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April 10, 2012 / zzirf

How to Age Your Brain Faster: Develop Fibromyagia

This video is 68 minutes long

What Primary Care Physicians Should Know About Fibromyalgia: Connecting the Dots between Diagnosis and Pain Management

This CME activity was copied from Medscape.  It is the transcript of the above video.

Vladimir Maletic, MD, MS: Hello, my name is Dr Vladimir Maletic, and I’m the Clinical Professor of Neuropsychiatry and Behavioral Sciences at University of South Carolina School of Medicine, and Consulting Associate in the Department of Psychiatry at Duke University. Welcome to our CME program entitled “What Primary Care Physicians Should Know About Fibromyalgia: Connecting the Dots Between Diagnosis and Pain Management.” Today, we’ll be discussing the neurobiology of fibromyalgia, the revised American College of Rheumatology (ACR) criteria and diagnosis, and finally, how to manage fibromyalgia pain effectively. (Enlarge Slide)(Enlarge Slide)
I’m joined today by two of my esteemed colleagues to discuss these important issues. Dr Charles Raison is Associate Professor and Clinical Director of the Mind-Body Program, Department of Psychiatry and Behavior Science, Emory University in Atlanta, Georgia. And, Dr Rakesh Jain is the Director of Psychopharmacology Research Incorporated, R&D Clinical Research, in Lake Jackson, Texas. Dr Raison, let’s start with you first. (Enlarge Slide)(Enlarge Slide)
Our understanding of the neurobiology of fibromyalgia has really evolved since the clinical community first recognized fibromyalgia, and this has guided research and new treatment strategies. Can you please provide us with the review of this material?Charles Raison, MD:Sure, Vlad, absolutely, and you’re absolutely right that the neurobiology and our understanding of mechanisms of fibromyalgia are really starting to bear fruit in better ways to intervene. So, let’s start with pain itself. Often, this is sort of the most typical characterization shown in this slide of different types of pain. Nociceptive pain is what one might call normal pain. It’s pain that is adaptive. It’s pain that exists because your tissues have been damaged. Now, nobody likes pain, but in fact there are people that are born without any sense of pain. They never survive childhood because without that sense of pain they burn themselves to death. They lose fingers and toes. Pain is absolutely essential for survival. And, so anything that damages your tissues—if it’s a broken bone, if it’s a bruise, all these sorts of things, if you’re cut—they cause pain. We all know that, and again, these are all examples of nociceptive pain.Now, on the other side of the ledger are examples of neuropathic pain. This is a type of pain that in fact is usually not of benefit. It’s not adaptive. It’s pain that arises from the nerves themselves. So, when nerves become damaged or they die, they can move into a situation where they begin to send pain signals to the central nervous system (CNS) in situations where there is really—if you’ll let me put it this way—nothing to complain about, so that the pain becomes freewheeling. It’s initiated by the nerves, and it doesn’t have much benefit. And, it causes people, of course, trouble, and this often leads to disease states. Examples of these types of disease states are things like diabetic neuropathy and trigeminal neuralgia.Then there are mixed pain states, which are a combination, usually, of these 2 types of pain. What’s interesting about mixed pain is that it really points to the fact that fibromyalgia can sometimes be a challenge. So, let me ask you gentlemen: what do we think these days about where fibromyalgia would fall in this type of simplified scheme of pain?Rakesh Jain, MD, MPH:What I would say is the more we know about fibromyalgia, the more we’re realizing it’s a problem with multiple heads. The simple classification no longer applies because components of all kinds of pain come in. I think mixed pain condition may be 1 way to look at it, though I think in a few minutes you’re going to help us understand the neurobiology better. But, I think this classification is important because nociceptive pain, too, can be physiologic and pathologic—Charles Raison, MD:—This is true—Rakesh Jain, MD, MPH:—and fibromyalgia is a great example of pathologic pain.Vladimir Maletic, MD, MS:Good points when talking about neuropathic pain is to emphasize that the neuropathic pain cannot only be generated by physical damage to the nerve fibers, it can also be a result of dysfunction of nerve fibers. So, some components of fibromyalgia are very much reminiscent of what we encounter in context of neuropathic pain. Wouldn’t you agree?Charles Raison, MD: Yes, absolutely. I think the fact that, when you look closely, conditions like fibromyalgia begin to blend these categories, it really suggests, in fact, how closely the mind and the body are connected and how processes that start in the periphery of the body can change neural functioning in the brain and the spinal cord. And conversely, as we’ll talk about a little bit, we know that it can flow the other direction, and changes in the brain and spinal cord can actually change how nerves and receptors function in the periphery. So, in a sense, part of what we learned about the neurobiology is that we shouldn’t be surprised that these types of simple classification schemes are useful, the ways to think about things, but the reality is more holistic and more complex. (Enlarge Slide)(Enlarge Slide)

Defining Fibromyalgia

Let’s talk about fibromyalgia in particular. Fibromyalgia is the classic condition of chronic widespread pain. Its meaning is the pain, as we’ll talk about in a little bit more detail later, needs to be represented in all 4 quadrants of the body. So, if somebody has purely localized pain, that is not fibromyalgia. By definition, fibromyalgia is a condition where the pain is typically diffuse and widespread. We know that, in general, people with fibromyalgia have heightened sensitivity to pain, which is called hyperalgesia. But, the changes that occur in their CNS will also produce unusual symptoms such that things that don’t usually cause pain, like light touch, are misperceived as being painful. That’s a process caused allodynia. Pain very seldom exists by itself, and that’s partly because the pathways in the brain that transduce pain are also very much involved with key biologic processes like sleep, cognition, memory, and mood. So, it’s not surprising that the fibromyalgia patients also are characterized by disturbances in sleep, disturbances in thinking and feeling, and very often have associated problems with depression and anxiety.Now, not only do they have pain, but they also have related symptoms such as stiffness, which can also be really as bad and the pain. We’ve talked a little bit about comorbid conditions. There are a number of psychiatric comorbid conditions, such as anxiety and depression. There’s a lot of other what we might call bodily symptom conditions, things like irritable bowel syndrome, chronic fatigue syndrome, and migraine headaches that are also highly comorbid and are very often seen in patients with fibromyalgia.Now, there’s a process that occurs not only in the periphery but really especially in the spinal cord and brain called central sensitization, which is a complex process. But, at the end of the day, what it means is that under conditions that give rise to fibromyalgia, it appears that the CNS becomes overly responsive, not only to pain signals, but sometimes signals that are not even directly pain related but get translated into the brain as representing pain. It really looks like this process of the CNS becoming overly sensitized is directly relevant to how fibromyalgia develops and probably how it’s maintained.Vladimir Maletic, MD, MS:I’m just curious about your thoughts. In psychiatry, there is a term “kindling” that is often applied to individuals who suffer from mood disorders and even possibly some of the anxiety disorders. Based on your clinical experience, would you think that there is some kind of relationship between kindling and central sensitization that we see in fibromyalgia? And, if so, what would be the clinical relevance of that?Charles Raison, MD:Yes. Dr Jain, do you want to—Rakesh Jain, MD, MPH:Oh, absolutely. What a great analogy you pulled, Vlad. The kindling phenomena are really literally what you just talked about, a sensitization of the CNS. Your example about fibromyalgia is literally kindling of, again, the CNS through the spinal column. So, here we have again the mind-body colliding again, and I think the clinical implications are quite evident. If you run into a scenario of pathologic pain, do your very best to stop it early, because the progression of the illness may be much more complicated than what we have at our hands right now.Charles Raison, MD: And, much more difficult to treat. And kindling, you know, originally arose from this idea of observation: that people with mood disorders often early in the disease need something psychologically painful, a social stressor, to have a depression, but that with each succeeding episode, the disease becomes less and less dependent on those external pains—emotional pains, if you will. And, it’s an exact analogy for what you see in central sensitization where fibromyalgia processes will often start with a physical pain—an accident or something that sets up tissue damage—and, especially when repeated, that can lead to the same sensitization you see in mood disorders. Of course, we know and will talk about the fact that the brain changes you see in chronic pain states such as fibromyalgia overlap very much with conditions of depression, which you can really reformulate as sort of like pain syndromes in response very often to psychological pain, whereas fibromyalgia often arises, although not exclusively, but can arise in response to physical pains. So, they have a lot of overlapping similarities, absolutely. That’s a great question. (Enlarge Slide)(Enlarge Slide)
Okay, so it turns out that fibromyalgia, like all complex modern illnesses, is a quintessential example of genetic vulnerability meeting environmental adversity. Fibromyalgia is not just caused by genes and is not just caused by things, either physical or emotional, that happen to people. It really looks like certain genes make people vulnerable to developing fibromyalgia in response to adversity. What’s interesting is that the adversity can be emotional. So, we know that psychological stress can be a big risk factor for developing fibromyalgia, but so can things like medical illness or damage to tissue like in a motor vehicle accident. These are all examples of adversity, and people that have genes that are more likely to respond by setting in motion these sensitization patterns are probably at risk for developing fibromyalgia. So, genes that make people more sensitive to their environment are risk factor genes for all these complex illnesses.A classic example is these genes shown in this slide, things like variance of the serotonin transporter allele or the serotonin 2A receptor. There are dopamine genes that have been implicated in fibromyalgia, and there are alleles or forms of the catechol-O-methyltransferase (COMT) gene that also set you up at risk for fibromyalgia. Interestingly, they set you up at risk for other conditions such as mood and anxiety disorders. There have also more recently been variances of opioid receptor genes, forms of the genes that are not as functional, that seem to increase the risk for fibromyalgia. Then, of great interest to people like me who study the immune system, gene forms for these proinflammatory cytokines that, if they’re given to people, can actually induce fibromyalgia symptoms and have also been implicated in fibromyalgia.Now, none of these genes can be said to cause the condition. These are all going to be polygenic disorders. So, conditions like fibromyalgia, what we’ll probably see as time passes, more and more clearly, is that people will have multiple risk genes, each one contributing a little bit. These genes usually need to be activated by adversity of environment. I really think that that is the way to think about how risk factors develop further disorders.Vladimir Maletic, MD, MS:Isn’t it really curious that, based on the genetics of fibromyalgia, there appears to be a monoaminergic dysfunction of signaling? Isn’t that something that we also have heard as it applies to anxiety and mood disorders?Rakesh Jain, MD, MPH:Absolutely. You gentlemen said it correctly. These are mind-body conditions, and there’s no reason to believe that serotonin, norepinephrine, or dopamine belong in the ZIP code of the brain. They’re exported everywhere. The connection between them is probably the reason why you describe fibromyalgia the way you did, as a mind-body disorder with pain symptoms but certainly a lot of stress symptoms, anxiety symptoms. You also mentioned sleep, for example. Yes, it makes perfect sense, doesn’t it?Charles Raison, MD: And, we know that emotional pain and physical pain ride the same rails—I like to put it that way. They go along the same pathways in the brain and the body. And that last, the cytokine, the interleukin-1 (IL-1) gene on the slide, interestingly, that’s also a risk factor gene for depression. And, we now know from imaging studies that that very gene affects activity in brain areas that are also abnormal in fibromyalgia. So, isn’t it amazing that a gene we further discovered as having to do with inflammation in the body turns out to have these roles in the CNS that set you up to develop pain disorders? There is a very beautiful, coherent story emerging about how, with something like fibromyalgia, we need to do away with our old categories for illnesses like this. We need to recognize that the mind and body are so intimately connected and that genes that drive bodily process like inflammation affect the CNS profoundly. Also, that genes we think of—and, of course Rakesh is exactly right, serotonin, dopamine, norepinephrine, these monoamine transporters are all over the body—but we think about them as being brain transmitters. These things are so linked that they all flow with each other and they drive each other. And, if one becomes abnormal, that can drive abnormalities in other systems. So, it’s a fascinating story that’s emerging. (Enlarge Slide)(Enlarge Slide)
Now, I’ve talked about central sensitization, and this is my favorite, all-time central sensitization study from the University of Michigan from Dan Clauw’s group. What they did was they put people without fibromyalgia and people with fibromyalgia in the scanner. They applied pain to them, and then they measured how much pain people felt. What you can see in the slide—the blue dot is the fibromyalgia people and the red dot is the normal folks—for the same amount of pain, people with fibromyalgia hurt a lot more. It’s classic example of the phenomenology of central sensitization. But, the people with fibromyalgia were in a brain scanner, and when they took pictures of their brain, they found that for that same amount of pain their brain also activated pain circuitry a great deal more.So, it is that their brains are super sensitive to pain signals in the periphery. Then, what that red dotted line shows is that they amped up the actual pain that was applied to the normal folks until they complained of as much pain as the fibromyalgia people. When they did that, they found very similar brain changes to what they saw in the people with fibromyalgia. So, it’s not that people with fibromyalgia are experiencing something that isn’t real. They are receiving the pain signal from the periphery, their brains are supersensitized, they are feeling more pain, and when you take normal folks and ratchet it up to where they feel the same amount of pain, their brains look very similar.Vladimir Maletic, MD, MS:And, there is some suspicion that signals may be even periphery amplified.Charles Raison, MD:Absolutely.Rakesh Jain, MD, MPH:Wow. So, this kind of takes away that whole notion that these are patients who just complain. All they’re doing, it seems to me—and correct me if I’m wrong—they’re just reporting what is happening.Charles Raison, MD:Exactly.Rakesh Jain, MD, MPH:They actually have more pain.Vladimir Maletic, MD, MS:Right.Charles Raison, MD: Absolutely. You know, you’d be complaining, too, if your brain told you the pain was at that level. They are normal people whose brains are processing and receiving amplified pain signals. And, as Vlad says, the amplification can start in the periphery of the body. What seems to happen is that the amplification runs from, you know, stem to stern. All through the body, up to the top of the brain, to be simplistic about it. But, that really is what it looks like. And so, a beautiful study showing that.

So, these data show that, in response to pain, fibromyalgia patients have different patterns of brain activity. Unfortunately, they also have changes in the structure of their brain. It’s not on this particular slide, but there’s increasing evidence that the functional abnormalities or the changes in how the brain functions probably over time damage the brain and lead to loss of brain volume and loss of brain material, in key brain areas.

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This slide shows that if you look at people with fibromyalgia vs age and sex that match the people who don’t have fibromyalgia, people with fibromyalgia have very specific losses of volume in the amygdala, in the rostral anterior cingulate cortex, and in the lateral prefrontal cortex.Now, interesting in this study is that the people who had been on medication longer had less volume loss. So, it suggested there may be something about medications that treat disorders that might be protective. We see this signal in other studies. It is very intriguing, but these areas of the brain that are abnormal in structure in fibromyalgia are also key players in modulating pain, modulating stress, and in controlling, sort of, how the brain controls systems in the body that drive bodily pain. These are key brain areas, so it’s very important and unfortunate that they’re damaged—appear to be damaged—in fibromyalgia.Vladimir Maletic, MD, MS:I realize this is emerging science, but what an important message, right? There is some suggestion that treatment may be actually associated with less gray matter volume loss or even preservation of gray matter volume. A very strong clinical message.Rakesh Jain, MD, MPH:This is 2 things for me: frightening and hopeful. The frightening thing is that pain is no longer a sensory phenomenon. I actually have to reject the notion that pain is a sensory phenomenon. It’s a sensory phenomenon with neuroendocrine, neuroimmune, neurostructure, and neurofunctioning implications. I guess the hope is if I can somehow stop this, the pain, as an external marker for a disease state, maybe then I could alter the course of this patient’s illness.Charles Raison, MD:That’s right. I agree. I have come to see things like, in this case, physical pain as a marker for disturbed functioning and structure underneath, in the brain and the body. And, we know from a number of lines of evidence, as you suggest, that if you can ameliorate the symptoms that are often associated with indications, you’re improving or at least stabilizing the changes in the brain and body that are so bad. Because one of the things that we know is that the loss of brain volume in all these types of disorders tends to predict a worsening disease state and reduced response to treatments. So, you really want to try to stop these processes from happening. It’s what you said. You want to try to get that pain early before it sets in motion this domino effect of downstream changes that then really ramify on themselves and worsen the disease.Vladimir Maletic, MD, MS:Would it be overstated then to say that maybe symptoms are observable correlates of the underlying metaphysiology?Charles Raison, MD: That’s what I think. They’re not perfect, but they’re at this point one of the best things we have and that’s the way to look at it. Symptoms are telling you that that person’s brain and body are in a dysregulated state that’s going to damage them. So, you really want to get a hold of the symptoms. And, when you’ve done that, you can have some confidence that, given the state of our current science, we’ve done what we can to at least stabilize the damage. (Enlarge Slide)(Enlarge Slide)
This slide actually is disturbing. This is another slide showing loss of brain volume with fibromyalgia patients compared with normal controls in these medial parts of the brain. The brain areas are slightly different in this study—parahippocampal gyrus areas, other areas of medial prefrontal cortex. A little bit further back in that cingular cortex. The point, though, that’s important about this study is that they looked at how these brain changes correlated with age in both the people with fibromyalgia and the healthy controls. What they found was that the brain loss was occurring at a faster rate in the people with fibromyalgia. Said more simply, their brains were aging at a more rapid rate. You could look at fibromyalgia as a condition of premature brain aging,which, you know, is highly disturbing and, again, points to how these are not just disorders that float around somewhere in the abstractions. These are disorders that are being driven and are driving damage to the brain that is very serious.Vladimir Maletic, MD, MS:And, if the parahippocampal area is damaged, then there would be some implications in terms of declarative memory endocrine regulation. Is that something that we do see in our clinical practice, that there are memory changes in people who have fibromyalgia? Are they more likely to have metabolic repercussions because of the neuroendocrine dysfunction that one would hypothetically encounter in this scenario?Rakesh Jain, MD, MPH: You know, this anatomic finding you’re talking about and the neurobiologic connection you’re drawing actually has not been proven in studies. The same group—I’m talking about Dan Clauw’s group—actually did neuropsychological testing and found that, on average, somebody with fibromyalgia cognitively performed as someone who is 20 years older than them.This is a disorder that finally is getting its due justice, and, unfortunately, the fingerprints of this disorder are everywhere.Charles Raison, MD: They’re all over the brain and body. So, fibromyalgia is a classic example of one of these modern conditions I sometimes call a wear-and-tear condition, right? It’s a condition associated with—we’ll see in a couple of slides examples of this—activation and release of chemicals in the brain and body that puts strain on tissues and wears them out. So, it’s not just metaphorical, it is a disorder of premature aging. And, you know, nobody wants to prematurely age. Life goes by rapidly enough, as we know. So, very important. (Enlarge Slide)(Enlarge Slide)
Now, this really highlights the fact that it’s a mind-body disorder. And this—you’d never say it, but this is your artwork, Vlad—it’s a great slide from a paper that we did together showing that these areas of the brain that are functionally and structurally abnormal in fibromyalgia play a key role in activating stress systems in the body that are crucially important in the brain’s ability to regulate pain. Conversely, these systems are also able to activate processes in the body, such as inflammation, that can then feed up to the brain and magnify these very problems—these very dysfunctional patterns. So, what happens in conditions like fibromyalgia is, it looks like this sad and unfortunate brain-body dance gets started, such that the brain activates stress pathways in ways that magnify pain symptoms that activate inflammatory pathways that then feed back up to the brain in ways that set people up to feel tired, achy, and painful. We know that inflammation can, in fact, cause all the symptoms of fibromyalgia. So, you get these very negative closed loops going that can be very difficult to disrupt. And, it really highlights the fact that people feel pain in their bodies, and it can have much to do with their brains. Or, people who feel more psychological pain and can have much to do with their body. We need to dispense with these false dichotomies, and one of the great things about fibromyalgia is it is a syndrome that really helps us do that. As we understand its physiology, we understand how essential it is to move past those old conceptions into a 21st-century view of how the mind and the body function.Vladimir Maletic, MD, MS:My disrealization, then, in former treatment approach, is that if it indeed is all interrelated, if it is cyclical, wouldn’t we be ahead of the game if we could interrupt this cycle at several points? Not only thinking about pharmacology but maybe thinking about other nonpharmacologic interventions?Rakesh Jain, MD, MPH:Absolutely. You know when you look at this slide it looks like a massive traffic snarl, doesn’t it? Nearly every system has gone haywire. And, I couldn’t agree with you more. With as massive an insult the body suffers and the brain suffers when you have fibromyalgia, I think you’re right. You really have to be polymorphic in your approach to it, and that I think precisely includes both pharmacologic and nonpharmacologic, because interestingly, both those interventions come and intersect at the same traffic junction of helping a patient biopsychosocially.Vladimir Maletic, MD, MS:So, in some ways, that boundary between psychosocial and pharmacologic treatments may be becoming more artificial lately.Charles Raison, MD: That’s absolutely right. And, we know that psychosocial interventions are effective for fibromyalgia. Not only do they have effects on behavior symptoms, but they have physiologic brain base defects, body base defects. For instance, there have been some nice studies showing that cognitive behavioral therapy (CBT), which has been proven many times to be effective for fibromyalgia, actually can turn down inflammation in the body. And, we know that medications that treat fibromyalgia will often do something similar. So yes, that’s absolutely right. These are old buckets that we’ve kept separate that we now need to rethink in more holistic ways. (Enlarge Slide)(Enlarge Slide)
And then, finally here’s an example of one of these hot, bothersome chemicals that’s increased in this case in the spinal fluid of people with fibromyalgia. You can see—this is across several studies—that high bar. There are much higher concentrations of substance P, which is a transmitter that really, when it gets activated, signals the brain to turn on pain pathways. And, it has inflammatory effects. It is an angry, hot chemical that, if it were injected into our spinal cords, we’d be yelping with pain ourselves, if you were perfectly normal. So, here’s an example of how you can find these markers of wear and tear disorder. Here is a classic wear and tear molecule that, you know, you want it to activate when the pain is important for behavior, but you don’t want it up chronically where it’s going to be causing people misery and dysfunction.Rakesh Jain, MD, MPH:This kind of evidence does something for me that I would like your thoughts on. You know, 10 years ago, I had real trouble believing in fibromyalgia. I really had a hard time. And, I think what these data do for me is justify the reality of this disorder, that the fingerprints are there. It’s a real disorder, and the suffering of these people is genuine and acute.Charles Raison, MD:Oh yeah. And, biologically based.Rakesh Jain, MD, MPH:And biologically, psychologically, and socially based.Charles Raison, MD: Because those are all different names for the same processes, of course. That’s absolutely right. I mean, what we’re seeing is that fibromyalgia, unlike conditions we understood say 30, 40, 50 years ago, is not the result of 1 blunt problem. What it is, is thousands, maybe millions, of subtle disturbances that are spread everywhere. So, it’s not huge signals in any 1 spot, but a million signals everywhere, And, now they’re beginning to understand these systems ways of looking at illness. Fibromyalgia is a classic example of that. (Enlarge Slide)(Enlarge Slide)
And, this slide just summarizes that. In fact, if you look at fibromyalgia, you see abnormalities in the nervous system, the endocrine system, and the immune system. You see abnormalities in the realm of physical pain, psychosocial functioning, and emotional functioning. The reason for this is because systems by which the brain and the body speak with each other are all interconnected and bidirectional, so abnormalities such as inflammation in the body drive brain changes. They are very similar to what you see in fibromyalgia. Anything that causes those brain changes sets people up, then, to develop pain in their body. So, this slide beautifully highlights the fact that these symptoms arise from dysfunctions in these widely distributed, integrated circuits.Vladimir Maletic, MD, MS:Great statement. It’s really intriguing that, no matter how we adjust magnification, if it’s microscopic or macroscopic, we will see residue of fibromyalgia. And, it’s widespread through the body. It’s in the brain, it’s in one’s mind—because one can make an argument that impacts on one’s psychology—and it’s clearly also in one’s body.Charles Raison, MD: It’s like a fractal, you know, where the pattern on every level is exactly sort of the same pattern. It has that remarkable quality. That’s exactly right. Beautifully said, Vlad. (Enlarge Slide)(Enlarge Slide)
So, to conclude this part of the talk, fibromyalgia is a consequence of complex interactions between vulnerability genes and environmental factors. Intense widespread pain may be a consequence of peripheral and central sensitization, so the mind and the body both get into the act most of the time. It’s associated with functional and structural changes in the brain, and these areas are involved in pain processing and related processes, like stress, activating inflammatory pathways. These changes contribute to the abnormalities you see in fibromyalgia. They probably predict bad outcomes, and certainly, it looks as if they do.One of the things we didn’t talk about so much in this talk, but some of the abnormalities in the spinal cord then set the brain up to be unable to turn down pain signals coming up from the body. So, you get too much coming up and too little sort of ability to dampen coming down from on top. Then finally, fibromyalgia is likely a manifestation of multilevel disturbances in the function of the CNS but also in systems such as autonomic nervous system, the hypothalamic-pituitary-adrenal (HPA) axis, and inflammatory pathways.Vladimir Maletic, MD, MS: Thank you very much for your elegant summary of this material. (Enlarge Slide)(Enlarge Slide)

Epidemiology of Fibromyalgia

Let us now proceed and talk a little bit more about the diagnosis of fibromyalgia. Why would diagnosis be relevant? Well, that is the beginning of the treatment. To come up with the diagnosis, we have to have an increased level of suspicion. And, I think that epidemiologic studies such as the one that we’re looking at can maybe give us a clue as to where we need to look for fibromyalgia. Number 1, fibromyalgia is not rare. Somewhere between 2% to 5% of people in this world may be suffering from fibromyalgia, which makes it one of the more frequently occurring pain disorders. But beyond that, it unfortunately, it discriminates based on gender. So, women are approximately 10 times more likely to develop fibromyalgia than men. And also, there is a little bit of age discrimination in that fibromyalgia tends to become apparent after age 35, usually between ages 35 and 60. So, I think we have some helpful clues if we’re looking for fibromyalgia. It may be a good idea to look for it in women who have multiple somatic complaints, ages 35 and above. Just curious, does that in any way reflect your clinical experience?Rakesh Jain, MD, MPH:Absolutely.Vladimir Maletic, MD, MS:And, would there be some other markers that you would bring in and fill some gaps in epidemiologic information that I have not shared so far?Rakesh Jain, MD, MPH:Yes, sure. Having been raised and born in a different country, I’m here to report sadly that you are right. It is not a cultural disorder. It’s a human condition. I think the age group you talked about is precisely correct. Women are more likely. My wife says it’s because women have to put up with men, but that’s a whole different story. But, I will also report a couple of other sad things to you, Vlad, from my clinical experience. The age seems to be getting younger. I’m now beginning to see women in their late teenage years, particularly if they have a heavy family history of mood and/or anxiety disorders or sadly they’ve been exposed to, say, sexual abuse or some other kind of horrendous psychosocial stressor.Charles Raison, MD:Early adversity.Rakesh Jain, MD, MPH: Yes. (Enlarge Slide)(Enlarge Slide)
Vladimir Maletic, MD, MS:And, it’s also interesting—talking about epidemiologic studies—that, fortunately, data to a degree reflect our diagnostic criteria. So, some of the most prominent symptoms of fibromyalgia include widespread pain and morning stiffness, but also fatigue and sleep disturbance. And, it’s really intriguing—you have talked, Charles, about the role of inflammation, the role of autonomic dysregulation—it’s interesting that people who have fibromyalgia are also much more likely to have headaches and irritable bowel, conditions that do imply some involvement of inflammation.Charles Raison, MD:Absolutely. And, in fact, there’s increasing evidence—you mentioned irritable bowel syndrome—that the types of abnormalities you see in the stress systems coming down from the brain in fibromyalgia might cause the gut to malfunction in ways that would, in fact, allow inflammatory pathways to increase in activity. So, these comorbidities and the symptoms you see, they’re not accidental. They all fit with how we’re understanding the mind-body dysregulation and disorder.Vladimir Maletic, MD, MS:So, it may not be purely casual coincidence. It may be partly causal.Charles Raison, MD: Absolutely. We know, for instance, you can take people and, if you induce sleep deprivation, if you mess up their sleep the way that it’s messed up with fibromyalgia, many people will develop pain symptoms. You can run these symptoms both directions, so I think there’s a lot of evidence that you can causally come into fibromyalgia through the symptoms themselves. (Enlarge Slide)(Enlarge Slide)
On that note, we can now transfer our attention to the next slide. We have known for a while—and there have been many studies that have similar findings—that individuals who have fibromyalgia are at a greater risk of developing anxiety disorders, mood disorders, and sleep disorders. But, now we have a better sense that it is a bidirectional relationship. We also see that individuals suffering from depression, anxiety, or sleep disorder are at a much greater risk of acquiring widespread pain within a 15-month observation period. But, the part that is really intriguing to me, especially if we look at the scores on anxiety and depression scales, it doesn’t take a whole lot. Even individuals who have subclinical symptoms, low-grade symptoms, run approximately a 40% to 80% greater risk of developing anxiety disorders and depression. I know you see many patients with mood disorders and anxiety disorders. Would this be a good reason to monitor these subclinical manifestations of anxiety and mood disorders? And, if patients are having more somatic complaints, should we focus more on those? Should we monitor those more closely?Rakesh Jain, MD, MPH:Your slide makes it mandatory we do, Vlad. I mean 40% to 80% risk? Even when they don’t have a full-blown disorder? If there’s ever an opportunity to do primary prevention, this is it. Mood control, anxiety control, and sleep control, all 3—the trifecta—if done well looks like it may change the trajectory for patient’s life.Charles Raison, MD:It might be protective. And, we might mention that, those subclinical mood anxiety and sleep symptoms, it’s not unique to fibromyalgia that you don’t need very many of them to have a setup for other illnesses. The same thing you see exactly in diabetes and heart disease, right? So, even minor levels of depression set people up for much greater risk of these other disorders that have these mind/body pattern dysregulations.So, fibromyalgia fits with many other modern conditions that involve these just back and forth between brain and body in that fact that, for all of these things, very minor levels of emotional disturbance, it’d actually be a serious wake-up call to intervene. (Enlarge Slide)(Enlarge Slide)

Diagnostic Paradigm for Fibromyalgia

Vladimir Maletic, MD, MS:And, therefore, these recommendations we are sharing with our primary care colleagues may be on target because we are suggesting that they should carefully screen individuals who present with any achiness, pain, or fatigue. It is not very difficult to do the ACR exam, wouldn’t you say? And, this is a fairly reliable diagnostic procedure. I’m curious about your thoughts and awareness that both sensitivity and specificity appear to be above 80%. Is this something that you would recommend be done routinely?Rakesh Jain, MD, MPH:Absolutely. I think one of the things we ought to do for our primary care colleagues is to literally infect them with the idea that fibromyalgia is real, but it can be readily and reliably diagnosed and also excluded if that’s necessary. And, I think when you look at, as you said, the ACR criteria sensitivity and specificity, I’m about to give you a shocker. Both of those numbers are around 85% or better. So, a primary care physician’s heart is always wanting to diagnose if they have it and exclude it if they don’t. I think I want to do my best to sell them on the idea that they have a best friend here: the ACR criteria.Vladimir Maletic, MD, MS:And, we have seen such variety of comorbid conditions. Not only is it relevant to think about mood disorders and anxiety disorders, other painful conditions, inflammatory disorders as maybe red flags, invite us to screen these patients more carefully. But, wouldn’t it carry some implication when it comes to our treatment choice?Rakesh Jain, MD, MPH:Think about it. If you’re trying to knock out 2 conditions, and if you’re able to find 1 intervention to do so, it’s just logical that you would do it. By the same token, if you were to accidentally leave out a paradigm that’s important in helping a patient, you then leave your patient hanging. That’s why I think the marriage between neurobiology that you presented so beautifully and the diagnostic and clinical implication is actually a very tight one.Charles Raison, MD: Absolutely. And, fibromyalgia can occur in the context of other medical illnesses, which is 1 of the brilliant things about the realization, the ACR criteria: that it is a description of a syndrome of these symptoms. And, when it occurs in any illness, it grossly reduces good outcomes. So, A) sometimes if you can deal with if there’s a comorbid condition, the fixing of which can alleviate the fibromyalgia symptoms, that is hugely important. But, B) dealing with fibromyalgia in any context, even in people who have conditions such as multiple sclerosis, can really help the quality of life and the outcome of that other condition. (Enlarge Slide)(Enlarge Slide)
Vladimir Maletic, MD, MS:It’s beautiful how your thoughts dovetail with the structured approach to obtaining history. Therefore, there are several elements that are relevant. Of course, we need to be aware both of somatic illness and psychiatric comorbidities. But, I think it’s probably a good idea to pay some attention to social history. You mentioned stress as being one of the major triggering effects, and then we have talked about genetics. So, it may be a good idea to inquire about family history, especially family history of some stress-related disorders or pain-related disorders.And finally, something that really comes to the point that you have made, when it comes to physical manifestations, aside from widespread pain, not too many clues when it comes to physical exam. Would you agree with that?Rakesh Jain, MD, MPH: Yes, I would agree with it. Though I would also say, the knock on the door when fibromyalgia comes to the primary care’s office is not always pain. And, one of the slides you showed is so gorgeous. It shows the extreme frequency of fatigue and memory and stress difficulties. So, no matter what the knock is, I think you are absolutely right asking those questions about chronic widespread pain. It’s easy to do, and patients reliably report it if asked. (Enlarge Slide)(Enlarge Slide)

ACR Criteria for Fibromyalgia

Vladimir Maletic, MD, MS: And, our very next slide actually summarizes what you have so eloquently pointed out just a few minutes ago. The ACR exam is not too difficult to conduct. And indeed, we see that there is very high specificity and sensitivity, both above 80%. For individuals to meet the criteria for fibromyalgia in addition to having positive 11 out of 18 tender points, the condition also needs to last for more than 3 months. It seems that widespread pain is the most common finding. But, it also reiterates something that you have mentioned: let’s also look for cognitive markers. Let’s also look at fatigue. Let’s also think about sleep. (Enlarge Slide)(Enlarge Slide)
So, it’s really intriguing talking about strong emotions and stress being triggers for fibromyalgia. There’s a very interesting study that was conducted. This was a study that encompassed 333 women and their experience of anger over a specified period, roughly a month, 4 weeks. What they compared were women who had high levels of anger and women who had low levels of anger during those 4 weeks. Not surprisingly what they found is that women who reported higher levels of anger also reported higher levels of pain over the course of the day. Would that be something that would surprise you?Rakesh Jain, MD, MPH:No. Look, both of you just pointed out that in the brain where emotion lives, particularly strong emotions—you know, the anterior, cingular, the medial, the hippocampus, etc.—those are also the seeds of pain management. So, I think from an anatomic, functional, neuroendocrine, or neuroimmune perspective, you two have really helped me understand when all of that collides, the shattering sound is about pain and emotional difficulties.Charles Raison, MD:Absolutely. We know that if you take anger—so in those women in the study that had fibromyalgia and had more pain with the anger—anger activates inflammation. If you give people inflammatory chemicals, which we sometimes do to treat things like hepatitis C, their anger goes way up. Anger is another marker of dysregulation in the system. So, it’s not surprising that, from a biologic point of view, if the dysregulation is manifesting this anger that is also a marker that the systems are in a state where people are likely to feel more pain. Emotional pain, physical pain—they lie on top of each other biologically.Vladimir Maletic, MD, MS: So, based on the summary that you two have provided, it then shouldn’t surprise us that patients who have encountered more stress in their life are also going to have more tender points on their examination, right? But, couldn’t that also be a diagnostic issue? Couldn’t it be also introducing an element of chains when we try to diagnose these patients? (Enlarge Slide)(Enlarge Slide)
Because, all of the sudden, the number of tender points is influenced by the stress the patient has experienced, by levels of anger. It is influenced by demographics. We know that patients who have lower socioeconomic status are likely to have more positive tender points on their tender-point exam. Also, women are likely to experience more pain, and, therefore, it will be reflected in more positive tender points.It’s really interesting that there have been studies that have tried to see how well we can reproduce the findings from the index exam. Unfortunately, but not maybe surprisingly, what we found out is that when it comes to test/retest reliability, although we have made diagnosis at 1 point in time, the chance of being able to reproduce that diagnosis several months later is a little bit better than flipping the coin. It’s somewhere in about the 60% range. (Enlarge Slide)(Enlarge Slide)
Our colleagues have been working hard on modifying the criteria, taking the learning that we have had so far and maybe incorporating it into a slightly different diagnostic system. For the large number of people with widespread pain—and the estimates would suggest that it’s anywhere between 15% and 25% of the population—this is huge, so that some of these individuals don’t become left behind. (Enlarge Slide)(Enlarge Slide)
So, now let us see what kind of thinking has taken place and how it has influenced these 2010 ACR criteria. This is a first major update after 1990 in the tender point exam that we have talked about. The essence of the new diagnostic approach is to look at more than just tender points. There are 19 body regions; in the interest of saving time, I will not go through each one of them.But, what we would like now to hear about is, have patients experienced pain in any of those 19 body regions? So, this is now self-report, in the course of last week. In addition to that, we want to know about their symptom intensity and pattern. Has it persisted for more than 3 months? But, what’s really now interesting, some of the phenomena-associated fibromyalgia are here center stage. (Enlarge Slide)(Enlarge Slide)
So, fibromyalgia is now diagnosed paying attention to unrefreshing sleep, paying attention to cognitive problems, paying attention to individuals who will have fatigue, and finally looking at other somatic manifestations. All of that now figures prominently in our attempts to diagnose fibromyalgia. (Enlarge Slide)(Enlarge Slide)
So, what might be a comprehensive diagnostic approach? What kind of workup would fibromyalgia patients have? Well, to a degree it depends on how long they have had their symptoms, right? You would not approach the patient who has newly emergent widespread pain in the same way as somebody who has had this condition for a number of years. Just curious, in your clinical practice, how would you approach these patients differently? Somebody who has new-onset widespread pain vs individuals who have had these experiences for a number of years, let’s say.Rakesh Jain, MD, MPH:Oh, very differently. You’re absolutely right. With new-onset, I’m much more suspicious about looking for an organic etiology. I’m really relying much more on investigations, laboratory and otherwise. With chronic pain, I’m not saying I’m not going to, but, typically, if I’m not finding any major issues, I’m much more likely to think about it more as fibromyalgia rather than something else of an acute nature I need to focus on. Though, I will say sometimes you can have patients with both, so one has to watch out.Vladimir Maletic, MD, MS:So, if somebody has an acute onset of pain, it might be a good idea to look for other rheumatologic reasons. Let’s say, do an erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP) test to look for other inflammatory disease, connective tissue disease, or cancer. Or, talking about vascular or hematologic illness, right? So, getting a blood count and running chemistry may be a good idea to eliminate some metabolic disease or electrolyte misbalances. And finally, endocrine conditions can mimic some of the symptoms. So, disturbances of thyroid function—be it hypo- or hyperthyroidism, parathyroid function, or a vitaminosis D—all can mimic some of the symptoms that patients who have fibromyalgia have. That was something that I think you wanted to suggest?Rakesh Jain, MD, MPH:Yes. I couldn’t agree with you more. Fibromyalgia is not a disorder of exclusion. However, just because you’re fibromyalgic doesn’t mean you couldn’t have something else. So, your recommendation about routine labs, including ESR, is excellent. Even if you’re pretty sure it’s fibromyalgia, getting those routine labs—which by the way only takes 2 or 3 days to get back in your clinic—is perfectly appropriate. And, ACR guidelines really support that.Vladimir Maletic, MD, MS: So, just to summarize, it is nice to see that diagnostic measures, including laboratory workup, are now reflecting the neurobiologic and mind/body nature that you have just so eloquently summarized. (Enlarge Slide)(Enlarge Slide)

Treatment for Fibromyalgia

Now that we have diagnosed this condition, now that we have a better understanding, what do we do about it?Rakesh Jain, MD, MPH:Yes. What we do about it is we do our very best to help these patients out. But, we help them out based on what you 2 gentlemen have taught us, which is understanding the neurobiology of the condition, which, to a clinician, means a lot. Because, how you look at it, how you conceptualize this, is how you treat it. And then, you have given us even better ways of diagnosing this condition, both inclusive and exclusive.But, at the end of the day, one has to help these patients out. And, to do so, what one really needs to do is to have a very diverse portfolio of options. As we tend to say in the fibromyalgia treatment world, know your patient well, know your options well, and know your community well, because you’re going to need all three. And, patients are very different with different needs. Your knowledge about interventions may be different, and you may need to bring it up a notch or 2, but know your community. It really requires multiple specialties to step in to help them out. So. know these 3 things well.Having said that, it is very important that we keep the nonpharmacologic treatments in mind, even if we are using monotherapy or dual therapy, for a simple reason. Physical exercise, for example, some of the best effect sizes we have had in the treatment of fibromyalgia have come from physical exercise. But, physical exercise is no longer physical exercise. It’s a biologic, psychological, and social intervention. Let’s never forget about physical exercise.What about CBT? Top notch, Level A evidence is that CBT, either in monotherapy or along with other interventions, can be very helpful. Now, sometimes clinicians say “I don’t have access to good CBT therapists.” True, but at least try, then, to refer patients on to Internet-based resources, where maybe they can learn more about it. Maybe to some readings, etc, that they might have access to. But, CBT is very important because stress, as you so eloquently taught us, Vlad, makes this condition worse. And, CBT could be a way to diminish those symptoms.Vladimir Maletic, MD, MS:Great point that you’re making. Very often if we emphasize the biologic nature of a condition, people are a little bit hesitant to rely on exercise or CBT. They appear to be 2 soft treatments. But, you have just pointed out that CBT actually influences inflammation.Charles Raison, MD:Inflammation.Vladimir Maletic, MD, MS:So it—Charles Raison, MD: Social intervention is profoundly biologic. It’s a mistake to think of them as not being biologic interventions. They are. Sometimes they can be more powerful than pharmacology.

Rakesh Jain, MD, MPH: And, think about exercise as increasing the tone of the descending pain pathway.

Charles Raison, MD: Turning down inflammation, yes. You know it.

Rakesh Jain, MD, MPH: As you said, it’s a traffic snarl, and if you’re trying to straighten it out it makes perfect sense to think along these lines. I think we really need to convince our primary care colleagues here to think about fibromyalgia as a pain condition, sure. But, it is so much more than that. And, thankfully, we have treatments that can really correct many of these difficulties. But, I’ll also say this, unless the clinician is convinced, it’s very difficult to convince the patient.

So, step 1, let’s become convinced based on evidence, not based on just us talking about it, that these 2 interventions are very top notch. By the way, psychotherapy is a reward that keeps on giving. There are studies now that even after psychotherapy has been withdrawn the benefits of that may continue longer-term.

Now, while I’ve talked about nonpharmacologic treatment, let me be the very first to report to you, often that is not enough. It’s a good place, has a certain place, but often it’s not enough. And, we in the United States are actually quite fortunate. We’re the only country, as far as I know, that actually has 3 FDA-approved medications. We are the envy of the world. When I travel the world and tell them we have 3 actually somewhat different treatment options, they are somewhat jealous. And, I’m okay with that. I’ve had the great privilege of being involved in all 3 of those medications’ clinical development programs, so I’m happy to show you some results of patients that came out of our clinic.

But the take-home message: multimodal. It is never a good idea to raise a child by yourself. You know, they talk about it takes a village. Well, if you really want to help a patient on fibromyalgia, create a village approach around the patient.

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Okay, why don’t we briefly look at the 3 different FDA-approved interventions that we have. The first one I have here for you gentlemen and our colleagues to look at is pregabalin. This is a medication that is called an alpha-2-delta ligand. It’s thought to decrease the influx of calcium and make the ascending pain pathway less responsive, to what you just talked about. There we go. And, what is the evidence for that? Here I am showing you a study that does show that with 150 mg/day, 300 mg/day, and 450 mg/day there was benefit with this medication.I will say 1 thing, though: patients with fibromyalgia are perhaps some of the most sensitive-to-medication side effect patients I have ever met.Vladimir Maletic, MD, MS:Would titration be part of your treatment approach?Rakesh Jain, MD, MPH:Absolutely. I think I run into so many patients who have this pseudo-resistance.Vladimir Maletic, MD, MS:Yes.Rakesh Jain, MD, MPH: But, they don’t have any resistance. They were just intolerant of medications. So, you are being very wise in advocating the need for individualized titration. Not just a plan, and I’m going to fit you into that. So. I really think pregabalin has good Level A evidence and is recommended by every fibromyalgia guideline that I have talked about. (Enlarge Slide)(Enlarge Slide)
There does seem to be a dose-response curve, which is further evidence to what you suggested. Let’s adjust the dose, but let’s not give up because ultimately it’s a dance between tolerability and efficacy. And, it seems that if you are able to adjust the dose, at whatever speed is necessary for the patient, you most likely, as I’m showing you on this slide, will have a higher—Vladimir Maletic, MD, MS:And, therefore the individualized approach is what you’re advocating.Rakesh Jain, MD, MPH: Absolutely. It is very much the tailor and Hong Kong approach. I feel very comfortable telling my patients that, that “I really understand that your disorder is unique to you. And, as a good clinician, I feel it is my job to fit it to your needs.” But, mechanistically it’s also important. We must understand where this is coming from. And, it really appears to be an ascending pain pathway intervention. (Enlarge Slide)(Enlarge Slide)
Here is some more good news to share with you gentlemen, which is we now have studies that show durability effect. It’s not just a flash in the pan effect that you have reductions in pain scores. But, if the patient is able to stay on medication—as you can see on this particular slide—there is good evidence that there are longer-term benefits, too. Keeping in mind, tolerability always is an important consideration.Vladimir Maletic, MD, MS:And, something else that we can deduce from this graph: it seems that onset of action of these medicines is fairly rapid, maybe much more rapid than what we are used to seeing in anxiety and depression. I know you have done many trials with fibromyalgia. Would that coincide with your impression?Rakesh Jain, MD, MPH:Yes, which is 1 more nail in the coffin of that thought that fibromyalgia is nothing but a kind of an anxiety disorder or a mood disorder. Not true. Not true based on—Charles Raison, MD:It responds differently to the same medicines. That’s right. So, you know, that is very understandable.Rakesh Jain, MD, MPH: Yes. That’s a very good point. There is no road for therapeutic nihilism, as we have talked about in taking care of fibromyalgia patients. A lot of clinicians do feel, “I’ll take care of any patient, but not fibromyalgia.” And, I would ask them why. Well, typically it’s because they feel frustrated, but they’re frustrated often because they don’t know their options. Remember, I said know your patient, know your options, and know your community. When you know those 3 things well, taking care of fibromyalgia patients, I genuinely believe, is an enormously rewarding line of work. (Enlarge Slide)(Enlarge Slide)
Let’s move on to the next medication that came into the US market, and this is duloxetine. This is a serotonin norepinephrine reuptake inhibitor (SNRI). Actually, this was one of the trials I was part of. What we are demonstrating here is that duloxetine at 60 mg/ day and 60 mg twice a day, take a look at the curve again, Vlad. It follows the same thing you talked about, early and sustained effects on pain when noticed. If you remember with depression it’s a little bit different, a little bit slower.Mechanistically, this proves something very important: that the descending pain pathway is important because this particular molecule is thought to downregulate the descending pain pathway norepinephrine. And, to some degree, norepinephrines are the reigning kings and queens, if you will, of that modulatory pathway.Vladimir Maletic, MD, MS: And, based on what you’re saying, that seems to be largely independent of duloxetine’s impact on more than anxiety. (Enlarge Slide)(Enlarge Slide)
Rakesh Jain, MD, MPH: Gosh, it scares me how much you can read my mind, Vlad. Because, if you look at this slide, that’s exactly what I’m trying to demonstrate. You are absolutely right. If you have depression and pain, sure there’s great evidence that these interventions work. You get 2 for the price of 1. On the other hand, if all you have is depression or all you have is fibromyalgia, it still works, lending further proof to our concept that these disorders are connected yet are different. Absolutely. And, that’s what an SNRI in this particular study demonstrated. (Enlarge Slide)(Enlarge Slide)
The final medication that has joined this trifecta of options we have available is right here. This one is milnacipran. Now, even though it’s classified as an SNRI, I don’t think that’s a very good description. A reverse description may be better—a norepinephrine serotonin reuptake inhibitor—because it’s actually 3 times more potent a norepinephrine than it is a serotonin. So, it may be a new category, and SNRI may be inappropriate.By the way, it is not available in America as an antidepressant, but it is approved in the United States as a medication for the management of fibromyalgia.Vladimir Maletic, MD, MS:And, if my memory serves me well, isn’t there a study also suggesting that its positive impact in the treatment of fibromyalgia, which also coincides with the functioning of circuitry involved in pain regulation based on imaging study?Rakesh Jain, MD, MPH:Absolutely.Charles Raison, MD:I was just thinking that same thing.Rakesh Jain, MD, MPH: We all have reviewed that study. So again, let’s go back to where we started. The brain, the person, their environment, their psychology, their sociology are not only intimately involved, we can now demonstrate that through hard evidence. This is 1 more reason why our primary care colleagues listening to us should feel very confident when they deal with fibromyalgia patients. It’s a real disorder with real pathology, and these patients deserve the best we can offer. I’m so glad you remembered that study, Vlad. (Enlarge Slide)(Enlarge Slide)
So here there is, again, Level 1 evidence that this medication is effective when taken twice a day. In this study, there was a once-a-day arm as well, though in the United States its approval at the moment is only for twice-a-day dosing. Same thing, I wanted to show you that there’s durability of effect. So, if you can, again remember titration: these patients are very sensitive to side effects. And, research patients are not the same thing as clinical patients. I have learned that the hard way.Charles Raison, MD:That is so true.Rakesh Jain, MD, MPH:It is so true.Vladimir Maletic, MD, MS:And, in a condition that has such a fluctuating course and that is subject to so many environmental changes, it is very encouraging to see that there are treatments that will have a sustained effect.Rakesh Jain, MD, MPH:Absolutely. Statistically speaking, we actually have really good evidence that these are effective treatments. By the way, the first treatment we talked about was an ascending pain pathway intervention. The last two are descending.Charles Raison, MD:Pregabalin was ascending, and duloxetine and milnacipran are descending pathways. So, they’re upping the power in that shock absorber pathway that went from the brain, down to the periphery, to diminish signaling.Vladimir Maletic, MD, MS:And, possibly even impacting the brain matrix.Rakesh Jain, MD, MPH:Absolutely.Vladimir Maletic, MD, MS: Pain matrix in the brain.

Rakesh Jain, MD, MPH: Absolutely. So again, here we go: mind-body illness personified, including its treatment outcomes. By the way, do we only treat pain when we are taking care of fibromyalgia patients?

Charles Raison, MD: No.

Rakesh Jain, MD, MPH: Ten years ago, I might have said yes, but today—wiser, older, and grayer—no more do I accept that. I’ve kicked it up a notch, so to speak. And I really want patient’s functioning to be better. I really want them to also admit and realize that they are better.

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So, when you look at this triple composite, which is a very high standard by the way, milnacipran shown at the 2 doses that I’m showing you as compared with placebo in being an effective intervention, not just for the pain but for the—Charles Raison, MD:Yes, for the functioning.Rakesh Jain, MD, MPH:Yes. As well as the patient.Charles Raison, MD:Which is so important.Rakesh Jain, MD, MPH: So important. So incredibly important. (Enlarge Slide)(Enlarge Slide)


Now, we’ve got to take it all in. This is a lot of information and our primary care colleagues deserve for us to put it in a way that makes sense. And, I have brought for us to view—and I wanted your thoughts on this, too—Dr Arnold, who’s a leading expert in this field, she really has a step 1, 2, 3 approach to it. Let me run this by you and let’s see if you think this is a good idea.Step 1) Identify what is going on. I have never yet met a fibromyalgia patient who only has pain. Never.Charles Raison, MD:Yes. It doesn’t happen.Vladimir Maletic, MD, MS:It doesn’t happen. It’s like a Texas dog with ticks and fleas. It’s most impossible just to have 1 difficulty. Look for comorbidities because you’ll find them. And, they matter: psychiatric and medical. Look for psychosocial stresses. And, so important, educate them about the disorder. If we don’t know about it, how are they supposed to know? I suggest giving them pamphlets and booklets. Remember their memory is not very good so they need a bit of help in that. And, they need to educate their family members, too.Charles Raison, MD:And, the education can actually be somewhat therapeutic in of itself.Rakesh Jain, MD, MPH:Yes. Knowledge is powerCharles Raison, MD:It is. That is right.Rakesh Jain, MD, MPH: And for fibromyalgia, the power of this education may be enormous. (Enlarge Slide)(Enlarge Slide)
Step 2) Individualized treatment, not fit them into a box you have created. Look at what their needs are. What are their bio/psychosocial needs and let’s go after that. And Dr Arnold’s recommendations—and I, by the way, agree with her—are, depending on symptom cluster, you’re welcome to choose either the alpha-2-delta ligand as your primary intervention or the newer family of SNRIs that would include duloxetine and milnacipran. Or, if you see that they have a partial response to one or the other, she actually goes out of her way, even though it’s not yet FDA approved to consider combining those 2 medications. Because as you said—Charles Raison, MD:Well it makes sense. You’re addressing different systems that are linked to each other, so you might get synergistic effect.Rakesh Jain, MD, MPH:Absolutely. And, we actually have trials going on, actually more than one, to see if that does end up being true. I suspect it will be but it must be proven.Charles Raison, MD:Yes, good to study.Rakesh Jain, MD, MPH: Absolutely. (Enlarge Slide)(Enlarge Slide)
And finally, let’s realize that the treatment of fibromyalgia is not simplistic. These interventions may not help. So, there are some recommendations about how possibly we may help them if there is a difficulty going on and that it’s okay to really think about multiple other issues, you know, that these patients can have obstructive airway disease. So that needs to be looked at, etc. (Enlarge Slide)(Enlarge Slide)
Step 3) Always she recommends—and I can’t agree more with her—thinking about adjunctive CBT—CBT is important. And, there we go, exercise rears itself again—such an important recommendation. And, I’m perfectly okay with patients starting low and slow as long as it is steady. Exercise, by the way, is effective not just in the treatment of fibromyalgia but also in prevention of relapse. And, of course, here we go, remember: know your patient, know your options, and know your community. If your community has support groups of patients with fibromyalgia, that is a very wonderful intervention to offer them. (Enlarge Slide)(Enlarge Slide)

Vladimir Maletic, MD, MS: Thank you very much for your elegant summaries of these topics. So, starting from the beginning, as you mentioned, we need to be aware of fibromyalgia in order for our successful treatment to proceed. And, it seems like time is of essence. We need to diagnose this condition as soon as possible. To do that there are certain red flags, certain symptom constellations, that should raise our awareness. And, that includes female gender.

That includes symptoms of widespread pain but also fatigue, sleep disturbance, anxiety, mood disorders, and multiple somatic complaints. We now have 2 diagnostic criteria at our disposal that can help us correctly identify the patient suffering from this condition. We see that laboratory workup is not too complex, that it should probably be reserved for patients who have newly emergent symptoms rather than individuals who have been suffering from this disease for a long time.

I’d be curious, if you wouldn’t mind summarizing for us, Charles, what are some of the relevant neurobiologic findings? And also, this is a program by clinicians for clinicians, so what are the clinical implications of these findings?

Charles Raison, MD: The essence of what appear to be the biologic abnormalities of fibromyalgia is that, through a combination of genetic risk meeting environmental adversity, patterns get set up in the brain and the body that lead to the release of chemicals that really exert wear and tear over time. This leads to loss of brain volume and abnormal brain function, areas that are key for regulating how the body perceives and processes pain, but also how it mediates mood and stress. These brain changes then set you up to have changes in the body and systems such as inflammation, which is then again feedback up to the brain and can induce feelings and symptoms that look just like fibromyalgia.

So, the point is, and I think from a clinical perspective, there is a progression. It looks like this is a disorder where these changes lead to a premature aging of the functioning and the structure of the brain and the body. So, you want to intervene as early as possible because you don’t want the damage to occur. And, you don’t want the damage to occur because the more that happens we know the harder it is for people to fully recover.

Vladimir Maletic, MD, MS: And, that clearly has some implications when it comes to treatment.

Rakesh Jain, MD, MPH: Absolutely. Look, we all have heroes in our life. And, in my life it’s a couple of teachers, my father, and the primary care doctors. They really are heroes. They take on everything. But, I think they have not embraced fibromyalgia as much as they could have or should have. I’m hoping this full discussion really tells them they are tough people, they have the instruments, the tools to diagnose. They have now 3 different FDA-approved options available to them. They now have Level 1 evidence for CBT, exercise, and multimodal therapies, which, by the way, they are extremely good at. Look what they have done to the hypertension world and the diabetes world. I think, “More power to them.”

But, I will say in my final comment, embrace the disorder. Don’t be afraid of it. It’s a condition that can be diagnosed and can be treated with effort.

Vladimir Maletic, MD, MS: Again, thank you very much for your sage observations, comments, and advice to our primary care colleagues. Of course, to have the full benefit of this presentation I would like to remind our audience member to click on “Earn CME Credit” to complete the posttest and evaluation and earn credit for this program. Thank you very much.

Rakesh Jain, MD, MPH: Thank you.


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