Restless Legs Syndrome Treatment Guidelines

Initial Assessment and Iron Supplementation

The American Academy of Sleep Medicine recommends checking morning fasting iron studies, including serum ferritin and transferrin saturation, before starting any medication, and supplementing with iron if ferritin ≤75 ng/mL or transferrin saturation <20% 1, 2, 4
IV ferric carboxymaltose is strongly recommended for rapid correction in patients meeting these iron parameters, while oral ferrous sulfate is an alternative but works more slowly 1, 2, 4

The American Academy of Sleep Medicine strongly recommends gabapentin, gabapentin enacarbil, or pregabalin as first-line therapy, with a strong recommendation and moderate certainty of evidence 1, 2
Gabapentin dosing should start at 300 mg three times daily and titrate by 300 mg/day every 3-7 days until reaching a maintenance dose of 1800-2400 mg/day, avoiding single nighttime dosing 2, 3
Pregabalin is a recommended alternative, allowing twice-daily dosing with potentially superior bioavailability compared to gabapentin, and is strongly recommended as first-line therapy with moderate certainty of evidence 1, 2, 4

The American Academy of Sleep Medicine suggests against the standard use of dopamine agonists, such as pramipexole, ropinirole, and transdermal rotigotine, due to high risk of augmentation, with conditional recommendations against standard use and moderate certainty 1, 4
Cabergoline is strongly recommended against use, with moderate certainty, while bupropion, carbamazepine, clonazepam, and valproic acid are conditionally recommended against, with varying levels of certainty 1, 4

Extended-release oxycodone and other low-dose opioids are conditionally recommended for moderate to severe refractory RLS, with evidence showing relatively low risks of abuse and overdose in appropriately screened patients, and are particularly effective for treating augmentation when transitioning off dopamine agonists 2, 4

Addressing exacerbating factors, such as eliminating or reducing alcohol, caffeine, and nicotine, and discontinuing antihistaminergic and serotonergic medications, is recommended, as well as screening for and treating untreated obstructive sleep apnea, and implementing moderate exercise 1, 4
Bilateral high-frequency peroneal nerve stimulation is conditionally recommended as a non-pharmacological option, with moderate certainty 1, 4

In patients with end-stage renal disease, gabapentin is conditionally recommended, with very low certainty, while IV iron sucrose is recommended if ferritin <200 ng/mL and transferrin saturation <20%, with moderate certainty, and vitamin C is conditionally recommended, with low certainty 1, 4
In pediatric RLS, ferrous sulfate is conditionally recommended in patients with ferritin <50 ng/mL, with very low certainty 1, 4