Restless Legs Syndrome: A Review.

Restless legs syndrome affects approximately 3% of US adults to a clinically significant extent, with 8% experiencing symptoms of any frequency annually.

• Approximately 8% of US adults experience RLS symptoms of any frequency annually.
• 3% experience moderately or severely distressing symptoms at least twice weekly.
• RLS prevalence is 10% in adults aged 65 years and older.
• Female sex is a risk factor, with a 2:1 ratio versus male sex.
• These figures are based on population-based studies.

RLS is associated with elevated rates of cardiovascular disease, depression, and suicidal ideation or self-harm.

• 29.6% of RLS patients had coronary artery disease, stroke, or heart failure.
• 30.4% of RLS patients had depression.
• Suicidal ideation or self-harm occurred at a rate of 0.35 cases per 1000 person-years.
• Patients with RLS also have impaired quality of life.

RLS is common among patients with several comorbid conditions and during pregnancy.

• RLS prevalence is 27.5% among patients with multiple sclerosis.
• RLS prevalence is 24% among patients with end-stage kidney disease.
• RLS prevalence is 23.9% among patients with iron deficiency anemia.
• RLS prevalence is 22% during pregnancy, especially in the third trimester.
• RLS prevalence is 21.5% with peripheral neuropathy (e.g., diabetic, idiopathic) and 20% with Parkinson disease.

RLS is diagnosed based on clinical history, and polysomnography is not recommended for diagnosis.

• Diagnosis relies on clinical history rather than objective sleep testing.
• Polysomnography is explicitly not recommended for RLS diagnosis.
• Symptoms are characterized by an overwhelming urge to move the limbs, often accompanied by unpleasant sensations such as achiness and tingling.
• Symptoms are provoked by immobility, relieved by movement, and are typically present or most severe in the evening or at night.

Iron supplementation is recommended as initial management for RLS patients with serum ferritin of 100 ng/mL or less or transferrin saturation less than 20%.

• Oral iron supplementation with ferrous sulfate 325–650 mg daily or every other day is recommended.
• Intravenous iron at a dose of 1000 mg is also an option.
• The threshold for treatment is serum ferritin level ≤100 ng/mL or transferrin saturation <20%.
• Iron supplementation is considered part of initial management before or alongside pharmacologic therapy.

Medications associated with RLS exacerbation, including serotonergic antidepressants, dopamine antagonists, and centrally acting H1 antihistamines, should be discontinued if possible.

• Serotonergic antidepressants are identified as medications associated with RLS.
• Dopamine antagonists are identified as medications associated with RLS.
• Centrally acting H1 antihistamines, such as diphenhydramine, are specifically named as exacerbating agents.
• Cessation of exacerbating medications is part of initial management.

Gabapentinoids are first-line pharmacologic therapy for RLS, with approximately 70% of treated patients showing much or very much improved symptoms versus approximately 40% with placebo.

• Gabapentinoids include gabapentin, gabapentin enacarbil, and pregabalin.
• In randomized clinical trials, approximately 70% of patients treated with gabapentinoids had much or very much improved RLS symptoms.
• Approximately 40% of placebo-treated patients had much or very much improved symptoms.
• The difference was statistically significant (P < .001).
• Gabapentinoids have replaced dopamine agonists as the recommended first-line treatment.

Dopamine agonists are no longer recommended as first-line medications for RLS due to the risk of augmentation.

• Dopamine agonists include ropinirole, pramipexole, and rotigotine.
• Augmentation is described as an iatrogenic worsening of RLS symptoms.
• The annual incidence of augmentation with dopamine agonists is 7% to 10%.
• This risk is the primary reason dopamine agonists have been downgraded from first-line status.

Low-dose opioids are recommended for patients who do not improve with first-line treatment or who have augmented RLS.

• Methadone at a dose of 5–10 mg daily is specifically cited as an example.
• Opioids are positioned as a treatment option for refractory or augmented RLS.
• This recommendation applies to patients who fail first-line gabapentinoid therapy.