Scicurious | Science News

Love Science? Welcome Home.

Support Amazing Science Journalism.

Create the New Science Generation.


A peek behind the science curtain

Bethany Brookshire



How scientists are hunting for a safer opioid painkiller

Researchers are raiding libraries, tweaking known drugs and taking innovative approaches

colorful selection of pills

People will always need pills of some kind to kill pain. Scientists are using different approaches to find new opioid painkillers that aren’t addictive and have fewer side effects.

Sponsor Message

An opioid epidemic is upon us. Prescription painkillers such as fentanyl and morphine can ease terrible pain, but they can also cause addiction and death. The Centers for Disease Control and Prevention estimates that nearly 2 million Americans are abusing or addicted to prescription opiates. Politicians are attempting to stem the tide at state and national levels, with bills to change and monitor how physicians prescribe painkillers and to increase access to addiction treatment programs.

Those efforts may make access to painkillers more difficult for some. But pain comes to everyone eventually, and opioids are one of the best ways to make it go away.  

Morphine is the king of pain treatment. “For hundreds of years people have used morphine,” says Lakshmi Devi, a pharmacologist at the Ichan School of Medicine Mount Sinai in New York City.  “It works, it’s a good drug, that’s why we want it. The problem is the bad stuff.”

The “bad stuff” includes tolerance — patients have to take higher and higher doses to relieve their pain. Drugs such as morphine depress breathing, an effect that can prove deadly. They also cause constipation, drowsiness and vomiting. But “for certain types of pain, there are no medications that are as effective,” says Bryan Roth, a pharmacologist and physician at the University of North Carolina at Chapel Hill.  The trick is constructing a drug with all the benefits of an opioid painkiller, and few to none of the side effects. Here are three ways that scientists are searching for the next big pain buster, and three of the chemicals they’ve turned up.

Raid the chemical library

To find new options for promising drugs, scientists often look to chemical libraries of known molecules. “A pharmaceutical company will have libraries of a few million compounds,” Roth explains. Researchers comb through these libraries trying to find those compounds that connect to specific molecules in the body and brain.

When drugs such as morphine enter the brain, they bind to receptors on the outside of cells and cause cascades of chemical activity inside. Opiate drugs bind to three types of opiate receptors: mu, kappa and delta. The mu receptor type is the one associated with the pain-killing — and pleasure-causing — activities of opiates. Activation of this receptor type spawns two cascades of chemical activity. One,  the Gi pathway, is associated with pain relief. The other — known as the beta-arrestin pathway — is associated with slowed breathing rate and constipation. So a winning candidate molecule would be one that triggered only the Gi pathway, without triggering beta-arrestin.

Roth and colleagues set out to find a molecule that fit those specifications. But instead of the intense, months-long process of experimentally screening molecules in a chemical library, Roth’s group chose a computational approach, screening more than 3 million compounds in a matter of days. The screen narrowed the candidates down to 23 molecules to test the old fashioned way — both chemically and in mice. Each of these potential painkillers went through even more tests to find those with the strongest bond to the receptor and the highest potency.

In the end, the team focused on a chemical called PMZ21. It activates only the pathway associated with pain relief, and is an effective painkiller in mice. It does not depress breathing rate, and it might even avoid some of the addictive potential of other opiates, though Roth notes that further studies need to be done. He and his colleagues published their findings September 8 in Nature.

Letting the computer handle the initial screen is “a smart way of going about it,” notes Nathanial Jeske, a neuropharmacologist at the University of Texas Health Science Center in San Antonio. But mice are only the first step. “I’m interested to see if the efficacy applies to different animals.”

Making an opiate 2.0

Screening millions of compounds is one way to find a new drug. But why buy new when you can give a chemical makeover to something you already have? This is a “standard medicinal chemistry approach,” Roth says: “Pick a known drug and make analogs [slightly tweaked structures], and that can work.”

That was the approach that Mei-Chuan Ko and his group at Wake Forest University School of Medicine in Winston-Salem, N.C., decided to take with the common opioid painkiller buprenorphine. “Compared to morphine or fentanyl, buprenorphine is safer,” Ko explains, “but it has abuse liability. Physicians still have concerns about the abuse and won’t prescribe it.” Buprenorphine is what’s called a partial agonist at the mu receptor — it can’t fully activate the receptor, even at the highest doses. So it’s an effective painkiller that is harder to overdose on —  so much so that it’s used to treat addiction to other opiates. But it can still cause a high, so doctors still worry about people abusing the drug.

So to make a version of buprenorphine with lower addictive potential, Ko and his colleagues focused on a chemical known as BU08028. It’s structurally similar to buprenorphine, but it also hits another type of opioid receptor called the nociceptin-orphanin FQ peptide (or NOP) receptor.

The NOP receptor is not a traditional target. This is partially because its effect in rodents — usually the first recipients of a new drug — is “complicated,” says Ko. “It does kill pain at high doses but not at low doses.” In primates, however, it’s another matter. In tests in four monkeys, BU08028 killed pain effectively at low doses and didn’t suppress breathing. The monkeys also showed little interest in taking the drug voluntarily, which suggests it might not be as addictive as classic opioid drugs. Ko and his colleagues published their results in the Sept. 13 Proceedings of the National Academy of Sciences.*

Off the beaten path

Combing through chemical libraries or tweaking drugs that are already on the market takes advantage of systems that are already well-established. But sometimes, a tough question requires an entirely new approach. “You can either target the receptors you know and love … or you can do the complete opposite and see if there’s a new receptor system,” Devi says.

Jeske and his group chose the latter option. Of the three opiate receptor types — mu, kappa and delta — most drugs (and drug studies) focus on the mu receptor. Jeske’s group chose to investigate delta instead. They were especially interested in targeting delta receptors in the body — far away from the brain and its side effects.

The delta receptor has an unfortunate quirk. When activated by a drug, it can help kill pain. But most of the time, it can’t be activated at all. The receptor is protected — bound up tight by another molecule — and only released when an area is injured. So Jeske’s goal was to find out what was binding up the delta receptor, and figure out how to get rid of it.

Working in rat neurons, Jeske and his group found that when a molecule called GRK2 was around, the delta receptor was inactive. “Knock down GRK2 and the receptor works just fine,” Jeske says. By genetically knocking out GRK2 in rats, Jeske and his group left the delta receptor free to respond to a drug — and to prevent pain. The group published their results September 6 in Cell Reports

It’s “a completely new target and that’s great,” says Devi. “But that new target with a drug is a tall order.” A single drug is unlikely to be able to both push away GRK2 and then activate the delta receptor to stop pain.

Jeske agrees that a single molecule probably couldn’t take on both roles. Instead, one drug to get rid of GRK2 would be given first, followed by another to activate the delta receptors.

Each drug development method has unearthed drug candidates with early promise. “We’ve solved these problems in mice and rats many times,” Devi notes. But whether sifting through libraries, tweaking older drugs or coming up with entirely new ones, the journey to the clinic has only just begun.

*Paul Czoty and Michael Nader, two authors on the PNAS paper, were on my Ph.D. dissertation committee. I have had neither direct nor indirect involvement with this research. 

Follow me on Twitter: @scicurious

Neuroscience,, Nutrition

The need to feed and eating for pleasure are inextricably linked

By Bethany Brookshire 4:44pm, August 27, 2015
Scientists used to think that the hunger and the pleasure from food could be easily distinguished. But new results show these systems are inextricably intertwined.
Biomedicine,, Science & Society

Building standards aren’t to blame for chilly offices

By Bethany Brookshire 4:26pm, August 11, 2015
A recent study made headlines for finding differences between men and women in comfort level for heating and cooling. But that’s not why women are cold in the office.
Nutrition,, Science & Society

How trans fats oozed into our diet and out again

By Bethany Brookshire 2:24pm, July 29, 2015
Trans fats are no longer “generally recognized as safe” by the FDA. In a world where we want to have our doughnuts and eat them, too, it’s back to the drawing board, and back to butter.

The weekly grind of social jetlag could be a weighty issue

By Bethany Brookshire 7:38am, July 20, 2015
Even those of us with nine-to-five jobs don’t always respect our body’s clocks. Research shows that even slight disruptions might be associated with obesity.
Physiology,, Health

Shifted waking hours may pave the way to shifting metabolism

By Bethany Brookshire 2:30pm, July 15, 2015
Shift workers are at higher risk for obesity and metabolic problems. Scientists are working hard to understand why the night shift makes our hormones go awry.
Physiology,, Health

Women blush when ovulating, and it doesn’t matter a bit

By Bethany Brookshire 4:59pm, July 9, 2015
Women don’t signal their fertility in obvious ways like nonhuman primates. A new study shows that even skin flushes are too subtle to detect.
Science & Society,, Health

No matter the language, disease risk is hard to communicate

By Bethany Brookshire 4:56pm, June 29, 2015
Reassuring messages about MERS might seem designed to stop panic. But in reality, people need to hear the truth, even if it’s uncertain.
Psychology,, Science & Society

The guilty pleasure of funny cat videos

By Bethany Brookshire 7:30am, June 25, 2015
Many people love posting and looking at cute kitty content online. A new survey shows that this could be because it helps us manage our emotions.
Science & Society

Home-brewed heroin: Hold the hype

By Bethany Brookshire 3:00pm, June 17, 2015
Now is the time to think about policy for synthetically produced morphine, but the process, if it bears out, is years away from working.

Diet and nutrition is more complex than a simple sugar

By Bethany Brookshire 4:04pm, May 26, 2015
A new study shows that fructose may leave you wanting more when compared to the same dose of glucose. But in studies of single nutrients, it’s important to be cautious.
Subscribe to RSS - Scicurious