Fibromyalgia: A Discrete Disease or the End of the Continuum

Daniel J. Clauw

Chad Brummett

Clinical practitioners commonly see patients with pain and other somatic symptoms that they cannot adequately explain based on the degree of damage or inflammation noted in peripheral tissues. In fact, this may be among the most common predicament for which patients seek medical attention.¹ Typically, an evaluation is performed looking for a “cause” for the pain. If none is found, these individuals are often given a diagnostic label that merely connotes that the patient has chronic pain in a region of the body, without an underlying mechanistic cause (e.g., chronic low back pain, headache, temporomandibular disorder [TMD]). In other cases, the label given alludes to an underlying mechanism that may or may not be responsible for the individual’s pain (e.g., “knee osteoarthritis”).

Fibromyalgia is merely the current term for individuals with chronic widespread musculoskeletal pain, for which no alternative cause can be identified. Gastroenterologists often see the exact same patients and focus on their gastroenterologic complaints and often use the terms functional gastrointestinal disorder, irritable bowel syndrome (IBS), nonulcer dyspepsia, noncardiac chest pain, or esophageal dysmotility to explain the patient’s symptoms.² Neurologists see these patients for their headaches and/or unexplained facial pain; urologists for pelvic pain and urinary symptoms (and use labels such as interstitial cystitis, chronic prostatitis, vulvodynia, and vulvar vestibulitis); dentists for TMD, and so on.³

Until recently, these unexplained pain syndromes perplexed researchers, clinicians, and patients. However, it is now clear that

Individuals will sometimes only have one of these “idiopathic” pain syndromes over the course of their lifetime. But more often, individuals with one of these entities, and their family members, are likely to have several of these conditions.⁴^,⁵ Many terms have been used to describe these coaggregating syndromes and symptoms, including functional somatic syndromes, somatization disorders, allied spectrum conditions, sensory sensitivity syndromes, chronic multisymptom illnesses, and medically unexplained symptoms. The most recent term coined by the National Institutes of Health in the United States is probably the best accepted at present: “chronic overlapping pain conditions” (COPCs).⁶^,⁷
Women are more likely to have these disorders than men, but the sex difference is much more apparent in clinical cohorts (especially tertiary care) when compared to population-based samples.⁸^,⁹
Groups of individuals with these conditions (e.g., fibromyalgia, IBS, headache, TMD) typically display diffuse hyperalgesia (increased pain to normally painful stimuli) and/or allodynia (pain to normally nonpainful stimuli) that is identifiable both via quantitative sensory testing and functional neuroimaging.¹⁰^,¹¹^,¹² In addition, a number of other central nervous system (CNS) mechanisms are reproducibly seen in these conditions. This suggests that these individuals have a fundamental problem with augmented pain and/or sensory processing rather than simply a nociceptive focus confined to the region of the body where the person is currently experiencing pain.
Similar types of therapies are efficacious for all of these conditions, including both pharmacologic (e.g., tricyclic compounds, serotonin norepinephrine reuptake inhibitors [SNRIs] and gabapentinoids) and nonpharmacologic treatments (e.g., education, exercise, cognitive-behavioral therapy). Conversely, individuals with these conditions typically do not respond to therapies that are typically more effective when pain is due to damage or inflammation of tissues (e.g., nonsteroidal anti-inflammatory drugs [NSAIDs], opioids, injections, surgical procedures).
Subsets of individuals with any chronic pain condition (e.g., low back pain, osteoarthritis, autoimmune disorders, sickle cell disease) also have the same phenotypic features and underlying mechanisms as those seen in fibromyalgia.³^,¹³ These individuals with subthreshold fibromyalgia display the same pathologic features and differential responsiveness to peripherally directed versus centrally directed therapies. Thus, it is critical that clinicians seeing patients with chronic pain evaluate individuals for the presence of this phenotype as it can dramatically affect which treatments will work, or not work, for a given individual with chronic pain.

Until perhaps a decade ago, these conditions were all on somewhat equal (and tenuous) scientific ground. But within a relatively short period of time, research methods such as experimental pain testing, functional imaging, and genetics have led to tremendous advances in the understanding of several of these conditions, most notably fibromyalgia, IBS, and TMD. Many in the pain field now feel that much chronic pain itself is a neural disease and that many of the underlying mechanisms operative in these heretofore considered “idiopathic” or “functional” pain syndromes may be similar no matter whether that pain is present throughout the body (e.g., in fibromyalgia) or localized to the low back, the bowel, or the bladder. Because of this, the more contemporary terms used to describe conditions such as fibromyalgia, IBS, TMD, vulvodynia, and many other entities include “centralized pain” or “central sensitization” to imply that the CNS is playing a prominent role in amplifying or causing the pain in most individuals with these syndromes.³^,¹⁴ This review of fibromyalgia in the following discussion focuses on our current understanding of this disorder as the prototypical “centralized pain syndromes.”

Historical Perspective

Although the term fibromyalgia is relatively new, this condition has been described in the medical literature since the early 1900s. Sir William Gowers coined the term “fibrositis” in 1904. During the next half century, fibrositis (as it was then called) was considered by some to be a common cause of muscular pain, by others to be a manifestation of “tension” or “psychogenic rheumatism,” and by the rheumatology community in general to be a nonentity.

The current concept of fibromyalgia was established by Smythe and Moldofsky¹⁵ in the mid-1970s. The name change reflected the fact that there was increasing evidence that there was no –itis (inflammation) in the connective tissues of
individuals with this condition but instead –algia (pain). These authors characterized the most common tender points (regions of extreme tenderness in these individuals) and reported that patients with fibromyalgia had disturbances in deep and restorative sleep and that selective stage 4 interruptions induced the symptoms of fibromyalgia.¹⁶ Yunus and colleagues¹⁷ then reported on the major clinical manifestations of patients with fibromyalgia seen in rheumatology clinics.

The next advance in fibromyalgia was the development of the American College of Rheumatology (ACR) criteria for fibromyalgia, which were published in 1990.¹⁸ These classification criteria required that an individual have both a history of chronic widespread pain (CWP) and the finding of ≥11 of a possible 18 tender points on examination. These ACR classification criteria were intended for research use to standardize definitions of fibromyalgia. In this regard, the criteria have been extremely valuable. Unfortunately, many practitioners use these criteria in routine clinical practice to diagnose individual patients, and this unintended use led to many of the current misconceptions regarding fibromyalgia that are discussed in the following text. New criteria that eliminate the need for the tender point exam were developed in 2010 and refined in 2011 and in 2016.¹⁹^,²⁰^,²¹ These criteria focus on identifying the cardinal symptoms seen in this condition including widespread pain, fatigue, sleep, memory, and mood disturbances.

Once structural damage to tissues or inflammation had been excluded as pathogenic factors in fibromyalgia, many groups of investigators began to explore neural mechanisms to explain the underlying pathogenesis of these disorders.²²^,²³ Fortuitously, newer neuroscience research techniques such as functional, chemical, and structural brain imaging were all becoming available tools to examine the CNS, in both healthy individuals and those with chronic pain.

Thus, the conditions we now mechanistically understand best within this spectrum include conditions where these central factors were first studied, including fibromyalgia, IBS (previously termed spastic colitis until the recognition that there was little -itis and that motility changes were not the major pathologic feature), and TMD (previously termed temporomandibular joint syndrome until it was recognized the problem was not largely within the joint²⁴^,²⁵^,²⁶^,²⁷) and urinary chronic pelvic pain syndromes (where again, the condition previously called interstitial cystitis is now called bladder pain syndrome²⁸^,²⁹^,³⁰^,³¹). This is not to say peripheral factors, or lowgrade inflammation that is not identifiable clinically, do not play some role in these entities. But it is relevant that clinicians who care for individuals with these conditions, and who are quite adept at identifying (with blood tests, imaging, or endoscopy) peripheral damage or inflammation, have generally concluded that these are not inflammatory or peripheral-based disorders.

Epidemiology

CHRONIC WIDESPREAD PAIN

Epidemiologic studies of the historical component of the ACR criteria for fibromyalgia, CWP, have been extremely instructive. CWP is typically operationalized as pain above and below the waist, involving the left and right sides of the body and also involving the axial skeleton. Population-based studies of CWP suggest that roughly 6% to 12% of the population has these features at any given point in time.³²^,³³ Chronic regional pain is found in 20% to 25% of the population. Both chronic widespread and regional pain occur about 1.5 times as commonly in women than men. These findings are very similar in different countries, ethnicities, and cultures, dispelling an early notion that this problem was somewhat unique to more developed countries.

FIBROMYALGIA

The original 1990 ACR criteria for fibromyalgia required that an individual has both a history of CWP and the finding of 11 or greater of 18 possible tender points on examination. Tender points represent nine paired predefined regions of the body, often over musculotendinous insertions.¹⁸ If an individual reports pain when a region is palpated with 4 kg of pressure, this is considered a positive tender point. Between 25% and 50% of individuals who have CWP will also have 11 or greater tender points and thus meet the 1990 criteria for fibromyalgia.³⁴ Just as with CWP, the prevalence of fibromyalgia is just as high in rural or nonindustrialized societies as it is in countries such as the United States.³⁵

SIGNIFICANCE OF TENDER POINTS

When the 1990 ACR criteria were published, it was thought that there may be some unique significance to the locations of tender points. In fact, a term “control points” was coined to describe areas of the body that should not be tender in fibromyalgia, and individuals were assumed to have a psychological cause for their pain is they were tender in these regions. Since then, we have learned that the tenderness in fibromyalgia extends throughout the entire body. Thus, relative to the pain threshold that a normal nonfibromyalgia patient would experience at the same points, “control” regions of the body such as the thumbnail and forehead are just as tender as in fibromyalgia tender points.³⁶

The tender point requirement in the ACR criteria not only misrepresents the nature of the tenderness in this condition (i.e., local rather than widespread) but also strongly influences the demographic and psychological characteristics of fibromyalgia. Women are only 1.5 times more likely than men to experience CWP but are 11 times more likely than men to have 11 or more tender points.³⁷ Because of this, women are approximately 10 times as likely to meet the 1990 ACR criteria for fibromyalgia than men. Yet, most of the men in the population who have CWP but are not tender enough to meet criteria for fibromyalgia likely have the same fundamental underlying pathophysiologic problems as the women who meet the ACR criteria for fibromyalgia.

Another unintended consequence of requiring both CWP and at least 11 tender points to be diagnosed with fibromyalgia is that many individuals with fibromyalgia will have high levels of distress. Wolfe³⁸ has described tender points as a “sedimentation rate for distress” because of population-based studies showing that tender points are more common in distressed individuals. Until recently, many assumed that because tender points were associated with distress, that tenderness (an individual’s sensitivity to mechanical pressure) was associated with distress. However, recent evidence suggests that this latter association is probably due to the standard tender point technique, which consists of applying steadily increasing pressure until reaching 4 kg. In this situation, individuals who are anxious or “expectant” have a tendency to “bail out” and report tenderness. Recently, more sophisticated measures of tenderness have been developed which give stimuli in a random, unpredictable fashion, and the results of these tests are independent of psychological status.³⁹^,⁴⁰ Because tender points are associated with high levels of distress, requiring 11 or greater tender points in order to diagnose someone with CWP with fibromyalgia dramatically increases the likelihood that these individuals will be female and/or and distressed, compared to individuals with CWP and <11 tender points. In fact, population-based studies suggest that the primary symptom of fibromyalgia, CWP, is only modestly associated with distress, and distress is only weakly associated with the subsequent development of CWP.⁴¹^,⁴² There are far more psychologically “normal” individuals who develop CWP than distressed or depressed people
who do, and most individuals with CWP do not have or subsequently develop distress or depression.

In summary, although many clinicians uniquely associate fibromyalgia with women who display high levels of distress, much of this is an artifact of (1) the 1990 ACR criteria that require 11 tender points and (2) the fact that most studies of fibromyalgia have originated from clinical samples from tertiary care centers, where health care seeking behaviors lead to the fact that psychological and psychiatric comorbidities are much higher.⁹ When all these biases are eliminated by examining CWP in population-based studies, a clearer picture of fibromyalgia can be gleamed, and CWP becomes much like chronic pain in any other region of the body.

OTHER FEATURES OF FIBROMYALGIA GLEANED FROM EPIDEMIOLOGIC OR OBSERVATIONAL STUDIES

Individuals who develop fibromyalgia nearly always have a lifelong history of chronic pain in various regions of the body as well as other CNS symptoms such as fatigue, sleep, memory, and mood difficulties. Most individuals who eventually develop fibromyalgia begin having pain in multiple body regions beginning earlier in life. The prevalence of any (regional or widespread) chronic musculoskeletal pain in the population is about 30%, so if a single individual has had chronic pain in multiple bodily regions early in his or her lifetime and he or she does not have an autoimmune or other disorder leading to widespread inflammation or damage, he or she is likely exhibiting a “chronic pain prone phenotype.” Often beginning in childhood or adolescence, individuals who eventually go on to develop fibromyalgia are more likely to experience headaches, dysmenorrhea, TMD, chronic fatigue, IBS and other functional gastrointestinal disorders, interstitial cystitis/painful bladder syndrome, endometriosis, and other regional pain syndromes (especially back and neck pain).⁴³^,⁴⁴ In fact, what often looks to one health care provider as a new episode of acute or subacute pain is in fact simply the latest region of the body experiencing pain.⁴⁵ Because of this, many experts in the pain field have begun to feel that especially these “centralized” pain states are best thought of as a single lifelong disease that merely tends to manifest in different bodily regions over time.¹⁴^,⁴⁶^,⁴⁷

In addition to fibromyalgia patients having a high personal lifetime history of chronic pain, there is often a strong family history of chronic pain identifiable. The first-degree relatives of fibromyalgia patients are 8 times as likely to have this condition as the family members of controls and also have very high rates of other chronic pain states.⁵ These studies also show that family members of individuals with fibromyalgia are much more tender than the family members of controls, regardless of whether they have pain or not. Family members of fibromyalgia patients are also much more likely to have IBS, TMD, headaches, and a host of other regional pain syndromes.⁴^,⁴⁸^,⁴⁹ This familial and personal coaggregation of conditions which includes fibromyalgia was originally collectively termed affective spectrum disorder⁵⁰ and more recently central sensitivity syndromes,⁵¹ chronic multisymptom illnesses,⁵¹ and chronic overlapping pain conditions. In population-based studies, the key symptoms besides pain that typically coaggregate together are fatigue, memory difficulties, and mood disturbances.⁷^,⁵² Twin studies suggest that approximately 50% of the risk of developing fibromyalgia or related pain conditions such as IBS and headache is genetic, and 50% environmental.⁵³ The strong familial predisposition to fibromyalgia is shared by many chronic pain conditions, and there has been an explosion of knowledge recently regarding the role of specific genetic factors in chronic pain states, which is partially reviewed in the following text.¹⁴^,⁵⁴

The environmental factors that are most likely to trigger the development of fibromyalgia are various types of “stressors,” typically that involve acute pain for at least a few weeks. (Table 36.1). Psychological stress, including childhood trauma, is but one such stressor. Fibromyalgia or similar illnesses are found at much higher than expected rates in individuals who have experienced certain types of infections⁵⁵ (e.g., Epstein-Barr virus, Lyme disease, Q fever, viral hepatitis), trauma⁵⁶ (motor vehicle collisions), and deployment to war.⁵⁷ Of note, each of these stressors only leads to CWP or fibromyalgia in approximately 5% to 10% of individuals who are exposed; the overwhelming majority of individuals who experience these same infections or other stressful events regain their baseline state of health. This is a contentious legal issue, and not all would agree that all of these events can seemingly trigger or exacerbate fibromyalgia.⁵⁸ Certainly assessing “cause and effect” in any given individual is almost impossible because all individuals experience intermittent stressors of the variety that seemingly can trigger fibromyalgia. It is also likely that part of the reasons these different stressors can seemingly lead to worsening of fibromyalgia or fibromyalgia symptoms is because of how these stressors affect activity level, sleep, or overall distress, any of which then can lead to worsening of pain and other symptoms.⁵⁹^,⁶⁰^,⁶¹^,⁶²^,⁶³

TABLE 36.1 “Stressors” Capable of Triggering Fibromyalgia and Related Condition

Ongoing inflammatory or nociceptive pain (e.g., autoimmune disorders, sickle cell disease, Ehlers-Danlos syndrome)
Infections (e.g., parvovirus, EBV, Lyme disease, Q fever; not common upper respiratory infections)
Physical trauma (e.g., automobile accidents)
Psychological stress/distress (e.g., sexual assault, early childhood trauma)
Hormonal alterations (e.g., hypothyroidism)
Drugs
Vaccines
Certain catastrophic events (war but not natural disasters)

EBV, Epstein-Barr virus.

Fibromyalgia also is very commonly seen as a comorbidity in other chronic pain conditions such as osteoarthritis, rheumatoid arthritis (RA), and lupus. The disorder is also associated with other regional pain conditions or autoimmune disorders.⁶⁴^,⁶⁵^,⁶⁶^,⁶⁷ This high rate of fibromyalgia in individuals with other chronic rheumatic or autoimmune disorders deserves special attention because of the relevance to practicing clinicians. As many as 25% of patients correctly diagnosed with generalized inflammatory disorders such as systemic lupus erythematosus (SLE), RA, and ankylosing spondylitis will also fulfill the clinical criteria for fibromyalgia.⁶⁸^,⁶⁹ However, in clinical practice, this coexpression may go unrecognized, especially when the fibromyalgia develops after the autoimmune disorder or regional pain syndrome. In this setting when comorbid fibromyalgia goes unrecognized, patients are often unnecessarily treated more aggressively with toxic immunosuppressive drugs leading to morbidity without the desired therapeutic effects.

This phenomenon had previously been termed secondary fibromyalgia, but because this is so common and might occur in a subset of nearly any chronic pain cohort, a more popular term we prefer to use for this phenomenon is that these individuals have “centralized” their pain. This simply connotes the fact that although peripheral nociceptive input might be responsible some or even much of that individual’s pain, superimposed CNS factors are also likely amplifying pain and leading to other comorbid symptoms such as fatigue, memory problems, and disturbances of sleep and mood.⁷⁰ The term central sensitization is also sometimes used to describe this phenomenon, but many experts feel that this particular term should be reserved for the original spinal mechanism that was identified and called by this name rather than the more general phenomenon we now believe can result via a multitude of different spinal and supraspinal
mechanisms.¹⁴^,⁷¹ Regardless of what term an individual uses to describe this phenomenon, it is becoming increasingly important to identify it because emerging evidence suggests that therapies that work best for peripheral, nociceptive pain (e.g., NSAIDs, opioids, injections, surgical procedures) are less likely to be effective in these individuals.⁷²^,⁷³

FIGURE 36.1 There are (at least) two different forms of fibromyalgia, one (top-down) that occurs most commonly in younger individuals who have many other chronic overlapping pain conditions, and may be a primary brain disorder, and the other (bottom-up) that occurs in many individuals with other nociceptive or neuropathic pain conditions, and may be partially driven by ongoing peripheral nociceptive input (i.e., central sensitization).

Most studies of fibromyalgia to date have excluded individuals with other conditions so nearly all studies to date have examined the pathophysiology of “primary” fibromyalgia. It is not yet clear if there are any key pathophysiologic differences between primary fibromyalgia (fibromyalgia as a stand-alone disorder, or accompanied by other COPCs, e.g., headache, IBS, TMD) and secondary fibromyalgia (i.e., central sensitization; Fig. 36.1). This latter group might be very responsive to peripherally directed therapies, if nociceptive input is driving central sensitization.

Fibromyalgia, especially the “primary” form, is also very comorbid with early life and current stress, and many if not most individuals will have a lifetime history of a psychiatric disorder such as depression or anxiety.⁷⁴ There is typically more psychiatric and psychological comorbidity seen in tertiary care settings or in individuals who are refractory to treatment. This bidirectional relationship between fibromyalgia and psychiatric conditions is likely due in part to the fact that there are common triggers to both sets of conditions (e.g., early life stress or trauma) as well as shared pathophysiology (i.e., most of the same neurotransmitters that affect pain transmission also affect mood, memory, fatigue, sleep). Other potentially modifiable risk factors for developing fibromyalgia include poor sleep, obesity, physical inactivity, and poor job or life satisfaction. Similarly, cognitive factors such as catastrophizing (the feeling that pain is very bad and associated with a poor prognosis for recovery) or fear of movement have been shown to be poor prognostic factors in fibromyalgia and other chronic pain states.

Etiology

ANIMAL MODELS OF FIBROMYALGIA

Although few would purport that there is an animal model that mimics all of the key clinical features of fibromyalgia, animal models can nonetheless be very helpful in understanding the pathogenesis of this condition. This topic has been covered in depth in a recent review.⁷⁵ For example, arguably the biggest controversy in the field of pain is what is the relative contribution of peripheral versus central factors in leading to chronic pain conditions. Some would argue that there must be some type of ongoing peripheral drive or input to cause chronic pain; however, this is almost certainly not the case. Animals develop the critical features of central sensitization or centralization of pain when exposed to swim stress,⁷⁶ neonatal separation from their mothers,⁷⁷ and many other nonpainful stimuli.⁷⁵ Features of central sensitization and animal pain behaviors consistent with diffuse pain are also seen when CNS neurotransmitters are purposefully altered in the direction found in fibromyalgia. For example, chronic reserpine administration which depletes bioamines leads to features consistent with fibromyalgia,⁷⁸^,⁷⁹ as does directly increasing glutamate levels in the insulae.⁸⁰ This latter model of increasing glutamate in the insulae was recently reverse translated to show that the findings of “small fiber neuropathy” could be induced simply by increasing CNS glutamate, as is known to occur in fibromyalgia.

GENETIC FACTORS

The strong familial predisposition to fibromyalgia and other chronic pain conditions has led many to study specific genetic polymorphisms that may be associated with a higher risk of developing fibromyalgia. First, candidate gene studies showed that genetic findings such as the serotonin 5-HT2A receptor polymorphism T/T phenotype, serotonin transporter, dopamine 4 receptor, and catechol-O-methyl transferase (COMT) polymorphisms all were noted in higher frequency in fibromyalgia patients than controls. Some subsequent studies confirmed some of these associations, whereas others did not.⁸¹^,⁸² Subsequent larger genome-wide linkage and candidate gene studies identified other putative targets.⁸³^,⁸⁴ The linkage studies confirmed the strong genetic contribution to fibromyalgia and suggested linkage of fibromyalgia to the chromosome 17p11.2-q11.2 region. The large candidate gene study identified significant differences in allele frequencies between cases and controls were observed for three genes: GABRB3 (rs4906902, p = 3.65 × 10^-6), TAAR1 (rs8192619, p = 1.11 × 10^-5) and GBP1 (rs7911, p = 1.06 × 10^-4). These three genes, and seven other genes with suggestive
evidence for association, were examined in a second, independent cohort of fibromyalgia patients and evidence of association in the replication cohort was observed for TAAR1, RGS4, CNR1, and GRIA4 genes. In light of the fact that classic genetic studies have not yet identified strong, reproducible polymorphisms or haplotypes associated with fibromyalgia, and because there is clear evidence of environmental factors such as stress playing a prominent role in the pathogenesis, other groups have postulated that epigenetic findings might be important in fibromyalgia.⁸⁵ This is a promising area that needs further research.

Many of the genes that have been identified to date in leading to increases or decreases in the frequency of chronic pain states, or of pain sensitivity, are involved in regulating the breakdown or binding of neurotransmitters that generally increase pain sensitivity (e.g., glutamate) or decrease pain sensitivity (serotonin, norepinephrine, γ-aminobutyric acid [GABA]). The fact that pain sensitivity is polygenic and that different individuals develop increased pain sensitivity because of imbalances or altered activity of many different neurotransmitters likely partly explains the “U-shaped curve” seen with many analgesics, wherein they either work fairly well or not at all.

EVIDENCE OF CENTRAL NERVOUS SYSTEM DISTURBANCES IN PAIN AND SENSORY PROCESSING

The physiologic hallmark of fibromyalgia, centralized pain, or central sensitization is augmented CNS pain processing. This was originally identified in fibromyalgia (and still can be clinically) by noting that an individual is diffusely tender to palpation. The scientific terms for this phenomenon are diffuse hyperalgesia (increased pain to normally painful stimuli) and/or allodynia (pain in response to normally nonpainful stimuli). In the absence of an identifiable diffuse “peripheral” inflammatory process involving the body tissues, this strongly suggests that the CNS (i.e., spinal cord and brain) is causing augmented pain processing. In 1990, when the original criteria for fibromyalgia were first published, this feature of diffuse tenderness was incorporated into the diagnostic criteria by requiring that an individual had a certain number of tender points (11 or greater) in addition to CWP order to qualify for this diagnosis.¹⁸ Subsequent studies using more sophisticated measures of experimental pain testing showed that individuals with fibromyalgia are more tender everywhere in the body, not just in the 18 regions considered to be “tender points.”⁸⁶^,⁸⁷ Subsequent experimental pain testing studies have identified multiple potential mechanisms that may be responsible for pain amplification in fibromyalgia, including a decrease in the activity of descending analgesic pathways.⁸⁸^,⁸⁹

EVIDENCE OF A GLOBAL INCREASE IN SENSORY PROCESSING OF NONPAINFUL STIMULI

Individuals with fibromyalgia do not just display disturbances in pain processing, they also as display heightened sensitivity to any type of sensory stimuli (e.g., auditory, visual, olfactory). Gerster and colleagues⁹⁰ were the first to demonstrate that fibromyalgia patients display a low noxious threshold to auditory tones, and this finding was subsequently replicated.⁹¹ However, both of these studies used ascending measures of auditory threshold, so these findings could theoretically be due to expectancy or hypervigilance. A study by Geisser and colleagues⁹² used an identical random staircase paradigm to test fibromyalgia patients’ threshold to the loudness of auditory tones and to pressure. This study found that fibromyalgia patients displayed low thresholds to both types of stimuli, and the correlation between the results of auditory and pressure pain threshold testing suggested that some of this was due to shared variance, and some unique to one stimulus or the other. The notion that fibromyalgia and related syndromes might represent biologic amplification of all sensory stimuli has significant support from functional imaging studies that suggest that the insula is the most consistently hyperactive region (see following text). This region has been noted to play a critical role in sensory integration, with the posterior insula serving a purer sensory role, and the anterior insula being associated with the emotional processing of sensations.⁹³^,⁹⁴^,⁹⁵^,⁹⁶ This finding also strongly supports a crucial role of the CNS in the pathogenesis of fibromyalgia because the changes in pain processing that have been identified could theoretically be due to a diffuse, systemic process involving peripheral nociception. It is difficult to imagine what type of peripheral process could lead to aberrant processing of any type of sensory stimuli.

BRAIN IMAGING STUDIES

These initial observations that individuals with fibromyalgia were diffusely tender led to subsequent functional, chemical, and structural brain neuroimaging studies that have been among the best “objective” evidence that the pain in fibromyalgia and related pain amplification syndrome is “real.”¹⁰ These methods such as functional magnetic resonance imaging (fMRI) clearly demonstrate that when individuals with fibromyalgia are given a mild pressure or heat stimuli that most individuals would feel as “touch” rather than “pain,” they experience pain, and similar brain activation patterns in brain areas involved in pain processing (Fig. 36.2).⁹⁷^,⁹⁸ fMRI has also proved useful in determining how comorbid psychological factors influence pain processing in fibromyalgia. For example, in fibromyalgia patients with variable degrees of comorbid depression, the authors found that the anterior insula and amygdala activations were correlated with depressive symptoms, consistent with these “medial” and prefrontal brain regions being involved with affective or motivational aspects of pain processing (and being more closely related to unpleasantness rather than the sensory intensity of pain).⁹⁹ However, the degree of neuronal activation in more lateral structures generally thought to be associated with the “sensory” processing of pain (i.e., where the pain is localized and how intense it is) were not associated with levels of depressive symptoms, or the presence or absence of major depression, consistent with a plethora of evidence in the pain field that pain and depression are largely independent but overlapping physiologic processes.

A more recent advance in the use of fMRI is to look at the extent brain regions are “connected” to each other, that is, simultaneously activated (or deactivated).¹⁰⁰ The advantage of resting state analysis is that it is a window into brain changes associated with chronic, ongoing spontaneous pain. Studies have shown that individuals with fibromyalgia have increased connectivity between brain regions involved in increasing pain transmission and neural networks not normally involved in pain such as the default mode network, and the degree of this hyperconnectedness is related to the severity of ongoing pain.¹⁰¹^,¹⁰² A different group has shown that during a painful stimulus, connectivity is decreased between key antinociceptive regions (e.g., the brainstem—the origin of descending analgesic pathways) and a region they had previously identified to be a potential source of dysfunctional pain inhibition in fibromyalgia.¹⁰³^,¹⁰⁴ Lopez-Sola et al.¹²^,¹⁰⁵ have performed imaging studies confirming quantitative sensory testing (QST) studies that these individuals are more sensitive to a number of nonpainful sensory stimuli other than pain (e.g., auditory, visual) and that machine learning paradigms can accurately distinguish fibromyalgia from nonfibromyalgia patients with over 90% accuracy using these results. Similarly, Harte et al.¹⁰⁶ used fMRI to show that an aversive visual stimulus caused greater evoked insula activity in fibromyalgia patients when compared to a control population and that this stimulus (as well as painful stimuli) was significantly attenuated by pregabalin.

Other imaging techniques have been used to identify the neurotransmitter abnormalities that may be driving the pain amplification seen in fibromyalgia and other chronic pain disorders. Wood and colleagues¹⁰⁷ used positron emission
tomography (PET) to show that attenuated dopaminergic activity may be playing a role in pain transmission in fibromyalgia, whereas Harris and colleagues¹⁰⁸ showed evidence of decreased µ-opioid receptor availability (possibly due to increased release of endogenous µ-opioids) in fibromyalgia. This latter finding as well as previous studies showing increases in endogenous opioids in the cerebrospinal fluid (CSF) of fibromyalgia patients¹⁰⁹ has been suggested as evidence of why opioid analgesics appear to have poor efficacy in fibromyalgia.

FIGURE 36.2 In top left panel, individuals with fibromyalgia (red) given a low-pressure stimulus have similar levels of pain and of neuronal activation in areas of the brain known to be involved in pain processing (ends of arrows) as controls given nearly twice as much pressure. Controls given the same low pressure that causes pain in fibromyalgia rate their pain as 2/20 instead of 12/20 and have no neuronal activation with this amount of pressure. IPL, inferior parietal lobule; SI, primary somatosensory cortex; SII, secondary somatosensory cortex; STG, superior temporal gyri. (Gracely RH, Petzke F, Wolf JM, et al. Functional magnetic resonance imaging evidence of augmented pain processing in fibromyalgia. Arthritis Rheum 2002;46[5]:1333-1343.)

Other groups have used proton magnetic resonance spectroscopy (H-MRS) to probe other neurotransmitters. Several groups have shown there are increases in brain concentrations of the body’s major excitatory neurotransmitter, glutamate, in pain processing regions such as the insula in fibromyalgia.¹¹⁰ This finding has also been noted in the CSF in fibromyalgia.¹¹¹ Drugs such as pregabalin and gabapentin are likely working in part in fibromyalgia by reducing glutamatergic activity.¹¹² This has been nicely demonstrated by Harris and colleagues¹¹ who showed that individuals with fibromyalgia that had the highest pretreatment levels of glutamate in the posterior insula were those most likely to respond to pregabalin. When pregabalin led to improvement in symptoms in these individuals, there was normalization of fMRI and connectivity findings, all suggesting that this neurotransmitter is playing a critical role in the pathogenesis of fibromyalgia in some individuals. An even more important finding from this study was the fact that individuals with fibromyalgia with normal or low baseline levels of glutamate in their posterior insula did not respond to pregabalin, even though this drug further lowered glutamate levels in these individuals as well. This helps us understand why no single class of CNS analgesic is likely to work in every patient with pain of CNS origin.

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