A Molecular Solution to the Opioid Epidemic

Ingrid Hein

November 06, 2019

To solve the opioid crisis, "we can't just focus on treatments for addiction, we need to turn our attention to developing safer opioid pain therapies without the respiratory side-effects responsible for overdose," said Gaspard Montandon, PhD, from St. Michael's Hospital in Toronto.

Addiction is an important component of the problem, but it is not the addiction per se that kills people, Montandon and his coauthor, Arthur Slutsky, MD, also from St. Michael's, write in their report on respiratory depression and opioids published in CHEST.

The main problem is "what happens to the brain during an overdose," Slutsky told Medscape Medical News.

"Opioid medications act on mu, delta, and kappa opioid receptors, which are expressed in discrete brain circuits," the pair explains. Potent opioids like fentanyl and oxycodone are selective for mu opioid receptors, which are expressed in neural circuits that are involved in the nervous system's response to pain and in breathing.

"If we can find a way to block respiratory depression, maybe we can design better pain therapies that aren't lethal," said Montandon, who leads a research program in the brain and breathing science lab at St. Michael's.

His team is studying the neural circuits and cellular mechanisms affected by opioids, looking for molecular targets to block opioid-induced respiratory depression.

"Once we identify a molecular target, we can design a new safer opioid formulation," he explained.

"Biased Ligands"

Teams of researchers are currently looking at "biased ligands," which are ligands that favor one signaling pathway downstream from the mu opioid receptor over another.

Recent studies of biased ligands have shown that they have the potential to produce potent analgesia, but overall results on adverse respiratory effects have been inconclusive, Montandon told Medscape Medical News.

Two studies have identified PZM21 and TRV130 as partial agonists of mu receptors that reduce respiratory depression, but a third study showed that PZM21 depresses respiration in a manner similar to morphine.

An alternate way to go about developing safer opioids would be to develop analgesics with molecular pathways distinct from the ones that regulate analgesia, he said.

"It is also possible that novel excitatory pathways exist that could stimulate respiratory circuits without targeting nociceptive circuits. A better understanding of these mechanisms is critical to help identify new pharmacologic targets that could provide potent analgesia without the lethal risk of respiratory depression," Montandon and Slutsky write.

To accelerate the discovery of possible drug combinations, the Toronto team is using FDA-approved drug libraries and zebrafish, "which are ideal for performing large-scale drug screening," Montandon said.

"Larval zebrafish have opioid gene receptors similar to a mammal," he explained. Multiple fish can be screened in a single day. "They are transparent and we can see right away if there is a positive effect on respiratory depression."

But funding for this type of lab research is not sufficient, according to Montandon and Slutsky.

The Research Portfolio Online Reporting Tools show that the National Institutes of Health is putting $188 million into grants to fund opioid research. But only $2 million of that is dedicated to understanding the effect of opioids on respiration, the pair reports.

The current clinical practice of decreasing opioid prescriptions is not going to solve the opioid epidemic, said Montandon. "It's self-defeating. When people don't get a prescription, they go to the streets and get drugs contaminated with fentanyl, which leads to a higher risk of dying from overdose."

Handing out naloxone kits isn't going to solve it either. "These are good antidotes for opioid overdose, but they can only be given after the overdose occurs, to block the effect of opioids," he added. Naloxone also eliminates the analgesic affect.

When you study a disease, you want to know how it works, said Montandon. "For cancer, you study cancer cells. To solve respiratory depression with opioid use, we need to look at the mechanisms to find the solution."

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