Treatment Options for Restless Legs Syndrome
First-line treatments for restless legs syndrome (RLS) should be alpha2-delta calcium channel ligands (gabapentin, pregabalin, or gabapentin enacarbil) and iron supplementation in patients with appropriate iron status, as these provide the best balance of efficacy and safety for long-term management. 1
First-Line Pharmacological Treatments
Alpha2-Delta Calcium Channel Ligands
These medications have strong recommendations with moderate certainty of evidence:
- Gabapentin enacarbil - Strongly recommended (first choice) 1
- Gabapentin - Strongly recommended 1
- Pregabalin - Strongly recommended 1
Iron Therapy
Iron status should be assessed in all RLS patients (ferritin and transferrin saturation):
- IV ferric carboxymaltose - Strongly recommended when ferritin ≤75 ng/mL or transferrin saturation <20% 1
- Oral ferrous sulfate - Conditionally recommended when ferritin ≤75 ng/mL or transferrin saturation <20% 1
- IV iron formulations (low molecular weight iron dextran, ferumoxytol) - Conditionally recommended in appropriate patients 1
Second-Line Treatments
- Dipyridamole - Conditionally recommended 1
- Extended-release oxycodone and other opioids - Conditionally recommended, particularly effective for severe or refractory cases 1, 2
- Bilateral high-frequency peroneal nerve stimulation - Conditionally recommended 1
Special Considerations for End-Stage Renal Disease (ESRD)
For patients with RLS and ESRD:
- Gabapentin - Conditionally recommended 1
- IV iron sucrose - Conditionally recommended when ferritin <200 ng/mL and transferrin saturation <20% 1
- Vitamin C - Conditionally recommended 1
Treatments to Avoid or Use with Caution
Dopamine Agonists
These medications are no longer recommended as first-line due to risk of augmentation (worsening of symptoms over time):
- Ropinirole - Not recommended for standard use despite proven efficacy in clinical trials 1, 3
- Pramipexole - Not recommended for standard use 1
- Rotigotine (transdermal) - Not recommended for standard use 1
- Levodopa - Not recommended for standard use 1
- Cabergoline - Strongly recommended against use 1
Other Medications Not Recommended
- Bupropion - Not recommended 1
- Carbamazepine - Not recommended 1
- Clonazepam - Not recommended 1
- Valproic acid - Not recommended 1
Non-Pharmacological Approaches
Before or alongside medication:
- Address exacerbating factors: alcohol, caffeine, antihistamines, serotonergic medications, antidopaminergic medications, and untreated sleep apnea 1
- Some evidence supports exercise, compression devices, and acupuncture 4
Treatment Algorithm
Initial assessment:
- Check iron status (ferritin and transferrin saturation)
- Identify and address exacerbating factors
- Assess symptom severity
First-line treatment:
- For mild-moderate symptoms: Start with alpha2-delta ligand (gabapentin, pregabalin, or gabapentin enacarbil)
- If iron deficient: Add iron supplementation (IV preferred if ferritin 75-100 ng/mL, oral or IV if ferritin <75 ng/mL)
If inadequate response:
- Optimize dose of alpha2-delta ligand
- Consider dipyridamole or peroneal nerve stimulation
For severe/refractory cases:
- Consider opioid therapy (extended-release oxycodone) 2
For patients with augmentation from prior dopamine agonist use:
- Add alpha2-delta ligand or opioid
- Once adequate symptom control is achieved, very slowly taper dopamine agonist 2
Important Caveats
- Dopamine agonists, while effective short-term, carry significant risk of augmentation with long-term use 2
- If dopamine agonists must be used, keep doses as low as possible and maintain high serum ferritin levels to help prevent augmentation 5
- When transitioning from dopamine agonists to other therapies, add the new medication first before attempting to taper the dopamine agonist to avoid rebound symptoms 2
- Opioids, while often avoided due to concerns about addiction, can be very effective and safe for severe RLS when properly monitored 5