What are the treatment options for restless legs syndrome?

Treatment of Restless Legs Syndrome

Alpha-2-delta ligands (gabapentin, gabapentin enacarbil, or pregabalin) are the first-line pharmacological treatment for RLS, with iron supplementation as initial therapy when ferritin ≤75 ng/mL or transferrin saturation <20%. 1

Initial Assessment and Iron Management

Before starting any medication, check serum iron studies in all patients with clinically significant RLS 1:

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

Address Exacerbating Factors

Identify and eliminate medications and substances that worsen RLS 1:

• Discontinue or substitute antihistamines, SSRIs/serotonergic medications, antipsychotics/dopamine antagonists 1
• Reduce or eliminate alcohol and caffeine intake 1
• Screen for and treat obstructive sleep apnea if present 1

First-Line Pharmacological Treatment

The American Academy of Sleep Medicine strongly recommends alpha-2-delta ligands as first-line therapy (strong recommendation, moderate certainty) 1:

• Gabapentin enacarbil (strong recommendation, moderate certainty) 1, 2
• Gabapentin (strong recommendation, moderate certainty) 1, 2
• Pregabalin (strong recommendation, moderate certainty) 1, 2

These agents are preferred over dopamine agonists because they do not cause augmentation—a paradoxical worsening of RLS symptoms with long-term use that occurs commonly with dopaminergic medications 1, 3.

Monitor for side effects including dizziness and somnolence, particularly in patients with untreated sleep apnea or COPD 1. There is increasing evidence these agents may be misused in certain populations, so evaluate risk factors for misuse before initiating treatment 1.

Medications to Avoid or Use with Extreme Caution

Dopamine agonists are NOT recommended for standard use due to high risk of augmentation 1, 2:

• The American Academy of Sleep Medicine suggests AGAINST standard use of pramipexole (conditional recommendation, moderate certainty) 1
• The American Academy of Sleep Medicine suggests AGAINST standard use of ropinirole (conditional recommendation, moderate certainty) 1
• The American Academy of Sleep Medicine suggests AGAINST standard use of levodopa (conditional recommendation, very low certainty) 1
• The American Academy of Sleep Medicine suggests AGAINST standard use of transdermal rotigotine (conditional recommendation, low certainty) 1

While ropinirole has FDA approval and demonstrated efficacy in clinical trials 4, the 2025 American Academy of Sleep Medicine guidelines now recommend against its standard use due to the significant long-term risk of augmentation 1. Dopamine agonists should only be considered for short-term treatment in patients who prioritize immediate symptom relief over long-term adverse effects 2.

The American Academy of Sleep Medicine strongly recommends AGAINST cabergoline (strong recommendation, moderate certainty) 1.

Additional medications to avoid 1:

• Bupropion (conditional recommendation, moderate certainty)
• Carbamazepine (conditional recommendation, low certainty)
• Clonazepam (conditional recommendation, very low certainty)
• Valproic acid (conditional recommendation, low certainty)

Second-Line and Refractory Treatment Options

For patients who fail first-line therapy or have severe refractory RLS 1:

• Extended-release oxycodone and other low-dose opioids (conditional recommendation) for moderate to severe cases, particularly when treating augmentation from dopaminergic agents 1
• Methadone and buprenorphine can be effective for refractory cases with relatively low risks of abuse and overdose in appropriately screened patients 1
• Bilateral high-frequency peroneal nerve stimulation (conditional recommendation, moderate certainty) as a non-pharmacological option 1

Critical caveat: Use opioids with caution due to risk of respiratory depression and central sleep apnea, especially in patients with untreated obstructive sleep apnea 1.

Managing Augmentation from Dopamine Agonists

If a patient develops augmentation (earlier onset of symptoms during the day, increased intensity, spread to other body parts) 1:

• Add an alpha-2-delta ligand or opioid BEFORE reducing the dopamine agonist to avoid profound rebound RLS and insomnia 3
• Once adequate symptom relief is achieved with the second agent, initiate very slow down-titration of the dopamine agonist 3
• Opioids are particularly effective for treating augmentation 1

Special Populations

End-stage renal disease patients 1:

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

Pregnancy 2:

• Treatment selection must consider pregnancy-specific safety profiles
• Non-pharmacologic approaches may be preferred
• Iron supplementation is particularly important

Pediatric RLS 1:

• Oral ferrous sulfate if ferritin <50 ng/mL (conditional recommendation, very low certainty)
• Monitor for constipation with iron supplementation

Non-Pharmacological Interventions

While evidence quality is limited, some interventions may provide benefit 5, 6:

• Regular physical activity should be recommended for RLS symptom treatment 5
• Pneumatic compression devices, near-infrared light therapy, and acupuncture show preliminary promise but require higher-quality trials 5, 6