The FDA Approves A New, Non-Opioid Painkiller

IRA FLATOW: This is Science Friday. I’m Ira Flatow.

FLORA LICHTMAN: And I’m Flora Lichtman. Later in the hour, why grief can feel like a punch in the gut. And could Uranus and Neptune have deep, multi-layered oceans?

IRA FLATOW: But first, last month, the Food and Drug Administration approved a new pain medicine, the first time it’s done so in 25 years. It’s called Journavx, made by Vertex Pharmaceuticals. And the big headline here is that it’s not an opioid, and it’s non-addictive.

So how does it work? Who should take it? Does it signal a new era for pain medication? Here to help break down this new painkiller is Dr. Sean Mackey. He’s a Professor of Anesthesiology and Medicine at Stanford and Chief of the Division of Pain Medicine at the university. Dr. Mackey, welcome to Science Friday.

SEAN MACKEY: Hey, thanks for having me on board.

IRA FLATOW: You’re welcome. OK. In a nutshell, how does this drug work?

SEAN MACKEY: Well, in a nutshell, we need to first understand that pain all comes about from signals that are transmitted on nerves, and we have specific types of nerves that will ultimately transmit those pain signals. Now, those signals are generated by an electrical impulse.

So when you get an injury, when you undergo surgery, those nerves are stimulated. That stimulation is caused by, in part, sodium channels. So what this particular drug does is it blocks those sodium channels.

What’s kind of cool about it is that, as you know, we’ve got nerves all over our body. Our brain, our heart, every organ has got nerves. And the last thing you want to do is give a drug that blocks the nerves that are serving particular vital functions, like our heart beating, like our brain working.

What’s cool about this particular drug is it targets only the sensory nerves out in the periphery of our body– specifically, a channel called NaV1.8. Na, If you remember from your high school–

IRA FLATOW: Sodium. Na.

SEAN MACKEY: Yeah. There you go. Na. It’s sodium. So it’s a particular sodium channel. That’s how it works.

IRA FLATOW: I get it. So it stays away from your brain, in other words.

SEAN MACKEY: That is the idea of it. And they’ve spent decades, pharmaceutical companies, to try to make this thing happen. And it looks like this company has pulled off a win with it.

IRA FLATOW: How is this medication different from an opioid or something like Tylenol?

SEAN MACKEY: So this medication works specifically on the peripheral nerves. It targets them, with a laser-type focus on a particular receptor, and blocks it. Opioids, on the other hand, predominantly are working in the spinal cord, the brainstem and the brain, and the central nervous system. And think of them as turning the volume down on pain.

So a completely different location for where they’re acting and a completely different mechanism of action. Tylenol– [LAUGHS] we’re still trying to figure out exactly how Tylenol works. We–

IRA FLATOW: Really?

SEAN MACKEY: –think it works– yeah, after all these years. It is a drug that works also centrally. It works in the brain. And it works by turning down some of these signals, if you will, in the brain. Now you add on the other common drug that we use, which are NSAIDs, Nonsteroidal Anti-Inflammatory drugs like the ibuprofens, the Naprosyns, those, interestingly, are not really pain relieving medications per se. They’re not analgesics. Sorry for the jargony word, but what it really means is they reduce inflammation that winds up pain.

And so the key is, if you can imagine, once again, our job typically in pain is to attack those pain pathways at different points and ideally identify where the source of the signals are coming from, where the injury is, and go after that specifically with the drug of choice.

IRA FLATOW: OK. Now, how effective is it compared to, let’s say, an opioid? And would it be a substitute for it?

SEAN MACKEY: Yeah. And that’s a big– that is the big question. What this study showed that they published in the New England Journal of Medicine back in ’23 is that when they compared it against a placebo, that that the highest dose beat placebo statistically. The lower doses did not.

They did not, in the paper, make a nice head-to-head comparison against an opioid. And the difference between the drug and placebo was, eh, mild. Rather mild difference. It met statistical significance, but it’s not a hit the ball out of the park major effect.

IRA FLATOW: So what’s the big excitement about then, if it’s hardly better than a placebo?

SEAN MACKEY: I think the big excitement is, one, this is the first new compound that’s been introduced in decades that gives promise for targeting different pain pathways than what we’ve done before. Two, as has been mentioned, it’s non-addictive. Most likely, there’s no chance that you’re going to get addiction to this particular medication.

Three, it does provide some benefit. And remember, when they do these studies, they look at averages of people. The thing is that we don’t treat an average. We treat a person. And so within this study, there was undoubtedly people who got a pretty profound effect, a benefit. And there were others who probably didn’t get much of any.

For those people who maybe they shouldn’t be taking an opioid, they’ve had problems with opioids from either side effects or otherwise, this is going to be a nice tool to be able to use. And in addition, the message that we’ve been saying in the pain space for years is there’s probably not a single magic bullet, meaning it’s going to be, if you will, a cocktail of different approaches. So maybe it’s using this drug with another medication where you’re going to get the real big effect sizes.

IRA FLATOW: So you’d have to test it out– I don’t mean literally on people, but say, try this, see if it works.

SEAN MACKEY: Yeah, I mean, that’s the nature of how we practice pain medicine right now, right?

IRA FLATOW: I know.

SEAN MACKEY: It’s kind of frustrating for patients and for the docs.

IRA FLATOW: Right. But almost it sounds to me like a proof of concept more than anything else. The sodium channels, we can block them, and it works.

SEAN MACKEY: Well, first of all, it is a real applicable drug with real utility. And you’re right, it demonstrates a proof of concept that, by targeting a specific type of sodium channel, you can provide pain relief, and it doesn’t look like there’s significant side effects.

What I’m particularly hopeful about this medication is that it may provide an additional tool in the future for use in chronic pain conditions. Right now, it’s only FDA approved for acute pain. This drug was studied for post-surgical pain, pain after surgery, but one could also see it being used after trauma. But they do have phase III clinical trials ongoing in diabetic peripheral neuropathy. Stay tuned.

IRA FLATOW: Stay tuned. And so we should stay tuned not only to see how this works, but what might come after it? Where does the research– I guess, where does it go from here?

SEAN MACKEY: Yeah, I think there’s a number of companies out there that are developing new agents that are going to be working in different places along the pain pathways. There’s a company right now that are in late-stage clinical trials focusing on what’s called the TRPV1 receptor, which is the capsaicin receptor. The receptor that causes red hot chili peppers to be hot.

IRA FLATOW: Right.

SEAN MACKEY: And so they’ve developed a drug that blocks that capsaicin. And it’s injected locally. And they’ve shown some long-term benefit after surgery in providing pain relief. So imagine you start to add a new drug like that, assuming it gets FDA approved, with a sodium channel blocker like this. All of a sudden, you start adding up to some real significant improvements in people’s pain control.

IRA FLATOW: Right. We’ve heard about personalized cancer treatment. Are we also talking here, then, personalized pain treatment?

SEAN MACKEY: Well, now you’re really talking to me, because this is a big focus of my research and a lot of others in the country, is to advance this notion of personalized pain medicine. So our lab focuses on developing objective biomarkers of pain so that we can ultimately identify the right pain treatment for the right patient and the right circumstance.

And you could say that oncology has been our muse. We’ve watched them, for the last several decades, advance this space and do amazing work in personalized cancer care. And we’re all sprinting to try to catch up with what they’ve done in cancer. And I’m particularly optimistic that we’re going to get there.

IRA FLATOW: Getting back to this drug here– and I know that you treat patients– do you plan on using this as a clinician?

SEAN MACKEY: Yeah, I think the questions for drugs like this are always, how effective is it? And we’ve got one published study showing it’s got mild effectiveness and has some clinical utility. Two, what are its side effects? We spend a lot of time thinking about how drugs are going to impact people. This seems to be pretty mild.

And three, cost. So on one hand, if you have a drug that is the same cost as Skittles, well, you’re going to use it a lot. On the other hand, if it’s priced as, say, a chemotherapy infusion, it’s thousands and thousands of dollars, then we’re going to be very selective with it.

IRA FLATOW: Yeah. Because as you say, if the studies show it doesn’t work much better than a placebo, then what’s the sense, until you try it out?

SEAN MACKEY: Yeah. I think one of the key things to note is this study that was done was done on a few hundred people. It’s also a rather homogeneous set of people. What I mean, it’s almost all women in these studies. We do know there’s sex differences in responses to pain, men and women.

We don’t yet know if this will work the same in men as we do in women. It probably will, based on our understanding of the physiology. But until we get it out there and start applying it in thousands, tens of thousands, hundreds of thousands of people, we’re not going to know.

We’re also going to, in this process, get a lot more experience with what other potential side effects are. Just take a look at the GLP-1 agents as an example. These are the drugs that cause weight loss. The Ozempic, the drugs that have been used to treat obesity. And people are seeing these used for many other indications.

But now, once you expose a public at large numbers, you now start to see potential side effects and the downsides to these medications. And it’s only when you use them in those large numbers that that comes to bear.

IRA FLATOW: Very interesting, Dr. Mackey. I want to thank you for taking time to be with us today.

SEAN MACKEY: Thank you so much for having me on.

IRA FLATOW: And good luck to you in your research. Dr. Sean Mackey, Professor of Anesthesiology and Medicine at Stanford University.

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