Are Alternatives to Addictive Opioids on the Way?

In the ideal world, Vertex’s drug would be so effective that it would simply make opioids obsolete, but it won’t.
In the ideal world, Vertex’s drug would be so effective that it would simply make opioids obsolete, but it won’t.


Vertex’s clinical trials mark a step toward finding treatments for pain without addiction risks.

“We’re going to cure the world of its pain" declared Richard Sackler (portrayed by Michael Stuhlbarg) in the Hulu miniseries “Dopesick," which chronicled how Purdue Pharma used deceptive practices to make OxyContin a blockbuster. Opioids didn’t cure pain, but they led to a nationwide scourge that has killed hundreds of thousands of Americans.

These days, doctors no longer prescribe opioids as easily. Unfortunately for millions of Americans still suffering from debilitating pain, the alternatives aren’t great, leaving a gap in care that is in urgent need of a medical solution.

In recent months, Vertex Pharmaceuticals announced positive results from studies of its experimental nonopioid painkiller. The excitement has added about $20 billion to the company’s market capitalization in recent months, with some Wall Street analysts describing the pain market as the next big opportunity after obesity. Yet the results, while encouraging, are far from being a home run. In two late-stage studies, the drug eased patients’ pain more than the placebo but failed to outperform Vicodin. In a bunion surgery trial, the opioid-based Vicodin outperformed Vertex’s drug on pain relief. The upshot is that while Vertex’s drug might not be a blockbuster, its success is likely to pave the way for better drugs down the line.

For decades, the hunt for safe and effective pain treatments has eluded the pharma industry. It isn’t that researchers don’t know how to stop pain. Drugs can target receptors in the brain to reduce it, as opioids do quite well, but not without also triggering feelings of euphoria, or dulling mental acuity. Crucially, there is also the potential for addiction.

Pain can also be blocked at the source by local anesthetics. Dentists do it all the time during dental procedures. But if you were to turn that into a pill, it would run the risk of blocking neuronal signaling within the brain, or affecting the heart’s rhythm, says Stephen Waxman, a Yale University neuroscientist. The challenge for drug developers has been how to create a highly selective pill that can target pain without compromising other bodily functions.

“We could block all pain, but we wouldn’t live very long," says Thomas Buchheit, director of Duke University’s Regenerative Pain Therapies Program.

In recent decades, scientists identified genetic mutations that made people either feel too much pain or made them unable to sense it. A child in Pakistan with a genetic mutation entertained street crowds by walking on hot coals and sticking knives through his arms. The discovery of the mutated gene, which encodes sodium channels that regulate the transmission of pain signals to the brain, offered a tantalizing target because it represented a way to potentially block pain at its source with limited side effects.

But relieving pain by blocking these channels, known as Nav1.7 and Nav1.8, has proved difficult, and companies including Teva, Roche and Biogen have undertaken clinical trials that failed to demonstrate conclusive evidence of pain relief. One issue is that these sodium channels are similar to others that regulate functions in the heart and brain. Another challenge, Waxman says, is that unlike cancer, for example, where a clear marker in the blood can be measured after a treatment is given, assessing pain is more subjective, with results often based purely on patients’ responses.

Vertex’s success, then, should be viewed in the context of a long string of failures. Think of the opportunity less as the GLP-1 bonanza remaking the treatment of obesity and more like the slow, but promising, progress being made in fighting Alzheimer’s. While its drug didn’t beat opioid-based Vicodin in acute-pain studies and didn’t outperform Lyrica, an older drug, in a separate study with diabetic neuropathy patients, the results are likely to unleash more investment and research into this class of sodium channel blockers. And since Vertex will be able to claim its drug isn’t addictive, it should establish a decent-size market.

“This is an important step forward because it establishes proof of concept that this approach can reduce pain," says Waxman. Latigo Biotherapeutics recently raised $135 million to focus on the same sodium channel as Vertex. Sean Harper, co-founding managing director at Westlake Village BioPartners, an investor behind Latigo, argues that so-called Nav inhibitors could follow a trajectory similar to that of statins. While the first drug wasn’t the most effective, it paved the way for subsequent ones with a better clinical profile. In the longer term, other approaches, such as gene therapies, could become available.

If approved, Vertex’s drug will initially be available for acute pain. That means it could be prescribed after surgery, when a patient needs a week or two of medication. While that is a multibillion-dollar market, the challenge is that doctors don’t mind prescribing opioids for short durations, says Myles Minter, an analyst at William Blair.

Price is a crucial factor. Opioid generics cost as little as 50 cents a pill, compared with an estimated $10 for Vertex’s drug, Minter says. Passage of the Nopain Act, legislation promoting the use of nonopioids, could help with the cost, but wouldn’t close the gap entirely. The bigger opportunity will be for neuropathic pain, which is treated chronically. After positive midstage results in people with painful diabetic peripheral neuropathy, Vertex is in talks with the Food and Drug Administration to conduct a broader study of people with neuropathic pain. Such chronic markets represent a much bigger opportunity because pills are taken for years and opioids aren’t as suitable because of their addictive nature, says Minter.

There is no arguing that pain, whether acute or chronic, is a huge market in desperate need of better drugs. In the ideal world, Vertex’s drug would be so effective that it would simply make opioids obsolete, but it won’t. In a field littered with failures and a dearth of options, though, it is a big step forward.

Write to David Wainer at

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