What is the diagnosis and treatment for Restless Legs Syndrome (RLS)?

From the Guidelines

Restless leg syndrome (RLS) should be treated with 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 treatment of RLS involves a combination of lifestyle modifications and pharmacological interventions. For mild RLS, lifestyle modifications such as regular exercise, maintaining good sleep hygiene, avoiding caffeine and alcohol, and practicing relaxation techniques are recommended first.

• Medications are often necessary for moderate to severe symptoms, with the AASM suggesting the use of ferrous sulfate over no ferrous sulfate in patients with appropriate iron status (conditional recommendation, moderate certainty of evidence) 1.
• Other treatment options include bilateral high-frequency peroneal nerve stimulation, extended-release oxycodone, and other opioids, although these are conditional recommendations with moderate certainty of evidence 1.
• The AASM suggests against the standard use of levodopa, pramipexole, transdermal rotigotine, ropinirole, bupropion, carbamazepine, clonazepam, valproic acid, and cabergoline, due to concerns about augmentation and adverse effects 1. The pathophysiology of RLS is complex and involves interactions between iron and dopamine systems, with brain iron deficiency likely playing a key role in the development of symptoms 1.
• Iron supplementation, particularly with ferrous sulfate, is an important treatment option for patients with RLS, especially those with low ferritin levels 1. Regular follow-up is crucial to monitor medication effectiveness and potential adverse effects, such as augmentation, which can worsen symptoms over time 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. 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 Leg Syndrome (RLS).

• The drug has been shown to reduce the severity of RLS symptoms, as measured by the International RLS Rating Scale (IRLS scale) and the Clinical Global Impression-Global Improvement (CGI-I) scores.
• The mean dose at Week 12 was approximately 2 mg/day for the 3 trials 2.
• Long-term maintenance of efficacy in the treatment of RLS was demonstrated in a 36-week trial 2.

From the Research

Definition and Characteristics of Restless Leg Syndrome

• Restless legs syndrome (RLS) is characterized by an uncomfortable urge to move the legs while at rest, relief upon movement or getting up to walk, and worsened symptom severity at night 3.
• RLS may be primary (idiopathic) or secondary to pregnancy or a variety of systemic disorders, especially iron deficiency, and chronic renal insufficiency 3.
• Genetic predisposition with a family history is common in RLS patients 3.

Treatment Options for Restless Leg Syndrome

• Non-pharmacological measures such as massage or temperate baths may provide adequate symptom control for some people with RLS 3.
• First-line management options include iron-replacement therapy, gabapentin, pregabalin, and dopamine agonists such as pramipexole, ropinirole, and rotigotine 3.
• Second-line therapies include intravenous iron infusion and opioids including tramadol, oxycodone, and methadone 3.
• Non-pharmacological interventions such as repetitive transcranial magnetic stimulation, exercise, compression devices, counterstrain manipulation, infrared therapy, and standard acupuncture may be beneficial for reducing RLS severity and enhancing sleep 4.

Management Algorithms for Restless Leg Syndrome

• The management of RLS can be considered under the following headings: General Considerations; Intermittent RLS; Chronic Persistent RLS; Refractory RLS; Special Circumstances; and Alternative, Investigative, and Potential Future Therapies 5.
• Nonpharmacologic approaches, including mental alerting activities, avoidance of substances or medications that may exacerbate RLS, and oral and intravenous iron supplementation, are outlined in the updated algorithm 5.
• The choice of an alpha2-delta ligand as first-line therapy for chronic persistent RLS with dopamine agonists as a second-line option is explained in the algorithm 5.

Pharmacologic and Nonpharmacologic Treatment

• Pharmacologic options may be considered for moderate to severe primary RLS, including iron suppletion, an α2δ ligand, a dopamine agonist, a combination of an α2δ ligand and a dopamine agonist, or oxycodone/naloxone 6.
• Nonpharmacologic management of RLS is an important part of the treatment and can represent the entire treatment or be used as an adjuvant to pharmacologic options 7.