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Neurotherapeutics

, Volume 11, Issue 1, pp 177–187 | Cite as

Treatment of Restless Legs Syndrome

  • Cynthia L. ComellaEmail author
Review

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.

Keywords

Restless leg syndrome Levodopa Dopamine agonists Alpha-2-delta ligands Opioids Placebo effect 

Notes

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Supplementary material

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References

  1. 1.
    Allen RP, Picchietti D, Hening WA, Trenkwalder C, Walters AS, Montplaisi 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.PubMedGoogle Scholar
  2. 2.
    Hening WA, Allen RP, Washburn M, Lesage SR, Earley CJ. The four diagnostic criteria for restless legs syndrome are unable to exclude confounding conditions ("mimics"). Sleep Med 2009;10:976–981.PubMedCentralPubMedGoogle Scholar
  3. 3.
    Allen RP, Bharmal M, Calloway M. Prevalence and disease burden of primary restless legs syndrome: results of a general population survey in the United States. Mov Disord 2011;26:114–120.PubMedGoogle Scholar
  4. 4.
    Allen RP, Walters AS, Montplaisir J, Hening W, Myers A, Bell TJ, et al. Restless legs syndrome prevalence and impact: REST general population study. Arch Intern Med 2005;165:1286–1292.PubMedGoogle Scholar
  5. 5.
    Ohayon MM, O'Hara R, Vitiello MV. Epidemiology of restless legs syndrome: a synthesis of the literature. Sleep Med Rev 2012;16:283–295.PubMedCentralPubMedGoogle Scholar
  6. 6.
    Berger K, Luedemann J, Trenkwalder C, John U, Kessler C. Sex and the risk of restless legs syndrome in the general population. Arch Intern Med 2004;164:196–202.PubMedGoogle Scholar
  7. 7.
    Earley CJ, Silber MH. Restless legs syndrome: understanding its consequences and the need for better treatment. Sleep Med 2010;11:807–815.PubMedGoogle Scholar
  8. 8.
    Ferri R. The time structure of leg movement activity during sleep: the theory behind the practice. Sleep Med 2012;13:433–441.PubMedGoogle Scholar
  9. 9.
    Winkelman JW, Shahar E, Sharief I, Gottlieb DJ. Association of restless legs syndrome and cardiovascular disease in the Sleep Heart Health Study. Neurology 2008;70:35–42.PubMedGoogle Scholar
  10. 10.
    Li Y, Walters AS, Chiuve SE, Rimm EB, Winkelman JW, Gao X. Prospective study of restless legs syndrome and coronary heart disease among women. Circulation 2012;126:1689–1694.PubMedCentralPubMedGoogle Scholar
  11. 11.
    Winkelman JW, Redline S, Baldwin CM, Resnick HE, Newman AB, Gottlieb DJ. Polysomnographic and health-related quality of life correlates of restless legs syndrome in the Sleep Heart Health Study. Sleep 2009;32:772–778.PubMedGoogle Scholar
  12. 12.
    Szentkiralyi A, Winter AC, Shurks M, Volzke H, Hoffmann W, Bruring JE, et al. Restless legs sndrome and all-cause mortality in four prospective cohort studies. BMJ 2012;2.Google Scholar
  13. 13.
    Freeman AA, Rye DB. The molecular basis of restless legs syndrome. Curr Opin Neurobiol 2013;23:895–900.PubMedGoogle Scholar
  14. 14.
    Winkelmann J, Polo O, Provini F, Nevsimalova S, Kemlink D, Sonka K, et al. Genetics of restless legs syndrome (RLS): State-of-the-art and future directions. Mov Disord 2007;22(Suppl. 18):S449-S458.PubMedGoogle Scholar
  15. 15.
    Yang Q, Li L, Chen Q, Foldvary-Schaefer N, Ondo WG, Wang QK. Association studies of variants in MEIS1, BTBD9, and MAP2K5/SKOR1 with restless legs syndrome in a US population. Sleep Med 2011;12:800–804.PubMedCentralPubMedGoogle Scholar
  16. 16.
    Schormair B, Plag J, Kaffe M, Gross N, Czamara D, Samtleben W, et al. MEIS1 and BTBD9: genetic association with restless leg syndrome in end stage renal disease. J Med Genet 2011;48:462–466.PubMedCentralPubMedGoogle Scholar
  17. 17.
    Winkelmann J, Czamara D, Schormair B, Knauf F, Schulte EC, Trenkwalder C, et al. Genome-wide association study identifies novel restless legs syndrome susceptibility loci on 2p14 and 16q12.1. PLoS Genet 2011;7:e1002171.PubMedCentralPubMedGoogle Scholar
  18. 18.
    Allen RP, Barker PB, Wehrl F, Song HK, Earley CJ. MRI measurement of brain iron in patients with restless legs syndrome. Neurology 2001;56:263–265.PubMedGoogle Scholar
  19. 19.
    Eisensehr I, Wetter TC, Linke R, Noachtar S, von Lindeiner H, Gildehaus FJ, et al. Normal IPT and IBZM SPECT in drug-naive and levodopa-treated idiopathic restless legs syndrome. Neurology 2001;57:1307–1309.PubMedGoogle Scholar
  20. 20.
    Michaud M, Soucy JP, Chabli A, Lavigne G, Montplaisir J. SPECT imaging of striatal pre- and postsynaptic dopaminergic status in restless legs syndrome with periodic leg movements in sleep. J Neurol 2002;249:164–170.PubMedGoogle Scholar
  21. 21.
    Ondo WG, Zhao HR, Le WD. Animal models of restless legs syndrome. Sleep Med 2007;8:344–348.PubMedGoogle Scholar
  22. 22.
    Earley CJ, Allen RP, Connor JR, Ferrucci L, Troncoso J. The dopaminergic neurons of the A11 system in RLS autopsy brains appear normal. Sleep Med 2009;10:1155–1157.PubMedCentralPubMedGoogle Scholar
  23. 23.
    Rizzo V, Arico I, Mastroeni C, Morgante F, Liotta G, Girlanda P, et al. Dopamine agonists restore cortical plasticity in patients with idiopathic restless legs syndrome. Mov Disord 2009;24:710–715.PubMedGoogle Scholar
  24. 24.
    Scalise A, Pittaro-Cadore I, Janes F, Marinig R, Gigli GL. Changes of cortical excitability after dopaminergic treatment in restless legs syndrome. Sleep Med 2010;11:75–81.PubMedGoogle Scholar
  25. 25.
    Godau J, Spinnler N, Wevers AK, Trenkwalder C, Berg D. Poor effect of guideline based treatment of restless legs syndrome in clinical practice. J Neurol Neurosurg Psychiatry 2010;81:1390–1395.PubMedGoogle Scholar
  26. 26.
    Rye DB, Trotti LM. Restless legs syndrome and periodic leg movements of sleep. Neurol Clin 2012;30:1137–1166.PubMedGoogle Scholar
  27. 27.
    Trenkwalder C, Paulus W. Restless legs syndrome: pathophysiology, clinical presentation and management. Nat Rev Neurol 2010;6:337–346.PubMedGoogle Scholar
  28. 28.
    Salas RE, Gamaldo CE, Allen RP. Update in restless legs syndrome. Curr Opin Neurol 2010;23:401–406.PubMedGoogle Scholar
  29. 29.
    Sun ER, Chen CA, Ho G, Earley CJ, Allen RP. Iron and the restless legs syndrome. Sleep 1998;21:371–377.PubMedGoogle Scholar
  30. 30.
    Cho YW, Allen RP, Earley CJ. Lower molecular weight intravenous iron dextran for restless legs syndrome. Sleep Med 2013;14:274–277.PubMedGoogle Scholar
  31. 31.
    Earley CJ. The importance of oral iron therapy in restless legs syndrome. Sleep Med 2009;10:945–946.PubMedGoogle Scholar
  32. 32.
    Wang J, O'Reilly B, Venkataraman R, Mysliwiec V, Mysliwiec A. Efficacy of oral iron in patients with restless legs syndrome and a low-normal ferritin: A randomized, double-blind, placebo-controlled study. Sleep Med 2009;10:973–975.PubMedGoogle Scholar
  33. 33.
    Trotti LM, Bhadriraju S, Becker LA. Iron for restless legs syndrome. Cochrane Database Syst Rev 2012;5:CD007834.PubMedGoogle Scholar
  34. 34.
    Oertel WH, Trenkwalder C, Zucconi M, Benes H, Borreguero DG, Bassetti C, et al. State of the art in restless legs syndrome therapy: practice recommendations for treating restless legs syndrome. Mov Disord 2007;22(Suppl. 18):S466-475.PubMedGoogle Scholar
  35. 35.
    Ondo WG. Intravenous iron dextran for severe refractory restless legs syndrome. Sleep Med 2010;11:494–496.PubMedGoogle Scholar
  36. 36.
    Allen RP, Adler CH, Du W, Butcher A, Bregman DB, Earley CJ. 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.PubMedGoogle Scholar
  37. 37.
    Earley CJ, Horska A, Mohamed MA, Barker PB, Beard JL, Allen RP. A randomized, double-blind, placebo-controlled trial of intravenous iron sucrose in restless legs syndrome. Sleep Med 2009;10:206–211.PubMedCentralPubMedGoogle Scholar
  38. 38.
    Morcos Z. Restless legs syndrome, iron deficiency and colon cancer. J Clin Sleep Med 2005;1:433.PubMedGoogle Scholar
  39. 39.
    Brocklehurst J. Restless legs syndrome as a presenting symptom in malignant disease. Age Ageing 2003;32:234.PubMedGoogle Scholar
  40. 40.
    Gigli GL, Adorati M, Dolso P, Piani A, Valente M, Brotini S, et al. Restless legs syndrome in end-stage renal disease. Sleep Med 2004;5:309–315.PubMedGoogle Scholar
  41. 41.
    Kavanagh D, Siddiqui S, Geddes CC. Restless legs syndrome in patients on dialysis. Am J Kidney Dis 2004;43:763–771.PubMedGoogle Scholar
  42. 42.
    Siddiqui S, Kavanagh D, Traynor J, Mak M, Deighan C, Geddes C. Risk factors for restless legs syndrome in dialysis patients. Nephron Clin Pract 2005;101:c155-160.PubMedGoogle Scholar
  43. 43.
    de Oliveira MM, Conti CF, Valbuza JS, de Carvalho LB, do Prado GF. The pharmacological treatment for uremic restless legs syndrome: evidence-based review. Mov Disord 2010;25:1335–1342.PubMedGoogle Scholar
  44. 44.
    Rottach KG, Schaner BM, Kirch MH, Zivotofsky AZ, Teufel LM, Gallwitz T, et al. Restless legs syndrome as side effect of second generation antidepressants. J Psychiatr Res 2008;43:70–75.PubMedGoogle Scholar
  45. 45.
    Yang C, White DP, Winkelman JW. Antidepressants and periodic leg movements of sleep. Biol Psychiatry 2005;58:510–514.PubMedGoogle Scholar
  46. 46.
    Brown LK, Dedrick DL, Doggett JW, Guido PS. Antidepressant medication use and restless legs syndrome in patients presenting with insomnia. Sleep Med 2005;6:443–450.PubMedGoogle Scholar
  47. 47.
    Hornyak M, Voderholzer U, Riemann D. Treatment of depression in patients with restless legs syndrome: what is evidence-based? Sleep Med 2006;7:301–302.PubMedGoogle Scholar
  48. 48.
    Hoque R, Chesson AL, Jr. Pharmacologically induced/exacerbated restless legs syndrome, periodic limb movements of sleep, and REM behavior disorder/REM sleep without atonia: literature review, qualitative scoring, and comparative analysis. J Clin Sleep Med 2010;6:79–83.PubMedGoogle Scholar
  49. 49.
    Frauscher B, Comella C. Sleep related movement disorders. In: Poewe W, Jankovic J (eds) Movement disorders in neurologic and systemic disease. Cambridge University Press, New York, (in press).Google Scholar
  50. 50.
    Fulda S, Wetter TC. Where dopamine meets opioids: a meta-analysis of the placebo effect in restless legs syndrome treatment studies. Brain 2008;131:902–917.PubMedGoogle Scholar
  51. 51.
    de la Fuente-Fernandez R. The powerful pre-treatment effect: placebo responses in restless legs syndrome trials. Eur J Neurol 2012;19:1305–1310.PubMedGoogle Scholar
  52. 52.
    Diederich NJ, Goetz CG. The placebo treatments in neurosciences: New insights from clinical and neuroimaging studies. Neurology 2008;71:677–684.PubMedGoogle Scholar
  53. 53.
    Aukerman MM, Aukerman D, Bayard M, Tudiver F, Thorp L, Bailey B. Exercise and restless legs syndrome: a randomized controlled trial. J Am Board Fam Med 2006;19:487–493.PubMedGoogle Scholar
  54. 54.
    Lettieri CJ, Eliasson AH. Pneumatic compression devices are an effective therapy for restless legs syndrome: a prospective, randomized, double-blinded, sham-controlled trial. Chest 2009;135:74–80.PubMedGoogle Scholar
  55. 55.
    Eliasson AH, Lettieri CJ. Sequential compression devices for treatment of restless legs syndrome. Medicine 2007;86:317–323.PubMedGoogle Scholar
  56. 56.
    Innes K, Selfe T, Agarawal P, Williams K, Flack K. Efficacy of an eight-week yoga intervention on symptoms of restless legs syndrome (RLS): a pilot study. J Altern Complement Med 2013;19:527–535.PubMedGoogle Scholar
  57. 57.
    Akpinar S. Treatment of restless legs syndrome with levodopa plus benserazide. Arch Neurol 1982;39:739.PubMedGoogle Scholar
  58. 58.
    Conti CF, de Oliveira MM, Andriolo RB, Saconato H, Atallah AN, Valbuza JS, et al. Levodopa for idiopathic restless legs syndrome: evidence-based review. Mov Disord 2007;22:1943–1951.PubMedGoogle Scholar
  59. 59.
    von Scheele C, Kempi V. Long-term effect of dopaminergic drugs in restless legs. A 2-year follow-up. Arch Neurol 1990;47:1223–1224.Google Scholar
  60. 60.
    Stiasny-Kolster K, Kohnen R, Moller JC, Trenkwalder C, Oertel WH. Validation of the "L-DOPA test" for diagnosis of restless legs syndrome. Mov Disord 2006;21:1333–1339.PubMedGoogle Scholar
  61. 61.
    Becker PM, Jamieson AO, Brown WD. Dopaminergic agents in restless legs syndrome and periodic limb movements of sleep: response and complications of extended treatment in 49 cases. Sleep 1993;16:713–716.PubMedGoogle Scholar
  62. 62.
    Collado-Seidel V, Kazenwadel J, Wetter TC, Kohnen R, Winkelmann J, Selzer R, et al. A controlled study of additional sr-L-dopa in L-dopa-responsive restless legs syndrome with late-night symptoms. Neurology 1999;52:285–290.PubMedGoogle Scholar
  63. 63.
    Allen RP, Earley CJ. Augmentation of the restless legs syndrome with carbidopa/levodopa. Sleep 1996;19:205–213.PubMedGoogle Scholar
  64. 64.
    Garcia-Borreguero D, Williams AM. Dopaminergic augmentation of restless legs syndrome. Sleep Med Rev 2010;14:339–346.PubMedGoogle Scholar
  65. 65.
    Garcia-Borreguero D, Allen RP, 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.PubMedGoogle Scholar
  66. 66.
    Garcia-Borreguero D, Kohnen R, Hogl B, Ferini-Strambi L, Hadjigeorgiou GM, Hornyak M, et al. Validation of the Augmentation Severity Rating Scale (ASRS): a multicentric, prospective study with levodopa on restless legs syndrome. Sleep Med 2007;8:455–463.PubMedGoogle Scholar
  67. 67.
    Trenkwalder C, Collado Seidel V, Kazenwadel J, Wetter TC, Oertel W, Selzer R, et al. One-year treatment with standard and sustained-release levodopa: appropriate long-term treatment of restless legs syndrome? Mov Disord 2003;18:1184–1189.PubMedGoogle Scholar
  68. 68.
    Hogl B, Garcia-Borreguero D, Kohnen R, Ferini-Strambi L, Hadjigeorgiou G, Hornyak M, et al. Progressive development of augmentation during long-term treatment with levodopa in restless legs syndrome: results of a prospective multi-center study. J Neurol 2010;257:230–237.PubMedCentralPubMedGoogle Scholar
  69. 69.
    Garcia-Borreguero D, Ferini-Strambi L, Kohnen R, O'Keeffe S, Trenkwalder C, Hogl B, et al. European guidelines on management of restless legs syndrome: report of a joint task force by the European Federation of Neurological Societies, the European Neurological Society and the European Sleep Research Society. Eur J Neurol 2012;19:1385–1396.PubMedGoogle Scholar
  70. 70.
    Hornyak M, Scholz H, Kohnen R, Bengel J, Kassubek J, Trenkwalder C. What treatment works best for restless legs syndrome? Meta-analyses of dopaminergic and non-dopaminergic medications. Sleep Med Rev 2013 Jun 6 [Epub ahead of print].Google Scholar
  71. 71.
    Aurora R, Kristo D, Bista S, Rowley J, Zak R, Casey K, et al. The treatment of restless legs syndrome and periodic limb movement disorder in adults-an update for 2012: practice parameters with an evidence-based systemic review and meta-analyses. Sleep 2012;35:1039–1062.PubMedGoogle Scholar
  72. 72.
    Wilt TJ, MacDonald R, Ouellette J, Khawaja IS, Rutks I, Butler M, et al. Pharmacologic therapy for primary restless legs syndrome: a systematic review and meta-analysis. JAMA Int Med 2013;173:496–505.Google Scholar
  73. 73.
    Hornyak M, Trenkwalder C, Kohnen R, Scholz H. Efficacy and safety of dopamine agonists in restless legs syndrome. Sleep Med 2012;13:228–236.PubMedGoogle Scholar
  74. 74.
    Trenkwalder C, Hening WA, Montagna P, Oertel WH, Allen RP, Walters AS, et al. Treatment of restless legs syndrome: an evidence-based review and implications for clinical practice. Mov Disord 2008;23:2267–2302.PubMedGoogle Scholar
  75. 75.
    de Biase S, Merlino G, Lorenzut S, Valente M, Gigli GL. ADMET considerations for restless leg syndrome drug treatments. Exp Opin Drug Metab Toxicol 2012;8:1247–1261.Google Scholar
  76. 76.
    Manconi M, Ferri R, Zucconi M, Oldani A, Giarolli L, Bottasini V, et al. Pramipexole versus ropinirole: polysomnographic acute effects in restless legs syndrome. Mov Disord 2011;26:892–895.PubMedGoogle Scholar
  77. 77.
    Walters A, Hening W, Kavey N, Chokroverty S, Gidro-Frank S. A double-blind randomized crossover trial of bromocriptine and placebo in restless legs syndrome. Ann Neurol 1988;24:455–458.PubMedGoogle Scholar
  78. 78.
    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. J Neural Transm 1997;104:461–468.PubMedGoogle Scholar
  79. 79.
    Stiasny-Kolster K, Benes H, Peglau I, Hornyak M, Holinka B, Wessel K, et al. Effective cabergoline treatment in diopathic restless legs sydnrome. Neurology 2004;63:2272–2279.PubMedGoogle Scholar
  80. 80.
    Trenkwalder C, Garcia-Borreguero D, Montagna P, Lainey E, de Weerd AW, Tidswell P, et al. Ropinirole in the treatment of restless legs syndrome: results from the TREAT RLS 1 study, a 12 week, randomised, placebo controlled study in 10 European countries. J Neurol Neurosurg Psychiatry 2004;75:92–97.PubMedGoogle Scholar
  81. 81.
    Walters AS, Ondo WG, Dreykluft T, Grunstein R, Lee D, Sethi K, et al. Ropinirole is effective in the treatment of restless legs syndrome. TREAT RLS 2: a 12-week, double-blind, randomized, parallel-group, placebo-controlled study. Mov Disord 2004;19:1414–1423.PubMedGoogle Scholar
  82. 82.
    Adler CH, Hauser RA, Sethi K, Caviness JN, Marlor L, Anderson WM, et al. Ropinirole for restless legs syndrome: a placebo-controlled crossover trial. Neurology 2004;62:1405–1407.PubMedGoogle Scholar
  83. 83.
    Allen R, Becker PM, Bogan R, Schmidt M, Kushida CA, Fry JM, et al. Ropinirole decreases periodic leg movements and improves sleep parameters in patients with restless legs syndrome. Sleep 2004;27:907–914.PubMedGoogle Scholar
  84. 84.
    Bogan RK, Fry JM, Schmidt MH, Carson SW, Ritchie SY, Group TRUS. 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.PubMedGoogle Scholar
  85. 85.
    Garcia-Borreguero D, Hogl B, Ferini-Strambi L, Winkelman J, Hill-Zabala C, Asgharian A, et al. Systematic evaluation of augmentation during treatment with ropinirole in restless legs syndrome (Willis-Ekbom disease): results from a prospective, multicenter study over 66 weeks. Mov Disord 2012;27:277–283.PubMedGoogle Scholar
  86. 86.
    Hogl B, Garcia-Borreguero D, Trenkwalder C, Ferini-Strambi L, Hening W, Poewe W, et al. Efficacy and augmentation during 6 months of double-blind pramipexole for restless legs syndrome. Sleep Med 2011;12:351–360.PubMedGoogle Scholar
  87. 87.
    Lipford MC, Silber MH. Long-term use of pramipexole in management of restless legs syndrome. Sleep Med 2012;13:1280–1285.PubMedGoogle Scholar
  88. 88.
    Oertel W, Trenkwalder C, Benes H, Ferini-Strambi L, Hogl B, Poewe W, et al. Long-term safety and efficacy of rotigotine transdermal patch for moderate-to-severe idiopathic restless legs syndrome: a 5-year open-label extension study. Lancet Neurol 2011;10:710–720.PubMedGoogle Scholar
  89. 89.
    Benes H, Garcia-Borreguero D, Ferini-Strambi L, Schollmayer E, Fichtner A, Kohnen R. Augmentation in the treatment of restless legs syndrome with transdermal rotigotine. Sleep Med 2012;13:589–597.PubMedGoogle Scholar
  90. 90.
    Allen RP, Ondo WG, Ball E, Calloway MO, Manjunath R, Higbie RL, et al. Restless legs syndrome (RLS) augmentation associated with dopamine agonist and levodopa usage in a community sample. Sleep Med 2011;12:431–439.PubMedGoogle Scholar
  91. 91.
    Garcia-Borreguero D, Larrosa O, Williams AM, Albares J, Pascual M, Palacios JC, et al. Treatment of restless legs syndrome with pregabalin: a double-blind, placebo-controlled study. Neurology 2010;74:1897–1904.PubMedGoogle Scholar
  92. 92.
    Frauscher B, Gschliesser V, Brandauer E, El-Demerdash E, Kaneider M, Rucker L, et al. The severity range of restless legs syndrome (RLS) and augmentation in a prospective patient cohort: association with ferritin levels. Sleep Med 2009;10:611–615.PubMedGoogle Scholar
  93. 93.
    Voon V, Schoerling A, Wenzel S, Ekanayake V, Reiff J, Trenkwalder C, et al. Frequency of impulse control behaviours associated with dopaminergic therapy in restless legs syndrome. BMC Neurol 2011;11:117.PubMedCentralPubMedGoogle Scholar
  94. 94.
    Winkelman JW, Bogan RK, Schmidt MH, Hudson JD, DeRossett SE, Hill-Zabala CE. Randomized polysomnography study of gabapentin enacarbil in subjects with restless legs syndrome. Mov Disord 2011;26:2065–2072.PubMedGoogle Scholar
  95. 95.
    Lee DO, Ziman RB, Perkins AT, Poceta JS, Walters AS, Barrett RW, et al. A randomized, double-blind, placebo-controlled study to assess the efficacy and tolerability of gabapentin enacarbil in subjects with restless legs syndrome. J Clin Sleep Med 2011;7:282–292.PubMedGoogle Scholar
  96. 96.
    Kushida CA, Becker PM, Ellenbogen AL, Canafax DM, Barrett RW, Group XPS. Randomized, double-blind, placebo-controlled study of XP13512/GSK1838262 in patients with RLS. Neurology 2009;72:439–446.PubMedGoogle Scholar
  97. 97.
    Ellenbogen AL, Thein SG, Winslow DH, Becker PM, Tolson JM, Lassauzet ML, et al. A 52-week study of gabapentin enacarbil in restless legs syndrome. Clin Neuropharmacol 2011;34:8–16.PubMedGoogle Scholar
  98. 98.
    Bogan RK, Bornemann MA, Kushida CA, Tran PV, Barrett RW, Group XPS. Long-term maintenance treatment of restless legs syndrome with gabapentin enacarbil: a randomized controlled study. Mayo Clinic Proc 2010;85:512–521.Google Scholar
  99. 99.
    Saletu M, Anderer P, Saletu-Zyhlarz GM, Parapatics S, Gruber G, Nia S, et al. Comparative placebo-controlled polysomnographic and psychometric studies on the acute effects of gabapentin versus ropinirole in restless legs syndrome. J Neural Transm 2010;117:463–473.PubMedGoogle Scholar
  100. 100.
    Allen R, Chen C, Soaita A, Wohlberg C, Knapp L, Peterson BT, et al. A randomized, double-blind, 6-week, dose-ranging study of pregabalin in patients with restless legs syndrome. Sleep Med 2010;11:512–519.PubMedGoogle Scholar
  101. 101.
    Garcia-Borreguero D, Kohnen R, Silber MH, Winkelman JW, Earley CJ, Hogl B, et al. 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 2013;14:675–684.PubMedGoogle Scholar
  102. 102.
    Walters A, Wagner M, Hening W, 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.PubMedGoogle Scholar
  103. 103.
    Hening W, Walters A, Kavey N, Gidro-Frank S, Cote L, Fahn S. Dyskinesias while awake and periodic movements in sleep in restless legs syndrome: treatment with opioids. Neurology 1986;36:1363.PubMedGoogle Scholar
  104. 104.
    Walters AS, Winkelmann J, Trenkwalder C, Fry JM, Kataria V, Wagner M, et al. Long-term follow-up on restless legs syndrome patients treated with opioids. Mov Disord 2001;16:1105–1119.PubMedGoogle Scholar
  105. 105.
    Ondo WG. Methadone for refractory restless legs syndrome. Mov Disord 2005;20:345–348.PubMedGoogle Scholar
  106. 106.
    Silver N, Allen RP, Senerth J, Earley CJ. A 10-year, longitudinal assessment of dopamine agonists and methadone in the treatment of restless legs syndrome. Sleep Med 2011;12:440–444.PubMedGoogle Scholar
  107. 107.
    Trenkwalder C, Benes H, Grote L, Garcia-Borreguero D, Hogl B, Hopp M, et al. Prolonged release oxycodone-naloxone for treatment of severe restless legs syndrome after failure of previous treatment: a double-blind, randomised, placebo-controlled trial with an open-label extension. Lancet Neurol 2013;12:1141–1150.PubMedGoogle Scholar
  108. 108.
    Saletu M, Anderer P, Saletu-Zyhlarz G, Prause W, Semler B, Zoghlami A, et al. Restless legs syndrome (RLS) and periodic limb movement disorder (PLMD): acute placebo-controlled sleep laboratory studies with clonazepam. Eur Neuropsychopharmacol 2001;11:153–161.PubMedGoogle Scholar
  109. 109.
    Chokroverty S. Long-term management issues in restless legs syndrome. Mov Disord 2011;26:1378–1385.PubMedGoogle Scholar
  110. 110.
    Aurora RN, Kristo DA, Bista SR, Rowley JA, Zak RS, Casey KR, et al. 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;35:1039–1062.PubMedGoogle Scholar
  111. 111.
    Trenkwalder C, Paulus W, Walters AS. The restless legs syndrome. Lancet Neurol 2005;4:465–475.PubMedGoogle Scholar
  112. 112.
    Ferini-Strambi L, Manconi M. Treatment of restless legs syndrome. Parkinsonism Relat Disord 2009;15(Suppl. 4):S65-S70.PubMedGoogle Scholar

Copyright information

© The American Society for Experimental NeuroTherapeutics, Inc. 2013

Authors and Affiliations

  1. 1.Movement Disorders Section, Department of Neurological SciencesRush Medical CollegeChicagoUSA

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