What are the recommended medications for treating restless legs syndrome (RLS)?

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From the Guidelines

The most effective treatment for restless legs syndrome (RLS) is the use of pregabalin, as recommended by the American Academy of Sleep Medicine (AASM) with a strong recommendation and moderate certainty of evidence 1.

Treatment Options for RLS

The treatment of RLS depends on the severity of symptoms and individual factors. The following options are recommended:

  • Pregabalin: Recommended by the AASM with a strong recommendation and moderate certainty of evidence 1.
  • Gabapentin: Recommended by the AASM with a strong recommendation and moderate certainty of evidence 1.
  • Gabapentin enacarbil: Recommended by the AASM with a strong recommendation and moderate certainty of evidence 1.
  • IV ferric carboxymaltose: Recommended by the AASM with a strong recommendation and moderate certainty of evidence for patients with appropriate iron status 1.
  • Ferrous sulfate: Suggested by the AASM for patients with low ferritin levels (below 75 ng/mL) 1.

Special Considerations

  • Opioids: May be considered for severe cases or those with inadequate response to other medications, with a conditional recommendation and moderate certainty of evidence 1.
  • Bilateral high-frequency peroneal nerve stimulation: A new noninvasive nonpharmacological treatment, with a conditional recommendation and moderate certainty of evidence 1.
  • Patients with end-stage renal disease (ESRD): Gabapentin, IV iron sucrose, and vitamin C are suggested with a conditional recommendation and moderate certainty of evidence 1.

Important Considerations

  • Start with low doses and gradually increase as needed.
  • Monitor for side effects like daytime sleepiness, impulse control disorders with dopamine agonists, or dependency with opioids and benzodiazepines.
  • Treatment should be taken 1-2 hours before symptoms typically begin, usually in the evening.

From the FDA Drug Label

1.2 Restless Legs Syndrome Ropinirole tablets are indicated for the treatment of moderate-to-severe primary Restless Legs Syndrome (RLS). 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.

Recommended Medication for Restless Legs Syndrome (RLS):

  • Ropinirole (PO) is indicated for the treatment of moderate-to-severe primary Restless Legs Syndrome (RLS) 2, 2, 2.
  • The medication has been shown to be effective in reducing symptoms of RLS in clinical trials, with a significant difference in mean change from baseline in the IRLS scale total score and percentage of patients rated as responders on the CGI-I compared to placebo.
  • The dosage of ropinirole for RLS is initiated at 0.25 mg once daily and titrated based on clinical response and tolerability over 7 weeks to a maximum of 4 mg once daily.

From the Research

Medications for Restless Legs Syndrome

The following medications are recommended for treating restless legs syndrome (RLS):

  • Dopaminergic agents, such as levodopa and dopamine agonists (e.g., ropinirole, pramipexole, cabergoline) 3, 4, 5
  • Anticonvulsants, such as gabapentin 4, 5, 6
  • Benzodiazepines, such as clonazepam 7
  • Opioids, although these are generally considered second-line treatment 4
  • Iron supplementation, which may be beneficial for some patients with RLS 5

First-Line Treatment

Dopaminergic agents, including ropinirole, are considered first-line therapy for RLS 3, 4, 5. Ropinirole has been shown to be effective in reducing symptoms of RLS and improving sleep quality 3, 5.

Second-Line Treatment

Gabapentin is considered a second-line treatment for RLS, but it has been shown to be effective in reducing symptoms and improving sleep quality in some patients 6, 7. Other second-line treatments include opioids and benzodiazepines 4, 7.

Special Considerations

In some cases, augmentation of RLS symptoms can occur with dopaminergic therapy, which may require a change in medication or the addition of other treatments 7. Additionally, certain antidepressants can exacerbate RLS symptoms, and alternative treatments such as agomelatine may be necessary 7.

References

Guideline

Guideline Directed Topic Overview

Dr.Oracle Medical Advisory Board & Editors, 2025

Research

Ropinirole treatment for restless legs syndrome.

Drugs of today (Barcelona, Spain : 1998), 2006

Research

Current treatment options for restless legs syndrome.

Expert opinion on pharmacotherapy, 2003

Research

Ropinirole for the treatment of restless legs syndrome.

Neuropsychiatric disease and treatment, 2006

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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