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

From the Guidelines

For refractory Restless Legs Syndrome (RLS), the most effective treatment option 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

The treatment of refractory RLS involves a multi-faceted approach, including pharmacological and non-pharmacological interventions. The AASM suggests the use of ferrous sulfate over no ferrous sulfate in patients with appropriate iron status 1.

• Dopaminergic medications like pramipexole or ropinirole may be used, but with caution due to the risk of augmentation.
• Alpha-2-delta ligands such as gabapentin or pregabalin are effective alternatives, with pregabalin being the preferred option due to its strong recommendation and moderate certainty of evidence 1.
• Low-dose opioids like oxycodone may be used in severe cases, but with caution due to addiction potential 1.
• Iron supplementation is essential if ferritin levels are below 75 ng/mL, with ferrous sulfate 325 mg daily and vitamin C recommended to enhance absorption.
• Non-pharmacological approaches include maintaining good sleep hygiene, regular exercise, avoiding caffeine and alcohol, and using pneumatic compression devices.

Special Considerations

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 against levodopa and rotigotine 1.

• Bilateral high-frequency peroneal nerve stimulation is a new non-invasive non-pharmacological treatment that receives a conditional recommendation from initial success in short-term sham-controlled studies and a longer observational extension 1.
• In pediatric RLS treatment, oral iron supplementation is recommended in cases of iron deficiency, with consideration of potential side effects such as constipation 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.

The treatment options for Refractory Restless Legs Syndrome (RLS) are not directly addressed in the provided drug labels. However, ropinirole is shown to be effective in the treatment of RLS in the provided trials 2 2.

• The dosage of ropinirole is titrated based on clinical response and tolerability, with a maximum dosage of 4 mg once daily.
• Ropinirole has been shown to be effective in reducing symptoms of RLS, 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. However, the provided drug labels do not provide information on treatment options for refractory RLS, which is defined as RLS that does not respond to standard treatments.

From the Research

Treatment Options for Refractory Restless Legs Syndrome (RLS)

• The treatment of refractory RLS may involve the use of oral prolonged release oxycodone-naloxone 3
• In cases of refractory RLS, opioids such as oxycodone-naloxone have demonstrated good efficacy 4
• 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
• Alternative or additional pharmacologic treatment with a lower level of overall quality of evidence includes opioids (codeine, tramadol, and oxycodone) and anticonvulsants (gabapentin, gabapentin enacarbil, and pregabalin) 5
• When RLS is refractory to first-line treatment, polytherapy, or opioid monotherapy should be considered 6

Pharmacological Treatment

• 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
• Chronic RLS should be treated with either a nonergot dopamine agonist or an α-2-δ calcium channel ligand 3
• α-2-δ ligands can alleviate chronic pain and may be helpful in treating anxiety and insomnia, the presence of any of these comorbidities may favor their use 3
• Dopamine agonists are associated with increased risk and should be spared, whereas α2δ calcium channel ligands are a first-line pharmacological approach 6

Management of Refractory RLS

• Addressing factors that worsen RLS (eg, iron deficiency, antidepressant or antihistamine administration, OSA) is an important first step in treatment 7
• If dopaminergic augmentation of RLS is present, substitution of an A2D or opioid for the DA is the primary goal 7
• Prevention strategies include managing lifestyle changes and a good sleep hygiene 4
• The final decision regarding the agent to use in treating severe RLS/WED symptoms should be tailored to the patient, taking into account the symptomatology, comorbidities, the availability of treatment and the history of the disease 4