By Daniel Oppenheimer
Editor, Texas Health Journal

The promise of Ken Hargreaves’ new drug, which is in its first round of human trials, isn’t a small one.

“In the animal studies, we have cured pain,” said Hargreaves, chair of the Department of Endodontics at UT Health San Antonio.

Not only has the drug eliminated or substantially diminished pain in animals, it has done so before the animals’ brains even get involved in mediating the reaction to pain. It therefore preempts the potential for dependence and addiction that the most popular class of pain drugs, opioids, carry.

“Synthetic opioids, and opiates like heroin, work by activating the brain’s own system for relieving pain,” said Hargreaves. “This can be very effective for treating pain. Unfortunately it also involves the brain’s learning and reward systems, and that’s where the risk of addiction comes in.”

The pain-blocking mechanism that Hargreaves and his colleagues are exploring is different. It acts at the point of injury, safely upstream of the brain, by short circuiting one of the body’s natural responses to harm, which is to generate a class of compounds known as oxidized linoleic acid metabolites (OLAMs). When we get a cut, bruise, burn or muscle pull, these OLAMS initiate a cascade of signals that travel to the brain and set off a variety of responses, including the subjective experience of pain.

There are good reasons for us to experience pain, said Hargreaves. Pain can minimize an injury, by prompting us to take our hand out of the flame, or push away the man with the knife in our side. It can promote healing, by making us much more likely to keep a broken arm immobile or a sunburn out of the sun. But it can also be a blunt instrument. The severity of pain, in response to some injuries, can exceed what’s necessary to reap the benefits. In some cases the whole pain system can go awry, producing chronic pain that has a physiological life of its own, separate from the initial injury.

“Pain has a very strong evolutionary value,” he said. “There are people who have mutations in certain genes that result in the lack of a formation of a pain system, and these people rarely survive out of their 20s. They don’t learn that knives are sharp. Chronic pain, however, doesn’t seem to offer much survival value. It’s an example of a system that has gotten turned on, but the normal compensatory mechanisms that would turn it off are either missing or dysfunctional.”

Hargreaves gives the example of fibromyalgia, a disorder that is characterized almost entirely by a feedback loop of pain. It can begin with an actual injury, but soon the pain becomes self-sustaining. Researchers believe it is a result of the brain assigning too much attention to pain signals that we would normally filter out.

“Humans have a really amazing ability to filter out and select information from the environment around us,” said Hargreaves. “Imagine you’re at a loud party. The music is loud. The conversations around you are loud. And yet you can still have a conversation with the person in front of you, because you are able to filter out the music . Someone says your name a few feet away, in another conversation, and you suddenly focus in on that. We can do that kind of selective filtering for noise, and for smell, and for pain too. From the acute pain perspective, this is useful. It amplifies a signal we need to hear. But in some instances we can also lose the ability to filter out pain and discomfort in all the normal ways we typically do. And that’s not useful.”

Opioids can treat this and other kinds of chronic pain, sometimes very effectively. But they carry the risk of addiction as well as the direct risks of too much opioid consumption, including overdose and death. Over-the-counter pain relievers like ibuprofen and aspirin can also alleviate pain, but with less potency than opioids. Anesthetics like novocaine and lidocaine can relieve acute pain for short periods of time, but they numb all sensation, and aren’t practical for long term use.

What’s needed are non-addictive medications that relieve pain as effectively as prescription opioids but don’t numb regular sensation. Such medications would have profound implications not just for chronic pain sufferers, but for acute pain sufferers as well.

For more than a decade, Hargreaves and his colleagues have been investigating whether OLAMs, and drugs that inhibit their production and action, might be at least part of the answer. They were one of the first labs to discover the release of these lipids at the point of injury. They’ve demonstrated that there are elevated levels of OLAMs in a range of different pain states. And they’ve developed drugs that block OLAMs, and in doing so diminish and in some cases eliminate pain. The brain simply doesn’t get the message that an injury has occurred. None of the systems that are involved in addiction are activated.

The team is now testing one type of OLAM inhibitor in burn patients at the US Army Institute for Surgical Research in San Antonio. They are looking, in particular, at how the inhibitors work to relieve pain at skin graft sites, which can be excruciatingly painful.

“We are applying the medication topically,” said Hargreaves, “and are placing a probe right on the bilateral skin graft, which is about the size of a business card.”

They’ll measure the patients’ experience of pain, as well as the degree to which OLAMs are or are not being produced. If the trial is successful, they may do more trials with burn patients, or test the drugs with other types of pain. The hope, if the trials continue to be successful, is that they will attract the level of funding from pharmaceutical companies that will enable the commercialization of the drug.

“Our outcomes have been phenomenal so far, so I’m optimistic,” he said, “but we really won’t know until we get results from our study in humans. The sad fact is that our field is littered with classes of compounds that have been wildly successful in pre-clinical assays, but have failed in humans.”

In the long term, Hargreaves is confident that solutions will be found, whether by his team or others. Our understanding of pain is advancing to the point that a better, less addictive pain medication should be achievable.

Such a drug, he said, could dramatically change the future trajectory of the opioid crisis. It won’t suddenly eradicate all the addictions, or the markets and social patterns that have emerged to service them. But it could transform the capacity of clinicians to treat their patients’ pain without fear of setting them on the road to addiction. It could, along with a host of other interventions, spell the beginning of the end of the crisis. It wouldn’t be a magic bullet, but it would be a powerful one.