What are the treatment options for restless legs syndrome?

Treatment Options for Restless Legs Syndrome

Alpha-2-delta ligands (gabapentin, gabapentin enacarbil, or pregabalin) are the first-line pharmacological treatment for restless legs syndrome, but iron status must be assessed and corrected first if ferritin ≤75 ng/mL or transferrin saturation <20%. 1

Initial Assessment and Iron Management

Before starting any medication, check morning fasting serum ferritin and transferrin saturation after avoiding iron supplements for at least 24 hours 1, 2:

• Iron supplementation is recommended if ferritin ≤75 ng/mL or transferrin saturation <20% in adults (note: this threshold is higher than general population guidelines) 1, 3
• In children with RLS, supplement if ferritin <50 ng/mL 1, 2
• Oral ferrous sulfate 325-650 mg daily or every other day is the first approach 1, 3
• IV ferric carboxymaltose (750-1000 mg in one or two infusions) is strongly recommended for patients who don't respond to oral iron after 3 months or cannot tolerate it 1, 3

Medication Review and Lifestyle Modifications

Discontinue or avoid medications that worsen RLS 1:

• Serotonergic antidepressants (SSRIs, SNRIs) 1, 3
• Dopamine antagonists (antipsychotics, metoclopramide) 1, 3
• Centrally acting H1 antihistamines (diphenhydramine, doxylamine) 1, 3

Implement lifestyle changes 1, 2:

• Eliminate or reduce alcohol, caffeine, and nicotine, especially within 3 hours of bedtime 1
• Moderate exercise (aerobic, resistance, flexibility) in morning/afternoon, but avoid vigorous exercise close to bedtime 1, 2
• Optimize sleep environment: dark, quiet, comfortable temperature 1

First-Line Pharmacological Treatment: Alpha-2-Delta Ligands

The American Academy of Sleep Medicine strongly recommends gabapentin, gabapentin enacarbil, or pregabalin as first-line therapy with moderate certainty of evidence 1, 3:

Gabapentin Dosing

• Start at 300 mg three times daily 1
• Titrate by 300 mg/day every 3-7 days until reaching maintenance dose of 1800-2400 mg/day divided three times daily 1
• Common side effects: somnolence and dizziness (typically transient and mild) 1

Pregabalin Dosing

• Allows twice-daily dosing with potentially superior bioavailability compared to regular gabapentin 1, 2
• Typical dosing range not specified in guidelines but generally 150-450 mg/day divided twice daily

Gabapentin Enacarbil

• Prodrug of gabapentin with improved pharmacokinetics 1
• FDA-approved specifically for RLS 3

In randomized trials, approximately 70% of patients treated with gabapentinoids had much or very much improved RLS symptoms versus 40% with placebo 3

Medications to Avoid or Use with Extreme Caution

Dopamine Agonists (No Longer First-Line)

The American Academy of Sleep Medicine suggests against the standard use of dopamine agonists due to high risk of augmentation 1, 4, 3:

• Pramipexole: conditional recommendation against standard use (moderate certainty) 1, 4
• Ropinirole: conditional recommendation against standard use (moderate certainty) 1, 5
• Rotigotine (transdermal): conditional recommendation against standard use (low certainty) 1
• Levodopa: conditional recommendation against standard use (very low certainty) 1
• Cabergoline: strong recommendation AGAINST use (moderate certainty) 1

Augmentation is an iatrogenic worsening characterized by 1, 3:

• Earlier onset of symptoms during the day
• Increased symptom intensity
• Spread of symptoms to arms or other body parts
• Annual incidence of 7-10% with dopamine agonists 3

Despite FDA approval of ropinirole for RLS 5, current guidelines prioritize long-term safety over short-term efficacy, as augmentation significantly worsens quality of life.

Other Medications to Avoid

• Clonazepam: conditional recommendation against (very low certainty) - does not reduce periodic limb movements, only improves subjective sleep quality 1
• Bupropion, carbamazepine, valproic acid, valerian: all conditionally recommended against 1

Second-Line and Refractory Treatment Options

Opioids for Refractory Cases

Extended-release oxycodone and other low-dose opioids are conditionally recommended for moderate to severe refractory RLS, particularly when treating augmentation from dopamine agonists 1, 3:

• Methadone 5-10 mg daily 3
• Buprenorphine (transdermal or sublingual) 1
• Extended-release oxycodone 1
• Long-term studies show relatively low risks of abuse/overdose in appropriately screened patients, with only small dose increases over 2-10 years 1
• Critical caution: Monitor for respiratory depression, especially in patients with untreated obstructive sleep apnea 1

Non-Pharmacological Option

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

Other Alternatives

• Dipyridamole: conditionally recommended (low certainty) 1

Special Populations

End-Stage Renal Disease (ESRD)

• Gabapentin: 100 mg post-dialysis or at bedtime, maximum 200-300 mg daily (conditional recommendation, very low certainty) 1, 2
• IV iron sucrose: if ferritin <200 ng/mL and transferrin saturation <20% (conditional recommendation, moderate certainty) 1, 2
• Vitamin C: conditionally recommended 1, 2
• Avoid pregabalin in ESRD due to increased hazard for altered mental status and falls 1

Pregnancy

• Iron supplementation is particularly important given pregnancy-specific RLS prevalence (22% overall, higher in third trimester) 3
• Oral iron formulations have favorable safety profile throughout gestation 1
• Carefully consider medication safety profiles for each agent 1

Pediatric RLS

• Oral ferrous sulfate: conditionally recommended if ferritin <50 ng/mL (very low certainty) 1
• Monitor for constipation with iron supplementation 1

Treatment Algorithm Summary

1. Check iron studies (morning fasting ferritin and transferrin saturation) 1, 2
2. Supplement iron if ferritin ≤75 ng/mL or transferrin saturation <20% 1, 3
3. Review and discontinue exacerbating medications (antidepressants, antipsychotics, antihistamines) 1, 3
4. Implement lifestyle modifications (avoid alcohol/caffeine/nicotine, moderate exercise, sleep hygiene) 1, 2
5. Start alpha-2-delta ligand (gabapentin 300 mg TID titrated to 1800-2400 mg/day, or pregabalin, or gabapentin enacarbil) 1, 3
6. For refractory cases: Consider IV iron if oral ineffective, or low-dose opioids (methadone, buprenorphine, oxycodone) 1, 3
7. Monitor regularly for treatment response, side effects, and iron status every 6-12 months 1

Critical Pitfalls to Avoid

• Do not start dopamine agonists as first-line therapy despite their FDA approval and short-term efficacy - the long-term risk of augmentation outweighs benefits 1, 3
• Do not use "normal" ferritin cutoffs - RLS requires higher brain iron levels, so supplement even with ferritin up to 75 ng/mL 1, 3
• Do not increase dopamine agonist doses if augmentation is suspected - this worsens the problem 1
• Do not prescribe gabapentin as single nighttime dose - RLS symptoms occur throughout the day in many patients, requiring divided dosing 1
• Do not use clonazepam or other benzodiazepines as primary RLS treatment - they only mask symptoms without addressing underlying pathophysiology 1