Nonaddictive Opioid Alternative Shows Promise in Monkey Study

With the opioid epidemic raging across America, many scientists are in search of an alternative painkilling drug — one that could be used in place of opioids, without the deadly side effects.

Now, a team of researchers in the U.S. and Japan said they've developed a promising new synthetic drug that could be as effective as opioids in relieving pain but without posing the risk of addiction. In a new study, the drug, called AT-121, successfully relieved pain in rhesus monkeys without resulting in harmful side effects or causing the monkeys to become addicted. Still, more research is needed before the drug could be evaluated in humans.

"I think this is pretty interesting," said Dr. Bryan Roth, a professor of pharmacology and a physician at the University of North Carolina at Chapel Hill, who was not involved in the study. "The results are really clear-cut, but there are a few things that still need to be done before it can ultimately go forward," he said.  

Although the number of opioids prescribed in the U.S. has decreased since its peak in 2010, the levels remain high. The Center for Disease Control and Prevention (CDC) found that there were more than 42,000 deaths from opioid overdoses in 2016, up from 33,000 deaths in 2015, Live Science previously reported. [America's Opioid-Use Epidemic: 5 Startling Facts]

"It's a huge problem. I don't think anyone disagrees about that," Roth told Live Science.

A new drug candidate

AT-121 is considered a bifunctional drug, according to the study, which means it targets and prohibits the function of two specific opioid receptors in the brain that inhibit the sensation of pain: the mu-opioid peptide (MOP) receptor and the nociceptin/orphanin FQ peptide (NOP) receptor. Similar drugs have been studied in experiments with mice, and although those medicines effectively relieved pain, they were found to be addictive and therefore were not viable alternatives to existing opioid painkillers.

"This is the first [painkiller drug] demonstrated in a nonhuman [primate] model to have such a promising profile," co-senior study author Mei-Chuan Ko, a professor of physiology and pharmacology at Wake Forest University in North Carolina, told Live Science.

The team tested the drug in 15 adult male and female rhesus monkeys (Macaca mulatta). Through a series of experiments, the researchers determined that monkeys given AT-121 didn't feel pain and didn't experience the typical side effects associated with similar drugs.

"The pain relief that was observed in the [animal experiments] was similar to that of morphine, yet the dose of AT-121 that was used was 100-fold lower than that of morphine," said co-senior study author Nurulain Zaveri, the president and chief scientific officer at Astraea Therapeutics, a pharmaceutical company involved with the study.

Not only did the drug relieve pain, but the monkeys also didn't become dependent on it. When the monkeys were given the ability to self-administer AT-121, by pressing a button, they repeatedly chose not to do so. This suggests that AT-121 doesn't produce a rewarding or reinforcing effect that would lead to addiction, at least in this short-term experiment.

The fact that the drug was studied in a primate model, rather than in a mouse model as is done in many similar studies, means that the effects of the drug are likely much closer to what scientists would expect to see in humans, Roth said. And the monkeys didn't experience any changes in respiratory health while taking AT-121, which suggests that an overdose would be unlikely to cause the harmful or fatal respiratory effects associated with an opioid overdose. "That would be a significant advance if that [result] is transferable to humans," Roth added.

One of the limitations of the study was that it didn't look at what's called "off-target activity," Roth said. This refers to interactions of the drug with other parts of the brain or areas outside the brain. "It's very important to find out — does [AT-121] interact with any other receptors or ion channels or transporters in the body?" Roth said. Such interactions could determine the potential for side effects outside of the ones examined in this study.

The scientists plan to continue their research by carrying out the safety and toxicology studies that are required by the U.S. Food and Drug Administration before proceeding with human clinical trials. "We want to move as fast as possible, because our results are exciting," Zaveri told Live Science. The scientists are also researching other compounds that have a similar profile as AT-121, she added.

"If we can really come up with these new types of compounds, they can potentially reduce a lot of medical burden," Ko said. "I perceive this will have huge impact in our society and global community." 

"This is one of several of these types of studies that have been published recently that suggest there may be hope for creating safe medications for treating pain," Roth said. "It gives me hope for the field that we may be turning a corner."

The researchers published their study today (Aug. 28) in the journal Science Translational Medicine.

Original article on Live Science.

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