What is the recommended treatment algorithm for restless‑leg syndrome, including evaluation of iron deficiency (serum ferritin) and first‑line pharmacologic options?

Treatment Algorithm for Restless Legs Syndrome

Alpha-2-delta ligands (gabapentin, gabapentin enacarbil, or pregabalin) are the strongly recommended first-line pharmacologic treatment for RLS, but only after checking and correcting iron deficiency (ferritin ≤75 ng/mL or transferrin saturation <20%). 1

Step 1: Initial Assessment and Iron Evaluation

Check morning fasting serum ferritin and transferrin saturation in all patients with clinically significant RLS, ideally after avoiding iron-containing supplements for at least 24 hours. 1, 2 This is a critical first step that must not be skipped, as iron deficiency plays a key role in RLS pathophysiology even when serum iron appears normal. 1

Iron Supplementation Thresholds (Different from General Population)

• Adults: Supplement if ferritin ≤75 ng/mL or transferrin saturation <20% 1, 3, 2
• Children: Supplement if ferritin <50 ng/mL 1

These thresholds are higher than standard anemia guidelines because brain iron deficiency drives RLS symptoms independently of systemic iron status. 1

Iron Supplementation Options

For oral iron: Start ferrous sulfate 325 mg daily or every other day (alternate-day dosing may improve absorption and reduce GI side effects). 3 Continue for 3-6 months after symptom improvement to replenish stores, then monitor every 6-12 months indefinitely as RLS may recur if iron stores decline. 1, 3

For IV iron: Use IV ferric carboxymaltose (strong recommendation, moderate certainty) when oral iron is not tolerated or ineffective after 3 months, or when ferritin is between 75-100 ng/mL. 1, 2 Dose: 750-1000 mg in one or two infusions. 1

Step 2: Address Exacerbating Factors

Before starting any medication, eliminate or reduce: 1, 2

• Alcohol, caffeine, and nicotine (especially within 3 hours of bedtime)
• Antihistaminergic medications (including over-the-counter sleep aids)
• Serotonergic medications (SSRIs, SNRIs)
• Antidopaminergic medications (antipsychotics, metoclopramide)
• Untreated obstructive sleep apnea

This step is non-negotiable—even moderate evening caffeine or alcohol can significantly worsen RLS symptoms and undermine pharmacologic treatment. 1

Step 3: First-Line Pharmacologic Treatment (Alpha-2-Delta Ligands)

If symptoms persist after iron correction and elimination of exacerbating factors, start an alpha-2-delta ligand. 1, 2 These agents have strong evidence (moderate certainty) and avoid the augmentation risk that plagues dopamine agonists. 1

Gabapentin (Strong Recommendation, Moderate Certainty)

• Starting dose: 300 mg three times daily (900 mg/day total) 1
• Titration: Increase by 300 mg/day every 3-7 days if symptoms persist 1
• Target maintenance: 1800-2400 mg/day divided three times daily 1
• Maximum studied dose: 3600 mg/day 1
• Common side effects: Somnolence and dizziness (typically transient and mild) 1

Critical pitfall: Single nighttime dosing fails to address daytime RLS symptoms and provides suboptimal 24-hour coverage. 1 Three-times-daily dosing is necessary for adequate symptom control.

Pregabalin (Strong Recommendation, Moderate Certainty)

• Starting dose: 75 mg once daily 1-2 hours before bedtime 3
• Titration: Increase to 150-300 mg daily as needed 3
• Advantages: Twice-daily dosing and potentially superior bioavailability compared to regular gabapentin 1, 3

Gabapentin Enacarbil (Strong Recommendation, Moderate Certainty)

• A prodrug of gabapentin with improved bioavailability 1
• Cost consideration: Regular gabapentin and pregabalin are equally effective but far less expensive than gabapentin enacarbil 1

Step 4: Special Populations

End-Stage Renal Disease (ESRD)

• Gabapentin: Start 100 mg post-dialysis or at bedtime; maximum 200-300 mg daily 1, 2
• Avoid pregabalin in ESRD due to increased hazard for altered mental status and falls (50-68% higher hazard) 1
• IV iron sucrose: Use if ferritin <200 ng/mL AND transferrin saturation <20% 1, 2
• Vitamin C supplementation: May enhance iron utilization 1, 2

Pregnancy

• Iron supplementation is particularly important given pregnancy-specific RLS prevalence, with a safety profile favoring oral formulations throughout gestation 1
• Consider pregnancy-specific safety profiles when selecting any pharmacologic treatment 2

Step 5: Refractory Cases and Second-Line Options

If alpha-2-delta ligands are ineffective or not tolerated at adequate doses:

Extended-Release Oxycodone and Other Opioids (Conditional Recommendation, Moderate Certainty)

• Reserved for moderate to severe refractory RLS 1, 4
• Long-term studies show relatively low risks of abuse/overdose in appropriately screened patients, with only small dose increases over 2-10 years 1
• Critical monitoring: Assess for respiratory depression, especially if untreated sleep apnea is present 1

Bilateral High-Frequency Peroneal Nerve Stimulation (Conditional Recommendation, Moderate Certainty)

• A newer noninvasive treatment option with initial success in short-term studies 1

Medications to AVOID

Dopamine Agonists (Pramipexole, Ropinirole, Rotigotine)

The American Academy of Sleep Medicine suggests AGAINST standard use of dopamine agonists due to high risk of augmentation—a paradoxical worsening of symptoms with long-term use. 1, 2, 4 Augmentation occurs in 7-10% annually and presents as: 1

• Earlier symptom onset during the day
• Increased symptom intensity
• Spread to arms or trunk
• Paradoxical worsening despite dose increases

If augmentation occurs: Do NOT increase the dopamine agonist dose. 1 Instead, add an alpha-2-delta ligand or opioid first, then slowly taper and discontinue the dopamine agonist. 4

Other Medications to Avoid (Strong or Conditional Recommendations Against)

• Cabergoline (strong recommendation against) 1, 2
• Levodopa (conditional recommendation against, very low certainty) 1, 2
• Clonazepam (conditional recommendation against, very low certainty—does not reduce objective disease markers) 1
• Bupropion, carbamazepine, valproic acid, valerian 1

Critical Pitfalls to Avoid

1. Do NOT start pharmacologic treatment without first checking and addressing iron status. 1, 3, 2 This is the most common error in RLS management.

2. Do NOT use dopamine agonists as first-line therapy. 1, 2 The augmentation risk (7-10% annually) makes them inappropriate for initial treatment despite their rapid symptom relief. 1

3. Do NOT assume "normal" ferritin (>50 ng/mL) means iron is adequate for RLS. 1 The threshold for RLS is ≤75 ng/mL, not the standard anemia cutoff. 1, 3, 2

4. Do NOT dose gabapentin once daily at bedtime. 1 Three-times-daily dosing is necessary for adequate 24-hour symptom control. 1

5. Do NOT continue iron supplementation indefinitely without monitoring. 1, 3 Recheck iron studies every 6-12 months to prevent both deficiency recurrence and iron overload. 1, 3

Monitoring and Follow-Up

• Reassess iron studies every 6-12 months even after symptom resolution 1
• Monitor for side effects of alpha-2-delta ligands (dizziness, somnolence) 1
• Evaluate improvement in both nighttime RLS symptoms and daytime functioning (alertness, concentration, mood) 1
• Screen for augmentation if dopamine agonists were ever used (earlier onset, increased intensity, anatomic spread) 1