FDA Approves A New, Non-Opioid Painkiller | Deep, Multi-Layer Oceans On Uranus And Neptune?

It’s the first FDA approval for a pain medication in 25 years. How does the drug work, and who is it for? Also, non-mixing layers of water and hydrocarbons thousands of miles deep could explain the icy planets’ strange magnetic fields.

Speaker names marked ? are inferred from speaking time and the show’s known hosts — they are not voice-verified.

• 0:00Speaker 00

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• 0:14Flora Lichtman?

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• 1:00Ira Flatow?

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• 1:20Ira Flatow?

  This is Science Friday. I'm Ira Flatow. Today on the podcast, could Uranus and Neptune have deep, multi-layered oceans? But first, we'll dive into the science behind the first new kind of pain medicine in over two decades.

• 1:34Speaker 03

  The difference between the drug and placebo was, eh, mild.

• 1:42Ira Flatow?

  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 Gernavix, 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. Sharon Mackey. He's a professor of anesthesiology and pain medicine at Stanford and chief of the Division of Pain Medicine at the university. Dr. Mackey, welcome to Science Friday.

• 2:20Speaker 03

  Hey, thanks for having me on board.

• 2:22Ira Flatow?

  You're welcome. Okay, in a nutshell, how does this drug work?

• 2:26Speaker 03

  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,

• 3:09Speaker 03

  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. N-A, if you remember from, you know, your high school.

• 3:41Ira Flatow?

  Sodium, N-A.

• 3:42Speaker 03

  Yeah, there you go, N-A, it's sodium. So it's a particular sodium channel. That's how it works.

• 3:47Ira Flatow?

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

• 3:50Speaker 03

  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.

• 4:01Ira Flatow?

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

• 4:07Speaker 03

  So this medication works specifically on the peripheral nerves. It targets them with a laser-type focus on a particular receptor and blocks it.

• 4:20Speaker 03

  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, we're still trying to figure out exactly how Tylenol works. We 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, you know, turning down some of these

• 5:01Speaker 03

  signals, if you will, in the brain. Now, you add on the other common drug that we use, which are NSAIDs, non-steroidal anti-inflammatory drugs like the ibuprofens, the naproxens. Those, interestingly, are not really pain-relieving medications per se. They're not analgesics. It's, 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, go after that specifically with the drug of choice.

• 5:47Ira Flatow?

  Okay, now, how effective is it compared to, let's say, an opioid? And would it be a substitute for it?

• 5:55Speaker 03

  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 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.

• 6:38Ira Flatow?

  So what's the big excitement about then, if it's hardly better than a placebo?

• 6:44Speaker 03

  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.

• 7:16Ira Flatow?

  Right.

• 7:16Speaker 03

  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

• 8:01Speaker 03

  to get the real big effect sizes.

• 8:03Ira Flatow?

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

• 8:08Speaker 03

  Yeah, I mean, that's the nature of how we practice pain medicine right now, right?

• 8:12Ira Flatow?

  I know.

• 8:13Speaker 03

  You know, it's kind of frustrating for patients and for the docs.

• 8:17Ira Flatow?

  Right. But, but is it, almost, it sounds to me like a proof of concept, more than anything else. You know, the sodium channels, we can block them and it works.

• 8:25Speaker 03

  Well, first of all, it is a real, applicable drug with, 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 dreaded for post-surgical pain, pain after surgery. But one could also see it being used after trauma, but they do have

• 9:10Speaker 03

  phase three clinical trials ongoing in diabetic peripheral neuropathy. Stay tuned.

• 9:17Ira 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?

• 9:28Speaker 03

  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 TRIP V1 receptor, which is the capsaicin receptor, you know, the receptor that causes red hot chili peppers to be hot?

• 9:50Ira Flatow?

  Right.

• 9:51Speaker 03

  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 and providing pain relief. So, you know, imagine you start to add, you know, 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.

• 10:19Ira Flatow?

  Right. You know, we've heard about personalized cancer treatment. Are we also talking here then? Personalized pain treatment?

• 10:27Speaker 03

  Well, now, now you're really talking to me because this is a big focus of my research and a lot of others in, 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 in the right circumstance. And, you know, you could say that oncology has been our muse. We've watched them for the last several decades, advanced 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.

• 11:13Ira Flatow?

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

• 11:22Speaker 03

  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, are you 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.

• 12:02Ira Flatow?

  Yeah, because as you say, if the studies show it doesn't work much better than a placebo, then what's the sense, right? Until you try it out.

• 12:10Speaker 03

  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 and 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 what our understanding of the physiology.

• 12:40Ira Flatow?

  Right.

• 12:41Speaker 03

  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.

• 13:24Ira Flatow?

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

• 13:29Speaker 03

  Thank you so much for having me on.

• 13:31Ira Flatow?

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

• 13:42Ira Flatow?

  After the break, you want to do some diving? Consider the oceans of Neptune or Uranus.

• 13:48Speaker 04

  So the upper layer is actually 8,000 kilometer steep. It's really, really thick. You could put the whole Earth in this layer.

• 14:03Speaker 00

  Science Friday is supported by PBS, presenting Going Wild. If you love learning about the natural world and meeting the scientists who help us understand it, be sure to check out the new season of Going Wild with Dr. Ray Wynn Grant. It's the chart-topping and Webby Award-winning podcast from the folks at Nature on PBS, now with a video companion series. In this season of Going Wild, host acclaimed wildlife ecologist Dr. Ray Wynn Grant heads out into the field to explore the animals, people, and stories that make nature worth saving. Stops include a hibernating black bear den in Arkansas and an underwater shipwreck site off the Florida coast. If you're looking for a place to start, check out the season's debut episode, where Ray joins beloved biologist and influencer Jordan King in the Florida Everglades to learn about

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• 15:50Ira Flatow?

  We've got a pretty good idea about what's beneath the surface of our nearest planetary neighbors, say Mars. But as you get further out into the solar system, our knowledge becomes scarce. For instance, what's inside the so-called ice giants of Neptune and Uranus? Recent research based on fluid simulation hints that the planets could contain vast, multi-layered oceans, as much as thousands of miles deep. Joining me now to talk about that is Burkhard Militzer, professor of Earth and planetary sciences at UC Berkeley. He wrote about this idea in the proceedings of the National Academy of Sciences. Welcome to Science Friday.

• 16:32Speaker 04

  Hello, it's good to be back.

• 16:34Ira Flatow?

  Nice to have you. Why is it so hard to know what's out there on these planets?

• 16:40Speaker 04

  I think the main reason is they're far away, and we have not visited them very much. We had just one spacecraft that flew to Uranus and Neptune and measured the magnetic field. And this single measurement told us they have weird magnetic fields. So that was the starting point of the study. But we haven't been there at all.

• 17:00Ira Flatow?

  So you made computer simulations to figure out why there are strange magnetic fields?

• 17:07Speaker 04

  Yes, we've done this for quite some time, and we put materials at high pressure, and we don't do lab experiments. That's what my colleagues do. I just pretend to do these things. I put it on a computer and then study what do the atoms do in this case. And in this particular case, when I put water and methane and ammonia in one box at really high pressure, the water mysteriously separated from the rest of it. That was the starting point of the study, because the water seems to not like at these conditions the carbon and the nitrogen system. And that gave us a clue what's probably going on in these ice giant planets we call them.

• 17:49Ira Flatow?

  And I have an image in my head of oil and vinegar in my salad dressing separating. Is that sort of the same thing?

• 17:54Speaker 04

  That is pretty much true. That's the way you should think about it. But the problem is planets are hot in the interior. And if you were to make the water and the vinegar really hot, it would mix. So what we're proposing that they don't mix or face separate, that is sort of radical. There's nobody has done this before. But we think it's real because it gives us a good explanation for this field.

• 18:17Ira Flatow?

  Okay, then now draw me a picture then, if your theories are correct. What might be on these planets? Describe them for me.

• 18:26Speaker 04

  Yes, so the traditional view is you have hydrogen and helium, which is a top layer. And it has a little bit of methane and it gives both of those planets a bluish color. So then the conventional wisdom was that there is this thick layer of water. So we're not saying we're the first one to say there's water there. That's the conventional wisdom. What we are saying that this thick layer, which we call the mantle, if you like, is split into two different layers. Just the upper layer is water. And then there is the carbon and the nitrogen that actually below. If you like, the oil is actually deeper at these things. And then there is rocks at the center of the planet.

• 19:09Speaker 04

  So what we're proposing new is that this middle layer, which people thought is just water, in fact, has two separate layers. The upper one is water and the one below is carbon and nitrogen.

• 19:21Ira Flatow?

  And how deep is this upper layer of water?

• 19:24Speaker 04

  So the upper layer is actually 8,000 kilometers deep. It's really, really thick. So that is, you could put the whole Earth in this layer. Because these planets are bigger, they're about four times the size of Earth. And therefore, everything, all the different layers we're proposing, they're very, very thick.

• 19:44Ira Flatow?

  So 8,000 kilometers, 8 times 6 is like 4,800 miles, something like that.

• 19:50Speaker 04

  Yeah, that's right. Yes, yes.

• 19:52Ira Flatow?

  All right. Now, if this idea is correct, it would check off, as you say, this question of why Voyager didn't see a magnetic field on these planets. Explain that a little bit more, why there would be the absence of the magnetic field.

• 20:05Speaker 04

  So to be precise, we did see a field, but we didn't see the type of field we expected. So if you look at Earth, it has a well-defined magnetic north pole and a magnetic south pole. And you find this on Jupiter and Saturn. And then you fly to Uranus in 1986, and the field is weird. It looks like many small north and south poles, and it doesn't have this well-organized structure that we see on the other planets. And that requires an explanation. Why is the field weird? And the proposal was, well, if you make this field just in a thin layer, rather than in a thick mantle,

• 20:46Speaker 04

  a thin layer would actually make such a disorganized field, but people didn't know what those thin layer might be. So the proposal we're now saying, this thin layer is this water layer that is not super thick, because this other layer underneath that doesn't make the field. So that's the novel interpretation, which we hope is right, but we don't really know it's right till we have another probe that tests these things.

• 21:11Ira Flatow?

  Yeah, yeah. Are there other possibilities for why there's this weird magnetic field?

• 21:17Speaker 04

  I'm sure there are, but the moment we are the one explanation that we find very plausible. Other people just said, it's just water all the way through in this mantle till you hit the rocks. And we find this implausible. I would say, at the moment, we have the most plausible explanation, but there could be others, and we don't really know it till we get more data from a future spacecraft.

• 21:41Ira Flatow?

  Now, these spacecraft were there. We're talking about Voyager and the data that came back many years ago, right? Why has it taken so long for your simulations to yield some results?

• 21:53Speaker 04

  So, we struggled with this. We had this idea, we pursued it in 2015, and we never saw this phase separation directly in the simulation. And the reason we now think was because we couldn't simulate enough atoms. So that we only had 100 atoms, but then machine learning methods came along, and I could simulate 500, and 500 atoms ironically turned out to be enough that the system would actually phase separate in two separate layers.

• 22:23Ira Flatow?

  Wow. Now, I know that some researchers have theorized that these planets might have other weird things like raining diamonds.

• 22:33Speaker 04

  Oh, yes. Oh, yes. I know Marvin Ross. We overlapped in Livermore. He was a good colleague of mine. That happens. But the question is whether it sort of happens at high pressure. There are lab experiments that showed us. The question is whether this is actually happening in Uranus and Neptune. And the simulation I've done is diamond would not rain out because it's too hot.

• 22:59Speaker 04

  So at least that's what we differ from the older theories. Yes.

• 23:03Ira Flatow?

  I get it. Now, of course, the only way to test this would be what? To send another probe out there?

• 23:08Speaker 04

  Well, there are two things. So first of all, I talked to my colleagues at the Center for Meta-AtOMIC Pressures, and they do lab experiments. They should just take these materials, shock it with a laser to reach these extreme conditions and see if they see the phase separation. That's a good test. And then the other test is actually to fly a spacecraft. And they will probably measure all sorts of things. And NASA is in the process of preparing a Uranus orbiter and probe mission. And I'm just advocating you should bring the right instruments to detect such a novel two-layer structure on the mantle. That's what we're advocating for.

• 23:45Ira Flatow?

  Ah, what instrument would that be?

• 23:47Speaker 04

  So it would be something that measures the oscillations of a planet.

• 23:53Speaker 04

  So it's been done for the earth. We call this free oscillations or normal modes that oscillate. That's you do this like with seismology. And it's done for the sun. You just look at the sun. It gets packed these vibrations. And now we wanna do this for Uranus and Neptune. And if the vibrations have the right frequency, then we can tell. So the frequency is a little bit like you're listening to a bell. Um, that you can tell, and that helps you understand what the bell is made of, for example.

• 24:22Ira Flatow?

  It's like when we detect earthquakes, we look for traveling through the earth, the right, the waves going through.

• 24:28Speaker 04

  Yes, so that our seismology colleagues, they do two things. When they wanna understand the earth, they look for earthquake waves that travel through the earth and some travel to the mantle and some to go to core. And you know how they travel, it tells us what's in the interior. But that is a different type of wave. And the earth is sort of vibrating but on its own without a triggering earthquake. And these are these free oscillations. And my seismology colleagues use both of those data sets to understand here.

• 25:00Ira Flatow?

  Dr. Militzer, I'm gonna give you my blank check question. If you had a blank check, you had all the money you needed. Would you wanna actually not land, but send the, let's say, a diver probe, a submarine, something like that into these planets?

• 25:15Speaker 04

  Well, yes. So but you have to look back what you did with other probes. So if you have a solid surface, then you can actually land on these things. On Uranus and Neptune, most likely, they don't have a solid surface. And you end up in this situation like with the Galileo probe that was dumped into Jupiter. And it had no mechanism to slow down. So it was flying in there. It was getting hot very quickly and it sort of got too hot at the modest pressures of twenty two bars. So basically, most likely, we'll have another, there is an entry probe. It will measure something maybe to a hundred bars. But if you have any way to slow it down, then you could make cool measurements.

• 25:57Speaker 04

  But the moment this the way it's going is probably there's no way to slow it down and therefore it will just die if it enters the atmosphere.

• 26:05Ira Flatow?

  Wow. Well, how soon do we think this probe might get out there?

• 26:10Speaker 04

  Well, that's a sad story, actually.

• 26:12Ira Flatow?

  Oh, no.

• 26:14Speaker 04

  Because if NASA is really fast and gets everything together and Congress provides all the money we need, we might get there by 2050 and get measurements. And if I think about where I will be at 2050, I will most likely be retired. So I'm helping getting this off the ground, but I will not be the person who does the analysis for sure.

• 26:38Ira Flatow?

  You and me both, Dr. Militzer.

• 26:40Speaker 04

  I guess so, yes.

• 26:41Ira Flatow?

  We'll meet back here. Thank you for -- this sounds fascinating. Thanks for taking time to talk with us today.

• 26:46Speaker 04

  Thank you so much.

• 26:48Ira Flatow?

  Berkhard Militzer is a professor of Earth and planetary sciences at UC Berkeley.

• 26:57Ira Flatow?

  That's about all the time we have for now. A lot of people helped make this show happen. Jordan Smudjic. Rasha Ureidi.

• 27:05Speaker 06

  Charles Bergquist. Shishana Buxbaum.

• 27:08Ira Flatow?

  I'm Ira Flatow. Thanks for listening.