What are the treatment options for a patient with Restless Legs 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 dopamine agonists now recommended against for standard use due to high augmentation risk. 1, 2, 3

Initial Assessment: Iron Status is Critical

Before starting any medication, check morning fasting iron studies including serum ferritin and transferrin saturation, ideally after avoiding iron-containing supplements for at least 24 hours. 1, 2, 3

Iron supplementation thresholds for RLS differ from general population guidelines:

• Supplement if ferritin ≤75 ng/mL OR transferrin saturation <20% 1, 2, 3
• This is higher than typical anemia thresholds because brain iron deficiency plays a key pathophysiologic role in RLS even when serum iron appears normal 1

Iron replacement options:

• IV ferric carboxymaltose: Strongly recommended for rapid correction in patients meeting iron parameters (strong recommendation, moderate certainty) 1, 3
• Oral ferrous sulfate: Conditional recommendation for appropriate iron parameters, but works more slowly than IV formulations 1, 3

Address Exacerbating Factors

Eliminate or modify these contributors before or concurrent with pharmacotherapy:

• Medications: Antihistamines, SSRIs/serotonergic agents, antipsychotics/dopamine antagonists 1
• Substances: Alcohol, caffeine, nicotine—particularly within 3 hours of bedtime 1
• Comorbidities: Screen for and treat obstructive sleep apnea 1

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

The evidence strongly favors these agents over dopamine agonists due to superior long-term safety profile and absence of augmentation risk. 1, 2, 3

Gabapentin (strongly recommended, moderate certainty): 1, 2, 3

• Start 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
• Critical pitfall: Single nighttime dosing fails to address daytime RLS symptoms and provides suboptimal coverage—three-times-daily dosing is necessary 1, 2

Pregabalin (strongly recommended, moderate certainty): 1, 2, 3

• Allows twice-daily dosing with potentially superior bioavailability compared to gabapentin 1, 3
• Preferred for patients who struggle with three-times-daily dosing adherence

Gabapentin enacarbil (strongly recommended, moderate certainty): 1, 3

• Prodrug of gabapentin with extended-release formulation
• Significantly more expensive than generic gabapentin or pregabalin with equivalent efficacy 1

Common side effects: Somnolence and dizziness, typically transient and mild 1

Medications to Avoid or Use with Extreme Caution

Dopamine agonists are now recommended AGAINST for standard use: 1, 2, 3

• Pramipexole: Conditional recommendation against (moderate certainty) 1, 3
• Ropinirole: Conditional recommendation against (moderate certainty) 1, 3, 4
• Rotigotine transdermal: Conditional recommendation against (low certainty) 1, 3
• Levodopa: Conditional recommendation against (very low certainty) 1, 3

Rationale: High risk of augmentation—a paradoxical worsening of symptoms characterized by earlier onset during the day, increased intensity, and spread to upper extremities or trunk. 1, 5 This iatrogenic complication occurs commonly with long-term dopamine agonist use and represents a major treatment failure. 5

May only be considered for short-term use in patients who place higher value on immediate symptom relief and lower value on long-term adverse effects. 1, 3

Strongly recommended AGAINST: 1, 3

• Cabergoline: Strong recommendation against (moderate certainty) 1
• Clonazepam: Conditional recommendation against (very low certainty)—improves subjective sleep but does not reduce objective RLS markers 1
• Bupropion, carbamazepine, valproic acid: All conditionally recommended against 1, 3

Second-Line Options for Refractory Cases

Extended-release oxycodone and other low-dose opioids (conditional recommendation, moderate certainty): 1, 2, 3

• Reserved for moderate to severe refractory RLS unresponsive to alpha-2-delta ligands
• Particularly effective for treating augmentation when transitioning off dopamine agonists 1, 5
• Long-term studies show relatively low risks of abuse/overdose in appropriately screened patients, with only small dose increases over 2-10 years 1
• Caution: Risk of respiratory depression, especially in patients with untreated obstructive sleep apnea 1

Other alternatives:

• Dipyridamole: Conditional recommendation (low certainty) 1
• Bilateral high-frequency peroneal nerve stimulation: Conditional recommendation as non-pharmacological option (moderate certainty) 1, 3

Managing Augmentation from Prior Dopamine Agonist Use

If a patient presents already on a dopamine agonist with augmentation symptoms (earlier onset, increased intensity, spread to arms/trunk): 5

1. Do NOT abruptly discontinue the dopamine agonist—this causes profound rebound RLS and insomnia 5
2. Add an alpha-2-delta ligand or opioid while maintaining the current dopamine agonist dose 5
3. Once adequate symptom control is achieved with the new agent, begin very slow down-titration of the dopamine agonist 5
4. Do NOT increase the dopamine agonist dose if augmentation is suspected—this worsens the problem 1

Special Populations

End-stage renal disease: 1, 3

• Gabapentin: Conditional recommendation (very low certainty), start 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% (moderate certainty) 1, 3
• Vitamin C: Conditional recommendation (low certainty) 1, 3

Pediatric RLS: 1, 3

• Ferrous sulfate if ferritin <50 ng/mL (conditional recommendation, very low certainty) 1, 3
• Monitor for constipation with oral iron 1

Pregnancy: 1

• Special consideration of medication safety profiles required
• Iron supplementation particularly important given pregnancy-specific RLS prevalence 1

Treatment Algorithm Summary

1. Check iron studies (ferritin, transferrin saturation) and supplement if ferritin ≤75 ng/mL or transferrin saturation <20% 1, 2, 3
2. Address exacerbating factors (medications, substances, sleep apnea) 1
3. Start alpha-2-delta ligand (gabapentin 300 mg TID or pregabalin) as first-line pharmacotherapy 1, 2, 3
4. Titrate to effect (gabapentin 1800-2400 mg/day divided TID) 1, 2
5. If refractory, consider opioids (extended-release oxycodone) or alternative options 1, 2, 3
6. Avoid dopamine agonists unless short-term use with clear understanding of augmentation risk 1, 2, 3

Monitoring and Follow-Up

• Reassess iron studies every 6-12 months 1
• Monitor for side effects of alpha-2-delta ligands (dizziness, somnolence) 1
• Evaluate improvement in both nighttime RLS symptoms and daytime functioning (alertness, concentration, mood) 1
• If using dopamine agonists, monitor closely for augmentation signs 1, 5