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

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Last updated: May 15, 2025View editorial policy

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From the Guidelines

The most effective pharmacotherapy for restless leg syndrome (RLS) is the use of gabapentin enacarbil, gabapentin, or pregabalin, as recommended by the American Academy of Sleep Medicine (AASM) with strong evidence 1. When considering treatment options for RLS, it's essential to prioritize medications that have the strongest evidence supporting their efficacy.

  • The AASM recommends the use of gabapentin enacarbil, gabapentin, or pregabalin over no treatment, with strong recommendations and moderate certainty of evidence 1.
  • These medications, particularly gabapentin enacarbil, have been shown to be effective in reducing RLS symptoms and improving quality of life 1.
  • In addition to these medications, iron supplementation with IV ferric carboxymaltose is also recommended for patients with appropriate iron status, as iron deficiency can exacerbate RLS symptoms 1.
  • Other treatment options, such as dopamine agonists like pramipexole and ropinirole, may be considered, but the evidence supporting their use is not as strong as that for gabapentin enacarbil, gabapentin, and pregabalin 1.
  • It's crucial to individualize treatment based on symptom severity, comorbidities, and potential side effects, and to monitor patients for augmentation, which may require switching to another drug class 1.

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. All trials employed flexible dosing, with patients initiating therapy at 0.25 mg ropinirole once daily. Patients were titrated based on clinical response and tolerability over 7 weeks to a maximum of 4 mg once daily. 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 recommended dosage is 0.25 mg once daily, titrated up to a maximum of 4 mg once daily based on clinical response and tolerability 2, 2. Common adverse reactions include nausea, vomiting, somnolence, dizziness, and asthenic condition 2.

From the Research

Restless Leg Syndrome Pharmacotherapy Treatment

  • Restless legs syndrome (RLS) is a common condition characterized by paresthesia and an urge to move, with symptoms occurring at rest in the evening or at night, and alleviated by moving the affected extremity 3.
  • Pharmacological treatment should be limited to those patients who suffer from clinically relevant RLS, that is, when symptoms impair the patient's quality of life, daytime functioning, social functioning or sleep 3, 4.
  • Treatment options for RLS include:
    • Dopamine agonists such as pramipexole, ropinirole, and rotigotine, which are considered first-line treatment for RLS 3, 4, 5.
    • α2δ calcium channel ligands, which are a first-line pharmacological approach for chronic persistent RLS 6.
    • Iron-replacement therapy in those with evidence for reduced body-iron stores 5.
    • Opioids such as tramadol, oxycodone, and methadone, which are considered second-line therapies for RLS 3, 6, 5.
  • For intermittent RLS, treatment on demand is a clinical need, and medications include carbidopa/levodopa, pramipexole, ropinirole, oxycodone, methadone, codeine, and tramadol 3.
  • For chronic RLS, treatment with either a nonergot dopamine agonist or an α-2-δ calcium channel ligand is recommended, with the choice of treatment depending on the presence of comorbidities such as depression, overweight, chronic pain, anxiety, and insomnia 3, 6.
  • For RLS present through much of the day and night, the use of long-acting agents such as the rotigotine patch or gabapentin enacarbil should be considered 3.
  • In refractory RLS, oral prolonged release oxycodone-naloxone should be considered 3, and polytherapy or opioid monotherapy may also be considered 6.

References

Guideline

Guideline Directed Topic Overview

Dr.Oracle Medical Advisory Board & Editors, 2025

Research

Pharmacotherapy for restless legs syndrome.

Expert opinion on pharmacotherapy, 2014

Research

Treatment options for restless legs syndrome.

Expert opinion on pharmacotherapy, 2009

Research

Restless Legs Syndrome: Contemporary Diagnosis and Treatment.

Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics, 2021

Professional Medical Disclaimer

This information is intended for healthcare professionals. Any medical decision-making should rely on clinical judgment and independently verified information. The content provided herein does not replace professional discretion and should be considered supplementary to established clinical guidelines. Healthcare providers should verify all information against primary literature and current practice standards before application in patient care. Dr.Oracle assumes no liability for clinical decisions based on this content.

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