What is the recommended treatment plan for an adult with restless‑leg syndrome, including lifestyle measures, iron assessment and supplementation, and first‑ and second‑line pharmacologic options?

Restless Leg Syndrome Treatment

Initial Assessment and Iron Management

Start by checking morning fasting serum ferritin and transferrin saturation after avoiding iron-containing supplements for at least 24 hours, and supplement with iron if ferritin ≤75 ng/mL or transferrin saturation <20%—this threshold is substantially higher than general population guidelines because brain iron deficiency plays a key role in RLS pathophysiology. 1, 2

• No other laboratory tests are necessary to establish the diagnosis of RLS, though a thorough neurologic exam should exclude secondary causes such as peripheral neuropathy or radiculopathy. 1
• For iron supplementation, use oral ferrous sulfate 325-650 mg daily or every other day as initial therapy (conditional recommendation, moderate certainty). 2, 3, 4
• If oral iron is not tolerated or ineffective after 3 months, or if ferritin is between 75-100 ng/mL, use IV ferric carboxymaltose 1000 mg (strong recommendation, moderate certainty). 1, 2, 3, 4

Eliminate Exacerbating Factors

Before starting pharmacologic therapy, eliminate or reduce substances and medications that worsen RLS:

• Discontinue or minimize: caffeine, alcohol, antihistaminergic medications (especially diphenhydramine), serotonergic antidepressants, and antidopaminergic medications. 1, 2, 3, 4
• Screen for and treat untreated obstructive sleep apnea, as this can significantly exacerbate RLS symptoms. 1, 2
• Avoid heavy meals or drinking within 3 hours of bedtime, as this can worsen nighttime symptoms. 2

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

The American Academy of Sleep Medicine strongly recommends alpha-2-delta ligands (gabapentin, pregabalin, or gabapentin enacarbil) as first-line pharmacological therapy for RLS due to their superior long-term safety profile and complete absence of augmentation risk (strong recommendation, moderate certainty of evidence). 1, 2, 3, 4

Gabapentin Dosing

• Start at 300 mg three times daily. 1
• Titrate upward by 300 mg/day every 3-7 days until reaching a maintenance dose of 1800-2400 mg/day divided three times daily. 1, 2
• Maximum studied dose is 3600 mg/day, which is well-tolerated in clinical studies. 2
• In randomized trials, approximately 70% of patients treated with gabapentinoids had much or very much improved RLS symptoms versus 40% with placebo (P < .001). 4

Pregabalin Dosing

• Start at 50 mg three times daily or 75 mg twice daily. 2
• After 3-7 days, increase to 300 mg per day; thereafter, raise by 150 mg every 3-7 days as tolerated. 2
• Maximum recommended dose is 600 mg per day. 2
• Pregabalin allows twice-daily dosing with potentially superior bioavailability compared to gabapentin, and may be preferred for patients who struggle with three-times-daily dosing schedules. 1, 2

Gabapentin Enacarbil

• This is a prodrug of gabapentin with once-daily dosing. 1
• Should be taken 1-3 hours before bedtime. 1
• Strongly recommended with moderate certainty of evidence. 2, 3

Critical Medications to Avoid

The American Academy of Sleep Medicine strongly recommends against starting dopamine agonists (pramipexole, ropinirole, rotigotine) as first-line therapy due to the high risk of augmentation—a paradoxical iatrogenic worsening of RLS characterized by earlier symptom onset during the day, increased intensity, and spread to arms or trunk. 1, 2, 3, 4

• Augmentation occurs in 7-10% of patients annually on dopamine agonists. 2, 4
• Dopamine agonists may be considered only for short-term treatment in patients who prioritize immediate symptom relief over long-term adverse effects, but this is explicitly not the standard approach. 2, 3
• Strongly recommend against: cabergoline (strong recommendation, moderate certainty). 2, 3
• Conditionally recommend against: levodopa (very low certainty), pramipexole (moderate certainty), ropinirole (moderate certainty), rotigotine (low certainty). 2, 3
• Also avoid: clonazepam, benzodiazepines, bupropion, carbamazepine, valproic acid, and valerian due to insufficient evidence of efficacy or safety concerns. 1, 2

Second-Line Treatment Options for Refractory Cases

If first-line alpha-2-delta ligands are ineffective or not tolerated:

• Extended-release oxycodone and other low-dose opioids (methadone 5-10 mg daily, buprenorphine) are conditionally recommended for moderate to severe refractory RLS, particularly when treating augmentation from dopamine agonists (conditional recommendation, moderate certainty). 1, 2, 5, 6, 4
• Long-term studies of methadone and buprenorphine show relatively low risks of abuse and overdose in appropriately screened patients, with only small dose increases over 2-10 years. 2, 5, 6
• Opioids are very effective for relieving worsening symptoms when decreasing or eliminating dopamine agonists. 2, 6
• Caution: Monitor for respiratory depression, especially in patients with untreated obstructive sleep apnea. 2

Non-Pharmacological Option

• Bilateral high-frequency peroneal nerve stimulation is conditionally recommended as a non-pharmacological option for patients who do not respond to pharmacological therapy (conditional recommendation, moderate certainty). 1, 2

Special Populations

End-Stage Renal Disease

• Gabapentin: start 100 mg post-dialysis or at bedtime; maximum 200-300 mg daily (conditional recommendation, very low certainty). 2, 3
• IV iron sucrose if ferritin <200 ng/mL and transferrin saturation <20% (conditional recommendation, moderate certainty). 2, 3
• Vitamin C supplementation (conditional recommendation, low certainty). 2, 3
• Avoid pregabalin in ESRD due to increased hazard for altered mental status and falls. 2

Pregnancy

• Treatment selection should consider pregnancy-specific safety profiles. 2, 3
• Iron supplementation is particularly important given pregnancy-specific RLS prevalence (22% in third trimester). 2, 4
• Non-pharmacologic approaches may be preferred during pregnancy. 3

Pediatric RLS

• Oral ferrous sulfate if ferritin <50 ng/mL (conditional recommendation, very low certainty). 2, 3
• Monitor for constipation with iron supplementation. 2

Common Pitfalls to Avoid

• Do not assume "normal" ferritin levels are adequate for RLS—the threshold for supplementation (≤75 ng/mL) is substantially higher than general population guidelines (typically 15-30 ng/mL). 1, 2
• Do not use single nighttime dosing of gabapentin—this fails to address daytime RLS symptoms and provides suboptimal 24-hour coverage. 2
• Do not increase dopamine agonist doses if augmentation is suspected—this worsens the problem; instead, transition to alpha-2-delta ligands or opioids. 2, 5
• Do not use clonazepam or benzodiazepines—there is insufficient evidence of efficacy on validated RLS outcomes. 1, 2

Lifestyle Modifications

• Avoid alcohol, caffeine, and nicotine too close to bedtime. 2
• Regular exercise in the morning and/or afternoon is recommended, but avoid vigorous exercise close to bedtime. 2
• Ensure sleep environment is dark, quiet, and at a comfortable temperature. 2
• Increase exposure to bright light during the day while avoiding bright light at night. 2