Restless Legs Syndrome (RLS), also known as Willis-Ekbom disease, is a neurological movement disorder characterized by an overwhelming urge to move the legs, often accompanied by uncomfortable sensations.

These symptoms typically worsen during periods of rest or inactivity and frequently disrupt sleep, profoundly impacting quality of life.

Despite its prevalence, RLS remains challenging to manage due to its complex and multifactorial nature. However, recent advances in understanding the pathophysiology and treatment options have ushered in modern approaches that optimize symptom control while minimizing adverse effects.

Pathophysiology and Symptom Triggers

RLS is believed to stem from dysfunction in the central nervous system's dopaminergic pathways, disrupted iron metabolism in the brain, and altered neurotransmitter activity—including gamma-aminobutyric acid (GABA) and glutamate.

Risk factors and exacerbating agents often include iron deficiency, certain medications (e.g., some antidepressants and antihistamines), caffeine, and comorbid conditions such as obstructive sleep apnea and pregnancy. Identifying and managing these factors is a vital initial step in treatment, as eliminating exacerbaters often alleviates symptom severity and frequency.

Pharmacologic Advances: Gabapentinoids as First-Line Therapy

A study change in RLS treatment guidelines in 2024 shifts the therapeutic focus away from dopamine agonists towards gabapentinoids—namely gabapentin enacarbil, gabapentin, and pregabalin—which now hold strong recommendations as first-line pharmacological agents.

These medications act by modulating calcium channels and neurotransmitter release, reducing the unpleasant sensations and urge to move that characterizes RLS.

Gabapentin enacarbil, a prodrug of gabapentin with improved absorption, is approved specifically for RLS and is taken in an extended-release formulation, enhancing compliance and steady symptom control. Pregabalin, another related compound, has demonstrated efficacy particularly in patients unresponsive to gabapentin.

Clinical trials substantiate that gabapentinoids improve disease severity and sleep quality with a lower risk of symptom augmentation—a phenomenon where symptoms paradoxically worsen over time, often seen with dopamine-based therapies.

Dopaminergic agents such as pramipexole and ropinirole, once the cornerstone of RLS management, are now discouraged as first-line treatments due to risks of augmentation, impulse-control disorders, excessive daytime sleepiness, and diminished long-term efficacy. This paradigm shift underscores the emphasis on safer, more sustainable treatment modalities.

Innovative Device-Based Therapies

Beyond pharmacology, non-pharmacologic interventions utilizing medical devices offer promising adjunctive benefits. Bilateral high-frequency peroneal nerve stimulation devices, recently approved by regulatory agencies, provide electrical stimulation to the peroneal nerve at the knee, activating leg muscles to mitigate RLS sensations.

This wearable technology is used during evening hours to prevent symptom onset and improve sleep without the systemic effects of medication.

Iron Repletion Strategies

Given the established link between brain iron deficiency and RLS, iron supplementation remains an essential component, particularly in individuals with low serum ferritin levels (typically below 75 µg/L). Intravenous formulations such as ferric carboxymaltose have garnered strong recommendations due to their rapid and sustained improvement in symptoms when preparations are insufficient or poorly tolerated.

Cautious Use of Opioids

For patients with refractory symptoms unresponsive to conventional measures, low-dose extended-release opioids have received conditional recommendations for RLS treatment. While opioids can provide symptom relief, their use is tempered by concerns regarding dependence, side effects, and long-term safety.

Dr. John Winkelman, a highly respected expert in the fields of sleep medicine and RLS, states, "This new clinical practice guideline represents an important turning point in RLS treatment. Our recommendations, guided by robust evidence, will enhance clinicians' ability to deliver patient-centered care that effectively controls symptoms while minimizing risks like augmentation, ultimately improving quality of life for those affected."

The management of Restless Legs Syndrome is undergoing a significant transformation as modern approaches supplant older paradigms. Moving away from dopamine agonists toward gabapentinoids as first-line therapy reflects a growing understanding of safety and long-term effectiveness.

Innovative device-based treatments, targeted iron repletion, and judicious opioid use offer a diversified therapeutic repertoire that addresses individual patient needs. Early identification and modification of exacerbating factors remain foundational to treatment success.