General Information

FM is a disease process characterized by chronic widespread musculoskeletal pain, non-restorative sleep, fatigue, headache, morning stiffness, poor memory, difficulty concentrating, paresthesias (numbness and tingling) and overall impaired functioning in both social and occupational settings.[1,3,15,16] The severity of the pain is typically more constant than other forms of pain and may come and go rapidly, move around to various parts of the body, and worsen with touch. For example, some fibromyalgia patients find their own clothing against their skin painful, particularly if it is tight clothing.[1]

Prevalence

Fibromyalgia is the 2nd most common disorder seen by rheumatologists, affecting roughly 2% of the population of the United States and 1.4% of the population of France.[1,4,12] Middle aged women are afflicted at a higher rate, with a prevalence of 3.4% for women, and 0.5% for men.[1,4] An Iceland study estimates the prevalence of children affected by fibromyalgia at 1.2% - 6.2%.[13]

Prevalence increases with age and diagnosis is most common in people aged 60 and 79 years.[4] Prevalence is higher in families, with relatives of patients suffering from fibromyalgia having an 8.5 fold higher risk of developing the disease.[2,5,6,7] Family members are also more likely to have other pain syndromes and tender points when compared to non-family members, suggesting an environmental or genetic component.[8]

Kato and colleagues used structural equation modeling to support the role of genetic factors, thus determining that these influences have a modest impact which explains 50% of the total variance in the likelihood of developing chronic widespread pain.[2,11] However, there is no particular gene that has been identified that leads to the disease.[2,11]

Diagnosis

The diagnosis of fibromyalgia is made by specific criteria from the American College of Rheumatology (ACR) after other potentially causative systemic conditions have been ruled out. A thorough physical and neurological exam with thyroid function testing is generally conducted before fibromyalgia is considered.[15,16]

The diagnosis [15,16] can be made with the presence of widespread pain for a period of at least three months, and either:
1. The presence pain at 11 of 18 tender point sites,
2. Or, the presence of at least 4 of the following:
· Generalized Fatigue
· Headache
· Sleep Disturbance
· Neuropsychiatric Complaints
· Numbness and/or Tingling
· Irritable Bowel Syndrome

Comorbidity

There are specific conditions which are frequently comorbid (occurring simultaneously) with fibromyalgia, including osteoarthritis, autoimmune disease, lupus, myalgic encephalomyelitis / chronic fatigue syndrome, migraines, irritable bowel syndrome, sleep problems, mood disturbances, nueroendocrine disorders, and hypothyroidism.[11,17] Bennett and colleagues conducted survey which showed the following prevalence of comorbid disorders:[3,9]
Low back pain 63%
Recurrent headaches 47%
Arthritis 46%
Muscle spasm 46%
Tingling 46%
Balance problems 45%
Irritable bowel syndrome 44%
Numbness 44%
Chronic fatigue 40%
Bloating 40%
Depression 40%
Anxiety 38%
Sinus problems 37%
Tooth disorders 32%
Restless legs 32%
Tinnitus 30%
Jaw pain 29%
Bladder problems 26%
Rashes 25%

Upon examination, no structural changes or muscular inflammation is detectable despite a widespread decreased pain threshold and peripheral sensitization indicative of changes in pain pathways with elevated cerebrospinal substance P levels and dysfunction of the hypothalamic pituitary adrenal (HPA) axis.[11,17,22,23]

Etiology (Cause)

The cause of fibromyalgia is not fully understood yet, though it may involve abnormalities in peripheral and central sensory processing,[23] which may be triggered by viral infections, Lyme disease, hepatitis C, hormonal and endocrine changes, drugs, vaccines, and physical trauma.[8,17,18,19,20,21,24,25,26].

Central sensitization leads to functional changes in the central nervous system which reduce pain threshold, enlarge neuron receptive fields, and increase spinal cord neuron excitability.[23] Once central sensitization has occurred, only minimal input is required for an increased response to pain and the maintenance of a chronic pain state.[23,27,28]

SPECT Scans
Nuclear medicine utilizes SPECT (Single Photon Emission Computerized Tomography) technology to perform brain scans.[39] This records brain functioning by measuring perfusion (blood flow).[39] In patients with fibromyalgia, cerebral blood flow is altered.[39] Furthermore, the larger alternations in perfusion have been linked to increased symptom reports. [39] Significant hyperperfusion has been found in regions of the brain known to be involved in the sensory dimension of pain processing.[40]

One SPECT study examined a blockade of facilitatory descending modulation of pain with ketamine.[41] Midbrain rCBF showed a greater increase after ketamine and was correlated with a reduction pain.[41]

Another SPECT study found that young women with fibromyalgia had a significantly higher radioactivity uptake ratio in the right and left caudate nucleus.[42] Significant correlations exist between regional cerebral blood flow, morning stiffness, and sleep disturbance.[42] There was a significant increase in rCBF of caudate nuclei, a reduction in the pons, some cortical regions activity, and a increase in IL 8, IL2r levels, findings which were more prominent in patients with low depression rates.[42]

Gi Protein
Gi protein is hypofunctional in fibromyalgia and unaltered in neuropathic pain, rheumatoid arthritis, and osteoarthritis. Furthermore, patients with fibromyalgia showed basal cAMP levels which were higher than the controls.[38]

Neurotransmitters
Reduced dopamine, norepinephrine, and serotonin levels have been found in the cerebrospinal fluid of fibromyalgia subjects.[29] Dopamine is an important neurotransmitter (messenger) which facilitates critical brain functions. Imbalanced dopamine activity can cause brain dysfunction and disease. Classified as a catecholamine, dopamine improves nerve conduction, is a natural pain killer, and assists in lessening movement disorders such as that seen in Parkinson’s disease.

Studies show an association between fibromyalgia and a disruption of dopaminergic neurotransmission, which results in reduced dopamine metabolism within the pain neuromatrix.[30,31] This has been demonstrated in both PET scans and an increased prolactin response to a buspirone challenge test.[30,31]

These reduced levels result in decreased presynaptic inhibition of pain-related primary afferent neurons.[33] Serotonin also has important roles in other domains often altered in fibormyalgia patients, including regulation of mood, sleep, and pain perception.[34,35]

Serotonin inhibits the release of substance P and other pain processing neurotransmitters.[32] Elevated levels of cerebrospinal substance P found in fibromyalgia patients may be related to reduced serotonin.[33,34] Patients with fibromyalgia detect pressure and stimuli at the same levels as control groups; however, they experience pain at lower levels than controls.[35,36]

Environmental Factors
Various “stressors” such as viral infection, physical trauma, and exercise can both initiate and trigger fibromyalgia.[8,37] Illness or injury may damage the corticotropin-releasing hormone nervous system that activates the sympathetic nervous system and reduces cellular immune function.[8,37] In patients with fibromyalgia this system functions suboptimally, leading to increased physiologic response.[8,37]

Environmental factors may trigger the development of chronic pain disorders in individuals with a genetic predisposition.[44] Intolerance to certain foods and chemicals is linked to fibromyalgia.[8] These intolerances are best described as hypersensitivities rather than immunoglobulin E-mediated allergic reactions.[8] Serum glutathione and catalase levels were significantly lower in subjects with fibromyalgia, a finding that was significantly correlated with the level of morning stiffness.[43] Furthermore, a significant correlation was found between serum nitric oxide levels and pain. [43]

Mimicking Conditions
There are several conditions which mimic fibromyalgia and should be ruled out and/or treated.[8] They include hypothyroidism, polymyalgia rheumatica, autoimmune disorders, hepatitis C, sleep apnea, chiari malformation, and celiac disease. [8]

Treatment

Medications alone are generally not effective for fibromyalgia.[1,45] A multidisciplinary approach is recommended by the American Pain Society Fibromyalgia Panel.[1,45]

Fibromyalgia may be treated using both conventional and alternative medicine to improve symptoms and generally involves patient education, exercise, physical therapy, supplementation, and pharmacologic therapy. Conventional medicine relies on pharmacological treatments to manage symptoms such as pain, fatigue, and sleep problems, while non-pharmacological treatments, such as exercise, may help with functional improvements.[46]

Patients may also benefit from psychosocial support, education about the disease, support groups, improved sleep, a supportive family, pacing, adopting a healthy lifestyle, avoiding chemical exposures (fragrances, pesticides, etc), and avoiding cigarettes and alcohol.[46]

Survey respondents rate the most effective treatment modalities as rest, heat, pain medications, antidepressants (for use other than depression), and hypnotics.[3]

Some pharmacological treatments that doctors may prescribe include:

Analgesics
Analgesics may be prescribed to block glutamate and substance p for pain relief.

Antidepressants
Low doses of antidepressant medications may be prescribed to improve sleep and reduce pain.[4,8,47] The beneficial effects of antidepressants in FM are independent of their antidepressant effects.[4,47] Tricyclic antidepressants are the most studied antidepressants which have been shown to improve the symptoms of pain, poor sleep, and fatigue in several randomized, controlled trials.[8] An example of some antidepressants includes amitriptyline, paroxetine, citalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline.[4,47]

SSRI’s and SSNI’s
Selective Serotonin Reuptake Inhibitors (SSRI’s) and/or Selective Norepinephrine Reuptake Inhibitors (SSNI’s) may be helpful to improve physical impairment and functioning, fatigue, pain and stiffness, and number of tender points.[8,45,47,48,49,50,51,52] An example some SSRI’s and SSNI’s include duloxetine, milnacipran, fluoxetine and sertraline appear to be the most effective.

Lidocaine / Hydrocortisone Injections
Lidocaine and/or hydrocortisone may be prescribed for persistent pain in one area.

Nonsteroidal Anti-inflammatory Drugs (NSAIDs)
NSAIDs may be used in some cases to reduce inflammation, though they are not often helpful in pain reduction.

GABA
Gamma-aminobutyric acid (GABA) antiepileptic drugs are commonly used for treatment of chronic pain.[53] Pregabalin is one gamma-aminobutyric acid (GABA) analog that is approved for the treatment of neuropathic pain and has been shown to be effective in the significant reduction of pain, sleep disturbances, fatigue, and quality of life.[54] Gabapentin has also been used to treat chronic pain states.[55]

Non-medication methods to relieve symptoms include regular sleep, regular stretching and exercise, hot compresses, gentle massage, and supplementation.[4,47] Low impact aerobic exercise has been shown effective at increasing functional capacity.[47,56]

Nutrition Therapy
Nutrition therapy with certain agents that down-regulate the nitric oxide and peroxynitrite (NO/ONOO-) cycle of biochemistry has also been recommended.[57] The following agents have been predicted to be useful to down-regulate the NO/ONOO- cycle and reduce symptoms in clinical trials:[57]

Nebulized Inhaled Reduced Glutathione (RX Only)
Nebulized Inhaled Hyroxocobalamin (RX Only)
Mixed Natural Tocopherols
Buffered Vitamin C
Magnesium as Malate
Four Different Flavonoid Sources:
Ginkgo Biloba Extract, Cranberry Extract, Silymarin, & Bilberry Extract
Selenium as Selenium-Grown Yeast
Coenzyme Q10
Folic Acid
Carotenoids Including Lycopene, Lutein and Alpha-carotene
Alpha-Lipoic acid
Zinc (modest dose)
Manganese (low dose)
Copper (low dose)
Vitamin B6 in the Form of Pyridoxal Phosphate
Riboflavin 5’-Phosphate (FMN)
Betaine (Trimethylglycine)
Green Tea Extract
Acetyl L-Carnitine

Different combinations of the above treatments may be tried to find the one that works best for each patient.