Fibromyalgia

Fibromyalgia is one of a variety of disorders categorized as chronic widespread pain by the American College of Rheumatology. "Muscle pain is typically aggravated by inactivity or exposure to cold. This condition is often associated with general symptoms, such as sleep disturbances, fatigue, stiffness, headaches, and occasionally depression. There is significant overlap between fibromyalgia and the chronic fatigue syndrome (fatigue syndrome, chronic). Fibromyalgia may arise as a primary or secondary disease process. It is most frequent in females aged 20 to 50 years." (From Adams et al., Principles of Neurology, 6th ed, p1494-95)".

Multiple comorbid symptoms and syndromes may accompany fibromyalgia, including tension/migraine headache, affective disorders, temporomandibular joint disorder, idiopathic low back pain, irritable bowel syndrome, nondermatomal paresthesias, fatigue, memory and cognitive difficulties, and others. Comorbid tension headache is present in over 70% of women and 50% of men with fibromyalgia.

Once a diagnosis concerned, the next steps involve identification, in this highly individual disease, of important symptom domains, their severity, and level of patient function. The only diagnostic instrument that has been validated for measure of function and quality of life in fibromyalgia is the Fibromyalgia Impact Questionnaire (FIQ). Patients should be evaluated for comorbid medical and psychiatric disorders, psychosocial stressors, level of fitness, and barriers to treatment. Education should be provided and treatment options should be reviewed.

Etiology/causation

Fibromyalgia appears to have a multifactorial pathophysiology, which includes a strong familial predisposition, central pain amplification, psychiatric comorbid conditions, and other factors, such as immune dysregulation and the role of neurohormones such as dopamine, and growth hormone. Magnetic resonance imaging studies have provided objective evidence to show that patients with fibromyalgia have a lower threshold for pain sensitivity.

Genetics

Using self-report of chronic widespread pain (CWP) as a surrogate marker for fibromyalgia, the Swedish Twin Registry suggests a modest genetic contribution:

• Monozygotic twins with CWP have a 15% chance that their twin sibling has CWP
• Dizygotic twins with CWP have a 7% chance that their twin sibling has CWP

Abnormal sleep

Fibromyalgia is associated with alpha sleep. However, it is unclear if this abnormal sleep pattern causes or follows fibromyalgia.

Vitamin D deficiency

Although initial studies suggest that low vitamin D levels may be associated with nonspecific musculoskeletal pain; more recent studies make this doubtful.

Symptoms

Symptoms from associated illnesses

Fluid retention might be associated with fibromyalgia. This is difficult to interpret as normal patients may have a 9 pound diurnal variation in weight.

Diagnosis

American College of Rheumatology diagnostic criteria

Specific ACR diagnostic criteria are:

• History of widespread pain, considered widespread when all of the following are present: pain in the left and right sides of the body, pain above and below below the waist, and axial skeletal pain (cervical spine or anterior chest or thoracic spine or low back). In this definition, shoulder and buttock pain is considered as pain for each involved side. "Low back" pain is considered lower segment pain.
• An examiner must be able to trigger what the patient describes as "pain", not "tenderness", with finger pressure of approximately 4 kg, at 11 of the following 18 sites:
  • Occiput: Bilateral, at the suboccipital muscle insertions.
  • Low cervical [spine]: bilateral, at the anterior aspects of the intertransverse spaces at C5-C7.
  • Trapezius muscle: bilateral, at the midpoint of the upper border.
  • Supraspinatus muscle: bilateral, at origins, above the scapula spine near the medial border.
  • Second rib: bilateral, at the second costochondral junctions, just lateral to the junctions on upper surfaces.
  • Lateral epicondyle: bilateral, 2 cm distal to the epicondyles.
  • Gluteal: bilateral, in upper outer quadrants of buttocks in anterior fold of muscle.
  • Greater trochanter: bilateral, posterior to the trochanteric prominence.
  • Knee: bilateral, at the medial fat pad proximal to the joint line.

The ACR diagnostic criteria have accuracy of:

• Sensitivity 88.4%
• Specificity 81.1%

Differential diagnosis

A cohort study found that widespread pain significantly increased risk of subsequent diagnosis of cancer, especially breast cancer and prostate cancer. The biological reason for this association is not clear.

Treatment

Clinical practice guidelines by the European League Against Rheumatism (EULAR) recommendations (parentheses contain levels of evidence and strength of recommendation) are included below.
General

1. "Full understanding of fibromyalgia requires comprehensive assessment of pain, function and psychosocial context. Fibromyalgia should be recognised as a complex and heterogeneous condition where there is abnormal pain processing and other secondary features" (IV D)
2. "Optimal treatment requires a multidisciplinary approach with a combination of non-pharmacological and pharmacological treatment modalities tailored according to pain intensity, function, associated features such as depression, fatigue and sleep disturbance in discussion with the patient" (IV D)

Despite different modes of action, a variety of neuromodulatory agents may improve the symptoms of fibromyalgia patients. These include antidepressants, analgesics, anticonvulsants, muscle relaxants, and sedative hypnotic drugs. Only 2 drugs are FDA-approved for the specific treatment of fibromyalgia: pregabalin (Lyrica®) and duloxetine hydrochloride (Cymbalta®).

Non-pharmacological management

According to the clinical practice guidelines:

1. "Heated pool treatment with or without exercise is effective in fibromyalgia" (IIa B)
2. "Individually tailored exercise programmes, including aerobic exercise and strength training can be beneficial to some patients" with fibromyalgia" (IIb C). Subsequent to the 2008 EULAR clinical practice guidelines, a meta-analysis of randomized controlled trials found "aerobic-only training has beneficial effects on physical function and some FM symptoms. Strength-only training may improve FM symptoms, but requires further study."
3. "Cognitive behavioural therapy may be of benefit to some patients with fibromyalgia" IV D)
4. "Other therapies such as relaxation, rehabilitation, physiotherapy and psychological support may be used depending on the needs of the individual patient (IIb C)

In addition:

• Tai Chi was helpful in an unblinded study.
• Cognitive behavioral therapy " provided a small incremental benefit over control interventions in reducing pain, negative mood and disability at the end of treatment and at long-term follow-up" according to the Cochrane Collaboration.
• Musculoskeletal manipulation may help.

Pharmacological management

Medications for fibromyalgia

Study	Patients	Intervention	Results
Amitriptyline
Üçeyler, 2008 Meta-analysis	multiple trials	Various doses of 10-100 mg per day	Did not pool comparative outcomes
Arnold, 2000 Meta-analysis	multiple trials	Various doses of 5-50 mg per day	Did not pool comparative outcomes
O'Malley, 2000 Meta-analysis	multiple trials	Various doses of 5-50 mg per day	Did not isolate the effect of amitriptyline
Carette, 1994 Randomized controlled trial	166 patients	10 to 50 mg per day	response at 6 months drug = 36% and placebo = 19%
Hannonen, 1998 Randomized controlled trial	97 patients	25 mg or 37.5 mg per day	At least minimal improvement: response at 3 months drug = 74% and placebo = 49%
Duloxetine
Arnold, 2004 Randomized controlled trial	207 patients	60 mg twice a day	No dichotomous results reported
Russell, 2008 Randomized controlled trial	194 patients	duloxetine 60 mg	30% reduction in their pain: response at 3 months, drug = 51% and placebo = 36%
Pregabalin
Mease, 2008 Randomized controlled trial	373 patients	pregabalin 450 mg	At least "much" improvement in their pain, drug = 43% and placebo = 35% At least "minimal" improvement in their pain, drug = 71% and placebo = 56%
Crofford, 2005 Randomized controlled trial	263 patients	pregabalin 450 mg	30% reduction in their pain: response at 3 months, drug = 48% and placebo = 27%
Milnacipran
Arnold, 2010Randomized controlled trial]]	1,025 patients	Milnacipran 100 mg	High dropout; industry sponsored

PD Image
Forest plot of selected randomized controlled trials of the treatment of fibromyalgia.

According to the clinical practice guidelines:

1. "Tramadol is recommended for the management of pain in fibromyalgia" (Ib A)
2. "Simple analgesics such as paracetamol and other weak opioids can also be considered in the treatment of fibromyalgia. Corticosteroids and strong opioids are not recommended (IV D)
3. "Antidepressants: amitriptyline, fluoxetine, duloxetine, milnacipran, moclobemide and pirlindole, reduce pain and often improve function, therefore they are recommended for the treatment of fibromyalgia" (Ib A)
4. Tropisetron, pramipexole and pregabalin reduce pain and are recommended for the treatment of fibromyalgia" (Ib A)

Pregabalin (Lyrica) is approved for use in the United States by the Food and Drug Administration (FDA) for fibromyalgia. As compared to placebo, pregabalin benefits about 1 of every 6 people who use it if they are similar to the patients in a randomized controlled trial. In this trial, 33% of the patients who took the drug had a reduction in their pain versus 13% of the patients who took placebo. In a second randomized controlled trial, 43% of the patients who took the drug had a reduction in their pain versus 35% of the patients who took placebo. In this second trial, one out of every twelve patients taking the drug benefited from the drug. Both trials were sponsored by Pfizer, the makers of Lyrica, which increases the likelihood of publication bias towards positive results.

Duloxetine (Cymbalta), a SNRI second-generation antidepressant, is approved for use in the United States by the Food and Drug Administration (FDA) for fibromyalgia. As compared to placebo, duloxetine 60 mg per day benefits about 1 of every 7 people who use it if they are similar to the patients in an randomized controlled trial. In this trial, 51% of the patients who took the drug had a 30% reduction in their pain versus 36% of the patients who took placebo (data not reported for 50% reduction). This trial was sponsored by the makers of Cymbalta which increases the likelihood of publication bias towards positive results.

Milnacipran, a SNRI second-generation antidepressant is approved for use in the United States by the Food and Drug Administration (FDA) for fibromyalgia.

New therapies

Sodium oxybate may help according to a randomized controlled trial that was funded by industry.