How is restless leg syndrome managed?

Management of Restless Legs Syndrome

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

Initial Assessment and Iron Evaluation

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

• Obtain morning ferritin and transferrin saturation after avoiding iron supplements for at least 24 hours 1
• Supplement iron if ferritin ≤75 ng/mL or transferrin saturation <20% (note this threshold is higher than general population guidelines) 1
• For IV iron therapy, use ferric carboxymaltose as a strong first-line option when oral iron fails or is not tolerated 1
• In end-stage renal disease patients, use IV iron sucrose if ferritin <200 ng/mL and transferrin saturation <20% 1

The higher ferritin threshold in RLS reflects the critical role of brain iron deficiency in disease pathophysiology, even when serum iron appears normal 1

Address Exacerbating Factors

Identify and eliminate medications or conditions worsening RLS:

• Discontinue or substitute antihistamines, SSRIs, tricyclic antidepressants, and antipsychotics (all worsen RLS through various mechanisms) 1
• Reduce or eliminate alcohol and caffeine intake 1
• Treat untreated obstructive sleep apnea if present 1
• Lurasidone and other antipsychotics specifically worsen RLS through dopamine antagonism and should be switched to alternatives with less dopamine blockade 1

First-Line Pharmacological Treatment

Alpha-2-delta ligands are now the preferred initial therapy:

• Gabapentin, gabapentin enacarbil, or pregabalin (strong recommendation, moderate certainty of evidence) 1
• These agents have lower augmentation risk compared to dopamine agonists and are effective for both symptom control and sleep improvement 1
• Monitor for dizziness and somnolence, particularly in patients with untreated sleep apnea or COPD 1
• Screen for misuse potential before initiating, as there is increasing evidence of abuse in certain populations 1

For end-stage renal disease patients specifically, gabapentin is conditionally recommended despite very low certainty of evidence 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:

• Pramipexole, ropinirole, and rotigotine are conditionally recommended against (moderate to low certainty) 1
• Levodopa is conditionally recommended against (very low certainty) 1
• Cabergoline is strongly recommended AGAINST (strong recommendation, moderate certainty) 1

Despite FDA approval, ropinirole demonstrated efficacy in three RLS trials with mean IRLS score improvements of 2.5-3.7 points over placebo at 12 weeks 2, but the long-term augmentation risk now outweighs these short-term benefits according to current guidelines 1

Augmentation warning signs include:

• Earlier onset of symptoms during the day 1
• Increased symptom intensity 1
• Spread of symptoms to arms or other body parts 1

If dopamine agonists must be used, consider them only for patients who prioritize immediate symptom relief over long-term adverse effects, and keep doses as low as possible 1

Second-Line and Refractory Treatment Options

For patients failing first-line therapy or experiencing augmentation:

• Extended-release oxycodone and low-dose opioids (conditional recommendation) are effective for refractory cases 1
• Methadone and buprenorphine show relatively low abuse risk in appropriately screened patients, with minimal dose escalation over 2-10 years 1
• Caution: Monitor for respiratory depression and central sleep apnea, especially with untreated OSA 1
• Opioids are particularly effective for managing augmentation when transitioning off dopamine agonists 1, 3

Alternative options:

• Bilateral high-frequency peroneal nerve stimulation (conditional recommendation, moderate certainty) 1
• Dipyridamole (conditional recommendation, low certainty) 1
• IV low molecular weight iron dextran or ferumoxytol if ferric carboxymaltose unavailable 1

Managing Augmentation from Dopamine Agonists

When augmentation occurs, do not abruptly discontinue the dopamine agonist as this causes severe rebound:

1. Add an alpha-2-delta ligand or opioid first 1, 3
2. Titrate the new agent to adequate symptom control 3
3. Only then begin very slow down-titration of the dopamine agonist 3
4. This gradual transition prevents profound rebound RLS and insomnia 3

Medications to Avoid

The American Academy of Sleep Medicine specifically recommends against:

• Bupropion (conditional, moderate certainty) 1
• Carbamazepine (conditional, low certainty) 1
• Clonazepam (conditional, very low certainty) 1
• Valproic acid (conditional, low certainty) 1
• Valerian (conditional, very low certainty) 1

Non-Pharmacological Interventions

While evidence quality is limited, some interventions show benefit:

• Regular physical activity/exercise reduces RLS severity and should be recommended 4, 5
• Compression devices may improve both RLS severity and sleep outcomes 4
• Repetitive transcranial magnetic stimulation, counterstrain manipulation, infrared therapy, and standard acupuncture showed efficacy in small trials 4
• Yoga and cryotherapy improved some sleep-related outcomes but not RLS severity 4

Special Populations

Pediatric RLS:

• Ferrous sulfate is conditionally recommended (very low certainty) 1
• Monitor for constipation with oral iron 1
• Supplement if ferritin <50 ng/mL in children 1

End-stage renal disease:

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

Pregnancy:

• Special consideration of medication safety profiles required 1
• Non-pharmacological approaches and iron supplementation preferred when possible 1

Critical Pitfalls to Avoid

• Do not start dopamine agonists as first-line therapy despite their FDA approval—guidelines have evolved beyond this 1
• Do not use general population ferritin thresholds—RLS requires ferritin ≤75 ng/mL, not the standard <15 ng/mL 1
• Do not abruptly stop dopamine agonists when augmentation occurs—add alternative therapy first 3
• Do not overlook medication-induced RLS—antipsychotics, antidepressants, and antihistamines commonly worsen symptoms 1