What are the treatment options for restless leg syndrome?

Treatment of Restless Legs Syndrome

Start with Iron Assessment and Correction

The American Academy of Sleep Medicine strongly recommends checking serum ferritin and transferrin saturation in all patients with RLS before initiating any pharmacologic therapy, as correcting iron deficiency is foundational to successful treatment. 1

• Check iron studies in the morning after avoiding iron supplements for at least 24 hours 1
• Provide iron supplementation if ferritin ≤75 ng/mL or transferrin saturation <20% (note this threshold is higher than general population guidelines) 1, 2
• Use oral ferrous sulfate for mild iron deficiency (conditional recommendation, moderate certainty) 2
• Use IV ferric carboxymaltose for more robust iron repletion (strong recommendation, moderate certainty), particularly when ferritin is 75-100 ng/mL or oral supplementation fails 1, 2

Eliminate Exacerbating Factors

Before starting medications, address factors that worsen RLS 1, 2:

• Discontinue or substitute antihistaminergic medications (common culprit in over-the-counter sleep aids) 1
• Discontinue or substitute serotonergic medications (SSRIs, SNRIs) 1
• Discontinue or substitute antidopaminergic medications (antipsychotics like lurasidone) 1
• Reduce or eliminate alcohol and caffeine 1
• Treat untreated obstructive sleep apnea if present 1

First-Line Pharmacologic Treatment: Alpha-2-Delta Ligands

The American Academy of Sleep Medicine strongly recommends gabapentin, gabapentin enacarbil, or pregabalin as first-line therapy for RLS (strong recommendation, moderate certainty of evidence) 1, 2:

• Gabapentin enacarbil is strongly recommended and offers once-daily dosing 1, 2
• Gabapentin is strongly recommended; start at 300 mg three times daily and titrate up to 1800-2400 mg/day divided three times daily based on response 1
• Pregabalin is strongly recommended and allows twice-daily dosing with potentially superior bioavailability 1, 2

Critical advantage: Alpha-2-delta ligands avoid augmentation, the paradoxical worsening of RLS symptoms that commonly occurs with dopamine agonists 1, 3

Common side effects include somnolence and dizziness, which are typically transient and mild 1

Dopamine Agonists: Use with Extreme Caution

The American Academy of Sleep Medicine now suggests AGAINST the standard use of dopamine agonists due to the high risk of augmentation 1, 2:

• Pramipexole: conditional recommendation against standard use (moderate certainty) 1, 2
• Ropinirole: conditional recommendation against standard use (moderate certainty) 1, 2
• Rotigotine transdermal: conditional recommendation against standard use (low certainty) 1
• Levodopa: conditional recommendation against standard use (very low certainty) 1, 2
• Cabergoline: strong recommendation AGAINST use (moderate certainty) 1, 2

Despite FDA approval of ropinirole for RLS 4, current guidelines reflect evolving understanding that augmentation occurs in a substantial proportion of patients on long-term dopaminergic therapy, leading to progressive worsening of symptoms with earlier onset, increased severity, and anatomic spread 3

These agents may only be considered for short-term treatment in patients who prioritize immediate symptom relief over long-term adverse effects 1, 2

Second-Line Options for Refractory Cases

When alpha-2-delta ligands and iron supplementation fail 1:

• Extended-release oxycodone and other low-dose opioids (methadone, buprenorphine) are conditionally recommended for refractory RLS 1

• Evidence suggests relatively low risks of abuse and overdose in appropriately screened patients, with only small dose increases over 2-10 years 1

• Opioids are particularly effective for treating augmentation when transitioning off dopamine agonists 1, 3

• Caution: Monitor for respiratory depression and central sleep apnea, especially in patients with untreated OSA or COPD 1

• Bilateral high-frequency peroneal nerve stimulation is a newer non-invasive option (conditional recommendation, moderate certainty) 1, 2

• Dipyridamole is conditionally recommended (low certainty) 1

Managing Dopaminergic Augmentation

If a patient is already on a dopamine agonist and develops augmentation 1, 3:

• Do not abruptly discontinue the dopamine agonist due to severe rebound RLS and insomnia 3
• Add an alpha-2-delta ligand or opioid first and titrate to therapeutic doses 3
• Once adequate symptom control is achieved with the second agent, perform very slow down-titration of the dopamine agonist over weeks to months 3

Augmentation is characterized by 1:

• Earlier onset of symptoms during the day
• Increased symptom intensity
• Spread of symptoms to other body parts (arms, trunk)

Special Populations

End-stage renal disease: 1, 2

• Gabapentin is conditionally recommended (very low certainty) 1
• IV iron sucrose if ferritin <200 ng/mL and transferrin saturation <20% (conditional recommendation, moderate certainty) 1
• Vitamin C is conditionally recommended (low certainty) 1

Pregnancy: 2

• Treatment selection must consider pregnancy-specific safety profiles 2
• Non-pharmacologic approaches are preferred when possible 2
• Iron supplementation is particularly important if deficient 2

Pediatric RLS: 1

• Ferrous sulfate is conditionally recommended if ferritin <50 ng/mL (very low certainty) 1
• Monitor for constipation with oral iron 1

Critical Pitfalls to Avoid

• Do not start dopamine agonists as first-line therapy despite their FDA approval and historical use—current evidence strongly favors alpha-2-delta ligands to avoid augmentation 1, 2
• Do not ignore iron status—even "normal" ferritin levels may be insufficient for RLS patients; the threshold is ≤75 ng/mL, not the general population cutoff 1, 2
• Do not use single nighttime dosing of gabapentin—this fails to address daytime symptoms and provides suboptimal coverage; use three-times-daily dosing 1
• Do not prescribe medications that worsen RLS (antihistamines, most antidepressants, antipsychotics) without considering alternatives 1
• Do not rapidly discontinue dopamine agonists if augmentation develops—add alternative therapy first, then taper slowly 3