What are the treatment options for restless leg syndrome?

Treatment of Restless Legs 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 recommended against for standard use due to the high risk of augmentation. 1, 2

Initial Assessment and Iron Optimization

Before initiating any pharmacological treatment, address the following critical steps:

• Check morning fasting serum ferritin and transferrin saturation in all patients with clinically significant RLS, ideally after avoiding iron-containing supplements for at least 24 hours. 1, 2

• 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 even when serum iron appears normal. 1, 2

• Use IV ferric carboxymaltose (strong recommendation, moderate certainty) for patients with appropriate iron parameters who don't respond to oral therapy, or when ferritin is between 75-100 ng/mL. 1, 2

• Use oral ferrous sulfate (conditional recommendation, moderate certainty) for milder iron deficiency. 1, 2

Eliminate Exacerbating Factors

• Discontinue or substitute medications that worsen RLS, including antihistamines, serotonergic antidepressants (SSRIs, SNRIs), antidopaminergic agents (antipsychotics like lurasidone), tricyclic antidepressants, and lithium. 1, 2

• Reduce or eliminate alcohol and caffeine, both of which can significantly worsen symptoms. 1, 2

• Screen for and treat obstructive sleep apnea, as untreated OSA can exacerbate RLS symptoms. 1, 2

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

The paradigm has shifted away from dopamine agonists due to augmentation risk. Alpha-2-delta ligands are now the clear first choice:

Gabapentin Enacarbil (Preferred for Convenience)

• Dose: 600 mg once daily at approximately 5 PM with food (FDA-approved dosing). 3
• This prodrug formulation allows once-daily dosing with superior bioavailability compared to regular gabapentin. 1

Gabapentin (Alternative)

• Starting dose: 300 mg once daily in the evening, titrate up to 1800-2400 mg/day divided into three doses (morning, afternoon, and evening) for optimal 24-hour symptom coverage. 1
• Single nighttime dosing is inadequate for patients with daytime symptoms. 1
• Common side effects include transient somnolence and dizziness, which typically improve with continued use. 1

Pregabalin (Alternative)

• Allows twice-daily dosing with potentially superior bioavailability compared to gabapentin. 1
• Strongly recommended with moderate certainty of evidence. 1, 2

Critical pitfall: In patients with end-stage renal disease, gabapentinoids carry a 31-68% higher hazard for altered mental status and falls even at low doses—use with extreme caution and start with 100 mg post-dialysis or at bedtime, maximum 200-300 mg daily. 1

Second-Line Treatment: Opioids for Refractory Cases

When alpha-2-delta ligands fail or are not tolerated:

• Extended-release oxycodone or low-dose opioids (methadone, buprenorphine) are conditionally recommended for moderate to severe refractory RLS. 1, 2

• Opioids are particularly effective for treating augmentation when transitioning off dopamine agonists, as they relieve the profound rebound RLS that occurs with DA dose reductions. 1, 4

• Long-term studies show relatively low risks of abuse and overdose in appropriately screened patients, with only small dose increases over 2-10 years. 1

• Caution: Screen for untreated OSA or COPD before initiating opioids due to respiratory depression risk. 1

Dopamine Agonists: Use with Extreme Caution

The American Academy of Sleep Medicine now suggests against standard use of all dopamine agonists (pramipexole, ropinirole, rotigotine) due to augmentation—a paradoxical worsening characterized by earlier symptom onset, increased intensity, and anatomic spread to other body parts. 1, 2, 4

• Levodopa: Conditional recommendation against (very low certainty), highest augmentation risk. 1, 2

• Pramipexole and ropinirole: Conditional recommendation against (moderate certainty). 1, 2

• Rotigotine transdermal: Conditional recommendation against (low certainty), higher fall risk due to dizziness and somnolence. 1

• Cabergoline: Strong recommendation against (moderate certainty)—do not use. 1, 2

If dopamine agonists are used (only for short-term treatment in patients prioritizing immediate relief over long-term safety), keep doses as low as possible and maintain high ferritin levels to reduce augmentation risk. 1, 5

Managing Augmentation

If augmentation develops on a dopamine agonist:

• Add an alpha-2-delta ligand or opioid first before attempting DA withdrawal, as even small dose reductions cause profound rebound RLS and insomnia. 1, 4

• Once adequate symptom control is achieved with the second agent, initiate very slow down-titration of the DA over weeks to months. 4

Non-Pharmacological Options

• Bilateral high-frequency peroneal nerve stimulation is conditionally recommended as a noninvasive option (moderate certainty). 1, 2

• Regular physical activity should be recommended based on available evidence. 6

• Pneumatic compression devices, yoga, and acupuncture have insufficient evidence but may be considered as adjunctive therapy. 6

Special Populations

Pregnancy

• Iron supplementation is particularly important given pregnancy-specific RLS prevalence, with oral formulations favored throughout gestation. 1
• Non-pharmacological approaches are preferred; if medications are necessary, consider pregnancy-specific safety profiles. 2

End-Stage Renal Disease

• Gabapentin is conditionally recommended (very low certainty), starting at 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% (moderate certainty). 1, 2
• Vitamin C is conditionally recommended (low certainty). 1

Pediatric RLS

• Oral ferrous sulfate for ferritin <50 ng/mL, monitoring for constipation. 1

Medications to Avoid

Never use the following for RLS treatment:

• Clonazepam (conditional recommendation against, very low certainty)—improves subjective sleep but doesn't reduce objective disease markers. 1
• Bupropion, carbamazepine, valproic acid, valerian (all conditional recommendations against). 1
• Ketamine—not supported by any evidence-based guidelines. 1

Long-Term Monitoring

• Continue iron supplementation indefinitely with surveillance every 6-12 months, as RLS symptoms may recur if iron stores decline below therapeutic thresholds. 1

• Monitor for augmentation if dopamine agonists are used, characterized by symptoms starting earlier in the day, increased intensity, or spread to arms/trunk. 1

• Reassess exacerbating factors periodically, as new medications or lifestyle changes may worsen symptoms. 1, 2