What are the causes and treatment options for a patient with restless legs syndrome (RLS)?

Restless Legs Syndrome: Causes and Treatment

Causes and Pathophysiology

Restless legs syndrome (RLS) results from a combination of genetic predisposition, brain iron deficiency, and dopaminergic system dysfunction, with secondary causes including iron deficiency anemia, uremia, polyneuropathies, pregnancy, and certain medications. 1, 2, 3

Primary RLS

• Strong genetic component with several identified genetic linkages and three causative genes 3
• Central nervous system pathology demonstrates reduced iron stores with altered homeostatic control of iron, not simply insufficient iron entering the brain 3
• Represents lower CNS levels of, or reduced responsiveness to, dopamine 4

Secondary RLS Triggers

• Iron deficiency (serum ferritin ≤75 ng/mL or transferrin saturation <20%) 1, 2
• Medications that worsen RLS: antihistamines, serotonergic antidepressants (SSRIs, tricyclics), antipsychotics (dopamine antagonists like lurasidone), lithium, and bupropion 1, 2
• Medical conditions: end-stage renal disease, pregnancy, untreated obstructive sleep apnea, polyneuropathies 1, 2, 3
• Lifestyle factors: alcohol, caffeine, and nicotine consumption, particularly in the evening 1, 2

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Treatment Algorithm

Step 1: Initial Assessment and Non-Pharmacological Management

Check morning fasting iron studies (ferritin and transferrin saturation) in all patients with clinically significant RLS, ideally after avoiding iron-containing supplements for at least 24 hours. 1, 2, 5

• Iron supplementation thresholds (different from general population):
  • Adults: Supplement if ferritin ≤75 ng/mL or transferrin saturation <20% 1, 2
  • Children: Supplement if ferritin <50 ng/mL 1, 2
  • IV iron (ferric carboxymaltose) strongly recommended if ferritin between 75-100 ng/mL 1

Address exacerbating factors immediately:

• Eliminate or reduce alcohol, caffeine, and nicotine, especially within 3 hours of bedtime 1, 2, 5
• Discontinue antihistaminergic, serotonergic, and antidopaminergic medications when possible 1, 2
• Screen for and treat untreated obstructive sleep apnea 1, 2
• Implement moderate exercise (morning/afternoon, not close to bedtime) 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, with strong recommendation and moderate certainty of evidence. 1, 2, 5

Gabapentin Dosing

• Start at 300 mg three times daily (not single nighttime dosing, which fails to address daytime symptoms) 2, 5
• Titrate by 300 mg/day every 3-7 days until reaching maintenance dose of 1800-2400 mg/day divided three times daily 2, 5
• Doses up to 3600 mg/day are well-tolerated in clinical studies 2
• Common side effects: somnolence and dizziness (typically transient and mild) 2

Pregabalin Alternative

• Allows twice-daily dosing with potentially superior bioavailability compared to gabapentin 2, 5
• Strongly recommended as first-line therapy with moderate certainty of evidence 1, 2

Gabapentin Enacarbil

• Prodrug of gabapentin, strongly recommended with moderate certainty of evidence 1, 2
• More expensive than regular gabapentin but equally effective 2

Step 3: Iron Supplementation (Concurrent with Alpha-2-Delta Ligands)

If ferritin ≤75 ng/mL or transferrin saturation <20%:

• Oral ferrous sulfate: Conditionally recommended, works more slowly 2, 5
• IV ferric carboxymaltose: Strongly recommended for rapid correction, especially if oral iron not tolerated or ineffective after 3 months 1, 2, 5
  • Dose: 750-1000 mg in one or two infusions 2
• IV low molecular weight iron dextran or ferumoxytol: Conditionally recommended alternatives 1

Continue iron supplementation indefinitely with monitoring every 6-12 months, as RLS symptoms may recur if iron stores decline 2

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Medications to AVOID or Use with Extreme Caution

Strongly Recommended AGAINST

The American Academy of Sleep Medicine suggests against the standard use of dopamine agonists (pramipexole, ropinirole, rotigotine, levodopa) due to high risk of augmentation—a paradoxical worsening of symptoms with long-term use. 1, 2, 5

• Augmentation characteristics: earlier symptom onset during the day, increased intensity, spread to upper extremities or trunk, worsening despite dose increases 2, 6
• Augmentation occurs more frequently with levodopa than dopamine agonists 4
• Cabergoline: Strongly recommended against with moderate certainty 1, 2

Conditionally Recommended AGAINST

• Clonazepam: Insufficient evidence of efficacy, does not reduce periodic limb movement index, causes sedation and potential hepatotoxicity 2
• Bupropion, carbamazepine, valproic acid, valerian: All conditionally recommended against 2, 5

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Second-Line Options for Refractory Cases

When First-Line Treatments Fail

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

• Long-term studies show relatively low risks of abuse/overdose in appropriately screened patients, with only small dose increases over 2-10 years 2
• Critical caution: Risk of respiratory depression and central sleep apnea, especially in patients with untreated obstructive sleep apnea 2

Non-Pharmacological Alternative

• Bilateral high-frequency peroneal nerve stimulation: Conditionally recommended with moderate certainty of evidence 1, 2, 5

Other Options

• Dipyridamole: Conditionally recommended with low certainty 2

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Special Populations

End-Stage Renal Disease

• Gabapentin: Conditionally recommended, start 100 mg post-dialysis or at bedtime, maximum 200-300 mg daily 2
• IV iron sucrose: If ferritin <200 ng/mL and transferrin saturation <20% (moderate certainty) 1, 2
• Vitamin C: Conditionally recommended (low certainty) 1, 2
• Avoid pregabalin: 50-68% higher hazard for altered mental status and falls in dialysis patients 2

Pregnancy

• Consider pregnancy-specific safety profile of each treatment 1
• Iron supplementation particularly important given pregnancy-specific RLS prevalence, favoring oral formulations 2

Pediatric RLS

• Ferrous sulfate: Conditionally recommended if ferritin <50 ng/mL, monitor for constipation 1, 2, 5

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Managing Dopamine Agonist Augmentation

If augmentation is present, DO NOT increase the dopamine agonist dose—this worsens the problem. 2, 6

Transition Strategy

1. Add gabapentin or pregabalin at therapeutic doses (do not stop dopamine agonist abruptly due to profound rebound RLS) 6
2. Once adequate symptom relief achieved with alpha-2-delta ligand, very slowly down-titrate and discontinue the dopamine agonist 6
3. Consider opioids for treating augmentation symptoms during transition 2, 6

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Critical Monitoring Points

• Reassess iron studies every 6-12 months even with symptom resolution, as brain iron deficiency may persist despite normal serum parameters 2
• Monitor for side effects of alpha-2-delta ligands: dizziness, somnolence (may increase fall risk in elderly) 2
• Evaluate for misuse potential with alpha-2-delta ligands, as there is increasing evidence these agents may be misused in certain populations 2
• Assess improvement in both nighttime RLS symptoms and daytime functioning (alertness, concentration, mood) 2

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Common Pitfalls to Avoid

• Never use single nighttime dosing of gabapentin—it fails to address daytime RLS symptoms and provides suboptimal coverage 2
• Never use magnesium or clonazepam as monotherapy without first addressing iron status and trying alpha-2-delta ligands 2
• Never assume "normal" ferritin levels (>50 ng/mL) are adequate for RLS—brain iron deficiency plays a key role even when serum iron appears normal, requiring higher targets (≥75 ng/mL) 2
• Never continue dopamine agonists long-term as first-line therapy—augmentation risk is too high despite FDA approval for ropinirole 1, 2, 7