Welcome to Chasing Life. If you've ever gone to the doctor to talk about pain, then you've probably had to go through some typical dance of giving that pain a score, from 1 to 10. Maybe you were shown a scale of smiley faces to sad faces, and maybe you also thought at that time, this is a little crazy. This is the best we can do to measure pain, with basically emojis. When a man named Ed Mowery stepped into Dr. Prasad Shirvalkar's office in 2021, he had undoubtedly answered that question hundreds of times. I'm not exaggerating. He was 51 years old and had been suffering from complex regional pain syndrome, chronic pain, since he was 15. He described it as a sharp stabbing burning over his entire body and he had no clear explanation why.

When I first met Ed, he was in dire straits. He had had 25 surgeries. He was unable to work. He essentially was living in New Mexico with a dream, a dream that he's held for 20 years of producing an album. He's a prolific musician, but it was the pain and everything that came along with the pain that really stood in the way of him meeting his dream.

Ed came to Dr. Shirvalkar because he's a specialist in pain medicine at the University of California, San Francisco, but also because he is one of the world's leading researchers in developing something that is really revolutionary. He's basically using deep brain stimulation therapies for really hard to treat pain disorders. It's a lot. It's brain surgery, but the idea is that if we can locate where an individual's brain is interpreting or generating the pain. Then perhaps that pain could be evaluated and even treated using personalized therapies and electrodes to stimulate that exact area. It's not easy. Pin pointing that particular spot in the brain is truly like finding a needle in a haystack.

The whole team were in there for 8 to 10 hours every day, you know, for 10 days, and we didn't find anything day after day, and I think it was day five or six that we had a kind of eureka moment when all of a sudden Ed says, my pain just washed off of me. I didn't know what to say. I could not understand how this could happen in a flash.

'What I can only imagine felt like the culmination of a decades-long battle for Ed also turned out to be a real turning point for Dr. Shirvalkar. His work, it seemed, was not a fool's errand. So I wanted to hear all about it. I invited Dr. Shirvalkar on the show today to talk about his research, the questions being, are we really close to finding a biomarker for pain? In other words, an objective, observable measurement. Think of it like blood pressure or cholesterol, so that we don't need to rely on smiley faces anymore. Is that where we're headed? And at the same time, could deep brain stimulation therapies work in tandem with existing pain modalities? It's a fascinating conversation. It's about the future and it's about something that affects 50 million people at least in the United States alone. I'm Dr. Sanjay Gupta, CNN's chief medical correspondent, and this is Chasing Life.

The FDA typically approves 40 to 50 new drugs a year on average for all sorts of different things. But in the last quarter century, not a single new drug for pain until this spring. Is there just not interest in this? Is it purely the complexity of it or what do you think is driving that?

'You know I think one of the big challenges is how do we develop a pain therapy that's not addictive, that doesn't have side effects that are going to harm people. For so long, I think there's been a bit of a monopoly from the opiate manufacturers on marketing and pain as well as distributing materials to physicians, where that was the kind of go-to. You go for the oxycodone or you go for the Norco. And I think people are making a lot of money with that approach, and so the money wasn't flowing elsewhere, and I think that was one policy obstacle.

It sort of sucked all the oxygen up in the room.

That's a good way to put it.

'Let's just, you know, when people think about pain, there's all sorts of different potential tools. They think about over the counter medications, going to the doctor for injections. Can you just sort of- you take care of pain patients. How do you sort of approach somebody who comes to you with pain in terms of diagnosing it, measuring it, and then treating it? So let's start with diagnosis.

The diagnosis for pain is mostly clinical, which means, you know, we talk to the patient, try to understand the symptoms that they're experiencing when they started, how they progressed, physical exam, you're trying to understand what is the pain generator? Are the nerves in your skin or peripheral nerves creating the pain? If the pain has been around long enough, it starts to change your spinal cord and change your brain to try to understand is this coming from the brain or the spinal cord. When we diagnose certain pain disorders, it's really using guidelines and criteria to try to understand what box people might fit in or certain syndromes might fit it. Of course, we still call a lot of diagnoses syndroms, which means it's a collection of symptoms and signs that we don't fully understand. But we diagnose them based on what fits together. Of course, just because we observe that certain symptoms fit together. It doesn't mean we understand why they occur. So it doesn't immediately tell you how to treat it. And so it can be really challenging to diagnose pain. And often people will go for years without an accurate diagnosis. And for so long, chronic pain was thought as to be a symptom of some other disease. We're now recognizing that chronic pain is truly a disease and it's all right.

So, you got a sense of how to diagnose then someone's pain. You figure out what's generating the pain, you ask them about their symptoms, objectifying the pain now, measuring it. How do you do that with a patient?

'For the longest time, pain was called the fifth vital sign, right? But unlike the other four vital signs, there's no objective measure. It's not like temperature or heart rate. So one of the holy grails of pain medicine has been coming up with a biomarker for measuring how intense or how severe somebody's pain is. And so we know that there's a lot of activity in the brain that seems to correlate or seems to even predict in healthy folks, you know, how hot something might be or in experimental tasks, for example, in fMRI, for the last 50 years, people have been trying to come up with a signature to predict how intense someone is experiencing pain. What we were able to do in my lab using wires implanted in the brain is actually identify not only experimental pain, but to try to understand how can we filter the brain signals. To come up with an objective measure or a biomarker for how severe someone's chronic pain, real-world pain is. And can we do that now? We are beginning to scratch the surface on that now. And I'd say, you know, in five to 10 years, this kind of growth is usually exponential. I'm hoping to see some kind of personalized marker that might at least help us get a handle on what category someone's in, whether they're low pain or high pain, and especially useful in the hospital. If someone can't communicate, you know, or if someone has dementia, for example, it's very hard often to know. And so a tool like this could be helpful, of course, for that population. But really, hopefully it'll help us understand how each person experiences pain uniquely so that we could treat their pain better.

Are there pain centers in the brain that you can measure?

Right. So, of the amazing things in the brains, there's no single pain center in the brain. Which is a real problem if you want to understand pain, and moreover, if you wanna stimulate an area of the brain to treat pain. And so pain seems to be represented really like a network, like a mesh distributed across the brain. That's how we often see it with the MRI or functional MRI studies. In reality, this network has a certain structure that we're only beginning to understand. And I kind of describe it like the weather system. You know, weather's extremely complicated. Meteorological science can now predict when it's gonna rain tomorrow, you know? What if we could predict when someone is gonna have a severe pain flare or pain crisis tomorrow? It's actually a lot of the same tools and modeling kind of techniques with machine learning that are derived from physics, meteorology, even astronomy that we're applying to brain.

We're going to talk a lot more about the stimulators and measuring that, but basically it sounds like what you're saying, if you have these probes that are in the brain, they can sort of listen in to what's happening, maybe figure out if a pain crisis or a pain event is coming before the person might even recognize it themselves.

'Exactly. And we know that there's only a limited part of what our brain does that actually reaches our awareness, right, or our consciousness. And so the hope is, if we can identify or pinpoint these signals, right? Before they actually become a problem or bother somebody that we could short-circuit them and try to treat pain that way. And so of all the tools in pain medicine, you know, that are available, we have medications, you know? We have physical therapy. Acupuncture and other conservative measures are super important. That's where you start. We have injections and nerve blocks that can help for a limited amount of time. And then there's this whole relatively new area of neuromodulation. It involves electrical stimulation of the spinal cord, of the brain, of a peripheral nervous system to try to actually reprogram what the nerves are doing.

'You do some pretty cool stuff, I gotta say. It's gotta be very gratifying to work in this area. Such a huge need in cutting edge science. Let me go somewhere decidedly low tech though, for a second, just in terms of you being a clinician. Someone comes in with pain, and whatever it might be, you want to treat them. Like making simple decisions, like using an anti-inflammatory, like ibuprofen versus Tylenol. How do you think about these things?

You know, when we're trying to figure out what medication to recommend to a patient, first I think about, okay, what category or what type of pain are they experiencing? Generally, we divide pain into at least three different categories. One of them is myofascial or muscular pain, which means, you know, it could be due to knots in the muscle or spastic muscles as a result of posture or even arthritis, which brings you, you now, the second type of pain is inflammation or arthritis related pain, which is by and large the most common type of pain in the world. And then, you know, we have this third category we call neuropathic pain, nerve pain. It's electric, it's tingly. So first I try to understand which one of these categories do I think is primarily playing a role. And then based on that as the patient, you know, essentially go through some medication options, you know, as well as kind of relying on a wealth of, of evidence from the literature really. And the state of the art right now for picking a medication for an individual patient is trial and error. So I'll, you now, I'll say, here are three drugs. You know, I've recommended this one cause it might have the best side effect profile for your nerve pain. And then they'll try it. And if they have bad symptoms and, you know, tell them to stop. And then we move on to the next one. But one of the key lessons I learned is, you know, we'll often use medications, and doctors and patients will give up on a drug because it doesn't work early on. But really, starting low, going slow, and being patient, increasing that drug very, very slowly is so critical. And so I really try to, I guess, communicate that patience, but also instill a sense of hope because it is trying to be your own guinea pig. And that's essentially what we're doing right now in pain medicine.

'There's all sorts of injuries that people probably would never come see you for. I mean, they just take care of it at home, sprained ankle, whatever it might be. In those situations, it seems like the mantra has been to tamp down the inflammation as much as possible in the beginning, taking anti-inflammatory medications, ibuprofen, things like that. Do you, do you think that's a good strategy or do we overdo that?

'Inflammation is not always a bad thing. Sometimes there's good inflammation, right? When we have an infection, we want to be able to fight that infection so that inflammation can actually help. There's some evidence or some reason to believe that overdoing anti-inflammatories or overdoing the, you know, suppressing the body's own natural healing process might actually make people more prone to chronic pain in the future. And so I think it's a really important question to ask and investigate. But fundamentally, you know, it's still a mystery. I think certainly the way that we treat something early on almost definitely influences the kind of trajectory. In neurology, we have this concept of medication overuse headache. People often have headaches, migraines are very common. They'll take a medication, right, and then they get used to taking that medication. And all of a sudden, you can develop a secondary headache from overusing a medication. And that can be really hard too.

You know, it's interesting that you've probably seen some of these studies, but this idea of predicting who's most likely to have chronic pain, there was some correlation with the lowest levels of inflammation at the time of injury. So people who had very low levels of inflammation, even though they may have had less acute pain, were more likely to have chronic pain. Which I thought was really interesting.

That is fascinating, right? What that tells me is that there's something genetic or hardwired that predisposes some folks to developing chronic pain. And understanding what that is is gonna be one of the big challenges in the next 10 years. It's almost certainly involves kind of genetics, our immune system, our microbiome in our gut, involves our upbringing, our history of trauma, all of this comes to bear. Because pain, it's not just an unpleasant sensation, right? It actually impacts the emotion. It impacts the way that we think. It impacts our relationships with family members. There's all these elements that bleed into almost every aspect of being human, which makes it so challenging to treat.

After the break, Dr. Shirvalkar breaks down the basics and the potential of this cutting edge research.

So tell me how you got interested in this idea of looking at implants in the brain to try and measure pain. Where did this come from?

'Believe it or not, deep brain stimulation or electrical stimulation of human brains was first studied for chronic pain in 1960. How it came about was there are a lot of people out there with either nerve pain or arthritis-related pain or pain, frankly, that comes from the brain after a stroke or even from Parkinson's disease. There are people out there that have been failed by all available therapies. They've tried over 25 different medications. They have had multiple injections and nerve blocks. They've even had spinal cord stimulators or peripheral stimulators and nothing can alleviate their suffering. So really how it came about was understanding or appreciating that the brain must be generating or perpetuating these pain signals in this person. After you appreciate that, the question then becomes, how can we identify what these signals are and really try to suppress them or short-circuit them?

If you were to look at some of the data from these deep brain stimulators, could you tell if someone was like if you knew nothing else about the patient and you're just looking at the brain, could you tell that this is a brain in pain?

'Right now, I would say we have computational models that can tell if a specific person was in a high pain state or a low pain state. We're talking about chronic pain, if someone's suffering from low back pain or even fibromyalgia. What needs to be done is to develop a model that generalizes to hundreds and thousands of people. We can't do that on a large scale yet, but hopefully we can develop new tools that will generalize to folks without having to insert probes in their brain, right, to do it in a non-invasive way.

In 2023, you write a paper. What was the conclusion? What were you trying to convey?

2023, we published this report that was the first in human description of an objective brain biomarker that tracked how severe chronic pain was in four individuals. You know, we have the clinical understanding and intuition. Chronic pain is not just a more enduring version of acute pain. You now, when you stub your toe, it's not like if that lasts for four months, it feels like what it is to have chronic foot pain, but, you know, it's never convincingly been scientifically shown or studied before. So we performed experiments to understand, okay, how's chronic pain represented in the brain? How's acute pain represented? And are those two overlapping or how are those too similar? And we found that there's actually quite distinct brain signatures for acute pain and chronic pain when we can predict the severity. So it provided kind of a proof of concept for, you know, everyday intuition.

What's the significance of that for you or for someone who's trying to treat it?

You know, it tells me that when someone has developed chronic pain, treating it with a single drug or an injection or some monotherapy probably isn't going to work. So when pain becomes chronic it starts to take on these other dimensions that include mood and motivation and involve attention and memory. And so when pain is chronic we have to address the cognitive aspect of it. We have to dress people's thinking patterns, make sure that they're eating well, exercising as much as possible, right? But that's a critical component for chronic pain of recovery. We have to make sure that they're not depressed, or if you have depression, that it's treated, because that will prevent you from recovering from chronic pain. And so it really requires that kind of a multimodal approach.

You know, it's really interesting. One of your colleagues in pain research said something to me, that chronic pain never occurs in isolation. It always comes with baggage attached, depression, anxiety. Is that your experience as well then?

Absolutely, and we know that having baggage may predispose you to chronic pain, but chronic pain it's like the unwelcome relative brings their own baggage. We know from a lot of literature, having a traumatic experience in your childhood, whether it's sexual abuse or whether it some kind of physical trauma can really increase the chance of having chronic pain later in life. And so it's possible, we try to make sense out of it, but it's possibly that the pain is arising to alert somebody of, you know, hey, this trauma is still there. You know, it's unaddressed, it is untreated. It may be as simple as that pain is a signal that our brain is screaming out to us trying to ask for help.

I guess, Prasad, what is interesting to me is the conversation we're having, I feel, is still an unusual conversation in medicine. The idea that, hey, look, psychological trauma from your childhood could be driving physical symptoms in your adulthood. A lot of people still get very squishy about this. They think it's too vague, too hard to describe. Patients think it's all in their head. Do you think we're getting better about that? Or are you a bit unusual in terms of how you think about it?

I would say I am unusual in that I'm a neurologist who's interested in pain. Western medicine, or our medical system, operates with all these kind of independent silos, where folks really are experts in what they do. But it's rare often to have a multidisciplinary approach where psychiatrists come together with neurologists, come together with anesthesiologists. Pain is most often in the hospital, in the Department of Anesthesiology, and it's been kind of historical. Even though the first pain center in this country was I believe started by a neurologist. And so I think I'm unusual in the sense that I'm interested in understanding how all of these disciplines kind of play in together. But I will tell you, there's a huge effort by a lot of really hardworking psychiatrists to develop a new biological psychiatry of the brain, to understand the circuit underpinning how did different electrical activity in the brain give rise to different psychiatric symptoms. And I think, one, hopefully that will help us to understand it better so we can treat diseases better. But two, really to destigmatize these diseases, to say, hey, this is the biomarker. This is a pattern that we're observing. And I can show it to you here on the screen. And I, I think that'll go a long way.

'It seems like a really worthy goal, but an audacious one at that. The idea that ultimately, by looking inside your brain, non-invasively or invasively, the idea that by looking in your brain you might be able to tell the quality and the amount or quantity of someone's pain, that's an extraordinary sort of idea.

Yeah, it sounds a bit like mind reading, right? Which is a scary thought. And, you know, I should say, there's a downside to this idea, right. If we can discover brain activity patterns that tell us about someone's thoughts or what they're feeling, we have to, I think, have some humility and acknowledge this is never gonna be the end all be all. You know, at the end of the day, the ground truth is what the person tells you, you know. And these biomarkers should never be used to undermine or distrust patients, you know. On the contrary, right, I think they can actually be used as a validation when there's no other evidence. You know, the MRIs are normal, you now, and your blood tests are normal. There's no other evidence that they're in pain. Finding a biomarker, I think, can go a long way to actually bring in closure to someone's experience and saying, hey, you, know, there's evidence, here it is. There's this really silly moment in the movie Contact, you know, where, who is it? I think Jodie Foster, you know? It's like out in outer space, or she's traveling between dimensions, and she looks out into the space. She's, you now, very accomplished scientist in the movie, astronaut, and she says, you they should have sent a poet, you know. The point is, there's attributes to being human that you can't put on paper. And so at the end of the day, even for understanding pain, understanding what an individual is going through, taking them at their word is the most important thing.

'You know, I gotta tell ya, I've been a journalist for a long time, and this was a conversation that really impacted me. Partly because of the remarkable science. I mean, think about it, a human brain has about 86 billion neurons. But somehow, researchers like Shirvalkar have been able to make sense of them in some way, enough so that we may be able to soon anticipate and even interrupt someone's chronic pain. But I think what really stayed with me was Dr. Shirvalkar's entire approach, because I think he's got this right. The point of developing these amazing technologies isn't to cast doubt on the patient. Patients like Ed, the 51-year-old musician who had lifelong pain that we met at the top of the episode. A patient's lived experience should always be the North Star no matter what the deep brain stimulators are telling you. But the technology can help. It can help point physicians in the right direction and hopefully provide better care. It is the future that people have been hoping for when it comes to chronic pain for a long time. And if you've enjoyed this conversation, consider checking out my new book. I write all about this because I found it so fascinating. The book is called It Doesn't Have to Hurt: Your Smart Guide to a Pain-Free Life. Thanks for listening.