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), based on their strong evidence of efficacy and lower risk of augmentation compared to dopaminergic agents. 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, and antidopaminergic medications 1

First-Line Pharmacological Treatment

• Gabapentin is strongly recommended for adults with RLS (strong recommendation, moderate certainty of evidence) 1
• Gabapentin enacarbil is strongly recommended for adults with RLS (strong recommendation, moderate certainty of evidence) 1
• Pregabalin is strongly recommended for adults with RLS (strong recommendation, moderate certainty of evidence) 1

Iron Therapy Options

• Oral ferrous sulfate is conditionally recommended for patients with appropriate iron parameters (ferritin ≤75 ng/mL or transferrin saturation <20%) 1
• IV ferric carboxymaltose is strongly recommended for patients with appropriate iron parameters who don't respond to oral therapy 1
• For patients with end-stage renal disease and RLS, IV iron sucrose is conditionally recommended if ferritin <200 ng/mL and transferrin saturation <20% 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
• Bilateral high-frequency peroneal nerve stimulation is conditionally recommended as a non-pharmacological option 1
• For patients with end-stage renal disease, vitamin C is conditionally recommended 1

Medications to Avoid or Use with Caution

• 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, 2
• Specifically, levodopa (conditional recommendation, very low certainty), pramipexole (conditional recommendation, moderate certainty), ropinirole (conditional recommendation, moderate certainty), and transdermal rotigotine (conditional recommendation, low certainty) should be avoided as standard treatment 1
• Despite FDA approval for RLS, ropinirole carries significant risk of augmentation, characterized by worsening and earlier onset of symptoms in patients initially controlled on medication 2, 3
• The American Academy of Sleep Medicine specifically recommends against bupropion, carbamazepine, clonazepam, and valproic acid for treating RLS 1

Managing Augmentation

• Augmentation is characterized by worsening and earlier onset of symptoms in patients initially controlled on medication, with signs including earlier symptom onset during the day, increased symptom intensity, and spread of symptoms to other body parts 1
• If dopaminergic augmentation is present, substitution of an alpha-2-delta ligand or opioid for the dopamine agonist is the primary goal 4
• Given the profound rebound RLS and insomnia that occurs with even small dose reductions of dopamine agonists, initially add the alternative treatment before slowly tapering the dopamine agonist 4

Special Populations

• For pediatric RLS, the American Academy of Sleep Medicine conditionally recommends ferrous sulfate with very low certainty of evidence 1
• In patients with end-stage renal disease and RLS, gabapentin is conditionally recommended (very low certainty of evidence) 1

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

Despite historical use of dopaminergic agents like ropinirole for RLS treatment, current guidelines strongly favor alpha-2-delta ligands as first-line therapy due to the significant risk of augmentation with dopaminergic medications, which can lead to worsening symptoms over time and treatment failure 1, 3.