What are the recommended tests and treatment options for a 30-year-old otherwise healthy patient with restless leg syndrome (RLS)?

Restless Leg Syndrome: Testing and Treatment in a Healthy 30-Year-Old

Start with morning fasting iron studies (ferritin and transferrin saturation) and initiate gabapentin, gabapentin enacarbil, or pregabalin as first-line pharmacological therapy if symptoms warrant treatment. 1, 2

Initial Diagnostic Testing

Check serum ferritin and transferrin saturation in the morning after avoiding iron-containing supplements for at least 24 hours. 1, 2 No other laboratory tests are necessary to establish the diagnosis of RLS. 1 The physical examination is typically unremarkable in primary RLS, but perform a thorough neurologic exam to exclude secondary causes such as peripheral neuropathy or radiculopathy. 1

Iron Supplementation Thresholds (Different from General Population)

• Supplement with oral ferrous sulfate if ferritin ≤75 ng/mL OR transferrin saturation <20% 1, 2
• Consider IV ferric carboxymaltose (strong recommendation) if ferritin ≤75 ng/mL or transferrin saturation <20%, particularly if oral iron fails or is not tolerated 1, 2
• These thresholds are higher than general population guidelines because brain iron deficiency contributes to RLS pathophysiology even when serum iron appears normal 2, 3

Address Exacerbating Factors Before Starting Medications

Eliminate or reduce the following substances and medications: 1, 2

• Caffeine and alcohol, especially within 3 hours of bedtime 2
• Antihistaminergic medications (including over-the-counter sleep aids) 1, 2
• Serotonergic medications (SSRIs, tricyclic antidepressants) 1
• Antidopaminergic medications (antipsychotics) 1
• Screen for and treat untreated obstructive sleep apnea 1, 2

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

The American Academy of Sleep Medicine strongly recommends alpha-2-delta ligands over dopamine agonists due to superior long-term safety profile and absence of augmentation risk. 1, 2

Gabapentin (Strong Recommendation, Moderate Certainty)

• Start 300 mg three times daily (900 mg/day total) 2
• Titrate upward by 300 mg/day every 3-7 days until reaching maintenance dose of 1800-2400 mg/day divided three times daily 2
• Doses up to 3600 mg/day are well-tolerated in clinical studies 2
• Common side effects: somnolence and dizziness (typically transient and mild) 2

Pregabalin (Strong Recommendation, Moderate Certainty)

• Allows twice-daily dosing with potentially superior bioavailability compared to gabapentin 2, 3
• May be preferred for patients who struggle with three-times-daily dosing schedules 3

Gabapentin Enacarbil (Strong Recommendation, Moderate Certainty)

• Prodrug of gabapentin with once-daily dosing 1, 2
• Take 1-3 hours before bedtime 1

Medications to AVOID in a 30-Year-Old

Dopamine Agonists (Conditional Recommendation AGAINST Standard Use)

The American Academy of Sleep Medicine suggests against standard use of pramipexole, ropinirole, and rotigotine due to high risk of augmentation—a paradoxical worsening of symptoms with long-term use. 1, 2 Augmentation is characterized by:

• Earlier onset of symptoms during the day 2
• Increased symptom intensity 2
• Spread of symptoms to arms or trunk 2
• Paradoxical worsening despite dose increases 2

While ropinirole is FDA-approved for RLS 4 and shows short-term efficacy, the 2025 American Academy of Sleep Medicine guidelines prioritize long-term outcomes and explicitly recommend against these agents for standard use. 1, 2

Levodopa (Conditional Recommendation AGAINST)

The American Academy of Sleep Medicine suggests against standard use of levodopa due to very low certainty of evidence and even higher augmentation risk than dopamine agonists. 1, 2

Other Medications to Avoid

• Cabergoline (strong recommendation against) 2
• Bupropion (conditional recommendation against) 2
• Carbamazepine (conditional recommendation against) 2
• Clonazepam (conditional recommendation against—insufficient evidence of efficacy on validated outcomes) 2
• Valproic acid (conditional recommendation against) 2

Second-Line Treatment Options (If First-Line Fails)

Extended-Release Oxycodone and Other Opioids

Conditionally recommended for moderate to severe refractory cases, particularly when treating augmentation from dopamine agonists. 1, 2 Long-term studies show relatively low risks of abuse/overdose in appropriately screened patients, with only small dose increases over 2-10 years. 2

IV Iron Formulations

• IV ferric carboxymaltose (strong recommendation if ferritin ≤75 ng/mL or transferrin saturation <20%) 1, 2
• IV low molecular weight iron dextran (conditional recommendation) 1
• IV ferumoxytol (conditional recommendation) 1

Non-Pharmacological Option

Bilateral high-frequency peroneal nerve stimulation (conditional recommendation, moderate certainty) 1, 2

Treatment Algorithm Summary

1. Confirm diagnosis using four essential criteria: urge to move legs with uncomfortable sensations, symptoms begin/worsen at rest, relief with movement, symptoms worse in evening/night 1

2. Check morning fasting ferritin and transferrin saturation 1, 2

3. Supplement with oral ferrous sulfate if ferritin ≤75 ng/mL or transferrin saturation <20% 1, 2

4. Address exacerbating factors: eliminate caffeine, alcohol, antihistamines, serotonergic medications; screen for OSA 1, 2

5. Initiate gabapentin (300 mg TID, titrate to 1800-2400 mg/day) OR pregabalin OR gabapentin enacarbil as first-line pharmacological treatment 1, 2

6. Monitor for efficacy and side effects; recheck ferritin every 6-12 months 2, 3

7. If inadequate response, consider IV iron (if appropriate iron parameters) or extended-release oxycodone for refractory cases 1, 2

Critical Pitfalls to Avoid

Do not start dopamine agonists as first-line therapy in a 30-year-old. 1, 2 While these agents show short-term efficacy, augmentation develops in a substantial proportion of patients with long-term use, leading to iatrogenic worsening that is difficult to reverse. 2, 5 In a young patient with decades of potential treatment ahead, prioritizing long-term safety over short-term efficacy is paramount.

Do not assume "normal" ferritin levels are adequate for RLS. 2, 3 The threshold for supplementation (≤75 ng/mL) is substantially higher than general population guidelines because brain iron deficiency plays a key pathophysiological role even when serum iron appears normal. 2, 3

Do not use clonazepam or other benzodiazepines. 2 These agents have insufficient evidence of efficacy on validated RLS outcomes and primarily improve subjective sleep quality without reducing the underlying periodic limb movement index. 2