What are the treatment options for restless leg syndrome?

Treatment of Restless Leg Syndrome

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

Initial Assessment and Iron Management

Before initiating pharmacological treatment, check serum iron studies in all patients with clinically significant RLS 1:

• Draw ferritin and transferrin saturation in the morning after avoiding iron supplements for at least 24 hours 1
• Provide iron supplementation if ferritin ≤75 ng/mL or transferrin saturation <20% (note this threshold is higher than general population guidelines) 1, 2
• For oral supplementation, use ferrous sulfate (conditional recommendation, moderate certainty) 1
• For patients not responding to oral iron or with ferritin 75-100 ng/mL, strongly consider IV ferric carboxymaltose (strong recommendation, moderate certainty) 1, 2

Address Exacerbating Factors

Identify and eliminate medications or substances that worsen RLS 1, 2:

• Alcohol and caffeine 1
• Antihistaminergic medications 1
• Serotonergic medications (SSRIs, tricyclic antidepressants) 1
• Antidopaminergic medications (antipsychotics like lurasidone) 1
• Treat untreated obstructive sleep apnea if present 1

First-Line Pharmacological Treatment

Alpha-2-delta ligands are now the preferred first-line agents (strong recommendation, moderate certainty of evidence) 1, 2:

• Gabapentin enacarbil (prodrug with better bioavailability) 1
• Gabapentin 1
• Pregabalin 1

Key advantages over dopamine agonists: Lower risk of augmentation, better long-term tolerability, and lower rates of dizziness/somnolence with chronic use 1

Important monitoring: Evaluate for misuse risk before initiating, as these agents have increasing evidence of potential misuse in certain populations; monitor for dizziness and somnolence, particularly in patients with untreated sleep apnea or COPD 1

Dopamine Agonists: Use with Extreme Caution

The American Academy of Sleep Medicine now suggests AGAINST standard use of dopamine agonists due to augmentation risk 1, 2:

• Pramipexole: Conditional recommendation against standard use (moderate certainty) 1, 3
• Ropinirole: Conditional recommendation against standard use (moderate certainty) 1, 3
• Transdermal rotigotine: 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

If dopamine agonists are used: Reserve only for short-term treatment in patients who prioritize immediate symptom relief over long-term adverse effects; keep doses to absolute minimum required 1, 4, 5

Understanding Augmentation

Augmentation is a paradoxical iatrogenic worsening characterized by 1, 4:

• Earlier onset of symptoms during the day
• Increased symptom intensity
• Spread of symptoms to other body parts (arms, trunk)
• Occurs in at least one-third of patients on dopamine agonists long-term 4

Second-Line and Refractory Treatment Options

For Refractory Cases or Augmentation

Opioids are conditionally recommended, particularly for severe refractory cases or when treating augmentation 1, 5:

• Extended-release oxycodone, methadone, or buprenorphine 1
• Evidence shows relatively low risks of abuse/overdose in appropriately screened patients 1
• Long-term studies demonstrate only small dose increases over 2-10 years 1
• Critical caveat: Use caution in patients with untreated obstructive sleep apnea due to respiratory depression risk 1

Non-Pharmacological Options

• Bilateral high-frequency peroneal nerve stimulation (conditional recommendation, moderate certainty) 1, 2
• Regular physical activity should be recommended 6

Medications to Avoid

The American Academy of Sleep Medicine specifically recommends against 1:

• Bupropion (conditional, moderate certainty)
• Carbamazepine (conditional, low certainty)
• Clonazepam (conditional, very low certainty)
• Valproic acid (conditional, low certainty)
• Valerian (conditional, very low certainty)

Special Populations

End-Stage Renal Disease

For patients with ESRD and RLS 1, 2:

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

Pregnancy

• Consider pregnancy-specific medication safety profiles 2
• Non-pharmacologic approaches may be preferred 2
• Iron supplementation is particularly important if deficient 2

Pediatric RLS

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

Treatment Algorithm for Augmentation Management

If augmentation develops on dopamine agonists 1, 4:

1. Add an alpha-2-delta ligand or opioid FIRST (do not immediately reduce dopamine agonist due to severe rebound) 4
2. Titrate the new agent to adequate symptom control 4
3. Only after achieving control with the second agent, begin very slow down-titration of the dopamine agonist 4
4. Complete discontinuation of the dopamine agonist often leads to dramatic long-term relief 4

Common Pitfalls to Avoid

• Do not start dopamine agonists as first-line therapy given current guideline recommendations favoring alpha-2-delta ligands 1
• Do not ignore iron status—even "normal" ferritin may be insufficient for RLS (target ≥75 ng/mL) 1
• Do not abruptly stop dopamine agonists if augmentation occurs—add alternative agent first 4
• Do not continue antipsychotics, antihistamines, or SSRIs without considering their role in worsening RLS 1
• Do not use high doses of dopamine agonists if they must be used—keep to minimum effective dose 4, 5