What are the recommended medications for treating restless leg syndrome?

Recommended Medications for Restless Leg Syndrome

Alpha-2-delta ligands (gabapentin, gabapentin enacarbil, or pregabalin) are strongly recommended as first-line therapy for patients with restless legs syndrome (RLS), due to their strong evidence of efficacy and lower risk of augmentation compared to dopaminergic agents. 1

Initial Assessment and Iron Therapy

• 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
• Consider iron supplementation if serum ferritin ≤75 ng/mL or transferrin saturation <20% 1
• Oral ferrous sulfate is conditionally recommended for patients with appropriate iron parameters 1
• IV ferric carboxymaltose is strongly recommended for patients with appropriate iron parameters who don't respond to oral therapy 1
• Address potential exacerbating factors, including alcohol, caffeine, antihistaminergic medications, serotonergic medications, antidopaminergic medications, and untreated obstructive sleep apnea 1

First-Line Pharmacological Treatment

• Alpha-2-delta ligands are strongly recommended with moderate certainty of evidence: 1
  • Gabapentin (strong recommendation, moderate certainty of evidence) 1
  • Gabapentin enacarbil (strong recommendation, moderate certainty of evidence) 1
  • Pregabalin (strong recommendation, moderate certainty of evidence) 1
• These medications have better long-term efficacy and lower risk of augmentation compared to dopaminergic agents 1, 2
• Prior to initiating alpha-2-delta ligands, evaluate risk factors for misuse and monitor for side effects including dizziness and somnolence 1

Second-Line and Alternative Treatments

• Extended-release oxycodone and other opioids are conditionally recommended, particularly for refractory cases or when treating augmentation from dopaminergic agents 1, 2
• Bilateral high-frequency peroneal nerve stimulation is conditionally recommended as a non-pharmacological option 1
• Dipyridamole is conditionally recommended (low certainty of evidence) 1

Medications to Use with Caution or Avoid

• The American Academy of Sleep Medicine suggests against the standard use of dopaminergic agents due to risk of augmentation - a paradoxical worsening of symptoms with long-term use: 1, 3
  • Levodopa (conditional recommendation, very low certainty of evidence) 1
  • Pramipexole (conditional recommendation, moderate certainty of evidence) 1
  • Ropinirole (conditional recommendation, moderate certainty of evidence) 1, 3
  • Transdermal rotigotine (conditional recommendation, low certainty of evidence) 1
• Dopaminergic agents may be considered only for short-term treatment in patients who prioritize immediate symptom relief over long-term adverse effects 1
• The American Academy of Sleep Medicine specifically recommends against bupropion, carbamazepine, clonazepam, valproic acid, and valerian for treating RLS 1

Special Populations

• For patients with end-stage renal disease and RLS, consider: 1
  • Gabapentin (conditional recommendation, very low certainty of evidence) 1
  • IV iron sucrose if ferritin <200 ng/mL and transferrin saturation <20% (moderate certainty of evidence) 1
  • Vitamin C (low certainty of evidence) 1
• For pediatric RLS, ferrous sulfate is conditionally recommended with very low certainty of evidence 1

Managing Augmentation

• Augmentation is characterized by worsening and earlier onset of symptoms in patients initially controlled on dopaminergic medication 1, 2, 4
• Signs include earlier symptom onset during the day, increased symptom intensity, and spread of symptoms to other body parts 1, 4
• Management options for augmentation include: 1, 2
  • Adding an alpha-2-delta ligand or opioid while maintaining the dopaminergic agent 2
  • Once adequate symptom relief is achieved with the second agent, very slowly down-titrate and discontinue the dopaminergic agent 2
  • Taking medication doses earlier in the day or splitting existing doses 1, 3

Treatment Algorithm

1. Check iron status and supplement if needed (ferritin ≤75 ng/mL or transferrin saturation <20%) 1
2. Start with an alpha-2-delta ligand (gabapentin, gabapentin enacarbil, or pregabalin) 1
3. If inadequate response, consider opioids for moderate to severe cases 1, 2, 5
4. For patients already on dopaminergic agents with augmentation, add an alpha-2-delta ligand or opioid, then slowly taper the dopaminergic agent 2, 4
5. Consider non-pharmacological options like bilateral high-frequency peroneal nerve stimulation 1