EVOLVING CONCEPTS ARTICLE
Fibromyalgia (FM) is a stress-related disorder that predominately affects women. FM’s outstanding clinical features are chronic widespread pain, paresthesias, allodynia, fatigue, sleep difficulties and cognitive impairment. Other FM associated symptoms relate to irritable bowel, temporo-mandibular dysfunction and interstitial cystitis .
FM pathogenesis has not been elucidated. Our group has proposed dysautonomia as an explanation to the multiplicity of FM symptoms including its main complaint; widespread pain. Along these lines, we have suggested that FM is a sympathetically maintained neuropathic pain syndrome. Recent publications describing small nerve fiber pathology in FM reinforce the proposal of FM as a sympathetically maintained neuropathic pain syndrome .
This article reviews the evidence favoring the notion of FM as a stress related disorder and a sympathetically-maintained neuropathic pain syndrome.
Sympathetic Nervous System as a Key Element of the Stress System Response
Vertebrate animals, including humans, adapt to stressful situations through the buffering action of their stress response system. This dynamic system is composed principally by a hormonal element: the hypothalamic – pituitary – adrenal axis, and a neural component; the sympathetic nervous system . Both parts of the stress response system are closely integrated and complementary.
The sympathetic nervous system is the “accelerating”part of the autonomic nervous system. Its antagonistic, calming counterpart, is the parasympathetic branch. The autonomic nervous system is in charge of maintaining homeostasis through the harmonious and opposing actions of these two branches. This balance maintains internal organ functions, and also maintains the vital signs.The peripheral sympathetic nervous system consists of a rich neural network that originates in the thoraco-lumbar section of the spinal column.The sympathetic network is highly interconnected. In response to physical and/or mental stressors, sympathetic activation induces a diffuse amplified response that puts the whole organism in a state of high alert, ready to ‘fight- or- flight’.
Catecholamines (norepinephrine and epinephrine) are the main post-ganglionic sympathetic neurotransmitters or hormones acting through stimulation of adrenergic receptors. Adrenergic receptors are expressed not only in the sympathetic nervous system, but also in virtually every cell type of the body. Lymphocytes and platelets have adrenergic receptors that are responsive to catecholamines. So, sympathetic activation may have coagulation and immune consequences .
Sympathetic nervous system dynamics are difficult to assess. Static blood or urinary measurements of catecholamines are unable to follow the constantly changing sympathetic activity. Fortunately, there is a new dynamic method based on computers that is able to estimate sympathetic and parasympathetic influence on heart rhythms. This method is referred to as heart rate variability analysis. This new technique has been widely used to study FM patients .
Sympathetic Nervous System and Pain; Animal Models
Animal models demonstrate that physical trauma and distress can lead to chronic pain through aberrant sympathetic transmission. Sciatic nerve ligation is a standard model used to study neuropathic pain. In rats, sciatic nerve injury induces abnormal connections between the sympathetic nervous system and the nociceptive system. Under normal circumstances there is not significant sympathetic innervation of dorsal root ganglia. Things change dramatically after nerve injury: There is sympathetic fiber sprouting via nerve growth factor over-expression. In such instances catecholamines or sympathetic activity are able to induce pain and hyperalgesia . Animal models also show how distress can lead to pain. In rats, distressing unpredictable noise can induce catecholamine mediated chronic mechanical hyperalgesia.
Dorsal root ganglia may also act as a sanctuary for infective agents. Herpes virus may lay dormant for years in these sites. Upon reactivation, herpes may induce dorsal root ganglia neuroplasticity. Postherpetic neuralgia may be the resulting clinical manifestation. A similar mechanism may operate in Lyme’s disease 
Dorsal Root Ganglia Sodium Channels; Pain Gatekeepers
Sodium channels located in dorsal root ganglia arethe molecular gatekeepers of pain detection at peripheral nociceptors. Nine sodium channel subunits have been identified (Nav1.1–Nav1.9), each with a unique centraland peripheral nervous system distribution.IsoformNav1.7 encoded in gene SCN9A of chromosome 2q24.3 is predominantly expressed in the dorsal root ganglia pain sensing neurons and sympathetic ganglia neurons. A singleNav1.7 mutation (L858H) induces electrical hyperactivity ofsensory neurons in dorsal root ganglia and, at the same time, produces hyporeactivity of sympathetic ganglia neurons .
Several sodium “channelopathies” have been associated with rare painful dysautonomic syndromes such as primary erythermalgia and paroxysmal extreme pain disorder (formerly familial rectal pain syndrome).
Physical and Emotional Distress in Fibromyalgia
Distress is defined as a maladaptive response to stressors leading to somatic and/or psychological harm. Both physical and emotional stressors are frequent FM triggers. Bodily trauma, particularly a whiplash injury during automobile accident, is a recognized FM trigger. Also, different types of infections have been associated with the development of FM. Agents implicated include viruses (e.g., hepatitis C, HIV, herpes) and Borrelia, which is the infecting agent in cases of Lyme’s disease. Women with FM have increased incidence of prior sexual or physical abuse.Moreover, FM patients are often immersed in a stressful lifestyle. A prospective investigation found that the development of this illness was associated in workplace bullying, high workload, and low decision-making possibilities . Anxiety and depression are frequent FM companions. Furthermore, many FM patients appear to have created their own “lifestyle stress” by physically or mentally overexerting themselves, being too perfectionist or over-committed at work, or engaging in disproportionate self-sacrificing behavior.
Sympathetic Dysautonomia in Fibromyalgia
Heart rate variability analyses have consistently shown that FM patients have changes suggestive of relentless sympathetic hyperactivity, particularly at night. Other studies have disclosed a sympathetic nervous system hypo-responsiveness to different stressors . Genetic studies support the presence of sympathetic dysautonomia in fibromyalgia. Catechol-O-methyltransferase (COMT) is the enzyme in charge of clearing catecholamines from the system. In healthy individuals, pain perception is related to COMT gene haplotypes linked toa defective catecholamine clearing enzyme. Several groups of investigators have shown COMT gene alterationsin FM patients .
Fibromyalgia as a Sympathetically Maintained Neuropathic Pain Syndrome
Our group has proposed that fibromyalgia is a neuropathic pain syndrome based on the following three arguments: (i) fibromyalgia is a stimulus-independent pain state; (ii) the presence of allodynia as an essential feature of fibromyalgia; and (iii) the presence of paresthesias as a distinctive feature of fibromyalgia. Among neuropathic syndromes, we propose that fibromyalgia pain is sympathetically maintained based on the following reasons: (i) the high frequency of physical, infectious or psychological stressors as a triggering event; (ii) diverse heart rate variability studies showing that patients with fibromyalgia have changes consistent with ongoing sympathetic hyperactivity and (iii) a double-blind study showing that norepinephrine injections rekindle fibromyalgia pain. Sympathetic hyperactivity provides a coherent explanation for other non-pain related fibromyalgia symptoms .
Dorsal Root Ganglia Sodium Channels and Fibromyalgia
In a pilot study, we described a particular SCN9A sodium channel gene variant (rs6754031 GG genotype) associated with severe fibromyalgia (8). On the other hand, Faber et al. reported that a gain of function in the mutated form of sodium channel NaV1.7, which render dorsal root ganglion neurons hyper-excitable, are present in a substantial proportion (28 %) of patients meeting strict criteria for small fiber neuropathy (6). These findings suggest that a sodium channelopathy may underlie some cases of fibromyalgia and of small fiber neuropathy.
Small Fiber Neuropathy and Fibromyalgia
Small fiber neuropathy is a disease of the most distal nociceptive and sympathetic fibers. The outstanding clinical features of small fiber neuropathy are pain, paresthesias and autonomic dysfunction. Neurological examination is usually normal, as are the electromyography and clinically available nerve conduction studies. The diagnosis of small fiber neuropathy is confirmed by skin biopsy showing decreased intra-epidermal nerve fiber density and also by skin quantitative sensory or autonomic testing. Corneal confocal microscopy is a new method to assess small nerve fiber pathology.
Recent publications show that when compared to healthy controls, subjects with fibromyalgia have decreased intra-epidermal nerve fiber density, abnormal sympathetic skin nerve fibers, altered epidermal autonomic function test and diminished corneal small fiber innervation. This new information demonstrates that small fiber neuropathy is frequent in fibromyalgia patients .
Sympathetic dysautonomia is frequent in FM. Such dysautonomia is characterized by relentless sympathetic hyperactivity accompanied by sympathetic hypo-reactivity to different stressors. Genetic make-up and/or chronic adverse life events may contribute to such autonomic dysfunction.
Sympathetic dysautonomia may explain FM multisystem features including its main complaint; chronic widespread pain. Recently gathered evidence showing that FM patients frequently have small fiber neuropathy reinforces the notion of FM as a sympathetically maintained neuropathic pain syndrome.
Manuel Martínez-Lavín, MD – Chief, Rheumatology Department, National Institute of Cardiology, Mexico City, Mexico.
- Martinez-Lavin M. Fibromyalgia when distress becomes (un) sympathetic pain. Pain Res Treat, 2012 (2012), ID: 981565.
- Ramírez M, Martínez-Martínez LA, Hernández-Quintela E Velazco-Casapía J, Vargas A, Martínez-Lavín M. Small fiber neuropathy in women with fibromyalgia. An in vivo assessment using corneal confocal bio-microscopy. Semin Arthritis Rheum, 2015 (Epub ahead of print).
- Elenkov IJ, Wilder RL, Chrousos GP, Vizi ES. The sympathetic nerve–an integrative interface between two supersystems: the brain and the immune system. Pharmacol Rev, 2000, 52:595-638.
- Lerma C, Martinez A, Ruiz N, Vargas A, Infante O, Martinez-Lavin M. Nocturnal heart rate variability parameters as potential fibromyalgia biomarker. Correlation with symptoms severity. Arthritis Res Ther, 2011, 13:R185.
- McLachlan EM, Janig W, Devor M, Michaelis M. Peripheral nerve injury triggers noradrenergic sprouting within dorsal root ganglia. Nature, 1993, 363:543-6.
- Faber CG, Hoeijmakers JG, Ahn HS, Cheng X, Han C, Choi JS, et al. Gain of function Nav1.7 mutations in idiopathic small fiber neuropathy. Ann Neurol, 2012, 71:26-39.
- Vargas-Alarcon G, Fragoso JM, Cruz-Robles D, Vargas A, Vargas A, Lao-Villadoniga JI, Garcia-Fructuoso F, Ramos-Kuri M, Hernandez F, Springall R, Bojalil R, Vallejo M, Martinez-Lavin M. Catechol-O-Methyl Transferase (COMT) gene haplotypes in Mexican and Spaniard patients with fibromyalgia. Arthritis Res Ther, 2007, 9:R110.
- Vargas-Alarcon G, Alvarez-Leon E, Fragoso JM, Vargas A, Martinez A, Vallejo M, Martinez-Lavin M. A SCN9A gene-encoded dorsal root ganglia sodium channel polymorphism associated with severe fibromyalgia. BMC Musculoskeletal Dis, 2012, 13:23.