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Compound may kill pain like opioids, without addiction risk

The drug also showed a reduced potential for addiction in experiments with mice, researchers report.

By Stephen Feller

WASHINGTON, Aug. 18 (UPI) -- Opioid painkillers allow doctors to perform a range of procedures knowing they can eliminate pain during recovery, but the drugs pose a risk to health because they suppress breathing and are highly addictive.

Researchers at four universities designed a compound that successfully killed pain while appearing not to suppress breathing or induce addictive behavior in mice, suggesting it has potential for safer use with humans, according to a study published in the journal Nature.

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Morphine has been used in medicine since the 19th century when chemists purified it for use in treatment. The main drawbacks of the drug, and others derived from the opium poppy such as oxycodone, codeine and fentanyl, come from side effects.

Opioid drugs bind to the mu opioid receptor in the brain, taking advantage of a chemical pathway to kill pain. When they do this, though, the chemicals also activate another pathway suppressing respiration. In overdose cases, the suppression of breathing is often the cause of hospitalization or death.

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Essential as the drugs are to medicine, when doctors carefully meter them out, opioids are highly addictive and in recent years have caused an epidemic of abuse, addiction and overdose. More than 28,000 people died in 2014 of overdoses from opioids or heroin, the most ever recorded, and the epidemic has not receded -- encouraging researchers to find less dangerous substances that serve the same medical purposes.

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"The field had wondered whether a small molecule with just the right chemical features to trip off one pathway, but not the other, could be designed," Dr. Aashish Manglik, a researcher at Stanford University, said in a press release.

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Researchers from Stanford, the University of California San Francisco, the University of North Carolina and the Friedrich-Alexander University Erlangen-N├╝rnberg collaborated to examine more than 2,500 compounds that computer simulations suggested could bind to opioid receptors, winnowing the list down to a few dozen candidates for testing.

After identifying one compound that activated painkilling-linked chemical pathways without affecting those suppressing breathing, the researchers found it did not bind to opioid receptors well enough. The researchers then modified the compound slightly, improving its ability to link up with receptors by about 1,000 times.

In tests with mice, PZM21 was found to be as powerful as morphine at eliminating pain while not interfering with the rodents' ability to breathe. Just as significant, when mice were offered a choice of solution with or without the drug, they appeared to show no preference -- unlike morphine, which rodents overwhelmingly pick if available.

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While the researchers say the tests do not show PZM21 is "truly non-addictive," the difference in behavior is notable and requires further testing in mice, as well as in humans.

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"Morphine transformed medicine," Dr. Brian Shoichet, a professor of pharmaceutical chemistry at the University of California San Francisco, said in a press release. "There are so many medical procedures we can do now because we know we can control the pain afterwards. But it's obviously dangerous too. People have been searching for a safer replacement for standard opioids for decades."

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