The Peter Attia Drive
#345 ‒ Chronic pain: pathways, treatment, and the path to physical and psychological recovery | Sean Mackey, M.D., Ph.D.
Mon, 21 Apr 2025
View the Show Notes Page for This Episode Become a Member to Receive Exclusive Content Sign Up to Receive Peter’s Weekly Newsletter Sean Mackey is a professor of pain medicine at Stanford University and the director of the Stanford Systems Neuroscience and Pain Lab, where his research explores the neural mechanisms of pain and the development of novel treatments for chronic pain. In this episode, Sean joins Peter for a wide-ranging discussion on the multifaceted nature of pain—as both a sensory and emotional experience—and its evolutionary purpose as a critical survival mechanism. He dives into how pain is transmitted through the nervous system, the different types of pain, and why different individuals perceive pain so differently. Sean shares insights into pain management strategies ranging from medications like NSAIDs and opioids to neuromodulation techniques such as transcutaneous electrical nerve stimulation (TENS). Additionally, this episode explores the interplay between sleep and chronic pain and the psychological and emotional dimensions of pain, and it includes a personal story from Peter about his own experience with pain and how Sean’s expertise helped him more than two decades ago. We discuss: The definition of pain, and how our understanding of pain has evolved from a simplistic body-mind separation to a nuanced biopsychosocial model [2:30]; The biological mechanisms behind how we perceive pain [9:30]; The role of consciousness in the perception of pain, and how nociception functions during unconscious states [14:30]; The four types of pain [22:00]; Using fMRI to identify objective biomarkers of pain in the brain [31:30]; The evolutionary role of pain in human behavior and survival [36:00]; How the brain processes and modulates pain signals, Gate Control Theory, the variability in individuals’ pain perception, and effectiveness of neuromodulation techniques like TENS [41:00]; The brain’s influence on pain: the role of emotion, beliefs, sleep, and individual differences in perception and tolerance [53:45]; Peter’s personal journey with chronic back pain, and how the emotional consequences of pain can be more distressing than the pain itself [1:04:30]; The pharmacology of common pain medications—NSAIDs, COX-2 inhibitors, and acetaminophen [1:09:30]; Muscle relaxants: benefits, drawbacks, and personalized strategies [1:20:30]; The definition of chronic pain [1:29:15]; The role of antidepressants in pain management [1:30:15]; Opioids: their controversial and nuanced role in pain management [1:33:45]; Alternative therapies: acupuncture and cannabis [1:54:15]; Fibromyalgia and chronic pain: clinical features, brain mechanisms, and emerging treatments like low-dose naltrexone [2:01:00]; Possible brain benefits of low-dose naltrexone (LDN) for people with mild cognitive impairment [2:15:00]; Peter’s recovery from severe chronic pain—how he went from immobility and high-dose opioids to full functionality [2:20:15]; Breaking the pain cycle: how physical rehabilitation and psychological recovery work together in chronic pain treatment [2:30:45]; Sean’s struggle with cluster headaches, and the value of knowledge, preparation, and empathy in both managing chronic pain and caring for patients [2:39:15]; and More. Connect With Peter on Twitter, Instagram, Facebook and YouTube
Chapter 1: What is the definition of pain?
Hey everyone, welcome to The Drive Podcast. I'm your host, Peter Attia. This podcast, my website, and my weekly newsletter all focus on the goal of translating the science of longevity into something accessible for everyone. Our goal is to provide the best content in health and wellness, and we've established a great team of analysts to make this happen.
It is extremely important to me to provide all of this content without relying on paid ads. To do this, our work is made entirely possible by our members, and in return, we offer exclusive member-only content and benefits above and beyond what is available for free.
If you want to take your knowledge of this space to the next level, it's our goal to ensure members get back much more than the price of a subscription. If you want to learn more about the benefits of our premium membership, head over to peteratiamd.com forward slash subscribe. I guess this week is Dr. Sean Mackey. Sean is a professor of pain medicine at Stanford University.
He also serves as the director of the Stanford Systems Neuroscience and Pain Lab. His research focuses on the neural mechanisms of pain and the development of innovative treatments for chronic pain conditions. In this episode, I talk a little bit about how Sean and I go way back and why it is that I really wanted to have Sean on this episode.
In this episode, we discuss the definition of pain as both a sensory and an emotional experience and why it's fundamental as a survival mechanism and the evolutionary purpose of pain, which obviously has been highly conserved across multiple species. We talk about how pain is transmitted through the nervous system, including the different types of fibers that are involved.
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Chapter 2: How has our understanding of pain evolved?
We talk about the different types of pain, such as nociceptive pain, visceral pain, neuropathic pain, etc. We talk about why pain perception varies so widely from person to person, even in the face of an identical stimulus, how psychological and emotional factors play a role into this. We talk about various approaches to pain management, including NSAIDs, opioids, and antineuropathic medications.
We talk about the effectiveness of neuromodulation techniques like TENS and how sleep deprivation affects pain sensitivity, as well as why chronic pain often leads to disrupted sleep cycles. We talk about this and many other things. Again, I share a very personal experience with my own pain and how Sean came to my rescue 25 years ago.
So without further delay, please enjoy my conversation with Dr. Sean Mackey. Oh, it's my pleasure. It's really good to see you again after a rather long time. Yeah, I was thinking about it. So this morning, my wife said, oh, what's the topic of the podcast today? And I said, it's going to be pain. And I said, she said, oh, who you have? And I said, Sean Mackey.
She goes, her face lit up and she doesn't know you. She's never met you, but she knows your name because she's heard me tell a story. She's heard me tell a story about my own experience through this. I then realized something, which is I haven't seen you since I was in medical school. Which is kind of weird.
So I'm sure we will get to how you and I met 25 years ago, exactly 25 years ago, and how you played an unbelievable role in bringing me back from arguably the brink of what could have been the end of my life, truthfully. But I want to start with some broader topics around pain. So There's nobody listening to us right now who doesn't know what pain is.
There's nobody listening to us right now who hasn't experienced pain. Yet, if you ask for a definition of pain, I think you'd get a lot of using the word to describe the thing, which isn't truly a definition. So if you were trying to explain to a Martian from another planet who doesn't experience pain what it is, what would you say?
There's the formal definition of pain, which is defined as an unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage. It's a mouthful. If you think of it as it's an unpleasant sensory and emotional experience, it's usually tied to something physically happening, but may not be.
I think sometimes what's missing in that definition, one of the things I wish they had put in but never did, is that pain is the great motivator. Pain is one of the most primitive experiences going back to, if you will, single-cell organisms. It's either pain or reward. You're either being driven towards oxygen, food, sex, or you're trying to get away from danger.
Pain is so wonderful because it's so terrible. It keeps us alive. Without pain, when we have these genetic issues of congenital insensitivity to pain, we would have never lived as a species. So pain is an unpleasant sensory and emotional experience. To understand pain, whether you're a Martian or you're a human now, I think you have to look back in history.
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Chapter 3: What are the types of pain and their characteristics?
To his credit, it was the first mechanistic foundation for pain because beforehand, pain was thought to be something mystical or religious. It was punishment of the gods. So he put this framework together that's often illustrated this famous picture of a little boy with his foot in the fire. And there's a little string from his foot going up into his brain.
And it ends up in the pineal gland, which was thought to be uniquely a human area. And the idea is the fire pulls on the little string, opens up pores in the pineal gland, rings a bell, and the boy withdraws his foot. The idea is in this dualistic model, there is a complete separation between body and mind. The body is where pain is generated. The mind is where it's perceived.
But the mind is simply a passive receptacle receiving these signals. That model put forward in the 17th century stuck with us for hundreds and hundreds of years and I would argue is with us today. And it has influenced medical care. It has influenced policy. It's influenced everything in our society about the way we think about pain. And it's utterly, completely wrong.
So, yes, he got Cartesian geometry right. But he really, complete bollocks, screwed it up when it came to pain. This biomedical model, this dualistic model, was with us for hundreds and hundreds and hundreds of years. And it's only been in the last number of decades that we've appreciated the nuance of what pain really is.
And instead of it being under this guise of this separate mind and body, we now appreciate it is this integrated biopsychosocial phenomenon. Meaning that, and I think this is one of the most important things that I'd like to drive across.
I'm going to introduce a term, we're going to get to a term called nociception, which are electrochemical injury signals that occur in the periphery, that what goes on in the body is And what goes on in the brain, the experience of pain, they may have nothing to do with each other or very little linkages. And we're going to hopefully unpack that.
So hundreds and hundreds of years, we're basing it on Rene Descartes' dualistic model. We still see this in medical care right now. You're a surgeon. For many, many, many, many years when I talked with the surgeons, They were firmly of the opinion that the amount of pain that a patient had after surgery was related to how much the scalpel cut and how much tissue damage was done.
And I think it's only more in the last 20 or so years I'm seeing surgeons really embracing this model that what people bring to the operating room table directly influences how much pain they have. Their early life experiences, all this stuff. And we'll talk about that.
And Sean, just to interrupt for a second, thinking through the history of medicine a little bit, the latter part of the 19th century brought a couple of other tools to pain. So between local anesthetics, cocaine down to lidocaine, and general anesthetics in the form of ether, which finally allowed surgeons to cut people without having to hold them down while they screamed.
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Chapter 4: How does the brain process and modulate pain signals?
They take chemical changes in the form of pH that can occur during infection. They convert those into action potentials that are then transmitted up nerves. These are little electrical impulses transmitting up generally two different nerve fiber types. These two different nerve fiber types, one is called a C-fiber, which is thinned. thin and slow. It's really pokey.
And I don't know if I'm getting ahead if you wanted to go more into that, but you got this pokey, slow C-fiber that transmits at about one meter a second. And the frame of reference, if it helps, is think about your thumb is about a meter from your brain. So an impulse on a C-fiber from your thumb to a brain takes about a second to two seconds to get there. The other nerve fiber type
It's called an A-delta fiber. It's got some nice insulation around it. It transmits 10 times faster. So it takes a little under a tenth of a second to get your thumb to your brain. And to give a real-world sense of the difference in C-fibers and A-delta fibers...
Think back to the last time you stepped on a tack in the carpet, you hit your thumb with a hammer, you twisted your ankle coming off a curb. What happened? Think back to that experience. You get this sharp jolt of pain that goes right to your brain.
Those are your A-delta fibers at 10 meters a second, rapidly getting up to your brain, rapidly putting into play systems to protect yourself from harm. You withdraw. You have a reflex that's occurring in your spinal cord. You're not even consciously aware of it. Your brain is setting into play escape mechanisms. The pain that you experience is sharp. It's well localized.
You know exactly where you stepped on that tack. Then about a second, two seconds later, you get this hot burning flooding sensation come over your thumb with you hit it with a hammer. And you think to yourself, oh, damn, this is really going to hurt. And it gets hot. It gets burning. Those are your C-fibers, unmyelinated, slow, getting up to your brain.
And what you also notice for the first time is you don't like this. This has an unpleasant quality to it that you didn't get as much with that A-delta sharp pain, but you're getting with those C-fibers. That's really clear.
The A-delta is doing two things, if I'm understanding this correctly. Is it creating the spinal reflex where I hit my thumb with the hammer, the signal goes into the spinal cord out through a motor neuron to pull back without me having to think about it?
That's exactly it. And it is synapse, and there are synapses in the ventral or anterior, the front portion of your spinal cord, which is, as you know, your motor part of that spinal cord. They're making synapses, and it's causing a classic withdrawal effect.
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Chapter 5: What role does consciousness play in pain perception?
Just thinking about this from an evolutionary lens, lots of debate about this in the animal kingdom. Like, does a goldfish feel pain? Do we have a clear sense as to how far from humans and or mammals you go where you still clearly have C-fibers and A-delta fibers?
You could go pretty deep in there, and I get the debate. It's a great debate over wine or beer, and I understand actually taking it seriously and having that debate. A lot of different opinions on this. I actually don't engage in that debate. I think you have to, first of all, define the thing that you're debating. You have to very clearly define the thing.
And in this case, our definition of pain is a rather human experience of pain.
This is where I was actually going to go, if I can just give you that window. Please. What I was really going to ask is a question about consciousness.
Yeah, yeah.
Is consciousness necessary for the internalization of this full gamut of pain?
Yes. I believe firmly it is, and I'm a recovering anesthesiologist. I haven't done it now in... Oh gosh, 20 years. But when I did it, and when you were operating on a patient, the patient is unconscious. They are not experiencing pain. You need a conscious brain for the experience of pain.
Now what people incorrectly made the leap of is thinking, well, they're not experiencing pain, so everything's okay. That would be a logical fallacy because all those signals are still coming from the body. still hitting the spinal cord and having their impact there, all those injury signals, because let's face it, when you do surgery, it's really nothing more than a controlled injury.
Yes. And I just want to point out, and this shows you how long I haven't been in surgery, but 20 years ago, my recollection is an anesthesiologist was giving not just one medication, but several. Yes. So they were giving something like halothane, which to my understanding, we didn't know how it worked then. Do we have any idea how it works today? Better.
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Chapter 6: How do sleep and psychological factors affect pain?
The anesthesiologist still had to give typically a narcotic. They were still typically giving something like fentanyl, even though the patient was unconscious. They were also often giving an amnesiac so that they wouldn't have any recollection of what was going on. But of course, we all hear the horror stories of the patient. And a paralytic on top of all that, right?
Exactly. Muscle relaxation.
So you hear these horrible stories of the patient who is paralyzed, but somehow conscious. You can miss on this state sort of thing. But just to make sure I understand, in theory, a paralytic and an inhaled anesthetic should be sufficient to eliminate the perception of pain in a patient who is being cut. Yeah.
Part of the challenge was, and now I'm starting to step outside of my wheelhouse, even though I was a member of the anesthesia tribe for a long time, is the levels of volatile gas anesthetic that you need to necessarily obliterate reflexes and full nociceptive impulses would be so high that it would depress one's blood pressure. And so you augment that with an opioid. Understood.
like fentanyl, like morphine, like whatever, and you combine those together, and that's why what the anesthesiologists do is quite magical.
Got it. So in other words, you give the inhaled anesthetic just to get unconsciousness, but not to fully suppress the nociceptic system. Instead, you bring on the opioid to do the remainder of that work.
They're working synergistically, and they're working at different mechanisms. Got it. And during that process, the patient is not feeling pain, If they're unconscious, because you do need a conscious, working, aware brain to feel pain, but all of the electrical impulses coming in from the body that are slamming into the spinal cord and the brain are open full bore.
They're impinging on all those brain systems responsible for stress responses.
So does that mean we are seeing a cortisol surge? We're seeing whatever one would expect a conscious person to experience with epinephrine, norepinephrine, cortisol, all those things still surging out in response to pain.
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Chapter 7: What are the pharmacological treatments for pain management?
So let's go back to something you said at the outset from an evolutionary perspective, which is pain and pleasure have been the driving factors that have been the engine of natural selection. But clearly those things have had to work in pre-conscious models. So that means that whatever we're defining as pain there did not include a perception of pain.
So what does that mean? That's where it gets muddy. And there's smarter people than I that would probably be more articulate, but This is why I think on first principles, you have to define the thing that you're talking about. When we typically talk about pain, we're talking about it from a uniquely human standpoint. Does a dog experience pain? Easier to accept. Easier to accept. I'm a dog person.
They experience pain. You move on down the evolutionary. At what point?
Right. Does a goldfish experience pain?
You see how muddy it gets. You go down rabbit holes pretty quickly, which is why I tend to stay with humans, which is hard enough by the way.
So how does everything you just said differ or overlap with neuropathic pain or that sort of burning pain that I'm sure some people are familiar with? Certainly I was familiar with it for several years. Yeah. Is that simply a subset of this? Are there various different types of pain that don't have a clear cause-effect relation to tissue damage?
So we have different ways of categorizing pain, putting it into different buckets, if you will. One is nociceptive pain. And you'll note that That word nociceptive sounds very similar to nociceptors, and it's by design. It means that it is pain caused by activation of primary nociceptors, whether it be in your skin or soft tissues or viscera. and it tends to have certain qualities.
It's very easy to localize. You know exactly where it is. It has a certain intensity. That nociceptive pain tends to be time-limited, responds well to short-term use of analgesic agents, acetaminophen, NSAIDs, COX-2 inhibitors, opioids, and it tends to go away. And this is the kind of pain that occurs after typically acute injuries. You then have visceral pain,
which as a former general surgeon, you understood this. This is due to activation of those primary nociceptors in our viscera. Now, the difference and why we bring up the distinction with visceral pain that is either in our thoracic viscera or abdominal or pelvic viscera is that the receptive fields, that means where those nociceptors serve and what we perceive are very diffuse and wide.
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Chapter 8: What are the emerging concepts in chronic pain?
Typical analgesics can be helpful, but identifying visceral-specific anti-nosusceptive drugs is still an area of hot research. These days, it's more about trying to identify the causes of visceral pain and reducing substances that are winding those nosusceptors up. Neuropathic pain, another bucket. Neuropathic pain means injury to either the peripheral or the central nervous system.
The nerves out in the body, it's either injury or dysfunction too. Nerves out in the body or the nervous system in your spinal cord or in your brain. Classic, you get nerve injury from a trauma from surgery. Classic qualities people describe burning, sharp, lancinating, stabbing, shock-like. This is the kind of pain that some people tragically get after a thalamic stroke in their brain.
Half their body's just like terrible burning pain and there's nothing going on out here. It's all central. This is the kind of pain that you get and you experienced. with radicular pain. And radicular pain means, in this case, injury to a nerve root coming out of your spine.
It's this sharp radiating pain, if you've got it in your lower back, that radiates down your leg, typically below your knee into your foot. This can be very challenging to treat with common analgesics. We tend to draw upon different categories of medications for this. These are, broadly speaking, anti-neuropathic pain drugs. And here, in our field, we steal from everybody.
There's only a few FDA-approved medications for pain, like a handful. So what we've learned to do is to steal, borrow drugs from the neurologists, their anti-convulsants, their anti-seizure medications. The gabapentinoids, the tegratols and their derivatives, their other anti-seizure medications, because they tend to have mechanisms of action that also work on nerve pain.
Gabapentin, I think you've had perhaps some experience with. Turns out it's a lousy anti-seizure drug. Terrible. But it's a pretty good anti-nerve pain drug. Four grams a day. Four grams a day. Yeah. Drowsy though. You know who gets credit by the way? I give credit to making gabapentin the blockbuster drug. George Clooney. How? You ever watched ER? Yeah. He was a pediatric ER doc.
Kid comes into the ER with a skateboarding injury. George Clooney puts the kid on gabapentin. Now, where that had all started was a case report from a couple of ED docs who had noted by putting people on gabapentin that their acute pain got better. So,
I felt like beforehand when I was practicing medicine, around the time I saw you practicing pain medicine, that I'd look like a genius if I put somebody on gabapentin because nobody heard of it. And then after that came out, floodgates opened, primary care docs started using it. Now everybody's tried it. And it's a very safe medication.
I should also make a mention when I'm talking about these meds or any treatments. I have zero industry relations with anybody. Nobody. I don't take any industry money. You can go look me up on Open Payments CMS, which is a public database. Okay. Neuropathic pain. There's another one. There's a new kid on the block called nociplastic pain. I don't know if this one has made much traction yet.
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