A Tulane University professor's 20-year quest to develop a nonaddictive opioid painkiller has cleared another major hurdle in its early phases of laboratory testing.

The drug, known as ZH853, has shown in recent tests to not only accelerate recovery from pain better than morphine, but also to sidestep a key problem with morphine and other prescription painkillers derived from the opium poppy.

Those painkillers, which include prescription drugs such as oxycodone, trigger an inflammatory response in the immune system that can cause patients to develop chronic pain just as the acute pain being treated begins to subside.

But according to a study published in May in the Journal of Neuroinflammation, ZH853 does not stimulate the same inflammatory response in laboratory tests on rats. What's more, ZH853 not only shortened the length of time that subjects were in pain by as much as half, but it was also shorter than the recovery time for rats given a placebo.

James Zadina, professor of medicine, pharmacology and neuroscience at the Tulane School of Medicine, and graduate student Amy Feehan went into the two-year blind study hoping the drug would simply match the recovery rate of the rats given a placebo.

To discover ZH853 actually shortened the length of time the rats demonstrated pain was nothing short of remarkable, they said.

"Our shock and surprise came when we saw that it accelerated the recovery," said Zadina, who is also director of the neuroscience laboratory at the Southeast Louisiana Veterans Health Care System.

"The fact that it is reducing the amount of time in chronic pain — that is going to take a huge burden off of hospitals and health care,” Feehan said. "I feel like this could be such a wonderful solution should it make it through clinical trials.”

The United States is in the midst of an epidemic of opioid addiction and misuse, which has created a backlash that means many patients suffering from chronic pain have found it difficult to get the drugs they need.

In 1997, Zadina was among those who began to question whether compounds found in humans or animals might work better than plant-based opioids. He isolated a molecule produced in the brains of cows and humans, and spent the next two decades working on various iterations that led to ZH853.

In 2016, Zadina led a study of ZH853 at Tulane to determine whether the drug was as addictive as morphine. In that study, rats taught to administer morphine and ZH853 to themselves went to great lengths to get doses of morphine and would gather in a chamber they were taught to associate with it. They did not exhibit the same behavior with ZH853, suggesting that it could in fact become an option less susceptible to abuse. 

A key reason for ZH853's success is likely that it is an engineered variant of the neurochemical endomorphin, which is found naturally in the body and therefore does not trigger inflammation in the immune system in defense.

With the 2016 study showing it was not likely to be addictive, the study published in May set out to test whether it was a superior painkiller. 

Feehan designed and ran the study, analyzed the data and wrote the manuscript with guidance from Zadina. The testing was on male rats with inflammatory and post-operative pain. One group was put on morphine, another was given ZH853, and a control group got only the solution used to administer the drugs.

Their pain responses were tested by applying heat with a laser or pressure with a plastic filament, while a third test involved measuring how their gait and movement were affected by any pain they might be feeling.

ZH853 reduced the duration of pain compared to morphine in every test. In one group, pain lasted 46 days for the rats on morphine, 32 days for those that got the placebo, and only 11 days for those getting ZH853.

"We were very pleasantly surprised when we broke the code," Zadina said.

While the chronic pain response created by plant-based opioids isn’t widely known by the general public, it has vexed public health officials and is a key drawback of the opioids currently in use.

Zadina's lab is among those exploring how various types of pain can be made worse by the use of morphine-like compounds. He said the chronic pain induced by those drugs is distinct from the withdrawal symptoms a patient might feel, but is interrelated with them and the other downsides of those drugs.

“Tolerance, withdrawal, dependence, addiction and the prolonged pain have some overlap, but they are distinct mechanisms,” he said.

As for whether ZH853 produces a sensation of euphoria — what would commonly be described as feeling high — Zadina said animal testing has indicated it doesn’t, though that won’t be known for sure until it is tested on humans.

The rats in the 2016 study were not in any pain and were responding only to which drug they desired, and they largely ignored ZH853 compared to morphine, Zadina noted, though he added that this question will be studied further in tests on rats.

The patents for ZH853 are held by Zadina, Feehan, Tulane and the Department of Veterans Affairs. The university has licensed them to Mirata Pharmaceuticals, which is now raising the funds to get ZH853 into clinical trials, which could begin in about a year.

Even if all goes well, it would be seven to nine years before the drug becomes available, Zadina said, and significant hurdles still need to be cleared.

The results have yet to be replicated, and many drugs that produce promising results in animals fail to replicate them in humans for a host of reasons. So statistically, the odds are that ZH853 will become another flash in the pan.

But based on the successes they've had so far, Zadina and Feehan are allowing themselves to be optimistic.

"We have done all of our testing as best we can to characterize these properties, and we don’t seem to see a lot of downside," Zadina said.

There are other, less addictive painkillers emerging as a potential replacement for the opioids now on the market, but Zadina said they haven't been tested as thoroughly as ZH853.

Zadina's work with the drug is now entering its third decade. He said it may seem like a long time, but in science, many people work on a problem for much longer, and success is never guaranteed.

"It’s been very rewarding," he reflected. "It’s part of science that more things fail than succeed. But it only takes a couple of successes to get you addicted to it — no pun intended.”


Follow Chad Calder on Twitter, @Chad_Calder.