What are the treatment options for restless leg syndrome?

Treatment Options for Restless Legs Syndrome

First-line treatments for restless legs syndrome (RLS) should include alpha2-delta calcium channel ligands (gabapentin, pregabalin, or gabapentin enacarbil) and iron supplementation for those with low iron parameters. 1

Initial Assessment and Non-Pharmacological Management

Before initiating medication, address potential exacerbating factors:

• Check serum iron studies (ferritin and transferrin saturation)

  • Supplement iron if ferritin ≤75 ng/mL or transferrin saturation <20%
  • Use oral iron for ferritin ≤75 ng/mL
  • Consider IV iron if ferritin is between 75-100 ng/mL 1

• Eliminate exacerbating factors:

  • Alcohol and caffeine
  • Antihistamines
  • Serotonergic medications
  • Antidopaminergic medications
  • Treat underlying obstructive sleep apnea 1

• Regular physical activity/exercise 2, 3

Pharmacological Treatment Algorithm

First-Line Treatments (Strong Recommendations)

1. Alpha2-delta calcium channel ligands:

   • Gabapentin enacarbil (strong recommendation, moderate evidence) 1
   • Gabapentin (strong recommendation, moderate evidence) 1
   • Pregabalin (strong recommendation, moderate evidence) 1

2. Iron therapy:

   • IV ferric carboxymaltose for appropriate candidates (strong recommendation, moderate evidence) 1
   • Ferrous sulfate for those with low iron parameters (conditional recommendation, moderate evidence) 1
   • IV iron formulations for those with ferritin between 75-100 ng/mL 1

Second-Line Treatments (Conditional Recommendations)

1. Dipyridamole (conditional recommendation, low evidence) 1

2. Opioids:

   • Extended-release oxycodone and other opioids (conditional recommendation, moderate evidence) 1
   • Particularly useful for severe cases that have failed other therapies 4

3. Bilateral high-frequency peroneal nerve stimulation (conditional recommendation, moderate evidence) 1

Treatments to Use with Caution

Dopamine agonists are no longer recommended as first-line due to risk of augmentation (paradoxical worsening of symptoms with long-term use) 1, 2:

• Ropinirole (suggested against standard use, moderate evidence) 1, 5
• Pramipexole (suggested against standard use, moderate evidence) 1
• Rotigotine transdermal patch (suggested against standard use, low evidence) 1
• Levodopa (suggested against standard use, very low evidence) 1

Treatments Not Recommended

The following are specifically recommended against:

• Bupropion (conditional recommendation against, moderate evidence) 1
• Carbamazepine (conditional recommendation against, low evidence) 1
• Clonazepam (conditional recommendation against, very low evidence) 1
• Valproic acid (conditional recommendation against, low evidence) 1
• Cabergoline (strong recommendation against, moderate evidence) 1
• Valerian (conditional recommendation against, very low evidence) 1

Special Populations

End-Stage Renal Disease (ESRD) Patients with RLS

• Gabapentin (conditional recommendation, very low evidence) 1
• IV iron sucrose for ferritin <200 ng/mL and transferrin saturation <20% (conditional recommendation, moderate evidence) 1
• Vitamin C (conditional recommendation, low evidence) 1

Children with RLS

• Ferrous sulfate for appropriate iron status (conditional recommendation, very low evidence) 1

Management of Augmentation

For patients experiencing augmentation on dopamine agonists:

1. Add an alpha2-delta ligand (gabapentin, pregabalin) or opioid while maintaining the dopamine agonist initially 2
2. Once adequate symptom control is achieved with the second agent, very slowly taper and discontinue the dopamine agonist 2

Non-Pharmacological Options with Some Evidence

• Compression devices may help reduce RLS severity and improve sleep 6
• Repetitive transcranial magnetic stimulation showed some benefit in reducing RLS severity 6
• Acupuncture may improve some sleep-related outcomes 6, 3

Common Pitfalls to Avoid

1. Starting with dopamine agonists - Despite their historical use as first-line agents, current evidence suggests alpha2-delta ligands should be preferred due to lower risk of augmentation 1, 2

2. Failing to assess iron status - Always check ferritin and transferrin saturation before initiating treatment 1

3. Abrupt discontinuation of dopamine agonists - Can lead to severe rebound symptoms; always taper very slowly 2

4. Using too high doses of dopamine agonists - If using dopamine agonists, keep doses to the minimum required for symptom control to reduce augmentation risk 7

5. Missing secondary causes of RLS - Always rule out conditions that mimic RLS symptoms (neuropathy, cramps) 7