The Daily - The Sunday Read: ‘Chronic Pain Is a Hidden Epidemic. It’s Time for a Revolution.’

Episode Date: February 2, 2025

Here’s a strange story: One day two summers ago, Jennifer Khan woke up because her arms, — both of them — hurt. Not the way they do when you’ve slept in a funny position, but as if the tendons in her forearms and hands were moving through mud. What felt like sharp electric shocks kept sparking in her fingers and sometimes up the inside of her biceps and across her chest. Holding anything was excruciating: a cup, a toothbrush, her phone. Even doing nothing was miserable. It hurt when she sat with her hands in her lap, when she stood, when she lay flat on the bed or on her side. The slightest pressure — a bedsheet, a watch band, a bra strap — was intolerable.Our understanding of pain, and especially chronic pain, is far behind where it should be. We don’t know what causes a person with an injury to develop chronic pain, or why it happens in some people and not others, or why it happens more often in women. At a genetic and cellular level, we don’t know which systems get out of whack, or why, or how to fix them. Unlock full access to New York Times podcasts and explore everything from politics to pop culture. Subscribe today at nytimes.com/podcasts or on Apple Podcasts and Spotify.

I used to think of pain as something that you got over. I did a lot of sports for most of my life, and so I've sprained my ankle pretty badly. I dislocated a shoulder, broke my hand. Sometimes it hurt for weeks or for months. But, you know, I would take some Advil or do some physical therapy and eventually the pain would go away until one day a couple of years ago it didn't. My name is Jennifer Kahn and I am a contributing writer for the New York Times Magazine. I write about the complex ways that

science and new technologies affect people. In the past, those stories weren't personal. This time was a little different. I was shocked to learn that until recently, it had been more than 20 years since a new pain drug was approved, at least one that was not an opioid. And I learned this because I developed chronic pain myself. Once I did, I realized there are so many people out there who are in the same position.

And for those people, pain is with them all the time. And it makes it difficult to do almost anything, to work, to exercise, to see your friends, even just to enjoy life. And learning that sent me on a reporting journey that you'll hear about in this week's Sunday read. As many as one in three Americans have chronic pain or have dealt with it at some point in their lives, but there are still only a handful of treatment options available. There are opioids, there are anti-inflammatories, certain drugs for nerve pain maybe, but not

all of them work well. And because there's no way for even an expert to see pain, it's not always taken seriously. Even doctors might say to you, well, maybe it's all in your head, or honestly, it's probably not that bad, right? In my case, for instance, I can feel electric sparks in my hands all the time, but it's impossible for a medical professional to detect them. All they can do is ask how I feel on a scale of one to ten, but you know, what does that mean relative to anybody else? So I started reaching out to experts because I wanted to know how we got here, and the more people I talked to, the more

I learned that while there's still no silver bullet, there actually is a revolution developing in chronic pain research right now. What we're seeing in medicine is this combination of actually trying to understand the deep root causes of pain and realizing that treatments need to be more targeted and more precise and more effective. Scientists are also starting to see chronic pain as a disease in its own right, a disease of the nervous system, where it used to be just a black box. I spoke with Alan Bassbaum, who oversees a pain research lab at the University of California, San Francisco, and he likened this moment to the breakthroughs we saw in cancer research

20 years ago. Doctors used to treat cancer based on where a tumor was located, like in the liver or the stomach, but once they were able to study tumors at a cellular level, they realized they needed to change their entire approach to treatment. That's the revolution we're seeing in chronic pain right now. We're understanding it at a cellular and molecular level to treat it more effectively. And the experts I talked to told me that they think we're actually going to see a lot of new treatments, even within the next five years, which is a stunning timeline for coming up with new drugs. So here's my story, read by Kirsten Potter.

Our audio producer today is Adrienne Hurst. The original music you'll hear was written and performed by Erin Esposito. Here's a strange story. One day, two summers ago, I woke up because my arms, both of them, hurt. Not the way they do when you've slept in a funny position, but as if the tendons in my forearms and hands were moving through mud.

What felt like sharp electric shocks kept sparking in my fingers and sometimes up the inside of my biceps and across my chest. Holding anything was excruciating, A cup, a toothbrush, my phone. Even doing nothing was miserable. It hurt when I sat with my hands in my lap, when I stood, when I lay flat on the bed or on my side. The slightest pressure, a bed sheet, a watch band, a bra strap was intolerable.

It was August, and every doctor seemed to be away on vacation. The ones I did manage to see were politely stumped. It wasn't carpal tunnel, tennis elbow, or any other injury they could identify. I did nothing unusual the day before, an hour of work on my laptop followed by a visit with a friend. We sat in her backyard and talked. For the first few weeks, I could barely sleep. Over the following months, I lost weight, almost a pound a week.

I couldn't drive or cook or use my laptop for work or even hold a book or a pen. I would have been bored, except the pain was so tiring that I could barely function. I spent the days shuffling around the house listening to audiobooks and doing voice to text searches for nerve pain, arms, with my phone flat on the table, then carefully, painfully scrolling through the results. I think we're past the point where I have to explain that chronic pain is not

the result of imbalanced humors or a wandering uterus or possession by demons. But for more modern skeptics, this is where I should add that chronic pain also isn't just all in your head or not really that bad or any of the other ways in which people who suffer from it are still regularly gaslit and dismissed. Personally, I never had to contend with not being believed. Almost certainly, because I'm an otherwise healthy, reasonably well-off white woman with a clean medical history and no significant record of anxiety or depression.

Instead, I was taken seriously. A whole gamut of tests was run. My wrists were x-rayed, I had an MRI on my cervical spine. Each new doctor ordered new blood tests, some for vitamin deficiencies, others for autoimmune diseases like rheumatoid arthritis. But when none of those tests could point to an obvious cause, I fell into the mystery bucket. Not the fascinating, fun kind of mystery that gets solved by a medical savant.

This was the other kind, in which you are punted from doctor to doctor until you run out of specialists, who, this being real life, are far too over-scheduled to fixate on one patient's oddball symptoms. Even if they had, it's not clear that they could have done much.

The options for treating pain are limited, and almost all have drawbacks. Many medications cause fatigue or nausea. A weird number cause constipation. When I started taking gabapentin, an anti-seizure drug that reduces the signal from the brain to the peripheral nerves, I became forgetful and started confusing words, saying Phoenix for pheasant or blue for green. That would have been fine if the medication actually worked. Instead, it just made things slightly less awful.

So like many people with chronic pain, I started trying things on my own. I went to a physical therapist, a chiropractor, and two different acupuncturists. I tried Feldenkrais and something called nerve flossing, a set of funky gliding arm movements, which helped a bit. When an appointment finally opened up at my local medical center's pain clinic six months later, the doctor there told me that this kind of unexplained nerve pain just

happens sometimes, and that it might get better in months or years or never. That was just how it went. And no one knew why. For a long time, I assumed that what happened to me was just bad luck. Everyone else seemed so hearty, going for jogs, typing away for hours in cafes. But what I discovered over the next year was that chronic pain is everywhere.

There was the colleague who developed an autoimmune-like disease after being bitten by a virus-carrying mosquito. A friend, John, who had a bad reaction to an antibiotic and ended up with disabling full-body nerve pain that lasted for years. A former student who dislocated her shoulder in a crash and now has chronic neck pain and tension headaches. Another friend's cousin who developed terrible pain after abdominal surgery, pain that left him incapacitated

for months until, bizarrely, another unrelated surgery caused it to disappear. I didn't know any of this before my own mystery ailment began because chronic pain, like chronic illness, is mostly invisible. My friend John told almost no one during the years he was disabled, in part because he didn't want to be defined by his condition. My colleague admitted that many of her coworkers would be surprised to learn the years he was disabled, in part because he didn't want to be defined by his condition. My colleague admitted that many of her co-workers would be surprised to learn that she had been working in pain for years.

Altogether, according to a 2011 Institute of Medicine report, roughly 100 million Americans — almost one-third of the U.S. population — have chronic pain, more than have diabetes, heart disease, and cancer combined. Globally, some studies put the number at 2 billion. The National Institutes of Health Despite this, the study of pain has long been neglected. The National Institutes of Health has no center devoted to pain, and for decades, pain research received only a fraction of the funding that went to the study of illnesses like heart disease

and diabetes. One reason for this, paradoxically, is that pain is a part of so many different conditions. It touches on cancer. It touches on neurodegeneration. It touches on diabetes. It touches on biomechanics and injury. It touches on neurodegeneration, it touches on diabetes, it touches on biomechanics and injury, it touches on mental health," says Robert Gereau, who directs the Washington University Pain Center in St. Louis. Because it's everywhere, it's sort of nowhere.

As a result, our understanding of pain, and especially chronic pain, is far behind where it should be. We don't know what causes a person with an injury to develop chronic pain, is far behind where it should be. We don't know what causes a person with an injury to develop chronic pain, or why it happens in some people and not others, or why it happens more often in women. At a genetic and cellular level, we don't know which systems get out of whack, or why, or how to fix them. It took the opioid epidemic to make government agencies

finally recognize the scale of the problem, and the fact that millions of people with chronic pain had frighteningly few options. Until recently, it had been two decades since a new drug, one that wasn't an opioid, was approved for treating pain. The aftermath of the epidemic caused other problems. Doctors increasingly suspected pain patients of feigning symptoms to get drugs,

leaving some people with chronic conditions scrambling for effective treatments. And the lack of alternatives escalated a longstanding sense of frustration and despair. The truth is that we've failed people in pain, one clinician admitted. If we had invested in understanding this years ago, we might have been able to prevent a lot of suffering.

Now that may finally be changing. In 2018, the National Institutes of Health started the $3.9 billion HEAL initiative, a major effort focused on addressing the opioid crisis and figuring out the underlying mechanisms of pain in order to develop more precise, sophisticated, and personalized treatments. Alan Bassbaum, who oversees a pain research lab at the University of California, San Francisco, made an analogy to recent breakthroughs in cancer research. For decades, cancer treatment focused on where a tumor was located.

Liver, stomach, lung. But when researchers were finally able to study those tumors at a genetic and cellular level, that insight led to far more targeted and individualized treatments, including the immunotherapies that recently won a Nobel Prize. Pain research today is where cancer research was 20 years ago. including the immunotherapies that recently won a Nobel Prize. Pain research today is where cancer research was 20 years ago, Bassbaum told me.

The good news is that we're able to move so much faster now. Scientists are already closing in on one biological mechanism with the potential to significantly lessen pain, and a number of other approaches are being explored. But the real revolution may be a new understanding of pain's complexity, an illumination of its hidden workings. One big reason chronic pain has been undertreated and shrugged off for decades is that medicine tends to trivialize conditions it lacks the tools to explain. The chronic pain revolution we need is one that won't end until we really

understand why millions of people are suffering and how to offer them meaningful relief. Chronic pain has traditionally been seen as a symptom. We die in pain, we don't die of pain. Now researchers are recognizing that chronic pain can be a disease in its own right, a disorder that happens when the nerves in our body, either peripheral ones, like those in our limbs, or central ones, like those running from our spinal cord to our brain,

become hyperactive or sensitized. This can happen for a host of reasons. Roughly one in seven people who have surgery to fix a hernia will develop chronic pain, and millions of people have hernia surgery every year. The risk for breast surgeries, including mastectomy, is even higher, between 40 and 60%. And the pain is frequently severe,

an average of eight on a 10-point scale, or roughly the same as patients who have had a limb amputated. Some of those people recover, or manage to get by, but others become so incapacitated that they can't work, and sometimes can barely function. People over a certain age, or who have diabetes or cancer, will often develop neuropathies, damaged nerves that cause constant burning and numbness. And then there are the car accidents, sports injuries, and other kinds of damage, injuries that people generally recover from. Except when they don't.

Mikkel Kuratalo, a clinician and researcher at the University of Washington Pain Management Center, describes seeing people whose lives have been utterly and unexpectedly derailed. I have patients, even very young patients, with headache who can't bear any kind of light, Corradolo says. They're always in the dark. They have a migraine 24-7. Another patient, in her 30s, was in such pain that she couldn't get out of bed without help, but no one could figure out why. For these patients, Karadolo says,

if they come to me, they can get maybe 20% or 30% relief, which is important, but they also don't have their life back in any way. The causes of these problems have long been mysterious. For years, researchers were baffled by the fact that some people with relatively mild tissue damage would experience terrible pain, while others with severe damage would feel mostly fine. This was true regardless of whether the injury was an endometrial lesion, whiplash, or osteoarthritis. No one understood how this could be true, Vaspalm says.

It just didn't make sense. Ordinarily, when a person is injured, the body releases a flood of chemicals that spur healing processes, like inflammation. Those same chemicals also activate our nociceptors, or pain fibers, a set of peripheral nerve endings that alert the brain to tissue damage and that exist in our skin, muscles, stomach, and even internal organs. Typically, that process lasts just while an injury is healing, but in some cases, those pain signals keep firing, driven by what researchers now think is a complex set of genetic, endocrinological,

and immunologic processes. The discovery that the pain signaling chain itself could become faulty was a crucial shift. Nociceptors are essentially bundles of sensors attached to long, thin nerves that run all the way up to the brain, which in turn send signals back down to the site of injury. Along the way, pain signals pass through gates, neurological filters located in the spinal cord that release chemicals to either amplify a pain signal or turn it down. It's now thought that chronic pain can be caused by problems at any point along the chain. In some cases, the problem might be the nociceptor itself, triggered by inflammation, as happens with autoimmune diseases

like rheumatoid arthritis and lupus. In others, the problem might be hyperactivity in the spinal cord, the brain, or both. In still other cases, the cause is unclear. Fibromyalgia and irritable bowel syndrome, which is considered a chronic pain condition, are both driven by overactive signaling, either by the central nervous system or by the nociceptors in our muscles or gut. But it's not clear how or why the switch for that hyperactivity gets flipped.

One of the big insights of the past decade is that chronic pain is a disorder of the central nervous system, Giraud told me. It has been a huge change in how we understand these conditions. Before we were basically just mystified by persistent pain. Part of why it took so long to grasp this is that there's no easy way to see someone's pain or to measure it, other than asking a person to rate their pain on a scale from 1 to 10. While it's possible to put electrodes into the spinal cords of mice to record nerve activity, or probes into the brains of macaque monkeys to observe how neurons fire in response to pain, there's

no ethical way to do the same thing in people. And while MRI and fMRI scans can show changes in the brains of people with chronic pain, those scans are too expensive and cumbersome to work as symptom trackers. With other diseases, you can measure the size of a tumor or see how much a person's cortex has shrunk from Alzheimer's, Gereau told me. There's not something measurable like that for pain. From a research perspective, that's been a real hurdle. To overcome that, one main project funded by HEAL is focused on studying the nervous systems of people with chronic pain more directly.

In part, by recovering malfunctioning dorsal root ganglia and trigeminal nerves from patients undergoing surgery for chronic pain, as well as from cadaveric donors. Those samples are then cultured and examined using a bevy of new technologies, things like proteomics, spatial transcriptomics, and metabolomics, to see how they differ from normal tissue. The goal, Gero explained, is to identify what changes happen at a cellular level when

pain becomes chronic, and to create an atlas of those mechanisms and variations. Understanding that, he added, would ultimately open the door to precision medicine, in which drugs could be designed to target those changes specifically, rather than simply blunting the pain with anti-inflammatories or opioids. In the beginning, everyone thought they were going to find this one breakthrough pain drug that would replace opioids, Giraud said. Increasingly, though, it's looking like chronic pain, like cancer, could end up having a range of genetic and cellular drivers that vary both by condition and by the particular makeup of the person experiencing it.

What we're learning is that pain is not just one thing, Jereau added. It's a thousand different things. All called pain. For patients, too, the landscape of chronic pain is wildly varied. Some people endure a miserable year of low back pain, only to have it vanish for no clear reason. Others aren't so lucky. A friend of a friend spent five years with extreme pain in his arms and face after rough housing with his son. He had to stop working, couldn't drive, couldn't even ride in a car without

a neck brace. His doctors prescribed endless medications, the maximum dose of gabapentin plus duloxetine and others. At one point, he admitted himself to a psychiatric ward because his pain was so bad that he'd become suicidal. There, he met other people who also became suicidal after years of living with terrible pain day in and day out. The thing that makes chronic pain so awful

is that it's chronic, a grinding distress that never ends. For those with extreme pain, that's easy to understand. But even less severe cases can be miserable. A pain rating of 3 or 4 out of 10 sounds mild, but having it almost all the time is grueling and limiting. Unlike a broken arm, which gets better, or tendonitis, which hurts mostly in response to overuse, chronic pain makes your whole world shrink. It's harder to work and to exercise, and even to do the many smaller things

that make life rewarding and rich. It's also lonely. When my arms first went crazy, I could barely function. But even after the worst had passed, I saw friends rarely. I still couldn't drive more than a few minutes or sit comfortably in a chair. And I felt guilty inviting people over when there wasn't anything to do. As Kristin Weasley, director and co-founder of the Chronic Pain Research Alliance, puts it, with acute pain, medications, if you take them,

they get you over a hump and you go on your way. What people don't realize is that when you have chronic pain, even if you're also taking meds, you rarely feel like you were before. At best, they can reduce your pain, but usually don't eliminate it. A cruel catch-22 around chronic pain is that it often leads to anxiety and depression, both of which can make pain worse. That's partly because focusing on a thing can reinforce it, but also because emotional states have physical effects. Both anxiety and depression are known to increase

inflammation, which can also worsen pain. As a result, pain management often includes cognitive behavioral therapy, meditation practice, or other coping skills. But while those tools are vital, it's notoriously hard to reprogram our reactions. Our minds and bodies have evolved both to anticipate pain and to remember it, making it hard not to worry.

And because chronic pain is so uncomfortable and isolating, it's also depressing. Bayla Travis, a pain psychologist based in the Bay Area, notes that because chronic pain has an emotional component, people may feel ashamed if they're not able to control their symptoms. With the self-help culture we have, there's this feeling like you should be able to fix it, Travis says. But the truth is that while things like cognitive behavioral therapy can help, you often won't

be able to eliminate the pain. It's still not clear why one person goes on to develop chronic pain when another doesn't. But research has increasingly shown that some people are more susceptible. Women are more likely to develop chronic pain conditions, possibly because, as Weasley noted, they're at higher risk for autoimmune disorders, and because hormonal fluctuations can aggravate pain. And once a person has one kind of chronic pain,

they're more likely to develop another. The idea, Weasley says, is that if your central nervous system isn't functioning properly, you're more likely to develop chronic pain of some kind. Migraine, temporomandibular disorders, back pain, pelvic pain. And then, because your body isn't processing pain the way it should, you're more likely

to develop other conditions. For instance, if you have chronic pain and undergo surgery for something unrelated, you're much more likely to end up with chronic pain in that other part of your body afterward. Weasley herself has had chronic pain for decades. As a teenager, she was hit by a car while biking home from camp and nearly killed. The impact broke all her ribs, fractured her leg, and collapsed her lung. She also lost a third of her liver and had severe internal bleeding. For years, just managing the resulting pain was the equivalent of a part-time job.

I was spending upward of 20 hours a week on physical therapy, chiropractor visits, exercise, heat, ice, all the stuff, Veesley told me, and it cost easily $25,000 a year out of pocket. The medications she tried were hit or miss, a common problem, because there's currently no way for doctors to know which pain drug is going to work for whom. They also had downsides. One made her mouth so dry that she was constantly drinking water. Others caused her to gain 20 pounds or to feel sedated and foggy.

Yet another made her entire body itch. Like it turned off the pain switch, but turned on the itch switch, she says. Ultimately, Veasley tried 14 different drugs before finding one that helped. I don't think people really get what goes into trying a new medication, she says. They think, what's the big deal? You just take it, and if it works, it works. If it doesn't, it doesn't. But what actually happens is that you have to start on this teensy-eensy dose, and then a week later, increase to the next dose and the next one,

and then you start to get the side effects. When it doesn't work, which is most of the time, either because the drug doesn't help or the side effects are too bad, you have to do the whole thing in reverse. So it takes forever, and in the meantime, you're in pain and trying to take care of your children and do your job and all the rest.

One day last fall, I met Jero at his lab in the anesthesiology department on the Washington University campus in St. Louis, where he directs one of four centers devoted to recovering and studying tissue samples taken from patients with chronic pain. Gereau is cheerful and funny, with a gray-blonde beard and the slightly distracted air of someone who would rather be getting back to work.

Once on a video call, he mentioned a colleague's research study, then stared silently into space. Sorry, he said, abashed. I was thinking about the study. The lab that day was packed with graduate students and post-docs working at different stations. Jereau led me to a back table where Brian Kopitz, a scientist who oversees tissue procurement, retrieved a small Ziploc bag from a tray of ice pellets. Inside was a tiny beige triangle, roughly like what you'd get if you

sliced off the very tip of your pinky. Copitz explained that it was a dorsal root ganglion, a cluster of cells that acts as a kind of switchboard, routing signals from the periphery to the central nervous system. This one had been recovered from a thoracic vertebra and is one of several responsible for managing nerve signals in the body's trunk. After gently returning it to the bag, he opened a different one and brought out a piece of a fresh-frozen spinal cord, a red-and-white streaked nugget that looked disconcertingly

like a piece of artificial crab. The ability to examine tissue recovered from patients with chronic pain is a major step forward. Until recently, researchers and pharmaceutical companies studying pain primarily used mice or other animals as human proxies, and would then invest years, often more than a decade, trying to develop a drug based on those findings. What we learned, unfortunately, is that some of the receptors we identified in mice weren't expressed at the same level or in the same place in people, Giroux said. When you go from animal to human and a drug fails, that's 20 years of work gone.

That high failure rate is why many pharmaceutical companies stopped trying to develop new pain medications more than a decade ago. So now the idea is to go the other way, to use these new technologies to identify drug targets based on changes in human tissue, Giroux said. As a first step in that process, Juliet Marighi, a postdoc in Giroux's lab, spent two months training an algorithm to identify different types of neurons and other cells in the ganglion. They bring fragments of live tissue here to the tissue culture room so

we can see how cells change their behavior in response to pain," Morigie told me. Morigie took me into a small cubby with a heavy black curtain around it and pulled up an image that looked like outer space, a blue-black cosmos dotted with cyan and pink galaxies. These are the different cells, she told me, pointing at the various colors. Sensory neurons, immune cells, Schwann cells, she told me, pointing at the various colors. Sensory neurons, immune cells, Schwann cells, those responsible for protecting and repairing nerves. The cyan ones are nociceptors.

Between the clumps of color, there were delicate gray threads that Morigui explained were axons, the long nerves that connect the neurons in the dorsal root ganglion to muscles and other tissue. A ganglion is like a bouquet of flowers, she said. The axons are the stems. Giroux and Morigui are currently studying a cannabinoid receptor known as CB1 in hopes of finding a way to harness its analgesic properties without activating the same receptors in the brain that make cannabis psychoactive. They're also finding new potential drug targets based on changes they see in the cells of chronic pain patients. These sorts of interventions have become possible, in part, because of radical advances in drug

design. Science is just different now, Gero said. Thanks to new imaging technologies and computing abilities, he explained, we can get information on the structure of receptors and how drugs attach to them on a time scale that was impossible ten years ago. Other advances are allowing researchers to rapidly gather data on the microscopic changes driving an individual patient's condition, what might be called their pain signature. That data, which could include gene and protein expression or immune phenotyping, also opens the door to tailor-made treatments.

It's really uncanny, Jereau added. Basically, it means that we're going to have a lot more detail that will allow us to move much more quickly. Roughly 20 years ago, scientists made a discovery that may well hold the key to the future of pain treatment, one that could allow them to create a kind of ozempic for pain. In 2006, a global search found that people with mutations in a particular gene

had radically different experiences of pain. Those with higher gene expression had constant burning pain. Just wearing clothes could be excruciating. People born with no expression had no pain at all, to the point where they would cheerfully walk around with broken bones or severe burns. For years, researchers and pharmaceutical companies struggled to create a drug that controlled the sodium ion channel encoded by that gene, NAV1.7. NAV channels are essential to many things in the body that run on electricity.

NAV1.5, for example, is crucial to regulating our heartbeat. NAV1.7 is striking because it seems to exist primarily in our nociceptors, where it acts as a kind of starting gate for pain signals, adjusting the permeability of cell membranes so that salts can flow through. Those salts, in turn, create an electrical current in sensory neurons that makes them more excitable. Maddeningly, none of those efforts to control NAV1.7 worked. Now, that may be shifting.

Last summer, the company Vertex Pharmaceuticals announced that it had had promising results for a painkiller, SosetraGene, which worked on a related channel, NAV 1.8. If approved, it will be one of the first non-opioid painkillers to reach patients in more than 20 years. The other so-called CGRP drugs were recently approved for migraines. Regardless of what happens with sasetrogen, most people I spoke to agreed that Vertex's NAV breakthrough would likely pave the way for more treatments. The prospect of a pill that would act as a kind of volume knob for pain is especially tantalizing because studies have shown that

interrupting the pain signaling circuit in nociceptors, say by damping down NAV1.7 or 1.8, quenches pain even in patients whose nerves have become sensitized. One thing we know drives long-term pain are these nociceptors. Notes William Renthal, whose lab at Harvard studies migraine and chronic pain. So if we can target those selectively, it gives us a lot of shots on goal, meaning therapeutics that will work on many, many, if not most people. Drugs in general work by binding to a particular receptor, sometimes with the goal of inhibiting it,

sometimes to make it speed up production of a particular molecule, which in turn triggers other processes. The problem, at least until now, is that the same receptors we target to dull pain also turn up elsewhere in our body. Opioid receptors, for instance, are everywhere, in our sensory nerve endings, but also in our gut and brain, which is why opioids block pain but also cause constipation and euphoria,

and can depress respiratory function. Even over-the-counter drugs like ibuprofen, Advil, have issues. Ibuprofen limits inflammation by inhibiting a set of enzymes known as cyclooxygenase. But doing that also inhibits production of prostaglandin, a molecule that, among other things, is involved in protecting and repairing the mucosa in our gut, which is why ibuprofen can cause peptic ulcers

and gastrointestinal bleeding. I'm a big believer in drugs, Basbaum, the UCSF scientist says. But drugs don't know where to go. To fix that, Basbaum is trying to create targeted analgesics, drugs that bind only to the nerve receptors controlling pain and not to receptors in the brain. This is a complicated problem of medicinal chemistry, Bassbaum admits, but not impossible. There's even a precedent of sorts.

Weirdly, the over-the-counter anti-diarrheal medication Imodium is an opioid, just one that binds to receptors in the gut but is kept out of the brain by guardian molecules known as transporters. Other efforts are also promising. Giraud told me about a colleague who developed a treatment, now being pursued by Eli Lilly, that may ease peripheral neuropathy by slowing degeneration in nerves. And researchers at Yale and the Veterans Administration recently found that blocking NAV 1.7 channels with carbamazepine, a drug used to treat epilepsy

and trigeminal neuralgia, could stop the joint damage and pain caused by osteoarthritis. There's also a growing awareness that chronic pain requires individualized treatment plans and ongoing support. Some medical centers have created pain clinics specifically for patients with chronic pain with resources including acupuncture and physical therapy, as well as specialized pain pharmacists, psychologists and physicians, all under one roof. For people living with chronic pain, it's almost like being in a long-term relationship.

Notes Uta Mayada, a clinical psychologist who specializes in helping people manage pain. An analogy I use with my clients is that your pain is like this destructive, obnoxious roommate that's always interfering in your daily life, But it's a roommate you cannot evict. So instead of feeling like you're battling your body every day, it's like, how do I work with this body on a daily basis and have a healthy coexistence with it? One day last fall, I drove to visit one of these new clinics, the Center for Pain Medicine at the University of California, San Francisco.

The center, which was previously located in a dingy, isolated building, now occupied part of a sunny, custom-built floor with tall windows overlooking the bay. Chris Abrecht, the medical director, led me through, pointing out procedure areas for ultrasound-guided nerve blocks, trigger point injections and other treatments, therapy offices, and even an infusion area where the psychoactive anesthetic ketamine or other drugs can be administered. Then he took me to see Julian Motzkin, a neurologist. That afternoon, Motzkin was meeting a new patient,

a soft-spoken former EMT in his 40s who had experienced chronic migraine headaches since childhood, and who had already tried an extensive list of medications and other treatments, most knew since 2020, when his symptoms abruptly became worse. As Motzkin typed notes, the man recalled that on a recent visit to another prestigious university pain clinic, the doctor opened by saying, I'm probably not going to be able to help you. For the next 90 minutes, Motskin asked questions and listened, as the man gave precise, medically detailed answers.

By the end, he had identified one possible overlooked cause and two potentially promising treatments. But what was most striking to me was the sheer power of Motzkin's attentiveness. Afterward, I felt relieved just to know that Motzkin existed and couldn't help wishing that I'd seen him when my own pain started. This kind of detailed, time-consuming approach is one that many patients with severe chronic pain need, but that is vanishingly hard to find. When I talked to Motzkin later, he told me that patients often come to him after having bad experiences with other doctors, or even other pain clinics.

It's kind of shocking to me, Motzkin said. For so many people with pain, interacting with the health care system often makes their suffering worse. It just drives me nuts. The profit-driven nature of medicine, with its insurance-coded procedures and increasingly high caseloads, is one part of the problem. But it's also true that doctors often aren't comfortable treating patients with chronic pain. One of the challenges is that, in many places,

pain is still a subspecialty rotation within anesthesia, Motzkin explained. So for medical students to get exposure to these issues in a meaningful way, they usually have to do an elective in anesthesia and then a sub-elective in pain. On top of that, many doctors simply don't like chronic pain patients, whom they often see as demanding and frustrating, an unsolvable problem they quickly tire of. A surprising number of doctors and nurses, when they hear what I do, say, I can't believe you deal with these difficult patients.

They're so hard. They're so terrible to work with," Motzkin said. It's so much stigma. Just the other day, Motzkin told me he saw a man who had a long history of back and muscle pain, but who was experiencing alarming new symptoms. Numbness, difficulty walking, and several months of extreme, escalating discomfort. And what he was told was, hey, you're a pain guy.

This is just some more pain that you're having. I don't know what to tell you. Maybe we can adjust your meds. After seeing the patient, Motzkin reviewed an MRI of his neck and found a lesion on his spinal cord, a possible sign of multiple sclerosis. When Motzkin told the man about the lesion and that it might be contributing to his new symptoms, the man started to cry. Not because of what the scan found, but

because someone had finally listened and taken his experience seriously. He'd basically given up, Motzkin said. He'd been treated like he was overreacting, that nothing had changed. But that wasn't true. This attitude is deeply rooted. For years, Motzkin noted, people with migraines were often institutionalized, and in some cases, even lobotomized. Then, in the 1950s, a drug called methasergide was discovered

that prevented migraine in a huge number of people. All of a sudden, he said, migraine stopped being a psychiatric diagnosis and became a medical condition. There are many similar examples, conditions that were initially misdiagnosed or dismissed, either because doctors didn't understand them or because they didn't yet have the right test or treatment. That continues to be true.

We still have no good way to measure dysfunction in pain and temperature nerves, and no way to reliably quantify changes in our brain's pain circuit. When it comes to pain, Motzkin said, we don't have the tools yet. Still, he thinks things are starting to change. We're getting very close to the kind of large-scale personalized medicine that will prevent a lot of patient suffering, he told me. Across the country and even around the world, pain research has been galvanized by a new awareness which in turn is leading to new initiatives and investments.

The European Pain Federation has already published a proposal to improve the current and future management of chronic pain in Europe. And in 2024, Britain announced an ongoing research consortium that aims to break through the complexity of pain and find new treatments for a wide spectrum of chronic conditions. It's been a real shift, Motzkin added. I'm profoundly optimistic about the future of chronic pain. As for me, a little more than a year after my arms went berserk,

they started to get better, gradually at first and then more quickly. I went from not being able to drive at all, to being able to make short local trips, to going all the way across the bridge into San Francisco. But just as no one could figure out what caused the pain, no one could explain why it got better. A physical therapist told me that nerves heal slowly, so time, I guess. Regardless, I'm now again able to chop vegetables and lift a pot of water onto the stove and use my laptop to write.

Even so, my arms still hurt every day and limit what I can do. In other words, while I'm thankful for my luck and deeply relieved to be able to work again, it's hard not to wish for a real fix. One in which I magically returned to the body that, for years, simply worked. A body that I don't constantly have to think about. And though the prospect of a new era of pain treatment has me hopeful, it's also still excruciatingly out of reach.

For me and for everyone else who has lost months or years or decades of their life to pain, the future can't come soon enough. you