What are the treatment options for Restless Leg Syndrome (RLS)?

Treatment 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 including serum ferritin and transferrin saturation, ideally after avoiding iron-containing supplements for at least 24 hours. 1, 2

Iron supplementation is critical when:

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

Iron supplementation options:

• Oral ferrous sulfate is conditionally recommended as first-line iron therapy 1
• IV ferric carboxymaltose is strongly recommended for patients who don't respond to oral therapy or meet the above iron parameters 1, 2
• IV iron sucrose is conditionally recommended for patients with end-stage renal disease when ferritin <200 ng/mL and transferrin saturation <20% 1

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

Gabapentin dosing:

• 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, 2
• Target maintenance dose: 1800-2400 mg/day divided three times daily 1
• Doses up to 3600 mg/day are well-tolerated in clinical studies 1

Gabapentin enacarbil (prodrug with improved bioavailability) is strongly recommended as an alternative 1

Pregabalin is strongly recommended and allows twice-daily dosing with potentially superior bioavailability compared to gabapentin 1, 2

Common side effects of alpha-2-delta ligands include somnolence and dizziness, which are typically transient and mild. 1 Monitor for misuse potential in at-risk populations. 1

Medications to Avoid or Use with Extreme Caution

Dopamine agonists are now recommended AGAINST for standard use due to high risk of augmentation:

• The American Academy of Sleep Medicine suggests against the standard use of pramipexole (conditional recommendation, moderate certainty) 1, 3
• The American Academy of Sleep Medicine suggests against the standard use of ropinirole (conditional recommendation, moderate certainty) 1
• The American Academy of Sleep Medicine suggests against the standard use of transdermal rotigotine (conditional recommendation, low certainty) 1
• The American Academy of Sleep Medicine suggests against the standard use of levodopa (conditional recommendation, very low certainty) 1

Despite FDA approval of ropinirole for RLS 4, current guidelines prioritize long-term outcomes over short-term symptom relief, and augmentation—a paradoxical worsening of symptoms with earlier onset, increased intensity, and anatomic spread—occurs commonly with dopaminergic agents. 1, 5

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

Other medications to avoid:

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

Second-Line and Refractory Treatment Options

For refractory cases or augmentation from dopamine agonists:

• Extended-release oxycodone and other low-dose opioids (methadone, buprenorphine) are conditionally recommended 1, 5
• Evidence shows relatively low risks of abuse and overdose in appropriately screened patients, with only small dose increases over 2-10 years 1
• Critical caution: Monitor for respiratory depression and central sleep apnea, especially in patients with untreated obstructive sleep apnea 1

Non-pharmacological option:

• Bilateral high-frequency peroneal nerve stimulation is conditionally recommended (moderate certainty of evidence) 1

Other conditionally recommended options:

• Dipyridamole (low certainty of evidence) 1

Managing Augmentation from Dopamine Agonists

Augmentation is characterized by:

• Earlier onset of symptoms during the day 1, 3
• Increased symptom intensity 1, 3
• Spread of symptoms to other body parts (arms, trunk) 1, 3

Management strategy when augmentation occurs:

1. Add an alpha-2-delta ligand or opioid BEFORE reducing the dopamine agonist 5
2. Once adequate symptom control is achieved with the new agent, initiate very slow down-titration of the dopamine agonist 5
3. Expect profound rebound RLS and insomnia with even small dose reductions of dopamine agonists 5

Addressing Exacerbating Factors

The American Academy of Sleep Medicine recommends eliminating or reducing:

• Alcohol and caffeine 2
• Antihistaminergic medications 1, 2
• Serotonergic medications (SSRIs, SNRIs) 1
• Antidopaminergic medications (antipsychotics like lurasidone) 1
• Untreated obstructive sleep apnea 1, 2

Implement concurrent interventions:

• Moderate exercise 2
• Smoking cessation 2

Special Populations

End-stage renal disease:

• Gabapentin is conditionally recommended (very low certainty) 1
• IV iron sucrose if ferritin <200 ng/mL and transferrin saturation <20% (moderate certainty) 1
• Vitamin C is conditionally recommended (low certainty) 1

Pediatric RLS:

• Oral iron supplementation if ferritin <50 ng/mL, monitoring for constipation 1

Pregnancy:

• Special consideration of medication safety profiles is essential 1

Clinical Algorithm Summary

1. Confirm diagnosis using the four essential RLS criteria 2
2. Check morning fasting ferritin and transferrin saturation 1, 2
3. Initiate iron supplementation if ferritin ≤75 ng/mL or transferrin saturation <20% 1, 2
4. Address exacerbating factors (medications, caffeine, alcohol, untreated OSA) 1, 2
5. Start gabapentin, gabapentin enacarbil, or pregabalin as first-line pharmacological treatment 1, 2
6. Avoid dopamine agonists for standard use due to augmentation risk 1, 3
7. Monitor for efficacy and side effects, particularly somnolence and dizziness 1, 2
8. Consider opioids for refractory cases or augmentation management 1, 5

Critical Pitfalls to Avoid

Do not start with dopamine agonists despite their FDA approval and short-term efficacy, as augmentation significantly worsens long-term morbidity and quality of life. 1, 5 The shift in guidelines reflects prioritization of long-term outcomes over immediate symptom relief.

Do not use magnesium as monotherapy without first addressing iron status and implementing guideline-recommended treatments. 1

Do not reduce dopamine agonists abruptly if augmentation occurs—add an alternative agent first to prevent severe rebound symptoms. 5

Do not overlook iron supplementation even in patients without anemia, as brain iron deficiency plays a key pathophysiological role in RLS. 1