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

00:00:00.000 Hey, everyone. Welcome to the Drive podcast. I'm your host, Peter Atiyah. This podcast,

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00:01:04.180 My guest this week is Dr. Sean Mackey. Sean is a professor of pain medicine at Stanford University.

00:01:11.740 He also serves as the director of the Stanford Systems Neuroscience and Pain Lab. His research

00:01:16.560 focuses on the neural mechanisms of pain and the development of innovative treatments for chronic

00:01:22.000 pain conditions. In this episode, I talk a little bit about how Sean and I go way back and why it is

00:01:28.400 that I really wanted to have Sean on this episode. In this episode, we discuss the definition of pain

00:01:32.940 as both a sensory and an emotional experience and why it's fundamental as a survival mechanism

00:01:37.980 and the evolutionary purpose of pain, which obviously has been highly conserved across multiple

00:01:42.820 species. We talk about how pain is transmitted through the nervous system, including the different

00:01:47.360 types of fibers that are involved. We talk about the different types of pain, such as nociceptive

00:01:52.160 pain, visceral pain, neuropathic pain, etc. We talk about why pain perception varies so widely from

00:01:58.000 person to person, even in the face of an identical stimulus, how psychological and emotional factors play

00:02:03.340 a role into this. We talk about various approaches to pain management, including NSAIDs, opioids, and

00:02:08.480 anti-neuropathic medications. We talk about the effectiveness of neuromodulation techniques like TENS

00:02:13.780 and how sleep deprivation affects pain sensitivity, as well as why chronic pain often leads to disrupted

00:02:19.920 sleep cycles. We talk about this and many other things. Again, I share a very personal experience

00:02:26.420 with my own pain and how Sean came to my rescue 25 years ago. So without further delay, please enjoy

00:02:32.800 my conversation with Dr. Sean Mackey. Sean, thank you so much for making the trip to Austin.

00:02:42.480 Oh, it's my pleasure. It's really good to see you again after a rather long time.

00:02:47.320 Yeah, I was thinking about it. So this morning, my wife said, oh, what's the topic of the podcast

00:02:51.520 today? And I said, it's going to be pain. And I said, she said, oh, who you have? And I said,

00:02:54.960 Sean Mackey. She goes, her face lit up and she doesn't know you. She's never met you, but she knows

00:02:58.900 your name because she's heard me tell a story. She's heard me tell a story about my own experience

00:03:04.880 through this. I then realized something, which is I haven't seen you since I was in medical school.

00:03:09.440 Yeah. Which is kind of weird. Yeah. So I'm sure we will get to how you and I met 25 years ago,

00:03:17.520 exactly 25 years ago. Wow. And how you played an unbelievable role in bringing me back from

00:03:25.200 arguably the brink of what could have been the end of my life, truthfully. But I want to start with

00:03:31.500 some broader topics around pain. So there's nobody listening to us right now who doesn't know what pain

00:03:37.000 is. There's nobody listening to us right now who hasn't experienced pain. Yet, if you ask for a

00:03:42.480 definition of pain, I think you'd get a lot of using the word to describe the thing, which isn't

00:03:47.500 truly a definition. So if you were trying to explain to a Martian from another planet who doesn't

00:03:55.000 experience pain, what it is, what would you say? There's the formal definition of pain, which is

00:04:01.360 defined as an unpleasant sensory and emotional experience associated with actual or potential

00:04:07.660 tissue damage or described in terms of such damage. It's a mouthful. If you think of it as

00:04:12.260 it's an unpleasant sensory and emotional experience, it's usually tied to something physically happening,

00:04:18.740 but may not be. I think sometimes what's missing in that definition, one of the things I wish they

00:04:23.740 had put in but never did is that pain is the great motivator. Pain is one of the most primitive

00:04:32.260 experiences going back to, if you will, single cell organisms. It's either pain or reward. You're either

00:04:40.640 being driven towards oxygen, food, sex, or you're trying to get away from danger. Pain is so wonderful

00:04:48.100 because it's so terrible. It keeps us alive. Without pain, when we have these genetic issues of

00:04:55.160 congenital insensitivity to pain, we would have never lived as a species. So pain is an unpleasant

00:05:00.240 sensory and emotional experience. To understand pain, whether you're a Martian or you're a human now,

00:05:07.800 I think you have to look back in history. And so I'm going to evoke René Descartes, 17th century

00:05:14.600 French philosopher, thought to be the father of modern philosophy. Incredible contributions brought

00:05:21.380 Cartesian geometry to us, which led to calculus. And he had this dualistic model of pain that he put

00:05:30.400 forward. To his credit, it was the first mechanistic foundation for pain because beforehand, pain was

00:05:37.720 thought to be something mystical or religious. It was punishment of the gods. So he put this

00:05:44.300 framework together that's often illustrated this famous picture of a little boy with his foot in the

00:05:50.240 fire. And there's a little string from his foot going up into his brain. And it ends up in the pineal

00:05:58.580 gland, which was thought to be uniquely a human area. And the idea is the fire pulls on the little string,

00:06:03.940 opens up pores in the pineal gland, rings a bell, and the boy withdraws his foot. The idea is in this

00:06:10.360 dualistic model, there is a complete separation between body and mind. The body is where pain is

00:06:17.560 generated. The mind is where it's perceived, but the mind is simply a passive receptacle receiving

00:06:24.480 these signals. That model put forward in the 17th century stuck with us for hundreds and hundreds

00:06:30.680 of years. And I would argue is with us today. And it has influenced medical care. It has influenced

00:06:37.800 policy. It's influenced everything in our society about the way we think about pain. And it's utterly

00:06:44.640 completely wrong. So yes, he got Cartesian geometry, right? But he really complete bollocks screwed it up

00:06:52.980 when it came to pain. This biomedical model, this dualistic model was with us for hundreds and hundreds

00:07:00.040 of years. And it's only been in the last number of decades that we've appreciated the nuance of what

00:07:08.020 pain really is. And instead of it being under this guise of this separate mind and body, we now

00:07:14.640 appreciate it is this integrated biopsychosocial phenomenon. Meaning that, and I think this is one

00:07:22.500 of the most important things that I'd like to drive across. I'm going to introduce a term, we're going to

00:07:27.220 get to a term called nociception, which are electrochemical injury signals that occur in the

00:07:32.200 periphery, that what goes on in the body and what goes on in the brain, the experience of pain,

00:07:38.160 they may have nothing to do with each other or very little linkages. And we're going to hopefully

00:07:43.160 unpack that. So hundreds and hundreds of years, we're basing it on Rene Descartes' dualistic model.

00:07:50.000 We still see this in medical care right now. You're a surgeon. For many, many, many,

00:07:54.960 many years when I talked with the surgeons, they were firmly of the opinion that the amount of pain

00:08:00.320 that a patient had after surgery was related to how much the scalpel cut and how much tissue damage

00:08:06.440 was done. And I think it's only more in the last 20 or so years, I'm seeing surgeons really embracing

00:08:13.720 this model that what people bring to the operating room table directly influences how much pain they

00:08:21.140 have, their early life experiences, all this stuff. And we'll talk about that.

00:08:27.120 And Sean, just to interrupt for a second, thinking through the history of medicine a little bit,

00:08:30.540 the latter part of the 19th century brought a couple of other tools to pain. So between local

00:08:37.560 anesthetics, cocaine down to lidocaine and general anesthetics in the form of ether, which finally allowed

00:08:44.600 surgeons to cut people without having to hold them down while they screamed, it sounds like that didn't

00:08:50.820 shed any new light. That was viewed in the one hand as just a blunting instrument, but it didn't change

00:08:56.800 the model.

00:08:57.760 Didn't change the model. Yeah. Had no influence on that model, which I think has had tragic consequences

00:09:04.360 in the care of people, particularly with chronic pain, particularly women with chronic pain,

00:09:09.980 who have felt stigmatized, invalidated, because absent something that's obviously wrong out in

00:09:16.800 the body of the periphery, they were just labeled as being histrionic housewives or being told it's

00:09:21.580 all in their head. Not just women, but also some men as well. And so it's only with that evolution of

00:09:28.460 our perception or our model into a biopsychosocial model that that's gotten much better.

00:09:34.040 Okay. Let's talk about, is there a pain receptor?

00:09:36.740 So let's break it down into the foundational stuff. So we have these things called nociceptors,

00:09:44.340 complicated name. It's basically a transducer, which is another technical name. Now your engineering

00:09:51.260 background, so you all know that a transducer is simply a device that converts one form of energy

00:09:57.880 into another form of energy. This microphone is converting sound energy into electrical energy.

00:10:02.860 The speakers convert electrical energy back into sound energy. We have these nociceptors that lie

00:10:08.600 in our skin, our soft tissues, our deep tissues, our viscera, and they're specialized. And they convert

00:10:15.280 different forms of energy into electrochemical impulses. They take pressure. They take heat,

00:10:22.460 cold. They take chemical changes in the form of pH that can occur during infection. They convert

00:10:28.160 those into action potentials that are then transmitted up nerves. These are little electrical

00:10:32.840 impulses transmitting up generally two different nerve fiber types. These two different nerve fiber

00:10:38.320 types, one is called a C-fiber, which is thin and slow. It's really pokey. And I don't know if I'm

00:10:46.800 getting ahead if you wanted to go more into it, but you got this pokey, slow C-fiber that transmits at

00:10:51.960 about one meter a second. And the frame of reference, if it helps, is think about your

00:10:56.480 thumb is about a meter from your brain. So an impulse on a C-fiber from your thumb to a brain

00:11:03.680 takes about a second to two seconds to get there. The other nerve fiber type, it's called an A-delta

00:11:08.600 fiber. It's got some nice insulation around it. It transmits 10 times faster. So it takes a little

00:11:16.000 under a tenth of a second to get your thumb to your brain. And to give a real world sense of the

00:11:22.580 difference in C-fibers and A-delta fibers, think back to the last time you stepped on a tack in the

00:11:29.900 carpet, you hit your thumb with a hammer, you twisted your ankle coming off a curb. What happened?

00:11:36.100 Think back to that experience. You get this sharp jolt of pain that goes right to your brain. Those are

00:11:39.780 eight delta fibers at 10 meters a second, rapidly getting up to your brain, rapidly putting into

00:11:46.580 play systems to protect yourself from harm. You withdraw. You have a reflex that's occurring in

00:11:52.560 your spinal cord. You're not even consciously aware of it. Your brain is setting into play

00:11:57.680 escape mechanisms. The pain that you experience is sharp. It's well-localized. You know exactly

00:12:03.820 where you stepped on that tack. Then about a second, two seconds later, you get this hot

00:12:09.720 burning flooding sensation come over your thumb with you, hit it with a hammer. And you think to

00:12:14.120 yourself, oh damn, this is really going to hurt. And it gets hot. It gets burning. Those are your 0.99

00:12:20.280 C-fibers, unmyelinated, slow, getting up to your brain. And what you also notice for the first time 0.51

00:12:26.460 is you don't like this. This has an unpleasant quality to it that you didn't get as much with

00:12:32.940 that A-delta sharp pain, but you're getting with those C-fibers. That's really clear. 0.93

00:12:36.740 The A-delta is doing two things, if I'm understanding this correctly. Is it creating

00:12:42.340 the spinal reflex where I hit my thumb with the hammer, the signal goes into the spinal cord

00:12:50.260 out through a motor neuron to pull back without me having to think about it, correct?

00:12:55.200 That's exactly it. And it is synapse. And there are synapses in the ventral or anterior,

00:13:00.160 the front portion of your spinal cord, which is, as you know, your motor part of that spinal cord.

00:13:04.040 They're making synapses and it's causing a classic withdrawal effect.

00:13:08.480 But am I also feeling the pain? Am I perceiving the pain? If you could do a thought experiment

00:13:13.620 where you could eliminate the C-fiber in an individual, would they still feel pain?

00:13:20.100 Yes. Yeah. They would still feel pain.

00:13:22.160 So there's still a central component to what the A-fiber is doing.

00:13:26.100 Those A-delta fibers are still-

00:13:27.700 They're still going up.

00:13:28.460 Going up. They're in the spinal cord. They cross over to the other side.

00:13:31.560 So there's an afferent and an efferent to the whole thing.

00:13:35.280 Indeed.

00:13:35.700 Okay.

00:13:36.180 Indeed. We think of these pathways. The main one that we all learn in medical school and we think

00:13:40.840 about is a spinal thalamic pathway. This goes from the spine up into your brain. We're going to get

00:13:46.600 there. But yes, if you had no C-fibers, you would still feel pain. That's one of the other things I 0.52

00:13:52.980 think it's important to understand about pain is we've been trying to knock this out for untold years.

00:13:59.540 And we've not been very successful with it. And part of the challenge is pain is so highly conserved

00:14:07.560 from an evolutionary standpoint. As I was alluding to, back to single-cell organisms, reward, pain.

00:14:13.140 We evolved over the years to have this complex experience of pain, but also redundancies.

00:14:21.220 You knock out one pathway related to pain. There's others there.

00:14:24.420 And they find their way up into the brain just about no matter what.

00:14:29.500 Just thinking about this through an evolutionary lens, lots of debate about this in the animal

00:14:33.260 kingdom. Like, does a goldfish feel pain? Do we have a clear sense as to how far from humans and

00:14:40.340 or mammals you go where you still clearly have C-fibers and A-delta fibers?

00:14:46.100 You could go pretty deep in there. And I get the debate. It's a great debate over wine or beer.

00:14:53.000 And I understand actually taking it seriously and having that debate. A lot of different opinions

00:14:58.320 on this. I actually don't engage in that debate. I think you have to, first of all, define the thing

00:15:06.520 that you're debating. You have to very clearly define the thing. And in this case, our definition of pain

00:15:14.080 is a rather human experience of pain. This is where I was actually going to go. If I can just

00:15:18.580 give you that window. Please. What I was really going to ask is a question about consciousness.

00:15:22.580 Yeah. Is consciousness necessary for the internalization of this full gamut of pain?

00:15:28.780 Yes. I believe firmly it is. And I'm a recovering anesthesiologist. I haven't done it now in,

00:15:35.660 oh gosh, 20 years. But when I did it and when you were operating on a patient, the patient is

00:15:42.980 unconscious. They are not experiencing pain. You need a conscious brain for the experience of pain.

00:15:50.960 Now, what people incorrectly made the leap of is thinking, well, they're not experiencing pain,

00:15:58.400 so everything's okay. That would be a logical fallacy. Because all those signals are still

00:16:03.980 coming from the body, still hitting the spinal cord and having their impact there. All those injury

00:16:09.080 signals. Because let's face it, when you do surgery, it's really nothing more than a controlled

00:16:14.460 injury. Yes. And I just want to point out, and this shows you how long I haven't been in surgery,

00:16:19.620 but 20 years ago, my recollection is an anesthesiologist was giving not just one medication,

00:16:26.680 but several. Yes. So they were giving something like halothane, which to my understanding,

00:16:31.280 we didn't know how it worked then. Do we have any idea how it works today?

00:16:34.260 Better. We still are trying to unlock the whole consciousness aspect of things, but we're

00:16:39.680 inching our way there. But it wasn't enough to give that. The anesthesiologist still had to give

00:16:45.160 typically a narcotic. They were still typically giving something like fentanyl, even though the

00:16:49.620 patient was unconscious. They were also often giving an amnesic so that they wouldn't have any

00:16:55.860 recollection of what was going on. But of course, we all hear the horror stories of the patient

00:17:00.780 and a paralytic on top of all that, right? Exactly. Muscle relaxation.

00:17:03.960 So you hear these horrible stories of the patient who is paralyzed, but somehow conscious. You can

00:17:11.180 miss on this state sort of thing. But just to make sure I understand, in theory, a paralytic and an

00:17:16.840 inhaled anesthetic should be sufficient to eliminate the perception of pain in a patient who is being cut.

00:17:24.720 Yeah. Part of the challenge was, and now I'm starting to step outside of my wheelhouse,

00:17:29.240 even though I was a member of the anesthesia tribe for a long time, is the levels of volatile gas

00:17:35.080 anesthetic that you need to necessarily obliterate reflexes and full nociceptive impulses would be so

00:17:43.840 high that it would depress one's blood pressure. And so you augment that with an opioid.

00:17:49.740 Understood.

00:17:50.520 Like fentanyl, like morphine, like whatever, and you combine those together. And that's why

00:17:55.620 what the anesthesiologists do is quite magical. Got it. So in other words, you give the inhaled

00:17:59.960 anesthetic just to get unconsciousness, but not to fully suppress the nociceptic system.

00:18:05.820 Instead, you bring on the opioid to do the remainder of that work.

00:18:09.480 They're working synergistically and they're working at different mechanisms.

00:18:12.680 Got it.

00:18:12.900 And during that process, the patient is not feeling pain if they're unconscious, because you do need a

00:18:20.240 conscious, working, aware brain to feel pain. But all of the electrical impulses coming in from the

00:18:28.540 body that are slamming into the spinal cord and the brain are open full bore. They're impinging on

00:18:34.380 all those brain systems responsible for stress responses.

00:18:37.240 So does that mean we are seeing a cortisol surge? We're seeing whatever one would expect a conscious

00:18:44.620 person to experience with epinephrine, norepinephrine, cortisol, all those things still

00:18:49.660 surging out in response to pain.

00:18:51.520 Yes. And in response to nociception.

00:18:56.060 Independent of perception of pain.

00:18:57.940 Right. And you notice that I'm trying to be precise in my language here, because since they're

00:19:03.520 unconscious, there's no pain, but there's plenty of nociception.

00:19:06.580 Arguably more than you would ever experience. Think about what we do in surgery. My God.

00:19:11.740 Take a scalpel and then take an electrocautery and start burning tissue. I mean, there's no

00:19:17.040 level of nociception you could ever experience like that while being awake, unless you're in a burning car.

00:19:22.320 Absolutely. That's exactly it. It's remarkable through modern medicine that we get people through

00:19:29.080 all this as a reflection of advancements in surgery, advancements in anesthesiology,

00:19:33.540 advancements in postoperative care. But it is no different than a controlled injury. It's done in

00:19:40.040 a nice sterile environment, but it is a massive injury that people are undergoing. They're just

00:19:44.800 not awake and it's nice and clean and sterile. But there is a stress response associated with that.

00:19:52.180 Most people recover well. One of the hot topics of research these days is why do most people recover,

00:19:59.660 but a certain percentage of people go on to have persistent pain after surgery. That's an area that

00:20:06.260 I used to research years ago. Many others are doing some great work in that space. Turns out that a lot

00:20:12.820 of the factors we're going to get to this is what people bring to your operating room table, meaning

00:20:18.620 early life events, levels of emotional health, cognitive health, and everything else.

00:20:24.180 So to answer your question and getting back to it, no, I don't believe there is the perception of pain

00:20:30.860 without a conscious brain. There's all sorts of nuances to that.

00:20:35.080 So let's go back to something you said at the outset from an evolutionary perspective, which is pain and

00:20:39.740 pleasure have been the driving factors that have been the engine of natural selection. But clearly those

00:20:46.360 things have had to work in pre-conscious models. So that means that whatever we're defining as pain,

00:20:54.040 there did not include a perception of pain. So what does that mean?

00:20:59.460 That's where it gets muddy. And there's smarter people than I that would probably be more articulate,

00:21:04.160 but this is why I think on first principles, you have to define the thing that you're talking about.

00:21:09.240 When we typically talk about pain, we're talking about it from a uniquely human standpoint. Does a dog

00:21:14.640 experience pain?

00:21:16.820 Easier to accept.

00:21:17.740 Easier to accept. I'm a dog person. They experience pain. You move on down the evolutionary. At what point?

00:21:23.360 Right. Does a goldfish experience pain?

00:21:25.300 Does it? Goldfish clearly experiences nociception. They clearly have all the classic withdrawal,

00:21:32.200 protection, survival aspects of it. But what level is there a conscious brain that is translating it?

00:21:38.780 And also on top of it, remember in our human definition of pain, we bake in, it's an unpleasant

00:21:45.340 sensory and emotional experience. Does a goldfish experience emotions? I leave that to the goldfish

00:21:52.740 experts. You see how muddy it gets. You go down rabbit holes pretty quickly, which is why I tend

00:21:58.720 to stay with humans, which is hard enough, by the way. So how does everything you just said

00:22:05.420 differ or overlap with neuropathic pain or that sort of burning pain that I'm sure some people

00:22:13.140 are familiar with? Certainly I was familiar with it for several years. Is that simply a subset of this?

00:22:18.660 Are there various different types of pain that don't have a clear cause effect relation to tissue

00:22:24.620 damage? So we have different ways of categorizing pain, putting it into different buckets, if you

00:22:30.600 will. One is nociceptive pain. And you'll note that that word nociceptive sounds very similar

00:22:38.180 to nociceptors and it's by design. It means that it is pain caused by activation of primary

00:22:46.040 nociceptors, whether it be in your skin or soft tissues or viscera. And it tends to have certain

00:22:52.600 qualities. It's very easy to localize. You know exactly where it is. It has a certain intensity.

00:22:57.980 That nociceptive pain tends to be time-limited, responds well to short-term use of analgesic agents,

00:23:04.680 acetaminophen, NSAIDs, COX-2 inhibitors, opioids, and it tends to go away. And this is the kind of pain

00:23:11.480 that occurs after typically acute injuries. You then have visceral pain, which as a former general

00:23:18.700 surgeon, you understood this. This is due to activation of those primary nociceptors in our

00:23:24.060 viscera. Now the difference and why we bring up the distinction with visceral pain that is either in

00:23:31.380 our thoracic viscera or abdominal or pelvic viscera is that the receptive fields, that means where those

00:23:39.720 nociceptors serve and what we perceive are very diffuse and wide. When you get a stomach ache,

00:23:46.100 you can't put your finger exactly where it hurts. You tend to put your whole hand over it and say,

00:23:52.220 it hurts here, it's diffuse. That's because the spinal cord and the brain have these diffuse

00:23:56.240 receptive fields which expand the area. The viscera don't typically respond to the same type of stimuli

00:24:03.140 that nociceptive pain does. You'll remember when you were taking a bovie to the bowel,

00:24:09.160 the small intestine, patients wouldn't normally move because the nociceptors don't respond to that.

00:24:16.540 But if you tug on it, if you pull that- Or inflate it.

00:24:19.120 Or inflate it. Boy, oh boy. Blood pressure goes up, heart rate goes up. Interesting characteristics

00:24:24.420 with visceral pain is there's something called viscerosomatic convergence, meaning that the

00:24:31.040 afference, the information coming in from the gut, from the thorax, converge with the same sensory

00:24:38.480 systems from the rest of our different parts of our body. So you may remember the old medical

00:24:44.100 school adage, C345 keeps the diaphragm alive. Okay. We all had these in med school. Well,

00:24:50.480 that means that the third, fourth, and fifth cervical nerve roots subserve our diaphragm,

00:24:55.080 which help us breathe. When the general surgeons or others are operating and they get blood under the

00:24:59.640 diaphragm, it irritates the diaphragm. And what patients will typically complain of,

00:25:04.900 shoulder pain, because the shoulder is subserved by the fourth and fifth cervical areas. And so

00:25:13.800 when they had shoulder pain, the answer wasn't something's wrong with their shoulder, it's they

00:25:18.920 had some irritation of blood under there. It's why when people have a heart attack, pain radiates out

00:25:24.340 into the arm because you've got the upper thoracic nerves subserving the heart that overlap

00:25:31.780 with the nerves that go down your arm and the nervous system gets confused. And that's how it's

00:25:38.080 expressed. And if you like the neurosciences, it's all pretty cool. If you're experiencing it,

00:25:42.560 not so cool. Let's get to neuropathic pain. And by the way, on visceral pain, what is the response

00:25:47.720 to treatments with respect to the way we saw in noceptive pain where, hey, great response to these

00:25:53.740 NSAIDs or opioids or whatever? Typical analgesics can be helpful, but identifying visceral specific

00:26:02.060 anti-noceptive drugs is still an area of hot research. These days, it's more about trying

00:26:08.300 to identify the causes of visceral pain and reducing substances that are winding those noceptors up.

00:26:17.800 Neuropathic pain, another bucket. Neuropathic pain means injury to either the peripheral

00:26:23.340 or the central nervous system. The nerves out in the body, it's either injury or dysfunction too.

00:26:31.060 Nerves out in the body or the nervous system in your spinal cord or in your brain.

00:26:36.700 Classic, you get nerve injury from a trauma, from surgery. Classic qualities people describe

00:26:42.580 burning, sharp, lancinating, stabbing, shock-like. This is the kind of pain that some people

00:26:49.000 tragically get after a thalamic stroke in their brain. Half their body's just like terrible burning

00:26:55.820 pain in it. There's nothing going on out here. It's all central. This is the kind of pain that you

00:27:01.220 get and you experienced with radicular pain. And radicular pain means, in this case, injury to a

00:27:08.760 nerve root coming out of your spine. It's this sharp radiating pain, if you've got it in your

00:27:14.360 lower back that radiates down your leg, typically below your knee into your foot. This can be very

00:27:21.540 challenging to treat with common analgesics. We tend to draw upon different categories of medications

00:27:29.280 for this. These are, broadly speaking, anti-neuropathic pain drugs. And here, in our field,

00:27:37.000 we steal from everybody. There's only a few FDA-approved medications for pain, like a handful.

00:27:44.440 So what we've learned to do is to steal, borrow drugs from the neurologists, their anti-convulsants,

00:27:53.360 their anti-seizure medications, the gabapentinoids, the tegratols and their derivatives, their other

00:28:02.600 anti-seizure medications, because they tend to have mechanisms of action that also work on nerve

00:28:10.480 pain. Gabapentin, I think you've had perhaps some experience with. Turns out it's a lousy anti-seizure

00:28:16.840 drug. Terrible. But it's a pretty good anti-nerve pain drug.

00:28:21.020 Four grams a day.

00:28:21.980 Four grams a day.

00:28:23.880 Drowsy, though.

00:28:24.960 You know who gets credit, by the way? I give credit to making gabapentin the blockbuster

00:28:30.540 drug. George Clooney. How? You ever watched ER?

00:28:34.780 Yeah.

00:28:35.240 He was a pediatric ER doc. Kid comes into the ER with a skateboarding injury. George Clooney

00:28:41.500 puts the kid on gabapentin. Now, where that had all started was a case report from a couple of ED

00:28:47.820 docs who had noted by putting people on gabapentin that their acute pain got better. So I felt like

00:28:54.200 beforehand when I was practicing medicine, around the time I saw you practicing pain medicine,

00:28:58.220 that I'd look like a genius if I put somebody on gabapentin because nobody heard of it. And then

00:29:03.080 after that came out, floodgates opened, primary care docs started using it. Now everybody's tried

00:29:07.620 it. And it's a very safe medication. I should also make a mention when I'm talking about these

00:29:12.320 meds or any treatments, I have zero industry relations with anybody, nobody. I don't take

00:29:18.220 any industry money. You can go look me up on open payment CMS, which is a public database.

00:29:22.600 Okay. Neuropathic pain. There's another one. There's a new kid on the block

00:29:26.240 called nociplastic pain. I don't know if this one has made much traction yet. This is a newly

00:29:33.820 introduced category of pain, which is thought to represent dysfunction in the central pain processing

00:29:42.420 system. And I'm not precisely defining it, but that's the gist of it. It means that in the absence

00:29:48.820 of an identifiable peripheral cause, there is dysfunction in the brain and the spinal cord

00:29:56.400 that is causing pain, perpetuating and amplifying pain, nociplastic pain. And it has been tied in

00:30:04.880 with conditions like fibromyalgia, temporomandibular disorders, some aspects of chronic low back pain,

00:30:13.140 irritable bowel syndrome, interstitial cystitis, and more. It's slowly starting to get traction.

00:30:20.080 When we talk about pain, both to study it, but also ideally to treat it, we put them

00:30:25.000 in these categories that we just described.

00:30:29.180 Yeah. I was about to say, before you gave your examples, I was going to say nociplastic pain

00:30:34.100 must be a huge bucket because it's everything for which we don't understand. It's sort of the

00:30:39.880 all else bucket, which is enormous, especially for chronic pain, right?

00:30:44.140 You're absolutely right. And I think the verdict is still out. In the end, does nociplastic pain

00:30:51.060 stick around? Or is the problem that in these conditions that we associate with nociplastic

00:30:58.240 pain, medical science hasn't caught up to identify a specific peripheral driver? I'm of the opinion

00:31:04.900 it's that latter. I think we're going to find peripheral drivers for fibromyalgia. There's

00:31:11.620 some controversy right now as to whether fibromyalgia represents a small fiber neuropathy.

00:31:17.220 And just because we may not be able to identify a lesion doesn't mean that there's not something

00:31:22.380 there. But as in all things, the truth will weigh out. We'll see how the story plays.

00:31:28.480 Now, there's no objective way to measure pain, correct?

00:31:33.100 Oh, the last 15 years of my career has been spent on doing that very thing.

00:31:38.640 And where do you think we are in that regard?

00:31:41.580 Much further along than I ever would have predicted. So a large chunk of my research early on, my early

00:31:50.100 research was in neuroimaging of pain. It was opening up windows into the brain to see where people

00:31:56.680 were thinking, processing, perceiving, magnifying pain. And I spent much of that publishing work

00:32:02.640 to understand the mechanisms of that. And we haven't yet actually finished our story of

00:32:08.200 pain going up to the brain and what's going on. And we'll get there. Over the years, I migrated

00:32:13.860 into the space of developing objective biomarkers of pain. So I love working with young, smart people.

00:32:21.660 I bet against it. I had some young grad students and others who said that they thought they could

00:32:27.320 do this. I told them how you would do it. And I said, it won't work. And I'm going to pay you.

00:32:32.380 I'm going to give you money to go scan people. And you're going to learn how it doesn't work because

00:32:36.680 failure is a great lesson in life. And they came back and they showed they could do it.

00:32:42.340 And it was all through developing patterns in the brain and using machine learning models

00:32:47.240 to then take that pattern, that signature, and be able to predict in other people whether they

00:32:53.220 were experiencing pain. I didn't think we could do that because of the hugely individual nature of

00:32:59.820 pain. It's so different from person to person. But it turns out that there are core patterns

00:33:06.280 in the brain that represent that experience of pain.

00:33:10.340 Sorry, you're capturing these through what modality?

00:33:13.180 The functional magnetic resonance imaging. It is a standard MRI that people go into, but

00:33:18.880 we do some fancy pulse sequences. We play some physics tricks where we can see where nerves,

00:33:27.000 the brain's being activated. And we've taken this, we and others have taken this from being able to

00:33:33.860 determine whether somebody is in a state of pain to predicting their long-term trajectory.

00:33:39.880 We're working right now. A big grant that I have is to actually create composite multimodal

00:33:46.380 biomarkers to predict their future state. We're getting there.

00:33:50.640 Let's just start with standard understanding. If you put me into an fMRI machine and I said to you,

00:33:56.840 hey guys, I'm not feeling any pain right now. I feel great. And then you scan me and then someone

00:34:01.280 came out and took a hammer to my thumb and I went through the classic response that you described

00:34:07.300 earlier. What would my fMRI show? You'd see rather dramatic increases in activity in brain regions

00:34:14.660 such as the thalamus, the posterior insular cortex, the anterior cingulate cortex,

00:34:21.660 between the dorsal anterior cingulate cortex, and a number of other areas.

00:34:26.540 And to be clear, this is distinct from the part of my cortex that is the homunculus for my thumb.

00:34:32.560 You would also see it in S1. You're right. And indeed, what we've learned through this,

00:34:38.480 that there's no one single pain region in the brain. That's another mistake that was made along

00:34:44.320 the way. We all thought we were going to find a brain region, then we can knock it out, right?

00:34:49.800 Just go cut it out. And it turns out that didn't work. It's not one brain region that generates

00:34:56.060 the experience of pain. It is a distributed network. It's all of these regions coming together

00:35:02.180 and working in harmony. Doing what? Generating the experience of pain and then generating typically

00:35:09.540 a response to that. Let me be very clear, because there was a lot of controversy when we and others

00:35:16.140 initially published our papers. We are not trying to take away the autonomy of the patient and the

00:35:22.700 self-report. I don't need an fMRI to see a patient and know if they have pain. I can just ask them.

00:35:28.640 I can use self-report measures to get it. That's another part of the research.

00:35:33.080 Where we're working to build these objective markers, this objectifying pain, is not to see

00:35:39.500 what they're in now, but can it give us useful information to predict treatment to a particular

00:35:45.640 therapy? Can we use it to predict their future state? Can we use it to predict their vulnerability

00:35:52.880 to an injury or surgery? Those are things that just asking a patient right now, probably not going

00:36:00.140 to get there. I don't know if you want to go back to the brain. Yeah. Okay. So let's go back to

00:36:04.360 the story of these four branches of pain, or at least the first three, and then how the sensory

00:36:09.840 component is impacting their perception. Roll with that. Give me a little bit more. I want to build off

00:36:14.380 it then. Okay. So we go back to no susceptive pain. So tissue injury occurs. I think where I derailed us

00:36:21.440 was in classifying all the different types of pain, but you had signal comes up, two signals coming up,

00:36:27.040 the C fiber, the A delta fiber. The immediate response is to get you out of pain. There's an

00:36:32.600 evolutionary logic to that. The C fiber is not there to get you out of pain because the A delta did that.

00:36:40.600 Is the C fiber there to remind you not to go back and do that again?

00:36:44.260 Perfect. Perfect. That is basically your longer term harm alarm. That is saying, Peter, don't go back

00:36:53.120 and do that again. Back in the cave people days, it would remind you maybe it's best to sit in the cave

00:36:59.680 and let the healing occur instead of going out and fighting the woolly mammoth or the saber-toothed

00:37:04.640 tiger. Because if you fought the saber-toothed tiger when you're injured, you got eaten. You

00:37:10.340 didn't get to pass your genes along. By the way, do we have any evidence, Sean, that there was enough

00:37:16.380 genetic heterogeneity around this that there were 200,000 years ago, there were members of

00:37:22.740 our tribe who simply didn't feel pain and therefore did not pass on their genes because

00:37:28.960 they made poor decisions? Wow. That's a great question. One, I don't know. Two, there was

00:37:36.880 undoubtedly genetic variations that led to behaviors, led to actions that did not promote survival of the

00:37:46.900 species. And nature takes care of that. Those people died out. I find it amazing to just sit

00:37:52.420 around and dream about how little convergence must have existed a quarter of a million years ago

00:37:58.380 in terms of things that ended up not being good for our species, like people who didn't experience 0.99

00:38:04.800 pain the same way or didn't have certain filters within themselves. There'd been lots of talk about

00:38:09.740 people who couldn't socialize. You couldn't evolve alone. So if you didn't have the right set of genes

00:38:14.860 that allowed you to at least be part of some sort of social tribe. And of course, we still probably

00:38:19.220 have people today that have escaped. We clearly have some antisocial folks among us, but they're the

00:38:24.400 exception and not the rule. So anyway, I just wondered if today we're much more homogeneous in

00:38:29.000 terms of what a human's response to pain is versus what it might've been. Probably. And when you go back

00:38:35.340 through some of the lower animal species, what happens when one of those animals gets injured in

00:38:42.180 the wild? I'm not a animal pain expert, but typically they're set off. They're ostracized. Those animals just

00:38:49.540 die out. What do we do? We come together as a community and we help those people. We developed

00:38:54.960 empathy for pain. I did some studies on that. And that has gotten hardwired into our brains to be able

00:39:03.420 to recognize when people are in distress and pain and to reach out and help them. That was clearly

00:39:08.940 beneficial to our species and conserved.

00:39:12.160 And I also think about certain things like childbirth prior to any anesthetic was obviously

00:39:18.800 brutal, both in terms of the pain and the mortality. And yet there's no evidence that people were

00:39:25.620 deciding, yeah, maybe we ought not to do this. In other words, the drive for procreation somehow

00:39:30.420 overcame what must've been brutal.

00:39:33.900 Absolutely. And I got to tell you, hats off to half the population that are women and the women that do 1.00

00:39:40.100 this, I can't imagine. I don't want to even go there. There is interesting protective aspects

00:39:47.200 during childbirth that doesn't take away necessarily the pain, but I think some of the

00:39:52.060 estrogens, the estradiols has not only an analgesic effect, but I sometimes just swear

00:39:58.980 they don't seem to remember sometimes just how painful it was and yet they do it again.

00:40:03.620 Those are the two things that I joke about with my friends, which is I still don't really

00:40:07.740 understand how our species is here for two reasons. One, women had to continually go back 1.00

00:40:13.560 to the well, because remember, if your reproductive rate isn't in excess of two,

00:40:17.820 the species collapse. So on average, every woman must be able to do this. And back then it had to be 1.00

00:40:23.820 reproductive rate of north of three.

00:40:25.560 Right.

00:40:25.960 Every woman had to do this three times. How she did it the second two times after how bad the first was 1.00

00:40:31.820 blows my mind. The second thing is just looking at how stupid adolescent males are. I'm sure you 1.00

00:40:37.900 can relate to this.

00:40:39.080 I was one.

00:40:39.800 Yes, as was I. And I look at my boys. I don't understand why males all didn't die from just

00:40:45.880 doing stupid, stupid things before the age of 20 or even before the age of like 15. Those two things 1.00

00:40:52.460 are a miracle to our species, that all the males didn't die and that all the females were willing to

00:40:57.840 have at least three kids. I repeatedly tell Beth, I sometimes wonder why I was not a Darwin Award

00:41:04.480 winner, if you've ever read the books. I remember the Darwin Awards fondly, yeah.

00:41:08.420 We'll link to them in the show notes, some of my favorites.

00:41:11.160 So we have these signals. I'm going to take these signals from the spinal cord,

00:41:15.780 because where it gets really interesting is when you take those A-delta C fibers,

00:41:20.400 you're in the spinal cord and there's a lot of processing going on there that we'll come back to.

00:41:23.800 And they head up to the brain and then they synapse, connect in a large number of brain regions.

00:41:32.140 One of the main one is the thalamus, which acts like grand central station in the brain. It's

00:41:36.180 taking lots of sensory input from different sources and it's sending it out to other areas.

00:41:42.520 Some of those areas that we alluded to, the anterior cingulate cortex. Now the anterior cingulate

00:41:48.260 cortex, each of these brain regions has some functions associated with it. The anterior cingulate

00:41:55.140 cortex is associated with some of the emotional aspects of pain or the unpleasantness of it.

00:42:01.140 For the neuroscientists out there, I'm grossly oversimplifying things. The anterior cingulate

00:42:05.760 cortex is also a salience detector, meaning it is taking those incoming inputs and it's determining,

00:42:12.600 is there something wrong here? Is there an error? Because in essence, our brains are prediction

00:42:18.980 machines. Everything that we're doing, we're forming an expected pattern of what we're going

00:42:26.840 to sense and we're making adjustments. When I reach out for my cup, I know where it is in space. I pick

00:42:31.620 it up. If instead of cold water in that, it's boiling hot water and I touch it, my brain is getting

00:42:38.540 different signals than it was expecting. That cingulate cortex as a salience detector is triggering

00:42:43.800 and it's putting into action for me to withdraw. Other areas of the brain include the insular cortex,

00:42:50.360 which lies on this little bit of the outer edge. It can be subdivided into multiple components,

00:42:55.600 the posterior, mid, and anterior insula. Let's just say that the back part of it is taking direct

00:43:03.560 information in from the body. But then as you get more and more towards the front of the insula,

00:43:09.480 it's integrating emotional and cognitive nuance to it. It is integrating in your emotional state

00:43:17.860 and what you're thinking. Now, there's also connections with your amygdala, this deep primitive

00:43:24.180 region of the brain involved with both threat detection as well as reward. And it's connected

00:43:30.780 into the circuit and then also has outlays into other areas that maybe we'll get to,

00:43:36.260 like the hippocampus and the stress response and onward. All that to say is all these regions

00:43:42.140 connected together generate that experience of pain. And at this point in time, I really haven't

00:43:49.040 done more than Rene Descartes has in telling this story because first pass, the brain is still

00:43:56.260 remaining a passive receptacle just taking these inputs. Where it gets interesting is we developed

00:44:02.860 descending control systems that come down from the brain that converge in the spinal cord. And what

00:44:09.760 they serve to do is turn down the signals that are heading up. Now, in part, this was first described

00:44:19.080 by Ron Melzack and Patrick Wall in, I think it was 1965, the gait control theory of pain. Brilliant

00:44:25.480 guys. Never had the pleasure of meeting them, but they just did seminal work. And this gait control

00:44:31.040 theory of pain posits that, yes, you have afferent information coming in to the spinal cord, but the

00:44:37.320 spinal cord is acting like a gate of opening and closing, turning up, turning down pain. And it is

00:44:46.360 altered by other fibers and systems from your brain. So let me give you an example to this.

00:44:52.940 Let's introduce another nerve fiber type, A-beta. A-beta fibers are your touch fibers.

00:45:00.080 When you touch or stroke your skin, those get activated. When you stand up and you stand on one

00:45:07.740 leg, they're also responsible for position sense. They have a heavy coat of insulation around them and

00:45:13.420 they are wicked fast. C fibers, one meter a second. A-delta fibers, 10. A-beta fibers, 100 meters a

00:45:20.540 second. Fast. That's why you can dance. That's why you can walk because you've got those fast

00:45:25.780 reacting A-beta fibers. Now, let's go back to your thumb, Peter. You just hit your thumb with a hammer.

00:45:31.960 Sharp jolt of pain goes to your brain. Got a little delay. Oh, damn, this is really going to hurt.

00:45:36.740 Hot burning flooding sensation comes over your thumb. What is the next thing that you do? 0.99

00:45:40.900 Everybody does this a little differently. Before or after swearing?

00:45:45.080 There you go. A lot of people swear, so it's after swearing. You swear and then-

00:45:50.180 Shake it. Shake. Okay. You're a shaker.

00:45:53.120 Or a squeeze proximal to it. There you go. You squeeze, you shake it. Sometimes you're

00:45:58.380 running underwater. What are you doing when you're squeezing it and shaking it?

00:46:02.680 Sometimes trying to create a distraction. Okay.

00:46:05.160 Sometimes, though, probably illogical trying to keep whatever humor is in there that's hurting

00:46:11.500 isolated like a tourniquet. Right.

00:46:13.740 Right? Obviously, if I'm using cold, especially if it's one of my kids that hurt themselves,

00:46:18.380 we'll put cold on hoping to anesthetize the area, presumably slow the circulation,

00:46:23.600 take down the swelling.

00:46:24.880 Yeah. That's beautiful. And you're talking about longer term things, which are all perfect

00:46:28.660 because cold does those things. And also cold, by the way, reduces action potential velocities

00:46:35.240 and firing in those A-delta C fibers. But what you're doing most of all when you rub it is you're

00:46:42.480 activating A-beta fibers. You're actually not influencing much your A-delta or C fibers,

00:46:49.440 those nociceptive fibers. You're not really impacting it there.

00:46:51.860 That horse left the barn.

00:46:52.760 That horse left the barn. You got horses still running out the barn. You can squeeze all you want

00:46:57.280 for the time being and the horses are still heading out and hitting your spinal cord. But where things

00:47:01.860 get interesting is the A-beta fibers, those touch fibers, they're coming into a slightly different

00:47:08.000 area of your spinal cord and they're sending over projections into where those nociceptive fibers are

00:47:14.720 in your spinal cord. And they have an inhibitory role. That's the take-home message. So the A-beta fibers

00:47:21.660 are inhibiting the signals coming in from where you hit your thumb with a hammer and preventing them

00:47:28.860 from going to your brain. It's a beautiful example of neuromodulation. You're doing your own neuromodulation

00:47:35.100 with that. And we're all hardwired to do that thing. And there's a medical device that takes advantage

00:47:43.020 of that. You're familiar with the TENS unit? Yep.

00:47:46.100 TENS is T-E-N-S, Transcutaneous Electrical Neural Stimulation. Now, what it originally did,

00:47:53.100 there's been modifications of it, is what you do with the TENS, I know you know this, is typically

00:47:58.500 little black pads that you put over the area that hurts. You put an electrical stimulation

00:48:04.060 through these pads. They're activating A-beta fibers. And so you do them over here,

00:48:10.680 and it's having a neuromodulatory effect back in the spinal cord. Pretty cool when it works.

00:48:17.080 And how do you predict patient comes to you and they're experiencing some pain? What are the clues

00:48:23.040 that would tell you, I think TENS is going to be successful here? In other words, I think that

00:48:28.060 activating A-beta fibers is going to be a tool that will reduce your perception of pain. Because

00:48:34.640 that's what we're doing. Everything that you do is, how do I reduce your perception of pain?

00:48:40.680 I can't necessarily take away. I mean, if they have an injury that needs to be resolved,

00:48:44.580 they shouldn't be seeing you. They should be seeing the surgeon or whoever fixes the physical

00:48:49.400 injury, right?

00:48:50.880 In short, yes. I would just build on that, that I would say my job, our job as pain docs is to help

00:48:57.480 reduce the pain and help them down a path of functional rehabilitation. So absent that second

00:49:05.500 piece, I typically fail. I'm leading them down a road of functional rehabilitation, which involves

00:49:12.580 physical, psychological, social, emotional health, all things you talked about beautifully in your book.

00:49:19.240 So who is the, I hate to use the word poster child, but who's the patient that when you see them,

00:49:25.420 your intuition says, TENS is going to really work for this person?

00:49:29.300 Somebody with, I think, more, you know, it's nociceptive musculoskeletal pain. I tend to think

00:49:35.340 of somebody for whom TENS is more likely to work, something that has more of a classic nociceptive

00:49:42.880 type of pain problem. Beyond that, Peter, it's a trial and error. That's part of the frustration

00:49:48.840 in pain management and in healthcare in general is the lack of a precision approach and the very

00:49:57.380 frustrating, laborious trial and error process until we get something that works.

00:50:01.680 So we talked about the gait control. We talked about TENS.

00:50:05.160 Can I put a bow on the gait control thing to make sure I understood it?

00:50:08.060 Yeah.

00:50:08.500 It seems like a very important idea, but I also think I might be missing the juice.

00:50:12.500 Is the idea that 10 people could experience the exact same peripheral injury? If you could map

00:50:21.300 the action potentials, they would look identical. You could even see identical

00:50:26.240 perceptions, but they could have 10 different gating channels within the spinal cord and therefore

00:50:32.420 perceive pain differently. I just want to make sure I've captured what the gating theory states.

00:50:35.920 You are right. You're right with that individual variability in pain. We haven't talked about the

00:50:42.060 brain's role in the gait control, which we're going to get to, but just getting to your question,

00:50:46.920 there's been some elegant studies. A guy named Kim, years ago, did a beautiful study where he applied

00:50:52.340 a 48 degrees Celsius stimulus to 500 people. 48 degrees Celsius, I think it's 121 degrees

00:50:59.600 Fahrenheit. Somebody will look it up. And you apply it to the arm, the hand, and then ask,

00:51:04.340 what's your pain score? And what he found was perfect distribution of people who said,

00:51:11.100 nah, this ain't painful. Ain't nothing. That's like zero, one out of 10. Some were like, yeah,

00:51:15.300 it's a little painful, two or three. And others were like, yeah, a little more moderate, four,

00:51:18.760 five, six. And you got all the way up to some people saying, oh my God.

00:51:22.500 You're burning me.

00:51:23.120 You're burning me. Take that off immediately. 10 out of 10. I do the same thing in a medical school 0.54

00:51:29.260 demonstration. Can't call it an experiment because I'm not getting IRB. But when I teach the neuroscience

00:51:35.420 class around pain, I bring in a circulating ice water bath. And you want it to circulate because

00:51:43.220 if you just stick your hand and leave it in still, you get a boundary.

00:51:46.720 It's warmer. Yep.

00:51:47.620 So circulating ice water bath. And I asked them to dip their arm in for 15 seconds,

00:51:52.520 pull it out, whisper in our research assistants here, what their pain score was.

00:51:57.180 We tabulate that all up. And at the end of the class, I show the medical students.

00:52:00.960 And it looks just like that line I showed you, I mentioned to you before. You got some people in

00:52:05.580 the class who say, I keep my hand in there all day. And there was others who were like, oh my God,

00:52:11.300 I couldn't even keep it in there at all. 10 out of 10. The whole point of that is to drive home

00:52:17.620 one of the key messages in our discussion. The amount of stimulus or nociception may have little

00:52:25.080 to nothing to do with your experience of pain. And why that is so important for healthcare

00:52:30.540 professionals to understand is because for so long, we have projected our own experiences onto

00:52:37.280 everybody else. So here's another experiment that you won't be able to do unless you get to teach

00:52:42.400 this class on multiple days, but it's to go one step further, which is to do the same thing every

00:52:47.560 day and see how they compare their score from day to day. I'll tell you my experience with that. I do

00:52:53.080 love to use a cold plunge. So my cold plunge is at 42 degrees with circulating water. So I don't know

00:52:59.620 what that makes it feel like, but it feels like it's somewhere in the thirties. There are days when I can

00:53:04.760 spend 10 minutes in there and feel like nothing is wrong. There are days when I'm not kidding,

00:53:12.460 30 seconds in my ankles hurt so bad. I want to scream. And I think what's different. It can't be

00:53:20.180 the circulation in my ankles is better one day to the next. They're a relatively avascular part of my

00:53:25.500 body. Why is it that one day I can spend 10 minutes and not know I'm in this water? I mean,

00:53:30.820 I know that I'm cold, but it's more like my core temp, but my joints don't hurt. And on another

00:53:35.660 day, the throbbing in my joints feels like somebody's hitting them with a hammer and I'm

00:53:41.680 the same person. So in other words, your point is well taken, but I would say there's a second

00:53:45.240 dimension to it, which is even as individuals, we can experience things differently from day to day.

00:53:50.660 You're absolutely right. And maybe that's a good opportunity to build on that

00:53:54.540 and introduce more of the brain. So we've talked about the functions of the brain,

00:54:01.660 the cingulate cortex being some of the more emotional as primary somatosensory cortex,

00:54:05.820 the homunculus being more sensory, the insular cortex has an introceptive state. It's like our

00:54:10.680 internal awareness of our bodily state. We talked about the amygdala. Now let's introduce also the

00:54:16.680 prefrontal cortex. The prefrontal cortex, the big thinking part of our brain up here, both the

00:54:22.140 ventral medial and the dorsal lateral play a key role in our modulation, our cognitive control of

00:54:30.080 pain. And these systems, the prefrontal cortex, the insular cortex, the cingulate cortex, all have

00:54:38.500 those descending projections back down to the spinal cord. So we talked about the gait control theory of

00:54:44.320 pain in the context of rubbing your finger out here, a peripheral neural modulation. Where it really

00:54:50.600 comes into play is when you introduce brain systems, the brain and your emotions, your cognitions,

00:54:58.060 your beliefs, your early history, and that influence on pain. That's where it gets really exciting.

00:55:04.760 And that's sending descending pathways down. So I would argue in part that your experience of cold

00:55:14.080 water in that moment may have been driven in large part by your mental state before you got in. And

00:55:24.220 maybe we'll talk more about the intersection of sleep and pain. Huge research in that space. Your state of

00:55:31.360 anxiety, apprehension around this, all sorts of cognitive emotional aspects weigh into your experience

00:55:40.520 pain. And yes, there's also circadian rhythm aspects related to this from hour to hour fluctuations.

00:55:47.100 But those individual differences are fascinating. And that is also an area that our group and others,

00:55:52.680 our lab and others are going into, is recognizing that one pain score averaged over a week may not

00:56:00.400 give us a lot of information that we need to take into account the within-subject, within-person

00:56:06.660 daily variations over time and model that. There seems to be kind of a, I guess I should ask this,

00:56:13.240 I'm not asserting this as the case. Is there kind of a moral judgment that comes to this at some level?

00:56:17.460 Like don't we as a society just tend to look more favorably at people that have a very high pain

00:56:23.340 tolerance? So when you go through that experiment you just did with the medical students, if everybody's

00:56:28.020 being brutally honest, aren't they kind of looking at the people who score 0, 1, 2 more favorably than

00:56:33.300 those that score 8, 9, and 10? Absolutely. Why do you think that is? If I'm being truthful, I do it.

00:56:39.380 Yeah. Yeah. That's what society values. That was my home life growing up. That's what my father

00:56:44.840 expected. I come from a very working class. My father had 12 brothers and sisters fighting for

00:56:52.600 whatever scraps of food. And he brought that into my world, our world as kids. And you just suck it up

00:56:58.820 and deal with it. And my father had back pain later in life. And he would never talk about it,

00:57:06.740 would never ask my opinion. And when I offered my opinion, he would never follow it. Had bad

00:57:12.200 consequences in the end, but we value that. That is just the way our society is.

00:57:17.780 Is that a male thing exclusively?

00:57:19.960 I think you need to get some women on the show and ask them. I think it crosses. Actually, 1.00

00:57:25.200 I do think there is a masculinity aspects of that. And I think I could be wrong here. I think that

00:57:32.260 that thing is also attractive for women. I think there's a certain attractiveness because that 1.00

00:57:37.820 person may be more likely to be a good provider than somebody who is weak and sensitive. But we're

00:57:45.200 getting a little out of my wheelhouse on that, but you're absolutely right.

00:57:49.780 I just think it's like a compatibility thing. I know when I do that type of an exercise compared to

00:57:54.380 others, I tend to just feel less pain. I also know my wife does as well. And so I almost wonder

00:58:01.900 if that's a compatibility. We both just have a high threshold for that when we're exercising,

00:58:07.340 when we're doing anything, even recreationally, that doesn't matter.

00:58:10.680 My fiance, we're now engaged, is a professor at Stanford, Beth Darnell. She's an ex-ultra marathon

00:58:16.140 runner. And I've always admired the fact that she can sit there in front of a computer or work on 0.99

00:58:22.220 something untold hours and not move. And she's just like, listen, I was really good with running

00:58:28.740 with a pebble in my shoe, putting one foot after another and just working my way through it. And I

00:58:34.280 similarly grew up in an environment where you learn to be tough and you learn to power through life's

00:58:40.940 adversities.

00:58:42.300 So what is the consequence of this? So we're acknowledging that it is an attractive trait to

00:58:48.060 have a high tolerance of pain. Society rewards it. And yet by definition, a significant subset of the

00:58:55.500 population, call it a third, call it a quarter if it's a normally distributed function, are going to

00:59:00.660 be a standard deviation on the other side. They're going to be on the side relative to people who have

00:59:06.060 a high tolerance for pain. These are people who are going to really perceive pain. And if we just did

00:59:10.960 this through the lens of the responsibility of the medical community, there's a pretty significant

00:59:15.140 consequence to that. Indeed. As with all things, it gets a little bit more nuanced. We talked about

00:59:20.540 cold, for instance. It turns out that some of the sensitivities are modality specific.

00:59:26.480 So just because you have a high threshold for cold, you could completely flip it on hot or pressure

00:59:32.300 or pinprick or whatever the other modality is. Somebody who runs a paint lab, I've had everything

00:59:37.320 done to me imaginable. I take heat really well. My son, Ian, takes heat really well. I've had thermal

00:59:44.580 devices on me where I've been there and ended up with second degree burns to find my seven out of

00:59:50.520 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

00:59:57.560 California. I lived in Arizona. I think there are genetic aspects of this. So we have to be mindful

01:00:03.260 modality specific. On top of it, these experimental protocols probably have little bearing on somebody's

01:00:11.200 experience of chronic pain. I was going to say, is there any way to put together a set of experimental

01:00:16.960 lab versions of this to basically generate predictive models of how people will respond to

01:00:27.040 real world pain? I think where you're going with chronic pain is even more relevant. So for example,

01:00:32.560 why do some people have a disc herniation that leads to manageable pain? Whereas for others,

01:00:39.600 the exact same injury by every metric available to us produces a totally different set of

01:00:45.480 consequences. And what do we do about that? This is now where we move out of that Descartesian

01:00:51.040 model. We appreciate the role of the brain and its modulatory capacity, its ability to turn the

01:00:57.900 amplifier down. And so if you're thinking about a stereo amplifier, we talked about how some people

01:01:04.060 to a certain stimulus might be a zero or one on the dial. Some might be a 10. But what we didn't talk

01:01:09.600 about are people's capacity to now manage their pain, cope with their pain, their level of self-efficacy

01:01:16.080 around their pain. Athletes learn how to manage their pain and suffering. Where they run into

01:01:25.180 problems is when the sports are over. They're retired. That's when I see them. So there are many

01:01:31.420 factors that predict how well somebody is going to do with chronic pain. They align with a lot of the

01:01:38.920 stuff in your book. So the level of a person's self-efficacy plays a role. There is the presence

01:01:46.300 or absence of whether they've got underlying depression, anger, anxiety, something called

01:01:52.020 catastrophizing. Terrible word, very important concept, probably one of the most predictive

01:01:57.480 of amplified pain.

01:02:00.280 What about other things? You talked about sleep deprivation. Any other physical things? Exercising,

01:02:04.940 not exercising, insulin resistance, non-insulin resistance. What are the other things that

01:02:09.540 might factor into this? Yes, yes, yes. One of the biggest predictors of diabetic neuropathic pain

01:02:13.920 is glucose control. So one of the first things we do if we have a person with diabetic neuropathy,

01:02:20.140 which the diabetes, the high blood sugar, as you know much better than I, causes injury to those

01:02:26.500 nociceptive fibers and also causes injury to the A-beta inhibitory fibers. That correlates with glucose

01:02:33.880 control by way of example. Diet plays a role because if you're eating things that are causing

01:02:39.580 inflammation, we didn't talk about all of the stuff that amplifies or winds up those peripheral

01:02:46.780 nociceptors. We treated those as a static thing when they're not. They're dynamic. So in the face of

01:02:54.040 inflammation, that causes something called peripheral sensitization. You've turned up the amplifier on

01:03:00.520 that nociceptor in the periphery. Sleep, huge topic. How much sleep deprivation does one need

01:03:07.380 for there to be an increase in pain perception? We're both out of residency long enough, but we

01:03:12.760 both pulled our old-nighters. How did you feel the next day? I mean, I felt awful. You felt worse

01:03:19.140 between 5 a.m. and 8 a.m., and then you get this second wind, usually about the time you're

01:03:25.200 operating, and then you usually feel pretty good. But overall, I mean, it's a haze.

01:03:31.060 It's a haze, and you're just powering your way through it. And if you think about it,

01:03:35.560 you're kind of feeling a little achy all over. Now, it's not that because of lack of sleep,

01:03:40.520 something has changed in your muscles. I don't think there's good evidence for that. What has changed

01:03:45.040 is your set point in your brain and your spinal cord for the perception of pain. You feel like

01:03:50.300 crap. Now, imagine if you're doing that day after day after day and not getting sleep. That really 1.00

01:03:58.580 messes up your central nervous system and that modulation around pain. What happens is it changes

01:04:04.800 your set point, and it impairs that prefrontal cortex and its ability to modulate pain. When you

01:04:11.160 went through, Peter, your bad episode of back pain, did it impact your sleep?

01:04:16.000 Yeah, for sure.

01:04:16.620 You're human. That impact on sleep ultimately further amplified your pain. On top of it,

01:04:23.940 how did you feel during that? And outside the pain, how was that affecting your overall

01:04:27.720 life and your thoughts and your emotions?

01:04:30.960 Total disaster.

01:04:32.200 Well, look, there's so much going on. I'm happy to tell my story because it's a great introduction to

01:04:36.740 the work you've done. So for folks that haven't heard it, I've shared this before,

01:04:40.720 and we were talking before the podcast. I don't remember how much of this is in the book because

01:04:44.500 at one point I wrote all of this out. I'm pretty sure much of it got cut out. But when I was in my

01:04:50.340 third year of medical student, I was having just a great old day, rode my bike to the gym, was just

01:04:54.940 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.

01:04:59.380 And it was enough that I decided not to work out, which says something, because I would have

01:05:04.080 worked out through any amount of discomfort. I limped home, laid down, and said, you know what?

01:05:10.620 I'm just going to sleep this off, and tomorrow will be fine. Tomorrow wasn't fine. I was in so

01:05:14.080 much pain I couldn't get out of bed. I had to actually call my roommate. We had separate phones

01:05:17.820 in the same house to come and get me up and out of bed. And the next two weeks proceeded to be

01:05:23.900 a really unbearable episode where I was doing an ICU rotation. This is back in the Wild West,

01:05:31.900 where I think the nurses and the residents were just shooting me up with Tordal every day,

01:05:35.760 nonstop, getting me through the day. But the nights were brutal. And what I now realized happened was I'd

01:05:41.660 had a really significant herniation. A piece of that L5-S1 disc broke off. I would later find out

01:05:48.640 it was a five centimeter piece, and it had extruded, broken off, was sitting on the S1 nerve root.

01:05:54.640 Every night now, I was going to bed feeling as though the skin on the bottom of my foot was being ripped

01:05:59.480 off. The only way I could sleep was to put my foot into a bag of ice and take some amount of

01:06:05.400 Benadryl that was enough to knock me out. This went on for about another week until the dean of

01:06:12.120 students saw me limping along and said, hey, Peter, what's going on? I told him. This was a Sunday

01:06:16.920 afternoon I was studying. He took me directly to the ER, got an MRI, showed all of this mess. The next

01:06:24.420 day I had surgery. As I've talked about in the past, everything went wrong in a series of surgeries.

01:06:30.060 And fast forward three months, three trips to the operating room, multiple discectomies,

01:06:37.520 laminotomies, multiple levels. In theory, my back should be fine. I'm anything but fine. I now have a

01:06:45.800 new pain. But this is unlike anything that was related to my back. This is where you come in.

01:06:51.040 I now have a pain that is so significant, and it sounds grotesque to explain it, but this is all

01:06:57.020 it was. It felt like someone was reaching in my body from my kidneys into my groin and tearing my

01:07:04.820 testicles out from the inside of my body. So needless to say, I was out of commission. I did not move. 0.55

01:07:11.880 I laid on a floor 24-7. And to your point, how did I feel? Well, it wasn't just that I was in so much

01:07:19.140 pain that I couldn't do anything. It was, I watched my life disappear. So it went from,

01:07:25.820 you're not going to graduate from medical school on time, to you're not going to get to do a sub

01:07:30.840 internship in surgery, to you're not going to be a surgeon, to you're never going to walk again.

01:07:37.380 So by that point, the overlap was how were the opioids that I was being prescribed to control the

01:07:44.300 pain, tripping into, these are a tool to numb me to this entire experience. So at this point,

01:07:50.740 I've talked about this in the past. At this point, I was taking, I think I was up to maybe 320 milligrams

01:07:56.140 of Oxycontin a day, which is kind of amazing because if you and I took that today, if you and I split that

01:08:01.320 right now, we would die. But I'm mainlining 320 milligrams of Oxycontin a day just to blunt the

01:08:08.820 emotional pain of this, I think says what we need to know. We can come back to the story of how I met

01:08:14.500 you and what, how my life turned around from that point. And it's still a miracle for me to believe

01:08:19.240 I actually graduated from medical school on time, despite that all happening now into my fourth

01:08:24.420 year. Cause this was my third year bleeding into my fourth year of medical school when all this was

01:08:28.600 going on. It's kind of amazing. A difficult time. Third year is tough. Yeah. So we'll come back to

01:08:33.200 what happened, but that's a long answer to a question, which is at some point it wasn't even

01:08:38.640 about the pain. The pain was unbearable, but it wasn't the most unbearable part. It was

01:08:43.480 the expectation of what that pain meant for the rest of my life that became much more unbearable.

01:08:50.620 Yeah. That's a terrible story. And I have to imagine one that is probably shaped you moving forward and

01:08:59.360 had a big impact on your life and what you've been doing. I call it the best worst experience of my

01:09:05.260 life. Yeah. More best today. The gratitude I have for that is, I mean, again, I wouldn't want to do it

01:09:10.960 again, but it has been such a positive impact on my life. Yeah. Well, I hope we can come back to that

01:09:17.380 and talk about it more in the influence of all this other stuff that was probably contributing to

01:09:24.140 your experience of pain and the bad stuff going on as a consequence of it. And it plays a role in

01:09:31.540 everybody else's life out there. And I think there's some key messages there. What would you

01:09:36.720 like to segue to? Before we go into the ins and outs of what pain doctors can do, let's just talk

01:09:44.460 about some of the bread and butter stuff on pharmacology. How can we navigate our way through

01:09:49.280 what NSAIDs do, what opioids do, what COX-2 inhibitors do? What should people be aware of

01:09:56.000 in using these things? Obviously, opioids are a remarkably controversial topic, but there's

01:10:01.140 probably a nuance to it that's missing from the broader discussion. But why don't we start with a

01:10:05.960 softball like NSAIDs? How do they work? Everybody's heard of Advil, Aleve, Naproxin, all of these things.

01:10:12.220 These medications are psychooxygenase inhibitors. What they do is a couple things. They reduce

01:10:19.900 some of the inflammation. They're anti-inflammatories. So I was alluding very briefly that there are

01:10:27.960 substances that can be released down in the periphery during injury that wind up that nociceptor

01:10:34.000 and amplify it. Prostaglandins, histamines, cytokines, interleukins, all of that, this inflammatory

01:10:40.440 soup that occurs after every single surgery, every single injury that we experience, you get this

01:10:47.020 inflammatory soup. And it's classically mediated by swelling, redness, temperature increases. And

01:10:54.660 aspirin and a COX-2 inhibitor NSAIDs do a nice job in reducing that inflammation. Now, this is where

01:11:02.100 medical science, you're going to probably be much more informed than I am on this, but medical science

01:11:06.360 has been slowly shifting in its view of this. We have historically thought, take these medications

01:11:11.280 in an acute injury. It knocks down that inflammation and all is well and good. Well, some of the data was

01:11:18.020 coming out in the orthopedic literature decades ago that people who were taking NSAIDs during total

01:11:24.960 joint replacements were getting non-fusion of that joint to the bone. They were getting failures.

01:11:32.220 And then more recently, there's been some question as to whether knocking down the inflammation is a

01:11:38.640 good thing after all, that maybe that inflammation is part of the healing process and that by giving

01:11:44.860 an NSAID, aspirin, we're delaying the natural healing effect and causing more problems. So where's the

01:11:52.500 truth? This is tough. One, I don't think we have the whole story yet on the NSAIDs. Two, I'm a gray

01:11:59.480 guy, meaning I don't live in black and white. And I'm also appreciated that every medical field has

01:12:07.760 their own lens that they look at in the world. And I think we have to appreciate the complexity of

01:12:13.440 the patient, meaning if it's perhaps something minor and they can get by without the NSAID and

01:12:19.500 it's not going to change significantly their level of function, then maybe not taking it will improve

01:12:24.200 healing. They can't get out of bed. They can't go to work, but a naproxen helps them to do that thing

01:12:31.600 so that they can engage with their family, with their friends, with work. Well, then heck yes,

01:12:37.280 take the NSAID if it's helping with that level of functional improvement.

01:12:41.360 Now, are you talking about this through the lens of acute pain or only through the lens of chronic pain

01:12:45.140 at this point? A little of both, but I think through chronic pain, we start to introduce all the

01:12:51.060 longer-term negative consequences of this impact on blood pressure, your heart, impact on your

01:12:56.740 kidneys with long-term NSAIDs, particularly if you're older. I remember, I think it was in your

01:13:03.820 book, you took Vioxx. Yes.

01:13:06.900 I loved Vioxx. I did too. And I still remember the day in, oh God, it must've been December 2001

01:13:13.640 when the FDA came down and said, no more Vioxx. And I looked at my last bottle and I was like,

01:13:18.400 oh God, no. I stockpiled it. I wish I did. I called up all the drug reps I knew

01:13:23.660 because they couldn't like give it out. And I'm like, can you just hook me up? So I ran out a

01:13:28.500 stockpile of that for a long time and cut this if it's too tangential, but every field looks at the

01:13:34.880 problem through their own lens. Here, you had a drug that was causing heart attacks.

01:13:40.360 I mean, in the world's most susceptible individuals at a relatively small absolute

01:13:47.340 rate. Yeah. I've already had this discussion with Eric Topol, which was like mistake, net negative.

01:13:53.700 Oh, is that right?

01:13:54.240 Absolutely. Net negative.

01:13:55.580 Yeah. Cause I've always wondered.

01:13:56.840 Merck's is faulted. They should have been much more transparent about this. Put a black box label

01:14:02.320 on it and we should all still have access to my house.

01:14:04.260 Use the 50 milligrams, use the 25s and you're right. Don't give it to unsusceptible people.

01:14:10.300 The baby got thrown out with the bathwater on that one. 0.98

01:14:12.360 We all do this. We look at the world through our own particular field. It's like with the

01:14:15.800 latest blood pressure guidelines, the cardiologists want it really low, but it screws up the kidneys. 0.61

01:14:21.540 And well, the cardiologists say, save the heart, screw the kidney. So great drug. Wish it was still

01:14:27.640 around.

01:14:28.460 Why do you think there hasn't been any drug that's come close to that? Like Celebrex is a joke. Like

01:14:33.620 none of the drugs that are in the...

01:14:35.700 Bextra had a valdecoxib, I think it was. A little bit close, but I think if I remember it had a

01:14:42.780 Stevens-Johnson bad rash with terrible consequence. I think the drug companies get scared of the

01:14:48.900 lawsuits. So NSAIDs nuance around taking the verdict is still...

01:14:54.520 Do you have a version on dose? I mean, do you say 800 milligrams of ibuprofen TID three times a day,

01:15:01.480 2,400 milligrams would be... You would tolerate that for how many days if a person needed it?

01:15:06.100 Week to two weeks on that. Make sure...

01:15:08.460 You're eating. Yeah.

01:15:09.800 Food in the stomach, fluids. If you're either older, you've got kidney issues,

01:15:16.100 you've got GI issues, talk to your doc first. Don't just go into this stuff blindly.

01:15:21.740 Yeah. It is interesting that we can buy acetaminophen and ibuprofen over the counter,

01:15:26.220 and yet they can cause a ton of damage if not taken correctly.

01:15:29.420 I mean, the ERs see people with acetaminophen, Tylenol overdoses, and it's a cause of...

01:15:35.540 Well, you know this.

01:15:35.900 Liver failure.

01:15:36.600 Liver failure.

01:15:37.400 Let's talk about acetaminophen for a while. When I last tried to understand it, there was no

01:15:42.360 clue as to how it worked. To this day, do we understand how it works?

01:15:45.960 Minimally more information. And I haven't... In full disclosure, I haven't read up on it a lot. I know

01:15:51.220 it has some cyclooxygenase. One impact, a lot of it is thought to be central. I haven't tracked it

01:15:57.520 much beyond that. I saw some interesting side studies where it seems to have some impact in

01:16:04.740 the brain around emotional modulation. And so there's a degree of emotional blunting

01:16:10.560 on acetaminophen. Now, whether it translates into a real world or if it's just an experimental

01:16:15.900 manipulation, I don't know.

01:16:17.360 But there's a nice synergy with acetaminophen and ibuprofen because different mechanism of action,

01:16:22.980 different organ systems are impacted. So you can take less of each when you combine them.

01:16:27.820 What's your take on that?

01:16:29.320 I think you just said it, Peter. You said it beautifully. I use those in combination

01:16:33.860 to get the twofer, to get that synergy. The one plus one is not two, but three.

01:16:39.980 So you can take Tylenol. Historically, we would say up to four grams a day.

01:16:44.400 More recently, there's been some push to try to reduce that to two grams a day.

01:16:50.320 Clearly, if you've got liver dysfunction, if you are drinking large amounts of alcohol,

01:16:55.220 less.

01:16:56.200 Yeah. My go-to stack, if I am actually in pain, a year ago, I had to get a crown put on a tooth

01:17:02.520 that had an old filling that broke. And it's the funniest thing because of how remarkable the teeth

01:17:07.340 are at sensation, but the crown was a little too high. Okay. So what's the impact of that? That

01:17:11.180 meant every time I took a bite, that one tooth was bearing the brunt of it. It was the last tooth

01:17:16.940 I had right in front of my wisdom tooth. And I'm talking to my dentist and he's like, yeah,

01:17:21.720 Peter, it's just too high. Just come in and let me shave a little bit of it off. Well,

01:17:24.800 I didn't have the time to go in. So for two months, I did not go in to get this thing shaved

01:17:29.980 off. The pain was, this is how stupid I am. Like I couldn't spare the two hours to go to the 1.00

01:17:35.620 dentist. And he was willing to see me nights and weekends. This is the most accommodating dentist in the

01:17:40.580 world. Everybody should have that kind of dentist. Tony Pacheco. I can't say enough about him.

01:17:44.280 And yet I couldn't make the time. So for two months, the pain got so bad that eventually

01:17:49.360 couldn't chew on that side at all. So my point is I had to be taking something to get through the day.

01:17:55.460 And the stack that worked was 400 of Advil, 500 of Tylenol, three times a day. Okay.

01:18:04.020 Took care of me. Now, let me ask you, does ibuprofen work better for you than Naproxen?

01:18:10.580 I don't know, but the reason I prefer it is that I can line up the dosing with the

01:18:16.040 acetaminophen because I believe Naproxen, you only take once a day, right?

01:18:19.820 Twice a day.

01:18:20.360 Twice a day. Okay.

01:18:21.080 You're right.

01:18:21.600 Yeah. Yeah. I wanted something where I could do it TID instead of BID.

01:18:24.860 The reason I ask is I find huge individual variability in responses to NSAIDs.

01:18:30.680 Okay.

01:18:31.280 Naproxen works beautifully for me at 500 twice a day. Ibuprofen, not so good.

01:18:36.220 At what dose?

01:18:37.040 800 three times a day.

01:18:38.160 Wow.

01:18:38.400 Yeah. With food and water.

01:18:40.620 Are there types of pains people should be thinking of where these things work especially well and

01:18:45.820 other areas where, yeah, that's just not going to have much efficacy?

01:18:49.380 I don't find it as effective in neuropathic pain. It might take a little bit of the edge off.

01:18:54.900 Nociceptive pain typically is your go-to. You're kind of your nociceptive or your nociceptive

01:19:00.620 inflammatory pain, the kind of pain you'd see in a joint. Those are your typical go-to.

01:19:05.200 Forms of back pain, particularly, you know, in acute situations, but also somewhat in chronic.

01:19:10.740 And I get a lot of patients that say, yeah, that didn't do it for me. But if you inquire and ask

01:19:16.640 questions, you find maybe it knocked it off a little. Because in our game, we're trying to knock

01:19:21.560 off pieces and pieces and pieces of their pain experience. The issues with the different responses

01:19:27.340 are very individually based. And I think in part, it has to do with a little bit of what we call

01:19:33.000 pharmacokinetics or where the drug is getting. And different NSAIDs can permeate different tissues

01:19:39.680 at different rates.

01:19:41.460 So you're saying maybe we should be empirical. In other words, try the naproxen, try the ibuprofen,

01:19:47.180 figure out which one works. Obviously, don't take them together.

01:19:49.760 Obviously, don't take them together. But your take-home message is spot on.

01:19:52.800 Do you have a concern with people taking acetaminophen and consuming alcohol? Do you

01:19:57.700 tell people to refrain from alcohol when they're taking Tylenol?

01:20:01.000 I just said a conserver, listen, don't do more than like a drink a day.

01:20:04.560 Is that the right amount? I don't know. But if I tell them one drink a day, they'll go do two.

01:20:09.860 They're probably still okay with that. And then I am looking in their chart just to make sure

01:20:14.860 they're not drinking four or eight and there's liver issues. What do you do?

01:20:18.620 I typically, when I'm taking acetaminophen, I don't drink much anyway. I'm probably going

01:20:22.980 to have four drinks in a week. So meaning four days a week, I will have a drink or three days

01:20:28.320 a week. But if I am taking Tylenol, I'm just going to refrain. Again, I don't have any evidence

01:20:32.880 to suggest that that's necessary.

01:20:34.900 Probably the safest.

01:20:35.720 It's the precautionary principle at its finest. Okay. I want to talk about muscle relaxants.

01:20:41.060 The other thing that has been a real favorite tool of mine is baclofen. Now, it's not a

01:20:50.000 particularly potent muscle relaxant, but it seems to, for me and for the patients of mine

01:20:55.040 in whom it works, offer something really potent like Valium. It doesn't bring all the baggage

01:21:00.040 of a Benzo or even a Flexeril where you can kind of get the drowsiness. And frankly, a lot of people

01:21:05.400 just, I mean, I used to even get nauseous on Flexeril. But something about baclofen, I don't even

01:21:09.800 know it's in me at 20 milligrams twice a day, but it actually takes the edge off. And where I

01:21:16.600 typically find this beneficial is if I slept wrong and I get a kink in my trap or I've been on a super

01:21:24.620 long drive and my QLs sort of flare a little bit. And I know that if I had all the time in the world,

01:21:32.100 I could go and stretch my way out of that. But sometimes I just don't have that time and I need

01:21:36.360 to kind of get right back to doing something awful like sitting. And just two or three days

01:21:42.360 of 20 milligrams of baclofen BID with a little NSAID and like, I'm as good as new. And I save

01:21:48.380 myself the real flare up. What are your experience with muscle relaxants?

01:21:53.200 Beautiful case example, by the way, for yourself of how we would use those. Baclofen is one of the

01:21:59.840 safest to use. It is not habit-forming like the somas and others that can be like a barbiturate,

01:22:08.260 can act, and people can get highly psychologically dependent on them. The Flexerils have a tricyclic

01:22:16.380 antidepressant property about them that may sometimes be helpful for people in various mixed

01:22:21.060 pain states, but also can cause sedation. The baclofen seems to be pretty benign.

01:22:26.080 We don't typically use muscle relaxants for long-term chronic conditions. The data hasn't

01:22:33.920 borne out. So how many days are you comfortable with a person?

01:22:36.780 Oh, I'm comfortable with a person being on baclofen all their life. It's just, forgive me

01:22:41.440 if I'm preaching to the choir here. Everything I'm doing is taken in the context of the person

01:22:46.800 in front of me and the cost and benefit of the treatments I'm providing them. Meaning there

01:22:54.160 are costs with baclofen. I don't mean monetary cost. It can cause sedation.

01:22:59.220 What dose is typically, or is it just individual?

01:23:01.360 I think it's individual, and obviously it is dose-dependent. The higher dose is more sedation.

01:23:05.480 We can use baclofen intrathecally. We put in intrathecal pumps for baclofen. This is a beautiful,

01:23:13.300 life-saving, minimal surgery that we do for people with a spinal cord injury, intractable spasticity,

01:23:21.200 because to get the spasms under control with oral doses, you just can't get there. So we

01:23:28.500 throw out a little catheter into the CSF and we deliver baclofen that way. Now, it, again,

01:23:33.620 is a clean, relatively safe medication, but I'm always evaluating long-term, is this person getting

01:23:40.480 benefit from this? Should we be talking about dialing it back and trying to wean? And if they're

01:23:45.980 not getting benefit, then why should they stay on the medication? I know you do the same types of

01:23:50.340 things in your practice. We use it. We can use it in acute, subacute. We'll use it in some chronic

01:23:55.160 conditions as a trial. What's a trial? Month, two months. And then we monitor data on every single

01:24:01.820 person. And what dose are you comfortable up to 20 milligrams three times a day?

01:24:05.920 Yeah, up to 80 milligrams, I believe, is the upper end. I don't usually get there.

01:24:09.220 Okay. You alluded to Neurontin earlier, and you alluded to the fact that it played a role in my

01:24:15.260 recovery because once we got the big stuff out of the way, I still had a couple of years of peripheral

01:24:22.840 nerve injury. And the only way to put the fire out in my foot was Neurontin. And unfortunately,

01:24:30.960 initially it required four grams a day. I was taking a gram four times a day or something like that.

01:24:37.580 And the good news is it worked. The bad news is you're pretty much always tired.

01:24:41.920 So I was very happy over time to get that dose down. And I think within 18 months I was completely

01:24:47.820 off the Neurontin and lo and behold, never experienced. Although interestingly, maybe

01:24:52.440 once every year I get like an enormous surge of fire into that same foot. Literally one shot of flame

01:25:00.140 that lasts seconds and it's gone, but essentially never again. Is Neurontin still a very powerful tool

01:25:08.260 in the use of neuropathic pain. You alluded to other drugs like antidepressants as well,

01:25:13.800 in addition to a rather impotent anti-seizure med. But what else do you have at your disposal for this

01:25:19.040 type of pain? The beauty of Neurontin or Gabapentin and its cousin, Pregabalin, which was introduced

01:25:26.700 immediately after Gabapentin's patent ran out.

01:25:30.160 Conveniently?

01:25:30.720 Very conveniently. Both have the same mechanism of action. They work on the alpha two delta subunit

01:25:35.920 of a calcium channel in the spinal cord in the brain. That's a little too jargony and technical,

01:25:42.380 but think of them as agents that turn down the signals that are in the spinal cord being processed

01:25:50.800 and in the brain. So they're really not impacting your nerve out here or in your leg. They can be

01:25:56.320 very effective. The beauty of these two drugs is there's no lethal dose. The only way they could

01:26:02.640 kill the rats when they were studying it was to drown them in it. 0.98

01:26:06.660 I used to say, or hit them over the head with the tablets. 0.93

01:26:08.840 And I would tell a patient somewhat jokingly, the only way you can be hurt taking this drug is if

01:26:13.600 you're struck by a truck that's carrying it. It's a little bit more nuanced than that because there

01:26:18.500 are side effects.

01:26:19.420 Yep. You could fall asleep driving.

01:26:20.920 You can fall asleep driving. I tell people don't operate heavy machinery. Don't go

01:26:25.780 doom buggy riding. Don't blah, blah, blah. There is an elderly patients in particular,

01:26:31.420 I warn them about falls because you can get a little unstable.

01:26:35.900 Now pre-gabalin can also lead to weight gain. Doesn't it also increase appetite?

01:26:40.500 Both. Well, it's more icy water retention. I see a little peripheral edema in both.

01:26:45.960 And they also both enhance sleep, especially pre-gabalin. And so there's a little bit of an

01:26:53.200 added benefit to patients who were using these to also put the pain out at night when it can be

01:26:59.360 most noticeable. There was actually a study, I don't know if I'll ever be able to find it. It was

01:27:03.740 sent to me that actually suggested pre-gabalin didn't just make you drowsy, which was obvious,

01:27:08.260 but also promoted appropriate sleep architecture.

01:27:11.580 I don't know the data on the sleep architecture, and that would be something I'd be putting out to

01:27:16.460 you or some of the sleep experts. I have taken it after surgery. I find that it makes me sedated.

01:27:24.340 I don't find the quality of the sleep.

01:27:25.500 Okay. I could be totally wrong on that, but it could be your experience.

01:27:28.900 That's it. That's it. It could just simply be my experience. The truth is I do tend to,

01:27:34.140 when I dose it, I'll dose lower in the day and then I'll wallop a little harder at night

01:27:39.040 for the very reason. So let's imagine gabapentin maybe in the day 300, 300, 600 at night. And I'm

01:27:46.420 trying to titrate that so that, one, it helps them sleep because you brought up an incredibly

01:27:50.980 important point, which is during the day, we've got all these modulatory things we can do around

01:27:57.520 our pain. Distraction, for instance. Other coping strategies at night, you're just trying to get into

01:28:04.040 this relaxed state. And that is the worst time for somebody with chronic pain. And so the gabapentin

01:28:10.140 and sometimes other agents can help with that. So yeah, I do use it to help people sleep.

01:28:16.340 No lethal dose. Max is out at around 900 to 1,000 milligrams at a dose because it's taken up by an

01:28:23.040 active transport system in the small intestine. Once you take more than about 1,000 milligrams,

01:28:28.380 the rest of it's just passed out your backside. Pregabalin is different. It has what's called a

01:28:34.540 linear kinetic profile, simply meaning the more you take, the more that gets in your system.

01:28:39.080 So the only times I will typically switch somebody from a gabapentin if they're getting benefit is when

01:28:45.080 they've maxed out the dose. They're getting benefit, but there's no point in giving them more. I'll switch

01:28:49.620 to pregabalin where I can drive more into their system.

01:28:52.740 And again, you're using these for the most recalcitrant neuropathic pain typically?

01:28:59.020 I'm using these for the most recalcitrant pain in general. So that's an important point.

01:29:05.320 While I can speak to perioperative pain, acute pain, subacute pain, and chronic pain,

01:29:12.180 Stanford, we tend to see, we're a tertiary referral center. I tend to see, we see people

01:29:17.720 after they've seen everybody else.

01:29:19.760 We didn't even do this. I'm sorry. We didn't define chronic pain, but how would you put a

01:29:23.960 definition on that?

01:29:25.120 There's various definitions. Some like to put a timeframe on it, which I think many of us believe

01:29:30.500 is a little artificial. It's not three months or six months. It is pain that persists beyond

01:29:35.580 the expected time of tissue healing. So it is nuanced. It's context specific. Meaning

01:29:42.400 if you have an inguinal hernia repair or a prostatectomy, which should heal up pretty quickly

01:29:50.780 and your pain should go away pretty quickly. But if you've got pain after a couple few months,

01:29:56.860 that's starting to get to that point where I'm a little worried something's going on from a chronic

01:30:00.720 pain. But if you had a total knee replacement, that is a massive, massive surgery and you're going

01:30:06.200 to have pain for quite some time. So I wouldn't call chronicity for a total knee.

01:30:11.620 Totally makes sense.

01:30:12.220 Context specific. This gets into also some of the whole issue around opioid prescribing

01:30:16.660 and these rigid timeframes for surgery and what have you, but persistence beyond the time of expected

01:30:23.200 tissue healing.

01:30:24.520 Antidepressants and their role in pain management?

01:30:26.440 These are credibly effective agents, not necessarily for their antidepressive properties. They frequently

01:30:35.200 work through modulating a couple neurotransmitters, serotonin and norepinephrine, and to varying extent.

01:30:42.460 We find that the classic, what we refer to as SSRIs, the selective serotonin reuptake inhibitors,

01:30:48.460 haven't been as effective for pain as the older dirty drugs of the tricyclic antidepressants.

01:30:54.880 We call them dirty, which simply means they act at multiple receptors. They hit multiple

01:31:02.020 systems. So these tricyclics hit the serotonin and norepinephrine systems, and then they also

01:31:07.620 happen to be pretty potent sodium channel blockers. Why the sodium channel blocking property is

01:31:14.380 important is when we talked earlier about the peripheral nerves. One of the main drivers of an

01:31:20.200 action potential is activity around the sodium channels. You block the sodium channels,

01:31:25.440 the action potential stops.

01:31:26.840 Do you remember how much you gave me?

01:31:28.700 Of?

01:31:29.480 How much sodium? Oh, sorry, how much lidocaine?

01:31:31.660 I hope it wasn't toxic.

01:31:33.380 I'll come back to the story. It's pretty funny.

01:31:34.740 I'm looking forward to it.

01:31:36.020 Which TCAs are the popular ones?

01:31:38.880 Everybody, I think there's about nine.

01:31:41.840 What are your top two or three?

01:31:43.060 Yeah, that's the thing. We all get comfortable with our top two or three of any class. My go-to

01:31:49.080 is disipramine, nortriptyline, and amitriptyline. They're broken up into different categories based

01:31:56.200 on mainly side effect profiles. So the-

01:32:00.480 After nortriptyline, what was it?

01:32:01.940 Amitriptyline or elevil.

01:32:02.840 Oh, amitriptyline. Yep, yep.

01:32:03.560 So elevil's an older tricyclic that has a lot of histamine release, a lot of sedating properties.

01:32:11.140 I would never give that to an older guy with a big prostate because he couldn't pee,

01:32:16.540 and he'll be very angry with me. I will never give that to a young woman who's looking to watch 1.00

01:32:22.820 her weight because she's going to get the munchies and she's going to put on 10 or 20 pounds and she's 1.00

01:32:27.200 going to hate me. Have I had that happen? Yes. And I still am embarrassed to this day.

01:32:30.980 Is it offset by GLP-1 agonists in the modern era?

01:32:33.920 I learned my lessons. I haven't run that experiment. That's a great idea. But I typically

01:32:40.340 use the amitriptyline when I need some sedating help at night for sleep and pain because of dual

01:32:46.380 action. I like the disipramine because it has less of that sedating property, and I'll tend to go to

01:32:53.120 that, and the nortriptyline. And you can titrate blood levels, for instance, like the nortriptyline.

01:32:58.040 And those drugs, so where do they work? They work in the brain. They work in the brainstem.

01:33:05.580 One of the classic areas down deep in the brainstem is a rostral ventral medullary

01:33:10.800 region where descending pathways are coming down. And some of the key neurotransmitters there are

01:33:16.940 serotonin and norepinephrine. So we're not necessarily using these drugs for their mood-changing

01:33:22.780 properties. We're using them because they hit the same systems as they do in pain. And that's the

01:33:29.320 beauty of them. And that's some of the messaging we have to give patients when we've prescribed

01:33:33.140 them an antidepressant is like, okay, Mrs. Jones, Mr. Smith, we're not doing this.

01:33:37.420 Because we think you're depressed.

01:33:38.640 You're depressed.

01:33:39.020 And that's what I'm saying, yep.

01:33:39.660 These are great, great, great pain drugs, but they were never FDA-approved.

01:33:43.680 Why were they not FDA-approved? Because we're off patent. There's no money to be made.

01:33:47.040 Not FDA-approved drug. Approved for pain is what you meant, yeah.

01:33:50.060 Thank you. Thank you for that correction.

01:33:51.460 Or FDA-approved for something else.

01:33:52.660 You're absolutely right.

01:33:53.920 Okay. Well, this brings us to opioids, which I saved for last because of, well, there's actually

01:34:00.360 more drugs I want to talk about, but in terms of the off-the-shelf typical stuff that people think

01:34:04.180 about. So a lot of hay has been made over this. There's no question that opioids have been overused

01:34:11.400 and abused. And there's no question that illicit use of these things has had a devastating

01:34:19.080 impact on our society. But it would be difficult to say that the field of medicine would be better

01:34:27.680 off having never had an opioid. We just talked about surgery, for example. Very challenging to

01:34:35.660 deliver medical care in a hospital without opioids. So the question becomes, what is the most responsible

01:34:43.060 case for oral opioids, which by definition are meant to be used outside of a hospital, not inside a

01:34:49.440 hospital? And as a pain specialist, I would imagine few people are better equipped to navigate the

01:34:56.660 nuance of that question. Yeah. It is a very nuanced question. I think a little preamble first. I don't

01:35:04.240 take money from either the opioid companies. I don't take money from the litigation that's ongoing

01:35:09.660 because there are tens and tens of billions of dollars at play right now. I don't take money.

01:35:15.000 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

01:35:25.140 as a tool much like the other medications, interventions, mind-body, physical rehabilitative

01:35:30.840 complementary tools that we use. They have a particular place. I have a personal, deep appreciation

01:35:37.840 for the destruction that these agents can cause. I come from a family very deep in addiction.

01:35:45.180 Very deep. I've lost close family members to opioid overdose. I've lost close family members to

01:35:51.580 alcoholism. I am personally petrified of these drugs. And I have gone through surgeries that the

01:35:58.280 surgeon said, you can't get through this without an opioid. And I'm like, I'll be fine because my

01:36:03.620 approach is avoidance. With that said, I've learned a long time ago not to project my personal

01:36:09.160 experiences onto my patients. That had to come through age, wisdom, whatever. It is true.

01:36:15.800 Prescription opioids were overprescribed. They were overmarketed. They were bad actors doing bad things.

01:36:21.960 But it's not that simple a story. I sometimes get frustrated because I feel like you can make really

01:36:27.780 simple sound bites out of this complex societal issue when it was a perfect storm that hit.

01:36:35.880 Yes, you had a letter to the editor of New England Journal saying that nobody got addicted,

01:36:40.880 like 38 patients or some nonsense. And Purdue and others ran with this. And I get that. And they did

01:36:46.680 bad things. You also have to put things in the context of what was going on in society. There was

01:36:52.840 growing awareness of pain, as there should be. There was growing pressures to do something about

01:36:58.120 it. People have brought up the pain as a fifth vital sign as an example. People have different

01:37:03.240 opinions about that. Did it have bad consequences? Yes. Did it have good consequences? Hell yes.

01:37:09.300 Run the counterfactual. Do you want to go back to a time when we're not asking patients after surgery

01:37:14.900 their pain? Do you want your mother, your daughter back in that time? And I think the answer is clearly no.

01:37:19.840 But also there was other pressures. And Peter, you witnessed those firsthand. What was going on back

01:37:25.220 in the 90s and the 2000s? After surgery, there was this massive push to get people out of the hospital

01:37:31.040 and put them in their home. We were replacing care in a hospital with care in the home.

01:37:37.040 In the hospital, we had time to see their trajectory. We could titrate their opioids or whatever,

01:37:43.600 get them tuned up, dialed in, and then send them home. Now, surgery, overnight, you're home. Let's

01:37:50.680 give you a bucket of whatever. And the reason for that was surgeons and docs don't like getting called

01:37:56.380 at 3 a.m. for pain control. So pressure to put people out in the home environment. On top of it,

01:38:03.280 docs get lousy training for pain. What is the average? Seven hours, I think, in medical school.

01:38:09.120 Well, that's, by the way, 40 hours of pain. So great if you've got a dog. Not so great for

01:38:14.380 patient. So you've got this pressure. And by the way, not only on top of that,

01:38:20.600 but now you've got the introduction of patient satisfaction scores. I have to imagine in your

01:38:25.700 private practice, you don't have to measure press gainy and patient satisfaction scores. But in

01:38:29.760 hospitals, everybody does. Or at least they did. I think they're coming to their senses. And so one way

01:38:34.900 of addressing the satisfaction, give more opioids. And there's more. There's many, many, many pressures

01:38:40.000 that came to bear that helped create this problem of which there were bad actors out there.

01:38:46.580 By the way, the perfect analogy to this is the mortgage crisis in 2006 to 2008. If you took a

01:38:54.560 zeroth order view, it would be really easy to blame one of the entities. But it is actually a

01:39:01.880 perfect storm. I have a slide. Yeah. On the opioid crisis, I call it the perfect storm.

01:39:07.560 You're absolutely right. And in the end, and here I'm going to be a little bit reductive when it comes

01:39:12.560 to the docs roles in this. I'm going to borrow from my friend, Professor Keith Humphreys. There are

01:39:18.080 three kinds of physicians out there. There are the majority of the physicians doing the right thing for

01:39:24.020 the right reasons. There are the next group, which is a much smaller group, physicians doing the wrong

01:39:30.180 thing for the right reasons. And at the very top of that pyramid, a little group, you got physicians

01:39:36.320 doing the wrong thing for the wrong reasons. Those people at the top take away their license,

01:39:41.860 put them in jail. But you had a group of people here in the middle that were doing the wrong thing

01:39:46.160 for the right reasons, that they either didn't have the right education. They thought they were

01:39:50.980 helping people. Did they contribute to the problem? Yes. Have they gotten educated? Yes.

01:39:55.820 I didn't answer your question though. And let me now circle back. And I hope you'll forgive that

01:40:00.740 little bit of soliloquy on my perspective of that 20 years. I don't use opioids as a first line agent

01:40:06.840 ever. Almost never. End of life. Cancer. But usually by then they've tried other things before they're

01:40:12.260 getting to us. I will use end of life. Cancer pain. I'll use opioids liberally as needed.

01:40:18.220 Just one thing, you are not taking care of somebody in the acute phase of expected pain typically. Is

01:40:26.400 that correct? In other words, that guy that just had a knee replacement, he's being managed by his

01:40:32.140 surgeon, correct? You know, frequently we have an acute pain service in the hospital that sees about

01:40:37.260 30 to 50 patients a day. Based on what? When is the big gun of your team's expertise being brought in

01:40:44.420 for a post-surgical routine case versus not? Most frequently when the outcome is not simple.

01:40:54.400 So when the surgeon needs some help, when the internal medicine doc needs help, and it's beyond

01:40:59.980 their comfort. You know, when we brought pain in for every case when I was in residency,

01:41:06.260 anytime we did a thoracotomy, it was a non-negotiable. Pain was consulted before the case,

01:41:11.680 just for people listening, a thoracotomy. We didn't do these often because a lot of times

01:41:15.320 by the time I was in residency, we did minimally invasive surgery in the chest. But sometimes you

01:41:19.920 had to actually make a huge incision under the ribs, and that's a very painful, you just know

01:41:25.640 this from experience, that that's such a painful experience. You cut this huge incision in the

01:41:31.040 intercostal muscles, you put rib spreaders in, you crank these things open so you can do this big

01:41:36.460 operation. We just know those patients are going to need an epidural catheter, and we want that in

01:41:43.260 before surgery, not after. And it makes all the difference in the world. So pain was a part of

01:41:48.820 that response. I don't remember us routinely bringing pain in otherwise, but things have changed,

01:41:55.860 I'm sure, in 20 years. So today, for a general abdominal case or a general orthopedic case,

01:42:02.060 are you brought in preoperatively? Yeah. These days, there's a lot of movement towards these

01:42:06.840 ARES protocols and enhanced recovery after surgery. And so fortunately, the field of medicine is moving

01:42:13.880 more and more towards a team-based healthcare model where surgeons, pain docs, anesthesiologists,

01:42:20.260 nursing, rehab are all working in a collaborative manner. They're putting together protocols to what is

01:42:25.760 the best optimal approach to prehab a patient before surgery, move them through the intraoperative

01:42:33.420 and then perioperative period. And it's gotten better and better and better. Can we still improve

01:42:38.860 it? Yes. But the acute pain service does get involved, particularly, as you alluded, when we put

01:42:43.740 in peripheral nerve catheters or epidural catheters. And this is where we're running that local anesthetic,

01:42:50.800 like the numbing medication that stops the nerve impulses to provide pain relief after surgery.

01:42:56.520 And so, yes, we do get deeply, deeply involved in that acute surgical pain space. And then also

01:43:03.200 with internal medicine docs when patients are admitted into the hospital for whatever cause.

01:43:08.940 If someone's listening to us and they're going to have elective surgery at some point,

01:43:13.680 I want to plant a seed in their head for someone who's going to have the knee replacement,

01:43:16.800 the hip replacement, the cholecystectomy, the api, whatever. Should they be requesting this of

01:43:21.560 their surgeon? Should they say, hey, I want to be diligent about my recovery. I want to minimize my

01:43:26.580 use of narcotics. Do you mind calling in a pain consult so that I can just have a team of docs who

01:43:32.620 are exclusively thinking about my pain? Because let's be honest, the surgeon, I got enough to worry

01:43:36.820 about. I got to make sure you didn't leak, that that anastomosis is fine, that you're not getting a

01:43:41.440 wound infection. Your pain is literally like third or fourth on the list of my concerns for you to

01:43:46.580 have the best outcome. Right. You are right. And if a patient is listening to this, a person is

01:43:52.060 listening and they have the ability, they have the wherewithal to go to their doc, their surgeon,

01:43:57.200 and ask, what will pain management be like? Is there an opportunity to interface with an acute pain

01:44:02.520 service, particularly if they're taking opioids now for a chronic pain problem, or even if they're not

01:44:08.300 taking opioids for a chronic pain problem? So we will see them in our clinic before surgery.

01:44:13.020 We will put together a pre-surgical plan for them, which will often include a regional anesthetic

01:44:19.280 approach, meaning those nerve blocks or the catheters. We sometimes involve intravenous ketamine

01:44:24.540 to augment. We will put together the whole plan, communicate with the anesthesiologist, make sure

01:44:30.540 there's a good handoff after surgery, and then we will follow them afterwards. And then we will

01:44:36.220 typically follow them outside the hospital and help the surgeon out with the medication management and

01:44:41.840 the pain management. All of this is not just solely to reduce pain, but to put that person in an optimal

01:44:48.360 state for rehab. How ubiquitous is the patient-controlled analgesic device, the PCA that we used to have?

01:44:54.460 Everywhere. Okay. So people are still typically getting fentanyl through a PCA in the immediate

01:44:58.900 post-operative phase? Fentanyl, morphine, Dilaudid, yeah. The PCA is a very common tool. And one, it puts

01:45:07.240 pain control in the hands of the patient. Two, studies have been shown that PCA-delivered medication,

01:45:13.840 opioids, they end up taking less than if it's nursing-delivered. And the goal is we want to get

01:45:20.340 you off an opioid, even oral, before you go home. Is that generally the stated objective of the medical

01:45:25.160 system now? Is whatever opioids you're going to need, let's try to deliver that to you in the

01:45:29.980 hospital? I wouldn't say necessarily, because I think there are some surgeries that are going to

01:45:34.100 clearly require prescribing an opioid after surgery. Remember, the name of the game is get people out of

01:45:40.460 the hospital and have the care take place in their home. And people are going to need some degree of

01:45:45.860 pain management and analgesics. And those analgesics can be Tylenol, NSAIDs. If it's more than

01:45:52.300 mild, moderate pain, it may involve an opioid. So how are you thinking about that? How are you

01:45:57.900 thinking about extracting the value of the opioid and minimizing the risk of long-term dependence?

01:46:04.880 What we have learned is that there are vulnerabilities that people bring to an injury or

01:46:12.440 surgery and being placed on opioids that set them up for more likelihood of persistent opioid use.

01:46:18.900 And we've characterized, we and others, through research studies, have characterized many of

01:46:25.440 these factors. So some of these factors include preoperative depression and anxiety, higher levels

01:46:33.200 of catastrophizing, early adverse child events, so history of PTSD, history of physical, sexual,

01:46:40.920 psychological trauma. All of these set someone up to have a higher likelihood of persistent pain and

01:46:47.760 persistent opioid use. Now, you will note, all these things I said, most of these things I said,

01:46:54.260 people would normally put under the psychological umbrella. The key message that I want to give,

01:47:00.540 I think everyone's getting this, is when we talk about psychology and psychological factors,

01:47:05.640 we're talking about neurosciences. We're talking about the brain. And we're talking about specific

01:47:10.020 brain systems, regions, networks. So we did a study several years ago. This was led by Jennifer Haw,

01:47:17.020 Ian Carroll, who's a key player, leader on this. And we found that higher depression scores preoperatively

01:47:23.840 predicted much more likelihood of persistent opioid use after surgery.

01:47:28.980 And how are you screening for this? What tests are you using?

01:47:32.440 Back then, we used something called the Beck Depression Inventory, which standard instrument,

01:47:36.620 we don't use that anymore. There's more modern tools. I thought what was cool about this,

01:47:41.660 we did a factor analysis on the original paper. And you can break the Beck down into different

01:47:47.760 components of depression, anhedonia, cognitive, blah, blah, blah. What we found is there was a

01:47:52.600 particular factor that drove almost entirely that prediction of depression, self-loathing. It was

01:48:00.980 feeling like really bad about yourself.

01:48:03.400 So if you have someone who just suffers from, not that anhedonia is anything but unpleasant,

01:48:08.220 but if they're only experiencing anhedonia, but no self-loathing, you would say, well,

01:48:13.400 the risk isn't as high.

01:48:15.100 Yeah. Conceptually, your argument holds. But now I'm going to come back to a lot of the things that

01:48:21.500 you write about, which is the danger of drawing inferences from small population studies and

01:48:28.440 generalizing that to the rest of the world.

01:48:30.980 Yeah. Especially without randomization, because what you really would like to be able to see is

01:48:35.060 you take a whole bunch of people in, you get their incoming metrics of anhedonia, dysthymia,

01:48:42.960 self-loathing, you categorize all the arms and tentacles of depression, and then you randomize

01:48:48.840 within each of those to with and without opioid strategies. I mean, this is a very complicated

01:48:54.360 thing to do, but if you want to know the answer, that's kind of the way you want to do it.

01:48:57.380 That's exactly it. Unfortunately, there's not much will to do that in society.

01:49:03.600 Even in the world we live in today, where we understand that for a non-zero, potentially

01:49:09.120 non-trivial segment of the population, the introduction to opioids that ultimately

01:49:14.880 destroys people's lives is delivered by the medical system?

01:49:18.800 I was on the Institute of Medicine panel, now the National Academy panel, and we did a report

01:49:23.740 called Relieving Pain in America, and I remember sitting around back in 2010, and we were talking

01:49:28.580 about the state of pain in the country and where we needed to go, identify a perfect vision,

01:49:32.660 and also identify what are the biggest research questions to ask and answer. And I remember a

01:49:39.280 really vigorous discussion here, and the one that I put forward and others put forward is,

01:49:43.860 we need to better understand what is the long-term effectiveness and safety of prescribing opioids

01:49:51.400 to people with chronic pain, meaning we need to figure out for whom opioids work. Today, we still

01:49:57.180 don't have an answer to that question, and there's very little will to do it because the whole message

01:50:01.800 in the scientific community is basically find non-opioid choices. So there's not a lot of interest

01:50:08.120 in funding the studies to figure out for whom it works. There is a lot of active interest still,

01:50:14.220 mainly through data-driven studies, to find out who's at risk. But that type of study that you're

01:50:20.600 talking about and others that are of longer term and bigger consequences, I just don't know when

01:50:26.720 they're going to get done, who's going to fund those. This is a little unrelated, but I remember this

01:50:31.380 when I was in residency. There was one of the attendings, and I don't even remember who it was,

01:50:36.220 but he had this belief. He used to quote this study, and I don't remember it, but it said that

01:50:42.440 if you injected bupivacaine into the injection site, sorry, the incision site. So I'm going to

01:50:48.440 make a midline incision, draw my little line, inject bupivacaine. So for the listener, this is a

01:50:54.020 long-acting sodium channel blocker. Wait some long period of time, like 10 minutes, then make the

01:51:00.960 incision, go about, do your surgery, and then immediately give that patient acetaminophen

01:51:06.360 and ibuprofen immediately post-operatively and keep them on it around the clock. You could

01:51:11.180 eliminate opioid use. And he was convinced that the only reason surgeons didn't want to do this

01:51:15.760 was because nobody wants to inject and stand there for 10 minutes with your thumb up your ass waiting 0.97

01:51:19.800 for the bupivacaine to seep into the tissues. And maybe it's anecdotal, but it really seemed to work. 0.99

01:51:25.240 Like it really seemed to work that you would do this inguinal hernia repair or at the time some

01:51:30.860 small laparotomy or whatever it was, anything. And if you were willing to put that bupivacaine in and

01:51:37.120 sit there and wait, and I'm trying to think, we might've used epi with lidocaine as well. So it

01:51:41.560 might've been a little epi with lidocaine plus bupivacaine or something like that. And you had to

01:51:44.900 be super due diligent about keeping the acetaminophen and ibuprofen levels up. Have you ever heard of

01:51:49.940 anything like that? Oh, all the time. Yeah. I mean, I think he was ahead of the curve.

01:51:53.460 Now, whether it completely eliminates any likelihood of opioids after surgery, that's a

01:51:58.400 little too strong a statement. Look, it just reduces the requirement, right?

01:52:01.380 I strongly believe that he was practicing good medicine and he was doing it ahead of his time.

01:52:07.780 Now, the idea of using a combination of lidocaine and marcaine and epi, as you well know, is lidocaine

01:52:13.900 short acting. So it's going to work pretty darn quick. And so you can get going with your surgery

01:52:19.180 while the marcaine, the bupivacaine's kicking in. The epi is going to not only provide hemostate,

01:52:25.200 it's going to reduce bleeding at the site, but it can keeps the local contained.

01:52:28.280 Which means you have to use less bovie, which means less tissue damage.

01:52:31.480 Yes.

01:52:31.800 Maybe he was using epi with bupivacaine. I don't remember.

01:52:34.860 Well, I mean, you told him-

01:52:35.500 But there's something there, right?

01:52:36.400 There is something there, there. And I think, I haven't asked surgeons these days,

01:52:40.020 and my sense is that's becoming more and more common practice,

01:52:43.160 that there's a greater appreciation of the role of this concept of preemptive, preventative

01:52:49.000 analgesia, anesthesia. I think it provides some benefit. There was a big hoopla on this like 20

01:52:55.060 years ago when everybody thought we were going to find a way just to basically eliminate post-operative

01:53:00.220 pain through these methods.

01:53:01.800 Presumably didn't pan out.

01:53:02.720 It just didn't pan out.

01:53:03.840 Yeah. But look, a 50% reduction in opioid requirement post-operatively would be enormous.

01:53:09.520 Huge. Absolutely. Getting back to your question,

01:53:12.780 I think we're at an interesting crux in research and clinical care where we're gathering more and

01:53:19.940 more high-quality data to better understand these vulnerabilities. And I think we're going to be

01:53:24.420 moving to the point of putting these into clinical decision support tools that can inform the docs

01:53:30.140 and help them to assess a risk of a patient so that you can have an informed conversation with

01:53:38.140 someone. Like you are at likelihood of having persistent opioid use because of what you bring.

01:53:44.240 Do patients receive that well? That's a hard discussion to have with a patient,

01:53:48.100 I would imagine.

01:53:49.240 I guess it a little bit is about their expectations. The challenge is when the ones who've had multiple

01:53:54.020 surgeries that have been on opioids, they're expecting opioids, a lot of it's expectations.

01:53:58.780 I think the more naive person, those go a little smoother. If you are professional,

01:54:05.000 explain to them, but also allow them to make their own choices. Don't say,

01:54:09.920 we're not going to give this to you.

01:54:11.760 Yeah. That makes sense.

01:54:12.940 But here you are at an increased risk. And that's always the discussion I have with patients,

01:54:17.720 whether in the acute space or particularly in the chronic space.

01:54:20.300 So let's talk about a couple other things that are related to this, but distinct. Let's talk

01:54:24.840 about acupuncture. What do you know about it? Well, let's talk about through the lens of chronic

01:54:30.220 pain. Yeah. Yeah. Yeah. All right. Clinically, some people get better. Some people don't get

01:54:35.240 better. I cannot yet predict who is going to respond and who's not going to respond.

01:54:40.940 Is it a part of the work that your department does?

01:54:43.780 Yeah. We actually have Dr. John T. Kong does the acupuncture. She's a pain doc. She does acupuncture.

01:54:50.300 And my view of acupuncture as a treatment, as a modality is if you can afford the wallet biopsy

01:54:56.860 and it doesn't cause you problems, then give it a try.

01:54:59.500 And you say wallet biopsy because the insurance doesn't typically cover it?

01:55:02.300 They do more so now on Medicare. And I think that the rules that went into place recently

01:55:07.540 helped with that for older patients. I don't honestly know if it's translated down to the

01:55:12.100 commercial carriers. So Medicare is covering something commercial payers or not?

01:55:16.320 Well, it's possible. Okay.

01:55:18.180 Yeah. Historically been hard to get that covered.

01:55:21.520 So notwithstanding, I like the idea of a wallet biopsy. I hadn't heard that before.

01:55:25.140 In your experience, where do you see it being most successful? What type of pain? What type of

01:55:30.960 clinical presentation?

01:55:32.600 Yeah. I've had some successes in back pain, musculoskeletal pain, migraines, headaches,

01:55:38.500 oddly. And it's highly variable. I studied this. I had a really large program project grant

01:55:45.360 to look at cortical mechanisms of this and predictors. We're putting in a paper now,

01:55:51.680 which is a prediction model of real acupuncture versus placebo acupuncture.

01:55:56.640 Puncture, but not in the appropriate spot?

01:55:58.520 Well, that's one option. And it turns out that many of these acupuncture points overlie peripheral

01:56:03.800 nerves. And so when you twiddle the needle or apply electroacupuncture, are you doing a peripheral

01:56:10.580 nerve stimulation? I don't know. But this is a Stridinger needle that looks for all intents and

01:56:15.280 purposes like an acupuncture needle. It causes a little pinprick, but it doesn't actually do

01:56:19.380 acupuncture. And it's been shown to be a good placebo. What do I know about the mechanisms?

01:56:24.940 Again, don't fully understand. I know that there is increases in peripheral adenosine that is released

01:56:31.820 with acupuncture that has an analgesic effect at the primary nociceptor. I know that cortically in the

01:56:39.220 brain, there are brain systems that are modulated with acupuncture, but heck if I know exactly how

01:56:48.020 it works. And we still don't have good ways of predicting who's going to respond and who's not

01:56:52.240 going to respond, but that's rather common amongst all of our pain treatments. You know, again, pretty

01:56:57.060 safe, absent some risk of infection. Make sure that the facility you're getting at practices good

01:57:03.340 hygienic approaches. How do we think of acupuncture differing from dry needling?

01:57:07.580 I think you'll want to get a true acupuncture specialist on to dry that.

01:57:11.920 In California, I think it's not legal to dry needle, but you can acupuncture. I even understand

01:57:16.260 the difference. If you're using the term dry needling from an intramuscular standpoint,

01:57:20.260 I don't know if that's where you're going. Maybe. I see acupuncture refers to just going

01:57:23.440 after a nerve specifically. Well, it's an acupuncture point.

01:57:26.540 Okay. It is a Chinese medicine list of acupuncture points. I'm way out of my wheelhouse here, folks.

01:57:33.320 When I think of dry needling, I tend to think of that in the context of trigger point injections,

01:57:38.300 which we do. Physicians do. In that, we're taking typically like a 30 or 27 gauge needle. We're

01:57:45.660 putting it intramuscularly into a trigger point muscle. It's where you get those knotty muscles.

01:57:53.320 And you can do dry needling. And what that does is it causes relaxation of the muscle. Acupuncture

01:57:59.000 is really quite different from that. Okay. Next question on chronic pain. What

01:58:05.000 is the role of cannabis in your experience here? Is it friend or foe? And again, I'm sure there's

01:58:10.200 a nuanced answer. Very nuanced. This is another one where I'm liable to get some hate mail on either

01:58:15.620 side of this. Here's what I'll tell you. One, the verdict is still way the heck out there.

01:58:21.020 You look at well-controlled randomized trials. There's very few of them, by the way, but some in

01:58:26.780 neuropathic pain that show analgesic benefit over a short period of time with cannabis. You look at

01:58:34.080 population level studies. Australia did one. They did not show benefit with cannabis. We collect data.

01:58:42.180 One of my other areas of both research, but also clinical care is I built a learning health system

01:58:49.280 that captures high quality data on every patient that comes in. And so we deeply characterize or

01:58:54.520 phenotype them. And we looked at people coming in on cannabis, not on cannabis. Bottom line,

01:58:59.420 people coming in on cannabis into Stanford are worse off and they stay worse off. Now there's

01:59:04.380 all these limitations to observational studies, no matter how well you conduct them. Let me distill

01:59:09.180 it down to some talking points. There's a huge number of cannabinoid receptors in the human brain

01:59:15.300 that are playing a role in analgesia. So I'm absolutely convinced that cannabinoids are playing a role

01:59:21.080 in pain relief. One. Two, the forms of cannabis that we take are dirty, meaning we don't know the

01:59:28.560 dose. We don't know the ratios. They've not been well studied and they've not been studied in different

01:59:34.260 groups. A major part of that is because it's a schedule one drug, which means that the DEA says

01:59:40.240 basically high abuse potential and no medical benefit. And it takes basically an act of Congress

01:59:46.300 to study cannabis. I don't prescribe it at Stanford. I don't screen people for it at Stanford. If I did

01:59:54.700 and if we kicked them all out, I wouldn't have anybody in the clinic. I mean, we're in Northern

01:59:59.160 California. That's interesting. So you can't study it. I would assume you couldn't study it with federal

02:00:04.960 dollars because of the federal DEA restriction. I would have assumed because it's legal in California,

02:00:11.820 if you were using non-federal dollars, you could study it in a state like California.

02:00:16.880 You can study it with federal dollars. NIDA will support funding of cannabis. The regulatory controls

02:00:22.980 you have to go through are crazy. I see. Because it's schedule one, the laboratory, it's actually

02:00:28.220 more demanding than how you would study cocaine. We used to make jokes. UCSF did some nice cannabis

02:00:33.660 research. And the word on the street was, is that they would deliver the cannabis

02:00:39.020 doobies in a Brinks armored truck with guys carrying M16s. Now, I think it's gotten better,

02:00:46.020 but it's just been challenging to study this. I'm firmly of the opinion, here's where I'm going

02:00:51.580 to upset people. I firmly believe we should make it a schedule two or schedule three drug.

02:00:55.560 If for no other reason to study it with less friction.

02:00:58.140 Which you said. Perfect.

02:00:59.800 Okay. There's a condition you've already alluded to today that I am sure everyone has heard of.

02:01:05.700 And yet, if you asked most people to define it, they wouldn't be able to define it.

02:01:10.060 And so, we're going to start with what it is, why someone might have it, what is the prevalence,

02:01:16.440 are there false positives? I'm talking about none other than fibromyalgia.

02:01:20.660 Yeah. Yeah. What was historically a garbage bag definition? Fibromyalgia is a condition of

02:01:28.840 widespread bodily pain that impacts people above and below the waist of the diaphragm. It's associated

02:01:35.140 with early morning stiffness, fatigue, mental fog, often some GI problems. It was historically,

02:01:43.760 based on American College Rheumatology definitions, based on tender points in 11 out of 18 places,

02:01:49.340 but that's been replaced by now criteria which involves multiple body sites affected and a symptom

02:01:56.260 severity score. The key thing when the audience hears, well, first of all, it's fibromyalgia

02:02:03.460 syndrome. And whenever the audience hears syndrome, what they should translate that to,

02:02:10.500 the definition of a syndrome is a constellation of signs and symptoms that define a disease,

02:02:16.200 but we don't understand the mechanism. So, fibromyalgia is a syndrome. We do not understand

02:02:22.140 its mechanisms. We know that historically, it tended to affect women more than men, about 80%-ish or so

02:02:30.460 women. With the newer definition, we're picking up a lot more men. The cognitive aspects of it are 1.00

02:02:37.340 really a problem. It's also associated, as I alluded to, with sleep disturbances. They get this weird,

02:02:43.280 what we call alpha wave intrusion into their EEG, which means alpha waves are typically in light

02:02:50.340 awakefulness. So, when you're supposed to be in deep sleep or REM sleep, your brain is in kind of a

02:02:56.960 light alert state instead. And so, they're not getting a restful sleep. This is a syndrome that's

02:03:03.280 caused untold problems, particularly for women. What's the prevalence according to the current

02:03:08.460 definition? I should know how many millions there are, Pete. I should know how many millions and I don't.

02:03:13.600 I can tell you just to give a frame of reference. Chronic pain, we think there's 50 to 100 million

02:03:19.140 Americans with chronic pain. That's a huge range, and it depends on the way you ask the question.

02:03:24.080 If you ask it more stringently, it's 50 million. If you ask it more liberally, it's 100.

02:03:28.160 We know that there are about 8% of the population are a little over 20-some-odd million with something

02:03:33.600 called high-impact chronic pain. This is a big one, and this is where I spend a lot of my research

02:03:38.840 and policy work on. These are the people that have substantial restrictions to their pain

02:03:44.140 in activities of daily living. These are the really challenging people. Of that 50 to 100

02:03:49.880 million, the most common chronic pain is low back pain at about 28%. Neck pain, 16%. Headaches around

02:03:58.180 16%. Societal burden of chronic pain is terrifying. It's astounding. We spend over half a trillion dollars

02:04:07.020 a year in chronic pain. The reason why, in part, it's not more appreciated is because we have

02:04:15.020 parceled it out. We've broken it into different categories. With heart disease, we lump it into

02:04:21.120 heart disease, cardiovascular disease, even though it's all these different subcomponents. With pain,

02:04:26.300 instead, we categorize it as it's either back pain, it's musculoskeletal pain, it's migraines,

02:04:32.280 it's abdominal pain, and it gets diluted out. But when you put it all together, you're dealing

02:04:37.740 with a half a trillion dollars. It's more than diabetes, heart disease, and cancer combined.

02:04:42.540 Fibromyalgia, again, I'm escaping the prevalence. Many millions of people, huge societal burden.

02:04:49.620 It is historically a disease of histrionic housewives is how they were mislabeled, tragically. 0.99

02:04:57.100 And we're having now a greater appreciation for what it is, what's affected. What we have learned

02:05:03.380 is that there are brain systems that are clearly abnormal in the processing of pain in people with

02:05:10.700 fibromyalgia. We find that for the same pressure stimulus, if you apply something like four kilograms

02:05:16.660 per square centimeter, healthy people will give a range of reporting in a certain range. People with

02:05:22.680 fibromyalgia, much, much higher. Here's another, I think this is an interesting pain concept to

02:05:28.520 introduce and talk about it. There's something called conditioned pain modulation. In the animal

02:05:34.260 world, we called it diffuse noxious inhibitory control, or DNIC. CPM. Think back to when you were

02:05:40.020 a kid, your arm hurt. You walk up to your buddy, you say, hey man, you know, and he's like, how you

02:05:45.100 doing? It's like, well, my arm's kind of hurting a lot. And what would he do?

02:05:48.700 Hit you? 0.94

02:05:49.040 He would hit you, of course. He'd hit you in your other arm. He'd stomp on your foot. And you're

02:05:52.680 like, well, the hell did you do that?

02:05:53.480 But by the way, this is a boy only thing. I can't imagine girls did this, but yes,

02:05:57.960 it's of course, this is what little boys do.

02:05:59.860 This is what little boys do. I was guilty of a lot of that. But then you'd say to your buddy,

02:06:04.240 like, don't you feel better? And the truth is you did. Because pain in another area reduces

02:06:10.100 the primary pain site. It's called conditioned pain modulation. We're all wired. It is a network,

02:06:16.900 predominantly, we think, in the brainstem, involving some of this periaqueductal gray

02:06:21.780 rostral ventral medullary regions. Labar's first described this in the mid-70s in animals.

02:06:27.360 So we all do it. We all have it. It's this endogenous tonic inhibitory tone that you can

02:06:32.840 activate when you cause pain in another site, unless you have fibromyalgia. If you have fibromyalgia,

02:06:39.700 particularly if you're a woman with fibromyalgia, you have impaired CPM. You don't inhibit.

02:06:44.400 Is there a high overlap with depression, anxiety, and fibromyalgia? And if so,

02:06:49.840 which is the arrow of causality?

02:06:52.560 Yeah, the chicken and egg. We used to think that there was a high preponderance of anxiety

02:06:57.640 and depression with fibromyalgia. And I think the current data doesn't support that there's any

02:07:05.200 higher prevalence than particularly any other pain conditions. I think you tend to see more of the

02:07:10.240 anxiety, depression, broadly speaking, in things like low back pain. I think what you see more of

02:07:15.240 in fibromyalgia is fatigue, unrelenting, fibro fog is what they call it, and then the sleep disturbances.

02:07:22.740 So what is the management for these patients? Is this a curable syndrome, or is it a syndrome that

02:07:28.760 is meant to be managed like HIV?

02:07:31.440 Yes and no. What do I mean? Well, one, we don't know exactly the mechanisms. There's different

02:07:37.120 prevailing thoughts. One thought, again, is it's a disruption in your central brain processing of pain

02:07:42.660 through reasons unknown. There are some that believe it is a disease, a condition of small

02:07:48.660 fiber neuropathy, because you can do punch biopsies, little, little skin biopsies here.

02:07:54.140 And what they find in some subsets of people with fibromyalgia is those C fibers, that there is

02:08:02.300 alterations, abnormalities of the C fibers in the skin. And that is synonymous with a small fiber

02:08:09.000 neuropathy that neurologists typically see. That's caused by what?

02:08:13.060 That's the thing. Is this infectious? What do people think is going on?

02:08:16.360 So fibromyalgia is frequently preceded by some event, something traumatic. That traumatic can be

02:08:24.120 physical, motor vehicle accident, but it could also be some emotional or sexual abuse. It can be an

02:08:30.200 infection. We frequently also hear that story. So there is some insult that people will frequently

02:08:37.720 identify. Getting back to your question on managing this, we frequently use the same medications that

02:08:43.880 we've described before, but we rely on more of those brain modulatory drugs. Another one like

02:08:49.700 the Loxetine, which is in the class of antidepressants, but it's a little cleaner, fewer side

02:08:55.860 effects. It's a serotonin norepinephrine reuptake inhibitor. This is actually a drug that got FDA

02:09:01.900 approval for pain. And so we go to this a lot. One of the drugs that I have studied with Jared Younger,

02:09:08.180 who's now at UAB, is a drug called low-dose naltrexone. This is a fascinating drug. It's got like this

02:09:16.220 underground reputation out there. It's all over the forums. The reason for it is because it's been

02:09:21.980 around for decades and off patent, there is zero money for any pharmaceutical company for it. What

02:09:26.260 is naltrexone? Naltrexone, when given at 50 milligrams, is used to block opioid receptors.

02:09:34.040 It's an opioid blocker. And so we use this in the treatment of opioid and alcohol addiction

02:09:38.840 because it blocks the rewarding experiences of alcohol or opioids. And so it's used as a treatment

02:09:46.700 for addiction. 50 milligrams. At 4.5 milligrams, one-tenth of the dose, it has been shown to block

02:09:54.460 toll-like 4 receptor on the microglia. Now, I just introduced this really technical concept, so

02:10:00.380 allow me to briefly explain. The microglia are these cells that hang around nerves but are not

02:10:08.240 neurons. And when I was in medical school, a few years, several years before you, what I was taught

02:10:13.960 was these microglia were like the warm fuzzy blanket that propped up the nerves. I don't know what you

02:10:19.340 were taught, but they provided structural support to the nerves. What I learned is that was only part

02:10:25.280 of the story, that they're key neural immune modulators. And so what I mean by that is in times

02:10:32.060 of stress, injury, fever, these microglia get activated. They release all sorts of inflammatory

02:10:39.080 mediators, chemicals that sensitize the central nerves responsible for pain perception, pain

02:10:47.360 transmission, pain perception. So you give low-dose naltrexone, it blocks that neuroinflammatory soup.

02:10:53.360 And in some patients, Peter, this drug's been magical, magical. I give it in 4.5 milligrams.

02:10:59.440 Silly question. Why not 5? Like 4.5 has a lot of specificity to it. Was there some reason why it

02:11:06.100 came in at such a dose? All right, here's my story. Linda Watkins and Mark Hutchinson did some of the

02:11:11.700 early work in the animal studies on this and showed this microglial effect. And they did it at a certain

02:11:18.140 dose. And so what we did is we did a milligram per kilogram conversion to 70 milligram. 70 kilo person.

02:11:24.520 70 kilo person. Thank you. And we get 4.5. And so when people ask me that, I'm like, wow,

02:11:30.420 it does make us sound pretty smart, doesn't it? There's no difference between 4.5 and 5.

02:11:34.900 What are the other areas where LDN is just captivating the world?

02:11:40.240 Complex regional pain syndrome. Very tragic pain condition that is a neuropathic pain condition

02:11:46.520 we see a fair amount of. I've got a clinical trial. I'm just wrapping up on that using low-dose

02:11:52.360 naltrexone funded by the RSDSA Association. Another is actually multiple sclerosis they've

02:11:58.960 used it in. And they found some reduction in reoccurrences of MS. I think they did that at UCSF

02:12:06.240 or UCLA. But it's in these weird neurodegenerative type conditions where they're seeing some help.

02:12:12.880 Now, I've had some wacky, really wacky patient responses. I can share one. He is dysarthric. He

02:12:21.500 can't speak. He's got weakness. He has hemibody pain, burning pain. This is that central pain.

02:12:28.100 Yeah, thalamic pain.

02:12:29.260 So, he comes to me several years later, can barely speak at all. He's tried everything.

02:12:35.000 Let's try low-dose naltrexone.

02:12:36.320 So, why does he come to a pain doc?

02:12:37.660 Because he's got terrible pain.

02:12:38.800 Okay. So, he wasn't coming to you for the speech issue?

02:12:40.760 No. No, no, no. He has a speech therapist. It's not getting any better. He's a couple

02:12:43.960 of years out. Stroke is stabilized.

02:12:45.480 Okay. So, it's this burning pain.

02:12:46.960 Burning pain.

02:12:47.440 On half his body.

02:12:48.420 Half his body. I trial him on four and a half milligrams of LDN. He goes away. He comes back

02:12:54.080 a couple months later. Pain is improved. But not only that,

02:12:58.020 he's now speaking and throwing a few words together for the first time since his stroke.

02:13:03.420 I'm like, what the hell? I bump up his dose. You cannot hurt yourself on this drug. I know

02:13:07.200 you know this. So, I go to nine. Why not 10? Well, because it's easy to take two capsules.

02:13:12.420 He comes back a few months later. He's now talking in sentences. I said, are you sure this isn't due

02:13:19.540 to your speech therapist? And they swear up and down. Absolutely not. I go up to 13 and a half.

02:13:25.180 And now he's having conversations.

02:13:27.800 And how's his pain?

02:13:28.880 Massively better on this. Really remarkable effect. The only way I can explain these things

02:13:36.220 is, you know, in a stroke, you've got dead tissue, you've got live tissue, you've got

02:13:40.240 these intermediate zones. And somehow with reducing maybe inflammation, you end up with

02:13:46.220 more functional brain.

02:13:47.780 Somehow, if that model makes sense, which at least teleologically does, something about

02:13:53.340 that inflammatory zone in the middle between what was clearly gone and not is poisoning

02:13:58.340 the part that's still okay. What is the downside of this? Meaning, what would one need to be

02:14:04.000 mindful of in trying an approach like this?

02:14:06.760 The beauty of this drug is the only side effects I see 20, 30% of people get vivid dreams. They

02:14:12.440 get technicolor dreams. Not bad dreams, not nightmares. Their dreams just take on a more

02:14:17.720 colorful nature. Every once in a while, I'll see somebody who they say it activates them. We

02:14:22.340 tell them to take it two hours before bedtime. And if it activates them a little bit, take

02:14:26.020 it in the morning instead. 0.80

02:14:27.860 Here's a silly question.

02:14:29.000 Yeah.

02:14:29.540 What's the scenario in which inflammation of the glia is a good thing?

02:14:34.280 It's a good thing after injury and after an infection because it mobilizes all of those

02:14:41.640 repair cells to come in and clean up the mess. The problem that we think is going on in pain,

02:14:46.820 the switches don't turn off and go back to normal. And indeed, that, Peter, which you did a beautiful

02:14:51.660 intro, is one of the things we think is playing a role in fibromyalgia. They got an insult,

02:14:58.200 activation of this neuroinflammatory system. In a healthy state, it turns off. And fibromyalgia,

02:15:04.280 it never turned off.

02:15:05.760 I guess where I'm going with this is we think that at least a subset of people with neurodegenerative

02:15:11.620 diseases, and you mentioned multiple sclerosis, but we think this is true in at least some cases

02:15:17.340 of Alzheimer's disease, that neuroinflammation is a part of the pathology. So would there be any

02:15:24.260 efficacy to a trial there in either an individual with MCI, mild cognitive impairment, or as crazy

02:15:32.260 as this sounds? Is there a reason to consider it prophylactically in high-risk individuals with

02:15:37.800 the caveat that, hey, by the way, if you happen to get an infection, this would be a good time to

02:15:41.620 stop it and ride it out and get better? I think the short answer is yes. A little bit of the longer

02:15:46.700 answer is, you know this, everything we do is weighing risk and benefits. This is one drug I am hard

02:15:54.360 pressed to come up with significant risks. We have decades and decades and decades of experience with

02:16:00.720 this drug in people with addiction. At 10x the dose. How long are they typically on that drug?

02:16:06.160 Lifetime.

02:16:06.940 So meaning for a subset of individuals, just putting them on the party dose of 50 milligrams of

02:16:13.160 naltrexone keeps them free of alcohol and opioids for life because it so blunts the pleasure center.

02:16:19.280 Yeah. The problem is, as all the addictionologists know, is that it's hard to keep people on this

02:16:24.560 because they can just stop it and go back and use.

02:16:26.620 Yeah. You have to want to be off.

02:16:28.220 You have to want to be off. They have injectable versions of this. It's not called Vivitrol,

02:16:33.600 is it? It's an injectable under the skin that lasts X number of days, months. But yeah,

02:16:39.940 we've got a lot of long-term data on this. And from a pilot standpoint, with informed consent,

02:16:47.400 obviously. And just, I would view that as a novel treatment in patients that one could try out,

02:16:53.580 monitor, do some objective measures, see what you get. I want to be careful. I wouldn't say that for a

02:17:00.500 lot of the things that we do because there's real risks with a lot of the medications that we provide,

02:17:05.320 a lot of the procedures we do. Not only that, there's big costs that come with them. Whereas this,

02:17:10.720 I'm going to make a plug here I have no relationship to, but we get our stuff out of

02:17:14.260 Balmar Pharmacy in Colorado. Why? They're a compounding pharmacy. They've got all the

02:17:20.260 certifications. The reason is you can't go to Safeway or Costco and get this.

02:17:24.500 Can't get low-dose naltrexone there, you mean? It has to be compounded at 4.5, you're saying?

02:17:28.220 You're right. And so we go through this pharmacy because they've got good customer service. They

02:17:32.020 take patients' credit cards over the phone and they will ship it to you immediately and they're

02:17:35.840 very responsive. You can probably find it in your local area at other compounding pharmacies.

02:17:40.400 It usually runs about $30 a month. So it's basically a free drug.

02:17:44.720 Insurance doesn't often cover it. They consider it experimental, but it's basically a free drug.

02:17:48.900 It's a buck a day. Yeah. So it's one that I use more and more and more because of its safety profile

02:17:54.900 and its potential for getting me a home run. Yeah. I'm very curious to see if anybody has looked at

02:18:02.680 LDN in any of the neuroinflammation stuff. We see the relationship between herpes simplex virus

02:18:08.440 and Alzheimer's disease, between shingles, especially ocular variants of it and Alzheimer's

02:18:15.760 disease. We know that there is some relationship between inflammation and this disease. And we know

02:18:20.580 that that's obviously not all paths cross through that. There are lipid-mediated paths, metabolic paths,

02:18:26.980 vascular paths. I think it would be very difficult to make the case there's not an inflammatory path

02:18:31.580 towards that condition. And so interesting to think about.

02:18:34.140 It is. And I need you to, just as ideally a good scientist, tell you that not everybody buys in

02:18:40.140 to the microglial model that I'm describing. There are friends and colleagues at Michigan,

02:18:45.500 Dan Claw, brilliant, brilliant guy who is very much in disagreement with me, who believes that even at

02:18:51.480 these low doses, you are antagonizing the opodergic system and in essence, kind of resetting it

02:18:57.200 in these chronic pain states so that you're normalizing the endogenous tone. And you know

02:19:02.800 what? That's the fun thing about science and why we try to keep our egos out of it. The truth will

02:19:07.280 come forward.

02:19:08.960 What's the evidence for the inhibition of the toll-like receptor? Is that in vitro?

02:19:12.840 Yeah, it is in vitro. Linda Watkins, Mark Hutchin did some really nice work in that and showed

02:19:18.020 people have had some difficulty in replicating it. But I have a hard time. We know the mechanism,

02:19:24.340 I think, seems pretty solid. But when I look at the clinical conditions that it has been applied

02:19:29.980 to and shown benefit, I mentioned multiple sclerosis, ulcerative colitis, I believe is

02:19:35.160 another one, and these weird neurodegenerative things. I have a hard time understanding why

02:19:42.400 mild antagonism of opioids is going to have an impact on those conditions.

02:19:48.420 Why do you think you see? I mean, that's an interesting one.

02:19:51.020 Well, it's another one of these weird degenerative-

02:19:55.660 Through a central effect?

02:19:57.940 Yeah.

02:19:58.560 Hmm.

02:19:58.980 Yeah, I don't have a good answer for you on that. I'm just spouting off some of the

02:20:02.560 headline in the studies that I've read where it's been used. I will have to go and look

02:20:07.000 just for kicks when I get back to the hotel room and just see about the whole mild cognitive

02:20:11.720 impairment, Alzheimer's aspects of it. I clearly don't treat these patients, but it is an intriguing

02:20:16.720 idea, isn't it?

02:20:17.620 Yeah. So when we met 25 years ago, how big was the department at Stanford in pain?

02:20:24.300 About 10 to 12 people in it. This is all the physicians and nurses, the trainees. It was

02:20:29.260 tiny, tiny, tiny, and we were in this small little clinic.

02:20:32.820 And today?

02:20:33.420 Probably 130, 150. We have a factor of 10 or more. And we've grown to be, I think, the

02:20:40.720 largest academic pain center west of the Mississippi. One of the top in NIH fund. It's really come

02:20:47.100 a long way. It's been really exciting to see the growth and the careers and the people we've

02:20:52.100 helped out.

02:20:52.900 I'll finish the story of how we met. So I'm in this state of total hell. In addition to

02:20:58.420 all the stuff I mentioned about this incredible pain, I couldn't even stand up. Literally couldn't

02:21:03.920 stand. And if I did, I had to be hunched over. And so at the time, I was dating an anesthesiology

02:21:11.440 resident. And she was the one that said, hey, we just need to get you in this pain clinic. We got 0.73

02:21:17.060 to break some stuff. This is going nowhere. You're circling the drain here, kid. I think she was in her

02:21:21.780 last year of anesthesiology. So I think she was doing a rotation through pain, maybe. That's probably

02:21:25.640 how she weaseled me in there. So I come and see you in clinic. By the way, at this point,

02:21:30.660 my mom had flown down from Toronto to take care of me. It's not like I could drive or do anything.

02:21:35.380 So my mom drives me into the hospital. Come in and see you. You hear the story. We'd ruled out

02:21:40.780 anything that required any more surgical intervention. In other words, I'd undergone

02:21:45.360 another MRI. I'd had a flexion extension film. I wasn't surgically unstable. And in fact,

02:21:52.100 where the original injury was didn't even seem to be what was driving the pain now.

02:21:56.620 So you said, look, the first thing we're going to do is we're going to give you

02:21:59.060 an IV lidocaine drip to see if we can just calm these sodium channels down.

02:22:05.480 Did it do anything?

02:22:06.220 So you said, well, how much do you weigh? I said, I weigh 80 kilos. You said, okay,

02:22:09.700 we're going to give you 400 milligrams of lidocaine intravenously. And I said,

02:22:14.180 Dr. Mackey, I just took my boards a year ago. That's a toxic dose. You said, don't worry,

02:22:19.200 we're going to do it in a cardiac monitored room. You will be on an EKG and we will be able to

02:22:24.020 defibrillate you if you have an arrhythmia. So I said, go for it. So in 20 minutes, I got 400

02:22:29.960 milligrams of lidocaine. Didn't touch the pain. Tried something else. Didn't touch the pain. By now,

02:22:35.240 it was eight o'clock at night. Oh, wow. And you said, okay, the only thing left to do at this point

02:22:41.120 is to go in there and do a series of injections at every single facet joint, every single

02:22:48.720 dorsal root, every nerve root, every dorsal root ganglia, the entire length of your spine.

02:22:54.300 I will not be able to diagnose what is wrong because I'm basically going to stop all the pain,

02:23:00.400 but then we will chip away at this over the coming months. And I said, great. Can we do it now? You

02:23:05.580 said, no, it's eight o'clock at night. We don't have an anesthesiologist. I'm the only one here.

02:23:09.300 I said, you're an anesthesiologist. You said, yes, but I'm the one that's doing the procedure.

02:23:13.480 So I said, well, why can't we do that? And then you said, well,

02:23:15.940 we won't be able to give you any sedation. And I'm about to stick 45 needles in your back. 0.99

02:23:20.460 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 0.93

02:23:26.740 proceeded to put, I think, hydrocortisone, bupivacaine, and you lit me up, up and down the

02:23:34.020 back. And two hours later, I stood up for the first time in three months. I was completely pain-free.

02:23:42.760 This was remarkable. So we get home, it's midnight. I say to my mom, I'm not going to bed.

02:23:49.100 I'm going to go for a walk because like I hadn't walked in three months. And you know,

02:23:54.580 the campus loop of Stanford? Yes. Yeah.

02:23:57.300 I walked it until the morning. It's a four mile loop.

02:24:01.120 I just walked around and around and around till nine o'clock in the morning, came back home,

02:24:06.920 went on to develop plantar fasciitis because when you don't walk for three months and then you don't

02:24:11.180 stop walking, but put that aside. And you told me, look, you're going to probably feel okay for a

02:24:16.500 few days and then the pain is going to come back. Well, it actually turned out to be two weeks that

02:24:20.020 I was pain-free and then the pain came back. And over the next three or four months, you repeated

02:24:27.820 comparable procedures, but with more and more precision, i.e. narrowing in at what the problem

02:24:33.820 was. And if my memory serves me correctly, it was mostly in the T12 L1 area. And I think the

02:24:39.980 ultimate diagnosis was, look, you lost so much disc space at L5 S1 through the multiple surgeries.

02:24:46.380 If you look at my MRI today, I basically don't have a disc at L5 S1 that you've now developed this

02:24:51.980 facet arthropathy that far up. And that's where those nerve roots are going into kidneys and testes. 0.96

02:24:58.260 But what was amazing was these injections allowed me to go and do rehab, which I took on like a

02:25:07.160 vengeance and basically rebuilt the strength in the musculature of my back. And so within nine months,

02:25:15.380 nine months of meeting you, a year of the injury, I was functional. Within two years, I could get to

02:25:22.640 the point where I forgot about it for days at a time. I'll give you an example. I could actually sneeze

02:25:27.380 without bracing. That was something I couldn't do. For a year, I couldn't lean over the sink to brush

02:25:33.260 my teeth. That's how weak I'd become. Just the moment arm of your torso leaning over, I couldn't

02:25:37.800 do that. I had to fully brace and support myself to just brush my teeth. So you asked, what was the

02:25:44.140 lasting impact of that? Well, and I've told this story many times, and of course my kids know it well.

02:25:48.740 One of the lasting impacts was my absolute love for parking as far as possible from wherever I'm going.

02:25:55.420 Because when I was going through this, they wanted to give me a wheelchair parking thing.

02:25:59.720 And I was like, I don't want it. Just a psychological thing. I was like, I don't want it.

02:26:03.260 I don't care how far I have to walk. And so now my kids know you celebrate your legs by parking far.

02:26:09.780 And in many ways that became part of this idea, this thesis I had of this centenary and decathlon,

02:26:15.140 this idea of like, what are you training for? You're training for life. Life is your sport. And that can

02:26:20.400 be something as mundane as being able to walk to the grocery store if there's no spot near where you

02:26:25.040 need to go. And can you push the cart to the car and all that kind of stuff? So the net net for me

02:26:29.840 is it has been incredibly positive. Again, I'm incredibly grateful, Sean, to you. Because again,

02:26:35.820 had I not been at Stanford, had I not had that girlfriend who I'll, I won't name her to embarrass

02:26:41.080 her. Although I think she's still on the faculty at Stanford, by the way. I just think there's a lot of

02:26:45.380 ways that story could have gone sideways. So I feel incredibly grateful. And the final part of

02:26:50.280 the gratitude is that I would go on to Hopkins for my residency in an emergency room that serviced

02:26:57.040 some of the most opioid addicted people on the planet. And based on my own experience with that,

02:27:03.840 I can say I always had a sense of humility about what they were going through. I always looked at it

02:27:09.900 as, oh God, I feel your pain. That is awful. And I could have been there, but by the grace. So

02:27:16.580 that's been my experience with it, which is 90% good.

02:27:20.760 That's a great story. I listened to that. And in one hand, I remember it. And another hand,

02:27:27.680 it's been so many years.

02:27:28.740 Yeah. It's one of a million stories.

02:27:30.300 You could have been talking about Bob as the doc. And I'm listening to this and I'm like, well,

02:27:36.400 yeah, that is the kind of thing I would have done late at night and just try to get it under control.

02:27:43.620 Put the fire out.

02:27:44.260 Yeah.

02:27:44.460 Just spray the hose. 0.99

02:27:45.500 Yeah. Because normally, to be clear to the audience, I would never approach that in a chronic

02:27:51.300 situation like that. It lacks all specificity. You can't learn anything from it. But I remember

02:27:58.260 you just being an extremist and we had to do something to help you.

02:28:04.000 So let me ask you a question, Sean, how common or uncommon is my story? Because when you meet

02:28:10.660 a person like me, is there a part of you that thinks we're never going to fix this guy? Like

02:28:14.660 this guy's life is over. He's on 320 milligrams of Oxy, hasn't walked in months. He's in so much

02:28:21.560 pain. The lethal dose of lidocaine did nothing. Is there a part of you that thinks this is a

02:28:26.820 chronic pain patient? This is a guy who's going to be in chronic pain the rest of his life. Or do

02:28:29.580 you look at a guy like that and say, no, no, we can fix this?

02:28:32.160 What I usually look at, I usually think of it is, I'm confident we can really help them.

02:28:38.400 I don't know what help means. Curing is such a strong word. Every once in a while, we can cure,

02:28:46.200 just eliminate, make it go away, never comes back.

02:28:48.960 Like my case.

02:28:50.020 Like your case, which honestly, I didn't even know about until recently.

02:28:55.180 I was lost to follow-up.

02:28:56.800 Lost to follow-up. I'll tell you maybe in just a little bit like how I did find out.

02:29:00.960 I don't use the word cure, maybe like a surgeon would use the word because I don't want to set

02:29:07.620 unrealistic expectations with patients. But I don't give up. I've never hit a point in my career

02:29:14.240 with a patient where I've ever said, we're done.

02:29:17.480 I got nothing.

02:29:18.300 I got nothing. We've got so many tools available to us now. Back when we first met, we had a handful

02:29:27.420 of procedures. We had a handful of medications, gabapentin, the new kid on the block, opioids,

02:29:32.260 NSAIDs, some tricyclics. But that was about it. And by the way, that also, that notion contributed

02:29:37.360 to the opioid crisis because we didn't have tools. Now, there's over 200 medications that have shown

02:29:43.500 to have analgesic properties. We have over 200 procedures that we do for pain, scores of mind-body

02:29:49.840 therapies, scores of complementary alternative therapies, and physical and rehabilitative

02:29:55.640 approaches. The toolbox that we can draw upon is so much larger. Often, the problem is not with all

02:30:01.720 the tools we have. It's trying to figure out the right tool for the right patient, the right context.

02:30:06.220 I frequently focus on getting people back to a good quality of life and giving them control

02:30:13.320 of their life and their pain, rather than a promise to eliminate pain. In the acute setting,

02:30:20.000 often it's eliminating pain because in an acute perioperative or acute injury situation,

02:30:24.480 you need to eliminate or significantly reduce it before you can get people moving,

02:30:28.920 which was kind of in your case.

02:30:30.980 I got to tell you, I was tempted. My memory of this was a little vague. I almost, for a moment,

02:30:35.800 I thought, maybe I just look up my records on Epic and just see what's what. I'm like,

02:30:40.860 no, man, that's what gets you fired. And so I didn't. I'm glad you filled in the memory gaps.

02:30:46.660 I'm literally just so happy for you. Can I ask you some questions about it all?

02:30:51.920 Sure.

02:30:52.320 Maybe build on some of the things we've been talking about. So some of the stuff that's going on

02:30:56.920 when you were in this is you were in distress. Clearly, there was a lot of catastrophizing going on,

02:31:04.840 if I can draw upon that term. You cut me off if I'm going off in tangents.

02:31:09.940 Catastrophizing is this concept that was introduced by Albert Ellis in 1962. He was a psychologist,

02:31:15.680 and he also liked neologisms. So he created catastrophizing. He created the word awfulizing.

02:31:22.840 Awfulizing didn't stick around. Catastrophizing was not related to pain, but got used for pain,

02:31:28.440 has three factors to it. Amplification of pain, rumination or repetitive thoughts about pain,

02:31:34.020 and a sense of helplessness or loss of control over your pain.

02:31:38.260 Check, check, check.

02:31:39.280 It's natural. We got a lot of controversy in the field on this term because it has such a pejorative

02:31:44.920 impact. And unfortunately, some of the docs have weaponized it against patient. Oh,

02:31:49.120 you're a catastrophizer. Tragic. But it has real neurobiologic consequences because when people 0.99

02:31:54.880 catastrophize, when they have a loss of self-control, when they have rumination, it negatively impacts

02:32:02.180 these prefrontal cortical circuits that I mentioned, these cognitive systems so that they

02:32:07.920 can no longer downregulate your pain. They have abnormal connections to hypothalamic regions,

02:32:14.820 which are key in hypothalamic pituitary adrenal axis, your HPA axis, which I know you're very familiar

02:32:20.940 with. And so in an acute situation, you get a release of cortisol for stress response. You know,

02:32:26.700 this is a surgeon. It's great. It keeps us alive chronically. Terrible. And so you get this allostatic

02:32:34.000 overload and it starts to thin out that brain region. You're no longer able to modulate.

02:32:41.480 And it's this worsening cycle that you get deeper and deeper in. A lot of what we do in pain is we try

02:32:48.120 to break those cycles. And it's not one thing. I use the interventions, the procedures to help

02:32:54.280 break an immediate cycle to get you on a path. We do this with other patients similarly. And then

02:33:00.400 it's learning skills. That's the very important point that I think shouldn't be lost on this.

02:33:05.140 Breaking the cycle isn't the cure. It sets you up to go after the cure. I mean, I had to go through

02:33:12.500 two hours a day of rehab for six months. Yeah. Wow.

02:33:18.660 I mean, I had to learn how to move again correctly. I had to strengthen the muscles that were going to

02:33:25.840 make up for doing what my spine would no longer do, but you couldn't do that if you were in pain.

02:33:31.940 So you had to learn to do that and you had to be at least pain-free enough to do it, but not push

02:33:37.840 yourself too hard that you would reactivate the injury. Like there was a balancing act and you'd

02:33:42.780 be able to sleep all these things. And you had to be able to clear your mind and get out of that

02:33:47.240 catastrophizing loop. Yeah, that's exactly it. And you had the resources to do this. I was reflecting

02:33:52.940 in your book in the early chapter, you described a friend's mother, I think Sophie, and you told the

02:33:59.820 story and maybe it was in the original version of it. It got trimmed out and edited. But when I read

02:34:05.240 that story of this woman who shoulder injury and then went down this bad path, can't golf, can't 1.00

02:34:12.140 garden, can't do anything. And it doesn't get mentioned in the book. Again, may have been left

02:34:17.400 out of the editorial, but all I'm thinking of is pain. All I'm thinking of is this poor woman probably 1.00

02:34:22.540 had severe, severe pain that was untreated and it put her down a spiraling path. And what happens in

02:34:29.080 these situations? Well, one of the things we're learning more and more is social functioning. So

02:34:36.740 we call pain a biopsychosocial model, but we tend to skip over the social, small s. But it turns out

02:34:43.740 we've done a lot of data analysis on our own patients. Social isolation, social functioning

02:34:48.620 plays a key role in your overall pain and quality of life. And you talk about this in your book from a

02:34:53.700 social functioning standpoint. My guess is she invariably withdrew. She became deconditioned. She may

02:34:59.260 very well had a lot of fear avoidance around moving her shoulder, which sets you up on a worsening 1.00

02:35:05.120 spiral. And what I think about, and when I think of Sophie, and I think about people as they get older,

02:35:12.200 we need to manage your sleep. We need to manage all the things you put beautifully in your book.

02:35:17.180 But I think we also need to help them better manage their pain so that they can have the

02:35:23.700 function and do all the things that you say so nicely in your book. I don't know what your

02:35:28.540 thoughts are. Actually, I was going to say that I was somewhere recently where I was asked to define

02:35:34.120 healthspan. And healthspan is squishy to define because there's like a medical definition that I've

02:35:39.220 repeatedly said I think is insufficient. So the medical definition of healthspan is the period of

02:35:43.400 time in which you're free of disability and disease. So not very helpful. And I prefer a more

02:35:48.160 functional version of healthspan. And unfortunately, it's too long for me to rattle off. But one of the

02:35:53.140 lines is freedom from pain. Just as it's important to have strength, stability, aerobic efficiency,

02:36:00.800 peak aerobic output, explosiveness. I mean, all of these things are going to reduce as you age,

02:36:06.480 but the longer you preserve them, the better. One of them is freedom from pain.

02:36:09.980 Yeah. Yeah. The data on elderly people who get a hip fracture spiral immediately downhill to death.

02:36:18.420 Yeah. The listeners of this podcast are not strangers to those statistics.

02:36:21.620 I'm sorry if I'm repeating things. No, no, no, no, no. But that particular one,

02:36:24.820 it's so tragic. Yeah. And I just keep thinking if we could better help get their pain under control

02:36:29.940 and address them from that holistic standpoint and just get them back to a level of functioning,

02:36:35.740 would this story be written differently? I'd like to believe it would. I hope it will.

02:36:39.920 When you went through all of this, you get through the rehab. Did you feel a greater

02:36:45.060 one understanding of your pain, what was causing it and the nature of your back and what you could do

02:36:53.440 and its safety? Yeah. And it's actually been yet another benefit of this experience is the ability

02:37:00.040 I now have to help my patients. If you just look at the population and understand the ubiquity and

02:37:05.960 frequency of lower back pain and you realize, I don't remember the numbers, but let's say a third

02:37:11.040 of people are going to go through some bout of lower back pain in their life. A number of my

02:37:15.340 patients have also been in the loop of chronic lower back pain. For these patients, one of the most

02:37:20.960 powerful messages I can deliver to them is learning that a setback is not permanent. So part of the

02:37:29.580 journey, because remember, it's not like in the nine months after this injury got better, I never had

02:37:36.520 another setback. No, within that period of time, I would have days where I felt bad again. Now,

02:37:42.180 fortunately, I never went back to laying on the floor for days. I never experienced that level of

02:37:47.700 discomfort again. But there were many days when I was very uncomfortable and it would wax and wane.

02:37:54.900 But over time and with every time that I would recover from one of those cycles, my confidence would

02:38:00.620 go up. The ability to know that this is going to pass and I'm going to have to make some adjustments

02:38:06.640 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

02:38:11.420 to do these exercises a little bit more, that's okay. This will pass. And so I actually just got

02:38:16.540 an email from a former patient. He's not even my patient anymore. And he said to me, hey, Peter,

02:38:20.500 just want to let you know, man, I have never forgotten what you said about this. And I just had a big

02:38:26.240 setback last week and this would have normally taken me down the spiral to hell. And I hear your

02:38:33.680 words telling me, it's okay. This will pass. And he's like, you know what? It's a week later. I'm

02:38:39.900 already on the mend. So there's no difference. It's not impacting physiology. It's impacting the

02:38:45.600 psychology and the psychology is what goes on to impact the physiology. So again, I think of that as

02:38:51.360 I tell patients, this is not going to be a monotonic improvement. It's going to look more

02:38:57.180 like the S&P 500, where if you step back 30 years, yes, it's monotonically going up. Look at it for a

02:39:03.820 given week. Not at all. It can go down. It's quite volatile. Now the volatility will decrease over time,

02:39:10.320 but it never goes to zero. Yeah, that's a great story. And it's helped you be a better doc

02:39:15.580 and help people. I listened to your story and everybody's story obviously is very different

02:39:21.920 and personal. I have my own variant of this and I don't talk about this much because I tend to be

02:39:28.000 a little private with these things. I suffer from cluster headaches and all my life, as far as I can

02:39:33.740 remember, I would get these headaches. It was like a bomb going off in my brain. How often?

02:39:39.160 Every two years, every two to three years. It's a classic fall spring cycle. And all through my

02:39:47.700 teens, my early adulthood, I'd get these two weeks being just terrible. The most insane pain I've ever

02:39:54.520 had. I've broken a lot of bones in sports, nothing trivial compared to that. And nothing I would do

02:40:00.740 would work. I'd occasionally go to the emergency department and they'd say it's a sinus headache and

02:40:05.520 they give me antihistamines and they'd prescribe them. And sure enough, they worked.

02:40:09.160 Because it always went away in a couple of weeks. I remember in residency, getting one of these in

02:40:14.300 the midst of a cardiac anesthesia rotation and barely able to get the patient to the recovery

02:40:20.700 room. And I just went into a call room and I just hung out. The thing is, nobody knew what they were.

02:40:26.000 I didn't know what they were, but I was scared. Every time these came on, I thought I had a brain

02:40:29.620 tumor. I was convinced. I thought this was going to kill me. And you get really scared that it's never

02:40:35.480 going away. I catastrophized. After the end of like a couple of weeks, I'm like, what the hell

02:40:41.360 am I going to do? I can't work like this. I can't live like this. Then I become a pain doc. And I'm

02:40:47.180 like, well, shit, I got cluster headaches. How are they treated now? 0.99

02:40:51.120 First of all, just to let people know what a cluster headache is, it typically manifests as

02:40:56.540 headaches that last anywhere from upwards of a couple hours. They can occur eight times a day to

02:41:04.120 every other day. They tend to have these weird characteristics. They're under a class of

02:41:10.360 trigeminal autonomic cephalages. Fancy term for simply meaning that you get eye tearing, redness in your eye.

02:41:16.900 I get what I refer to as a sticky eye sensation, like my eyelid gets heavy and it droops. I get my

02:41:22.700 nasal congestion. But one of the major characteristics is extreme agitation, extreme agitation. Meaning

02:41:30.460 Beth would say, well, you better to lie down. I'm like, no, it doesn't matter. And I just pace. You pace

02:41:35.820 and you pace and you pace until it goes away. So what I did in the period of all this fear, I learned every

02:41:42.480 damn thing I can learn about cluster headaches. Every single thing.

02:41:47.160 How many people get these? What percentage of the population?

02:41:49.640 It's under a rare condition. It's one of those rare ones that affects men more than women,

02:41:53.480 but women do get them. You'd think I would know the prevalence of this too. 1.00

02:41:56.520 But less prevalent than migraines?

02:41:58.060 Yeah. Yeah. Less prevalent than migraines. Common treatments for these, there's abortive and there

02:42:03.400 is preventative. What the preventative are like, calcium channel blockers that you can take.

02:42:09.900 Abortive is the typical migraine medications, the triptans. So I have stockpiles of triptans.

02:42:16.900 High flow oxygen. So I knew I was getting one. Before these happen, I get this prodromal phase

02:42:22.720 with weird appetite. Sleep gets disrupted, I know, and a sticky eye sensation. I was giving a talk at

02:42:27.940 the Napa pain conference and I knew they were coming on. So I threw a tank of oxygen in the back

02:42:32.300 of the car and showed up.

02:42:33.060 And that'll rescue it now?

02:42:34.020 If I can get it in time, if you can abort these things in time, you can save yourself several

02:42:39.940 hours of absolute agony and you can catch it in like a half an hour. So the long and the short of

02:42:47.080 it is, it was through that journey of learning that I became informed and I developed self-efficacy.

02:42:54.740 So when I got these attacks, when I knew what they were, I no longer had a huge amount of fear

02:43:00.320 that would further amplify things. I was fearful it was a brain tumor. I was fearful like I was

02:43:06.240 having a subarachnoid bleed. I knew what it was. It didn't change the sensory dimensions of the pain.

02:43:12.460 It didn't change the agitation. But I knew even if I didn't catch it, it was going away in a couple

02:43:16.940 hours. And that gives you control. So when these happen, I know I'm prepared. I know it's going to be

02:43:24.560 a shitty two weeks and I buckle up, but I know how to deal with it. I know I'll come out of it.

02:43:31.060 And it makes a huge difference in quality of life. And that's what I messages I would try to give

02:43:36.480 patients is it's about learning as much as you can about your condition, being informed and putting

02:43:45.420 that to use and ideally giving yourself a degree of self-efficacy over your health. And when I listened

02:43:52.540 to your story, it had parallels there. That journey that you have, you've clearly used it and maybe

02:43:59.000 tried to say, make you a better person. And yeah, I have a lot of empathy for people as a consequence.

02:44:04.800 Well, Sean, this has been a great discussion. I think we're certainly better off today as a species

02:44:09.200 having a medical discipline that is devoted to pain. We have the luxury of caring about this now.

02:44:15.860 There was a time when just not dying was the highest priority. And now it's,

02:44:20.440 we need more than that. It's not just that we don't want to die. It's that we want to be able

02:44:23.980 to live pain-free, not to be confused with discomfort-free. I'm still a big proponent

02:44:28.700 of discomfort as I'm sure are you. We should be out there working out hard, experiencing discomfort,

02:44:33.400 but chronic pain can be inflammatory to the psyche. And it's not something I would wish on

02:44:38.760 anybody. So it's great to know that since my time as a patient there, that department has increased

02:44:44.040 log fold. And I hope that's true and trust that it's true around the country. So thanks for

02:44:48.620 the work you're doing. Thank you, Peter. It's been 20 some odd years since we've seen each other.

02:44:53.660 And if I can just say, I remember when I saw you, you were kind of an intense guy.

02:44:59.460 I've mellowed.

02:45:00.260 Have you?

02:45:00.860 I've mellowed since then.

02:45:02.840 I remember thinking to myself, this guy is either going to crash and burn or he's going to do something

02:45:08.540 really awesome. And then decades go by and I get this phone call from Ian and he's like,

02:45:14.280 dad, Peter just gave you a shout out on one of his podcasts about how you helped him. And he's

02:45:20.160 like, how do you feel about that? And I said, I'm just so happy for him. I had no idea that he's

02:45:27.580 done so well for himself. And you have, yes, you're seeing one patient at a time and providing great

02:45:32.240 care. But I think this format is reaching so many people. And this is what we need more of. We need

02:45:36.760 more Peter Atiyas. We need you delivering these messages that are empowering people. You're making a

02:45:41.920 big impact out there. And I just appreciate you inviting me on to spend some time with you. So

02:45:45.740 thank you.

02:45:46.540 Thanks, Sean.

02:45:47.760 Thank you for listening to this week's episode of The Drive. Head over to peteratiyamd.com

02:45:53.920 forward slash show notes. If you want to dig deeper into this episode, you can also find me on YouTube,

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02:46:40.480 and they should seek the assistance of their healthcare professionals for any such conditions.

02:46:45.260 Finally, I take all conflicts of interest very seriously. For all of my disclosures and the companies

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02:46:58.340 and active list of all disclosures.

02:47:04.660 Thank you.

The Peter Attia Drive - April 21, 2025

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

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