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: [email protected]. 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 Nature Precedings : hdl:10101/npre.2008.2595.1 : Posted 3 Dec 2008 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. Nature Precedings : hdl:10101/npre.2008.2595.1 : Posted 3 Dec 2008 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 Nature Precedings : hdl:10101/npre.2008.2595.1 : Posted 3 Dec 2008 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 Nature Precedings : hdl:10101/npre.2008.2595.1 : Posted 3 Dec 2008 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 Nature Precedings : hdl:10101/npre.2008.2595.1 : Posted 3 Dec 2008 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 Nature Precedings : hdl:10101/npre.2008.2595.1 : Posted 3 Dec 2008 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 Nature Precedings : hdl:10101/npre.2008.2595.1 : Posted 3 Dec 2008 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 Nature Precedings : hdl:10101/npre.2008.2595.1 : Posted 3 Dec 2008 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 Nature Precedings : hdl:10101/npre.2008.2595.1 : Posted 3 Dec 2008 pathogenesis of this enigmatic syndrome that causes substantial morbidity and not infrequently disability, and may lead to new avenues of treatment. Nature Precedings : hdl:10101/npre.2008.2595.1 : Posted 3 Dec 2008 References 1) Virchow, R. Über parenchymatöse entzündung. Arch. Pathol. 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Neurotensin mediates rat bladder mast cell degranulation triggered by acute psychological stress. Urology. 53, 1035-40 (1999). 37) Eutamene, H., Theodorou, V., Fioramonti, J. & Bueno, L. Acute stress modulates the histamine content of mast cells in the gastrointestinal tract through interleukin-1 and corticotropin-releasing factor release in rats. J. Physiol. 553, 959-966 (2003). 38) Huguenin, L.K. Myofascial trigger points: the current evidence. Phys. Ther. Sports. 5, 2-12 (2004). 39) Shah, J.P. et al. Biochemicals associated with pain and inflammation are elevated in sites near to and remote from active myofascial trigger points. Arch. Phys. Med. Rehabil. 89, 16-23 (2008). 40) Bradley, R.A. et al. Abnormal regional cerebral blood flow in the caudate nucleus among fibromyalgia patients and non-patients is associated with insidious symptom onset. J Musculoskel. Pain. 7, 285-292 (1999). 41) Gracely, R.H., Petzke, F., Wolf, J.M. & Clauw, D.J. Functional magnetic resonance imaging evidence of augmented pain processing in fibromyalgia. Arthritis Rheum. 46, 1333-1343 (2002). 42) Lambert, G.W. et al. Internal jugular venous spillover of noradrenaline and metabolites and their association with sympathetic nervous activity. Acta. Physiol. Scand. 163, 155-163 (1998). 43) Quintner J. & Cohen M. Referred pain of peripheral nerve origin: an alternative to the myofascial pain construct. Clin. J. Pain. 10, 243–251 (1994). Nature Precedings : hdl:10101/npre.2008.2595.1 : Posted 3 Dec 2008 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% Nature Precedings : hdl:10101/npre.2008.2595.1 : Posted 3 Dec 2008 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 Nature Precedings : hdl:10101/npre.2008.2595.1 : Posted 3 Dec 2008 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 Nature Precedings : hdl:10101/npre.2008.2595.1 : Posted 3 Dec 2008 Legends Figure 1. Detailed Neurophysiology of Positive Feedback Loop in Fibromyalgia Figure 2. Peripheral Sensitization Mechanisms Figure 3. Simplified Positive Feedback Loop in Fibromyalgia Nature Precedings : hdl:10101/npre.2008.2595.1 : Posted 3 Dec 2008 Nature Precedings : hdl:10101/npre.2008.2595.1 : Posted 3 Dec 2008 Nature Precedings : hdl:10101/npre.2008.2595.1 : Posted 3 Dec 2008 Nature Precedings : hdl:10101/npre.2008.2595.1 : Posted 3 Dec 2008 Comments are closed.
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