Management of Restless Legs Syndrome
Alpha-2-delta ligands (gabapentin, gabapentin enacarbil, or pregabalin) are strongly recommended as first-line pharmacological therapy for patients with restless legs syndrome due to their efficacy and lower risk of augmentation compared to dopaminergic agents. 1
Initial Assessment and Iron Status
- Check serum iron studies in all patients with clinically significant RLS, including ferritin and transferrin saturation, ideally in the morning after avoiding iron-containing supplements for at least 24 hours 1
- Consider iron supplementation if serum ferritin ≤75 ng/mL or transferrin saturation <20%, which is a higher threshold than general population guidelines 1
- Address potential exacerbating factors, including alcohol, caffeine, antihistaminergic medications, serotonergic medications, antidopaminergic medications, and untreated obstructive sleep apnea 1
Treatment Algorithm
First-Line Treatments
Iron Therapy (if iron deficient):
Pharmacological First-Line:
Second-Line and Alternative Treatments
- Extended-release opioids for refractory cases or when treating augmentation from dopaminergic agents (conditional recommendation) 1, 2
- Bilateral high-frequency peroneal nerve stimulation as a non-pharmacological option (conditional recommendation, moderate certainty) 1, 3
- For patients with end-stage renal disease: gabapentin (conditional recommendation, very low certainty) and IV iron sucrose if ferritin <200 ng/mL (conditional recommendation, moderate certainty) 1
Medications to Avoid or Use with Caution
- Dopaminergic agents are not recommended for standard use due to risk of augmentation - a paradoxical worsening of symptoms with long-term use 1, 2
- Specifically recommended against: cabergoline, bupropion, carbamazepine, clonazepam, and valproic acid 1
Managing Augmentation
- Augmentation is characterized by worsening and earlier onset of symptoms in patients initially controlled on dopaminergic medications 1, 2
- Signs include earlier symptom onset during the day, increased symptom intensity, and spread of symptoms to other body parts 1
- Management approach:
- Add an alpha-2-delta ligand or opioid while maintaining the current dopaminergic agent 2
- Once adequate symptom control is achieved with the new agent, very slowly down-titrate and discontinue the dopaminergic medication 2, 4
- Opioids are particularly effective for treating augmentation symptoms during dopaminergic withdrawal 2, 4
Non-Pharmacological Approaches
- Regular physical activity is recommended for symptom management 3, 5
- Some evidence supports compression devices, acupuncture, and infrared therapy, though evidence quality is limited 3
- Vitamin supplementation (C, D, E) may be considered if deficient, though evidence specifically for RLS is limited 5
Special Considerations
- In pediatric RLS, oral iron supplementation is conditionally recommended with monitoring for side effects, particularly constipation 1
- For pregnant patients with RLS, special consideration of medication safety profiles is necessary 1
- Distinguish RLS from mimics such as neuropathy, akathisia, positional discomfort, and nocturnal leg cramps 1
Treatment Monitoring
- Regular monitoring for augmentation is essential when using dopaminergic agents 1, 2
- Monitor for side effects of alpha-2-delta ligands, particularly in patients with untreated obstructive sleep apnea or chronic obstructive pulmonary disease 1
- Maintain optimal ferritin levels (≥75 ng/mL) for long-term management 1