Dr. Sean Mackey: Tools to Reduce & Manage Pain

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29:08I 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? So what are some of the interactions that these things can have? As far as I know, caffeine actually touches into the prostaclanin pathway, doesn't it? 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 end said with a lot of coffee, have some food in your stomach.

29:51You know, you brought up earlier a seat of menophan or Tylenol. Tylenol doesn't have the same side effect or adverse event profile that the end sets 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 two grams, some say four grams. The key here is around your liver. So 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.

30:39There are versions of the end said that we refer to as Cox 2 inhibitors. They're very selective like celacoxib 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 nappersin and the ibuprofen. So talk with your clinician to try to tease those apart. If you have problems in your stomach with the end sets 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 end sets. Very useful information. Thank you. Here we're talking about chemical interventions to the pain process.

31:28What about mechanical interventions? So I was taught in my basic neuroscience about I think it's Melzack and Walls 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 and you rub it and that rubbing response is actually contributing to the activation of a neural pathway that does indeed reduce the pain through a legitimate neural inhibition. Tell me if this is still 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 like maybe massage above or below the site of pain, maybe acupuncture.

32:13So 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 can imagine using manual stimulation or rubbing around it or perhaps we can also talk about heat and cold. So we explore that space a bit. Absolutely. And first you're right. So 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 no susceptors going to the spinal signals going to the spinal cord heading up to the brain where the perception of pain occurs.

32:59That'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. So from the periphery, we've got also fibers called touch fibers. These are the ones where they could 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 no susceptive fibers. So with that grounding, imagine what you said, you hit your thumb with a hammer, you bang something on an extremity.

33:48What is the first thing you do when you hit your thumb with a hammer? Some people rub it. Some people swear and it turns out there are studies that show that swearing works really swearing reduces pain better than using non -explicative loud vocalizations. Yes, swearing works. I don't know why, but there's been it. It got some press when that paper came out and you know, I don't write I'm not giving carte blanche. We're not saying everybody can go out and swear every time they're in pain. Well, they can, but they'll have to bear the consequences on an individual basis. We're not we're we're absolving ourselves of any responsibility.

34:25So rubbing shaking is another one, which basically is activating those touch fibers. Oh, it is putting it. I do that. Yeah. Everybody does everybody does running it underwater, which you know, it doesn't matter whether you know, in this case, it's hotter. 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 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 in the neck. This is the cheapest free version of what we refer to as neuro modulation.

35:05It'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 no -susceptive 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, you know, parents come and rub it. It works. What about the kiss the kids sometimes really want to kiss? You know, or a romantic partner will sometimes like injure themselves. I guess it depends on the nature of the relationship and they'll say like, can you kiss it? Of course. You know, and you kiss it and then like they feel better.

35:40Is that purely psychological? Well, okay. 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 that. No, no, forgive me. I have to be careful with the wording that I use. That's my fault. 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.

36:23What interesting, while in Melzac 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 neural 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. It's cool stuff. It's very cool.

37:06And 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.

37:52And it could be the context as well. If you're, you know, 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. Maybe it's all, you know, 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 stubbed 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.

38:33I think I'd see them stub their toe and they're like, and then, you know, 10 minutes later, they're still feeling the ache. So whose pain threshold is higher? It's a, 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. Yeah. So what is pain threshold? Yeah, no, it's a, it's a great place to start.

39:13And 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. Yeah. For you mean, no, no, no, you're, 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, you know, when you turn up the heat, it's, 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, like 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.

40:00And that's normal. That first onset of pain. Again, those are those fast fibers, those Adelta 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 Adelta fibers are converging into concessaries 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.

40:40You 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 thresholds, you asked one of the other questions is, do men and women have different pain thresholds? The answer, the short answer is yes. This has been established. And I want to be careful here. We're saying a couple 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. Right? You know, what we do is we take a group of people, in this case men and women.

41:32And 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. Right, because the tough part is a subjective label. Right? 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 yours serves a more adaptive function. It's fewer injuries, et cetera.

42:15I mean, I guess it gets into the implications of what we mean by, quote unquote, tougher. 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 pull things, you end up with that difference.

43:00Unfortunately, when things are picked up and you want a quick sound bite out of it, that's what it gets to still down to. So it's not unlike height for that matter. There are a lot of women that are taller than men. That's exactly it. But on average, men are taller than women. On average. And I would say within this area of pain threshold differences, it's even closer. It's even tighter. You know, it would be, I'm making this up, the equivalent. I think the average height of a woman is at 5, 3, 5, 4, the average height of a man, 5, 9, 5, 10. And this is imagining the average height being, you know, 5, 6, 4, 1, and 5, 8, 4, a man.

43:38You know, it's not a huge difference. There's a lot of things that play into changes in pain thresholds. How much, and this is where the brain comes in, because, you know, much of the no -susception, much of the signals that were transducing, were transmitting, you know, 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. Does increased anxiety increase one's perceived pain? Yes. Okay. Yeah, it does. Your early life experiences with this.

44:29So if you had traumatic experiences in the past, that alters brain circuits. 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, you know, don't be a was, 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 was 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, it's like pretty tough adult, right?

45:16Because they're not crying out in pain. So do we have any, are there any experiments that have explored that? I don't know. You're getting into, this is a good point, getting into pediatric pain and, you know, if there's been experiments in that space, I stay mainly in the adult area. And my experience with raising a child is an end of one with one son. He's done great. Thank you. I know him very well. He's what you call a great example of highly successful reproduction. So, you know, say what do they say? It's better to be lucky than good. Sure. I'm sure there was a lot involved. So don't, don't, don't, don't discard any credit.

45:57Thank you. Thank you. You know, my approach with Ian was not to say, you know, necessarily suck it up, but I would, you know, make light of it. I'd have fun with it. And I would kind of laugh and I'm like, wait a go buddy. And I would find he would often laugh. You know, so I think a lot of it is the cues they're taking off the parents. You know, and again, this is, this is just my one of end parent is if they see you freaking out, the kid's going to freak out too. But does there get to be a point where you're ignoring your child or your loved ones, painful issue? Yeah, now you're getting into some maladaptive, some bad space where I think it's sending that person the wrong message.

46:42And they may very well have problems later on. I will tell you just a very brief anecdote. When I was growing up, I observed a total of zero children and friends who, you know, cried out in pain or complained of pain who were told, you know, that was an inappropriate response. Sometimes I might have heard parents say, you know, I just suck it up or like, or rub it, you'll be okay. 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.

47:26He 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. Yeah. But clearly had no regard for the pain that the that the injury probably caused. Now I haven't followed up with that kid. Yeah. I think we can all agree that by today's standards that would be considered abusive parenting or perhaps, you know, one could say that was, you know, on the far extreme of a response.

48:04But 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? Yeah. Can 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.

48:41So there's another cool phenomenon in pain that pain inhibits pain. So what I mean by that is when you were, you know, this guy, this kid, but are yourself growing up, did you ever walk up to your buddy? And say, you know, my arm really hurts. You know, I injured it the other day. And what did what did your buddy do? They'd stomp on your foot. And you'd say, why the heck did you do that? You know, I'm just growing up with the same frozen. And they table now doesn't, doesn't your arm feel better? And I mean, like, well, yeah, it does. And yeah, I did grow up with those friends. I tell this story to some people.

49:18And I sometimes just get the wide eyes. Like they did what? Yeah, we are not making recommendations here. We're not making recommendations, but it's a real phenomenon. It was described by LeBarr's late 70s, 78 or something like that in rodent models initially. And what happens is that when you engage a no -susceptive stimulus or a painful stimulus in a site distal different from where the primary pain is, it engages a brainstem circuit that has descending pathways to the spinal cord and inhibits pain. Amazing. Pain inhibits pain. It works. It also has some contributions from higher brain centers.

49:57We call this whole phenomenon LeBarr's called this phenomenon diffuse, noxious inhibitory control or Deneck. 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 pain fly. You know, 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. I wanted to make him feel worse so he didn't go near the bandsaw without being more cautious. But it probably did reduce the pain a little bit to some extent.

50:33Now 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 Deneck doesn't work, like fibromyalgia being won. So pain inhibits pain is another neuroscience concept related to pain that's rather cool. Well, and I'm sorry I missed your question. Could you repeat what you answered? 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.

51:17Incredible. 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, you know, a, you know, a bruise that really aches or maybe even a break or a sprain or heat. You know, in the world of sport physio, cold is now heavily debated, localized cold is heavily debated. You know, you get people saying things. I don't know if this is true that, you know, it creates a sludging of the, of the fluids trying to head in and out of the injuries. So cold is not as good as heat. He'd allows for the inclusion and removal of waste products.

51:59And they, you know, they're 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, if you get things hot enough, you get them cold enough, you can create pain with heater cold. But let's assume we're not getting to that level of heat or cold. And one is in pain. You know, when I was a kid, we had a hot water bottle that four times when we were sick or something. But sometimes, you know, if I felt an ache on the side, I'd put some hot water in the hot water bottle.

52:34Lie on that thing, watch some cartoons. I definitely felt better. Sure. Sure. Well, putting aside the contemporary controversies over the mechanisms you describe, 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 no -susceptor.

53:17And 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 no -susceptors that are firing and you put cold, it's slowing the number of signals coming up. And by definition, it's reducing the, the 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, what do I tell people, you know, in part I tell people use whichever works best for them.

54:07I 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 know, you'll get a frostbite. So, you know, take care with that. How cold should one make the point of 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? You know, get past that point where it's a little bit painful. And then that, you know, basically you're shutting down some neural pathways and you don't feel anything there.

54:49It's numb. And then you let the blood flow return when you remove the cold pack. Is that I mean, that's a reasonable suggestion. Yeah. All right. Well, people I think we'll appreciate that the specifics of that because, you know, and of course listeners of this podcast often are interested in a whole body, deliberate cold, immersion, you know, cold showers, ice baths, et cetera. Most people experience those as somewhat painful as they get into them. Yeah. 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.

55:26It's not too cold. And or through, you know, we were talking about sports earlier, but just in general, like, can we raise our pain threshold so that life is less painful? 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.

56:09I 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 their cross modality changes in pain thresholds. I mean, if you expose yourself a lot to cold, does it change your heat threshold? I don't, I would surprise, be surprised if it did. Yeah, I would your pressure. Those are separate parallel pathways. Yeah, 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.

56:57Can 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, you know, 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.

57:50Because the guys did not want to look like a was 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. Has the reverse experiment also been done? I don't know. I don't know. 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 movement exercise. You know, clearly changes those thresholds over time. You are probably building up some increased inhibitory tone through that process. 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.

59:08So for people who have chronic pain, maybe it's in a small area of the body that experiences chronic pain, pain quite often, aka 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, or what we call neuroscientists, you and I top down mechanisms for things like, okay, 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 a, and again, this becomes a very opaque, right?

59:48We 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? 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.

1:00:24So one is attentional distraction, where you are distracting yourself from the thing that is causing pain. It 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 in your prefrontal cortex, some in your singular cortex, and other regions, which are clearly involved with distraction.

1:01:17It'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. It's during the daytime, you can read that book, you can spend time with friends and family, but people with chronic pain that have a 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.

1:01:56Now what you said, I mean the second piece, you said kind of 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 John Cabodzin originally developed mindfulness -based stress reduction, people with low back pain. Plenty of studies have shown that it works.

1:02:43I'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 of you will of the pain. Sorry, MBSR is back and in for mindfulness -based stress reduction. MBSR, everybody should do MBSR. 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. It takes a little bit of time to learn it. And it can be in some people effective and helpful for pain.

1:03:33And 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.

1:04:27The 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? It's so interesting. It's something you said about understanding the pain but not over interpreting 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.

1:05:12It's like I'm hurt, but am I injured? That's the first question. I've rolled an ankle, like, oh, I'm limping this hurt. Am I injured? Meaning am I going to be back at it in an hour, tomorrow, versus I've broken bones. 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. Knowing the difference between being hurt and being injured is something that's kind of that key moment. For me, it's always been experienced as a moment of anxiety after feeling pain, especially in a sports year. Like, oh, am I going to have to take two weeks off or is this just pain?

1:05:51I 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. 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. 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.

1:06:30And so be remiss if we didn't talk about emotional pain as well. Yeah, so what you just said, your spot, your spot on Andrew, and that one of the key messages, the key, you know, makkeys tips for pain management is to understand the distinction between hurt versus harm. I like that better. versus harm. Critical. Absolutely critical. Let me allow me to illustrate with patient I saw. Well, name names some time ago. Guys 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. He 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.

1:07:25And 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 examine 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 like this bundle 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 explain this to the guy and he looks at me with like this light bulb goes off. And he's like, you mean I can play tennis?

1:08:09And 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 pleased 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, you know, a 45 minute or 60 minute education session and, you know, back to the tennis court. He's 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.

1:08:53And I think that's what we first have to learn is does that pain that we're experiencing represent something that is harming us? That something that we either need to seek a medical attention now or sometimes 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.

1:09:44We 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? 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 harmed.

1:10:30I mean, I'm not asking you to comment on societal or generational shifts. But you know, 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, right? 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. Right? And if anything, I'm here to validate the fact that emotional pain is valid like any other pain accepted is different because it becomes very hard to point to a specific kind of threshold reason that we're to lot today.

1:11:16But I think it's appropriate here threshold between hurt and harmed. Whereas if I tell you that my left foot hurts, which you did a lot in high school. And then you took an extra of my foot in high school, you'd say your foot's 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 harm clearly going to harm myself worse. So I had to heal up. But when it comes to psychological pain, you know, psychiatry has all these thresholds for normal functioning versus abnormal functioning. Are you sleeping well, normal relationship and on and on.

1:11:48We 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. Yeah, great, great set of questions. There's a lot in there. Let me first start off with something very simple.

1:12:27I don't try to distinguish between this notion of psychological pain, physical pain, its pain, end up, end up. 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 at 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.

1:13:14It's all wrapped up. And so we want to treat the whole person.

1:13:22Sometimes we get easy. We get easy ones and we just go do a nerve block and 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 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. I do 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.

1:14:19And we use that data to target therapies to understand how much their depressive symptoms are anxiety, anger, anger, big issue in pain, huge in pain. Does it make it worse or better? Invariably it makes it worse. And you know, you can break anger down in a couple different categories. John Burns and others has broken it into like 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, you know, would quickly turn anything into an angry tie rate, anger out, expressive yelling at the news. Yes. Yelling at somebody cuts you off in traffic.

1:15:07Usually yelling at the man because he hated his job. Anger in, boiling, simmering, you know, self -contained, seething, that's anger in. Data seems to support anger in his worse, it's bad. 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. Beautifully stated, beautifully stated. So we can't, you know, 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.

1:15:53It'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 no -susception 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 real rehabilitative approaches on top of it. And yes, the medications we have now, you know, we touched based on a few earlier, but we have over 200 medications available for pain.

1:16:37Very few of them FDA approved. We tend to steal from all the other fields. So you're talking about more than 200 medications that can be yes prescribed for pain, but as off -label treatments 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 psychiatrist, 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 anti -seizure medications because those medications while reducing separately seizures for people who don't have seizures, they work on eye on channels, they work on other neuromodulators that also are involved in pain circuitry.

1:17:33We can take from the cardiologist medications that work on the heart anti -aridmy our 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 and 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.

1:18:22I find that's where we get the best results. And it is typically bringing a lot of tools to bear. Speaking of tools to bear, what role if any does nutrition play in local or whole body pain? 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.

1:18:58And incredibly underappreciated area. You know, 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. What's 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.

1:19:45Classic and what we refer to as fod maps. You know, it's one of the fod maps and I have now some issues with the others. And manifested by just severe severe up abdominal pain. And not many other symptoms, but you know, it put me on this journey where severe abdominal pain didn't know why couldn't sleep. Couldn't sleep went like I go months without having a restful night 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 do we all do? We isolated. We started eating the same foods.

1:20:28And 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, but you know, no onions. No onions. And what else? Salish, chives, scallions, leeks, anything in the onion family. You know, not all of them. I'm fine with garlic. And you know, by healthy eating, by identifying something, by triggers, changed my life and returned to a degree of normalcy.

1:21:12I think the key for people is, you know, 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. 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 quality of nutrition matters, defining what quality nutrition is is really difficult. There's still, you know, avid even we could call them rancorous debates about this, you know, vegan versus omnivore versus this.

1:21:56And, you know, 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, you know, 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, like not knowing how to go about doing the sorts of experiments that you did would be difficult. Impossible. I'm sorry, I know I interrupt you. I just want to at least 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 on your family, it's pain for two weeks.

1:22:33Wow. It is. So the thing is 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, you know, 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. Well, this may be a case for elimination diets, which are 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 whatever would have you.

1:23:15But that by limiting the total number of foods of the eat to like eight 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 a, 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 like why onions would create that kind of gut pain? This has been a journey I've been on now for a few years to answer this.

1:23:50One of our GI pain docs that we have come to the clinic to win and sent me a paper from, I know, 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. You know, I saw a Stanford allergist, Hannah Watford who's awesome by the way.

1:24:36And after I had this, I think figured out and I went in and I'm like, well, you know, Dr. Watford or 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, you know, 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 said, this isn't unusual. I said, no, I see this thing all the time. This is meaning sensitivity to certain, no, to certain to different, these different food groups and this, this thing that occurs later in life.

1:25:14Something 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. And is because I'm seeing I, Dr. Watford, I'm seeing increasing amounts of this as we go forward. 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 to explore how foods are impacting the local and systemic pain response.

1:25:54Yeah, I got in. You know, 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 as you can go make friends. Yeah, Justin Sonnenberg, who's been a guest on this podcast is one of the world experts on the gut microbiome. We have a few others too. There you go. So friendly guy. I'm sure he'll collaborate. We go, we go make friends and people who understand the microbiome, we collect the samples.

1:26:24And that's where team science is magical. And once again, the idea, looking at the whole person. As long as we're talking about the gut, let's talk about pain inside the body. Because we talked about narcisseptives on the surface of the body and the pain that most people immediately think of when you have a discussion about pain is, you know, pain on the surface or a broken bone or maybe hit pain or knee pain or back pain. But what about pain that resides deeper in the viscera? You know, gut pain, irritable bowel syndrome, these things are, I'm learning a far more common than that I knew I'm fortunate that if I have a stomach ache or a headache, I mean, something's wrong.

1:27:09I rarely get those. I've sometimes been called that you don't 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. Like pain that they feel is really deep within their system. Typically, how is that sort of pain dealt with at a clinical level? 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.

1:27:46I could jump down anything, anytime, anywhere. And so, you know, 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. 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 are alluding to is the no -susceptors there, very precisely localized 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 a visceral pain, what you have are very diffuse what we refer to as receptive fields.

1:28:39Think about last time you had a stomach ache. It's not that you put your thumb right here. You said it. It kind of hurts like this. Your whole stomach. Your 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 visceral meaning, the lungs, the abdomen, the pelvis, they all head into the spinal cord too.

1:29:31And it just so happens that they make kind of indirect 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.

1:30:25People have pain in their pelvis and then also over their abdomen. Classic one that we're aware of. We see this in the TV, the movies, and unfortunately real life or 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 in similar regions that subserve sensation under the arm. And up here, that's why people will often say they've got pain with a heart attack radiating down into their arm. The left arm, typically. The left arm, the heart is on the left side, exactly.

1:31:08After people get abdominal surgery, sometimes some blood can leak out and it'll slip underneath the diaphragm. To also cover your shoulder. And so you'll get people after abdominal surgery, they said, my shoulder's really hurting me, Doc. And what we do is we first check to see, you know, could something have happened during anis, you know, 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. It seems like a good point to bring up referenced pain. Or is what you're describing an example of referenced pain.

1:31:58So my understanding of referenced pain is that, you know, like, for instance, I've got a slight bulge head, I think, like my Lumbar 34 disc 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 disc 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, okay, there must be wallet induced sciatica, back pocket wallet induced sciatica.

1:32:40But what I eventually realized is that, well, it's this dis bulge that just so happens at 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. Or, 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 referenced pain? Perfectly. The examples also I referred to of a heart attack causing referred pain. Or also the pelvic region associated with back pain is a way of referred pain.

1:33:22What 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, you know, 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.

1:34:09It 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 disc bulge is the vast majority of time the discs reabsorb. Yeah, I have to be careful to not do too much spinal flexion like sit -ups and stuff. I thought that that would help, but that actually doesn't strengthen the back. It was actually a symmetry between the abdominal muscles and the lower back muscles.

1:34:50So it was 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? I don't want to get too abstract here, but more and more of 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.

1:35:32Then 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? Not at all.

1:35:46A simplistically referring to is, you know, there's people are undergoing stress. And we have, 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 in 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.

1:36:47And 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 outline 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 car accident when I was 16. A fortune to walk away from it got bad whiplash.

1:37:39If 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. 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.

1:38:33As 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. Yeah, I think there's several cool things about that study that I'd love to share. One is how it all came about. So, you know, us neuroscience geeks often go to the society for neuroscience as an annual meeting. And I was hanging out in a sharing room with Art Aaron who studies passionate love. And he and his wife study passionate love.

1:39:14And we were having a glass or two of wine and a mask and art. If you ever, you know, you ever studied pain? He's like, no, I study love. And he's like, have you ever studied love? No, I study pain. If there's anybody who ever studied the intersection, another glass of wine. No, let's do it. So, we came back to Stanford and there was a young postdoc Jared Younger, who's now a professor at the University of Alabama. And I said, Jared, we were either going to fall flat on her face or we're going to, this is going to be a cool study. And Jared took this on. Great job. So, what we did is we advertised on campus for couples in an early phase of a romantic relationship.

1:39:54Because there's a reason for choosing that. And 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? I mean, it's that yearning. I don't know. It's, it can be a pleasant experience. But addictions, you know, for the people who are using the substance can find it, you know, 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.

1:40:34Interesting. 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 intentionally 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?

1:41:21Okay. Frisbee. Hockey. Boxing. Boxing. Okay. That's intentionally demanding. Think about every vegetable that's not green. And, you know, so you're running that through your head and we're causing you pain. It's an attentional distraction task. So, we flash people, pictures of their beloved, cost -paying, flash people of their acquaintance, cost -paying, and then distraction. Okay. What do we find? Love works great. Love works great. It was a wonderful analgesic. It's significantly reduced people's pain. And it turned out the more in love you were, the more pain relief you got. When viewing the photo of the person you love.

1:42:09Now, how did we know how much in love 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? Oh goodness, you just sent people now off to give their partners the passionate love scale. That's right. That's a great question. How much time they're spending thinking about them? Yeah. We had Stanford students, some of them, thinking about their beloved 80 % of the day. I wanted to use this as a example. This is a screening tool for our resident applicants because I want them focusing on patients, not their beloved.

1:42:43And that is, by the way, a joke, that bad joke. But it probably is real world. We're not just talking about Stanford. Oh, no. 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. Yeah. So the other, 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.

1:43:30One of the descending brainstem regions called the substantioneigra, which is coming down from the brain through that area to the spinal cord to inhibit pain. So classic addiction pathways. 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 Jared went back a year later and we assessed the student's strength of their relationship, if Sumi was still ongoing. And he found that there was a rather high correlation between the love and doostanolgizia and brain activity and the caught ate nucleus and in the insular with the strength of the relationship of your later.

1:44:28It was, so we had a brain scan that was a predictor of future strength of a relationship. 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. Well, in this limited sample, it meant that it was going to be very strong a year later. Understand, and 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.

1:45:10No, but we can explore it in a playful way now and people can do with it what they will. It does sort of speak to something important though, assuming that result would hold up if the same experiment were done and many hundreds or thousands of people. It sort of 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 of the opposite way as well, which is, you know, Fools Russian or that things that start fast and fast or things like that.

1:45:53But 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. 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 the, you know, again, the different circuits for different approaches to reducing pain, fascinating. Again, that gets to the question you asked me earlier.

1:46:34Is 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. 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, that 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.

1:47:15So I would 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 creatum, 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. Yeah, so we all have these endogenous and kephalins and endorphins that act as pain killers. They are analgesics. They are natural substances and all of us that get expressed. There is a certain endogenous tone to these that some have done research on here again, Jared did research on this and Stephen Bruehl and others on showing that higher endogenous opioid levels may lead to less emotional reactivity, for instance.

1:48:16Thank God we have endogenous opioids or we just couldn't handle it. What chemists have figured out is how to bring in an exogenous opioids and morphine was the prototypical one from the from the poppy. And since then medicinal chemists have built on variations of morphine and created other compounds. Some again variations on morphine, some are purely synthetic like the oxycodone. Could ask a question because I'm fascinated by the history of these things. How did or when 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 thousands of years ago.

1:49:05So poppies have been used for a very long long time. These things have been around. So this is 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 I feel like I have to you know you have to understand the speaker Mike in this case me my you know 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.

1:49:58And 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 frontline 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.

1:51:01It's a it's a highly nuanced topic. So what what what more would you like to talk about opioids well I think that most people hear about the opioid crisis and just assume that they are quote unquote over prescribed that people are given opioid drugs as a frontline 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 like if people can't fill their prescriptions and tolerance to the opioids creating issues where people then need more of them there do it.

1:51:51I have a not close family member but a you know distant family member who had his entire life in arranged beautifully is 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 when you know 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 right so and I think there are many examples of that that we hear about in those are very salient and very disturbing very saddening.

1:52:32So I think that most people including myself here 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 perfectly and and that's again where we 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 over prescribed I think everybody agrees to that in this country and we went through a period of time with massive over prescribing 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 that naran's get 40 it's great if you're taking I think your dog's name is Castello yeah unfortunately he passed but he took some pain meds for a short while but I found an alternative treatment that worked for better perfect which turned out to be by the way low dose testosterone he was castrated like he was fixed on his younger and I it's interesting I've gone I've said publicly on very large scale podcasts that I gave my dog low dose testosterone later in life and it humiliated a lot of his aches and pains at least from what I understood because he started moving better and I'm not going to be a little bit more patient and I'm not going to be a little bit more patient and I'm not going to be a little bit more patient and I'm not going to be a little bit patient and I'm not going to be a little bit more patient and I'm not going to be a little bit patient and I'm not going to be a little bit patient and I'm not going to be a little bit patient and I'm not going to be a little bit more patient and feeling better and sleeping better and I expected the veterinary community come after me with Pitchforx not won 【No.

1:54:16two. We didn't get to see the goalie. The mountain incision finding. Look at he, the, the anak of those against the ADD report and the fact that never felt distressed had an accident animal and health, that health. Great. Well, that's hopefully your healthy too. You get the point. Yeah. But when it comes to the opioid crisis in this discussion, you know, I think it's become so laden with the idea that like doctors are on the take, like 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.

1:55:02Here's the thing. Were there bad docs doing bad things? Yes. I'm going to invoke a good friend of mine, Keith Humphries at St. Oh, yeah. Terrific. Terrific. Psychologist, who was an addiction medicine psychologist and public policy person. And the way he breaks it down and I have a subscribe to this is, you know, 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, fast 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.

1:55:49There 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 over prescribe 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 is my heart goes out to them. You know, what do they get? 14 minutes or so with a patient. They gave them something that they thought would help. They were doing the wrong thing for the right reasons, but they believed that they were helping.

1:56:38They didn't have. They weren't catching financial incentives or got it. That's right. Those people, we need to educate them. We need to train them on proper pain management, opioid prescribing, deep prescribing. 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 lot. They need to go to jail and the thing is, is that that little group at the top and the million or so physicians we have in this country, it represents such a small representation, but it got blown out by the media.

1:57:23And everybody else, particularly those docs doing the right thing for the right reasons, got caught up in it, an engendered huge amount of fear, huge amount of fear on the physician's 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, a doc cut her off from a little bit of Ike had in that she was taken 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 for, and the docs prescribing opioids for that.

1:58:16And they went after the docs thinking that if they targeted the docs doing that, it would lead to a reduce, 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 fentanyls coming in via Mexico, China and others is withdrawing most of the deaths.

1:59:02Keith, 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 just huge complexity in this space. I understand you're going to do an episode, some time on it in the future.

1:59:49I hope the audience has more opportunity to listen to this. Other questions I can answer for you on that. 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. 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's in pain and they had something that worked and now they don't.

2:00:39They're going to go looking for things that are similar to that thing. 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. 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 trosh. The trosh 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. So it took a while to get a better handle on it. But I think, you know, we do now.

2:01:19Yes, 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.

2:02:09The answer is yes. My partner, Beth, is just finishing up a study on that and, you know, showing that with compassionate care, a number of these patients can be weaned down who voluntarily want to come down. And sometimes they 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. Could you list off some of the more commonly used opioids? You know, morphine and its commercial derivatives, MS content, which is a long -lasting version of morphine oxycodone, which by itself is a short -acting medication.

2:02:57But 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 tram at all, which is kind of a weak opioid, but also has what's called serotonin and oraprinephrine, reuptake inhibition. We've got dilated, which is a version of trading 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.

2:03:50People go to methadone clinics. It's a long -lasting opioid in the right person in certain circumstances that 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.

2:04:37When 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. Is there any role for benzodiazepines in pain relief? Rarely. Many of my colleagues would say, you know, Sean, it's just a hard no.

2:05:09I'd have to come up with an edge condition of somebody who has a generalized anxiety disorder untruthily treated with anti -angiolytic 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. What about cratum? I had an odd experience with cratum 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.

2:05:57And that there was huge variation in terms of the amount of cratum in the various products and how much people were taking. Some people talking about cratum as something that 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 cratum, the scientific literature, is that it had a lot of property similar to opioids, although different as well. And that it seemed kind of odd and maybe even problematic that it was so widely available.

2:06:34And I got bombarded with, I don't want to call them cratum enthusiasts because what I soon discovered was that these people were angry with me for placing even a partial shadow on cratum. 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 cratum had helped them get off prescription opioids and that they heavily rely on cratum in various levels of dosage in ways that they felt really help them. And so two things happen. One, I've been put in the crosshairs of the pro -cratum 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 cratum.

2:07:23I'm going to be interviewing one of the laboratories that's done a lot of the research on cratum later in 2024. But also, it's made me realize that 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 cratum, or perhaps what receptors does it tickle? And what are your thoughts about cratum and people using cratum? And maybe I'm pronouncing it wrong. I've also heard cratum, cratum. I'm calling it cratum.

2:07:57Yeah. Cratum is this natural substance that does have, as you said, opiodurgic 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 cratum, 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 cratum 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.

2:08:43And it makes perfect sense. A methadone does that. A buprenorphine, which I didn't mention before, but is an interesting opioid that binds to these receptors and it reduces craving.

2:09:00Where I have challenges is just because something is natural doesn't mean that it is safe. We are seeing an increased number of overdose deaths associated with cratum. Is it polysubstance? Yeah, in some cases it is, but I think there's a lot we don't know. So polysubstance people taking cratum, but also alcohol, benzoes getting back to the benzoes.

2:09:34Personally, I think we need to put a lot of research into this agent and if it merits that 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, the purity, 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. You mentioned cannabis is cannabis effective and by extension is CBD effective for managing pain.

2:10:20There's another controversial one. You'll get a few comments about whatever I say. 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 to 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 cratum 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. We do read all the comments.

2:10:56Those comments often, as I mentioned in my earlier anecdote, about that tweet, often direct us to explore things further. We can always have a second discussion about this down the line. We invite all your comments and criticism. Cannabis. Well, here's what we know. And 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 -tropetic neurology, 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.

2:11:55There'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. The bad news is that we're probably going to see some real untoward consequences of it and we're 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 creatin.

2:12:42Cannabis is not cannabis is not cannabis. You know, the T .H .C .B. To CBD ratios, the dose, yes, all of that. We don't know what you're getting. It remains a scheduled one drug by the DEA. I, in some of my leadership roles and others have called for scheduling of it as a scheduled two. Why? Why? Not to purposely try to restrict use, but by making it a scheduled two 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 one drugs. Could you explain schedule one versus schedule two? Thank you. So the scheduling of drugs is a categorization that describes their abuse liability.

2:13:31And so you have drugs like PCP, heroin, cannabis, which are schedule one, which are defined as having high addiction potential and no utility. Which is just wild because when I think about PCP, fanciklydine, 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, you know, rarely is this discussed, but ketamine is now widely used as a therapeutic. Presumably ketamine isn't scheduled to, maybe even schedule three. Yes. So some of the stuff that's thrown into schedule one makes no sense. It's historical. It's all, it's decades and decades ago of history and clearly cannabis should not be a schedule one.

2:14:24Hands down. No question. By scheduling it though, you will have this societal benefit of being able to make it more easy to study. And then you 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 modulation of pain. I just don't know what those are. 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.

2:15:21I 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 that's creatum, perhaps, right? We're remaining open about that. Or cannabis, the THC, or the CBD, or some combination.

2:15:57I 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? 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.

2:17:04Five, 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 Huwerman 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.

2:17:49To a lot of people listening to us right now, they go, yeah, acupuncture. I mean, this is a thousands or tens of thousands of years 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? Yes, yes there is. Do I understand what's going on with acupuncture?

2:18:30Having completed an acup - and then I each funded acupuncture study. I just saw that published. No. You know, 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 acupuncture 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.

2:19:15Where does this fit into my clinical use? My usual statement is that if you can afford the wallet biopsy, give it a try. Although find a really good acupunctureist. 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 won't, if I go to acupuncture, I don't put anything, don't put any needles in my face. Because I'll take an angioma in my leg or whatever I don't care.

2:19:55And 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 docket Stanford, I always call somebody at UCSF and crosscheck.

2:20:28And I don't tell them that I'm crosschecking. And I'll do the reverse as well when I was at UC San Diego, I would check up with Stanford. So, 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 waiting into the abyss of acupuncturists of physicians. I mean, how do our people supposed to navigate this? You found a perfect way to do it. 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.

2:21:03So, you're right with acupuncture. Most of the ones I've been associated with, we use in the clinic or outside, are 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.

2:21:47With regard to clinicians, pain physicians, for instance, that's tough. There's five to ten thousand of us that are sub -specialty 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. So, is there a centralized website where people can say, okay, I live in the state of Iowa, or I'm, you know, a lot of our listeners are overseas, or you know, 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.

2:22:31There have been studies on this. People tend to, if you see a negative review, those tend to grab your attention, even if they're 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 patient experience, right? Yeah, I got to tell you, the patient ratings, it's a highly manipulated situation. Also? Well, you can pay companies to help jack up your ratings. I see. That's, it's rather easy. I see it in the community. So, inflation of ratings. Oh my, yes. Inflation of ratings. And so, then you inflate it and it overcomes any of the negative ones.

2:23:11We haven't, have taken an approach on this. And maybe that's naive of us. You know, 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. I, you know, to see Hannah Watford, the allergist, I asked my primary care doctor, Sanford. Who's the best? Who is the person that knows the most about food related issues?

2:23:53Well, some really entrepreneurial guy or gal or group of guy or gals will put together a website or an app or something that really addresses this problem head on. Well, that's part of it. 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.

2:24:32A 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 manipulates 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.

2:25:12Can it help pain? Can it help back pain, neck pain, whole body pain? 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 found acupuncture to be useful. And it's worth a try. CMS, a center of Medicare, is now paying for acupuncture for people over the age of 65. Medicare for Medicare patients. That's something recent.

2:25:53And 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 involves, that doesn't involve kind of, you know, 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. What is a vertebral artery dissection? One of the main arteries that goes from the body to the brain and the back portion of it is called the vertebral artery.

2:26:51And when you do these high velocity manipulations, there is a risk, albeit small, of having a dissection or an embolus thrown off. So it's like a stroke. It is a stroke. 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, right? But a couple of few hours later, it's kind of worn off. It's a nice experience in the moment for most people.

2:27:44If 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 practices, 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 in -road 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.

2:28:40You 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. Yes, certainly in my case, anytime 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.

2:29:22What if any is the role for physical therapists in the treatment of chronic pain? Absolutely crucial. Absolutely crucial. Despite being a physician, not a physical therapist, I've great appreciation and respect for what the physical rehabilitative approach is due. 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 are tying in with good physical therapist, occupational therapist, people who can do goal setting, absolutely critical.

2:30:09All of the treatments that I provide typically are meant to help support and 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 therapist or 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.

2:30:57Now this isn't just exclusive to the physical therapist. The psychologist 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.

2:31:45It'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 have 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.

2:32:41On 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 a 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. 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.

2:33:27And 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 are talking to the physician. But I guess this is the reason for referrals, right? Why somebody has a primary care doc, then it radiates down to the rest. Is that why? And 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.

2:34:12This 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. What is your view on non -prescription compounds, so -called supplements or nutraceuticals, for the treatment of pain? 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, acetylal carnitine is one of them.

2:34:59Acetylal carnitine is thought to work on mitochondrial metabolism and in proven mitochondrial health, and it's been used, I believe, as an anti -aging and maybe even an agnative enhancement agent. It's been studied out of an Australian study. I think it was called the Sydney Trials, actually. And what they found is 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.

2:35:42And a normal nerve, nerve -bulb pulses move at a certain rate. And when they're injured from diabetes, they, you know, it's much slower and you lose signal. This actually improves nerve health. Now you have to take this at higher doses. It's typically 2 ,000, 3 ,000 grams. It's pretty large dose. These are oral doses. Oral doses. You can buy those at a vitamin shop, 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.

2:36:29And 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, you know, again, just an N of 1. What I found though is you have T -type calcium channels in your heart. And I do hit a 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.

2:37:23The 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 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, you know, the anachdata that we joke about, the anachdotal. There's actually good randomized control 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.

2:38:18Meaning, get educated about the side effects in the adverse events, get educated about the drug drug interactions, the age and age and 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. Isn't vitamin C one such substance that causes excessive bleeding or some people report that high levels of omega -3s can increase. The, um, can reduce the viscosity of the blood, meaning you bleed easier. The omega -3s of fish oils, yes.

2:39:06Absolutely. The vitamin C, I'm not familiar honestly with that. As a blood thing agent, maybe I'm misinformed there or maybe I'm just forgetting it, but that's one I don't usually think of as a blunt thinner. Someone will put in the show notes, comments one way or the other, get corrected. I, 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. The innocuous meaning they don't cause harm at the, at reasonable dose is, but they can't have positive effects. Well, perfectly stated. Yeah. Well, thank you for sharing that list.

2:39:43I think, as you mentioned, many compounds that are only available, prescription overseas are indeed available over the counter in the US in this area of 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, you know, a, formally trained physician and, and scientists who embraces so many different approaches in, 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. Again, absolutely critical in the management of people with, you know, wide range of pain problems.

2:40:26And recall what we talked about is, you know, this is no exception. These are the signals coming up to the brain. Once it hits the brain, you know, we're dealing with everything that person is lived through. And also is currently experiencing, meaning there are 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 early in life impacts us as adults and stays with us.

2:41:22It 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, you know, talking about, you know, 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, you know, a little bit with this medication, a little bit with this procedure, some days, this procedure, a bit with psychology.

2:42:14We're trying to hit all of these pathways in aggregate to make a real difference. The pain psychologist used 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, and Silicon Valley where I practice the engineers love the biofeedback. I'm an engineer by formal trainings, I get it, but it's that closed loop feedback because remember, the brain is controlling the periphery and controlling the sympathetic nervous system.

2:43:12And when we're in pain, our sympathetic nervous system gets wrapped up. When the sympathetic nervous system gets wrapped 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 rest 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.

2:43:56Not 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. Is that the plan for this abbreviated but equally effective cognitive behavioral therapy? Yes, now you're getting into kind of my Beth's and my life mission. So, you know, 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.

2:44:58And 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. I said, this is a life mission. We both have been blessed to be at Stanford where we have everything. But, you know, you go just 30 miles, 40 miles outside of the Bay Area and you're in a health care desert.

2:45:49And 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. 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.

2:46:42Darnell, Beth Darnell to develop as at least one of them. So now that that answer was given by me, then you can freeze up the opportunity for you to give another answer. What is the, if you had one wish for the feel that pain medicine going forward, what would that wish be? 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.

2:47:27We 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 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 was well thought out. It's the one that we have for our country. It's noncontroversial, nonpartisan. It is motherhood and apple pie.

2:48:17And it's if we just actually implement what we put forward, it'll make a huge difference in the lives of people living with pain. Is there anything that people listening to this podcast can do to try and move the implementation of that initiative? Are there Congress people to call? Yes. That's how 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.

2:48:57Beautifully stated, you're absolutely right. And in fact, the nitus 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, the 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. So that means calling your congressman and congresswoman, leaving messages.

2:49:44I hear this works. I mean, I know people they're doing this for other initiatives. And one call to calls doesn't make much of a difference. But that if people are saying, you know, this is important to them that people didn't power eventually start taking action. 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.

2:50:27Because 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. Well, Sean, Dr. Mackie, 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.

2:51:08We 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. Thank you, Dr. Hubertman. I appreciate the opportunity to come on and spend some time and you're giving a platform to help educate and inform people out there. I got to tell you nobody does it better.

2:51:42You've been absolutely amazing and thank you again. Thank you. It's a labor of love and I appreciate the kind words come back again. Thank you. Thank you for joining me today for my discussion all about pain and ways to control pain with Dr. Sean Mackie. 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. Mackie mentioned during today's episode. Please refer to the show note captions. If you're learning from and you're enjoying this podcast, please subscribe to our YouTube channel. That's a terrific zero cost way to support us.

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