How is restless leg syndrome managed?

Management of Restless Legs Syndrome (RLS)

Alpha-2-delta ligands (gabapentin, gabapentin enacarbil, or pregabalin) are now recommended as first-line therapy for patients with RLS, representing a significant change from previous treatment paradigms that favored dopamine agonists. 1

Initial Assessment and Iron Status

• 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 differs from general population guidelines 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 Treatments

• Alpha-2-delta ligands: Strong recommendation with moderate certainty of evidence 1
  • Gabapentin
  • Gabapentin enacarbil
  • Pregabalin

Iron Therapy Options

• IV ferric carboxymaltose: Strong recommendation with moderate certainty for patients with appropriate iron parameters (ferritin ≤75 ng/mL or transferrin saturation <20%) 1
• Oral ferrous sulfate: Conditional recommendation with moderate certainty for patients with appropriate iron parameters (ferritin ≤75 ng/mL or transferrin saturation <20%) 1

Second-Line Treatment

• Opioids: For refractory cases, opioids can be effective, particularly methadone and buprenorphine 2
  • While there are risks of abuse and overdose, evidence suggests these risks are relatively low in appropriately screened RLS patients 2
  • Long-term studies show only small dose increases in RLS patients followed over extended periods (2-10 years) 2

Non-Pharmacological Options

• Bilateral high-frequency peroneal nerve stimulation: A newer noninvasive treatment option with conditional recommendation based on initial success in short-term studies 2
• Exercise: Regular physical activity should be recommended for symptom relief 3, 4

Medications to Use with Caution or Avoid

• Dopamine agonists (pramipexole, ropinirole): Previously first-line treatments but now downgraded due to risk of augmentation with long-term use 1
  • The American Academy of Sleep Medicine suggests against standard use of pramipexole (conditional recommendation, moderate certainty) 1
  • Despite FDA approval and demonstrated efficacy 5, dopamine agonists are no longer first-line due to augmentation risk 1
• Levodopa: Conditional recommendation against standard use (very low certainty) 1
• Cabergoline: Strong recommendation against use (moderate certainty) 1

Special Populations

End-Stage Renal Disease (ESRD)

• Gabapentin: Conditional recommendation with very low certainty 1
• IV iron sucrose: Conditional recommendation with moderate certainty if ferritin <200 ng/mL and transferrin saturation <20% 1
• Vitamin C: Conditional recommendation 2

Pediatric RLS

• Oral iron supplementation: Recommended in cases of iron deficiency 2
• Monitor for side effects, particularly constipation 2

Managing Augmentation

Augmentation is characterized by worsening and earlier onset of symptoms in patients initially controlled on medication 2. Signs include:

• Earlier symptom onset during the day
• Increased symptom intensity
• Spread of symptoms to other body parts (e.g., from calves to thighs) 2

Management options include:

• Taking medication doses earlier in the day 2
• Splitting existing doses into early evening and bedtime doses 2
• Switching to alpha-2-delta ligands 1
• Consider opioids for treating augmentation, as they are effective for relieving worsening symptoms when decreasing or eliminating dopamine agonists 6

Clinical Pearls and Pitfalls

• Distinguish RLS from mimics such as neuropathy, akathisia, positional discomfort, and nocturnal leg cramps 1
• Augmentation is the main complication of long-term dopaminergic treatment and represents a significant shift in treatment recommendations 2, 1
• Keeping dopamine agonist doses as low as possible may help prevent augmentation development if these agents must be used 6
• Consider medication safety profiles carefully when treating RLS in pregnancy 1
• While many non-pharmacological interventions show promise (compression devices, acupuncture, yoga), evidence quality is not high for most of these approaches 3