What are the treatment options for a patient experiencing restless legs syndrome (RLS) at night?

Treatment of Restless Legs Syndrome at Night

Start with alpha-2-delta ligands (gabapentin, gabapentin enacarbil, or pregabalin) as first-line pharmacological therapy after checking and correcting iron status—avoid dopamine agonists like ropinirole due to high risk of augmentation despite FDA approval. 1, 2

Initial Assessment and Iron Correction

Before starting any medication, check morning fasting iron studies (ferritin and transferrin saturation) after avoiding iron supplements for at least 24 hours. 1, 2

Supplement with iron if ferritin ≤75 ng/mL or transferrin saturation <20%—this threshold is higher than general population guidelines because brain iron deficiency drives RLS pathophysiology even when serum iron appears normal. 1, 2

• IV ferric carboxymaltose is strongly recommended for rapid correction in patients meeting these iron parameters (strong recommendation, moderate certainty). 1, 2
• Oral ferrous sulfate is an alternative but works more slowly (conditional recommendation, moderate certainty). 1, 2

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

Gabapentin should be started at 300 mg three times daily (not as a single nighttime dose) and titrated by 300 mg/day every 3-7 days until reaching a maintenance dose of 1800-2400 mg/day divided three times daily. 1, 2 Single nighttime dosing fails to address daytime RLS symptoms and provides suboptimal coverage. 1

Pregabalin is an equally strong first-line option that allows twice-daily dosing with potentially superior bioavailability compared to gabapentin (strong recommendation, moderate certainty). 1, 2, 3

Gabapentin enacarbil (a prodrug of gabapentin) is also strongly recommended as first-line therapy with moderate certainty of evidence. 1

Common side effects include somnolence and dizziness, which are typically transient and mild. 1 These agents avoid the augmentation phenomenon seen with dopamine agonists. 1

Critical Medications to Avoid

Dopamine agonists (pramipexole, ropinirole, rotigotine) are NOT recommended for standard use despite FDA approval for ropinirole, due to high risk of augmentation—a paradoxical worsening of symptoms with earlier onset, increased intensity, and anatomic spread to other body parts. 1, 2, 4 The American Academy of Sleep Medicine suggests against their standard use (conditional recommendation, moderate certainty). 1, 2

• Cabergoline is strongly recommended against use (strong recommendation, moderate certainty). 1, 2
• Clonazepam is not recommended—it improves subjective sleep quality but does not reduce periodic limb movements and has insufficient efficacy evidence (conditional recommendation, very low certainty). 1
• Levodopa is suggested against due to very low certainty of evidence and high augmentation risk. 1

Non-Pharmacological Interventions

Address exacerbating factors before or alongside medication initiation: 1, 2, 3

• Eliminate or reduce alcohol, caffeine, and nicotine, especially within 3 hours of bedtime. 1
• Discontinue antihistaminergic medications (e.g., diphenhydramine, meclizine) and serotonergic medications (SSRIs, SNRIs) if possible, as these worsen RLS. 1
• Screen for and treat untreated obstructive sleep apnea, which exacerbates RLS symptoms. 1, 2, 3
• Implement moderate exercise (morning or afternoon, not close to bedtime). 1

Bilateral high-frequency peroneal nerve stimulation is conditionally recommended as a non-pharmacological option (conditional recommendation, moderate certainty). 1, 2

Second-Line Options for Refractory Cases

If first-line therapy fails or is not tolerated:

• Extended-release oxycodone and other low-dose opioids (methadone, buprenorphine) are conditionally recommended for moderate to severe refractory RLS, with evidence showing relatively low risks of abuse and overdose in appropriately screened patients (conditional recommendation, moderate certainty). 1, 2 These are particularly effective for treating augmentation when transitioning off dopamine agonists. 1, 2
• Dipyridamole may be considered (conditional recommendation, low certainty). 1

Special Populations

End-stage renal disease patients: Gabapentin is conditionally recommended starting at 100 mg post-dialysis or at bedtime with maximum doses of 200-300 mg daily (very low certainty). 1 IV iron sucrose is recommended if ferritin <200 ng/mL and transferrin saturation <20% (moderate certainty). 1, 2

Pediatric RLS: Ferrous sulfate is conditionally recommended if ferritin <50 ng/mL (very low certainty). 1, 2

Pregnancy: Special consideration of medication safety profiles is required, with iron supplementation particularly important given pregnancy-specific RLS prevalence. 1

Monitoring and Follow-Up

Reassess iron studies every 6-12 months even with symptom resolution, as brain iron deficiency may persist despite normal serum parameters. 1 Monitor for side effects of alpha-2-delta ligands (dizziness, somnolence) and evaluate improvement in both nighttime RLS symptoms and daytime functioning (alertness, concentration, mood). 1