking the withdrawal reflex from a noxious stimulus can lead to injury.

Scherrer, whose lab was responsible for testing the analgesic properties of PZM21, and his team looked at mouse behavior to a hot stimulus in detail.

"We see the withdrawal reflex," he said, "but also what happens to the mouse right after that."

"What we noticed with this compound, which is striking, is that . . . we don't see a change in reflexive pain," but animals showed fewer affective behaviors such as paying attention to the paw in the form of biting or licking.

Five of the co-authors – Aashish Manglik, Brian Kobilka, Peter Gmeiner, Bryan Roth and Brian Shoichet – have co-founded a startup, Epiodyne Inc., which hopes to commercialize the findings.

The authors wrote that their approach of very large-scale bioinformatics screening followed by structure optimization that altered compounds at the level of individual atoms "portend a general approach to the problem of new tool and lead discovery" for GPCRs, which have historically been the source of a significant fraction of the biopharmaceutical industry's success stories.

And Scherrer said that PZM21 in particular "could also be a great research tool to understand the difference between [reflexive and affective] pain circuits."

Source