What are the treatment options for Restless Leg Syndrome (RLS)?

Treatment Options for Restless Leg Syndrome

Alpha-2-delta ligands (gabapentin, gabapentin enacarbil, or pregabalin) are strongly recommended as first-line therapy for patients with Restless Leg Syndrome (RLS) due to their efficacy and lower risk of augmentation compared to dopaminergic agents. 1

Initial Assessment and Non-Pharmacological Management

• Check serum iron studies in all patients with clinically significant RLS, including ferritin and transferrin saturation, ideally in the morning after avoiding iron-containing supplements for at least 24 hours 1
• Consider iron supplementation if serum ferritin ≤75 ng/mL or transferrin saturation <20% 1
• Address potential exacerbating factors including:
  • Alcohol and caffeine consumption 1
  • Medications that can worsen RLS (antihistamines, serotonergic medications, antidopaminergic medications) 1
  • Untreated obstructive sleep apnea 1

Pharmacological Treatment Algorithm

First-Line Treatments

• Alpha-2-delta ligands (strong recommendation, moderate certainty of evidence):
  • Gabapentin 1
  • Gabapentin enacarbil 1
  • Pregabalin 1

Iron Therapy (for patients with ferritin ≤75 ng/mL or transferrin saturation <20%)

• Oral ferrous sulfate (conditional recommendation, moderate certainty) 1
• IV ferric carboxymaltose (strong recommendation, moderate certainty) for patients who don't respond to oral therapy 1
• IV low molecular weight iron dextran and IV ferumoxytol (conditional recommendation) 1

Second-Line and Alternative Treatments

• Extended-release opioids (conditional recommendation) for refractory cases or when treating augmentation from dopaminergic agents 1, 2
• Bilateral high-frequency peroneal nerve stimulation (conditional recommendation) as a non-pharmacological option 1

Medications to Use with Caution or Avoid

• Dopaminergic agents are not recommended for standard use due to risk of augmentation - a paradoxical worsening of symptoms with long-term use 1, 2
  • Levodopa (conditional recommendation against standard use, very low certainty) 1
  • Pramipexole (conditional recommendation against standard use, moderate certainty) 1
  • Ropinirole (conditional recommendation against standard use) 1, 3
  • Rotigotine (conditional recommendation against standard use, low certainty) 1
• Cabergoline (strong recommendation against use, moderate certainty) 1

Special Considerations

Augmentation Management

• Augmentation is characterized by worsening and earlier onset of symptoms in patients initially controlled on dopaminergic medications 1, 2
• Signs include earlier symptom onset during the day, increased symptom intensity, and spread of symptoms to other body parts 1
• Management options:
  • Taking medication doses earlier in the day 1
  • Splitting existing doses into early evening and bedtime doses 1
  • Consider opioids for treating augmentation 1, 2
  • When switching from dopamine agonists, add the new medication first before slowly tapering the dopamine agonist to prevent rebound symptoms 2

End-Stage Renal Disease

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

Practical Approach to Treatment

1. First assess and address iron status, with supplementation if ferritin ≤75 ng/mL or transferrin saturation <20% 1
2. For patients requiring pharmacological treatment, start with an alpha-2-delta ligand (gabapentin, gabapentin enacarbil, or pregabalin) 1
3. If alpha-2-delta ligands are ineffective or poorly tolerated, consider opioids for refractory cases 1, 2
4. Dopaminergic agents should be reserved for cases where other treatments have failed, and patients should be monitored closely for augmentation 1, 2
5. Keep dopamine agonist doses as low as possible if they must be used 4