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

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 These agents have replaced dopamine agonists due to superior long-term safety profiles and lack of augmentation risk. 1

Specific dosing recommendations:

• Gabapentin: Start at 300 mg three times daily (900 mg/day total), titrate by 300 mg/day every 3-7 days until reaching maintenance dose of 1800-2400 mg/day divided three times daily. 1
• Pregabalin: Allows twice-daily dosing with potentially superior bioavailability. 1
• Gabapentin enacarbil: A prodrug of gabapentin, also strongly recommended. 1

Common side effects include somnolence and dizziness, which are typically transient and mild. 1

Why NOT Dopamine Agonists as First-Line?

Despite FDA approval and historical use, the American Academy of Sleep Medicine now suggests against the standard use of dopamine agonists (pramipexole, ropinirole, rotigotine) due to the significant risk of augmentation - a paradoxical worsening of symptoms with long-term use characterized by earlier onset during the day, increased intensity, and spread to other body parts. 1, 2

• Pramipexole receives a conditional recommendation against standard use with moderate certainty. 1
• Ropinirole and rotigotine similarly are not recommended for standard use. 1
• Levodopa is specifically recommended against with very low certainty of evidence. 1

While these agents show efficacy in short-term trials 3, the long-term augmentation risk (affecting at least one-third of patients) 4 makes them inappropriate as first-line therapy.

Addressing Exacerbating Factors Concurrently

The American Academy of Sleep Medicine recommends eliminating or reducing:

• Alcohol and caffeine 1
• Antihistaminergic medications 1
• Serotonergic medications (SSRIs, SNRIs) 1
• Antidopaminergic medications (antipsychotics) 1
• Screen for and treat untreated obstructive sleep apnea 1

Clinical Algorithm Summary

1. Confirm diagnosis using the four essential criteria: urge to move legs with uncomfortable sensations, worsening with rest, relief with movement, and evening/nighttime predominance. 5
2. Check morning fasting ferritin and transferrin saturation. 5
3. Initiate iron supplementation if ferritin ≤75 ng/mL or transferrin saturation <20%. 5
4. Start gabapentin (300 mg TID, titrate to 1800-2400 mg/day) or pregabalin as first-line pharmacological treatment. 5
5. Address exacerbating factors (medications, substances, sleep apnea). 5
6. Monitor for efficacy and side effects. 5

Common Pitfalls to Avoid

• Do not start with dopamine agonists despite their FDA approval - augmentation risk makes them second-line at best. 1
• Do not use clonazepam as monotherapy - it only improves subjective sleep quality without reducing objective disease markers and has insufficient efficacy evidence. 1
• Do not overlook iron deficiency - correcting iron status may dramatically improve symptoms independent of other medications. 1
• Do not use single nighttime dosing of gabapentin - this fails to address daytime symptoms and provides suboptimal coverage. 1