The Peter Attia Drive - #345 ‒ Chronic pain: pathways, treatment, and the path to physical and psychological recovery | Sean Mackey, M.D., Ph.D.

Episode Date: April 21, 2025

View the Show Notes Page for This Episode Become a Member to Receive Exclusive Content Sign Up to Receive Peter’s Weekly Newsletter Sean Mackey is a professor of pain medicine at Stanford Univers...ity and the director of the Stanford Systems Neuroscience and Pain Lab, where his research explores the neural mechanisms of pain and the development of novel treatments for chronic pain. In this episode, Sean joins Peter for a wide-ranging discussion on the multifaceted nature of pain—as both a sensory and emotional experience—and its evolutionary purpose as a critical survival mechanism. He dives into how pain is transmitted through the nervous system, the different types of pain, and why different individuals perceive pain so differently. Sean shares insights into pain management strategies ranging from medications like NSAIDs and opioids to neuromodulation techniques such as transcutaneous electrical nerve stimulation (TENS). Additionally, this episode explores the interplay between sleep and chronic pain and the psychological and emotional dimensions of pain, and it includes a personal story from Peter about his own experience with pain and how Sean’s expertise helped him more than two decades ago. We discuss: The definition of pain, and how our understanding of pain has evolved from a simplistic body-mind separation to a nuanced biopsychosocial model [2:30]; The biological mechanisms behind how we perceive pain [9:30]; The role of consciousness in the perception of pain, and how nociception functions during unconscious states [14:30]; The four types of pain [22:00]; Using fMRI to identify objective biomarkers of pain in the brain [31:30]; The evolutionary role of pain in human behavior and survival [36:00]; How the brain processes and modulates pain signals, Gate Control Theory, the variability in individuals’ pain perception, and effectiveness of neuromodulation techniques like TENS [41:00]; The brain’s influence on pain: the role of emotion, beliefs, sleep, and individual differences in perception and tolerance [53:45]; Peter’s personal journey with chronic back pain, and how the emotional consequences of pain can be more distressing than the pain itself [1:04:30]; The pharmacology of common pain medications—NSAIDs, COX-2 inhibitors, and acetaminophen [1:09:30]; Muscle relaxants: benefits, drawbacks, and personalized strategies [1:20:30]; The definition of chronic pain [1:29:15]; The role of antidepressants in pain management [1:30:15]; Opioids: their controversial and nuanced role in pain management [1:33:45]; Alternative therapies: acupuncture and cannabis [1:54:15]; Fibromyalgia and chronic pain: clinical features, brain mechanisms, and emerging treatments like low-dose naltrexone [2:01:00]; Possible brain benefits of low-dose naltrexone (LDN) for people with mild cognitive impairment [2:15:00]; Peter’s recovery from severe chronic pain—how he went from immobility and high-dose opioids to full functionality [2:20:15]; Breaking the pain cycle: how physical rehabilitation and psychological recovery work together in chronic pain treatment [2:30:45]; Sean’s struggle with cluster headaches, and the value of knowledge, preparation, and empathy in both managing chronic pain and caring for patients [2:39:15]; and More. Connect With Peter on Twitter, Instagram, Facebook and YouTube

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Starting point is 00:00:00 Hey everyone, welcome to the Drive Podcast. I'm your host, Peter Attia. This podcast, my website, and my weekly newsletter all focus on the goal of translating the science of longevity into something accessible for everyone. Our goal is to provide the best content in health and wellness, and we've established a great team of analysts to make this happen. It is extremely important to me to provide all of this content without relying on paid ads. To do this, our work is made entirely possible by our members, and in return, we offer exclusive member-only content and benefits above and beyond what is available for free.
Starting point is 00:00:46 If you want to take your knowledge of this space to the next level, it's our goal to ensure members get back much more than the price of a subscription. If you want to learn more about the benefits of our premium membership, head over to PeterAtiyaMD.com forward slash subscribe. I guess this week is Dr. Sean Mackey. Sean is a professor of pain medicine at Stanford University. He also serves as the director of the Stanford Systems Neuroscience and Pain Lab. His research focuses on the neural mechanisms of pain and the development of innovative treatments for chronic pain conditions. In this episode, I talk a little bit about how Sean and I go way back and why it is that
Starting point is 00:01:28 I really wanted to have Sean on this episode. In this episode, we discuss the definition of pain as both a sensory and an emotional experience and why it's fundamental as a survival mechanism and the evolutionary purpose of pain, which obviously has been highly conserved across multiple species. We talk about how pain is transmitted through the nervous system, including the different types of fibers that are involved. Talk about the different types of pain, such as nociceptive pain, visceral pain, neuropathic pain, et cetera. We talk about why pain perception varies so widely from person to person, even in the face of an identical stimulus, how psychological and emotional factors play a
Starting point is 00:02:03 role into this. Talk about various approaches to pain management, including NSAIDs, opioids, and anti-neuropathic medications. We talk about the effectiveness of neuromodulation techniques like TENS and how sleep deprivation affects pain sensitivity, as well as why chronic pain often leads to disrupted sleep cycles. We talk about this and many other things. Again, I share a very personal experience with my own pain and how Sean came to my rescue 25 years ago. Without further delay, please enjoy my conversation with Dr. Sean Mackey. Sean, thank you so much for making the trip to Austin. Oh, it's my pleasure. It's really good to see you again after a rather long time.
Starting point is 00:02:47 Yeah, I was thinking about it. So this morning my wife said, oh, what's the topic of the podcast today? And I said, it's going to be pain. And I said, she said, oh, who you have? And I said, Sean Mackie. She goes, her face lit up. And she doesn't know you. She's never met you, but she knows your name because she's heard me tell a story.
Starting point is 00:03:02 She's heard me tell a story about my own experience through this. I then realized something, which is I haven't seen you since I was in medical school. Yeah. Which is kind of weird. Yeah. So I'm sure we will get to how you and I met 25 years ago, exactly 25 years ago.
Starting point is 00:03:18 Wow. And how you played an unbelievable role in bringing me back from arguably the brink of what could have been the end of my life truthfully. But I want to start with some broader topics around pain. So there's nobody listening to us right now who doesn't know what pain is. There's nobody listening to us right now who hasn't experienced pain. Yet if you ask for a definition of pain, I think you'd get a lot of using the word to describe the
Starting point is 00:03:46 thing which isn't truly a definition. If you were trying to explain to a Martian from another planet who doesn't experience pain what it is, what would you say? There's the formal definition of pain, which is defined as an unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage. It's a mouthful. If you think of it as it's an unpleasant sensory and emotional experience, it's usually tied to something physically happening, but may not be. I think sometimes what's missing in that definition, one of the things I wish they had put in but never did, is that pain is the great motivator. Pain is one of the most primitive experiences going back to, if you will, single cell organisms. It's either pain or reward. You're either being
Starting point is 00:04:40 driven towards oxygen, food, sex, or you're trying to get away from danger. Pain is so wonderful because it's so terrible. It keeps us alive. Without pain, when we have these genetic issues of congenital insensitivity to pain, we would have never lived as a species. Pain is an unpleasant sensory and emotional experience. To understand pain, whether you're a Martian or you're a human
Starting point is 00:05:07 now, I think you have to look back in history. And so I'm going to evoke René Descartes, 17th 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. To his credit, it was the first mechanistic foundation for pain, because beforehand, pain was thought to be something mystical or religious. It was punishment of the gods. So he put this framework together that's often illustrated this famous picture of a little boy with his foot in the fire and there's a little string from his foot going up into his brain and it ends up in the pineal gland which was thought
Starting point is 00:05:59 to be uniquely a human area. And the idea is the fire pulls on the little string, opens up pores, and the pineal gland rings a bell and the boy withdraws his foot. The idea is in this dualistic model, there is a complete separation between body and mind. The body is where pain is generated, the mind is where it's perceived, but the mind is simply a passive receptacle receiving these signals. That model put forward in the 17th century stuck with us for hundreds and hundreds of years and I would argue is with us today. And it has influenced medical care, it has influenced policy, it's influenced everything in our society about the way we think about pain and it's utterly completely wrong. So yes, he got Cartesian geometry right, but he really complete bollocks screwed it up when
Starting point is 00:06:53 it came to pain. This biomedical model, this dualistic model was with us for hundreds and hundreds and hundreds of years and it's only been in the last number of decades that we've appreciated the nuance of what pain really is. And instead of it being under this guise of this separate mind and body, we now appreciate it is this integrated biopsychosocial phenomenon. Meaning that, and I think this is one of the most important things that I'd like to drive across, I'm going to introduce a term, we're going to get to a term called nociception, which are electrochemical injury signals that occur in the periphery that what goes on in the body and what goes on in the brain, the experience of pain, they may have nothing to do with each other or very
Starting point is 00:07:40 little linkages. And we're going to hopefully unpack that. So hundreds and hundreds of years, we're basing it on Rene Descartes' dualistic model. We still see this in medical care right now. You're a surgeon for many, many, many, many years when I talked with the surgeons. They were firmly of the opinion that the amount of pain that a patient had after surgery was related to how much the scalpel cut and how much tissue damage was done. I think it's only more in the last 20 or so years, I'm seeing surgeons really embracing this model that what people bring to the operating room table directly influences how much pain they have, their early life experiences, all this stuff, and we'll talk about that.
Starting point is 00:08:27 And Sean, just to interrupt for a second, thinking through the history of medicine a little bit, the latter part of the 19th century brought a couple of other tools to pain. So between local anesthetics, cocaine down to lidocaine, and general anesthetics in the form of ether, which finally allowed surgeons to cut people without having to hold them down while they screamed.
Starting point is 00:08:49 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 change the model. Didn't change the model. Yeah, had no influence on that model, which I think has had tragic consequences in the care of people, particularly with chronic pain, particularly women with chronic pain who have felt stigmatized and validated because absent something that's obviously wrong out in the body of the periphery, they were just labeled as being histrionic housewives or being told it's all in their head,
Starting point is 00:09:22 not just women, but also some men as well. It's only with that evolution of our perception or our model into a biopsychosocial model that that's gotten much better. Okay. Let's talk about, is there a pain receptor? Let's break it down into the foundational stuff. We have these things called nociceptors, foundational stuff. So we have these things called nociceptors, complicated name. It's basically a transducer, which is another technical name. Now you're engineering background, so you all know that a transducer is simply a device that converts one form of energy into another form of energy. This microphone is converting sound energy into electrical energy, the speakers convert electrical energy back
Starting point is 00:10:05 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 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
Starting point is 00:10:26 occur during infection. They convert those into action potentials that are then transmitted up nerves. These are little electrical impulses transmitting up generally two different nerve fiber types. These two different nerve fiber types, one is called a C fiber, which is thin and slow. It's really pokey and I don't know if I'm getting ahead if you wanted to go more into it 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
Starting point is 00:11:04 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 ten times faster. So it takes a little under a tenth of a second to get your thumb to your brain. And to give a real world sense of the difference in C fibers and A delta fibers. Think back to the last time you stepped on a tack in the carpet, you hit your thumb with a hammer, you twisted your ankle coming off a curb. What happened? Think back to that experience. You get this sharp jolt of pain that goes right to your brain. Those are your A delta fibers at 10 meters a second, rapidly getting up to your brain, rapidly putting
Starting point is 00:11:46 into play systems to protect yourself from harm. You withdraw. You have a reflex that's occurring in your spinal cord. You're not even consciously aware of it. Your brain is setting into play escape mechanisms. The pain that you experience is sharp. It's well localized. You know exactly where you stepped on that tack.
Starting point is 00:12:05 Then about a second, two seconds later, you get this hot burning flooding sensation come over your thumb with you hit it with a hammer and you think to yourself, oh damn, this is really 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. The A delta is doing two things, if I'm understanding this correctly, is it creating the spinal reflex where, hit my thumb
Starting point is 00:12:45 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? That's exactly it. And it is synapsing. There are synapses in the ventral or anterior, the front portion of your spinal cord, which is, as you know, your motor part of that spinal cord. They're making synapses and it's causing a classic withdrawal effect. But am I also feeling the pain?
Starting point is 00:13:10 Am I perceiving the pain? If you could do a thought experiment where you could eliminate the C fiber in an individual, would they still feel pain? Yes. Yeah, they would still feel pain. So there's still a central component to what the A fiber is doing. Those A delta fibers are still- They're still going up.
Starting point is 00:13:28 Going up. They're in the spinal cord. They cross over to the other side. There's an afferent and an efferent to the whole thing. Indeed. Indeed. We think of these pathways. The main one that we all learn in medical school and we think about is a spinal thalamic pathway, this goes from the spine up into your brain, we're going to get there. But yes, if you had no C fibers, you would still feel pain. That's one of the other things 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,
Starting point is 00:14:10 back to single cell organisms, reward, pain, 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 just about no matter what. Just thinking about this through an evolutionary lens, lots of debate about this in the animal
Starting point is 00:14:33 kingdom. Like does a goldfish feel pain? Do we have a clear sense as to how far from humans and or mammals you go where you still clearly have C fibers and A delta fibers? You could go pretty deep in there and I get the debate. It's a great debate over wine or beer and I understand actually taking it seriously and having that debate. A lot of different opinions on this. I actually don't engage in that debate. I think you have to first of all,
Starting point is 00:15:05 define the thing that you're debating. You have to very clearly define the thing. And in this case, our definition of pain is a rather human experience of pain. This is where I was actually gonna go, if I can just give you that window. Please. What I was really gonna ask
Starting point is 00:15:21 is a question about consciousness. Yeah, yeah. Is consciousness necessary for the internalization of this full gamut of pain? Yes. I believe firmly it is, and I'm a recovering anesthesiologist. I haven't done it now in, oh gosh, 20 years. But when I did it, and when you were operating on a patient, the patient is unconscious. They are not experiencing
Starting point is 00:15:46 pain. You need a conscious brain for the experience of pain. Now what people incorrectly made the leap of is thinking, well, they're not experiencing pain, so everything's okay. That would be a logical fallacy because all those signals are still coming from the body, still hitting the spinal cord and having their impact there. All those injury signals because let's face it, when you do surgery, it's really nothing more than a controlled injury. Yes.
Starting point is 00:16:16 And I just want to point out, and this shows you how long I haven't been in surgery, but 20 years ago, my recollection is an anesthesiologist was giving not just one medication, but several. Yes. So they were giving something like halothane, which to my understanding, we didn't know how it worked then. Do we have any idea how it works today? Better. We still are trying to unlock the whole consciousness aspect of things, but we're inching our way
Starting point is 00:16:40 there. But it wasn't enough to give that. The anesthesiologist still had to give typically a narcotic. They were still typically giving something like fentanyl even though the patient was unconscious. They were also often giving an amnesiac so that they wouldn't have any recollection of what was going on. But of course we all hear the horror stories of the patient and a paralytic on top of all
Starting point is 00:17:02 that, right? Exactly. Muscle relaxant. So you hear these horrible stories of the patient who is paralyzed, but somehow conscious. You can miss on this state sort of thing, but just to make sure I understand, in theory, a paralytic and an inhaled anesthetic should be sufficient to eliminate the perception of pain in a patient who is being cut. Yeah. Part of the challenge was, and now I'm starting to step outside of my wheelhouse, even though I was a member of the anesthesia tribe for a long time, is the levels of volatile gas
Starting point is 00:17:34 anesthetic that you need to necessarily obliterate reflexes and full nociceptive impulses would be so high that it would depress one's blood pressure. So you augment that with an opioid. Understood. Like fentanyl, like morphine, like whatever, and you combine those together. That's why what the anesthesiologists do is quite magical. Got it. In other words, you give the inhaled anesthetic just to get unconsciousness, but not to fully
Starting point is 00:18:03 suppress the nociceptic system. Instead you bring on the opioid to do the remainder of that work. They're working synergistically and they're working at different mechanisms. Got it. And during that process, the patient is not feeling pain if they're unconscious because you do need a conscious, working, aware brain to feel pain, but all of the electrical impulses coming in from the body that are slamming into the spinal cord and the brain are open full bore. They're impinging on all those brain systems responsible for stress responses and autonomic control.
Starting point is 00:18:37 So does that mean we are seeing a cortisol surge? We're seeing whatever one would expect a conscious person to experience with epinephrine, norepinephrine, cortisol, all these things still surging out in response to pain. Yes. And in response to nociception. Independent of perception of pain. Right. And you notice that I'm trying to be precise in my language here because since they're
Starting point is 00:19:03 unconscious there's no pain, but there's plenty of nociception. Arguably more than you would ever experience. Think about what we do in surgery. My God. Take a scalpel and then take an electro-cottery and start burning tissue. There's no level of nociception you could ever experience like that while being awake unless you're in a burning car. Absolutely.
Starting point is 00:19:23 That's exactly it. It's remarkable through modern medicine that we get people through all this is a reflection of advancements in surgery, advancements in anesthesiology, advancements in post-operative care, but it is no different than a controlled injury. It's done in a nice sterile environment, but it is a massive injury that people are undergoing. They're just not awake and it's nice and clean and sterile, but there is a stress response associated with that. Most people recover well. One of the hot topics of research these days is why do most people recover, but a certain percentage of people go on to have persistent pain after surgery. That's an area that I used to research years ago. Many others are doing some great work in that space.
Starting point is 00:20:11 Turns out that a lot of the factors we're going to get to this is what people bring to your operating room table, meaning early life events, levels of emotional health, cognitive health, and everything else. So to answer your question and getting back to it, no, I don't believe there is the perception of pain without a conscious brain. There's all sorts of nuances to that. So let's go back to something you said at the outset from an evolutionary perspective, which is pain and pleasure have been the driving factors that have been the engine of natural selection. But clearly,
Starting point is 00:20:45 those things have had to work in pre-conscious models. So, that means that whatever we're defining as pain there did not include a perception of pain. So, what does that mean? That's where it gets muddy. And there's smarter people than I that would probably be more articulate. But this is why I think on first principles, you have to define the thing that you're talking about. When we typically talk about pain, we're talking about it from a uniquely human standpoint. Does a dog experience pain?
Starting point is 00:21:16 Easier to accept. Yeah. Easier to accept. I'm a dog person. They experience pain. You move on down the evolutionary. At what point? Right. Does a goldfish experience pain? Gold move on down the evolutionary. At what point? Right, does a goldfish experience pain? Does it? Goldfish clearly experiences no suception. They clearly have all the classic withdrawal,
Starting point is 00:21:32 protection, survival aspects of it, but what level is there a conscious brain that is translating it? And also on top of it, remember in our human definition of pain, we bake in, it's an unpleasant sensory and emotional experience. Does a goldfish experience emotions?
Starting point is 00:21:51 I leave that to the goldfish experts. You see how muddy it gets. You go down rabbit holes pretty quickly, which is why I tend to stay with humans, which is muddy enough. Which is hard enough, by the way. Yeah. Which is hard enough by the way. So how does everything you just said differ or overlap with neuropathic pain or that sort of burning pain
Starting point is 00:22:12 that I'm sure some people are familiar with? Certainly I was familiar with it for several years. Is that simply a subset of this? Are there various different types of pain that don't have a clear cause effect relation to tissue damage? So, we have different ways of categorizing pain, putting it into different buckets, if you will.
Starting point is 00:22:31 One is nociceptive pain. And you'll note that that word nociceptive sounds very similar to nociceptors, and it's by design. It means that it is pain caused by activation of primary nociceptors, whether it be in your skin or soft tissues or viscera. And it tends to have certain qualities. It's very easy to localize. You know exactly where it is. It has a certain intensity. That nociceptive pain tends to be time-limited, responds well to short-term use of analgesic agents, acetaminophen, NSAIDs, COX-2 inhibitors, opioids, and it tends to go away.
Starting point is 00:23:10 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 stomach ache, you can't put your finger exactly where it hurts. You tend to put your whole hand over and say, it hurts here, it's diffuse. That's because the spinal cord and the brain have these diffuse receptive fields which
Starting point is 00:23:57 expand the area. The viscera don't typically respond to the same type of stimuli that nociceptive pain does. You'll remember when you were taking a bovie 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- Or inflate it. Or inflate it.
Starting point is 00:24:20 Boy, oh boy. Blood pressure goes up, heart rate goes up. 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 thorax converge with the same sensory systems from the rest of our different parts of our body. So you may remember the old medical school adage, C345 keeps the diaphragm alive. Okay. We all had these in med school. Well, that means that the third, fourth and fifth cervical nerve roots subserve our diaphragm, which help us breathe.
Starting point is 00:24:56 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 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,
Starting point is 00:25:22 pain radiates out into the arm because you've got the upper thoracic nerves 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. If you like the neurosciences, it's all pretty cool. If you're experiencing it, not so cool. Now let's get to neuropathic pain. By the way, on visceral pain, what is their response to treatments with respect to the way we saw in noceptive pain where, hey, great response to these NSAIDs or opioids or whatever? Typical analgesics can be helpful, but identifying visceral specific
Starting point is 00:26:02 antinosusceptive drugs is still an area of hot research. These days it's more about trying to identify the causes of visceral pain and reducing substances that are winding those nosusceptors up. Neuropathic pain, another bucket. Neuropathic pain means injury to either the peripheral or the central nervous system, the nerves out in the body It's either injury or dysfunction to nerves out in the body or the nervous system in your spinal cord or in your brain Classic you get nerve injury from a trauma from surgery Classic qualities people describe burning sharp
Starting point is 00:26:44 Lancinating stab, shock-like. This is the kind of pain that some people tragically get after a thalamic stroke in their brain. Half their body is just like terrible burning pain and there's nothing going on out here. It's all central. This is the kind of pain that you get and you experienced with radicular pain. Radicular pain means, in this case, injury to a nerve root coming out of your spine. It's this sharp radiating pain, if you've got it in your lower back, that radiates down your leg, typically below your knee into your foot.
Starting point is 00:27:20 This can be very challenging to treat with common analgesics. We tend to draw upon different categories of medications for this. These are, broadly speaking, anti-neuropathic pain drugs. And here, in our field, we steal from everybody. There's only a few FDA-approved medications for pain, like a handful. So what we've learned to do is to still borrow drugs from the neurologists, their anti-convulsants, their anti-seizure medications,
Starting point is 00:27:55 the gabapentinoids, the tageratols and their derivatives, their other anti-seizure medications because they tend to have mechanisms of action that also work on nerve pain. Gabapentin, I think you've had perhaps some experience with. Turns out it's a lousy anti-seizure drug. Terrible, but it's a pretty good anti-nerve pain drug. Four grams a day. Four grams a day. Drowsy though. You know who gets credit
Starting point is 00:28:25 by the way? I give credit to making Gabapentin, the blockbuster drug, George Clooney. How? You ever watched ER? Yeah. He was a pediatric ER doc. Kid comes into the ER with a skateboarding injury. George Clooney puts the kid on Gabapentin. Now where that had all started was a case report from a couple of ED docs who had noted by putting people on gabapentin that their acute pain got better. So I felt like beforehand when I was practicing medicine around the time I saw you practicing pain medicine that I'd look like a genius if I put somebody on gabapentin because nobody heard of it. And then after that came out, floodggates open primary care doc started using it
Starting point is 00:29:06 Now everybody's tried it and it's a very safe medication I should also make a mention when I'm talking about these meds or any treatments. I have zero industry relations with anybody Nobody I don't take any industry money. You can go look me up on open payment CMS, which is a public database Okay, neuropathic pain. There's another one. There's a new kid on the block called no-see plastic pain. I don't know if this one has 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.
Starting point is 00:29:46 It means that 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, no see plastic pain. And it has been tied in with conditions like fibromyalgia, temporomandibular disorders, some aspects of chronic low back pain, irritable bowel syndrome, interstitial cystitis and more.
Starting point is 00:30:17 It slowly starting to get traction. 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. Yeah, I was about to say before you gave your examples, I was going to say nociplastic pain must be a huge bucket because it's everything for which we don't understand. It's sort of the all else bucket, which is enormous, especially for chronic pain, right? You're absolutely right. And I think the verdict is still out.
Starting point is 00:30:48 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 ladder. I think we're gonna find peripheral drivers for fibromyalgia. There's some controversy right now as to whether fibromyalgia represents
Starting point is 00:31:14 a small fiber neuropathy. 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. We'll see how the story plays. Now, there's no objective way to measure pain, correct? Oh, the last 15 years of my career has been spent on doing that very thing.
Starting point is 00:31:38 And where do you think we are in that regard? Much further along than I ever would have predicted. So a large chunk of my research early on, my early research was in neuroimaging of pain. It was opening up windows into the brain to see where people 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.
Starting point is 00:32:11 And we'll get there. Over the years, I migrated into the space of developing objective biomarkers of pain. So I love working with young, smart people. I bet against it. I had some young grad students and others who said that they thought they could do this. I told them how you would do it and I said, it won't work. And I'm gonna pay you, I'm gonna give you money
Starting point is 00:32:33 to go scan people and you're gonna 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.
Starting point is 00:32:54 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. Sorry, you're capturing these through what modality? 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 see where nerves, the brain's being activated.
Starting point is 00:33:28 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. 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. Let's just start with standard understanding. If you put me into an fMRI machine and I said to you, hey guys, I'm not feeling any pain right now, I feel great.
Starting point is 00:33:59 And then you scan me and then someone came out and took a hammer to my thumb and I went through the classic response that you described earlier. What would my fMRI show? You'd see rather dramatic increases in activity in brain regions such as the thalamus, the posterior insular cortex, the anterior cingulate cortex, through the dorsal anterior cingulate cortex and a number of other areas. To be clear, this is distinct from the part of my cortex that is the homunculus for my thumb. You would also see it in S1. You're right. Indeed, what we've learned through this,
Starting point is 00:34:38 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 going to find a brain region, then we can knock it out, right? Just go cut it out. And it turns out that didn't work. 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. Doing what? Generating the experience of pain and then generating typically a response to that.
Starting point is 00:35:12 Let me be very clear, because 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. I can use self-report measures to get it. That's another part of the research. Where we're working to build these objective markers, this objectifying pain,
Starting point is 00:35:38 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 going to get there. I don't know if you want to go back to the brain. Yeah. Okay. So let's go back to the story of these four branches of pain or at least
Starting point is 00:36:07 the first three and then how the sensory component is impacting their perception. Roll with that. Give me a little bit more. I want to build off it then. Okay. So we go back to no septive pain. So tissue injury occurs. I think where I derailed us was in classifying all the different types of pain, but you had signal comes up, two signals coming up, the C fiber, the A delta fiber. The immediate response is to get you out of pain. There's an evolutionary logic to that. 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?
Starting point is 00:36:44 Perfect. Perfect. That is basically your longer term harm alarm. That is saying, Peter, don't go back and do that again. Back in the cave people days, 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 woolly mammoth or the saber-toothed 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. By the way, do we have any evidence, Sean,
Starting point is 00:37:14 that there was enough genetic heterogeneity around this that there were, 200,000 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. Wow. That's a great question. One, I don't know. Two, there was undoubtedly genetic variations that led to behaviors, led to actions that did not promote survival of the species. And nature takes care of that. Those people died out.
Starting point is 00:37:49 I find it amazing to just sit around and dream about how little convergence must have existed a quarter of a million years ago in terms of things that ended up not being good for our species, like people who didn't experience pain the same way or didn't have certain filters within themselves. There've been lots of talk about people who couldn't socialize. 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. We clearly have some anti-social folks among us, but they're the exception and not the rule. So anyway, I just wondered if today we're much more homogeneous in terms of what a
Starting point is 00:38:29 human's response to pain is versus what it might've been. 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, I'm not an animal pain expert, but typically they're set off, they're ostracized, 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.
Starting point is 00:38:59 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. And I also think about certain things like childbirth prior to any anesthetic was obviously brutal, both in terms of the pain and the mortality. And yet there's no evidence that people were deciding, eh, maybe we ought not to do this. In other words, the drive for procreation
Starting point is 00:39:30 somehow overcame what must have been brutal. Absolutely. And I got to tell you, hats off to half the population that are women and the women that do this. 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 think some of the estrogens, the estradiols has not only an analgesic effect, but I sometimes just
Starting point is 00:39:58 swear they don't seem to remember sometimes just how painful it was and yet they do it again. 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, the species collapse. On average, every woman must be able to do this and back then it had to be reproductive rate of north of three. Every woman had to do this. And back then it had to be reproductive rate of north of three.
Starting point is 00:40:25 Right. Every woman had to do this three times. How she did it the second two times after how bad the first was blows my mind. The second thing is just looking at how stupid adolescent males are. I'm sure you can relate to this. I was one.
Starting point is 00:40:39 Yes, as was I. And I look at my boys. I don't understand why males all didn't die from just doing stupid, stupid things before the age of 20 or even before the age of like 15. Those two things are a miracle to our species, that all the males didn't die and that all the females were willing to have at least three kids. I repeatedly tell Beth, I'm like, I sometimes wonder why I was not a Darwin Award winner, if you've ever read the books.
Starting point is 00:41:06 I remember the Darwin Awards fondly, yeah. We'll link to them in the show notes, some of my favorites. So we have these signals. I'm going to take these signals from the spinal cord because where it gets really interesting is when you take those A delta C fibers, 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. One of the main one is the thalamus which acts like grand central station in the brain.
Starting point is 00:41:36 It's taking lots of sensory input from different sources and it's sending it out to other areas. Some of those areas that we alluded to, the anterior cingulate cortex. Now the anterior cingulate cortex, each of these brain regions has some functions associated with it. 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. Everything that we're doing, we're forming an expected pattern of what we're going to sense and we're making adjustments.
Starting point is 00:42:28 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 saline detector is triggering and it's putting into action for me to withdraw. Other areas of the brain include the insular cortex which lies on this little bit of the outer edge. It can be subdivided into multiple components the posterior, mid, and anterior insula.
Starting point is 00:42:59 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 emotional state and what you're thinking. Now there's also connections with your amygdala, this deep primitive region of the brain involved with both threat detection as well as reward. And it's connected into the circuit and then also has outlays into other areas that maybe
Starting point is 00:43:35 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 Rene Descartes has in telling this story because first pass, the brain is still remaining a passive receptacle just taking these inputs. 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.
Starting point is 00:44:16 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 they just did seminal work. And this gate control theory of pain 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 systems from your brain. So let me give you an example to this. Let's introduce another nerve fiber type, A beta. A beta fibers are your touch fibers. When you touch or stroke your skin, those get activated. When you stand up and you stand on one leg, they're also responsible for position sense.
Starting point is 00:45:10 They have a heavy coat of insulation around them and they are wicked fast. C fibers, one meter a second, A delta fibers, 10, A beta fibers, 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 going to hurt. Hot burning flooding sensation comes over your thumb. What is the next thing that you do? Everybody does this a little differently. Before or after swearing? There you go. A lot of people swear, so it's after swearing.
Starting point is 00:45:48 You swear and then- Shake it. Shake. Okay. You're a shaker. Or a squeeze proximal to it. Squeeze. There you go.
Starting point is 00:45:57 You squeeze, you shake it, sometimes you run it underwater. What are you doing when you're squeezing it and shaking it? Sometimes trying to create a distraction. Okay. Sometimes though probably illogical, trying to keep whatever humor is in there that's hurting, isolated like a tourniquet. Right. Right. Obviously if I'm using cold,
Starting point is 00:46:16 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. Yeah, that's beautiful. And you're talking about longer term things, which are all perfect, 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. You're actually not influencing much your A delta or C fibers, those nociceptive fibers. You're not really impacting it there.
Starting point is 00:46:51 That horse left the barn. That horse left the barn. You got horses still running out the barn. 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.
Starting point is 00:47:19 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. 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? Yep.
Starting point is 00:47:45 TENS is T-E-N-S, transcutaneous electrical neural stimulation. Now, what it originally did, there's been modifications of it, is what you do with the TENS, 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 spinal cord. Pretty cool when it works. And how do you predict patient comes to you and they're experiencing some pain?
Starting point is 00:48:22 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. Everything that you do is how do I reduce your perception of pain? 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 the physical injury, right? In short, yes. I would just build on that, that I would say my job, our job as pain docs is to help reduce the pain and help them down a path of functional rehabilitation. So absent that second piece, I typically fail. I'm leading them down a road of functional rehabilitation,
Starting point is 00:49:11 which involves physical, psychological, social, emotional health, all things you talked about beautifully in your book. So who is the, I hate to use the word poster child, but who's the patient that when you see them, your intuition says, tens is going to really work for this person. Somebody with, I think more, you know, it's nociceptive musculoskeletal pain. I tend to think of somebody for whom tens is more likely to work.
Starting point is 00:49:40 Something that has more of a classic nociceptive type of pain problem. Beyond that, Peter, it's a trial and error. That's part of the frustration in pain management and in healthcare in general is the lack of a precision approach and the very frustrating, laborious trial and error process until we get something that works. So we talked about the gait control, we talked about tens. Can I put a bow on the gate control thing to make sure I understood it? Yeah.
Starting point is 00:50:08 It seems like a very important idea, but I also think I might be missing the juice. Is the idea that 10 people could experience the exact same peripheral injury, if you could map the action potentials, they would look identical. You could even see identical perceptions, but they could have 10 different gating channels within the spinal cord and therefore perceive pain differently. I just want to make sure I've captured what the gating theory states.
Starting point is 00:50:35 You are right. You're right with that individual variability in pain. We haven't talked about the brain's role in the gait control, which we're going to get to, but just getting to your question, there's been some elegant studies. A guy named Kim years ago did a beautiful study where he applied a 48 degrees Celsius stimulus to 500 people. 48 degrees Celsius, I think it's 121 degrees Fahrenheit. Somebody will look it up. And you apply it to the arm, the hand, and then ask what's your pain score. And what he found was perfect distribution of people who said, nah, this ain't painful. Ain't nothing. That's like zero, one out of 10. Some were like,
Starting point is 00:51:15 yeah, it's a little painful, two or three. And others were like, yeah, a little more moderate, four or five, six. And you got all the way up to some people saying, oh my God. You're burning me. You're burning me. Take that off immediately. 10 out of 10. I do the same thing in a medical school demonstration. Can't call it an experiment because I'm not getting IRB. But when I teach the neuroscience class around pain, I bring in a circulating ice water bath and you want it to circulate because if you just stick your hand and leave it in still, you get a boundary. It's warmer. Yep. So circulating ice water bath and you want it to circulate because if you just stick your hand and leave it in still, you get a boundary-
Starting point is 00:51:46 It's warmer, yeah. So circulating ice water bath and I asked them to dip their arm in for 15 seconds, pull it out, whisper in our research assistants here what their pain score was. We tabulate that all up and at the end of the class, I show the medical students and it looks just like that line I showed you, I mentioned to you before. You got some people in the class who say, I could keep my hand in there all day. And there was others who were like, oh my God, I couldn't even keep it in there at all. 10 out of 10. The whole point of that
Starting point is 00:52:16 is to drive home one of the key messages in our discussion. The amount of stimulus or nociception may have little to nothing to do with your experience of pain. Why that is so important for healthcare professionals to understand is because for so long we have projected our own experiences onto everybody else. Here's another experiment that you won't be able to do unless you get to teach this class on multiple days, but it's to go one step further, which is to do the same thing every day and see how they compare their score from day to day. I'll tell you my experience with that. I do love to use a cold plunge. So my cold plunge is at 42 degrees with circulating water. So I don't know what that makes
Starting point is 00:53:00 it feel like, but it feels like it's somewhere in the 30s. There are days when I can spend 10 minutes in there and feel like, but it feels like it's somewhere in the thirties. There are days when I can spend 10 minutes in there and feel like nothing is wrong. There are days when I'm not kidding. 30 seconds in my ankles hurt so bad. I want to scream and I think what's different. It can't be the circulation in my ankles is better one day to the next. They're a relatively a vascular part of my body. Why is it that one day I can spend 10 minutes and not know I'm in this water?
Starting point is 00:53:30 I mean, I know that I'm cold, but it's more like my core temp, but my joints don't hurt. And on another day, the throbbing in my joints feels like somebody's hitting them with a hammer and I'm the same person. So in other words, your point is well taken, but I would say there's a second dimension to it, which is even as individuals, we can experience things differently from day to day. You're absolutely right. And maybe that's a good opportunity to build on that and introduce more of the brain.
Starting point is 00:53:57 So we've talked about the functions of the brain, a cingulate cortex being some of the more emotional as primary somatosensory cortex, the homunculus being more sensory, the insular cortex has an introspective state. It's like our internal awareness of our bodily state. We talked about 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 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 neural modulation,
Starting point is 00:54:49 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. So I would argue in part that your experience of cold water in that moment
Starting point is 00:55:16 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. Huge research in that space, your state of anxiety, apprehension around this, all sorts of cognitive emotional aspects weigh into your 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, within
Starting point is 00:56:06 person daily variations over time and model that. There seems to be kind of a, yes, I should ask this. I'm not asserting this is 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
Starting point is 00:56:31 zero, one, two more favorably than those that score eight, nine, and 10? Absolutely. Why do you think that is? If I'm being truthful, I do it. Yeah. Yeah. That's what society values. That was my home life growing up. That's what my father expected. I came from a very working class. 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.
Starting point is 00:57:08 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 society is. Is that a male thing exclusively? I think you need to get some women on the show and ask them. I think it crosses, actually. I do think there is a masculinity aspects of that. And I think I could be wrong here.
Starting point is 00:57:31 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 than somebody who is weak and sensitive. But we're getting a little out of my wheelhouse on that, but you're absolutely right. I just think it's like a compatibility thing. 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. And so, I almost wonder if that's a compatibility. We both just have a high threshold for that when we're exercising, when we're doing anything
Starting point is 00:58:08 even recreationally that doesn't matter. My fiance, we're now engaged, is a professor at Stanford, Beth Darnell. She's an ex-ultra marathon runner. 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 she's just like, listen, I was really good with running with a pebble in my shoe, putting one foot after another and just working my way through it. And I similarly grew up in an environment where you learn to be tough and you learn
Starting point is 00:58:38 to power through life's adversities. So what is the consequence of this? So we're acknowledging that it is an attractive trait to have a high tolerance of pain. Society rewards it. And yet, by definition, a significant subset of the population, call it a third, call it a quarter, if it's a normally distributed function, are going to be a standard deviation on the other side.
Starting point is 00:59:03 They're going to be on the side relative to people who have a high tolerance for pain. These are people who are going to be a standard deviation on the other side. They're gonna be on the side 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. Indeed. As with all things, it gets a little bit more nuanced.
Starting point is 00:59:20 We talked about cold, for instance. It turns out that some of the sensitivities are modality specific. So just because you have a high threshold about cold, for instance. It turns out that some of the sensitivities are modality specific. So just because you have a high threshold for cold, you could completely flip it on hot or pressure or pinprick or whatever the other modality is. Somebody who runs a paint lab, I've had everything done to me imaginable.
Starting point is 00:59:39 I take heat really well. My son, Ian, takes heat really well. I've had thermal devices on me where I've been there and ended up with second degree burns to find my seven out of 10. I hate the cold. I hate the cold. I'm a wuss when it comes to the cold. That's why I live in California. I lived in Arizona. I think there are genetic aspects of this. So we have to be mindful modality specific. On top of it, these experimental protocols probably have little bearing on somebody's experience of chronic pain.
Starting point is 01:00:12 I was going to say, is there any way to put together a set of experimental lab versions of this to basically generate predictive models of how people will respond to real world pain. I think where you're going with chronic pain is even more relevant. So for example, why do some people have a disc herniation that leads to manageable pain, whereas for others, the exact same injury
Starting point is 01:00:41 by every metric available to us produces a totally different set of consequences and what do we do about that? This is now where we move out of that Descartesian model. We appreciate the role of the brain and its modulatory capacity, its ability to turn the amplifier down. And so if you're thinking about a stereo amplifier, we talked about how some people to a certain stimulus might be a zero or one on the dial, some might be a 10.
Starting point is 01:01:08 But what we didn't talk about are people's capacity to now manage their pain, cope with their pain, their level of self-efficacy around their pain. Athletes learn how to manage their pain and suffering. Where they run into problems is when the sports are over, they're retired. That's when I see them. So there are many factors that predict how well somebody is going to do with chronic pain. They align with a lot of the stuff in your book. So the level of person self-efficacy plays a role. There is the presence or absence of whether they've got underlying depression, anger, anxiety, something called catastrophizing,
Starting point is 01:01:53 terrible word, very important concept, probably one of the most predictive of amplified pain. What about other things you talked about? Sleep deprivation, any other physical things, exercising, not exercising, insulin resistance, non-insulin resistance. What are the other things that might factor into this? Yes, one of the biggest predictors of diabetic neuropathic pain is glucose control. One of the first things we do if we have a person with diabetic neuropathy, which the diabetes, the high blood sugar, as you know much better than I, causes injury
Starting point is 01:02:25 to those nociceptive fibers and also causes injury to the A-beta inhibitory fibers. That correlates with glucose control by way of example. Diet plays a role because if you're eating things that are causing inflammation, we didn't talk about all of the stuff that amplifies or winds up those peripheral nociceptors. We treated those as a static thing when they're not, they're dynamic. So in the face of inflammation, that causes something called peripheral sensitization. You've turned up the amplifier on that nociceptor in the periphery.
Starting point is 01:03:03 Sleep, huge topic. How much sleep deprivation does one need for there to be an increase in pain perception? We're both out of residency long enough, but we both pulled our old-nighters. How did you feel the next day? I mean, I felt awful. You felt worse between 5 AM and 8 AM,
Starting point is 01:03:21 and then you get this second wind, usually about the time you're operating. And then and 8 a.m. and then you get this second wind usually about the time you're operating and then you usually feel pretty good. But overall, I mean, it's a haze. It's a haze and you're just powering your way through it. And if you think about it, you're kind of feeling a little achy all over. Now, it's not that because of lack of sleep, something has changed in your muscles. I don't think there's good evidence for that. What has changed is your set point in your brain and your spinal cord for the perception of pain. You feel like crap. Now, imagine if you're doing that day after day after day and not getting
Starting point is 01:03:56 sleep. That really messes up your central nervous system and that modulation around pain. What happens is it changes your set point and it impairs that prefrontal cortex and its ability to modulate pain. When you went through, Peter, your bad episode of back pain, did it impact your sleep? Yeah, for sure. You're human. That impact on sleep ultimately further amplified your pain. On top of it, how did you feel during that? And outside the pain, how was that affecting your overall life and your thoughts and your
Starting point is 01:04:29 emotions? Total disaster. Well, look, there's so much going on. I'm happy to tell my story because it's a great introduction to the work you've done. So for folks that haven't heard it, 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.
Starting point is 01:04:47 I'm pretty sure much of it got cut out. But when I was in my third year of medical student, I was having just a great old day, 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. It was enough that I decided not to work out, which says something because 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
Starting point is 01:05:11 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. In the next two weeks proceeded to be a really unbearable episode where I was doing an ICU
Starting point is 01:05:29 rotation. This is back in the Wild West where I think the nurses and the residents were just shooting me up with tortol every day, nonstop, getting me through the day. 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 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 bed feeling as though the skin on the bottom of my foot was being ripped off. The only way I could sleep was to put my foot into a bag of ice and take some amount of Benadryl
Starting point is 01:06:05 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.
Starting point is 01:06:39 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.
Starting point is 01:07:07 Needless to say, I was out of commission. I did not move. I laid on a floor 24-7. 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 going to graduate from medical school on time to you're not going to get to do a sub internship in surgery to you're not going to be a surgeon to you're never going to walk again. So by that point, 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 talked about this in the past.
Starting point is 01:07:52 At this point, I was taking, I think I was up to maybe 320 milligrams of OxyContin a day, which is kind of amazing because if you and I took that today, if you and I split that right now, we would die. But I'm mainlining 320 milligrams of Oxycontin a day just to blunt the emotional pain of this, I think says what we need to know. We can come back to the story of how I met you and how my life turned around from that
Starting point is 01:08:16 point and it's still a miracle for me to believe I actually graduated from medical school on time despite that all happening now into my fourth year because this was my third year bleeding into my fourth year of medical school when all this was going on. It's kind of amazing. A difficult time. Third year is tough. Yeah. So we'll come back to 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 the rest of my life that became much more unbearable. Yeah, that's a terrible story.
Starting point is 01:08:53 And I have to imagine one that has probably shaped you moving forward and had a big impact on your life and what you've been doing. I call it the best worst experience of my life. Yeah. More best today. The gratitude I have for that is, I mean, again, I wouldn't want to do it again,
Starting point is 01:09:11 but it has been such a positive impact on my life. Yeah. Well, I hope we can come back to that 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 everybody else's life out there. And I think there's some key messages there.
Starting point is 01:09:36 What would you like to segue to? Before we go into the ins and outs of what pain doctors can do, let's just talk about some of the bread and butter stuff on pharmacology. 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. But why
Starting point is 01:10:05 don't we start with a softball like NSAIDs? How do they work? Everybody's heard of Advil, Aleve, Naproxen, all of these things. These medications are cyclooxygenase inhibitors. What they do is a couple of 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 nociceptor and amplify it. Prostaglandins, histamines, 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 classically mediated by swelling, redness, temperature increases, and aspirin
Starting point is 01:10:55 and cox-2-inhiberence heads do a nice job in reducing that inflammation. Now this is where medical science, you're going to probably be much more 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. And then more recently, there's been some question as to whether knocking down the inflammation is a good thing after all,
Starting point is 01:11:39 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 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
Starting point is 01:12:19 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 naperson 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 if it's helping with that level of functional improvement. Now, are you talking about this through the lens of acute pain or only through the lens of chronic pain at this point?
Starting point is 01:12:45 A little of both, but I think through chronic pain, we start to introduce all the longer term negative consequences of this. Impact on blood pressure, your heart, impact on your kidneys with long term NSAIDs, particularly if you're older. I remember, I think it was in your book, you took Vioxx. Yes. I loved Vioxx. I did too.
Starting point is 01:13:09 And I still remember the day in, oh God, it must've 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. I stockpiled it. I wish I did. I called up all the drug reps I knew because they couldn't like give it out and I'm like, can you just hook me up? So I ran out of stockpile of that for a long time and cut this if it's too tangential.
Starting point is 01:13:32 But every field looks at the problem through their own lens. Here you had a drug that was causing heart attacks. I mean, in the world's most susceptible individuals at a relatively small absolute rate. Yeah. At the highest dose. I've already had this discussion with Eric Topol, which was like mistake, net negative. Oh, is that right? Absolutely, net negative. Yeah, because I've always wondered-
Starting point is 01:13:56 Merck's is faulted. They should have been much more transparent about this, put a black box label on it and we should all still have access to Merck's. Stop using the 50 milligrams, use the 25s, and you're right, don't give it in susceptible people. The baby got thrown out with the bath water on that one. That's right, we all do this, we look at the world through our own particular field. It's like with the latest blood pressure guidelines,
Starting point is 01:14:17 the cardiologists want it really low, but it screws up the kidneys, and well, the cardiologists say, save the heart, screw the kidney. So great drug, wish it was still around. Why do you think there hasn't been any drug that's come close to that? Like Celebrex is a joke, like none of the drugs
Starting point is 01:14:34 that are in the- Bextra had a Valdicoxib, I think it was, little bit close, but I think it, if I remember it had a Stevens-Johnson bad rash with terrible consequence. I think the drug companies get scared of the lawsuits. So NSAIDs nuance around taking the verdict is so- Do you have a version on dose? I mean, do you say 800 milligrams of ibuprofen TID three times a day, 2,400 milligrams would
Starting point is 01:15:02 be... You would tolerate that for how many days if a person needed it? Week to two weeks on that. Make sure- You're eating, yeah. Food in the stomach, fluids. If you're either older, you've got kidney issues, you've got GI issues, talk to your doc first. Don't just go into this stuff blindly.
Starting point is 01:15:21 Yeah, it is interesting that we can buy acetaminophen and ibuprofen over the counter, and yet they can cause a ton of damage if not taken correctly. I mean, the ERs see people with acetaminophen, Tylenol overdoses, and it's a cause of, well, you know, it's liver failure. Let's talk about acetaminophen for a while. When I last tried to understand it,
Starting point is 01:15:41 there was no clue as to how it worked. To this day, do we understand how it works? Minimally more information and I haven't – in full disclosure, I haven't read up on it a lot. I know it has some cyclooxygenase one impact. A lot of it is thought to be central. I haven't tracked it much beyond that. I saw some interesting side studies where it seems to have some impact in the brain around emotional modulation. And so there's a degree of emotional blunting on acetaminophen. Now whether it translates into a real world or if it's just an experimental manipulation,
Starting point is 01:16:16 I don't know. But there's a nice synergy with acetaminophen and ibuprofen because different mechanism of action, different organ systems are impacted so you can take less of each when you combine them. What's your take on that? I think you just said it, Peter. You said it beautifully. I use those in combination to get the twofer, to get that synergy.
Starting point is 01:16:37 The one plus one is not two, but three. So you can take Tylenol. Historically, we would say up to four grams a day. More recently, there's been some push So you can take Tylenol, historically we would say up to four grams a day. More recently there's been some push to try to reduce that to two grams a day. Clearly if you've got liver dysfunction, if you are drinking large amounts of alcohol less. Yeah.
Starting point is 01:16:56 My go-to stack if I am actually in pain, a year ago I had to get a crown put on a tooth that had an old filling that broke. And it's the funniest thing because of how remarkable the teeth are at sensation, but the crown was a little too high. Okay, so what's the impact of that? That meant every time I took a bite, that one tooth was bearing the brunt of it. It was the last tooth I had right in front of my wisdom tooth. And I'm talking to my dentist and he's like, yeah, Peter, it's just too high.
Starting point is 01:17:22 Just come in and let me shave a little bit of it off. Well, I didn't have the time to go in. So for two months, I did not go in to get this thing shaved off. The pain was, this is how stupid I am. I couldn't spare the two hours to go to the dentist and he was willing to see me nights and weekends. This is the most accommodating dentist in the world. Everybody should have that kind of dentist.
Starting point is 01:17:42 Tony Pacheco, I can't say enough about him and yet I couldn't make the world. Everybody should have that kind of dentist. Tony Pacheco, I can't say enough about him, and yet I couldn't make the time. So for two months, the pain got so bad that eventually couldn't chew on that side at all. So my point is I had to be taking something to get through the day. And the stack that worked was 400 of Advil, 500 of Tylenol, three times a day. Okay.
Starting point is 01:18:04 Took care of me. Now let me ask you, does ibuprofen work better for you than Naprosyn? I don't know, but the reason I prefer it is that I can line up the dosing with the obsedaminophen because I believe Naprosyn you only take once a day, right? Twice a day. Twice a day, okay. You're right. Yeah, I wanted something where I could do it TID instead of BID. The reason I ask is I find huge individual variability in responses to NSAIDs.
Starting point is 01:18:30 Okay. Naperson works beautifully for me at 500 twice a day. Ibuprofen, not so good. At what dose? 800 three times a day. Wow. Yeah, with food and water. Are there types of pains people should be thinking of where these things work especially
Starting point is 01:18:44 well and other areas where, yeah, that's just not going to have much efficacy? I don't find it as effective in neuropathic pain. It might take a little bit of the edge off. Nociceptive pain typically is your go-to. You're kind of your nociceptive or your nociceptive inflammatory pain, the kind of pain you'd see in a joint. Those are your typical go-to forms of back pain, particularly in acute situations, but also somewhat in chronic. And I get a lot of patients that say, yeah, that didn't do it for me. But if you inquire and ask questions, you find maybe it knocked it off a little because in our game, we're trying to knock off pieces and pieces and pieces of their pain experience. The issues with
Starting point is 01:19:26 the different responses are very individually based. And I think in part it has to do with a little bit of what we call pharmacokinetics or where the drug is getting. And different NSAIDs can permeate different tissues at different rates. So you're saying maybe we should be empirical. In other words, try the naproxen, try the ibuprofen, figure out which one works. Obviously don't take them together. Obviously don't take them together, but your take home message is spot on. Do you have a concern with people taking acetaminophen and consuming alcohol? Do you tell people to refrain from alcohol when they're taking Tylenol?
Starting point is 01:20:00 I just said a conserver, listen, don't do more than like a drink a day. Is that the right amount? I just said a conserver, listen, don't do more than like a drink a day. Is that the right amount? I don't know. But if I tell them one drink a day, they'll go do two. They're probably still okay with that. And then I am looking in their chart just to make sure they're not drinking four or eight and there's liver issues. What do you do?
Starting point is 01:20:19 I typically when I'm taking acetaminophen, I don't drink much anyway. I'm probably going to have four drinks in a week. So meaning four days a week, I will have a drink or three days a week. But if I am taking Tylenol, I'm just going to refrain. Again, I don't have any evidence to suggest that that's necessary. Probably the safest. It's the precautionary principle at its finest. Okay. I want to talk about muscle relaxants. So the other thing that has been a real favorite tool of mine is Baclofen.
Starting point is 01:20:49 Now it's not a particularly potent muscle relaxant, but it seems to, for me and for the patients of mine and whom it works, offer something really potent like Valium. Doesn't bring all the baggage of a Benzo or even a Flexeril where you can kind of get the drowsiness. And frankly, a lot of people just, I mean, I used to even get nauseous a Flexeril where you can kind of get the drowsiness and frankly a lot of people just, I mean, I used to even get nauseous on Flexeril, but something about Baclofen, I don't even know it's in me at 20 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 or I've been on a super long drive and my QLs flare a little bit. I know that if I had all the time in the world, I could go and stretch my way out of that,
Starting point is 01:21:34 but sometimes I just don't have that time and I need to get right back to doing something awful like sitting. Just two or three days of 20 milligrams of Baclofen BID with a little NSAID and like, I'm as good as new and I save myself the real flare up. What are your experience with muscle relaxants? Beautiful case example, by the way, for yourself of how we would use those. Baclofen is one of the safest to use. It is not habit forming like the somas and others that can be like a barbiturate, can act and people can get highly psychologically dependent on them. The flexorules have a tricyclic antidepressant property about them that may sometimes be helpful for people in various mixed pain states but also can cause sedation. The baclofen seems to be pretty benign.
Starting point is 01:22:26 We don't typically use muscle relaxants for long-term chronic conditions. The data hasn't borne out. So how many days are you comfortable with a person? Oh, I'm comfortable with a person being on baclofen all their life. It's just, 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
Starting point is 01:22:48 and the cost and benefit of the treatments I'm providing them. Meaning there are costs with baclofen. I don't mean monetary cost. It can cause sedation. What dose is typically or is it just individual? I think it's individual and obviously it is dose dependent. The higher dose is more sedation. We can use baclofen intrathecally. We put in intrathecal pumps for baclofen. This is a beautiful, life-saving, minimal surgery that we do for people with a spinal cord injury, intractable spasticity,
Starting point is 01:23:21 because to get the spasms under control with oral doses, you just can't get there. So, we've thread a little catheter into the CSF and we deliver Baclofen that way. Now, it again is a clean relatively safe medication, but I'm always evaluating long-term, is this person getting benefit from this? Should we be talking about dialing it back and trying to wean? And if they're not getting benefit, then why should they stay on the medication? I know you do the same types of things in your practice. We use it, we can use it in acute, subacute. We'll use it in some chronic conditions as a trial. What's a trial? Month, two months. And then we monitor data on every single person. And what dose are you comfortable up to 20 milligrams three times a day?
Starting point is 01:24:05 Yeah, up to 80 milligrams, I believe is the upper end. I don't usually get there. Okay. You alluded to Neurontin earlier and you alluded to the fact that it played a role in my recovery because once we got the big stuff out of the way, I still had a couple of years of peripheral nerve injury. And the only way to put the fire out in my foot was Neurontin. Unfortunately, initially, it required four grams a day. I was taking a gram
Starting point is 01:24:34 four times a day or something like that. The good news is it worked. The bad news is you're pretty much always tired. I was very happy over time to get that dose down. I think within 18 months, I was completely off the Neurontin and lo and behold, never experienced. Although, interestingly, maybe once every year, I get an enormous surge of fire into that same foot. Literally, one shot of flame that lasts seconds and it's gone. Essentially, never again. Is Neurontin still a very powerful
Starting point is 01:25:07 tool in the use of neuropathic pain? You alluded to other drugs like antidepressants as well, in addition to a rather impotent anti-seizure med. But what else do you have at your disposal for this type of pain? The beauty of Neurontin or gabapentin and its cousin, Pregabalin, which was introduced immediately after Gabapentin's patent ran out. Conveniently. Very conveniently. Both have the same mechanism of action. They work on the alpha two delta subunit of a calcium channel in the spinal cord in the
Starting point is 01:25:38 brain. That's a little too jargony and technical, but think of them as agents that turn down the signals that are in the spinal cord being processed and in the brain. So they're really not impacting your nerve out here or in your leg. They can be very effective. The beauty of these two drugs is there's no lethal dose. The only way they could kill the rats when they were studying it was to drown them in it.
Starting point is 01:26:06 I used to say, or hit them over the head with the tablets. And I would tell a patient somewhat jokingly, the only way you can be hurt taking this drug is if you're struck by a truck that's carrying it. It's a little bit more nuanced than that because there are side effects. You could fall asleep driving. You can fall asleep driving. I tell people don't operate heavy machinery, don't go doom buggy riding, don't blah, blah, blah. There is an elderly patients in particular, I warned them about falls because you can
Starting point is 01:26:34 get a little unstable. Now, pre-gablin can also lead to weight gain. It also increase appetite? Both. Both. Both. Okay. Well, it's more icy water retention.
Starting point is 01:26:44 Got it. I see a little peripheral edema in both. And they also both enhance sleep, especially pregabalin. And so there's a little bit of an added benefit to patients who were using these to also put the pain out at night when it can be most noticeable. There was actually a study, I don't know if I'll ever be able to find it. It was sent to me that actually suggested pregablin didn't just make you drowsy, which was obvious, but also promoted appropriate sleep architecture. I don't know the data on the sleep architecture and that would be something I'd be putting
Starting point is 01:27:16 out to you or some of the sleep experts. I have taken it after surgery. I find that it makes me sedated. I don't find the quality of the sleep. I could be totally wrong on that, but it could be your experience. That's it, that's it. It could just simply be my experience.
Starting point is 01:27:32 The truth is, I do tend to, when I dose it, I'll dose lower in the day, and then I'll wallop a little harder at night for the very reason. So let's imagine Gabapentin, maybe in the day 300, 300, 600 at night. And I'm trying to titrate that so that one, it helps them sleep because you brought up an incredibly important point, which is during the day, we've got all these modulatory things we can
Starting point is 01:27:57 do around our pain, distraction, for instance, other coping strategies at night. You're just trying to get into this relaxed state. And that is the worst time for somebody with chronic pain. And so the gabapentin, and sometimes other agents can help with that. So yeah, I do use it to help people sleep. No lethal dose maxes out at around 900 to 1000 milligrams at a dose because it's taken up by an active transport system in the small intestine. Once you take more than about a thousand milligrams, the rest of it's just passed out your backside. Pregablin is different.
Starting point is 01:28:33 It has what's called a linear kinetic profile, simply meaning the more you take, the more that gets in your system. So the only times I will typically switch somebody from a Gabapentin if they're getting benefit is when they've maxed out the dose. They're getting benefit, but there's no point in giving them more. I'll switch to pre-gablin where I can drive more into their system.
Starting point is 01:28:53 And again, you're using these for the most recalcitrant neuropathic pain typically? I'm using these for the most recalcitrant pain in general. So that's an important point. While I can speak to perioperative pain, acute pain, subacute pain, and chronic pain, Stanford, we tend to see, we're a tertiary referral center. I tend to see, we see people after they've seen everybody else.
Starting point is 01:29:20 We didn't even do this, I'm sorry. We didn't define chronic pain, but how would you put a definition on that? 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
Starting point is 01:29:37 of tissue healing. So it is nuanced, it's context specific, meaning if you have an inguinal hernia repair or a prostatectomy, which should heal up pretty quickly and your pain should go away pretty quickly. But if you've got pain after a couple of 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 going to have pain for quite some time. So I wouldn't call chronicity for a total knee, Totally makes sense.
Starting point is 01:30:12 context specific. This gets into also some of the whole issue around opioid prescribing and these rigid timeframes for surgery and what have you, but persistence beyond the time of expected tissue healing. Antidepressants and their role in pain management? 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 selective serotonin
Starting point is 01:30:47 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.
Starting point is 01:31:26 Do you remember how much you gave me? Of? How much sodium? Sorry, how much lidocaine? I hope it wasn't toxic. I'll come back to the story. It's pretty funny. I'm looking forward to it. Which TCAs are the popular ones? Everybody, I think there's about nine.
Starting point is 01:31:42 What are your top two or three? Yeah, that's the thing. We all get comfortable with our top two or three of any class. My go to is Dicipramine, Nortriptyline, and Amitriptyline. They're broken up into different categories based on mainly side effect profiles. After Nortriptyline, what was it? Amitriptyline or Elaville. Oh, Amitriptyline. Yep, yep. So Elaville is an older tricyclic that has a lot of histamine release, a lot of sedating properties.
Starting point is 01:32:11 I would never give that to an older guy with a big prostate because he couldn't pee 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?
Starting point is 01:32:29 Yes, and I still embarrass to this day. Is it offset by GLP-1 agonists in the modern era? I've learned my lessons. I haven't run that experiment. That's a great idea, but I typically use the amitriptyline when I need some sedating help at night for sleep and pain because of dual action.
Starting point is 01:32:47 I like the dicipramine because it has less of that sedating property and I'll tend to go to that and the nortriptyline. And you can titrate blood levels, for instance, like the nortriptyline. And those drugs, so where do they work? They work in the brain. They work in the brain. They work in the brainstem. One of the classic areas down deep in the brainstem is a rostral-ventral medullary region where descending pathways are coming down and some of the key neurotransmitters are
Starting point is 01:33:16 serotonin and 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've prescribed them an antidepressant is like, okay, Mrs. Jones, Mr. Smith, we're not doing this. Because we think you're depressed and that's why we're saying, yeah. These are great, great, great pain drugs, but they were never FDA approved. Why were they not
Starting point is 01:33:44 FDA approved? Because they're off patent. There's no money to be made. Not FDA approved drug, approved for pain is what you meant. Yeah. Thank you. Thank you for that correction. FDA approved for something else. You're absolutely right. Okay. Well, this brings us to opioids, which I saved for last because of, well, there's actually more drugs I want to talk about, but in terms of the off-the-shelf
Starting point is 01:34:02 typical stuff that people think about. So a lot of hay has been made over this. There's no question that opioids have been overused and abused. And there's no question that illicit use of these things has had a devastating impact on our society. But it would be difficult to say that the field of medicine would be better off having never had an opioid. 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
Starting point is 01:34:47 outside of a hospital, not inside a hospital. And as a pain specialist, I would imagine few people are better equipped to navigate the nuance of that question. Yeah. It is a very nuanced question. I think a little preamble first. I don't take money from either the opioid companies. I don't take money from either the opioid companies. I don't take money from the litigation that's ongoing because there are tens and tens of billions of dollars at play right now. 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
Starting point is 01:35:33 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 because 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. It is true, prescription opioids were overprescribed, they were over marketed, they were bad actors doing bad things. But it's not that
Starting point is 01:36:23 simplest story. 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, you had a letter to the editor of New England Journal saying that nobody got addicted, like 38 patients or some nonsense and Purdue and others ran with this 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. There was growing pressures to do something about it.
Starting point is 01:36:59 People have brought up the pain as a vital sign as an example. People have different opinions about that. 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?
Starting point is 01:37:15 Do you want your mother, your daughter back in that time? I think the answer is clearly no. But also there was other pressures and Peter, you witnessed those firsthand. What was going on back in the 90s and the 2000s? 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.
Starting point is 01:37:37 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 bucket of whatever. And the reason for that was surgeons and docs don't like getting called at 3 a.m. for pain control. So pressure to put people out in the home environment. On top of it, docs get lousy training for pain. What is the average? Seven hours, I think, in medical school. That's, by the way, 40 hours of pain. So great if you've got a dog, not so great for a patient. So you've got this pressure. And by the way, not only on top
Starting point is 01:38:19 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 gaining 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. 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. By the way, the perfect analogy to this is the mortgage crisis in 2006 to 2008. If you took a zeroth order view, it would be really easy to blame one of the entities, but it is actually a perfect storm. I have a slide yet on the opiocard,
Starting point is 01:39:05 I call it the perfect storm. 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, I'm gonna borrow from my friend, Professor Keith Humphries. There are three kinds of physicians out there. There are the majority of the physicians doing the right thing for the right reasons.
Starting point is 01:39:25 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. 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. Did they contribute to the problem? Yes. Have they gotten educated? Yes. I didn't answer your question though. Let me now circle back,
Starting point is 01:39:59 and I hope you'll forgive that little bit of soliloquy on my perspective of that 20 years. I don't use opioids as a first line agent ever, almost never. End of life, cancer. But usually by then they've tried other things before they're getting to us. I will use end of life, cancer pain, I'll use opioids liberally as needed. Just one thing, 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? Frequently, we have an acute pain service in the hospital that sees about 30 to 50 patients a day. Based on what? When is the big gun of your team's expertise being brought in for a post-surgical routine case versus not?
Starting point is 01:40:49 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. You know, when we brought pain in for every case when I was in residency, anytime we did a thoracotomy, it was a non-negotiable. 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. But sometimes you had to actually make a huge incision under the ribs and that's a very
Starting point is 01:41:24 painful, you just know this from experience, that that's such a painful experience. You cut this huge incision in the intercostal muscles, you put ribs, spreaders in, you crank these things open so you can do this big operation. We just know those patients are going to need an epidural catheter. And we want that in before surgery not after and it makes all the difference in the world. So pain was a part of that response.
Starting point is 01:41:50 I don't remember us routinely bringing pain in otherwise, but things have changed, I'm sure in 20 years. So today for a general abdominal case or a general orthopedic case, are you brought in preoperatively? Yeah. These days, there's a lot of movement towards these ERRAS protocols and enhanced recovery after surgery. And so fortunately, the field of medicine is moving more and more towards a team-based
Starting point is 01:42:15 healthcare model where surgeons, pain docs, anesthesiologists, nursing, rehab are all working in a collaborative manner. They're putting together protocols to what is the best optimal approach to prehab a patient before surgery, move them through the intraoperative and then perioperative period. And it's gotten better and better and better. Can we still improve it? Yes. But the acute pain service does get involved, particularly as you alluded when we put in peripheral nerve catheters or epidural catheters. And this is where we're running that local anesthetic,
Starting point is 01:42:50 the numbing medication that stops the nerve impulses to provide pain relief after surgery. And so yes, we do get deeply, deeply involved in that acute surgical pain space. And then also with internal medicine docs, when patients are admitted into the hospital for whatever cause. If someone's listening to us and they're going to have elective surgery at some point, I want to plant a seed in their head for someone who's going to have the knee replacement, the hip replacement, the cholecystectomy, the api, whatever. Should they be requesting this of their surgeon? Should they say, hey, I want to be diligent about my recovery. I want to minimize my use of narcotics.
Starting point is 01:43:27 Do you mind calling in a pain consult so that I can just have a team of docs who are exclusively thinking about my pain? Because let's be honest, the surgeon, I got enough to worry about. I got to make sure you didn't leak, that that anastomosis is fine, that you're not getting a wound infection. Your pain is literally like third or fourth on the list of my concerns for you to have the best outcome. Right. You are right. And if a patient is listening to this, a person is listening and they have the ability, they have the wherewithal to go to their doc, their surgeon and ask
Starting point is 01:43:58 what will pain management be like? Is there an opportunity to interface with an acute pain service, particularly if they're taking opioids now for a chronic pain problem or even if they're not taking opioids for a chronic pain problem? So we will see them in our clinic before surgery. We will put together a pre-surgical plan for them, which will often include a regional anesthetic approach, meaning those nerve blocks or the catheters. We sometimes involve intravenous ketamine to augment.
Starting point is 01:44:26 We will put together the whole plan, communicate with the anesthesiologist, make sure there's a good handoff after surgery, and then we will follow them afterwards. And then we will typically follow them outside the hospital and help the surgeon out with the medication management and the pain management. All of this is not just solely to reduce pain, but to put that person in an optimal state for rehab. How ubiquitous is the patient controlled analgesic device, the PCA that we used to work?
Starting point is 01:44:54 Everywhere. Okay, so people are still typically getting fentanyl through a PCA in the immediate post-operative phase? Fentanyl, morphine, diluted, yeah. The PCA is a very common tool. And one, it puts pain control in the hands of the patient. Two, studies have been shown that PCA-delivered medication, opioids, they end up taking less
Starting point is 01:45:16 than if it's nursing-delivered. And the goal is we want to get you off an opioid, even oral, before you go home. Is that generally the stated objective of the medical system now is, whatever opioids you're going to need, let's try to deliver that to you in the hospital? I wouldn't say necessarily,
Starting point is 01:45:32 because I think there are some surgeries that are gonna clearly require prescribing an opioid after surgery. Remember, the name of the game is get people out of the hospital and have the care take place in their home. And people are gonna need some degree of pain management and analgesics. And those analgesics can be Tylenol NSAIDs if it's more than mild, moderate pain that
Starting point is 01:45:53 may involve an opioid. So how are you thinking about that? How are you thinking about extracting the value of the opioid and minimizing the risk of long-term dependence. What we have learned is that there are vulnerabilities that people bring to an injury or surgery and being placed on opioids that set them up for more likelihood of persistent opioid use. And we've characterized, we and others through research studies have characterized many of these factors.
Starting point is 01:46:27 Some of these factors include preoperative depression and anxiety, higher levels of catastrophizing, early adverse child events, so history of PTSD, history of physical, sexual, psychological trauma. All of these set someone up to have a higher likelihood of persistent pain and persistent opioid use. Now, you will note all these things I said, most of these things I said, people would normally put under the psychological umbrella. The key message that I want to give, I think everyone's getting this, is when we talk about psychology and psychological factors, we're talking about neurosciences, we're talking about the brain, and we're talking
Starting point is 01:47:09 about specific brain systems, regions, networks. So we did a study several years ago. This was led by Jennifer Ha. Ian Carroll was a key player leader on this. And we found that higher depression scores preoperatively predicted much more likelihood of persistent opioid use after surgery. And how are you screening for this? What tests are you using? Back then we used something called the Beck Depression Inventory, which standard instrument
Starting point is 01:47:36 we don't use that anymore. There's more modern tools. I thought what was cool about this, we did a factor analysis on the original paper and you can break the back down into different components of depression, anhedonia, cognitive, blah, blah, blah. What we found is there was a particular factor that drove almost entirely that prediction of depression, self-loathing. It was feeling like really bad about yourself. So if you have someone who just suffers from, not that anhedonia is anything but unpleasant,
Starting point is 01:48:08 but if they're only experiencing anhedonia, but no self-loathing, you would say, well, the risk isn't as high. Yeah, conceptually, your argument holds, but now I'm gonna come back to a lot of the things that you write about, which is the danger of drawing inferences from small population studies and generalizing that to the rest of the world. Yeah, especially without randomization, because what you really would like to be able to see is
Starting point is 01:48:35 you take a whole bunch of people in, you get their incoming metrics of anedonia, dysthymia, self-loathing, you categorize all the arms and tentacles of depression, and then you randomize within each of those to with and without opioid strategies. I mean, this is a very complicated thing to do, but if you want to know the answer, that's kind of the way you want to do it. That's exactly it. Unfortunately, there's not much will to do that in society. Even in the world we live in today where we understand that for a non-zero potentially non-trivial segment of the population, the introduction to opioids that ultimately destroys people's lives is delivered by the
Starting point is 01:49:17 medical system. I was on the Institute of Medicine panel, now the National Academy panel, and we did a report called Relieving Pain in America. And I remember sitting around back in 2010, and we were talking about the state of pain in the country and where we needed to go identify a perfect vision and also identify what are the biggest research questions to ask and answer. And I remember a really vigorous discussion here. And the one that I put forward and others put forward is we need to better understand what is the long-term effectiveness and safety of prescribing opioids to people
Starting point is 01:49:51 with chronic pain, meaning we need to figure out for whom opioids work. Today, we still don't have an answer to that question. And there's very little will to do it because the whole message in the scientific community is basically find non-opioid choices. So, there's not a lot of interest in funding the studies to figure out for whom it works. There is a lot of active interest still mainly through data-driven studies to find out who's at risk. But that type of study that you're talking about and others that are of longer term and bigger consequences.
Starting point is 01:50:25 I just don't know when they're going to get done, who's going to fund those. This is a little unrelated, but I remember this when I was in residency. There was one of the attendings and I don't even remember who it was. But he had this belief, he used to quote this study and I don't remember it, but it said that if you injected bupivacaine into the injection site, sorry, the incision site, so I'm going to make a midline incision, draw my little line, inject bupivacaine, so for the listener, this is a long acting sodium channel blocker, wait some long period of time, like 10 minutes, then make the incision go about, do your surgery, and then immediately give that patient acetaminophen and ibuprofen immediately post-operatively and keep them on it around the clock.
Starting point is 01:51:11 You could eliminate opioid use. And he was convinced that the only reason surgeons didn't want to do this was because nobody wants to inject and stand there for 10 minutes with your thumb up your ass, waiting for the bupivicaine to seep into the tissues. And maybe it's anecdotal, but it really seemed to work. Like it really seemed to work that you would do this inguinal hernia repair or at the time, some small laparotomy or whatever it was, anything. And if you were willing to put that bupivacane in and sit there and wait, and I'm trying to think,
Starting point is 01:51:39 we might've used epi with lidocaine as well. So it might've been a little epi with lidocaine plus bupivacane or something like that. And you had to be super due diligent about keeping the acetaminophen and ibuprofen levels up. Have you ever heard of anything like that? Oh, all the time. Yeah. I mean, I think he was ahead of the curve. Now, whether it completely eliminates any likelihood of opioids after surgery, that's a little too strong a statement. Look, it just reduces the requirement, right?
Starting point is 01:52:01 I strongly believe that he was practicing good medicine and he was doing it ahead of his time. Now, the idea of using a combination of lidocaine and marcaine and epi, as you well know, is lidocaine short acting, so it's going to work pretty darn quick. And so you can get going with your surgery while the marcaine, the bupivacaine is kicking in, the epi is going to not only provide hemostate, it's going to reduce bleeding at the site, but it can keep the local contained. Which means you have to use less bovey, which means less tissue damage.
Starting point is 01:52:31 Yes. Maybe he was using epi with bupivacane. I don't remember. Well, I mean, you told it. But there's something there, right? There is something there, there. And I think I have an ass surgeon these days, and my sense is that's becoming more and more common practice, that there's a greater appreciation
Starting point is 01:52:45 of the role of this concept of preemptive, preventative, analgesia, anesthesia. I think it provides some benefit. There was a big hoopla on this like 20 years ago, when everybody thought we were going to find a way just to basically eliminate post-operative pain through these methods. Presumably didn't pan out.
Starting point is 01:53:02 It just didn't pan out. Yeah. But look, a 50% reduction in opioid requirement post-operatively would be enormous. Huge. Absolutely. Getting back to your question, I think we're in an interesting crux in research and clinical care
Starting point is 01:53:17 where we're gathering more and more high quality data to better understand these vulnerabilities. And I think we're going to be moving to the point of putting these into clinical decision support tools that can inform the docs and help them to assess a risk of a patient so that you can have an informed conversation with someone like you are at likelihood of having persistent opioid use because of what you bring. Do patients receive that well? That's a hard discussion to have with a patient, I would imagine.
Starting point is 01:53:48 I guess it a little bit is about their expectations. The challenge is when the ones who've had multiple surgeries that have been on opioids, they're expecting opioids, a lot of it's expectations. I think the more naive person, those go a little smoother. If you are professional, explain to them, but also allow them to make their own choices. Don't say, we're not going to give this to you. Yeah, that makes sense. But here you are at an increased risk and that's always the discussion I have with patients, whether in the acute space or particularly in the chronic space.
Starting point is 01:54:20 So let's talk about a couple other things that are related to this, but distinct. Let's talk about acupuncture. What do you know about it? Well, let's talk about through the lens of chronic pain. Yeah, yeah, yeah. All right. Clinically, some people get better, some people don't get better. I cannot yet predict who is going to respond and who's not going to respond. Is it a part of the work that your department does? Yeah. We actually have Dr. John TTi Cong does the acupuncture. She's a pain doc. She does acupuncture.
Starting point is 01:54:51 And my view of acupuncture is a treatment, is a modality, is if you can afford the wallet biopsy and it doesn't cause you problems, then give it a try. And you say wallet biopsy because the insurance doesn't typically cover it? 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. So Medicare is covering something commercial payers or not? Well, it's possible. Okay. Yeah. Historically been hard to get that covered.
Starting point is 01:55:21 So notwithstanding, I like the idea of a wallet biopsy. I hadn't heard that before. In your experience, where do you see it being most successful? What type of pain? What type of clinical presentation? Yeah. I've had some successes in back pain, muscles, skeletal pain, migraines, headaches, oddly. And it's highly variable.
Starting point is 01:55:41 I studied this. I had a really large program project grant to look at cortical mechanisms of this and predictors. We're putting in a paper now, which is a prediction model of real acupuncture versus placebo acupuncture. Puncture, but not in the appropriate spot? Well, that's one option. And it turns out that many of these acupuncture points overlie peripheral nerves. And so when you twiddle the needle or apply electroacupuncture, are you doing a peripheral nerve stimulation?
Starting point is 01:56:11 I don't know. But this is a striding or needle that looks for all intents and purposes like an acupuncture needle. It causes a little pinprick, but it doesn't actually do acupuncture. And it's been shown to be a good placebo. What do I know about the mechanisms? Again, don't fully understand.
Starting point is 01:56:27 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. We still don't have good ways of predicting who's going to respond and who's not going to respond, but that's rather common amongst all of our pain treatments. Again, pretty safe.
Starting point is 01:56:58 Absent some risk of infection, make sure that the facility you're getting at practices good hygienic approaches. How do we think of acupuncture differing from dry needling? I think you'll want to get a true acupuncture specialist to dry that. In California, I think it's not legal to dry needle, but you can acupuncture. I even understand the difference. If you're using the term dry needling from an intramuscular standpoint, I don't know if that's where you're going. Maybe. I see acupuncture refers to just going after a nerve specifically. Well, it's an acupuncture point.
Starting point is 01:57:26 Okay. It is a Chinese medicine list of acupuncture points. I'm way out of my wheelhouse here, folks. When I think of dry needling, I tend to think of that in the context of trigger point injections, which we do, physicians do. In that, we're taking typically like a 30 or 27 gauge needle. We're putting it intramuscularly into a trigger point muscle. It's where you get those knotty muscles. You can do dry needling. What that does is it causes relaxation of the muscle. Acupuncture is really quite different from that. Okay. Next question on chronic pain. What is the role of cannabis in your experience here? Is it friend or foe?
Starting point is 01:58:09 And again, I'm sure there's a nuanced answer. Very nuanced. This is another one where liable to get some hate mail on either side of this. Here's what I'll tell you. One, the verdict is still way the heck out there. You look at well-controlled randomized trials. There's very few of them, by the way, but some in neuropathic pain that show analgesic benefit over a short period of time with cannabis. You look at population level studies. Australia did one. They did
Starting point is 01:58:38 not show benefit with cannabis. We collect data. One of my other areas of both research but also clinical care, is I built a learning health system that captures high quality data on every patient that comes in. And so we deeply characterize or phenotype them. And we looked at people coming in on cannabis, not on cannabis. Bottom line, people coming in on cannabis into Stanford are worse off and they stay worse off. Now, there's all these limitations to observational studies no matter how well you conduct them. Let me distill it down to some talking points. There's a huge number of cannabinoid receptors in the human brain that are playing a role
Starting point is 01:59:16 in analgesia. So I'm absolutely convinced that cannabinoids are playing a role in pain relief. One. Two, the forms of cannabis that we take are dirty, meaning we don't know the dose, we don't know the ratios, they've not been well studied, and they've not been studied in different groups. A major part of that is because it's a schedule one drug, which means that the DEA says basically high abuse potential and no medical benefit. And it takes basically an act of Congress to study cannabis.
Starting point is 01:59:48 I don't prescribe it at Stanford. I don't screen people for it at Stanford. If I did and if we kicked them all out, I wouldn't have anybody in the clinic. I mean, we're in Northern California. That's interesting. So you can't study it. I would assume you couldn't study it with federal dollars because of the federal DEA restriction. I would have assumed because it's legal in
Starting point is 02:00:11 California, if you were using non-federal dollars, you could study it in a state like California. You can't study it with federal dollars. NIDA will support funding of cannabis. The regulatory controls you have to go through are crazy. I see. Because it's schedule one, the laboratory. It's actually more demanding than how you would study cocaine. We used to make jokes. UCSF did some nice cannabis research. And the word on the street was is that they would deliver the cannabis doobies in a Brinks armored truck with guys carrying M16s. Now, I think it's gotten better, but it's just been challenging to study this.
Starting point is 02:00:49 I'm firmly of the opinion, here's where I'm gonna upset people. I firmly believe we should make it a schedule two or schedule three drug. If for no other reason to study it with less friction. What you said, perfect. Okay, there's a condition you've already alluded to today that I am sure everyone has heard of,
Starting point is 02:01:05 and yet if you asked most people to define it, they wouldn't be able to define it. And so we're going to 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. Yeah. Yeah. What was historically a garbage bag definition? Fibromyalgia is a condition of widespread bodily pain that impacts people above and below the waist, the diaphragm. It's associated with early morning stiffness, fatigue, mental fog, often some GI problems. It was historically based on American College of Rheumatology definitions
Starting point is 02:01:46 based on tender points in 11 out of 18 places, but that's been replaced by now criteria 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 a newer definition, we're picking up a lot more men. The cognitive aspects of it are really a problem. It's also associated, as I alluded to,
Starting point is 02:02:40 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 syndrome that's caused untold problems, particularly for women.
Starting point is 02:03:06 What's the prevalence according to the current definition? I should know how many millions there are, Pete. I should know how many millions and I don't. I can tell you just to give a frame of reference. 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.
Starting point is 02:03:24 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 have 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
Starting point is 02:04:15 parceled it out. We've broken it into different categories. 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 back pain, it's musculoskeletal pain, it's migraines, it's abdominal pain, and it gets 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, a huge societal burden. It is historically a disease of histrionic
Starting point is 02:04:53 housewives is how they were mislabeled tragically. And we're having now a greater appreciation for what it is, 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, I think this is an interesting pain concept to introduce and talk about it. There's something called conditioned pain modulation.
Starting point is 02:05:33 In the animal world, we call it diffuse noxious inhibitory controller, DNIC. CPM, 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? Hit you? He would hit you. Of course. He'd itch in your other arm. He'd stomp on your foot. And you're like, well, the hell did you do that? By the way, this is a boy only thing. I can't imagine girls did this, but yes, it's of course, this is what little boys do.
Starting point is 02:05:59 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 periaqueductal gray rostral ventral medullary regions. Labar's first described this in the mid-70s in animals.
Starting point is 02:06:27 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 have impaired CPM.
Starting point is 02:06:43 You don't inhibit. Is there a high overlap with depression, anxiety, with fibromyalgia, you have impaired CPM. You don't inhibit. 06. Is there a high overlap with depression, anxiety, and fibromyalgia? And if so, which is the arrow of causality? 07. Yeah. We used to think that there was a high preponderance of anxiety and depression with fibromyalgia. And I think the current data doesn't support that there's any higher prevalence than particularly any other pain conditions.
Starting point is 02:07:08 I think you tend to see more of the anxiety, depression, broadly speaking, in things like low back pain. I think what you see more of in fibromyalgia is fatigue, unrelenting fibro fog is what they call it, and then the sleep disturbances. 06 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? Yes and no. What do I mean? Well, one, we don't know exactly the mechanisms.
Starting point is 02:07:36 There's different prevailing thoughts. One thought again is it's a disruption in your central brain processing a pain through reasons unknown. 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 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 that's caused by what?
Starting point is 02:08:13 That's the thing. Is this infectious? What do people think is going on? So fibromyalgia is frequently preceded by some event, something traumatic. That traumatic can be physical motor vehicle accident, but it could also be some emotional, something traumatic. That traumatic can be physical, motor vehicle accident, but it could also be some emotional or sexual abuse. It can be an infection. We frequently also hear that story.
Starting point is 02:08:34 So there is some insult that people will frequently identify. 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. Another one like diloxetine, which is in the class of antidepressants, but it's a little cleaner, fewer side effects. It's a serotonin-norepinephrine reuptake inhibitor.
Starting point is 02:08:59 This is actually a drug that got FDA approval for pain. And so we go to this a lot. One of the drugs that I have studied with Jared Younger, who's now at UAB, is a drug called low dose naltrexone. This is a fascinating drug. It's got like this underground reputation out there. It's all over the forums. 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 50 milligrams, is used to block opioid receptors. It's an opioid blocker.
Starting point is 02:09:35 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 treatment for addiction, 50 milligrams. At four and a half milligrams, one tenth of the dose, it has been shown to block toll-like four receptor on the microglia. Now I just introduced 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
Starting point is 02:10:13 was these microglia were like the warm fuzzy blanket that propped up the nerves. I don't know what you were taught, but 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 neuroinflammatory soup. And in some patients, Peter,
Starting point is 02:10:55 this drug has been magical, magical. I give it in four and a half milligrams. Silly question. Why not five? Like 4.5 has a lot of specificity to it. Was there some reason why it came in at such a dose? 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 God, just extrapolated that. To 70 milligram person. 70 kilo person. 70 kilo person, thank you.
Starting point is 02:11:26 And we get four and a half. And so when people ask me that, I'm like, wow, it does make us sound pretty smart, doesn't it? There's no difference between four and a half and five. What are the other areas where LDN is just captivating the world? Complex regional pain syndrome, very tragic pain condition that is a neuropathic pain
Starting point is 02:11:46 condition we see a fair amount of. I've got a clinical trial and just wrapping up on that using low-dose naltrexone funded by the RSDSA Association. Another is actually multiple sclerosis they've used it in and they found some reduction in recurrences of MS. I think they did that at UCSF or UCLA, but it's in these weird neurodegenerative type conditions where they're seeing some help. Now I've had some wacky, really wacky patient responses. I can share one. He is dysarthric. He can't speak. He's got weakness. He has hemi-body pain, burning pain.
Starting point is 02:12:26 This is that central pain. Yeah, thalamic pain. So he comes to me several years later, can barely speak at all. He's tried everything. Let's try low-dose naltrexel. So why does he come to a pain doc? Because he's got terrible pain. Okay, so he wasn't coming to you for the speech issue.
Starting point is 02:12:40 No, no, no, no. He has a speech therapist, it's not getting any better. He's a couple of years out. Stroke is stabilized. Okay. So it's this burning pain on half his body. Half his body. I trial him on four and a half milligrams of LDN.
Starting point is 02:12:52 He goes away. He comes back a couple months later. Pain is improved. But not only that, he's now speaking and throwing a few words together for the first time since his stroke. I'm like, what the hell? I bump up his dose. You cannot hurt yourself on this drug.
Starting point is 02:13:07 I know you know this. So I go to nine. Why not 10? Well, because it's easy to take two capsules. He comes back a few months later. He's now talking in sentences. I said, are you sure this isn't due to your speech therapist? And they swear up and down.
Starting point is 02:13:23 Absolutely not. I go up to 13 and a half and now he's having conversations. And how's his pain? Massively better on this. Really remarkable effect. The only way I can explain these things is, you know, in a stroke, you've got dead tissue, you've got live tissue, you've got these intermediate zones and somehow with reducing maybe inflammation, you end up with more functional brain.
Starting point is 02:13:48 Some how, if that model makes sense, which at least teleologically does, something about that inflammatory zone in the middle between what was clearly gone and not is poisoning the part that's still okay. What is the downside of this? Meaning what would one need to be mindful of in trying an approach like this? The beauty of this drug is the only side effects I see. 20, 30% of people get vivid dreams. They get technicolor dreams, not bad dreams, not nightmares.
Starting point is 02:14:16 Their dreams just take on a more colorful nature. Every once in a while, I'll see somebody who they say it activates, then we tell them to take it two hours before bedtime. And if it activates them a little bit, take it in the morning instead. Here's a silly question. What's the scenario in which inflammation of the glia is a good thing? It's a good thing after injury and after an infection because it mobilizes all of those repair cells to come in and clean up the mess.
Starting point is 02:14:44 The problem that we think is going on in pain, the switches don't turn off and go back to normal. And indeed, that Peter, which you did a beautiful intro, is one of the things we think is playing a role in fibromyalgia. They got an insult, activation of this neuroinflammatory system, in a healthy state it turns off, and fibromyalgia never turned off.
Starting point is 02:15:05 I guess where I'm going with this is 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 neuroinflammation is a part of the pathology. So would there be any efficacy to a trial there in either an individual with MCI, mild cognitive impairment, or as crazy as this sounds, is there a reason to consider it prophylactically in high risk individuals? With the caveat that, hey, by the way, if you happen to get an infection, this would be a good time to stop it and ride it out and get better. I think the short answer is yes.
Starting point is 02:15:45 A little bit of the longer answer is, you know this, everything we do is weighing risk and benefits. This is one drug I am hard pressed to come up with significant risks. We have decades and decades and decades of experience with this drug in people with addiction. At 10x the dose, how long are they typically on that drug? Lifetime. Meaning 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's so blunts the
Starting point is 02:16:18 pleasure center. Yeah. The problem is, as all the addictionologists know, is that it's hard to keep people on this because they can just stop it and go back and use. Yeah. You have to want to be off. You have to want to be off. They have injectable versions of this.
Starting point is 02:16:32 Is it not called Vivitrol? It's an injectable under the skin that lasts X number of days, months. But yeah, we've got a lot of long-term data on this. And from a pilot standpoint, with informed consent, obviously, and just I would view that as a novel treatment in patients that one could try out, monitor, do some objective measures, see what you get. I want to be careful. I wouldn't say that for a lot of the things that we do because there's real risks with
Starting point is 02:17:03 a lot of the medications that we provide, a lot of the procedures we do. Not only that, there's big costs that come with them. Whereas this, I'm going to 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. The reason is you can't go to Safeway or Costco and get this. Can't get low dose Naltrex on there. You mean it has to be compounded at 4.5, you're saying? You're right. And so we go through this pharmacy because they've got good customer service.
Starting point is 02:17:31 They take patients' credit cards over the phone and they will ship it to you immediately and they're very responsive. You can probably find it in your local area at other compounding pharmacies. It usually runs about $30 a month. So it's basically a free drug. Insurance doesn't often cover it. They consider it experimental, but it's basically a free drug. It's a buck a day. Yeah. So 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. Yeah. I'm very curious to see if anybody has looked at LDN and any of the neuroinflammation stuff.
Starting point is 02:18:05 We see the relationship between herpes simplex virus and Alzheimer's disease, between shingles, especially ocular variants of it and Alzheimer's disease. We know that there is some relationship between inflammation and this disease and we know that that's obviously not all paths cross through that. There are lipid mediated paths, metabolic paths, vascular paths. I think it would be very difficult to make the case there's not an inflammatory path towards that condition. And so interesting to think about. Dr. John Baxter It is. And I need you to, just as ideally a good scientist, tell you that not everybody buys in to the microglial model that I'm describing. There are friends and colleagues at Michigan,
Starting point is 02:18:45 Dan Klaw, brilliant, brilliant guy who is very much in disagreement with me who believes that even at these low doses, you are antagonizing the opidurgic system and in essence kind of resetting it in these chronic pain states so that you're normalizing the endogenous tone. And you know what, that's the fun thing about science
Starting point is 02:19:04 and why we try to keep our egos out of it. The truth will come forward. What's the evidence for the inhibition of the toll-like receptor? Is that in vitro? Yeah, it is in vitro. Linda Watkins, Mark Hutchinson did some really nice work in that and showed people have had some difficulty
Starting point is 02:19:19 in replicating it. But I have a hard time. We know the mechanism, I think, seems pretty solid. But when I look at the clinical conditions that it has been applied to and shown benefit, I mentioned multiple sclerosis, all sort of colitis, I believe is another one, and these weird neurodegenerative things, I have a hard time understanding why mild antagonism of opioids is going to have an impact on those conditions. Why do you think you see? I mean, that's an interesting one. Well, it's another one of these weird degenerative-
Starting point is 02:19:55 Through a central effect? Yeah. Yeah, I don't have a good answer for you on that. I'm just spouting off some of the headline in the studies that I've read where it's been used. I will have to go and look just for kicks when I get back to the hotel room and just see about the whole mild cognitive impairment, Alzheimer's aspects of it. I clearly don't treat these patients, but it is an intriguing idea, isn't it? Yeah. So when we met 25 years ago, how big was the department at Stanford in pain? About 10 to 12 people in it. This is all the physicians and nurses, the trainees. It was tiny, tiny, tiny, and we were in this small little clinic.
Starting point is 02:20:33 And today? 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, one of the top in NIH fund, it's really come a long way. It's been really exciting to see the growth and the careers and the people we've helped out. I'll finish the story of how we met.
Starting point is 02:20:54 So I'm in this state of total hell. In addition to all the stuff I mentioned about this incredible pain, I couldn't even stand up, literally couldn't stand. And if I did, I had to be hunched over. And so at the time I was dating an anesthesiology resident and she was the one that said, Hey, we just need to get you in this pain clinic. We got to break some stuff. This is going nowhere. You're circling the drain here kid. I think she was in her last year of anesthesiology. So think she was doing a rotation through pain maybe. That's probably how she weaseled me in there. 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
Starting point is 02:21:33 not like I could drive or do anything. 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, I wasn't surgically unstable. In fact, where the original injury was didn't even seem to be what was driving the pain now. You said, look, the first thing we're going to do is we're going to give you an IV lidocaine drip to see if we can just calm these sodium channels down. Did it do anything?
Starting point is 02:22:06 So you said, well, how much do you weigh? I said, I weigh 80 kilos. You said, okay, we're going to 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 going to 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.
Starting point is 02:22:26 So I said, go for it. So in 20 minutes, I got 400 milligrams of lidocaine, didn't touch the pain. Tried something else, didn't touch the pain. By now, it was eight o'clock at night. Oh, wow. And you said, okay, the only thing left to do at this point is to go in there
Starting point is 02:22:42 and do a series of injections at every single facet joint, every single dorsal root, every nerve root, every dorsal root ganglia, the entire length of your spine. 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.
Starting point is 02:23:10 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. 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. So we go into the OR and you proceeded to put, I think, hydrocortisone, 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
Starting point is 02:23:41 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 going to go for a walk because I hadn't walked in three months. And you know the campus loop of Stanford? Yes. Yeah. I walked it until the morning. It's a four-mile loop.
Starting point is 02:24:01 I just walked around and around and around until nine o'clock in the morning, came back home, went on to develop plantar fasciitis because when you don't walk for three months and then you don't stop walking, but put that aside. You told me, look, you're going to probably feel okay for a few days and then the pain is going to 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 it what
Starting point is 02:24:33 the problem was. And if my memory serves me correctly, it was mostly in the T12 L1 area. And I think the ultimate diagnosis was, look, you lost so much disc space at L5S1 through the multiple surgeries. If you look at my MRI today, I basically don't have a disc at L5S1 that you've now developed this facet arthropathy that far up and that's where those nerve roots are going into kidneys and testes. But what was amazing was these injections allowed me to go and do rehab, which I took on like a vengeance and basically rebuilt the strength
Starting point is 02:25:10 in the musculature of my back. And so within nine months, nine months of meeting you a year of the injury, I was functional. Within two years, I could get to the point where I forgot about it for days at a time. I'll give you an example. I could actually sneeze without bracing. That was something I couldn't do.
Starting point is 02:25:30 For a year, I couldn't lean over the sink to brush my teeth. That's how weak I'd become. Just the moment arm of your torso leaning over, I couldn't do that. I had to fully brace and support myself to just brush my teeth. So you asked, what was the lasting impact of that? Well, and I've told this story many times and of course my kids know it well, one of the lasting impacts was my absolute love for parking as far as possible from wherever I'm going. Because when I was going through this, they wanted to give me a wheelchair parking thing. And I was like, I don't want it,
Starting point is 02:26:01 just a psychological thing. I was like, I don't want it. I don't care how far I have to walk. And so now my kids know you celebrate your legs by parking far. And in many ways, that became part of this idea, this thesis I had of the centenary into Catholic on this idea of like, what are you training for? You're training for life. Life is your sport. And that can be something as mundane as being
Starting point is 02:26:21 able to walk to the grocery store. If there's no spot near where you need to go. And can you push the cart to the car and all that kind of stuff. So the net-net for me is it has been incredibly positive. Again, I'm incredibly grateful, Sean, to you. Because again, had I not been at Stanford, had I not had that girlfriend who I won't name her to embarrass her, although I think she's still in the faculty at Stanford, by the way, I just think there's a lot of ways that story could have gone sideways.
Starting point is 02:26:47 So I feel incredibly grateful. And the final part of the gratitude is that I would go on to Hopkins for my residency in an emergency room that serviced some of the most opioid addicted people on the planet. And based on my own experience with that, I can say I always had a sense of humility about what they were going through. I always looked at it as, oh God, I feel your pain. That is awful. And I could have been there.
Starting point is 02:27:15 Wow. But by the grace. So that's been my experience with it, which is 90% good. That's a great story. I listened to that and in one hand, I remember and in another hand it's been so many years. Yeah, it's one of a million stories. You could have been talking about Bob as the doc and I'm listening to this and I'm like,
Starting point is 02:27:36 well, yeah, that is the kind of thing I would have done late at night and just try to get it under control. Put the fire out. Yeah. Just spray the hose. Yeah, because normally to be clear to the audience, I would never approach that in a chronic situation like that. It lacks all specificity.
Starting point is 02:27:55 You can't learn anything from it, but I remember you just being an extremist and we had to do something to help you. So let me ask you a question, Sean. How common or uncommon is my story? Because when you meet a person like me, is there a part of you that thinks we're never going to fix this guy?
Starting point is 02:28:14 This guy's life is over. He's on 320 milligrams of oxy, hasn't walked in months, he's in so much pain, the lethal dose of lidocaine did nothing. Is there a part of you that thinks this is a chronic pain patient, this is a guy who's going to 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? What I usually look at, I usually think of it as I'm confident we can really help them. I don't know what help means. Curing is such a strong word. Every once in a while we can cure, just eliminate, make it go away, never comes back. Like my case. Like your case, which honestly I didn't even know about
Starting point is 02:28:53 until recently. I was lost to follow up. Lost to follow up. I'll tell you maybe in just a little bit like how I did find out. I don't use the word cure, maybe like a surgeon would use the word because I don't want to set unrealistic expectations with patients, but I don't give up. I've never hit a point in my career with a patient where I've ever said, we're done. I got nothing. I got nothing. We've got so many tools available to us now. Back when we first met, we had a handful of procedures, we had a handful of medications, gabapentin, the new kid on the block, opioids, NSAIDs, some tricyclics, but that was about it.
Starting point is 02:29:36 And by the way, that also, that notion contributed to the opioid crisis because we didn't have tools. Now, there's over 200 medications that have shown to have analgesic properties. We have over 200 procedures that we do for pain, scores of mind-body therapies, scores of complementary alternative therapies, and physical and rehabilitative approaches. The toolbox that we can draw upon is so much larger. Often the problem is not with all the tools we have, it's trying to figure out the right tool for the right patient, the right context.
Starting point is 02:30:07 I frequently focus on getting people back to a good quality of life and giving them control of their life and their pain, rather than a promise to eliminate pain. In the acute setting, often it's eliminating pain, because in an acute perioperative or acute injury situation, you need to eliminate or significantly reduce it before you can get people moving, which
Starting point is 02:30:29 was kind of in your case. I got to tell you, I was tempted. My memory of this was a little vague. I almost for a moment, I thought maybe I just look up my records on Epic and just see what's what. And I'm like, no, man, that's what gets you fired. And so I didn't. I'm glad you filled in the memory gaps.
Starting point is 02:30:46 I'm literally just so happy for you. Can I ask you some questions about it all? Sure. Maybe build on some of the things we've been talking about. 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 catastrophizing going on, if I can draw upon that term. You cut
Starting point is 02:31:06 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 neologisms. So he created catastrophizing, he created the word awfulizing. Awfulizing didn't stick around. Catastrophizing was not related to pain, but got used for pain, has three factors to it. Amplification of pain, rumination or repetitive thoughts about pain, and a sense of helplessness or loss of control over your pain. Check, check, check. It's natural.
Starting point is 02:31:40 We've got 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 hypothalamic regions, which are key in hypothalamic-pituitary
Starting point is 02:32:17 adrenal axis, your HPA axis, which I know you're very familiar with. And so in an acute situation, you get a release of cortisol for stress response. You know this is a surgeon. It's great. It keeps us alive chronically, terrible. And so you get this 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. 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. 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.
Starting point is 02:33:01 That's the very important point that I think shouldn't be lost on this. 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. Yeah, wow. I mean, I had to learn how to move again correctly. I had to strengthen the muscles that were gonna make up for doing
Starting point is 02:33:27 what my spine would no longer do, 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 balancing act, and you'd be able to sleep, all these things.
Starting point is 02:33:44 And you had to be able to clear your mind and get out of that catastrophizing loop. 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 and edited. But when I read that story of this woman who shoulder injury and then went down this bad path.
Starting point is 02:34:11 Can't golf, can't garden, can't do anything. 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 social functioning. So we call pain a biopsychosocial
Starting point is 02:34:39 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. My guess is she invariably withdrew. She became deconditioned.
Starting point is 02:34:58 She may very well had a lot of fear avoidance around moving her shoulder, which set you up on a worsening spiral. What I think about and what I think of Sophie, and I think about people as they get older, we need to manage your sleep. We need to manage all the things you put beautifully in your book. But I think we also need to help them better manage their pain so that they can have the function and do all the things that you say so nicely in your book. I don't know what your thoughts are.
Starting point is 02:35:29 Actually, I was going to say that I was somewhere recently where I was asked to define health span and health span is squishy to define because there's like a medical definition that I've repeatedly said I think is insufficient. So the medical definition of health span is the period of time in which you're free of disability and disease. So not very helpful. And I prefer a more functional version of health span. And unfortunately, it's too long for me to rattle off. But one of the lines is freedom from pain.
Starting point is 02:35:54 Yeah. Just as it's important to have strength, stability, 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. One of them is freedom from pain. Yeah. Yeah. The data on elderly people who get a hip fracture spiral immediately downhill to death. Yeah. The listeners of this podcast are not strangers to those statistics. I'm sorry if I'm repeating things.
Starting point is 02:36:23 No, no, no, no, no, but that particular one, it's so tragic. Yeah, and I just keep thinking, if we could better help get their pain under control and address them from that holistic 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 will.
Starting point is 02:36:40 When you went through all of this, you get through the rehab, 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? Yeah, and it's actually been yet another benefit of this experience is the ability I now have to help my patients.
Starting point is 02:37:02 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 let's say a third of people are going to go through some bout of lower back pain in their life. A number of my patients have also been in the loop of chronic lower back pain. 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.
Starting point is 02:37:42 Now, fortunately, I never went back to laying on the floor for days. I never experienced that level of discomfort again. But there were many days when I was very uncomfortable and it would wax and wane. But over time and with every time that I would recover from one of those cycles my confidence would go up. The ability to know that this is going to pass and I'm going to have to make some adjustments and I'm going to have to not sit and I'm going to have to change the way I lay and I'm going to have to do these exercises a little bit more. That's okay. This will pass. And so, I actually just got an email from a former patient. He's not even my patient anymore.
Starting point is 02:38:18 And he said to me, Hey, Peter, just want to let you know, man, I have never forgotten what you said about this and I just had a big setback last week and this would have normally taken me down the spiral to hell. And I hear your words telling me it's okay. This will pass. And he's like, you know what? It's a week later. I'm already on the mend. You're a good doc.
Starting point is 02:38:42 So there's no difference. It's not impacting physiology. It's impacting the psychology and the psychology is what goes on to impact the mend. You're a good doc. So there's no difference. It's not impacting physiology. It's impacting the psychology, and the psychology is what goes on to impact the physiology. So again, I think of that as I tell patients, this is not going to be a monotonic improvement. It's going to look more like the S&P 500, where if you step back 30 years, yes, it's monotonically going up. Look at it for a given week, not at all. It can go down.
Starting point is 02:39:06 It's quite volatile. Now, the volatility will decrease over time, but it never goes to zero. Yeah, that's a great story and it's helped you be a better doc and help people. I listened to your story and everybody's story obviously is very different and personal. I have my own variant of this and I don't talk about this much because I tend to be a little private with these things. I suffer from cluster headaches and all my life as far as I can remember, I would get these headaches. It was like a bomb going off in my brain. How often? Every two years, every two to three years, it's a classic fall, spring cycle.
Starting point is 02:39:46 And all through my teens, my early adulthood, I'd get these two weeks being just terrible, the most insane pain I've ever had. I've broken a lot of bones in sports, nothing trivial compared to that. And nothing I would do would work. I'd occasionally go to the emergency department and they'd say it's a sinus headache and they'd give me antihistamines and they'd prescribe them and sure enough, they worked because it always went away in a couple of weeks. I remember in residency getting one of these in the midst of a cardiac anesthesia rotation and barely able to get the patient to the recovery room. And I just went into a call room and I just hung out.
Starting point is 02:40:24 The thing is nobody knew what they were. I didn't know what they were, but I was scared. Every time these came on, I thought I had a brain tumor. I was convinced. I thought this was going to kill me. And you get really scared that it's never going away. I catastrophized. After the end of like a couple of weeks, I'm like, what the hell am I going to do?
Starting point is 02:40:41 I can't work like this. I can't live like this. I can't live like this. Then I become a pain doc and I'm like, well, shit, I got cluster headaches. How are they treated now? First of all, just to let people know what a cluster headache is, it typically manifests as headaches that last anywhere from upwards of a couple hours. They can occur eight times a day to upwards of a couple hours, they can occur eight times a day to every other day. They tend to have these weird characteristics. They're under a class of trigeminal autonomic cephalgias. Fancy term for simply meaning that you get eye tearing, redness in your eye.
Starting point is 02:41:16 I get what I refer to as a sticky eye sensation, like my eyelid gets heavy and it droops. I get my nasal congestion. But one of the major characteristics is extreme agitation, extreme agitation, meaning Beth would say, well, you better to lie down. And like, no, it doesn't matter. And I just pace, you pace and you pace and you pace until it goes away.
Starting point is 02:41:38 So what I did in the period of all this fear, I learned every damn thing I can learn about cluster headaches, every single thing. How many people get these, or percent of the population? It's under a rare condition. It's one of those rare ones that affects men more than women, but women do get them. You think I would know the prevalence of this too. But less prevalent than migraines?
Starting point is 02:41:58 Yeah, yeah, less prevalent than migraines. Common treatments for these, there's abortive and there is preventative. What the preventative are like calcium channel blockers that you can take. Abortive is the typical migraine medications, the tryptans. So I have stockpiles of tryptans, high flow oxygen. So I knew I was getting one. It's before these happen, I get this prodromal phase with weird appetite, sleep gets disrupted on a note and a sticky eye sensation. I was giving a talk at the Napa Pain Conference and I knew they were coming on, so I threw a tank of oxygen in the back of the car and shat it. And that'll rescue it now?
Starting point is 02:42:34 If I can get it in time, if you can abort these things in time, you can save yourself several hours of absolute agony and you can catch it in like a half an hour. hours of absolute agony and you can catch it in like a half an hour. So the long and the short of it is it was through that journey of learning that I became informed and I developed self-epicacy. So when I got these attacks, when I knew what they were, I no longer had a huge amount of fear that would further amplify things. I was fearful it was a brain tumor. I was fearful like I was having a subarachnoid bleed. I knew what it was. It didn't change the sensory dimensions of the pain. It didn't change the agitation, but I knew even if I didn't catch it, it was going away
Starting point is 02:43:16 in a couple of hours. And that gives you control. So when these happen, I know I'm prepared. I know it's going to be a shitty two weeks and I buckle up, but I know how to deal with it and I know I'll come out of it. And it makes a huge difference in quality of life. And that's what I messages I would try to give patients is it's about learning as much as you can about your condition, being informed, and putting that to use, and
Starting point is 02:43:47 ideally giving yourself a degree of self-efficacy over your health. And when I listened to your story, it had parallels there, that journey that you have. You've clearly used it, maybe tried to say, make you a better person. And yeah, I have a lot of empathy for people as a consequence. Well, Sean, this has been a great person. And yeah, I have a lot of empathy for people as a consequence. Well, Sean, this has been a great discussion. I think we're certainly better off today as a species having a medical discipline that is devoted to pain. We have the luxury of caring about this now. There was a time when just not dying was the highest priority. And now it's we need more than that. It's not just that we don't want to die. It's that we want to be able
Starting point is 02:44:23 to live pain-free, not to be able to live pain free. Not to be confused with discomfort free. I'm still a big proponent of discomfort as I'm sure are you. We should be out there working out hard, experiencing discomfort. But chronic pain can be inflammatory to the psyche and it's not something I would wish on anybody. So it's great to know that since my time as a patient there, that department has increased log fold and I hope that's true and trust that it's true around the country.
Starting point is 02:44:47 So thanks for the work you're doing. Thank you, Peter. It's been 20 some odd years since we've seen each other. And if I can just say, I remember when I saw you, you were kind of an intense guy. I've mellowed. Have you? I've mellowed since then. I remember thinking to myself, this guy is either going to crash and burn or he's going
Starting point is 02:45:07 to do something really awesome. And then decades go by and I get this phone call from Ian and he's like, Dad, Peter just gave you a shout out on one of his podcasts about how you helped him. And he's like, how do you feel about that? And I said, I'm just so happy for him. I had no idea that he's done so well for himself. And you have. Yes, you're seeing one patient at a time
Starting point is 02:45:31 and providing great care. But I think this format is reaching so many people. And this is what we need more of. We need more Peter Atiyahs. We need you delivering these messages that are empowering people. You're making a big impact out there. And I just appreciate you inviting me
Starting point is 02:45:44 on to spend some time with you. So thank you. Thanks, Sean. Thank you for listening to this week's episode of The Drive. Head over to PeterAteaMD.com forward slash show notes if you want to dig deeper into this episode. You can also find me on YouTube, Instagram, and Twitter, all with the handle PeterAteaMD. You can also leave us review on Apple podcasts or whatever podcast player you use. This podcast is for general informational purposes only and does not constitute the practice of medicine, nursing, or other professional healthcare services,
Starting point is 02:46:17 including the giving of medical advice. No doctor-patient relationship is formed. The use of this information and the materials linked to this podcast is at the user's own risk. The content on this podcast is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Users should not disregard or delay in obtaining medical advice from any medical condition they have, and they should seek the assistance of their healthcare professionals for any
Starting point is 02:46:44 such conditions. Finally, I take all conflicts of interest very seriously. For all of my disclosures and the companies I invest in or advise, please visit peteratiamd.com forward slash about where I keep an up-to-date and active list of all disclosures.

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