What are the treatment options for Restless Legs Syndrome (RLS)?

Treatment Options for Restless Legs Syndrome

Start with alpha-2-delta ligands (gabapentin, gabapentin enacarbil, or pregabalin) as first-line pharmacological treatment, but only after checking and correcting iron deficiency. 1, 2

Initial Assessment: Iron Status First

Before starting any medication, check morning fasting iron studies including serum ferritin and transferrin saturation 2, 3:

• Supplement with iron if ferritin ≤75 ng/mL or transferrin saturation <20% (note: this threshold is higher than general population guidelines) 1, 4
• IV ferric carboxymaltose is strongly recommended for rapid correction in patients meeting these iron parameters 1, 2
• Oral ferrous sulfate is an alternative but works more slowly 1, 4

This iron threshold differs critically from standard anemia guidelines because brain iron deficiency plays a key role in RLS pathophysiology even when serum iron appears "normal" 4, 3.

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

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

Gabapentin Dosing

• Start at 300 mg three times daily (900 mg/day total) 2, 3
• Titrate by 300 mg/day every 3-7 days until reaching maintenance dose of 1800-2400 mg/day divided three times daily 2, 3
• Avoid single nighttime dosing—it fails to address daytime RLS symptoms and provides suboptimal 24-hour coverage 2
• Doses up to 3600 mg/day are well-tolerated in clinical studies 2

Pregabalin Alternative

• Allows twice-daily dosing with potentially superior bioavailability compared to gabapentin 2, 4
• Strongly recommended as first-line therapy with moderate certainty of evidence 1, 4

Why alpha-2-delta ligands are now preferred: They avoid the augmentation phenomenon (paradoxical worsening of symptoms) seen with dopamine agonists, which was the primary reason for the major shift away from dopaminergic agents in 2025 guidelines 1, 5.

Medications to Avoid or Use with Extreme Caution

Dopamine Agonists (No Longer First-Line)

The American Academy of Sleep Medicine suggests against the standard use of dopamine agonists due to high risk of augmentation 1, 5:

• Pramipexole: conditional recommendation against standard use (moderate certainty) 1, 4
• Ropinirole: conditional recommendation against standard use (moderate certainty) 1, 6
• Transdermal rotigotine: conditional recommendation against standard use (low certainty) 1, 4
• Levodopa: conditional recommendation against standard use (very low certainty) 1, 4

These agents may only be considered for short-term use in patients who prioritize immediate symptom relief over long-term adverse effects 1, 4. However, this represents a major departure from 2012 guidelines where dopamine agonists were first-line 5, 7.

Strongly Contraindicated

• Cabergoline: strong recommendation against use (moderate certainty) 1, 4

Other Medications to Avoid

• Bupropion (conditional recommendation against, moderate certainty) 1, 4
• Carbamazepine (conditional recommendation against, low certainty) 1, 4
• Clonazepam (conditional recommendation against, very low certainty) 1, 4
• Valproic acid (conditional recommendation against, low certainty) 1, 4

Second-Line Options for Refractory Cases

Extended-release oxycodone and other low-dose opioids are conditionally recommended for moderate to severe refractory RLS 2, 4:

• Evidence shows relatively low risks of abuse and overdose in appropriately screened patients 2, 8
• Particularly effective for treating augmentation when transitioning off dopamine agonists 4, 8
• Long-term studies show only small dose increases over 2-10 years 4
• Caution: Risk of respiratory depression and central sleep apnea, especially in patients with untreated obstructive sleep apnea 4

Non-Pharmacological Interventions

Address exacerbating factors 4, 3:

• Eliminate or reduce: alcohol, caffeine (especially in evening), nicotine 4, 3
• Discontinue if possible: antihistaminergic medications, serotonergic medications (SSRIs, SNRIs), antidopaminergic medications 1, 4
• Screen for and treat: untreated obstructive sleep apnea 1, 3
• Implement: moderate exercise (but avoid vigorous exercise close to bedtime) 4

Bilateral high-frequency peroneal nerve stimulation is conditionally recommended as a non-pharmacological option (moderate certainty) 1, 4.

Special Populations

End-Stage Renal Disease (ESRD)

• Gabapentin is conditionally recommended (very low certainty) 1, 4
• IV iron sucrose if ferritin <200 ng/mL and transferrin saturation <20% (conditional recommendation, moderate certainty) 1, 4
• Vitamin C is conditionally recommended (low certainty) 1, 4

Pediatric RLS

• Ferrous sulfate is conditionally recommended in patients with ferritin <50 ng/mL (very low certainty) 1, 4

Critical Pitfalls to Avoid

• Never start dopamine agonists as first-line therapy due to augmentation risk 2, 5
• Never use single nighttime dosing of gabapentin—three-times-daily dosing is necessary 2
• Never ignore iron deficiency even if ferritin appears "normal"—RLS patients require ferritin ≥75 ng/mL 2, 4
• If a patient is already on a dopamine agonist, do not abruptly discontinue—add an alpha-2-delta ligand or opioid first, then slowly taper the dopamine agonist to avoid profound rebound RLS 8
• Monitor for augmentation in any patient on dopamine agonists: earlier symptom onset during the day, increased intensity, spread to other body parts 4, 8