What is the recommended treatment approach for restless‑leg syndrome, including lifestyle modifications, iron repletion, and pharmacologic options?

Treatment of Restless Leg Syndrome

Alpha-2-delta ligands (gabapentin, gabapentin enacarbil, or pregabalin) are the strongly recommended first-line pharmacological treatment for restless leg syndrome, after addressing iron deficiency and eliminating exacerbating factors. 1, 2, 3

Initial Assessment and Non-Pharmacological Management

Iron Status Evaluation

• Check morning fasting serum ferritin and transferrin saturation after avoiding iron-containing supplements for at least 24 hours in all patients with clinically significant RLS 1, 2, 3
• Supplement iron if ferritin ≤75 ng/mL or transferrin saturation <20% (note: this threshold is substantially higher than general population guidelines) 1, 2, 3
• In children, supplement if ferritin <50 ng/mL 2

Iron Repletion Options

• Oral ferrous sulfate 325 mg once daily or every other day for mild iron deficiency 2, 3
• IV ferric carboxymaltose 750-1000 mg in one or two infusions is strongly recommended for patients who cannot tolerate oral iron, fail oral therapy after 3 months, or have ferritin 75-100 ng/mL despite oral treatment 1, 2, 3
• Alternative IV formulations include low molecular weight iron dextran and ferumoxytol 1

Eliminate Exacerbating Factors

• Remove or reduce alcohol, caffeine, and nicotine—particularly within 3 hours of bedtime 1, 2, 3
• Discontinue or switch antihistaminergic medications (including over-the-counter sleep aids), serotonergic antidepressants, and antidopaminergic medications 1, 2, 3
• Screen for and treat obstructive sleep apnea, as untreated OSA significantly worsens RLS symptoms 1, 2, 4

Lifestyle Modifications

• Engage in regular exercise in the morning or afternoon, but avoid vigorous exercise close to bedtime 1
• Optimize sleep environment: dark, quiet, comfortable temperature 1
• Increase bright light exposure during the day while avoiding bright light at night 1
• Avoid heavy meals within 3 hours of bedtime 1

First-Line Pharmacological Treatment

Alpha-2-Delta Ligands (Strong Recommendation, Moderate Certainty)

These agents are now preferred over dopamine agonists because they do not cause augmentation—a paradoxical worsening of symptoms that occurs in 7-10% of patients annually with dopaminergic therapy. 1, 2

Gabapentin

• Start 300 mg three times daily 1, 2
• Titrate upward by 300 mg/day every 3-7 days 1, 2
• Target maintenance dose: 1800-2400 mg/day divided three times daily 1, 2
• Maximum studied dose is 3600 mg/day 2
• Common side effects include transient somnolence and dizziness 2

Pregabalin

• Allows twice-daily dosing with potentially superior bioavailability compared to gabapentin 1, 2
• Start 50 mg three times daily or 75 mg twice daily 2
• After 3-7 days, increase to 300 mg/day; thereafter may raise by 150 mg every 3-7 days 2
• Maximum dose: 600 mg/day 2

Gabapentin Enacarbil

• Prodrug of gabapentin with once-daily dosing 1, 2
• Take 1-3 hours before bedtime 1
• Particularly useful for patients who struggle with multiple daily doses 1

Second-Line and Refractory Treatment Options

Opioids (Conditional Recommendation, Moderate Certainty)

Extended-release oxycodone and other low-dose opioids are conditionally recommended for moderate to severe refractory cases, particularly when treating augmentation from dopamine agonists. 1, 2, 4, 5

• Methadone 5-10 mg daily or buprenorphine (transdermal or sublingual) provide 24-hour coverage with stable long-term dosing 1, 2
• Long-term studies show only small dose increases over 2-10 years with relatively low abuse risk in appropriately screened patients 1, 2
• Screen for opioid-use-disorder risk and untreated obstructive sleep apnea before initiating 2
• Monitor for respiratory depression, particularly during the first weeks of therapy 2
• Prophylactic stool softeners or laxatives should be prescribed for constipation 2

Non-Pharmacological Option

• Bilateral high-frequency peroneal nerve stimulation is conditionally recommended as a non-invasive alternative for patients who do not respond to pharmacological therapy 1, 2, 6

Medications to Avoid or Use with Extreme Caution

Dopamine Agonists (Conditional Recommendation AGAINST Standard Use)

The American Academy of Sleep Medicine now recommends against standard use of dopamine agonists (pramipexole, ropinirole, rotigotine) due to high augmentation risk. 1, 2, 3

• Augmentation occurs in 7-10% of patients annually and manifests as earlier daily symptom onset (afternoon instead of evening), increased intensity, and spread to arms or trunk 1, 2, 4
• These agents may be considered only for short-term treatment in patients who prioritize immediate symptom relief over long-term safety 2, 3
• Never increase dopamine agonist doses when symptoms worsen—this likely reflects augmentation and will make the problem worse 1, 2, 4

Strongly Recommended Against

• Cabergoline (strong recommendation against): associated with cardiac valvular fibrosis 2, 3
• Clonazepam (conditional recommendation against): provides only sedation without reducing periodic limb movements; insufficient evidence of efficacy on validated RLS outcomes 1, 2
• Bupropion, carbamazepine, valproic acid, valerian (conditional recommendations against): limited efficacy and/or significant safety concerns 2

Managing Dopaminergic Augmentation

If a patient develops augmentation on a dopamine agonist, the following transition strategy is recommended:

1. Add an alpha-2-delta ligand (e.g., gabapentin 300 mg TID, titrated to 1800-2400 mg/day) or an opioid BEFORE tapering the dopamine agonist 2, 4
2. Once adequate symptom control is achieved, down-titrate the dopamine agonist very slowly (reduce by 0.125-0.25 mg pramipexole-equivalent every 1-2 weeks) 2, 4
3. Anticipate rebound RLS and insomnia during the taper; short-acting opioids may serve as temporary bridge therapy 2, 4
4. For severe augmentation, bypass alpha-2-delta ligands and transition directly to an opioid 2

Special Populations

End-Stage Renal Disease

• Gabapentin 100 mg post-dialysis or at bedtime (maximum 200-300 mg daily) is conditionally recommended 1, 2, 3
• Avoid pregabalin in ESRD due to markedly increased hazard of altered mental status and falls (50-68% higher hazard) 2
• IV iron sucrose if ferritin <200 ng/mL and transferrin saturation <20% 1, 2, 3
• Vitamin C supplementation may improve iron utilization 1, 2

Pregnancy

• Iron supplementation is particularly important given pregnancy-specific RLS prevalence, with oral formulations favored throughout gestation 2
• Treatment selection should consider pregnancy-specific medication safety profiles 2, 3
• Non-pharmacological approaches may be preferred when possible 3

Pediatric RLS

• Oral ferrous sulfate if ferritin <50 ng/mL, with monitoring for constipation 1, 2

Monitoring and Follow-Up

• Reassess RLS severity at 4-6 weeks after treatment initiation 2
• Repeat iron studies every 6-12 months, as brain iron deficiency may persist despite clinical improvement 2
• Evaluate both nighttime symptom relief and daytime functional outcomes (alertness, mood, quality of life) 2
• Monitor for side effects of alpha-2-delta ligands (dizziness, somnolence), particularly in patients with untreated obstructive sleep apnea or COPD 2

Critical 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 1, 2
• Do not start dopamine agonists as first-line therapy due to high augmentation risk and current guideline recommendations favoring alpha-2-delta ligands 1, 2
• Do not increase dopamine agonist doses when symptoms worsen—this reflects augmentation and will worsen the condition 1, 2, 4
• Do not use clonazepam as monotherapy—it only provides sedation without addressing the underlying RLS pathology 1, 2
• Do not label RLS as refractory without first optimizing iron status—patients with ferritin 75-100 ng/mL may still benefit from IV iron 2
• Do not combine multiple sedating agents (opioids + alpha-2-delta ligands + benzodiazepines) without first treating obstructive sleep apnea due to additive respiratory depression risk 2