YuLin Zhen, Photography Editor

Last week, the Food and Drug Administration approved Journavx, the first non-addictive opioid-like pain medication. Scientific discoveries at Yale were key to the development of the drug.

Journavx, developed by Vertex Pharmaceuticals, provides an alternative to addictive opioid painkillers prescribed to millions of Americans every year. The biological target of the drug was first discovered in the late 1990s in the lab of Professor Stephen Waxman at the School of Medicine. 

“The approval is so important because Journavx is the first and only nonopioid oral pain signal inhibitor, which means that it is a medicine that combines effective pain relief with a favorable safety profile, and it is non-addictive,” Vertex spokesperson wrote to the News. “Every time a physician can prescribe a nonopioid medicine instead of an opioid, it’s an opportunity to avoid their potential liabilities and bend the curve in the right direction.”

According to the most recent Centers for Disease Control and Prevention data, approximately 125 million people were prescribed opioids in 2023, which while effective, have significant safety and tolerability concerns and addictive potential. In fact, around 85,000 people annually develop opioid use disorder within the first year of being prescribed an opioid for acute pain.

Although Journavx is a step forward, some scientists the News spoke to argued that the drug has considerable limitations.

“We shouldn’t also be expecting magic bullets. Some people might be disappointed that the drug won’t cure all pain,” said Sulayman Dib-Hajj, professor of neurology at the School of Medicine, who participated in the original research at Yale.

Yale roots of Journavx

Action potentials, brief electrical signals that muscles and nerves use to communicate, cause pain sensations. These wave-like transmissions move along neurons like an electrical signal through a wire. 

“All neurons communicate with each other by producing nerve impulses,” Waxman told the News. “They’re called action potentials, and they’re due to the opening of sodium channels, and that causes a tiny rush of sodium that becomes explosive, and you get this all or none, little explosion of depolarization.”

During the molecular revolution of the 1980s, scientists discovered an entire family of sodium channels. 

Some of these channels specifically allow for pain signaling. Professor Dib-Hajj explains that local anesthetics, like Novocaine, which dentists use, block all sodium channels in the injection site, preventing pain signals from reaching the brain.

“The problem with using non-selective sodium channel blockers like local anesthetics or drugs is that they have a lot of side effects,” Dib-Hajj explained. “Just think about getting out of the dentist chair. Your cheek feels a lot bigger. You’re slurring your speech.”

Waxman added that if these medications were put into a pill, sodium channels in other areas like the heart and the brain would also be affected, leading to numerous health complications.

The goal is to find a sodium channel uniquely involved in pain transmission, so that blocking it would not affect other important functions, such as heart or cognitive functions, Dib-Hajj said.

“Once it was clear that there were more than one sodium channel, the question came up, might there be one or more types of sodium channels that are present only in peripheral nerves and are important for pain signaling,” Dr. Waxman said.

So, in the late 1990s, Waxman’s lab at Yale began investigating the peripheral sodium channels that propel pain signals.

They eventually deduced that three of these channels — Nav 1.7, 1.8, and 1.9 — work together to produce the nerve impulses in pain signaling.

Nav 1.8, the target for the Journavx drug, is a channel primarily involved in pain transmission that was discovered in 1995 at University College in London, said Dib-Hajj. Waxman and Dib-Hajj immediately started working on studying and targeting the Nav1.8 sodium channel as a potential non-opioid treatment for pain.

At Yale, scientists investigated how this channel behaves at the cellular level through observing it in environments such as human embryonic cell lines, neurons and in its native environment.

However, studying Nav 1.8 in lab settings presented a challenge because the channel does not express well in models. Waxman, Dib-Hajj and their team worked on developing experimental methods to properly express and analyze Nav1.8.

Journavx’s limitations and future research

Three decades later, the FDA has approved Journavx to treat acute pain. However, Dib-Hajj said, more work needs to be done, and Journavx has limitations, especially in its efficacy in treating chronic pain.

“Don’t get me wrong, it’s very exciting that we have something new, especially it’s not addictive, but the effect is not very big, and we still don’t know how effective it’s going to be for chronic pain,” said Dib-Hajj. “That is still a work in progress.”

Dib-Hajj explained that different approaches still need to be researched in order to find drugs that can treat severe pain, such as that caused by chemotherapy. He is also interested in Journavx’s effects on chronic pain.

He explained that he is still looking for “a bigger clinical effect than what this currently improved drug is producing.”

Waxman and Dib-Hajj’s lab plans to move in a different direction from Vertex. Instead of focusing on developing drugs that block Nav1.8 channels, they aim to decrease the total number of these channels on neurons. Fewer Nav1.8 channels mean less pain signal transmission, potentially offering a more long-term solution for chronic pain.

This approach is closer to gene therapy, where a biological agent, such as a virus or RNA-based therapy, reduces the expression of Nav1.8 in neurons. 

Biologic reagents, a type of drug that affects gene expression rather than just blocking the channel at the cell surface, is another possibility. Designing antibodies is another approach Dib-Hajj is investigating to regulate Nav 1.8, as antibody-based therapies are already used in some diseases and could be a non-opioid, long-term pain treatment.

Dib-Hajj explains that drugs like Vertex’s work quickly and are better suited for acute pain, whereas gene therapy or biologics might take longer to show effects, making them more suitable for chronic pain. The goal is to create a “menu” of pain treatments — allowing doctors to choose the best treatment for each patient.

Waxman and Dib-Hajj both emphasized that Vertex’s development underscores the importance of basic science research in academia.

“This channel was discovered in 1996. It’s almost now, 30 years later, and it’s only now that we potentially have something to go to the patients with,” Dib-Hajj said. “Drug development takes time. There are many unsung heroes who are still working at the lab bench.”

Vertex Pharmaceuticals was founded in 1989.