What are the treatment options for restless legs syndrome (RLS)?

Treatment Options for Restless Legs Syndrome (RLS)

Alpha-2-delta ligands (gabapentin, gabapentin enacarbil, or pregabalin) are strongly recommended as first-line therapy for restless legs syndrome due to their efficacy and lower risk of augmentation compared to dopaminergic agents. 1, 2

Initial Assessment and Management

• Check serum iron studies, including ferritin and transferrin saturation, in all patients with clinically significant RLS, ideally in the morning after avoiding iron-containing supplements for at least 24 hours 1, 2
• Address potential exacerbating factors, including alcohol, caffeine, antihistaminergic medications, serotonergic medications, antidopaminergic medications, and untreated obstructive sleep apnea 1, 2
• Consider iron supplementation if serum ferritin ≤75 ng/mL or transferrin saturation <20% (higher threshold than general population guidelines) 1, 2

First-Line Pharmacological Treatment

• Alpha-2-delta ligands are strongly recommended with moderate certainty of evidence: 1, 2
  • Gabapentin
  • Gabapentin enacarbil
  • Pregabalin
• These medications have better long-term efficacy and significantly lower risk of augmentation compared to dopaminergic agents 1

Iron Therapy Options

• Oral ferrous sulfate is conditionally recommended for patients with appropriate iron parameters (ferritin ≤75 ng/mL or transferrin saturation <20%) 1, 2
• IV iron formulations should be considered when oral supplementation is ineffective: 1
  • IV ferric carboxymaltose (strong recommendation, moderate certainty)
  • IV low molecular weight iron dextran (conditional recommendation)
  • IV ferumoxytol (conditional recommendation)

Second-Line and Alternative Treatments

• Extended-release oxycodone and other opioids are conditionally recommended, particularly for refractory cases or when treating augmentation from dopaminergic agents 1
• Bilateral high-frequency peroneal nerve stimulation is conditionally recommended as a non-pharmacological option 1
• Dipyridamole is conditionally recommended (low certainty of evidence) 1

Medications to Use with Caution or Avoid

• The American Academy of Sleep Medicine suggests against the standard use of dopaminergic agents due to risk of augmentation - a paradoxical worsening of symptoms with long-term use: 1, 2, 3
  • Levodopa (conditional recommendation against, very low certainty)
  • Pramipexole (conditional recommendation against, moderate certainty)
  • Ropinirole (conditional recommendation against, moderate certainty)
  • Transdermal rotigotine (conditional recommendation against, low certainty)
• Despite FDA approval and demonstrated efficacy in clinical trials 4, dopaminergic agents like ropinirole are not recommended for standard use due to the significant risk of augmentation with long-term use 1, 3
• Specifically recommended against: cabergoline (strong recommendation), bupropion, carbamazepine, clonazepam, and valproic acid 1

Special Populations

• For patients with end-stage renal disease and RLS: 1
  • Gabapentin (conditional recommendation, very low certainty)
  • IV iron sucrose if ferritin <200 ng/mL and transferrin saturation <20% (moderate certainty)
  • Vitamin C (low certainty)
• For pediatric RLS, ferrous sulfate is conditionally recommended with very low certainty 1
• Treatment selection for RLS in pregnancy should consider pregnancy-specific safety profiles 2

Managing Augmentation

• Augmentation is characterized by earlier symptom onset during the day, increased symptom intensity, and spread of symptoms to other body parts 3, 5
• If augmentation develops with dopaminergic agents, consider: 3, 5
  • Taking medication doses earlier in the day
  • Splitting existing doses into early evening and bedtime doses
  • Switching to an alpha-2-delta ligand
  • Adding an opioid while slowly tapering the dopaminergic agent 5

Treatment Algorithm

1. Assess and correct iron deficiency if present (ferritin ≤75 ng/mL or transferrin saturation <20%) 1, 2
2. Start with alpha-2-delta ligands as first-line therapy 1, 2
3. If inadequate response, consider adding or switching to alternative therapies 1
4. For refractory cases, consider opioids or combination therapy 1, 5
5. Dopaminergic agents should be reserved only for short-term treatment in patients who prioritize immediate symptom relief over long-term adverse effects 1, 6

Monitoring and Follow-up

• Regularly monitor for augmentation if using dopaminergic agents 3
• Monitor for side effects of alpha-2-delta ligands, particularly in patients with untreated obstructive sleep apnea or chronic obstructive pulmonary disease 1
• Prior to initiating alpha-2-delta ligands, evaluate risk factors for misuse 1