What are the treatment options for Restless Legs Syndrome (RLS)?

Treatment of Restless Legs Syndrome

Alpha-2-delta ligands (gabapentin, gabapentin enacarbil, or pregabalin) are the first-line pharmacological treatment for RLS, with dopamine agonists now recommended against for standard use due to high risk of augmentation. 1, 2

Initial Assessment and Iron Management

Before initiating pharmacological therapy, address the following critical steps:

• Check serum ferritin and transferrin saturation in all patients with clinically significant RLS, ideally in the morning after avoiding iron-containing supplements for at least 24 hours 1, 2
• Provide iron supplementation if ferritin ≤75 ng/mL or transferrin saturation <20%—note this threshold is higher than general population guidelines because brain iron deficiency plays a key role in RLS pathophysiology 1, 2
• Use IV ferric carboxymaltose (strong recommendation, moderate certainty) for patients with appropriate iron parameters who don't respond to oral therapy 1, 2
• Consider oral ferrous sulfate (conditional recommendation, moderate certainty) for mild iron deficiency 1, 2

Identify and Address Exacerbating Factors

• Eliminate or reduce alcohol, caffeine, antihistaminergic medications (including over-the-counter sleep aids), serotonergic antidepressants (SSRIs, SNRIs), and antidopaminergic medications (antipsychotics like lurasidone) 1, 2
• Screen for and treat untreated obstructive sleep apnea, which commonly worsens RLS symptoms 1, 2

First-Line Pharmacological Treatment

The treatment paradigm has shifted away from dopamine agonists due to augmentation risk:

• Gabapentin enacarbil (strong recommendation, moderate certainty): Start at 600 mg once daily, taken 1-3 hours before bedtime; can titrate to maximum 1200 mg daily 1, 2
• Gabapentin (strong recommendation, moderate certainty): Start at 300 mg three times daily (900 mg/day total), titrate up to 1800-2400 mg/day divided three times daily for optimal 24-hour coverage 1, 2
• Pregabalin (strong recommendation, moderate certainty): Allows twice-daily dosing with superior bioavailability compared to gabapentin 1, 2

Common side effects of alpha-2-delta ligands include somnolence and dizziness, which are typically transient and mild 1. Monitor for misuse potential in at-risk populations 1.

Medications to Avoid or Use with Extreme Caution

Dopamine Agonists (Now Recommended Against)

• Pramipexole: conditional recommendation AGAINST standard use (moderate certainty) 1, 2
• Ropinirole: conditional recommendation AGAINST standard use (moderate certainty) 1, 2, 3
• Transdermal rotigotine: conditional recommendation AGAINST standard use (low certainty) 1
• Levodopa: conditional recommendation AGAINST standard use (very low certainty) 1, 2
• Cabergoline: STRONG recommendation AGAINST use (moderate certainty) 1, 2

The critical issue with dopamine agonists is augmentation—a paradoxical worsening of RLS characterized by earlier symptom onset during the day, increased intensity, and spread to other body parts 1, 4. While ropinirole demonstrated efficacy in FDA trials with 73.3% responders versus 56.5% placebo 3, the long-term augmentation risk outweighs short-term benefits.

Other Medications to Avoid

• Bupropion, carbamazepine, clonazepam, valproic acid, and valerian are all conditionally recommended AGAINST 1

Second-Line and Refractory Treatment Options

For patients who fail first-line therapy or have severe refractory RLS:

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

Non-Pharmacological Options

• Bilateral high-frequency peroneal nerve stimulation (conditional recommendation, moderate certainty) is a newer noninvasive option with initial success in short-term studies 1, 2
• Regular physical activity should be recommended based on available evidence 5, 6
• Compression devices, counterstrain manipulation, infrared therapy, and standard acupuncture may reduce RLS severity 5

Special Populations

End-Stage Renal Disease

• Gabapentin (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 (conditional recommendation, low certainty) 1

Pregnancy

• Treatment selection must consider pregnancy-specific safety profiles 2
• Non-pharmacologic approaches are preferred during pregnancy 2
• Iron supplementation is safe and should be prioritized if ferritin is low 2

Pediatric RLS

• Oral ferrous sulfate is conditionally recommended for serum ferritin <50 ng/mL in children (very low certainty) 1

Managing Dopaminergic Augmentation

If a patient is already on a dopamine agonist and develops augmentation:

• Add an alpha-2-delta ligand or opioid FIRST before attempting to reduce the dopamine agonist, as even small dose reductions cause profound rebound RLS and insomnia 4
• Once adequate symptom control is achieved with the second agent, initiate very slow down-titration of the dopamine agonist 4
• This substitution strategy can lead to dramatic long-term relief 4

Critical Pitfalls to Avoid

• Do not use dopamine agonists as first-line therapy despite their FDA approval—current guidelines prioritize long-term outcomes over short-term efficacy 1, 2
• Do not ignore iron status—even ferritin levels between 75-100 ng/mL may benefit from IV iron supplementation 1
• Do not prescribe antipsychotics (like lurasidone) to patients with RLS without careful consideration, as dopamine antagonism will worsen symptoms 1
• Do not treat periodic limb movements found incidentally on polysomnography without confirming they cause clinically significant symptoms 7