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, with iron supplementation for patients with ferritin ≤75 ng/mL or transferrin saturation <20%. 1

Initial Assessment and Iron Optimization

Before initiating any pharmacological treatment, check morning fasting iron studies (serum ferritin and transferrin saturation) after avoiding iron-containing supplements for at least 24 hours. 1, 2

Iron supplementation is critical and should be initiated if:

• Serum ferritin ≤75 ng/mL (note: this threshold is higher than general population guidelines) 1
• Transferrin saturation <20% 1

Iron supplementation options:

• Oral ferrous sulfate as first-line iron therapy (conditional recommendation, moderate certainty) 1
• IV ferric carboxymaltose for patients not responding to oral therapy (strong recommendation, moderate certainty) 1, 2
• IV low molecular weight iron dextran or IV ferumoxytol as alternatives (conditional recommendation) 1

Address Exacerbating Factors

Eliminate or reduce medications and substances that worsen RLS symptoms: 1, 2

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

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

Gabapentin dosing algorithm: 1

• Start at 300 mg three times daily (900 mg/day total) 1
• Titrate by 300 mg/day every 3-7 days based on response 1
• Target maintenance dose: 1800-2400 mg/day divided three times daily 1
• Maximum dose: 3600 mg/day (well-tolerated in clinical studies) 1

Pregabalin is an equally strong first-line option with the advantage of twice-daily dosing and potentially superior bioavailability. 1, 2

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

Common side effects to monitor: somnolence and dizziness, which are typically transient and mild. 1 However, evaluate risk factors for misuse before initiating, as there is increasing evidence these agents may be misused in certain populations. 1

Medications to AVOID

The American Academy of Sleep Medicine specifically recommends AGAINST the following dopaminergic agents due to high risk of augmentation (paradoxical worsening of symptoms with long-term use): 1

• Pramipexole (conditional recommendation against, moderate certainty) 1
• Ropinirole (conditional recommendation against, moderate certainty) 1
• Levodopa (conditional recommendation against, very low certainty) 1
• Transdermal rotigotine (conditional recommendation against, low certainty) 1
• Cabergoline (strong recommendation AGAINST, moderate certainty) 1

Critical pitfall: While ropinirole has FDA approval for RLS 3 and demonstrated efficacy in clinical trials, current guidelines recommend against its standard use due to the high risk of augmentation—a progressive, iatrogenic worsening characterized by earlier symptom onset, increased severity, and anatomic spread. 1, 4

Other medications to avoid: 1

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

Second-Line and Refractory Treatment Options

For patients who fail first-line therapy or have refractory RLS:

• Extended-release oxycodone and other low-dose opioids (methadone, buprenorphine) are conditionally recommended, particularly for refractory cases or when treating augmentation from dopaminergic agents. 1, 4 Evidence suggests relatively low risks of abuse and overdose in appropriately screened patients, with long-term studies showing only small dose increases over 2-10 years. 1
• Caution: Monitor for respiratory depression and central sleep apnea, especially in patients with untreated obstructive sleep apnea or chronic obstructive pulmonary disease. 1

Non-pharmacological option:

• Bilateral high-frequency peroneal nerve stimulation (conditional recommendation, moderate certainty) 1

Dipyridamole is conditionally recommended with low certainty of evidence. 1

Managing Augmentation from Dopamine Agonists

If a patient develops augmentation (characterized by earlier symptom onset during the day, increased intensity, and spread to other body parts): 1

• Add an alpha-2-delta ligand (gabapentin or pregabalin) or opioid FIRST 1, 4
• Once adequate symptom control is achieved with the second agent, initiate very slow down-titration of the dopamine agonist 4
• Critical pitfall: Never abruptly discontinue dopamine agonists, as this causes profound rebound RLS and insomnia. 4

Special Populations

End-stage renal disease patients: 1

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

Pediatric RLS:

• Oral ferrous sulfate if ferritin <50 ng/mL (conditional recommendation, very low certainty) 1

Pregnancy:

• Special consideration of medication safety profiles is essential. 1

Non-Pharmacological Interventions

While evidence quality is not high, some interventions may provide benefit: 5, 6

• Regular moderate exercise (should be recommended based on available evidence) 1, 6
• Smoking cessation 2
• Compression devices 5
• Repetitive transcranial magnetic stimulation 5
• Counterstrain manipulation 5
• Infrared therapy 5
• Standard acupuncture 5

Note: Vibration pads, cryotherapy, and transcranial direct current stimulation were ineffective in reducing RLS severity. 5

Treatment Algorithm Summary

1. Confirm diagnosis using the four essential criteria (urge to move legs, worsening with rest, relief with movement, evening/night predominance) 2
2. Check morning fasting ferritin and transferrin saturation 2
3. Initiate iron supplementation if ferritin ≤75 ng/mL or transferrin saturation <20% 2
4. Address exacerbating factors (medications, substances, sleep apnea) 2
5. Start gabapentin or pregabalin as first-line pharmacological treatment 2
6. Monitor for efficacy and side effects (somnolence, dizziness) 2
7. For refractory cases, consider opioids or bilateral high-frequency peroneal nerve stimulation 1