What are the treatments for Restless Legs Syndrome (RLS)?

From the Guidelines

The most effective treatment for Restless Legs Syndrome (RLS) is the use of 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.

Treatment Options

The AASM suggests several treatment options for RLS, including:

• Ferrous sulfate for patients with appropriate iron status (conditional recommendation, moderate certainty of evidence) 1
• Dipyridamole (conditional recommendation, low certainty of evidence) 1
• Extended-release oxycodone and other opioids (conditional recommendation, moderate certainty of evidence) 1
• Bilateral high-frequency peroneal nerve stimulation (conditional recommendation, moderate certainty of evidence) 1

Medications to Avoid

The AASM suggests against the standard use of several medications, including:

• Levodopa (conditional recommendation, very low certainty of evidence) 1
• Pramipexole (conditional recommendation, moderate certainty of evidence) 1
• Transdermal rotigotine (conditional recommendation, low certainty of evidence) 1
• Ropinirole (conditional recommendation, moderate certainty of evidence) 1
• Bupropion (conditional recommendation, moderate certainty of evidence) 1
• Carbamazepine (conditional recommendation, low certainty of evidence) 1
• Clonazepam (conditional recommendation, very low certainty of evidence) 1
• Valproic acid (conditional recommendation, low certainty of evidence) 1
• Cabergoline (strong recommendation, moderate certainty of evidence) 1

Special Considerations

For adults with RLS and end-stage renal disease (ESRD), the AASM suggests the use of gabapentin, IV iron sucrose, and vitamin C (conditional recommendations, varying levels of certainty of evidence) 1.

Key Takeaways

• Ferrous sulfate is the recommended treatment for RLS in patients with appropriate iron status 1
• Medications should be individualized and started at the lowest effective dose to minimize side effects
• Treatment may need to be adjusted over time as symptoms can fluctuate or worsen with age

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 Three of the controlled trials utilized the change from baseline in the IRLS scale at the Week 12 endpoint as the primary efficacy outcome. 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

Treatments for Restless Legs Syndrome (RLS) include:

• Ropinirole: a dopamine agonist that has been shown to be effective in reducing symptoms of RLS in clinical trials 2 Key points:
• Ropinirole is taken once daily, 1-3 hours before bedtime
• The maximum dosage is 4 mg once daily
• Efficacy was demonstrated in a 36-week trial, showing long-term maintenance of efficacy in the treatment of RLS 2

From the Research

Treatment Options for Restless Legs Syndrome (RLS)

The treatment of RLS can be categorized into pharmacological and non-pharmacological approaches.

• Pharmacological treatment should be limited to patients who suffer from clinically relevant RLS, where symptoms impair the patient's quality of life, daytime functioning, social functioning, or sleep 3.
• Treatment on demand is a clinical need in some RLS patients, and medications include carbidopa/levodopa, pramipexole, ropinirole, oxycodone, methadone, codeine, and tramadol 3.
• Chronic RLS should be treated with either a nonergot dopamine agonist or an α-2-δ calcium channel ligand 3.

Pharmacological Treatment

• Dopamine agonists such as oral pramipexole and ropinirole, as well as transdermal rotigotine, are effective treatment options for RLS 4.
• Gabapentinoid agents such as gabapentin enacarbil and pregabalin have shown comparable short-term efficacy to dopaminergics with a lower risk of augmentation of the RLS symptoms 4.
• Oxycodone-naloxone can be used in treatment-resistant RLS 4.
• Iron supplementation therapy, including treatment with ferric carboxymaltose, can be used if iron stores are low 4.

Non-Pharmacological Treatment

• Regular physical activity should be recommended for the treatment of RLS symptoms 5.
• Oral iron supplementation should be considered for people with RLS who have low ferritin levels 5.
• Good sleep hygiene and avoidance of alcohol, caffeine, and nicotine may improve symptoms 6.
• Supplementation for low levels of vitamins E, C, and D could be considered, although evidence specifically in RLS is limited 5.

Special Considerations

• 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.
• The presence of comorbidities such as depression, anxiety, and insomnia may influence the choice of treatment 3, 7.