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European Neurological Review Highlights Treatment Options for Idiopathic Restless Legs Syndrome Félix Javier Jiménez-Jiménez, 1 Hortensia Alonso-Navarro, 2 Elena García-Martín 3 and José AG Agúndez 4 1. Chairman of the Section of Neurology; Professor of Neurology, Hospital Universitario del Sureste, Arganda del Rey, Madrid, Spain; 2. Consultant Neurologist, Section of Neurology, Hospital Universitario del Sureste, Arganda del Rey, Madrid, Spain; 3. Professor of Pharmacology, Universidad de Extremadura, Cáceres, Spain; 4. Full Professor of Pharmacology, Universidad de Extremadura, Cáceres, Spain Abstract The emergence of new effective therapies for idiopathic restless legs syndrome (iRLS) or Willis–Ekbom disease (WED) during the last 15 years resulted in an exponential increase of reports regarding this syndrome and, especially, treatment options. In this review, we summarise the main findings related to neuropharmacological aspects and non-pharmacological therapies of idiopathic RLS (iRLS). As was previously reported in several guidelines, dopamine agonists (fundamentally nonergotic derivatives), gabapentin and pregabalin should be considered as first-line therapies, as well as opiates as an alternative drug group. Preliminary results suggest that several non-pharmacological therapies should be promising as alternatives or adjuvants to drug treatments. Keywords Restless legs syndrome, therapy, dopamine agonists, gabapentin, pregabalin, opiates, non-pharmacological therapies Disclosures: Félix Javier Jiménez-Jiménez, Hortensia Alonso-Navarro, Elena García-Martín and José AG Agúndez have no conflicts of interest to declare. Research at authors’ laboratories is financed by grants PS09/00943, PS09/00469, PI12/00241, PI12/00324 and RETICS RD12/0013/0002 from Fondo de Investigación Sanitaria, Instituto de Salud Carlos III, Spain, Innovation and GR10068 from Junta de Extremadura, Spain. Financed in part by FEDER funds from the European Union. No funding was received for the publication of this article. Open Access: This article is published under the Creative Commons Attribution Noncommercial License, which permits any non-commercial use, distribution, adaptation and reproduction provided the original author(s) and source are given appropriate credit. Received: 27 February 2015 Accepted: 15 April 2015 Citation: European Neurological Review, 2015;10(1):45–55 Correspondence: Félix Javier Jiménez-Jiménez, C/Marroquina 14, 3º B, E-28030 Madrid, Spain. E:; Supplementary Material: Supplementary material to this article is available online at Restless legs syndrome (RLS), or Willis–Ekbom disease (WED), is a sensorimotor disorder having well-known standardised diagnostic criteria 1 that have been revised recently by the International Restless Legs Syndrome Study Group. 2 The genetic basis of RLS has not been definitively established, 3 but the most important biochemical findings are dopaminergic dysfunction and iron deficiency. 4 The interest for RLS is relatively recent, with the number of publications on this issue growing exponentially. A current PubMed search shows 3,601 papers on this topic from 1966 to today, 2,967 published from 2000 to 2015 (541 from 2000 to 2004; 1,045 from 2005 to 2009; 1,381 from 2010 to February 24, 2015). Many of these reports are related to the development of efficacious drugs – especially dopamine agonists, the most effective for the treatment of RLS/WED. In this review, we summarise the main findings related to neuropharmacological aspects of idiopathic RLS (iRLS) and to non- pharmacological therapies. Search Strategy References for this review were identified by searching PubMed from 1966 until February 25, 2015. The term “restless legs syndrome” was 116 crossed with “pharmacology”, “neuropharmacology”, “treatment” and “therapy”. This search retrieved 2,192 references, which were individually examined, with related references of interest (n=274) selected. According to this search, drugs essayed for the treatment of iRLS are summarised in Table 1. Drugs Enhancing Dopaminergic Neurotransmission Levodopa The results of studies on the efficacy of levodopa (the precursor of dopamine) in the treatment of iRLS are summarised in Supplementary Table 1. All these studies, independent of their design, showed significant improvement of RLS symptoms and/or periodic limb movements (PLMS). 5– 17 Some of them mentioned the presence of a rebound phenomenon in the last part of the sleep time when using regular-release levodopa, 7,14–16 which was improved by the use of sustained-release levodopa alone 15,16 or combined with regular-release levodopa. 14 Stiasny-Kolster et al. 18 validated the so-called “levodopa test” for the diagnosis of RLS. This consisted of the application of a single dose of benserazide/levodopa 25/100 mg with a subsequent 2-hour period of observation, considering as “positive” a 50 % improvement Touch ME d ica l ME d ia