Therapies for Restless Legs in Parkinson’s Disease

  • Valérie Cochen De CockEmail author
Sleep Disorders (A Iranzo, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Sleep Disorders


Purpose of review

The aim of this article was to review the options and particularities of the treatment of restless legs syndrome (RLS) in Parkinson’s disease (PD).

Recent findings

RLS is more frequent in PD than in the general population. Even if these two disorders share some specificity (dopa-sensitivity), they also differ in many features (iron load, genetic profile, dopaminergic cell count), resulting in different adaptations of the treatment. Only one study has specifically explored and demonstrated the efficacy of a treatment (rotigotine) in RLS with PD, constraining us to treat RLS with PD by analogy as idiopathic RLS in the other cases. However, arrangements linked to the peculiar population and pathology of PD are required.


The treatment of RLS in PD consists in adaptation of dopaminergic treatment and introduction of alpha-2-delta ligands and, in refractory cases, of opioids or deep brain stimulation. Iron deficiency should probably not be compensated.


Restless legs syndrome Periodic limb movements Parkinson’s disease Dopamine agonists Alpha-2-delta ligands Opioids Iron Deep brain stimulation 


Compliance with Ethical Standards

Conflict of Interest

The author declares that she has no competing interests.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

References and Recommended Reading

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Allen RP, Picchietti DL, Garcia-Borreguero D, Ondo WG, Walters AS, Winkelman JW, et al. Restless legs syndrome/Willis-Ekbom disease diagnostic criteria: Updated International Restless Legs Syndrome Study Group (IRLSSG) consensus criteria - history, rationale, description, and significance. Sleep Med. 2014;15:860–73.PubMedCrossRefGoogle Scholar
  2. 2.
    Hughes AJ, Daniel SE, Kilford L, Lees AJ. Accuracy of clinical diagnosis of idiopathic Parkinson’s disease: a clinico-pathological study of 100 cases. J Neurol Neurosurg Psychiatry. 1992;55:181–4.PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Fereshtehnejad SM, Shafieesabet M, Shahidi GA, Delbari A, Lökk J. Restless legs syndrome in patients with Parkinson’s disease: a comparative study on prevalence, clinical characteristics, quality of life and nutritional status. Acta Neurol Scand. 2015;13:211–8.CrossRefGoogle Scholar
  4. 4.
    Bhalsing K, Suresh K, Muthane UB, Pal PK. Prevalence and profile of restless legs syndrome in Parkinson’s disease and other neurodegenerative disorders: a case-control study. Parkinsonism Relat Disord. 2013;19:426–30.PubMedCrossRefGoogle Scholar
  5. 5.
    Rijsman RM, Schoolderman LF, Rundervoort R, Louter M. Restless legs syndrome in Parkinson’s disease. Park Relat Disord. 2014;20:S5–9.CrossRefGoogle Scholar
  6. 6.
    Peralta CM, Frauscher B, Seppi K, Wolf E, Wenning GK, Högl B, et al. Restless legs syndrome in Parkinson’s disease. Mov Disord. 2009;24:2076–80.PubMedCrossRefGoogle Scholar
  7. 7.
    Garcia-Borreguero D, Egatz R, Winkelmann J, Berger K. Epidemiology of restless legs syndrome: the current status. Sleep Med Rev. 2006;10:153–67.PubMedCrossRefGoogle Scholar
  8. 8.
    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;13:1286–92.CrossRefGoogle Scholar
  9. 9.
    Trenkwalder C, Allen R, Hogl B, Paulus W, Winkelmann J. Restless legs syndrome associated with major diseases a systematic review and new concept. Neurology. 2016;86:1336–43.PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Wetter TC, Collado-Seidel V, Pollmächer T, Yassouridis A, Trenkwalder C. Sleep and periodic leg movement patterns in drug-free patients with Parkinson’s disease and multiple system atrophy. Sleep. 2000;23:361–7.PubMedCrossRefGoogle Scholar
  11. 11.
    Montplaisir J, Boucher S, Poirier G, Lavigne G, Lapierre O, Lespérance P. Clinical, polysomnographic, and genetic characteristics of restless legs syndrome: a study of 133 patients diagnosed with new standard criteria. Mov Disord. 1997;12:61–5.PubMedCrossRefGoogle Scholar
  12. 12.
    Pittock SJ, Parrett T, Adler CH, Parisi JE, Dickson DW, Ahlskog JE. Neuropathology of primary restless leg syndrome: absence of specific tau- and alpha-synuclein pathology. Mov Disord. 2004;19:695–9.PubMedCrossRefGoogle Scholar
  13. 13.
    Earley CJ, Connor J, Garcia-Borreguero D, Jenner P, Winkelman J, Zee PC, et al. Altered brain iron homeostasis and dopaminergic function in restless legs syndrome (Willis-Ekbom disease). Sleep Med. 2014;15:1288–301.PubMedCrossRefGoogle Scholar
  14. 14.
    Connor JR, Wang XS, Allen RP, Beard JL, Wiesinger JA, Felt BT, et al. Altered dopaminergic profile in the putamen and substantia nigra in restless leg syndrome. Brain. 2009;132:2403–12.PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    Connor JR, Wang XS, Patton SM, Menzies SL, Troncoso JC, Earley CJ, et al. Decreased transferrin receptor expression by neuromelanin cells in restless legs syndrome. Neurology. 2004;11:1563–7.CrossRefGoogle Scholar
  16. 16.
    Connor JR, Boyer PJ, Menzies SL, Dellinger B, Allen RP, Ondo WG, et al. Neuropathological examination suggests impaired brain iron acquisition in restless legs syndrome. Neurology. 2003;16:304–9.CrossRefGoogle Scholar
  17. 17.
    Gan-Or Z, Alcalay RN, Bar-Shira A, Leblond CS, Postuma RB, Ben-Shachar S, et al. Genetic markers of restless legs syndrome in Parkinson disease. Park Relat Disord. 2015;21:582–5.CrossRefGoogle Scholar
  18. 18.
    Vilariño-Güell C, Soto AI, Young JE, Lin SC, Uitti RJ, Wszolek ZK, et al. Susceptibility genes for restless legs syndrome are not associated with Parkinson disease. Neurology. 2008;71:222–3.PubMedCrossRefGoogle Scholar
  19. 19.
    Walters AS, LeBrocq C, Dhar A, Hening W, Rosen R, Allen RP, et al. Validation of the International Restless Legs Syndrome Study Group rating scale for restless legs syndrome. Sleep Med. 2003;4:121–32.PubMedCrossRefGoogle Scholar
  20. 20.
    Trenkwalder C, Kohnen R, Högl B, Metta V, Sixel-Döring F, Frauscher B, et al. Parkinson’s disease sleep scale-validation of the revised version PDSS-2. Mov Disord. 2011;26:644–52.PubMedCrossRefGoogle Scholar
  21. 21.
    De Cock VC, Bayard S, Yu H, Grini M, Carlander B, Postuma R, et al. Suggested immobilization test for diagnosis of restless legs syndrome in Parkinson’s disease. Mov Disord. 2012;27:743–9.PubMedCrossRefGoogle Scholar
  22. 22.
    Perez-Lloret S, Rey M, Bondon-Guitton E, Rascol O, Montastruc JL. Drugs associated with restless legs syndrome: a case/noncase study in the French pharmacovigilance database. J Clin Psychopharmacol. 2012;32:824–7.PubMedCrossRefGoogle Scholar
  23. 23.
    Loddo G, Calandra-Buonaura G, Sambati L, Giannini G, Cecere A, Cortelli P, et al. The treatment of sleep disorders in Parkinson’s disease: from research to clinical practice. Front Neurol. 2017;16:42.Google Scholar
  24. 24.
    Garcia-Borreguero D, Silber M, Winkelman JW, Hogl B, Bainbridge J, Buchfuhrer M. Guidelines for the first-line treatment of restless legs syndrome/Willis-Ekbom disease, prevention and treatment of dopaminergic augmentation: a combined task force of the IRLSSG, EURLSSG, and the RLS-foundation. Sleep Med. 2016;21:1–11.PubMedCrossRefGoogle Scholar
  25. 25.
    Grolez G, Moreau C, Sablonnière B, Garçon G, Devedjian JC, Meguig S, et al. Ceruloplasmin activity and iron chelation treatment of patients with Parkinson’s disease. BMC Neurol. 2015;15:74.PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    •• Winkelmann J, Allen RP, Högl B, Inoue Y, Oertel W, Salminen AV, et al. Treatment of restless legs syndrome: evidence-based review and implications for clinical practice (revised 2017). Mov Disord. 2018;33:1077–91. The newest evidence-based review on the treatment of idiopathic RLS.PubMedCrossRefGoogle Scholar
  27. 27.
    Perez-Perez J, Pascual-Sedano B, Campolongo A, Kulisevsky J. Duodopa for the treatment of severe restless legs syndrome. Mov Disord. 2016;31:S304Poster953.Google Scholar
  28. 28.
    Pagonabarraga J, Piñol G, Cardozo A, Sanz P, Puente V, Otermín P, et al. Transdermal rotigotine improves sleep fragmentation in parkinson’s disease: results of the multicenter, prospective SLEEP-FRAM study. Parkinsons Dis. 2015;2015:1315–8.Google Scholar
  29. 29.
    Kim J, Chung S, Kim J, Jeon B, Singh P, Thierfelder S, et al. Rotigotine transdermal system as add-on to oral dopamine agonist in advanced Parkinson’s disease: an open-label study. BMC Neurol. 2015;15:17.PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Vallderiola F, Compta Y, Aparicio J, Tarradellas J, Salazar G, Oliver J, et al. Effects of night-time use of rotigotine on nocturnal symptoms in Parkinson’s disease. Parkinsons Dis. 2015;2015:475630.CrossRefGoogle Scholar
  31. 31.
    Wang Y, Yang YC, Lan DM, Wu HJ, Zhao ZX. An observational clinical and video-polysomnographic study of the effects of rotigotine in sleep disorder in Parkinson’s disease. Sleep Breath. 2017;21:319–25.PubMedCrossRefGoogle Scholar
  32. 32.••
    Trenkwalder C, Kies B, Rudzinska M, Fine J, Nikl J, Honczarenko K, et al. Rotigotine effects on early morning motor function and sleep in Parkinson’s disease: a double-blind, randomized, placebo-controlled study (RECOVER). Mov Disord. 2011;26:90–9 The only randomized double blind study on the efficacy of a treatment in RLS with PD.PubMedCrossRefGoogle Scholar
  33. 33.
    Reuter I, Ellis CM, Chaudhuri KR. Nocturnal subcutaneous apomorphine infusion in Parkinson’s disease and restless legs syndrome. Acta Neurol Scand. 2009;100:163–7.CrossRefGoogle Scholar
  34. 34.
    Priano L, Albani G, Brioschi A, Guastamacchia G, Calderoni S, Lopiano L, et al. Nocturnal anomalous movement reduction and sleep microstructure analysis in parkinsonian patients during 1-night transdermal apomorphine treatment. Neurol Sci. 2003;24:207–8.PubMedCrossRefGoogle Scholar
  35. 35.
    Iftikhar IH, Alghothani L, Trotti LM. Gabapentin enacarbil, pregabalin and rotigotine are equally effective in restless legs syndrome: a comparative meta-analysis. Eur J Neurol. 2017;24:1446–56.PubMedCrossRefGoogle Scholar
  36. 36.
    Parsons B, Argoff CE, Clair A, Emir B. Improvement in pain severity category in clinical trials of pregabalin. J Pain Res. 2016;9:779–85.PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Jost WH, Buhmann C. The challenge of pain in the pharmacological management of Parkinson’s disease. Expert Opin Pharmacother. 2019;10:1–8.Google Scholar
  38. 38.
    Cochen De Cock V, Bayard S, Jaussent I, Charif M, Grini M, Croisier Langenier M, et al. Daytime sleepiness in Parkinson’s disease: a reappraisal. PLoS One. 2014;9:e107278.PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    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;48:82–6.Google Scholar
  40. 40.
    Allen RP, Chen C, Garcia-Borreguero D, Polo O, DuBrava S, Miceli J, et al. Comparison of pregabalin with pramipexole for restless legs syndrome. N Engl J Med. 2014;370:621–31.PubMedCrossRefGoogle Scholar
  41. 41.
    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;11:512–9.PubMedCrossRefGoogle Scholar
  42. 42.
    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;74:1897–904.PubMedCrossRefGoogle Scholar
  43. 43.
    Perez Lloret S, Amaya M, Merello M. Pregabalin-induced parkinsonism: a case report. Clin Neuropharmacol. 2009;32:353–4.PubMedCrossRefGoogle Scholar
  44. 44.
    Erol C, Ozben S, Ozer F, Cetin S, Tiras R. Bilateral ballism induced by gabapentin in idiopatic Parkinson’s disease. Clin Neurol Neurosurg. 2009;111:397.PubMedCrossRefGoogle Scholar
  45. 45.
    Raju PM, Walker RW, Lee MA. Dyskinesia induced by gabapentin in idiopathic Parkinson’s disease. Mov Disord. 2007;15:288–9.CrossRefGoogle Scholar
  46. 46.
    Inoue Y, Hirata K, Uchimura N, Kuroda K, Hattori N, Takeuchi M. Gabapentin enacarbil in Japanese patients with restless legs syndrome: a 12-week, randomized, double-blind, placebo-controlled, parallel-group study. Curr Med Res Opin. 2013;29:13–21.PubMedCrossRefGoogle Scholar
  47. 47.
    Lal R, Ellenbogen A, Chen D, Zomorodi K, Atluri H, Luo W, et al. A randomized, double-blind, placebo-controlled, dose-response study to assess the pharmacokinetics, efficacy, and safety of gabapentin enacarbil in subjects with restless legs syndrome. Clin Neuropharmacol. 2012;35:165–73.PubMedCrossRefGoogle Scholar
  48. 48.
    Lee D, Ziman R, Perkins A, Poceta J, Walters A, Barrett R. 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;7:282–92.Google Scholar
  49. 49.
    Walters AS, Ondo WG, Kushida CA, Becker PM, Ellenbogen AL, Canafax DM, et al. Gabapentin enacarbil in restless legs syndrome: a phase 2b, 2-week, randomized, double-blind, placebo-controlled trial. Clin Neuropharmacol. 2009;32:311–20.PubMedCrossRefGoogle Scholar
  50. 50.
    Kushida CA, Walters AS, Becker P, Thein SG, Perkins AT, Roth T, et al. A randomized, double-blind, placebo-controlled, crossover study of XP13512/GSK1838262 in the treatment of patients with primary restless legs syndrome. Sleep. 2009;32:159–68.PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Kushida C, Becker P, Ellenbogen A, Canafax D, Barrett R. Randomized, double-blind, placebo-controlled study of XP13512/GSK1838262 in patients with RLS. Neurology. 2009;72:439–49.PubMedCrossRefGoogle Scholar
  52. 52.
    Bogan R, Bornemann M, Kushida C, Tran P, Barrett R. Long-term maintenance treatment of restless legs syndrome with gabapentin enacarbil: a randomized controlled study. Mayo Clin Proc. 2010;85:512–21.PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Fujishiro H. Effects of gabapentin enacarbil on restless legs syndrome and leg pain in dementia with Lewy bodies. Psychogeriatrics. 2014;14:132–4.PubMedCrossRefGoogle Scholar
  54. 54.
    Walters AS, Wagner ML, Hening WA, 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;16:327–32.PubMedCrossRefGoogle Scholar
  55. 55.
    Trenkwalder C, Beneš H, Grote L, García-Borreguero D, Högl 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;12:1141–50.PubMedCrossRefGoogle Scholar
  56. 56.
    Trenkwalder C, Chaudhuri KR, Martinez-Martin P, Rascol O, Ehret R, Vališ M, et al. Prolonged-release oxycodone-naloxone for treatment of severe pain in patients with Parkinson’s disease (PANDA): a double-blind, randomised, placebo-controlled trial. Lancet Neurol. 2015;14:1161–70.PubMedCrossRefGoogle Scholar
  57. 57.
    Silber MH, Becker PM, Buchfuhrer MJ, Earley CJ, Ondo WG, Walters AS, et al. The appropriate use of opioids in the treatment of refractory restless legs syndrome. Mayo Clin Proc. 2018;93:59–67.PubMedCrossRefGoogle Scholar
  58. 58.
    Earley CJ, Allen RP. Restless legs syndrome augmentation associated with tramadol. Sleep Med. 2006;7:592–3.PubMedCrossRefGoogle Scholar
  59. 59.
    Vetrugno R, La Morgia C, D’Angelo R, Loi D, Provini F, Plazzi G, et al. Augmentation of restless legs syndrome with long-term tramadol treatment. Mov Disord. 2007;22:424–7.PubMedCrossRefGoogle Scholar
  60. 60.
    Chokroverty S. Opioid-induced hyperalgesia and dopamine-induced augmentation in an intractable and refractory case of RLS. Sleep Med. 2015;16:1304.PubMedCrossRefGoogle Scholar
  61. 61.
    Carlos K, Prado GF, Teixeira CDM, Conti C, de Oliveira MM, Prado LBF, et al. Benzodiazepines for restless legs syndrome. Cochrane Database Syst Rev. 2017;3:CD006939.PubMedGoogle Scholar
  62. 62.
    Shpirer I, Miniovitz A, Klein C, Goldstein R, Prokhorov T, Theitler J, et al. Excessive daytime sleepiness in patients with parkinson’s disease: a polysomnography study. Mov Disord. 2006;21:1432–8.PubMedCrossRefGoogle Scholar
  63. 63.
    Benabid AL, Chabardes S, Mitrofanis J, Pollak P. Deep brain stimulation of the subthalamic nucleus for the treatment of Parkinson’s disease. Lancet Neurol [Internet]. 2009;8:67–81.Available from:. Scholar
  64. 64.
    Chahine LM, Ahmed A, Sun Z. Effects of STN DBS for Parkinson’s disease on restless legs syndrome and other sleep-related measures. Park Relat Disord. 2011;17:208–11.CrossRefGoogle Scholar
  65. 65.
    Driver-Dunckley E, Evidenter VGH, Adler CH, Hillman R, Hernandez J, Fletcher G, et al. Restless legs syndrome in Parkinson’s disease patients may improve with subthalamic stimulation. Mov Disord. 2006;21:1287–9.PubMedCrossRefGoogle Scholar
  66. 66.
    Klepitskaya O, Liu Y, Tsai J. Deep brain stimulation (DBS) of the subthalamic nucleus (STN) improves restless leg syndrome (RLS) in patients with Parkinson disease (PD). Mov Disord. 2017;91:e1013–21.Google Scholar
  67. 67.
    Kedia S, Moro E, Tagliati M, Lang AE, Kumar R. Emergence of restless legs syndrome during subthalamic stimulation for Parkinson disease. Neurology. 2004;63:2410–2.PubMedCrossRefGoogle Scholar
  68. 68.•
    Marques A, Fantini ML, Morand D, Pereira B, Derost P, Ulla M, et al. Emergence of restless legs syndrome after subthalamic stimulation in Parkinson’s disease: a dopaminergic overstimulation? Sleep Med. 2015;16:583–8 Interesting discussion on the mechanism of RLS and its improvement by DBS.PubMedCrossRefGoogle Scholar
  69. 69.
    Rye D, DeLong M. Amelioration of sensory limb discomfort of restless legs syndrome by pallidotomy. Ann Neurol. 1999;46:800–1.PubMedCrossRefGoogle Scholar
  70. 70.
    Zhao H, Zhu W, Pan T, Xie W, Zhang A, Ondo WG, et al. Spinal cord dopamine receptor expression and function in mice with 6-OHDA lesion of the A11 nucleus and dietary iron deprivation. J Neurosci Res. 2007;85:1065–76.PubMedCrossRefGoogle Scholar
  71. 71.
    Okun MS, Fernandez HH, Foote KD. Deep brain stimulation of the GPi treats restless legs syndrome associated with dystonia. Mov Disord. 2005;20:500–1.PubMedCrossRefGoogle Scholar
  72. 72.
    de la Fuente-Fernandez R, Stoessl AJ. The placebo effect in Parkinson’s disease. Trends Neurosci. 2002;25:302–6.PubMedCrossRefGoogle Scholar
  73. 73.
    Fulda S, Wetter TC. Where dopamine meets opioids: a meta-analysis of the placebo effect in restless legs syndrome treatment studies. Brain. 2008;13:902–17.CrossRefGoogle Scholar
  74. 74.
    De la Fuente-Fernández R, Ruth TJ, Sossi V, Schulzer M, Calne DB, Stoessl AJ. Expectation and dopamine release: mechanism of the placebo effect in Parkinson’s disease. Science. 2001;293:1164–6.PubMedCrossRefGoogle Scholar
  75. 75.•
    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. The only randomized study on a non-drug therapy of idiopathic RLS.PubMedCrossRefPubMedCentralGoogle Scholar

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Authors and Affiliations

  1. 1.Sleep and Neurology unitBeau Soleil ClinicMontpellierFrance
  2. 2.EuroMovUniversité de MontpellierMontpellierFrance

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