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Narrative Review: The Pathophysiology of Fibromyalgia

Aryeh M. Abeles, MD; Michael H. Pillinger, MD; Bruce M. Solitar, MD; and Micha Abeles, MD
[+] Article, Author, and Disclosure Information

From the New York University School of Medicine, New York University Hospital for Joint Diseases, and New York Harbor Healthcare System, New York, New York, and University of Connecticut School of Medicine, Farmington, Connecticut.

Note: Drs. A.M. Abeles and Pillinger contributed equally to this manuscript.

Potential Financial Conflicts of Interest: None disclosed.

Requests for Single Reprints: Aryeh M. Abeles, MD, Department of Rheumatology, New York University Hospital for Joint Diseases, 301 East 17th Street, Suite 410, New York, NY 10003.

Current Author Addresses: Drs. A.M. Abeles and Pillinger: Department of Rheumatology, New York University Hospital for Joint Diseases, 301 East 17th Street, Suite 1410, New York, NY 10003.

Dr. Solitar: Department of Rheumatology, New York University Hospital for Joint Diseases, 333 East 34th Street, Suite 1C, New York, NY 10016.

Dr. M. Abeles: Division of Rheumatology, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT 06030.

Ann Intern Med. 2007;146(10):726-734. doi:10.7326/0003-4819-146-10-200705150-00006
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Primary fibromyalgia is a common yet poorly understood syndrome characterized by diffuse chronic pain accompanied by other somatic symptoms, including poor sleep, fatigue, and stiffness, in the absence of disease. Fibromyalgia does not have a distinct cause or pathology. Nevertheless, in the past decade, the study of chronic pain has yielded new insights into the pathophysiology of fibromyalgia and related chronic pain disorders. Accruing evidence shows that patients with fibromyalgia experience pain differently from the general population because of dysfunctional pain processing in the central nervous system. Aberrant pain processing, which can result in chronic pain and associated symptoms, may be the result of several interplaying mechanisms, including central sensitization, blunting of inhibitory pain pathways, alterations in neurotransmitters, and psychiatric comorbid conditions. This review provides an overview of the mechanisms currently thought to be partly responsible for the chronic diffuse pain typical of fibromyalgia.


fibromyalgia ; pain


Grahic Jump Location
Figure. Nociceptive information arrives in the spinal cord via primary afferent nerves (C and Aδ fibers that converge on second-order afferent neurons in the spinal cord). These second-order neurons, which make up the spinothalamic tract (the primary ascending pain pathway), end at the thalamus. Neurons from the thalamus then distribute nociceptive information to the somatosensory cortex, where the sensory–discriminative aspect of pain is processed, and to other subcortical brain centers, such as the cingulate gyrus and the limbic system, where affective–motivational information about pain is processed.
The ascending pain pathway.
Grahic Jump Location




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Sympathetic nervous system dysfunction in fibromyalgia
Posted on May 15, 2007
Manuel Martinez-Lavin
National Institute of Cardiology, Mexico
Conflict of Interest: None Declared

In their review of fibromyalgia (Annals of Internal Medicine 2007;146:726-734), Abeles et al ignored the body of evidence suggesting that sympathetic nervous system dysfunction may play a central role in the pathogenesis of this complex syndrome.

Novel non-linear instruments (heart rate variability analysis and tilt table testing) have shown that fibromyalgia patients have changes suggestive of relentless sympathetic hyperactivity associated to hypo- reactivity to stress. This anomaly represents the most consistent alteration described so far in fibromyalgia (reviewed in 1). Sympathetic dysfunction provides a coherent explanation for FM multisystem features including its defining characteristics (widespread pain and widespread allodynia) (2).

Emerging genomic evidence supports the sympathetically-maintained pain concept. Healthy women with particular gene polymorphism associated to a defective catecholamine-clearing (COMT) enzyme, are more prone to develop painful conditions (3).

Complex diseases such fibromyalgia and similar maladies (chronic fatigue syndrome and gulf war syndrome) cannot be appreciated through the prevailing linear-reductionist medical model. New paradigms derived from the Chaos and Complexity Theory may help our understanding of this major health problem of contemporary women (4).

1. Martinez-Lavin M. Fibromyalgia as a sympathetically maintained pain syndrome. Curr Pain Headache Rep. 2004;8:385-389.

2. Martinez-Lavin M, Hermosillo AG. Autonomic nervous system dysfunction may explain the multisystem features of fibromyalgia. Semin Arthritis Rheum. 2000;29:197-199.

3. Diatchenko L, Nackley AG, Slade GD, Bhalang K, Belfer I, Max MB et al. Catechol-O-methyltransferase gene polymorphisms are associated with multiple pain-evoking stimuli. Pain. 2006;125:216-224.

4. Martinez-Lavin M, Infante O, Lerma C. The Chaos and Complexity Theory may help our understanding of fibromyalgia and similar maladies. Semin Arthritis Rheum. 2007 (in press).

Conflict of Interest:

None declared

Deconstructing Fibromyalgia
Posted on May 20, 2007
James H. Lampman
Specialty Clinics of St. Alexius Medical Center, Bismarck ND
Conflict of Interest: None Declared

The review of fibromyalgia by Abeles et. al. (1) articulates the three premises of the fibromyalgia hypothesis (pain felt coterminous with but not originating within musculotendinous structures; tender points as abstract signals of central nervous system dysfunction; and linkage of non -locomotor symptoms). The mantra-like authoritative repetition of these premises is a hallmark of the many hundreds of publications in this field. The review's search terms such as central sensitization, fibromyalgia, and chronic widespread pain, may select for studies which implicitly contain these premises, and which in turn provide an envelope around the conclusions. The authors note the "murky waters" and nosologic problem surrounding this topic despite extensive research. Could the starting points for fibromyalgia, like those of Ptolemaic astronomy, constrain an explanatory system which is more of a cultural statement than a scientific analysis?

Invisible in the review is any notice of the human locomotor system as a diverse and flawed mechanobiologic structure with stereotypical anatomic strain points. In fact, most discussions of fibromyalgia immediately lose any mooring points in the actual structure of muscles, muscle-tendon transitions, entheses, and bursae. Older literature demonstrates a tug-of-war between the pragmatic science of muscle-tendon health and fibromyalgia theory (2, 3). Evidently some think it a strong argument that when an isolated link (e.g. muscle) of a locomotor chain is found to be normal, any complaint from the patient must be referable to the ever-elusive sensitized neurologic system (4). The pragmatic clinician nonetheless is able to quickly identify the many common fleshy resiliency disorders in practice, including popular themes in the trapezio-cervical, shoulder, epicondylar, iliolumbar, and trochanteric regions. These represent the shared heritage of human anatomy, with the weaker links in normal catenated kinetic structures painfully revealed by seemingly normal activities and postures. In some regions conventional imaging studies may reveal underlying damage (4). True, if several key regions are involved for long enough, the individual may seek medical attention with a complaint of "I hurt all over," reflecting a flooding of reportage rather than literal pathology. True, many cases are women, and many have unrelated somatic or psychogenic dysfunctions which may act as selectors for clinical visits. Nonetheless, specific anatomically-informed examination reveals very rational findings which need no arcane system of explanation.

The three curious neurobehavioral premises of fibromyalgia are flawed. The situation needs a different kind of scrutiny with plausible, researchable premises and a substitute nosology based on locomotor resiliency.

1. Aryeh M. Abeles, Michael H. Pillinger, Bruce M. Solitar, and Micha Abeles. Narrative Review: The Pathophysiology of Fibromyalgia. Ann Intern Med 2007; 146: 726-734

2. Good M. Five Hundred Cases of Myalgia in the British Army. Ann Rheum Dis 1942:3; 118-3138. [PMCID: 1011529]

3. Niepel GA, Sit'aj S. Enthesopathy. Clinics in Rheumatic Diseases 1979;5:857-872

4. Simms RW. Fibromyalgia is not a muscle disorder. Am J Med Sci. 1998;315:346-50. [PMID: 9638890]

5. Bird PA, Oakley SP, Shnier R, Kirkham BW. Prospective evaluation of magnetic resonance imaging and physical examination findings in patients with greater trochanteric pain syndrome. Arthritis Rheum 2001;44;9:2138-45. [PMID: 11592379]

Conflict of Interest:

None declared

Fibromyalgia is a fiction
Posted on May 29, 2007
George Ehrlich
U Penn
Conflict of Interest: None Declared

Fibromyalgia does not exist as a separate entity, a disease or a syndrome. It is part of the spectrum of chronic pain, and all studies purporting to rationalize its existence and to account for its manifestations are circulare reasoning. As Hadler said, it is the medicalization of misery. This lengthy paper is an embarrassment to the College and to the Annals.

Conflict of Interest:

None declared

What's "Nonorganic"?
Posted on June 5, 2007
Harvey E. Golden
Rush Medical COllege
Conflict of Interest: None Declared

In their excellent review of the pathophysiology of Fibromyalgia the authors use the common but lamentable term "nonorganic" when referring to "Patients with nonorganic somatic symptoms...". What can possibly explain those "nonorganic" symptoms in an organism such as we are? Is there a "nonorganic" way for us to feel pain?

In the next sentence the authors use the term "unexplained somatic symptoms". Our flawed and incomplete understanding of our complicated somas comfortably explains that sort of mystery, and justifies the term "unexplained".

Authors and editors should eliminate the misleading and obscurant term "nonorganic" from the scientist's list of adjectives.

Conflict of Interest:

None declared

FM Is More Than Pain
Posted on June 6, 2007
Daniel G. Arkfeld
USC Keck School of Medicine
Conflict of Interest: None Declared

I must commend the Annals editorial board for publishing the article entitled" Narrative Review: The Pathophysiology of Fibromyalgia:" by Aryeh M. Abeles et al which succinctly reviews much of what is known in the field of pain in fibomyalgia. However, it avoids several key areas of disabling symptoms to FM patients and rather focuses on the area of depression. These include the area of chronic fatigue, irritable bowel and bladder, and cognitive dysfunction and others all of which are common in FM making clinical assessment difficult. Rather they discuss the area of depression and pyschiatric illness in FM giving it a higher degree of importance. This leads to fueling of the long standing bias that much of FM is pyschiatric based which has been reputed in several studies in the past 10 years. Perhaps it would be more beneficial to subtype fibromyalgia patients for future studies into groups such as FM with fatigue, FM without fatigue, FM with irritable bowel syndrome, FM with neurocardiogenic syncope etc. In this way a better understanding of the complex pathophysiology of FM could be explored which may lead to the discoveries on involved pathways in these subgroups.

The Frustration of Fibromyalgia: Look for Lyme Disease.
Posted on July 4, 2007
Raphael B. Stricker
Conflict of Interest: None Declared

In attempting to dissect the pathogenesis of fibromyalgia, Abeles and colleagues (May 15) mention infection with hepatitis or human immunodeficiency virus as a trigger for this mysterious and frustrating symptom complex. The authors postulate that "central nervous system cytokine activation...and subsequent glial activation" by viral infection may play a role in the etiology of the symptoms.

A more likely cause of fibromyalgia is infection with Borrelia burgdorferi, the spirochetal agent of Lyme disease (1-5). B. burgdorferi induces central nervous system cytokine and microglial activation in murine and monkey models of Lyme disease (1,2), and the spirochete has recently been shown to cause non-cytopathic infection and activation in human neuronal and glial cells (3). From a clinical standpoint, symptoms of fibromyalgia have been associated with Lyme disease, although these symptoms failed to respond to standard short-course (2-4 week) therapy with intravenous antibiotics (4). Longer courses of oral antibiotics may be more effective for this manifestation of tick-borne disease (5).

As pointed out by Abeles and colleagues, the term "fibromyalgia" refers to a complex of pain and other symptoms rather than a disease entity in itself. The search for an underlying trigger for this symptom complex should start with a Lyme test.


1. Rasley A, Anguita J, Marriott I. Borrelia burgdorferi induces inflammatory mediator production by murine microglia. J Neuroimmunol 2002;130:22-31.

2. Ramesh G, Alvarez AL, Roberts ED, Dennis VA, Lasater BL, Alvarez X, Philipp MT. Pathogenesis of Lyme neuroborreliosis: Borrelia burgdorferi lipoproteins induce both proliferation and apoptosis in rhesus monkey astrocytes. Eur J Immunol 2003;33:2539-50.

3. Livengood JA, Gilmore RD. Invasion of human neuronal and glial cells by an infectious strain of Borrelia burgdorferi. Microbes Infect 2006;8:2832- 40.

4. Dinerman H, Steere AC. Lyme disease associated with fibromyalgia. Ann Intern Med 1992;117:281-5.

5. Stricker RB. Counterpoint: Long-term antibiotic therapy improves persistent symptoms associated with Lyme disease. Clin Infect Dis 2007;45:149-57.

Conflict of Interest:

None declared

Fibromyalgia: spontaneous or evoked pain?
Posted on August 8, 2007
Gerhard K.M. Endresen
Department of Rheumatology, The National Hospital Oslo
Conflict of Interest: None Declared

Fibromyalgia may now present as a neurophysiologic disorder. Sceptics to the FM construct may perhaps use the term "pseudo-neurology".

Brought into focus are widespread allodynia (i.e. pain in response to normally non-painful stimuli), abnormal central pain processing, central sensitization, etc. It is even proposed to redefine fibromyalgia as chronic widespread allodynia. The tender points represent lowered pressure pain thresholds below an arbitrary level of ca. 4 kg at specific sites, and the tender point count tells us how widespread low pain threshold is. The magic about tender points may be lost long ago.

Chronic widespread pain for at least 3 months is still the important classification criterion for fibromyalgia. Clinical factors for the development and persistence of this pain have more or less been replaced by the neurosciences.

It is often stated that chronic widespread pain represents widespread allodynia, and that fibromyalgia patients have widespread static mechanic allodynia in terms of pain to even light touch. What is difficult to find, however, is whether the self-reported chronic widespread pain (i.e. spontaneous pain) is the same as widespread allodynia (i.e. stimulus- dependent or evoked pain). Or simpler, are fibromyalgia patients able to report widespread allodynia, or is the allodynia still an evoked phenomenon that, like the tender points, is mostly unknown to the patient? I am not able to imagine patients reporting pain after having their cloths on for at least 3 months.

Conflict of Interest:

None declared

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