Building a Better Painkiller

Amid a public health crisis, the hunt for an opioid alternative is on.

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Back in the late 1980s, researchers at the Max Planck Institute of Psychiatry injected the right hind paw of a rat with Freund’s complete adjuvant, a compound that triggers inflammation, as part of a test of chronic pain treatments. One of the first painkillers they administered was morphine.

When they probed the paw for tenderness, they found the morphine had numbed the flesh as expected.

But the scientists also noticed something strange. The other hind paw, which they did not inflame beforehand, remained sensitive to touch. With all the morphine coursing through the rodent’s veins, that foot should have been numb as well. According to the textbooks, morphine does its analgesic magic in the brain and central nervous system. Therefore, the injection should have desensitized the rat’s whole body equally.

The Planck Institute experiment suggested that the drug was acting locally. Somehow the nerve cells, or neurons, in the inflamed paw were responding to morphine, and something about the inflammation gave the painkiller its zing.

At first, “we didn’t have an explanation,” says Christoph Stein, who led the research.

The puzzling results of Stein’s experiment would open new avenues for painkiller research, a field that would receive greater scrutiny in the years to come. By the early 2000s, opioid dependency was emerging as a national epidemic. Today, between 21 and 29 percent of the people prescribed opioids for chronic pain misuse them. Even more vexing, illicit forms of pharmaceutical opioids sold as street drugs may be 50 to 5,000 times more potent than heroin. In 2015, 2 million Americans suffered from prescription opioid addiction, and more than 33,000 died of an opioid overdose. In 2016, the number of fatalities rose to more than 42,000. In October 2017, the federal government declared the opioid epidemic a public health emergency.

While misuse of early opioids such as morphine goes back centuries, the roots of today’s crisis began in the 1990s when the health care industry made pain management a priority and pharmaceutical companies marketed their products as non-habit-forming. Physicians started to prescribe powerful new opioids, sometimes to alleviate even minor complaints. As a result, pharmaceuticals chemically inspired by the opium poppy became as ubiquitous as Band-Aids.

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Initially, quality of life improved for many patients. But as users’ tolerance of opioids increased, health care professionals prescribed ever-larger doses to maintain the drugs’ painkilling efficacy. And larger doses amplified the dangers posed by adverse side effects. In particular, opioids block pain through a mechanism that’s connected to other crucial biological functions in the body. Tinker with one, and the others can be thrown out of whack.

“Pain processing ... is a pretty complex system that has evolved over hundreds of millions of years,” explains Edward Bilsky, an opioid pharmacologist and provost at Pacific Northwest University of Health Sciences. “There are opioid receptors in many parts of the brain and spinal cord.”

Some of these receptors dampen the signals sent by neurons when the body is injured. Others activate the release of dopamine, causing euphoria as well as cravings for more dopamine. And still others regulate breathing. During an opioid overdose, the respiratory system becomes less responsive to rising carbon dioxide levels in the bloodstream. “People lose consciousness,” Bilsky says. “Within minutes, they’re dead.”

Yet opioids remain essential to modern medicine. “Clinically, opioids are still one of the best ways to take pain away,” says Nathaniel Jeske, an associate professor in the School of Dentistry at UT Health San Antonio. “They’re not going to go away anytime soon.”

Innovative opioid researchers — including Jeske, Bilsky and Stein — recognize the medical necessity of opioids and the need to address serious side effects. Although their approaches differ, they all aim to biochemically control the cycle of addiction: to make opioids that kill the pain without killing the patient.

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Acid Trip

Stein’s accidental late-’80s discovery of a connection between analgesia and inflammation opened a new pathway to pain treatment. Opioids block pain by fitting into specialized receptors on the surface of neurons. These receptors are like switches. They turn off the pain signal when opioid molecules fit inside them.

Scientists were already familiar with this mechanism and had found opioid receptors distributed throughout the brain and central nervous system. But when Stein showed that morphine acted locally on a rat’s inflamed hind paw, he demonstrated for the first time that the whole body has receptors for opioids distributed on the surfaces of neurons outside the brain and spinal cord, from head to toe.

His research suggested that these peripheral receptors were unusual. Unlike receptors in the brain, which are always receptive to opioids, something special about inflammation opened peripheral receptors to the painkillers. Because inflamed tissue is considerably more acidic than tissue without inflammation, he surmised that the molecular structure of the receptors was somehow altered by the acidity. He believed the change in pH could help the opioids and receptors fit together.


Guided by Inflammation

Researchers have identified peripheral opioid receptors throughout the body, outside the brain and central nervous system, that are triggered by inflammation. A compound in development, NFEPP, targets these receptors only in the inflamed tissue, providing local pain relief. The approach may lead to a painkiller without the side effects of currently available opioids.

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Stein reckoned that he could make a new class of synthetic opioids that would kill pain where it hurts and leave everything else alone. But in order to design a drug, he needed to see how the receptor structure is altered by changes in pH.

Partnering with mathematicians and building on earlier research that created three-dimensional visualizations of opioid receptors, Stein made a computer model that could re-create the acidity associated with inflammation. “We ran simulations under different pH conditions,” he says. He found that acidity not only alters the receptor, but also modifies the opioid molecule. Both changes are needed for the receptor to be activated in the body.

Stein’s big idea, building on this observation, was to create a new opioid that would function entirely outside the brain. It would be activated only at high acidity, beyond the brain’s natural pH level, and therefore would never bind to the brain’s receptors. By changing a single atom in fentanyl, a popular synthetic opioid, he made a highly targeted compound dubbed NFEPP.

Stein, who is now chair of the anesthesiology department at the Charité hospital and Free University of Berlin, has tested NFEPP on rats inflamed with Freund’s complete adjuvant, and the initial results are encouraging. “When we compared the analgesic effect of the new compound to regular fentanyl, we found very similar potency,” he says. And he has detected none of the adverse side effects of fentenyl, including respiratory depression, constipation and the euphoria associated with addiction: “It works almost 100 percent outside of the brain.”

Yet even as Stein refines NFEPP for human trials — a process that will cost about $6 million and take several years — he does not claim that it will cure the opioid epidemic on its own. He and other researchers note that some kinds of pain, such as chronic pain that develops after severe burns, don’t involve inflammation. The very mechanism that makes the drug safer may make it ineffective for some of the people who need pain relief.

Kill the Craving

Bilsky started giving rodents drugs in the late 1980s. Early in his career, he worked with cocaine and MDMA. After repeatedly injecting rats with one of these drugs over a period of days, he used a test known as conditioned place preference to see whether they’d develop a liking for the drug: He observed whether the rats favored the part of the cage where they regularly got their fix, even when no drugs were offered. Not surprisingly, the rodents loitered there.

But when Bilsky injected the rats with cocaine or MDMA and a chemical called CGS 10746B, the effect was completely different. CGS 10746B inhibits the release of dopamine in the brain. Without the exposure to dopamine, rats never developed a craving.

These results make sense, according to Bilsky, when you consider how dopamine works and why the body uses it in the first place. Dopamine is a neurotransmitter — a chemical that facilitates communication between neurons — one purpose of which is to reinforce behavior. “It’s very primal,” he says. For instance, when an animal finds a good food source, the release of dopamine helps the creature learn and remember to return for more. The dopamine is a natural reward.

“But when you’re taking a drug of abuse, that’s a much stronger stimulus,” he says. The dopamine released by the brain under the influence of cocaine still affects learning and memory, “but in this case, it’s pathological. It’s so strong that we start to drown out all those natural rewards.”

Since opioids hijack the natural reward system in a way similar to cocaine, researchers at the University of Valencia tested the effect of CGS 10746B on morphine in the early 2000s. Their results matched Bilsky’s, but both teams faced the same problem. Dopamine is essential for other functions, including control of the motor system. Various kinds of dopamine receptors manage those functions, so Bilsky and his colleagues had to identify specific sub-subtypes of dopamine receptors with the greatest potential for targeting. One of the most promising, in terms of sidelining side effects, is a receptor known as D3.

D3 receptors are most densely concentrated in the learning and memory centers of the brain. Like all receptors, they can be activated by certain chemicals called agonists. Other chemicals, called antagonists, shut down the receptors by preventing the agonists from entering. Bilsky’s idea was to identify a D3 antagonist that would barricade the D3 receptor without affecting other dopamine pathways. He found that an antagonist called SR 21502 did the trick. To test the effect of combining it with opioids, Bilsky and colleagues have been dosing mice with SR 21502 and observing their behavior after injecting them with a chemical that induces morphine withdrawal. Ordinarily the drug would make the mice very jumpy — literally. The mice would jump up and down. Initial results show that SR 21502 neutralizes that symptom as well as others, including diarrhea.

There are trade-offs, however. While SR 21502 doesn’t appear to affect motor coordination, it does seem to diminish the painkilling effect of the morphine. Higher doses are needed, which may be impractical to administer, or might cause other side effects. Bilsky aspires to make the antagonist more potent and more readily effective. Other labs, meanwhile, are experimenting with different chemicals that block D3 receptors completely or partially. “Drug development is a very long and drawn-out process,” Bilsky says. “You have to make sure it’s going to be both safe and effective in clinical populations.”

Delta Force

Most of the opioids on the market today interact with just one kind of receptor. Designated with the Greek letter mu (μ), it’s responsible for both the analgesic and side effects of morphine and fentanyl. But mu is not the only receptor for opioids. Researchers have identified two others, kappa (κ) and delta (δ). Although they can cause everything from seizures to mood changes when indiscriminately activated, these receptors may offer alternative pathways to managing pain.

Bilsky is particularly interested in the delta receptors, and the opioids that activate them, because they don’t engage the brain’s dopamine system in the same way as mu agonists. They seem not to induce euphoria as strongly, at least in rats, and therefore are likely to be less addictive in humans. (As a bonus, they also tend not to depress respiration.) Even though researchers still don’t know how effective these agonists will be in reducing pain for people, Bilsky is already working to develop compounds that target delta receptors in the brain.

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Jeske concurs with Bilsky about the greater safety of delta agonists, but like Stein, he’s focused on targeting peripheral opioid receptors. In contrast to Stein — whose strategy is to target mu receptors during inflammation — Jeske wants opioids to work even in the non-acidic conditions of chronic pain from burns. “It’s an untapped need,” he says.

Jeske has spent the past several years investigating the delta opioid receptors in rats. By observing the receptors in both normal and inflammatory conditions, he has identified a protein, called GRK2, that works as an opioid receptor gatekeeper. When the inflammation surpasses a threshold, a cascade of chemical reactions takes place, he explains, eventually pulling GRK2 away and effectively unlocking the gate, allowing the opioid to activate the receptor.

Jeske is now searching for chemicals that decouple GRK2 from receptors on contact. He seeks to combine these with delta opioids in what he describes as a “two-pronged approach” that will simultaneously pull away the GRK2 gate and load the receptors with painkillers.

Kappa receptors also have recently become more promising targets for analgesia. In January, a group led by University of North Carolina at Chapel Hill pharmacologist Bryan Roth announced that it had successfully imaged the structure of the kappa receptor while the receptor was activated by an opioid. That’s exceptionally difficult to achieve since receptors aren’t static during activation. Having a clear image allows researchers to see how the pieces interact. The hope is that understanding how the receptor takes up the agonist will make it possible to alter the agonist for better targeting of the specific receptor type.

Roth used the image to design an agonist that binds selectively and strongly to kappa receptors. He has validated the computer simulations by testing the drug on cell cultures in the lab. By activating only the kappa receptor, the chemical shouldn’t cause any of the side effects associated with the mu. The next challenge will be to mitigate the kappa system’s own adverse side effects, which can include hallucination and dysphoria, or uneasiness. Roth believes that may be possible by controlling exactly where and how the drug interacts with the receptor. His model of the activated kappa can help guide the discovery process.

The pioneering work of Roth and these other researchers represents a new level of innovation inspired by crisis. “All we’re trying to do is to try to get a better way of using opioids that doesn’t produce the negative side effects that are contributing to the opioid epidemic,” says Jeske. At the same time, their work reflects a rising awareness of the drug industry’s limitations.

“We’ve been searching for these broad-spectrum drugs, these blockbuster drugs,” says Bilsky. “We’ve got to readjust so we can target smaller populations that might benefit from one of these nuanced therapies.”

Ending the opioid epidemic depends on more than just clever chemistry. We’ll also need to cure our addiction to easy solutions.

Pinpointing the Source of Opioid Prescriptions

Researchers and health experts are drilling down into data to help find a solution to the country’s opioid epidemic. A recent review of data from 1996 to 2012 found prescriptions for the painkillers have been decreasing in emergency rooms, while doctor’s offices saw a significant uptick. This knowledge could assist policymakers on where to direct their efforts.
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