What are the treatment options for a patient diagnosed with Restless Legs Syndrome (RLS)?

Treatment for Restless Legs Syndrome

The American Academy of Sleep Medicine strongly recommends alpha-2-delta ligands (gabapentin, gabapentin enacarbil, or pregabalin) as first-line pharmacological treatment for RLS, with dopamine agonists now relegated to limited use due to high augmentation risk. 1, 2, 3

Initial Assessment: Iron Status First

Before starting any medication, check morning fasting iron studies including serum ferritin and transferrin saturation, ideally after avoiding iron supplements for at least 24 hours. 1, 2, 3

Critical threshold difference from general population: Supplement with iron if ferritin ≤75 ng/mL or transferrin saturation <20%—this is higher than standard anemia thresholds because brain iron deficiency drives RLS pathophysiology even when serum levels appear "normal." 1, 2, 3

Iron Supplementation Options:

• IV ferric carboxymaltose (1000 mg): Strongly recommended for rapid correction in hospitalized patients or those not responding to oral therapy, with moderate certainty of evidence. 1, 2, 3
• Oral ferrous sulfate (325-650 mg daily or every other day): Alternative option but works more slowly, with moderate certainty of evidence. 1, 2, 4

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

Gabapentin Dosing:

Start at 300 mg three times daily (900 mg/day total), then titrate by 300 mg/day every 3-7 days until reaching maintenance dose of 1800-2400 mg/day divided three times daily. 1, 2, 3

Critical pitfall to avoid: Never use single nighttime dosing—this fails to address daytime RLS symptoms and provides suboptimal 24-hour coverage. Three-times-daily dosing is necessary for adequate symptom control. 1

Pregabalin:

Alternative first-line option allowing twice-daily dosing with potentially superior bioavailability compared to gabapentin, strongly recommended with moderate certainty of evidence. 1, 2, 3

Gabapentin Enacarbil:

Prodrug of gabapentin, strongly recommended with moderate certainty of evidence, though significantly more expensive than generic gabapentin or pregabalin without superior efficacy. 3, 4

Expected outcomes: Approximately 70% of patients treated with gabapentinoids show much or very much improved RLS symptoms versus 40% with placebo. 4

Medications to Avoid or Use with Extreme Caution

Dopamine Agonists (Pramipexole, Ropinirole, Rotigotine):

The American Academy of Sleep Medicine suggests against standard use due to high risk of augmentation—an iatrogenic worsening characterized by earlier symptom onset during the day, increased intensity, and spread to upper extremities or trunk, with annual incidence of 7-10%. 1, 2, 3, 5, 4

Limited exception: May be considered only for short-term use in patients who place higher value on immediate symptom relief and lower value on long-term adverse effects. 1, 2

Note on FDA approval: While ropinirole remains FDA-approved for RLS with demonstrated efficacy in clinical trials, current guidelines prioritize long-term safety over short-term efficacy given augmentation risks. 6

Strongly Recommended Against:

• Cabergoline: Strong recommendation against use with moderate certainty. 2, 3
• Bupropion, carbamazepine, clonazepam, valproic acid: Conditional recommendations against with varying certainty levels. 1, 2, 3

Addressing Exacerbating Factors

Eliminate or reduce the following before escalating pharmacotherapy: 2, 3

• Alcohol, caffeine, and nicotine (especially within 3 hours of bedtime)
• Antihistaminergic medications (e.g., diphenhydramine)
• Serotonergic antidepressants
• Antidopaminergic medications
• Screen for and treat untreated obstructive sleep apnea

Second-Line Options for Refractory Cases

Low-Dose Opioids:

Extended-release oxycodone (5-10 mg daily) or methadone are conditionally recommended for moderate to severe refractory RLS, with evidence showing relatively low risks of abuse and overdose in appropriately screened patients. 1, 2, 3, 5, 4

Particularly effective for: Treating augmentation when transitioning off dopamine agonists, as they relieve worsening symptoms during DA down-titration. 2, 5

Long-term safety data: Studies show only small dose increases over 2-10 years in appropriately screened patients. 3, 5

Non-Pharmacological Option:

Bilateral high-frequency peroneal nerve stimulation: Conditionally recommended with moderate certainty of evidence. 2, 3

Special Populations

End-Stage Renal Disease:

• Gabapentin: Conditionally recommended starting at 100 mg post-dialysis or at bedtime, maximum 200-300 mg daily (very low certainty). 2, 3
• IV iron sucrose: Recommended if ferritin <200 ng/mL and transferrin saturation <20% (moderate certainty). 2, 3
• Avoid pregabalin: Higher hazard for altered mental status and falls in dialysis patients. 3

Pediatric RLS:

Ferrous sulfate: Conditionally recommended if ferritin <50 ng/mL (very low certainty), with monitoring for constipation. 2, 3

Pregnancy:

Iron supplementation particularly important given pregnancy-specific RLS prevalence of 22%, with safety profile favoring oral formulations throughout gestation. 3, 4

Managing Dopaminergic Augmentation

If a patient is already on a dopamine agonist experiencing augmentation: 5

1. Do not abruptly discontinue the DA—this causes profound rebound RLS and insomnia
2. Add an alpha-2-delta ligand or low-dose opioid first
3. Once adequate symptom relief achieved with the second agent, initiate very slow down-titration of the DA
4. Never increase the DA dose if augmentation is suspected—this worsens the problem

Treatment Monitoring

• Reassess iron studies every 6-12 months, as brain iron deficiency may persist despite normal serum parameters. 3
• Monitor for side effects of alpha-2-delta ligands including dizziness and somnolence, particularly in patients with untreated OSA or COPD. 3
• Evaluate improvement in both nighttime RLS symptoms and daytime functioning (alertness, concentration, mood). 3