How is restless leg syndrome managed?

Management of Restless Legs Syndrome

The American Academy of Sleep Medicine strongly recommends alpha-2-delta ligands (gabapentin, gabapentin enacarbil, or pregabalin) as first-line therapy for patients with restless legs syndrome due to their efficacy and lower risk of augmentation compared to dopaminergic agents. 1

Initial Assessment and Iron Status Evaluation

• 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%, which are different thresholds than for the general population 1
• Address potential exacerbating factors, including alcohol, caffeine, antihistaminergic medications, serotonergic medications, antidopaminergic medications, and untreated obstructive sleep apnea 1

Pharmacological Treatment Algorithm

First-Line Therapy

• Alpha-2-delta ligands are strongly recommended as first-line therapy with moderate certainty of evidence:
  • Gabapentin 1
  • Gabapentin enacarbil 1
  • Pregabalin 1
• Prior to initiating alpha-2-delta ligands, evaluate risk factors for misuse, as there is increasing evidence these agents may be misused in certain populations 2
• Monitor for side effects including dizziness and somnolence, which may influence treatment decisions 2

Iron Therapy Options

• IV ferric carboxymaltose is strongly recommended for patients with appropriate iron parameters (ferritin ≤75 ng/mL or transferrin saturation <20%) who don't respond to oral therapy 1, 2
• Oral ferrous sulfate is conditionally recommended for patients with appropriate iron parameters, though absorption may be limited in those with ferritin >50-75 ng/mL 1, 2
• IV low molecular weight iron dextran and IV ferumoxytol are conditionally recommended for patients with appropriate iron parameters 1
• IV iron sucrose is conditionally recommended for patients with RLS and end-stage renal disease with transferrin saturation <20% 2

Second-Line and Alternative Treatments

• Extended-release oxycodone and other low-dose opioids are conditionally recommended for moderate to severe cases, particularly for refractory cases or when treating augmentation from dopaminergic agents 2
• Caution should be used with opioids due to risk of respiratory depression and central sleep apnea, especially in patients with untreated obstructive sleep apnea 2
• Bilateral high-frequency peroneal nerve stimulation is conditionally recommended as a non-pharmacological option 1

Medications to Use with Caution or Avoid

• Dopaminergic agents are no longer recommended as first-line therapy due to risk of augmentation - a paradoxical worsening of symptoms with long-term use 1, 3
• The American Academy of Sleep Medicine suggests against standard use of:
  • Levodopa (conditional recommendation, very low certainty) 1
  • Pramipexole (conditional recommendation, moderate certainty) 1
  • Ropinirole (conditional recommendation, moderate certainty) 1
  • Transdermal rotigotine (conditional recommendation, low certainty) 1
• The American Academy of Sleep Medicine specifically recommends against:
  • Cabergoline (strong recommendation, moderate certainty) 1
  • Bupropion, carbamazepine, clonazepam, and valproic acid (conditional recommendations) 1

Managing Augmentation

• Augmentation is characterized by worsening and earlier onset of symptoms in patients initially controlled on dopaminergic medication 1, 3
• Signs include earlier symptom onset during the day, increased symptom intensity, and spread of symptoms to other body parts 1
• If augmentation occurs, add an alternative agent (alpha-2-delta ligand or opioid) before attempting to reduce the dopaminergic medication 3
• Once adequate symptom relief is achieved with the second agent, very slow down-titration and discontinuation of the dopaminergic agent is recommended 3

Special Populations

• For patients with end-stage renal disease and RLS, consider:
  • 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, low certainty) 1
• For pediatric RLS, ferrous sulfate is conditionally recommended with very low certainty of evidence 1

Treatment Monitoring

• Regular monitoring for augmentation is essential when using dopaminergic agents 2, 3
• Keep dopamine agonist doses as low as possible to prevent augmentation 4
• Maintain high serum ferritin levels to help prevent augmentation 4
• Monitor for side effects of alpha-2-delta ligands, particularly in patients with untreated obstructive sleep apnea or chronic obstructive pulmonary disease 2