345 ‒ Chronic pain: pathways, treatment, and the path to physical and psychological recovery

1. 0:00 – 1:34

   Intro

   1. PAPeter Attia0:00

      Is consciousness necessary for the internalization of this full gamut of pain?

   2. SMSean Mackey0:06

      Yes. Now what people incorrectly thinking, well, they're not experiencing pain, so everything's okay.

   3. PAPeter Attia0:13

      What is the most responsible case for oral opioids?

   4. SMSean Mackey0:17

      I am not pro-opioid. I am not anti-opioid. I am pro-patient. Prescription opioids were over-prescribed, they were over-marketed. There were bad actors doing bad things. But it's, it's not that simple a story. Did it have bad consequences? Yes. Did it have good consequences? Hell yes.

   5. PAPeter Attia0:36

      I am sure everyone has heard of, and yet if you asked most people to define it, they wouldn't be able to define it. I'm talking about none other than fibromyalgia.

   6. SMSean Mackey0:44

      Fibromyalgia is frequently preceded by some event. Societal burden of chronic pain is terrifying. It's astounding. It's more than diabetes, heart disease, and cancer combined.

   7. PAPeter Attia0:57

      What are the other areas where LDN is just captivating the world?

   8. SMSean Mackey1:02

      It, it's one that I use more and more and more because of its safety profile and its potential for getting me a home run.

   9. PAPeter Attia1:10

      Is there a part of you that thinks, "This is a guy who's gonna be in chronic pain the rest of his life," or do you look at a guy like that and say, "No, no, we can fix this"?

   10. SMSean Mackey1:17

       I've never hit a point in my career with a patient where I've ever said, "We're done." Like-

   11. PAPeter Attia1:24

       I got nothing.

   12. SMSean Mackey1:25

       I got nothing.

   13. PAPeter Attia1:25

       [upbeat music] Hey, everyone, welcome to the Drive podcast. I'm your host, Peter Attia.

2. 1:34 – 9:42

   The definition of pain, & how our understanding of pain has evolved from a simplistic to a nuanced biopsychosocial model

   1. PAPeter Attia1:36

      Sean, thank you so much for making the trip to Austin.

   2. SMSean Mackey1:39

      Oh, it's my pleasure, and it's, uh, it's really good to see you again after a rather long time.

   3. PAPeter Attia1:45

      Yeah, I was thinking about it. Th- so this morning my wife said, "Oh, who's, who, what, what's the topic of the podcast today?" And I said, "It's gonna be pain." And I said, uh, she said, "Oh, who you having?" I said, "Sean Mackey." She goes, you know, and sh- 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, right? She's heard me tell a story about my own experience through this. And I then realized something, which is I haven't seen you since I was in medical school.

   4. SMSean Mackey2:11

      Yeah. Yeah.

   5. PAPeter Attia2:11

      That's, which is kinda weird.

   6. SMSean Mackey2:13

      Yeah.

   7. PAPeter Attia2:13

      Right? Um, so I'm sure we will get to how you and I met twenty-five years ago, exactly twenty-five years ago.

   8. SMSean Mackey2:22

      Wow.

   9. PAPeter Attia2:23

      Um, and how you played an unbelievable role in bringing me back from arguably the brink of what, what could have been the end of my life, truthfully. Um, but I wanna start with kind of some broader topics around pain, right? 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. Um, 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.

   10. SMSean Mackey2:59

       Yeah.

   11. PAPeter Attia3:00

       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?

   12. SMSean Mackey3:09

       Yeah. Yeah. There's the formal definition of pain, which is, uh, 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. It's, if you think of it as it's an unpleasant sensory and emotional experience, and it is 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. You know, it's either pain or reward. You're either being driven towards oxygen, food, sex, or you're trying to get away from danger. And so pain is this, pain is so wonderful because it's so terrible. It keeps us alive. Without pain, you know, when we have these, as you know, genetic issues of congenital insensitivity to pain, we would have never lived as a s- 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. And so I'm gonna evoke René Descartes.

   13. PAPeter Attia4:40

       Hmm.

   14. SMSean Mackey4:41

       Seventeenth century French philosopher, thought to be the father of modern philosophy. Incredible contributions, brought Cartesian geometry to us, which led to calculus. And he had this dualistic model of pain that he put forward. Now, h- to his credit, it was the first mechanistic foundation for pain, because beforehand, pain was thought to be something mystical or, um, uh, religious. It was punishment of the gods. So he put this framework together that's often illustrated, this, 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, you know, 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 gonna introduce a term, we're gonna get to a term called nociception, which are the, uh, electrochemical injury signals that occur in the periphery, that what goes on in the body 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 gonna hopefully unpack that. So hundreds and hundreds of years, we've got-- we're, we're basing it on Rene Descartes' dualistic model. We still see this in medical care right now. You're a surgeon, you know. 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, you know, 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, like their early life experiences, all this stuff, and we'll talk about that.

   15. PAPeter Attia8:26

       And, and Sean, just to interrupt for a second, thinking through the, the history of medicine a little bit, the, the latter part of the 19th century brought a couple of other tools to pain, right? 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, it sounds like that didn't shed any new light. That was viewed in the one hand as just a blunting instrument, but it didn't, didn't change the model. Is that-

   16. SMSean Mackey8:59

       Didn't change the model.

   17. PAPeter Attia9:00

       Okay.

   18. SMSean Mackey9:01

       Yeah, had no influence on that model, which just I, I think has had tragic consequences in the care of people, particularly with chronic pain, particularly women with chronic pain, who have felt stigmatized, invalidated, because absent something that's obviously wrong out in the body or the periphery, they were just labeled as being histrionic housewives or being told it's all in their head. Not just women, but also some men as well. And so it's only with that evolution of our perception or our model into a, a biopsychosocial model that that's gotten much better.

   19. PAPeter Attia9:41

       Okay. So let's,

3. 9:42 – 15:15

   The biological mechanisms behind how we perceive pain

   1. PAPeter Attia9:43

      let's talk about i- is there a pain receptor?

   2. SMSean Mackey9:46

      Yeah.

   3. PAPeter Attia9:47

      Right?

   4. SMSean Mackey9:47

      So let's break it down into the, the foundational stuff. So we have these things called nociceptors. Complicated name. It's basically a transducer, which is another technical name. Now, your engineering background, so you'll a- all know that a transducer is simply a device that converts one form of energy into another form of energy. This, this microphone is converting sound energy into electrical energy. The speakers convert electrical energy back into sound energy. We have these nociceptors that lie in our skin, our soft tissues, our deep tissues, our viscera, and they're specialized, and they convert, well, different forms of energy into electrochemical impulses. They take pressure, they take heat, cold, 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. So these are little electrical impulses transmitting up generally two different nerve fiber types. These two different n- nerve fiber types, one is called a C fiber, which is 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 is 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, uh, 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, uh, 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, um, escape mechanisms. Y- 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 where you hit it with the hammer, and you think to yourself, "Oh, damn, this is really gonna 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.

   5. PAPeter Attia13:08

      And Sean, the A delta is doing two things. It's, if I'm understanding this correctly, is it creating the spinal reflex where 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, correct?

   6. SMSean Mackey13:30

      That's exactly it. And, um, you know, it is synapse, and there are synapses in the ventral or anterior, the front portion of your spinal cord, which is your, as you know, your motor part of that spinal cord. They're making synapses, and it's causing a classic withdrawal effect.

   7. PAPeter Attia13:44

      But am I also feeling the pain? Am I perceiving the pain? And if you could do a thought experiment-

   8. SMSean Mackey13:50

      Yeah

   9. PAPeter Attia13:50

      ... where you could eliminate the C fiber in an individual-

   10. SMSean Mackey13:54

       Yes

   11. PAPeter Attia13:54

       ... would they still feel pain?

   12. SMSean Mackey13:56

       Yes. Yeah, they would still feel pain.

   13. PAPeter Attia13:58

       So there's still a central component to what the A fiber is doing.

   14. SMSean Mackey14:02

       Those A delta fibers are still-

   15. PAPeter Attia14:04

       They're still going up

   16. SMSean Mackey14:04

       ... going up.

   17. PAPeter Attia14:05

       Okay.

   18. SMSean Mackey14:05

       They're, they're in the spinal cord. They cross over to the other side. They head up through-

   19. PAPeter Attia14:10

       So there's an afferent and an efferent to the whole thing.

   20. SMSean Mackey14:14

       Indeed.

   21. PAPeter Attia14:14

       Okay.

   22. SMSean Mackey14:15

       Indeed. We, we think of these pathways, the main one that we all learn in medical school and we think about is a spinothalamic pathway. This goes from the spine up into your brain. We're gonna get there. But yes, if you had no C fibers, you would still feel pain. That's one of the other things is I think it's important to understand about pain is we've been trying to knock this out for untold years, and we've not been very successful with it, and part of the challenge is pain is so highly conserved from an evolutionary standpoint. As I was alluding to, back to single-cell organisms, reward, pain, you know, we evolved over the years to have this complex experience of pain, but also redundancies. You knock out one pathway related to pain, there's others there, and they find their way up into the brain, uh, just about no matter what.

4. 15:15 – 24:02

   The role of consciousness in the perception of pain

   1. PAPeter Attia15:15

      Just thinking about this through an evolutionary lens, um, lots of debate about this in the animal kingdom, right? Like, does a goldfish feel pain?

   2. SMSean Mackey15:22

      Yeah.

   3. PAPeter Attia15:23

      Right? Um, 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?

   4. SMSean Mackey15:36

      You could go pretty deep in there, and I get the, the debate. It, it, it's a great debate over wine or beer, and, and I understand actually taking it seriously and having that debate. Lot of different opinions on this. I actually don't engage in that debate, you know, because 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.

   5. PAPeter Attia16:11

      Well, that's, this is where I was actually gonna go, if I can just give you that window so you'll know.

   6. SMSean Mackey16:15

      Please.

   7. PAPeter Attia16:15

      It, uh, what I was really gonna ask is a question about consciousness.

   8. SMSean Mackey16:18

      Yeah, yeah.

   9. PAPeter Attia16:18

      Is consciousness necessary for the internalization of this full gamut of pain?

   10. SMSean Mackey16:24

       Yes. This is-

   11. PAPeter Attia16:25

       You believe it is?

   12. SMSean Mackey16:26

       I believe firmly it is, and, you know, I'm a recovering anesthesiologist. You know, I haven't done it now in, oh gosh, uh, uh, 20 years. Um, but when I did it, and when you were, you know, operating on a patient, um, 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-

   13. PAPeter Attia17:12

       Mm-hmm

   14. SMSean Mackey17:12

       ... 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.

   15. PAPeter Attia17:24

       Yes, and I just wanna point out, and, 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.

   16. SMSean Mackey17:37

       Yes.

   17. PAPeter Attia17:37

       So they were giving something like halothane, which to my understanding, we, we didn't know how it worked then. Do we have any idea how it works today?

   18. SMSean Mackey17:45

       Better. We still are trying to unlock the whole consciousness aspect of things, but we're, we're inching our way there.

   19. PAPeter Attia17:51

       But it wasn't enough to give that.

   20. SMSean Mackey17:53

       Right.

   21. PAPeter Attia17:53

       We still, when I say we, the anesthesiologist still had to give typically a narcotic. They were st- they were still typically giving something like fentanyl, even though the patient was unconscious.

   22. SMSean Mackey18:04

       Yes.

   23. PAPeter Attia18:04

       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, a- and a paralytic on top of all that, right?

   24. SMSean Mackey18:15

       And a pa- Exactly.

   25. PAPeter Attia18:15

       So-

   26. SMSean Mackey18:16

       Muscle relaxants, yeah.

   27. PAPeter Attia18:16

       So you hear these horrible stories of the patient who is paralyzed But somehow conscious, y- y- you, 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.

   28. SMSean Mackey18:38

       Yeah. Part of the challenge was, and now here 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, um, reflexes and full nociceptive impulses would be so high that it would depress one's blood pressure.

   29. PAPeter Attia19:02

       Got it.

   30. SMSean Mackey19:03

       And so you augment that with an opioid-
5. 24:02 – 35:17

   The four types of pain

   1. PAPeter Attia24:02

      So okay. 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.

   2. SMSean Mackey24:17

      Yeah.

   3. PAPeter Attia24:18

      Um, is that simply a subset of this? Are there various different types of pain that don't have a clear, um, cause-effect relation to tissue damage?

   4. SMSean Mackey24:28

      Yeah. So we have different ways of Categorizing pain, putting it into different buckets, if you will. Um, 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 in our viscera, and it tends to have certain qualities. It's very easy to localize. Uh, 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, uh, acetaminophen, uh, uh, NSAIDs, COX-2 inhibitors, uh, 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 in 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. When you get a stomachache, you can't put your finger exactly where it hurts. You tend to put your whole hand over it and say, "I'm kinda... It hurts here. It's diffuse." That's because the brain, the spinal cord and the brain have these diffuse receptive fields which expand the area. The viscera don't typically respond to the same type of stimuli that, uh, nociceptive pain does. You'll remember when you were taking a Bovie, um, to the bowel, the small intestine, patients wouldn't normally move because the nociceptors don't respond to that. But if you tug on it, if you pull that-

   5. PAPeter Attia26:34

      Or inflate it

   6. SMSean Mackey26:35

      ... or inflate it-

   7. PAPeter Attia26:36

      Yeah

   8. SMSean Mackey26:36

      ... boy, oh boy. Blood pressure goes up, heart rate goes up. Um, interesting characteristics with visceral pain is there's something called viscerosomatic convergence, meaning that the afferents, the information coming in from the gut, from the, uh, thorax, converge with the same sensory systems from the rest of our b- different parts of our body. So, um, you know, you may remember the old medical school adage, uh, "C3, four, five keeps the diaphragm-"

   9. PAPeter Attia27:09

      "Alive." [laughs]

   10. SMSean Mackey27:10

       "... alive." Okay. We all, we all had these in, in med school. Well, that means that the third, fourth, and fifth cervical nerve roots subserve our diaphragm, which help us breathe. When the general surgeons or others are operating and they get blood under the diaphragm, it irritates the diaphragm. And what patients will typically complain of, shoulder pain, because the shoulder is subserved by the fourth and fifth cervical areas. And so when they had shoulder pain, the answer wasn't, you know, something's wrong with their shoulder. It's they had some irritation of blood under there. It's why when people have a heart attack, pain radiates out into the arm because you've got the upper thoracic nerves subserving the heart that overlap with the nerves that go down your arm, and the nervous system gets confused, and that's how it's expressed. And if you like the neurosciences, it's all pretty cool. If you're experiencing it, not so cool. Let's get to neuropathic pain.

   11. PAPeter Attia28:13

       And by the way, on visceral pain, what is the response to treatments with respect to the way we saw in nociceptive pain where, hey, great response to these NSAIDs or opioids or whatever?

   12. SMSean Mackey28:25

       Yeah. Uh, typical analgesics can be helpful. Um, but identifying visceral specific anti-nociceptive drugs is still an area of hot research. Um, these days it's more about trying to identify the causes of visceral pain and, you know, reducing substances that are winding those nociceptors 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 know, you know, you get nerve injury from a trauma, from surgery. Um, classic qualities people describe burning, sharp, lancinating, stabbing, shock-like. Um, this is the kind of pain that some people tragically get after a thalamic stroke in their brain.

   13. PAPeter Attia29:39

       Mm.

   14. SMSean Mackey29:40

       You know, half their body's just, like, terrible burning pain and it... and just there's nothing going on out here. It's all central. Um, th- this is the kind of pain that you get and you experienced with radicular pain, and radicular pain means, uh, 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 in, 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. Um, and here In our field, we steal from everybody. You know, 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 anticonvulsants, their anti-seizure medications, the, uh, gabapentinoids, the Tegretols 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. Um, turns out it's a lousy anti-seizure drug. Terrible. But it's a pretty good, you know, anti-nerve pain drug.

   15. PAPeter Attia31:28

       Four grams a day.

   16. SMSean Mackey31:29

       Four grams a day.

   17. PAPeter Attia31:30

       [laughs] I was awfully drowsy, though.

   18. SMSean Mackey31:34

       You know who gets credit, by the way, for making, uh... I give credit to, uh, making gabapentin the blockbuster drug? George Clooney. How? You ever watched ER?

   19. PAPeter Attia31:48

       Uh, yeah, yeah.

   20. SMSean Mackey31:48

       Yeah. He was a pediatric ER doc.

   21. PAPeter Attia31:51

       That's right.

   22. SMSean Mackey31:52

       Kid comes into the ER with a skateboarding injury. Um, George Clooney puts the kid on gabapentin.

   23. PAPeter Attia31:59

       [laughs]

   24. SMSean Mackey32:01

       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.

   25. PAPeter Attia32:26

       [laughs]

   26. SMSean Mackey32:26

       And it's a very safe medication. I have, like, 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, uh, made much traction yet. This is a newly introduced category of pain which is thought to represent dysfunction in the central pain processing system, and I'm not precisely defining it, but that's the gist of it. It means that in the, in the absence of an identifiable peripheral cause, there is dysfunction in the brain and the spinal cord that is causing pain, perpetuating, and amplifying pain. Nociplastic pain, and it has been tied in with conditions like fibromyalgia, temporomandibular disorders, uh, some aspects of chronic low back pain, uh, irritable bowel syndrome, interstitial cystitis, uh, and more. It, it's slowly starting to get traction. So when we, when we talk about pain, both to study it, but also ideally to treat it, we put them in these categories that we just described.

   27. PAPeter Attia34:03

       Yeah, I was about to say, before you gave your examples, I was gonna say nociplastic pain must be a huge bucket because it's everything for which we don't understand one of the three... Uh, it, it's sort of the all else bucket, which is enormous, especially for chronic pain, right?

   28. SMSean Mackey34:19

       You're absolutely right, and I think the verdict is still out. In the end, does nociplastic pain stick around, or is the problem that in these conditions that we associate with nociplastic pain, medical science hasn't caught up to identify a specific peripheral driver? I'm of the opinion it's that latter. Like, I think we're gonna find peripheral drivers for fibromyalgia. There's some controversy right now as to whether fibromyalgia represents a small fiber neuropathy, um, and just because we may not be able to identify a lesion doesn't mean that there's not something there. But as in all things, the truth will weigh out, and, uh, we'll see how the story plays.

6. 35:17 – 40:38

   Using fMRI to identify objective biomarkers of pain in the brain

   1. PAPeter Attia35:17

      There's no objective way to measure pain, correct?

   2. SMSean Mackey35:20

      Oh, the last, uh, 15 years of my career has been spent on doing that very thing.

   3. PAPeter Attia35:28

      And where do you think we are in that regard?

   4. SMSean Mackey35:30

      Much further along than I ever would have predicted. So a large chunk of my research early on, my, uh, early research was in neuroimaging of pain. It was opening up windows into the brain to see where people s- were thinking, processing, perceiving, magnifying pain, and I spent much of that publishing work to understand the mechanisms of that, and we haven't yet actually finished our story of pain going up to the brain and what's going on-

   5. PAPeter Attia36:03

      Okay. Well-

   6. SMSean Mackey36:03

      ... and we'll get there.

   7. PAPeter Attia36:04

      Yep.

   8. SMSean Mackey36:06

      Over the years, I migrated into the space of developing objective biomarkers of pain, and it, it's one of those things where I-- This is why I love working with young, smart people. Um, I bet against it. I had some young grad students and others who said that they knew, they, they thought they could do this. I told them how you would do it, and I said it won't work. And I'm going to pay you, I'm going to give you money to go scan people, and you're going to learn how it doesn't work because failure is a great lesson in life. And they came back, and they showed they could do it. And it was all through developing patterns in the brain and using machine learning models to then take that pattern, that signature, and be able to predict in other people whether they were experiencing pain. I didn't think we could do that because of the hugely individual nature of pain. It's so different from person to person. But it turns out that there are core patterns in the brain that represent that experience of pain. And so now we've-- others-

   9. PAPeter Attia37:21

      And, and sorry, you're capturing these through what modality?

   10. SMSean Mackey37:24

       F- fMRI

   11. PAPeter Attia37:24

       FMRI?

   12. SMSean Mackey37:24

       Functional magnetic resonance imaging. It is a standard MRI that people go into, but we do some fancy pulse sequences. We play some physics tricks where we can, uh, see where nerves, the brain's being activated. And we've taken this, we and others, have taken this from being able to determine whether somebody is in a state of pain to predicting their long-term trajectory, and we're, we're working right now, a big grant that I have, is to actually create composite multimodal biomarkers to predict their future state. We're getting there.

   13. PAPeter Attia38:05

       So j- let's just start with standard understanding. If you put me into an fMRI machine, and I said to you, uh, "Hey guys, I'm not feeling any pain right now. I feel great."

   14. SMSean Mackey38:15

       Yeah.

   15. PAPeter Attia38:16

       And then you scan me, and then someone came out and took a hammer to my thumb-

   16. SMSean Mackey38:20

       Yeah

   17. PAPeter Attia38:20

       ... and I went through the classic response that you described earlier, what would my fMRI show?

   18. SMSean Mackey38:26

       Yeah. You would see, you'd see rather dramatic increases in activity in brain regions such as the thalamus, the posterior insular cortex, the anterior cingulate cortex, particularly the dorsal anterior cingulate cortex, and a number of other distributed, a number of other areas.

   19. PAPeter Attia38:47

       And to be clear, this is distinct from the part of my cortex that is the homunculus for my thumb.

   20. SMSean Mackey38:53

       You would also see it in S1.

   21. PAPeter Attia38:55

       Yeah.

   22. SMSean Mackey38:55

       You're right. Um, and indeed, what we've learned through this, that there's no one single pain region in the brain. That's another mistake that was made along the way. We all thought we were gonna find a brain region-

   23. PAPeter Attia39:11

       Yep

   24. SMSean Mackey39:11

       ... then we can knock it out.

   25. PAPeter Attia39:13

       Hmm.

   26. SMSean Mackey39:13

       Right? Just go cut it out.

   27. PAPeter Attia39:14

       [laughs]

   28. SMSean Mackey39:14

       And it turns out that didn't work. And it's not one brain region that generates the experience of pain. It is a distributed network. It's all of these regions coming together and working in harmony.

   29. PAPeter Attia39:28

       Doing what?

   30. SMSean Mackey39:29

       [sighs] Generating the experience of pain and then generating a r- typically a response to that. And let me be very clear, 'cause there was a lot of controversy when we and others initially published our papers. We are not trying to take away the autonomy of the patient and the self-report. I don't need an fMRI to see a patient and know if they have pain. I can just ask them. And I can use self-report measures to get at it, and I do-- that's another part of the research. Where we're working to build these objective markers, this objectifying pain, is not to see what they're in now, but can it give us useful information to predict treatment to a particular therapy? Can we use it to predict their future state? Can we use it to predict their vulnerability to an injury or surgery? Those are things that just asking a patient right now, probably not gonna get there. I don't know

7. 40:38 – 46:52

   The evolutionary role of pain in human behavior & survival

   1. SMSean Mackey40:38

      if you want to go back to the brain.

   2. PAPeter Attia40:39

      Let's-- Yeah, let-- I, I took you a little-

   3. SMSean Mackey40:41

      Sorry, I, I, I think I-

   4. PAPeter Attia40:41

      No, no, no, that's a-

   5. SMSean Mackey40:42

      I get a little tangential, so bear with me.

   6. PAPeter Attia40:43

      Yeah. Okay, so let's go back to the story of these, these four branches of pain, or at least the first three, and then kind of how they're, how they're, how the periphery and-

   7. SMSean Mackey40:52

      Yeah

   8. PAPeter Attia40:52

      ... uh, the, how the, how the sensory component is impacting the perception.

   9. SMSean Mackey40:57

      Roll with that. Give me a little bit more. I wanna, I'll build off it then.

   10. PAPeter Attia41:00

       Okay, so we go back to nociceptive pain.

   11. SMSean Mackey41:02

       Yes.

   12. PAPeter Attia41:02

       Right? So tissue injury occurs. Um, I think where we, where I derailed us was in classifying all the different types of pain, but you had, okay, a signal comes up, right?

   13. SMSean Mackey41:13

       Yeah, yeah.

   14. PAPeter Attia41:14

       Two signals coming up, the C fiber, the A delta fiber. The immediate response is to get you out of pain, right? So that makes-- there's an evolutionary logic to that.

   15. SMSean Mackey41:24

       Right.

   16. PAPeter Attia41:25

       The C fiber is not there to get you out of pain because the A delta did that. Is the C fiber there to remind you not to go back and do that again?

   17. SMSean Mackey41:34

       Perfect.

   18. PAPeter Attia41:35

       Okay.

   19. SMSean Mackey41:35

       Perfect. That is basically your longer term harm alarm. That is saying, "Peter, don't go back and do that again." Um, back in the cave people days-

   20. PAPeter Attia41:49

       Hmm

   21. SMSean Mackey41:49

       ... it would remind you, maybe it's best to sit in the cave and let the healing occur instead of going out and fighting the wooly mammoth or the saber-toothed tiger, tiger. Because if you fought the saber-toothed tiger when you're injured, you got eaten. You didn't get to pass your genes along.

   22. PAPeter Attia42:07

       By the way, do we have any evidence, Sean, that there was enough genetic heterogeneity around this, that there were, you know, two hundred thousand years ago, there were members of our tribe who simply didn't feel pain and therefore did not pass on their genes because they made poor decisions?

   23. SMSean Mackey42:27

       Wow, that's a great question. One, I don't know. Um, two, there was undoubtedly genetic variations that led to behaviors, led to actions that did not promote survival of the species. And, you know, nature takes care of that. Those people died out.

   24. PAPeter Attia42:51

       I find it amazing to just sit around and dream about how much, how, how little convergence must have existed a quarter of a million years ago in terms of things that just ended up not being good for our species. Like, you know, uh, people who didn't, didn't experience pain the same way or didn't have certain filters within, within themselves. Um, you know, there've been lots of talk about people who couldn't socialize, right? And how, where, you know, we, we could, you couldn't evolve alone, so if you didn't have the right set of genes that allowed you to at least be part of some sort of social tribe. And of course, we still probably have people today that have escaped, and, and we, we clearly have some antisocial folks among us, but they're the exception and not the rule. So anyway, I just wondered if, um, today we're much more homogeneous in terms of what a human's response to pain is versus what it might have been.

   25. SMSean Mackey43:46

       Probably. And when you go back through some of the lower animal species, what happens when one of those animals gets injured in the wild? You know, and again, I, I'm not a animal pain expert, but typically they're set off, they're ostracized. Those, those animals just die out. What do we do? We come together as a community and we help those people. We developed empathy for pain. I did some studies on that. And that has gotten hardwired into our brains to be able to recognize when people are in distress and pain and to reach out and help them. That was clearly beneficial to our species and conserved.

   26. PAPeter Attia44:38

       And I also think about certain things like, um, childbirth prior to any anesthetic was obviously brutal, uh, both in terms of the pain and the mortality, and yet there's no evidence that, like, you know, people were deciding, "Yeah, maybe we not, ought not to do this." In other words, the drive for procreation-

   27. SMSean Mackey44:59

       Yes

   28. PAPeter Attia45:00

       ... somehow overcame what must have been, you know, brutal.

   29. SMSean Mackey45:05

       Absolutely. And I gotta tell you, hats off to half the population that are women that, that, and the, and the women that do this. Uh, I can't imagine. I don't want to even go there. There is interesting protective aspects during childbirth that doesn't take away necessarily the pain, but I, I think some of the, uh, estrogens, the estradiols, has not only an analgesic effect, but I sometimes just swear p- they don't seem to remember sometimes just how painful it was, and yet we do it a- they do it again.

   30. PAPeter Attia45:41

       Yeah, yeah. Th- those are the two things that I joke about with my friends, which is I still don't really understand how our species is here for two reasons. One, women had to continually go back to the well, because remember, if your reproductive rate isn't in excess of two-
8. 46:52 – 1:01:36

   How the brain processes & modulates pain signals, Gate Control Theory, the variability in individuals’ pain perception, & effectiveness of neuromodulation techniques like TENS

   1. SMSean Mackey46:52

      Um, we have these signals. I'm gonna take these signals from the spinal cord, 'cause where it gets really interesting is when you take those A delta C fibers, you, you're in the spinal cord, and there's a lot of processing going on there that we'll come back to, and they head up to the brain, and then they synapse, connect in a large number of brain regions. Uh, one of the main one is the thalamus, which acts like Grand Central Station in the brain. It's taking lots of sensory input from different sources, and it's sending it out to other areas. S- some of those areas that we alluded to, um, the anterior cingulate cortex. Now, the anterior cingulate cortex, each of these brain regions has some functions associated with it. Uh, the anterior cingulate cortex is associated with some of the emotional aspects of pain or the unpleasantness of it. For the neuroscientists out there, I'm grossly oversimplifying things. The anterior cingulate cortex is also a salience detector, meaning it is taking those incoming inputs, and it's determining, is there something wrong here? Is there an error? Because in essence, our brains are prediction machines. Um, everything that we're doing, we're forming an expected pattern of what we're going to sense, and we're making adjustments. When I reach out for my cup, I know where it is in space, I pick it up. If instead of cold water in that, it's boiling hot water and I touch it, my brain is getting different signals than it was expecting. That cingulate cortex as a salience detector is triggering, and it's putting into action for me to withdraw Other areas of the brain include the insular cortex, which, uh, lies on this little bit of the outer edge. It can be subdivided into multiple components, the posterior, mid, and anterior insula. Let's just say that the back part of it is taking direct information in from the body. But then as you get more and more towards the front of the insula, it's integrating emotional and cognitive nuance to it. It is integrating in your emotion, your sta- your emotional state and what you're thinking. Now, there's also connections with your, your amygdala, this deep, um, primitive region of the brain involved with both, um, threat detection as well as reward, and it's connected, uh, into the circuit and then also has outlays into other areas that maybe we'll get to, like the hippocampus and the stress response and onward. All that to say is, all these regions connected together generate that experience of pain. And at this point in time, I really haven't done more than René Descartes has in telling this story because at first pass, the brain is still remaining a passive receptacle just taking these inputs, right? Where it gets interesting is we developed descending control systems that come down from the brain that converge in the spinal cord, and what they serve to do is turn down the signals that are heading up. Now, in part, this was first described by Ron Melzack and Patrick Wall in, I think it was 1965, the Gate Control Theory of Pain. Brilliant guys. Never had the pleasure of meeting them, but, you know, they, they just did seminal work. And this Gate Control Theory of Pain, you know, posits that, yes, you have afferent information coming in to the spinal cord, but the spinal cord is acting like a gate of opening and closing, turning up, turning down pain, and it is altered by other fibers and, uh, and systems from your brain. So let me give you an example to this. We-- Let's introduce another nerve fiber type, A-beta. A-beta fibers are your touch fibers. When you touch or scro- stroke your skin, um, those get activated. When you stand up and you stand on one leg, they're also responsible for position sense. They have a heavy coat of insulation around them, and they are wicked fast. C fiber is one meter a second, A-delta fiber is 10, A-beta fiber is 100 meters a second. Fast. That's why you can dance. That's why you can walk, because you've got those fast-reacting A-beta fibers. Now, let's go back to your thumb, Peter. You just hit your thumb with a hammer. Sharp jolt of pain goes to your brain. Got a little delay. Oh, damn, this is really gonna hurt. Hot, burning, flooding sensation comes over your thumb. What is the next thing that you do? Everybody does this a little differently.

   2. PAPeter Attia52:18

      Before or after swearing.

   3. SMSean Mackey52:21

      There you go. Um, a lot of people swear, so it's after swearing. You swear and then-

   4. PAPeter Attia52:27

      Shake it

   5. SMSean Mackey52:27

      ... shake. Okay. You, you're a shaker. Some people-

   6. PAPeter Attia52:31

      Or squeeze-

   7. SMSean Mackey52:32

      Squeeze

   8. PAPeter Attia52:32

      ... proximal to it.

   9. SMSean Mackey52:33

      There you go.

   10. PAPeter Attia52:34

       Yeah.

   11. SMSean Mackey52:34

       You squeeze, you shake it, sometimes you run it under water. What are you doing when you're squeezing it and shaking it?

   12. PAPeter Attia52:42

       Sometimes trying to create a distraction.

   13. SMSean Mackey52:44

       Okay.

   14. PAPeter Attia52:45

       Um, sometimes, though probably illogical, trying to keep whatever humor is in there that's hurting-

   15. SMSean Mackey52:52

       Yeah

   16. PAPeter Attia52:52

       ... isolated like a tourniquet.

   17. SMSean Mackey52:54

       Right.

   18. PAPeter Attia52:54

       Right? Uh, obviously, if I'm using cold, especially if it's one of my kids that hurt themselves, we'll put cold on, hoping to anesthetize the area, presumably slow the circulation, take down the swelling.

   19. SMSean Mackey53:06

       Yeah. You're-- That's beautiful, and you're talking about longer term things, which are all perfect, um, because cold does those things, and also cold, by the way, reduces action potential velocities and firing in those A-delta, C fibers. But what you're doing most of all when you rub it is you're activating A-beta fibers.

   20. PAPeter Attia53:26

       Hmm.

   21. SMSean Mackey53:27

       You're actually not influencing much your A-delta or C fibers, those nociceptive fibers. You're not really impacting it there.

   22. PAPeter Attia53:34

       That horse left the barn.

   23. SMSean Mackey53:35

       That horse left the barn, and that, that horse is-- You got horses still running out the barn. You're-- You can squeeze all you want for the time being, and the horses are still heading out and hitting your spinal cord. But where things get interesting is the A-beta fibers, those touch fibers, they're coming into a slightly different area of your spinal cord, and they're sending over projections into where those nociceptive fibers are in your spinal cord, and they have an inhibitory role. That's the take-home message. So the A-beta fibers are inhibiting the signals coming in from where you hit your thumb with a hammer and preventing them from going to your brain. It's a beautiful example of neuromodulation. You're doing your own neuromodulation with that.

   24. PAPeter Attia54:24

       Hmm.

   25. SMSean Mackey54:25

       And we're all hardwired to do that thing, and there's a medical device that takes advantage of that. You're familiar with the TENS unit?

   26. PAPeter Attia54:37

       Yep.

   27. SMSean Mackey54:39

       TENS is T-E-N-S, transcutaneous electrical nerve stimulation. Now, what TENS frequently, what it originally did, there's been modifications of it, is when you turn on the, uh, you, w- what you do with the TENS, and I, I know you know this, is typically little black pads that you put over the area that hurts. You put an electrical stimulation through these pads. They're activating A beta fibers. And so you do them over here, and it's having a neuromodulatory effect back in the ver- in the spinal cord. Pretty cool when it works.

   28. PAPeter Attia55:20

       And how do you predict, patient comes to you and they're experiencing some pain, what are the, what are the clues that would tell you, "I think TENS is going to be successful here"? In other words, I think that activating A beta fibers is going to be a tool that will reduce your perception of pain, 'cause that's what we're doing, right? Everything that you do is, "How do I reduce your perception of pain?" I can't take, I can't necessarily take away... I mean, if they have an injury that needs to be resolved, they shouldn't be seeing you. They should be seeing the surgeon or whoever fixes-

   29. SMSean Mackey55:55

       Yeah

   30. PAPeter Attia55:55

       ... the physical injury, right?
9. 1:01:36 – 1:14:38

   The brain’s influence on pain: the role of emotion, beliefs, sleep

   1. PAPeter Attia1:01:36

      things differently from day to day.

   2. SMSean Mackey1:01:37

      You're absolutely right, and maybe that's a good opportunity to build on that and introduce more of the brain. So we've talked about the functions of the brain, um, the, um, anterior s- uh, cingulate cortex being some of the more emotional, the s- primary somatosensory cortex, the homunculus being more sensory. The insular cortex has an interoceptive state. It's like our internal awareness of our bodily state. Uh, we talked about, um, the amygdala. Now let's introduce also the prefrontal cortex. The prefrontal cortex, the big thinking part of our brain up here, both the ventral medial and the dorsal lateral, play a key role in our modulation, our cognitive control of pain. And these systems, the prefrontal cortex, the anterior insular cort- uh, sorry, the insular cortex, the cingulate cortex, all have those descending projections back down to the spinal cord. So we talked about the gate control theory of pain in the context of rubbing your finger out here, a peripheral neuromodulation. Where it really comes into play is when you introduce brain systems, the brain and your emotions, your cognitions, your beliefs, your early history, and that influence on pain. That's where it gets really exciting, and that's sending descending pathways down. Um, so I would argue, i- in part, that your experience of cold water in that moment may have been driven, in large part, by your mental state before you got in, and maybe we'll talk more about the intersection of sleep and pain. May, you know, but h- huge research in that space. Um, you know, your, your state of, uh, uh, of, you know, of anxiety, apprehension around this, your, um... All sorts of cognitive, emotional aspects weigh into your, uh, experience of pain. And yes, there's also circadian rhythm aspects related to this from hour to hour fluctuations. But those individual differences are fascinating, and that is also an area that our group and others, our lab and others are going into, is recognizing that one pain score averaged over a week may not give us a lot of information, that we need to take into account the within subject, the within person daily variations over time and model that.

   3. PAPeter Attia1:04:30

      Now, there's, there, there seems to be kind of, um, like a, a... It-- Uh, I guess I should ask this 'cause I don't, I'm not asserting this as the case. Is there kind of a moral judgment that comes to this at some level? Like, don't we as a society just tend to look more favorably at people that have a very high pain tolerance? So when you go through that experiment you just did with the medical students, if everybody's being brutally honest, aren't they kind of looking at the people who score zero, one, two more favorably than those that score eight, nine, and ten?

   4. SMSean Mackey1:05:01

      Absolutely.

   5. PAPeter Attia1:05:02

      Why do you think that is?

   6. SMSean Mackey1:05:04

      Because that's what-

   7. PAPeter Attia1:05:04

      'Cause if I'm being truthful, I do it.

   8. SMSean Mackey1:05:06

      Yeah. Yeah. That's what society values. That's, that was my home life growing up. That's what my father expected.

   9. PAPeter Attia1:05:14

      Sure.

   10. SMSean Mackey1:05:14

       I come from a very working class, you know. My father had 12 brothers and sisters fighting for whatever scraps of food, and he brought that into my world, our world as kids, and you just suck it up and deal with it. And my father had back pain later in life, and he would never talk about it, would never ask my opinion, and when I offered my opinion, he would never follow it. Had bad consequences in the end, but we value that. That is just the way our, our society is.

   11. PAPeter Attia1:05:49

       Is that a male thing exclusively?

   12. SMSean Mackey1:05:52

       I think you need to get some women on the show and ask them. Um, I think, I think it crosses, actually. I do think there is a masculinity aspects of that, and I think, I could be wrong here, I think that that thing is also attractive for women. I think there's a certain attractiveness because that person may be more likely to be a good provider-

   13. PAPeter Attia1:06:18

       Hmm

   14. SMSean Mackey1:06:18

       ... than somebody who is weak and, uh, sensitive. But, you know, we're getting a little out of my wheelhouse on that, but you're, you're, you're, you're absolutely right.

   15. PAPeter Attia1:06:30

       I, I just think it's like a compatibility thing. Like, I know when I do that type of an exercise compared to others, I tend to just feel less pain. I also know my wife does as well.

   16. SMSean Mackey1:06:41

       Yeah.

   17. PAPeter Attia1:06:41

       And, uh, and so I almost wonder if that's a compatibility. Like, we both just have a high threshold for that when we're exercising, when we're doing anything, even recreationally, that doesn't matter.

   18. SMSean Mackey1:06:54

       My, uh, partner, my- Fiancée. We're now engaged. Um, is a professor at Stanford, Beth Darnall, and, uh, she's an ex-ultra-marathon runner. And I've always admired the fact that she can sit there in front of a computer or work on something untold hours and not move, and I ha- I'd ask her, like, and she's just like, "Listen, I was really good with running with a pebble in my shoe, putting one foot after another, and just w- working my way through it." And I similarly grew up in an environment where, you know, you learn to be tough and you learn to power through life's adversities.

   19. PAPeter Attia1:07:33

       So what is the consequence of this? So we're acknowledging that it is an attractive trait-

   20. SMSean Mackey1:07:39

       Yeah

   21. PAPeter Attia1:07:39

       ... to have a high tolerance of pain.

   22. SMSean Mackey1:07:40

       Yeah.

   23. PAPeter Attia1:07:41

       Society rewards it, and yet by definition, a, a significant subset of the per- of the population, call it a third, call it a quarter if it's a normally distributed function-

   24. SMSean Mackey1:07:52

       Yeah

   25. PAPeter Attia1:07:52

       ... are going to be a standard deviation on the other side. The, may- right.

   26. SMSean Mackey1:07:57

       Yeah.

   27. PAPeter Attia1:07:57

       They, they're gonna be in the, they're gonna be on the side where, hey, they're relative to people who have a high tolerance for pain, these are people who are gonna really perceive pain. And if we just did this through the lens of the responsibility of the medical community, there's a pretty significant consequence to that, right?

   28. SMSean Mackey1:08:12

       In- indeed. Now, as with all things, it, it gets a little bit more nuanced. We talked about cold, for instance.

   29. PAPeter Attia1:08:18

       Hmm.

   30. SMSean Mackey1:08:19

       It turns out that some of the sensitivities are modality specific.
10. 1:14:38 – 1:20:00

    Peter’s personal journey with chronic back pain

    1. PAPeter Attia1:14:38

       look, there's so much going on. I mean, we can-- I, I'm happy to tell my story because it's a great introduction to, to kind of the, the work you've done. So for folks that haven't heard it, and I've, I've shared this before, and we were talking before the podcast, I don't remember how much of this is in the book because at one point I wrote all of this out. I'm pretty sure much of it got cut out. But, um, when I was in my third year of medical student, I was having just a great old day, uh, rode my bike to the gym, was just about to go in the gym, and I get off the bike, and I feel a pain in my back like I've never felt before, and it was enough that I decided not to work out, which says something, 'cause I would have worked out through any amount of discomfort. I limped home, laid down, and said, "You know what? I'm just gonna sleep this off, and tomorrow will be fine." Tomorrow it wasn't fine. I was in so much pain I couldn't get out of bed. Had to actually call my roommate, we had separate phones in the same house, to come and get me up and out of bed. And the next two weeks proceeded to be a really unbearable episode where I was doing an ICU rotation, and, you know, this is back in the Wild West, where I think the nurses and the residents were just shooting me up with Toradol every day, nonstop, getting me through the day.

    2. SMSean Mackey1:15:48

       Yeah.

    3. PAPeter Attia1:15:49

       But the nights were brutal, and what I now realized happened was I'd had a really significant herniation. A piece of that L5, S1, um, disc broke off. I would later find out it was a five-centimeter piece, and it had extruded, broken off, was sitting on the S1 nerve root. Every night now I was going to pain, uh, going to bed feeling as though the skin on the bottom of my foot was being ripped off.

    4. SMSean Mackey1:16:15

       Yeah.

    5. PAPeter Attia1:16:15

       So the, the only way I could sleep was to put my bag, my foot into a bag of ice and take some amount of Benadryl that was enough to knock me out. This went on for about another week until the dean of students saw me limping along and said, "Hey, Peter, what's going on?" I told him. This was a Sunday afternoon. I was studying. He took me directly to the ER, got an MRI, showed all of this mess. The next day I had surgery. As I've talked about in the past, everything went wrong in a series of surgeries. And fast-forward three months, three trips to the operating room, multiple discectomies, laminotomies, multiple levels. In theory, my back should be fine. I'm anything but fine. I now have a new pain, but this is unlike anything that was related to my back. This is where you come in. I now have a pain that is so significant, and it sounds grotesque to explain it, but this is all it was. It felt like someone was reaching in my body from my kidneys into my groin and tearing my testicles out from the inside of my body. So needless to say, I was out of commission. I did not move. I laid on a floor twenty-four/seven. Um, and to your point, how did I feel? Well, it wasn't just that I was in so much pain that I couldn't do anything. It was I watched my life disappear. So it went from, "You're not gonna graduate from medical school on time," to, "You're not gonna get to do a sub-internship in surgery," to, "You're not gonna be a surgeon," to, "You're never gonna walk again." So by that point-

    6. SMSean Mackey1:18:11

       Yeah

    7. PAPeter Attia1:18:11

       ... the overlap was how were the opioids that I was being prescribed to control the pain tripping into, "These are a tool to numb me to this entire experience"? So at this point I've, and I've talked about this in the past, at this point I was taking over-- I think I was up to maybe three hundred and twenty milligrams of OxyContin a day, which is kind of amazing, 'cause if you and I took that today, if you and I split that right now, we would die [laughs] . So that I'm, you know, that I'm mainlining three hundred and twenty milligrams of OxyContin a day just to pr- you know, m- blunt the emotional pain of this-

    8. SMSean Mackey1:18:47

       Yeah

    9. PAPeter Attia1:18:48

       ... um, I think says what we need to know. We can come back to the story of how I met you and, and, and what, how my life turned around from that point, and it's still a miracle for me to believe I actually graduated from medical school on time. Despite that all happening now-

    10. SMSean Mackey1:19:04

        Yeah

    11. PAPeter Attia1:19:04

        ... into my fourth year, 'cause this was my third year, uh, bleeding into my fourth year of medical school when all this was going on. It's kind of amazing.

    12. SMSean Mackey1:19:10

        A difficult time.

    13. PAPeter Attia1:19:11

        Yeah.

    14. SMSean Mackey1:19:11

        Third year is tough.

    15. PAPeter Attia1:19:12

        But anyway, so we'll come back to the-

    16. SMSean Mackey1:19:13

        Okay

    17. PAPeter Attia1:19:13

        ... what happened, but that's a long answer to a question, which is at some point, it wasn't even about the pain. The pain was unbearable, but it wasn't the most unbearable part. It was the expectation of what that pain meant for-

    18. SMSean Mackey1:19:28

        Yeah

    19. PAPeter Attia1:19:28

        ... the rest of my life that became much more unbearable.

    20. SMSean Mackey1:19:32

        It's a terrible story, and I have to imagine one that has probably shaped you moving forward and, you know, had a big impact on your life and what you've been doing.

    21. PAPeter Attia1:19:45

        I call it the best, worst experience of my life.

    22. SMSean Mackey1:19:48

        Yeah.

    23. PAPeter Attia1:19:49

        Mo- more, more best today. The gratitude I have for that is... I mean, I, again, wouldn't wanna do it again, but it has been such a positive impact on my life.

    24. SMSean Mackey1:19:58

        Yeah. Yeah.

11. 1:20:00 – 1:33:19

    The pharmacology of common pain medications—NSAIDs, COX-2 inhibitors, & acetaminophen

    1. SMSean Mackey1:20:00

       Well, I hope we can come back to that, um, and talk about it more and the influence of all this other stuff that was probably contributing to your experience of pain and the bad stuff going on as a consequence of it, and plays a role in, like, everybody else's life out there. Uh, and I think there's some key messages there. Um, what would you like to segue to?

    2. PAPeter Attia1:20:28

       Before we go into kind of like the ins and outs of what pain doctors can do-

    3. SMSean Mackey1:20:34

       Yeah

    4. PAPeter Attia1:20:34

       ... let's just talk about some of the bread and butter stuff on pharmacology.

    5. SMSean Mackey1:20:38

       Okay.

    6. PAPeter Attia1:20:38

       Right? So how, how can we navigate our way through what NSAIDs do, what opioids do, what COX-2 inhibitors do? What should people be aware of in using these things? Obviously, opioids are a remarkably controversial topic, but there's probably a nuance to it that's missing from the broader discussion. Um, but why don't we start with a softball like NSAIDs?

    7. SMSean Mackey1:21:00

       Yeah.

    8. PAPeter Attia1:21:00

       How do they work? You know, everybody's heard of Advil.

    9. SMSean Mackey1:21:03

       Yeah.

    10. PAPeter Attia1:21:03

        You know, Aleve, Naproxen, all of these things.

    11. SMSean Mackey1:21:05

        Sure. So these, uh, these medications are, uh, cyclooxygenase inhibitors. They reduce, uh, prostaglandins. They redu- they... What they do is a couple things. They reduce some of the inflammation. They're anti-inflammatories. So I was alluding very briefly that there are substances that can be released out in the periphery during injury that wind up that s- that nociceptor and amplify it. Prostaglandins, histamine, cytokines, interleukins, all of that, this inflammatory soup that occurs after every single surgery, every single injury that we experience, you get this inflammatory soup, and it's classibly- classically mediated by swelling, redness, temperature increases, and aspirin and a COX-2 inhi- uh, COX-2 inhibitor NSAIDs do a nice job in reducing that inflammation. Now, this, this is where medical science... I, I, n- I, you're, you're gonna probably be much more informed on me- informed than I am on this, but medical science has been slowly shifting in its view of this. We have historically thought, take these medications in an acute injury. It knocks down that inflammation, and all is well and good. Well, some of the data was coming out in the orthopedic literature decades ago that people who were taking NSAIDs during total joint replacements were getting non-fusion of that joint to the bone. They were getting failures.

    12. PAPeter Attia1:22:46

        Hmm.

    13. SMSean Mackey1:22:46

        And then more recently, there's been some question as to whether knocking down the inflammation is a good thing after all, that maybe that inflammation is part of the healing process, and that by giving an NSAID aspirin, we're delaying the natural healing effect and causing more problems. So where's the truth? This is tough. One, I don't think we have the whole story yet on the NSAIDs. Two, I'm a gray guy, meaning I don't live in black and white, and I'm also appreciated that every medical field has their own lens that they look at, uh, in the world, and I think we have to appreciate the complexity of the patient, meaning if it's perhaps something minor, and they can get by without the NSAID, and it's not gonna change significantly their level of function, then maybe not taking it will improve healing. They can't get out of bed. They can't go to work. But a n- Naprosyn helps them to do that thing so that they can engage with their family, with their friends, with work. Well, then heck yes, take the NSAID. You know, if it's, if it's helping with that level of functional improvement. And-

    14. PAPeter Attia1:24:07

        Now, are you talking about this through the lens of acute, acute pain or only through the lens of chronic pain at this point?

    15. SMSean Mackey1:24:13

        A little of both, but I think through, uh, chronic pain, we start to introduce all the broader, the longer term negative consequences of this, you know, impact on blood pressure, your heart, impact on your kidneys with long-term NSAIDs, particularly if you're older. Um, I remember, I think it was in your book, you took Vioxx.

    16. PAPeter Attia1:24:39

        Yes.

    17. SMSean Mackey1:24:40

        I loved Vioxx.

    18. PAPeter Attia1:24:41

        I did too, and I still remember the day in, oh God, it must have been December 2001 when the FDA came down and said, "No more Vioxx," and I looked at my last bottle, and I was like, "Oh God, no."

    19. SMSean Mackey1:24:53

        I stockpiled it.

    20. PAPeter Attia1:24:54

        I wish I did.

    21. SMSean Mackey1:24:55

        I called up all the drug reps I knew 'cause they couldn't, like, give it out, and I'm like, "Can you just hook me up?" And so I ran out a stockpile of that for a long time, and you know, this is another classic thing. If you, uh, you can cut this if it's too tangential, but you know, every field looks at the problem through their own lens. Here, you had a drug that was causing, um, heart attacks. Well

    22. PAPeter Attia1:25:21

        I mean, in the world's most susceptible individuals at a relatively small absolute rate. Yeah.

    23. SMSean Mackey1:25:28

        At the, at the highest dose.

    24. PAPeter Attia1:25:29

        I've already had this discussion with Eric Topol-

    25. SMSean Mackey1:25:31

        Okay

    26. PAPeter Attia1:25:31

        ... which was like mistake.

    27. SMSean Mackey1:25:33

        Yeah.

    28. PAPeter Attia1:25:33

        Net negative.

    29. SMSean Mackey1:25:34

        Oh, is that right?

    30. PAPeter Attia1:25:34

        Absolutely. Net negative.
12. 1:33:19 – 1:43:25

    Muscle relaxants: benefits, drawbacks, & personalized strategies

    1. SMSean Mackey1:33:19

       Yeah

    2. PAPeter Attia1:33:19

       ... okay, I wanna talk about muscle relaxants. So the other thing that has been a real, uh, favorite tool of mine is baclofen. Now, it's not a particularly potent muscle relaxant, um, but it seems to, for me, and for the patients of mine in whom it works, offer something that something really potent like Valium doesn't bring all the baggage of, of, of a benzo-

    3. SMSean Mackey1:33:48

       Yeah

    4. PAPeter Attia1:33:48

       ... or even a Flexeril where you can kinda get the drowsiness, and frankly, a lot of people just... I mean, I used to even get nauseous on Flexeril.

    5. SMSean Mackey1:33:54

       Okay.

    6. PAPeter Attia1:33:55

       But something about baclofen, I don't even know it's in me-

    7. SMSean Mackey1:33:58

       Yeah

    8. PAPeter Attia1:33:58

       ... at twenty milligrams twice a day, but it actually takes the edge off. And where I typically find this beneficial is if I slept wrong, and I get a kink in my trap-

    9. SMSean Mackey1:34:09

       Yeah

    10. PAPeter Attia1:34:09

        ... or I've been on a super long drive, and my QLs sort of flare a little bit, and I know that if I had all the time in the world, I could go and stretch my way out of that, but sometimes I just don't have that time, and I need to kinda get right back to doing something awful like sitting. And just, you know, two or three days of twenty milligrams of baclofen BID with a little NSAID, and, like, I'm as good as new, and I save myself the, you know, the real flare up. So what, what are your-

    11. SMSean Mackey1:34:41

        Yeah

    12. PAPeter Attia1:34:41

        ... experience with muscle relaxants?

    13. SMSean Mackey1:34:43

        Beautiful case example, by the way, for yourself of how we would use those. Um, baclofen's one of the safest to use. It is not habit-forming like the Somas-

    14. PAPeter Attia1:34:57

        Yep

    15. SMSean Mackey1:34:57

        ... and others that can be, uh, like a barbiturate, can act, and people can get highly psychologically dependent on them. The Flexerils have a, uh, anti-- have a tricyclic antidepressant property about them that may sometimes be helpful for people in various mixed-

    16. PAPeter Attia1:35:18

        Mm

    17. SMSean Mackey1:35:19

        ... pain states, but also can cause sedation.

    18. PAPeter Attia1:35:21

        Yep.

    19. SMSean Mackey1:35:22

        The baclofen seems to be pretty benign. Um, we don't typically use muscle relaxants for long-term chronic conditions. The data hasn't borne out. Now, with that said-

    20. PAPeter Attia1:35:36

        So how many days are you comfortable with a person-

    21. SMSean Mackey1:35:38

        Oh, I'm, I'm comfortable with a person being on baclofen all their life, to be clear.

    22. PAPeter Attia1:35:41

        Oh, you are? Okay.

    23. SMSean Mackey1:35:41

        Oh, yeah, yeah. It's just everything I'm doing-- I, I know I'm-- Forgive me if I'm preaching to the choir here. Everything I'm doing is taken in the context of the person in front of me and the cost and benefit of the treatments I'm providing them, meaning there are costs with baclofen. I don't mean monetary cost.

    24. PAPeter Attia1:36:05

        Yep.

    25. SMSean Mackey1:36:05

        It can cause sedation.

    26. PAPeter Attia1:36:06

        What dose is typically, or is it just individual? Like I-

    27. SMSean Mackey1:36:08

        I think it's, it's individual, and obviously it is dose dependent. The higher-

    28. PAPeter Attia1:36:12

        Yep

    29. SMSean Mackey1:36:12

        ... dose is more sedation. Um, we can use baclofen intrathecally. We put in-

    30. PAPeter Attia1:36:19

        Hmm
13. 1:43:25 – 1:44:43

    The definition of chronic pain

    1. PAPeter Attia1:43:25

       so by definition... What's the, we didn't even do this. I'm sorry. We didn't define chronic pain, but w- how would you put a definition on that?

    2. SMSean Mackey1:43:31

       There's various definitions. Some like to put a timeframe on it, which I think many of us believe is a little artificial. It's not three months or six months. It is pain that persists beyond the expected time of tissue healing. So it is nuanced. It's context-specific, meaning if you have an inguinal hernia repair or a prostatectomy, which, you know, should heal up pretty quickly, and your pain should go away pretty quickly. But if you've got pain after couple, few months, that's starting to get to that point where I'm a little worried something's going on from a chronic pain. But if you had a total knee replacement, that is a massive, massive surgery, and you're gonna have pain for quite some time.

    3. PAPeter Attia1:44:21

       Mm-hmm.

    4. SMSean Mackey1:44:22

       So I wouldn't call that, I wouldn't call chronicity for a total knee-

    5. PAPeter Attia1:44:26

       No, it makes sense

    6. SMSean Mackey1:44:26

       ... You would, I'm, okay.

    7. PAPeter Attia1:44:27

       That totally makes sense.

    8. SMSean Mackey1:44:28

       Context specific. Um, this gets into also some of the whole issue around opioid prescribing and these rigid timeframes for surgery and, and what have you. But persistence beyond the time of expected tissue healing.

14. 1:44:43 – 1:49:11

    The role of antidepressants in pain management

    1. PAPeter Attia1:44:43

       Antidepressants and their role in pain management?

    2. SMSean Mackey1:44:46

       Yeah. These are incredibly effective agents, not necessarily for their antidepressive properties. They frequently work through modulating a couple neurotransmitters, serotonin and norepinephrine, and to varying extent. We find that the classic, what we refer to as SSRIs, the seroton- the selective serotonin reuptake inhibitors, haven't been as effective for pain as the older dirty drugs of the tricyclic antidepressants. We call them dirty, which simply means they act at multiple receptors. They hit multiple systems. So these tricyclics hit the serotonin and norepinephrine systems, and then they also happen to be pretty potent sodium channel blockers. Why the sodium channel blocking property is important is when we talked earlier about the peripheral nerves, one of the main drivers of an action potential is activity around the sodium channels. You block the sodium channels, the action potential stops.

    3. PAPeter Attia1:45:56

       Do you remember how much you gave me?

    4. SMSean Mackey1:45:58

       Of?

    5. PAPeter Attia1:45:59

       How much sodium? Uh, sorry, how much lidocaine?

    6. SMSean Mackey1:46:03

       Back then, I ho- I hope it wasn't toxic. Uh-

    7. PAPeter Attia1:46:06

       We'll, I'll come back to the story. It's pretty funny.

    8. SMSean Mackey1:46:07

       I'm looking forward to it. Um-

    9. PAPeter Attia1:46:09

       Um, which, which TCAs, uh, are the, are the popular ones?

    10. SMSean Mackey1:46:13

        Everybody... D- you know, there's, I think there's about nine sort of your core-

    11. PAPeter Attia1:46:18

        What are your, what are your top two or three?

    12. SMSean Mackey1:46:20

        Yeah, that's the thing. We all get comfortable with our top two or three of any class, and so mine's, my go-to is desipramine, nortriptyline, and amitriptyline. Um, they're broken up into different categories based on mainly side effect profiles. So the-

    13. PAPeter Attia1:46:41

        After nortriptyline, what was it?

    14. SMSean Mackey1:46:43

        Uh, amitriptyline or Elavil.

    15. PAPeter Attia1:46:44

        Oh, amitriptyline. Yep, yep.

    16. SMSean Mackey1:46:45

        So Elavil's an older tricyclic that has a lot of histamine release, a lot of sedating properties. I would never give that to an older guy with a big prostate 'cause he couldn't pee.

    17. PAPeter Attia1:46:57

        Yeah.

    18. SMSean Mackey1:46:58

        And he'll be very angry with me. I will never give that to a young woman who's looking to watch her weight because she's gonna get the munchies, and she's gonna put on 10 or 20 pounds, and she's gonna hate me. Have I had that happen? Yes, and I still embarrassed to this day. Um, but if I have some-

    19. PAPeter Attia1:47:16

        Is it offset by GLP-1 agonists in the modern era?

    20. SMSean Mackey1:47:19

        Oh, you know, this was 20-- I've learned my lessons. I haven't, I haven't run that experiment.

    21. PAPeter Attia1:47:25

        Hmm.

    22. SMSean Mackey1:47:25

        That's a great idea. But I typically use the amitriptyline when I need some sedating help at night for sleep and pain 'cause it dual, the dual action. I like the desipramine 'cause it has less of that histam- that sedating property, and I'll tend to go to that and the nortriptyline. Um, and you can titrate blood levels of, for instance, like the nortriptyline. And those drugs, so where do they work? They work in the brain. They work in the brainstem. One of the classic, um, areas down deep in the brainstem is a rostral ventral medullary region where descending pathways are coming down, and some of the key neurotransmitters there are serotonin, norepinephrine. So we're not necessarily using these drugs for their mood-changing properties. We're using them because they hit the same systems as they do in pain, and that's the beauty of them. And that's some of the messaging we have to give patients when we, when we prescribe them an antidepressant is like, "Okay, you know-"

    23. PAPeter Attia1:48:32

        Yeah.

    24. SMSean Mackey1:48:33

        "... uh, you know, Mrs. Jones, Mr. Smith, we're not doing this-"

    25. PAPeter Attia1:48:37

        Because we think we're, you're depressed, and that's why we're doing it.

    26. SMSean Mackey1:48:39

        You're depressed.

    27. PAPeter Attia1:48:39

        Yep.

    28. SMSean Mackey1:48:40

        These are great, great, great pain drugs, but they were never FDA approved. Why were they not FDA approved? 'Cause they're off patent. There's no money to be made.

    29. PAPeter Attia1:48:48

        Yeah, F- not, not FDA approved drug, uh, uh, approved for pain is what you meant. Yeah.

    30. SMSean Mackey1:48:52

        Thank you.
15. 1:49:11 – 2:13:04

    Opioids: their controversial & nuanced role in pain management

    1. PAPeter Attia1:49:12

       um, a lot of hay has been made over this. Um, there's no question that, um, opioids have been overused and abused, and there's no question that, um, illicit use of these things has had a devastating, uh, impact on our society. Um, but it would be difficult to say that the field of medicine would be better off having never had an opioid To, you know, we just talked about surgery, for example. Very challenging to deliver medical care in a hospital without opioids. So the question becomes, what is the most responsible case for oral opioids, which by definition are meant to be used outside of a hospital, not inside a hospital? Um, and as a pain specialist, I c- I would imagine few people are better equipped to navigate the nuance of that question.

    2. SMSean Mackey1:50:17

       Yeah. It is a very nuanced question. Um, I think a, a little preamble first. I don't take money from either the opioid companies, I don't take money from the litigation that's ongoing, 'cause there are tens and tens of billions of dollars at play right now.

    3. PAPeter Attia1:50:34

       Yep.

    4. SMSean Mackey1:50:35

       Uh, I don't take money, end of. I am not pro-opioid. I am not anti-opioid. I am pro-patient. I view them as a tool. I view them as a tool much like the other medications, interventions, mind, body, physical, rehabilitative, complementary tools that we use. They have a particular place. I have a personal deep appreciation for the destruction that these agents can cause. I come from a family very deep in addiction, very deep. I've lost close family members to opioid overdose. I've lost close family members to alcoholism. I am personally petrified of these drugs, and I have gone through surgeries that the surgeon said, "You can't get through this without an opioid," and I'm like, "I'll be fine."

    5. PAPeter Attia1:51:32

       [chuckles]

    6. SMSean Mackey1:51:33

       'Cause my approach is avoidance. With that said, I've learned a long time ago not to project my personal experiences onto my patients. That had to come through age, wisdom, whatever. Um, it is true, prescription opioids were overprescribed, they were over-marketed, they were, you know, there were bad actors doing bad things. It came at a time, but it's, it's not that simple a story. I, I sometimes get frustrated because I feel like you can make really simple sound bites out of this complex societal issue when it was a perfect storm that hit. Yes, um, you had a letter to the editor of New England Journal saying that nobody got addicted to on a s- like 38 patients or some nonsense, and-

    7. PAPeter Attia1:52:31

       [chuckles]

    8. SMSean Mackey1:52:32

       ... Purdue and others ran with this. I, and I get that, and they did bad things. You also have to put things in the context of what was going on in society. There was growing awareness of pain, as there should be. Um, there was growing pressures to do something about it. Uh, people have brought up the pain as a fifth vital sign as an example, and people have different opinions about that. Uh, did it have bad consequences? Yes. Did it have good consequences? Hell yes. Run the counterfactual. Do you want to go back to a time when we're not asking patients after surgery their pain? Do you want your mother, your daughter back in that time? And I think the answer is clearly no. But also there was other pressures, and Peter, you were, you witnessed those firsthand. What was going on back in the '90s and the 2000s, and s- after surgery, there was this massive push to get people out of the hospital and put them in their home. We were replacing care in a hospital with care in the home. In the hospital, we had time to see their trajectory. We could titrate their opioids or whatever, get them tuned up, dialed in, and then send them home. Now, surgery, overnight, you're home, let's give you a, a bucket of whatever, and the reason for that was surgeons and docs don't like getting called at 3:00 AM for pain control. So pressure to put people out in the, uh, in the home environment. On top of it, docs get lousy training for pain. Like, what is the average? Seven hours, I think, uh, in medical school. Vets, by the way, 40 hours of pain. So great if you've got a dog, not so great for a patient.

    9. PAPeter Attia1:54:26

       [laughs]

    10. SMSean Mackey1:54:27

        So you got this pressure, and by the way, not only on top of that, but now you've got the introduction of patient satisfaction scores. I have to imagine in your private practice, you don't have to measure Press Ganey and patient satisfaction scores, but in hospitals, everybody does, or at least they did. I think they're coming to their senses. And so one way of addressing the satisfaction, give more opioids. So there's... And there's more. There's many, many, many pressures that came to bear that helped create this problem, of which there were bad actors out there.

    11. PAPeter Attia1:55:02

        By the way, the perfect analogy to this is the, uh, mortgage crisis, uh, in 2006 to 2008-

    12. SMSean Mackey1:55:10

        Yeah

    13. PAPeter Attia1:55:10

        ... where if you took a zeroth order view, it would be really easy to blame one of the entities.

    14. SMSean Mackey1:55:18

        Yeah.

    15. PAPeter Attia1:55:19

        But it is actually a perfect storm, right?

    16. SMSean Mackey1:55:22

        I have a slide, yeah, on the opioid crisis. I call it the perfect storm.

    17. PAPeter Attia1:55:26

        Yeah.

    18. SMSean Mackey1:55:27

        Uh, you're absolutely right. And in the end, and here I'm gonna be a little bit reductive when it comes to the docs' roles in this, and I'm gonna borrow from my friend, uh, Professor Keith Humphreys. There are three kinds of physicians in the, out there. There are the majority of the physicians doing the right thing for the right reasons There are the next group, which is a much smaller group, physicians doing the wrong thing for the right reasons. And at the very top of that pyramid, a little group, you got physicians doing the wrong thing for the wrong reasons. Bad. Those people at the top, take away their license, put them in jail. But you had a group of people here in the middle that were doing the wrong thing for the right reasons, that they either didn't have the right education. They thought they were helping people. Um, they, did they contribute to the problem? Yes. Uh, have they gotten educated? Have we? Um, yes. I didn't answer your question, though, and let me now circle back, and, and I hope you'll forgive that little bit of soliloquy, uh, on my perspective of that 20 years. Um, I don't use opioids as a first line agent ever. Almost never. Uh, end of life, cancer, but usually by then they've tried other things before they're getting to us. And, uh, I will use end of life cancer pain, I'll use opioids liberally as needed.

    19. PAPeter Attia1:56:58

        Now, just one thing-

    20. SMSean Mackey1:56:59

        Please

    21. PAPeter Attia1:56:59

        ... Sean, you are not taking care of somebody in the acute phase of expected pain typically, is that correct? In other words, that guy that just had a knee replacement, he's being managed by his surgeon, correct?

    22. SMSean Mackey1:57:13

        You know, frequently, uh, we have an acute pain service-

    23. PAPeter Attia1:57:16

        Okay

    24. SMSean Mackey1:57:16

        ... in the hospital that sees about 30 to 50 patients a day.

    25. PAPeter Attia1:57:20

        Based on what? When is a patient being, when is the big gun of your team's expertise being brought in for a post-surgical routine case versus not?

    26. SMSean Mackey1:57:31

        When, most frequently, when the outcome is not simple. So when the surgeon needs some help, when the internal medicine doc needs help, and it's beyond their comfort.

    27. PAPeter Attia1:57:45

        Hmm. You know, when we brought pain in for every case when I was in residency, uh, was, uh, any time we did a thoracotomy, it was a non-negotiable.

    28. SMSean Mackey1:57:54

        Yeah.

    29. PAPeter Attia1:57:54

        Pain was consulted before the case. Just for people listening, a thoracotomy, we didn't do these often because a lot of times, by the time I was in residency, we did minimally invasive surgery in the chest.

    30. SMSean Mackey1:58:03

        Yeah.
16. 2:13:04 – 2:21:09

    Alternative therapies: acupuncture & cannabis

    1. PAPeter Attia2:13:05

       let's talk about, um, acupuncture.

    2. SMSean Mackey2:13:07

       [laughs]

    3. PAPeter Attia2:13:09

       What do you know about it?

    4. SMSean Mackey2:13:10

       [gasps] Well, there's a lot of-

    5. PAPeter Attia2:13:15

       Let's talk about through the lens, let's talk about through the lens of chronic pain.

    6. SMSean Mackey2:13:17

       Yeah, yeah, yeah. All right. Clinically. Uh, some people get better, some people don't get better. I cannot yet predict who is gonna respond and who's not gonna respond. This idea-

    7. PAPeter Attia2:13:30

       Is it a part of the work that your department does?

    8. SMSean Mackey2:13:33

       Yeah. We actually have Dr. Jean T. Kong does the acupuncture. She's a pain doc. She does acupuncture. And my view of acupuncture as a mo- as a treatment, as a modality, is if you can afford the wallet biopsy and it doesn't cause you problems, then give it a try.

    9. PAPeter Attia2:13:51

       And you say wallet biopsy because the insurance doesn't typically cover it?

    10. SMSean Mackey2:13:54

        They do more so now on Medicare, and I think that the rules that went into place recently helped with that for older patients. I don't honestly know if it's translated down to the commercial carriers.

    11. PAPeter Attia2:14:05

        So Medicare's covering something commercial payers are not?

    12. SMSean Mackey2:14:08

        Well- It's possible.

    13. PAPeter Attia2:14:10

        Okay.

    14. SMSean Mackey2:14:11

        Yeah. I- it has historically been hard to get that-

    15. PAPeter Attia2:14:13

        Got it

    16. SMSean Mackey2:14:13

        ... uh, covered.

    17. PAPeter Attia2:14:14

        So notwithstanding, I like the idea of a wallet biopsy. I hadn't heard that before. Um, in your experience, where do you see it being most successful? What type of pain? What type of clinical presentation?

    18. SMSean Mackey2:14:28

        Yeah. I've had some successes in back pain, musculoskeletal pain, migraines-

    19. PAPeter Attia2:14:34

        Mm-hmm

    20. SMSean Mackey2:14:34

        ... headaches, oddly. Um, and it's highly variable. I studied this. I had a really large program project grant to look at cortical mechanisms of this and, um, predictors. And, you know, we're putting in a paper now, which is a prediction model of, uh, real acupuncture versus placebo acupuncture, uh, sham.

    21. PAPeter Attia2:14:59

        How do you do placebo, placebo acupuncture? You, you-

    22. SMSean Mackey2:15:01

        It is-

    23. PAPeter Attia2:15:01

        ... puncture but not in the appropriate spot?

    24. SMSean Mackey2:15:04

        Well, that's one option.

    25. PAPeter Attia2:15:05

        Okay.

    26. SMSean Mackey2:15:05

        And it turns out that many of these acupuncture points overlie peripheral nerves.

    27. PAPeter Attia2:15:09

        Hmm.

    28. SMSean Mackey2:15:10

        And so when you, you know, twiddle the needle or apply ac- electroacupuncture, are you doing a peripheral nerve stimulation? I don't know. Um, but this is a Stridinger needle that looks for all intents and purposes like an acupuncture needle. It causes a little pin prick, but it doesn't actually do acupuncture, and it's been shown to be a good, uh, placebo. What do I know about the mechanisms? Again, um, don't fully understand. I know that there is increases in peripheral adenosine that is released with acupuncture that has an analgesic effect at the primary nociceptor. I know that cortically in the brain, there are brain systems that are modulated with acupuncture, but heck if I know exactly how it works. Um, there's... And, and we still don't have good ways of predicting who's gonna respond and who's not gonna respond, but that's rather common amongst all of our pain treatments. But, uh, you know, again, uh, pretty safe. You know, absent, um, some risk of infection. You know, make sure that the facility you're getting at, uh, practices good hygienic approaches. Pretty safe.

    29. PAPeter Attia2:16:28

        How do we think of acupuncture differing from dry needling?

    30. SMSean Mackey2:16:31

        Yeah, I think you need to wa- I think you'll wanna get an, a true acupuncture specialist on to-
17. 2:21:09 – 2:38:24

    Fibromyalgia & chronic pain: clinical features, brain mechanisms, & emerging treatments like low-dose naltrexone

    1. PAPeter Attia2:21:09

       you've already alluded to today that I am sure everyone has heard of, and yet if you asked most people to define it, they wouldn't be able to define it. And so we're gonna start with what it is, why someone might have it, what is the prevalence, are there false positives? I'm talking about none other than fibromyalgia.

    2. SMSean Mackey2:21:30

       Yeah. Yeah. What was historically a garbage bag definition. Um, fibromyalgia is, um, a condition of widespread bodily pain that impacts people above and below the waist, the diaphragm. It's associated with, um, early morning stiffness, fatigue, mental fog, uh, often, you know, some GI problems. It is, uh, was historically, uh, based on American College Rheumatology definitions based on tender points in 11 out of 18 places, but that's been replaced by now criteria w- which involves multiple body sites affected and a symptom severity score. The key thing when the audience hears... Well, first of all, it's fibromyalgia syndrome, and whenever the audience hears syndrome, what they should translate that to, the definition of a syndrome, is a constellation of signs and symptoms that define a disease, but we don't understand the mechanism. So fibromyalgia is a syndrome. We do not understand its mechanisms. We know that historically it tended to affect women more than men, about 80%-ish or so women. With the newer definition, we're picking up a lot more men. Um, the cognitive aspects of it are really a problem. It's also associated, as I alluded to, with sleep disturbances. They get this weird, what we call alpha wave intrusion into their EEG, which means alpha waves are typically in light awakefulness. So when you're supposed to be in deep sleep or REM sleep, your brain is in kind of a light alert state instead, and so they're not getting a restful sleep. This is a d- syndrome that's caused untold problems, particularly for women.

    3. PAPeter Attia2:23:42

       What's the prevalence according to the current definition?

    4. SMSean Mackey2:23:46

       I can't tell. I, I should know how many millions there are, Pete. Um, that's a, that's a... I should know how many millions, and I don't. What I, I can tell you just to give a frame of reference, um, chronic pain, we think there's 50 to 100 million Americans with chronic pain. That's a huge range, and it depends on the way you ask the question. Um, if you ask it more stringently, it's 50 million. If you ask it more liberally, it's 100. We know that there are about 8% of the population, or a little over 20 some odd million, with something called high impact chronic pain. This is a big one, and this is where I spend a lot of my research and policy work on. These are the people that has substantial restrictions to their pain in activities of daily living. These are the really challenging people. Of that 50 to 100 million, the most common chronic pain is low back pain at about 28%, neck pain 16%, headaches around 16%. Societal burden of chronic pain is terrifying. It's astounding. We spend over half a trillion dollars a year in chronic pain, and the reason why, in part, it's not more appreciated is because we have parceled it out. We've broken it into different categories. You know, with heart disease, we lump it into heart disease, cardiovascular disease, even though it's all these different subcomponents. With pain, instead, we categorize it as it's either, you know, it's back pain, it's musculoskeletal pain, it's migraines, it's abdominal pain, and it gets dis- diluted out. But when you put it all together, you're dealing with a half a trillion dollars. It's more than diabetes, heart disease, and cancer combined. Fibromyalgia, again, I'm escaping the prevalence. Many millions of people. Huge societal burden. It is historically, uh, a disease of histrionic housewives is how they were mislabeled tragically, and we're having now a greater appreciation for what it is, um, what's affected. What we have learned is that there are brain systems that are clearly abnormal in the processing of pain in people with fibromyalgia We find that for the same pressure stimulus, if you apply something like four kilograms per square centimeter, healthy people will give a range of reporting in certain range. People with fibromyalgia, much, much higher. Here's another interest. I think this is an interesting, um, pain concept to introduce and talk about it. There's something called conditioned pain modulation. In the animal world, we called it diffuse noxious inhibitory controller, DINIC. CPM. Okay. Think back to when you were a kid. Your arm hurt. You walk up to your buddy, you say, "Hey, man," you know, and he's like, "How you doing?" It's like, "Well, my arm's kind of hurting a lot." And what would he do?

    5. PAPeter Attia2:27:00

       Hit you?

    6. SMSean Mackey2:27:00

       He would hit you, of course. He'd hit you in your other arm, he'd stomp on your foot, and you're like, "Why the hell did you do that?"

    7. PAPeter Attia2:27:05

       But by the way, this is a boy only thing. Like, I can't imagine girls did this, but yes, it's of course this is what little boys do.

    8. SMSean Mackey2:27:11

       This is what little boys do. I was guilty of a lot of that. But then you'd say to your buddy, like, "Don't you feel better?" And the truth is you did, because pain in another area reduces the primary pain site. It's called conditioned pain modulation. We're all wired. It is a network predominantly, we think, in the brainstem involving some of this, uh, periaqueductal gray, rostral ventral medullary regions. Labar first described this in the mid eight- mid-'70s in animals. So we all do it. We all have it. It's this endogenous tonic inhibitory tone that you can activate when you cause pain in another site, unless you have fibromyalgia. If you have fibromyalgia, particularly if you're a woman with fibromyalgia, you, you have impaired CPM. You don't inhibit.

    9. PAPeter Attia2:28:08

       Now, is there a high overlap with depression, anxiety, and fibromyalgia, and if so, which is the-

    10. SMSean Mackey2:28:16

        Precursor

    11. PAPeter Attia2:28:16

        ... order of causality?

    12. SMSean Mackey2:28:17

        Yeah, the chicken and egg. We used to think that there was a high preponderance of anxiety and depression, um, with fibromyalgia, and I think the current data doesn't support that there's any higher prevalence than, uh, particularly any other pain conditions. I think you tend to see more of the anxiety, depression, broadly speaking, in things like low back pain.

    13. PAPeter Attia2:28:40

        Mm-hmm.

    14. SMSean Mackey2:28:41

        I think what you see more of in fibromyalgia is fatigue, unrelenting fibro fog is what they call it, and, uh-

    15. PAPeter Attia2:28:50

        What is the-

    16. SMSean Mackey2:28:50

        And then the sleep disturbances.

    17. PAPeter Attia2:28:52

        And so what is the management for these patients? Is this a curable syndrome, or is it a syndrome that is meant to be managed like HIV?

    18. SMSean Mackey2:29:03

        Yes and no. What do I mean? Well, one, we don't know exactly the mechanisms. There's different prevailing thoughts. Um, one thought again is it's a disruption in your central brain processing of pain through reasons unknown. Uh, there are some that believe it is a disease, a condition of small fiber neuropathy because you can do punch biopsies, little, little skin biopsies here, and what they find in some subsets of people with fibromyalgia is those C fibers, [lip smack] that there is alterations, abnormalities of the C fibers in the skin, and that is synonymous with a small fiber neuropathy that neurologists typically see. Now-

    19. PAPeter Attia2:29:50

        But that's caused by what?

    20. SMSean Mackey2:29:51

        Yeah, that's the thing.

    21. PAPeter Attia2:29:52

        Is this infectious? What do people think is going on?

    22. SMSean Mackey2:29:55

        So fibromyalgia is frequently preceded by some event, um, something traumatic. That traumatic can be a physical motor vehicle accident, but it could also be some, uh, emotional or sexual abuse. It can be an infection. We frequently s- you know, also hear that story. So there is some insult that people will frequently identify. Uh, getting back to your question on managing this, we frequently use the same medications that we've described before, but we rely on more of those brain modulatory drugs.

    23. PAPeter Attia2:30:35

        The TCAs are the big...

    24. SMSean Mackey2:30:38

        Um, another one's like duloxetine, which is in the class of antidepressants, but it's a little cleaner, fewer side effects. It's a serotonin norepinephrine reuptake inhibitor. This is actually a drug that got FDA approval for pain, and so we go to this a lot. Uh, one of the drugs that I have studied, uh, with Jared Younger, who's now at UAB, is a drug called low-dose naltrexone.

    25. PAPeter Attia2:31:08

        Mm.

    26. SMSean Mackey2:31:09

        This is a fascinating drug, [lip smack] and it's got like this underground reputation out there that's all over the forums, and the reason for it is because it's been around for decades and off patent, there is zero money for any pharmaceutical company for it. What is naltrexone? Naltrexone, when given at fifty milligrams, is used to block opioid receptors. It's an opioid blocker, and so we use this in the treatment of opioid and alcohol addiction because it blocks the rewarding experiences of alcohol or opioids, and so it's used as a, as a treatment for addiction. Fifty milligrams. At four and a half milligrams, one tenth of the dose, it has been shown to activate, to block toll-like four receptor on the microglia. Now, I just introduced like this really technical concept, so allow me to briefly explain. The microglia are these cells that hang around nerves but are not neurons. And when I was in medical school a few years, several years before you, what I was taught was these microglia were like the warm, fuzzy blanket that propped up the nerves. I don't know what you were taught, but-

    27. PAPeter Attia2:32:33

        [laughs]

    28. SMSean Mackey2:32:34

        ... um, they provided structural support to the nerves. What I learned is that was only part of the story, that they're key neural immune modulators. And so what I mean by that is, in times of stress, injury, fever, these microglia get activated. They release all sorts of inflammatory mediators, chemicals, that sensitize the central nerves responsible for pain perception, pain transmission, pain perception. So you give low-dose naltrexone, it blocks that. It blocks that neuroinflammatory soup. And in some patients, Peter, this drug's been magical. Like, magical. Uh, I give it in four and a half milligrams.

    29. PAPeter Attia2:33:22

        Uh, silly question. Why not five? Like, uh, 4.5 has a lot of specificity to it. Was there some reason why it came in at such a dose?

    30. SMSean Mackey2:33:30

        All right, here's my story. Linda Watkins and Mark Hutchinson did some of the early work in the animal studies on this and showed this microglial effect, and they did it at a certain dose. And so what we did is we did a milligram per kilogram conversion-
18. 2:38:24 – 2:44:38

    Possible brain benefits of low-dose naltrexone (LDN) for people with mild cognitive impairment

    1. PAPeter Attia2:38:24

       we think that at least a subset of people with neurodegenerative diseases, and you mentioned multiple sclerosis, but we think this is true in at least some cases of Alzheimer's disease, that, that neuroinflammation is a part of the pathology.

    2. SMSean Mackey2:38:40

       Yeah.

    3. PAPeter Attia2:38:41

       So would there be any efficacy to a trial there in either an individual with MCI, mild cognitive impairment, or a- as crazy as this sounds, is there a reason to consider it prophylactically-

    4. SMSean Mackey2:38:54

       Yeah

    5. PAPeter Attia2:38:54

       ... in high-risk individuals? W- with the caveat that, hey, by the way, if you happen to get an infection, like this would be a good time to stop it and ride it out and get better.

    6. SMSean Mackey2:39:03

       I think the short answer, short answer is yes. A little bit of the longer answer is everything-- I know you, you know this. Everything we do is weighing risk and benefits.

    7. PAPeter Attia2:39:15

       Yep.

    8. SMSean Mackey2:39:17

       This is one drug I am hard-pressed to come up with significant risks. We ha- we have decades and decades and decades of experience with this drug in people with addiction.

    9. PAPeter Attia2:39:30

       At 10X the dose.

    10. SMSean Mackey2:39:32

        At 10X the dose.

    11. PAPeter Attia2:39:32

        And how long are they typically on that drug?

    12. SMSean Mackey2:39:34

        Lifetime.

    13. PAPeter Attia2:39:35

        So meaning for, for a subset of individuals, just putting them on the party dose of 50 milligrams of naltrexone keeps them free of alcohol and opioids for life because it so blunts the pleasure center.

    14. SMSean Mackey2:39:48

        Yeah. The, the problem is, as all the addictionologists know, is that, um, it's hard to keep people on this 'cause they can just stop it and go back and use.

    15. PAPeter Attia2:39:56

        Yeah.

    16. SMSean Mackey2:39:57

        You know, so that's why you've got-

    17. PAPeter Attia2:39:58

        No, you have to want to be off.

    18. SMSean Mackey2:39:59

        You have to want to be off. They have injectable, uh, versions of this. It's not called Vivitrol, is it? It's, it's an injectable, uh, under the skin that lasts X number of days, months. Um, but yeah, we've got a lot of long-term data on this. And from a pilot standpoint, with informed consent, obviously, and just, you know, I would view that as a kind of a novel treatment in patients that one could try out, monitor, um, do some objective measures and, uh, see what, what, see what you get. Um, I wouldn't say that. I, I wanna be careful. I wouldn't say that for a lot of the things that we do because there's real risks with a lot of the medications that we provide, a lot of the procedures we do.

    19. PAPeter Attia2:40:51

        Mm.

    20. SMSean Mackey2:40:51

        Not only that, there's big costs that come with them, whereas this, I'm gonna make a plug here I have no relationship to, but we get our stuff out of Balmar Pharmacy in Colorado. Why? They're a compounding pharmacy. They've got all the certifications. Oh, y- the reason is you can't go to Safeway or Costco and get this.

    21. PAPeter Attia2:41:10

        You can't get low-dose naltrexone there, you mean? You have to-- It has to be compounded at 4.5, you're saying?

    22. SMSean Mackey2:41:15

        You're right.

    23. PAPeter Attia2:41:15

        Okay.

    24. SMSean Mackey2:41:16

        And so we go through this pharmacy because they've got good customer service. They take patients' credit cards over the phone, and they will ship it to you immediately, and they're very responsive. Um, you can probably find it in your local area at other compounding pharmacies. It usually runs about $30 a month.

    25. PAPeter Attia2:41:32

        So it's basically a free drug.

    26. SMSean Mackey2:41:33

        Insurance doesn't often cover it because it's exper-- they consider it experimental, but it's basically a free drug.

    27. PAPeter Attia2:41:38

        So it's a buck a day, yeah.

    28. SMSean Mackey2:41:40

        Yeah. So I, uh-- It, it's one that I use more and more and more 'cause of its safety profile and its potential for getting me a home run.

    29. PAPeter Attia2:41:52

        Yeah. My, my, my wheels are turning on-- I'm very curious to see if anybody has looked at LDN and, um, and, and, and, and, and any of the neuroinflammation stuff because, uh, look, we, we, you know, we see the relationship between herpes simplex virus and, uh, Alzheimer's disease-

    30. SMSean Mackey2:42:12

        Yeah
19. 2:44:38 – 2:57:14

    Peter’s recovery from severe chronic pain—how he went from immobility & high-dose opioids to full functionality

    1. PAPeter Attia2:44:38

       So when we met 25 years ago, how big was the department at Stanford in pain?

    2. SMSean Mackey2:44:44

       Division? Oh, we had, uh, about 10 to 12 people in it, and this is all the physicians, the nurses, the trainees. It was tiny, tiny, tiny, and we were in this small little clinic.

    3. PAPeter Attia2:44:55

       And today?

    4. SMSean Mackey2:44:56

       Probably 130, 150. We have a factor of 10 or more, and we've grown to be, I think, the largest academic pain center west of the Mississippi. We... One of the top in NIH fund. It's really come a long way. It's been really exciting to see the growth and, and, uh, the careers and the people we've helped out.

    5. PAPeter Attia2:45:19

       So I'll, I'll, I'll finish the story of, of how we met. So I'm in this state of, um, total hell. Um, in addition to all the stuff I mentioned about, you know, this incredible pain, I couldn't even stand up, literally couldn't stand. Um, and if I did, I had to be hunched over. And so at the time, I was dating an anesthesiology resident, uh, and she was the one that said, "Hey, we just need to get you in this pain clinic. Like, we just, we just gotta, we gotta break some stuff. Like, this is, this is going nowhere. You're circling the drain here, kid." And so I think she was at the time doing her-- She was in her last year of anesthesiology, so I think she was doing a rotation through pain maybe. That's, that's, that's probably how, you know, she, she weaseled me in there. So I come and see you in clinic. By the way, at this point, my mom had flown down from Toronto to take care of me. It's not like I could drive or do anything, right?

    6. SMSean Mackey2:46:16

       Yeah.

    7. PAPeter Attia2:46:16

       So my mom drives me into the hospital, come in and see you. You hear the story. We'd ruled out anything that required any more surgical intervention. In other words, I'd undergone another MRI. I'd had a flexion extension film. It, it wa- I, I wasn't surgically unstable. Um, and in fact, where the original injury was didn't even seem to be what was driving the pain now. So you said, "Look, the first thing we're gonna do is we're gonna give you an IV lidocaine drip to see if we can just calm these sodium channels down."

    8. SMSean Mackey2:46:51

       Did it do anything?

    9. PAPeter Attia2:46:52

       So you said, "Well, how much do you weigh?" I said, "I weigh 80 kilos." You said, "Okay, we're gonna give you 400 milligrams of lidocaine intravenously." And I said, "Dr. Mackey, I just took my boards a year ago. That's a toxic dose." You said, "Don't worry, we're gonna do it in a cardiac monitored room. You will be on an EKG, and we will be able to defibrillate you if you have an arrhythmia." So I said, "Go for it." So in 20 minutes, I got 400 milligrams of lidocaine, didn't touch the pain. D- Tried something else, didn't touch the pain. By now, it was eight o'clock at night.

    10. SMSean Mackey2:47:26

        Oh, wow.

    11. PAPeter Attia2:47:27

        And you said, "Okay, the only thing left to do at this point is to go in there and do a series of injections at every single facet joint, every single dorsal root, uh, n- every nerve root, every dorsal root ganglia, the entire length of your spine."

    12. SMSean Mackey2:47:44

        Yeah.

    13. PAPeter Attia2:47:44

        "I will not be able to diagnose what is wrong because I'm basically going to stop all the pain, but then we will chip away at this over the coming months." And I said, "Great. Can we do it now?" You said, "No, it's eight o'clock at night. We don't have an anesthesiologist. I'm the only one here." I said, "You're an anesthesiologist." You said, "Yes, but I'm the one that's doing the procedure." So I said, "Well, why can't we do that?" And then you said, "Well, we won't be able to give you any sedation, and I'm about to stick 45 needles in your back." And I said, "I don't care. That's how much pain I am in right now."

    14. SMSean Mackey2:48:16

        Yeah.

    15. PAPeter Attia2:48:17

        So we go into the OR, and you proceeded to put, I think, you know, hydrocortisone, b- you know, bupivacaine, and you lit me up, up and down the back. And two hours later, I stood up for the first time in three months. I was completely pain-free. This was remarkable. So we get home. It's midnight. I say to my mom, "I'm not going to bed. I'm gonna go for a walk," because, like, I hadn't walked in three months. And you know the campus loop of Stanford?

    16. SMSean Mackey2:48:52

        Very well. I've ran it... Yes. Yeah.

    17. PAPeter Attia2:48:55

        I walked it until the morning.

    18. SMSean Mackey2:48:57

        It's a four-mile loop. It's-

    19. PAPeter Attia2:48:58

        Yeah. I just walked around-

    20. SMSean Mackey2:49:00

        Wow

    21. PAPeter Attia2:49:00

        ... and around and around till nine o'clock in the morning, came back home, went on to develop, uh, plantar fasciitis-

    22. SMSean Mackey2:49:08

        [laughs]

    23. PAPeter Attia2:49:08

        ... because when you don't walk for three months and then you don't stop walking, but put that aside.

    24. SMSean Mackey2:49:12

        Yeah.

    25. PAPeter Attia2:49:12

        And you told me, "Look, you're gonna probably feel okay for a few days, and then the pain is gonna come back." Well, it actually turned out to be two weeks that I was pain-free, and then the pain came back. And over the next three or four months, you repeated comparable procedures, but with more and more precision, i.e., narrowing in at what the problem was. And if my memory serves me correctly, it was mostly in the T12, L1 area.

    26. SMSean Mackey2:49:41

        Oh, what?

    27. PAPeter Attia2:49:41

        Th- those... A- And, and I think the ultimate diagnosis was, "Look, you lost so much disk space at L5, S1 through the multiple surgeries." If you look at my MRI today, I basically don't have a disk at L5, S1. "That you've now developed this facet arthropathy that far up, and that's where those nerve roots are going into kidneys and testes." Um, but what was amazing was these injections allowed me to go and do rehab, which I took on, like, a vengeance-

    28. SMSean Mackey2:50:13

        Yeah

    29. PAPeter Attia2:50:14

        ... and basically rebuilt the strength in the musculature of my back. And so within nine months, I was, like, back to-- Nine months of meeting you, a year of the injury Like, I was, I was functional. Um, within two years, I, I could, I could get to the point where I forgot about it for days at a time. Like, uh, I'll give you an example. I could actually sneeze without bracing.

    30. SMSean Mackey2:50:46

        Wow.
20. 2:57:14 – 3:07:08

    Breaking the pain cycle: how physical rehabilitation & psychological recovery work together

    1. SMSean Mackey2:57:14

       And I'm just-- I'm literally just so happy for you. Um, can I ask you some questions about it all?

    2. PAPeter Attia2:57:19

       Sure.

    3. SMSean Mackey2:57:19

       You know, and kinda maybe build on some of the things we've been talking about. So to what degree-- so one of the-- so some of the stuff that's going on when you were in this is you were in distress. Clearly, there was a lot of, um, catastrophizing going on, if I can draw upon that term. You cut me off if I'm going off in tangents. Catastrophizing is this concept that was introduced by Albert Ellis in 1962. He was a psychologist, and he also liked, uh, neologisms. So he created, uh, catastrophizing. He created the word awfulizing.

    4. PAPeter Attia2:57:59

       Mm-hmm.

    5. SMSean Mackey2:57:59

       Awfulizing didn't stick around. Um, catastrophizing was not related to pain but got used for pain, has three factors to it. Uh, amplification of pain, rumination or repetitive thoughts about pain, and a sense of helplessness or loss of control over your pain.

    6. PAPeter Attia2:58:19

       Check, check, check. [laughs]

    7. SMSean Mackey2:58:20

       Yeah. It's natural. There's nothing like-- people-- we get a lot of controversy in the field on this term because it has such a pejorative impact, and unfortunately, some of the docs have weaponized it against patient, "Oh, you're a catastrophizer." Tragic. But it has real neurobiologic consequences because when people catastrophize, when they have a loss of self-control, when they have rumination, it negatively impacts these prefrontal cortical circuits that I mentioned, these cognitive systems, so that they can no longer down-regulate your pain. They have abnormal connections to, uh, hypothalamic regions, which are key in hypothalamic pituitary adrenal axis, your HPA axis, which I know you're very familiar with. And so what you, you know, in an acute situation, you get a release of cortisol for s- you know, for stress response. You know this as a surgeon. It's great. It keeps us alive. Chronically, terrible. And so you get this allosteric, allostatic overload, and it starts to thin out that brain region. You're no longer able to modulate, and it's this worsening cycle that you get deeper and deeper in. A lot of what we do in pain is we try to break those cycles, and it's not one thing. Like, I use the interventions, the procedures to help break an immediate cycle to get you on a path. We do this with other patients similarly, and then it's learning skills.

    8. PAPeter Attia3:00:02

       Yeah, that's a very important point that I think shouldn't be lost on this, which is the, the cy-- breaking the cycle isn't the cure. It sets you up to go after the cure. I mean, I had to go through two hours a day of rehab for six months.

    9. SMSean Mackey3:00:21

       Yeah. Wow.

    10. PAPeter Attia3:00:22

        I mean, I had to learn how to move again correctly. I had to strengthen the muscles that were gonna make up for doing what my spine would no longer do.

    11. SMSean Mackey3:00:33

        Yeah.

    12. PAPeter Attia3:00:33

        But you couldn't do that if you were in pain. So you had to learn to do that, and you had to be at least pain-free enough to do it, but not push yourself too hard that you would reactivate the injury. Like, there was a, there was a balancing act. But then, you know, and you had to be able to sleep. Y- All these things, and you had to be able to clear your mind and get out of that catastrophizing loop.

    13. SMSean Mackey3:00:54

        Yeah. That's exactly it, and you had the resources to do this. I was reflecting in your book, in the early chapter, you described a friend's mother, I think Sophie, and you told the story, and maybe it was in the original version of it. It got trimmed out in the edited, but when I read that story, who-- of this woman who, shoulder injury, and then went down this bad path.

    14. PAPeter Attia3:01:17

        Yep. Can't golf, can't garden, can't do anything.

    15. SMSean Mackey3:01:21

        All I-- And it doesn't get mentioned in the book. Again, may have been left out of the editorial, but all I'm thinking of is pain. All I'm thinking of is this poor woman probably had severe, severe pain that was untreated, and it put her down a spiraling path. And what happens in these situations? Well, one of the things we're learning more and more is, uh, social functioning. So we call pain a biopsychosocial model, but we tend to skip over the social, small s. But it turns out we've done a lot of data analysis on our own patients. Social isolation, social functioning plays a key role in your overall pain and quality of life, and you talk about this in your book from a social functioning standpoint. So, you know, my guess is she invariably withdrew. She became deconditioned. She may very well had a lot of fear avoidance around moving her shoulder, which sets you up on a worsening spiral. And what I think about and when I think of Sophie, and I think about people as they get older, that we need to manage your sleep. We need to manage all the things you put beautifully in your book. But I think be- we, we, we also need to help them better manage their pain so that they can have the function and do all the things that you, you say so nicely in your book. I don't know whether, what your thoughts are.

    16. PAPeter Attia3:02:47

        Actually, I was gonna say that, um, I was somewhere recently where I was asked to define healthspan, and healthspan is squishy to define 'cause there's, like, a medical definition that I've repeatedly said I think is insufficient, right? So the medical definition of healthspan is the period of time in which you're free of disability and disease.

    17. SMSean Mackey3:03:05

        Yeah.

    18. PAPeter Attia3:03:05

        So not very helpful. Um, and I prefer a more functional version of healthspan, and unfortunately, it's too long for me to rattle off, but one of the lines is freedom from pain.

    19. SMSean Mackey3:03:16

        Yeah.

    20. PAPeter Attia3:03:17

        So that's, you know, just as it's important to have strength, stability, um, aerobic efficiency, peak aerobic output, explosiveness. I mean, all of these things are going to reduce as you age, but the longer you preserve them, the better.

    21. SMSean Mackey3:03:31

        Yeah.

    22. PAPeter Attia3:03:31

        But one of them is freedom from pain.

    23. SMSean Mackey3:03:33

        Yeah, yeah. You know, the data on elderly people who get a hip fracture, and then it's in a, like, spiral immediately downhill to death.

    24. PAPeter Attia3:03:43

        Yeah, the listeners of this podcast are not, uh, [laughs] they're not strangers to those statistics.

    25. SMSean Mackey3:03:48

        Oh, and I'm sorry if I'm repeating things you've already-

    26. PAPeter Attia3:03:50

        No, no, no, no, but that particular one is so, I mean, it's, it's so tragic.

    27. SMSean Mackey3:03:55

        Yeah, and I just keep thinking, "If we could better help get their pain under control and address them from that holistic s- you know, that standpoint and just get them back to a level of functioning, would this story be written differently?" I'd like to believe it would. I hope it w- I hope it will. Um, yeah, you know, when you went through all of this and you, you get through the rehab, like, did you feel a greater, one, understanding of your pain, what was causing it, and the nature of your back and what you could do and its safety?

    28. PAPeter Attia3:04:30

        Yeah, and it's actually been yet another benefit of this experience is the ability I now have to help my patients.

    29. SMSean Mackey3:04:38

        Yeah.

    30. PAPeter Attia3:04:39

        So if you just look at the population and understand the ubiquity and frequency of lower back pain and you realize, I don't remember the numbers, but, like, let's say a third of people are gonna go through some bout of lower back pain in their life. Um, a number of my patients have also been in the loop of chronic lower back pain, right? And for these patients, one of the most powerful messages I can deliver to them is learning that a setback is not permanent. So part of the journey, because remember, it's not like in the nine months after this injury got better, I never had another setback. No. Within that period of time, I would have days where I felt bad again. Now, fortunately, I never went back to laying on the floor for days.

Episode duration: 3:15:35