What are the causes and treatments of Restless Legs Syndrome (RLS)?

From the Guidelines

Restless leg syndrome (RLS) should be primarily managed with ferrous sulfate, as the American Academy of Sleep Medicine suggests its use over no ferrous sulfate in patients with appropriate iron status 1. When considering treatment options for RLS, it's essential to prioritize those with the most substantial evidence supporting their efficacy.

• The use of ferrous sulfate is recommended for adults with RLS, given its moderate certainty of evidence 1.
• Other suggested treatments include dipyridamole, extended-release oxycodone, and bilateral high-frequency peroneal nerve stimulation, although the certainty of evidence varies from low to moderate 1.
• On the other hand, the standard use of levodopa, pramipexole, transdermal rotigotine, ropinirole, bupropion, carbamazepine, clonazepam, valproic acid, and cabergoline is suggested against due to varying levels of certainty of evidence 1. Key considerations in managing RLS include:
• Identifying and addressing underlying iron deficiency, as low iron levels are linked to RLS symptoms 1.
• Exploring alternative treatment options, such as gabapentin, for adults with RLS and end-stage renal disease (ESRD) 1.
• Recognizing the importance of individualized treatment plans, as patients may place different values on symptom reduction and potential adverse effects 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 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 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 treating Restless Legs Syndrome (RLS). The drug has been shown to significantly improve symptoms of RLS, as measured by the International RLS Rating Scale (IRLS) and Clinical Global Impression-Global Improvement (CGI-I) scores, in three randomized, double-blind, placebo-controlled trials 2.

• The mean change in total IRLS scale score at Week 12 was significantly greater for ropinirole compared to placebo in all three trials.
• The percentage of patients rated as responders on the CGI-I at Week 12 was also significantly higher for ropinirole compared to placebo in all three trials.

From the Research

Restless Leg Syndrome Overview

• Restless legs syndrome (RLS) is a common disorder characterized by restlessness in the legs associated with abnormal sensations that start at rest and are improved by activity, occurring with a diurnal pattern of worsened symptoms at night and improvement in the morning 3.
• RLS is the cause of impaired quality of life in those more severely afflicted, and its etiopathogenesis is still unknown, although the rapid and dramatic improvement of RLS with dopaminergic agents suggests that dopaminergic system dysfunction may be a basic mechanism 4.

Treatment Options

• Several classes of medications have demonstrated efficacy in treating RLS, including dopaminergic agents and alpha-2-delta ligands 3.
• Dopaminergic agents, such as levodopa, ropinirole, pramipexole, and rotigotine patch, are effective, although side effects like daytime sleepiness, impulse control disorders, and augmentation may limit their usefulness 3, 4.
• Alpha-2-delta ligands, including gabapentin, gabapentin enacarbil, and pregabalin, are effective for RLS without known occurrence of augmentation or impulse control disorders, although sedation and dizziness can occur 3.
• Other agents, such as opioids and clonazepam, do not have sufficient evidence to recommend them as treatment for RLS, although they may provide benefit in individual patients 3, 5.

Efficacy Comparison

• A model-based meta-analysis approach was employed to quantitatively compare the efficacies of five first-line RLS drugs, including dopaminergic agonists and alpha-2-delta ligands, and found that the therapeutic effect of dopaminergic agonists was associated with baseline symptom severity 6.
• In RLS patients with more severe symptoms, the therapeutic effect of dopaminergic agonists tended to be better than that of alpha-2-delta ligands 6.
• The Movement Disorder Society (MDS) commissioned a task force to perform an evidence-based review of the medical literature on treatment modalities used to manage patients with RLS, and classified the therapeutic efficacy of each drug as being either efficacious, likely efficacious, investigational, nonefficacious, or lacking sufficient evidence to classify 5.

ADMET Considerations

• The Absorption, Distribution, Metabolism, Elimination, and Toxicology (ADMET) characteristics of the most used medications for RLS were discussed, including dopaminergic agents, anticonvulsants, and iron 7.
• Clinical trials have shown that non-ergolic dopamine agonists are efficacious and safe for patients affected by moderate to severe idiopathic RLS, although no head-to-head study has compared the long-term effects of the three dopamine agonists approved by the FDA for RLS 7.