What are the remedies for restless leg syndrome?

Treatment of Restless Legs Syndrome

The American Academy of Sleep Medicine now strongly recommends alpha-2-delta ligands (gabapentin, gabapentin enacarbil, or pregabalin) as first-line pharmacological therapy for RLS, replacing the older paradigm of dopamine agonists due to the high risk of augmentation. 1

Initial Assessment: Check Iron Status First

Before starting any medication, obtain morning fasting iron studies after avoiding iron supplements for at least 24 hours 1:

• Check serum ferritin and transferrin saturation in all patients with clinically significant RLS 1
• Supplement with iron if ferritin ≤75 ng/mL or transferrin saturation <20%—this threshold is higher than general population guidelines because brain iron deficiency plays a key role in RLS pathophysiology 1
• IV ferric carboxymaltose is strongly recommended for rapid correction (strong recommendation, moderate certainty) 1
• Oral ferrous sulfate is an alternative but works more slowly (conditional recommendation, moderate certainty) 1

Address Exacerbating Factors

Eliminate or reduce these substances and medications before escalating pharmacotherapy 1:

• Alcohol, caffeine, and nicotine—especially within 3 hours of bedtime 1
• Antihistaminergic medications (including over-the-counter sleep aids) 1
• Serotonergic medications (SSRIs, SNRIs) 1
• Antidopaminergic medications (antipsychotics like lurasidone) 1
• Screen for and treat untreated obstructive sleep apnea 1

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

Start with gabapentin, gabapentin enacarbil, or pregabalin (strong recommendation, moderate certainty) 1:

Gabapentin Dosing

• Start at 300 mg three times daily (900 mg/day total) 1
• Titrate by 300 mg/day every 3-7 days until reaching maintenance dose of 1800-2400 mg/day divided three times daily 1
• Avoid single nighttime dosing—it fails to address daytime RLS symptoms and provides suboptimal 24-hour coverage 1
• Common side effects include somnolence and dizziness, which are typically transient and mild 1

Pregabalin Alternative

• Pregabalin allows twice-daily dosing with potentially superior bioavailability compared to gabapentin (strong recommendation, moderate certainty) 1, 2
• This may improve adherence for some patients 1

What NOT to Use: Dopamine Agonists

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

• Pramipexole: conditional recommendation against, moderate certainty 1
• Ropinirole: conditional recommendation against, moderate certainty 1, 3
• Rotigotine (transdermal): conditional recommendation against, low certainty 1
• Levodopa: conditional recommendation against, very low certainty 1
• Cabergoline: strong recommendation AGAINST use, moderate certainty 1

This represents a major shift from 2009 guidelines that recommended dopamine agonists as first-line therapy 3. The change is driven by the high risk of augmentation—a paradoxical worsening of symptoms with earlier onset, increased intensity, and anatomic spread that occurs in many patients on long-term dopaminergic therapy 1, 4.

Understanding Augmentation

Augmentation manifests as 1:

• Symptoms beginning earlier in the day
• Increased symptom intensity
• Spread of symptoms to other body parts (arms, trunk)
• Occurs despite initial good response to medication

Second-Line Options for Refractory Cases

If alpha-2-delta ligands fail or are not tolerated 1, 2:

• Extended-release oxycodone and other low-dose opioids (methadone, buprenorphine) are conditionally recommended for moderate to severe refractory RLS 1
• Evidence shows relatively low risks of abuse and overdose in appropriately screened patients, with only small dose increases over 2-10 years 1
• Opioids are particularly effective for treating augmentation when transitioning off dopamine agonists 1, 4
• Caution: monitor for respiratory depression and central sleep apnea, especially in patients with untreated OSA 1

Non-Pharmacological Interventions

• Bilateral high-frequency peroneal nerve stimulation (conditional recommendation, moderate certainty) 1
• Regular moderate exercise in morning/afternoon—avoid vigorous exercise close to bedtime 1
• Optimize sleep environment: dark, quiet, comfortable temperature 1
• Increase bright light exposure during the day, avoid at night 1

Special Populations

End-Stage Renal Disease

• Gabapentin (conditional, very low certainty)—start with 100 mg post-dialysis or at bedtime, maximum 200-300 mg daily 1
• IV iron sucrose if ferritin <200 ng/mL and transferrin saturation <20% (conditional, moderate certainty) 1
• Vitamin C (conditional, low certainty) 1
• Warning: Gabapentinoids carry 31-68% higher hazard for altered mental status and falls in dialysis patients 1

Pediatric RLS

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

Pregnancy

• Iron supplementation is particularly important given pregnancy-specific RLS prevalence 1
• Oral formulations are favored throughout gestation for safety 1

Medications to Explicitly Avoid

The American Academy of Sleep Medicine recommends against 1:

• Clonazepam (conditional, very low certainty)—improves subjective sleep but doesn't reduce periodic limb movements 1
• Bupropion (conditional, moderate certainty) 1
• Carbamazepine (conditional, low certainty) 1
• Valproic acid (conditional, low certainty) 1
• Valerian (conditional, very low certainty) 1

Monitoring and Follow-Up

• Reassess iron studies every 6-12 months even with symptom resolution, as brain iron deficiency may persist despite normal serum parameters 1
• Monitor for side effects of alpha-2-delta ligands, particularly dizziness and somnolence 1
• Evaluate improvement in both nighttime RLS symptoms and daytime functioning (alertness, concentration, mood) 1
• Continue iron supplementation indefinitely with ongoing monitoring, as RLS symptoms may recur if iron stores decline 1

Critical Pitfalls to Avoid

• Do not use single nighttime dosing of gabapentin—it provides inadequate 24-hour coverage 1
• Do not start dopamine agonists as first-line therapy despite their FDA approval—current guidelines prioritize long-term safety over short-term efficacy 1, 3
• Do not assume "normal" ferritin levels are adequate—RLS requires ferritin >75 ng/mL, higher than general population thresholds 1
• Do not use magnesium or clonazepam as monotherapy without first addressing iron status and trying guideline-recommended treatments 1