Treatment of Restless Legs Syndrome: an Evidence-Based Review and Implications for Clinical Practice

Movement Disorders Vol. 23, No. 16, 2008, pp. 2267–2302 Ó 2008 Movement Disorder Society Review Treatment of Restless Legs Syndrome: An Evidence-Based Review and Implications for Clinical Practice Clauder Trenkwalder, MD,1,2y* Wayne A. Hening, MD, PhD,3{ Pasquale Montagna, MD,4{ Wolfgang H. Oertel, MD,5{ Richard P. Allen, PhD,6# Arthur S. Walters, MD,7ˆ Joao Costa, MD,8{ Karin Stiasny-Kolster, MD,5{ and Cristina Sampaio, MD, PhD8§ 1Paracelsus-Elena Hospital, Kassel, Germany 2Department of Clinical Neurophysiology, University of Go¨ttingen, Germany 3Department of Neurology, UMDNJ-RW Johnson Medical School, New Brunswick, New Jersey, USA 4Department of Neurological Sciences, University of Bologna, Bologna, Italy 5Department of Neurology, Philipps-University Marburg, Marburg, Germany 6Department of Neurology and Sleep Medicine, Johns Hopkins University, Baltimore, Maryland, USA 7New Jersey Neuroscience Institute, JFK Medical Center, Edison, and Seton Hall University School of Graduate Medical Education, New Jersey, USA 8Neurological Clinical Research Unit, Institute of Molecular Medicine, Lisbon, Portugal Abstract: Only in the last three decades, the restless legs published literature using electronic databases. The therapeu- syndrome (RLS) has been examined in randomized controlled tic efficacy of each drug was classified as being either effica- trials. The Movement Disorder Society (MDS) commissioned cious, likely efficacious, investigational, nonefficacious, or a task force to perform an evidence-based review of the med- lacking sufficient evidence to classify. Implications for clini- ical literature on treatment modalities used to manage cal practice were generated based on the levels of evidence patients with RLS. The task force performed a search of the and particular features of each modality, such as adverse Produced by a task force commissioned by The Movement Disor- Schwarz Pharma and has received consultant honoraria from der Society. Boehringer Ingelheim, Hoffmann LaRoche, and Schwarz Pharma; Additional Supporting Information may be found in the online ver- Richard P. Allen, PhD, has received consultant honoraria from sion of this article. GlaxoSmithKline, Boehringer Ingelheim, UCB, Xenoport, Sepracor, yChairperson RLS EBM task force. Norvatis, Orion Pharma. Respironics, IM systems. Pfizer, Jazz, {RLS EBM task force member. Schwarz Pharama, and Neurogen. He has received grant support #Representative of the World Association of Sleep Medicine from the NIH, GlaxoSmithKline and Sepracor; Arthur S. Walters, (WASM) MD, has been an advisor for GlaxoSmithKline, Boehringer Ingel- ˆ Representative of the International RLS study group (IRLSSG). heim, Xenoport, UCB/Schwarz Pharma, and Orion/Novartis. He has §Chairperson of task force on EBM in movement disorders. received research funding from GlaxoSmithKline, Boehringer Ingel- *Correspondence to: Claudia Trenkwalder, Paracelsus-Elena Hos- heim, Xenoport, UCB/Schwarz Pharma and Kyowa; Karin Stiasny- pital, Center of Parkinsonism and Movement Disorders, Klinikstr. 16, Kolster, MD, has been an advisor for Boehringer Ingelheim, Orion, 34128 Kassel, Germany. E-mail: [email protected] Mundipharma, Pfizer, Schwarz Pharma, Synosia and UCB and has Potential conflicts of interest: Claudia Trenkwalder, MD, has been received consultant honoraria from Schwarz Pharma, UCB, and an advisor for Boehringer Ingelheim, Cephalon, Mundipharm, Orion Boehringer Ingelheim; Cristina Sampaio, MD, PhD and Joao Cos- Pharma and Schwarz Pharma. She has received consultant honoraria ta’s, MD, department has received grants from or payments from from GlaxoSmithKline, Boehringer Ingelheim GmbH, UCB/Schwarz the following companies: Kyowa, Schering-Plough, Lundbeck, Pharma, and Novartis; Wayne A. Hening, MD, PhD, has received UCB, Neurobiotech, Solvay, Servier, Xytis, Gruenthal, Eisai, Novar- grant support from GlaxoSmithKline, and consultancy and speaking tis, Fujisawa/Astellas, Neuron/Serono, Bial, GlaxoSmithKline and honoraria from Boehringer Ingelheim, and consultancy honoraria Novartis. In no circumstances were these grants/payments related to from Schwarz-Pharma; Pasquale Montagna, MD, has received a development program concerning RLS. research funding from GlaxoSmithKline and Schwarz Pharma, and Received 21 January 2008; Revised 20 June 2008; Accepted 6 has received consultant honoraria from Boehringer Ingelheim July 2008 GmbH; Wolfgang H. Oertel, MD, has been an advisor for Boeh- Published online 16 October 2008 in Wiley InterScience (www. ringer Ingelheim, GlaxoSmithKline, Novartis and Orion, and interscience.wiley.com). DOI: 10.1002/mds.22254 2267 2268 C. TRENKWALDER ET AL. events. All studies were classed according to three levels of investigational. Sumanirole is nonefficacious. Intravenous evidence. All Level-I trials were included in the efficacy iron dextran is likely efficacious for the treatment of RLS tables; if no Level-I trials were available then Level-II trials secondary to end-stage renal disease and investigational in were included or, in the absence of Level-II trials, Level-III RLS subjects with normal renal function. The efficacy of oral studies or case series were included. Only studies published iron is considered investigational; however, its efficacy in print or online before December 31, 2006 were included. appears to depend on the iron status of subjects. Cabergoline All studies published after 1996, which attempted to assess and pergolide (and possibly lisuride) require special monitor- RLS augmentation, were reviewed in a separate section. The ing due to fibrotic complications including cardiac valvulop- following drugs are considered efficacious for the treatment athy. Special monitoring is required for several other medica- of RLS: levodopa, ropinirole, pramipexole, cabergoline, per- tions based on clinical concerns: opioids (including, but not golide, and gabapentin. Drugs considered likely efficacious limited to, oxycodone, methadone and tramadol), due to pos- are rotigotine, bromocriptine, oxycodone, carbamazepine, val- sible addiction and respiratory depression, and some anticon- proic acid, and clonidine. Drugs that are considered investi- vulsants (particularly, carbamazepine and valproic acid), due gational are dihydroergocriptine, lisuride, methadone, trama- to systemic toxicities. Ó 2008 Movement Disorder Society dol, clonazepam, zolpidem, amantadine, and topiramate. Key words: restless legs syndrome (RLS); evidence-based Magnesium, folic acid, and exercise are also considered to be medicine; guidelines; MDS recommendations; therapy; treatment EXTENDED SUMMARY evaluated, and implications for clinical practice were reported. All studies with ‡5 subjects and a minimum treatment and follow-up duration of 1 week were clas- BACKGROUND sified according to three levels of evidence. All Level-I It is only in the last 3 decades that restless legs syn- trials were included in the efficacy tables (Table S3); if drome (RLS) has been examined in randomized con- no Level-I trials were available then Level-II trials trolled trials. The Movement Disorder Society (MDS) were included, if neither Level-I nor -II were available commissioned a task force to perform an evidence- then Level-III studies were included. The qualitative based review of current treatment strategies commonly approach taken by the task force seeks to highlight the used to manage patients with RLS. In this review, the available evidence and the areas that require further task force evaluates the therapeutic efficacy of each research. For the separate section on augmentation, all drug and reports on implications for clinical practice trials (irrespective of level of evidence) published after and research according to standardized methods of evi- 1996 that mentioned or described augmentation within denced-based medicine. The task force has also chosen the trial were included. to include a section on augmentation, which is considered an important therapy-related side effect specific to RESULTS RLS. The task force’s recommendations for practical use are given in the implications for clinical practice Dopaminergic Agents section after the review of each drug or class of drugs. Levodopa/benserazide or levodopa/carbidopa, at dos- Because of varied country-specific regulations, the task ages of 100/25 to 200/50 mg is considered efficacious force can only provide general recommendations for for the treatment of RLS, however, the number of clinical practice. The different levels of efficacy used patients (n = 462) involved in Level-I studies is not in this review can be seen in Table S1; definitions for large when compared with other dopaminergic drugs, specific recommendations are given in Table S2; Table and the duration of double-blind studies only exceeded S3 contains the data of all trials included in this review 4 weeks in one study.1–9 The 4-week side-effect profile (Tables S1–S3 can be consulted online). of levodopa is favorable; however, problems with augmentation develop with higher dosages and longer METHODS treatment duration. Long-term prospective studies are needed in order to better assess and quantify the risk The task force performed a search of the published of side effects. (print or online before December 31, 2006) literature using electronic databases (Medline [Pubmed; 1966-2/ 2007, Embase (1980-3/2007], the Cochrane Central Nonergot-Derived Dopamine Agonists Register of Controlled Trials [CENTRAL; issue 1, General considerations: The nonergot derived dopa- 2007], and systematic checking of reference lists pub- mine

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