What is the initial management for a patient diagnosed with Restless Legs Syndrome (RLS)?

Initial Management of Restless Legs Syndrome

Begin with iron assessment and correction, followed by alpha-2-delta ligands (gabapentin, gabapentin enacarbil, or pregabalin) as first-line pharmacological therapy, while simultaneously addressing exacerbating factors.

Step 1: Confirm Diagnosis and Assess Iron Status

• Check morning fasting serum ferritin and transferrin saturation before initiating any medication, ideally after avoiding iron supplements for at least 24 hours 1, 2, 3.
• The diagnostic criteria require: (1) urge to move legs with uncomfortable sensations, (2) symptoms begin/worsen with rest, (3) relief with movement, and (4) symptoms worse in evening/night 4.
• Perform a thorough neurologic examination to exclude secondary causes such as peripheral neuropathy or radiculopathy 4.

Iron supplementation thresholds differ from general population guidelines:

• Supplement if ferritin ≤75 ng/mL or transferrin saturation <20% in adults 1, 2, 3, 5.
• In children, supplement if ferritin <50 ng/mL 1, 3.

Step 2: Iron Supplementation (When Indicated)

For patients meeting iron parameters:

• Oral ferrous sulfate 325-650 mg daily or every other day is the initial approach 1, 5.
• IV ferric carboxymaltose (750-1000 mg in one or two infusions) is strongly recommended for rapid correction if oral iron is not tolerated or ineffective after 3 months 1, 2, 3.
• Alternative IV formulations include low molecular weight iron dextran and ferumoxytol 1.

Step 3: Address Exacerbating Factors

Discontinue or reduce the following:

• Medications that worsen RLS: serotonergic antidepressants (SSRIs, tricyclics), dopamine antagonists (antipsychotics like lurasidone), centrally acting antihistamines (diphenhydramine), lithium, and bupropion 4, 1, 5.
• Lifestyle factors: eliminate or reduce caffeine, alcohol, and nicotine, particularly in the evening 1, 2, 3.
• Screen for and treat untreated obstructive sleep apnea, which can exacerbate RLS 1, 2, 3.

Step 4: First-Line Pharmacological Treatment

Alpha-2-delta ligands are now first-line therapy, NOT dopamine agonists:

Gabapentin

• Start at 300 mg three times daily (not single nighttime dosing, which is inadequate) 1, 2, 3.
• Titrate by 300 mg/day every 3-7 days until reaching maintenance dose of 1800-2400 mg/day divided three times daily 1, 2, 3.
• Doses up to 3600 mg/day are well-tolerated in clinical studies 1.

Gabapentin Enacarbil

• FDA-approved prodrug with potentially superior bioavailability 1.
• Allows for more convenient dosing compared to regular gabapentin 1.

Pregabalin

• Allows twice-daily dosing with potentially superior bioavailability compared to gabapentin 1, 2, 3.
• Equally effective as gabapentin enacarbil 1.

In randomized trials, approximately 70% of patients treated with gabapentinoids had much or very much improved symptoms versus 40% with placebo (P < .001) 5.

Step 5: What NOT to Use as First-Line Treatment

Dopamine agonists (pramipexole, ropinirole, rotigotine) are NO LONGER recommended for standard first-line use:

• These agents carry a 7-10% annual risk of augmentation—a paradoxical worsening of symptoms with earlier onset, increased intensity, and anatomic spread 1, 5, 6.
• While FDA-approved and previously considered first-line 7, current guidelines strongly recommend against their standard use due to augmentation risk 1, 3.
• May only be considered for short-term treatment in patients who prioritize immediate symptom relief over long-term adverse effects 1.

Other medications to avoid:

• Strongly recommend against: cabergoline 1, 3.
• Conditionally recommend against: levodopa, clonazepam, valproic acid, carbamazepine, bupropion, and valerian 1, 3.

Step 6: Non-Pharmacological Interventions

Implement concurrently with pharmacological treatment:

• Moderate exercise (aerobic, resistance, flexibility) in morning/afternoon, but avoid vigorous exercise close to bedtime 1, 2, 8.
• Sleep hygiene: dark, quiet, comfortable temperature; avoid heavy meals within 3 hours of bedtime 1.
• Smoking cessation 2, 3.
• Bilateral high-frequency peroneal nerve stimulation is a newer non-invasive option with conditional recommendation 1, 3.

Step 7: Monitoring and Follow-Up

• Monitor for side effects of alpha-2-delta ligands, particularly dizziness and somnolence, which are typically transient and mild 1.
• Reassess iron studies every 6-12 months as brain iron deficiency may persist despite normal serum parameters 1.
• Evaluate improvement in both nighttime RLS symptoms and daytime functioning (alertness, concentration, mood) 1.

Common Pitfalls to Avoid

• Do not use single nighttime dosing of gabapentin—this fails to address daytime symptoms and provides suboptimal coverage 1.
• Do not start dopamine agonists as first-line therapy despite their FDA approval—the augmentation risk outweighs benefits for initial management 1, 5.
• Do not assume "normal" ferritin levels are adequate—RLS requires higher thresholds (≤75 ng/mL) than general population guidelines 1, 5.
• Do not overlook medication review—many commonly prescribed drugs (antidepressants, antihistamines, antipsychotics) can trigger or worsen RLS 4, 1.

Special Populations

End-stage renal disease:

• Gabapentin 100 mg post-dialysis or at bedtime, maximum 200-300 mg daily 1, 3.
• IV iron sucrose if ferritin <200 ng/mL and transferrin saturation <20% 1, 3.
• Vitamin C supplementation 1, 3.

Pregnancy:

• Iron supplementation is particularly important given 22% prevalence in third trimester 5.
• Consider medication safety profiles carefully 1.

Older adults:

• Particular consideration for drug interactions, orthostatic hypotension risk, and fall risk with any sedating medications 4.