What are the recommended medications for treating Restless Legs Syndrome (RLS)?

Recommended Medications for Restless Legs Syndrome (RLS)

First-line treatment for RLS should be alpha2-delta calcium channel ligands (gabapentin, gabapentin enacarbil, or pregabalin) rather than dopamine agonists due to their strong recommendation status and lower risk of augmentation. 1

First-Line Pharmacological Options

Alpha2-Delta Calcium Channel Ligands

These medications have the strongest recommendations from the American Academy of Sleep Medicine (AASM):

1. Gabapentin enacarbil (strong recommendation, moderate certainty) 1
2. Gabapentin (strong recommendation, moderate certainty) 1
3. Pregabalin (strong recommendation, moderate certainty) 1

Iron Supplementation

For patients with appropriate iron status:

• IV ferric carboxymaltose (strong recommendation, moderate certainty) 1
• IV low molecular weight iron dextran (conditional recommendation, very low certainty) 1
• IV ferumoxytol (conditional recommendation, very low certainty) 1
• Oral ferrous sulfate (conditional recommendation, moderate certainty) 1

Second-Line Options

1. Dipyridamole (conditional recommendation, low certainty) 1
2. Extended-release oxycodone and other opioids (conditional recommendation, moderate certainty) 1
3. Bilateral high-frequency peroneal nerve stimulation (conditional recommendation, moderate certainty) 1

Medications to Use with Caution

The AASM suggests against standard use of dopamine agonists due to risk of augmentation, though they may be considered for short-term use in specific situations:

• Pramipexole (conditional recommendation against standard use) 1
• Ropinirole (conditional recommendation against standard use) 1
• Transdermal rotigotine (conditional recommendation against standard use) 1
• Levodopa (conditional recommendation against standard use) 1

Medications to Avoid

• Cabergoline (strong recommendation against use) 1
• Bupropion (conditional recommendation against use) 1
• Carbamazepine (conditional recommendation against use) 1
• Clonazepam (conditional recommendation against use) 1
• Valproic acid (conditional recommendation against use) 1
• Valerian (conditional recommendation against use) 1

Special Populations

End-Stage Renal Disease (ESRD) Patients

• Gabapentin (conditional recommendation) 1
• IV iron sucrose for patients with ferritin < 200 ng/mL and transferrin saturation < 20% (conditional recommendation) 1
• Vitamin C (conditional recommendation) 1

Children with RLS

• Ferrous sulfate for appropriate iron status (conditional recommendation) 1

Treatment Algorithm

1. First step: Address exacerbating factors (iron deficiency, antihistamines, serotonergic medications, antidopaminergic medications, untreated OSA) 2

2. Check iron status: Consider iron supplementation if ferritin is below 75-100 ng/mL in adults or below 50 ng/mL in children 1

3. Initial pharmacotherapy:

   • Start with an alpha2-delta calcium channel ligand (gabapentin, pregabalin, or gabapentin enacarbil)
   • Titrate to effective dose while monitoring for side effects

4. If inadequate response:

   • Consider adding dipyridamole or switching to another first-line agent
   • Consider opioid therapy for refractory cases

5. For patients already on dopamine agonists with augmentation:

   • Add an alpha2-delta ligand or opioid
   • Once adequate symptom control is achieved, very slowly taper and discontinue the dopamine agonist 2

Important Caveats

• Augmentation risk: Dopamine agonists (including ropinirole) can cause augmentation—a paradoxical worsening of symptoms with long-term use characterized by earlier symptom onset, increased severity, and spread to other body parts 2

• Dosing timing: Most RLS medications should be taken 1-3 hours before bedtime 3

• Dose minimization: When using dopamine agonists, keep doses to the minimum required for acceptable symptom reduction to reduce augmentation risk 4

• Treatment threshold: RLS requires treatment only if it significantly impacts nighttime sleep or daily activities 4