What is the treatment for restless leg syndrome (RLS)?

Treatment of Restless Legs Syndrome (RLS)

Alpha-2-delta ligands (gabapentin, gabapentin enacarbil, or pregabalin) are strongly recommended as first-line therapy for adults with 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%, which is different from general population guidelines 1, 2

Treatment Algorithm

First-Line Pharmacological Treatment

• Alpha-2-delta ligands are strongly recommended as first-line therapy with moderate certainty of evidence 1, 2:
  • Gabapentin 1, 2
  • Gabapentin enacarbil 1, 2
  • Pregabalin 1, 2

Iron Therapy Options

• For patients with ferritin ≤75 ng/mL or transferrin saturation <20%:
  • Oral ferrous sulfate is conditionally recommended with moderate certainty 1, 2
  • IV ferric carboxymaltose is strongly recommended for patients who don't respond to oral therapy 1
  • IV low molecular weight iron dextran and IV ferumoxytol are conditionally recommended 1

Second-Line and Alternative Treatments

• Extended-release 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

Medications to Avoid or Use with Caution

• Dopaminergic agents are not recommended for standard use due to risk of augmentation - a paradoxical worsening of symptoms with long-term use 1, 2, 3:

  • Levodopa (conditional recommendation against standard use, very low certainty) 1, 2
  • Pramipexole (conditional recommendation against standard use, moderate certainty) 1, 2, 3
  • Ropinirole (conditional recommendation against standard use, moderate certainty) 1, 4
  • Rotigotine transdermal (conditional recommendation against standard use, low certainty) 1
  • Cabergoline (strong recommendation against use, moderate certainty) 1, 2

• Other medications specifically recommended against include 1:

  • Bupropion (conditional recommendation, moderate certainty)
  • Carbamazepine (conditional recommendation, low certainty)
  • Clonazepam (conditional recommendation, very low certainty)
  • Valproic acid (conditional recommendation, low certainty)

Special Populations

End-Stage Renal Disease

• Gabapentin is conditionally recommended (very low certainty) 1, 2
• IV iron sucrose if ferritin <200 ng/mL and transferrin saturation <20% (moderate certainty) 1, 2
• Vitamin C (low certainty) 1

Pregnancy

• Treatment selection should consider pregnancy-specific safety profiles 2
• Non-pharmacologic approaches may be preferred 2

Pediatric RLS

• Ferrous sulfate is conditionally recommended with very low certainty 1

Managing Augmentation

• Augmentation is characterized by worsening and earlier onset of symptoms in patients initially controlled on dopaminergic medications 1, 3
• Signs include earlier symptom onset during the day, increased symptom intensity, and spread of symptoms to other body parts 1, 3
• Management options include 1, 3, 5:
  • Taking medication doses earlier in the day
  • Splitting existing doses into early evening and bedtime doses
  • Adding an alpha-2-delta ligand while slowly tapering the dopaminergic agent
  • Considering opioids for treating severe augmentation

Treatment Monitoring

• Regular monitoring for augmentation is essential when using dopaminergic agents 1
• Monitor for side effects of alpha-2-delta ligands, particularly in patients with untreated obstructive sleep apnea or chronic obstructive pulmonary disease 1
• Evaluate risk factors for misuse before initiating alpha-2-delta ligands 1

Clinical Pitfalls to Avoid

• Don't miss iron deficiency - brain iron deficiency plays a key role in RLS pathophysiology, even when serum iron appears normal 1, 2
• Don't start with dopaminergic agents despite their short-term efficacy - long-term augmentation risk outweighs benefits 1, 2, 5
• Don't overlook augmentation signs when using dopaminergic agents - early recognition can prevent severe symptom worsening 3, 5
• Don't confuse RLS with mimics such as neuropathy, akathisia, positional discomfort, and nocturnal leg cramps 1