296
Views
2
CrossRef citations to date
0
Altmetric
Review

An update on the treatment of Restless Legs Syndrome/Willis-Ekbom Disease: prospects and challenges

, , , &
Pages 705-713 | Received 05 Jun 2018, Accepted 08 Aug 2018, Published online: 22 Aug 2018

References

  • American Academy of Sleep Medicine. International classification of sleep disorders. 3rd ed. Darien, IL: American Academy of Sleep Medicine; 2014.
  • Ohayon MM, O’Hara R, Vitiello MV. Epidemiology of restless legs syndrome: a synthesis of the literature. Sleep Med Rev. 2012;16:283–295.
  • Winkelman JW, Armstrong MJ, Allen RP, et al. Practice guideline summary: treatment of RLS/WED in adults: report of the guideline development, dissemination, and implementation subcommittee of the American Academy of Neurology. Neurology. 2016;87(24):2585–2593.
  • Merlino G, Serafini A, Robiony F, et al. Restless legs syndrome: differential diagnosis and management with rotigotine. Neuropsychiatr Dis Treat. 2009;5:67–80.
  • Wilt TJ, MacDonald R, Ouellette J, et al. Pharmacologic therapy for primary restless legs syndrome: a systematic review and meta-analysis. JAMA Intern Med. 2013;173:496–505.
  • Trenkwalder C, Beneš H, Grote L, et al. Prolonged release oxycodone– naloxone for treatment of severe restless legs syndrome after failure of previous treatment: a doubleblind, randomised, placebo-controlled trial with an open-label extension. Lancet Neurol. 2013;12:1141–1150.
  • Mackie S, Winkelman JW. Long-term treatment of restless legs syndrome (RLS): an approach to management of worsening symptoms, loss of efficacy, and augmentation. CNS Drugs. 2015;29:351–357.
  • Garcia-Borreguero D, Silber MH, Winkelman JW, et al. 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.
  • Aurora RN, Kristo DA, Bista SR, 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(8):1039–1062.
  • Winkelmann J, Allen RP, Högl B, et al. Treatment of restless legs syndrome: evidence-based review and implications for clinical practice. Mov Disord. May 14 2018. [Epub ahead of print] Review. DOI:10.1002/mds.27260.
  • Giorgi L, Asgharian A, Hunter B. Ropinirole in patients with restless legs syndrome and baseline IRLS total scores ≥ 24: efficacy and tolerability in a 26-week, double-blind, parallel-group, placebo-controlled study followed by a 40-week open-label extension. Clin Ther. 2013 Sep;35(9):1321–1336.
  • Ferini-Strambi L, Marelli S, Galbiati A. Clinical pharmacology and efficacy of rotigotine (Neupro® patch) in the treatment of restless leg syndrome. Expert Opin Drug Metab Toxicol. 2016;12:967–975.
  • Högl B, Oertel WH, Stiasny-Kolster K, et al. Treatment of moderate to severe restless legs syndrome: 2-year safety and efficacy of rotigotine transdermal patch. BMC Neurol. 2010;10:86.
  • Garcia-Borreguero D, Cano-Pumarega I, Marulanda R. Management of treatment failure in restless legs syndrome (Willis-Ekbom disease). Sleep Med Rev. 2018. Epub ahead of print. Doi:10.1016/j.smrv.2018.01.001
  • Rinaldi F, Galbiati A, Marelli S, et al. Defining the phenotype of restless legs syndrome/Willis-Ekbom disease (RLS/WED): a clinical and polysomnographic study. J Neurol. 2016;263:396–402.
  • Lee DO, Ziman RB, Perkins AT, 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.
  • Inoue Y, Hirata K, Uchimura N, et al. 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 Jan;29(1):13–21.
  • Winkelman JW, Bogan RK, Schmidt MH, et al. Randomized polysomnography study of gabapentin enacarbil in subjects with restless legs syndrome. Mov Disord. 2011 Sep;26(11):2065–2072.
  • Happe S, Klösch G, Saletu B, et al. Treatment of idiopathic restless legs syndrome (RLS) with gabapentin. Neurology. 2001;57:1717–1719.
  • Garcia-Borreguero D, Larrosa O, De La Llave Y, et al. Treatment of restless legs syndrome with gabapentin: a double-blind, cross-over study. Neurology. 2002;59:1573–1579.
  • Garcia-Borreguero D, Kohnen R, Mh S, 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.
  • Allen RP, Chen C, Garcia-Borreguero D, et al. Comparison of pregabalin with pramipexole for restless legs syndrome. N Engl J Med. 2014;370:621–631.
  • Mackie SE, Winkelman JW. Utility of opioids for restless legs syndrome. Drugs. 2017;77(12):1337–1344.
  • Walters AS, Ondo WG, Zhu W, et al. Does the endogenous opiate system play a role in the RLS/WED? A pilot post-mortem study. J Neurol Sci. 2009;279(1–2):62–65.
  • De Oliveira CO, Carvalho LB, Carlos K, et al. Opioids for restless legs syndrome. Cochrane Database Syst Rev. 2016;(6):CD006941.
  • Trenkwalder C, Zieglgänsberger W, Ahmedzai SH, et al. Pain, opioids, and sleep: implications for restless legs syndrome treatment. Sleep Med. 2017;31:78–85.
  • Walters AS, Winkelmann J, Trenkwalder C, et al. Long-term follow-up on RLS/WED patients treated with opioids. Mov Disord. 2001;16(6):1105–1109.
  • Ondo WG. Methadone for refractory RLS/WED. Mov Disord. 2005;20(3):345–348.
  • Silver N, Allen RP, Senerth J, et al. A 10-year, longitudinal assessment of dopamine agonists and methadone in the treatment of RLS/WED. Sleep Med. 2011;12(5):440–444.
  • Earley CJ, Allen RP. Restless legs syndrome augmentation associated with tramadol. Sleep Med. 2006;7:592–593.
  • Hornyak M, Kaube H. Long-term treatment of a patient with severe restless legs syndrome using intrathecal morphine. Neurology. 2012;79D24]:2361–2362.
  • Rinaldi F, Galbiati A, Marelli S, et al. Treatment options in intractable Restless Legs Syndrome/Willis-Ekbom Disease (RLS/WED). Curr Treat Options Neurol. 2016;18(2):7.
  • Brand S, Beck J, Hatzinger M, et al. Patients suffering from restless leg syndrome have low internal locus of control and poor psychological functioning compared to healthy controls. Neuropsychobiology. 2013;68:51–58.
  • Carlos K, Prado GF, Teixeira CDM, et al. Benzodiazepines for restless legs syndrome. Cochrane Database Syst Rev. 2017;3:CD006939.
  • Ferré S, Earley C, Gulyani S, et al. In search of alternatives to dopaminergic ligands for the treatment of restless legs syndrome: iron, glutamate, and adenosine. Sleep Med. 2017;31:86–92.
  • The International Restless Legs Syndrome Study Group (IRLSSG). White paper summary of recommendations for the prevention and treatment of RLS/WED augmentation. 2015. Available from: http://irlssg.org/wp-content/uploads/2015/05/Summary-of-recommendations-RLS-Augmentation-13Aug2015.pdf.
  • Earley CJ, Connor J, Garcia-Borreguero D, et al. Altered brain iron homeostasis and dopaminergic function in restless legs syndrome (Willis-Ekbom Disease). Sleep Med. 2014;15:1288–1301.
  • Silber MH, Ehrenberg BL, Allen RP, et al. An algorithm for the management of restless legs syndrome. Mayo Clin Proc. 2004;79(7):916–922. Erratum in: Mayo Clin Proc. 2004 Oct;79(10):1341.
  • Allen RP, Picchietti DL, Auerbach M, et al. Evidence-based and consensus clinical practice guidelines for the iron treatment of restless legs syndrome/Willis-Ekbom disease in adults and children: an IRLSSG task force report. Sleep Med. 2018;41:27–44.
  • Wang J, O’Reilly B, Venkataraman R, et al. 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(9):973–975.
  • Earley CJ, Connor JR, Beard JL, et al. Abnormalities in CSF concentrations of ferritin and transferrin in restless legs syndrome. Neurology. 2000;54:1698e700.
  • Connor JR, Zhang X, Nixon AM, et al. Comparative evaluation of nephrotoxicity and management by macrophages of intravenous pharmaceutical iron formulations. PLoS One. 2015;10:e0125272.
  • Allen RP, Adler CH, Du W, et al. Clinical efficacy and safety of IV ferric carboxymaltose (FCM) treatment of RLS/WED: a multi-centred, placebo-controlled preliminary clinical trial. Sleep Med. 2011;12:906–913.
  • Schneider J, Krafft A, Manconi M, et al. Open-label study of the efficacy and safety of intravenous ferric carboxymaltose in pregnant women with restless legs syndrome. Sleep Med. 2015;16:1342–1347.
  • Cho YW, Allen RP, Earley CJ. Clinical efficacy of ferric carboxymaltose treatment in patients with restless legs syndrome. Sleep Med. 2016;25:16–23.
  • Trenkwalder C, Winkelmann J, Oertel W, et al. Ferric carboxymaltose in patients with restless legs syndrome and nonanemic iron deficiency: a randomized trial. Mov Disord. 2017;32(10):1478–1482.
  • Bayard M, Bailey B, Acharya D, et al. Bupropion and restless legs syndrome: a randomized controlled trial. J Am Board Fam Med. 2011;24:422–428.
  • Quiroz C, Gulyani S, Ruiqian W, et al. Adenosine receptors as markers of brain iron deficiency: implications for restless legs syndrome. Neuropharmacology. 2016;111:160e8.
  • Garcia-Borreguero D, Guitart X, Garcia Malo C, et al. Treatment of restless legs syndrome/Willis-Ekbom disease with the non-selective ENT1/ENT2 inhibitor dipyridamole: testing the adenosine hypothesis. Sleep Med. 2018;45:94–97.
  • Liguori C, Mercuri NB, Stefani A, et al. Effective treatment of restless legs syndrome by safinamide in Parkinson’s disease patients. Sleep Med. 2018;41:113–114.
  • Garcia-Borreguero D, Cano I, Granizo JJ. Treatment of restless legs syndrome with the selective AMPA receptor antagonist perampanel. Sleep Med. 2017;34:105–108.
  • Decerce J, Smith LF, Gonzalez W, et al. Effectiveness and tolerability of istradefylline for the treatment of restless legs syndrome: an exploratory study in five female patients. Curr Ther Res Clin Exp. 2007;68:349–359.
  • Nuermaimaiti M, Oyama G, Kasemsuk C, et al. Istradefylline for restless legs syndrome associated with Parkinson’s disease. Tremor Other Hyperkinet Mov (N Y). 2018;8:521.
  • Xu XM, Liu Y, Jia SY, et al. Complementary and alternative therapies for restless legs syndrome: an evidence-based systematic review. Sleep Med Rev. 2018;38:158–167.
  • Aukerman MM, Aukerman D, Bayard M, et al. Exercise and restless legs syndrome: a randomized controlled trial. J Am Board Fam Med. 2006;19:487–493.
  • Giannaki CD, Hadjigeorgiou GM, Karatzaferi C, et al. A single-blind randomized controlled trial to evaluate the effect of 6 months of progressive aerobic exercise training in patients with uraemic restless legs syndrome. Nephrol Dial Transplant. 2013 Nov;28(11):2834–2840.
  • Giannaki CD, Sakkas GK, Karatzaferi C, et al. Effect of exercise training and dopamine agonists in patients with uremic restless legs syndrome: a six-month randomized, partially double-blind, placebo-controlled comparative study. BMC Nephrol. 2013 Sep;11(14):194.
  • Hornyak M, Grossmann C, Kohnen R, et al. Cognitive behavioural group therapy to improve patients’ strategies for coping with restless legs syndrome: a proof-of-concept trial. J Neurol Neurosurg Psychiatry. 2008 Jul;79(7):823–825.
  • 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.
  • Pan W, Wang M, Li M, et al. Actigraph evaluation of acupuncture for treating restless legs syndrome. Evid Based Complement Alternat Med. 2015;2015:343201.
  • Lin YC, Feng Y, Zhan SQ. Repetitive transcranial magnetic stimulation for the treatment of Restless Legs Syndrome. Chin Med J (Engl). 2015;128(13):1728–1731.
  • Koo YS, Kim SM, Lee C, et al. Transcranial direct current stimulation on primary sensorimotor area has no effect in patients with drug-naïve restless legs syndrome: a proof-of-concept clinical trial. Sleep Med. 2015;16:280–287.
  • Heide AC, Winkler T, Helms HJ, et al. Effects of transcutaneous spinal direct current stimulation in idiopathic restless legs patients. Brain Stimul. 2014;7(5):636–642.
  • Anderson JC, Fritz ML, Benson JM, et al. Nerve decompression and restless legs syndrome: a retrospective analysis. Front Neurol. 2017;8:287.
  • Ondo W. Deep brain stimulation (DBS) for severe restless legs syndrome: therapeutic and physiologic considerations. Sleep Med. 2017;31:93–94.
  • Rye DB, DeLong MR. Amelioration of sensory limb discomfort of restless legs syndrome by pallidotomy. Ann Neurol. 1999;46:800–801.
  • Okun MS, Fernandez HH, Foote KD. Deep brain stimulation of the GPi treats restless legs syndrome associated with dystonia. Mov Disord. 2005;20:500–501.
  • Ondo W. VIM deep brain stimulation does not improve pre-existing restless legs syndrome in patients with essential tremor. Parkinsonism Relat Disord. 2006;12:113–114.
  • Ondo WG, Jankovic J, Simpson R, et al. Globus pallidus deep brain stimulation for refractory idiopathic restless legs syndrome. Sleep Med. 2012;13:1202–1204.
  • Holland MT, Rettenmaier LA, Flouty OE, et al. Epidural spinal cord stimulation: A novel therapy in the treatment of restless legs syndrome. World Neurosurg. 2016;92:582.e15–8.
  • Silva MA, Duarte GS, Camara R, et al. Placebo and nocebo responses in restless legs syndrome: a systematic review and meta-analysis. Neurology. 2017;88(23):2216–2224.
  • De La Fuente-Fernandez R, Stoessl AJ. The placebo effect in Parkinson’s disease. Trends Neurosci. 2002;25:302–306.
  • Pecina M, Zubieta JK. Molecular mechanisms of placebo responses in humans. Mol Psychiatry. 2015;20:416–423.
  • Wise RA, Rompre PP. Brain dopamine and reward. Annu Rev Psychol. 1989;40:191–225.
  • Allen RP, Ondo WG, Ball E, et al. Restless legs syndrome (RLS) augmentation associated with dopamine agonist and levodopa usage in a community sample. Sleep Med. 2011;12:431–439.
  • Patatanian E, Claborn MK. Drug-induced restless legs syndrome. Ann Pharmacother. 2018;52:662–672.
  • 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.
  • Becker PM, Novak M. Diagnosis, comorbidities, and management of restless legs syndrome. Curr Med Res Opin. 2014;30:1441–1460.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.