A morphine alternative with less overdose risk?
The compound is so new it doesn’t have a name, just a number. It’s only been tested in mice, and it needs years of additional animal studies before researchers can even start trials to see if it works safely in humans.
But initial results in mice suggest the new drug might be less addictive than morphine and other opiate painkillers and avoid a side effect known as respiratory depression that results in overdose deaths, scientists say.
That’s because the compound activates nerve-cell surface receptors responsible for morphine’s painkilling effects without activating receptors involved in controlling breathing or in releasing the pleasure-related chemical dopamine.
So unlike opiates, the new medicine might not trigger a surge in dopamine, a brain chemical involved in emotions like addiction, pleasure and pain, said Brian Shoichet, senior author of a paper on the new drug published on Wednesday in Nature.
“The dopamine circuit is one of the primary reward circuits in the brain, and its over-activation leads to repeated seeking of the reward stimulus – in this case, morphine (or related opioids),” said Shoichet, a researcher in pharmaceutical chemistry at the University of California, San Francisco.
“This ultimately becomes addiction,” Shoichet added. “Early animal results suggest the new compound does not stimulate the dopaminergic circuit.”
Another potential advantage of the new medicine is that tests so far in mice suggest it may not turn on cellular signals that suppress breathing, a leading cause of overdose deaths.
Globally, an estimated 15 million people are addicted to morphine and other opiates, according to the World Health Organization. About 69,000 people die from overdoses of these drugs each year.
Opiates include morphine and the prescription painkillers codeine, oxycodone, oxycontin, hydrocodone and fentanyl as well as illegal drugs such as heroin.
Scientists have been searching for years for alternative painkillers that might be less addictive, harder to abuse and safer.
Shoichet and his colleagues took advantage of computer modeling to test more than 3 million known chemicals against the structure of human cell receptors that are activated by morphine. They narrowed down these leads to the most promising one, then chemically tweaked it to further refine its ability to activate only the desired receptor subtypes.
Even the most promising experimental medicines in mice, however, rarely prove safe and effective in humans and reach the market, noted Pinar Karaca-Mandic, a health policy researcher at the University of Minnesota.
Often, these medicines never cross the first hurdle – getting from animal tests to preliminary human trials, Karaca-Mandic, who wasn’t involved in developing this new pain medicine, said by email.
At best, “the odds seem to be 1 in 10,” Karaca-Mandic said.
More tests in animals need to explore whether this compound, known for now as PZM21, is safe and effective before it could move to human trials, said Shoichet.
Additional tests in animals are being done by San Francisco-based Epiodyne, a biotech company founded by Shoichet and three other authors of the paper in Nature. Epiodyne has funding from Brook Byers of Kleiner Perkins Caufiled and Byers, and by Doug Crawford of Mission Bay Capital, Shoichet said.
Work to date has been done by a team of researchers at the University of California, San Francisco, Stanford University, the University of North Carolina, and Friedrich Alexander University in Erlangen, Germany.