How is restless leg syndrome managed?

Management 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 iron supplementation if ferritin ≤75 ng/mL or transferrin saturation <20%. 1

Initial Assessment and Iron Optimization

Before initiating any pharmacological treatment, check morning fasting serum ferritin and transferrin saturation (ideally after avoiding iron supplements for at least 24 hours). 1, 2

Iron supplementation is indicated when:

• Serum ferritin ≤75 ng/mL, OR
• Transferrin saturation <20% 1, 2

Note that these thresholds are higher than general population guidelines because brain iron deficiency plays a key pathophysiologic role in RLS, even when serum iron appears normal. 1

Iron supplementation options:

• Oral ferrous sulfate (conditionally recommended, moderate certainty) 1
• IV ferric carboxymaltose (strongly recommended for patients not responding to oral therapy, moderate certainty) 1, 2
• IV iron sucrose for end-stage renal disease patients if ferritin <200 ng/mL and transferrin saturation <20% 1

Address Exacerbating Factors

Eliminate or reduce medications and substances that worsen RLS symptoms:

• Antihistaminergic medications 1
• Serotonergic medications (SSRIs, tricyclic antidepressants) 1
• Antidopaminergic medications (antipsychotics like lurasidone) 1
• Alcohol and caffeine 1, 2
• Screen for and treat untreated obstructive sleep apnea 1, 2

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

Gabapentin dosing:

• Start at 300 mg three times daily (900 mg/day total) 1, 2
• Titrate by 300 mg/day every 3-7 days based on response 1
• Target maintenance dose: 1800-2400 mg/day divided three times daily 1
• Maximum dose: 3600 mg/day (well-tolerated in clinical studies) 1
• Common side effects: somnolence and dizziness (typically transient and mild) 1

Gabapentin enacarbil (prodrug with potentially better bioavailability) is also strongly recommended. 1

Pregabalin is strongly recommended as an alternative, allowing twice-daily dosing with potentially superior bioavailability compared to gabapentin. 1, 2

Critical advantage over dopamine agonists: Alpha-2-delta ligands avoid the augmentation phenomenon (paradoxical worsening of symptoms with long-term use) that commonly occurs with dopamine agonists. 1

Medications to AVOID or Use with Extreme Caution

The American Academy of Sleep Medicine suggests AGAINST standard use of:

• Pramipexole (conditional recommendation, moderate certainty) - despite FDA approval 1
• Ropinirole (conditional recommendation, moderate certainty) - despite FDA approval 1, 3
• Transdermal rotigotine (conditional recommendation, low certainty) 1
• Levodopa (conditional recommendation, very low certainty) 1

While ropinirole has FDA approval and demonstrated efficacy in clinical trials 3, current guidelines prioritize long-term outcomes. These dopamine agonists carry high risk of augmentation—a progressive, iatrogenic worsening characterized by earlier symptom onset, increased intensity, and anatomic spread. 1, 4

The American Academy of Sleep Medicine strongly recommends AGAINST:

• Cabergoline (strong recommendation, moderate certainty) 1
• Bupropion, carbamazepine, clonazepam, valproic acid, and valerian 1

Second-Line and Refractory Treatment Options

For patients who fail alpha-2-delta ligands or have refractory symptoms:

Opioids (conditionally recommended):

• Extended-release oxycodone, methadone, or buprenorphine 1
• Particularly effective for refractory cases and treating dopamine agonist-related augmentation 1, 4
• Evidence shows relatively low risks of abuse and overdose in appropriately screened patients 1
• Long-term studies demonstrate only small dose increases over 2-10 years 1
• Critical caution: Monitor for respiratory depression and central sleep apnea, especially in patients with untreated obstructive sleep apnea or COPD 1

Non-pharmacological options:

• Bilateral high-frequency peroneal nerve stimulation (conditional recommendation, moderate certainty) 1
• Regular physical activity and moderate exercise 2, 5, 6

Managing Dopamine Agonist Augmentation

If a patient is already on a dopamine agonist and develops augmentation (earlier symptom onset, increased intensity, anatomic spread):

Do NOT abruptly discontinue the dopamine agonist - this causes profound rebound RLS and insomnia. 4

Recommended approach:

1. Add gabapentin, pregabalin, or an opioid while maintaining the dopamine agonist 1, 4
2. Titrate the new agent to adequate doses for symptom control 4
3. Once stable, initiate very slow down-titration of the dopamine agonist 4
4. This approach leads to dramatic long-term relief and improved sleep 4

Special Populations

End-stage renal disease:

• Gabapentin (conditional recommendation, very low certainty) 1
• IV iron sucrose if ferritin <200 ng/mL and transferrin saturation <20% 1
• Vitamin C (conditional recommendation, low certainty) 1

Pediatric RLS:

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

Pregnancy:

• Special consideration of medication safety profiles required 1

Non-Evidence-Based Treatments

Magnesium: Not included in American Academy of Sleep Medicine guidelines as a recommended treatment. 1 While magnesium citrate 200 mg daily or magnesium oxide 250 mg daily may be considered as adjunctive therapy after addressing iron deficiency and implementing first-line treatments, it should never be used as monotherapy for clinically significant RLS. 1

Ketamine: Not recommended and does not appear in any current evidence-based treatment guidelines. 1

Clinical Algorithm Summary

1. Confirm diagnosis using the four essential criteria (urge to move legs, worsening with rest, relief with movement, evening/night predominance) 2
2. Check morning fasting ferritin and transferrin saturation 1, 2
3. Supplement iron if indicated (ferritin ≤75 ng/mL or transferrin saturation <20%) 1, 2
4. Address exacerbating factors (medications, caffeine, alcohol, OSA) 1, 2
5. Initiate gabapentin or pregabalin as first-line pharmacological treatment 1, 2
6. Monitor for efficacy and side effects 2
7. Consider opioids or non-pharmacological interventions for refractory cases 1