I'm honored this evening to introduce Dr. Daniel Claw, a professor of anesthesiology, medicine, rheumatology, and psychiatry, and the director of the Chronic Pain and Fatigue Research Center at the University of Michigan. He's a renowned expert on pain research and pain treatment. We are very fortunate to have him join us today to speak about some of the underlying mechanisms of chronic pain, as well as some of the treatment options that are informed by these mechanisms. These topics are obviously very important to any physiatry practice, regardless of specialization or type of practice that each of us are in. So I know this will be a very engaging and interesting talk for all of us physiatrists in the audience. So without further ado, I will turn over to Dr. Claw, who can take over a great talk for us for this evening. Please ask any questions as you have them, and I'll help tailor them over for Dr. Claw. Great, thanks so much, Andrew. And thanks for inviting me tonight. Here's a disclosure slide. I do a lot of consulting with pharmaceutical companies that are trying to develop new non-opioid analgesics. And you'll hear in the talk, I've never been a big fan of using opioids to treat chronic pain. I actually have testified against opioid manufacturers. So I almost always start any talk that I'm giving on pain with this slide and showing two different individuals' knee X-rays and posing the question, who has pain? Because I think many of us were taught in our training that the person on the right with advanced osteoarthritis of the knee would almost always have pain if they have that X-ray, and that the person on the left would rarely have pain. But in fact, studies in osteoarthritis have made clear that that's not at all the case, that about 40% of people in the United States that have a radiograph like the one on the right, either grade three or grade four, Kellgren-Lawrence osteoarthritis, about 40% of those individuals actually are not experiencing pain. And about 10% of individuals that have knee pain in epidemiologic studies will have an entirely normal knee X-ray. So I use osteoarthritis and knee X-rays as exemplars today, but there's not any chronic pain state where anything that we can see on a plain X-ray, an MRI, actually predicts who's going to be experiencing pain or how severe that pain is going to be. So why is that? Why is there always a tremendous disparity between what we see on a radiograph or an MRI and whether someone's experiencing pain or how severe that pain is? Well, first, a little bit more about osteoarthritis. This slide encompasses about 30 years of research on osteoarthritis, roughly about how long I've been in the field. So 30 years or so when I was trained as a rheumatologist, we were taught that osteoarthritis, in fact, was our classic peripheral pain condition and that if someone hurt in their knee, they probably had something wrong on X-rays. But starting about 20, 25 years ago, population-based studies showed that there was a terrible relationship between what you see on a knee radiograph and whether someone's having pain or not. Again, especially showing that a sizable number of individuals who have quite severe radiographic damage don't have any pain whatsoever. Then in the osteoarthritis field, after these studies showed this disparity between what you see on an X-ray and whether someone's experiencing pain, people said, well, if someone's complaining of pain and they have a normal X-ray, they must have an underlying psychological problem. And in fact, a lot of research was done looking at that. And in fact, classic psychological factors actually explained very little of the variance between what we see on an X-ray and whether someone's experiencing pain. Yes, if someone has anxiety or depression or catastrophizing, their pain might be a little bit worse, but very little of the variance between what you see on an X-ray or an MRI and whether someone's experienced pain is accounted for by classic psychological factors. And then the bottom of this slide, I think, is interesting because we sometimes delude ourselves into thinking that our current therapies work well. Again, I'm old. I remember that when we first started using nonsteroidals in osteoarthritis of the knee, we thought that they worked well in most people with osteoarthritis of the knee, but it turns out the effect size for using nonsteroidals in osteoarthritis of the knee is almost identical to the effect size of a drug like pregabalin or duloxetine in fibromyalgia. It turns out that all of our drugs in any chronic pain condition typically only work well in about one out of three individuals that we give them to. And for osteoarthritis, whether we're talking about nonsteroidals, acetaminophen, opioids, which practice guidelines strongly recommend against use of opioids, but nonetheless, all of these drugs that we're accustomed to using actually have quite small effect sizes when you really look critically at them. And even if you replace the knee, even if you take someone with a damaged knee and put in a shiny new titanium knee joint, 30% of those individuals fail to have improvement of their pain, even after arthroplasty. So why is this? What helps explain this difference between what we're seeing on x-rays and whether someone's experiencing pain? Well, I'm gonna talk a little bit about fibromyalgia. And I think today I'm gonna talk about fibromyalgia in a way different than how you classically heard about fibromyalgia, I hope I do anyway, but I'm gonna also move through 30 years in one slide where the original criteria for fibromyalgia that were published in 1990, oops, were that two elements, that the individual had chronic widespread pain and they had a certain number of tender points, 11 or greater out of a possible 18 tender points. That version of fibromyalgia did help start research and standardized research in fibromyalgia, but it didn't do the disorder of fibromyalgia any favors because there was a lot that was wrong about that definition. It posed that fibromyalgia was a discrete illness. I'm gonna try to convince you that you should think of that different people have different degrees of fibromyalgia and some people have a lot and we call that fibromyalgia and some people don't have as many, but literally it's really a lot more accurate to think of fibromyalgia of the degree of someone that fibromyalgia that someone has rather than yes or no. One of the real problems with that definition in doing tender point counts is it misled people into thinking there was something wrong in those areas of the body that were considered to be tender points. And obviously 30 years ago, the pathophysiology of fibromyalgia was poorly understood and most people thought it either didn't exist at all or that it was a primarily a psychological problem. Well, now fast forward 30 years and if you're not a pain researcher, you probably wouldn't know that fibromyalgia is thought to be a very legitimate pain condition by pain researchers. And in fact, it's the poster child for a third new mechanism of pain that two years ago, the International Association for the Study of Pain, IASP formally voted, their membership voted and agreed that the evidence now was significant suggesting this third new mechanism of pain that we used to call central sensitization. Now the term that's being preferred in the pain field is nociplastic pain. I'll talk about some of these terms, but the bottom line is that fibromyalgia is really considered to be the poster child for this third mechanism of pain where central nervous system factors are more so contributing to the pain that these individuals are experiencing rather than peripheral factors. And in fact, the phenotype that can help you identify individuals that have fibromyalgia or degrees of fibromyalgia is not just their pain and how widespread it is. It is these comorbid symptoms that also come from the central nervous system like fatigue, sleep problems, memory problems, and sensitivity to other types of sensory stimuli other than pain. People with fibromyalgia are just as sensitive to the brightness of light or the loudness of noises as they are to pain if you do quantitative sensory testing. And so if you look at this table here, it's a fairly busy table, but if you start out at the top, the two mechanisms of pain on the left, nociceptive and neuropathic, we've known about forever. But this third mechanism here, what we still like to call centralized pain, because I think people understand what that means more, but the new scientific term that the pain field is trying to adopt is nociplastic pain, that this pain is, again, a mechanism that can either exist in isolation in conditions like fibromyalgia, functional GI disorders, temporomandibular joint disorder, tension headache, interstitial cystitis are conditions that are thought to be primarily this type of pain. But we also know that this type of pain, centralized pain or nociplastic pain, very common co-occurs with neuropathic pain or with nociceptive pain. So for example, we know that 20 or 30% of people with osteoarthritis, 30 or more percent of people with autoimmune disorders or cancer pain also have this mechanism of pain here. So what we're moving towards is realizing that we used to think that everyone with osteoarthritis only had this kind of pain, and thus they were all going to respond well to these treatments. And we actually used to think the converse in fibromyalgia, that everyone with fibromyalgia only had this kind of pain, and they were primarily going to respond to CNS acting drugs and non-pharmacologic therapies, the mainstays of therapy of fibromyalgia. But we know a lot of people with fibromyalgia have a little bit of neuropathic pain and a little bit of nociceptive pain. And we know that a lot of people with primarily nociceptive pain states, like osteoarthritis, like rheumatoid arthritis, or neuropathic pain states, that a lot of these individuals also have this other mechanism of pain. So it's becoming increasingly important to try to phenotype people in clinical practice for which of these pain mechanisms is operative. And in many individuals, it's more than one pain mechanism. And the treatments that are going to work for an individual across the exam room from you are going to more so be dictated by what underlying mechanisms of pain are operative in that person, rather than the disease label and saying, well, all that fibromyalgia patients are going to respond to are these therapies, and all that osteoarthritis patients are going to respond to are these therapies. So one of the analogies that I started using about 15 years or so ago to explain all of this to patients, and it works for healthcare providers as well, is that the amount of pain that someone is experiencing is analogous to the loudness of an electric guitar. And you all know that there's two ways to make an electric guitar louder, or the noise coming out of the guitar louder. You can either strum the strings harder, or you can turn up the amplifier. If you strum an individual string, it only makes that one string louder, but if you turn up the amplifier, all the strings are louder, regardless of how hard you strum them. So now going back to those two knees that I showed you earlier, I'll try to explain why there's such a disparity between what we see on an X-ray and how much pain someone is experiencing. And that's because this information that comes from the knee has to go through the spinal cord and up to the brain to be felt as pain. So these people have a very sort of permissive pain processing system that virtually everything that's going on in their periphery, they feel as being painful. These are individuals that have, if you will, a high amplifier setting. They're very pain sensitive. And the pediatric term for this spectrum of illness even is amps. It's a very apt term. It's literally that the amplifier is turned up too high. But I also wanna point out that this explains these individuals over here. The individuals over here that have a bad looking knee and aren't experiencing any pain are probably pain insensitive people. And in the US, almost all the people in the epidemiologic studies that have an X-ray that looks like this that don't experience any pain are men because on average males have a much lower amplifier setting than females. Males are less sensitive to nociceptive pain. Males are also less sensitive to, if you present different intensities of visual stimuli or auditory stimuli, males are less sensory sensitive than females. I always like stopping here because the women in the audience are cringing when I'm saying that. But if I flip it around, it may make you a little more satisfied. You've always known that men are insensitive and research actually shows that that's true, that men are inherently less sensitive to sensory stimuli than women are. But this is what accounts for nearly every chronic pain state is about one and a half to two times more common in women than in men. And the reason is this amplifier difference between women and men. Women don't have any higher rates on average of damage to peripheral tissues, but they do have markedly different pain processing. And if it wasn't annoying enough to be a female, if you're still actively menstruating female, you often become even more pain and sensory sensitive in the premenstrual phase of your cycle. And again, this is just something that is innately different about pain processing in men and women. This is just another way of showing in a classic bell-shaped curve that you see that graph on the right, that you're looking at different people that are different degrees of tenderness. And tenderness is, if you will, a measure of how overall mechanically pain sensitive people are. And so you can measure or push in different areas of the body to try to get an idea of whether people are tender or not. And that does in fact help you confirm the diagnosis of fibromyalgia. But those measures are not very accurate if you're just doing like a digital palpation. And that's why the new criteria for fibromyalgia have entirely eliminated tender points because they really don't provide much useful information. But what's on this slide is useful that if you do as several studies have done where they just take people in the population and they do quantitative sensory testing and see how tender they are, and then they follow them for five years, the more tender someone is, the more likely they're going to develop new chronic pain over the next five years. And again, the reason for this is that they have a higher amplifier setting. So everything that happens to them will be experienced as being more painful than someone that happens to be lucky enough to have a low amplifier setting. So now I'll introduce another term that's increasingly being used, and that's chronic overlapping pain conditions. This is a term that's now been coined first by the National Institutes of Health and now is being used more widely. And in Europe, this is actually being called primary care pain, actually, is all these pain conditions that we think now are more so a central nervous system, nociplastic fibromyalgia-like condition, headache, fibromyalgia, irritable bowel, temporomandibular joint disorder, interstitial cystitis. These conditions now are by the NIH called chronic overlapping pain conditions because they really have a lot more in common with them than they are different. And in fact, a lot of these are just merely terms that have been adopted for people that have pain in an area of the body, but you can't find anything wrong in that area of the body to blame their pain for. And what we also know is that the same underlying mechanisms that are front and center in people with these chronic overlapping pain conditions play a significant role in people with osteoarthritis, rheumatoid arthritis, sickle cell disease. Again, those individuals that we used to label as having more nociceptive or neuropathic pain states, a sizable proportion of those also have overlapping central sensitization or nociplastic pain that's playing a prominent role. And because of that, you're gonna have to use treatments in those individuals that are more directed towards the central nervous system or more of the non-pharmacologic therapies that work in these central pain states. Fred Wolf is a rheumatologist that's written about fibromyalgia a long time. I don't agree with a lot of things that Fred writes because he still thinks that this is a primarily psychological problem. But I like pointing out that early in his career, he got right this fact that we really should talk about fibromyalgia as different people having different degrees of fibromyalgia because he actually showed that in osteoarthritis, low back pain, rheumatoid arthritis, lupus, that what someone scored on a continuous measure of fibromyalgia, the degree of fibromyalgia they had was a bigger predictor of how much pain or disability they would have than things like in rheumatoid arthritis, a sedimentation rate, a C-reactive protein, which we as rheumatologists hang our hats on as being good measures of inflammation, but it's not as good a predictor of how much pain someone with RA is in as their fibromyalgianess score. So these are the new criteria for fibromyalgia that you can either use as a way of diagnosing people with fibromyalgia to say, yes, no, they have fibromyalgia. I hope though that instead you use them to look at the degree of fibromyalgia they have. And so if you look at this diagram here, on the left side of the diagram, there are 19 sites and we're asking people to check all the different areas that they have pain. So the more widespread the pain is, the higher the degree of fibromyalgia that someone has. And if they have pain in every area of their body, they are scored 19 points here. They basically get one point for every checkbox that they have on this widespread pain index on the left. And then the patients move over to the right and they are asked about the presence and severity of the central nervous system symptoms like fatigue, sleep problems, and memory problems that are so prominent in nosoplastic pain, central sensitization. If they say they don't have that problem, they are scored a zero. If they get a slight, they get a one, moderate is a two, severe is a three. So each of these symptoms, fatigue, memory problems, and sleep disturbances are scored from zero to three. And so you can get a total of nine points on this measure here. And then they get one point each year for having irritable bowel depression or headache. But this fibromyalgia measure can be scored from zero to 31 and a score of 13 or greater is thought to be now the diagnosis of fibromyalgia. Let me just show you what we're trying to get at here with sort of the widespreadness of pain. Imagine that someone came into you with knee pain and you were considering doing some kind of procedure to their knee. It would be sort of intuitive to you that if they had knee pain and they only had pain in their knee, that they might respond differently to therapy than if they had knee pain. And if that knee that you were supposed to take care of was in this body. This is a classic fibromyalgia patient, but there's a fair number of people that have this sort of phenotype that go in and present with regional pain and no one really asks about how much pain they have elsewhere really looks for this. And so it really is important I think at least once when you first start seeing a new chronic pain patient give them that fibromyalgia measure, see how high they score and often it's surprising to you that people score fairly high even if they don't score 13 and you call them a fibromyalgia patient if they score higher than 7 or 8 then the types of treatments that we use for fibromyalgia might work quite well in those individuals and what that means is they don't have a purely nociceptive or neuropathic pain state even if you're otherwise your inclination is to use a diagnostic term like osteoarthritis or diabetic painful neuropathy. And so I really like using this analogy that the people that we label as having fibromyalgia in clinical settings are really the tip of the iceberg. Any study you do will suggest that there's much greater numbers of people with centralized pain where the label they have is osteoarthritis or low back pain or any number of other labels and in those individuals they often then get treatments that are more directed towards the periphery because people don't really think of them being a fibromyalgia-like patient who I should treat a little more like my fibromyalgia patients like my than my pure OA patients. I'll just very briefly present some studies that we've done at the University of Michigan. They were led by Chad Brummett who was a mentee of mine at the time now he's a colleague of mine and in these studies our hypotheses were that in these cohorts like individuals that were getting knee replacement surgery for osteoarthritis or women that were getting a hysterectomy for chronic pelvic pain that if we gave them that fibromyalgia measure we hypothesized that the higher they scored on that fibromyalgia measure right before surgery the more opioids that they would need to control their pain because I'll get to this later but this kind of pain is inherently less opioid responsive than no susceptive pain but also we hypothesized that the higher the fibromyalgia score in someone getting knee replacement surgery the less likely they would be to benefit from that procedure because less of their pain was coming from the knee and more of their pain was coming from the brain and if you operate on the knee you're only going to make the component of the pain that's coming from the knee better. In these studies we didn't just look at the fibromyalgia score we looked at psychological factors like depression, anxiety, catastrophizing but we it was really the first time that anyone did a series of studies using this fibromyalgia measure as a surrogate measure of the degree to which the brain is causing pain in a lot of these chronic pain states. Again I showed you already how this is scored and now I'll just show you I'm going to present for you the knee arthroplasty data but the data were almost identical in the hysterectomy cohort. Again I think most people in PMR are more used to a osteoarthritis analogy so I'll present those data but for each one point increase in the fibromyalgia score from 0 to 31 people needed nine milligrams more of oral morphine equivalents to control their acute pain in the inpatient stay in the hospital. At the time we did this study of knee arthroplasty our arthroplasty patients were in the hospital 24 to 36 hours now a lot of them are being done same day surgery but this was the amount of opioids just in the first 36 hours a marked increase in opioid need for each one point increase in the fibromyalgia score that's about one hydrocodone is nine OMEs. A one point increase in the fibromyalgia score also led to a 25 percent increase in the likelihood that people would not respond to knee replacement surgery and this was linear the degree it didn't matter and this is why I am sort of pleading with you to not use a a cut point of 13 with the fibromyalgia measure and say fibromyalgia is yes or no. Each one point increase in the fibromyalgia measure going from zero to the mid-20s made people less opioid responsive and less surgery responsive. There was nothing magical about the 13 point at which we say this person has fibromyalgia and even more importantly although I think a lot of people when you see people with fibromyalgia in clinic these are individuals that that usually are labeled with fibromyalgia they have very high rates of psychological and psychiatric comorbidities but if you strip that away and you look at the studies that we did these phenomena that I'm talking about are independent of psychological factors this what's going on in their brain in many cases there is comorbid anxiety depression catastrophizing but that's not what's causing it and treating this as though it's a primary psychiatric problem will not work because that psychiatrist won't know what to do with these people either. This is really an increase in the amplifier setting and increase in the volume control. Here's a data slide from these studies down at the bottom of the slide is the fibromyalgia measure which I told you can go from zero to 31 on the y-axis here are the number of people that had the score so you can see there were about 700 people in this study. The median fibromyalgia score in the people at the University of Michigan getting knee replacement surgery was five but you see that there's some people at higher scores and there were 55 out of 700 people in this study at the University of Michigan that when on the day of surgery we gave them the fibromyalgia measure we saw that they would meet criteria for fibromyalgia they scored 13 or higher this red line the right side of the red line these people all would be said to be diagnostic of fibromyalgia. None of these 55 people that were being seen at U of M for and were getting knee replacement surgery had ever been diagnosed as having fibromyalgia. The label in the chart in all 55 of them was osteoarthritis. No one had picked up on the fact that their osteoarthritis looked a lot different than osteoarthritis where on the left side of the continuum where someone has you know one or two sites of pain and that's a really different type of osteoarthritis than someone that has osteoarthritis and has a fibromyalgia score of 10, 12, 13 or 15. Let me just show you now how stark this is. So you see here that neither of these people that got knee replacement surgery has fibromyalgia. This person has a really low fibromyalgia score because he just has pain in his knee and a little bit of fatigue. This people person has a much higher score because he has pain in his knee as well as a couple other sites has some sleep problems some fatigue but he doesn't yet cross the line to fibromyalgia. Look at how different these two people are with respect to their opioid requirements and with respect to whether surgery would work to treat their pain. This person here is five times less likely to get a 50% improvement in his knee pain if he has knee replacement surgery than this person here and again in most instances none all of these people just have the diagnosis of osteoarthritis regardless of whether they're at this end of the continuum or they're at this end of the continuum even though we could see that they were markedly different with respect to what worked to treat their pain. And so when I go back to this here it's really important to see that all pain states are mixed pain states. This sort of antiquated notion that there's one mechanism of pain in these conditions and one in these and one in these is just simply we know not to be the case and so now all the NIH networks that our group and others are involved in are really trying to do better phenotyping of individuals at baseline to figure out which of these pain mechanisms they have because that really is going to determine what works and what doesn't work with respect to treatments. And this is just sort of a random slide showing the conditions like osteoarthritis and rheumatoid arthritis roughly a third of the people will have some central component to their pain. Sickle cell disease, hypermobility syndromes, low back pain it's 50% or more will have centralized pain and these conditions again are primarily centralized pain but again a point of emphasis is some people with fibromyalgia some people with tension headache have peripheral nociceptive pain and they'll do well if you put them on a non-steroidal or if you treat them as though they have some of their pain that's coming from that underlying mechanism. To show you some really some studies really quickly if you see that someone has a high fibromyalgia score it doesn't just tell you what isn't going to work it tells you what is going to work. Duloxetine is a drug that not only was approved for fibromyalgia it was also approved for use in chronic low back pain and osteoarthritis and now we know the subset of people with osteoarthritis and chronic low back pain it works in it works in the subset of people with chronic low back pain that have more widespread pain that have a higher fibromyalgia score. This is a Lilly study that they've done more recently after the drug duloxetine went off patent in the United States. They're still trying to get this drug approved you would know it as Cymbalta as a brand name drug in China and Japan so they're still doing studies and in this study I'm sorry what they showed is that if they gave someone that that body map that we developed that I showed you earlier the Michigan body map if they had five or more sites of pain besides back pain they were 60 percent more likely to respond to duloxetine than if they had low back pain and a single site of pain in the back. So one of the best things you can do to tell whether someone has this kind of pain or nociceptive pain is look at how widespread the pain is give them a body map and the more sites of pain they have now the more pain they've had over the course of their lifetime in different areas of the body the more likely their fundamental problem is an amplifier problem rather than a guitar problem. This is a series of studies that Yvonne Lee a rheumatologist that studies comorbid fibromyalgia comorbid nociplastic pain in rheumatoid arthritis patients and without going through all of this one of the drugs that is approved for use in fibromyalgia didn't get used much but it's a drug similar to duloxetine milnasopran that is a serotonin norepinephrine reuptake inhibitor as duloxetine is this drug actually worked only in the rheumatoid arthritis patients that had comorbid fibromyalgia but at least this showed proof of concept that there's a lot of people with rheumatoid arthritis and more and more now that as our biologics have gotten so good at treating the underlying autoimmune component of of our autoimmune diseases we see more and more of our patients with autoimmune disorders that are still doing very poorly not because they still have active inflammation but because they have comorbid nociplastic pain or fibromyalgia that the rheumatologist doesn't pick up on. This is still a big problem in rheumatology where rheumatologists are myopically focused on treating the inflammation and they don't see all the non-inflammatory pain in patients with autoimmune diseases. This is a drug that's under development now I do consulting with this company this is a drug that we hope would be one of the first disease modifying drugs for osteoarthritis it's a drug that's injected right into the knee joint and I happen to do consulting with this company and I said you know why don't you put a body map in your studies because I'll bet if your drug works it won't work nearly as well in the osteoarthritis patients that have widespread pain as the osteoarthritis patients that have pain in a single joint because the ones that have widespread pain their pain is coming a lot of it from their brain and again injecting their knee isn't going to make them better. Sure enough when they did their phase two studies that's exactly what they found. They found that the regular the whole group of osteoarthritis patients they didn't see much separation at all between their drug and placebo but when they looked at the people that did not have widespread pain that had unilateral osteoarthritis the ones in whom their pain was clearly coming from their knee the drug worked quite well so now if that drug marches towards approval the label for it will say use it in osteoarthritis patients without widespread pain because again it's going to work a lot better in people with that phenotype. So how do we know all of what I'm saying is real is biological again I don't have time to do this but our group and others have spent the last couple decades doing things like functional brain imaging quantitative sensory testing. This is the first fMRI study in fibromyalgia was done by our group almost 20 years ago just as functional MRI was becoming available as a research technique and this study was a big deal when it was first published because it was really the first study that showed that fibromyalgia was real and all we really showed in the study is that people weren't faking we showed that when a fibromyalgia patient is given a low intensity stimulus here of just two and a half kilograms the controls don't feel that as being very painful at all they feel it as only a two out of 20 on a pain scale but the fibromyalgia patients feel that two and a half kilogram stimulus as being moderately painful and we could see when we gave the fibromyalgia patients that stimulus in the scanner that areas like the primary and secondary somatosensory cortices lit up so we could see that was causing pain even though the amount of stimulus we were giving them was not enough to cause pain in a normal individual it was only enough to cause pain in these people that had the higher amplifier setting. This study effectively showed that this is a at least in part an amplifier problem. These are more recent studies done by our group and others looking at the degree to which different brain regions are either too connected to each other or not connected enough to each other this is a very consistent abnormality you see in individuals with fibromyalgia even the size and the shape of the brain changes in people that have this kind of pain because the central nervous system is undergoing neuroplasticity. I've said this several times that this is a common problem in rheumatoid arthritis patients. This is a recent study that we did with Neil Basu from Glasgow where we showed that in rheumatoid arthritis patients if you gave that fibromyalgia measure the higher the rheumatoid arthritis patients scored on that fibromyalgia measure the more their brain looked like a fibromyalgia patient that some of these connectivity patterns that we see consistently in people with fibromyalgia were seen more and more consistently as people's fibromyalgia scores got higher and higher but conversely this is another study that we published just after that in Nature Communications that if you look at the rheumatoid arthritis patients with low fibromyalgia scores whose pain seems to be driven by active inflammation they have an entirely different pattern on functional conductivity so there may be a time in the not too distant future where resting state brain scans can be ordered clinically and we can look at different patterns to see you know does that RA patient's pain look like it's coming from inflammation or does that RA patient's brain look like it's coming from comorbid fibromyalgia but until that occurs you can get this information by simply giving someone that questionnaire or just getting better and better at picking up on comorbid fibromyalgia and nociplastic pain. Again in case you still are of the mindset that there's no objective underpinnings of fibromyalgia this is a study from a different group not our group we agree with these findings where they took a group of fibromyalgia patients and a group of controls they did functional MRI and they looked at sensory processing not just pain processing I mean what they found is that they could predict with 92 percent sensitivity and 94 specificity the fibromyalgia patients from controls by just looking at their brain scans. So again there's a lot of objective underpinnings of fibromyalgia if you didn't do this type of research you're not aware of these findings but using things like functional MRI we can separate fibromyalgia patients from controls with a very high degree of certainty. Why is this all important oops sorry Andrew's going to take questions about sort of pathophysiology here and then I'll talk the last 15 or 20 minutes about treatment and we'll take questions at the end about that. Yes and I have a few questions about treatment as well which I'll jump in where they fall in your talk about treatment but I have a few questions from the audience about some of the pathophysiology or other things related to diagnosis. One of the questions related to testing for fibromyalgia is if you could comment on the FMA test or that a genetic test that's available to try to help with diagnosis of fibromyalgia. Totally worthless. No scientific underpinnings to a single study done at a single institution never replicated but they're selling a lot of that test. If you look carefully at how the how the FDA approves tests there's two different FDA approvals for tests what the more stringent is that they say it can be used to diagnose a condition that is not what that test the FDA approval that test got it got CLIA approval which means they are performing the test consistently from one time to the other but it didn't it does not have FDA approval as a diagnostic test for fibromyalgia nor does genetic test there is no test that can be used for fibromyalgia even in these NIH networks that we're in now there's you know we hope that we might be able to develop or identify a serum or a plasma biomarker for pain or for fibromyalgia but there is none at present and these diagnostic tests are just people out there trying to make money not really help you make the diagnosis of fibromyalgia. Great another question is do you believe there's a clinical value to assessing adverse childhood experiences in chronic pain patients? Absolutely we did a study with Mark Lumley at Wayne State a couple years ago and he had developed a new type of therapy called emotional awareness therapy specifically aimed at getting people that have had past traumatic or stressful events to actually journal and talk about those in the context of if you will a new type of therapy for in for chronic pain patients and what we found in the study was that the average response rate to that emotional awareness therapy was not any greater than the pain CBT but in the emotional awareness therapy we saw a much higher proportion of people that had improvements have 60, 70, 80 percent improvements in their pain so I very much believe that there is a subset of individuals with chronic pain that's had a lot of trauma and those are probably individuals you should think of sending for not just to a psychologist but for this type of therapy that's specifically aimed at trauma and trying to get people to work through some of the traumatic things that have happened to them earlier that is not the kind of and just by the way we develop and help disseminate a lot of web-based and online self-management programs including a lot of CBT content this type of therapy needs to be done by a psychologist because you need to have the appropriate training if you're going to start working with people and uncovering early life trauma you have to also be therapeutically willing and able to deal with that because sometimes it'll transiently make the people worse. Yeah and then one other specific question for this time then I will get to more of these questions throughout the next portion of your talk and then we can grab some more at the end. Is there an idea of the prevalence of nociplastic pain, such as a FM score of greater than seven or eight in the general population? It's much worse since the COVID pandemic, that's for sure. I'm writing the University of Michigan post COVID grant, there's a big push now for research and actually wrote an editorial in the Journal of Pain six weeks after the pandemic started predicting exactly what post COVID syndrome was going to look like. Because you see this fibromyalgia like phenotype occur after a lot of different infections after Epstein-Barr virus, Lyme virus, all sorts of different infections. And so it seems to be sort of a stereotypical response that we see. But pre-COVID, there was sort of a gradual recognition, the CDC has only been doing epidemiologic studies that include pain for only 10 to 15 years, but it does appear as though just in general chronic pain is increasing in the US population and it's likely to be more this kind of pain than, you know, pain that is due to joint damage. Great. And I know a few of the questions that were asked about some aspects of this for the treatment will be coming up in the next few slides. So as you're going over those, I'll jump in with some of those questions if that's okay with you. Yep, absolutely. So first talking about drugs, you see down at the bottom the classic drugs we use to treat nociceptive or acute pain, opioids, NSAIDs, corticosteroids. None of those really seem to work at all for nociplastic pain or fibromyalgia. The preferred drugs are tricyclic drugs, serotonin, norepinephrine, reuptake inhibitors. By the way, it seems as though norepinephrine is the more important of the neurotransmitters than serotonin. So if you're taking care of a pain patient that is on an SSRI, unless they are on one of the older SSRIs, you see down here that the older SSRIs like fluoxetine, sertraline, usually are more noradrenergic than the newer ones like citalopram and escitalopram. But if your patient is on citalopram or escitalopram, which are highly selective serotonin reuptake inhibitors and they have pain, it's probably a good idea to switch them over to an SNRI because the norepinephrine is the more important of the two neurotransmitters for pain. So again, we have tricyclic drugs, SNRIs, and gabapentinoids that are the drugs that have the best evidence. And again, these only work at best in one out of three individuals. They have a lot of side effects. I'm not saying these are magical drugs, but they work a lot better in someone with fibromyalgia than these drugs down here. And you see some other drugs that have been shown to be effective but are not in this widespread use. Gamma hydroxybutyrate, that drug was trying to be approved as the fourth drug to be approved for fibromyalgia. It worked really well. The FDA didn't approve it because GHB is the date rape drug and they were very concerned about diversion and all sorts of other problems. But GHB is available in the US. It can be prescribed for narcolepsy, cataplexy, and a lot of sleep medicine physicians will actually use it in people with conditions like fibromyalgia. Low-dose naltrexone, we actually think that no-dose naltrexone is working by blocking the endogenous opioid system. I'll show you the next slide why we think that in fibromyalgia, you would want to actually be blocking the opioid system rather than giving an opioid agonist. But anyway, you see here the drug therapies that seem to work in these centralized pain states are quite different than the drug therapies that work in no-susceptive pain. And then let me just... Two questions. Yep, yep, yep. Let me just get this slide and then I'll do the... Now go ahead. Okay, perfect. One about low-dose naltrexone that you just brought up was about what dose would be recommended typically and if there's a contraindication if a patient's using another opioid or tramadol. I don't think there... The low dose that's being used is between two and a half and six milligrams. I don't use... I don't do clinical care anymore, so I'm not using it a lot myself. The people that I know use it a lot really think, again, that it's working well in 25 or 30% of people. They don't have a good way of predicting in advance who it's working in. It seems to be okay if people are on low doses of opioids, something like tramadol. It probably isn't a good idea to use it, obviously, if someone's on a higher dose of an opioid. It is a low dose, but it's still naltrexone. The low dose is purposeful. That low dose of an opioid antagonist might actually just be inhibiting some of the feedback loops of opioids that are leading the brain to think... The next couple of slides actually show that what we see in people with fibromyalgia is it looks like the endogenous opioid system is hyperactive. Because they have pain, they're releasing a lot of their own endorphins and enkephalins, their own endogenous opioids, and those endogenous opioids are causing what we call opioid-induced hyperalgesia in that fibromyalgia brain. That's the cautionary tale about that opioids in this kind of pain not only don't work to make the pain better, they often will make these people worse because the endogenous opioid system actually appears to be participating in the pathogenesis of nociplastic pain. You had another question, Andrew, about... That's great for now. I'll jump in with some others as we go. This slide just shows that one of the reasons that none of these drugs work in more than 30% of people is that... The neurotransmitters on the left side of the screen generally increase pain sensitivity and sensory sensitivity. The neurotransmitters on the right side of the screen generally decreased sensory sensitivity and pain sensitivity. You see that the arrows here are the direction of these neurotransmitters in the brains of people with fibromyalgia. Glutamate levels are high. Our group has done a bunch of work showing that glutamate levels are increased throughout the brain of people with fibromyalgia, and the GABA levels are low. Glutamate is the major excitatory neurotransmitter in the brain. GABA is the major inhibitory neurotransmitter in the brain. When a brain region has high glutamate or low GABA, it becomes hyperactive. One of the regions where we've shown that repeatedly in fibromyalgia is the insula. Not surprisingly, insula is the brain region that's involved in pain or sensory processing. If you have a hyperactive insula because your glutamate's too high, a GABA pentanoid or ketamine or memantine will reduce your glutamate. If you have a hyperactive insula because your GABA's too low in your insula, then you would need to use a GABA-ergic drug. By the way, epidemiologic studies have shown that one drink a day seems to protect against this type of pain. More than that, just like a lot of other things with alcohol, it's a U-shaped curve, so I'm not recommending alcohol as a therapy. If you have a patient with chronic pain that's drinking one glass of wine a night, don't tell them to stop it because the evidence actually suggests that a little bit of alcohol because of its GABA agonist property might actually be helpful in conditions like fibromyalgia. All of the drugs that either work or don't work seem to match up with neurotransmitters. Again, you see here that studies that our group has done have suggested that the endogenous opioid system is hyperactive, which is why we're trying to antagonize it with drugs like naltrexone. This is probably also why, very anecdotally, that the only opioid that might be useful for people with a condition like fibromyalgia is a drug like buprenorphine. It's probably the opioid antagonist properties of buprenorphine that make it a more useful opioid for this kind of pain than the opioid agonist properties of bup. This is an editorial I wrote in the journal Pain a couple of years ago talking about this problem and why it's so hard to get people off of chronic opioid therapy because the endogenous opioid system in the human body does a lot of things other than control pain. It helps with social attachment. It helps with motivation. It helps with things. When you give someone chronic opioids and you keep increasing the dose of opioids to control their pain as they get more and more tolerant, what it basically does is shut down the functions of the endogenous opioid system. A lot of these individuals that are on chronic opioid therapy have what we call complex dependency. They don't really meet criteria for opioid misuse or opioid use disorders, but you can't get them off of the opioids because they're dependent, they're tolerant, and they actually don't think they think the opioids are working a lot better than they really are. This is the study I was alluding to earlier where we simultaneously did functional MRI and PET with carfentanil, which is a very potent opioid, and we showed that the brain regions that are most hyperactive in people with fibromyalgia are the brain regions where the mu receptor occupancy was most abnormal, i.e. along the lines of what I was saying earlier, that there's increased amounts of endogenous opioids and down regulation of the receptors. I don't have enough time to talk about all the ways you can try to get people off opioids. It's an hour-long talk in and of itself, but I would say that we still use too many opioids in the U.S. and that, again, it's not clear that they really work very well for any type of chronic pain, but I think you have to be especially cautious about using opioids in this type of pain, the nociplastic pain. I'll talk for a couple minutes. I give hour-long talks on cannabinoids, but since I hear that you haven't gotten one in these Grand Rounds recently, I'll give you a five-minute version of cannabinoids. So regardless of whether you come into cannabinoids thinking that they're terrible, i.e. the sort of reefer madness end of the visual analog scale or, great, the Cheech and Chong end of the scale, we are starting to understand sort of scientifically how cannabinoids can be useful. We now have a lot of NIH funding to study the optimal dosing of THC and CBD in a number of conditions, osteoarthritis, multiple sclerosis. Even in perioperative settings now, we hope to start doing work. There's a lot of evidence that CBD, cannabidiol, can be effective in pain, especially the pain condition where the best study has been done thus far is osteoarthritis, that cannabidiol alone can work in osteoarthritis. So because cannabidiol is so much safer than THC, it's not psychoactive, it's not addictive, it doesn't show up on a drug screen, that we really strongly recommend if someone wants to go the cannabinoid route, that because of safety, they try CBD first. Start at 5 to 10 milligrams twice a day. In some people, that's enough CBD to work. Some people need to take as much as 100 milligrams twice a day. The main side effect of CBD is cost. It really is incredibly well tolerated. But people should only be going past CBD alone to adding a low amount of THC if they don't respond to CBD alone. And the THC is probably going to be needed if you're treating more centralized pain conditions like fibromyalgia, the ones I've been talking about before. But a couple cautionary notes. First is, it's very clear that THC has a U-shaped curve, that a low dose of THC works better to treat pain than a high dose of THC. So without any guidance, what's happening is that all of our states that pass medical marijuana laws or legalize marijuana and then people that have chronic pain, without any guidance from their healthcare providers, are going and trying cannabis for their pain. Almost all of them are using too much THC. So they're getting high, and they're not getting pain relief. So they have to start at a really low amount of THC, and it's best to use a low amount of THC in a low THC, high CBD strain of either an oil or an edible or whatever. And again, really limit the exposure to THC, because that's where all the side effects occur. And actually, THC has a pretty narrow therapeutic window, the dose that works in someone versus the dose that'll cause them to be high or be impaired. So I'm very bullish on CBD as far as cannabinoids are go. I think we have to be really cautious about THC, and we certainly have to not replicate the experiment that we did with opioids. If you just flood the endogenous cannabinoid system with THC, someone takes this really high-potency THC, they're just going to become a slug sitting on a couch that doesn't move, just like the classic high-dose opioid patient. They're not going to actually benefit from that therapy. The oral dosing is better because it lasts a lot longer, and it's much less likely to be reinforcing. The inhaled route of administration is good if you're trying to get high, but it's not good if you're trying to get a stable level of a drug for a longer period of time. And then last thing is, for those of you that are seeing kids, there are specific side effects of THC in particular that are present in people under age 25. The rate of becoming dependent on cannabis is about double if someone's exposure to THC is before age 25 versus after. We also know that there's about a one and a half to two times higher rate of developing a psychotic disorder if your first exposure to cannabis is before the age of 25. So the value proposition for THC is not great to start with, but it goes down considerably if you're taking care of people that are under age 25. And Dr. Clark, could you talk a little bit about quality control in CBD and certification of labs are getting kind of appropriate dosing when we don't know what's being sold? Yeah. So I don't know, you know, all states are different. We had a terrible medical marijuana law in the state of Michigan for a decade until a year ago. Then they passed a law legalizing marijuana. And part of that law for the first time mandated testing of all the products that were being sold in the state of Michigan. So now in the state of Michigan, if someone goes into one of the dispensaries, they know exactly what they're getting. It's tested by a state lab, it's labeled. But there had been a real problem and there still is a problem if people are getting this on the black market, or if you're getting in a state that hasn't mandated testing, then there's a real issue with purity. A lot of those problems that we heard of three or four years ago with vaping, those were all due to contaminants of the cannabinoids, not from the cannabinoids themselves or the nicotine themselves. This is meant as a joke. This is a poppy plant talking to a, I mean, a cannabis plant talking to a poppy plant. Again, I don't love using cannabinoids for pain, but I really hate opioids. This is really trying to expand upon what I was saying earlier is that the drugs are going to work differentially and whether the pain is more nociceptive when NSAIDs and opioids and surgery are going to work versus if it's more nociplastic where you're going to have to use tricyclics, SNRIs, and gabapentinoids. That's also true of cannabinoids. You're going to have to use a little bit of THC if you think the person's pain is more central nervous system driven, and you might get along with CBD alone if they have more nociceptive pain, or if their pain has a mild inflammatory component to it. THC seems to work in part as an analgesic, as a weak anti-inflammatory drug. I don't talk at the end for just five or 10 minutes about non-pharm therapy because I think that they're that important. I talk because most people know more about them and know less about what I've been talking until then, but the mainstay of treating pain and the mainstay of treating this kind of pain that I've been talking about in particular today is to use non-pharmacologic therapies. One of the things that we're learning is that the process of centralization, the reason that someone might start out with pure osteoarthritis or rheumatoid arthritis or sickle cell disease, but then over time develop a higher and higher component of their pain that's coming from the central nervous system is we know that after you have pain, your sleep gets bad, you decrease your activity level, you get more stressed. All of these things here will feed up to the central nervous system. The longer people have pain, the more likely some of these downstream consequences of pain have caused them to centralize their pain, so we're really aggressive first and foremost in people with this kind of pain, get them sleeping better. Some of the studies that we're doing of new onset of fibromyalgia in children and some of the longitudinal studies, what we're seeing is the sleep disturbances come before the pain and the mood disturbances come after the pain, but more and more data are suggesting how important sleep is. Really work on getting your pain patients sleeping better, sleeping deeply, and I don't have to tell a group of physiatrists to increase people's activity level. You knew this before anyone, but getting ... I've said this for 20 years. It's probably music to your ears, but exercise is the most effective therapy across all chronic pain states. I don't think there's any doubt about it. I think what we are learning is that virtually any type of exercise can be helpful. We used to think that it was primarily aerobic exercise that helped fibromyalgia, but stretching helps, strengthening helps. Just getting people moving, just having them do more of their activities of daily living can help a lot. The other symptom that gets better even more rapidly than pain when people become more active is fatigue. Fatigue is rapidly ... It gets rapid improvement if people can increase their activity level a bit. I'm going to interrupt for just one second to let people know that it is nine o'clock and we've reached the official end of our program, but we are going to continue with just these last few slides and to provide more answers to some of the questions. Everyone's welcome to stay on for a little while longer, but I do want to just be thoughtful of people's time and let them know that it is nine o'clock as well. Thank you, Dr. Call. Keep going, but I just wanted to make sure to make an announcement for everyone. Yeah, I just have a couple more slides and then I'll take questions until you tell me not to. This slide is probably the slide that's changed the most in the 20 years I've been giving this kind of talk where I had an evidence base. It used to be that a lot of these things that are now up in modest evidence were either in weak evidence or no evidence, but now I say that the only thing that's in no evidence with respect to non-pharmacologic therapy is to do nothing, and that's the best way to have a chronic pain patient continue to have chronic pain is to not prod them, probe them, do whatever you can to get them to try three, four, five, six of these non-pharmacologic therapies. We still can't predict which one is going to work and in whom, but this really now, this more integrative approach is really the mainstay. This is a website that our group developed. It used to be called FibroGuide. Now it's called painguide.com. I'd highly recommend you send your patients to PainGuide. It's got a ton of self-management information in it. It has acupressure, yoga. It allows people to track their symptoms. And we're working a lot on developing apps and these web-based programs that we're finding work fairly well, especially if you do different types of sort of digital tailoring of the intervention based on what's gonna work in people. This is PainGuide, it's free. Go to it, use it. If you wanna do a research study with PainGuide, talk to us, we'll create a new instance of the website for you to use, because we really think that these web-based tools can be really helpful for you to use with your patients to get them to adopt more self-management strategies. Not gonna really talk about any of these unless someone asks me. We're doing a lot of work on diet and nutrition. We were surprised to find in a study that we did in a rapid weight loss clinic where people were getting a 900 calorie a day diet to try to, these were people with morbid obesity, that when we looked before and after this weight loss program, that there had been a really significant improvement in pain, fatigue, depression, fibromyalgia scores. And we published this article in Pain a couple of years ago. What we haven't published yet is a more granular where we started looking every week after someone started this diet. And these improvements that we noted here at 12 to 16 weeks are actually happening within a week or two of someone going on a very low calorie diet. So we now are thinking that intermittent caloric restriction, different types of dietary interventions might actually be quite helpful, especially for this kind of central nervous system driven pain. We're doing a lot of work and sometime in the future, I hope to come back and talk more about how we might be able to use diet therapeutically. But I like showing these couple of slides at the end. The healthcare systems in the United States that really get it the most about how to manage pain are the VA and the DOD. They have developed these really cool care models, these step care models that are really strongly recommended. They exist in very few places now because they're not reimbursed very well, but all of us are trying to move in this direction. But I like showing this slide as my last slide in part because I never would have imagined 30 years ago when I was being trained as a rheumatologist at Georgetown University that 30 years later I'd be showing a slide advocating the use of acupuncture, massage, chiropractic manipulation, yoga, tai chi, and mindfulness. But I am a scientist and the data tell us that these things work. And this is really, I think, one of the challenges we have now is to figure out how to more and more integrate these integrative therapies and get our third party payers to reimburse for them because they work really well. And again, I think a lot of us are finding that if we can offer people more and more of these therapies, they often find one or two that work well for them. They keep using them. And those are the chronic pain patients that are improving a lot. The ones that do nothing, not pharmacologically, not surprisingly, don't get better either. So I'll stop there and take any questions. All right, so I can read out some of the questions. I think you can see some of them if you're particularly interested. But one question is often the patients with these types of pain conditions have trouble remaining at work, but also have trouble being approved for disability benefits. Do you think fibromyalgia could reasonably cause impairment and what symptoms or exam findings would potentially support that decision? It's interesting you should ask that. I was just asked by the Social Security Disability Administration to give a talk on fibromyalgia. And not surprisingly, I gave the same talk and they were a little bothered by the fact that their system doesn't make any sense. The system by which they adjudicate disability doesn't make any sense. But they were really cool about it. And we had a good discussion. I told them I'd love to work with them, but there simply is no objective test for fibromyalgia. I think some of these things that have been purported to be picking up on malingering and things like that, I'm not sure they work very well. I haven't, in my practice of, again, I don't do clinical care anymore, but I saw a lot of pain patients for a long time. The number of individuals that I ever saw that were truly malingering, truly faking was so low, but I think we're doing a disservice to teach people that that occurs commonly enough that you should cast a negative light on all people with fibromyalgia because there might be one out of 200 that's somehow faking or magnifying their symptoms to get disability. Having said that, I think it's a really bad idea to put people with fibromyalgia on long-term disability. They get worse because they stop moving. They stop interacting with other people. And I talked a lot to the Social Security Disability Administration. I said, the process of people trying to prove that they're sick to get their health insurance because they can't work makes them sicker and sicker. And I don't have a great solution. All I'm saying is the way that you do it now is makes people worse. It's not scientifically accurate. Let's try to think of a way to do it better. But a cautionary tale, I used to early in my career be very liberal about giving my fibromyalgia patients long-term disability because it was like, I think you deserve it. You've tried everything I've asked you to try. You're trying to get better and you just are not getting better. But then five or 10 years later, I stopped doing it because I was seeing that every one of those people I gave disability that I saw them get worse when they went on disability because they sat at home, they didn't exercise. All the things that I showed them, I think the downstream consequences of having chronic pain get worse when someone goes on long-term disability. So what I try to do with my patients instead is if someone asks about disability, I say, I can't talk about that now. Schedule a long follow-up appointment next time. Let's talk about this. And it usually is a cry for help. And so what I got to do was sit down with the person and talk to them about things I would do that I'd give them short-term disability. So they could do PT, they could do rehab, they could do things like that. But I didn't think it was a good idea for them to be off work permanently. That I thought that that was actually gonna make their fibromyalgia worse. And I'm a doctor, I'm gonna treat your underlying medical problem. I'm not gonna do something, i.e. sign a disability form. Even if I think you deserve disability, if I think that that is gonna make your underlying medical condition worse. But if you have an honest discussion with your patient about that, and it's clear to them that you're on their side, they're actually often quite accepting. They just, it really was just a cry for help. Great. One question was about your recommended, or if you recommend CBT for fibromyalgia and then how people can locate practitioners near their clinic that are familiar with CBT for fibromyalgia. Try first that website, because it has all the CBT principles. So if you don't have a CBT provider, if you have a CBT provider, send them to that provider. But they are few and far between. It's not well reimbursed by third party payers. The website, if you can get people, if you tell as their provider, if you tell people that they need to do the website and you actually tell them what module on the website to do, they'll do it. If you elevate it to the same importance like that you do a drug you're prescribing. Like when I was doing clinical care, right after I asked people their list of medications, I'd say, how much exercise are you doing? And it reinforced in their mind that I thought that was as important as the drugs I was prescribing. But we're very powerful in getting our patients to do things. And if you just keep sort of prodding them to really again, try the non-pharm therapies. If there's anything I can say is that's where the evidence base is increasing, increasing, wrap more non-pharm therapies. The other thing that I'll say is, and again, different providers are gonna be differentially comfortable doing that. I got to the point where I told my patients, if you're not willing to try three or four new non-drug therapies this year, then I don't think I need to keep seeing you. If you don't wanna do anything, then I can't make you better. And I don't really want you to come in every three months and tell me how bad you feel. Cause I'm not surprised you feel bad, you haven't done anything. And if you tell people that one of two things happens, either they go to a different practice cause they don't wanna be confronted or it's a stick of dynamite underneath them. And they say, okay, maybe I do have to, cause it's not easy being a chronic pain patient and they get beat down and whatever, but you have to try to figure out a way to motivate them and say, please try, again, try a couple new treatments. You're in a rut, you think you're doing poorly, but try a couple new treatments. And you might be surprised at some of these things that used to be dismissive of acupuncture, acupressure, things that might help you. There were a few questions, I know you mentioned sleep pretty importantly in this talk. And there were a few questions about sleep, including how you address sleep, if you recommend sleep studies for these patients, if there are certain medications that seem to be most effective for sleep in these patients. Yeah, I don't recommend sleep studies cause sleep studies pick up on a lot of sleep apnea and things that doesn't seem like it has anything to do with this. And the studies actually have shown that if you do sleep studies in people with chronic pain and you identify sleep apnea and you give them CPAP, it doesn't typically make their pain better. So I don't think the sleep studies are helpful, but I think start with just classic sleep hygiene as it is. That term isn't liked anymore by the sleep people, but again, the kinds of things that used to be called sleep hygiene, don't exercise right before bedtime, don't drink alcohol, those kinds of things. And then CBT-I, CBT for insomnia works incredibly well for pain. If you have a provider that does CBT-I and there's some apps that people can download for CBT for insomnia that work really well as well. So that's a good therapy. In the drug therapy, I love cyclobenzaprine. It's my favorite fibromyalgia drug. You know, it was originally marketed as a muscle relaxant, but it's almost identical structurally to amitriptyline and five, 10 milligrams of cyclobenzaprine a couple hours before bedtime is one of my favorite drugs for this kind of pain. It's really cheap, it's really well tolerated. And it's my tricycle of choice. I think it actually works better than things like amitriptyline and nortriptyline. The other drug that I use some, if they don't tolerate cyclobenzaprine, use a gabapentinoid at bedtime. That before the pregabalin went off patent, Pfizer had done studies suggesting that about 40% of the benefit from gabapentin in pain was from the sleep improvement that occurs. And when I give a gabapentinoid, I give it as a single dose at bedtime, not as a BID drug because there's no reason to give it as a twice a day drug. The way that it works in the brain, it stays in the brain for weeks after, the effect stays for weeks after you give it. So you reduce side effects by giving it only at nighttime and you might increase the beneficial effects using it as a hypnotic. And then the third one is trazodone. You know, if pregabalin or gabapentin or cyclobenzaprine aren't tolerated, then I'll use trazodone. Trazodone doesn't have any independent analgesic effects like cyclobenzaprine or gabapentinoids, but it's a pretty good drug, you know, a hypnotic that isn't gonna cause some of the problem that benzos will cause. There's a question about if you have any recommendations for people who have acute episodes of severe pain in the setting of fibromyalgia or like fibro flares, whether or not you recommend short courses of opioids or any other acute treatment for those patients? I just tell them what not to do. Don't go to the emergency room because they don't have anything to offer you and it's gonna be a bad encounter between the you and the ER physician because they might give you a little bit of an opioid and it doesn't work at all because it won't work for your fibromyalgia pain. And then all of a sudden you have this dynamic of, is this a drug seeker? It's like, just don't, just skip the ER visit because it's gonna be unpleasant for all parties involved. I just try to get people to use self-management, you know, learn deep breathing, learn things, learn there's so many different things in pain guide or that are part of a cognitive behavioral therapy program. But I really try to get people to use behavioral strategies if possible. And this might be the only instance, I might regret saying this, but this might be the only instance. I'd rather someone takes a puff or two from a vape pen of THC than goes to the ER and gets an opioid. It'll chill them a little, it'll calm them down, it'll probably reduce their pain and it works fast. So that, again, I'm not necessarily advocating it, I'm just saying that from a pure pharmacologic standpoint, they probably should have vape pens with THC in the ED so that when the fibromyalgia patients come in, they at least give them a therapy that would work rather than an opioid that's gonna actually just cause just a bad dynamic. There's a question about neurotransmitters and their integral role in nociplastic and centralized pain. Do you have any comments on the role of neuromodulation in current or future treatment for fibromyalgia? Yeah, I think it's gonna be, you know, a big part of therapy. I think different neurostimulatory therapies are gonna get more and more effective as we can stimulate deeper regions in the brain in particular. I think vagal nerve, there's now some peripheral vagal nerve stimulators that you don't have to, you know, implant deep inside of people. I think those are really promising. A lot of the improvement from exercise might be driven by improvements in vagal tone. I mean, the first thing that goes down rapidly when people are sedentary is their parasympathetic tone and that's known to play an important role in pain processing. So I don't know if that was the kind of neuromodulation the question was asking about. I think any kind. There's other things where people use more biofeedbacky things and they call that neuromodulation. But I think it is a brain problem. And I think that therapies that are directed towards the brain, we're also be gonna within the next year or two start doing studies of psychedelics in pain, see if we can reboot people with drugs like psilocybin. You need a lot of therapy, psychotherapy along with it. But from a neuroscience standpoint, what we learn about neuroscience is that the way the brain works is it creates percepts. It creates like, you know, the reason that I know that Andrew, that you're a male is I, you know, we've learned that and our brain works on. And the problem is that when people have chronic pain, their pain becomes part of their percept, like of what their brain is perceiving. And it might really be important to try to sort of wipe that clean by, you know, rebooting electrically or with a drug like a psychedelic and then overlaying some psychotherapy that says you don't have any pain anymore. You can do things you don't think you can do. Yeah. There's some questions about the use of psychiatric medications and about kind of using multiple psychiatric medications and risks of serotonin syndrome and how high you're willing to go on some of those medications before thinking about that risk. What are your thoughts about combining psychiatric medications or higher doses of those medications? I think a couple of the drugs are particularly bad actors. I've had more problems myself with tramadol than any other drug. But I think, and if you talk to psychiatrists, they say the same thing is that serotonin syndrome is way more common as a warning that comes up, you know, to the pharmacist than a real problem. Most psychiatrists that throw these drugs around with much more so than most of us are comfortable say they've never seen serotonin syndrome or rarely seen it. So I don't think it's a big problem, but I do think, you know, where I've had a couple of patients that have had problems is when they're on multiple serotonergic drugs that lower the seizure threshold. And so I think I do get concerned, but I also get concerned in general about sort of polypharmacy is that you also, there's a lot of these patients that just, you know, they go from one doctor to another, a doctor starts a drug and Dr. B doesn't, you know, they don't have a PCP that's trying to coordinate and everything. And they accumulate a bunch of drugs that it's not clear whether they really are helping them or not. I think in many cases, they're hurting them more than helping them. And in a lot of these chronic pain patients, you almost have to take one drug at a time, pull them off the drug, see if they're benefiting or not, usually not. And then almost restart with a cleaner slate, but the people that come in on eight or 10 different, you know, psychoactive drugs, if you will, you know, that's just, again, that used to happen to me, it happens to everyone, but in hindsight, it's sort of bad management. You just, we'd really like to try to prevent that and do a better job of counseling pain patients that they have to do these end of one experiments is that they're the only one that can tell us. I can tell if an RA patient responds to a rheumatoid arthritis drug by doing, you know, an exam and seeing decreased swelling or checking their set rate or CRP. The only way I know if a pain patient's better is by what they tell me. So they should only try one new treatment at a time, try it for a month or so. If it works, keep it. If it doesn't work, discard it. And I'll say that again, if it doesn't work, discard it. Don't accumulate these treatments that you're not sure are helping you. But that unfortunately happens to a lot of chronic pain patients. So we're a little over 20 minutes over. I do have one more question. I apologize to everyone else for the number of questions I was not able to answer. There's a lot of people that have engaged thoughtfully in some of these questions, some of these comments and topics. But for students, are there textbooks or resources that you recommend to learn more about chronic or nociplastic pain? Have them go to Pain Guide. It's, we have a lot of information about different types of pain there, but it's made for patients, but it's, you know, it's educational for most providers as well, because it's new information. But everything in Pain Guide is presented sort of through the same prism. And if people have questions that they want to ask me, just send me an email. I might not get to it to the weekend, but first initial, last name, D-C-L-A-U-W at umich.edu. But I'm happy to, you know, send me questions. I'm happy to answer the question. Great. There were a lot of other great questions, and I apologize to everyone that we don't have time to keep them forever. But I really want to thank Dr. Clough for spending his evening with us and helping give us a ton of information about some pain mechanisms and some approaches towards treating pain based upon those mechanisms. So thank you again, Dr. Clough. And thank you everyone for joining us.

chronic pain

central sensitization

fibromyalgia

opioid requirements

neuroplastic changes

individualized treatment

nociplastic pain

non-pharmacologic therapies

tricyclic antidepressants

SNRIs

gabapentinoids

pain management