How is restless leg syndrome managed?

Management of Restless Legs Syndrome

The American Academy of Sleep Medicine strongly recommends alpha-2-delta ligands (gabapentin, gabapentin enacarbil, or pregabalin) as first-line pharmacological therapy for RLS, but only after checking and correcting iron status if ferritin ≤75 ng/mL or transferrin saturation <20%. 1, 2

Initial Assessment and Iron Repletion

Before initiating any medication, obtain morning fasting iron studies (serum ferritin and transferrin saturation) after avoiding iron-containing supplements for at least 24 hours. 1, 2 This higher ferritin threshold (≤75 ng/mL) differs from general population guidelines because brain iron deficiency plays a key pathophysiologic role in RLS even when serum iron appears normal. 1

Iron supplementation options when ferritin ≤75 ng/mL or transferrin saturation <20%:

• Oral ferrous sulfate (conditionally recommended, moderate certainty) 1, 2
• IV ferric carboxymaltose (strongly recommended for non-responders to oral therapy, moderate certainty) 1, 2
• IV low molecular weight iron dextran or IV ferumoxytol (conditionally recommended) 1

First-Line Pharmacological Treatment: Alpha-2-Delta Ligands

Gabapentin dosing algorithm: 1, 2

• Start at 300 mg three times daily (900 mg/day total)
• Titrate by 300 mg/day every 3-7 days based on response
• Target maintenance dose: 1800-2400 mg/day divided three times daily
• Maximum well-tolerated dose: 3600 mg/day
• Common side effects include somnolence and dizziness, typically transient and mild 1

Pregabalin is equally strongly recommended and offers the advantage of twice-daily dosing with potentially superior bioavailability compared to gabapentin. 1, 2

Gabapentin enacarbil (a prodrug of gabapentin) is also strongly recommended with moderate certainty of evidence. 1

Critical advantage over dopamine agonists: Alpha-2-delta ligands avoid augmentation—a paradoxical worsening of RLS symptoms with earlier onset, increased intensity, and anatomic spread that occurs with long-term dopamine agonist use. 1, 3

Medications to Avoid or Use with Extreme Caution

The American Academy of Sleep Medicine suggests AGAINST standard use of dopamine agonists (pramipexole, ropinirole, rotigotine) due to high risk of augmentation with long-term use, despite their historical use as first-line agents. 1, 3 These may only be considered for short-term treatment in patients prioritizing immediate symptom relief over long-term adverse effects. 1

Strongly recommended AGAINST: 1

• Cabergoline (strong recommendation, moderate certainty)
• Levodopa (conditional recommendation, very low certainty—high augmentation risk)
• Bupropion, carbamazepine, clonazepam, valproic acid, valerian (all conditionally recommended against)

Addressing Exacerbating Factors

Eliminate or reduce the following before or concurrent with pharmacological treatment: 1, 2

• Alcohol and caffeine
• Antihistaminergic medications (including over-the-counter sleep aids)
• Serotonergic medications (SSRIs, SNRIs)
• Antidopaminergic medications (antipsychotics like lurasidone) 1
• Screen for and treat untreated obstructive sleep apnea 1, 2

Second-Line and Refractory Treatment Options

For refractory cases or dopamine agonist-induced augmentation: 1, 3

• Extended-release oxycodone and other low-dose opioids (methadone, buprenorphine) are conditionally recommended
• Evidence shows relatively low risks of abuse and overdose in appropriately screened patients, with only small dose increases over 2-10 years 1
• Caution: Monitor for respiratory depression and central sleep apnea, especially in patients with untreated OSA or COPD 1

Non-pharmacological options: 1, 4

• Bilateral high-frequency peroneal nerve stimulation (conditionally recommended, moderate certainty)
• Regular physical activity/exercise (may reduce RLS severity) 4, 5
• Pneumatic compression devices (may improve sleep outcomes) 4

Special Populations

End-stage renal disease patients with RLS: 1

• Gabapentin (conditionally recommended, very low certainty): start 100 mg post-dialysis or at bedtime, maximum 200-300 mg daily
• IV iron sucrose if ferritin <200 ng/mL and transferrin saturation <20% (conditionally recommended, moderate certainty)
• Vitamin C (conditionally recommended, low certainty)
• Critical safety warning: Gabapentinoids carry 31-68% higher hazard for altered mental status and falls in dialysis patients even at low doses 1

Pediatric RLS: 1

• Ferrous sulfate if ferritin <50 ng/mL (conditionally recommended, very low certainty)
• Monitor for constipation with oral iron supplementation 1

Pregnancy: 1

• Special consideration of medication safety profiles required
• Address iron deficiency as primary intervention

Managing Augmentation from Dopamine Agonists

Augmentation is characterized by: 1

• Earlier symptom onset during the day
• Increased symptom intensity
• Spread of symptoms to other body parts (arms, trunk)

Management strategy: 1, 3

• Add alpha-2-delta ligand or opioid FIRST before reducing dopamine agonist (to avoid profound rebound RLS and insomnia)
• Once adequate symptom control achieved with second agent, initiate very slow down-titration of dopamine agonist
• Consider opioids particularly effective for treating augmentation symptoms 1

Common Pitfalls to Avoid

• Do not use single nighttime gabapentin dosing—this fails to address daytime RLS symptoms and provides suboptimal 24-hour coverage. 1
• Do not start dopamine agonists as first-line therapy—current guidelines have shifted away from this approach due to augmentation risk. 1, 3
• Do not ignore iron status—correcting iron deficiency can significantly improve RLS symptoms independent of other medications. 1, 2
• Do not use magnesium as monotherapy—while it may be considered as adjunctive therapy, it should not replace guideline-recommended treatments for clinically significant RLS. 1
• Monitor for misuse potential with alpha-2-delta ligands, as there is increasing evidence these agents may be misused in certain populations. 1