What is the next step after levodopa (L-dopa) for a patient with inadequate symptom control?

Next Pressor After Levodopa in Restless Legs Syndrome

If levodopa fails or causes augmentation in RLS, switch to gabapentin or pregabalin as first-line alternatives, or consider IV iron therapy if iron parameters are appropriate. 1

Context: Levodopa is No Longer Recommended for Standard RLS Treatment

The 2025 American Academy of Sleep Medicine guidelines represent a major shift away from dopaminergic agents including levodopa:

• The AASM suggests against the standard use of levodopa (conditional recommendation, very low certainty of evidence) 1
• Levodopa may only be considered for short-term use in patients who prioritize immediate symptom reduction over long-term adverse effects, particularly augmentation 1
• This recommendation applies to both general RLS patients and those with end-stage renal disease 1

First-Line Alternatives After Levodopa Failure

Alpha-2-Delta Ligands (Preferred)

Gabapentin and pregabalin are now the strongly recommended first-line agents:

• AASM recommends gabapentin (strong recommendation, moderate certainty of evidence) 1
• AASM recommends pregabalin (strong recommendation, moderate certainty of evidence) 1
• These agents avoid the augmentation risk that plagues dopaminergic therapies 1
• In ESRD patients with RLS, gabapentin remains a suggested option 1

Intravenous Iron Therapy (If Appropriate)

Before switching to other medications, assess iron status:

• AASM recommends IV ferric carboxymaltose in patients with appropriate iron parameters (strong recommendation, moderate certainty of evidence) 1
• The guideline emphasizes checking iron status before treatment decisions 1
• In ESRD patients, IV iron sucrose is suggested when ferritin < 200 ng/mL and transferrin saturation < 20% 1

Other Dopaminergic Agents Are Also Not Recommended

All dopamine agonists face similar recommendations against standard use:

• Pramipexole: AASM suggests against standard use (conditional recommendation, moderate certainty of evidence) 1
• Ropinirole: AASM suggests against standard use (conditional recommendation, moderate certainty of evidence) 1
• Transdermal rotigotine: AASM suggests against standard use (conditional recommendation, low certainty of evidence) 1
• All share the same caveat as levodopa—may be used short-term if patients prioritize immediate symptom relief over augmentation risk 1

Third-Line Options

If alpha-2-delta ligands and iron therapy are insufficient:

• Extended-release oxycodone and other opioids are suggested (conditional recommendation, moderate certainty of evidence) 1
• Dipyridamole is suggested (conditional recommendation, low certainty of evidence) 1
• Bilateral high-frequency peroneal nerve stimulation is suggested (conditional recommendation, moderate certainty of evidence) 1

Agents to Avoid

The AASM recommends or suggests against several medications:

• Cabergoline: Strong recommendation against use (moderate certainty of evidence) 1
• Bupropion, carbamazepine, clonazepam, valproic acid: All have conditional recommendations against use 1

Critical Pitfall: Augmentation

The primary reason for moving away from levodopa and other dopaminergic agents is augmentation—a paradoxical worsening of RLS symptoms with earlier onset, increased intensity, and spread to other body parts with chronic dopaminergic therapy 1. This complication significantly impacts long-term quality of life and is the driving force behind the 2025 guideline shift toward gabapentin and pregabalin as preferred agents 1.