Understanding Fibromyalgia

We are often asked whether we can help patients with fibromyalgia. While there is no quick cure for most people with fibromyalgia there are many ways in which the condition can be helped. Before getting into management of this very troublesome condition in a subsequent blog entry it may be helpful to first look at an excellent summary of the current scientific understanding of what is going on at a biochemical, physiological and neurological level in people with fibromyalgia. Her is an excellent article from the Mayo Clinic. It is quite technical but don't worry; I shall try to simplify this in another post soon. 


Fibromyalgia: A Unifying Neuroendocrinologic Model for Understanding Its
Pathophysiology
Peter T. Dorsher, MS, MD
From the Department of Physical Medicine and Rehabilitation, Mayo Clinic, Jacksonville,
Florida
Address reprint requests to Peter T. Dorsher, MD, Department of Physical
Medicine and Rehabilitation, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224.
E-mail: dorsher.peter@mayo.edu. Phone 904-953-2823 Fax 904-953-0276
Text word count: 1682 (2956 with references, tables, and legends)
Abstract word count: 121
Introduction word count: 246
Discussion word count: 273
No. of tables: 3
No. of figures/parts: 3
©2008 Mayo Foundation for Medical Education and Research
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Abstract
Fibromyalgia is believed to affect at least 2% of the population. Despite advances in the
scientific understanding of the derangements of central and peripheral pain processing
mechanisms in fibromyalgia, no current models of its pathophysiology account for the
other clinical conditions associated with it such as fatigue, migraine headache, irritable
bowel syndrome, and sleep cycle abnormalities. A neuroendocrinologic model of
fibromyalgia is presented that accommodates both its known central and peripheral pain
mechanisms as well as the myriad of hormonal, visceral, and psychological symptoms
associated with that disorder. This model also provides a unifying pathophysiologic basis
of fibromyalgia and chronic muscle pain, and offers the potential for developing new
avenues of research and treatment for these enigmatic, frequently disabling medical
conditions.
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Introduction
In 1852, Virchow first described “muscular rheumatism” 1 and five decades later
Gowers described persons with widespread pain symptoms he termed “fibrositis” 2. The
fibromyalgia and myofascial pain histories have overlapped, with Kelly 3 in 1945
discussing the concept of distant referred-pain produced by “fibrositis” nodules. The
historical overlap of these conditions is not surprising, since both the myofascial pain and
fibromyalgia syndromes are pain conditions characterized by tender soft tissue
(especially muscle) sites that may generate referred-pain distant to those sites.
There are significant clinical differences between the fibromyalgia and myofascial
pain syndromes, however. Fibromyalgia afflicts females seven times more frequently
than males, while myofascial pain syndrome afflicts genders equally 4. Myofascial pain
syndrome often affects only one body region, though widespread myofascial pain has
been described 5. In contrast, the diagnosis of fibromyalgia requires the presence of
widespread soft tissue tenderness in multiple body regions 6. Both conditions may be
associated with sleep disturbances, but fibromyalgia is also associated with other clinical
conditions (Table 1) including irritable bowel syndrome, interstitial cystitis, and migraine
headaches 7. These conditions are 4-25 times more common in individuals diagnosed
with fibromyalgia 7.
Widespread body pain affects approximately 3.6% of adults in the United States 8,
with fibromyalgia diagnosed in 5 million (2%) of adults 4. In terms of rheumatologic
disorders, only osteoarthritis and gout 9 have higher prevalence than fibromyalgia; yet
fibromyalgia is associated with the highest disability rate (up to 26.5%) of all
rheumatologic disorders 10, 11.
A Neuroendocrinologic Model of Fibromyalgia and Chronic Muscle Pain
The sympathetic autonomic nervous system (SANS) subserves the body’s “fight
or flight” responses to dangerous or stressful stimuli, while the parasympathetic
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autonomic nervous system (PANS) subserves its vegetative, “rest and digest” functions
(S. Bakewell, http://www.nda.ox.ac.uk/wfsa/html/u05/u05_010.htm). Most body
structures, including muscle, have dual sympathetic and parasympathetic innervation. As
shown in Table 2, SANS and PANS responses have opposite physiologic effects, with the
hypothalamus controlling the balance of those responses (D. Molavi,
http://thalamus.wustl.edu/course/hypoANS.html). As an example relevant to
musculoskeletal pain, SANS activation increases resting skeletal muscle tone while
PANS activation reduces it 12.
The clinical conditions associated with fibromyalgia (Table 1) are postulated to
result from imbalance or instability of the autonomic nervous system (Table 3). SANS
abnormalities have been described for many of those conditions, including migraines 13,
irritable bowel syndrome 14, interstitial cystitis 15, endometriosis 16, idiopathic urethritis
17, chronic prostatitis 18, and temporomandibular joint pain 19. Thus, abnormal regulation
of SANS/PANS outflow balance by the hypothalamus could result in these clinical
conditions seen in fibromyalgia patients. The circadian rhythms of sleep 20, appetite
regulation 21, mood 22, and temperature 23 also are regulated at the hypothalamic level;
and the abnormalities of those physiologic functions often described by fibromyalgia
patients are also consistent with hypothalamic dysfunction.
Though the insular cortex is believed to be mainly a viscerosensory structure, the
right insular cortex is believed to provide sympathetic outflow to the hypothalamus and
the left insular cortex its parasympathetic outflow 24. The orbitofrontal and medial
prefrontal cortex areas of the limbic system have direct anatomic input to the
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hypothalamus, allowing emotions to directly influence autonomic balance there 25. The
amygdala serves to integrate behavioral and autonomic responses from the
somatosensory cortex and limbic system structures including the medial prefrontal cortex,
orbitofrontal cortex, cingulate gyrus, hippocampus, anterior thalamic nuclei, and medial
thalamic nuclei 26. The amygdala is thought to have inhibitory influence on the
hypothalamus to attenuate SANS output 27. These thalamic and cortical influences on the
hypothalamus are demonstrated in Figure 1.
Hypothalamic SANS output arises from its posterolateral nuclei that ultimately
innervate the interomediolateral nuclei of the spinal cord, while its PANS output arises
from its anteromedial nuclei that ultimately course to peripheral structures via the vagus
nerve (D. Molavi, http://thalamus.wustl.edu/course/hypoANS.html). The hypothalamus
also regulates the release of cortisol and norepinephrine through the hypothalamicpituitary-
adrenal (HPA) axis, which provides systemic SANS activation with slower
onset and longer duration (D. Molavi, http://thalamus.wustl.edu/course/hypoANS.html).
Further, hypothalamic output regulates brainstem structures (rostroventral medulla,
periaqueductal gray, and locus ceruleus) whose descending pathways to the dorsal horn
of the spinal cord modulate pain transduction in nociceptive neurons there, as shown in
Figure 1 28.
The systemic norepinephrine release via the HPA axis, accentuated SANS tone
through hypothalamic output to the interomediolateral cells of the spinal cord, and
reduced descending pain inhibition at the spinal cord level are then postulated in this
neuroendocrinologic model to produce sensitization of primary nociceptors in
fibromyalgia patients. Clinical research supporting this includes documentation that
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fibromyalgia patients have elevated plasma catecholamine levels, which are associated
with hyperalgesia 29,30. Approximately 8% of spinal nerve fibers are postganglionic
sympathetic fibers 31, which also invest the arteries that accompany spinal nerves and
their branches to the extremities 32 (H. Gray, http://www.bartleby.com/107/214.html).
Neurogenic inflammation is a physiologic phenomenon 33 in which efferent
outflow from the spinal cord (dorsal root reflexes) causes nociceptive C-fibers to release
substance P (sP), calcitonin gene related peptide (cGRP) and somatostatin from their
terminal axons. These substances then cause local vasculature (plasma), platelets, and
macrophages to release bradykinin, histamine, and serotonin, which serve to activate
those nociceptive neurons 34, as illustrated in Figure 2. Thus, a local positive feedback
loop is produced as neurogenic inflammation ultimately produces release of substances
from the terminal axons that activate the primary nociceptors. Efferent or systemic SANS
activation can further sensitize these nociceptive neurons (Figures 1 and 2). The
abnormally high metabolic activity seen in the thalamus, amygdala, hippocampus,
cingulate gyrus, and other limbic system structures in fibromyalgia patients 35 is
consistent with abnormal central nervous system (CNS) autonomic efferent activity
contributing to nociceptor sensitization and neurogenic inflammation peripherally.
Psychological stress alone can cause degranulation of mast cells (many of which are
estrogen receptor positive) to initiate neurogenic inflammation 36,37, which may help
explain the predominance of fibromyalgia in females. Neurogenic inflammation causes
local edema (fibromyalgia nodules) and tenderness without histological presence of
inflammatory cells 38. Continuing activation of dorsal root reflexes and propriospinal
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pathways produces ascending and descending sensitization of nociceptors in adjacent
spinal levels, providing a mechanism for the spread of tender regions to increasingly
larger areas of the body 34. This is consistent with Shah’s findings 39 that trigger points
have markedly increased concentrations of inflammatory mediators, but also that muscle
sites distant from the trigger points in those subjects have lesser elevations of these
inflammatory mediators (higher than normal), suggesting systemic nervous system
sensitization as predicted by this neuroendocrinologic model. Efferent output of these
sensitized primary nociceptors also leads to activation of wide dynamic range neurons in
the deeper lamina of the spinal cord, which have wider cutaneous receptive fields and
visceral sensory input.
Primary nociceptors relay information through the lateral spinothalamic tract to
the lateral thalamus then on to the somatosensory cortex to localize painful stimuli, while
wide dynamic range neurons send information through the paleospinothalamic tract to the
anterior and medial thalamus then on to limbic system structures that subserve the
emotional and behavioral reactions to painful stimuli 34. These ascending pathways are
largely anatomically independent of each other. As shown in Figure 1, abnormal
activation of the neospinothalamic and paleospinothalamic pathways then forms the final
link in a positive feedback loop to produce excessive activation of the thalamus,
neocortex, and limbic system structures that regulate autonomic balance centrally.
Abnormal activation of hypothalamic and limbic system structures provides an anatomic
substrate that could account for the excessive behavioral reactions to noxious stimuli seen
in chronic pain patients 40,41. This may represent the central mechanism of the lowering
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of pain perception threshold (“thermostat”) in chronic pain patients, which in its extreme
progresses from hyperpathia to allodynia.
There is also pharmacologic evidence that supports this neurogenic model of
fibromyalgia. Drugs that demonstrate the most efficacy for treating fibromyalgia are in
the anti-convulsant (e.g. pregabalin) and anti-depressant (e.g. duloxitene) classes, which
act on the central and peripheral nervous systems. Fibromyalgia symptoms are relatively
resistant to opioids and anti-inflammatory drugs, which are efficacious for treating
musculoskeletal pain conditions.
Discussion
Functional MRI and neurophysiologic studies have demonstrated objective
evidence of abnormal central nervous system pain sensitization in patients with
fibromyalgia, even though its cause remains enigmatic. The recent work of Shah 39
demonstrates physiologic evidence of similar central nervous system sensitization in
myofascial pain syndrome.
Though both fibromyalgia and myofascial pain syndrome share the phenomenon
of tender muscular regions, only fibromyalgia is associated with other conditions such as
chronic headaches, irritable bowel syndrome, interstitial cystitis, and temporomandibular
joint pain syndrome. Clinical and experimental evidence of the role of neurogenic
inflammation and autonomic nervous system dysfunction in those disorders continues to
accumulate.
This neuroendocrinologic model of fibromyalgia provides an anatomically and
physiologically based conceptualization of the central and peripheral physiologic
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mechanisms that can produce the widespread muscular tenderness and visceral
dysfunction seen clinically in fibromyalgia patients. The model integrates the known
clinical and experimental findings of abnormal hypothalamic- pituitary- adrenal axis
activation and abnormal and/or unstable autonomic nervous system balance that are
associated with widespread pain and visceral dysfunction in fibromyalgia patients (Figure
3).
The clinical syndrome of fibromyalgia, then, can be initiated by excessive
noxious input at any point along this loop by a wide variety of causes. Excessive
psychological trauma or stress is postulated to initiate this positive feedback loop
centrally at the level of the paleocortex (limbic system). Visceral injury or recurrent insult
(myocardial infarct, “leaky gut syndrome” after antibiotic administration, recurrent
prostatitis) then initiates this positive feedback loop through severe or recurrent abnormal
visceral nociceptor activation. Similarly, severe and or recurrent musculoskeletal or
peripheral nerve injuries can activate this positive feedback loop through A-delta and Cfiber
activation with neurogenic inflammation.
Conclusion
The model of fibromyalgia presented herein as dysfunction of the autonomic
nervous system with sensitization of central nervous system nociception can unify the
multiple clinical findings noted in that disorder including cognitive impairment,
depression, sleep disturbance, widespread pain, and organ dysfunction such as irritable
bowel syndrome and interstitial cystitis. This model offers a novel view of the
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pathogenesis of this enigmatic syndrome that causes substantial morbidity and not
infrequently disability, and may lead to new avenues of treatment.
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Table 1. Clinical Conditions Associated with Fibromyalgia
Clinical Condition % fibromyalgia patients % general populaton
Chronic headache 50% 5%
Dysmenorrhea 60% 15%
Endometriosis 15% 2%
Interstitial cystitis 25% <1%
Irritable bladder/ urethra 15% <1%
Irritable bowel syndrome 60% 10%
Mitral valve prolapse 75% 15%
Multiple chemical sensitivities 40% 5%
Restless legs syndrome 30% 2%
TMJ syndrome 25% 5%
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Table 2. Autonomic Nervous System and Its Clinical Effects
SANS Effects PANS Effects
“fight or flight” “rest and digest”
↑ alertness/vigilance ↓ alertness/vigilance
↑ heart rate and contractility ↓ heart rate and contractility
↑ breathing rate with
bronchodilitation
↓ breathing rate with
bronchoconstriction
↑ cardiac and skeletal
muscle blood flow
↓ cardiac and skeletal
muscle blood flow
↓ gut blood flow ↑ gut blood flow
↓ cutaneous blood flow ↑ cutaneous blood flow
↑ blood sugar ↓ blood sugar
↑ temperature ↓ temperature
↓ gut contractility ↑ gut contractility
↓ bladder contractility ↑ bladder contractility
↓salivation ↑ salivation
↓lacrimation ↑ lacrimation
↓digestion ↑ digestion
SANS= sympathetic autonomic nervous system
PANS= parasympathetic autonomic nervous system
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Table 3. Autonomic Nervous System Imbalance in Fibromyalgia (relative degree of tonus)
Clinical Condition SANS PANS
Migraine ↑ initial phase ↑later phase
IBS, diarrhea predominant ↓ ↑
IBS, constipation predominant ↑ ↓
Interstitial Cystitis ↑ ↑
Raynaud’s-like phenomenon ↑ ↓
Endometriosis ↑ ↓
Aseptic Prostatitis ↑ ↓
Idiopathic Urethritis ↑ ↓
Skeletal Muscle Tone ↑ -
IBS= irritable bowel syndrome
SANS= sympathetic autonomic nervous system
PANS= parasympathetic autonomic nervous system
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Legends
Figure 1. Detailed Neurophysiology of Positive Feedback Loop in Fibromyalgia
Figure 2. Peripheral Sensitization Mechanisms
Figure 3. Simplified Positive Feedback Loop in Fibromyalgia
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