What are the treatment options for restless leg syndrome?

Treatment for Restless Leg Syndrome

The American Academy of Sleep Medicine strongly recommends alpha-2-delta ligands (gabapentin, gabapentin enacarbil, or pregabalin) as first-line pharmacologic therapy for RLS, with dopaminergic agents now relegated to short-term use only due to the significant risk of augmentation. 1

Initial Assessment and Management

Before initiating any pharmacologic therapy, address exacerbating factors and iron status:

• Check serum ferritin and transferrin saturation in all patients with clinically significant RLS, ideally in the morning after avoiding iron-containing supplements and foods for at least 24 hours. 1

• Identify and eliminate medications that worsen RLS, including antihistamines (over-the-counter sleep aids and allergy medications), serotonergic antidepressants, antipsychotics, and anti-nausea drugs. 1, 2

• Screen for and treat untreated obstructive sleep apnea, as this can exacerbate RLS symptoms. 1

• Counsel patients to avoid alcohol, caffeine, and nicotine, particularly in the evening, as these substances trigger or worsen symptoms. 2

Iron Supplementation Strategy

Iron therapy should be prioritized based on laboratory values:

• Provide iron supplementation if serum ferritin ≤75 ng/mL or transferrin saturation <20%—note this threshold is higher than general population guidelines because brain iron deficiency plays a key role in RLS pathophysiology. 1

• Start with oral ferrous sulfate for mild iron deficiency (conditional recommendation, moderate certainty). 1

• Use IV ferric carboxymaltose when ferritin is between 75-100 ng/mL or when oral supplementation is ineffective (strong recommendation, moderate certainty). 1

• For patients with end-stage renal disease and RLS, use IV iron sucrose if ferritin <200 ng/mL and transferrin saturation <20%. 3

First-Line Pharmacologic Treatment

Alpha-2-delta ligands are now the preferred initial pharmacologic approach:

• Gabapentin enacarbil is strongly recommended (strong recommendation, moderate certainty of evidence). 1

• Gabapentin is strongly recommended (strong recommendation, moderate certainty of evidence). 1

• Pregabalin is strongly recommended (strong recommendation, moderate certainty of evidence). 1

• Monitor for side effects including dizziness and somnolence, which may increase fall risk, particularly in elderly patients. 3

• Evaluate risk factors for misuse before initiating alpha-2-delta ligands, as there is increasing evidence these agents may be misused in certain populations. 3

Dopaminergic Agents: Use with Extreme Caution

The paradigm has shifted away from dopaminergic agents as first-line therapy:

• The American Academy of Sleep Medicine suggests against standard use of dopaminergic agents (levodopa, pramipexole, ropinirole, rotigotine) due to the risk of augmentation—a paradoxical worsening of symptoms with long-term use characterized by earlier onset during the day, increased intensity, and spread to other body parts. 1, 3

• Reserve dopaminergic agents only for short-term treatment in patients who prioritize immediate symptom relief over long-term adverse effects. 1

• The American Academy of Sleep Medicine conditionally recommends against levodopa (conditional recommendation, very low certainty). 1

• The American Academy of Sleep Medicine conditionally recommends against pramipexole (conditional recommendation, moderate certainty). 1

• The American Academy of Sleep Medicine strongly recommends against cabergoline (strong recommendation, moderate certainty). 1

While ropinirole has FDA approval for RLS and demonstrated efficacy in clinical trials with mean IRLS score reductions of 2.5-3.7 points compared to placebo 4, current guidelines prioritize long-term safety over short-term efficacy given the high risk of augmentation with chronic dopaminergic therapy.

Managing Augmentation from Dopaminergic Agents

If a patient is already on a dopaminergic agent and develops augmentation:

• Add an alpha-2-delta ligand or opioid first before attempting to reduce the dopamine agonist, as even small dose reductions cause profound rebound RLS and insomnia. 5

• Once adequate symptom relief is achieved with the second agent, initiate very slow down-titration and discontinuation of the dopaminergic agent. 5

• Consider low-dose opioids (extended-release oxycodone, methadone, or buprenorphine) for refractory augmentation cases, with evidence showing relatively low risks of abuse and only small dose increases over 2-10 years in appropriately screened patients. 3

Alternative and Adjunctive Treatments

For patients who cannot tolerate or do not respond adequately to first-line therapies:

• Extended-release oxycodone and other low-dose opioids are conditionally recommended, particularly for refractory cases (conditional recommendation). 3

• Caution: Monitor for respiratory depression and central sleep apnea with opioids, especially in patients with untreated obstructive sleep apnea or chronic obstructive pulmonary disease. 3

• Bilateral high-frequency peroneal nerve stimulation is conditionally recommended as a non-pharmacological option (conditional recommendation, moderate certainty). 3

• Dipyridamole is conditionally recommended (low certainty of evidence). 3

Special Populations

Pregnancy:

• Non-pharmacologic approaches are preferred during pregnancy. 1
• Treatment selection should consider pregnancy-specific safety profiles. 1

End-Stage Renal Disease:

• Gabapentin is conditionally recommended (very low certainty). 3
• IV iron sucrose if ferritin <200 ng/mL and transferrin saturation <20% (moderate certainty). 3
• Vitamin C is conditionally recommended (low certainty). 3

Pediatric RLS:

• Ferrous sulfate is conditionally recommended (very low certainty). 3
• Supplement if serum ferritin <50 ng/mL in children. 3

Medications to Avoid

• Never use bupropion, carbamazepine, clonazepam, valproic acid, or valerian for RLS treatment. 3

• Avoid antipsychotics like lurasidone, as dopamine antagonism is a well-established mechanism for triggering or worsening RLS symptoms. 3

Common Pitfalls

• Do not start with dopaminergic agents as first-line therapy—this outdated approach leads to augmentation in a substantial proportion of patients, creating a more difficult-to-treat condition. 1, 5

• Do not use general population ferritin thresholds—RLS requires higher ferritin targets (≥75 ng/mL) for optimal neurological function. 1, 3

• Do not abruptly discontinue dopaminergic agents if augmentation develops—this causes severe rebound symptoms; always add alternative therapy first. 5

• Do not overlook medication-induced RLS—many commonly prescribed drugs (antihistamines, SSRIs, antipsychotics) worsen symptoms and should be discontinued when possible. 1, 2