Dr. Sean Mackey: Tools to Reduce & Manage Pain

ANDREW HUBERMAN: Welcome to the Huberman Lab podcast, where we discuss science and science based tools for everyday life. I'm Andrew Huberman, and I'm a professor of neurobiology and ophthalmology at Stanford School of Medicine.

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My guest today is Dr. Sean Mackey. Dr. Sean Mackey is a medical doctor, that is he treats patients, as well as a PhD, meaning he runs a laboratory. He is the Chief of the Division of Pain Medicine and a professor of both anesthesiology and neurology at Stanford University School of Medicine.

Today we discuss what is pain. Most of us are familiar with the notion of pain from having a physical injury or some sort of chronic pain or a headache. Today Dr. Mackey makes clear what the origins of pain are, both in the nervous system and outside the nervous system. That is the interactions between the brain and the body that give rise to this thing that we call pain. Indeed, we discuss the critical link between physical pain and emotional pain and how altering one's perception of emotional or physical pain can often change the other.

We also discuss some of the changes in the nervous system that occur when we experience pain and how that can give rise to chronic pain. We also, of course, cover different methods to reduce pain safely. And those methods include behavioral tools, psychological tools, nutrition, supplementation, and of course, prescription drugs.

We discuss the intimate relationship between temperature, that is heat and cold, and pain and pain relief. So if you're interested in the use of heat or cold to modulate pain, that conversation ought to be of interest as well.

We also touch on some highly controversial topics such as opioids. Opioids are a substance that your body naturally makes. But of course, many people are familiar with exogenous opioids. That is, opioids that are available as drugs and the so called opioid crisis. Dr. Mackey makes very clear which specific clinical circumstances warrant the use of exogenous opioids with, of course, a warning about their potent addictive potential. And we get into a bit of discussion about where the opioid crisis and the use of opioid drugs to control pain is and is going.

Before we begin, I'd like to emphasize that this podcast is separate from my teaching and research roles at Stanford. It is, however, part of my desire and effort to bring 0 cost to consumer information about science and science related tools to the general public. In keeping with that theme, I'd like to thank the sponsors of today's podcast.

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And now for my discussion with Dr. Sean Mackey. Dr. Mackey, welcome.

SEAN MACKEY: Oh, it's a pleasure to be here. Thank you.

ANDREW HUBERMAN: This is a long time coming. We're colleagues at Stanford and I'm familiar with your work. But today we're going to take a pretty broad and deep survey of this thing called pain. So I'll just start off very simply and ask what is pain?

SEAN MACKEY: Pain is this complex and subjective experience that serves a crucial role for all of us to keep us away from injury or harm. It is both a sensory and an emotional experience. And I think that gets lost on people that it includes this emotional component to it. And it is incredibly individual. And we'll get more into that hopefully as time goes by that your pain is different from my pain and is different from everybody else's.

It takes an incredible toll on society when it goes chronic, when it becomes persistent to the tune of about 100 million Americans and at last count about a half a trillion dollars a year in medical expenses. So an astounding problem we're facing in society and one that's only getting worse.

And I'm hoping during the course of this discussion that we can break down a little bit of the foundation of pain and kind of build it back up. Because unfortunately, in society there's a lot of misunderstanding about what pain is. And I think hopefully we can build that foundation and then layer on some useful treatments and useful options for people.

ANDREW HUBERMAN: I'm glad you pointed out this link between the sensory and the emotional experience. Every once in a while I'll pull something or I'll have a kink in my neck or my back. And fortunately for me, it resolves pretty quickly. But I notice that when I'm experiencing that kind of pain that I become slightly more irritable, perhaps much more irritable depending on who you ask, and that everything becomes more challenging. Thinking is harder. Sleeping is harder. Concentrating on anything besides the pain. It's as if something's nagging from the inside. And so that raises the next question that I have, which is, is pain something that's in our brain, in our body, or both?

SEAN MACKEY: It's clearly in our brain. And can I take a moment to lay a little foundation for some of that, to help clear up some of the mystery of pain? We know that pain, most pain, all starts with some stimulus, whether it be that kink in your neck or your shoulder from working out or turning the wrong way. And what's going on there in your body is not pain.

What's going on is that there are sensors in our skin or soft tissue or deep tissues called nociceptors. And these nociceptors are sensing elements. And they sense different types of stimuli. They can sense temperature, heat, cold. They sense pressure. They can sense pH changes due to, for instance, inflammation that may occur from something going on in your neck or your shoulder.

Those send signals up nerve fiber types. And the two that we refer to are A delta and C fibers. One transmits very fast. It's responsible that sharp jolt of pain that goes to your brain when we step on a tack or put our hand on a hot stove. And there's another fiber called a C fiber, which is much slower and responsible for that dull, achy pain.

Now, these signals, they go to the spinal cord. Lie up and down from our head down to our back. And they're shaped, they're changed a little bit. They then are sent up to the brain. And it's once they hit the brain and they converge with this magical mystery set of nerves in the brain that it becomes the experience of pain.

And if there's one key message I'd like to get to the audience is that what goes on out here, what goes on in your shoulder, in your neck is not pain. That's nociception. Those are electrical signals, electrochemical impulses being transmitted. And that is to be distinguished from what becomes the subjective experience of pain that you have.

And why it's critical is that our brain serves so many functions of emotions, cognitions, memory, action. All of that shapes those signals coming in from our body to create your unique experience of pain that's different from everybody else's. And I think that's important to note, because we are frequently left with this notion of this one to one concordance between the stimulus and the experience of pain.

Rene Descartes, that French philosopher, I think 17th century, was the one who first postulated this idea of this direct linkage between the body and our actions and the stimulus and the response. And it's wrong. And unfortunately, even in medical care, we have this biomedical model that still is perpetuating this idea of a one to one relationship.

And that's a critically important point to get across, in large part because frequently, as humans, we tend to project onto others our own experiences of pain. And when we see somebody who's got an injury or something else going on, we immediately put that on them. And that has also been a problem with many people suffering in chronic pain, which is often viewed as the invisible disease.

ANDREW HUBERMAN: So when you say we put that on them, you mean when somebody reports being in pain, we have a hard time understanding what they are experiencing because it's going to be very different than the way that we experience pain. Conversely, if somebody is in pain, they tend to assume that people are experiencing pain the way that they are. Do I have that right?

SEAN MACKEY: You have it perfectly right. And actually, if I can build on that, it gets worse, because sometimes you have conditions like fibromyalgia that maybe we'll get into where outwardly, visibly, you don't see anything wrong. We're used to thinking of pain as a fractured bone, as a swollen ankle. We see that. And then we're like, OK, well, you've got pain. You've got legitimate pain. Whereas this invisible disease of chronic pain frequently, you don't have something outwardly that you're seeing. But we bring in our own history of pain and we put that on other people.

ANDREW HUBERMAN: I have a question that's somewhat mechanistic, but we'll keep it accessible to anybody, regardless of their background. So you mentioned the nociceptors are in the body and everywhere in the body and on the surface of the body to be able to detect certain kinds of stimuli. And then those signals are sent up into the brain and the brain creates this subjective experience that we call pain. Is there a dedicated set of areas in the brain that are something akin to like a pain pathway?

And the reason I ask this is that for vision, for hearing, for touch, we probably all experience those somewhat differently. Your perception of red is probably a little different than my perception of red. We don't know for sure, but experiments support that idea. But there's a major difference between people experiencing the same thing differently according to a mysterious mechanism in the brain as opposed to an area in the brain that we can look and say, hey, that's where pain is represented. That's where all these inputs from the body are put together to create this thing that we call pain.

Is there an area of the thalamus, a structure in the middle of the brain, that takes incoming sensory information that we could say, oh, that's the pain pathway? Is there a part of our neocortex, the outer shell of the brain more or less, beneath the skull, but nonetheless on the outer portion of the human brain, that we could say, oh, that's where pain exists? Or is it a distributed phenomenon?

SEAN MACKEY: Yeah, that's a great question. Because we'd all love if there was a pain center in the brain that we could just go knock out. But it's not that simple. And in part because pain is such a conserved phenomenon, it is there, it is so wonderful because it is so terrible unless it goes wrong. But when you knock out one pathway going to the brain, there's others there that will carry that system forward. And you'll still experience pain and it's there to keep us all alive.

Now, to get to your point, no, there's not one pain brain area. It is thought to be more of a distributed network of different brain systems. We at one point in time called it the pain matrix, which represented areas such as the insular cortex, the cingulate cortex, the amygdala, a number of these brain regions that all subserve different functions. We're moving away from that, because it seems like every year or so we pick up another region of the brain that's contributing to this network that subserves some additional functions, some nuanced layer to it.

That said, we have been able to identify some common signatures, common brain networks that seem to represent the experience of pain. And this is where the development of brain based biomarkers has come in. And this is some of the work that I've done starting, gosh, well over a dozen years ago and others have been building on. And what we're finding is that there does seem to be this conserved region, set of distributed regions that do represent the experience of pain.

ANDREW HUBERMAN: So when somebody takes a so called painkiller, let's take a typical over-the-counter painkiller like an ibuprofen or acetaminophen, to lessen pain of some kind. Where is that drug or drugs acting? Is it in the body or is it at the level of the brain or both?

SEAN MACKEY: Yeah. And this is where some of the challenges we get into with language, because technically NSAIDs, nonsteroidal anti-inflammatory drugs like ibuprofen, like Naprosyn, they're actually not analgesics. They're not technically pain killers.

ANDREW HUBERMAN: So an analgesic is the descriptor for a quote unquote "painkiller"?

SEAN MACKEY: Yeah, that would be more correct. Like an opioid would fit into that category. The NSAIDs are anti-inflammatory drugs. There's another, this is a technical term, they're anti-hyperalgesic drugs.

And so one of the things that happens after an injury is that we get sensitization of the area that's injured. And it's a beautiful thing, because it sends a message to us to protect it. What the NSAIDs do is they reduce some of that sensitization out in the periphery and then back in the spinal cord and in the brain.

But they don't actually-- so for instance, I was going to say try this at home, but probably not. You can in a normal situation hit your hand with a fork. Measure the amount of pain. Now go take an NSAID like ibuprofen. If you hit your hand with that same fork, there'll be no difference.

ANDREW HUBERMAN: Folks, please don't do that.

SEAN MACKEY: Don't do that at home, please.

ANDREW HUBERMAN: Or anywhere, for that matter. Or anywhere, for that matter. But you're describing pain and the local inflammation response and the hyperalgesia, the increase in pain in that general area, as something very adaptive, very important. So it raises the question, what is the threshold for saying that somebody should treat their pain, reduce their pain?

I mean, any time I've done surgeries on animals, which I don't do anymore in the laboratory, but we used to, you would give them painkillers postoperatively. I've had surgeries before. I've had painkillers postoperatively, although I don't like taking them. I don't like the way they make my brain feel. But we of course know that if you increase the dose of any pain medication too much, then that animal or a human can potentially injure themselves worse or not protect that injured area.

So it raises a whole set of medical ethical but also just purely biological questions. How do you set the threshold for, yes, blunt pain versus, no, allow the pain to be there as an adaptive way of protecting yourself and healing? Presumably the inflammation is part of the healing process too. And as you mentioned before, pain is so subjective and it's different between all of us. I mean, how do we decide whether or not it's a good or a bad idea to blunt that pain?

SEAN MACKEY: Yeah. I think the threshold is when it's impacting your quality of life and your ability to take care of the activities of daily living, engage with family, friends, go to work. And that serves kind of your threshold for whether it's reasonable to take a medication or not. So a lot of controversy in the space right now. It used to be we all recommended just NSAIDs for any type of acute injury.

ANDREW HUBERMAN: So NSAID is non-steroid anti-inflammatory drugs?

SEAN MACKEY: Indeed.

ANDREW HUBERMAN: Could we maybe list off a few of those? So I mentioned ibuprofen, acetaminophen, so sometimes referred to as the classic Advil, Tylenol, we won't throw out name brands there. But what are some others? Naproxen?

SEAN MACKEY: Naproxen is another one. Toradol or ketorolac is another one. The two over-the-counter NSAIDs, the prototypical over-the-counter ones, are ibuprofen and Naprosyn. Those are the ones you can buy over the counter without a prescription. Tylenol actually has a slightly different mechanism of injury but still fits in that same general class. It tends to be more centrally acting, Tylenol or acetaminophen.

ANDREW HUBERMAN: When you say centrally, you mean brain?

SEAN MACKEY: Brain. Thank you. Thank you.

ANDREW HUBERMAN: And is aspirin considered an NSAID? I don't believe--

SEAN MACKEY: Yeah. Aspirin would fit into that category of basically a cox, cyclooxygenase inhibitor. This is one of the chemical mediators that gets released during injury. And that chemical substance has a tendency to wind up or amplify the nociceptors so that after an injury, you note that you're more sensitive there.

After a sunburn, you end up having more sensitization. That is what we refer to as peripheral sensitization. Because it's out in the periphery, we're winding up or amplifying the response. Aspirin, NSAIDs in general will reduce that inflammation. They're anti-hyperalgesic. And pardon again the jargony terms that we use.

ANDREW HUBERMAN: We're bringing people along as we go.

SEAN MACKEY: But to your point, you don't want to, for instance, let's imagine you have a fractured ankle. You don't want to be reaching for a very potent opioid just so that you can continue walking on a fractured ankle that you haven't gotten evaluated by a clinician and perhaps casted. That wouldn't be safe. Those are rather extreme examples. We get into those debates in professional sports where they send the person back out on the field with a broken bone having given them an injection or something. I'm hoping that doesn't go on anymore.

ANDREW HUBERMAN: I'm sure it goes on. Well, there's all sorts of other things. I get contacted all the time professional teams and athletes asking how they can get back in quicker. Nowadays the big thing are these peptides that can certainly accelerate healing. People are traveling out of country to get stem cell injections, all with very few randomized controlled trials. But I assure you that courtside and in the locker room, mainly in the locker room, there are corticosteroid injections, there are painkiller injections. I mean, it's not play at any expense, but it's not far from that.

SEAN MACKEY: Well, when you're making millions of dollars a year, and I get the being back on the field. But for the rest of us mere mortals, I think that's where we would want to draw a line. Get medical attention if you've got an acute injury.

ANDREW HUBERMAN: Going a little bit deeper into mechanism, because I think it's going to serve us well now and going forward, you mentioned the NSAIDs and this C-O-X, cox. Is it in the family of prostaglandins?

SEAN MACKEY: Yeah.

ANDREW HUBERMAN: Can we talk about prostaglandins? Because I think there are a lot of people nowadays we hear about inflammation. Inflammation is bad, inflammation is bad. But one of the things that we talk about a lot on this podcast is the fact that cortisol isn't bad. Inflammation isn't bad. These things serve an important biological role.

So the prostaglandins seem to be one of the main ways that our immune system responds to a physical or chemical injury and creates inflammation. And as you said, that inflammation sensitizes an area, makes it literally more sensitive. And then we introduce these drugs to restore normal functioning and living. Could we establish what normal functioning is?

I mean, for instance, if we make this really concrete, could we say, well, if you can fall asleep at night and stay asleep or perhaps go back to sleep after you've woken up in the middle of the night, then, well, you heal during sleep. And so take as little painkiller as possible but enough that still lets you sleep well at night. Is that sort of normal functioning? Because when I have a kink in my neck, I don't want to do much of anything. I try but it's really frustrating. So I mean, as a physician and as a patient, how do we determine normal functioning?

SEAN MACKEY: Yeah. And you're getting into the nuance, the complexity of this problem. Because we've been talking about NSAIDs, the ibuprofens and Naprosyns. And as I said early on, we used to just give these out all the time. But then the research comes out and shows that by blocking inflammation, by blocking that, we may be blocking the normal healing process. And so we've seen delays in fracture repair. We've been seeing delays in tissue repair.

And so now you've got on one hand a medication that may help with pain, help you improve function. You've got on the other hand something you're taking that may delay the process. Where do you draw the line? As a physician, my approach is really basically what you said. It's balancing the fact that if you're not sleeping at night, you're not going to heal and you're not going to be able to do what you need to do the next day. And if taking an NSAID helps you sleep and helps you engage with what you need to do, take it at the lowest dose that you can get away with.

ANDREW HUBERMAN: I've heard before that NSAIDs be taken no more than once every six hours. People will alternate different types of NSAIDs every three hours. That's usually to try and reduce fever, another situation where an adaptive response fever, people go out of their way to block it, to prevent the brain from cooking. But again, it opens up the same set of issues.

And so I'm wondering if somebody has some pain that makes moving about frustrating and it's difficult but they can sleep at night reasonably well, maybe not as well as they normally do, would your suggestion to that person, if their goal is to heal as quickly as possible, to just not take anything?

SEAN MACKEY: Yeah. So we've got a lot more data on the benefits of NSAIDs, this class of medication reducing pain, than we have data showing the bad consequences of it. And so we're still needing more data on the whole healing message. I think that a lot of the orthopedic surgeons out there prefer people not to be on NSAIDs after, for instance, a total hip replacement, a total knee replacement. Because I think that's pretty clear. But that's not what we're talking about right now.

So one of the other interesting things about NSAIDs, like we mentioned ibuprofen and Naprosyn, huge individual variability around those. So personally, ibuprofen is not very effective for me. Naprosyn is. For others it may be just exactly the opposite. So there's value in rotating them and finding out which works best for your particular situation.

You mentioned the timing of it. Ibuprofen is typically given no more than three times a day. It's got a short half life. Naprosyn, twice a day. What's critical, I need to give this message, is in both situations, make sure that you have food in your stomach. Make sure you're not taking it on an empty stomach. Make sure you're drinking plenty of fluids. And if you've got any GI issues, if you've got any bleeding issues, if you've got kidney issues, if you've got heart issues, talk to your doc. Talk to your clinician before you embark on this, because these medications do have side effects and adverse consequences in vulnerable people.

ANDREW HUBERMAN: And what about aspirin? I've heard that aspirin can benefit heart health. So I take a baby aspirin every day. And if I have a pain that is just too intense for normal functioning, as we're defining it, then I'll increase that dose of aspirin. And I just assume aspirin is the healthiest NSAID for me because, well, it's also good for heart health and it's killing pain in those instances as opposed to taking anything else. Is my logic flawed? And if it is, feel free to tell me.

SEAN MACKEY: No. For you, your logic is perfect. And that's where it gets to the individual person. And for a lot of people, that model would work as well. So baby aspirin 81 milligrams a day acts as an antiplatelet agent. It helps here even though we're getting controversy over the role of baby aspirin if you dive into the current literature.

ANDREW HUBERMAN: Even baby aspirin is controversial?

SEAN MACKEY: Even baby aspirin these days. And now what they're doing with the data is defining age ranges when they say baby aspirin yes, baby aspirin no. And so we're learning a lot more about that. I still take a baby aspirin.

ANDREW HUBERMAN: Every day?

SEAN MACKEY: Yeah. I take a baby aspirin. You get to the higher doses, say four times as much, up around 325 milligrams or so, it's now an anti-inflammatory. It's now acting more like the ibuprofen and the Naprosyn. So different mechanisms of action at different doses.

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I promise we won't go into every medication in such detail, but these are the most commonly used over-the-counter treatments for pain, as far as I know. Are there any issues with people who drink caffeine who then are taking these drugs? What are some of the interactions that these things can have? As far as I know, caffeine actually touches into the prostaglandin pathway, doesn't it?

SEAN MACKEY: Yes. And that's where caffeine can be used effectively for headaches, for migraines. And it can help potentiate the analgesic response. Some people get stomach irritation though with caffeine. So just, again, mind that you take an NSAID with a lot of coffee, have some food in your stomach.

You brought up earlier acetaminophen or Tylenol. Tylenol doesn't have the same side effect or adverse event profile that the NSAIDs do. So Tylenol is safe on the stomach. Where you need to be careful about Tylenol is not to exceed 4,000 milligrams or 4 grams per day in divided doses. So two Extra Strength Tylenol done four times a day for many people is safe. Some say 2 grams, some say 4 grams. The key here is around your liver. So if you've got good liver function, if you're not abusing alcohol, that's a general rule of thumb that you can use for Tylenol. But it's not going to upset your stomach.

There are versions of the NSAIDs that we refer to as cox2 inhibitors. They're very selective, like celecoxib, that is less irritating on the stomach. That's by prescription only though. But you can think of it as working very much the same as the Naprosyn and the ibuprofen. So talk with your clinician to try to tease those apart. If you have problems in your stomach with the NSAIDs and they're really effective for you, you can be given other types of medications that help block or reduce the GI issues associated with the NSAIDs.

ANDREW HUBERMAN: Very useful information. Thank you. Here we're talking about chemical interventions to the pain process. What about mechanical interventions? So I was taught in my basic neuroscience about I think it's Melzack and Wall's gate theory of pain. Do I have this right?

Where we all have this instinctual response, animals have it too, if you bump your knee or your toe that you grab it and you rub it and that that rubbing response is actually contributing to the activation of a neural pathway that does indeed reduce the pain through a legitimate neural inhibition. And tell me if this is still considered correct and then I'll let you elaborate on it.

But I think that is an opportunity for us to also talk more generally or for you to educate us more generally on the mechanistic interventions for pain. Maybe massage above or below the site of pain. Maybe acupuncture. So again, there will be chemical consequences of any mechanical intervention, as we know, because that's the language of the nervous system, electricity, and chemicals. But as opposed to taking a drug, you could imagine using manual stimulation or rubbing around it or perhaps we can also talk about heat and cold. So can we explore that space a bit?

SEAN MACKEY: Absolutely. And first, you're right in your first part. Patrick Wall, Ron Melzack, luminaries in the field of pain back in the '60s, defined the gate control theory of pain. And one of the things to build on the story that we talked about with nociceptors going to the spinal-- signals going to the spinal cord, heading up to the brain where the perception of pain occurs, that's not where the story ends. It turns out there are pathways that come down from the brain, down from the brain to the spinal cord that act in an inhibitory role. And we'll build on those also.

From the periphery, we've got also fibers called touch fibers. These are the ones where they get activated with light touch, stroking. They're referred to as A beta fibers. They're fast conducting. They head back to the spinal cord, and they make some connections with those nociceptive fibers.

So with that grounding, imagine what you said. You hit your thumb with a hammer you. You bang something on an extremity. What is the first thing you do when you hit your thumb with a hammer? Some people rub it.

ANDREW HUBERMAN: I yell.

SEAN MACKEY: Some people swear. And it turns out there are studies that show that swearing works.

ANDREW HUBERMAN: Really?

SEAN MACKEY: Swearing reduces pain.

ANDREW HUBERMAN: Better than using non-explicative loud vocalizations?

SEAN MACKEY: Yes. Swearing works. I don't know why. But it got some press when that paper came out. And I'm not giving carte blanche. We're not saying everybody can go out and swear every time they're in pain.

ANDREW HUBERMAN: Well, they can, but they'll have to bear the consequences on an individual basis. We're absolving ourselves of any responsibility.

[LAUGHS]

SEAN MACKEY: So rubbing, shaking is another one, which basically is activating those touch fibers.

ANDREW HUBERMAN: Oh, it is. Because I do that.

SEAN MACKEY: Everybody does that. Everybody does that. Running it under water, which it doesn't matter whether, in this case, it's hot or it's cold water. It's the running of the water underneath it. And what is it doing? We all think it's reducing the stimulus out here and it is not.

ANDREW HUBERMAN: In the periphery?

SEAN MACKEY: In the periphery. What's magical about that, I think, which is so cool is you're actually changing the signals in your spinal cord way back here.

ANDREW HUBERMAN: In the neck.

SEAN MACKEY: This is the cheapest free version of what we refer to as neuromodulation that's ever been discovered. You're actually, by doing that, you're changing things, the connections, back in your spinal cord. And it's reducing the nociceptive signals coming in here. That's why we do it. And it works. It works beautifully. That's why when a kid gets their boo boo, parents come and rub it. It works.

ANDREW HUBERMAN: What about the kiss that kids sometimes they want a kiss? Or a romantic partner will sometimes injure themselves. I guess it depends on the nature of the relationship. And they'll say, can you kiss it?

SEAN MACKEY: Of course.

ANDREW HUBERMAN: And you kiss it and then they feel better. Is that purely psychological?

SEAN MACKEY: Well, OK, I think an important point to ground here when it comes to the experience of pain is that everything, when we say psychological, means neuroscience. I know you know.

ANDREW HUBERMAN: Yeah, no, forgive me. I have to be careful with the wording that I use. That's my fault.

SEAN MACKEY: But it's accurate still. It is psychological, but it is neuroscience based. I mean, they're really becoming one and the same. But to answer your question, yes, by kissing it, you're activating touch fibers. We can also agree that there's a positive emotional salience that's associated with that. And that positive emotional salience is reducing pain too.

What's interesting, Wall and Melzack sometime later, there was the introduction of a device to take advantage of this called the tens device. And tens is an acronym. Transcutaneous electrical nerve stimulation. And what the tens device is doing, and there's many versions of it now, but there are those black electrodes you put over the area. And they're hooked up to wires. And when you turn it on, it causes a buzzing sensation. And that buzzing sensation is activating those touch fibers, the A beta fibers. And so it's causing that neuromodulation back in the spinal cord.

ANDREW HUBERMAN: Amazing.

SEAN MACKEY: It's cool stuff.

ANDREW HUBERMAN: It's very cool. And I love that you emphasize that when we're rubbing the periphery or shaking our hand, the periphery again being the body surface away from the brain, that the real mechanism of action is taking place back in the spinal cord. Because it really speaks to the body wide and the circuit wide, the nervous system wide nature of this thing that we call pain. It's happening out, quote unquote, "out here" in the periphery, but it's being modulated in the neck level of the spinal cord approximately. And then it's being interpreted at the level of the brain.

What explains different pain thresholds? I could imagine it could be any or all of the locations that we've been discussing. And it could be the context as well. I've heard before, and I don't know if this is true, that if you have a lot of adrenaline, epinephrine, in your system that your threshold for pain goes way, way up. There's probably a chemical basis for that. And maybe it's all anecdote.

But certainly people have different thresholds for pain. I, for instance, do not have a high pain threshold, but I've noticed I have a very quick pain response. So if I stub my toe, it feels like the most painful thing I could possibly experience. But then it's gone very quickly. So it's like a quick inflection and then down. Other people I know, we've never done the experiment, I see them stub their toe and they're like, ugh, and then 10 minutes later, they're still feeling the ache.

So whose pain threshold is higher? It depends on how you define pain threshold. So how do we define pain threshold? What determines pain threshold? And I guess the $6 million question, are there different pain thresholds between men and women? As it relates to the whole story about childbirth being very painful and that women, quote unquote, have "higher pain thresholds." I just sent you about 10 questions. So forgive me. So what is pain threshold?

SEAN MACKEY: Yeah, no, it's a great place to start. And maybe, I don't know if you want to circle back around at some point to the heat and cold to finish up the mechanical.

ANDREW HUBERMAN: Yeah, forgive me.

SEAN MACKEY: No, no, no. Let me answer your-- get to your pain threshold. So the pain threshold is that stimulus intensity that results in the onset of the experience of pain, the first onset of the experience of pain. So when you turn up the heat, it's not when it's warm. It's not when it's just hot. It's when the heat becomes the perception of pain. When it becomes painfully hot at that point in time. The same works for cold.

You mentioned some of the distinction between your experiences of pain to a stimulus and your buddies. And that's normal. That first onset of pain, again, those fast fibers, those A delta fibers, boom, right to your brain. Those are the protective ones that when we put our hand on a hot stove, we immediately jerk it back. We don't even have a conscious perception yet that we did that.

And then it's a moment later when the C fibers are getting up to the brain and the other A delta fibers are converging into conscious areas of brain that were like, oh wow, that stove is really hot. And the C fibers in particular are converging on more emotional regions in the brain that are conveying an unpleasantness to that experience. You don't like it. And you don't want it to happen again, which is why it encodes memories. So you only had to do that once as a child.

Now, getting into the pain threshold. You asked one of the other questions is do men and women have different pain thresholds. The short answer is yes. This has been established. And I want to be careful here with saying a couple of things. One is in general, men have higher pain thresholds to things like heat stimulus than women.

And what people have to also, though, understand, as scientists, we make a big deal out of small differences. What we do is we take a group of people, in this case, men and women, and we apply the same thermal stimulus to them. And we draw averages. The average man has this stimulus. The average woman has this stimulus. And we say, well, women have a little bit more sensitivity to that heat stimulus. And so we then go into the press and we say, men are tougher than women. That's a terrible statement.

ANDREW HUBERMAN: Right. Because the tough part is a subjective label. I mean, it gets to a whole bunch of different issues around the adaptive role of pain. I mean, one could argue that if your threshold for pain is lower, that it serves a more adaptive function. Fewer injuries, et cetera. I mean, I guess it gets into the implications of what we mean by, quote unquote, "tougher."

SEAN MACKEY: It does. But it also misses, I think, the big point, which is people are not averages. So what I mean by that is while the average for a woman may be somewhat less than a man, if you look at the distribution of the curves, they highly overlap. Meaning the individual variability within men and within women is much greater than the difference between men and women. There's plenty of women on that curve that have much greater heat thresholds than men do. But when you pool things, you end up with that difference. Unfortunately, when things are picked up and you want a quick soundbite out of it, that's what it gets distilled down to.

ANDREW HUBERMAN: So it's not unlike height, for that matter. I mean, there are a lot of women that are taller than men.

SEAN MACKEY: That's exactly it.

ANDREW HUBERMAN: But on average, men are taller than women.

SEAN MACKEY: On average. And I would say within this area of pain threshold differences, it's even closer. It's even tighter. It would be, I'm making this up, I think the average height of a woman is 5' 3'', 5' 4'', the average height of a man 5' 9'', 5' 10''. This is imagining the average height being 5' 6'' for a woman and 5' 8'' for a man. It's not a huge difference.

There's a lot of things that play into changes in pain thresholds. And this is where the brain comes in. Because much of the nociception, much of the signals that we're transducing, we're transmitting, in many of us, it's very much the same. It's when it gets to the brain now it's shaped. And it's shaped by things such as your beliefs about that stimulus, your expectations around it, how much anxiety you're having at the moment.

ANDREW HUBERMAN: Does increased anxiety increase one's perceived pain?

SEAN MACKEY: Yes. Yeah, it does. Your early life experiences with this. So have you had traumatic experiences in the past? That alters brain circuits.

ANDREW HUBERMAN: Can I interject a question? If one was told just suck it up a lot or if one whimpered or cursed when they hurt themselves, if they were told, don't be a wuss, don't be a wimp, do we know whether or not that increases or decreases the subjective feeling of pain later?

I could imagine it going either way. I could imagine the kid that was told, don't be a wuss when they cried as a consequence of expressing pain or an experience of pain secretly feeling more pain because they aren't able to express the emotionality around the pain. But that if we just look from the outside, we say wow, they're a pretty tough adult, because they're not crying out in pain. So do we have any-- are there any experiments that have explored that?

SEAN MACKEY: I don't know. You're getting into, this is a good point, getting into pediatric pain and if there's been experiments in that space. I stay mainly in the adult area. And my experience with raising a child is an n of 1 with one son.

ANDREW HUBERMAN: He's done great.

SEAN MACKEY: Thank you.

ANDREW HUBERMAN: I happen to know him very well. He's what you call a great example of highly successful reproduction.

SEAN MACKEY: What do they say? It's better to be lucky than good.

ANDREW HUBERMAN: I'm sure there was a lot involved. So don't discard any credit.

SEAN MACKEY: Thank you. Thank you. My approach with Ian was not to say necessarily suck it up. But I would make light of it. I'd have fun with it. And I would kind of laugh and I'm like, way to go, buddy. And I would find he would often laugh. So I think a lot of it is the cues they're taking off the parents. And again, this is just 1 of n parent is if they see you freaking out, kids are going to freak out too.

But does there get to be a point where you're ignoring your child or your loved one's painful issue? Yeah. Now you're getting into some maladaptive, some bad space where I think it's sending that person the wrong message. And they may very well have problems later on.

ANDREW HUBERMAN: I will tell just a very brief anecdote. When I was growing up, I observed a total of 0 children and friends who cried out in pain or complained of pain who were told that was an inappropriate response. Sometimes I might have heard parents say, come on, just suck it up or rub it. You'll be OK. That kind of thing.

But once and only once we had some friends. I won't tell you what country they were from. But they lived not far from where both Ian and I grew up, since we grew up near one another. And I'll never forget that the younger brother of a friend of mine ran over to the father. He had cut his thumb on the bandsaw. And it wasn't particularly deep, but he was crying in pain. And the father wrapped it, picked up his chin, and smacked him across the face and said, don't ever do that again.

And so what I think he was doing was compounding the lesson about the saw, but clearly had no regard for the pain that the injury probably caused. Now, I haven't followed up with that kid. I think we can all agree that by today's standards, that would be considered abusive parenting or perhaps one could say that was on the far extreme of a response. But I'll never forget that.

And I went home and I told my mom. And she said, oh yeah, when I was growing up, that was actually a more frequent response to kids hurting themselves, especially boys. And so things have really changed in terms of how we react to children in pain. But the reason I find this interesting is that ultimately what we're talking about is how should we interpret our own pain?

SEAN MACKEY: Yeah. I can I make a commentary about that scenario? And I want to bring in another neuroscience concept that that dad may have been doing inadvertently. And that's something called conditioned pain modulation. So there's another cool phenomenon in pain that pain inhibits pain. So what I mean by that is when this guy, this kid, or yourself growing up, did you ever walk up to your buddy and say, my arm really hurts. I injured it the other day. And what did your buddy do? They'd stomp on your foot. And you'd say, why the heck did you do that?

ANDREW HUBERMAN: You and I must have grown up with the same friends.

SEAN MACKEY: Oh yeah, yeah. And they'd say, well, now doesn't your arm feel better? And I'd be like, well yeah, it does. And yeah, I did grow up with those friends. I tell this story to some people and I sometimes just get the wide eyes like, they did what?

ANDREW HUBERMAN: Yeah, we are not making recommendations here.

SEAN MACKEY: We're not making recommendations. But it's a real phenomenon. It was described by Le Bars, late '70s, '78 or something like that, in rodent models initially. And what happens is that when you engage a nociceptive stimulus or a painful stimulus in a site distal, different from where the primary pain is, it engages a brain stem circuit that has descending pathways to the spinal cord and inhibits pain.

ANDREW HUBERMAN: Amazing.

SEAN MACKEY: Pain inhibits pain. It works. It also is thought to have some contributions from higher brain centers. We call this whole phenomenon, Le Bars called this phenomenon Diffuse Noxious Inhibitory Control or DNIC. The human version of this is called conditioned pain modulation.

Why I bring this up, not only to help explain that father's actions, somehow I don't think that he was thinking, oh, my kids got a painful hand or finger. He cut himself. I'm going to slap him off the side of the head. He'll feel better. I don't think that's what was going through his head.

ANDREW HUBERMAN: No, he wanted to make him feel worse so he didn't go near the bandsaw without being more cautious.

SEAN MACKEY: But it probably did reduce the pain a little bit to some extent. Now, where it's key is, and maybe we'll get into it later with chronic pain is, in some chronic painful conditions, the CPM or the DNIC doesn't work, fibromyalgia being one. So pain inhibits pain is another neuroscience concept related to pain that's rather cool. And I'm sorry, I missed your question. Could you repeat?

ANDREW HUBERMAN: No, you answered the question and expanded on it in a completely surprising and far more interesting way than I ever anticipated. So thank you. I'm betting that 98% of people listening to this, including myself, have never heard that pain inhibits pain. Incredible.

Let's go back to heat and cold. We briefly touched on heat, but let's talk about the use of, quote unquote, "therapeutic heat" or therapeutic cold, a cold pack for a bruise that really aches or maybe even a break or a sprain or heat. In the world of sport physio, cold is now heavily debated, localized cold, is heavily debated.

You get people saying things, I don't know if this is true, that it creates a sludging of the fluids trying to head in and out of the injury. So cold is not as good as heat. Heat allows for the inclusion and removal of waste products. And there are all sorts of just so stories that people make up, some of which might be true. I don't know.

But what do we know about heat and cold as physiological stimuli in terms of their ability to ameliorate, to help pain? Because of course, you get things hot enough or you get them cold enough, you can create pain with heat or cold. But let's assume we're not getting to that level of heat or cold and one is in pain. When I was a kid, we had a hot water bottle that for times when we were sick or something. But sometimes if I felt an ache on the side, I'd put some hot water in the hot water bottle and lie on that thing and watch some cartoons. I definitely felt better.

SEAN MACKEY: Sure, sure. Well, putting aside the contemporary controversies over the mechanisms you described, which are, I think, very real and need to be sorted out, traditionally, historically we tend to think of applying cold for the first 48 hours or so after an acute injury and then heat thereafter.

Cold has some really cool effects. Cold reduces inflammation. So it reduces some of the release of those inflammatory chemicals. We talked about prostaglandins, cytokines, histamines, other chemokines, all these fancy terms for substances that sensitize the primary nociceptor. And it reduces the release of those and it reduces inflammation.

Another cool thing often not appreciated is nerves don't fire as fast when they're cold. And so if you've got nociceptors that are firing and you put cold, it's slowing the number of signals coming up. And by definition, it's reducing ultimately the pain you're experiencing.

Now, heat, heat has an obvious effect of increasing blood flow. It's going to help relax muscles and get blood into those muscles. And that's probably why you're putting that hot water bottle on. And it just darn feels good.

And so what do I tell people? In part, I tell people use whichever works best for them. I find there's huge individual variability in whether people like heat or like cold. And within reason, they're safe. What do I mean within reason? Don't go putting an ice pack on an extremity for two hours. You'll get a frostbite. So take care with that.

ANDREW HUBERMAN: How cold should one make the point on their body that's in pain? Assuming, of course, that they're not going to give themselves frostbite. Meaning do you want to numb the area, get past that point where it's a little bit painful and then basically you're shutting down some neural pathways and you don't feel anything there. It's numb and then you let the blood flow return when you remove the cold pack.

SEAN MACKEY: I mean, that's a reasonable suggestion. Yeah.

ANDREW HUBERMAN: All right. Well, people I think will appreciate the specifics of that. And of course, listeners of this podcast often are interested in whole body deliberate cold immersion, cold showers, ice baths, et cetera. Most people experience those as somewhat painful as they get into them and then can experience some numbness when they get out.

Is it possible to raise one's pain threshold through the regular exposure to pain in ways that are safe, such as deliberate cold exposure, assuming that one doesn't stay in too long and it's not too cold? And/or through we were talking about sports earlier, but just in general, can we raise our pain threshold so that life is less painful?

SEAN MACKEY: The short answer to your last question is yes. The answer to your other question about extreme cold and cold exposure, which I know you have a lot of expertise and you can teach me a lot. I'm going to stay in my wheelhouse, because I'm not up on the literature in that space, even in its intersection with pain. It's an intriguing concept. I have to imagine that it makes sense you would get some habituation with that repeated exposure.

I think one of the questions that would come up with, for instance, the cold exposure, and I don't know the answer to this, but I'm sure maybe somebody out there does, is there cross-modality changes in pain thresholds? I mean, if you expose yourself a lot to cold, does it change your heat thresholds? I would be surprised if it did.

ANDREW HUBERMAN: Yeah, I would be too.

SEAN MACKEY: Or your pressure.

ANDREW HUBERMAN: Because those are separate parallel pathways.

SEAN MACKEY: Yeah. And as an aside, I hate the cold, but I do really well with the heat. And so does Ian. I think there's something genetic there. So I mentioned earlier around men and women and heat thresholds and I chose that specifically. But each of these are different depending on the stimulus modality.

Can you change ultimately your thresholds? Yeah. Where that involves is a lot of cognitive control. It's a lot of cognitive training around that space. And there's clearly approaches to that. People have learned that there's different manipulations around that. So one experiment, this wasn't intended, at least I don't believe so, they were measuring heat thresholds on college students. And we experiment a lot on students, as we all know. We pay them well.

And what they found is that when they're studying guys, studying dudes, when there was an attractive woman who was delivering the stimulus, the thresholds were higher. Because the guys did not want to look like a wuss in front of this attractive young woman. And that's been pretty well established. So the experimenter, their gender plays a big role in that.

ANDREW HUBERMAN: Has the reverse experiment also been done?

SEAN MACKEY: I don't know. I don't know.

ANDREW HUBERMAN: Interesting.

SEAN MACKEY: But getting back to your point, yes, I think through a number of cognitive manipulations, you can ultimately over time change those thresholds. Another one area is exercise, is movement, exercise clearly changes those thresholds over time. You're probably building up some increased inhibitory tone through that process.

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One thing I'm fascinated by in the whole mindfulness space is this idea of whether or not under conditions of stress, or in this case pain, whether or not the most adaptive mindset, assuming it's not a tissue damaging level of pain, would be to think about something else, distract oneself from the pain. Or conversely, whether or not one should, quote unquote, "go into the pain."

So for people who have chronic pain, maybe it's in a small area of the body that experiences chronic pain, pain quite often, a.k.a. chronic pain, or maybe it's whole body pain. I don't think it really matters for the question I'm asking. And people are trying to develop some cognitive ways, so what we call as neuroscientists, you and I, top down mechanisms for things like, OK, I'm going to distract myself from the pain. I'm going to focus on other things I really enjoy.

Or rather I'm going to really go into the pain, meet the pain, and realize, I don't know, somehow that it's not as bad, like somehow there's-- and again, this becomes very opaque. We don't really know what we're talking about when we do these sorts of protocols. But those sorts of things are out there in the mindfulness space. And I think I certainly take mindfulness seriously as an intervention.

But what always bothers me about those sorts of interventions is that they lack the specificity and the granularity and there's no kind of mechanistic logic to explain them. So what are your thoughts on meeting the pain versus distracting oneself from the pain?

SEAN MACKEY: Let's break that down, because there's two concepts there, as you alluded to. And they're both effective and they both work differently. So one is attentional distraction where you are distracting yourself from the thing that is causing pain. Clearly works in a lot of people. And that's why one of the strategies that we recommend for patients, for people living with pain, is to engage in distracting activities. Read a book. Go for a walk. Spend time with friends and family in particular, in the community, and work to get your mind off of pain.

What we've learned is that attentional distraction engages specific brain networks. They tend to be some of the outer layer of brain networks and your prefrontal cortex, some in your cingulate cortex, and other regions which are clearly involved with distraction. It's not necessarily that distraction is going to completely eliminate one's pain, but it can reduce it significantly. And this is why the biggest problem with distraction from a time of the day is at night.

It's when people are trying to sleep. Because during the daytime, you can read that book. You can spend time with friends and family. But people with chronic pain that have it 24/7, you can't distract yourself at night when you're trying to get into a relaxed state and fall asleep. And that's why sleep is such a big issue for people with chronic pain. So attentional distraction, it works. Distraction works.

Now, what you said, I mean the second piece, you said let's meet the pain, if you will. And there's different approaches to meeting the pain. One approach that you invoked with mindfulness is addressing the pain from a non-judgmental, accepting manner. I'm aware the pain is there. I am not going to judge it. I'm not going to put a value on its bad, it's good, or anything. I'm just going to note its presence. And that has been shown to work as well.

In fact, actually when Jon Kabat-Zinn originally developed mindfulness based stress reduction, people with low back pain. Plenty of studies have shown that it works. I've completed just some recent studies in MBSR as well. And we're diving deeply into the data. So it's this non-judgmental acceptance, if you will, of the pain.

ANDREW HUBERMAN: Sorry, MBSR is the acronym for?

SEAN MACKEY: Mindfulness Based Stress Reduction. MBSR, everybody should do MBSR. Let me be clear. I have no financial relationship with any of this, by the way. But mindfulness based stress reduction has been shown effective for anxiety, for depression, for pain, just about everything. I think they should put it into all the schools.

It's a great skill to learn. No side effects. Takes a little bit of time to learn it. And it can be in some people effective and helpful for pain. And that's the key that we're going to keep coming back to is some of these things work for some of the people some of the time.

There's a third aspect of meeting the pain. And that is more of a direct cognitive reframing about the meaning of the pain. Now you're coming at the pain and you have an approach. You're making effort on what you're thinking of the pain. Is that pain damaging, threatening, harmful, or do you view it as, yeah, it hurts, but it's not harming me. That is a critical, critical aspect of pain management. And that serves as a foundation for something called cognitive behavioral therapy.

The cool thing about a number of these is that there's actually different neural circuits engaged with these different approaches. And I think the key that we have to figure out, and this is where research is going, is which approach works for which person under which circumstance.

ANDREW HUBERMAN: So interesting. Something you said about understanding the pain but not overinterpreting or catastrophizing the pain seems important. Knowing the difference between being hurt or feeling hurt versus being injured has been something that's been important to me. I've been involved in sports where clearly pain was involved.

It's like, I'm hurt, but am I injured? That's the first question. I've rolled an ankle. I'm limping. This hurts. Am I injured? Meaning am I going to be back at it in an hour or tomorrow versus I've broken bones and it's a great empathy for anybody that does. When you're injured, you feel the snap and you know you're out for a while in some cases.

So I think knowing the difference between being hurt and being injured is something that's kind of that key moment. And for me, it's always been experienced as a moment of anxiety after feeling pain, especially in sports. You're oh, am I going to have to take two weeks off? Or is this just pain? So I think for people to be able to recognize when pain is reporting an injury versus when pain is just reporting a temporary sensation is really important.

And perhaps also for psychological hurt versus psychological injury. I mean, that gets to some larger context themes these days of somebody says something. It upsets us. Are we hurt or are we injured? I think it gets very murky. So how does one determine if they are hurt versus injured? And then maybe we could even stretch into the psychological realm. Neither of us are psychologists. But it sounds like so much of what you do represents the bridge from the body into the mind. And so we'd be remiss if we didn't talk about emotional pain as well.

SEAN MACKEY: Yeah. So what you just said, you're spot on, Andrew. And one of the key messages, the key Mackey's tips for pain management is to understand the distinction between hurt versus harm. Hurt versus harm. Critical. Absolutely critical. Let me allow me to illustrate with patient I saw, I won't name names, some time ago.

Guy's in his 40s, a master's level tennis player. Tennis is his life. He works as some executive somewhere but he lives for tennis. Comes hobbling in on crutches. Sits down and he's got pain in his foot. And he was told not to put pressure on his foot because he's got this injury and it's going to be worse. And this has been going on now for months. And he's now depressed because he can't play tennis. Tennis is his life. This guy's life is tennis.

So I examined this guy. And it turns out what he has is something called a Morton's neuroma. And a Morton's neuroma is a fibrous thickening of tissue around the nerves that go to your toes. And it gets to be this bundled tissue, nerves, and it's really painful. It's very painful. But it's not causing harm. There's no harm there. It's really painful.

So I explained this to the guy. And he looks at me and this light bulb goes off. And he's like, you mean I can play tennis? And I'm like, yeah, guy, you can go play all the tennis you want. It's just going to hurt. He got up. He left the crutches in the exam office and he walked away.

Now, that's an extreme example. I don't want people, please, to think that that kind of thing occurs all the time. It doesn't. Chronic pain conditions are often incredibly complicated and need much more than a 45 minute or 60 minute education session and back to the tennis court. He still had pain in his foot, by the way. But he could play.

But that gives that example of addressing that fear and the anxiety around that issue. And I think that's what we first have to learn is does that pain that we're experiencing represent something that is harming us, something that we either need to seek medical attention now or sometime soon, and whether does continued activity worsen the tissue injury or not?

In my world where I'm carrying mostly for people with chronic pain, we've moved beyond the tissue healing. By definition, by one of the definitions for chronic pain, is that the pain persists beyond the time of tissue healing. So in many of our sessions, our times, we're educating people, hurt versus harm. It's back pain. We evaluate the spine. We make sure is the spine stable? Is there anything sinister causing damage? In most of the cases, it's not. And we help people understand that distinction. Critical, critical for people.

And yet at the same time, you don't want to just ignore something that is a real medical issue that's getting worse and needs medical attention. And that's where the complexity of all this comes in. Did I answer your question?

ANDREW HUBERMAN: Yeah, beautifully. I think this distinction between hurt versus harmed is so important for people to hear. Perhaps you're willing to expand a little bit in terms of the psychological hurt versus harm. I mean, I'm not asking you to comment on societal or generational shifts.

But we'd be avoiding the obvious if we didn't say that in the last really 10 to 15 years, there's been a pretty dramatic shift in terms of how society at large interprets emotional pain. People hearing things or seeing things. And the idea that emotional pain could be related to physical pain or at least similar enough to it that people's emotional pain is valid. And if anything, I'm here to validate the fact that emotional pain is valid, like any other pain, except it is different because it becomes very hard to point to a specific kind of threshold.

We're using that word a lot today, but I think it's appropriate here. Threshold between hurt and harmed. Whereas if I tell you that my left foot hurts, which it did a lot in high school, and then you took an X-ray of my foot in high school, you'd say your foot is broken, because it was broken a lot in high school. And that's harmed. I mean, to continue to do what I was doing to break it in the first place, I was clearly going to harm myself worse. So I had to I had to heal up.

But when it comes to psychological pain, psychiatry has all these thresholds for normal functioning versus abnormal functioning. Are you sleeping well, normal relationships, and on and on. We don't want to go there, because that's not our place. But how do you, when you see patients, how do you take into account the level or the thresholds for their emotional pain? Because that's part of your job.

So I'm asking you this from the perspective of somebody who treats pain. How do you gauge somebody's psychological pain? Is it by how intensely they vocalize their pain? Or does it always go back to how well or poorly their life is being managed at the level of sleep, nutrition, relationships, and so forth?

SEAN MACKEY: Yeah, great, great set of questions. There's a lot in there. Let me first start off with something very simple. I don't try to distinguish between this notion of psychological pain, physical pain. It's pain. End of. End of. I think once I get into or you get into this trying to distinguish is this psychological pain or psychogenic pain, which was a terrible term, or physical pain, you end up putting value judgments on people. And I don't think it serves us well when we're caring for the person in front of us. If they're in pain, I'm addressing the pain.

The thing to note is that least in people that come into our Stanford Pain Management Center and other pain centers is that remember pain is a sensory and emotional experience. It's all wrapped up. And so we want to treat the whole person. Sometimes we get easy. We get easy ones and we just go do a nerve block and the pain goes away and that's simple.

But usually it's much more complex where we're seeing the interaction of an expression of pain that includes a significant amount of anxiety, of depression. You mentioned this term catastrophizing, which we can break down if you'd like. And that's probably one of the biggest predictors, factors in an amplification of pain and worsening pain and poor treatment response is catastrophizing.

I try to treat the whole person and not really parcel out all this. At Stanford, I built a digital health system that captures, measures a lot of data around a patient's experience across physical, psychological, and social functioning. And we use that data to target therapies, to understand how much their depressive symptoms are, anxiety, anger. Anger, big issue and pain. Huge in pain.

ANDREW HUBERMAN: Does it make it worse or better?

SEAN MACKEY: Invariably, it makes it worse. And you can break anger down in a couple of different categories . John Burns and others has broken it into anger in versus anger out. I don't know if that term is familiar with you. Anger out, that's my father. Loud, loud, angry, boisterous, banging. Would quickly turn anything into an angry tirade. Anger out, expressive.

ANDREW HUBERMAN: Yelling at the news.

SEAN MACKEY: Yes.

ANDREW HUBERMAN: Yelling at somebody who cuts you off in traffic.

SEAN MACKEY: Usually yelling at the man, because he hated his job. Anger in. Boiling, simmering, self contained, seething. That's anger in. Data seems to support anger in is worse. It's bad.

ANDREW HUBERMAN: So it's not necessarily whether or not it's directed at someone external. In both cases, anger in and anger out can be directed at someone external. It's a question of whether or not it's expressed outwardly or contained inside.

SEAN MACKEY: Beautifully stated. Beautifully stated. So anger, depression, anxiety. We capture fatigue, sleep. And so what we try to do is, again, look at the whole person, because they're not just a back, if that's where they're having pain, or not just a neck or a shoulder in your case. It's impacting the whole person. And we just got done talking earlier about how all of these circuits interact with each other.

And so sometimes we can't just eliminate the nociception and the periphery. Sometimes we can reduce it. But what we have to do is target everything. And we have to try to target all these circuits up here. And in many cases, what we're doing is through education, through pain psychology, through physical therapy and rehabilitative approaches on top of it. And yes, the medications we have now. We touched base on a few earlier, but we have over 200 medications available for pain. Very few of them FDA approved. We tend to steal from all the other fields.

ANDREW HUBERMAN: So you're talking about more than 200 medications that can be, yes, prescribed for pain, but as off label treatments?

SEAN MACKEY: Perfectly stated, yeah. There's only a few medications that are actually FDA approved specifically for pain. So what we do is we borrow or steal from the psychiatrists some of their antidepressants, which will frequently work very effectively for pain and work on those pain related circuits in the brain. We take from the neurologist some of the antiseizure medications, because those medications while reducing separately seizures for people who don't have seizures, they work on ion channels. They work on other neuromodulators that also are involved in pain circuitry.

We can take from the cardiologists medications that work on the heart, anti-arrhythmia or heart rhythm drugs. They are potent sodium channel blockers. And the sodium channels, as you know, are responsible for the action potential that generates the nerve impulse signal. And so they're like an oral local anesthetic that you take. And so we take from everybody in our field on the medications.

Getting back to what you said, so just summarizing, one, I don't really distinguish psychological versus physical pain in my world. I find it better just to treat it as pain and look at the person holistically and go after all the components at once. I find that's where we get the best results. And it is typically bringing a lot of tools to bear.

ANDREW HUBERMAN: Speaking of tools to bear, what role, if any, does nutrition play in local or whole body pain?

SEAN MACKEY: Critical. And I think we're learning more and more and more about the role of good nutrition, of healthy eating, anti-inflammatory diets, avoidance of foods that are triggers. And an incredibly underappreciated area.

I've had my experiences with chronic pain. I developed an abdominal chronic pain problem shortly after I turned 50. I was throwing a happy hour for our pain psychologists of all people. Went to a Mexican restaurant. I won't name which one. Got food poisoning. That's why I'm not naming it. Good Mexican food, bad food poisoning. And ever since that event, I can't eat anything in the onion family.

ANDREW HUBERMAN: I'm familiar with onions, but what else is in the onion family? I'm sure you've researched this now pretty thoroughly considering what you're describing.

SEAN MACKEY: Classic in what we refer to as FODMAPs. It's one of the FODMAPs. And I have now some issues with the others and manifested by just severe, severe upper abdominal pain. And not many other symptoms, but it put me on this journey where severe abdominal pain, didn't know why, couldn't sleep. Couldn't sleep. I'd go months without having a restful night's sleep. I thought I was getting early Alzheimer's because I felt like I was getting stupid.

And what actually benefited me was, of all things, the pandemic. Why? Because what did we all do? We isolated and we started eating the same foods. And I started noticing I was feeling better when I was eating certain foods. My abdominal pain went away. And I'd start doing, as a scientist, experiments.

And I finally was able to isolate and determine what the problem was. So now I have complete avoidance on that. I'm a little difficult to go out to a restaurant and have dinner.

ANDREW HUBERMAN: So no onions.

SEAN MACKEY: No onions.

ANDREW HUBERMAN: And what else?

SEAN MACKEY: Shallots, chives, scallions, leeks, anything in the onion family. Not allium. I'm fine with garlic. And by healthy eating, by identifying something by triggers changed my life and returned to a degree of normalcy. I think the key for people is if you have any kind of similar issues, identify those triggers. Sometimes isolation of foods or restrictions and using a journal. And then as you learn from that, slowly build foods back into your diet.

ANDREW HUBERMAN: I think it's so important for people to hear this. And thanks for sharing your personal story around this. Because I think that nutrition, while every physician seems to appreciate that the quality of nutrition matters, defining what quality nutrition is really difficult. There's still avid even we could call them rancorous debates about this. Vegan versus omnivore versus this. But it sounds like this is a case where it can become very individualized.

But I could imagine somebody going to their physician and that physician not being you and saying, yeah, I notice that when I eat certain foods I'm in a lot of pain. And the physician simply saying, well, don't eat those foods. But unless that person is a trained scientist, not knowing how to go about doing the sorts of experiments that you did would be difficult.

SEAN MACKEY: Impossible. I'm sorry, I know I interrupted you, I just want to build on that if I can. One of the key things, I simplified my story. But the key thing is if I eat onions or anything that onion family, it's pain for two weeks.

ANDREW HUBERMAN: Wow.

SEAN MACKEY: So the thing is if you get repeated exposures, it never stops and it gets very, very hard to figure out what it was. So it's not like you eat something, you get pain, it goes away. Where we can all do that pattern recognition. Here you have to be able to think back what happened two weeks ago that may have influenced it. So it's not easy.

ANDREW HUBERMAN: Well, this may be a case for elimination diets, provided they're done safely, where people restrict the number of foods they eat to a very limited number of foods, make sure they still get enough calories and macronutrients that they need, protein, fats, and carbohydrates or what have you. But that by limiting the total number of foods that they eat to 8 or 10 basic things, then you can build things in and then explore what triggers the pain or what removes the pain. I don't really see any other way.

I am intrigued by the onion example, even though it's your case in particular and we don't want to extrapolate too broadly. Is there something about onions that's triggering a particular neurochemical or immune pathway? Do we have any knowledge of why onions would create that kind of gut pain?

SEAN MACKEY: This has been a journey I've been on now for a few years to answer this. One of our GI pain docs that we have in the clinic, Linda Nguyen, sent me a paper from Cell or Nature that showed that after a gut infection, it can change the genetic expression related to sensitizing you to food antigens. I know I threw out a lot of jargon there.

Basically the short answer is you get an infection, and your gut no longer responds properly to a normal food item. And so one explanation may be I got this infection. I was at a Mexican restaurant. A lot of onions. And I got sensitized through that infection now subsequently to onions.

I saw a Stanford allergist, Hannah Watford, who's awesome, by the way. And after I'd had this I think figured out and I went in and I'm like, well, Dr. Watford, is there anything I can do for this? And she laughed and she's like, no, you're doing everything. It's all just avoidance. And I, thinking I was rather unique and special about this thing, I said, do you ever see this? And she said, oh yeah, I see this all the time. Every day. I see this all the time. And I was like, this isn't unusual? And she's like, no, I see this thing all the time.

ANDREW HUBERMAN: This thing meaning sensitivity to onions?

SEAN MACKEY: Sensitivity to certain, no, to these different food groups and this thing that occurs later in life. Something, an event that happens to somebody that triggers. And I said, well, gosh, that sounds like a public health problem. And she's like, that's what we're debating right now in the allergy community is whether this is representing more of a public health issue. Because I'm seeing, I Dr. Watford, I'm seeing increasing amounts of this as we go forward.

ANDREW HUBERMAN: How interesting. Well, this is not a time to plug the philanthropic arm of our premium podcast, but I'm very involved in science philanthropy. This sounds like an area to devote some funding to explore how foods are impacting the local and systemic pain response.

SEAN MACKEY: So I'm running a large biomarker study to characterize people deeply. And one of the things that I wanted to put in there is microbiome characterization. Now, to be clear, that's out of my wheelhouse. But the beauty of being at Stanford and other major institutions is you can go make friends.

ANDREW HUBERMAN: Yeah, Justin Sonnenburg, who's been a guest on this podcast, is one of the world experts on the gut microbiome. We have a few others too.

SEAN MACKEY: There you go.

ANDREW HUBERMAN: He's a friendly guy. I'm sure he'll collaborate.

SEAN MACKEY: We go make friends and people who understand the microbiome. We collect the samples. And that's where team science is magical. And once again, the idea looking at the whole person.

ANDREW HUBERMAN: As long as we're talking about the gut, let's talk about pain inside the body. Because we talked about nociceptors on the surface of the body and the pain that most people immediately think of when you have a discussion about pain is pain on the surface or a broken bone or maybe hip pain or knee pain or back pain. But what about pain that resides deeper in the viscera? Gut pain, irritable bowel syndrome, these things I'm learning are far more common than I knew.

I'm fortunate that if I have a stomachache or a headache, it means something's wrong. I rarely get those. I've sometimes been called I have a stomach of steel, not because it's hard from the outside, but because I can eat pretty much anything, although I eat pretty cleanly. A lot of people write to me and ask questions on social media about irritable bowel syndrome and other forms of gut pain and viscera pain, pain that they feel is really deep within their system. Typically how is that sort of pain dealt with at a clinical level?

SEAN MACKEY: Absolutely. Visceral pain is a different thing than what we've been describing, a lot of which is somatic pain. By the way, I'll say as an aside, I used to have a gut of steel also. I could chomp down anything, anytime, anywhere. And so there was a lot of grief and loss associated with not being able to eat certain foods. And that's also something people have to come to grips with it.

But getting back to visceral pain. So the thing about somatic pain, that's another term now, somatic meaning the soma, the extremity that you were alluding to, is the nociceptors there very precisely localize where the stimulus, the painful stimulus, is coming from. When you hit your thumb with a hammer, you know exactly where that pain occurred. With the visceral pain, what you have are very diffuse what we refer to as receptive fields. Think about the last time you had a stomachache. It's not that you put your thumb right here. We said it kind of hurts like this.

ANDREW HUBERMAN: Your whole stomach.

SEAN MACKEY: Whole stomach. It's because those receptive fields are very large. They're broad. They're not as well localized. And in part, the reason for that type of broad receptive field is you're not trying to get away from localized danger. So when people get stomachaches, it's often a very broad area. When you get pelvic pain, it's the same type of thing.

Now, there's some fascinating stuff that occurs with visceral pain, because those fibers that extend from the viscera, meaning the lungs, the abdomen, the pelvis, they all head into the spinal cord too. And it just so happens that they make kind of indirect direct connections with the same level that represents the body.

So let's think about pelvic pain, for instance. You frequently will find people that have pelvic pain that will describe having lower back pain too. And it's because of this visceral somatic convergence in the spinal cord. It's not that there's something going on in their back. It's that these signals that are being driven heavily from the pelvis are coming in and connecting with the same regions from the back. And the convergence of that is now being perceived as pain in both.

And we're seeing that more and more in the research this visceral somatic convergence. People have pain in their pelvis and then also over their abdomen. Classic one that we're aware of, we see this in the TV and the movies and unfortunately real life, are heart attacks. So the visceral fibers that subserve the heart, typically the first through the fourth thoracic region, well, those converge in the spinal cord and similar regions that subserve sensation under the arm up here. That's why people will often say they've got pain with a heart attack radiating down into their arm.

ANDREW HUBERMAN: The left arm typically.

SEAN MACKEY: The left arm. The heart is on the left side. Exactly. After people get abdominal surgery, sometimes some blood can leak out and it will slip underneath the diaphragm. The diaphragm is subserved by some of those neck regions, three, four, and five of the cervical, which happens to also cover your shoulder. And so you'll get people after abdominal surgery they said, man, my shoulder's really hurting me, doc. And what we do is we first check to see could something have happened during placement. Just make sure there's nothing wrong. But frequently, it's due to irritation. That's, again, one of the magical mysteries that's so fascinating about pain.

ANDREW HUBERMAN: This seems like a good point to bring up referenced pain. Or is what you're describing an example of referenced pain? So my understanding of reference pain is that, for instance, I've got a slight bulge at I think my lumbar three, four disk or something. I had a whole body scan recently, just an exploration scan because I had the opportunity, not anything serious, fortunately. And there's a slightly bulged disk there. And every once in a while if I do certain movements in the gym, I'll get pain down in my right hip and sometimes going down my leg.

And I used to think it was sciatica, because you assume anything on the right back side, it must be wallet induced sciatica. Back pocket wallet induced sciatica. But what I eventually realized is that, well, it's this disk bulge. It just so happens that the nerves that emit from that region, they branch out to a bunch of different areas. And so you think the pain is in your leg, but the issue is someplace else. And occasionally indeed I feel the pain elsewhere in my body as well. It's sort of like a matching of regions for pain that seem unrelated. Is that a way to think about reference pain?

SEAN MACKEY: Perfectly. The examples also I referred to of a heart attack causing referred pain or also the pelvic region associated with back pain as a way of referred pain. What you're describing is the fact that pain doesn't have to start with an injury or a stimulus in the periphery. You could damage the nerves anywhere along the way and that will be perceived as pain. We refer to that as neuropathic pain.

So that's another distinction you brought up nicely. Good segue into there's thought to be several different types or categories of pain. We have been talking through much of this time about somatic pain, injury out here. We talked about visceral pain. And when you have damage to a peripheral nerve, damage, injury to a peripheral nerve or the central nervous system, we refer to that as neuropathic pain.

It frequently has different qualities, different characteristics. People will refer to it as shooting, stabbing, shock-like, burning. It can frequently when there's a damage to a nerve or damage to certain regions of the brain be incredibly challenging to treat. By the way, the good news is with that light disk bulge is the vast majority of time, the disks reabsorb.

ANDREW HUBERMAN: Yeah, I have to be careful to not do too much spinal flexion, like sit ups and stuff. I thought that would help. But that actually doesn't strengthen the back. It was actually a asymmetry between the abdominal muscles and the lower back muscles. So provided I do a lot of back extension type training, then that bulge more or less stays in. I just have to be a little cautious, not too cautious fortunately.

As long as we're talking about referenced pain, somatic, visceral, and all the rest, what about associative or referenced pain where it's psychological? And I don't want to get too abstract here, but more and more these days I hear from people who say, I was in this job and the job sucked. Or I was in this relationship and the relationship sucked. And I had terrible back pain, really acute, localized back pain or chronic headaches or migraines. And then they go on vacation or they change their circumstances and lo and behold, the pain goes away. Does that surprise you as an expert in pain?

SEAN MACKEY: Not at all. Not at all. What you're simplistically referring to is people are undergoing stress. And we clearly know that the brain is not a passive recipient of information coming in from the body. It's a two way street. The brain is causing downstream consequences in the body.

The brain controls our sympathetic nervous system and parasympathetic nervous system, the sympathetic being the fight and flight response. It controls the tone of cortisol that's being released. And we all know that in acute situations, rapid increases of cortisol and noradrenaline is keeps us away from the lions and tigers and the bears, oh my.

But in a chronic situation, and Robert Sapolsky, as you know, at Stanford has built a career around chronic stress at least in part. And very bad for us. And so these chronic stressors impact the end organ, the tissue. And it's real pain. It doesn't mean that we need to go get back surgery. It means that probably we need to identify the stressors that are contributing to that and address those. And we'll often find that in the scenarios you outlined that the pain gets better.

Some of those targets are interesting. There's a lot of memory associated with pain. This is where early life events occur. And those early life events and injuries can sensitize us to future vulnerability. So I was in a bad car accident when I was 16. Fortunate to walk away from it. Got bad whiplash. If I get stressed, a lot of my pain manifests in my neck.

For me as a pain doc, it's a signal to me that's like, go work out. Go for a walk in the forest. And take some time away from the computer. Again, that's a simplistic message. And my experience doesn't translate into everybody else. But I'm just validating everything that you said.

ANDREW HUBERMAN: Let's consider the opposite scenario, which is positive emotions. You've done some very nice studies exploring how being in positive relationships, being in love, in fact, can change our perception that is our experience of pain and probably does so at real physiological levels. As you mentioned earlier, psychological is physiological and vice versa. It's hard to separate the two. But could you share with us what you did in that study and what you found? Because I find it really interesting and it also points to the incredible power of love in how we experience life.

SEAN MACKEY: Yeah. Yeah, I think there are several cool things about that study that I'd love to share. One is how it all came about. So us neuroscience geeks often go to the Society for Neuroscience as an annual meeting. And I was hanging out and sharing a room with Art Aron, who studies passionate love. And he and his wife study passionate love.

And we were having a glass or two of wine and I'm asking Art, have you ever studied pain? He's like no, I study love. And he's like, have you ever studied love? No, I study pain. Has anybody ever studied the intersection? Another glass of wine. No. Let's do it.

So we came back to Stanford. And there was a young post-doc Jarred Younger, who's now a professor at the University of Alabama. And I said, Jarred, we're either going to fall flat on our face or this is going to be a cool study. And Jarred took this on. Great job.

So what we did is we advertised on campus for couples in an early phase of a romantic relationship. Because there's a reason for choosing that. In an early phase of a romantic relationship, you are deeply focused on your beloved. They're on your mind all the time. You feel great when you're with them. You feel terrible when you're not with them. Doesn't that just sound like an addiction?

ANDREW HUBERMAN: I mean, it's that yearning. I don't know. It can be a pleasant experience.

SEAN MACKEY: But addictions for the people who are using the substance can find it in that early phase very pleasant. But it turns out that the early phase of a romantic relationship engages the same neural circuitries as addiction.

ANDREW HUBERMAN: Interesting.

SEAN MACKEY: Same reward circuitry. All that. So we chose that. And so we said come to us and bring pictures of your beloved and bring pictures of an equally attractive acquaintance clothed. This isn't sex that we're studying. Clothed. And we caused them pain in the scanner. And we paid them afterwards.

We needed a control condition for this, because thinking about your beloved is very attentionally demanding. Remember we talked about attentional distraction earlier. So we gave people what's called a word generation task. Very simply, can you think about every sport that doesn't involve a ball. Frisbee, hockey.

ANDREW HUBERMAN: Boxing.

SEAN MACKEY: Boxing. OK. That's attentionally demanding. Think about every vegetable that's not green. So you're running it through your head and we're causing you pain. It's an attentional distraction task. So we flash people pictures of their beloved, cause pain, flash people of their acquaintance, cause pain, and then distraction.

What do we find? Love works great. Love works great. It was a wonderful analgesic. It significantly reduced people's pain. And it turned out the more in love you were, the more pain relief you got.

ANDREW HUBERMAN: When viewing the photo of the person you love?

SEAN MACKEY: Yes, when viewing the photo of the person you love. Now, how did we know they were? It turns out the psychologists have got scales for everything, and one of them is a passionate love scale, which asks, what percentage of the day are you preoccupied thinking about your beloved.

ANDREW HUBERMAN: Oh goodness, you just sent people now off to give their partners the passionate love scale to figure out how much time they're spending thinking about them.

SEAN MACKEY: Yeah, we had Stanford students, some of them, thinking about their beloved 80% of the day. I wanted to use this as a screening tool for our resident applicants, because I want them focusing on patients, not their beloved. And that is, by the way, a joke. A bad joke.

ANDREW HUBERMAN: But probably is real world. We're not just talking about Stanford.

SEAN MACKEY: Oh no.

ANDREW HUBERMAN: But when somebody is writing you a script or a prescription that is or giving you advice, you might want to know if they are in a new romantic relationship.

SEAN MACKEY: So I thought the other cool thing about this study was attention worked also. But attention and love worked on different circuits. So attentional distraction, they worked equally well, attention, again, worked on some of these prefrontal regions, these outer cortical areas. Love worked on more of what we classically think of as these reward based circuits, the nucleus accumbens, the amygdala. One of the descending brain stem regions called the substantia nigra, which is coming down from the brain through that area to the spinal cord to inhibit pain.

ANDREW HUBERMAN: So classic addiction pathways.

SEAN MACKEY: Classic. And so the key, again, message for people is different what we would think of as psychological approaches engaging different brain circuits to reduce pain.

I'll leave you with one last side note that we didn't publish on. And that is Jarred went back a year later and we assessed the students' strength of their relationship, assuming it was still ongoing. And he found that there was a rather high correlation between the love induced analgesia and brain activity and the caudate nucleus and in the insular with the strength of their relationship a year later. So we had a brain scan that was a predictor of future strength of a relationship.

ANDREW HUBERMAN: Could you tell us the direction of those results? So if a new romantic partnership is creating high levels of activity in these two brain areas you just mentioned, then it is a very good predictor that the relationship will, yes, survive over time?

SEAN MACKEY: Well, in this limited sample it meant that it was going to be very strong a year later. Understand, and Andrew, we always have to put these caveats, unpublished, non peer reviewed. It was a fun post-hoc data analysis that I'm not sure if anybody's ever run with those kind of things.

ANDREW HUBERMAN: No, but we can explore it in a playful way now and people can do with it what they will. It does speak to something important though, assuming that result would hold up if the same experiment were done in many hundreds or thousands of people. It speaks to the idea that the activation of these addiction-like circuits in the early phase of a passionate love relationship set in motion a certain number of things that create stability in that relationship, which on the face of it makes sense.

But we've also all heard it the opposite way as well, which is fools rush in or that things that start fast end fast or things like that. But here you're talking about the early phase of passion serving this interesting role in terms of analgesia alleviating pain, but also predicting some stability of the relationship over time. It's kind of interesting.

SEAN MACKEY: It's fascinating to talk about. I feel like I have to put that caveat in that not generalize, but a fun thing to talk about. And it's where I think cool scientific ideas can come from for future exploration. I think that's also what's pretty neat.

I find, again, the different circuits for different approaches to reducing pain fascinating. Again, that gets to the question you asked me earlier. Is there one circuit? And the answer is no. What we have to do is figure out what is the best circuit for a particular person or set of circuits?

ANDREW HUBERMAN: If you're willing, I'd like to talk about opioids. First, if you could educate us on endogenous opioids, the opioids that we make inside of our body that we don't-- meaning nobody takes as a drug. And then how that informs opioids that people take. I mean, clearly the so called opioid crisis is a concern. Many people addicted to opioids. People have died from taking too many opioids. But presumably, some people have benefited from these opioid drugs as well. So we'd like to talk about that.

And then I'd like to also talk about some of the things that are adjacent to the prescription, opioids things like kratom, which right now are sort of called into question as to whether or not they will continue to be legally available over the counter. So first and foremost, what are the endogenous opioids? How do they work? And that I think will set the stage for the rest.

SEAN MACKEY: Yeah. So we all have these endogenous enkephalins and endorphins that act as painkillers. They are analgesics. They are natural substances in all of us that get expressed. There is a certain endogenous tone to these that some have done research on. Here again, Jarred did research on this and [? Stephen ?] [? Brule ?] and others on showing that higher endogenous opioid levels may lead to less emotional reactivity, for instance. Thank God we have endogenous opioids or we just couldn't handle it.

What chemists have figured out is how to bring in exogenous opioids. And morphine was the prototypical one from the poppy. And since then, medicinal chemists have built on variations of morphine and created other compounds. Again, variations on morphine. Some are purely synthetic, like the oxycodone.

ANDREW HUBERMAN: Could I ask a question? Because I'm fascinated by the history of these things. How did and/or when did somebody look at the poppy and then say, oh, I'm going to start eating poppies or isolating things from poppies and realize that morphine--

SEAN MACKEY: Thousands of years ago.

ANDREW HUBERMAN: So poppies have been used for a very long time.

SEAN MACKEY: Long, long time these things have been around. So this is old school work that's only been refined in more contemporary history. And the whole topic of opioids is such an incredibly controversial area. And I feel like I have to understand the speaker, in this case me, my once position on this. My usual mantra is I am not pro opioid. I am not anti opioid. I am pro patient.

So I have seen opioids positively transform people's lives, help them get back to work, spend time with friends and family, relieve suffering, particularly in situations end of life but also in people with chronic pain. And I have seen opioids destroy lives. At a personal level, I come from a family background deep, deep in addiction. I have lost close loved family members to addiction. And I'm respectful of that.

What I've learned is to not get into this binary mode of thinking. It's either this or it's this. But to treat opioids, as a clinician, as a tool to be used in certain circumstances in some people, not typically as a front line or first line agent. Typically much later down if they have failed other therapies. You cannot approach the challenge of opioids without appreciating the deep complexity that we're faced with, particularly now in society with all of the litigation ongoing and all the money involved. It's a highly nuanced topic. So what more would you like to talk about opioids?

ANDREW HUBERMAN: Well, I think that most people hear about the opioid crisis and just assume that they are, quote unquote, "overprescribed," that people are given opioid drugs as a front line treatment perhaps more than they should, that the addictive component, which I understand is very real, the potential for addiction is very real, as well as the potential for cross interactions with other things like alcohol and perhaps even other illicit drugs, street drugs perhaps. If people can't fill their prescriptions and tolerance to the opioids creating issues where people then need more of them.

I have a not close family member but a distant family member who had his entire life arranged beautifully. He was a practicing lawyer with a beautiful wife and family. Had a back injury. Was prescribed OxyContin. It helped him initially, but then it set off some behavioral psychological pathways that had him seeking more, forging prescriptions. He understood the law. He was a lawyer. He eventually went to jail, got out. The same thing happened again. He eventually ended up dead.

And I think there are many examples of that that we hear about, and those are very salient and very disturbing, very saddening. So I think that most people, including myself, hear the opioid crisis and assume that what we really should be doing is seeking a better alternative. But what I'm hearing from you is that there are use cases where opioids make a great deal of sense and that they've really helped improve people's lives and that none of what I just described or anything like it is experienced by those people. In fact, quite the opposite. Do I have that right?

SEAN MACKEY: Perfectly. And that's, again, where we need to treat these at an individual level on a case by case basis. And that one size doesn't fit all. Yes, opioids were overprescribed. I think everybody agrees to that in this country. And we went through a period of time with massive overprescribing.

And there's a lot of nuance and reasons why in large part. Physicians, we get terrible education around pain and we don't know how to treat it in general. Coming out of medical school, we get about seven hours of education on pain. Veterinarians get 40. It's great if you're taking, I think your dog's name is Costello.

ANDREW HUBERMAN: Yeah, unfortunately he passed, but he took some pain meds for a short while. But I found an alternative treatment that worked far better.

SEAN MACKEY: Perfect.

ANDREW HUBERMAN: Which turned out to be, by the way, low dose testosterone. He was castrated. He was fixed when he was younger. And it's interesting. I've said publicly on very large scale podcasts that I gave my dog low dose testosterone later in life and it ameliorated a lot of his aches and pains, at least from what I understood, because he started moving better and feeling better and sleeping better. And I expected the veterinary community to come after me with pitchforks. Not one.

SEAN MACKEY: Wow.

ANDREW HUBERMAN: Did that. And yet I heard from hundreds of veterinarians that said, yes, we wish that we could prescribe those sorts of things to people who castrate their male dogs later in life to ameliorate their symptoms. So that opened up to me a whole world of understanding about some of the restrictions that vets face in terms of what they prescribe. There's a whole discussion to be had about that. We'll do a series on animal and pet health, vet health.

SEAN MACKEY: Great.

ANDREW HUBERMAN: Well, the vets hopefully are healthy too. You get the point. But when it comes to the opioid crisis in this discussion, I think it's become so laden with the idea that doctors are on the take. They're getting paid to give opioids to patients and that's why they're doing that. And I don't believe that necessarily be the case, but I think that's what the public perception is, that it's all financial.

SEAN MACKEY: Here's the thing. Were there bad docs doing bad things? Yes. I'm going to invoke a good friend of mine, Keith Humphreys at Stanford.

ANDREW HUBERMAN: Oh Yeah. Terrific.

SEAN MACKEY: Terrific psychologist who is an addiction medicine psychologist and public policy person. And the way he breaks it down, and I have subscribed to this, is there's three types of physicians. Remember, there's about a million physicians in this country. About a million. You've got physicians doing the right thing for the right reasons. Vast majority of docs. We need to leave them alone. We need to support them. We need to help them do their job and not put more obstructions in their way.

There is a much smaller group of docs doing the wrong thing for the right reasons. What I mean by that is these are docs who did overprescribe opioids in this case, in this context. They did buy into the marketing messages that were put forward. They did not have much education around alternatives in treating pain.

And they thought by handing out pills, just pills in their very brief visits with patients. Remember, primary care docs, my heart goes out to them. What do they get, 14 minutes or so with the patient? They gave them something that they thought would help. They were doing the wrong thing for the right reasons.

ANDREW HUBERMAN: But they believed that they were helping. They didn't have--

SEAN MACKEY: They believed.

ANDREW HUBERMAN: They weren't catching financial incentives. OK.

SEAN MACKEY: That's right. Those people, we need to educate them. We need to train them on proper pain management, opioid prescribing, deprescribing. And then you've got the tiny little group at the top of this, if you will, pyramid, these are docs doing the wrong thing for the wrong reasons. These are bad docs. These are your pill mills. These are people breaking the law. They need to go to jail. End of.

The thing is that little group at the top in the million or so physicians we have in this country, it represents such a small representation, but it got blown out by the media and everybody else. Particularly those docs doing the right thing for the right reasons got caught up in it. It engendered a huge amount of fear. A huge amount of fear on the physician side. And then what happened is the docs just started abandoning patients. They cut their patients off.

I had a young housewife, two young kids. Doc cut her off from a little bit of Vicodin that she was taking intermittently for some back pain that had been well managed on this. She was doing all the right things. Cut her off. She turned to black tar heroin.

California, great state of California, tried an experiment where they monitored death certificates in our state and the Doc's prescribing opioids for that. And they went after the docs thinking that if they targeted the docs doing that, it would lead to a reduction in opioid deaths. It led to a doubling. I know, counterintuitive. Because what happened is the docs abandoned the patients.

And so we have to be aware of the negative consequences of this. Now, the current-- I'm not trying to minimize the opioid crisis, because it's real. But we also now need to put some context. The opioid crisis is being driven by the illicit fentanyls. It is more, if you just look at the CDC data, it's very clear that the fentanyl is coming in via Mexico, China, and others is what's driving most of the deaths.

Keith, getting back to Keith, led a beautiful Lancet Stanford commission on the North American opioid crisis and put together a very rational plan. I just finished serving as a senior advisor to the medical board of California where we revised our prescribing guidelines here. They were very draconian before, hard limits. Made people fearful, both patients and docs. And we've shifted it back over to put the control back in the hands of the physician patient relationship. We're hoping it'll make a difference.

You can see I'm going on a bit here. There's this huge complexity in this space. I understand you're going to do an episode, some time on it in the future. And I hope the audience has more opportunity to listen to this. Other questions I can answer for you though on that.

ANDREW HUBERMAN: I really appreciate the thoroughness of your answer. I think that you set a picture and a context that I certainly didn't understand or appreciate. And it sounds like one, certainly not the only, but one of the major issues is the creation and the propagation of a black market by doctors cutting off patients, presumably out of fear, those patients then seeking not any but illicit or black market routes to treating their pain.

Which you can understand why they would do that. I mean, I'm not justifying anyone doing anything illegal. But somebody is in pain and they had something that worked and now they don't, and they're going to go looking for things that are similar to that thing. And you're telling us that fentanyl in street drugs, basically, is what's killing people, presumably. I doubt it's fentanyl prescribed by physicians. Or perhaps it is.

SEAN MACKEY: It's not. No, there used to be a bit of confusion around that, because fentanyl is a prescribed medication in a patch form and in a troche, the troche used for end of life cancer pain. But unfortunately, some of the coding used by the CDC, in other words, got that confused with the illicit. And so it took a while to get a better handle on it. But I think we do now. Yes, most of it is being driven by the fentanyls.

And we're just seeing this incredible epidemic wave of it. It can be made so cheaply, brought across the borders reasonably easily. Something we definitely need to address. We want to be careful about not conflating that crisis with the issue of pain, which is an epidemic in its own right, and for the segment of people who are using opioids responsibly and effectively for their pain. And that's where, again, that nuance comes in.

Are there patients who are also on opioids that have been weaned down? You can wean them down gently, compassionately, and they do better. The answer is yes. My partner Beth is just finishing up a study on that and showing that with compassionate care, a number of these patients can be weaned down who voluntarily want to come down. And sometimes I find their pain actually improves. And part of that improvement may be that opioids have degrees of side effects. And by elimination of those side effects and the other aspects, they're seeing improvement.

ANDREW HUBERMAN: Could you list off some of the more commonly used opioids?

SEAN MACKEY: Morphine and its commercial derivatives MS Contin, which is a long lasting version of morphine. Oxycodone, which by itself is a short acting medication. But when you encapsulate it in a long acting version, it becomes OxyContin, which was the trade name that Purdue put forward. Fentanyl we mentioned comes in a patch form. There are mixed agents like tramadol, which is a kind of a weak opioid but also has some what's called serotonin and norepinephrine, reuptake inhibition. We've got Dilaudid, which is a version of trade name for hydromorphone.

So there's a slew. There's, I don't know, more than 20 different opioids within that list of 200 medications that we have. Methadone is another one. People usually think of methadone is a medication used to treat addiction. People go to methadone clinics. It's a long lasting opioid. In the right person in certain circumstances, it can be used effectively for chronic pain.

By and large, they all have the same or similar mechanisms of actions, working on opioid receptors. This is getting back to your original question to me about where these things work. There are opioid receptors in the periphery. There are rich sources of opioid receptors in the spinal cord and the dorsal-- the back part of the spinal cord.

And then there are many areas in the brain that are rich in opioid receptors. It's all a naturally occurring area. And when we put in an opioid by mouth, we're binding to those receptors and activating those neural circuits. In many cases when I say activating, they have an inhibitory role. I mean, that's one of the major parts.

ANDREW HUBERMAN: Is there any role for benzodiazepines in pain relief?

SEAN MACKEY: Rarely. Many of my colleagues would say Sean, it's just a hard no. Andrew, I'd have to come up with an edge condition of somebody who has a generalized anxiety disorder, poorly treated with anti anxiolytics with chronic pain. And when you find you treat their anxiety with like a benzo, it helps with their pain as well. But these are edge conditions. By and large no.

ANDREW HUBERMAN: Got it. What about kratom? I had an odd experience with kratom and I've never taken it. The experience was the following. I started learning about it, hearing about it from listeners on the podcast. Realized by doing a little bit of a web search that it's available over the counter and that certain people like to take it often, like every day at low doses or even higher doses, and that there was huge variation in terms of the amount of kratom in the various products and how much people were taking. Some people talking about kratom as something it was as if it were innocuous. And we can ask whether or not indeed it is innocuous.

And so I put out a tweet. I guess now that Twitter is called X, I guess I put out an X? Anyway, it doesn't matter. And I said that my first pass view of the literature on kratom, the scientific literature, is that it had a lot of properties similar to opioids although different as well and that it seemed kind of odd and maybe even problematic that it was so widely available. And I got bombarded with I don't want to call them kratom enthusiasts, because what I soon discovered was that these people were angry with me for placing even a partial shadow on kratom.

But what was interesting to me was that they were saying that in their case, and I'm assuming they were telling the truth, that kratom had helped them get off prescription opioids and that they heavily rely on kratom in various levels of dosage in ways that they felt really help them. And so two things happened. One, I've been put in the crosshairs of the pro-kratom community. Not to a severe extent. But perhaps the more important thing is, and I want to thank that community in part, for now it's inspired me to do a deep dive search on kratom. I'm going to be interviewing one of the laboratories that's done a lot of the research on kratom later in 2024.

But also it's made me realize there are these compounds that are available over the counter that many people feel so passionately about because they really feel like it's helped them. I'm not saying it has. I'm not saying it hasn't. But then again, I've never taken it. What is kratom? Or perhaps what receptors does it tickle? And what are your thoughts about kratom and people using kratom? And maybe I'm pronouncing it wrong. I've also heard "krah-tom." I'm calling it "kray-tam."

SEAN MACKEY: Yeah. Kratom is this natural substance that does have, as you said, opioidergic properties as well as others that is not fully understood. It's been available, well, naturally for many, many years, brought in to the United States. And I've heard the same stories. And I just want you to be prepared that anything I say about kratom, there's going to be some angry people after this. And it is what it is.

I have heard the same stories that you have heard about people taking kratom and saying it's helping them to stay off of prescription opioids or illicit opioids. And I get that. I think in some way it's binding opioid receptors and reducing the natural craving for these other substances. And it makes perfect sense. Methadone does that. Buprenorphine, which I didn't mention before, but is an interesting opioid that binds to these receptors and it reduces craving.

Where I have challenges is in just because something is natural doesn't mean that it is safe. We are seeing an increased number of overdose deaths associated with kratom. Is it polysubstance? Yeah, in some cases, it is. But I think there's a lot we don't know.

ANDREW HUBERMAN: So polysubstance, people taking kratom but also--

SEAN MACKEY: Alcohol, benzos, getting back to the benzos. Personally, I think we need to put a lot of research into this agent. And if it merits it, I think it should be a prescribed substance. I think part of the challenge that we have is that we don't understand the quality of the purity of the dose that people are taking of this thing. Similar type of story with cannabis, by the way.

So I'm hoping that we're going to get the research that we need to really understand what it's doing and whether it is safe and effective. I'm left with a lot of unknowns right now.

ANDREW HUBERMAN: You mentioned cannabis. Is cannabis effective? And by extension, is CBD effective for managing pain?

SEAN MACKEY: Yeah, there's another controversial one. You'll get a few comments about whatever I say.

ANDREW HUBERMAN: In general, listeners of this podcast, yes, they tell us where they're upset. They'll also tell us where they agree. Our goal here is never to satisfy everybody. But just some of this lands in the realm of highly educated opinion. Some of it is still, as you pointed out, speculation because we don't really know what kratom sources people are taking or cannabis, et cetera.

But I think you'll find, and my experience has been, that people appreciate that we're having the conversation. And we do read all the comments. And those comments often, as I mentioned in my earlier anecdote about that tweet, often direct us to explore things further. And we can always have a second discussion about this down the line. So we invite all your comments and criticism.

SEAN MACKEY: Cannabis. Well, here's what we know. In carefully controlled laboratory situations, cannabis has been shown to reduce neuropathic pain. That's that nerve related pain from people who have either nerve injury, diabetic neuropathy, post-herpetic neuralgia, terrible burning nerve pain condition. It has been shown to reduce that in small samples.

From larger scale epidemiology studies and even larger clinic based studies that I've done, we find it has not been particularly helpful on average compared to people not on cannabis. There's a lot we don't know about the causality of that and the direction of it. But all to say that there are many, many questions that remain.

I think the challenge that I personally have is that we're running huge population level experiments as we speak right now by providing unfettered use of cannabis. And the bad news is that we're probably going to see some real untoward consequences of it. And we already are. The good news is I'm hoping that at a state level, we'll be able to use that data to really inform what's going on with cannabis. I mean, some of the challenges are what I refer to with kratom. Cannabis is not cannabis is not cannabis.

ANDREW HUBERMAN: Edibles, smoke, vape.

SEAN MACKEY: The THC to CBD ratios, the dose. Yes, all of that. We don't know what you're getting. It remains a Schedule I drug by the DEA. I in some of my leadership roles and others have called for scheduling of it as a Schedule II. Why? Why? Not to purposely try to restrict use. But by making it a Schedule II drug, you've now made it so much easier to research. I don't know if people understand how many barriers there are to scientists studying Schedule I drugs.

ANDREW HUBERMAN: Could you explain Schedule I versus Schedule II?

SEAN MACKEY: Thank you. Yeah. So the scheduling of drugs is a categorization that describes their abuse liability. And so you have drugs like PCP, heroin, cannabis which are Schedule I, which are defined as having high addiction potential and no utility.

ANDREW HUBERMAN: Which is just wild, because when I think about PCP, phencyclidine, I certainly don't want people to run out and start taking PCP. But chemically and physiologically, PCP is ever so similar to ketamine. And rarely is this discussed, but ketamine is now widely used as a therapeutic. Presumably ketamine is Schedule II, maybe even Schedule III.

SEAN MACKEY: Yes.

ANDREW HUBERMAN: And so some of the stuff that's thrown into Schedule I makes no sense.

SEAN MACKEY: It's historical. It's decades and decades ago of history. And clearly cannabis should not be a Schedule I. Hands down, no question. By scheduling it though, you will have the societal benefit of being able to make it more easy to study. And then you'll get the NIH and the FDA into this. And we can start really getting answers to the questions.

Which do I think it works at the end of the day? Do I think there is some variation of cannabis, THC, CBD ratios that will provide some benefit? Oh, absolutely. There's too many receptors in our brain that are involved with the modulation of pain. I just don't know what those are. A friend of mine, Mark Wallace, runs pain at UC San Diego, has come up with a really nice recipe cocktail of ratios of THC to CBD that he feels very strongly that he can help people using that as an active agent.

ANDREW HUBERMAN: Yeah, I know that in Colorado, there's a strain of cannabis where it's pure CBD, no THC. I think they call it Charlotte's Web. And parents of children with intractable epilepsy will actually move to the state of Colorado in order to get it, because it seems to be effective for the treatment of certain forms of pediatric epilepsy. That was shared with me with one of our colleagues, Nolan Williams, when he was a guest on the podcast.

So these plant based compounds have their place, whether or not it's kratom, perhaps, we're remaining open about that, or cannabis, the THC, or the CBD or some combination. I think it's really interesting. I think as long as we're talking about plant compounds, how do you view the fields that are what I would call somewhat adjacent to traditional medicine? So things like acupuncture, chiropractic, physical therapy, and so forth.

SEAN MACKEY: As a pain physician within the field of pain medicine or pain management, I think about six broad categories of therapies that we provide for people with chronic pain. One of these is the medications. And there's a whole large group of categories of medications, 200 or so available. Two, nerve blocks and procedures. These range everything from trigger point injections to nerve blocks with local anesthetic and steroid on up to minimally invasive procedures like spinal cord stimulators, implantation of drug delivery pumps.

Three, psychological and behavioral therapies. Pain, psychology which has many forms now. Can be very effective. Four, physical and occupational therapy approaches to chronic pain. Five, this is what we typically call complementary alternative medicine approaches. It's a little bit of an outdated term. But I think of that as acupuncture, nutraceuticals. These are the over-the-counter agents that have actually shown to have benefit in pain that you can get over the counter.

And last but not least, six, what I call self empowerment or increasing your agency. And here it's about education. It's about learning skills. It's about being here on the Huberman Lab podcast learning about pain. It's that self empowerment. And what we find is that those six categories all brought together typically have the best benefit for people living with chronic pain.

ANDREW HUBERMAN: To a lot of people listening to us right now, they think, oh yeah, acupuncture. I mean, this is a thousands or tens of thousands of years old practice that clearly is grounded in a lot of clinical data and clearly works. And then other people will go, oh my goodness, they're talking about acupuncture, like sticking needles in the body.

Are they just like pain treats pain? Is that what it is about? But as you and I both know, unless it's being performed incorrectly, acupuncture is not painful to receive. Does acupuncture help treat certain forms of pain? Is there any scientific basis?

SEAN MACKEY: Yes. Yes, there is. Do I understand what's going on with acupuncture, having completed an NIH funded acupuncture study?

ANDREW HUBERMAN: I just saw that published.

SEAN MACKEY: No. I'm just being straight. We still don't know exactly how acupuncture is working. We do know that there's a nice study that showed activation of peripheral adenosine receptors that have a peripheral analgesic effect. We know that acupuncture as compared to sham acupuncture engages different brain regions. It's interesting that many of the acu points overlie peripheral nerves. And so by needling those nerves, are we causing a central change? We're turning down the amplifier, if you will, in the brain maybe. Where does this fit into my clinical use? My usual statement is that if you can afford the wallet biopsy, give it a try.

ANDREW HUBERMAN: Although find a really good acupuncturist.

SEAN MACKEY: Oh yeah.

ANDREW HUBERMAN: I've had acupuncture done I wouldn't say many times but several times. And I will say this. One of the acupuncturists I went to put needles in my face and I ended up having to go to Stanford derm to get some of the angiomas that were like blood vessel growth that was the consequence of those needle insertions. And so to the point where I go to acupuncture, I'm like, don't put any needles in my face. Because I'll take an angioma on my leg or whatever. I don't care.

And it's not vanity, but I didn't like the way that the needles were introducing angiomas to my face. Now, that was probably because this acupuncturist wasn't doing things correctly. I'm not saying all acupuncturists do that. But here's the problem. How do you know which acupuncturists are reliable versus not? And for that matter, how do you know which physician is reliable versus not?

I mean, I work at an institution like Stanford where I can ask a lot of people, and I still, my senior administrators won't like this, but when I get a recommendation from a doc at Stanford, I always call somebody at UCSF and cross check. And I don't tell them that I'm cross checking. And I'll do the reverse as well. When I was at UC San Diego, I would check up with Stanford.

But most people don't have access to that kind of community. I mean, I can pick up the phone and contact somebody in pretty much any medical specialty and at multiple institutions. But for most people, they're wading into the abyss of acupuncturists, of physicians. I mean, how are people supposed to navigate this?

SEAN MACKEY: You found a perfect way to do it. And many of us do the same thing. And for those who don't have access to high quality experts, you can use variations of that. So you're right with acupuncture. Most of the ones I've been associated with we use in the clinic or outside all have been high quality.

The recommendation would be to try to get a referral or recommendation from somebody who refers to that acupuncturist. Docs want to have relationships with people, with other clinicians that do a really good job. We don't want to be referring to somebody who's bad, because it reflects badly on us. So it's really doing what, in a way, what you were doing. So, try to connect with your primary care doctor, others, and get some recommendation for who is high quality.

With regard to clinicians, pain physicians for instance, that's tough. There's 5,000 to 10,000 of us that are subspecialty trained out there. If your pain is really complicated, a complex pain problem, you're probably better off with a tertiary referral center that can provide comprehensive services where possible.

ANDREW HUBERMAN: So is there a centralized website where people can say, OK, I live in the state of Iowa. Or a lot of our listeners are overseas. Or where people can find out the ratings based on patient experience? Although that can be complicated. I confess, sure, the one star out of five star ratings are a little bit more salient. There have been studies on this. People tend to if you see a negative review, those tend to grab your attention even if there are fewer of them than the many thousands of positive reviews. But I mean, patients should be able to get the information that they want about previous patients' experience, right?

SEAN MACKEY: Yeah. I got to tell you, the patient ratings, it's a highly manipulated situation.

ANDREW HUBERMAN: How so?

SEAN MACKEY: Well, you can pay companies to help jack up your ratings.

ANDREW HUBERMAN: I see.

SEAN MACKEY: It's rather easy. I see it in the community all the time.

ANDREW HUBERMAN: So the inflation of ratings.

SEAN MACKEY: Oh my, yes. Inflation of ratings. And so then you inflate it and it overcomes any of the negative ones. We haven't taken an approach on this. And maybe that's naive of us. We see 25,000 patient visits a year and only a tiny percentage of them put some rating. And it's probably the extremes, undoubtedly. But we don't manage it. I know that in many community settings that they do.

I didn't answer your question. Is there a reliable source of quality? I still think at the end it's going to be relationships and word of mouth and referral. I do the same thing you do. To see Hannah Watford the allergist, I asked my primary care doc at Stanford, who's the best? Who is the person that knows the most about food related issues?

ANDREW HUBERMAN: Well, some really entrepreneurial guy or gal or a group of guys or gals will put together a website or an app or something that really addresses this problem head on. Because I could think of very few things more useful than a truly independent way of understanding prior patient experience and finding the best person for a particular problem. And I think AI can help with this. But I think AI and human interface-- anyway, somebody out there should do it.

I'm curious about chiropractic. For a lot of people, not chiropractors, let's not talk about the people specifically, but chiropractic. A lot of people put acupuncture and chiropractic adjacent to one another. But my understanding is that insurance often will cover acupuncture but not chiropractic work. Maybe I got that backwards or maybe I'm just all out wrong. But with chiropractic work, you're talking about often the attempt to relieve compression of nerves.

Certainly nerves are being manipulated if any part of the body is being manipulated. I guess manipulated it's kind of a word that implies something sinister is happening. It's being adjusted. What are your thoughts about chiropractors? Assuming the chiropractor is well trained and responsible. Can it help pain? Can it help back pain, neck pain, whole body pain?

SEAN MACKEY: Yeah. First of all, acupuncturists and chiropractic are two entirely different professions, just to be clear for people. And they sometimes get lumped into a similar category of pain treatments. And that may be where that comes from. Just closing out on the acupuncture again, just to summarize, yes, in some patients in some circumstances, I've found acupuncture to be useful.

And it's worth a try. CMS, Center for Medicare, is now paying for acupuncture for people over the age of 65. Medicare for Medicare patients, that's something recent. And we were happy to see that. I believe that was for back pain. That should be fact checked.

But chiropractic, mixed data. Well controlled studies, some have shown that it can be helpful for low back pain. Some have shown it isn't. It's truly not clear. The type of chiropractic that doesn't involve the fast, high velocity manipulation, as a physician, I have some concerns about that, particularly around the neck. I've taken care of patients that have had vertebral artery dissections from that rapid wrenching.

ANDREW HUBERMAN: What is a vertebral artery dissection?

SEAN MACKEY: One of the main arteries that goes from the body to the brain and the back portion of it is called the vertebral artery. And when you do these high velocity manipulations, there is a risk, albeit small, of having a dissection or an embolus thrown off. And I've had--

ANDREW HUBERMAN: So it's like a stroke?

SEAN MACKEY: It is, yeah, it's like a stroke. But there's a lot of approaches that can be done that in some patients have shown some benefit. I think the key with a number of these therapies, and I don't want to single out acupuncture or chiropractic, if you go to them, ask yourself, am I getting durable benefit?

Meaning everybody feels good after a massage. But a couple few hours later, it's kind of worn off. It's a nice experience in the moment for most people. If you're finding that for acupuncture, chiropractic, or anything, for that matter, ask yourself, is it really providing you durable benefit that is worth the effort? Or is it just rapid, it feels good in the moment?

We tend to use that in our clinical practice as a threshold. And we like to see things that last for a longer period of time. And in many of these treatments, whether it be acupuncture, chiropractic, we use those as an inroad into more of a functional rehabilitative approach. Meaning when you get chronic pain, you tend to withdraw. You tend to stop exercising. You stop moving. Your muscles atrophy. You become deconditioned because of the pain.

And so we want to use these tools that we've been talking about as a way to get people engaged in activity, to correct the underlying biomechanical issues that may be present. And so they all need to be appropriately staged. And that's where working with a good clinician can help with that.

ANDREW HUBERMAN: Yes. Certainly in my case any time I've had back pain, even when it was very severe, provided I wasn't harmed and I was just hurt, continuing to move and not becoming sedentary was absolutely the fastest route to recovery. And in particular, doing certain exercises that were particular to my case. What, if any, is the role for physical therapists in the treatment of chronic pain?

SEAN MACKEY: Absolutely crucial. Absolutely crucial. Despite being a physician, not a physical therapist, I have great appreciation and respect for what the physical rehabilitative approaches do. Because at the end of the day, we're trying to get people back to an improved quality of life and physical functioning. I mean, that is often what people are most looking for. Control over their pain, control over their life. Yes, reduction in pain, but more being able to do more things.

And they're tying in with good physical therapist, occupational therapists, people who can do goal setting. Absolutely critical. All of the treatments that I provide typically are meant to help support an increase in physical rehabilitative approaches. And so when I do nerve blocks or procedures or give a medication and if we end up reducing some pain, we want to tie that in with more activity.

And what the physical therapists are great, particularly those trained in chronic pain, is knowing that difference between hurt and harm. They can work with people to know what's safe for them to do to rehabilitate. They can teach them more about body mechanics and help improve endurance and strength. They can work around pacing. Pacing is so critical for people with chronic pain.

Now, this isn't just exclusive to the physical therapists. The psychologists do pacing. I do pacing. What is pacing? Here's the problem with chronic pain, one of the many problems. It waxes and wanes. And so what happens is you go out and have a good day. You go out like gangbusters and you go do everything that you haven't been able to do for the last week because you've been in pain.

And then you pay the price. And when you pay the price, you're back in bed or you're on the couch and you're not moving. And what happens is you go into this roller coaster of activity and no activity at all. And what happens is it entrains in our brain. It's a classic negative reinforcement model. This is classic psychology. And so then people become fearful of more movement. And as a consequence, they get more and more disuse, atrophy, and then more disability.

So the key. What do you do about that? The key is you set small goals, baby steps. If you can walk comfortably for a block right now, great. Walk that block tomorrow. Maybe walk a block plus an extra 50 feet. And maybe the next day another 50 feet. No more. No more. If you're having a great day, don't go do five blocks. You're training for a marathon. You're training for the long win.

Now, what's going to happen along the way is that you're going to have good days and you're going to have bad days. On the good days, don't go out and exceed it. Set a threshold. Time it on your watch set a distance. On the bad days, recognize we all have bad days. Everybody has bad days. And you may need some rest during those bad days. But then the next day, get up and restart where you were. And that's the type of thing a physical therapist, good pain psychologist, good physician can help you with. And tying that in, by the way, with these other therapies.

ANDREW HUBERMAN: Very interesting. I've never heard of pacing, but it makes total sense. And I can see how people could really hinder their own progress without that basic understanding, which thanks to you we now have. And it's something that hopefully all these therapeutic modalities keep in mind. I mean, I don't know whether or not the acupuncturists are talking to the physical therapists or talking to the physician. But I guess this is the reason for referrals, somebody has a primary care doc, and it radiates down to the rest. Is that why?

SEAN MACKEY: In an ideal, utopian world, that's exactly it. I mean, outside of comprehensive pain centers that have all of the stuff co-located, you are dependent on a doc to play quarterback and bring all those referrals together. It's incredibly challenging for a primary care doc to do that with the limited amount of time they're given to see a person. This is where we're trying to use technology to help better with that integration. And I do think there's hope for the future we'll have better ways of managing that and handling it.

ANDREW HUBERMAN: What is your view on non-prescription compounds, so called supplements or nutraceuticals, for the treatment of pain?

SEAN MACKEY: Fascinating topic. This country is rather unique in having a wide slew of over-the-counter agents that are actually prescription in Europe and in other countries. And there are over-the-counter agents that have been shown to be effective for a number of pain conditions.

So for neuropathic pain, acetyl-l-carnitine is one of them. Acetyl-l-carnitine is thought to work on mitochondrial metabolism and improve mitochondrial health. And it's been used, I believe, as a anti-aging and maybe even a cognitive enhancement agent. And it's been studied out of an Australian study, I think it was called the Sydney trials actually. And what they found, it's one of the few over-the-counter agents that actually had disease modifying properties.

Meaning they studied this in diabetic neuropathy. The clinical endpoint was not pain reduction. The clinical endpoint was nerve conduction velocity changes. And that's how we monitor nerve health is in a normal nerve, nerve impulses move at a certain rate. And when they're injured from diabetes, it's much slower and you lose signal. This actually improved nerve health. You can buy those at a Vitamin Shoppe, order them online.

Alpha lipoic acid is another one. Alpha lipoic acid, at least two mechanisms. One is it's a free radical scavenger. And second that's been more recent is it is a T type calcium channel modulator. And calcium channels are in our nerves. And it turns those down and it can have some benefit for neuropathic pain. People have taken alpha lipoic acid for a general sense of well being. And it is generally well tolerated. It can cause a little bit of stomach upset.

I will tell you I took this one myself for a while. And this is, again, just an n of 1, what I found, though, is you have T-Type calcium channels in your heart. And I do HIIT, High Intensity Interval Training, and I was finding I couldn't get my heart rate over 150. So I stopped it. That's not an adverse event. That's just an annoyance. But that's useful.

Vitamin C. So if you're going in for surgery and it's maybe a nerve related surgery that you're going to have, they found vitamin C prophylactically can reduce the likelihood of having certain nerve pain conditions after surgery. Fish oil, the omega 3s have been found to be beneficial around chronic pain.

More recently, the data here is on smaller numbers, creatine, which I imagine you've probably talked about it at some length. But creatine has shown in small pilot studies some benefit in fibromyalgia and some other types of conditions. So there are a number of these substances that are backed up beyond the anecdata that we joke about, the anecdotal. There's actually good randomized controlled trials. And this is something that people can easily take advantage of.

Just be mindful that just because it's natural, just because it's over the counter doesn't equate with 100% safety. Meaning get educated about the side effects and the adverse events. Get educated about the drug-drug interactions, the agent-agent interactions. And for instance, there are these over-the-counter agents, some of which you want to be careful of and not taking when you're going into surgery because they can be platelet inhibitors and they can cause you to bleed more.

ANDREW HUBERMAN: Isn't vitamin C one such substance?

SEAN MACKEY: That causes--

ANDREW HUBERMAN: Excessive bleeding. Or some people report that high levels of omega 3s can reduce the viscosity of the blood, meaning you bleed easier.

SEAN MACKEY: The omega 3s, the fish oils, yes. Absolutely. The vitamin C, I'm not familiar, honestly with that.

ANDREW HUBERMAN: As a blood thinning agent? Maybe I'm misinformed there.

SEAN MACKEY: Or maybe I'm just forgetting it. But that's one I don't usually think of as a blood thinner.

ANDREW HUBERMAN: Someone will put it in the show note comments one way or the other.

SEAN MACKEY: We'll get it corrected. But there's a number of these over-the-counter agents that are available. The vast majority are innocuous that I've mentioned. That I've mentioned.

ANDREW HUBERMAN: Innocuous meaning they don't cause harm at reasonable doses?

SEAN MACKEY: Thank you.

ANDREW HUBERMAN: But they can have positive effects.

SEAN MACKEY: Perfectly stated, yeah.

ANDREW HUBERMAN: Well, thank you for sharing that list. I think, as you mentioned, many compounds that are only available by prescription overseas are indeed available over-the-counter in the US in this area. Nutraceuticals like supplements is still an area that's actively debated depending on people's stance. But it's refreshing to hear somebody who's a formally trained physician and scientist who embraces so many different approaches in the treatment of pain. Along those lines, perhaps you'd be willing to talk about the psychological treatments that can be effective for pain.

SEAN MACKEY: Again, absolutely critical in the management of people with a wide range of pain problems. And recall what we talked about is this is nociception. These are the signals coming up to the brain. Once it hits the brain, we're dealing with everything that person has lived through and also is currently experiencing. Meaning their levels of anxiety, depression, how they cope with pain in the past, how they cope with it now. Early life experiences.

There's a paper that just came out in JAMA literally in the last few days where they did a meta analysis of brain imaging studies on people with early adverse life events. And what they found is abnormalities in emotional processing, emotional functioning in people who have these. Giving strong evidence that what happens to you early in life impacts us as adults and stays with us. It changes our wiring.

Now, this is where in part pain psychologists, behavioral therapists can come in. They can help with some of the maladaptive coping, the thought processes involved with pain. They can help teach skills. So for the vast majority of pain psychology, this is not your typical psychoanalytic lying on a couch talking about whatever. This is about teaching people skills. Incredibly helpful.

Does it eliminate pain? Few of the things that we do actually eliminate pain. What we're trying to do is chip away a little bit with this medication, a little bit with this procedure, a bit with psychology. We're trying to hit all of these pathways in aggregate to make a real difference. The pain psychologists use classically techniques like cognitive behavioral therapy, which involves often recognizing these unhelpful thoughts and patterns that we all get into around pain and even life to interrupting those thoughts to helping people, again, with goal setting and pacing to teach people relaxation techniques through deep breathing.

Things like biofeedback. In Silicon Valley where I practice, the engineers love the biofeedback. I'm an engineer by formal training, so I get it. But it's that closed loop feedback. Because remember, the brain is controlling the periphery and controlling the sympathetic nervous system. And when we're in pain, our sympathetic nervous system gets revved up.

When the sympathetic nervous system gets revved up, blood vessels constrict. Heart rate goes up. Our muscles get tense. And we need sometimes ways of learning how to calm down that sympathetic nervous system. Cognitive behavioral therapy, mindfulness based, stress reduction, acceptance and commitment therapy are some of the tools that they use.

My partner Beth has developed a brief intervention called empowered relief. Yes, I'm biased. It works. We've studied this in an NIH funded study. And it's a way of getting eight weeks of cognitive behavioral therapy in two hours. Not meant to replace CBT but as an additional tool. And you're going to see as time goes by, more and more of these tools come out.

And the beauty of them is they're going to be much easier to disseminate broadly to the public than, for instance, a pill. We can't just go put into FedEx or the US Post Office, start sending out pills to everybody. But we can develop treatments online that can teach people skills and really help.

ANDREW HUBERMAN: Is that the plan for this abbreviated but equally effective cognitive behavioral therapy?

SEAN MACKEY: Yes. Now you're getting into Beth's and my life mission. So I've spent the last 12 years building a digital platform, a health platform that we've integrated into clinics and capture high quality data, covering all aspects of people's physical, psychological, and social functioning. And the reason for that is to address a critical need that we have on better quality data about people. The data and the information that we have on people with pain and many health conditions is terrible.

And so I created this platform to be able to capture high quality data, put it to use, use AI in the background for prediction. And now Beth has created these brief interventions, which we're integrating. And the notion is to make that widely available for free. We're giving it all away. Like I said, this is a life mission. We both have been blessed to be at Stanford where we have everything.

But you go just 30 miles, 40 miles outside of the Bay Area, and you're in a health care desert. And I don't say that disparaging to any docs working out there. But it's different. There's only a handful of large academic centers and large practices in the country. When you get outside those catchment areas, people struggle with how to get good quality care. You asked that question earlier. How do you find good quality care? And so we're working to make that available to everybody.

ANDREW HUBERMAN: Fantastic. I was going to ask you as a final question what is your-- if you had one wish for the future of pain medicine and the treatment of pain, what that would be. Before you answer that, I'll just add an answer that you already gave, which is it sounds like the implementation of this incredible set of tools and database that you've collaborated with Dr. Darnall, Beth Darnall, to develop is at least one of them.

So now that that answer was given by me, then it frees up the opportunity for you to give another answer. If you had one wish for the field of pain medicine going forward, what would that wish be?

SEAN MACKEY: Yeah. So a few years ago, I co-led for the country the development of the National Pain Strategy. And this was sponsored by the NIH and Health and Human Services. And I co-led this with Dr. Linda Porter from the NIH. We brought together 80 national experts in pain research, pain clinical care, pain policy, and people with lived experience with pain. And we put together a strategic plan for the country on how to enact a cultural transformation and change the way we assess care for people with pain, how we educate professionals, how we communicate with the public.

My wish would be for full implementation of the National Pain Strategy. It unfortunately took a back seat when it was released the same time with the CDC opioid guidelines. And the opioid guidelines sucked all the oxygen out of the room. But the strategic plan, it was well thought out. It's the one that we have for our country. It's non-controversial, nonpartisan. It is motherhood and apple pie. And if we just actually implement what we put forward, it'll make a huge difference in the lives of people living with pain.

ANDREW HUBERMAN: Is there anything that people listening to this podcast can do to try and move the implementation of that initiative up? Are there Congress people to call? I mean, I learned in junior high school and high school, what little I attended. And by the way, go to school, folks. I had to catch up a lot. But I do remember them saying that this was a democracy, is a democracy, and that those phone calls and letters can often matter for what gets sent up the flagpole and what ultimately gets approved and implemented.

SEAN MACKEY: Beautifully stated. You're absolutely right. And in fact, the nidus for the National Pain Strategy originally came about through a number of concerned citizens with pain doing that very thing. And lobbying what became a bipartisan, you don't hear that much anymore, bipartisan effort to put forward a National Pain Care Act that got put into the Affordable Care Act that called for the development of an Institute of Medicine report on pain that led to the National Pain Strategy, all starting with concerned people making those phone calls and writing those letters.

ANDREW HUBERMAN: So that means calling your Congressman and Congresswoman, leaving messages. I hear this works. I mean, I know people that are doing this for other initiatives. And one call, two calls doesn't make much of a difference. But that if people are saying this is important to them that people in power eventually start taking action.

SEAN MACKEY: The legislators, they listen. And in part, again, part of this life mission, both to develop this platform, I've created a nonprofit called Pain USA. And its main mission is to help advance the implementation of the National Pain Strategy. And baked within that is this platform also to use high quality data to better inform the care of patients of people with pain and to deliver high quality treatments. Because we do know also that people listen to data. And we need good quality data to influence those messages. But please, yes, make those calls. Write those letters. It does work.

ANDREW HUBERMAN: , Well, Sean Dr. Mackey, thank you so much for everything that you're doing. You took us on quite a tour in terms of depth and breadth of the thing that we think of and unfortunately in some cases experience as pain. Although we also learned it's highly adaptive in some cases, can protect us, does indeed protect us.

Thank you for taking us on that tour of the biology, the psychology, the various treatments, the context in which all of this exists. We touched into some somewhat controversial areas, but I really appreciate the thoroughness and the nuance and the sensitivity with which you touch into all of those issues. And just on behalf of myself and everybody listening, I just really want to thank you. You've contributed a great deal today to the public education of what pain is, what it isn't, and how to treat it. So thank you ever so much.

SEAN MACKEY: Thank you, Dr. Huberman. I appreciate the opportunity to come on and spend some time and you giving a platform to help educate and inform people out there. I got to tell you, nobody does it better. You've been absolutely amazing. And thank you again.

ANDREW HUBERMAN: Thank you. It's a labor of love, and I appreciate the kind words. Come back again.

SEAN MACKEY: Thank you.

ANDREW HUBERMAN: Thank you for joining me today for my discussion all about pain and ways to control pain with Dr. Sean Mackey. I hope you found the conversation to be as interesting and as informative as I did. To learn more about and explore some of the resources that Dr. Mackey mentioned during today's episode, please refer to the show note captions.

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