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Movement Disorders Restless Legs Syndrome

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Movement Disorders Restless Legs Syndrome Movement Disorders Restless Legs Syndrome Treatment Options for Idiopathic Restless Legs Syndrome Félix Javier Jiménez-Jiménez,1 Hortensia Alonso-Navarro,2 Elena García-Martín3 and José AG Agúndez4 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 DOI: 10.17925/ENR.2015.10.01.45 Correspondence: Félix Javier Jiménez-Jiménez, C/Marroquina 14, 3º B, E-28030 Madrid, Spain. E: [email protected]; [email protected] Supplementary Material: Supplementary material to this article is available online at http://www.touchneurology.com/ Restless legs syndrome (RLS), or Willis–Ekbom disease (WED), is a Drugs Enhancing Dopaminergic sensorimotor disorder having well-known standardised diagnostic Neurotransmission criteria1 that have been revised recently by the International Restless Levodopa Legs Syndrome Study Group.2 The genetic basis of RLS has not been The results of studies on the efficacy of levodopa (the precursor of definitively established,3 but the most important biochemical findings are dopamine) in the treatment of iRLS are summarised in Supplementary dopaminergic dysfunction and iron deficiency.4 Table 1. All these studies, independent of their design, showed significant improvement of RLS symptoms and/or periodic limb movements The interest for RLS is relatively recent, with the number of publications (PLMS).5–17 Some of them mentioned the presence of a rebound on this issue growing exponentially. A current PubMed search shows phenomenon in the last part of the sleep time when using regular- 3,601 papers on this topic from 1966 to today, 2,967 published from release levodopa,7,14–16 which was improved by the use of sustained- 2000 to 2015 (541 from 2000 to 2004; 1,045 from 2005 to 2009; 1,381 release levodopa alone15,16 or combined with regular-release levodopa.14 from 2010 to February 24, 2015). Many of these reports are related to the development of efficacious drugs – especially dopamine agonists, Stiasny-Kolster et al.18 validated the so-called “levodopa test” for the the most effective for the treatment of RLS/WED. 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 In this review, we summarise the main findings related to observation, considering as “positive” a 50 % improvement in “symptoms neuropharmacological aspects of idiopathic RLS (iRLS) and to non- in the legs” (sensitivity 80 %; specificity 100 %) and “urge to move the pharmacological therapies. legs” (sensitivity 88 %; specificity 100 %) in 15-minute intervals. Search Strategy Guilleminault et al.19 investigated the rebound phenomenon in 20 RLS References for this review were identified by searching PubMed from patients treated with a bedtime dose of controlled-release carbidopa/ 1966 until February 25, 2015. The term “restless legs syndrome” was levodopa 25/100 mg. Even though at 4 to 7 weeks none of the patients crossed with “pharmacology”, “neuropharmacology”, “treatment” exhibited subjective RLS symptoms, and PLMS reduced by 80 % after and “therapy”. This search retrieved 2,192 references, which were 11±2 months of follow-up, seven subjects reported the re-emergence of individually examined, with related references of interest (n=274) disturbing RLS symptoms between 8:00 pm and 11:00 pm. This rebound selected. According to this search, drugs essayed for the treatment of phenomenon disappeared in four patients after drug withdrawal iRLS are summarised in Table 1. (with reappearance of the RLS symptoms) and reappeared after its TOUCH MEDICAL MEDIA 45 Jimenez (paper2)_FINAL.indd 45 13/05/2015 12:51 Movement Disorders Restless Legs Syndrome Table 1: Classification of Drugs Assayed for after levodopa treatment.24 These findings suggest increased circadian Treatment of Restless Legs Syndrome variations in dopaminergic function in iRLS patients. A) Drugs enhancing dopaminergic transmission Two systematic reviews, including nine eligible trials, concluded that the 1. Levodopa short-term treatment of RLS and PLMs with levodopa showed efficacy 2. Nonergotic dopamine agonists: ropinirole, pramipexole, rotigotine, and safety; however, the assessment of the usefulness of long-term talipexole, piribedil, apomorphine treatment and the development of the augmentation phenomenon has 3. Ergotic dopamine agonists: pergolide, cabergoline, bromocriptine, alpha- not been investigated sufficiently.25,26 dihydroergocryptine, terguride, lisuride 4. Amantadine (inhibitor of dopamine uptake, mild action as D agonist, 2 Shariff27 reported increased duration of the action of carbidopa/ inhibitor of N-methyl-D-aspartate receptors) levodopa induced by entacapone (a peripheral inhibitor of catechol- 5. Aripiprazole (partial agonist of D receptor) 2 ortho-methyl-transferase [COMT]) in a patient who had RLS. Afterwards, 6. Monoamine oxidase B inhibitors (selegiline, rasagiline) 28 7. Bupropion (inhibitor of dopamine and noradrenalin uptake) Polo et al. confirmed that the association of entacapone to carbidopa/ B) Antiepileptic drugs levodopa was useful to prolong symptom control in a randomised, 1. Gabapentin double-blind, crossover study with polysomnography. 2. Pregabalin 3. Valproate Dopamine Agonists 4. Other (carbamazepine, topiramate, lamotrigine, levetiracetam, The studies of ropinirole,29–41 pramipexole,42–73 rotigotine,74–85 pergolide86–94 oxcarbazepine) and cabergoline,95–101 respectively, in the treatment of iRLS are summarised C) Opiate drugs: by Supplementary Tables 2, 3, 4, 5, and 6. All these studies comparing 1. Morphine dopamine agonists with placebo showed a significant improvement 2. Tramadol in the severity of RLS (assessed with several scales, being the most 3. Oxycodone frequently used the International RLS Study Group Scale), in the IRLS 4. Methadone frequency of “responder” rates (improvement in >50 %), in the Clinical D) Benzodiazepines Global Impression Improvement (CGI-I) and Patient Global Impression 1. Clonazepam 2. Triazolam Improvement (PGI-I), in the quality of life (QoL) and in polysomnographic 3. Alprazolam (PSG) measurements. 4. Zolpidem E) Iron (oral or intravenous) The efficacy, safety and tolerability of sumanirole (a highly selective F) Botulinum toxin D2 agonist) has been assessed in a double-blind, placebo-controlled, G) Other drugs (described in the text) randomised, parallel-group, dose-response study involving 270 patients with iRLS randomised to sumanirole 0.5,1.0, 2.0, 4.0 mg or placebo.102 reintroduction. Rebound phenomenon was adequately controlled in the Even though this drug was well tolerated, only the dose of sumanirole 4.0 seven patients after placing them on two doses of controlled-release showed improvement in the International Restless Legs Scale-10 (IRLS- carbidopa/levodopa 25/100 mg (at night and in the morning). 10) compared with placebo or with lower doses of sumanirole. PSG variables, especially the periodic leg movements index (PLMI), improved The other important long-term side effect of levodopa (and dopamine in a dose-related manner during sleep.102 agonists) is the augmentation phenomenon, defined as a loss of circadian recurrence with progressively earlier daily onset and increase in Other dopamine agonists, including bromocriptine,103 talipexole,104 the duration, intensity and distribution of symptoms.20 This complication amantadine,105 alpha-dihydroergocryptine,106 piribedil,107 terguride,108 has been found in up
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