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Brief Highlights of Fibromyalgia Research History

1904

  • A paper describing fibrositis was written by Sir William Gowers.
  • Dr. Ralph Stockman published a paper regarding fibrositis nodules.

1915 – Llewelly and Jones published a book describing fibrositis

1953The Management of Pain by Dr. Jon Bonica was published.

1975 – Harvey Moldofsky, MD, discovered patients deprived of Stage 4 sleep developed tender points in symmetrical locations in the same areas of the body.

1977 – Hugh Smythe, MD, discovered and classified 18 tender points located in specific areas of the body in most of his fibrositis patients.  These tender points are in the same areas as those identified by Dr. Moldofsky in patients with Stage 4 sleep deprivation.

1981 – M. B. Yunus, MD, had a paper entitled, “Primary Fibromyalgia,” published in Semin’s Arthritis and Rheumatism Journal.

1984 – Robert Bennett, MD, “Fibrositis:  Does it exist and can it be treated?”  Journal of Musculoskeletal Medicine.

1987 – Don Goldenberg, MD, “Fibromyalgia syndrome an emerging but controversial condition,” Journal of American Medicine. 

1989 – Harvey Moldofsky, MD, “The relevance of sleep in chronic pain,” Rheumatic Disease Clinics North America.

1990 – Dr. Frederick Wolfe, Hugh Smythe, Muhammad Yunus, Robert Bennett, et al, established the American College of Rheumatology’s Criteria for the Classification of Fibromyalgia.

1992 – Robert Bennett, MD, “Low levels of somatocedin C in patients with fibromyalgia syndrome,” Arthritis and Rheumatism.

1993 – Carol Burckhardt, PhD, “Fibromyalgia and quality of life,” Journal of Rheumatology.

1994

  •  I. Jon Russell, MD, “Elevated cerebrospinal fluid levels of substance P in patients with the fibromyalgia syndrome,” Arthritis and Rheumatism.
  •  Leslie Crofford, MD, “Hypothalamic-pituitary-adrenal axis perturbations in patients with fibromyalgia,” Arthritis and Rheumatism.

1995 – James Mountz, MD, “Fibromyalgia in Women:  Abnormalities in regional cerebral blood flow in the thalamus and the caudate nucleus are associated with low pain threshold levels,” Arthritis and Rheumatism.

1996 – Leslie Crofford, MD, “Evidence for and pathophysiological implications of hypothalamic-pituitary-adrenal axis dysregulation in FM and CFIDS, “ Rheumatic Diseases Clinic of North America.

1997

  • Michael J. Rosner, MD, “Decompression of craniovertebral stenosis leads to improvements in FMS and CFIDS symptoms,” New Dimensions in Fibromyalgia symposium, Portland, OR.
  • Dan Buskila, MD, “Increased Rates of Fibromyalgia following cervical spine injury,” Arthritis and Rheumatism.
  • Dr. Bou-Holaigah, MD, “Provocation of hypotension and pain during upright tilt table testing in adults with fibromyalgia,” Clin. Exp. Rheumatology.

1998

  • Dr. Martin Charf, PhD, “Effect of gammahydroxybutyrate on pain, fatigue and the alpha sleep anomaly in patients with fibromyalgia,” Journal of Rheumatology. 
  • Robert Bennett, MD, “A randomized, double-blind, placebo-controlled study of growth hormone in the treatment of fibromyalgia,” Arthritis and Rheumatism.

1999

  • Robert Bennett, MD, “Emerging concepts in the neurobiology of chronic pain; Evidence of abnormal sensory processing in fibromyalgia,” Mayo Clinic Proceedings.
  • Muhammad Yunus, MD, “Genetic linkage analysis of multicase families with fibromyalgia syndrome,” Journal of Rheumatology.

2001 – Roland Staud, MD, “The effect of maximal exercise on temporal summation of second pain (windup in patients with fibromyalgia syndrome),” Journal of Pain.

2002 – Daniel Clauw, MD, “Functional magnetic resonance imaging evidence of augmented pain processing of fibromyalgia,” Arthritis and Rheumatism.

2004 – Dan Heffez, MD, “Clinical evidence of cervical myelop thy due to Chiari malformation and spinal stenosis in a non-randomized group of patients with the diagnosis of fibromyalgia,” European Spine Journal.

2004 – Present – Fibromyalgia research continues to advance including the development of better medications specifically for the treatment of fibromyalgia in the not too distant future.

Research Overview

There are several categories of medical research: Basic Science, Epidemiological Population-based Research, and Clinical Research. The label “Basic Science” refers to research that seeks to understand the biological under-pinning’s of disorders.  “Epidemiological Research” helps us to understand the incidence and prevalence of a disorder in the population at large or how disorders interact with communities.  Finally, “Clinical Research” refers to the study of patients in a clinical setting (i.e., in the hospital or a health clinic) and may include clinical trials of treatments to improve the condition.

The scientific approach to understanding FM has involved all three approaches to medical research. In each case, a researcher has raised a question, formed a hypothesis, and tested that hypothesis either in the laboratory, in a sample of people with FM, or in the population at large. Once a study is completed, researchers typically write a paper about the study which is sent to a scientific medical journal where it is read and reviewed by other scientists. This review is called “peer-review.”  Credible science will always need to experience “peer-review” before being published. If the paper is judged worthy of publication, it then appears in the journal, thereby making the information available to clinicians who may then apply new ideas to their clinical decision-making. In this way, our understanding of fibromyalgia and the effective means of treatment improves.

Central Pain Mechanisms in Rheumatic Diseases: Future directions

Kristine Phillips, MD, PhD and Daniel J. Clauw, MD

Introduction

Pain is a prominent component of many rheumatologic conditions, and is the result of a complex physiologic interaction of central and peripheral nervous system signaling that results in a highly individualized symptom complex. Pain is frequently categorized as acute or chronic (generally greater than three months duration). Chronic pain is not simply acute pain that has lasted longer, and is more likely to be influenced by input from the central
nervous system, whereas acute pain is often attributable primarily to inflammation and/or damage in peripheral structures (i.e., nociceptive input).The prominent role of central factors in chronic pain is highlighted by the fact that there is currently no chronic pain condition in which the degree of tissue inflammation or damage alone (e.g., as measured by radiographs, magnetic resonance imaging (MRI), or endoscopy) accurately predicts the presence or severity of pain. Central factors alter pain processing by setting the “gain”, such that when peripheral input is present, it is processed against a background of central factors that can enhance or diminish the experience of pain. There are very large inter-individual differences in these central nervous system factors that influence pain perception, such that some individuals with significant peripheral nociceptive input (e.g. from joint damage or inflammation) will feel little or no pain, whereas others are very pain sensitive, and they can experience pain with minimal or no identifiable abnormal peripheral nociceptive input. This emerging knowledge has important implications for pain management in individuals with chronic rheumatologic disorders. Pain in rheumatologic disorders Although most patients seen by rheumatologists have pain as their presenting complaint, most rheumatologists have little formal training about contemporary theories regarding pain processing or pain management. Because of this, educating rheumatologists and others involved in the care of individuals with musculoskeletal pain has become a priority. The American College of Rheumatology Pain Management Task Force highlighted this in an initiative to increase awareness and call for organized research and education in chronic pain 1. Chronic pain may encompass pathology of the joint, skin, muscles, or peripheral nerves associated with rheumatologic diseases. A better understanding of chronic pain mechanisms will help us understand individual differences in pain among patients with rheumatic disease, and this will in turn allow for a more targeted approach to treatment (i.e., personalized analgesia)

2. Address for correspondence and reprint requests: Daniel Clauw M.D., Chronic Pain and Fatigue Center, University of Michigan Medical School, Domino’s Farms, Lobby M, PO Box 385, 24 Frank Lloyd Wright Drive, Ann Arbor, MI 48106, USA, .

Disclosures: None

NIH Public Access Author Manuscript  Arthritis Rheum. Author manuscript; available in PMC 2014 February 01.

Published in final edited form as: Arthritis Rheum. 2013 February ; 65(2): 291–302. doi:10.1002/art.37739. NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript

The concept of centralized pain

 The term “central pain” was originally used to describe individuals with pain following a stroke or spinal cord lesion that subsequently developed pain. In this case “central” refers to the fact that the lesion leading to pain occurred within the CNS. More recently, however, the term has expanded to describe any CNS dysfunction or pathology that may be contributing to the development or maintenance of chronic pain 3, which includes but is not at all limited to important contributions from psycho-social aspects of pain perception. Another term that has often been used to describe this same phenomenon is “central sensitization”. The term central sensitization was originally used to describe a state where the spinal cord amplifies afferent signals out of proportion to peripheral tissue changes. This term has the same problem as the term “central pain” because it originally referred to a specific mechanism,representing only one potential cause of augmented CNS pain processing 4. For clarity, we will use terms such as central augmentation or amplification to refer more broadly to central mechanisms that enhance the perception or modulation of pain differentially between individuals. We will use the term “centralization” of pain to refer to a common process that seems to occur to a vulnerable subset of individuals with any chronic pain state, wherein pain primarily due to peripheral nociceptive input is subsequently amplified by central factors, such that both peripheral and central factors are then contributing to the perception of pain by an individual. This latter phenomenon is particularly important for rheumatologists to identify, because these are individuals in whom our commonly used peripherally directed therapies (e.g. DMARDs, surgery) are unlikely to be effective as sole therapies. Centralized pain was originally thought to be confined to individuals with rare structural causes of pain or to the idiopathic or functional pain syndromes, such as fibromyalgia (FM), headache, irritable bowel syndrome (IBS), temporomandibular joint disorder (TMJD), and interstitial cystitis (IC)5. These pain syndromes have been shown to be very familial/genetic. For example, the risk of developing FM is eight-fold higher in first-degree relatives of patients with FM) and to co-aggregate in families 3,6. Twin studies also support a strong familial basis for pain as well as for this cluster of co-aggregating symptoms 7,8. Even if these individuals are originally thought to have a new onset of a regional pain syndrome, closer questioning often reveals that the individual has had many different regions of chronic pain over the course of their lifetime, or even at present 9. Thus, taking both a personal and family history of chronic pain is a clinical pearl that can be helpful in identifying individuals that have (or who are at risk for) prominent centralization of pain. Another way that “central” pain can be identified is when multifocal pain occurs in conjunction with other centrally mediated symptoms, such as fatigue, insomnia, memory difficulties, and mood disturbances 10,11. One of the simplest ways to identify individuals who have centralized their pain is to suspect that this has occurred when individuals with chronic pain have several of these other symptoms as co-morbidities3,12. Regarding the clustering of co-occurring somatic symptoms, as well as higher than expected rates of mood disorders, the leading pathophysiologic theory within these central pain states is that centrally acting neurotransmitters that are known to be abnormal and likely play a role in causing the pain in these conditions (e.g. low norepinephrine, GABA, or serotonin and high glutamate or Substance P) also play prominent roles in controlling sleep, mood, alertness, etc 3,13. This hypothesis is best supported by the fact that when centrally acting analgesics such as serotonin norepinephrine reuptake inhibitors (SNRIs), gabapentinoids, tricyclics or gamma-hydroxybutyrate are effective in a given chronic pain patient, these drugs typically lead to improvements in one or more of these other symptom domains besides pain14–16.

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In addition to the study of symptom domains in central pain states, significant advances have been made in our understanding of chronic pain pathogenesis. The hallmark biological finding common to these “centrally-driven” conditions is that most individuals have a diffuse CNS hyperalgesic state identifiable using quantitative sensory testing (QST) and corroborated by functional neuroimaging 6,17–19. Data from QST and functional neuroimaging studies suggest wide individual variation in pain and sensory sensitivity that adheres to a bell-shape distribution across a wide variety of chronic pain states, with a subset of individuals displaying hyperalgesia or augmented CNS activity across pain states.3,6,18,20,21 Some of the discrete conditions originally identified as being central pain states because of the presence of diffuse hyperalgesia and a lack of obvious, ongoing peripheral nociceptive input include FM, IBS, TMJD, tension headache, interstitial cystitis,and vulvodynia.22–29 The baseline presence of hyperalgesia and/or the absence of descending analgesic activity has not just been shown to be present in individuals with these centralized pain states, but also has been shown to be an important risk factor for a number of adverse pain outcomes, including predicting the subsequent intensity of an acute painful experience, analgesic requirements following surgery, and the subsequent development of chronic pain.30–32 This latter phenomenon was first demonstrated in a study by Diathchenko and colleagues, who performed a longitudinal study of 202 young pain-free women, and followed them for two years with the outcome of interest being those women who developed new onset TMJD.33 An individual’s pain threshold at baseline (i.e., while asymptomatic) was a strong predictor of the development of TMJD, since any individual on the “hyperalgesic side” of a bell-shaped curve of pain sensitivity at baseline was nearly three times as likely to develop TMJD as an individual in the bottom half of pain sensitivity. This was amongst the first studies to highlight the strong role that certain genes play in turning up the “gain” on pain processing6,33,34, and in identifying one cause of a “chronic pain prone phenotype”. Hypersensitivity of non-painful stimuli in sensitized pain patients is a hallmark of patients with chronic pain. The early genetic data were consistent with studies performed by Zubieta, who several years earlier had shown that COMT polymorphisms predicted pain threshold (as measured both by QST and functional neuroimaging) in healthy normal individuals.35 The same COMT gene risk allele has subsequently been shown to be more common in conditions such as FM and exerts a relatively large effect in human experimental pain sensitivity, as well as responsiveness to and side effects from commonly used analgesics.35–39 Just as we know of tremendous variability in pain sensitivity between strains of rodents, there similarly is great variability in pain sensitivity in humans. 40 There are at least five sets of genes that have are associated with an individual’s pain sensitivity, and increase their likelihood of developing one or more chronic pain states. These include COMT (a estrogen-sensitive enzyme that may play a more prominent role in females), GTP (guanosine triphosphate) cyclohydroxylase, types 2 and 3 adrenergic receptors, a P2X7 receptor pore, and sodium or potassium channel genes 35,41–46. While some genes have been consistently shown to confer a higher risk of pain sensitivity or the development of chronic  pain, but this is a rapidly evolving area and not all studies demonstrate the same associations41,47–49. Kato and colleagues, using a large Swedish twin registry, have performed a series of studies first showing the co-morbidities with chronic widespread pain, and then later examined a number of these central or “functional” pain syndromes and the relationship of these symptoms to those of depression and anxiety 50. These studies clearly demonstrated that functional somatic syndromes such as FM, CFS, IBS, and headache have latent traits (e.g. multifocal pain, fatigue, memory and sleep difficulties) that are different than (but overlap somewhat with) psychiatric conditions such as anxiety and depression.

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These findings are also concordant with the results of functional neuroimaging studies. For example, individuals with FM alone primarily have increased activity in the regions of the brain that code for the sensory intensity of stimuli (e.g., the primary and secondary somatosensory cortices, posterior insula, thalamus) whereas the FM patients with co-morbid depression also have increased activation in brain regions coding for the affective processing of pain, such as the amygdala and anterior insula 51. The notion that there are two overlapping sets of traits, one being pain and sensory amplification, and the other being mood and affect, is also supported by genetic studies of idiopathic pain syndromes 6. Twin studies have also been useful in helping tease out potential underlying mechanisms versus “epiphenomena”. These investigators have suggested that there is evidence of a problem with biological sensory amplification in the affected twins 52. As with most illnesses that may have a familial or genetic underpinning, environmental factors may play a prominent role in triggering the development of FM and other centralized pain states. Environmental “stressors” temporally associated with the development of widespread pain include early life trauma, physical trauma (especially involving the trunk), certain infections such as Hepatitis C, Epstein Barr virus, parvovirus, Lyme disease, and emotional stress. The disorder is also associated with other regional pain conditions or autoimmune disorders 53–55. Of note, each of these “stressors” only triggers the development of fibromyalgia and/or chronic fatigue syndrome in approximately 5 – 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.In fact, emerging evidence from a number of different areas in the pain field suggests that the same characteristics that are often attributable to FM patients, in fact more broadly epresents a “pain prone phenotype”. Figure #1 portrays the fact that female sex, early life trauma, a personal or family history of chronic pain, a personal history of other centrallymediated symptoms (insomnia, fatigue, memory problems, mood disturbances), and cognitions such as catastrophizing, all have been shown to be present is subsets of individuals with any chronic pain state, and predict which individuals are more likely to transition from acute to chronic pain. Functional neuroimaging studies, especially those using functional MRI (fMRI), also corroborate the QST findings of diffuse hyperalgesia/pain augmentation, by demonstrating that individuals with central pain states have increased neuronal activity in pain processing regions of the brain when they are exposed to stimuli that healthy individuals find innocuous56–59. Several meta-analyses of fMRI studies have summarized the brain regions that show activation when experimental pain is applied to human subjects, and these generally agree with SPECT (single photon emission computed tomography) and PET(positron emission tomography) studies noted above. The main components of this pain processing matrix are the primary and secondary somatosensory cortex (SI and SII), the insular cortex (IC), the anterior and midcingulate cortex (ACC), the posterior cingulate gyrus (PCC) and the thalamus i.e. the pain system involves somatosensory, limbic and associative brain structures 60,61. Within a single brain region such as the insula, the posterior insula is more involved in sensory processing, and the anterior more involved in affective processing, and even the left-to-right balance of insular activity may be associated with the emotional valence of pain 62. Many potential mechanisms can cause augmented central pain processing. The two receiving the most attention and study have been increased wind-up and diminished descending analgesia or conditioned pain modulation. Wind-up is a perceived increase in pain intensity when a stimulus is repeated above a certain rate and is mediated by C fibers.

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Descending analgesia is a function of descending neural pathways that form a pain-modulating circuit. The integrity and magnitude of this conditioned pain modulation (CPM) or diffuse noxious inhibitory control (DNIC) system can be tested by using two separate painful stimuli and observing that experiencing the first can reduce the perceived intensity of the second. While both wind-up and CPM can be tested experimentally, data thus far suggest that the study of descending endogenous analgesic pathways holds the most promise for successfully “segmenting” chronic pain patients into those with a central predominance to their pain. For example, attenuated descending analgesic activity (experimentally observed as reduced DNIC or CPM) is seen in 10–20% of controls, but approximately 60 – 80% of individuals with conditions such as FM or IBS 63–68 demonstrate this deficit. Neither diffuse hyperalgesia nor reduced DNIC/CPM (deficiencies in descending analgesic activity) are generally seen in individuals with psychiatric disorders such as depression 51,69. An analogy of an increased “volume control” or gain” setting on pain and sensory processing is supported by studies from a variety of sources. Elevated levels of neurotransmitters that tend to be pro-nociceptive (i.e. on the left side of Figure 2) or reduced levels of neurotransmitters that inhibit pain transmission (i.e. on the right side of Figure 2) have a tendency to increase the volume control, and drugs that block neurotransmitters on the left or augment activity of those on the right will typically be found to be effective treatments, at least for a subset of individuals with this spectrum of illness. As noted there is evidence for increases in the CSF levels of Substance P, glutamate, nerve growth factor, and brain derived neurotrophic factor, and low levels of the metabolites of serotonin, norepinephrine, dopamine, and GABA can lead to an “increase in the volume control” and augmented pain and sensory processing 70–74. The only neurotransmitter system that has been studied to date and not found to be out of line in a direction that would cause augmented pain transmission is the endogenous opioid system. This may be one reason why opioid drugs do not work well to treat FM and related centralized pain conditions 75,76. Potential role of peripheral factors in central pain states Immunological cascades have a role in the maintenance of central sensitivity and chronic pain which is enhanced through release of pro-inflammatory cytokines by CNS glial cells; thus, the traditional paradigm regarding inflammatory versus non-inflammatory pain may gradually become less dichotomous. As may be expected in any complex biological system, a delicate apparatus of checks and balances is at work in the spinal transmission of pain. Furthermore, studies suggest that maintenance of central augmentation requires persistent noxious peripheral input, even in syndromes such as IBS and FM, which are characterized by the absence of well-defined, localized, pain-causing lesions.77 In fact a recent study of 68 ibromyalgia patients with myofascial pain syndromes and 56 fibromyalgia patients with regional joint pain showed that peripheral trigger point injections and hydroelectrophoresis ameliorate fibromyalgia pain and increase pain thresholds at sites distant from the therapeutic interventions, providing further evidence that painful peripheral stimuli contribute to the perpetuation of central augmentation interventions 78. The Role of Centralized Pain in Classic Rheumatic Disorders Rheumatologists have known for some time that as many as 15–30% of individuals with classic autoimmune or rheumatic disorders also suffer from co-morbid FM, once referred to as “secondary FM”79. These rates are much higher than the prevalence of FM in the general population (2%), suggesting that pain and/or stress accompanying chronic rheumatic diseases is one way that conditions such as FM can be triggered. Triggering of a centralized pain state can also be seen with certain types of trauma such as motor vehicle collisions, by infections such as Lyme or EBV, and following surgery or war deployment80–83.

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This suggests that many biological stressors, especially those accompanied by acute pain, are capable of triggering centralization or chronic pain. Wolfe coined the term “fibromyalgia-ness” (FMness) to connote the fact that regardless of whether individuals with rheumatic disorders have FM as a “categorical” diagnosis (i.e. yes or no) or whether this construct is measured as a continuous variable, the more general construct of FM is highly associated with levels of pain and disability across all rheumatic disorders.84,85 Fibromyalgia (dichotomous diagnosis) and fibromyalgia-ness (measured as a continuous variable) directly impact traditional measures of disease activity and severity, and have implications for clinical practice86. Partial fulfillment of the revised 2010 criteria for FM may prove useful in discerning patients at risk of developing chronic pain but who do not meet diagnostic criteria for fibromyalgia. The degree of fibromyalgianess also influences objective and subjective responses to biologic and non-biologic disease modifying anti-rheumatic drug (DMARD) therapy in RA and predicts worse pain and functional status post-total joint arthroplasty and back surgery. Osteoarthritis Historically, the “disease” of OA has been viewed primarily as damage to the cartilage and bone. As such, the magnitude of damage or inflammation of these structures should predict symptoms. Population-based studies suggest otherwise; 30–50% of individuals with moderate to severe radiographic changes of OA are asymptomatic, and approximately 10% of individuals with moderate to severe knee pain have normal radiographs 87,88. Psychological factors do account for some of this variance in pain and other symptoms, but only to a small degree 89,90. The fact that central factors may be playing a pivotal role in OA helps explain the fact that co-morbid somatic symptoms known to be associated with central pain conditions (e.g., fatigue, sleep problems) are very commonly present in OA, and are not explained by a purely “peripheral” model of this disorder 91–93. Moreover, for some time there have been small studies suggesting that OA patients display diffuse hyperalgesia to mechanical or heat stimuli 94. Kosek demonstrated that individuals with OA of the hip had reduced descending analgesic activity, which partially normalized following hip arthroplasty, suggesting that the central factors were being at least partly driven by peripheral nociceptive input 95. Since then, larger and more comprehensive studies have been performed showing that groups of individuals with osteoarthritis have lower overall pain thresholds than controls, and have less efficient descending analgesic activity 94,96. Most recently, Gwilym and colleagues used both experimental pain testing and more sophisticated functional neuroimaging procedures to show evidence of augmented CNS processing of pain in 20 OA patients, and then showed in a separate study that atrophy of the thalamus was seen at baseline on OA, and improved following arthroplasty 20,97. Finally, recent RCTs have demonstrated that compounds that alter pain neurotransmitters centrally such as serotonin and norepinephrine (e.g., duloxetine, tricyclics) are efficacious in OA 98,99. This does not at all mean that peripheral factors are unimportant in OA. A recent study by Neogi and colleagues elegantly demonstrated that in individuals with asymmetric KOA, the pain levels in each knee strongly related to joint space narrowing in the affected knee 100. Rather, the aggregate data suggest that in some individuals central factors are superimposed upon the more traditional peripheral factors (targeted by NSAIDs, non-steroidal antiinflammatory drugs for example) leading to the need for a broader and more flexible approach to diagnosis and treatment.

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For some time, it has been suspected that FM is common as a co-morbid condition in SLE and confounds both the diagnosis and treatment of SLE.101–103 For example, just as with other rheumatic disorders, neither the degree of inflammation nor damage is highly associated with pain, fatigue, function, or other symptoms of SLE.104–106 Instead, the presence or absence of co-morbid FM (which occurs in approximately 20% of patients with SLE as well as other autoimmune disorders) is often the largest predictor of pain, fatigue, and function in SLE patients.107,108 FM and phenotypic features of centralized pain are more related to quality of life measures than disease activity per se.109 As individual domains, the presence of FM in SLE is most closely associated with fatigue, sleep disturbances, psychiatric disturbances, and work disability.110–112 Additional studies are needed to explore the role that the “centralization prone phenotype” plays in predicting which SLE patients go on to develop co-morbid FM, or centralization of their pain. There has been very little QST performed to date in SLE. The presence of hyperalgesia in SLE, as crudely measured by a tender point count, is abnormal in groups of SLE patients, and is related to measures of health status and disease activity.113 Only a single published study has used functional neuroimaging in SLE. Areas of CNS hypoperfusion were noted in individuals with SLE that overlapped with those with FM alone, and SLE and FM in combination.114 Rheumatoid Arthritis In contrast to FM and OA, RA is characterized by systemic inflammation. Although inflammation contributes to pain in RA, it may not be the only factor. For many patients, pain does not improve despite treatment with anti-inflammatory disease-modifying ntirheumatic drugs (DMARDs) 84. Although few studies have specifically examined the role of central pain processing mechanisms in RA, studies utilizing dolorimetry to assess pain thresholds suggest that these other pathways may include deficits in central pain processing. Early small studies have suggested that groups of RA patients displayed deficits in central pain processing, including impaired descending analgesic activity 115,116. Wolfe has shown that fibromyalgia is very prevalent in rheumatoid arthritis patients117, and there is increased morbidity in patients who have both rheumatoid arthritis and fibromyalgia compared to fibromyalgia alone118,119. It is important to remember that centralization of pain may also have an impact on traditional measures of disease activity such as the DAS28 (Disease activity score for 28 joints). Lee and colleagues recently showed that in RA the relationships between inflammation, psychosocial factors and peripheral and central pain processing are intricately entwined. In a study of 59 female RA patients, they demonstrated that C-reactive protein levels were inversely associated with pain thresholds at joint but not non-joint sites, consistent with peripheral sensitization 120. In Lee’s study, sleep disturbances were associated with pain thresholds at both joint and non-joint sites, indicating that central mechanisms (i.e. central sensitization) likely underlies the link between overall pain sensitivity, and sleep problems.

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Future directions

Current and future studies in rheumatic diseases can be leveraged to take advantage of both “primary” and “secondary” manifestations of FM and centralized pain, both to learn more bout FM and also to learn more about the pathogenesis and underpinnings of chronic pain more generally. Subsets of individuals in the population are more susceptible to developing chronic pain and somatic symptoms following exposure to sustained peripheral nociception and stress, and the clinical and biological features of these susceptible individuals are reminiscent of sub-clinical FM that has been characterized as a “centralization-prone phenotype” as outlined in Figure 3. When these individuals are exposed to the ongoing pain and stress associated with a chronic rheumatic disease, full-blown FM may be triggered in susceptible individuals. Individuals with osteoarthritis (OA), rheumatoid arthritis (RA), or systemic lupus erythematosus (SLE) who have already “centralized” their pain may show higher measures of pain intensity and disease status for the same degree of inflammation or structural damage, and may be less responsive to classic peripherally-directed pharmacologic (DMARDs) and non-pharmacologic (surgery) therapies.19,121 There is significant support for this idea, especially given recent evidence for prominent CNS contributions to pain in conditions such as OA, RA, and low back pain.20,29,44,99,122,123 Across rheumatic disorders, individuals with higher degrees of FMness may preferentially respond to “centrally-acting” drugs (e.g. tricyclics, SNRIs, gabapentinoids), whereas those without evidence of centralization of their pain will preferentially respond to drug classes historically believed to work better on peripheral/nociceptive pain (e.g., NSAIDs, opioids, DMARDs, surgery). Support for these hypotheses would tremendously advance our ability to offer personalized analgesia in routine clinical practice. The overall direction of chronic pain research is a paradigm shift in the diagnosis and treatment of pain in individuals with rheumatic disorders. Instead of considering pain and other symptoms associated with OA, RA, and SLE to be primarily due to peripheral damage or inflammation (i.e., nociception), the appropriate “phenotyping (recognition of patients with traits and states associated with chronic pain risk)” of chronic pain patients can identify subsets of individuals with these disorders that have prominent CNS contributions to their symptoms. Individuals with these diseases will likely respond differentially to DMARDs and non-drug therapies (such as surgical procedures performed for pain). Since arthroplasty and other surgical procedures performed to relieve chronic pain are very expensive procedures, and it is acknowledged that 20–40% of individuals receiving this procedure continue to have significant knee pain at 1–2 years, 124 a tremendous opportunity exists in developing paradigms to identify good (or poor) candidates for this or other “analgesic surgeries”, rather than subjecting individuals to a procedure from which they would be unlikely to benefit. The same holds true for many other procedures performed to treat pain, as well as for the use of biologic immunosuppressives in patients with persistent pain but equivocal evidence of ongoing inflammation. While there is knowledge to be gained from prior studies in other centrally mediated syndromes, rheumatologists should lead the way in developing and field-testing new phenotyping or identification measures for patients with rheumatologic diseases that will allow us to infer which underlying mechanisms are causing an individual’s pain, so that treatment(s) can be appropriately directed. The pain field has moved well past the point where we can consider all individuals with RA, SLE, OA – or for that matter any chronic pain state – to have the same underlying mechanism for pain and other somatic symptoms that they experience. All of these symptoms are experienced in the brain – so as a field we need to better understand the brain in order to better treat pain. Identifying subsets of OA, SLE and RA patients with prominent CNS factors might also help explain a longstanding conundrum in our fundamental understanding of these disorders. Disease models in OA, RA, and SLE are incomplete because peripherally based models do not explain a tremendous amount of variance in pain, fatigue, sleep, memory problems, and functional disability that is not accounted for by peripheral factors alone. For example, although the pathological focus in OA is the joint and surrounding structures, multifocal pain in areas not affected by osteoarthritis is common in individuals identified as having knee OA.125 Similarly, other somatic symptoms not explainable by a purely peripheral problem are often seen. For example, studies show fatigue to be a prominent problem in individuals with knee OA, and, in many individuals, a more functionally limiting symptomthan pain.126 The current peripherally based theories regarding the pathogenesis of OA, SLE and RA simply do not explain why these other somatic symptoms so commonly occur, and are often refractory to standard peripherally-based therapies.

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Conclusions

Chronic pain is an important component of many rheumatic diseases. One current limitation is the identification of patients in routine clinical settings who have greater contributions from centrally mediated mechanisms. Practical evidence-based strategies need to be developed that will more readily identify these patients at the point of care and also in the context of randomized clinical trials that include pain as an outcome measure. Centrally targeted therapies have the potential to change the treatment of chronic pain in many diseases. Several classes of centrally-acting agents (e.g., tricyclics, serotonin-norepinephrine reuptake inhibitors, gabapentinoids) may prove to be more effective in individuals with rheumatic disorders with central pain overlay than classes of drugs that are typically more effective for peripherally-based nociceptive pain states (e.g., NSAIDs) but additional studies are needed to prove this.. Newly developed pain cohort studies should identify these subsets of RA, SLE, and OA patients who are preferentially predisposed to respond to these centrally, in addition to peripherally acting treatments, including non-pharmacologic therapy. There are few published results examining the role of combination therapy in chronic pain, but it is likely that such regimens will improve outcomes to the extent that they are influenced by multiple distinct mechanisms. These future studies will direct the development of new therapeutic options for millions of individuals with painful rheumatic disorders.

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Figure 1.

Development of expanded pain regions in patients prone to central pain.

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Figure 2.

Recent studies have demonstrated that an individual’s “set point” or “volume control setting” for pain is set by a variety of factors, including the levels of neurotransmitters on the left that either facilitate pain transmission (turn up the gain or volume control) or those on the right that reduce pain transmission. Thus high levels of neurotransmitters on the left, or low levels of those on the right, would be capable of causing the diffuse hyperalgesia (increased volume control) seen in a variety of chronic pain states.

Figure 3.

Characteristics of patients with rheumatologic diseases that may have contributions from central pain mechanisms.

General Background

Wolfe F, Clauw DJ, Fitzcharles MA, et al. The American College of Rheumatology preliminary diagnostic criteria for fibromyalgia and measurement of symptom severity. Arthritis care & research 2010;62:600-10.

Wolfe F, Clauw DJ, Fitzcharles MA, et al. Fibromyalgia criteria and severity scales for clinical and epidemiological studies: a modification of the ACR Preliminary Diagnostic Criteria for Fibromyalgia. The Journal of rheumatology 2011;38:1113-22.

Fitzcharles MA, Ste-Marie PA, Goldenberg DL, et al. 2012 Canadian Guidelines for the diagnosis and management of fibromyalgia syndrome: executive summary. Pain research & management : the journal of the Canadian Pain Society = journal de la societe canadienne pour le traitement de la douleur 2013;18:119-26.

Whipple MO, McAllister SJ, Oh TH, Luedtke CA, Toussaint LL, Vincent A. Construction of a US Fibromyalgia Registry using the Fibromyalgia Research Survey criteria. Clinical and translational science 2013;6:398-9.

Basic Research 

Hassett AL, Epel E, Clauw DJ, et al. Pain is associated with short leukocyte telomere length in women with fibromyalgia. J Pain 2012;13:959-69.

Loggia ML, Berna C, Kim J, et al. Disrupted brain circuitry for pain-related reward/punishment in fibromyalgia. Arthritis & rheumatology 2014;66:203-12.

Valim V, Natour J, Xiao Y, et al. Effects of physical exercise on serum levels of serotonin and its metabolite in fibromyalgia: a randomized pilot study. Revista brasileira de reumatologia 2013;53:538-41.

Docampo E, Escaramis G, Gratacos M, et al. Genome-wide analysis of single nucleotide polymorphisms and copy number variants in fibromyalgia suggest a role for the central nervous system. Pain 2014.

Diatchenko L, Fillingim RB, Smith SB, Maixner W. The phenotypic and genetic signatures of common musculoskeletal pain conditions. Nature reviews Rheumatology 2013;9:340-50.

Arnold LM, Fan J, Russell IJ, et al. The fibromyalgia family study: a genome-wide linkage scan study. Arthritis and rheumatism 2013;65:1122-8.

Xiao Y, Haynes WL, Michalek JE, Russell IJ. Elevated serum high-sensitivity C-reactive protein levels in fibromyalgia syndrome patients correlate with body mass index, interleukin-6, interleukin-8, erythrocyte sedimentation rate. Rheumatology international 2013;33:1259-64.

Brown CA, El-Deredy W, Jones AK. When the brain expects pain: common neural responses to pain anticipation are related to clinical pain and distress in fibromyalgia and osteoarthritis. The European journal of neuroscience 2014;39:663-72.

Epidemiological Research

McBeth J, Lacey RJ, Wilkie R. Predictors of new-onset widespread pain in older adults: results from a population-based prospective cohort study in the UK. Arthritis & rheumatology 2014;66:757-67.

Vincent A, Lahr BD, Wolfe F, et al. Prevalence of fibromyalgia: a population-based study in Olmsted County, Minnesota, utilizing the Rochester Epidemiology Project. Arthritis care & research 2013;65:786-92.

Queiroz LP. Worldwide epidemiology of fibromyalgia. Current pain and headache reports 2013;17:356.

Clinical Research 

Hassett AL, Williams DA. Non-pharmacological treatment of chronic widespread musculoskeletal pain. Best practice & research Clinical rheumatology 2011;25:299-309.

Sil S, Kashikar-Zuck S. Understanding why cognitive-behavioral therapy is an effective treatment for adolescents with juvenile fibromyalgia. International journal of clinical rheumatology 2013;8.

Wepner F, Scheuer R, Schuetz-Wieser B, et al. Effects of vitamin D on patients with fibromyalgia syndrome: a randomized placebo-controlled trial. Pain 2014;155:261-8.

Vincent A, Clauw D, Oh TH, Whipple MO, Toussaint LL. Decreased Physical Activity Attributable to Higher Body Mass Index Influences Fibromyalgia Symptoms. PM & R : the journal of injury, function, and rehabilitation 2014.

Garza-Villarreal EA, Wilson AD, Vase L, et al. Music reduces pain and increases functional mobility in fibromyalgia. Frontiers in psychology 2014;5:90.

Li YH, Wang FY, Feng CQ, Yang XF, Sun YH. Massage therapy for fibromyalgia: a systematic review and meta-analysis of randomized controlled trials. PloS one 2014;9:e89304.

McAllister SJ, Vincent A, Hassett AL, et al. Psychological Resilience, Affective Mechanisms and Symptom Burden in a Tertiary-care Sample of Patients with Fibromyalgia. Stress and health : journal of the International Society for the Investigation of Stress 2013.

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