How should restless legs syndrome be evaluated and treated, including assessment for reversible causes, iron supplementation dosing, and first‑line medication options?

Restless Legs Syndrome: Evaluation and Treatment

Initial Assessment and Iron Status

Check morning fasting serum ferritin and transferrin saturation after withholding iron supplements for at least 24 hours in all patients with clinically significant RLS. 1, 2

• Supplement with oral ferrous sulfate 325–650 mg daily (or every other day) if ferritin ≤ 75 ng/mL or transferrin saturation < 20%—these thresholds are higher than general population guidelines because brain iron deficiency drives RLS pathophysiology even when serum iron appears normal 1, 2, 3
• Consider IV ferric carboxymaltose 750–1000 mg (strong recommendation, moderate certainty) if oral iron fails after 3 months or for rapid correction in severe cases 1, 2
• In children, supplement if ferritin < 50 ng/mL 1, 2

Address Exacerbating Factors Before Starting Medications

Eliminate or reduce the following, as they directly worsen RLS symptoms 1, 2, 4:

• Alcohol, caffeine, and nicotine—especially within 3 hours of bedtime 2, 4
• Antihistamines (diphenhydramine, centrally acting H1 blockers) 1, 3
• Serotonergic antidepressants (SSRIs, tricyclics) 1, 4, 3
• Antidopaminergic medications (antipsychotics like lurasidone, metoclopramide) 1, 2, 4
• Untreated obstructive sleep apnea 1, 2, 4

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

The American Academy of Sleep Medicine strongly recommends gabapentin, gabapentin enacarbil, or pregabalin as first-line treatment (strong recommendation, moderate certainty of evidence)—these agents do not cause augmentation, unlike dopamine agonists. 1, 2, 3

Gabapentin Dosing

• Start 300 mg three times daily (900 mg/day total) 2
• Increase by 300 mg/day every 3–7 days as tolerated 2
• Target maintenance dose: 1800–2400 mg/day divided TID 2
• Maximum studied dose: 3600 mg/day 2
• Common side effects: somnolence and dizziness (typically transient and mild) 2

Pregabalin Dosing

• Start 75 mg twice daily or 50 mg three times daily 2
• After 3–7 days, increase to 300 mg/day 2
• Titrate by 150 mg every 3–7 days as needed 2
• Maximum dose: 600 mg/day 2
• Advantage: twice-daily dosing with potentially superior bioavailability compared to regular gabapentin 2, 5

Gabapentin Enacarbil

• Prodrug of gabapentin with improved absorption 2
• Strong recommendation, moderate certainty of evidence 1, 2

Medications to Avoid or Use with Extreme Caution

Dopamine Agonists (Pramipexole, Ropinirole, Rotigotine)

The American Academy of Sleep Medicine conditionally recommends AGAINST standard use of dopamine agonists due to a 7–10% annual risk of augmentation—a paradoxical worsening of symptoms characterized by earlier daily onset, increased intensity, and spread to arms or trunk. 1, 2, 3

• These agents may be considered only for short-term use in patients who prioritize immediate symptom relief over long-term safety 1, 2
• This represents a major shift from older 2012 guidelines that listed dopamine agonists as first-line 2
• If augmentation develops, do NOT increase the dopamine agonist dose—this worsens the condition 2

Strongly Recommended Against

• Cabergoline (strong recommendation against; cardiac valvular fibrosis risk) 1, 2
• Clonazepam (conditional recommendation against; provides only sedation without reducing periodic limb movements; insufficient efficacy evidence) 1, 2, 6
• Bupropion, carbamazepine, valproic acid, valerian (conditional recommendations against) 1, 2

Second-Line and Refractory RLS Treatment

When to Consider Second-Line Therapy

Refractory RLS is defined as persistent symptoms despite: (1) optimized iron status (ferritin > 75 ng/mL, transferrin saturation > 20%), (2) therapeutic trials of alpha-2-delta ligands at adequate doses, and (3) elimination of aggravating factors 2

Opioids for Refractory Cases

The American Academy of Sleep Medicine conditionally recommends extended-release oxycodone and other low-dose opioids (methadone 5–10 mg daily, buprenorphine) for moderate to severe refractory RLS, particularly when treating augmentation from dopamine agonists (conditional recommendation, moderate certainty of evidence). 1, 2, 3

• Long-term studies show only modest dose escalation over 2–10 years with relatively low abuse risk in appropriately screened patients 1, 2
• Screen for opioid-use-disorder risk before initiating 2
• Evaluate for untreated obstructive sleep apnea—opioids increase respiratory depression and central sleep apnea risk 2
• Monitor for constipation (most common adverse effect); prescribe prophylactic stool softeners 2

Other Second-Line Options

• Bilateral high-frequency peroneal nerve stimulation (conditional recommendation, moderate certainty) as a non-invasive alternative 1, 2
• Dipyridamole (conditional recommendation, low certainty) 1
• IV low molecular weight iron dextran or ferumoxytol (conditional recommendations) for patients with appropriate iron parameters 1

Special Populations

End-Stage Renal Disease (ESRD)

• Gabapentin 100 mg post-dialysis or at bedtime (maximum 200–300 mg daily) is conditionally recommended 1, 2, 4
• IV iron sucrose if ferritin < 200 ng/mL AND transferrin saturation < 20% (conditional recommendation, moderate certainty) 1, 2
• Vitamin C supplementation may enhance iron utilization (conditional recommendation, low certainty) 1, 2
• Avoid pregabalin in ESRD—markedly increases hazard of altered mental status and falls 2

Pregnancy

• Consider pregnancy-specific safety profile of each treatment 1
• Iron supplementation is particularly important given 22% prevalence of RLS in third trimester 3
• Oral iron formulations are favored throughout gestation 2

Pediatric RLS

• Supplement with oral ferrous sulfate if ferritin < 50 ng/mL (conditional recommendation, very low certainty) 1, 2
• Monitor for constipation with oral iron 2

Managing Dopaminergic Augmentation

If a patient on dopamine agonists develops augmentation (earlier symptom onset, increased intensity, spread to arms/trunk) 2:

1. Add an alpha-2-delta ligand (gabapentin 300 mg TID, titrated to 1800–2400 mg/day) or an opioid before tapering the dopamine agonist 2
2. Once symptom control is achieved, down-titrate the dopamine agonist very slowly (reduce by 0.125–0.25 mg pramipexole-equivalent every 1–2 weeks) 2
3. Anticipate rebound RLS and insomnia; short-acting opioids or clonidine may serve as temporary bridge therapy 2
4. For severe augmentation, bypass alpha-2-delta ligands and transition directly to an opioid 2

Monitoring and Follow-Up

• Reassess RLS severity at 4–6 weeks after treatment initiation 2
• Repeat iron studies every 6–12 months—brain iron deficiency may persist despite clinical improvement 2
• Evaluate both nighttime symptom relief and daytime functional outcomes (alertness, mood, quality of life) 2
• Monitor for side effects of alpha-2-delta ligands (dizziness, somnolence) and opioids (constipation, respiratory depression) 2

Critical Pitfalls to Avoid

• Do not start pharmacologic therapy without first checking and optimizing iron status—patients with ferritin 75–100 ng/mL may still benefit from IV iron 1, 2
• Do not use dopamine agonists as first-line therapy given current evidence favoring alpha-2-delta ligands and high augmentation risk 1, 2, 3
• Do not increase dopamine agonist doses when symptoms worsen—this likely reflects augmentation 2
• Do not use clonazepam as monotherapy—it provides only sedation without addressing underlying RLS pathology 2, 6
• Do not combine multiple sedating agents (opioids + alpha-2-delta ligands + benzodiazepines) without first treating obstructive sleep apnea 2
• Do not assume "normal" caffeine or alcohol consumption is acceptable—even moderate amounts, especially in the evening, significantly worsen RLS symptoms 2, 4