How should restless leg syndrome be diagnosed and managed, including work‑up, iron supplementation, pharmacologic and non‑pharmacologic therapies?

Restless Legs Syndrome: Diagnosis and Management

Diagnostic Criteria

Restless legs syndrome is diagnosed clinically when all four of the following criteria are met: an urge to move the legs (usually with uncomfortable sensations such as achiness, tingling, or crawling feelings); symptoms begin or worsen during rest or inactivity; symptoms are relieved by movement such as walking or stretching; and symptoms are worse in the evening or at night. 1, 2

• Polysomnography is not recommended for diagnosis—RLS is a clinical diagnosis based on history alone. 2
• Approximately 90% of RLS patients have periodic limb movements during sleep, but this is not required for diagnosis. 1, 3
• Differentiate RLS from mimics including peripheral neuropathy, akathisia, positional discomfort, nocturnal leg cramps, and vascular claudication by confirming all four diagnostic criteria. 4

Initial Work-Up and Iron Assessment

Check morning fasting serum ferritin and transferrin saturation in all patients with clinically significant RLS after withholding iron-containing supplements and foods for at least 24 hours. 4, 5

• Adults: Initiate iron supplementation when ferritin ≤ 75 ng/mL or transferrin saturation < 20%. 4, 6
• Children: Initiate iron supplementation when ferritin < 50 ng/mL. 1, 4
• These thresholds are higher than general population cutoffs because brain iron deficiency in the substantia nigra—not systemic iron deficiency—drives RLS pathophysiology by impairing dopamine synthesis and transport. 5

Iron Supplementation Strategy

For ferritin ≤ 75 ng/mL or transferrin saturation < 20%, use either oral ferrous sulfate 325–650 mg daily (or every other day) or intravenous ferric carboxymaltose 1000 mg as first-line iron therapy. 4, 6

• IV ferric carboxymaltose receives a strong recommendation with moderate certainty of evidence and is the only IV iron formulation with this level of support—it is superior because slow-release, high-dose formulations enable H-ferritin binding and macrophage iron uptake necessary for CNS penetration. 6
• For ferritin 75–100 ng/mL, use IV iron only (not oral) because oral absorption is poor in this range. 4, 6
• IV iron may require up to 12 weeks to achieve full clinical benefit. 6
• Oral ferrous sulfate receives a conditional recommendation; common side effects include constipation. 4, 6
• Repeat iron studies every 6–12 months during ongoing therapy. 4, 6

Special Populations for Iron Therapy

• End-stage renal disease: Use IV iron sucrose (not ferric carboxymaltose) when ferritin < 200 ng/mL and transferrin saturation < 20%; the higher ferritin threshold reflects altered iron metabolism in ESRD. 1, 4, 6
• Pregnancy: Oral iron formulations are preferred throughout gestation due to favorable safety profile. 4, 6
• Pediatric patients: Use oral ferrous sulfate when ferritin < 50 ng/mL; monitor for constipation. 1, 4

Identify and Eliminate Exacerbating Factors

Before starting pharmacologic therapy, address potential RLS-worsening medications and comorbidities: alcohol, caffeine (especially in the evening), antihistaminergic medications (e.g., diphenhydramine), serotonergic antidepressants (SSRIs, SNRIs), antidopaminergic medications (antipsychotics, metoclopramide), and untreated obstructive sleep apnea. 4, 2

• Discontinue these medications if clinically feasible—even moderate caffeine or alcohol consumption in the evening can significantly worsen RLS symptoms. 4
• Lurasidone and other antipsychotics block dopamine receptors and can trigger or worsen RLS; consider alternative agents with less dopamine antagonism if RLS develops. 4

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

Alpha-2-delta ligands (gabapentin, gabapentin enacarbil, or pregabalin) are strongly recommended as first-line pharmacologic treatment for RLS with moderate certainty of evidence. 1, 4, 2

• Gabapentin: Start 300 mg three times daily; increase by 300 mg/day every 3–7 days; target maintenance dose 1800–2400 mg/day divided TID; maximum studied dose 3600 mg/day. 4
• Pregabalin: Start 50 mg TID or 75 mg BID; after 3–7 days increase to 300 mg/day; thereafter increase by 150 mg every 3–7 days as tolerated; maximum 600 mg/day. 4
• Gabapentin enacarbil is a prodrug with superior bioavailability and allows once- or twice-daily dosing. 4
• Common side effects include somnolence and dizziness, which are typically transient and mild. 4
• Alpha-2-delta ligands do not cause augmentation, unlike dopamine agonists. 1, 4

Renal Dosing Adjustments

• End-stage renal disease: Gabapentin 100 mg post-dialysis or at bedtime; maximum 200–300 mg daily. 1, 4
• Avoid pregabalin in ESRD because it markedly increases the hazard of altered mental status and falls (50–68% higher hazard). 4

Dopamine Agonists: Not Recommended as First-Line

The American Academy of Sleep Medicine suggests against the standard use of dopamine agonists (pramipexole, ropinirole, rotigotine) due to a 7–10% annual risk of augmentation—a paradoxical worsening of RLS symptoms. 1, 4, 2

• Augmentation presents as earlier daily symptom onset (afternoon instead of evening), increased intensity, and spread to arms or trunk. 1, 4
• Dopamine agonists may be considered only for short-term use in patients who prioritize immediate symptom relief over long-term safety, but this is not the standard approach. 1, 4
• Do not increase dopamine agonist doses when symptoms worsen—this likely reflects augmentation and will make the problem worse. 4

Transitioning from Dopamine Agonists to Alpha-2-Delta Ligands

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

Second-Line and Refractory RLS Treatment

For moderate to severe refractory RLS (persistent symptoms despite optimized iron status, adequate trial of alpha-2-delta ligands, and elimination of exacerbating factors), extended-release oxycodone and other low-dose opioids are conditionally recommended. 1, 4, 2

• Extended-release oxycodone 5–10 mg at bedtime is the primary opioid recommended by the American Academy of Sleep Medicine. 4
• Methadone 5–10 mg daily provides 24-hour symptom coverage with low augmentation risk and stable dosing. 4
• Buprenorphine (transdermal or sublingual) has a similar safety profile. 4
• Long-term studies show only modest dose escalation over 2–10 years and relatively low risk of abuse when patients are appropriately screened. 4, 2
• Screen for opioid-use-disorder risk using validated assessment tools before initiating therapy. 4
• Evaluate for untreated obstructive sleep apnea because opioids increase the risk of respiratory depression and central sleep apnea. 4
• Monitor for constipation (the most common adverse effect) and prescribe prophylactic stool softeners or laxatives. 4

Non-Pharmacologic Alternative for Refractory RLS

• Bilateral high-frequency peroneal nerve stimulation receives a conditional recommendation with moderate certainty of evidence as a non-invasive option for patients who refuse or cannot tolerate opioids. 1, 4

Medications to Avoid

The American Academy of Sleep Medicine strongly recommends against the following agents for RLS treatment:

• Cabergoline (strong recommendation against use)—associated with cardiac valvular fibrosis. 1, 4
• Bupropion (conditional recommendation against use)—limited efficacy. 1, 4
• Carbamazepine (conditional recommendation against use)—unclear benefit, risk of adverse effects. 1, 4
• Clonazepam (conditional recommendation against use)—provides only sedation without reducing periodic limb movements; does not address underlying RLS pathology. 1, 4
• Valproic acid (conditional recommendation against use)—hepatotoxicity and teratogenicity risks. 1, 4
• Valerian (conditional recommendation against use)—very low certainty of evidence. 1, 4
• Tizanidine—not included in guidelines as a treatment option for RLS. 4

Non-Pharmacologic Management

• Regular exercise in the morning and/or afternoon is recommended, but avoid vigorous exercise close to bedtime. 4
• Avoid alcohol, caffeine, and nicotine too close to bedtime. 4
• Avoid heavy meals or drinking within 3 hours of bedtime. 4
• Ensure the sleep environment is dark, quiet, and at a comfortable temperature. 4
• Increase exposure to bright light during the day while avoiding bright light at night. 4
• Massage, temperate baths, and leg stretching may provide symptom relief. 7

Special Considerations

• Pregnancy: Iron supplementation is particularly important given pregnancy-specific RLS prevalence (22% overall, higher in third trimester); oral iron formulations are preferred throughout gestation. 4, 2
• End-stage renal disease: Gabapentin (100 mg post-dialysis or at bedtime, max 200–300 mg daily), IV iron sucrose (if ferritin < 200 ng/mL and transferrin saturation < 20%), and vitamin C supplementation are conditionally recommended. 1, 4
• Comorbid conditions: RLS is common in multiple sclerosis (27.5%), end-stage kidney disease (24%), iron deficiency anemia (23.9%), peripheral neuropathy (21.5%), and Parkinson disease (20%). 2

Monitoring and Follow-Up

• Reassess RLS severity with the International RLS Study Group Rating Scale at 4–6 weeks after treatment initiation. 4
• Repeat iron studies every 6–12 months, as brain iron deficiency may persist despite clinical improvement. 4
• Monitor for side effects of alpha-2-delta ligands (dizziness, somnolence) and opioids (constipation, sedation, respiratory depression). 4
• Evaluate both nighttime symptom relief and daytime functional outcomes (alertness, mood, quality of life). 4

Critical Pitfalls to Avoid

• Do not use general population ferritin cutoffs (< 15–30 ng/mL) for RLS—the disease-specific threshold is ≤ 75 ng/mL in adults. 4, 6
• Do not perform iron studies while the patient is taking iron supplements—wait ≥ 24 hours after the last iron-containing product. 4, 6
• Do not use dopamine agonists as first-line therapy given the high augmentation risk and current guideline recommendations favoring alpha-2-delta ligands. 1, 4, 2
• Do not increase dopamine agonist doses when symptoms worsen—this likely reflects augmentation and will worsen the problem. 4
• Do not assume all IV iron formulations are equivalent—only ferric carboxymaltose has strong evidence in RLS; iron sucrose lacks efficacy except in dialysis patients. 6
• Do not withhold opioids from appropriately screened patients with severe refractory RLS—evidence supports their use with low long-term abuse risk. 4, 2
• Do not combine multiple sedating agents (opioids + alpha-2-delta ligands + benzodiazepines) without first treating obstructive sleep apnea. 4

Clinical Impact

• RLS causes clinically significant sleep disturbance in approximately 90% of patients and is associated with elevated rates of cardiovascular disease (≈ 30%), depression (≈ 30%), suicidal ideation or self-harm (0.35 cases/1000 person-years), and reduced quality of life. 4, 2
• Approximately 3% of US adults experience moderately or severely distressing RLS symptoms at least twice weekly. 2