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

Hey everyone. Welcome to the Drive Podcast. I'm your host, Peter Attia. This podcast, my website and my weekly newsletter all focus on the goal of translating the science of longevity into something accessible for everyone. Our goal is to provide the best content in health and wellness and we've established a great team of analysts to make this happen. It is extremely important, important to me to provide all of this content without relying on paid ads to do this. Our work is made entirely possible by our members and in return we offer exclusive member only content and benefits above and beyond what is available for free. If you want to take your knowledge of this space to the next level, it's our goal to ensure members get back much more than the price of a subscription. If you want to learn more about the benefits of our premium membership, head over to peterattiamd.com subscribe I guess this week is Dr. Sean Mackey. Sean is a Professor of Pain medicine at Stanford University. He also serves as the Director of the Stanford Systems Neuroscience and Pain Lab. His research focuses on the neural mechanisms of pain and the development of innovative treatments for chronic pain conditions. In this episode I talk a little bit about how Sean and I go way back and why it is that I really wanted to have Shawn on this episode. In this episode we discuss the definition of pain as both a sensory and an emotional experience and why it's fundamental as a survival mechanism and the evolutionary purpose of pain, which obviously has been highly conserved across multiple species. We talk about how pain is transmitted through the nervous system, including the different types of fibers that are involved. Talk about the different types of pain such as nociceptive pain, visceral pain, neuropathic pain, et cetera. We talk about why pain perception varies so widely from person to person, even in the face of an identical stimulus, how psychological and emotional factors play a role into this. Talk about various approaches to pain management, including NSAIDs, opioids and anti neuropathic medications. We talk about the effectiveness of neuromodulation techniques like tens and how sleep deprivation affects pain sensitivity, as well as why chronic pain often leads to disrupted sleep cycles. We talk about this and many other things. Again, I share a very personal experience with my own pain and how Sean came to my rescue 25 years ago. So without further delay, please enjoy my conversation with Dr. Sean Mackey. Sean, thank you so much for making the trip to Austin.

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

Yeah, I was thinking about it. So this morning my wife said, oh, what's the topic of the podcast today. And I said, it's going to be pain. And I said. She said, oh, who you have. And I said, shawn Mackey. She goes, her face lit up and she doesn't know you. She's never met you, but she knows your name because she's heard me tell a story. She's heard me tell a story about my own experience through this. I then realized something, which is I haven't seen you since I was in medical school, which is kind of weird. Yeah. So I'm sure we will get to how you And I met 25 years ago. Exactly 25 years ago.

Wow.

And how you played an unbelievable role in bringing me back from arguably the brink of what could have been the end of my life, truthfully. But I want to start with some broader topics around pain. So there's nobody listening to us right now who doesn't know what pain is. There's nobody listening to us right now who hasn't experienced pain yet. If you ask for a definition of pain, I think you'd get a lot of using the word to describe the thing, which isn't truly a definition. So if you were trying to explain to a Martian from another planet who doesn't experience pain what it is, what would you say?

There's the formal definition of pain, which is defined as an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage. It's a mouthful if you think of it as it's an unpleasant sensory and emotional experience. It's usually tied to something physically happening, but may not be. I think sometimes what's missing in that definition, one of the things I wish they had put in but never did, is that pain is the great motivator. Pain is one of the most primitive experiences going back to, if you will, single cell organisms. It's either pain or reward. You're either being driven towards oxygen, food, sex, or you're trying to get away from danger. Pain is so wonderful because it's so terrible. It keeps us alive without pain. You know, when we have these, as you know, genetic issues of congenital insensitivity to pain, we would have never lived as a species. So pain is an unpleasant sensory and emotional experience. To understand pain, whether you're a Martian or you're a human now, I think you have to look back in history. And so I'm going to evoke Rene Descartes, 17th century French philosopher, thought to be the father of modern philosophy. Incredible contributions brought Cartesian geometry to us, which led to Calculus. And he had this dualistic model of pain that he put forward to his credit. It was the first mechanistic foundation for pain, because beforehand pain was thought to be something mystical or religious. It was punishment of the gods. So he put this framework together that's often illustrated. This famous picture of a little boy with his foot in the fire. And there's a little string from his foot going up into his brain, and it ends up in the pineal gland, which was thought to be uniquely a human area. And the idea is the fire pulls on the little string, opens up pores in the pineal gland, rings a bell, and the boy withdraws his foot. The idea is, in this dualistic model, there is a complete separation between body and mind. The body is where pain is generated, the mind is where it's perceived. But the mind is simply a passive receptacle receiving these signals. That model put forward in the 17th century stuck with us for hundreds and hundreds of years, and I would argue is with us today. And it has influenced medical care, it has influenced policy, it's influenced everything in our society about the way we think about pain, and it's utterly, completely wrong. So, yes, he got Cartesian geometry right, but he really complete bollocks screwed it up when it came to pain. This biomedical model, this dualistic model was with us for hundreds and hundreds and hundreds of years. And it's only been in the last number of decades that we've appreciated the nuance of what pain really is. And instead of it being under this guise of this separate mind and body, we now appreciate it is this integrated biopsychosocial phenomenon, meaning that. And I think this is one of the most important things that I'd like to drive across. I'm going to introduce a term, we're going to get to a term called nociception, which are electrochemical injury signals that occur in the periphery. That what goes on in the body and what goes on in the brain, the experience of pain, they may have nothing to do with each other or very little linkages. And we're going to hopefully unpack that. So hundreds and hundreds of years, we're basing it on Rene Descartes dualistic model. We still see this in medical care right now. You're a surgeon for many, many, many, many years. When I talked with the surgeons, they were firmly of the opinion that the amount of pain that a patient had after surgery was related to how much the scalpel cut and how much tissue damage was done. And I think it's only more in the last 20 or so years, I'm seeing surgeons really embracing this model that what people bring to the operating room table directly influences how much pain they have, their early life experiences, all this stuff. And we'll talk about that.

And, Sean, just to interrupt for a second, thinking through the history of medicine a little bit, the latter part of the 19th century brought a couple of other tools to pain. So between local anesthetics, cocaine, down to lidocaine, and general anesthetics in the form of ether, which finally allowed surgeons to cut people without having to hold them down while they screamed, it sounds like that didn't shed any new light. That was viewed in the one hand as just a blunting instrument, but it didn't change the model.

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

Okay, let's talk about. Is there a pain receptor?

So let's break it down into the foundational stuff. So we have these things called nociceptors. Complicated name. It's basically a transducer, which is another technical name. Now, your engineering background. So you all know that a transducer is simply a device that converts one form of energy into another form of energy. This microphone is converting sound energy into electrical energy. The speakers convert electrical energy back into sound energy. We have these nociceptors that lie in our skin, our soft tissues, our deep tissues, our viscera. And they're specialized. And they convert different forms of energy into electrochemical impulses. They take pressure, they take heat, cold. They take chemical changes in the form of ph that can occur during infection. They convert those into action potentials that are then transmitted up nerves. So these are little electrical impulses transmitting up, generally two different nerve fiber types, these two different nerve fiber types. One is called a C fiber, which is thin and slow. It's really pokey. And I don't know if I'm getting ahead, if you wanted to go more into that, but you got this pokey, slow C fiber that transmits at about 1 meter a second. And the frame of reference, if it helps, is think about your thumb is about a meter from your brain. So an impulse on a C fiber from your thumb to a brain takes about a second to two seconds to get there. The other nerve fiber type is called an a delta fiber. It's got some nice insulation around it. It transmits ten times faster. So it takes a little under a tenth of a second to get your thumb to your brain and to give a real world sense of the difference in C fibers and a delta fibers, Think back to the last time you stepped on a tack in the carpet. You hit your thumb with a hammer, you twisted your ankle coming off a curb. What happened? Think back to that experience. You get this sharp jolt of pain that goes right to your brain. Those are your a delta fibers. At 10 meters a second, Rapidly getting up to your brain, rapidly putting into play systems to protect yourself from harm, you withdraw. You have a reflex that's occurring in your spinal cord. You're not even consciously aware of it. Your brain is setting into play escape mechanisms. The pain that you experience is sharp, it's well localized. You know exactly where you stepped on that tack. Then about a second, two seconds later, you get this hot, burning, flooding sensation come over your thumb when you hit it with a hammer. And you think to yourself, oh, damn, this is really going to hurt. And it gets hot, it gets burning. Those are your C fibers, unmyelinated, slow getting up to your brain. And what you also notice for the first time is you don't like this. This has an unpleasant quality to it that you didn't get as much with that a delta sharp pain, but you're getting with those C fibers. That's really clear.

The A delta is doing two things, if I'm understanding this correctly. Is it creating the spinal reflex where I hit my thumb with the hammer? The signal goes into the spinal cord, out through a motor neuron to pull back without me having to think about it.

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

But am I also feeling the pain? Am I perceiving the pain? If you could do a thought experiment where you could eliminate the C fiber in an individual, Would they still feel pain?

Yes. Yeah, they would still feel pain.

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

Those A delta Fibers are still, they're.

Still going up, going up.

They're in the spinal cord, they cross over to the other side.

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

Indeed.

Okay.

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

Just thinking about this from an evolutionary lens, lots of debate about this in the animal kingdom, like, does a goldfish feel pain? Do we have a clear sense as to how far from humans and or mammals you go where you still clearly have C fibers and A delta fibers?

You could go pretty deep in there. And I get the debate. It's a great debate over wine or beer. And I understand actually taking it seriously and having that debate. Lot of different opinions on this. I actually don't engage in that debate. I think you have to first of all define the thing that you're debating. You have to very clearly define the thing. And in this case, our definition of pain is a rather human experience of pain.

This is where I was actually gonna go. If I can just give you that window, please. What I was really gonna ask is a question about consciousness. Is consciousness necessary for the internalization of this full gamut of pain?

Yes, I believe firmly it is. And I'm a recovering anesthesiologist. I haven't done it now in, oh gosh, 20 years. But when I did it, and when you were operating on a patient, the patient is unconscious, they are not experiencing pain. You need a conscious brain for the experience of pain. Now, what people incorrectly made the leap of is thinking, well, they're not experiencing pain, so everything's okay. That would be a logical fallacy because all those signals are still coming from the body, still hitting the spinal cord and having their impact there. All those injury Signals. Because let's face it, when you do surgery, it's really nothing more than a controlled injury.

Yes. And I just want to point out, and this shows you how long I haven't been in surgery, but 20 years ago, my recollection is an anesthesiologist was giving not just one medication, but several.

Yes.

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

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

But it wasn't enough to give that. The anesthesiologists still had to give, typically a narcotic. They were still typically giving something like fentanyl, even though the patient was unconscious. They were also often giving an amnesiac so that they wouldn't have any recollection of what was going on. But, of course, we all hear the horror stories of the patient. And a paralytic on top of all that. Right?

Exactly. Muscle relaxant.

So you hear these horrible stories of the patient who is paralyzed but somehow conscious. You can miss on this state sort of thing. But just to make sure, I understand, in theory, a paralytic and an inhaled anesthetic should be sufficient to eliminate the perception of pain in a patient who is being cut.

Yeah. Part of the challenge was. And now I'm starting to step outside of my wheelhouse, even though I was a member of the anesthesia tribe for a long time, is the levels of volatile gas anesthetic that you need to necessarily obliterate reflexes. And full nociceptive impulses would be so high that it would depress one's blood pressure. And so you augment that with an opioid, understood, like fentanyl, like morphine, like whatever. And you combine those together. And that's why what the anesthesiologists do is quite magical.

Got it. So in other words, you give the inhaled anesthetic just to get unconsciousness, but not to fully suppress the nociceptic system. Instead, you bring on the opioid to do the remainder of that work.

They're working synergistically, and they're working at different mechanisms.

Got it.

And during that process, the patient is not feeling pain if they're unconscious, because you do need a conscious, working, aware brain to feel pain. But all of the electrical impulses coming in from the body that are slamming into the spinal cord and the brain are open full bore. They're impinging on all those Brain systems responsible for stress responses. And so does that mean we are.

Seeing a cortisol surge? We're seeing whatever one would expect a conscious person to experience with epinephrine, norepinephrine, cortisol, all these things still surging out in response to pain. Yes.

And in response to nociception independent of perception of pain. Right. And you notice that I'm trying to be precise in my language here, because since they're unconscious, there's no pain. But there's plenty of nociception, arguably more.

Than you would ever experience. Think about what we do in surgery. My God, take a scalpel and then take an electrocautery and start burning tissue. I mean, there's no level of nociception you could ever experience like that while being awake, unless you're in a burning car.

Absolutely. That's exactly it. It's remarkable through modern medicine that we get people through all this as a reflection of advancements in surgery, advancements in anesthesiology, advancements in post operative care. But it is no different than a controlled injury. It's done in a nice sterile environment, but it is a massive injury that people are undergoing. They're just not awake. And it's nice and clean and sterile. But there is a stress response associated with that. Most people recover. Well, one of the hot topics of research these days is why do most people recover? But a certain percentage of people go on to have persistent pain after surgery. That's an area that I used to research years ago. Many others are doing some great work in that space. Turns out that a lot of the factors we're going to get to, this is what people bring to your operating room table, meaning early life events, levels of emotional health, cognitive health, and everything else. So to answer your question, and getting back to it, no, I don't believe there is the perception of pain without a conscious brain. There's all sorts of nuances to that.

So let's go back to something you said at the outset from an evolutionary perspective, which is pain and pleasure have been the driving factors that have been the engine of natural selection. But clearly those things have had to work in preconscious models. So that means that whatever we're defining as pain there did not include a perception of pain. So what does that mean?

That's where it gets muddy. And there's smarter people than I that would probably be more articulate. But this is why I think on first principles, you have to define the thing that you're talking about when we typically talk about pain. We're talking about it from a uniquely human standpoint. Does a dog experience pain?

Does a. Easier to accept.

Yeah, easier to accept. I'm a dog person. They experience pain. You move on down the evolutionary. At what point.

Right. Does a goldfish experience.

Does it. Goldfish clearly experiences no susception. They clearly have all the classic withdrawal, protection, survival aspects of it. But what level is there a conscious brain that is translating it? And also on top of it. Remember, in our human definition of pain, we bake in. It's an unpleasant sensory and emotional experience. Does a goldfish experience emotions? I leave that to the goldfish experts. You see how muddy it gets. You go down rabbit holes pretty quickly, which is why I tend to stay with humans, which is mud enough, by the way.

Yeah. So how does everything you just said differ or overlap with neuropathic pain or that sort of burning pain that I'm sure some people are familiar with? Certainly I was familiar with it for several years.

Yeah.

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

So we have different ways of categorizing pain, putting it into different buckets, if you will. One is nociceptive pain. And you'll note that that word nociceptive sounds very similar to nociceptors. And it's by design. It means that it is pain caused by activation of primary nociceptors, whether it be in your skin or soft tissues or viscera. And it tends to have certain qualities. It's very easy to localize. You know exactly where it is, it has a certain intensity. That nociceptive pain tends to be time limited, responds well to short term use of analgesic agents, acetaminophen, NSAIDs, COX2 inhibitors, opioids. And it tends to go away. And this is the kind of pain that occurs after typically acute injuries. You then have visceral pain, which as a former general surgeon, you understood this. This is due to activation of those primary nociceptors in our viscera. Now, the difference in why we bring up the distinction with visceral pain that is either in our thoracic viscera or abdominal or pelvic viscera. Is that the receptive fields. That means where those nociceptors serve and what we perceive are very diffuse and wide. When you get a stomachache, you can't put your finger exactly where it hurts. You tend to put your whole hand over it and say it hurts. Here, it's diffuse. That's because the spinal cord and the brain have these diffuse receptive fields which expand the area. The viscera don't typically respond to the same type of stimuli that nociceptive pain does. You'll remember when you were taking a Bovie to the bowel, the small intestine patients wouldn't normally move because the nociceptors don't respond to that. But if you tug on it, if you pull that or inflate it or inflate it, boy, oh boy, blood pressure goes up, heart rate goes up. Interesting characteristics with visceral pain is there's something called viscero somatic convergence, meaning that the afferents, the information coming in from the gut, from the thorax, converge with the same sensory systems from the rest of our different parts of our body. So you may remember the old medical school adage, C3, 4, 5 keeps the diaphragm alive. Okay, we all had these in med school. Well, that means that the third, fourth and fifth cervical nerve roots subserve our diaphragm, which help us breathe. When the general surgeons or others are operating and they get blood under the diaphragm, it irritates the diaphragm. And what. Patients will typically complain of shoulder pain because the shoulder is subserved by the 4th and 5th cervical areas. And so when they had shoulder pain, the answer wasn't something's wrong with their shoulder, it's they had some irritation of blood under there. It's why when people have a heart attack, pain radiates out into the arm because you've got the upper thoracic nerves subserving the heart that overlap with the nerves that go down your arm. And the nervous system gets confused, and that's how it's expressed. And if you like the neurosciences, it's all pretty cool. If you're experiencing it, not so cool. Let's get to neuropathic pain.

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

Typical analgesics can be helpful, but identifying visceral specific antinociceptive drugs is still an area of hot research these days. It's more about trying to identify the causes of visceral pain and reducing substances that are winding those nociceptors up. Neuropathic pain, another bucket. Neuropathic pain means injury to either the peripheral or the central nervous system, the nerves out. In the body, it's either injury or dysfunction, too. Nerves out in the body or the nervous system, in your spinal cord or in your brain. Classic. You get nerve injury from a trauma, from surgery. Classic qualities people describe. Burning, sharp, lancinating, stabbing shock. Like this is the kind of pain that some people tragically get after a thalamic stroke. In their brain, half their body's just like terrible burning pain. And there's nothing going on out here. It's all central. This is the kind of pain that you get and you experienced with radicular pain. And radicular pain means in this case injury to a nerve root coming out of your spine. It's this sharp radiating pain, if you've got it in your lower back, that radiates down your leg, typically below your knee, into your foot. This can be very challenging to treat with common analgesics we tend to draw upon different categories of medications for this. These are broadly speaking antineuropathic pain drugs. And here in our field we steal from everybody. There's only a few FDA approved medications for pain, like a handful. So what we've learned to do is to steal borrow drugs from the neurologists, their anticonvulsants, their anti seizure medications, the gabapentinoids, the tegretols and their derivatives, their other anti seizure medications because they tend to have mechanisms of action that also work on nerve pain. Gabapentin I think you've had perhaps some experience with. Turns out it's a lousy anti seizure drug. Terrible. But it's a pretty good anti nerve pain drug.

Four grams a day.

Four grams a day.

Drowsy though.

You know who gets credit by the way? I give credit to making gabapentin the blockbuster drug. George Clooney. How you ever watched er? Yeah, he was a pediatric ER doc. Kid comes into the ER with a skateboarding injury. George Clooney puts the kid on gabapentin. Now where that had all started was a case report from a couple of ED docs who had noted by putting people on gabapentin that their acute pain got better. So I felt like beforehand when I was practicing medicine, around the time I saw you practicing pain medicine, that I'd look like a genius if I put somebody on gabapentin because nobody heard of it. And then after that came out, floodgates opened, primary care docs started using it. Now everybody's tried it and it's a very safe medication. I should also make a mention when I'm talking about these meds or any treatments. I have zero industry relations with anybody. Nobody. I don't take Any industry money. You can go look me up on open payments cms, which is a public database. Okay. Neuropathic pain. There's another one. There's a new kid on the block called nociplastic pain. I don't know if this one has made much traction yet. This is a newly introduced category of pain which is thought to represent dysfunction in the central pain processing system. And I'm not precisely defining it, but that's the gist of it. It means that in the absence of an identifiable peripheral cause, there is dysfunction in the brain and the spinal cord that is causing pain, perpetuating and amplifying pain. No C. Plastic pain. And it has been tied in with conditions like fibromyalgia, temporomandibular disorders, some aspects of chronic low back pain, irritable bowel syndrome, interstitial cystitis, and more. It's slowly starting to get traction when we talk about pain, both to study it, but also ideally, to treat it. We put them in these categories that we just described.

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

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

Now, there's no objective way to measure pain, correct?

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

And where do you think we are in that regard?

Much further along than I ever would have predicted. So a large chunk of my research early on, my early research was in neuroimaging and pain. It was opening up windows into the brain to see where people were thinking, processing, perceiving, magnifying pain. And I spent much of that publishing work to understand the mechanisms of that. And we haven't yet actually finished our story of pain going up to the brain and what's going on and we'll get there. Over the years, I migrated into this space of developing objective biomarkers of pain. That's why I love working with young, smart people. I bet against it. I had some young grad students and others who said that they thought they could do this. I told them how you would do it and I said, it won't work and I'm going to pay you, I'm going to give you money to go scan people and you're going to learn how it doesn't work because failure is a great lesson in life. And they came back and they showed they could do it. And it was all through developing patterns in the brain and using machine learning models to then take that pattern, that signature, and be able to predict in other people whether they were experiencing pain. I didn't think we could do that because of the hugely individual nature of pain. It's so different from person to person. But it turns out that there are core patterns in the brain that represent that experience of pain.

Sorry, you're capturing these through what modality?

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

Let's just start with standard understanding. If you put me into an FMRI machine and I said to you, hey guys, I'm not feeling any pain right now, I feel great. And then you scan me. And then someone came out and took a hammer to my thumb and I went through the classic response that you described earlier. What would my FMRI show?

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

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

You would also see it in S1.

You're right.

And indeed, what we've learned through this, that there's no one single pain region in the brain. That's another mistake that was made along the way we all thought we were going to find a brain region, then we can knock it out, right? Just go cut it out. And it turns out that didn't work. It's not one brain region that generates the experience of pain. It is a distributed network. It's all of these regions coming together and working in harmony.

Doing what?

Generating the experience of pain and then generating typically a response to that. Let me be very clear because there was a lot of controversy when we and others initially published our papers. We are not trying to take away the autonomy of the patient and the self report. I don't need an FMRI to see a patient and know if they have pain. I can just ask them. I can use self report measures to get it. That's another part of the research where we're working to build these objective markers. This objectifying pain is not to see what they're in now, but can it give us useful information to predict treatment to a particular therapy? Can we use it to predict their future state? Can we use it to predict their vulnerability to an injury or surgery? Those are things that just asking a patient right now, probably not going to get there. I don't know if you want to go back to the brain.

Yeah. Okay, so let's go back to the story of these four branches of pain, or at least the first three. And then how the sensory component is impacting the perception.

Roll with that. Give me a little bit more. I want to build off it then.

Okay, so we go back to nociceptive pain. So tissue injury occurs. I think where I derailed us was in classifying all the different types of pain. But you had signal comes up, two signals coming up. The C fiber, the A delta fiber. The immediate response is to get you out of pain. There's an evolutionary logic to that. The C fiber is not there to get you out of pain because the A delta did that. Is the C fiber there to remind you not to go back and do that again?

Perfect. Perfect. That is basically your longer term harm alarm. That is saying, peter, don't go back and do that again. Back in the cave people days, it would remind you maybe it's best to sit in the cave and let the healing occur instead of going out and fighting the woolly mammoth or the saber toothed tiger. Because if you fought the saber toothed tiger when you're injured, you got eaten. You didn't get to pass your genes along.

By the way, do we have any evidence, Sean, that there was enough genetic heterogeneity around this that there were 200,000 years ago, there were members of our tribe who simply didn't feel pain and therefore did not pass on their genes because they made poor decisions.

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

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

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

And I also think about certain things. Like childbirth prior to any anesthetic was obviously brutal, both in terms of the pain and the mortality. And yet there's no evidence that people were deciding, yeah, maybe we ought not to do this. In other words, the drive for procreation somehow overcame what must have been brutal.

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

Those are the two things that I joke about with my friends, which is, I still don't really understand how our species is here. For two reasons. One, women had to continually go back to the well, because remember, if your reproductive rate isn't in excess of 2, the species collapse. So on average, every woman must be able to do this. And back then, it had to be a reproductive rate of north of three.

Right.

Every woman had to do this three times. How she did it the second two times after how bad the first was, blows my mind. The second thing is just looking at how stupid adolescent males are, I'm sure you can relate to this.

I was one.

Yes. As was I. And I look at my boys. I don't understand why males all didn't die from just doing stupid, stupid things before the age of 20 or even before the age of like 15. Those two things are a miracle to our species that all the males didn't die and that all the females were willing to have at least three kids.

I repeatedly tell Beth, I'm like, I sometimes wonder why I was not a Darwin Award winner. If you've ever read the book, I.

Remember the Darwin Awards fondly. Yeah. We'll link to them in the show notes, some of my favorites.

So we have these signals. I'm gonna take these signals from the spinal cord. Cause where it gets really interesting is when you take those A delta C fibers, you're in the spinal cord and there's a lot of processing going on there that we'll come back to. And they head up to the brain, and then they synapse connect in a large number of brain regions. One of the main one is the thalamus, which acts like grand central station in the brain. It's taking lots of sensory input from different sources and it's sending it out to other areas. Some of those areas that we alluded to the anterior cingulate cortex. Now, the anterior cingulate cortex, each of these brain regions has some functions associated with it. The anterior cingulate cortex is associated with some of the emotional aspects of pain or the unpleasantness of it for the neuroscientists out there. I'm grossly oversimplifying things. The anterior cingulate cortex is also a salience detector, meaning it is taking those incoming inputs and it's determining, is there something wrong here? Is there an error? Because in essence, our brains are prediction machines. Everything that we're doing, we're forming an expected pattern of what we're going to Sense and we're making adjustments. When I reach out for my cup, I know where it is in space. I pick it up. If instead of cold water in that, it's boiling hot water and I touch it. My brain is getting different signals than it was expecting. That cingulate cortex as a salience detector is triggering and it's putting into action for me to withdraw. Other areas of the brain include the insular cortex, which lies on this little bit of the outer edge. It can be subdivided into multiple components. The posterior, mid and anterior insula. Let's just say that the back part of it is taking direct information in from the body. But then as you get more and more towards the front of the insula, it's integrating emotional and cognitive nuance to it. It is integrating in your emotional state and what you're thinking. Now there's also connections with your amygdala, this deep primitive region of the brain involved with both threat detection as well as reward. And it's connected into the circuit and then also has outlays into other areas that maybe we'll get to, like the hippocampus and the stress response and onward. All that to say is all these regions connected together generate that experience of pain. And at this point in time, I really haven't done more than Rene Descartes has in telling this story, because first pass, the brain is still remaining a passive receptacle, just taking these inputs. Where it gets interesting is we developed descending control systems that come down from the brain that converge in the spinal cord. And what they serve to do is turn down the signals that are heading up. Now, in part, this was first described by Ron Melzack and Patrick Wall in, I think it was 1965, the gate control theory of pain. Brilliant, guys. Never had the pleasure of meeting them, but they just did seminal work. And this gate control theory of pain posits that yes, you have afferent information coming in to the spinal cord, but the spinal cord is acting like a gate of opening and closing, turning up, turning down pain. And it is altered by other fibers and systems from your brain. So let me give you an example to this. Let's introduce another nerve fiber, type A beta. A beta fibers are your touch fibers when you touch or stroke your skin. Those get activated when you stand up and you stand on one leg. They're also responsible for position sense. They have a heavy coat of insulation around them and they are wicked fast. C fibers, 1 meter a second, a delta fibers, 10 a beta fibers, 100 meters a second fast. That's why you can dance, that's why you can walk, because you've got those fast reacting A beta fibers. Now let's go back to your thumb, Peter. You just hit your thumb with a hammer. Sharp jolt of pain goes to your brain. Got a little delay. Oh, damn. This is really going to hurt. Hot, burning, flooding sensation comes over your thumb. What is the next thing that you do? Everybody does this a little differently.

Before or after swearing.

There you go. A lot of people swear. So it's after swearing, you swear and then shake it.

Shake.

Okay. You're a shaker or squeeze.

Squeeze proximal to it.

Yeah, you go, you squeeze, you shake it. Sometimes you run it underwater. What are you doing when you're squeezing it and shaking it?

Sometimes trying to create a distraction.

Okay.

Sometimes, though, probably illogical, trying to keep whatever humor is in there that's hurting isolated. Like a tourniquet.

Right?

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

Yeah, that's beautiful. And you're talking about longer term things which are all perfect because cold does those things. And also cold, by the way, reduces action potential velocities and firing in those A delta C fibers. But what you're doing most of all when you rub it is you're activating A beta fibers. You're actually not influencing much. Your A delta or C fibers, those nociceptive fibers, you're not really impacting it there.

That horse left the barn.

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

Yep.

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

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

In short, yes. I would just build on that. That I would say my job, our job as pain docs is to help reduce the pain and help them down a path of functional rehabilitation. So absent that second piece, I typically fail. I'm leading them down a road of functional rehabilitation which involves physical, psychological, social, emotional health. All things you talked about beautifully in your book.

So who is the, I hate to use the word poster child, but who's the patient that when you see them, your intuition says TENS is gonna really work for this person?

Somebody with, I think, more, you know, there's no susceptive musculoskeletal pain. I tend to think of somebody for whom TENS is more likely to work. Something that has more of a classic nociceptive type of pain problem. Beyond that, Peter, it's a trial and error. That's part of the frustration in pain management and in healthcare in general is the lack of a precision approach and the very frustrating, laborious trial and error process until we get something that works. So we talked about the gait control. We talked about tens.

Can I put a bow on the gait control thing to make sure I understood it? Yeah, it seems like a very important idea, but I also think I might be missing the juice. Is the idea that 10 people could experience the exact same peripheral injury. If you could map the action potentials, they would look identical. You could even see identical perceptions. But they could have 10 different gating channels within the spinal cord and therefore perceive pain differently. I just want to make sure I've captured what the gating theory states.

You are right. You're right. With that individual variability and pain, we haven't talked about the brain's role in the gate control, which we're going to get to. But just getting to your question, there's been some elegant studies. A guy named Kim years ago did a beautiful study where he applied a 48 degree Celsius stimulus to 500 people. 48 degrees Celsius, I think it's 121 degrees Fahrenheit. Somebody will look it up and you apply it to the arm, the hand, and then ask, what's your pain score? And what he found was perfect distribution of people who said, nah, this ain't painful, ain't nothing. That's like zero. One out of ten. Some are like, yeah, it's a little painful. Two or three. And others are like, ah, a little more moderate. Four, five, six. And you got all the way up to some people saying, oh my God.

You'Re burning me, you're burning me.

Take that off immediately. 10 out of 10. I do the same thing in a medical school demonstration. Can't call it an experiment because I'm not getting irb. But when I teach the neuroscience class around pain, I bring in a circulating ice water bath. And you want it to circulate because if you just stick your hand and leave it in still, you get a boundary.

It's warmer. Yep.

So circulating ice water bath. And I ask them to dip their arm in for 15 seconds, pull it out, whisper, and our research assistant's ear what their pain score was. We tabulate that all up and at the end of the class I show the medical students and it looks just like that line I showed you. I mentioned to you before. You got some people in the class who say, I could keep my hand in there all day. And there was others who were like, oh my God, I couldn't even keep it in there at all. 10 out of 10. The whole point of that is to drive home one of the key messages in our discussion. The amount of stimulus or nociception may have little to nothing to do with your experience of pain. And why that is so important for healthcare professionals to understand is because for so long, we have projected our own experiences onto everybody else.

So here's another experiment that you won't be able to do unless you get to teach this class on multiple days. But it's to go one step further, which is to do the same thing every day and see how they compare their score from day to day. I'LL tell you my experience with that. I do love to use a cold plunge. So my cold plunge is at 42 degrees with circulating water. So I don't know what that makes it feel like, but it feels like it's somewhere in the 30s. There are days when I can spend 10 minutes in there and feel like nothing is wrong. There are days when I'm not kidding. 30 seconds in, my ankles hurt so bad I want to scream. And I think, what's different? It can't be. The circulation in my ankles is better one day to the next. They're a relatively avascular part of my body. Why is it that one day I can spend 10 minutes and not know I'm in this water? I mean, I know that I'm cold, but it's more like my core temp. But my joints don't hurt. And on another day, the throbbing in my joints feels like somebody's hitting them with a hammer. And I'm the same person. So, in other words, your point is well taken. But I would say there's a second dimension to it, which is even as individuals, we can experience things differently from day to day.

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

Seems to be kind of. I guess I should ask this. I'm not asserting this is the case. Is there kind of a moral judgment that comes to this at some level? Like, don't we as a society just tend to look more favorably at people that have a very high pain tolerance? So when you go through that experiment you just did with the medical students, if everybody's being brutally honest, aren't they kind of looking at the people who score.012 more favorably than those that score 8, 9, and 10?

Absolutely.

Why do you think that is? If I'm being truthful, I do it.

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

Is that a male thing exclusively?

I think you need to get some women on the show and ask them. I think it crosses, actually. I do think there is a masculinity aspect to that, and I think I could be wrong here. I think that that thing is also attractive for women. I think there's a certain attractiveness because that person may be more likely to be a good provider than somebody who is weak and sensitive. But we're getting a little out of my wheelhouse on that. But you're absolutely right.

I just think it's like a compatibility thing. Like, I know when I do that type of an exercise compared to others, I tend to just feel less pain. I also know my wife does as well. And so I almost wonder if that's a compatibility. We both just have a high threshold for that when we're exercising, when we're doing anything, even Recreationally, that doesn't matter.

My fiance, we're now engaged, is a professor at Stanford. Beth Darnell. She's an ex ultra marathon runner. And I've always admired the fact that she can sit there in front of a computer or work on something untold hours and not move. And she's just like, listen, I was really good with running with a pebble in my shoe, putting one foot after another and just working my way through it. And I similarly grew up in an environment where you learn to be tough and you learn to power through life's adversities.

So what is the consequence of this? So we're acknowledging that it is an attractive trait to have a high tolerance of pain. Society rewards it. And yet by definition, a significant subset of the population, call it a third, call it a quarter, if it's a normally distributed function, are going to be a standard deviation on the other side. They're going to be on the side relative to people who have a high tolerance for pain. These are people who are going to really perceive pain. And if we just did this through the lens of the responsibility of the medical community, there's a pretty significant consequence to that.

Indeed. As with all things, it gets a little bit more nuanced. We talked about cold, for instance. It turns out that some of the sensitivities are modality specific.

So just because you have a high threshold for cold, you could completely flip it on hot or pressure or pinprick or whatever. The other modality is somebody who runs a paint lab.

I've had everything done to me imaginable. I take heat really well. My son Ian takes heat really well. I've had thermal devices on me where I've been there and ended up with second degree burns. Define my 7 out of 10. I hate the cold. I hate the cold. I'm a wuss when it comes to the cold. So I live in California, I lived in Arizona. I think there are genetic aspects of this. So we have to be mindful modality specific on top of it. These experimental protocols probably have little bearing on somebody's experience of chronic pain.

I was going to say, is there any way to put together a set of experimental lab versions of this to basically generate predictive models of how people will respond to real world pain? I think where you're going with chronic pain is even more relevant. So, for example, why do some people have a disc herniation that leads to manageable pain, whereas for others, the exact same injury, by every metric available to us, produces a totally different set of consequences? And what do we do about that?

This is now where we move out of that Descardian model. We appreciate the role of the brain and its modulatory capacity, its ability to turn the amplifier down. And so if you're thinking about a stereo amplifier, we talked about how some people to a certain stimulus might be a 0 or a 1 on the dial, some might be a 10. But what we didn't talk about are people's capacity to now manage their pain, cope with their pain, their level of self efficacy around their pain. Athletes learn how to manage their pain and suffering. Where they run into problems is when the sports are over, they're retired, that's when I see them. So there are many factors that predict how well somebody is going to do with chronic pain. They align with a lot of the stuff in your book. So there's the level of a person's self efficacy plays a role. There is the presence or absence of whether they've got underlying depression, anger, anxiety, something called catastrophizing. Terrible word, very important concept. Probably one of the most predictive of amplified pain.

What about other things you talked about? Sleep deprivation, any other physical things? Exercising, not exercising, Insulin resistance, non insulin resistance. What are the other things that might factor into this?

Yes, yes, yes. One of the biggest predictors of diabetic neuropathic pain is glucose control. So one of the first things we do if we have a person with diabetic neuropathy, which is the diabetes, the high blood sugar, as you know much better than I, causes injury to those nociceptive fibers and also causes injury to the A beta inhibitory fibers that correlates with glucose control. By way of example, diet plays a role because if you're eating things that are causing inflammation. We didn't talk about all of the stuff that amplifies or winds up those peripheral nociceptors, we treated those as a static thing. When they're not, they're dynamic. So in the face of inflammation that causes something called peripheral sensitization, you've turned up the amplifier on that nociceptor in the periphery. Sleep. Huge topic.

How much sleep deprivation does one need for there to be an increase in pain perception?

We're both out of residency long enough, but we both pulled our all nighters. How did you feel the next day?

I mean, I felt awful. You felt worse between 5am and 8am and then you get this second wind, usually about the time you're operating. And then you usually feel pretty good. But overall, I mean it's a haze.

It'S A haze, and you're just powering your way through it. And if you think about it, you're kind of feeling a little achy all over. Now, it's not that because of lack of sleep, something has changed in your muscles. I don't think there's good evidence for that. What has changed is your set point in your brain and your spinal cord for the perception of pain. You feel like crap. Now, imagine if you're doing that day after day after day and not getting sleep. That really messes up your central nervous system. And that modulation around pain, what happens is it changes your set point and it impairs that prefrontal cortex and its ability to modulate pain. When you went through Peter, your bad episode of back pain, did it impact your sleep?

Yeah, for sure.

You're human. That impact on sleep ultimately further amplified your pain on top of it. How did you feel during that and outside the pain, how was that affecting your overall life and your thoughts and your emotions?

Total disaster. Well, look, there's so much going on. I'm happy to tell my story because it's a great introduction to the work you've done. So for folks that haven't heard it, I've shared this before, and we were talking before the podcast. I don't remember how much of this is in the book, because at one point I wrote all of this out. I'm pretty sure much of it got cut out. But when I was in my third year of medical student, I was having just a great old day. Rode my bike to the gym, was just about to go in the gym, and I get off the bike, and I feel a pain in my back like I've never felt before. And it was enough that I decided not to work out, which says something, because I would have worked out through any amount of discomfort. I limped home, laid down, and said, you know what? I'm just gonna sleep this off and tomorrow'll be fine. Tomorrow it wasn't fine. I was in so much pain, I couldn't get outta bed. Had to actually call my roommate. We had separate phones in the same house to come and get me up and out of bed. And the next two weeks proceeded to be a really unbearable episode where I was doing an ICU rotation. This is back in the Wild west, where I think the nurses and the residents were just shooting me up with Tordol every day, nonstop, getting me through the day. But the nights were brutal. And what I now realized happened was I'd had a really significant herniation, a piece of that L5S1 disc broke off. I would later find out it was a 5 centimeter piece and it had extruded. Broken off, was sitting on the S1 nerve root. Every night now, I was going to bed feeling as though the skin on the bottom of my foot was being ripped off. The only way I could sleep was to put my foot into a bag of ice and take some amount of Benadryl that was enough to knock me out. This went on for about another week until the dean of students saw me limping along and said, hey, Peter, what's going on? I told him this was a Sunday afternoon, I was studying. He took me directly to the er, got an mri, showed all of this mess. The next day I had surgery. As I've talked about in the past, everything went wrong in a series of surgeries and fast forward three months, three trips to the operating room, multiple discectomies, laminotomies, multiple levels. In theory, my back should be fine. I'm anything but fine. I now have a new pain, but this is unlike anything that was related to my back. This is where you come in. I now have a pain that is so significant and it sounds grotesque to explain it, but this is all it was. It felt like someone was reaching in my body from my kidneys into my groin and tearing my testicles out from the inside of my body. So needless to say, I was out of commission. I did not move. I laid on a floor 24 7. And to your point, how did I feel? Well, it wasn't just that I was in so much pain that I couldn't do anything. It was. I watched my life disappear. So it went from you're not going to graduate from medical school on time to you're not going to get to do a sub internship in surgery to you're not going to be a surgeon, to you're never going to walk again. So by that point, the overlap was how were the opioids that I was being prescribed to control the pain tripping into these are a tool to numb me to this entire experience. So at this point, I've talked about this in the past, at this point, I was taking, I think I was up to maybe 320 milligrams of OxyContin a day. Which is kind of amazing because if you and I took that today, if you and I split that right now, we would die. But I'm mainlining 320mg of Oxycontin a day just to blunt the emotional pain of This, I think, says what we need to know. We can come back to the story of how I met you and what. How my life turned around from that point. And it's still a miracle for me to believe I actually graduated from medical school on time, despite that all happening now into my fourth year, because this was my third year bleeding into my fourth year of medical school when all this was going on.

It's kind of amazing, a difficult time. Third year's tough. Yeah.

But anyway, so we'll come back to the. What happened. But that's a long answer to a question which is at some point, it wasn't even about the pain. The pain was unbearable, but it wasn't the most unbearable part. It was the expectation of what that pain meant for the rest of my life that became much more unbearable.

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

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

Yeah.

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

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

Before we go into the ins and outs of what pain doctors can do? Let's just talk about some of the bread and butter stuff on pharmacology. How can we navigate our way through what NSAIDS do, what opioids do, what COX2 inhibitors do? What should people be aware of in using these things? Obviously, opioids are a remarkably controversial topic, but there's probably a nuance to it that's missing from the broader discussion. But why don't we start with a softball like NSAIDs. How do they work? Everybody's heard of Advil, Aleve, Naproxen, all of these things.

These medications are cyclooxygenase inhibitors. What they do is a couple things. They reduce some of the inflammation. They're anti inflammatories. So I was alluding very briefly that there are substances that can be released down in the periphery during injury that wind up that nociceptor and amplify it. Prostaglandins, histamines cytokines, interleukins, all of that. This inflammatory soup that occurs after every single surgery, every single injury that we experience, you get this inflammatory soup and it's classically mediated by swelling, redness, temperature increases, and aspirin and a COX2 inhibitor. NSAIDs do a nice job in reducing that inflammation. Now this is where medical science, you're going to probably be much more informed than I am on this. But medical science has been slowly shifting in its view of this. We have historically thought, take these medications in an acute injury, it knocks down that inflammation and all is well and good. Well, some of the data was coming out in the orthopedic literature decades ago that people who were taking NSAIDs during total joint replacements were getting non fusion of that joint to the bone, they were getting failures. And then more recently, there's been some question as to whether knocking down the inflammation is a good thing after all, that maybe that inflammation is part of the healing process and that by giving an NSAID aspirin, we're delaying the natural healing effect and causing more problems. So where's the truth? This is tough. One, I don't think we have the whole story yet on the NSAIDs. Two, I'm a gray guy, meaning I don't live in black and white. And I'm also appreciated that every medical field has their own lens that they look at in the world. And I think we have to appreciate the complexity of the patient. Meaning if it's perhaps something minor and they can get by without the NSAID and it's not going to change significantly their level of function, then maybe not taking it will improve healing. They can't get out of bed, they can't go to work. But anaprosyn helps them to do that thing so that they can engage with their family, with their friends, with work. Well then heck yes, take the NSAID if it's helping with that level of functional improvement.

Now are you talking about this through the lens of acute pain or only through the lens of chronic pain? At this point, a little of both.

But I think through chronic pain we start to introduce all the longer term negative consequences of this. Impact on blood pressure, your heart, impact on your kidneys, with long term NSAIDs, particularly if you're older. I remember, I think it was in your book, you took Vioxx. Yes, I loved Vioxx.

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

I stockpiled it.

I wish I did.

I called up all the drug reps I knew because they couldn't, like, give it out. And I'm like, can you just hook me up? So I ran out a stockpile of that for a long time. And cut this if it's too tangential. But every field looks at the problem through their own lens. Here you had a drug that was causing heart attacks.

I mean, in the world's most susceptible individuals at a relatively small absolute rate. Yeah. I've already had this discussion with Eric Topol, which was like, mistake. Net negative.

Oh, is that right?

Absolutely. Net negative.

Yeah. Because I've always wondered.

Merckx is faulted. They should have been much more transparent about this. Put a black box label on it and we should all still have access to that.

Stop using the 50mg, use the 25s. And you're right, don't give it in susceptible people.

The baby got thrown out with the bathwater on that one.

We all do this. We look at the world through our own particular field. It's like with the latest blood pressure guidelines, the cardiologists want it really low, but it screws up the kidneys and, well, the cardiologists say save the heart, screw the kidney. So great drug. Wish it was still around.

Why do you think there hasn't been any drug that's come close to that? Like Celebrex is a joke. Like none of the drugs that are.

In the Bextra had a Valdocoxib. I think it was little bit close, but I think if I remember, it had a Stevens Johnson bad rash with terrible consequences. I think the drug companies get scared of the lawsuits. So nsaids nuance around taking.

The verdict is, do you have a version on dose? I mean, do you say 800 milligrams of ibuprofen TID three times a day? 2,400 milligrams would be. You would tolerate that for how many days if a person needed it?

Week to two weeks on that.

Make sure you're eating. Yeah.

Food in the stomach, fluids. If you're either older, you've got kidney issues, you've got GI issues, talk to your doc first. Don't just go into this stuff blindly.

Yeah. It is interesting that we can buy acetaminophen and ibuprofen over the counter, and yet they can cause a ton of damage if not taken correctly.

I mean, the ERs see people with acetaminophen Tylenol overdoses. And it's a cause of, well, you know, liver failure. Liver failure.

Let's talk about acetaminophen. For a while, when I last tried to understand it, there was no clue as to how it worked. To this day, do we understand how it works?

Minimally. More information, and I haven't, in full disclosure, I haven't read up on it a lot. I know it has some cyclooxygenase 1 impact. A lot of it is thought to be central. I haven't tracked it much beyond that. I saw some interesting side studies where it seems to have some impact in the brain around emotional modulation. And so there's a degree of emotional blunting around on acetaminophen. Now, whether it translates into a real world or if it's just an experimental manipulation, I don't know.

But there's a nice synergy with acetaminophen and ibuprofen, because different mechanism of action, different organ systems are impacted. So you can take less of each when you combine them. What's your take on that?

I think you just said it, Peter. You said it beautifully. I use those in combination to get the twofer, to get that synergy. The one plus one is not two, but three. So you can take Tylenol. Historically, we would say up to 4 grams a day. More recently, there's been some push to try to reduce that to two grams a day. Clearly, if you've got liver dysfunction, if you are drinking large amounts of alcohol less.

Yeah, my go to stack if I am actually in pain. A year ago, I had to get a crown put on a tooth that had an old filling that broke. And it's the funniest thing because of how remarkable the teeth are at sensation. But the crown was a little too high. Okay, so what's the impact of that? That meant every time I took a bite, that one tooth was bearing the brunt of it. It was the last tooth I had right in front of my wisdom tooth. And I'm talking to my dentist and he's like, yeah, Peter, it's just too high. Just come in and let me shave a little bit of it off. Well, I didn't have the time to go in. So for two months, I did not go in to get this thing shaved off. The pain was. This is how stupid I am. Like, I couldn't spare the two hours to go to the dentist. And he was willing to see me nights and weekends. This is the most accommodating dentist in the world.

Everybody should have that kind of dentist Tony Pacheco.

I can't say enough about him. And yet I couldn't make the time. So for two months, the pain got so bad that eventually couldn't chew on that side at all. So my point is I had to be taking something to get through the day. And the stack that worked was 400 of Advil, 500 of Tylenol, three times a day.

Okay.

Took care of me.

Now let me ask you, does ibuprofen work better for you than naprosyn?

I don't know. But the reason I prefer it is that I can line up the dosing with the acetaminophen because I believe naprosyn, you only take once a day, right?

Twice a day.

Twice a day. Okay, but you're right, bottom line, I wanted something where I could do it tid instead of bid.

The reason I ask is I find huge individual variability in responses to NSAIDs.

Okay.

Naprosyn works beautifully for me at 500 twice a day. Ibuprofen, not so good at what dose? 800 three times a day.

Wow.

Yeah. With food and water.

Are there types of pains people should be thinking of where these things work especially well and other areas where. Yeah, that's just not gonna have much efficacy.

I don't find it as effective in neuropathic pain. It might take a little bit of the edge off nociceptive pain. Typically is your go to your kind of your nociceptive or your nociceptive inflammatory pain, the kind of pain you'd see in a joint. Those are your typical go to forms of back pain, particularly in acute situations, but also somewhat in chronic. And I get a lot of patients that say, yeah, that didn't do it for me. But if you inquire and ask questions, you find maybe it knocked it off a little because in our game were trying to knock off pieces and pieces and pieces of their pain experience. The issues with the different responses are very individually based. And I think in part it has to do with a little bit of what we call pharmacokinetics or where the drug is getting. And different NSAIDs can permeate different tissues at different rates.

So you're saying maybe we should be empirical. In other words, try the naproxen, try the ibuprofen, figure out which one works. Obviously don't take them together.

Obviously don't take them together, but your take home message is spot on.

Do you have a concern with people taking acetaminophen and consuming alcohol? Do you tell people to refrain from alcohol when they're taking Tylenol.

I just said a conservative. Listen, don't do more than like a drink a day. Is that the right amount? I don't know. But if I tell them one drink a day, they'll go do two. They're probably still okay with that. And then I am looking in their chart just to make sure they're not drinking four or eight. And there's liver issues. What do you do?

I typically when I'm taking acetaminophen, I don't drink much anyway. I'm probably going to have four drinks in a week. So meaning four days a week I will have a drink or three days a week. But if I am taking Tylenol, I'm just going to refrain again. I don't have any evidence to suggest that that's necessary.

Probably the safest.

It's the precautionary principle at its finest. Okay, I want to talk about muscle relaxants. So the other thing that has been a real favorite tool of mine is Baclofen. Now, it's not a particularly potent muscle relaxant, but it seems to for me and for the patients of mine in whom it works, offer something really potent like Valium. Doesn't bring all the baggage of a benzo or even a Flexeril where you can kind of get the drowsiness. And frankly, a lot of people just. I mean, I used to even get nauseous on Flexeril, but something about baclofen, I don't even know. It's in me at 20 milligrams twice a day, but it actually takes the edge off. And where I typically find this beneficial is if I slept wrong and I get a kink in my trap or I've been on a super long drive and my qls sort of flare a little bit. And I know that if I had all the time in the world I could go and stretch my way out of that. But sometimes I just don't have that time and I need to kind of get right back to doing something awful like sitting and just two or three days of 20 milligrams of Baclofen B I D with a little NSAID and like I'm as good as new and I save myself the real flare up. What are your experience with muscle relaxants?

Beautiful case example, by the way for yourself of how we would use those. Baclofen is one of the safest to use. It is not habit forming like the Somas and others that can be like a barbiturate can act and People can get highly psychologically dependent on them. The flexerils have a tricyclic antidepressant property about them that may sometimes be helpful for people in various mixed pain states, but also can cause sedation. The Baclofen seems to be pretty benign. We don't typically use muscle relaxants for long term chronic conditions. The data hasn't worn out.

So how many days are you comfortable with a person?

Oh, I'm comfortable with a person being on Baclofen all their life. It's just, forgive me if I'm preaching to the choir here. Everything I'm doing is taken in the context of the person in front of me and the cost and benefit of the treatments I'm providing them. Meaning there are costs with Baclofen? I don't mean monetary cost. It can cause sedation.

What doses typically or is it just individual?

I think it's individual and obviously it is dose dependent. The higher doses, more sedation. We can use Baclofen intrathecally. We put in intrathecal pumps for Baclofen. This is a beautiful life saving, minimal surgery that we do for people with a spinal cord injury. Intractable spasticity, because to get the spasms under control with oral doses you just can't get there. So we thread a little catheter into the CSF and we deliver Baclofen that way. Now it again is a clean, relatively safe medication. But I'm always evaluating long term, is this person getting benefit from this? Should we be talking about dialing it back and trying to wean? And if they're not getting benefit, then why should they stay on the medication? I know you do the same types of things in your practice. We use it. We can use it in acute, subacute. We'll use it in some chronic conditions as a trial. What's a trial? Month, two months. And then we monitor data on every single person.

And what dose are you comfortable? Up to 20 milligrams, three times a day?

Yeah, up to 80 milligrams, I believe is the upper end. I don't usually get there.

Okay, you alluded to Neurontin earlier and you alluded to the fact that it played a role in my recovery because once we got the big stuff out of the way, I still had a couple years of peripheral nerve injury. And the only way to put the fire out in my foot was Neurontin. And unfortunately, initially it required 4 grams a day. I was taking a gram four times a day or something like that. And the good News is it worked. The bad news is you're pretty much always tired. So I was very happy over time to get that dose down. And I think within 18 months I was completely off the Neurontin and lo and behold, never experienced. Although interestingly, maybe once every year I get like an enormous surge of fire into that same foot. Literally one shot of flame that lasts seconds and it's gone. But essentially never again. Is Neurontin still a very powerful tool in the use of neuropathic pain. You alluded to other drugs like antidepressants as well, in addition to a rather impotent anti seizure med. But what else do you have at your disposal for this type of pain?

The beauty of Neurontin or Gabapentin and its cousin pregabalin, which was introduced immediately after gabapentin's patent ran out. Conveniently, very conveniently, both have the same mechanism of action. They work on the Alpha 2 Delta subunit of a calcium channel in the spinal cord in the brain. That's a little too jargony and technical, but think of them as agents that turn down the signals that are in the spinal cord being processed and in the brain. So they're really not impacting your nerve out here or in your leg. They can be very effective. The beauty of these two drugs is there's no lethal dose. The only way they could kill the rats when they were studying it was to drown them in it.

I used to say, or hit them over the head with the tablets.

And I would tell a patient, somewhat jokingly, the only way you can be hurt taking this drug is if you're struck by a truck that's carrying it. It's a little bit more nuanced than that because there are side effects.

Yep. You could fall asleep driving.

You can fall asleep driving. I tell people, don't operate heavy machinery, don't go dune buggy riding, don't blah, blah, blah. There is in elderly patients in particular, I warn them about falls because you can get a little unstable.

Now, pregabalin can also lead to weight gain. Doesn't it also increase appetite? Both of them do.

Well, it's more. I see water retention.

Got it.

I see a little peripheral edema in both.

And they also, both enhance sleep, especially pregabalin. And so there's a little bit of an added benefit to patients who are using these to also put the pain out at night when it can be most noticeable. There was actually a study. I don't know if I'll ever be able to find it. It was sent to me that actually suggested pregabalin didn't just make you drowsy, which was obvious, but also promoted appropriate sleep architecture.

I don't know the data on the sleep architecture, and that would be something I'd be putting out to you or some of the sleep experts. I have taken it after surgery. I find that it makes me sedated. I don't find the quality of the sleep.

Okay, I could be totally wrong on that, but could be your experience.

That's it. That's it. It could just simply be my experience. The truth is, I do tend to when I dose it, I'll dose lower in the day, and then I'll wallop a little harder at night for the very reason. So let's imagine gabapentin maybe in the day, 300, 300, 600 at night. And I'm trying to titrate that so that one. It helps them sleep. Because you brought up an incredibly important point, which is during the day, we've got all these modulatory things we can do around our pain. Distraction, for instance, other coping strategies. At night, you're just trying to get into this relaxed state, and that is the worst time for somebody with chronic pain. And so the gabapentin and sometimes other agents can help with that. So, yeah, I do use it to help people sleep. No lethal dose max is out at around 900-1000mg at a dose because it's taken up by an active transport system in the small intestine. Once you take more than about 1,000 milligrams, the rest of it's just passed out your backside. Pregabalin is different. It has what's called a linear kinetic profile, simply meaning the more you take, the more that gets in your system. So the only times I will typically switch somebody from a gabapentin if they're getting benefit is when they've maxed out the dose. They're getting benefit, but there's no point in giving them more. I'll switch to pregabalin, where I can drive more into their system.

And again, you're using these for the most recalcitrant neuropathic pain.

Typically, I'm using these for the most recalcitrant pain in general. So that's an important point. While I can speak to perioperative pain, acute pain, subacute pain, and chronic pain, Stanford, we tend to see. We're a tertiary referral center. I tend to see we see people after they've seen everybody else.

We didn't even do this. I'm sorry, we didn't define chronic pain, but how would you put a definition on that?

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

Totally makes sense.

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

Antidepressants and their role in pain management.

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

Do you remember how much you gave me of how much sodium? Sorry, how much lidocaine?

I hope it wasn't toxic.

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

I'm looking forward to it.

Which TCAs are the popular ones?

Everybody? I think there's about nine.

What are your top two or three?

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

After nortriptyline, what was it?

Amitriptyline or eldritptyline?

Yep, yep.

So Elavil's an older tricyclic that has a lot of histamine release, a lot of sedating properties. I would never give that to an older guy with a big prostate because he couldn't pee and he'll be very angry with me. I will never give that to a young woman who's looking to watch her weight because she's gonna get the munchies and she's gonna put on 10 or 20 pounds and she's gonna hate me. Have I had that happen? Yes. And I still embarrassed to this day.

Is it offset by GLP1 agonists in the modern era?

I learned my lessons. I haven't run that experiment. That's a great idea. But I typically use the amitriptyline when I need some sedating help at night for sleep and pain because a dual action. I like the dispramine because it has less of that sedating property. And I'll tend to go to that and the nortriptyline and you can titrate blood levels, for instance, like the nortriptyline and those drugs. So where do they work? They work in the brain. They work in the brainstem. One of the classic areas down deep in the brainstem is a rostral ventral medullary region where descending pathways are coming down. And some of the key neurotransmitters there are serotonin and norepinephrine. So we're not necessarily using these drugs for their mood changing properties. We're using them because they hit the same systems as they do in pain. And that's the beauty of them. And that's some of the messaging we have to give patients when we've prescribed them an antidepressant is like, okay, Mrs. Jones, Mr. Smith, we're not doing this.

Because we think you're depressed. And that's what I think. Yeah.

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

Not FDA approved drug approved for pain is what you meant.

Yeah. Thank you. Thank you for that. Correct.

We're FDA approved for something else.

You're absolutely right.

Okay, well, this brings us to opioids, which I saved for last because of. Well, there's actually more drugs I want to talk about. But in terms of the off the shelf, typical stuff that people think about. So a lot of hay has been made over this. There's no question that opioids have been overused and abused, and there's no question that illicit use of these things has had a devastating impact on our society. But it would be difficult to say that the field of medicine would be better off having never had an opioid. We just talked about surgery, for example. Very challenging to deliver medical care in a hospital without opioids. So the question becomes, what is the most responsible case for oral opioids, which by definition are meant to be used outside of a hospital, not inside a hospital. And as a pain specialist, I would imagine few people are better equipped to navigate the nuance of that question.

Yeah, it is a very nuanced question. I think a little preamble first. I don't take money from either the opioid companies. I don't take money from the litigation that's ongoing because there are tens and tens of billions of dollars at play right now. I don't take money. And I am not pro opioid. I am not anti opioid. I am pro patient. I view them as a tool. I view them as a tool. Much like the other medications, interventions, mind, body, physical, rehabilitative, complementary tools that we use. They have a particular place. I have a personal, deep appreciation for the destruction that these agents can cause. I come from a family very deep in addiction, very deep. I've lost clothes, family members to opioid overdose. I've lost close family members to alcoholism. I am personally petrified of these drugs. And I have gone through surgeries that the surgeon said, you can't get through this without an opioid. And I'm like, I'll be fine. Because my approach is avoidance. With that said, I have learned a long time ago not to project my personal experiences onto my patients. That had to come through age, wisdom, whatever. It is true prescription opioids were overprescribed. They were over marketed, they were bad actors doing bad things. But it's not that simple a story. I sometimes get frustrated because I feel like you can make really simple soundbites out of this complex societal issue. When it was a perfect storm that hit. Yes. You had a letter to the editor of New England Journal saying that nobody got addicted to like 38 patients or some nonsense. And Purdue and others ran with this, and I get that. And they did bad things. You also have to put things in the context of what was going on in society. There Was growing awareness of pain as there should be. There was growing pressures to do something about it. People have brought up the pain as a fifth vital sign as an example. People have different opinions about that. Did it have bad consequences? Yes. Did it have good consequences? Hell yes. Run the counterfactual. Do you want to go back to a time when we're not asking patients after surgery their pain? Do you want your mother, your daughter back in that time? And I think the answer is clearly no. But also there was other pressures. And Peter, you witnessed those firsthand. What was going on back in the 90s and the 2000s after surgery there was this massive push to get people out of the hospital and put them in their home. We were replacing care in a hospital with care in the home. In the hospital we had time to see their trajectory. We could titrate their opioids or whatever, get them tuned up, dialed in and then send them home. Now surgery overnight, you're home. Let's give you a bucket of whatever. And the reason for that was surgeons and docs don't like getting called at 3am for pain control. So pressure to put people out in the home environment, on top of it, docs get lousy training for pain. What is the average seven hours, I think in medical school vets, by the way, 40 hours of pain. So great if you've got a dog, not so great for patients. So you got this pressure. And by the way, not only on top of that, but now you've got the introduction of patient satisfaction scores. I have to imagine in your private practice you don't have to measure press gain and patient satisfaction scores, but in hospitals everybody does, or at least they did. I think they're coming to their senses. And so one way of addressing the satisfaction give more opioids. And there's more. There's many, many, many pressures that came to bear that helped create this problem of which there were bad actors out there.

By the way, the perfect analogy to this is the mortgage crisis in 2006-2008. If you took a 0th order view, it would be really easy to blame one of the entities. But it is actually a perfect storm.

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

Just one thing. You are not taking care of somebody in the acute phase of expected pain, typically. Is that correct? In other words, that guy that just had a knee replacement, he's being managed by his surgeon? Correct.

You know, frequently we have an acute pain service in the hospital that sees about 30 to 50 patients a day.

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

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

You know, when we brought pain in for every case, when I was in residency, anytime we did a thoracotomy, it was a non negotiable pain was consulted before the case just for people listening. A thoracotomy. We didn't do these often because a lot of times by the time I was in residency, we did minimally invasive surgery in the chest. But sometimes you had to actually make a huge incision under the ribs and that's a very painful. You just know this from experience, that that's such a painful experience. You cut this huge incision in the intercostal muscles, you put rib spreaders in, you crank these things open so you can do this big operation. We just know those patients are going to need an epidural catheter and we want that in before surgery, not after. And it makes all the difference in the world. So pain was a part of that response. I don't remember us routinely bringing pain in otherwise. But things have changed, I'm sure, in 20 years. So today for a general abdominal case or a general orthopedic case, are you brought in preoperatively?

Yeah. These days there's a lot of movement towards these ARES protocols and enhanced recovery after surgery. And so fortunately, the field of medicine is moving more and more towards a team based healthcare model where surgeons, pain docs, anesthesiologists, nursing rehab are all working in a collaborative manner. They're putting together protocols to what is the best optimal approach to prehab a patient before surgery, move them through the intraoperative and then perioperative period, and it's gotten better and better and better. Can we still improve it? Yes, but the acute pain service does get involved, particularly as you alluded, when we put in peripheral nerve catheters or epidural catheters. And this is where we're running that local anesthetic, the numbing medication that stops the nerve impulses to provide pain relief after surgery. And so, yes, we do get deeply, deeply involved in that acute surgical pain space. And then also with internal medicine docs, when patients are admitted into the hospital.

For whatever cause, if someone's listening to us and they're going to have elective surgery at some point, I want to plant a seed in their head for someone who's going to have the knee replacement, the hip replacement, the cholecystectomy, the app, whatever. Should they be requesting this of their surgeon? Should they say, hey, I want to be diligent about my recovery, I want to minimize my use of narcotics. Do you mind calling in a pain consult so that I can just have a team of docs who are exclusively thinking about my pain? Because let's be honest, the surgeon, I got enough to worry about. I got to make sure you didn't leak that that anastomosis is fine, that you're not getting a wound infection. Your pain is literally like third or fourth on the list of my concerns for you to have the best outcome.

Right. You are right. And if a patient is listening to this, a person is listening and they have the ability, they have the wherewithal to go to their doc, their surgeon, and ask, what will pain management be like? Is there an opportunity to interface with an acute pain service, particularly if they're taking opioids now for a chronic pain problem, or even if they're not taking opioids for a chronic pain problem. So we will see them in our clinic before surgery. We will put together a pre surgical plan for them, which will often include a regional anesthetic approach, meaning those nerve blocks or the catheters we sometimes involve intravenous ketamine to augment. We will put together the whole plan, communicate with the anesthesiologist, make sure there's a good handoff after surgery, and then we will follow them afterwards. And then we will typically follow them outside the hospital and help the surgeon out with the medication management and the pain management. All of this is not just solely to reduce pain, but to put that person in optimal state for rehab.

How ubiquitous is the patient controlled analgesic device, the PCA that we used to bring everywhere. Okay, so people are still typically getting fentanyl through a PCA in the immediate postoperative phase.

Fentanyl, morphine, dilaudid. Yeah, the PCA is a very common tool. And one, it puts pain control in the hands of the patient. Two studies have been shown that PCA delivered medication opioids. They end up taking less than if it's nursing delivered.

And the goal is we want to get you off an opioid, even oral, before you go home. Is that generally the stated objective of the medical system now is whatever opioids you're going to need, let's try to deliver that to you in the hospital?

I wouldn't say necessarily because I think there are some surgeries that are going to clearly require prescribing an opioid after surgery. Remember, the name of the game is get people out of the hospital and have the care take place in their home. And people are going to need some degree of pain management and analgesics. And those analgesics can be Tylenol, NSAIDs. If it's more than mild, moderate pain, it may involve an opioid.

So how are you thinking about that? How are you thinking about extracting the value of the opioid and minimizing the risk of long term dependence?

What we have learned is that there are vulnerabilities that people bring to an injury or surgery and being placed on opioids that set them up for more likelihood of persistent opioid use. And we've characterized, we and others through research studies have characterized many of these factors. So some of these factors include preoperative depression and anxiety, higher levels of catastrophizing, early adverse child events. So a history of ptsd, history of physical, sexual, psychological trauma, all of these set someone up to have a higher likelihood of persistent pain and persistent opioid use. Now you will note all these things I said most of these things I said people would normally put under the psychological umbrella. The key message that I want to give, I think everyone's getting this is when we talk about psychology and psychological factors, we're talking about neurosciences, we're talking about the brain, and we're talking about specific brain systems, regions, networks. So we did a study several years ago. This was led by Jennifer Hannah. Ian Carroll was a key player leader on this. And we found that higher depression scores preoperatively predicted much more likelihood of persistent opioid use after surgery.

And how are you screening for this? What tests are you using?

Back then we used something called the Beck Depression Inventory, which standard instrument. We don't use that anymore. There's more modern tools. I thought what was cool about this, we did a factor analysis on the original paper. And you can break the Beck down into different components of depression, anhedonia, cognitive, blah, blah, blah. What we found is there was a particular factor that drove almost entirely that prediction of depression, self loathing. It was feeling really bad about yourself.

So if you have someone who just suffers from, not that anhedonia is anything but unpleasant, but if they're only experiencing anhedonia but no self loathing, you would say, well, the risk isn't as high.

Yeah, conceptually your argument holds. But now I'm going to come back to a lot of the things that you write about, which is the danger of drawing inferences from small population studies and generalizing that to the rest of the world.

Yeah, especially with that randomization. Because what you really would like to be able to see is you take a whole bunch of people in, you get their incoming metrics of anhedonia, dysthymia, self loathing, you categorize all the arms and tentacles of depression, and then you randomize within each of those to with and without opioid strategies. I mean, this is a very complicated thing to do, but if you want to know the answer, that's kind of the way you want to do it.

That's exactly it. Unfortunately, there's not much will to do that in society, even in the world.

We live in today, where we understand that for a non zero, potentially non trivial segment of the population, the introduction to opioids that ultimately destroys people's lives is delivered by the medical system.

I was on the Institute of Medicine panel, now the National Academy panel, and we did a report called Relieving Pain in America. And I remember sitting around back in 2010 and we were talking about the state of pain in the country and where we needed to go identify a perfect Vision and also identify what are the biggest research questions to ask and answer. And I remember a really vigorous discussion here and the one that I put forward and others put forward is we need to better understand what is the long term effectiveness and safety of prescribing opioids to people with chronic pain. Meaning we need to figure out for whom opioids work. Today we still don't have an answer to that question and there's very little will to do it because the whole message and the scientific communities basically find non opioid choices. So there's not a lot of interest in funding the studies to figure out for whom it works. There is a lot of active interest still, mainly through data driven studies to find out who is at risk. But that type of study that you're talking about and others that are of longer term and bigger consequences, I just don't know when they're going to get done, who's going to fund those.

This is a little unrelated, but I remember this when I was in residency, there was one of the attendings and I don't even remember who it was, but he had this belief, he used to quote this study, and I don't remember it, but it said that if you injected bupivacaine into the injection site, sorry, the incision site. So I'm going to make a midline incision, draw my little line, inject bupivacaine. So for the listener, this is a long acting sodium channel blocker. Wait some long period of time, like 10 minutes, then make the incision, go about, do your surgery and then immediately give that patient acetaminophen and ibuprofen immediately postoperatively and keep them on it round the clock, you could eliminate opioid use. And he was convinced that the only reason surgeons didn't want to do this was because nobody wants to inject and stand there for 10 minutes with your thumb up your ass waiting for the bupivacaine to seep into the tissues. And maybe it's anecdotal, but it really seemed to work like it really seemed to work that you would do this inguinal hernia repair or at the time some small laparotomy or whatever it was, anything. And if you were willing to put that bupivacaine in and sit there and wait, and I'm trying to think, we might have used EPI with lidocaine as well. So it might have been a little EPI with lidocaine plus bupivacaine or something like that. And you had to be super Due diligent about keeping the acetaminophen and ibuprofen levels up. Have you ever heard of anything like that?

Oh, all the time. Yeah. I mean, I think he was ahead of the curve. Now, whether it completely eliminates any likelihood of opioids after surgery, that's a little too strong a statement.

It just reduces the requirement. Right.

I strongly believe that he was practicing good medicine and he was doing it ahead of his time. Now the idea of using a combination of lidocaine and marcaine and EPI as you well know, is lidocaine short acting. So it's gonna work pretty darn quick. And so you can get going with your surgery. While the marcaine, the bupivacaine's kicking in, the EPI is gonna not only provide hemostat, it's gonna reduce bleeding at the site, but it keeps the local contained.

Which means you have to use less Bovie, which means less tissue damage.

Yes.

Maybe he was using EPI with bupivacaine, I don't remember. But there's something there.

There is something there, there. And I think I haven't asked surgeons these days and my sense is that's becoming more and more common practice, that there's a greater appreciation of the role of this concept of preemptive preventative analgesia anesthesia. I think it provides some benefit. There was a big hoopla on this like 20 years ago when everybody thought we were gonna find a way just to basically eliminate postoperative pain through these methods.

Presumably didn't pan out.

It just didn't pan out.

Yeah, but look, a 50% reduction in opioid requirement postoperatively would be enormous.

Huge. Absolutely. Getting back to your question, I think we're at an interesting crux in research and clinical care where we're gathering more and more high quality data to better understand these vulnerabilities. And I think we're going to be moving to the point of putting these into clinical decision support tools that can inform the docs and help them to assess a risk of a patient so that you can have an informed conversation with someone. Like you are at likelihood of having persistent opioid use because of what you bring.

Do patients receive that? Well, that's a hard discussion to have with a patient, I would imagine.

I guess it a little bit is about their expectations. The challenge is when the ones who've had multiple surgeries that have been on opioids, they're expecting opioids. A lot of it's expectations. I think the more naive person those go A little smoother. If you are professional, explain to them, but also allow them to make their own choices. Don't say, we're not going to give this to you.

Yeah, that makes sense.

But here you are at an increased risk. And that's always the discussion I have with patients, whether in the acute space or particularly in the chronic space.

So let's talk about a couple other things that are related to this but distinct. Let's talk about acupuncture. What do you know about it? Well, let's talk about through the lens of chronic pain.

Yeah, yeah, yeah. All right. Clinically, some people get better, some people don't get better. I cannot yet predict who is going to respond and who's not going to respond.

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

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

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

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

So Medicare is covering something, commercial payers or not?

Well, it's possible.

Okay.

Yeah. Historically been hard to get that covered.

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

Yeah, I've had some successes in back pain, musculoskeletal pain, migraines, headaches, oddly, and it's highly variable. I studied this. I had a really large program project grant to look at cortical mechanisms of this and predictors. We're putting in a paper now which is a prediction model of real acupuncture versus placebo. Acupuncture.

Puncture. But not in the appropriate spot.

Well, that's one option. And it turns out that many of these acupuncture points overlie peripheral nerves. And so when you twiddle the needle or apply electroacupuncture, are you doing a peripheral nerve stimulation? I don't know. But this is a stridinger needle that looks, for all intents and purposes, like an acupuncture needle. It causes a little pinprick, but it doesn't Actually do acupuncture and it's been shown to be a good placebo. What do I know about the mechanisms? Again, don't fully understand. I know that there is increases in peripheral adenosine that is released with acupuncture that has an analgesic effect at the primary nociceptor. I know that cortically in the brain. There are brain systems that are modulated with acupuncture. But hecavi know exactly how it works. And we still don't have good ways of predicting who's going to respond and who's not going to respond. But that's rather common amongst all of our pain treatments. You know, again, pretty safe absent some risk of infection. Make sure that the facility you're getting at practices good hygienic approaches.

How do we think of acupuncture differing from dry needling?

I think you'll want to get a true acupuncture specialist on to dry that.

In California, I think it's not legal to dry needle, but you can acupuncture. I even understand the difference if you're.

Using the term dry needling from an intramuscular standpoint. I don't know if that's where you're going.

Maybe. I see acupuncture refers to just going after a nerve specifically.

Well, it's an acupuncture point.

Okay.

It is a Chinese medicine list of acupuncture points. I'm way out of my wheelhouse here, folks. When I think of dry needling, I tend to think of that in the context of trigger point injections, which we do, physicians do, and that we're taking typically like a 30 or 27 gauge needle. We're putting it intramuscularly into a trigger point muscle. It's where you get those knotty muscles and you can do dry needling. And what that does is it causes relaxation of the muscle. Acupuncture is really quite different from that.

Okay, next question on chronic pain. What is the role of cannabis in your experience here? Is it friend or foe? And again, I'm sure there's a nuanced answer.

Very nuanced. This is another one where liable to get some hate mail on either side of this. Here's what I'll tell you. One, the verdict is still way the heck out there. You look at well controlled randomized trials. There's very few of them, by the way, but some in neuropathic pain that show analgesic benefit over a short period of time. With cannabis, you look at population level studies, Australia did one, they did not show benefit. With cannabis, we collect data. One of my other areas of both research, but also clinical care, is I built a learning health system that captures high quality data on every patient that comes in. And so we deeply characterize or phenotype them. And we looked at people coming in on cannabis, not on cannabis. Bottom line, people coming in on cannabis into Stanford are worse off and they stay worse off. Now, there's all these limitations to observational studies, no matter how well you conduct them. Let me distill it down to some talking points. There's a huge number of cannabinoid receptors in the human brain that are playing a role in analgesia. So I'm absolutely convinced that cannabinoids are playing a role in pain relief. One, two, the forms of cannabis that we take are dirty, meaning we don't know the dose, we don't know the ratios. They've not been well studied and they've not been studied in different groups. A major part of that is because It's a Schedule 1 drug, which means that the DEA says basically high abuse potential and no medical benefit. And it takes basically an act of Congress to study cannabis. I don't prescribe it at Stanford. I don't screen people for it at Stanford. If I did, and if we kicked them all out, I wouldn't have anybody in the clinic. I mean, we're in Northern California.

That's interesting. So you can't study it. I would assume you couldn't study it with federal dollars because of the federal DEA restriction. I would have assumed because it's legal in California, if you were using non federal dollars, you could study it in a state like California.

You can study it with federal dollars. NIDA will support funding of cannabis. The regulatory controls you have to go through are crazy.

I see. Because it's Schedule one, the laboratory, it's actually more demanding than how you would study.

Co. We used to make jokes. UCSF did some nice cannabis research and the word on the street was is that they would deliver the cannabis doobies in a Brinks armored truck with guys carrying M16s. Now, I think it's gotten better, but it's just been challenging to study this. I'm firmly of the opinion. Here's where I'm going to upset people. I firmly believe we should make it a Schedule 2 or Schedule 3 drug.

If for no other reason, to study it with less friction.

What you said. Perfect.

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

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

What's the prevalence according to the current definition?

I should know how many millions there are, Pete. I should know how many millions and I don't. I can tell you, just to give a frame of reference, chronic pain. We think there's 50 to 100 million Americans with chronic pain. That's a huge range. And it depends on the way you ask the question. If you ask it More stringently, it's 50 million. If you ask it more liberally, it's 100. We know that there are about 8% of the population, or a little over 20, some odd million with something called high impact chronic pain. This is a big one. And this is where I spend a lot of my research and policy work on. These are the people that has substantial restrictions to their pain in Activities of daily living. These are the really challenging people. Of that 50 to 100 million, the most common chronic pain is low back pain at about 28%. Neck pain, 16%, headaches around 16%. Societal burden of chronic pain is terrifying. It's astounding. We spend over half a trillion dollars a year in chronic pain. And the reason why, in part, it's not more appreciated is because we have parceled it out. We've broken it into different categories. With heart disease, we lump it into heart disease, cardiovascular disease, even though it's all these different sub components with pain, instead we categorize it as it's either back pain, it's musculoskeletal pain, it's migraines, it's abdominal pain, and it gets diluted out. But when you put it all together, you're dealing with a half a trillion dollars. It's more than diabetes, heart disease and cancer combined. Fibromyalgia. Again, I'm escaping the prevalence many millions of people, huge societal burden. It is historically a disease of histrionic housewives is how they were mislabeled tragically. And we're having now a greater appreciation for what it is, what's affected. What we have learned is that there are brain systems that are clearly abnormal in the processing of pain. In people with fibromyalgia, we find that for the same pressure stimulus, if you apply something like 4 kg per square centimeter, healthy people will give a range of reporting in certain range. People with fibromyalgia, much, much higher. Here's another. I think this is an interesting pain concept to introduce and talk about it. There's something called conditioned pain modulation in the animal world we called diffuse noxious inhibitory control or dinic cpm. Think back to when you were a kid, your arm hurt, you walk up to your buddy, you say, hey, man, you know, and he's like, how you doing? It's like, well, my arm's kind of hurting a lot. And what would he do?

Hit you?

He would hit you. Of course he'd hit you in your other arm. He'd stomp on your foot. And you're like, why the hell did you do that?

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

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

Is there a high overlap with depression, anxiety and fibromyalgia? And if so, which is the arrow of causality?

Yeah, the chicken and egg. We used to think that there was a high preponderance of anxiety and depression with fibromyalgia. And I think the current data doesn't support that there's any higher prevalence than particularly any other pain conditions. I think you tend to see more of the anxiety, depression, broadly speaking, and things like low back pain. I think what you see more of in fibromyalgia is fatigue, unrelenting fibro fog is what they call it, and then the sleep disturbances.

So what is the management for these patients? Is this a curable syndrome or is it a syndrome that is meant to be managed like hiv?

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

That's caused by what?

That's the thing.

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

So fibromyalgia is frequently preceded by some event, something traumatic. That traumatic can be physical, motor vehicle accident, but it could also be some emotional or sexual abuse. It can be an infection. We frequently also hear that story. So there is some insult that people will frequently identify. Getting back to your question on managing this, we frequently use the same medications that we've described before, but we rely on more of those brain modulatory drugs. Another one like Duloxetine, which is in the class of antidepressants, but it's a little cleaner, fewer side effects. It's a serotonin norepinephrine reuptake inhibitor. This is actually a drug that got FDA approval for pain. And so we go to this a lot. One of the drugs that I have studied with Jared Younger, who's now at uab, is a drug called low dose naltrexone. This is a fascinating drug. It's got like this underground reputation out there that's all over the forums. The reason for it is because it's been around for decades and off patent, there is zero money for any pharmaceutical company for it. What is naltrexone? Naltrexone, when given at 50 milligrams, is used to block opioid receptors. It's an opioid blocker. And so we use this in the treatment of opioid and alcohol addiction because it blocks the rewarding experiences of alcohol or opioids. And so it's used as a treatment for addiction. 50 milligrams, at four and a half milligrams, one tenth of the dose, it has been shown to block toll like four receptor on the microglia. Now, I just introduced this really technical concept, so allow me to briefly explain. The microglia are these cells that hang around nerves but are not neurons. And when I was in medical school several years before you, what I was taught was these microglia were like the warm fuzzy blanket that propped up the nerves. I don't know what you were taught, but they provided structural support to the nerves. What I learned is that was only part of the story that they're key neural immune modulators. And so what I mean by that is in times of stress, injury, fever, these microglia get activated. They release all sorts of inflammatory mediators, chemicals that sensitize the central nerves responsible for pain perception, pain transmission, pain perception. So you give low dose naltrexone, it blocks that neuroinflammatory soup. And in some patients, Peter, this drug's been magical. Magical. I give it in 4 and a half milligrams.

Silly question. Why not 5? Like 4.5 has a lot of specificity to it. Was there some reason why it came in at such a dose?

All right, here's my story. Linda Watkins and Mark Hutchinson did some of the early work in the animal studies on this and showed this microglial effect. And they did it at a certain dose. And so what we did is we did a milligram per kilogram conversation. 70 milligram.

70 kilo person.

70 kilo person. Thank you. And we get four and a half. And so when people ask me that, I'm like, wow, it does make us sound pretty smart, doesn't it? There's no difference between four and a half and five.

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

Complex regional pain syndrome. Very tragic pain condition. That is a neuropathic pain condition. We see a fair amount of. I've got a clinical trial, I'm just wrapping up on that using low dose naltrexone funded by the RSDSA Association. Another is actually multiple sclerosis. They've used it in and they found some reduction in reoccurrences of Ms. I think they did that at UCSF or ucla. But it's in these weird neurodegenerative type conditions where they're seeing some help. Now I've had some wacky, really wacky patient responses. I can share one. He is dysarthric. He can't speak. He's got weakness. He has hemi, body pain, burning pain.

This is that central pain, thalamic pain.

So he comes to me several years later, can barely speak at all. He's tried everything. Let's try low dose naltrexone.

So why does he come to a pain doc?

Cause he's got terrible pain.

Okay, so he wasn't coming to you for the speech issue?

No, no, no, no. He has a speech therapist. It's not getting any better. He's a couple, few years out. Stroke is stabilized.

Okay, so it's this burning pain on half his body.

Half his body. I trial him on four and a half milligrams of ldn. He goes away. He comes back a couple months later. Pain has improved. But not only that, he's now speaking and throwing a few words together for the first time since his stroke. I'm like, what the hell? I bump up his dose. You cannot hurt yourself on this drug. I know you know this. So I go to nine. Why not ten? Well. Cause it's easy to take two capsules. He comes back a few months later. He's now talking in sentences. I said, are you sure this isn't due to your speech therapist? And they swear up and down, absolutely not. I go up to 13 and a half. And now he's having conversations.

And how's his pain?

Massively better on this really remarkable effect. The only way I can explain these things is, you know, in a stroke you've got Dead tissue, you've got live tissue, you've got these intermediate zones. And somehow with reducing maybe inflammation, you end up with more functional brain.

Somehow, if that model makes sense, which it at least teleologically does, something about that inflammatory zone in the middle between what was clearly gone and not is poisoning the part that's still okay. What is the downside of this? Meaning, what would one need to be mindful of in trying an approach like this?

The beauty of this drug is the only side effects I see 20, 30% of people get vivid dreams. They get Technicolor dreams. Not bad dreams, not nightmares. Their dreams just take on a more colorful nature. Every once in a while I'll see somebody who they say it activates them. We tell them to take it two hours before bedtime, and if it activates them a little bit, take it in the morning instead.

Here's a silly question.

Yeah.

What's the scenario in which inflammation of the glia is a good thing?

It's a good thing after injury and after an infection because it mobilizes all of those repair cells to come in and clean up the mess. The problem that we think is going on in pain, the switches don't turn off and go back to normal. And indeed, that, Peter, which you did a beautiful intro, is one of the things we think is playing a role in fibromyalgia. They got an insult activation of this neuroinflammatory system. In a healthy state, it turns off. And fibromyalgia, it never turned off.

I guess where I'm going with this is we think that at least a subset of people with neurodegenerative diseases, and you mentioned multiple sclerosis, but we think this is true in at least some cases of Alzheimer's disease, that neuroinflammation is a part of the pathology. So would there be any efficacy to a trial there in either an individual with mci, mild cognitive impairment, or. As crazy as this sounds, is there a reason to consider it prophylactically in high risk individuals with the caveat that, hey, by the way, if you happen to get an infection, this would be a good time to stop it and ride it out and get better?

I think the short answer is yes. A little bit of the longer answer is, you know, this. Everything we do is weighing risk and benefits. This is one drug I am hard pressed to come up with significant risks. We have decades and decades and decades of experience with this drug. In people with addiction.

At 10x the dose, how long are they typically on that drug lifetime. So meaning for a subset of individuals, just putting them on the party dose of 50mg of naltrexone keeps them free of alcohol and opioids for life because it so blunts the pleasure center.

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

Yeah, you have to want to be off.

You have to want to be off. They have injectable versions of this. Isn't that called Vivitrol, is it? It's an injectable under the skin that lasts X number of days, months. But yeah, we've got a lot of long term data on this and from a pilot standpoint, with informed consent, obviously. And just I would view that as a novel treatment in patients that one could try out, monitor, do some objective measures, see what you get. I want to be careful. I wouldn't say that for a lot of the things that we do because there's real risks with a lot of the medications that we provide, a lot of the procedures we do. Not only that, there's big costs that come with them. Whereas this. I'm going to make a plug here. I have no relationship to. But we get our stuff out of Balmar Pharmacy in Colorado. Why? They're a compounding pharmacy. They've got all the certifications. The reason is you can't go to Safeway or Costco and get this.

Can't get low dose naltrexone there. You mean it has to be compounded at 4.5?

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

So it's basically a free drug.

Insurance doesn't often cover it. They consider it experimental, but it's basically a free drug.

It's a buck a day.

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

Yeah, I'm very curious to see if anybody has looked at LDN and any of the neuroinflammation stuff. We see the relationship between herpes simplex virus and Alzheimer's disease, between shingles, especially ocular variants of it, and Alzheimer's disease. We know that there is some relationship between inflammation and this disease. And we know that that's obviously not all paths cross through that. There are lipid mediated paths, metabolic paths, vascular paths. I think it would be very difficult to make the case there's not an inflammatory path towards that condition. And so interesting to think about it is.

And I need you to just as a, ideally a good scientist, tell you that not everybody buys in to the microglial model that I'm describing. There are friends and colleagues at Michigan, Dan Claw, brilliant, brilliant guy who is very much in disagreement with me, who believes that even at these low doses, you are antagonizing the opidergic system and in essence kind of resetting it in these chronic pain states so that you're normalizing the endogenous tone. And you know what? That's the fun thing about science and why we try to keep our egos out of it. The truth will come forward.

What's the evidence for the inhibition of the toll like receptor? Is that in vitro?

Yeah, it is in vitro. Linda Watkins, Mark Hutchinson did some really nice work in that and showed people have had some difficulty in replicating it. But I have a hard time. We know the mechanism I think seems pretty solid. But when I look at the clinical conditions that it has been applied to and shown benefit. I mentioned multiple sclerosis, ulcerative colitis, I believe is another one. And these weird neurodegenerative things. I have a hard time understanding why mild antagonism of opioids is gonna have an impact on those conditions.

Why do you think? Uc, I mean, that's an interesting one.

Well, it's another one of these weird degenerative.

Through a central effect.

Yeah, yeah. I don't have a good answer for you on that. I'm just spouting off some of the headline and the studies that I've read where it's been used. I will have to go and look just for kicks when I get back the hotel room and just see about the whole mild cognitive impairment, Alzheimer's aspects of it. I clearly don't treat these patients, but it is an intriguing idea, isn't it?

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

About 10 to 12 people in it. This is all the physicians, the nurses, the trainees. It was tiny, tiny, tiny. And we were in this small little clinic. And today probably 130, 150, we have a factor of 10 or more. And we've grown to be, I think, the largest academic pain center west of the Mississippi. We one of the top in NIH fund. It's really come a long way. It's been really exciting to see the growth and the careers and the people we've helped out.

I'll finish the story of how we met. So I'm in this state of total hell. In addition to all the stuff I mentioned about this incredible pain, I couldn't even stand up. Literally couldn't stand. And if I did, I had to be hunched over. And so at the time, I was dating an anesthesiology resident, and she was the one that said, hey, we just need to get you in this pain clinic. We got to break some stuff. This is going nowhere. You're circling the drain here, kid. I think she was in her last year of anesthesiology, so I think she was doing a rotation through pain. Maybe that's probably how she weaseled me in there. So I come and see you in clinic. By the way, at this point, my mom had flown down from Toronto to take care of me. It's not like I could drive or do anything. So my mom drives me into the hospital, come in and see you. You hear the story. We'd ruled out anything that required any more surgical intervention. In other words, I'd undergone another mri. I'd had a flexion extension film. I wasn't surgically unstable. And in fact, where the original injury was didn't even seem to be what was driving the pain now. So you said, look, the first thing we're gonna do is we're gonna give you an IV lidocaine drip to see if we can just calm these sodium channels down.

Did it do anything?

So you said, well, how much do you weigh? I said, I weigh 80 kilos. You said, okay, we're going to give you 400 milligrams of lidocaine intravenously. And I said, Dr. Mackey, I just took my boards a year ago. That's a toxic dose. You said, don't worry. We're going to do it in a cardiac monitored room. You will be on an ekg and we will be able to defibrillate you if you have an arrhythmia. So I said, go for it. So in 20 minutes, I got 400 milligrams of lidocaine. Didn't touch the pain. Tried something else. Didn't touch the pain. By now, it was 8 o' clock at night.

Oh, wow.

And you said, okay, the only thing left to do at this point is to go in there and do a series of injections at every single facet joint Every single dorsal root, every nerve root, every dorsal root ganglia, the entire length of your spine. I will not be able to diagnose what is wrong because I'm basically going to stop all the pain. But then we will chip away at this over the coming months. And I said, great, can we do it now? You said, no, it's 8 o' clock at night. We don't have an anesthesiologist. I'm the only one here. I said, you're an anesthesiologist? You said, yes, but I'm the one that's doing the procedure. So I said, well, why can't we do that? And then you said, well, we won't be able to give you any sedation and I'm about to stick 45 needles in your back. And I said, I don't care. That's how much pain I am in right now. So we go into the or and you proceeded to put, I think hydrocortisone, bupivacaine. And you lit me up, up and down the back. And two hours later, I stood up for the first time in three months. I was completely pain free. This was remarkable. So we get home, it's midnight. I say to my mom, I'm not going to bed, I'm gonna go for a walk. Because like, I hadn't walked in three months. And you know the campus loop of Stanford?

Yes.

Yeah, I walked it until the morning.

It's a four mile loop.

I just walked around and around and around till 9 o' clock in the morning, came back home, went on to develop plantar fasciitis. Because when you don't walk for three months and then you don't stop walking, but put that aside. And you told me, look, you're gonna probably feel okay for a few days and then the pain is gonna come back. Well, it actually turned out to be two weeks that I was pain free. And then the pain came back. And over the next three or four months, you repeated comparable procedures, but with more and more precision. That is narrowing in it. What the problem was, and if my memory serves me correctly, it was mostly in the T12L1 area. And I think the ultimate diagnosis was, look, you lost so much disc space at L5S1 through the multiple surgeries. If you look at my MRI today, I basically don't have a disc at L5S1 that you've now developed this facet arthropathy that far up. And that's where those nerve roots are going into kidneys and testes. But what was Amazing was these injections allowed me to go and do rehab, which I took on like a vengeance, and basically rebuilt the strength in the musculature of my back. And so within nine months. Nine months of meeting you, a year of the injury, I was functional. Within two years, I could get to the point where I forgot about it for days at a time. I'll give you an example. I could actually sneeze without bracing. That was something I couldn't do for a year. I couldn't lean over the sink to brush my teeth. That's how weak I'd become. Just the moment. Arm of your torso leaning over. I couldn't do that. I had to fully brace and support myself to just brush my teeth. So you asked what was the lasting impact of that? Well, and I've told this story many times, and of course, my kids know it well. One of the lasting impacts was my absolute love for parking as far as possible from wherever I'm going. Because when I was going through this, they wanted to give me a wheelchair parking thing. And I was like, I don't want it. Just a psychological thing. I was like, I don't want it. I don't care how far I have to walk. And so now my kids know you celebrate your legs by parking far. And in many ways, that became part of this idea, this thesis I had of this centenarian decathlon, this idea of, like, what are you training for? You're training for life. Life is your sport. And that can be something as mundane as being able to walk to the grocery store if there's no spot near where you need to go, and can you push the cart to the car and all that kind of stuff. So the net. Net for me is it has been incredibly positive. Again, I'm incredibly grateful, Sean, to you, because again, had I not been at Stanford, had I not had that girlfriend, who I won't name her, to embarrass her, although I think she's still on the faculty at Stanford, by the way. I just think there's a lot of ways that story could have gone sideways. So I feel incredibly grateful. And the final part of the gratitude is that I would go on to Hopkins for my residency in an emergency room that serviced some of the most opioid, addicted people on the planet. And based on my own experience with that, I can say I always had a sense of humility about what they were going through. I always looked at it as, oh, God, I feel your pain. That is awful. And I could have been there.

Wow.

But by the Grace. So that's been my experience with it, which is 90% good.

That's a great story. I listened to that, and in one hand, I remember it, and on the other hand, it's been so.

It's one of a million stories.

You could have been talking about Bob as the doc. And I'm listening to this, and I'm like, well, yeah, that is the kind of thing I would have done late at night and just try to get it under control.

Put the fire out. Yeah, just spray the hose.

Yeah. Because normally, to be clear to the audience, I would never approach that in a chronic situation like that. It lacks all specificity. You can't learn anything from it. But I remember you just being an extremist, and we had to do something to help you.

So let me ask you a question, Sean. How common or uncommon is my story? Because when you meet a person like me, is there a part of you that thinks, we're never gonna fix this guy? Like, this guy's life is over. He's on 320 milligrams of oxy, hasn't walked in months. He's in so much pain, the lethal dose of lidocaine did nothing. Is there a part of you that thinks this is a chronic pain patient, this is a guy who's gonna be in chronic pain the rest of his life? Or do you look at a guy like that and say, no, no, we can fix this?

What I usually look at, I usually think of it as I'm confident we can really help them. I don't know what help means. Curing is such a strong word. Every once in a while, we can cure. Just eliminate, make it go away, never comes back. Like my case, like your case, which, honestly, I didn't even know about until recently.

I was lost to follow up.

Lost to follow up. I'll tell you, maybe in just a little bit, like how I did find out. I don't use the word cure. Maybe like a surgeon would use the word, because I don't want to set unrealistic expectations with patients. But I don't give up. I've never hit a point in my career with a patient where I've ever said, we're done.

I got nothing.

I got nothing. We've got so many tools available to us now. Back when we first met, we had a handful of procedures, we had a handful of medications. Gabapentin, the new kid on the block, opioids, NSAIDs, some tricyclics, but that was about it. And by the way, that also that notion contributed to the opioid crisis because we didn't have tools. Now there's over 200 medications that have shown to have analgesic properties. We have over 200 procedures that we do for pain, scores of mind body therapies, scores of complementary alternative therapies, and physical and rehabilitative approaches. The toolbox that we can draw upon is so much larger. Often the problem is not with all the tools we have, it's trying to figure out the right tool for the right patient in the right context. I frequently focus on getting people back to a good quality of life and giving them control of their life and their pain, rather than a promise to eliminate pain in the acute setting. Often it's eliminating pain because in an acute perioperative or acute injury situation, you need to eliminate or significantly reduce it before you can get people moving, which was kind of in your case. I gotta tell you, I was tempted. My memory of this was a little vague. I almost, for a moment I thought maybe I just look up my records on EPIC and just see what's what. And I'm like, no, man, that's what gets you fired. And so I didn't. I'm glad you filled in the memory gaps. I'm literally just so happy for you. Can I ask you some questions about it all? Maybe build on some of the things we've been talking about? So some of the stuff that's going on when you were in this is you were in distress. Clearly there was a lot of catastrophizing going on. If I can draw upon that term. You cut me off if I'm going off on tangents. Catastrophizing is this concept that was introduced by Albert Ellis in 1962. He was a psychologist and he also liked neologisms. So he created catastrophizing. He created the word awfulizing. Awfulizing didn't stick around. Catastrophizing was not related to pain, but got used for pain. Has three factors to it. Amplification of pain, rumination or repetitive thoughts about pain, and a sense of helplessness or loss of control over your pain.

Check, check, check.

It's natural. We get a lot of controversy in the field on this term because it has such a pejorative impact. And unfortunately, some of the docs have weaponized it against patient. Oh, you're a catastrophizer. Tragic. But it has real neurobiologic consequences. Because when people catastrophize, when they have a loss of self control, when they have rumination, it negatively impacts these Prefrontal cortical circuits that I mentioned, these cognitive systems so that they can no longer downregulate your pain. They have abnormal connections to hypothalamic regions which are key in hypothalamic pituitary adrenal axis, your HPA axis, which I know you're very familiar with. And so in an acute situation, you get a release of cortisol for stress response. You know, this is a surgeon. It's great. It keeps us alive. Chronically terrible. And so you get this allostatic overload, and it starts to thin out that brain region. You're no longer able to modulate, and it's this worsening cycle that you get deeper and deeper in. A lot of what we do in pain is we try to break those cycles. And it's not one thing. I use the interventions, the procedures to help break an immediate cycle, to get you on a path. We do this with other patients similarly. And then it's learning skills.

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

Yeah. Wow.

I mean, I had to learn how to move again correctly. I had to strengthen the muscles that were gonna make up for doing what my spine would no longer do. But you couldn't do that if you were in pain. So you had to learn to do that. And you had to be at least pain free enough to do it, but not push yourself too hard, that you would reactivate the injury like there was a balancing act, and you had to be able to sleep all these things, and you had to be able to clear your mind and get out of that catastrophizing loop.

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

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

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

Actually, I was going to say that I was somewhere recently where I was asked to define healthspan. And healthspan is squishy to define because there's like, a medical definition that I've repeatedly said I think is insufficient. So the medical definition of healthspan is the period of time in which you're free of disability and disease. So not very helpful. And I prefer a more functional version of healthspan, and unfortunately, it's too long for me to rattle off. But one of the lines is freedom from pain. Yeah. Just as it's important to have strength, stability, aerobic efficiency, peak aerobic output, explosiveness. I mean, all of these things are going to reduce as you age, but the longer you preserve them, the better. One of them is freedom from pain. Yeah.

Yeah. The data on elderly people who get a hip fracture spiral immediately downhill to death.

Yeah. The listeners of this podcast are not strangers to those statistics.

And I'm sorry if I'm repeating things.

No, no, no, no. But that particular one, it's so tragic.

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

Yeah. And it's actually been yet another benefit of this experience is the ability I now have to help my patients. If you just look at the population and understand the ubiquity and frequency of lower back pain and you realize I don't remember the numbers, but let's say a third of people are gonna go through some bout of lower back pain in their life. A number of my patients have also been in the loop of chronic lower back pain. For these patients, one of the most powerful messages I can deliver to them is learning that a setback is not permanent. So part of the journey, because remember, it's not like in the nine months after this injury got better, I never had another setback. No. Within that period of time, I would have days where I felt bad again. Now, fortunately, I never went back to laying on the floor for days. I never experienced that level of discomfort again. But there were many days when I was very uncomfortable and it would wax and wane. But over time and with every time that I would recover from one of those cycles, my confidence would go up. The ability to know that this is going to pass and I'm going to have to make some adjustments and I'm gonna have to not sit and I'm gonna have to change the way I lay and I'm gonna have to do these exercises a little bit more. That's okay, this will pass. And so I actually just got an email from a former patient. He's not even my patient anymore. And he said to me, hey, Peter, just wanna let you know, man, I have never forgotten what you said about this. And I just had a big setback last week. And this would have normally taken me down the spiral to hell. And I hear your words telling me, it's okay, this will pass. And he's like, you know what? It's a week later. I'm already on the mend.

You're a good dog.

There's no difference. It's not impacting physiology, it's impacting the psychology. And the psychology is what goes on to impact the physiology. So again, I think of that as I tell patients, this is not going to be a monotonic improvement. It's going to look more like the S&P 500, where if you step back 30 years. Yes, it's monotonically going up. Look at it for a given week, not at all. It can go down. It's quite volatile now. The volatility will decrease over time, but it never goes to zero.

Yeah, that's a great story. And it's helped you be a better doc and help People, I listen to your story, and everybody's story, obviously, is very different and personal. I have my own variant of this, and I don't talk about this much because I tend to be a little private with these things. But I suffer from cluster headaches. And all my life, as far as I can remember, I would get these headaches. It was like a bomb going off in my brain.

How often?

Every two years. Every two to three years. It's a classic fall, spring cycle. And all through my teens, my early adulthood, I'd get these two weeks being just terrible. The most insane pain I've ever had. I've broken a lot of bones in sports. Nothing trivial compared to that. And nothing I would do would work. I'd occasionally go to the emergency department, and they'd say, it's a sinus headache, and they give me antihistamines. And they'd prescribe them. And sure enough, they worked because it always went away in a couple weeks. I remember in residency getting one of these in the midst of a cardiac anesthesia rotation and barely able to get the patient to the recovery room. And I just went into a call room and I just hung out. The thing is, nobody knew what they were. I didn't know what they were, but I was scared every time these came on, I thought I had a brain tumor. I was convinced. I thought this was going to kill me. And you get really scared that it's never going away. I catastrophized after the end of, like, a couple weeks. I'm like, what the hell 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 like, well, shit, I got cluster headaches.

How are they treated?

Now, first of all, just to let people know what a cluster headache is, it typically manifests as headaches that last anywhere from upwards of a couple hours. They can occur eight times a day to every other day. They tend to have these weird characteristics. They're under a class of trigeminal autonomic cephalgias. Fancy term for simply meaning that you get eye tearing, redness in your eye. I get what I refer to as a sticky eye sensation. Like, my eyelid gets heavy and it droops. I get my nasal congestion. But one of the major characteristics is extreme agitation. Extreme agitation, meaning Beth would say, well, you better to lie down. And like, no, it doesn't matter. And I just pace. You pace and you pace and you pace until it goes away. So what I did in the period of all this fear, I learned every damn thing. I can learn about cluster headaches. Every single thing.

How many people get these? Or percentage of the population.

It's under a rare condition. It's one of those rare ones that affects men more than women, but women do get them. You think I would know the prevalence of this too.

But less prevalent than migraines.

Yeah, yeah, less prevalent than migraines. Common treatments for these, there's abortive and there is preventative. What? The preventative are like calcium channel blockers that you can take abortives, the typical migraine medications, the triptans. So I have stockpiles of triptans, high flow oxygen. So I knew I was getting one of these before these happen. I get this prodromal phase with weird appetite, sleep gets disrupted. I know. And a sticky eye sensation. I was giving a talk at the Napa pain conference and I knew they were coming on so I threw a tank of oxygen in the back of the car and shook.

And that'll rescue it now if I.

Can get it in time. If you can abort these things in time, you can save yourself several hours of absolute agony and you can catch it in like a half an hour. So the long and the short of it is it was through that journey of learning that I became informed and I developed self efficacy. So when I got these attacks, when I knew what they were, I no longer had a huge amount of fear that would further amplify things. I was fearful it was a brain tumor. I was fearful like I was having a subarachnoid bleeding. I knew what it was. It didn't change the sensory dimensions of the pain, it didn't change the agitation. But I knew even if I didn't catch it, it was going away in a couple hours. And that gives you control. So when these happen, I know I'm prepared. I know it's going to be a shitty two weeks and I buckle up, but I know how to deal with it. I know I'll come out of it. And it makes a huge difference in quality of life. And that's what messages I would try to give patients is. It's about learning as much as you can about your condition, being informed and putting that to use and ideally giving yourself a degree of self efficacy over your health. And when I listened to your story, it had parallels there. That journey that you have, you've clearly used it maybe trite to say, make you a better person. And yeah, I have a lot of empathy for people as a consequence well.

Sean, this has been a great discussion. I think we're certainly better off today as a species having a medical discipline that is devoted to pain. We have the luxury of caring about this now. There was a time when just not dying was the highest priority, and now it's we need more than that. It's not just that we don't want to die, it's that we want to be able to live pain free, not to be confused with discomfort free. I'm still a big proponent of discomfort, as I'm sure are you. We should be out there working out hard, experiencing discomfort. But chronic pain can be inflammatory to the psyche and it's not something I would wish on anybody. So it's great to know that since my time as a patient there, that department has increased log fold. And I hope that's true and trust that it's true around the country. So thanks for the work you're doing.

Thank you. Peter. It's been 20 some odd years since we've seen each other, and if I can just say, I remember when I saw you, you were kind of an intense guy.

I've mellowed.

Have you?

I've mellowed since then.

I remember thinking to myself, this guy is either going to crash and burn or he's going to do something really awesome. And then decades go by and I get this phone call from Ian and he's like, dad, Peter just gave you a shout out on one of his podcasts about how you helped him. And he's like, how do you feel about that? And I said, I'm just so happy for him. I had no idea that he's done so well for himself. And you have. Yes, you're seeing one patient at a time and providing great care, but I think this format is reaching so many people and this is what we need more of. We need more Peter Attias. We need you delivering these messages that are empowering people. You're making a big impact out there and I just appreciate you inviting me on to spend some time with you. So thank you.

Thanks, Sean. Thank you for listening to this week's episode of the Drive. Head over to peterattiamd.com shownotes if you want to dig deeper into this episode. You can also find me on YouTube, Instagram and Twitter, all with the handle Peteratti MD. You can also leave us review on Apple Podcasts or whatever podcast player you use. This podcast is for general informational purposes only and does not constitute the practice, practice of medicine, nursing or other professional health care services. Including the giving of medical advice. No doctor patient relationship is formed. The use of this information and the materials linked to this podcast is at the user's own risk. The content on this podcast is not intended to be a substitute for professional medical advice, diagnosis or treatment. Users should not disregard or delay in obtaining medical advice from any medical condition they have, and they should seek the assistance of their healthcare professionals for any such conditions. Finally, I take all conflicts of interest very seriously. For all of my disclosures and the companies I invest in or Advise, please visit PeterAttiamD.com about where I keep an up to date and active list of all disclosures.