Tools to Reduce & Manage Pain | Dr. Sean Mackey

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. My guest today is Dr. Shawn Mackey. Dr. Shawn 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 and 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 zero 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. Our first sponsor is AeroPress. AeroPress is similar to a French press for making coffee, but is in fact a much better way to make coffee. The aeropress was developed by Alan Adler, who's an engineer at Stanford. I knew of Alan because I used to see him in my hometown of Palo Alto test flying the so called aerobic Frisbee. So he was sort of famous around my town as this brilliant engineer that would create these unusual products. So when I heard about the Aeropress, I got it. I I tried it and I absolutely loved it because it does indeed create the best tasting cup of coffee or loose leaf tea. With Aeropress you can brew an incredible tasting coffee or tea and clean up the whole process in less than two minutes. The key thing to know about the Aeropress is that it's not just some trivial variation on the French press that shortened brewing time that the AeroPress uses really changes the flavor of your cup of coffee or tea. It makes it exceptionally smooth. If you'd like to try Aeropress, you can go to aeropress.com huberman that's a E R O P R-E-S-S.com huberman to get 20% off any Aeropress coffee maker. Aeropress ships anywhere in the USA, Canada and over 60 other countries around the world. Again, that's Aeropress.com huberman to get 20% off today's episode is also brought to us by Levels. 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Again, that's betterhelp.comhuberman and now for my discussion with Dr. Sean Mackey. Dr. Mackey, welcome.

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

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?

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 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 kind of 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. Some useful treatments and useful options for people.

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, you know, like 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 pain. It's as if something's nagging from the inside. And so that raises the. The next question that I have, which is, is pain something that's in our brain, in our body, or both?

It's clearly in our brain. And can I take a moment to kind of 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, our soft tissue, our 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 for 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 no susception. 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. You know, 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.

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's in pain, they tend to assume that people are experiencing pain the way that they are. Do I have that right?

You have it perfectly right. And it 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, okay, 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.

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, you know, 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, like a mysterious mechanism in the brain, as opposed to like an area in the brain that we can look and say, like, hey, like, like, that's where pain is represented. That's where all these, these inputs from the body are put together to create this thing that we call pain. Like, is there an area of the, 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?

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 function, 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.

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

Yeah, and this is where some of the challenges we get into with language because technically NSAIDs, non steroidal anti inflammatory drugs like ibuprofen, like naprosyn, they're actually not analgesics, they're not technically painkillers.

So an analgesic is the descriptor for a quote unquote painkiller.

Yeah, that would be more correct. Like an opioid would fit into that category. The NSAIDs are anti inflammatory drugs. They're also, 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.

Folks, please don't do that, don't do.

That at home, please.

Yeah, or anywhere. 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, anytime 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 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 sort 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 bad idea to blunt that pain?

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. There's a lot of controversy in the space right now. It used to be we all recommended just NSAIDs for any type of acute injury.

Ibuprofen, non steroid anti inflammatory drugs.

Indeed.

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.

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, you know, still fits in that same general class. It tends to be more centrally acting. Tylenol or acetaminophen.

But when you say centrally, you mean brain.

Brain. Thank you. Thank you.

And is aspirin considered an nsat? I don't believe.

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 along as we go. But you know, to your point, you don't Want to, for instance, 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. You know, we get into those debates, right, in professional sports where, you know, they. They send the person back out on the field with a broken bone, you know, having given them an injection or something. I'm hoping that doesn't go on anymore.

But I'm sure it goes on.

Okay.

Yeah, 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, get stem cell injections, all with. 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.

Okay. Yeah, yeah. 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.

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 Cox. Cox is one. Is it in the family of prostaglandins? Can we talk about prostaglandins? Because I think there are a lot of people nowadays, we hear about inflammation. Inflammation's bad, inflammation's 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 sleep, 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 a 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 what is?

I mean, as a physician and as a patient, how do we determine normal functioning?

Yeah, and you're getting into the nuance, the complexity of this problem because we've been talking about NSAIDs, the Ibuprofens and naprosins. 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.

I've heard before that NSAID should 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, 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?

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 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.