How should I manage a patient with restless‑legs syndrome (RLS), including confirming the diagnosis, evaluating for secondary causes, correcting low ferritin, implementing lifestyle measures, and selecting appropriate pharmacologic therapy?

Management of Restless Legs Syndrome

Start with alpha-2-delta ligands (gabapentin, gabapentin enacarbil, or pregabalin) as first-line pharmacologic therapy after confirming the diagnosis and optimizing iron status—dopamine agonists are no longer recommended for standard use due to a 7–10% annual risk of augmentation. 1, 2

Diagnostic Confirmation

Confirm RLS using the four essential clinical criteria 3, 1:

• Urge to move the legs accompanied by uncomfortable or unpleasant sensations 3
• Symptoms begin or worsen during rest or inactivity (sitting, lying down) 3
• Partial or complete relief with movement (walking, stretching) that lasts as long as the activity continues 3
• Symptoms worse or only occur in the evening or night 3

No polysomnography is required for diagnosis—the diagnosis is made by clinical history alone in the majority of cases. 3, 4

Perform a thorough neurologic examination to identify secondary causes such as peripheral neuropathy or radiculopathy, though the physical exam is usually unremarkable in primary RLS. 3

Evaluate for Secondary Causes and Exacerbating Factors

Check morning fasting serum ferritin and transferrin saturation after withholding iron supplements for at least 24 hours before starting any medication. 1, 2

Eliminate or reduce medications that exacerbate RLS 3, 1, 2:

• Tricyclic antidepressants and SSRIs 3
• Dopamine antagonists (antipsychotics) 3
• Centrally acting H1 antihistamines (diphenhydramine) 4
• Lithium 3

Address lifestyle factors that worsen symptoms 3, 1:

• Eliminate or reduce caffeine and alcohol, especially within 3 hours of bedtime 1
• Implement moderate exercise (avoid vigorous exercise close to bedtime) 1
• Encourage smoking cessation 1
• Screen for and treat untreated obstructive sleep apnea 1, 2

Iron Supplementation

Initiate iron supplementation if ferritin ≤75 ng/mL OR transferrin saturation <20%—these thresholds are higher than general population guidelines because brain iron deficiency plays a key role in RLS pathophysiology. 5, 1, 2

Oral Iron Options

Start ferrous sulfate 325 mg daily or every other day (alternate-day dosing may improve absorption and reduce gastrointestinal side effects). 5, 1

• Take on an empty stomach or with vitamin C to enhance absorption 5
• Continue for 3–6 months after symptoms improve to replenish iron stores 5
• Monitor ferritin every 6–12 months indefinitely, as RLS symptoms may recur if iron stores decline 5, 2

Intravenous Iron

IV ferric carboxymaltose 750–1000 mg (one or two infusions) is strongly recommended for patients who do not respond to oral therapy, cannot tolerate oral iron, or have ferritin 75–100 ng/mL despite oral treatment. 1, 2

Alternative IV formulations include low molecular weight iron dextran and ferumoxytol (conditional recommendations). 2

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

Alpha-2-delta ligands are strongly recommended as first-line therapy with moderate certainty of evidence because they effectively reduce RLS symptoms without causing augmentation. 5, 1, 2

Gabapentin Dosing

• Start 300 mg three times daily 1, 2
• Titrate by 300 mg/day every 3–7 days until reaching maintenance dose 1
• Target maintenance dose: 1800–2400 mg/day divided three times daily 1, 2
• Maximum studied dose is 3600 mg/day, which is well-tolerated in clinical studies 1

Pregabalin Dosing

• Start 75 mg once daily 1–2 hours before bedtime 5
• Titrate to 150–300 mg daily as needed 5
• Pregabalin allows twice-daily dosing and has potentially superior bioavailability compared to regular gabapentin 5, 1

Gabapentin Enacarbil

Gabapentin enacarbil is a prodrug of gabapentin that is also strongly recommended as first-line therapy. 1, 2

Common side effects of alpha-2-delta ligands include somnolence and dizziness, which are typically transient and mild. 1

Medications to Avoid or Use with Extreme Caution

Dopamine Agonists (Pramipexole, Ropinirole, Rotigotine)

The American Academy of Sleep Medicine suggests AGAINST standard use of dopamine agonists due to a 7–10% annual risk of augmentation—a paradoxical worsening of RLS symptoms. 5, 1, 2

Augmentation presents as 1, 2:

• Earlier onset of symptoms during the day (afternoon instead of evening)
• Increased symptom intensity
• Spread of symptoms to arms or trunk
• Paradoxical worsening despite dose increases

Dopamine agonists may be considered only for short-term use in patients who prioritize immediate symptom relief over long-term safety, but this is explicitly not the standard approach. 2

Other Medications to Avoid

Strong or conditional recommendations against 1, 2:

• Cabergoline (cardiac valvular fibrosis risk)
• Clonazepam (insufficient efficacy evidence, sedation, fall risk)
• Levodopa (high augmentation risk)
• Bupropion, carbamazepine, valproic acid, valerian

Second-Line and Refractory RLS Treatment

When to Consider Second-Line Therapy

If symptoms persist after 3 months of optimized iron supplementation and adequate trials of alpha-2-delta ligands (gabapentin 1800–2400 mg/day or pregabalin up to 600 mg/day), consider second-line options. 5, 1

Opioid Therapy for Refractory RLS

Extended-release oxycodone and other low-dose opioids (methadone 5–10 mg daily, buprenorphine) are conditionally recommended for moderate to severe refractory RLS, particularly when treating augmentation from dopamine agonists. 1, 2, 4

Long-term studies show relatively low risks of abuse and overdose in appropriately screened patients, with only small dose increases over 2–10 years. 5, 2

Before initiating opioids 2:

• Screen for opioid-use-disorder risk using validated tools
• Evaluate for untreated obstructive sleep apnea (opioids increase respiratory depression risk)
• Monitor respiratory status closely during the first weeks
• Prescribe prophylactic stool softeners or laxatives for constipation

Non-Pharmacologic Alternative

Bilateral high-frequency peroneal nerve stimulation is conditionally recommended as a non-invasive option with moderate certainty of evidence. 1, 2

Special Populations

End-Stage Renal Disease

• Gabapentin: Start 100 mg post-dialysis or at bedtime; maximum 200–300 mg daily 1, 2
• IV iron sucrose if ferritin <200 ng/mL AND transferrin saturation <20% 1, 2
• Avoid pregabalin in ESRD due to increased hazard of altered mental status and falls 5, 2
• Vitamin C supplementation may enhance iron utilization 1, 2

Pediatric RLS

• Iron supplementation if ferritin <50 ng/mL (lower threshold than adults) 1, 2
• Monitor for constipation with oral iron 5, 2

Pregnancy

Iron supplementation is particularly important given pregnancy-specific RLS prevalence, with a safety profile favoring oral formulations throughout gestation. 2

Managing Dopaminergic Augmentation

If a patient is already on a dopamine agonist and develops augmentation 2:

1. Do NOT increase the dopamine agonist dose—this worsens augmentation
2. Add an alpha-2-delta ligand (gabapentin 300 mg TID, titrated to 1800–2400 mg/day) or an opioid before tapering the dopamine agonist
3. Once symptom control is achieved, taper the dopamine agonist very slowly (reduce by 0.125–0.25 mg pramipexole-equivalent every 1–2 weeks)
4. Anticipate rebound RLS and insomnia during the taper

Critical Pitfalls to Avoid

• Do not use dopamine agonists as first-line therapy given the high augmentation risk and current guideline recommendations favoring alpha-2-delta ligands 1, 2
• Do not label RLS as refractory without first optimizing iron status—patients with ferritin 75–100 ng/mL may still benefit from IV iron 2
• Do not apply general-population ferritin cut-offs to RLS—the disease-specific threshold is ≤75 ng/mL for adults 1, 2
• Do not increase dopamine-agonist doses when symptoms worsen, as this likely reflects augmentation rather than disease progression 2
• Do not use clonazepam as monotherapy for RLS—it provides only sedation without addressing the underlying disorder 1, 2
• Do not combine multiple sedating agents (opioids + alpha-2-delta ligands + benzodiazepines) without first treating obstructive sleep apnea 2