What are the first-line and second-line treatment options for medication management of restless legs syndrome (RLS)?

Medication Management of Restless Legs Syndrome (RLS)

Based on the most recent 2025 American Academy of Sleep Medicine (AASM) guidelines, first-line treatment for RLS should be alpha-2-delta ligands (gabapentin, pregabalin, or gabapentin enacarbil) or intravenous iron supplementation for patients with appropriate iron status, rather than dopamine agonists which were previously considered first-line therapy. 1

First-Line Treatment Options

Alpha-2-Delta Ligands

The AASM strongly recommends the following medications as first-line options:

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

Iron Therapy

For patients with iron deficiency:

• IV ferric carboxymaltose (strong recommendation, moderate certainty of evidence) for patients with appropriate iron parameters 1
• Oral ferrous sulfate (conditional recommendation, moderate certainty of evidence) for patients with appropriate iron parameters 1
• IV low molecular weight iron dextran or IV ferumoxytol (conditional recommendations, very low/low certainty of evidence) 1

Second-Line Treatment Options

If first-line treatments are ineffective or poorly tolerated, consider:

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

Important Paradigm Shift in Treatment

This represents a significant change from previous practice where dopamine agonists (pramipexole, ropinirole, rotigotine) were considered first-line therapy. The AASM now suggests against the standard use of these medications due to the risk of augmentation (worsening of symptoms with long-term use) 1, 2.

The guideline specifically recommends against standard use of:

• Pramipexole (conditional recommendation, moderate certainty)
• Ropinirole (conditional recommendation, moderate certainty)
• Transdermal rotigotine (conditional recommendation, low certainty)
• Levodopa (conditional recommendation, very low certainty)

Special Populations

End-Stage Renal Disease (ESRD) Patients with RLS

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

Children with RLS

• Ferrous sulfate for appropriate iron status (conditional recommendation, very low certainty) 1

Clinical Pearls and Caveats

1. Augmentation risk: The major reason for avoiding dopamine agonists as first-line therapy is the risk of augmentation, which is characterized by earlier symptom onset, increased symptom intensity, and spread of symptoms to other body parts 3.

2. Iron parameters: Always check iron status before initiating treatment. Low iron stores contribute to RLS symptoms and should be corrected.

3. Medication timing: For dopamine agonists (if used), administer 1-3 hours before bedtime 4.

4. Dopamine agonist withdrawal: When transitioning from dopamine agonists to other medications due to augmentation, add the new medication first, then very slowly taper the dopamine agonist to minimize rebound symptoms 3.

5. Medications to avoid in RLS patients:

   • Bupropion
   • Carbamazepine
   • Clonazepam
   • Valproic acid
   • Cabergoline (strong recommendation against)
   • Certain antidepressants and antihistamines may worsen symptoms 3

The treatment approach for RLS has evolved significantly, with alpha-2-delta ligands and iron therapy now preferred over dopaminergic agents due to better long-term safety profiles and reduced risk of symptom augmentation.