How is restless leg syndrome managed?

Management 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, but only after checking and correcting iron status if ferritin ≤75 ng/mL or transferrin saturation <20%. 1, 2

Initial Assessment and Iron Repletion

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

• Check morning fasting iron studies (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 1, 2

• IV ferric carboxymaltose is strongly recommended for patients meeting these iron parameters who don't respond to oral therapy (strong recommendation, moderate certainty) 1, 2

• Oral ferrous sulfate is conditionally recommended as an alternative iron supplementation option for patients with low ferritin or transferrin saturation 1, 2

Address Exacerbating Factors

Before or concurrent with pharmacological treatment:

• Eliminate or reduce caffeine and alcohol 2

• Discontinue medications that worsen RLS: antihistaminergic medications, serotonergic medications (SSRIs, tricyclic antidepressants), antidopaminergic medications (antipsychotics like lurasidone), and lithium 1, 2

• Screen for and treat untreated obstructive sleep apnea, as this can significantly worsen RLS symptoms 1, 2

• Implement moderate exercise and smoking cessation 2

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

Gabapentin, gabapentin enacarbil, or pregabalin are strongly recommended as first-line therapy (strong recommendation, moderate certainty of evidence) 1, 2:

• Gabapentin dosing: Start at 300 mg three times daily (900 mg/day total), titrate by 300 mg/day every 3-7 days until reaching maintenance dose of 1800-2400 mg/day divided three times daily, with doses up to 3600 mg/day well-tolerated 1, 2

• Pregabalin allows for twice-daily dosing and may have superior bioavailability compared to gabapentin 1, 2

• Gabapentin enacarbil is a prodrug of gabapentin that is also strongly recommended 1

• Common side effects include somnolence and dizziness, which are typically transient and mild 1

• Critical advantage: Alpha-2-delta ligands avoid the augmentation phenomenon (paradoxical worsening of symptoms with long-term use) seen with dopamine agonists 1

Medications to Avoid or Use with Extreme Caution

The American Academy of Sleep Medicine has shifted away from dopamine agonists due to high risk of augmentation:

• Pramipexole, ropinirole, and rotigotine are suggested AGAINST for standard use (conditional recommendation, moderate certainty) due to risk of augmentation - a paradoxical worsening characterized by earlier symptom onset during the day, increased intensity, and spread to other body parts 1, 3

• Levodopa is suggested AGAINST (conditional recommendation, very low certainty) 1

• Cabergoline is strongly recommended AGAINST (strong recommendation, moderate certainty) 1

• Also avoid: bupropion, carbamazepine, clonazepam, valproic acid, and valerian 1

Important caveat: While ropinirole is FDA-approved for RLS and demonstrated efficacy in clinical trials 3, current guidelines prioritize alpha-2-delta ligands due to the long-term risk of augmentation with dopamine agonists. Dopamine agonists may only be considered for short-term treatment in patients who prioritize immediate symptom relief over long-term adverse effects 1.

Second-Line and Refractory Treatment Options

For patients who fail first-line therapy or develop augmentation:

• Extended-release oxycodone and other low-dose opioids (methadone, buprenorphine) are conditionally recommended for moderate to severe cases, particularly for refractory RLS or treating augmentation from dopaminergic agents 1, 4

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

• Caution with opioids: Risk of respiratory depression and central sleep apnea, especially in patients with untreated obstructive sleep apnea 1

• Bilateral high-frequency peroneal nerve stimulation is conditionally recommended as a non-pharmacological option (conditional recommendation, moderate certainty) 1, 2

• Dipyridamole is conditionally recommended (low certainty of evidence) 1

Special Populations

End-stage renal disease patients with RLS:

• Gabapentin is conditionally recommended (very low certainty), starting with 100 mg post-dialysis or at bedtime, maximum 200-300 mg daily 1

• IV iron sucrose is conditionally recommended if ferritin <200 ng/mL and transferrin saturation <20% (moderate certainty) 1

• Vitamin C is conditionally recommended (low certainty) 1

• Critical safety warning: Gabapentinoids are associated with 31-68% higher hazard of altered mental status and falls in dialysis patients, even at low doses 1

Pediatric RLS:

• Oral ferrous sulfate is conditionally recommended if ferritin <50 ng/mL (very low certainty), with monitoring for constipation 1

Pregnancy:

• Special consideration of medication safety profiles is required 1

Non-Pharmacological Interventions with Limited Evidence

While guidelines prioritize pharmacological approaches after iron correction, some non-pharmacological options show preliminary benefit:

• Repetitive transcranial magnetic stimulation, exercise, compression devices, counterstrain manipulation, infrared therapy, and standard acupuncture were significantly more effective than control conditions in reducing RLS severity in small trials 5, 6

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

• However, the American Academy of Sleep Medicine guidelines do not include these as primary recommendations, prioritizing the evidence-based algorithm of iron correction followed by alpha-2-delta ligands 1, 2

Critical Pitfalls to Avoid

• Do not start pharmacological treatment without first checking and addressing iron status - this is a fundamental error that can lead to treatment failure 1, 2

• Do not use dopamine agonists as first-line therapy despite their FDA approval - current evidence strongly favors alpha-2-delta ligands due to augmentation risk 1

• Do not use single nighttime dosing of gabapentin - this fails to address daytime RLS symptoms and provides suboptimal coverage; use three-times-daily dosing 1

• Do not ignore exacerbating medications - discontinuing offending agents (antihistamines, SSRIs, antipsychotics) may dramatically improve symptoms 1, 2

• Monitor for augmentation if dopamine agonists are used - characterized by earlier symptom onset, increased intensity, and anatomic spread 1, 4