In search of alternatives to dopaminergic ligands for the treatment of restless legs syndrome: iron, glutamate, and adenosine

Dopaminergic drugs have been used as the first-line treatment for restless legs syndrome (RLS) for many years and are considered to be, at least over the short-term, effective and safe. However, the main long-term complication of dopaminergic treatment is augmentation, which is an overall increase in symptom severity and intensity, with symptoms starting earlier in the afternoon and expanding to previously unaffected parts of the body. Augmentation is a common complication, with prevalence rates of nearly 50%, and is a common cause of treatment failure. Furthermore, augmentation occurs almost exclusively during treatment with dopaminergic drugs. Due to its frequency, there is a strong clinical need for treatment alternatives to dopaminergic drugs. Moreover, recent treatment guidelines recommend that treatment be initiated, whenever possible, with non-dopaminergic drugs (ie, α₂δ ligands). Alternative treatments such as intravenous iron preparations directly address iron deficiency, as well as the consequences of iron deficiency in regard to glutamate and adenosine. This article also reviews current knowledge supporting an involvement of glutamatergic and adenosinergic neurotransmission in the pathophysiology of RLS, and explores the potential development of drugs acting on both systems.