What is the first line of treatment for restless legs syndrome?

First-Line Treatment for Restless Legs Syndrome

Alpha-2-delta ligands (gabapentin, gabapentin enacarbil, or pregabalin) are the first-line pharmacological treatment for restless legs syndrome, but iron status must be assessed and corrected first if ferritin ≤75 ng/mL or transferrin saturation <20%. 1

Initial Assessment: Iron Status Takes Priority

Before starting any medication, check morning fasting serum ferritin and transferrin saturation (after avoiding iron supplements for at least 24 hours). 1 This is critical because:

• Iron supplementation is recommended if 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
• Oral ferrous sulfate receives a conditional recommendation with moderate certainty of evidence. 1
• IV ferric carboxymaltose is strongly recommended for patients who don't respond to oral therapy. 1

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

The American Academy of Sleep Medicine strongly recommends alpha-2-delta ligands as first-line therapy with moderate certainty of evidence. 1, 2 These agents have replaced dopamine agonists due to superior long-term safety profiles and avoidance of augmentation (paradoxical worsening of symptoms). 1

Specific Dosing Recommendations:

Gabapentin: 1, 2

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

Pregabalin: 1, 2

• Allows twice-daily dosing
• May have superior bioavailability compared to gabapentin
• Strongly recommended with moderate certainty of evidence

Gabapentin enacarbil: 1

• Prodrug of gabapentin
• Strongly recommended with moderate certainty of evidence

Common Side Effects to Monitor:

• Somnolence and dizziness (typically transient and mild) 1
• Monitor particularly in patients with untreated obstructive sleep apnea or COPD 1

Why NOT Dopamine Agonists as First-Line?

Despite FDA approval and historical use, the American Academy of Sleep Medicine now suggests against standard use of dopamine agonists (pramipexole, ropinirole, rotigotine) due to the significant risk of augmentation with long-term use. 1, 3 While these agents show short-term efficacy 4, augmentation occurs commonly and is characterized by:

• Earlier onset of symptoms during the day 3
• Increased symptom intensity 3
• Spread of symptoms to other body parts 3

The American Academy of Sleep Medicine specifically recommends against cabergoline (strong recommendation), and suggests against pramipexole, ropinirole, and rotigotine for standard use. 1

Address Exacerbating Factors Concurrently

The American Academy of Sleep Medicine recommends eliminating or reducing: 1, 2

• Alcohol and caffeine
• Antihistaminergic medications
• Serotonergic medications (SSRIs, SNRIs)
• Antidopaminergic medications (antipsychotics)
• Screen for and treat untreated obstructive sleep apnea

Clinical Algorithm Summary

1. Confirm diagnosis using the four essential criteria (urge to move legs with uncomfortable sensations, worsening with rest, relief with movement, evening/nighttime predominance) 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. Start gabapentin or pregabalin as first-line pharmacological treatment 1, 2
5. Address exacerbating factors (medications, substances, sleep apnea) 2
6. Monitor for efficacy and side effects 2

Critical Pitfall to Avoid

Never start with dopamine agonists as first-line therapy despite their FDA approval and short-term efficacy. 1, 3 The long-term risk of augmentation makes them inappropriate for initial treatment, and switching away from them later becomes extremely difficult due to profound rebound RLS and insomnia with dose reductions. 5