What are the treatment options for restless leg syndrome?

Treatment Options for Restless Leg Syndrome

First-line treatment for restless legs syndrome (RLS) should be alpha2-delta calcium channel ligands (gabapentin, pregabalin, or gabapentin enacarbil) due to their strong efficacy and lower risk of augmentation compared to dopamine agonists. 1

Initial Assessment and Non-Pharmacological Management

• Check iron status in all patients with RLS:

  • Supplement iron if ferritin ≤75 ng/mL or transferrin saturation <20% in adults
  • For children, supplement if ferritin <50 ng/mL
  • Morning blood draw recommended (avoid iron supplements for 24 hours prior)

• Address exacerbating factors:

  • Eliminate alcohol and caffeine
  • Discontinue medications that worsen RLS (antihistamines, serotonergic drugs, antidopaminergic medications)
  • Treat underlying obstructive sleep apnea if present

Pharmacological Treatment Algorithm

First-Line Medications (Strong Recommendations)

1. Alpha2-delta calcium channel ligands:

   • Gabapentin enacarbil (strong recommendation, moderate evidence)
   • Gabapentin (strong recommendation, moderate evidence)
   • Pregabalin (strong recommendation, moderate evidence)

2. Iron therapy (for patients with appropriate iron status):

   • IV ferric carboxymaltose (strong recommendation, moderate evidence)
   • IV low molecular weight iron dextran (conditional recommendation)
   • IV ferumoxytol (conditional recommendation)
   • Oral ferrous sulfate (conditional recommendation)

Second-Line Medications (Conditional Recommendations)

1. Dipyridamole (conditional recommendation, low evidence)
2. Extended-release oxycodone and other opioids (conditional recommendation, moderate evidence)
3. Bilateral high-frequency peroneal nerve stimulation (conditional recommendation, moderate evidence)

Medications to Avoid or Use with Caution

• Dopamine agonists (suggested against standard use due to augmentation risk):

  • Pramipexole, ropinirole, rotigotine, and levodopa can be effective short-term but have significant risk of augmentation with long-term use 1, 2
  • If used, keep doses as low as possible and monitor closely for augmentation 2

• Other medications to avoid:

  • Bupropion
  • Carbamazepine
  • Clonazepam
  • Valproic acid
  • Cabergoline (strong recommendation against)

Special Populations

End-Stage Renal Disease (ESRD) Patients

• Gabapentin (conditional recommendation)
• IV iron sucrose if ferritin <200 ng/mL and transferrin saturation <20%
• Vitamin C (conditional recommendation)
• Avoid levodopa and rotigotine unless benefits outweigh risks

Children with RLS

• Ferrous sulfate for appropriate iron status (conditional recommendation)

Managing Augmentation

Augmentation is a paradoxical worsening of symptoms caused by dopaminergic medications, characterized by:

• Earlier symptom onset during the day
• Increased symptom intensity
• Spread to other body parts
• Shorter latency to symptom onset during rest

If augmentation occurs:

1. Add an alpha2-delta ligand or opioid while maintaining the current dopamine agonist dose
2. Once adequate symptom control is achieved with the new medication, very slowly taper and discontinue the dopamine agonist 2
3. Do not abruptly discontinue dopamine agonists due to severe rebound symptoms

Non-Pharmacological Interventions

Several non-pharmacological approaches may provide additional benefit:

• Exercise programs
• Compression devices
• Repetitive transcranial magnetic stimulation
• Acupuncture
• Infrared therapy

These can be particularly useful for milder cases or as adjuncts to medication 3.

Treatment Selection Pitfalls

• Failing to check iron status before initiating treatment
• Using dopamine agonists as first-line therapy despite augmentation risk
• Abruptly discontinuing dopamine agonists in patients with augmentation
• Not recognizing secondary causes of RLS (pregnancy, renal failure, anemia)
• Using medications that can worsen RLS (antihistamines, antidepressants)

While dopamine agonists like ropinirole have demonstrated efficacy in clinical trials 4, the long-term risk of augmentation makes them less desirable as first-line agents compared to alpha2-delta ligands, which provide similar efficacy with better long-term tolerability 1, 2.