Fibromyalgia: Update on Mechanisms and Management.

1: J Clin Rheumatol. 2007 Apr;13(2):102-109.

Clauw DJ.

From the *Division of Rheumatology, Chronic Pain and Fatigue Research Center, daggerClinical and Translational Research, University of Michigan Medical Center, Ann Arbor, Michigan.

PMID: 17414543 [PubMed – as supplied by publisher]

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3 Responses to Fibromyalgia: Update on Mechanisms and Management.

  1. Fibromyalgia: Update on Mechanisms and Management

    April 7th, 2007 by fmsglobalnews

    1: J Clin Rheumatol. 2007 Apr;13(2):102-109.

    Clauw DJ.

    PMID: 17414543 [PubMed – as supplied by publisher]



    The American College of Rheumatology criteria have been both bad and good for fibromyalgia.1 When they were published in 1990, this is what we thought fibromyalgia was: chronic widespread pain and the 11 of 18 tender points. If this is your view of fibromyalgia, then fibromyalgia is really no different than other rheumatic diseases like osteoarthritis or rheumatoid arthritis or lupus-a discrete illness. In 1990, we also thought that the tenderness was confined to certain areas of the body, or at least more accentuated in certain areas of the body, which we refer to as tender points. Finally, another misconception that exists to this day in many
    people’s mind is that psychological and behavioral factors are always present in people with fibromyalgia and always make them worse.
    A more contemporary view of fibromyalgia is that rather than being a discrete illness, it is a part of a huge continuum of pain and somatic syndromes. It happens to be what we, as rheumatologists, are most comfortable calling it. But these individuals have pain throughout their entire body that isn’t due to damage or inflammation, and there’s a great deal of scientific evidence that this is one large spectrum of illness that includes fibromyalgia, irritable bowel, and temporomandibular joint (TMJ)
    syndrome-as well as a number of other conditions that I’ll talk about later. Even if we use the American College of Rheumatology (ACR) criteria to diagnose fibromyalgia (i.e., on the basis of widespread tenderness and pain), people don’t just have tenderness and pain. They have a lot of other somatic symptoms besides pain and tenderness. And, again, psychological and
    behavioral factors only play negative roles in some individuals.

    We also now know that the entire individual with fibromyalgia is tender, and that there is nothing magical about tender points. These are merely areas where everyone is more tender. But fibromyalgia patients are also much more tender wherever you apply pressure, including areas previously considered to be control points. In fact, in our research group, when performing sophisticated imaging studies, we push on the thumbnail because
    we found that the thumbnail is just as tender (relative to that same region in a healthy control) as any of the tender points. Fred Wolfe was the first to point this out. He suggested that we should abandon this old term that used to be called control points and call them high-threshold tender points; areas like the forehead and the thumbnail and the anterior tibial region are just areas where all of us have a higher pain threshold.

    These are many other problems with ACR criteria and specifically with tender points. We didn’t know any of this in 1990, so I’m not being critical of the people who were involved in developing the ACR criteria because they have been wonderful in standardizing research into fibromyalgia. But we didn’t know that tender points are actually not a very good measure of tenderness. In 1997, Wolfe published an article where he looked at some of the data that he collected in population-based studies.
    He had found that the number of tender points an individual has is highly correlated with the number of measures of distress-of anxiety, depression, and distress.2 What he said in that article was that tender points are a sedimentation rate for distress. Since then, our group and others have shown that other more sophisticated measures of tenderness, such as where you give people stimuli randomly when they can’t anticipate what the next stimulus is going to be, are just as abnormal in people with fibromyalgia, but these are not at all related to the level of distress of the individual.3 So people with fibromyalgia are indeed much more tender, or they have what we would call a left-shift in their stimulus-response
    function with respect to pressure. So the take-home message is that fibromyalgia patients are much more tender even using more sophisticated measures that are not confounded by distress. However, tender points are not a very good measure of tenderness. Tender points are part a measure of tenderness and part a measure of how anxious and depressed an individual is.

    I might be the first author that I know of that’s been able to get away with writing a chapter in textbook regarding fibromyalgia without having an illustration of a woman with 18 dots on it, because I think that the longer that we highlight the ACR criteria and highlight these 18 areas of the body, the longer physicians are going to think that there is something uniquely wrong with those 18 areas of the body rather than realize that this is a diffuse, central problem with pain processing. This gives an inappropriate impression about the nature of fibromyalgia when you put those 18 dots and they all happen to be located over muscle-tendon junctions and people sort of think, Well, that’s where the problem is, rather than realizing that this is a problem in the central nervous system with the way people are processing pain or sensory information. Our group hypothesizes that this is actually a more global problem with sensory processing, not just pain processing, because people with this spectrum of illness are sensitive to a number of different types of stimuli rather than just somatic pain.

    I think one of the other disservices that the ACR criteria has done is that they’ve deluded us into thinking that fibromyalgia occurs almost exclusively in women. If you use the ACR criteria, 92% of the people in the population who are identified as meeting those criteria are females. But if you break down the criteria into the 2 elements, (1) chronic widespread pain and (2) 11 of 18 tender points, women are only 1[1/2] times as likely
    as men to have chronic widespread pain, but women are 11 times as likely as men to have 11 of 18 tender points. So what we’ve done with the ACR criteria is take an illness that is probably only about 1[1/2] times more commonly in women and make physicians think that this occurs only in females. This is similar to what we did a couple of decades ago when I was trained as a rheumatologist, when we were taught that ankylosing spondylitis only occurred in males. When that’s what we were taught, then we only thought of the diagnosis of ankylosing spondylitis in men, even though later data showed that the prevalence of AS is very similar in men
    and women.

    The same thing happens now with women versus men in chronic pain. Men who come in with the same exact symptoms and physical examination as women with fibromyalgia are more likely to be labeled with regional pain syndromes such as osteoarthritis, because if you do X-ray after X-ray (or worse yet MRI after MRI) you will always find something wrong. I used to have a diagnostic test called the X-ray jacket sign because when we went to the VA
    clinic, they would pull the X-ray jackets on all patients (before the
    X-rays were digitalized). I joked that if you could pull 10 consecutive musculoskeletal X-rays out and none of them were abnormal, that was a diagnostic test for fibromyalgia. And we had many men in the rheumatology clinic that we were seeing who had been labeled as osteoarthritis or chronic low back pain, who clearly had fibromyalgia. But the diagnosis carried for years and years in their chart was a regional pain syndrome such as osteoarthritis, even though there were inadequate radiographic findings to support this, and they typically did not respond very well to
    treatments for peripheral pain.

    Then the last thing that people should be aware of with tender points, and that is that 11 is a totally arbitrary number. Robert Katz has published articles recently talking about how different types of criteria function equally well. And he and I, and almost everyone in the fibromyalgia field, agree that the ACR criteria should not be used in clinical practice to diagnose fibromyalgia. They never were intended for that purpose. They were
    intended to standardize research studies. And they don’t function very well at all when you use them in routine clinical practice.

    Every subspecialist that I know, except perhaps radiologists and
    pathologists, sees patients that was as rheumatologists call fibromyalgia and has one or more names for the symptoms in the area of the body they are responsible for. It is not until you realize the entirety of the problem, like the pharmaceutical industry now does, that you understand that this is one large problem that needs to be addressed in primary care, rather than something that’s just been bestowed upon us in rheumatology because we have
    to deal with these fibromyalgia patients.


    So to summarize, there’s nothing wrong with thinking that fibromyalgia is a discrete disorder. But I’m going to talk of it as being more of the end of the continuum, or the way the pharmaceutical industry is viewing this right now, which is that it is the prototypical central pain state, where people can get pain and other somatic symptoms without having anything really wrong in their peripheral tissues that would cause a nociceptive problem.

    Regarding the underlying mechanisms in this spectrum of illness, we didn’t know in 1990 what we know now about pain sensitivity. In 1990, the thought was that there were sort of 2 groups of people in the population: a small group of people who were very tender and thus met criteria for fibromyalgia, and the rest of the population, who had a normal pain threshold. But in the last 15 or so years, there have been a number of different studies of pain sensitivity in the population. And we now know that pain sensitivity in the population occurs over a wide continuum, a classic bell-shaped curve, just like almost any other physiologic variable.
    We’re also learning that genetics have a lot to do with where you are on this continuum. I am quite comfortable saying that in 5-10 years we will have gene chips that will have been developed that will predict with a reasonable accuracy where people are on this bell-shaped curve, because polymorphisms and a number of different genes that involve the breakdown and metabolism of neurotransmitters involved in sensory transmission will
    predict with a fair amount of accuracy where someone is going to sit on this curve. And if you happen to be in the top quartile or tertile of that bell-shaped curve, on the far right where you’re very sensitive to pain, you probably can develop pain without having any inflammation or damage in your peripheral tissues; and that can either be regional or widespread pain.

    So this is really the emerging notion of what’s going on in these fields like fibromyalgia, TMJD, and irritable bowel. People, because of a combination of the genes they are born with and the environment that they grew up in, move to the right end of this bell-shaped curve and can develop pain and other somatic symptoms because of what’s going on in their central nervous system rather than because of any damage or inflammation in their peripheral tissues.

    The best work showing the genetic and familial nature of fibromyalgia has been done by Lesley Arnold and her colleagues.4 They showed that if someone has fibromyalgia, the risk of one of their first-degree relatives having fibromyalgia is 8-fold greater. To put it in context, in lupus and rheumatoid arthritis, the odds ratio is 2 to 3; and we think of those diseases as being somewhat familial. But fibromyalgia is incredibly familial. And one of the nice things about this study is that it somewhat challenged an earlier notion that Jim Hudson, who was actually a coauthor of this study, published in the mid 1980s where he called this an affective
    spectrum, because he felt that depression and anxiety coaggregated strongly with fibromyalgia. The new studies, which he was also involved in, partially proved his theory, but the coaggregate between these disorders and fibromyalgia is weaker than previously suggested by studies done entirely in tertiary care centers. So there is a weaker coaggregation with mood disorders genetically, whereas there is a very strong coaggregation
    with other pain syndromes like fibromyalgia and irritable bowel syndrome and TMJ syndrome, and other psychiatric disorders such as obsessive compulsive disorder and bipolar disorder.

    One of the best studies looking at the precise genetic cause of conditions related to fibromyalgia was done by Luda Diatchenko and Bill Maixner at the University of North Carolina.5 They looked at a large cohort of women who were pain-free and followed them for 3 years to see who developed the TMJD syndrome, and showed that how tender an individual was at baseline, and
    polymorphisms in the COMT gene, predicted who went on to develop the TMJD syndrome over the 3-year period. That’s just one single polymorphism, and there are a number of different polymorphisms that are probably playing a role in pain.

    There probably will be 20 or so genes that end up predicting with a
    reasonable amount of accuracy where someone is on this continuum of pain processing. But where I think it’s going to be incredibly useful in 5 to 10 years is to figure out what drugs to give people who have this spectrum of illness because if I see that one person might have developed fibromyalgia because of an abnormality in catecholamine synthesis because of COMT or
    ß-adrenergic receptors, then these individuals might respond very well to, for example, a mixed reuptake inhibitor or low doses of a ß blocker.
    Whereas individuals who have different polymorphisms might be more responsive to drugs like pregabalin or gabapentin, or other classes of drugs, which will be developed in the future, that act on other neurotransmitters that either increase or decrease an individual’s pain sensitivity.

    Given that nearly all illnesses are due to some combination of genes and environment, we also are beginning to better understand the environmental factors that seem to be important in triggering fibromyalgia. Most may be acting as stressors. One stressor that is clearly capable of causing fibromyalgia is to begin by having a peripheral pain syndrome (i.e., pain due to damage or inflammation of peripheral tissues). I’m not sure what percentage of rheumatologists are aware of this, but 20 to 25% of people
    with RA, lupus, and ankylosing spondylitis, have comorbid fibromyalgia.6 I see young and old rheumatologists who make the diagnosis of an autoimmune disease and then hone in and inordinately focus their treatment on autoimmunity. Every time that patient has pain or fatigue, we raise their dose of immunosuppressives because we think that’s what is causing their
    pain and their fatigue. But if a quarter of the people with autoimmune diseases have comorbid fibromyalgia, maybe they need a low dose of amitryptiline or some aerobic exercise rather than a cytotoxic drug or 10 more milligrams of prednisone.

    Another stressor that can trigger this spectrum of illness is infections. Four different infections that have been shown in case-controlled studies to trigger either fibromyalgia or chronic fatigue syndrome: Epstein-Barr virus, parvovirus, Lyme disease, and Q fever.7 There are 2 studies published in the Lancet showing that the common cold isn’t capable of triggering either chronic fatigue syndrome or fibromyalgia. Now, in almost all of my talk, you could substitute the word IBS for fibromyalgia and give the exact same talk, and it would be accurate. But this is one area where
    fibromyalgia and IBS would differ. The infections that trigger irritable bowel syndrome are virtually any infections that cause acute infectious colitis-nearly all have been shown in case-control studies to lead to the subsequent development of IBS. Likewise, a number of different genitalurinary infections have been shown to be capable of triggering the development of interstitial cystitis

    So depending on where in the area of the body responsible for one of the syndromes, different infections that attack that area of the body seem to be capable of triggering it. But only about 4 to 7% of people with these infections go on to develop fibromyalgia, IBS, or interstitial cystitis, whereas the overwhelming majority of individuals that have these same infections recover fully and go on to their baseline state of health. So, again, it’s probably some interplay between the genes the people are born with and the infections that they get.
    Physical trauma is another stressor that is capable of triggering the
    development of fibromyalgia. But one of the fascinating things about this is that this occurs much more frequently in some countries than others. In Lithuania, motor vehicle accidents trigger almost no chronic regional or chronic widespread pain; whereas in the United States, they trigger a fair amount of it.8 It’s not the patient’s fault. It has little to do with the insurance systems because this happens in no-fault and in other insurance
    systems. And it probably doesn’t even have much to do with the disability and litigation systems. It may have more to do with what we as physicians (and the healthcare system) lead people to expect what will or won’t happen after acute musculoskeletal trauma.

    In Lithuania, when you come in after a motor vehicle accident, and you see an emergency room physician, there is no expectation that there will be any chronic symptoms after that; you are given a few days worth of anti-inflammatory or analgesic medications, and told to go back to work. In the United States and many other countries, we give people opioids, tell them they might develop chronic pain, and tell them to rest. We haven’t learned our lesson from good research in conditions such as acute low back
    pain, where we now know that the worst thing to do with someone with low back pain is to make them expect they might develop chronic pain, and tell them to stop moving and rest. So it may actually may be our health systems and the expectations that we as physicians set up with our patients when they come in with acute pain rather than being litigation or disability.

    With respect to stressors, there’s actually weak data that psychologic stress and distress directly causes fibromyalgia. One of the fascinating things is I’m always surprised, being a scientist, at how often my clinical judgment ends up being wrong. When I was first doing research in fibromyalgia, I, like many of you, was always smacked in the face by the psychologic comorbidity that a lot of fibromyalgia patients come in and express. But the data suggest that many types of psychologic stress don’t seem to trigger or worsen fibromyalgia. We were doing a study in Washington, D.C., where we were beginning to work with a company that was
    doing clinical trials in fibromyalgia, and they wanted to do more
    innovative outcome measures of fibromyalgia patients. So we were having fibromyalgia patients in Washington, D.C., wearing Palm pilots that beeped 5 times a day and they had to record their pain, their fatigue, their stress levels 5 times daily. As is not unusual in research, some of the best things that happen to you are serendipitous; and the 9/11 attacks on the Pentagon happened right smack in the middle of the study. So we had about 20 people who had been recording their pain, their fatigue, and their other symptoms, before and after the Pentagon attack, miles away from where all of these patients were living.

    We expected that we would see pain, fatigue, and stress levels go sky high in people with fibromyalgia after 9/11, but there was absolutely no change. Karen Raphael was doing a population-based epidemiologic study in New Jersey where she had collected baseline data in people right across the river from the World Trade Center in New Jersey, and similarly found no increase in symptoms.9 So you have to be very careful about attributing
    emotional stress to the development of fibromyalgia. It likely is very important what type of stress, and interpersonal stress may be much more likely to exacerbate or trigger fibromyalgia than the type of stress seen after 9/11.

    Finally, war is another thing that triggers the development of this
    spectrum of illness. The Department of Defense provides funding for our research group and many others because of the recognition that after the first Gulf War and, in fact, maybe after every war, one of the major postdeployment health problems is the development of chronic pain, fatigue, and what we would call either fibromyalgia, chronic fatigue syndrome, IBS, etc.10


    One of the most controversial questions in this illness is what is the
    relationship between physiologic or neurobiologic factors and psychologic and behavioral factors. If you do research in this area, you quickly realize that the old dualist notion of organic versus functional illnesses needs to be abandoned, because everything that is psychologic or behavioral likely has neurobiologic and physiologic underpinnings, and psychologic and behavioral factors play significant roles in even the most biologic of illnesses. In fact, I think that one of the big tragedies regarding this spectrum of illness is that 30 or so years ago, fibromyalgia was on had
    equally poor credibility as a real disease with mental health disorders such as bipolar disease, major depression, and schizophrenia. But now these latter conditions are more credible than fibromyalgia, in large part because scientific studies have shown that there are strong biologic underpinnings to these illnesses. The research showing strong biologic underpinnings is equally strong in this spectrum of illness, but most physicians and the lay public are not yet aware of these findings. This
    will likely change rapidly in the next few years as new drugs are approved specifically for fibromyalgia, and the companies marketing these drugs will do a thorough job of educating both physicians and patients about these conditions.

    Until then, though, these patients are shunned and inappropriately treated in our current health care systems. Everyone is averting their eyes and acting like they’re not part of the problem here. But we are. Rheumatologists don’t want fibromyalgia. Gastroenterologists don’t want IBS. None of the subspecialties want this. So there never has been an advocacy campaign like the psychiatrists and other mental health professionals mounted to legitimize psychiatric conditions.

    Having said that I’m not a dualist, it can actually be very helpful when you’re sitting across the examination room from a fibromyalgia patient, to be a bit dualistic, and ask yourself how much social, cognitive, behavioral, and psychological factors are playing a role in symptom expression. Not all fibromyalgia patients are the same. Some of them respond very well to a little bit of a tricyclic drug and a little bit of education, and they never come back because they do fine. Others don’t get better no matter what we do. We did a study published in Arthritis & Rheumatism a couple of years ago where we tried to develop subgroups based
    on 3 different domains. One domain was neurobiological; that was how tender people were using these more sophisticated measures of pressure pain threshold. One domain was whether they were depressed or anxious. And then the third domain was cognition, how they think about their pain. There are 2 particular cognitive patterns that are known to be very negative in pain.
    One is catastrophizing, which means that people have a very negative, pessimistic view of what their pain is and what it’s doing to them. The other is an external locus of control, which basically means that people feel as though they can’t do anything about their pain, so they can’t control their pain. This study that I referred to earlier looked at 97 patients that we had been seeing at Georgetown, and 50 of them fell into the group we refer to as primary-care fibromyalgia patients.11 These people all met ACR criteria for fibromyalgia, but this subgroup was not depressed,
    they weren’t anxious, they weren’t very tender. They had enough tender points to meet the ACR criteria, but they weren’t very tender using more sophisticated measures of pressure pain threshold. And they didn’t have any negative cognitive factors, in that they didn’t catastrophize, and had a moderate sense that they could control their pain. So in these people, they didn’t have psychologic factors that seemed to be driving their pain to be
    worse, yet they had fibromyalgia. These people likely do fairly well with the kinds of treatments that we now recommend giving people with fibromyalgia.

    At the beginning of this talk, I usually ask people to remember a
    fibromyalgia patient, and when I get to this point of the talk, I say that that fibromyalgia patient that you remembered is in the second subgroup, that we refer to as tertiary care fibromyalgia patients. You, as a rheumatologist, are not well equipped to make this person better, because what’s going on in their spinal cord and brain with respect to their pain processing is the least of their problems. In addition to being tender, they’re depressed, anxious, they catastrophize, they have no sense they can control their pain. These are people that have very prominent psychological
    factors above and beyond what might be contributing to their tenderness. These are people that even the best multidisciplinary pain programs have difficulty making better, and they certainly are not going to get better by just giving them a drug that somehow modifies pain processing in the brain or spinal cord. It is naive to think that you’re going to make this kind of person better by just giving them a drug, because superimposed on a central nervous system problem with pain processing, these individuals have had
    significant social, cognitive, behavioral, and psychologic consequences of years or decades of untreated pain and other somatic symptoms.

    The third subgroup that we identified in this study was very interesting. This group was the most tender of the three, suggesting that there was something quite wrong with how they processed pain. But despite this, these people were not anxious, they weren’t depressed, they weren’t catastrophizing. They actually had a moderate sense they could do something about their pain. These are individuals in whom psychologic resiliency seems to be buffering them against the neurobiological effects of fibromyalgia. In spite of what’s going on in their brain and their spinal cord that is increasing their volume control setting and moving them to the
    right side of the bell-shaped curve, somehow they’re coping and they’re dealing with this condition much better than the other 2 groups. Several groups are now exploring whether it is possible to instill this resiliency into chronic pain patients. This is a relatively new thing in psychology; psychologists until recently focused on psychopathology, on anxiety, on depression, on the bad things that happen in psychology.

    I’ve noted several times that the fundamental problem with this spectrum of illness is in pain processing or sensory processing. One of the things that you should be aware of is that in fibromyalgia, as well as in IBS and most of the other conditions in this spectrum, it is not just painful stimuli to which these people are more sensitive. They are more sensitive to auditory loudness, bright lights, odors, and other sensory stimuli. In fact, accounts for the overlap between multiple chemical sensitivity (which is a
    misnomer) and fibromyalgia. Thus, it is appearing that this is not multiple chemical sensitivity; it is really multiple sensory sensitivity. People are just sensitive to a lot of different sensory stimuli.

    Back to talking about the sensation of pain, there are a number of
    different ways that people can theoretically move to the right end of this bell-shaped curve, and have an increased volume control in pain processing. Some of these mechanisms by which this occur involve peripheral nerves, whereas others are central mechanisms, involving the brain or spinal cord.
    One of the primary problems in fibromyalgia patients appears to be not that there is too much input coming from the pressure nociceptors or the thermal nociceptors, but rather that there is inadequate filtering of that activity, perhaps because of decreased activity of descending antinociceptive pathways.12,13 These pathways begin in the brain and brainstem and descend into the dorsal horn of the spinal cord and are normally responsible for inhibiting the upward transmission of pain. It appears that these pathways are not working properly in individuals withfibromyalgia. So a lot of nociceptive information that may be filtered out
    in normal individuals may not be filtered out in fibromyalgia patients.

    In addition to these studies that have used experimental pain testing to elucidate some of the underlying mechanisms in fibromyalgia, one of the other tools that you can use to look at pain processing in conditions like fibromyalgia is functional imaging. Our group, led by Rick Gracely, has performed many functional imaging studies in fibromyalgia. One of the big advantages of using functional brain imaging is that, because of animal and then later human studies that have been going on for the past 3 decades, we
    now know the regions of the brain that are involved in pain processing.
    Thus, we can give people painful stimuli under different conditions and image the neuronal activation patterns to infer how pain processing is different in fibromyalgia patients and controls. The areas of the brain that are involved in the sensory dimension of pain, which is basically where the pain located, and how much it hurts, are the primary and secondary somatosensory cortex and thalamus.

    There are other regions of the brain that are more involved in the
    affective dimension of pain or the emotional valance of pain, or in how they think about their pain, and these include regions such as the insula, anterior cingulated, amygdale, and prefrontal cortex. In the first study that used functional MRI to study pain processing in fibromyalgia, we gave fibromyalgia patients a 2.5 kg stimulus to their thumb and asked them how much it hurt on a 0 to 20 visual analog pain scale. We knew that they would experience moderate pain at the same level of pressure that nonfibromyalgia patients, healthy controls, experienced no pain. So we put the fibromyalgia
    patients in the scanner and gave them the low amount of pressure, which in them led to moderate pain, and then gave a group of healthy controls the same amount of pressure (which they rated as barely painful), and then the same amount of pain (by giving them twice as much pressure).

    The hypothesis was very simple. If we saw similar neuronal activation patterns in fibromyalgia patients getting the low pressure (which they felt as moderately painful), and the controls getting the same amount of pressure (which they barely felt), then that would indicate that fibromyalgia is some type of a perceptual problem, because although the fibromyalgia patients were having the same brain activation patterns, they were perceiving it differently. In contrast, we saw that the fibromyalgia patient’s brain activation patterns were very similar with 2.5 kg of pressure as the controls getting 4.5 kg of pressure. This was the first objective evidence that there is augmented central pain processing in
    people with fibromyalgia.14 We published another functional MRI study a couple of years ago that showed that the level of depression that a fibromyalgia patient has doesn’t at all influence the level of pain in the sensory areas of the brain.15 That suggests that depression and pain, when they are present simultaneously, are really somewhat independent constructs. We also have seen evidence of this in the clinical trials of drugs that are mixed reuptake inhibitors or tricyclics in that whether someone is depressed or not doesn’t predict at all whether they’re going to
    respond to one of these drugs as an analgesic.16

    In contrast, how people think about their pain might actually influence the sensory processing of pain. In another fMRI study, we showed that fibromyalgia patients that catastrophize actually have augmented neuronal activation in the secondary somatosensory cortex.17 Dave Williams in our group is just finishing a NIH-funded study that does functional imaging at
    baseline in fibromyalgia patients who have an external locus of pain control and then gives them several brief interventions to increase their locus of control. We hypothesize that changing patient’s cognitions (in this case locus of pain control) will change the processing of pain in the brain, even in brain regions thought to be involved in the sensory processing of pain. Finally, we performed another fMRI study showing that individuals with chronic idiopathic low back pain (low back pain with normal lumbar MRIs) were indistinguishable from fibromyalgia patients with
    respect to their pain sensitivity at their thumbnail and with respect to their functional MRI findings.18 In aggregate, these and many other studies in this spectrum of illness suggest that there is neurobiological evidence of augmented central pain processing, and that in this setting, individuals can experience pain even without appropriate peripheral nociceptive input.


    Now that I have outlined some of the underlying mechanisms in fibromyalgia and related conditions, I’ll finish by discussing treatment. Clinical-based evidence advocates a multifaceted program emphasizing education, certain medications, exercise, and cognitive therapy.19 However, the overwhelming majority of fibromyalgia patients are not being appropriately treated at
    present. Market surveys suggest that the no. 1 class of drugs currently used to treat fibromyalgia in the United States is NSAIDs, whereas opioids are no. 3 or 4, even though there is no evidence that either of these classes of drugs works in fibromyalgia. Moreover, most fibromyalgia
    patients are not being adequate education about their disease, nor are they given access to exercise and cognitive behavioral therapy programs. So it should not be surprising that these patients are frustrated and trying to prove that they really have something wrong with them when they come in to see us.


    Once a physician rules out other potential disorders, an important and at times controversial step in the management of fibromyalgia is making the diagnosis. Despite some assumptions that being labeled with fibromyalgia may adversely affect patients, a study by White et al. indicated that patients had significant improvement in health satisfaction and symptoms after being given this label.20 Nonetheless, in certain selected individuals, i.e., adolescents, or individuals who may use the label as an excuse for maladaptive illness behavior, I prefer not to use this label but instead recommend the same type of treatment I would for a fibromyalgia
    patient. Regardless of the label used or not used, although the diagnosis of this condition should be coupled with patient education, an intervention shown to be effective in many randomized controlled trials.


    The most frequently studied pharmacological therapy for fibromyalgia is low doses of tricyclic compounds. Most tricyclic antidepressants (TCAs) increase the concentrations of serotonin and/or norepinephrine by directly blocking their respective reuptake. Despite tolerability issues, the use of TCAs (particularly amitriptyline and the biologically similar cyclobenzaprine) to treat the symptoms of pain, poor sleep, and fatigue associated with fibromyalgia is supported by several randomized, controlled
    trials.21 The tolerability of TCAs can be improved by beginning at very low doses (e.g., 5 to 10 mg of the above compounds), giving the dose a few hours before bedtime, and very slowly escalating the dose.

    Because of a better side-effect profile, newer antidepressants, i.e.,
    selective serotonin reuptake inhibitors (SSRIs), are frequently used in fibromyalgia. The SSRIs fluoxetine, citalopram, and paroxetine have each been evaluated in randomized, placebo controlled trials in fibromyalgia, and in general, the less selective drugs are effective at high doses. The newer highly selective serotonin reuptake inhibitors, e.g., citalopram, seem to be less efficacious than the older SSRIs in both animal and human
    studies, perhaps because these latter compounds have noradrenergic activity at higher doses.22

    Because TCAs (and high doses of certain SSRIs such as fluoxetine and sertraline) that have the most balanced reuptake inhibition are the most effective analgesics, many in the pain field have concluded that dual receptor inhibitors [serotonin-norepinephrine and norepinephrine-serotonin reuptake inhibitors (SNRIs and NSRIs)] may be of more benefit than pure serotonergic drugs. These drugs are pharmacologically similar to some TCAs
    in their ability to inhibit the reuptake of both serotonin and
    norepinephrine, but differ from TCAs in being generally devoid of
    significant activity at other receptor systems. This selectivity results in diminished side effects and enhanced tolerability. The first available SNRI, venlafaxine, has data to support its use in the management of neuropathic pain, and retrospective trial data demonstrate that this compound is also effective in the prophylaxis of migraine and tension headaches. Two studies in fibromyalgia have had conflicting results, with the one using a higher dose showing efficacy.

    Two new SNRIs, milnacipran and duloxetine, have undergone recent multicenter trials.16,23 In the phase II trial evaluating milnacipran, statistically significant positive differences were noted in overall improvement, physical functioning, level of fatigue, and degree of reported physical impairment. In the trial of duloxetine when compared with placebo, participants treated with duloxetine had decreased self-reported pain and stiffness and a reduced number of tender points. In the 2 above studies as well as most studies that have used antidepressants as analgesics, the
    benefits on pain and other symptoms were independent of the drug effect on mood, thus suggesting that the analgesic and other positive effects of this class of drugs in fibromyalgia is not simply because of their antidepressant effects.

    Antiepileptic drugs are widely used in the treatment of various chronic pain conditions including postherpetic neuralgia and painful diabetic neuropathy. Pregabalin is a ?-aminobutyric acid (GABA) analog and approved for the treatment of neuropathic pain. A recent randomized, double-blinded, placebo-controlled trial demonstrated efficacy of pregabalin against pain, sleep disturbances, and fatigue in fibromyalgia.24 Similar results have
    also been recently noted with gabapentin, a compound with similar
    pharmacology to pregabalin.

    Sedative-hypnotic compounds are widely used by fibromyalgia patients. A handful of studies have been published on the use of certain nonbenzodiazepine hypnotics in fibromyalgia, such as zopiclone and zolpidem. These reports have suggested that these agents can improve the sleep and, perhaps, fatigue of fibromyalgia patients, though they had no significant effects upon pain. On the other hand, ?-hydroxybutyrate (also known as sodium oxabate), a precursor of GABA with powerful sedative properties, was recently shown to be useful in improving fatigue, pain, and sleep architecture in patients with fibromyalgia.25 Note, however, that
    this agent is a scheduled substance due to its abuse potential. Pramipexole is a dopamine agonist indicated for Parkinson disease that has shown utility in the treatment of periodic leg movement disorder, and a recent study suggests that this compound may improve both pain and sleep in fibromyalgia patients.26 Tizanidine is a centrally acting a2-adrenergic agonist approved by the FDA for the treatment of muscle spasticity associated with multiple sclerosis and stroke, and a recent trial reported significant improvements in several parameters in fibromyalgia, including
    sleep, pain, and measures of quality of life.27

    There have been no adequate, randomized controlled clinical trials of opiates in fibromyalgia, and many in the field (including myself) have not found this class of compounds to be effective in anecdotal experience. Tramadol is a compound that has some opioid activity (weak mu agonist activity) combined with serotonin/norepinephrine reuptake inhibition. This compound does appear to be somewhat efficacious in the management of fibromyalgia, as both an isolated compound and as fixed-dose combination with acetaminophen.28 Nonsteroidal anti-inflammatory drugs (NSAIDs)and acetaminophen are used by a large number of fibromyalgia patients. Although numerous studies have failed to confirm their effectiveness as analgesics in fibromyalgia, there is limited evidence that patients may experience enhanced analgesia when treated with combinations of NSAIDs and other agents. This phenomenon may be a result of concurrent peripheral pain
    conditions (i.e., osteoarthritis, tendonitis), which may be present in some individuals, and/or that these comorbid peripheral pain generators might lead to central sensitization and worsening of central pain.


    The 2 best-studied nonpharmacological therapies are cognitive behavioral therapy and exercise. Both of these therapies have been shown to be efficacious in the treatment of fibromyalgia, as well as a plethora of other medical conditions.29 Both of these treatments can lead to sustained (e.g., greater than 1 year) improvements and are very effective when an individual complies with therapy.

    Alternative therapies have been explored by patients managing their own illness, as well as health care providers. As with other diseases, there are few controlled trials to advocate their general use. Trigger-point injections, chiropractic manipulation, acupuncture, and myofascial release therapy are among the more commonly used modalities, which achieve varying levels of success. Two recent randomized, sham-controlled trial of
    acupuncture in fibromyalgia showed no difference between the efficacy in active treatment and sham groups.30,31 There is some evidence that the use of alternative therapies give patients a greater sense of control over their illness. In instances where this sense of control is accompanied by an improved clinical state, the decision to use these therapies is between physicians and patients themselves.


    Chronic pain and fatigue syndromes such as fibromyalgia represent a part of a clinical spectrum of overlapping disorders that afflict a significant portion of the general proportion. Data suggest that there is a familial tendency to develop these disorders, and that exposure to physical, emotional, or environmental stressors’ may trigger the initiation of symptoms. Once the illness develops, the majority of the symptoms are likely mediated by central nervous system mechanisms.

    Management strategies are similar to other chronic illnesses, where empathetic health care providers should develop a partnership with their patients. At one end of the continuum, there are some individuals with fibromyalgia that respond to a single medication or a graded, low-impact exercise program. At the other end of the continuum is the tertiary care patient with high levels of distress who has no sense of control of their illness, little social support, and has looked toward disability and compensation systems to try to solve their problem. For this individual,
    and many in between, multimodal programs that integrate nonpharmacological (especially exercise, CBT) and pharmacological therapies are required.


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    © 2007 Lippincott Williams & Wilkins, Inc.

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