Restless Legs Syndrome (RLS) Management

Introduction to RLS

Restless legs syndrome (RLS) is primarily caused by brain iron deficiency, which can be related to genetic or secondary factors, including iron deficiency, pregnancy, end-stage renal disease (ESRD), and neurological disorders, affecting a significant population 1

Brain iron deficiency is a well-established mechanism in RLS, leading to dopaminergic dysfunction, even in patients with normal serum iron levels, and affects specific brain regions 1
Reduced iron stores in brain regions can occur despite normal peripheral iron levels, contributing to RLS pathophysiology 1

Patients with end-stage renal disease (ESRD) on dialysis have a high prevalence of RLS, potentially related to uremic toxins and altered iron metabolism 1

The American Academy of Sleep Medicine recommends initial testing for RLS patients to include serum iron studies (ferritin and transferrin saturation), which should be done in the morning, avoiding iron-containing supplements/foods for at least 24 hours prior to blood draw 1
Clinicians should assess symptoms by asking specific questions, such as "What does it feel like?" and "Is it relieved by movement?" to evaluate suspected RLS 2

Iron supplementation may be effective in treating brain iron deficiency, even with normal serum iron studies, and is a major treatable cause of RLS 1
The treatment approach has shifted from dopamine agonists to alpha-2-delta ligands and iron therapy due to the risk of augmentation 1
Serotonergic reuptake inhibitors can worsen RLS symptoms, and their use should be avoided 1

The American Academy of Sleep Medicine recommends gabapentin or pregabentin as first-line treatment for RLS, rather than dopamine agonists, due to the risk of augmentation (strong recommendation, moderate evidence) 1
For patients with ferritin ≤ 75 ng/mL or transferrin saturation < 20%, the American Academy of Sleep Medicine recommends initiating iron supplementation with oral ferrous sulfate (conditional recommendation, moderate evidence) 1
IV iron therapy, such as IV ferric carboxymaltose (strong recommendation, moderate evidence), may be considered for patients with inadequate response to oral iron 1
Alpha-2-delta ligands, including gabapentin enacarbil, gabapentin, and pregabalin, are recommended as first-line treatment (strong recommendations, moderate evidence) 1
The following treatments may be considered for RLS: dipyridamole (conditional recommendation, low evidence), bilateral high-frequency peroneal nerve stimulation (conditional recommendation, moderate evidence), and extended-release oxycodone or other opioids (conditional recommendation, moderate evidence) 1
The American Academy of Sleep Medicine recommends against the use of valproic acid (conditional recommendation), cabergoline (strong recommendation), levodopa (conditional recommendation), and valerian (conditional recommendation) for the treatment of RLS 1

Regularly reassess iron status, particularly if symptoms worsen, and monitor for medication side effects, such as dependence, tolerance, and side effects (constipation, nausea, somnolence) when using opioids 3