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

From the Guidelines

The most effective treatment for restless leg syndrome (RLS) is ferrous sulfate, which is recommended over no ferrous sulfate in patients with appropriate iron status, as suggested by the American Academy of Sleep Medicine (AASM) in their 2025 clinical practice guideline 1. The AASM suggests the use of ferrous sulfate over no ferrous sulfate in patients with appropriate iron status, with a conditional recommendation and moderate certainty of evidence. Some key points to consider when treating RLS include:

• The use of dipyridamole, extended-release oxycodone, and bilateral high-frequency peroneal nerve stimulation may also be effective in treating RLS, although the evidence for these treatments is not as strong as for ferrous sulfate.
• The AASM suggests against the standard use of levodopa, pramipexole, transdermal rotigotine, ropinirole, bupropion, carbamazepine, clonazepam, and valproic acid for the treatment of RLS, due to concerns about augmentation and other adverse effects.
• In adults with RLS and end-stage renal disease (ESRD), the AASM suggests the use of gabapentin, IV iron sucrose, and vitamin C, with conditional recommendations.
• Lifestyle modifications, such as regular exercise, avoiding caffeine and alcohol, and maintaining good sleep hygiene, should also be recommended to patients with RLS, as these can help alleviate symptoms and improve quality of life. The treatment of RLS should be individualized, taking into account the patient's symptoms, medical history, and other factors, and should be guided by the most recent and highest-quality evidence available, such as the 2025 AASM clinical practice guideline 1, 2, 3, 4, 5.

From the FDA Drug Label

The effectiveness of ropinirole in the treatment of RLS was demonstrated in randomized, double-blind, placebo-controlled trials in adults diagnosed with RLS using the International Restless Legs Syndrome Study Group diagnostic criteria Patients were required to have a history of a minimum of 15 RLS episodes/month during the previous month and a total score of ≥15 on the International RLS Rating Scale (IRLS scale) at baseline. A variety of measures were used to assess the effects of treatment, including the IRLS scale and Clinical Global Impression-Global Improvement (CGI-I) scores In all 3 trials, a statistically significant difference between the treatment group receiving ropinirole and the treatment group receiving placebo was observed at Week 12 for both the mean change from baseline in the IRLS scale total score and the percentage of patients rated as responders (much improved or very much improved) on the CGI-I

Ropinirole is effective in the treatment of Restless Legs Syndrome (RLS). The medication has been shown to significantly reduce symptoms of RLS, as measured by the International RLS Rating Scale (IRLS) and Clinical Global Impression-Global Improvement (CGI-I) scores, in three randomized, double-blind, placebo-controlled trials 6.

• Key findings: + Statistically significant difference between ropinirole and placebo in mean change from baseline in IRLS scale total score + Statistically significant difference between ropinirole and placebo in percentage of patients rated as responders on CGI-I + Long-term maintenance of efficacy in the treatment of RLS was demonstrated in a 36-week trial 6

From the Research

Restless Leg Syndrome Medication

• The International Restless Legs Syndrome Study Group (IRLSSG) has established guidelines for the long-term pharmacologic treatment of restless legs syndrome/Willis-Ekbom disease (RLS/WED) 7.
• Pregabalin has been established as effective for up to 1 year in treating RLS/WED, while pramipexole, ropinirole, and rotigotine have been established as effective for up to 6 months 7.
• Gabapentin enacarbil, pramipexole, and ropinirole have been established as probably effective for durations ranging from 1 to 5 years, with levodopa and rotigotine also showing probable effectiveness 7.
• Dopaminergic agents, such as pramipexole and ropinirole, are considered first-line treatment for RLS, with extensive data available to support their use 8.
• α2δ ligands, such as pregabalin and gabapentin enacarbil, may be considered as an alternative to dopaminergic agents, with a lower risk of augmentation 9.
• The choice of medication should be based on the patient's severity of RLS/WED symptoms, cognitive status, history, and comorbid conditions 7.
• A model-based meta-analysis has compared the efficacies of 5 first-line RLS drugs, including dopaminergic agonists and α-2-δ ligands, and found that the therapeutic effect of dopaminergic agonists is associated with baseline symptom severity 10.

Prevention and Treatment of Augmentation

• The IRLSSG has developed consensus-based strategies for the prevention and treatment of complications, such as augmentation, that may develop with the long-term pharmacologic treatment of RLS/WED 7.
• α2δ ligands may be considered for initial RLS/WED treatment to prevent augmentation, with dopaminergic drugs also being effective but carrying a higher risk of augmentation 9.
• Treatment of existing augmentation should be initiated with the elimination/correction of extrinsic exacerbating factors, and may involve switching to an α2δ ligand or rotigotine, or using an opioid in severe cases 9.

Pharmacological Treatment

• Pharmacological treatment should be limited to patients who suffer from clinically relevant RLS with impaired sleep quality or quality of life 8.
• A treatment on demand is a clinical need in RLS cases that present intermittent symptoms 8.
• The Absorption, Distribution, Metabolism, Elimination, and Toxicology (ADMET) characteristics of RLS medications, including dopaminergic agents and anticonvulsants, have been reviewed, highlighting the need for further studies on the long-term effects of these medications 11.