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Winkelman JW, Berkowski JA, DelRosso LM, Koo BB, Scharf MT, Sharon D, Zak RS, Kazmi U, Carandang G, Falck-Ytter Y, Shelgikar AV, Trotti LM, Walters AS. Treatment of restless legs syndrome and periodic limb movement disorder: an American Academy of Sleep Medicine systematic review, meta-analysis, and GRADE assessment. J Clin Sleep Med 2025; 21:153-199. [PMID: 39324664 DOI: 10.5664/jcsm.11392] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/27/2024]
Abstract
INTRODUCTION This systematic review provides supporting evidence for the accompanying clinical practice guideline on the treatment of restless legs syndrome and periodic limb movement disorder. METHODS The American Academy of Sleep Medicine commissioned a task force of experts in sleep medicine. A systematic review was conducted to identify studies that compared the use of pharmacological or nonpharmacological treatment to no treatment to improve patient-important outcomes. Statistical analyses were performed to determine the clinical significance of using various interventions to treat restless legs syndrome and periodic limb movement disorder in adults and children. The Grading of Recommendations Assessment, Development, and Evaluation process was used to assess the evidence for making recommendations. RESULTS The literature search resulted in 3,631 studies out of which 148 studies provided data suitable for statistical analyses. The task force provided a detailed summary of the evidence along with the certainty of evidence, the balance of benefits and harms, patient values and preferences, and resource use considerations. CITATION Winkelman JW, Berkowski JA, DelRosso LM, et al. Treatment of restless legs syndrome and periodic limb movement disorder: an American Academy of Sleep Medicine systematic review, meta-analysis, and GRADE assessment. J Clin Sleep Med. 2025;21(1):153-199.
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Affiliation(s)
- John W Winkelman
- Departments of Psychiatry and Neurology, Massachusetts General Hospital, Boston, Massachusetts
- Harvard Medical School, Boston, Massachusetts
| | | | | | - Brian B Koo
- Department of Neurology, Yale University, New Haven, Connecticut
- Connecticut Veterans Affairs Healthcare System, West Haven, Connecticut
| | - Matthew T Scharf
- Comprehensive Sleep Center, Division of Pulmonary and Critical Care, Departments of Medicine and Neurology, Rutgers/Robert Wood Johnson Medical School, New Brunswick, New Jersey
| | - Denise Sharon
- Keck Medical Center of University of Southern California Sleep Disorder Center, Division of Pulmonary, Critical Care and Sleep Medicine, Keck School of Medicine of University of Southern California, Los Angeles, California
- Adult and Children Sleep Disorders Center, Pomona Valley Hospital and Medical Center, Claremont, California
| | - Rochelle S Zak
- Sleep Disorders Center, University of California, San Francisco, San Francisco, California
| | - Uzma Kazmi
- American Academy of Sleep Medicine, Darien, Illinois
| | | | - Yngve Falck-Ytter
- Case Western Reserve University, Cleveland, Ohio
- Department of Gastroenterology and Hepatology, Veterans Affairs Northeast Ohio Healthcare System, Cleveland, Ohio
| | - Anita V Shelgikar
- University of Michigan Sleep Disorders Center, University of Michigan, Ann Arbor, Michigan
| | - Lynn Marie Trotti
- Department of Neurology, Emory University School of Medicine, Atlanta, Georgia
| | - Arthur S Walters
- Department of Neurology, Vanderbilt University, Nashville, Tennessee
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Spektor E, Fietze I, Poluektov MG. Periodic Limb Movements Syndrome in Patients With Cerebral Small Vessel Disease: Protocol for a Prospective Observational Study. Front Neurol 2021; 12:700151. [PMID: 34646228 PMCID: PMC8503532 DOI: 10.3389/fneur.2021.700151] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2021] [Accepted: 08/17/2021] [Indexed: 11/23/2022] Open
Abstract
Background: Cerebrovascular diseases are the leading cause of cognitive decline and dementia. Therefore, the investigation of the potential ways to slow down the disease progression is an important research field. Periodic limb movements in sleep (PLMS) are known to be associated with transient changes in heart rate and blood pressure. These changes might influence the course of cerebral small vessel disease (cSVD). Nevertheless, the clinical significance of PLMS, particularly its influence on cardiovascular diseases course, is still controversial and underinvestigated. Methods/design: Patients from 60 to 75 years old diagnosed with cSVD will undergo nocturnal polysomnography. Subjects with apnea/hypopnea index under 5 will be enrolled. Sleep quality and daytime functioning will be assessed at baseline with self-reported questionnaires. Brain MRI and cognitive assessment will be performed at baseline and in the 2-year follow-up. Progression of cSVD markers and cognitive dysfunction will be compared between patients with PLMS index (PLMI) equal to or more than 15 movements per hour of sleep and controls (PLMI <15/h). Discussion: The negative role of PLMS in cSVD progression and related cognitive decline is expected. We suppose that patients with PLMS tend to worsen in cognitive performance more rapidly than age-, gender-, and comorbidity-matched controls. We also expect them to have more rapid white matter hyperintensities and other cSVD marker progression. The limitations of the study protocol are the short follow-up period, the absence of a treatment group, and inability to make a conclusion about causality.
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Affiliation(s)
- Ekaterina Spektor
- Department of Sleep Medicine, Chair of Neurology and Neurosurgery, University Clinical Hospital No. 3, I.M. Sechenov First Moscow State Medical University, Moscow, Russia
| | - Ingo Fietze
- Center of Sleep Medicine, Charité - Universitätsmedizin Berlin, Berlin, Germany.,The Fourth People's hospital of Guangyuan, Guangyuan City, China.,The Federal State Autonomous Educational Institution of Higher Education, I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation, Moscow, Russia
| | - Mikhail G Poluektov
- Department of Sleep Medicine, Chair of Neurology and Neurosurgery, University Clinical Hospital No. 3, I.M. Sechenov First Moscow State Medical University, Moscow, Russia
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Colzato LS, Zhang W, Brandt MD, Stock AK, Beste C. Cognitive profile in Restless Legs Syndrome: A signal-to-noise ratio account. CURRENT RESEARCH IN NEUROBIOLOGY 2021; 2:100021. [PMID: 36246509 PMCID: PMC9559071 DOI: 10.1016/j.crneur.2021.100021] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Revised: 07/05/2021] [Accepted: 07/29/2021] [Indexed: 11/19/2022] Open
Abstract
Restless legs syndrome (RLS) is a common neurological disorder characterized by a sensorimotor condition, where patients feel an uncontrollable urge to move the lower limbs in the evening and/or during the night. RLS does not only have a profound impact on quality of life due to the disturbed night-time sleep, but there is growing evidence that untreated or insufficiently managed RLS might also cause cognitive changes in patients affected by this syndrome. It has been proposed that RLS is caused by alterations in the signal-to-noise ratio (SNR) and in dopamine (DA) neurotransmission in the nervous system. Based on this evidence, we propose the “SNR-DA hypothesis” as an explanation of how RLS could affect cognitive performance. According to this hypothesis, variations/reductions in the SNR underlie RLS-associated cognitive deficits, which follow an inverted U-shaped function: In unmedicated patients, low dopamine levels worsen the SNR, which eventually impairs cognition. Pharmacological treatment enhances DA levels in medicated patients, which likely improves/normalizes the SNR in case of optimal doses, thus restoring cognition to a normal level. However, overmedication might push patients past the optimal point on the inverted U-shaped curve, where an exaggerated SNR potentially impairs cognitive performance relying on cortical noise such as cognitive flexibility. Based on these assumptions of SNR alterations, we propose to directly measure neural noise via “1/f noise” and related metrics to use transcranial random noise stimulation (tRNS), a noninvasive brain stimulation method which manipulates the SNR, as a research tool and potential treatment option for RLS.
Restless legs syndrome (RLS) is a common neurological disorder. RLS is caused by alterations in the SNR ratio and in DA neurotransmission. The SNR- DA hypothesis how RLS affects cognitive performance is presented.
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Affiliation(s)
- Lorenza S. Colzato
- Cognitive Neurophysiology, Department of Child and Adolescent Psychiatry, Faculty of Medicine, TU Dresden, Germany
- Cognitive Psychology, Faculty of Psychology, Shandong Normal University, Jinan, China
- University Neuropsychology Center, Faculty of Medicine, TU Dresden, Germany
| | - Wenxin Zhang
- Cognitive Psychology, Faculty of Psychology, Shandong Normal University, Jinan, China
| | - Moritz D. Brandt
- Department of Neurology, University Hospital, Technische Universität Dresden, Dresden, Germany
- German Center for Neurodegenerative Diseases (DZNE) Dresden, Dresden, Germany
| | - Ann-Kathrin Stock
- Cognitive Neurophysiology, Department of Child and Adolescent Psychiatry, Faculty of Medicine, TU Dresden, Germany
- University Neuropsychology Center, Faculty of Medicine, TU Dresden, Germany
- Biopsychology, Faculty of Psychology, TU Dresden, Dresden, Germany
| | - Christian Beste
- Cognitive Neurophysiology, Department of Child and Adolescent Psychiatry, Faculty of Medicine, TU Dresden, Germany
- Cognitive Psychology, Faculty of Psychology, Shandong Normal University, Jinan, China
- University Neuropsychology Center, Faculty of Medicine, TU Dresden, Germany
- Corresponding author. Cognitive Neurophysiology, Department of Child and Adolescent Psychiatry, Faculty of Medicine of the TU Dresden, Germany Schubertstrasse 42, D-01309, Dresden, Germany.
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Maung SC, El Sara A, Chapman C, Cohen D, Cukor D. Sleep disorders and chronic kidney disease. World J Nephrol 2016; 5:224-232. [PMID: 27152260 PMCID: PMC4848147 DOI: 10.5527/wjn.v5.i3.224] [Citation(s) in RCA: 93] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2015] [Revised: 11/26/2015] [Accepted: 03/09/2016] [Indexed: 02/06/2023] Open
Abstract
Sleep disorders have a profound and well-documented impact on overall health and quality of life in the general population. In patients with chronic disease, sleep disorders are more prevalent, with an additional morbidity and mortality burden. The complex and dynamic relationship between sleep disorders and chronic kidney disease (CKD) remain relatively little investigated. This article presents an overview of sleep disorders in patients with CKD, with emphasis on relevant pathophysiologic underpinnings and clinical presentations. Evidence-based interventions will be discussed, in the context of individual sleep disorders, namely sleep apnea, insomnia, restless leg syndrome and excessive daytime sleepiness. Limitations of the current knowledge as well as future research directions will be highlighted, with a final discussion of different conceptual frameworks of the relationship between sleep disorders and CKD.
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Liu GJ, Wu L, Wang SL, Ding L, Xu LL, Wang YF, Chang LY. Incidence of Augmentation in Primary Restless Legs Syndrome Patients May Not Be That High: Evidence From A Systematic Review and Meta-Analysis. Medicine (Baltimore) 2016; 95:e2504. [PMID: 26765466 PMCID: PMC4718292 DOI: 10.1097/md.0000000000002504] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
Augmentation is a common complication of primary restless legs syndrome (RLS) during treatment; however, its incidence rate remains unclear.The aim of this study is investigate the rate of augmentation during RLS treatment.We searched 6 databases, including PubMed, OVID, Embase, Wiley citations, Web of Science research platform (including SciELO Citation Index, Medline, KCI Korean Journal Database, the Web of Science™ Core Collection), and the Cochrane library, and screened the reference lists of the included trials and recently published reviews.Randomized controlled trials and observational studies that reported augmentation events during RLS treatment.Primary RLS patients older than 18 years.No restrictions regarding intervention types were applied.Three investigators independently extracted and pooled the data to analyze the augmentation rate of the total sample and of patient subgroups with different interventions, treatment durations and drug regimens and different geographic origins. Fixed-effects or random-effects model was used for pooled analysis.A total of 60 studies involving 11,543 participants suggested an overall augmentation rate of 5.6% (95% confidence intervals (CI), 4.0-7.7). The augmentation incidence was 6.1% (95% CI, 4.1-9.1) for long-term treatment and 3.3% (95% CI, 1.4-7.3) for short-term treatment. In addition, 27.1% (95% CI, 12.3-49.5) of the levodopa-treated patients, 6.0% (95% CI, 4.1-8.8) of the patients treated with dopamine agonists, and 0.9% (95% CI, 0.2-3.3) of the patients taking pregabalin or gabapentin developed augmentation. Augmentation occurred in 7.2% (95% CI, 5.0-10.3) of the patients taking immediate-release drugs and in 1.7% (95% CI, 0.6-5.0) of the patients taking transdermal application.The main limitations are that the augmentation rates were not evaluated according to drug dosage, gender, and age and symptom severity.Approximately 5 to 6 in 100 RLS patients developed augmentation during treatment.
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Affiliation(s)
- Guang Jian Liu
- From the Department of Neurology, Taihe Hospital Affiliated to Hubei University of Medicine, Shiyan City, Hubei Province, China (GJL, SLW, LD, LLX, YFW); Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt University School of Medicine, Nashville, TN (LW); Center for Clinical and Translational Science, Mayo Clinic, Rochester, MN (LW); and Department of Neurology, Xiangyang Center Hospital Affiliated to Hubei University of Arts and Science, Xiangyang City, Hubei Province, China (LYC)
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Zak RS, Walters AS. Dopaminergic Therapy for Restless Legs Syndrome/Willis-Ekbom Disease. Sleep Med Clin 2015; 10:279-85, xiii. [DOI: 10.1016/j.jsmc.2015.05.012] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022]
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Trenkwalder C, Winkelmann J, Inoue Y, Paulus W. Restless legs syndrome-current therapies and management of augmentation. Nat Rev Neurol 2015. [PMID: 26215616 DOI: 10.1038/nrneurol.2015.122] [Citation(s) in RCA: 56] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
Idiopathic restless legs syndrome (RLS) can severely affect quality of life and disturb sleep, so that pharmacological treatment is necessary, especially for elderly patients. Treatment guidelines recommend initiation of therapy with dopamine agonists (pramipexole, ropinirole or the rotigotine transdermal patch, all approved in most countries) or α-2-δ ligands (gabapentin enacarbil, approved in the USA and Japan), depending on the country and availability. Where approved, opioids (prolonged release oxycodone-naloxone, approved in Europe) are also recommended as a second-line therapy for severe RLS. Several iron formulations can be effective but are not yet approved for RLS therapy, whereas benzodiazepines and other anticonvulsants are not recommended or approved. Less is known about effective management of RLS that is associated with other conditions, such as uraemia or pregnancy. Furthermore, very little data are available on the management of RLS when first-line treatment fails or patients experience augmentation. In this Review, we summarize state-of-the-art therapies for RLS in the context of the diagnostic criteria and available guidelines, based on knowledge ranging from Class I evidence for the treatment of idiopathic RLS to Class IV evidence for the treatment of complications such as augmentation. We consider therapies, including combination therapies, that are used in clinical practice for long-term management of RLS, despite a lack of trials and approval, and highlight the need for practical long-term evaluation of current trials.
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Affiliation(s)
- Claudia Trenkwalder
- 1] Paracelsus Elena Klinik, Centre of Parkinsonism and Movement Disorders, Kassel, Klinikstrasse 16, 34128 Kassel, Germany. [2] Department of Neurosurgery, University Medical Centre Göttingen, Robert-Koch-Strasse 40, 37075 Göttingen, Germany
| | - Juliane Winkelmann
- 1] Department of Neurology and Neurological Sciences and Centre for Sleep Sciences and Medicine, Stanford University, 3165 Porter Drive Palo Alto, CA 94304, USA. [2] Neurologische Klinik und Poliklinik, Klinikum rechts der Isar, Technische Universität München, Ismaningerstrasse 22, 81675 Munich, Germany
| | - Yuichi Inoue
- 1] Japan Somnology Center, Neuropsychiatric Research Institute, 1-17-7-301 Yoyogi, Shibuya-ku, Tokyo 151-0053, Japan. [2] Department of Somnology, Tokyo Medical University, Nishi-Shinjuku 6-7-1, Shinjuku-ku, Tokyo 160-0023, Japan
| | - Walter Paulus
- Department of Clinical Neurophysiology, University Medical Centre Göttingen, Robert-Koch-Strasse 40, 37075 Göttingen, Germany
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Huot P. L-DOPA-induced dyskinesia, is striatal dopamine depletion a requisite? J Neurol Sci 2015; 351:9-12. [DOI: 10.1016/j.jns.2015.02.041] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2014] [Revised: 01/04/2015] [Accepted: 02/10/2015] [Indexed: 01/05/2023]
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Wijemanne S, Jankovic J. Restless legs syndrome: clinical presentation diagnosis and treatment. Sleep Med 2015; 16:678-90. [PMID: 25979181 DOI: 10.1016/j.sleep.2015.03.002] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2014] [Revised: 02/28/2015] [Accepted: 03/02/2015] [Indexed: 12/27/2022]
Abstract
Restless legs syndrome (RLS) is a circadian disorder of sensory-motor integration that may be related to genetically determined dysregulation of iron transport across the blood-brain barrier. Dopamine agonists (DAs) have been considered the first-line therapy, but with the growing appreciation of problems associated with long-term treatment, particularly augmentation and impulse control disorder, alpha-2-delta drugs, such as gabapentin, are now considered the first line of treatment in patients with troublesome RLS. Opioids can be considered as an alternative therapy, particularly in patients with DA-related augmentation. In more severe cases, a combination therapy may be required. Intravenous iron therapy may be considered on those patients with refractory RLS.
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Affiliation(s)
- Subhashie Wijemanne
- Parkinson's Disease Center and Movement Disorders Clinic, Baylor College of Medicine, Houston, Texas, USA
| | - Joseph Jankovic
- Parkinson's Disease Center and Movement Disorders Clinic, Baylor College of Medicine, Houston, Texas, USA.
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Ferini-Strambi L, Marelli S. Pharmacotherapy for restless legs syndrome. Expert Opin Pharmacother 2014; 15:1127-38. [DOI: 10.1517/14656566.2014.908850] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
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Garcia-Borreguero D, Kohnen R, Silber MH, Winkelman JW, Earley CJ, Högl B, Manconi M, Montplaisir J, Inoue Y, Allen RP. The long-term treatment of restless legs syndrome/Willis-Ekbom disease: evidence-based guidelines and clinical consensus best practice guidance: a report from the International Restless Legs Syndrome Study Group. Sleep Med 2014; 14:675-84. [PMID: 23859128 DOI: 10.1016/j.sleep.2013.05.016] [Citation(s) in RCA: 200] [Impact Index Per Article: 18.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2013] [Revised: 05/29/2013] [Accepted: 05/31/2013] [Indexed: 12/14/2022]
Abstract
A Task Force was established by the International Restless Legs Syndrome Study Group (IRLSSG) to develop evidence-based and consensus-based recommendations for the long-term pharmacologic treatment of restless legs syndrome/Willis-Ekbom disease (RLS/WED). The Task Force reviewed the results of all studies of RLS/WED treatments with durations of 6 months or longer presented at meetings over the past 2 years, posted on Web sites of pharmaceutical companies, or published in peer-reviewed journals, asking the questions, "What is the efficacy of this treatment in patients with RLS/WED?" and "What is the safety of this treatment in patients with RLS/WED?" The Task Force developed guidelines based on their review of 61 papers meeting inclusion criteria, and using a modified evidence-grading scheme. Pregabalin has been established as effective for up to 1 year in treating RLS/WED (Level A evidence). Pramipexole, ropinirole, and rotigotine have been established as effective for up to 6 months in treating RLS/WED (Level A). The following drugs have been established as probably effective (Level B) in treating RLS/WED for durations ranging from 1 to 5 years: gabapentin enacarbil, pramipexole, and ropinirole (1 year); levodopa (2 years); and rotigotine (5 years). Because of associated safety concerns, pergolide and cabergoline should not be used in the treatment of RLS/WED unless the benefits clearly outweigh the risks. Other pharmacologic therapies have insufficient evidence to support their long-term use in treating RLS/WED. The IRLSSG Task Force also developed consensus-based strategies for the prevention and treatment of complications (such as augmentation, loss of efficacy, excessive daytime sleepiness, and impulse control disorders) that may develop with the long-term pharmacologic treatment of RLS/WED. The use of either a dopamine-receptor agonist or α2δ calcium-channel ligand is recommended as the first-line treatment of RLS/WED for most patients, with the choice of agent dependent on the patient's severity of RLS/WED symptoms, cognitive status, history, and comorbid conditions.
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[Practical guidelines for diagnosis and therapy of restless legs syndrome]. DER NERVENARZT 2014; 85:9-10, 12-4, 16-8. [PMID: 24414246 DOI: 10.1007/s00115-013-3888-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Abstract
Restless legs syndrome (RLS) is the most common neurological sleep disorder affecting 10 % of the Caucasian population. The disorder is characterized by painful sensations in the lower limbs, especially during the evening, at night and during rest, resulting in an urge to move the legs and insomnia. As a result the quality of life is significantly reduced. Dopaminergic agents, opioids and anticonvulsants have proven to be effective for RLS with only the former being currently licensed; however, affected patients have to be identified, which is not always the case, especially in outpatient settings. Possible impediments to the adequate management of patients with RLS may include a lack of awareness, comorbidities and other medical conditions mimicking RLS. To overcome some of these difficulties practical guidelines for the diagnosis and therapy of RLS are provided.
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Abstract
Restless legs syndrome (RLS) is a common disorder diagnosed by the clinical characteristics of restlessness in the legs associated often 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. RLS is the cause of impaired quality of life in those more severely afflicted. Treatment of RLS has undergone considerable change over the last few years. Several classes of medications have demonstrated efficacy, including the dopaminergic agents and the alpha-2-delta ligands. Levodopa was the first dopaminergic agent found to be successful. However, chronic use of levodopa is frequently associated with augmentation that is defined as an earlier occurrence of symptoms frequently associated with worsening severity and sometimes spread to other body areas. The direct dopamine agonists, including ropinirole, pramipexole, and rotigotine patch, are also effective, although side effects, including daytime sleepiness, impulse control disorders, and augmentation, may limit usefulness. The 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. Other agents, including the opioids and clonazepam do not have sufficient evidence to recommend them as treatment for RLS, although in an individual patient, they may provide benefit.
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Affiliation(s)
- Cynthia L Comella
- Movement Disorders Section, Department of Neurological Sciences, Rush Medical College, 1725 West Harrison Street, Suite 755, Chicago, IL, 60612, USA,
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Shi L, Hodges M, Yurgin N, Boye KS. Impact of dose frequency on compliance and health outcomes: a literature review (1966-2006). Expert Rev Pharmacoecon Outcomes Res 2012; 7:187-202. [PMID: 20528445 DOI: 10.1586/14737167.7.2.187] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
In order for treatments to be effective, patients must be compliant with their medication regimens. Currently, patient compliance is seen as one of the most challenging issues in treating patients with chronic diseases. Studies in which dose frequency has been changed have been reviewed across several different diseases to examine the impact of a change in dose frequency on compliance and health outcomes, as well as efficacy and tolerability. In general, reducing dose frequency may improve medication compliance and effectiveness, and reduce adverse events, while possibly reducing healthcare costs. Suggestions for future research have been presented, including a need to measure compliance with injectable formulations and a standardized definition of compliance.
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Affiliation(s)
- Lizheng Shi
- Assistant Professor, Tulane University, Department of Health Systems Management, School of Public Health and Tropical Medicine, 1440 Canal Street, Suite 1900, New Orleans, LA 70112, USA.
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Aurora RN, Kristo DA, Bista SR, Rowley JA, Zak RS, Casey KR, Lamm CI, Tracy SL, Rosenberg RS. The treatment of restless legs syndrome and periodic limb movement disorder in adults--an update for 2012: practice parameters with an evidence-based systematic review and meta-analyses: an American Academy of Sleep Medicine Clinical Practice Guideline. Sleep 2012; 35:1039-62. [PMID: 22851801 PMCID: PMC3397811 DOI: 10.5665/sleep.1988] [Citation(s) in RCA: 89] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
A systematic literature review and meta-analyses (where appropriate) were performed to update the previous AASM practice parameters on the treatments, both dopaminergic and other, of RLS and PLMD. A considerable amount of literature has been published since these previous reviews were performed, necessitating an update of the corresponding practice parameters. Therapies with a STANDARD level of recommendation include pramipexole and ropinirole. Therapies with a GUIDELINE level of recommendation include levodopa with dopa decarboxylase inhibitor, opioids, gabapentin enacarbil, and cabergoline (which has additional caveats for use). Therapies with an OPTION level of recommendation include carbamazepine, gabapentin, pregabalin, clonidine, and for patients with low ferritin levels, iron supplementation. The committee recommends a STANDARD AGAINST the use of pergolide because of the risks of heart valve damage. Therapies for RLS secondary to ESRD, neuropathy, and superficial venous insufficiency are discussed. Lastly, therapies for PLMD are reviewed. However, it should be mentioned that because PLMD therapy typically mimics RLS therapy, the primary focus of this review is therapy for idiopathic RLS.
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Affiliation(s)
- R Nisha Aurora
- Johns Hopkins University, School of Medicine, Baltimore, MD, USA
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de Biase S, Merlino G, Lorenzut S, Valente M, Gigli GL. ADMET considerations for restless leg syndrome drug treatments. Expert Opin Drug Metab Toxicol 2012; 8:1247-61. [PMID: 22808933 DOI: 10.1517/17425255.2012.708023] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
INTRODUCTION Restless legs syndrome (RLS) is a common neurological disorder that might impair nocturnal rest causing decreased alertness, depressed mood, reduced job performance, and poor quality of life. In patients affected by severe RLS, a pharmacological treatment is mandatory. AREAS COVERED The present review is based on a search using PubMed from 1994 to 2012. It is focused on the Absorption, Distribution, Metabolism, Elimination and Toxicology (ADMET) characteristics of the most used medications for RLS. In particular, the ADMET characteristics of dopaminergic agents, anticonvulsants able to improve neuropathic pain, and iron were discussed. EXPERT OPINION Clinical trials have showed that non-ergolic dopamine agonists are efficacious and safe for patients affected by moderate to severe idiopathic RLS. However, no head-to-head study has compared the long-term effects of the three dopamine agonists approved by the FDA for RLS (ropinirole, pramipexole, and rotigotine). Moreover, further studies should investigate the extended-release formulation of ropinirole and pramipexole in RLS patients affected by all day long distressing symptoms. A standardized treatment for symptomatic forms of RLS is lacking. Randomized, placebo-controlled trials should be performed at least in RLS patients with peripheral neuropathic and chronic kidney disease. Concerning RLS due to iron deficiency, a head-to-head study comparing efficacy, safety and compliance of oral iron versus intravenous one seems to be needed.
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Affiliation(s)
- Stefano de Biase
- Department of Neurosciences, Santa Maria della Misericordia University Hospital, Udine, Italy
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Augmentation in the treatment of restless legs syndrome with transdermal rotigotine. Sleep Med 2012; 13:589-97. [PMID: 22503658 DOI: 10.1016/j.sleep.2011.09.016] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2011] [Revised: 08/31/2011] [Accepted: 09/15/2011] [Indexed: 12/27/2022]
Abstract
OBJECTIVE To assess the risk of augmentation under treatment with the transdermally delivered dopamine agonist rotigotine for restless legs syndrome (RLS). METHODS Experts in RLS augmentation retrospectively reviewed data from two double-blind, placebo-controlled 6-month trials (745 rotigotine and 214 placebo subjects, NCT00136045 and NCT00135993) and from two open-label 1-year trials (620 rotigotine subjects, NCT00498108 and NCT00263068). All study visits were systematically evaluated applying the Max Planck Institute (MPI) criteria for the diagnosis of both augmentation and clinically relevant augmentation. RESULTS MPI criteria for augmentation were met on at least one visit by 8.2% of all subjects in the double-blind trials with 12 subjects meeting the criteria for clinically relevant augmentation: 11 under rotigotine (1.5%) and one under placebo treatment. In the open-label trials, 9.7% of all subjects met the MPI criteria for augmentation and 2.9% met the criteria for clinically relevant augmentation. None of the patients treated with rotigotine for up to 1.5 years (double-blind plus open-label trial) discontinued prematurely owing to augmentation. Neither could dose-dependency or a time pattern for clinically relevant augmentation episodes be detected. CONCLUSIONS Our analyses suggest that the risk for clinically relevant augmentation for the duration of up to 18 months of rotigotine treatment is low.
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Earley CJ, Allen RP, Hening W. Restless legs syndrome and periodic leg movements in sleep. HANDBOOK OF CLINICAL NEUROLOGY 2011; 99:913-48. [PMID: 21056236 DOI: 10.1016/b978-0-444-52007-4.00015-1] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
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Trenkwalder C, Paulus W. Restless legs syndrome: pathophysiology, clinical presentation and management. Nat Rev Neurol 2010; 6:337-46. [PMID: 20531433 DOI: 10.1038/nrneurol.2010.55] [Citation(s) in RCA: 205] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
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Progressive development of augmentation during long-term treatment with levodopa in restless legs syndrome: results of a prospective multi-center study. J Neurol 2009; 257:230-7. [PMID: 19756826 PMCID: PMC3085743 DOI: 10.1007/s00415-009-5299-8] [Citation(s) in RCA: 61] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2008] [Revised: 07/29/2009] [Accepted: 08/14/2009] [Indexed: 10/26/2022]
Abstract
The European Restless Legs Syndrome (RLS) Study Group performed the first multi-center, long-term study systematically evaluating RLS augmentation under levodopa treatment. This prospective, open-label 6-month study was conducted in six European countries and included 65 patients (85% treatment naive) with idiopathic RLS. Levodopa was flexibly up-titrated to a maximum dose of 600 mg/day. Presence of augmentation was diagnosed independently by two international experts using established criteria. In addition to the augmentation severity rating scale (ASRS), changes in RLS severity (International RLS severity rating scale (IRLS), clinical global impression (CGI)) were analyzed. Sixty patients provided evaluable data, 35 completed the trial and 25 dropped out. Augmentation occurred in 60% (36/60) of patients, causing 11.7% (7/60) to drop out. Median time to occurrence of augmentation was 71 days. The mean maximum dose of levodopa was 311 mg/day (SD: 105). Patients with augmentation compared to those without were significantly more likely to be on higher doses of levodopa (> or =300 mg, 83 vs. 54%, P = 0.03) and to show less improvement of symptom severity (IRLS, P = 0.039). Augmentation was common with levodopa, but could be tolerated by most patients during this 6-month trial. Patients should be followed over longer periods to determine if dropout rates increase with time.
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Nelles S, Köberlein J, Grimm C, Pittrow D, Kirch W, Rychlik R. [Socioeconomic relevance of the idiopathic restless legs syndrome (RLS) in Germany: cost-of-illness study]. ACTA ACUST UNITED AC 2009; 104:363-71. [PMID: 19444417 DOI: 10.1007/s00063-009-1075-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2008] [Accepted: 02/16/2009] [Indexed: 10/20/2022]
Abstract
BACKGROUND AND PURPOSE 1.3% of German adults suffer from clinically relevant restless legs syndrome (RLS). A cost-of-illness study was conducted to evaluate the costs for diagnosis and therapy of the idiopathic RLS. METHODS A clinical pathway based on expert guidelines was developed. The costs for the 1st year of treatment in idiopathic RLS were calculated with the Markov Model. Relevant published clinical study data were used for the model as well as questioning of physicians. RESULTS Costs per patient with approved drug treatment are 989.80 Euro for sickness funds and 1,285.26 Euro from the societal perspective. Drug costs are the main cost components for sickness funds and the society with 69% and 61%, respectively. Less than half of the patients continue an L-dopa therapy longer than 1 year. About one quarter of all RLS patients need off-label therapy after the 1st year of treatment. CONCLUSION The costs for a guideline-oriented therapy for all patients with clinically relevant RLS in Germany are about 1,135 billion Euro, representing 0.5% of all health-related costs in Germany. Further controlled clinical trials are required to provide evidence for the efficacy of different treatment options including drugs without an approval for RLS and long-term use. Health services research is required for cost-utility analysis, to evaluate the costs of inadequate treatment, and to obtain additional information to improve the resource allocation in RLS treatment.
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Affiliation(s)
- Sandra Nelles
- Institut für Empirische Gesundheitsökonomie, Burscheid, Germany.
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Frauscher B, Gschliesser V, Brandauer E, El-Demerdash E, Kaneider M, Rücker L, Poewe W, Högl B. The severity range of restless legs syndrome (RLS) and augmentation in a prospective patient cohort: association with ferritin levels. Sleep Med 2009; 10:611-5. [PMID: 19200780 DOI: 10.1016/j.sleep.2008.09.007] [Citation(s) in RCA: 76] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/13/2008] [Revised: 09/11/2008] [Accepted: 09/12/2008] [Indexed: 11/30/2022]
Abstract
OBJECTIVES The aim of the study was to prospectively examine all patients with a diagnosis of RLS consulting a sleep disorders clinic and to assess RLS severity and augmentation and their associations, including ferritin levels. METHODS Patients were stratified into patients with RLS as ancillary diagnosis, RLS sufferers without current augmentation and RLS sufferers with current augmentation. Work-up included RLS severity scales and blood biochemical variables including indices of iron metabolism. RESULTS In an 18-month period, 302 patients with RLS (183 women, 119 men; mean age, 59.1+/-13.7 years) were recruited. RLS was considered idiopathic in 291 patients (96.4%). Most patients (240, 79.5%) were RLS sufferers, whereas the remaining 62 (20.5%) had RLS as ancillary diagnosis. Nineteen out of 162 patients treated with dopaminergic agents (11.7%) had current augmentation. Almost one-third of all patients (31.1%) had ferritin levels <50microg/l. Patients with an ancillary diagnosis of RLS had higher ferritin levels than RLS sufferers without current augmentation. The lowest ferritin levels were present in RLS sufferers with current augmentation 132.8+/-98.0microg/l vs. 100.6+/-84.5microg/l vs. 55.8+/-43.6microg/l; p=0.002). Patients with augmentation did not differ from non-augmented patients regarding age, gender, RLS etiology, presence of previous augmentation, or any other documented comorbidity (p>0.05). CONCLUSION The severity spectrum of RLS in this clinical cohort ranged from the ancillary diagnosis of RLS to augmented RLS. There was an inverse correlation between RLS severity and ferritin levels. Patients with current augmentation had the lowest ferritin levels. Our data further strengthen a putative role of low iron stores as a potential aggravator of idiopathic RLS. Moreover, low ferritin might represent a potential biomarker of RLS augmentation under dopaminergic therapy.
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Affiliation(s)
- Birgit Frauscher
- Department of Neurology, Innsbruck Medical University, Anichstrasse 35, A-6020 Innsbruck, Austria
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Abstract
Restless legs syndrome (RLS) is clinically defined by the presence of (i) an urge to move the legs with or without an actual paraesthesia; (ii) a worsening of symptoms with inactivity; (iii) improvement with activity; and (iv) a worsening of symptoms in the evening and at night. Patients may use a variety of semantic phrases to describe their symptoms but all must have an urge to move. Most people with RLS also have periodic limb movements during sleep, although this is not part of the clinical diagnostic criteria. RLS is very common. About 10% of all Caucasian populations have RLS, although it may be mild in the majority of cases. Women generally outnumber men by about 2:1. As a general rule, RLS severity worsens through the first seven to eight decades of life, but may actually lessen in old age. The aetiology of RLS is only partly understood. There is a strong genetic component, and several genetic linkages and three causative genes have been identified worldwide. Several medical conditions, including renal failure, systemic iron deficiency and pregnancy, and possibly neuropathy, essential tremor and some genetic ataxias, are also associated with high rates of RLS. In all cases to date, the actual CNS pathology of RLS demonstrates reduced iron stores, in a pattern that suggests that the homeostatic control of iron is altered, not just that there is not enough iron entering the brain. The relationship between reduced CNS iron levels and the clinical phenotype or treatment response to dopaminergics is not known but generates promising speculation. Treatment of RLS is usually rewarding. Most patients respond robustly to dopamine receptor agonists. Over time, response may lessen, or the patients may develop 'augmentation', whereby they have a worsening of symptoms, usually in the form of an earlier onset. Other treatment options include gabapentin, or similar antiepileptic drugs, and opioids. High-dose intravenous iron is a promising but still experimental approach.
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Affiliation(s)
- Pankaj Satija
- Department of Neurology, Baylor College of Medicine, Houston, Texas 77030, USA
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Oertel WH, Benes H, Garcia-Borreguero D, Geisler P, Högl B, Trenkwalder C, Tacken I, Schollmayer E, Kohnen R, Stiasny-Kolster K. One year open-label safety and efficacy trial with rotigotine transdermal patch in moderate to severe idiopathic restless legs syndrome. Sleep Med 2008; 9:865-73. [PMID: 18753003 DOI: 10.1016/j.sleep.2008.04.012] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2007] [Revised: 03/28/2008] [Accepted: 04/03/2008] [Indexed: 10/21/2022]
Abstract
BACKGROUND Long-term efficacy and tolerability data are not yet available for patch formulations of dopamine agonists in restless legs syndrome. METHODS Efficacy and safety of rotigotine (0.5-4mg/24h), formulated as a once-daily transdermal system (patch), were investigated in an open extension (SP710) of a preceding 6-week placebo-controlled trial (SP709, 341 randomized patients) in patients with idiopathic restless legs syndrome. For efficacy assessment the international RLS severity scale (IRLS), the RLS-6 scales, the clinical global impressions (CGI) and the QoL-RLS questionnaire were administered. In addition, long-term tolerability and safety were assessed. RESULTS Of 310 patients who finished the controlled trial, 295 (mean age 58+/-10 years, 66% females) with a mean IRLS score of 27.8+/-5.9 at baseline of SP709 were included. We report results after one year of this ongoing long-term trial. Two hundred twenty patients (retention rate=74.6%) completed the 12-month follow-up period. The mean daily dose was 2.8+/-1.2mg/24h with 4mg/24h (40.6%) being the most frequently applied dose; 14.8% were sufficiently treated with 0.5 or 1.0mg/24h. The IRLS total score improved by ?17.4+/-9.9 points between baseline and end of Year 1 (p<0.001). The other measures of severity, sleep satisfaction and quality of life supported the efficacy of rotigotine (p<0.001 for pre-post-comparisons of all efficacy variables). The tolerability was described as "good" or "very good" by 80.3% of all patients. The most common adverse events were application site reactions (40.0%), which led to withdrawal in 13.2%. Further relatively frequent adverse events were nausea (9.5%) and fatigue (6.4%). Two drug-related serious adverse events, nausea and syncope, required hospitalization. Symptoms of augmentation were not reported by the patients. CONCLUSION Rotigotine provided a stable, clinically relevant improvement in all efficacy measures throughout one year of maintenance therapy. The transdermal patch was safe and generally well tolerated by the majority of patients. Comparable to any transdermal therapy, application site reactions were the main treatment complication.
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Abstract
Restless legs syndrome (RLS) is a chronic neurologic disorder, with a prevalence rate in the general population of 5% to 10%. The diagnosis of RLS is straightforward; it is based on symptom history alone and uses the four essential diagnostic criteria for RLS. Owing to the heterogeneity of the disorder, the sensory and motor symptoms of RLS are often attributed to other disorders, and many patients remain undiagnosed and untreated. The symptoms of RLS are thought to result from a central dopaminergic dysfunction. Dopamine agonists are considered first-line treatment for moderate-to-severe primary RLS, although other nondopaminergic therapies are sometimes used to ease the symptoms of RLS. This article will guide primary care and internal medicine specialists through the diagnosis and management options of primary RLS.
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Trenkwalder C, Kohnen R, Allen RP, Benes H, Ferini-Strambi L, Garcia-Borreguero D, Hadjigeorgiou GM, Happe S, Högl B, Hornyak M, Klein C, Nass A, Montagna P, Oertel WH, O'Keeffe S, Paulus W, Poewe W, Provini F, Pramstaller PP, Sieminski M, Sonka K, Stiasny-Kolster K, de Weerd A, Wetter TC, Winkelmann J, Zucconi M. Clinical trials in restless legs syndrome--recommendations of the European RLS Study Group (EURLSSG). Mov Disord 2008; 22 Suppl 18:S495-504. [PMID: 17530666 DOI: 10.1002/mds.21538] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
The European Restless Legs Syndrome (RLS) Study Group (EURLSSG) is an association of European RLS experts who are actively involved in RLS research. A major aim of the Study Group is the development and continuous improvement of standards for diagnosis and treatment of RLS. Several members developed study designs and evaluation methods in investigator-initiated trials early in the 1990s, and all members have since contributed to many pivotal and nonpivotal drug trials for the treatment of RLS. The recommendations on clinical investigations of pharmacological treatment of RLS patients summarize the group's expertise and knowledge acquired through clinical trials. The recommendations primarily address how to plan and conduct confirmatory, randomized clinical studies in patients with idiopathic RLS. Advice is presented for the diagnosis of RLS and clinical and polysomnographic inclusion and exclusion criteria. Primary and secondary endpoints for an evaluation of efficacy are based on a critical description of validated methods for both short- and long-term trials, also in special populations (children, pregnant women, elderly patients). The recommendations include the assessment of augmentation. Finally, general issues including the evaluation of safety and tolerability, as well as specific neurological and cardiovascular risks and sleep attacks/daytime somnolence, are discussed. The aim of these recommendations is to support research groups or pharmaceutical companies in the design of optimized study protocols.
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Affiliation(s)
- Claudia Trenkwalder
- Paracelsus-Elena Hospital, Center of Parkinsonism and Movement Disorders, Klinikstr. 16, 34128 Kassel, Germany.
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Polo O, Ylä-Sahra R, Hirvonen K, Karvinen J, Vahteristo M, Ellmén J. Entacapone prolongs the reduction of PLM by levodopa/carbidopa in restless legs syndrome. Clin Neuropharmacol 2007; 30:335-44. [PMID: 18090458 DOI: 10.1097/wnf.0b013e31805930c2] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
OBJECTIVES Levodopa is effective in the treatment of restless legs syndrome (RLS). However, due to the short duration of action of conventional levodopa/decarboxylase inhibitor formulations, multiple dosing may be required in individual patients with persisting symptoms. We assessed whether a new levodopa formulation containing levodopa, carbidopa, and entacapone (LCE) improves levodopa action in RLS. METHODS Twenty-eight RLS patients with periodic limb movement (PLM) received single doses of Stalevo 50 (LCE50; 50/12.5/200 mg), Stalevo 100 (LCE100; 100/25/200 mg), Stalevo 150 (LCE150; 150/37.5/200 mg), Sinemet 100 (LC100; 100/25 mg), or placebo in a randomized, double-blind, crossover study with polysomnography. Periodic limb movements per hour (PLM/h) during total sleep time and PLM during total time in bed were the primary and secondary variables, respectively. RESULTS Mean PLM/h during total sleep time after Stalevo 50 (12.6/h, P < 0.05), LCE100, LCE150, and LC100 (6.4/h, 3.5/h and 9.5/h, respectively; P < 0.01) were significantly reduced compared with placebo (25.7/h). Improvement was also observed in PLM/h during total time in bed for all treatments (P < 0.01) and a significant dose response observed between LCE doses (P < 0.05). Compared with LC100, LCE100 and LCE150 reduced PLMs during the second half (P = 0.06 and P < 0.001, respectively) or during the last 3 early morning hours (hours 5-7 from the start of recording) of the night (P < 0.05 and P < 0.01, respectively). All formulations were well tolerated. CONCLUSIONS Single doses of LCE tablets decreased PLMs in a dose-related manner in RLS patients. Prolonged effects of levodopa on PLMs suggest that, compared with standard levodopa, this new levodopa formulation provides longer symptom control throughout the night in patients with previously untreated RLS.
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Affiliation(s)
- Olli Polo
- Sleep Research Unit, Department of Physiology, University of Turku and Tampere University Hospital, Finland
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Conti CF, de Oliveira MM, Andriolo RB, Saconato H, Atallah AN, Valbuza JS, Coin de Carvalho LB, do Prado GF. Levodopa for idiopathic restless legs syndrome: Evidence-based review. Mov Disord 2007; 22:1943-51. [PMID: 17659645 DOI: 10.1002/mds.21662] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Abstract
Restless legs syndrome (RLS) is a sensory motor disorder characterized by a distressing urge to move the legs and sometimes also other parts of the body usually accompanied by a marked sense of discomfort or pain in the leg or other affected body part. The prevalence of RLS is estimated at 2.7 to 5% of adults and it is more common in women. The treatment of RLS with levodopa has been reported thus a systematic synthesis of evidence is necessary to evaluate the effectiveness and safety of levodopa for RLS. Systematic review of randomized or quasi-randomized, double blind trials on levodopa. Relief of restless legs symptoms marked on a validated scale, subjective sleep quality, sleep quality measured by night polysomnography and actigraphy, quality of life measured by subjective measures, adverse events associated with the treatments. Nine eligible clinical trials were included. The subjective analyses of these studies showed contradictory results, although the objective analyses showed that treatment group had a statistically significant improvement of periodic leg movement (PLM) index, favoring the treatment group. The most commonly adverse event seen was gastrointestinal symptoms. The short-term treatment with levodopa was demonstrated effective and safety for PLM, but there was only few trials assessing long-term treatment and the augmentation phenomenon in RLS. Further long-term randomized controlled trials using standard follow-up measurements as the International RLS Study Group Rating Scale are necessary.
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Affiliation(s)
- Cristiane Fiquene Conti
- Department of Emergency Medicine and Evidence Based Medicine, Federal University of Sao Paulo (UNIFESP), Sao Paulo, Brazil
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García-Borreguero D, Kohnen R, Högl B, Ferini-Strambi L, Hadjigeorgiou GM, Hornyak M, de Weerd AW, Happe S, Stiasny-Kolster K, Gschliesser V, Egatz R, Cabrero B, Frauscher B, Trenkwalder C, Hening WA, Allen RP. Validation of the Augmentation Severity Rating Scale (ASRS): A multicentric, prospective study with levodopa on restless legs syndrome. Sleep Med 2007; 8:455-63. [PMID: 17543579 DOI: 10.1016/j.sleep.2007.03.023] [Citation(s) in RCA: 90] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2007] [Revised: 03/06/2007] [Accepted: 03/17/2007] [Indexed: 11/19/2022]
Abstract
BACKGROUND Augmentation is the main complication during long-term dopaminergic treatment of restless legs syndrome (RLS) and reflects an overall increase in RLS severity. Its severity varies considerably from a minor problem to a devastating exacerbation of disease. Despite its clinical relevance, systematic evaluations have rarely been undertaken and there has been no development of methods to assess the severity of augmentation. To fill this gap, the European RLS Study Group (EURLSSG) has developed the Augmentation Severity Rating Scale (ASRS), using three items that assess the degree of change in three specific dimensions of augmentation. The changes in each dimension are summed to give an ASRS total score. METHODS The ASRS was developed to cover the basic dimensions defining RLS augmentation. The items were developed by an interactive process involving professional and patient input. The ASRS that was evaluated included four major items and two alternative forms of one item. The validation was conducted using 63 (85%) mostly untreated RLS patients from six centers, who were treated for six months with levodopa (L-Dopa) (up to 500 mg/day, as clinically needed). Two consecutive assessments before and at baseline measured test-retest reliability. Consecutive ASRS ratings by two independent raters on a subsample of patients evaluated inter-rater reliability. Comparison with clinical severity ratings of two independent experts provided external validation of the ASRS. Comparison of patients with and without augmentation with regard to the items and the total score of the ASRS added discriminant validity. RESULTS Sixty patients (63% females, mean age: 53 years, baseline International RLS Severity Rating (IRLS) score 24.7+/-5.2) were treated with a median daily dose of 300 mg L-Dopa (range: 50-500 mg). Thirty-six patients (60%) experienced augmentation. Item analyses indicated that one item could be removed as it did not contribute significantly to the test score and only one form of the duplicated item needed to be used. The final ASRS then included three items. Test-retest reliability for the total score was rho=0.72, and inter-rater reliability was rcc=0.94. Cronbach's alpha was 0.62. Validity as assessed by the correlation between the worst ASRS total score during the trial and the expert rating was rho=0.72. ASRS total score differed between patients without versus with augmentation (mean: 7.4 (standard deviation (SD)=4.0) vs. 2.0 (2.7) (P<0.0001). CONCLUSIONS The ASRS is a reliable and valid scale to measure the severity of augmentation. Due to the need to systematically quantify augmentation for both long-term efficacy and tolerability, the ASRS may become a useful tool to monitor augmentation in future clinical trials.
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García-Borreguero D, Allen RP, Kohnen R, Högl B, Trenkwalder C, Oertel W, Hening WA, Paulus W, Rye D, Walters A, Winkelmann J, Earley CJ. Diagnostic standards for dopaminergic augmentation of restless legs syndrome: report from a World Association of Sleep Medicine-International Restless Legs Syndrome Study Group consensus conference at the Max Planck Institute. Sleep Med 2007; 8:520-30. [PMID: 17544323 DOI: 10.1016/j.sleep.2007.03.022] [Citation(s) in RCA: 186] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2007] [Revised: 03/06/2007] [Accepted: 03/17/2007] [Indexed: 12/14/2022]
Abstract
OBJECTIVES Augmentation of symptom severity is the main complication of dopaminergic treatment of restless legs syndrome (RLS). The current article reports on the considerations of augmentation that were made during a European Restless Legs Syndrome Study Group (EURLSSG)-sponsored Consensus Conference in April 2006 at the Max Planck Institute (MPI) in Munich, Germany, the conclusions of which were endorsed by the International RLS Study Group (IRLSSG) and the World Association of Sleep Medicine (WASM). The Consensus Conference sought to develop a better understanding of augmentation and generate a better operational definition for its clinical identification. DESIGN AND METHODS Current concepts of the pathophysiology, clinical features, and therapy of RLS augmentation were evaluated by subgroups who presented a summary of their findings for general consideration and discussion. Recent data indicating sensitivity and specificity of augmentation features for identification of augmentation were also evaluated. The diagnostic criteria of augmentation developed at the National Institutes of Health (NIH) conference in 2002 were reviewed in light of current data and theoretical understanding of augmentation. The diagnostic value and criteria for each of the accepted features of augmentation were considered by the group. A consensus was then developed for a revised statement of the diagnostic criteria for augmentation. RESULTS Five major diagnostic features of augmentation were identified: usual time of RLS symptom onset each day, number of body parts with RLS symptoms, latency to symptoms at rest, severity of the symptoms when they occur, and effects of dopaminergic medication on symptoms. The quantitative data available relating the time of RLS onset and the presence of other features indicated optimal augmentation criteria of either a 4-h advance in usual starting time for RLS symptoms or a combination of the occurrence of other features. A paradoxical response to changes in medication dose also indicates augmentation. Clinical significance of augmentation is defined. CONCLUSION The Consensus Conference agreed upon new operational criteria for the clinical diagnosis of RLS augmentation: the MPI diagnostic criteria for augmentation. Areas needing further consideration for validating these criteria and for understanding the underlying biology of RLS augmentation are indicated.
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Paulus W, Dowling P, Rijsman R, Stiasny-Kolster K, Trenkwalder C, de Weerd A. Pathophysiological concepts of restless legs syndrome. Mov Disord 2007; 22:1451-1456. [PMID: 17516488 DOI: 10.1002/mds.21533] [Citation(s) in RCA: 71] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Pathophysiological concepts of restless legs syndrome (RLS) are based mainly on neuroimaging and on neurophysiological data. Furthermore treatment effects contribute essentially to the present understanding of the disease, unless the genetic progress expected in the near future will clarify substantially open issues. The concept agreed on assumes a dysfunction of the dopaminergic system, possibly on the level of striatal and/or spinal dopamine receptors, and the A11 neuron group localized in the hypothalamus as an integrated part of the system. These neurons modulate spinal excitability, alterations of which in turn affect sensory processing predominantly of leg afferents in brain stem structures. Neurophysiologically excitability alterations can be measured by a variety of methods such as determination of pain thresholds, H-reflex testing, and quantitative sensory testing.
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Affiliation(s)
- Walter Paulus
- Department of Clinical Neurophysiology, University of Göttingen, Göttingen, Germany
| | - Pascal Dowling
- Department of Clinical Neurophysiology, University of Göttingen, Göttingen, Germany
| | - Roselyne Rijsman
- Department of Clinical Neurophysiology and Sleepcenter. MCHaaglanden, Westeinde Hospital, The Hague, The Netherlands
| | | | - Claudia Trenkwalder
- Paracelsus Elena Klinik, Centre of Parkinsonism and Movement Disorders, Kassel, Germany
| | - Al de Weerd
- Sleepcenter and Department of Clinical Neurophysiology, SEIN Zwolle, Zwolle, The Netherlands
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García-Borreguero D, Allen RP, Benes H, Earley C, Happe S, Högl B, Kohnen R, Paulus W, Rye D, Winkelmann J. Augmentation as a treatment complication of restless legs syndrome: Concept and management. Mov Disord 2007; 22 Suppl 18:S476-84. [PMID: 17580331 DOI: 10.1002/mds.21610] [Citation(s) in RCA: 69] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Abstract
Augmentation constitutes the main complication of long-term dopaminergic treatment in restless legs syndrome (RLS). Although this condition was first described in 1996, and is characterized by an overall increase in severity of RLS symptoms (including earlier onset of symptoms during the day, faster onset of symptoms when at rest, expansion to the upper limbs and trunk, and shorter duration of the treatment effect), precise diagnostic criteria were not established until 2003. These criteria have recently been updated to form a new definition of augmentation based on multicentric studies. The present article reviews our current knowledge on clinical diagnosis, evaluation, pathophysiology, and treatment recommendations for this condition.
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Trenkwalder C, Benes H, Grote L, Happe S, Högl B, Mathis J, Saletu-Zyhlarz GM, Kohnen R. Cabergoline compared to levodopa in the treatment of patients with severe restless legs syndrome: Results from a multi-center, randomized, active controlled trial. Mov Disord 2007; 22:696-703. [PMID: 17274039 DOI: 10.1002/mds.21401] [Citation(s) in RCA: 84] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022] Open
Abstract
We report the first large-scale double-blind, randomly assigned study to compare two active dopaminergic therapies for Restless Legs Syndrome (RLS), the dopamine agonist cabergoline (CAB) and levodopa/benserazide (levodopa). Patients with idiopathic RLS were treated with fixed daily doses of 2 or 3 mg CAB or 200 or 300 mg levodopa for 30 weeks. Efficacy was assessed by changes in the IRLS (International RLS Severity Scale) and by time to discontinuation of treatment due to loss of efficacy or augmentation. 361 of 418 screened patients (age 58 +/- 12 years, 71% females) were randomly assigned and treated (CAB: n = 178; levodopa: n = 183) in 51 centers of four European countries. Baseline IRLS total score was 25.7 +/- 6.8. The baseline-adjusted mean change from baseline to week 6 in IRLS sum score was d = -16.1 in the CAB group and d = -9.5 in the levodopa group (d = -6.6, P < 0.0001). More patients in the levodopa group (24.0%) than in the CAB group (11.9%, P = 0.0029, log-rank test) discontinued because of loss of efficacy (14.2% vs. 7.9%, P = 0.0290) or augmentation (9.8% vs. 4.0%, P = 0.0412). Adverse events (AEs) occurred in 83.1% of the CAB group and in 77.6% of the levodopa group. In both groups, most frequent AEs were gastrointestinal symptoms (CAB: 55.6%, levodopa: 30.6%, P < 0.0001). This first large-scale active controlled study in RLS showed superior efficacy of cabergoline versus levodopa after a 30-week long-term therapy. Tolerability was found more favorable with levodopa than with cabergoline.
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Vignatelli L, Billiard M, Clarenbach P, Garcia-Borreguero D, Kaynak D, Liesiene V, Trenkwalder C, Montagna P. EFNS guidelines on management of restless legs syndrome and periodic limb movement disorder in sleep. Eur J Neurol 2006; 13:1049-65. [PMID: 16987157 DOI: 10.1111/j.1468-1331.2006.01410.x] [Citation(s) in RCA: 114] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
In 2003, the EFNS Task Force was set up for putting forth guidelines for the management of the Restless Legs Syndrome (RLS) and the Periodic Limb Movement Disorder (PLMD). After determining the objectives for management and the search strategy for primary and secondary RLS and for PLMD, a review of the scientific literature up to 2004 was performed for the drug classes and interventions employed in treatment (drugs acting on the adrenoreceptor, antiepileptic drugs, benzodiazepines/hypnotics, dopaminergic agents, opioids, other treatments). Previous guidelines were consulted. All trials were analysed according to class of evidence, and recommendations formed according to the 2004 EFNS criteria for rating. Dopaminergic agents came out as having the best evidence for efficacy in primary RLS. Reported adverse events were usually mild and reversible; augmentation was a feature with dopaminergic agents. No controlled trials were available for RLS in children and for RLS during pregnancy. The following level A recommendations can be offered: for primary RLS, cabergoline, gabapentin, pergolide, ropinirole, levodopa and rotigotine by transdermal delivery (the latter two for short-term use) are effective in relieving the symptoms. Transdermal oestradiol is ineffective for PLMD.
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Affiliation(s)
- L Vignatelli
- Department of Neurological Sciences, University of Bologna Medical School, Bologna, Italy
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Paulus W, Trenkwalder C. Less is more: pathophysiology of dopaminergic-therapy-related augmentation in restless legs syndrome. Lancet Neurol 2006; 5:878-86. [PMID: 16987735 DOI: 10.1016/s1474-4422(06)70576-2] [Citation(s) in RCA: 108] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Therapy-related augmentation of the symptoms of restless legs syndrome (RLS) is an important clinical problem reported in up to 60% of patients treated with levodopa and, to a lesser extent, with dopamine agonists. The efficacy of low-dose dopaminergic drugs for RLS has been established, but the mode of action is unknown. Here, we review the existing data and conclude that augmentation is a syndrome characterised by a severely increased dopamine concentration in the CNS; overstimulation of the dopamine D1 receptors compared with D2 receptors in the spinal cord may lead to D1-related pain and generate periodic limb movements; iron deficiency may be a main predisposing factor of augmentation, probably caused by a reduced function of the dopamine transporter; therapy with levodopa or dopamine agonists should remain at low doses and; iron supplementation and opiates are the therapy of choice to counter augmentation.
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Affiliation(s)
- Walter Paulus
- Department of Clinical Neurophysiology, University of Göttingen, Göttingen, Germany.
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Paulus W, Schomburg ED. Dopamine and the spinal cord in restless legs syndrome: Does spinal cord physiology reveal a basis for augmentation? Sleep Med Rev 2006; 10:185-96. [PMID: 16762808 DOI: 10.1016/j.smrv.2006.01.004] [Citation(s) in RCA: 51] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
The pathophysiology of restless legs syndrome (RLS) is incompletely understood. L-DOPA, as the precursor of dopamine, as well as dopamine agonists, plays an essential role in the treatment of RLS leading to the assumption of a key role of dopamine function in the pathophysiology of RLS. Periodic limb movements in sleep are a key feature of RLS. They are generated in the spinal cord. Here we review RLS phenomenology on the basis of known dopaminergic influence on spinal control, which has been studied a great deal in recent decades in animals. In particular, we propose that the differential effects of l-DOPA and opioids on early and late flexor reflexes may be linked to the phenomenon of augmentation.
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Affiliation(s)
- Walter Paulus
- Department of Clinical Neurophysiology, University of Göttingen, Robert Koch Str. 40, 37075 Göttingen, Germany.
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Abstract
Restless legs syndrome (RLS) is characterised by an urge to move the legs, uncomfortable sensations in the legs and worsening of these symptoms during rest with at least temporary relief brought on by activity. RLS occurs in 3-15% of the general population and in 10-30% of patients on maintenance dialysis. RLS may lead to severe sleep onset or maintenance insomnia, and greatly impaired quality of life. Current recommendations suggest dopaminergic therapy (levodopa or dopamine receptor agonists: pramipexol, ropinirole, pergolide or cabergoline) as the first-line treatment for RLS. This group of medications is effective in reducing RLS symptoms in the general population; limited information is available on the effect of these drugs in patients with renal failure. However, it must be noted that most published studies in uraemic patients had short treatment periods and insufficient statistical power because of small sample size. Frequent adverse effects of levodopa, seen mainly with continuous use, may limit its use significantly. Rebound and augmentation, problems relatively frequently seen with levodopa, seem to be less prevalent with the use of dopamine receptor agonists, although properly designed comparative trials are still needed to address this question. Alternative treatment options for RLS are gabapentin, benzodiazepines and opioids. For all of these medications, there are only very limited data available on their effectiveness and safety profile in patients on maintenance dialysis. Referral to a specialist for RLS management should be considered for patients with refractory RLS.
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Affiliation(s)
- Miklos Z Molnar
- Institute of Behavioral Sciences, and 1st Department of Internal Medicine, Semmelweis University, Budapest, Hungary
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Bogan RK, Fry JM, Schmidt MH, Carson SW, Ritchie SY. Ropinirole in the treatment of patients with restless legs syndrome: a US-based randomized, double-blind, placebo-controlled clinical trial. Mayo Clin Proc 2006; 81:17-27. [PMID: 16438474 DOI: 10.4065/81.1.17] [Citation(s) in RCA: 122] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
OBJECTIVE To assess the efficacy, safety, and tolerability of the dopamine agonist ropinirole in the treatment of patients with moderate to severe primary restless legs syndrome (RLS). PATIENTS AND METHODS This multicenter, 12-week, double-blind, placebo-controlled, flexible-dose study enrolled US patients and was conducted between September 2003 and May 2004. Patients were randomized to ropinirole or placebo, 0.25-4.0 mg as needed and tolerated, once daily, 1 to 3 hours before bedtime. The primary end point was mean change from baseline to week 12 in International Restless Legs Scale (IRLS) total score. Key secondary efficacy measures included the Clinical Global Impression-Improvement scale. RESULTS A total of 381 patients were enrolled; 164 (87.7%) of 187 patients randomized to ropinirole and 167 (86.1%) of 194 randomized to placebo completed the study. Significant treatment differences favoring ropinirole, compared with placebo, were observed for change in IRLS total score at week 12 (adjusted mean treatment difference, -3.7; 95% confidence interval, -5.4 to -2.0; P < .001) and for all 3 key secondary end points: mean change from baseline in IRLS total score at week 1 and proportion of patients who were much/very much improved on the Clinical Global Impression Improvement scale at weeks 1 and 12. Ropinirole was associated with significantly greater Improvements in subjective measures of sleep disturbance, quantity, and adequacy; quality of life; and anxiety. Although treatment differences favoring ropinirole in daytime somnolence were observed, they were not statistically significant (P = .10). Ropinirole was generally well tolerated, with an adverse-event profile consistent with other dopamine agonists. CONCLUSION This study confirms that ropinirole improves RLS symptoms and subjective measures of sleep, quality of life, and anxiety and that it is generally well tolerated.
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Affiliation(s)
- Richard K Bogan
- SleepMed of South Carolina, 1333 Taylor St, Columbia, SC 29201, USA.
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Abstract
The restless legs syndrome is a common disorder that encompasses an idiopathic form of genetic or unknown origin and symptomatic forms associated with many causes. Symptomatic forms occur during pregnancy and are coincident with uraemia, iron depletion, polyneuropathy, spinal disorders, and rheumatoid arthritis. For the hereditary forms, at least three gene loci, located on chromosomes 12, 14, and 9, have been traced so far. Prevalence in the general population is between 3% and 9%, increases with age, and is higher in women than in men. Treatment is needed only in the moderate to severe forms of the disorder and mostly in elderly people. Pathophysiology and treatment may be closely linked to the dopaminergic system and iron metabolism. Dopaminergic treatment with levodopa and dopamine agonists is the first choice in idiopathic restless legs syndrome, but augmentation and rebound should be monitored in long-term treatment. Various other drugs, such as opioids, gabapentin, and benzodiazepines, provide alternative treatment possibilities.
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Affiliation(s)
- Claudia Trenkwalder
- Paracelsus Elena Klinik, Centre of Parkinsonism and Movement Disorders, Kassel, Germany.
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Rijsman RM, Stam CJ, de Weerd AW. Abnormal H-reflexes in periodic limb movement disorder; impact on understanding the pathophysiology of the disorder. Clin Neurophysiol 2005; 116:204-10. [PMID: 15589198 DOI: 10.1016/j.clinph.2004.07.022] [Citation(s) in RCA: 45] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/19/2004] [Indexed: 11/21/2022]
Abstract
OBJECTIVE To get more insight in the pathophysiological basis of periodic limb movement disorder (PLMD) with or without restless legs syndrome (RLS), we investigated whether these patients have spontaneous changes in H-reflexes or show altered reflex patterns after (external) inhibition or excitation of the relevant spinal segment. METHODS The ratio of the peak-to-peak values of the maximal soleus H-reflex and the maximal direct muscle potential (H/M ratio), H-reflex recruitment curves, vibratory inhibition and recovery curves of the soleus H-reflex in double stimulus experiments were measured in 9 PLMD patients and 11 controls. RESULTS In comparison to controls the vibratory inhibition, predominantly reflecting pre-synaptic inhibitory action, was depressed in PLMD patients. The soleus H-reflex recovery curves showed increased late facilitation and depressed late inhibition, both reflecting diminished inhibition due to post-synaptic central activity. CONCLUSIONS Our data indicate diminished inhibition at spinal level in PLMD patients. This is probably due to altered function of the descending spinal tracts, peripheral influence or changes at the inter-neural circuitry at spinal level itself, or combinations of these 3 possibilities. SIGNIFICANCE The results of this study give further insight in the pathophysiology of PLMD and RLS by stressing the importance of diminished central inhibition.
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Affiliation(s)
- R M Rijsman
- Department of Clinical Neurophysiology, Centre for Sleep and Wake Disorders, MCH-Westeinde Hospital, Lijnbaan 32, Post Box 432, 2501 CK The Hague, The Netherlands.
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Clavadetscher SC, Gugger M, Bassetti CL. Restless legs syndrome: clinical experience with long-term treatment. Sleep Med 2004; 5:495-500. [PMID: 15341896 DOI: 10.1016/j.sleep.2004.05.006] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2003] [Revised: 05/11/2004] [Accepted: 05/15/2004] [Indexed: 11/20/2022]
Abstract
BACKGROUND AND PURPOSE There are limited data on long-term treatment efficacy, and almost none on predictors of treatment response in patients with restless legs syndrome (RLS). To assess: (1) long-term efficacy of RLS treatment in a clinical setting, (2) predictors of a good treatment response, and (3) the value of the RLS-severity score according to the criteria of the International Restless Legs Syndrome Study Group (IRLSSG). PATIENTS AND METHODS Over three years 70 patients (36 men, 34 women; mean age: 59 years; range: 29-79) with RLS were prospectively assessed. Diagnosis of RLS was made according to international criteria Severity of RLS symptoms was were assessed at the outset by the IRLSSG rating scale. Treatment was chosen individually according to clinical judgement. After a mean follow-up time of 16 months (range: 1-106 months) evolution of symptoms was assessed by both overall clinical impression and IRLSSG rating scale. Clinical characteristics and treatment effect were compared between patients never treated for RLS before this study ('naïve'=N-pts) and those with previous treatment ('treated'=T-pts). Predictors of treatment response were sought for comparing patients with good treatment response (good, better or much better on follow-up) and those with bad (B-pts) treatment response. RESULTS There were 40 N-pts and 30 T-pts. The mean IRLSSG score (hereinafter, IRLSSG) at baseline was 26 (range 12-38). No significant differences were found between N-and T-pts in age, gender, etiology and duration of RLS, positive family history, presenting sleep complaint, IRLSSG, or percentage of patients with periodic limb movements in sleep (PLMS) on polysomnography (PSG). At final follow-up 30 (76%) of 40 N-pts and 23 (77%) of 30 T-pts had a good (G-pts) treatment response. The mean IRLSSG at follow-up was 19 (range:1-36). There was a significant correlation between improvement of overall clinical impression (better or much better on final follow-up) and reduction of IRLSSG (P<0.0001). PLMS were more common in B- than G-pts (100 vs 58% of patients, P=0.02). In all other variables considered the two groups were similar. CONCLUSION (1) A good long-term treatment response can be obtained and maintained in a clinical setting in about 80% of RLS patients. (2) Patients with RLS and without PLMS may have a better long-term treatment response, and (3) the IRLSSG is a useful tool for assessment of evolution of RLS symptoms over time in individual patients.
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Trenkwalder C, Paulus W. Why do restless legs occur at rest?—pathophysiology of neuronal structures in RLS. Neurophysiology of RLS (part 2). Clin Neurophysiol 2004; 115:1975-88. [PMID: 15294200 DOI: 10.1016/j.clinph.2004.01.031] [Citation(s) in RCA: 89] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/25/2004] [Indexed: 11/24/2022]
Abstract
Restless legs syndrome (RLS) is a heterogeneous disorder encompassing genetically caused types with early onset and acquired varieties occurring later in life. Genetic studies in the near future will most likely discover more than one causative gene. The acquired cases too have different etiologies ranging from idiopathic types to secondary forms with uremia, iron depletion, polyneuropathy and others. Here we aim to correlate typical RLS symptoms, such as the sensory symptoms at rest, the reduction of the complaint in response to movement or other physical stimuli, the dominant involvement of the legs, pain, circadian rhythm, and the responsiveness to dopaminergic drugs with neurophysiological features of the central nervous system. We outline the complexity of the neural structures involved and their connections. A diversity of hypothetical affections of different neuronal levels might lead to various combinations of RLS symptomatology. No single pathophysiological explanation has yet been developed that covers all clinical features.
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Affiliation(s)
- C Trenkwalder
- Department of Clinical Neurophysiology, University of Göttingen, Göttingen, Germany.
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Abstract
In the past 10 years, restless legs syndrome (RLS) has gained recognition as a common sleep disorder. There are several therapeutic options in treating patients with RLS. RLS causes significant sleep disturbance and negatively impacts on patient quality of life. Pharmacologic treatment can result in improved sleep and quality of life issues. RLS patients should be evaluated for iron deficiency anemia; iron replacement in deficient patients may lead to a resolution of symptoms or may reduce the severity of their symptoms. For patients with daily symptoms, the initial therapy is dopamine agonists. Low doses given in the evening or 2 hours before bed provide adequate relief of symptoms for many RLS patients. Augmentation can be seen with all dopamine agents, but is most prevalent with levodopa. Levodopa therapy is best used for milder intermittent symptoms or in aggravating situations, such as long car rides. Opiates and antiepileptics remain a beneficial therapy for RLS and are useful in patients who experience pain as part of their RLS. Newer anticonvulsants may provide additional treatment options, but they have yet to undergo clinical trials. Intravenous iron also may provide relief of RLS symptoms; however, dosing and safety issues have not been fully evaluated in a RLS population.
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Affiliation(s)
- Suzanne Lesage
- Department of Neurology, Johns Hopkins Bayview Medical Center and the Johns Hopkins Center for Restless Legs Syndrome, 5501 Hopkins Bayview Circle, AAC-1B-82, Baltimore, MD 21224, USA.
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