Why is it so hard to create new types of pain relievers?

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This week I’ve been thinking about America’s addiction to opioids. The statistics are staggering. Since 2010, opioid overdose deaths have nearly quadrupled. More than 80,000 people died from an opioid overdose last year. That’s one death every six and a half minutes.

Opioid use disorder is a particularly difficult disease to treat. But we do have safe and effective medications. These drugs help curb withdrawal symptoms, reduce illegal opioid use, and help people stay in treatment. They also reduce the risk of death from overdose. A study published Monday, however, shows that just one in five people with opioid use disorder receives these drugs.

Clearly, we need to do better. That means improving treatment, but it also means finding alternative methods for controlling pain, a task that has proved exceedingly difficult. A study published last week suggests the Boston-based biotech Vertex may be making headway with its compound VX-548, a pill that aims to relieve pain in the wake of surgery. The highest dose of the compound offered greater pain relief than a placebo after bunion removal or tummy tuck surgery. That’s good news in a space that has had more than its fair share of setbacks.

Treating pain is complicated because pain itself is complicated. Doctors categorize pain by how long it lasts—acute vs. chronic—and also how it begins. Some pain starts with damage to the body—a cut, a burn, a broken arm, a tumor. Sensory nerves (neurons) in our body detect the damage and send pain signals to the brain. Some pain, such as the stinging and burning that comes with diabetic nerve damage, begins with injury to the neurons themselves.

Opioids—heroin, morphine, fentanyl and all the rest—work by masking pain. They bind to receptors in the brain and spinal cord, initiating a series of reactions that help block pain signals. Prescription opioids are extremely good at pain relief in certain situations. But they don’t just block pain. Activating the opioid receptors also prompts a rush of dopamine, which makes us feel good—even euphoric. The feeling doesn’t last. And the more a person takes, the more is needed to get the same rush. That’s why these drugs are ripe for abuse. 

Non-opioid painkillers already exist, of course—things like ibuprofen, aspirin, acetaminophen, and naproxen sodium. You’re probably familiar with many of them because they’re available over the counter. They don’t trigger a dopamine release and aren’t addictive like opioids, but these medications come with some serious drawbacks: ulcers, bleeding, heart problems, and more. Most (with the exception of acetaminophen) belong to a class called nonsteroidal anti-inflammatory drugs, or NSAIDS for short. As the name suggests, they target inflammation in the body, blocking the production of chemicals that cause us to feel pain. But they don’t work for pain of many other types.

The effort to develop new classes of pain medicines has hit many roadblocks. Just last year Regenron pulled the plug on development of a compound to treat osteoarthritis and chronic back pain; an experimental pain therapy from the Illinois-based biotech Aptinyx failed in a trial to help people with fibromyalgia; and the California company Acadia reported that its compound performed no better than a placebo in people who had undergone bunion removal surgery*.  In 2021, Eli Lilly and Pfizer halted development of  tanezumab, a monoclonal antibody to treat pain in people with osteoarthritis. Why each of these failures occurred isn’t entirely clear, which makes it difficult to find the best path forward.

Vertex’s new compound is part of a class of drugs that target sodium channels on the pain-sensing nerves themselves. Stephen Waxman, a Yale neurologist who studies pain, describes them as “tiny molecular batteries” that drive the production of nerve impulses. Some sodium channel blockers already exist—the numbing agent lidocaine, for example. But because they block all sodium channels, even crucial ones on heart cells and in the brain, they are often administered only as local anesthetics.

VX-548 targets a specific channel called Nav1.8 that is found only on pain-sensing neurons. That means it can work broadly on those neurons throughout the body without blocking the function of the heart or brain. Because it doesn’t activate opioid receptors, it also doesn’t trigger a release of dopamine, giving people pain relief without an accompanying high. 

Phase 2 trials of the drug enrolled people with moderate to severe pain following a tummy tuck or bunion removal. Patients who requested pain medication were randomized to one of several groups. Some participants received VX-548 at one of three dosage levels, some got a placebo pill, and some took a pill that contained hydrocodone (an opioid). Those taking the highest dose of VX-548 experienced greater reductions in pain than those in the other groups.

An editorial accompanying the study noted that the effect was “small.” But the results are exciting, in part because the hunt for non-opioid painkillers has had so few successes of any size. “Here we have a clinical study in humans that shows that you can target one of these peripheral sodium channels and reduce pain in human subjects without adverse side effects,” Waxman told the New England Journal of Medicine. “I see us at the first stage in humans of a new generation of pain medications.” 

We can hope. 

*You might wonder, as my editor did, why so many pain medicine trials include patients undergoing bunionectomies. It’s one of the classic surgical models of acute pain. Dental extraction is another. The more you know.

Read more from Tech Review’s archive

Adam Piore wrote about the quest to develop nonaddictive painkillers way back in 2016. 

Could an ingestible capsule keep tabs on whether patients are taking too many prescription opioids? Emily Mullin covered this new technology in 2017. 

Neuroscientist Fan Wang is looking for the brain circuits that control pain. Georgina Gustin profiled Wang and her work in 2021. 

Recorded brain waves can help quantify pain, which could upend some types of treatment, Rhiannon Williams reported in May. 

Another thing: 

Twenty-five years have passed since researchers isolated the first embryonic stem cells, but we’re still waiting for stem-cell therapies. Antonio Regalado looks at the hype and the hope. 

Who gets access to experimental treatments—especially some of the ultra-novel treatments that are just beginning to emerge? Jessica Hamezlou dives into this thorny ethical question in a story for MIT Technology Review’s ethics issue. 

From around the web:

Data from a landmark study show that the obesity drug Wegovy slashed the risk of heart attacks, strokes, and cardiovascular deaths by 20%, according to the drug’s maker. (The New York Times)

This week the FDA approved the very first therapy exclusively for postpartum depression. (Stat News)

The US has a new covid variant. Meet Eris. (Washington Post)

And if you want more about the opioid crisis, the podcast Serial has a new season out called  The Retrievals, which offers a devastating case study on how opioid abuse can affect patients. The series is about a nurse who stole fentanyl vials and replaced the contents with saline, and the women who underwent egg retrievals without fentanyl as a result. It’s horrifying, but very much worth your time.