What treatment works best for restless legs syndrome? Meta-analyses of dopaminergic and non-dopaminergic medications

Sleep Medicine Reviews

Volumn 18, Issue 2, 2014, Pages 153-164

  Hornyak, Magdolna ^a,b   Scholz, Hanna ^b   Kohnen, Ralf ^c,d   Bengel, Juergen ^e   Kassubek, Jan ^a   Trenkwalder, Claudia ^f,g  

^a UNIVERSITY OF ULM   (Germany)

^b UNIVERSITY OF FREIBURG   (Germany)

^c RPS   (United Kingdom)

^d UNIVERSITY OF ERLANGEN NUREMBERG   (Germany)

^e UNIVERSITY OF FREIBURG   (Germany)

^f Ctr Parkinsonism Movement Disord   (Germany)

^g UNIVERSITY OF GÖTTINGEN   (Germany)

Author keywords

2 Ligand; Anticonvulsant; Depression; Dopamine agonist; Iron; Meta analysis; Opioid; Quality of life; Restless legs syndrome (RLS); Treatment; Willis Ekbom disease

Indexed keywords

ANTICONVULSANT; DEPRESSION; DOPAMINE AGONIST; IRON; META-ANALYSIS; OPIOID; QUALITY OF LIFE; RESTLESS LEGS SYNDROME (RLS); TREATMENT; WILLIS-EKBOM DISEASE; Α(2)Δ LIGAND;

ANALGESICS, OPIOID; ANTICONVULSANTS; DOPAMINE AGENTS; DOPAMINE AGONISTS; HUMANS; IRON COMPOUNDS; LEVODOPA; RESTLESS LEGS SYNDROME; TREATMENT OUTCOME;

EID: 84894932546     PISSN: 10870792     EISSN: 15322955     Source Type: Journal    
DOI: 10.1016/j.smrv.2013.03.004     Document Type: Review

References (80)

1. Allen R.P., Picchietti D., Hening W.A., Trenkwalder C., Walters A.S., Montplaisir J. Restless legs syndrome: diagnostic criteria, special considerations, and epidemiology. A report from the restless legs syndrome diagnosis and epidemiology workshop at the National Institutes of Health. Sleep Med 2003, 4:101-119.
2. Allen R.P., Stillman P., Myers A.J. Physician-diagnosed restless legs syndrome in a large sample of primary medical care patients in Western Europe: prevalence and characteristics. Sleep Med 2010, 11:31-37.
3. Hening W., Walters A.S., Allen R.P., Montplaisir J., Myers A., Ferini-Strambi L. Impact, diagnosis and treatment of restless legs syndrome (RLS) in a primary care population: the REST (RLS epidemiology, symptoms, and treatment) primary care study. Sleep Med 2004, 5:237-246.
4. Allen R.P., Walters A.S., Montplaisir J., Hening W., Myers A., Bell T.J., et al. Restless legs syndrome prevalence and impact: REST general population study. Arch Intern Med 2005, 165:1286-1292.
5. Hornyak M., Kopasz M., Berger M., Riemann D., Voderholzer U. Impact of sleep-related complaints on depressive symptoms in patients with restless legs syndrome. JClin Psychiatry 2005, 66:1139-1145.
6. Jung K.Y., Koo Y.S., Kim B.J., Ko D., Lee G.T., Kim K.H., et al. Electrophysiologic disturbances during daytime in patients with restless legs syndrome: further evidence of cognitive dysfunction?. Sleep Med 2011, 12:416-421.
7. Kushida C., Martin M., Nikam P., Blaisdell B., Wallenstein G., Ferini-Strambi L., et al. Burden of restless legs syndrome on health-related quality of life. Qual Life Res 2007, 16:617-624.
8. Pearson V.E., Allen R.P., Dean T., Gamaldo C.E., Lesage S.R., Earley C.J. Cognitive deficits associated with restless legs syndrome (RLS). Sleep Med 2006, 7:25-30.
9. Saletu B., Anderer P., Saletu M., Hauer C., Lindeck-Pozza L., Saletu-Zyhlarz G. EEG mapping, psychometric, and polysomnographic studies in restless legs syndrome (RLS) and periodic limb movement disorder (PLMD) patients as compared with normal controls. Sleep Med 2002, 3(Suppl.):S35-S42.
10. Winkelmann J., Prager M., Lieb R., Pfister H., Spiegel B., Wittchen H.U., et al. "Anxietas tibiarum". Depression and anxiety disorders in patients with restless legs syndrome. JNeurol 2005, 252:67-71.
11. Hening W. The clinical neurophysiology of the restless legs syndrome and periodic limb movements. Part I: diagnosis, assessment, and characterization. Clin Neurophysiol 2004, 115:1965-1974.
12. 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, 115:1975-1988.
13. Trenkwalder C., Paulus W. Restless legs syndrome: pathophysiology, clinical presentation and management. Nat Rev Neurol 2010, 6:337-346.
14. Baker W.L., White C.M., Coleman C.I. Effect of nonergot dopamine agonists on symptoms of restless legs syndrome. Ann Fam Med 2008, 6:253-262.
15. Conti C.F., de Oliveira M.M., Andriolo R.B., Saconato H., Atallah A.N., Valbuza J.S., et al. Levodopa for idiopathic restless legs syndrome: evidence-based review. Mov Disord 2007, 22:1943-1951.
16. Quilici S., Abrams K.R., Nicolas A., Martin M., Petit C., Lleu P.L., et al. Meta-analysis of the efficacy and tolerability of pramipexole versus ropinirole in the treatment of restless legs syndrome. Sleep Med 2008, 9:715-726.
17. Scholz H., Trenkwalder C., Kohnen R., Riemann D., Kriston L., Hornyak M. Dopamine agonists for restless legs syndrome. Cochrane Database Syst Rev 2011, CD006009.
18. Scholz H., Trenkwalder C., Kohnen R., Riemann D., Kriston L., Hornyak M. Levodopa for restless legs syndrome. Cochrane Database Syst Rev 2011, CD005504.
19. Talati R., Phung O.J., Mather J., Coleman C.I. Effect of non-ergot dopamine agonists on health-related quality of life of patients with restless legs syndrome. Ann Pharmacother 2009, 43:813-821.
20. Zintzaras E., Kitsios G.D., Papathanasiou A.A., Konitsiotis S., Miligkos M., Rodopoulou P., et al. Randomized trials of dopamine agonists in restless legs syndrome: a systematic review, quality assessment, and meta-analysis. Clin Ther 2010, 32:221-237.
21. Earley C.J., Silber M.H. Restless legs syndrome: understanding its consequences and the need for better treatment. Sleep Med 2010, 11:807-815.
22. Godau J., Spinnler N., Wevers A.K., Trenkwalder C., Berg D. Poor effect of guideline based treatment of restless legs syndrome in clinical practice. JNeurol Neurosurg Psychiatry 2010, 81:1390-1395.
23. García-Borreguero D., Williams A.M. Dopaminergic augmentation of restless legs syndrome. Sleep Med Rev 2010, 14:339-346.
24. Allen R.P., Ondo W.G., Ball E., Calloway M.O., Manjunath R., Higbie R.L., et al. Restless legs syndrome (RLS) augmentation associated with dopamine agonist and levodopa usage in a community sample. Sleep Med 2011, 12:431-439.
25. Garcia-Borreguero D., Allen R.P., Kohnen R., Hogl B., Trenkwalder C., Oertel W., et al. 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, 8:520-530.
26. Silber M.H., Ehrenberg B.L., Allen R.P., Buchfuhrer M.J., Earley C.J., Hening W.A., et al. An algorithm for the management of restless legs syndrome. Mayo Clin Proc 2004, 79:916-922.
27. Trenkwalder C., Beneš H., Hornyak M., Riemann D., Stiasny-Kolster K., Winkelmann J. Restless legs syndrome and periodic limb movement disorder. Leitlinien für die Diagnostik und Therapie in der Neurologie 2008, Georg Thieme Verlag. H.C. Diener, N. Putzki (Eds.).
28. Sandyk R., Bamford C.R., Gillman M.A. Opiates in the restless legs syndrome. Int J Neurosci 1987, 36:99-104.
29. Telstad W., Sorensen O., Larsen S., Lillevold P.E., Stensrud P., Nyberg-Hansen R. Treatment of the restless legs syndrome with carbamazepine: a double blind study. Br Med J (Clin Res Ed) 1984, 288:444-446.
30. Walters A.S., Winkelmann J., Trenkwalder C., Fry J.M., Kataria V., Wagner M., et al. Long-term follow-up on restless legs syndrome patients treated with opioids. Mov Disord 2001, 16:1105-1109.
31. Adler C.H. Treatment of restless legs syndrome with gabapentin. Clin Neuropharmacol 1997, 20:148-151.
32. Happe S., Klosch G., Saletu B., Zeitlhofer J. Treatment of idiopathic restless legs syndrome (RLS) with gabapentin. Neurology 2001, 57:1717-1719.
33. Micozkadioglu H., Ozdemir F.N., Kut A., Sezer S., Saatci U., Haberal M. Gabapentin versus levodopa for the treatment of Restless Legs Syndrome in hemodialysis patients: an open-label study. Ren Fail 2004, 26:393-397.
34. Conti C.F., Oliveira M.M., Valbuza J.S., Prado L.B., Carvalho L.B., Prado G.F. Anticonvulsants to treat idiopathic restless legs syndrome: systematic review. Arq Neuropsiquiatr 2008, 66:431-435.
35. Garcia-Borreguero D., Larrosa O., de la Llave Y., Verger K., Masramon X., Hernandez G. Treatment of restless legs syndrome with gabapentin: a double-blind, cross-over study. Neurology 2002, 59:1573-1579.
36. Lundvall O., Abom P.E., Holm R. Carbamazepine in restless legs. A controlled pilot study. Eur J Clin Pharmacol 1983, 25:323-324.
37. Trotti L.M., Bhadriraju S., Becker L.A. Iron for restless legs syndrome. Cochrane Database Syst Rev. 2012, 5:CD007834.
38. Higgins JPT, Green S. Cochrane handbook for systematic reviews of interventions version 5.1.0: The cochrane collaboration; 2011. Available from: [updated March 2011]. http://www.cochrane-handbook.org.
39. Hornyak M., Trenkwalder C., Kohnen R., Scholz H. Efficacy and safety of dopamine agonists in restless legs syndrome. Sleep Med 2012, 13:228-236.
40. Hening W.A. Current guidelines and standards of practice for restless legs syndrome. Am J Med 2007, 120:S22-S27.
41. Trenkwalder C., Hening W.A., Montagna P., Oertel W.H., Allen R.P., Walters A.S., et al. Treatment of restless legs syndrome: an evidence-based review and implications for clinical practice. Mov Disord 2008, 23:2267-2302.
42. Walters A.S. Toward a better definition of the restless legs syndrome. The International Restless Legs Syndrome Study Group. Mov Disord 1995, 10:634-642.
43. Walters A.S., LeBrocq C., Dhar A., Hening W., Rosen R., Allen R.P., et al. Validation of the international restless legs syndrome study group rating scale for restless legs syndrome. Sleep Med 2003, 4:121-132.
44. Clinical global impressions. ECDEU assessment manual for psychopharmacology 1976, National Institute of Mental Health (NIMH), NIMH, Rockville, MD, Rev. ed. W. Guy (Ed.).
45. Abetz L., Vallow S.M., Kirsch J., Allen R.P., Washburn T., Earley C.J. Validation of the restless legs syndrome quality of life questionnaire. Value Health 2005, 8:157-167.
46. Kohnen R., Benes H., Heinrich C., Kurella B. Development of the disease-specific restless legs syndrome quality of life (RLS-QoL) questionnaire. Mov Disord 2002, 17:P743.
47. Cohen J. Statistical power analysis for the behavioral sciences 1988, Erlbaum Associates, Hillsdale, NJ. 2nd ed.
48. DerSimonian R., Laird N. Meta-analysis in clinical trials. Control Clin Trials 1986, 7:177-188.
49. Adler C.H., Hauser R.A., Sethi K., Caviness J.N., Marlor L., Anderson W.M., et al. Ropinirole for restless legs syndrome: a placebo-controlled crossover trial. Neurology 2004, 62:1405-1407.
50. Benes H., Kurella B., Kummer J., Kazenwadel J., Selzer R., Kohnen R. Rapid onset of action of levodopa in restless legs syndrome: a double-blind, randomized, multicenter, crossover trial. Sleep 1999, 22:1073-1081.
51. Eisensehr I., Ehrenberg B.L., Rogge Solti S., Noachtar S. Treatment of idiopathic restless legs syndrome (RLS) with slow-release valproic acid compared with slow-release levodopa/benserazid. JNeurol 2004, 251:579-583.
52. Trenkwalder C., Stiasny K., Pollmacher T., Wetter T., Schwarz J., Kohnen R., et al. L-DOPA therapy of uremic and idiopathic restless legs syndrome: a double-blind, crossover trial. Sleep 1995, 18:681-688.
53. Walker S.L., Fine A., Kryger M.H. L-DOPA/carbidopa for nocturnal movement disorders in uremia. Sleep 1996, 19:214-218.
54. Walters A.S., Wagner M.L., Hening W.A., Grasing K., Mills R., Chokroverty S., et al. Successful treatment of the idiopathic restless legs syndrome in a randomized double-blind trial of oxycodone versus placebo. Sleep 1993, 16:327-332.
55. Wetter T.C., Stiasny K., Winkelmann J., Buhlinger A., Brandenburg U., Penzel T., et al. Arandomized controlled study of pergolide in patients with restless legs syndrome. Neurology 1999, 52:944-950.
56. Bassetti C.L., Bornatico F., Fuhr P., Schwander J., Kallweit U., Mathis J. Pramipexole versus dual release levodopa in restless legs syndrome: a double blind, randomised, cross-over trial. Swiss Med Wkly 2011, 141:w13274.
57. Kushida C.A., Walters A.S., Becker P., Thein S.G., Perkins A.T., Roth T., et al. Arandomized, double-blind, placebo-controlled, crossover study of XP13512/GSK1838262 in the treatment of patients with primary restless legs syndrome. Sleep 2009, 32:159-168.
58. Montplaisir J., Nicolas A., Denesle R., Gomez-Mancilla B. Restless legs syndrome improved by pramipexole: a double-blind randomized trial. Neurology 1999, 52:938-943.
59. UCB 2006. Efficacy and tolerability of levetiracetam in the treatment of restless legs syndrome: a double-blind placebo controlled crossover trial. Presented at the meeting of the American Neurological Association; 2006.
60. Staedt J., Wassmuth F., Ziemann U., Hajak G., Ruther E., Stoppe G. Pergolide: treatment of choice in restless legs syndrome (RLS) and nocturnal myoclonus syndrome (NMS). A double-blind randomized crossover trial of pergolide versus L-DOPA. JNeural Transm 1997, 104:461-468.
61. Winkelman J.W., Bogan R.K., Schmidt M.H., Hudson J.D., Derossett S.E., Hill-Zabala C.E. Randomized polysomnography study of gabapentin enacarbil in subjects with restless legs syndrome. Mov Disord 2011, 26:2065-2072.
62. Blum R.A., Comstock T.J., Sica D.A., Schultz R.W., Keller E., Reetze P., et al. Pharmacokinetics of gabapentin in subjects with various degrees of renal function. Clin Pharmacol Ther 1994, 56:154-159.
63. Wong M.O., Eldon M.A., Keane W.F., Turck D., Bockbrader H.N., Underwood B.A., et al. Disposition of gabapentin in anuric subjects on hemodialysis. JClin Pharmacol 1995, 35:622-626.
64. Borenstein M., Hedges L.V., Higgins J.P.T., Rothstein H.R. Introduction to meta-analysis 2008, John Wiley & Sons, Chichester, UK.
65. Egger M., Davey Smith G., Schneider M., Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ 1997, 315:629-634.
66. Benes H. TULIR study group. Transdermal lisuride in patients with idiopathic restless legs syndrome: results from a placebo-controlled, double-blind, randomized, multicenter, 12-week dose-finding study. Sleep Med 2005, 6:S156.
67. Sloand J.A., Shelly M.A., Feigin A., Bernstein P., Monk R.D. Adouble-blind, placebo-controlled trial of intravenous iron dextran therapy in patients with ESRD and restless legs syndrome. Am J Kidney Dis 2004, 43:663-670.
68. Stiasny-Kolster K., Benes H., Peglau I., Hornyak M., Holinka B., Wessel K., et al. Effective cabergoline treatment in idiopathic restless legs syndrome. Neurology 2004, 63:2272-2279.
69. Hening W.A., Allen R.P., Ondo W.G., Walters A.S., Winkelman J.W., Becker P., et al. Rotigotine improves restless legs syndrome: a 6-month randomized, double-blind, placebo-controlled trial in the United States. Mov Disord 2010, 25:1675-1683.
70. Trenkwalder C., Kohnen R., Allen R.P., Benes H., Ferini-Strambi L., Garcia-Borreguero D., et al. Clinical trials in restless legs syndrome-recommendations of the European RLS Study Group (EURLSSG). Mov Disord 2007, 22(Suppl. 18):S495-S504.
71. Neuro 2006 Efficacy and safety of topiramate in restless legs syndrome. Ann Neurol 2006, 60:S73.
72. Allen R.P., Adler C.H., Du W., Butcher A., Bregman D.B., Earley C.J. Clinical efficacy and safety of IV ferric carboxymaltose (FCM) treatment of RLS: a multi-centred, placebo-controlled preliminary clinical trial. Sleep Med 2011, 12:906-913.
73. Davis B.J., Rajput A., Rajput M.L., Aul E.A., Eichhorn G.R. Arandomized, double-blind placebo-controlled trial of iron in restless legs syndrome. Eur Neurol 2000, 43:70-75.
74. Trenkwalder C., Benes H., Grote L., Happe S., Hogl B., Mathis J., et al. 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.
75. Benes H., Kohnen R. Transdermal lisuride in patients with severe restless legs syndrome: results from a placebo- and ropinirole-controlled, double-blind, randomized, multicenter, 12-week efficacy and tolerability study. TULIR 03/01. Sleep 2008, 31:A266.
76. Fulda S., Wetter T.C. Where dopamine meets opioids: a meta-analysis of the placebo effect in restless legs syndrome treatment studies. Brain 2008, 131:902-917.
77. Hornyak M., Scholz H., Kiemen A., Kassubek J. Investigating the response to intravenous iron in restless legs syndrome: an observational study. Sleep Med 2012, 13:732-735.
78. Sixel-Döring F., Trautmann E., Mollenhauer B., Trenkwalder C. Age, drugs or disease - what alters the macrostructure of sleep in Parkinson's disease?. Sleep Med 2012, 13:1178-1183.
79. Patrick D.L., Guyatt G.H. Cochrane patient reported outcomes methods group. About The Cochrane Collaboration (Methods Groups) 2007, 3. Art. no. CE000141.
80. Scholz H., Benes H., Happe S., Bengel J., Kohnen R., Hornyak M. Psychological distress of patients suffering from restless legs syndrome: a cross-sectional study. Health Qual Life Outcomes 2011, 9:73.