Treatment for Restless Leg Syndrome
For adults with restless legs syndrome (RLS), gabapentin or gabapentin enacarbil is strongly recommended as first-line treatment based on moderate certainty of evidence. 1, 2
First-Line Treatments
Alpha-2-Delta Ligands
Gabapentin: Strong recommendation (300-1200 mg daily) 1, 2
- Start at 300 mg 1-2 hours before bedtime
- Titrate by 300 mg increments every 3-7 days based on response
- Target dose: 600 mg for moderate symptoms, 900-1200 mg for severe symptoms
- For patients with end-stage renal disease: 200-300 mg after each hemodialysis session
Gabapentin enacarbil: Strong recommendation 1
Pregabalin: Strong recommendation 1
Iron Therapy
IV iron therapy: Strongly recommended when appropriate iron parameters are met 1
- IV ferric carboxymaltose (strong recommendation)
- IV low molecular weight iron dextran (conditional recommendation)
- IV ferumoxytol (conditional recommendation)
Oral iron therapy: Conditionally recommended 1, 2
- Consider when ferritin ≤75 ng/mL or transferrin saturation <20%
- For children: supplement if serum ferritin <50 ng/mL
Second-Line Treatments
Dopaminergic Agents
Ropinirole: Effective but not first-line due to risk of augmentation 3
- Start at 0.25 mg once daily 1-3 hours before bedtime
- Titrate based on response over 7 weeks to maximum 4 mg daily
- Clinical trials showed significant improvement in IRLS scores compared to placebo 3
Levodopa: Not recommended for standard use due to high risk of augmentation 1, 2
- May be considered for short-term use only when immediate symptom relief is prioritized
Other Pharmacological Options
Opioids: Conditionally recommended for severe cases 1, 2
- Extended-release oxycodone and other opioids are effective for treatment-resistant cases
- Consider for patients with augmentation from dopaminergic agents
Dipyridamole: Conditionally recommended 1
Non-Pharmacological Approaches
Address exacerbating factors first: 1, 2
- Eliminate/reduce alcohol and caffeine
- Review medications that may worsen RLS (antihistamines, serotonergic drugs, antidopaminergics)
- Treat underlying obstructive sleep apnea if present
- Bilateral high-frequency peroneal nerve stimulation (conditional recommendation)
- Regular exercise, particularly aerobic and resistance training
- Compression devices may help some patients
Treatment Algorithm
Initial assessment:
- Check iron status (ferritin, transferrin saturation)
- Identify and address exacerbating factors
First-line treatment:
- If iron deficient: Iron supplementation (IV if ferritin 75-100 ng/mL, oral or IV if ferritin ≤75 ng/mL)
- Regardless of iron status: Start gabapentin, gabapentin enacarbil, or pregabalin
If inadequate response:
- Increase dose of alpha-2-delta ligand to maximum tolerated dose
- Consider adding non-pharmacological approaches
For treatment-resistant cases:
- Consider opioids (extended-release oxycodone)
- Consider bilateral high-frequency peroneal nerve stimulation
Special Considerations
- Pregnancy: Treatment safety profiles differ significantly during pregnancy 1
- Renal impairment: Adjust gabapentin dosing in patients with kidney disease 2
- Augmentation: A major concern with dopaminergic agents, characterized by earlier symptom onset, increased intensity, and spread to other body parts 5
- Keep dopamine agonist doses as low as possible
- Consider switching to alpha-2-delta ligands or opioids if augmentation occurs
Monitoring
- Regularly assess symptom control using standardized scales (e.g., IRLS)
- Monitor for side effects (somnolence, dizziness, fatigue with gabapentin)
- Periodically reassess iron status in patients with initial iron deficiency
Alpha-2-delta ligands (gabapentin, pregabalin) have replaced dopaminergic agents as first-line therapy due to lower risk of augmentation with long-term use, representing an important shift in RLS treatment paradigm 1, 2, 5.