What are the symptoms and treatment options for a patient with restless legs syndrome, considering potential underlying conditions like iron deficiency, kidney disease, or diabetes?

Restless Legs Syndrome: Symptoms and Treatment

Clinical Symptoms

Restless legs syndrome is diagnosed by four essential clinical criteria: an urge to move the legs (often with uncomfortable sensations like achiness or tingling), symptoms that begin or worsen during rest or inactivity, relief with movement or walking, and worsening in the evening or at night. 1, 2, 3

• Patients describe the sensations using varied terms—crawling, pulling, throbbing, aching, or electric-like feelings—but all must report an overwhelming urge to move 3, 4
• Approximately 90% of RLS patients also experience periodic limb movements during sleep, though this is not required for diagnosis 2, 4
• The condition significantly impairs sleep onset and maintenance, leading to daytime somnolence, impaired concentration, and reduced quality of life 3, 4
• RLS affects approximately 3% of US adults to a clinically significant degree (symptoms at least twice weekly that are moderately or severely distressing) 3

Initial Assessment and Workup

Check morning fasting serum ferritin and transferrin saturation in all patients with clinically significant RLS, ideally after avoiding iron-containing supplements for at least 24 hours. 2, 5, 6

• RLS-specific iron thresholds differ from general population standards: supplement if ferritin ≤75 ng/mL or transferrin saturation <20% in adults 2, 5, 6
• For children with RLS, supplement if ferritin <50 ng/mL 1, 5
• For end-stage renal disease patients, use higher thresholds: ferritin <200 ng/mL and transferrin saturation <20% 1, 5
• Identify and discontinue exacerbating medications: serotonergic antidepressants, dopamine antagonists (including antipsychotics like lurasidone), centrally acting antihistamines (diphenhydramine), alcohol, and caffeine 2, 6, 3
• Screen for secondary causes: end-stage kidney disease (24% prevalence), pregnancy (22% prevalence, especially third trimester), iron deficiency anemia (23.9%), peripheral neuropathy (21.5%), multiple sclerosis (27.5%), and Parkinson disease (20%) 3

Treatment Algorithm

Step 1: Iron Supplementation (When Indicated)

For ferritin ≤75 ng/mL or transferrin saturation <20%, initiate oral ferrous sulfate 325-650 mg daily (or every other day to improve absorption and reduce side effects). 2, 5, 3

• Oral ferrous sulfate receives a conditional recommendation with moderate certainty of evidence 2, 5
• For patients not responding to oral iron after 3 months, or with severe symptoms requiring rapid correction, use IV ferric carboxymaltose 1000 mg (strong recommendation, moderate certainty of evidence). 2, 5, 3
• Alternative IV formulations include low molecular weight iron dextran and ferumoxytol (conditional recommendations) 2
• Continue iron supplementation indefinitely with monitoring every 6-12 months, as RLS symptoms recur if iron stores decline 2
• For ferritin 75-100 ng/mL, use IV iron exclusively—oral iron is poorly absorbed and ineffective in this range 2

Step 2: First-Line Pharmacological Treatment

The American Academy of Sleep Medicine strongly recommends alpha-2-delta ligands (gabapentin, gabapentin enacarbil, or pregabalin) as first-line therapy for RLS (strong recommendation, moderate certainty of evidence). 1, 2, 6, 3

Gabapentin Dosing:

• Start 300 mg three times daily (900 mg/day total) 2, 6
• Titrate by 300 mg/day every 3-7 days until reaching maintenance dose of 1800-2400 mg/day divided three times daily 2, 6
• Maximum dose 3600 mg/day is well-tolerated in clinical studies 2
• In randomized trials, approximately 70% of patients treated with gabapentinoids had much or very much improved symptoms vs 40% with placebo 3

Pregabalin Alternative:

• Allows twice-daily dosing with potentially superior bioavailability compared to gabapentin 2, 6
• Strong recommendation with moderate certainty of evidence 1, 2

Special Renal Dosing:

• For end-stage renal disease, start gabapentin 100 mg post-dialysis or at bedtime, maximum 200-300 mg daily 2
• Avoid pregabalin in ESRD due to 50-68% higher hazard for altered mental status and falls 2

Step 3: Medications to Avoid or Use with Extreme Caution

The American Academy of Sleep Medicine suggests against the standard use of dopamine agonists (pramipexole, ropinirole, rotigotine) due to high risk of augmentation—a paradoxical worsening of symptoms with long-term use (conditional recommendations, moderate certainty of evidence). 1, 2, 3

• Augmentation occurs in 7-10% annually with dopamine agonists, characterized by earlier symptom onset during the day, increased intensity, and spread to arms or trunk 2, 3, 7
• These agents may only be considered for short-term use in patients who prioritize immediate symptom relief over long-term adverse effects 1, 2
• The American Academy of Sleep Medicine strongly recommends against cabergoline (strong recommendation, moderate certainty of evidence). 1, 2
• Avoid bupropion, carbamazepine, clonazepam, and valproic acid—all receive recommendations against use 1, 2

Step 4: Second-Line Options for Refractory Cases

For patients failing first-line therapy or experiencing augmentation from dopamine agonists, extended-release oxycodone and other low-dose opioids (methadone 5-10 mg daily, buprenorphine) are conditionally recommended. 2, 3

• Long-term studies show relatively low risks of abuse/overdose in appropriately screened patients, with only small dose increases over 2-10 years 2
• Opioids are particularly effective for treating augmentation when decreasing or eliminating dopamine agonists 2
• Caution: monitor for respiratory depression, especially in patients with untreated obstructive sleep apnea 2

Bilateral high-frequency peroneal nerve stimulation is conditionally recommended as a non-pharmacological option (moderate certainty of evidence). 1, 2

Special Population Considerations

End-Stage Renal Disease:

• Gabapentin (conditional, very low certainty) 1, 2
• IV iron sucrose if ferritin <200 ng/mL and transferrin saturation <20% (conditional, moderate certainty) 1, 2
• Vitamin C (conditional, low certainty) 1, 2

Pregnancy:

• Iron supplementation is particularly important given 22% RLS prevalence in pregnancy 2
• Consider medication safety profiles carefully; oral iron has favorable safety throughout gestation 2

Pediatric RLS:

• Ferrous sulfate if ferritin <50 ng/mL (conditional, very low certainty) 1, 5
• Monitor for constipation with oral iron 2

Non-Pharmacological Interventions

Eliminate caffeine and alcohol, especially within 3 hours of bedtime, as these significantly worsen evening and nighttime RLS symptoms. 2, 6

• Avoid heavy meals within 3 hours of bedtime 2
• Implement regular morning/afternoon exercise, but avoid vigorous exercise close to bedtime 2
• Ensure dark, quiet, comfortable sleep environment 2
• Screen for and treat untreated obstructive sleep apnea, which exacerbates RLS 2, 6

Critical Pitfalls to Avoid

• Never use general population ferritin cutoffs (<15-30 ng/mL) for RLS—this misses the majority of patients who would benefit from iron therapy 5
• Do not start dopamine agonists as first-line therapy—augmentation risk makes them inappropriate for standard use 1, 2, 3
• Do not test iron studies while patients are taking supplements—wait at least 24 hours after the last iron-containing product 2, 5
• Do not use oral iron for ferritin 75-100 ng/mL—it will be ineffective; use IV iron exclusively in this range 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
• Monitor for side effects of alpha-2-delta ligands (dizziness, somnolence), which are typically transient and mild but may increase fall risk in elderly patients 2