What is the recommended treatment approach for a patient with restless leg syndrome?

Treatment of Restless Legs Syndrome

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

Initial Assessment and Iron Status Evaluation

Before initiating any pharmacological treatment, check serum iron studies in all patients with clinically significant RLS 1, 2:

• Draw blood in the morning after avoiding all iron-containing supplements and foods for at least 24 hours 1, 3
• Measure ferritin and transferrin saturation (calculated from iron and total iron binding capacity) 1, 3
• Supplement with oral or IV iron if ferritin ≤75 ng/mL or transferrin saturation <20% 1, 2, 3
• Use only IV iron if ferritin is between 75-100 ng/mL 2, 3
• In children, supplement when ferritin <50 ng/mL 1, 3

This iron threshold is fundamentally different from general population guidelines because brain iron deficiency plays a central pathophysiological role in RLS, even when serum iron appears normal 2.

Address Exacerbating Factors First

Before pharmacological treatment, eliminate or modify 1, 2, 4:

• Alcohol, caffeine, and nicotine, especially within 3 hours of bedtime 2, 4
• Medications that worsen RLS: antihistamines, SSRIs, tricyclic antidepressants, antipsychotics (dopamine antagonists), lithium 1, 2, 4
• Untreated obstructive sleep apnea 1, 2, 4

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

The American Academy of Sleep Medicine provides strong recommendations with moderate certainty of evidence for 1, 2:

• Gabapentin: Start 300 mg three times daily (900 mg/day), titrate up to 1800-2400 mg/day divided three times daily 2
• Gabapentin enacarbil: Prodrug with superior bioavailability, allows once-daily dosing 2
• Pregabalin: Allows twice-daily dosing with potentially superior bioavailability compared to regular gabapentin 2

Common side effects include somnolence and dizziness, which are typically transient and mild 2. Monitor for misuse potential, as there is increasing evidence these agents may be misused in certain populations 2.

Iron Supplementation Options

Based on iron parameters 2, 3:

• Oral ferrous sulfate: Conditional recommendation with moderate certainty for ferritin ≤75 ng/mL or transferrin saturation <20% 2, 3
• IV ferric carboxymaltose: Strong recommendation with moderate certainty for patients not responding to oral therapy 2
• IV low molecular weight iron dextran and IV ferumoxytol: Conditional recommendations 2

Continue iron supplementation indefinitely with ongoing monitoring, as RLS symptoms may recur if iron stores decline below therapeutic thresholds 2, 3. Recheck iron studies every 6-12 months 2.

Second-Line Options for Refractory Cases

If alpha-2-delta ligands fail or are poorly tolerated 2, 5, 6:

• Extended-release oxycodone or other low-dose opioids (methadone, buprenorphine): Conditional recommendation with moderate certainty for refractory RLS 2, 5
  • Long-term studies show relatively low risks of abuse/overdose in appropriately screened patients 2
  • Small dose increases over 2-10 years 2
  • Critical caveat: Monitor for respiratory depression, especially in patients with untreated sleep apnea 2
• Bilateral high-frequency peroneal nerve stimulation: Conditional recommendation with moderate certainty as non-pharmacological option 2
• Dipyridamole: Conditional recommendation with low certainty 2

Medications to Avoid or Use with Extreme Caution

The American Academy of Sleep Medicine now recommends against standard use of dopamine agonists due to augmentation risk 1, 2, 5:

• Pramipexole: Conditional recommendation against, moderate certainty 2
• Ropinirole: Conditional recommendation against, moderate certainty 2, 7
• Transdermal rotigotine: Conditional recommendation against, low certainty 2
• Levodopa: Conditional recommendation against, very low certainty 2
• Cabergoline: Strong recommendation against, moderate certainty 2

Augmentation is characterized by earlier symptom onset during the day, increased intensity, spread to upper extremities or trunk, and paradoxical worsening despite dose increases 2, 5. This iatrogenic complication occurs commonly with dopamine agonists and represents a major treatment failure 5, 8.

The American Academy of Sleep Medicine also recommends against 2:

• Bupropion (conditional, moderate certainty)
• Carbamazepine (conditional, low certainty)
• Clonazepam (conditional, very low certainty)
• Valproic acid (conditional, low certainty)
• Valerian (conditional, very low certainty)

Special Populations

End-Stage Renal Disease

• Gabapentin: Conditional recommendation, very low certainty; start 100 mg post-dialysis or at bedtime, maximum 200-300 mg daily 2, 4
• IV iron sucrose: Conditional recommendation, moderate certainty if ferritin <200 ng/mL AND transferrin saturation <20% 2, 4
• Vitamin C: Conditional recommendation, low certainty 2

Critical warning: Gabapentinoids carry 31-68% higher hazard for altered mental status and falls in dialysis patients, even at low doses 2.

Pregnancy

• RLS is common in pregnancy 1
• Consider pregnancy-specific safety profiles for each treatment 1, 2
• Iron supplementation is particularly important, favoring oral formulations throughout gestation 2

Pediatric Patients

• Oral ferrous sulfate: Conditional recommendation, very low certainty for ferritin <50 ng/mL 2, 3
• Monitor for constipation 2

Managing Dopamine Agonist Augmentation

If augmentation is present on dopamine agonists 2, 5:

1. Do not increase the dopamine agonist dose—this worsens the problem 2
2. Add an alpha-2-delta ligand or opioid first before attempting to taper the dopamine agonist 5
3. Once adequate symptom control is achieved with the second agent, initiate very slow down-titration of the dopamine agonist 5
4. Expect profound rebound RLS and insomnia with even small dose reductions 5

Critical Pitfalls to Avoid

• Do not assume RLS is primary without excluding secondary causes: end-stage renal disease, pregnancy, peripheral neuropathy, iron deficiency 4, 8
• Do not start dopamine agonists as first-line therapy—the 2025 guidelines represent a paradigm shift away from these agents 1, 2
• Do not ignore iron status—this is a mandatory first step that can dramatically improve outcomes independent of other medications 1, 2, 3
• Do not use "normal" ferritin cutoffs—RLS requires higher thresholds (≤75 ng/mL) than general population guidelines 2, 3
• Do not prescribe clonazepam as monotherapy—it lacks efficacy on objective disease markers and carries significant side effects 2
• Do not assume lifestyle modifications are optional—eliminating caffeine, alcohol, and offending medications is essential 1, 2, 4

Monitoring and Follow-Up

• Reassess iron studies every 6-12 months 2
• Monitor for side effects of alpha-2-delta ligands (dizziness, somnolence) 2
• Evaluate improvement in both nighttime RLS symptoms and daytime functioning (alertness, concentration, mood) 2
• Screen for augmentation if dopamine agonists are used 2, 5