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Clinical management of restless legs syndrome in end-stage renal disease patients

  • Zeyad T. Sahli (a1) (a2), Jae Jo (a3), Shaker A. Mousa (a3) and Frank I. Tarazi (a1)


Restless legs syndrome (RLS) is a common neurological movement disorder, characterized by restless and unpleasant sensations in the deep inside of legs. The symptoms of RLS are less noticeable during daytime, but more prevalent at night. Therefore, the disorder can induce low quality of life, insomnia, and impairment of daytime activity. RLS in end-stage renal disease (ESRD) patients is especially problematic due to premature discontinuation of dialysis and increased mortality. The prevalence of RLS among dialysis patients is much higher compared to the prevalence of the same disorder in patients with normal renal functions. Even though there are recommended treatment guidelines for the general population established by Medical Advisory Board of the RLS foundation, which include the use of dopamine agonists, levodopa, gabapentin, benzodiazepines, and opioids, limited information is available on the effects of these therapies in ESRD patients. Since the existing clinical data were extrapolated from small sample sizes in short-term clinical trials, further clinical studies are still needed to better assess the efficacy, safety, and tolerability of these medications in patients with ESRD.


Corresponding author

*Address for correspondence: Dr. F. I. Tarazi, Harvard Medical School and McLean Hospital, 115 Mill Street, Belmont, MA 02478, USA. (Email:


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1. Ekbom, K, Ulfberg, J. Restless legs syndrome. J Intern Med. 2009; 266(5): 419431.
2. Winkelman, JW, Chertow, GM, Lazarus, JM. Restless legs syndrome in end-stage renal disease. Am J Kidney Dis. 1996; 28(3): 372378.
3. Benz, RL, Pressman, MR, Hovick, ET, Peterson, DD. Potential novel predictors of mortality in end-stage renal disease patients with sleep disorders. Am J Kidney Dis. 2000; 35(6): 10521060.
4. Lin, CH, Sy, HN, Chang, HW, et al. Restless legs syndrome is associated with cardio/cerebrovascular events and mortality in end‐stage renal disease. Eur J Neurol. 2015; 22(1): 142149.
5. Nichols, DA, Allen, RP, Grauke, JH, et al. Restless legs syndrome symptoms in primary care: a prevalence study. Arch Intern Med. 2003; 163(19): 23232329.
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(2): 196202.
7. Al-Jahdali, HH, Al-Qadhi, WA, Khogeer, HA, Al-Hejaili, FF, Al-Ghamdi, SM, Al Sayyari, AA. Restless legs syndrome in patients on dialysis. Saudi J Kidney Dis Transpl. 2009; 20(3): 378385.
8. Lee, J, Nicholl, DD, Ahmed, SB, et al. J Clin Sleep Med. 2013; 9(5): 455459.
9. Möller, C, Wetter, TC, Köster, J, Stiasny-Kolster, K. Differential diagnosis of unpleasant sensations in the legs: prevalence of restless legs syndrome in a primary care population. Sleep Med. 2010; 11(2): 161166.
10. Lohr, JB, Eidt, CA, Alfaraj, AA, Soliman, MA. The clinical challenges of akathisia. CNS Spectr. 2015; 20(S1): 116.
11. Sachdev, P. Akathisia and Restless Legs. New York, USA: Cambridge University Press; 2006.
12. Allen, RP, Picchietti, DL, Garcia-Borreguero, D, 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(8): 860873.
13. Pichler, I, Hicks, A, Pramstaller, P. Restless legs syndrome: an update on genetics and future perspectives. Clin Genet. 2008; 73(4): 297305.
14. Young, JE, Vilariño-Güell, C, Lin, S-C, Wszolek, ZK, Farrer, MJ. Clinical and genetic description of a family with a high prevalence of autosomal dominant restless legs syndrome. Mayo Clin Proc. 2009; 84(2): 134138.
15. Scheller, D, Ullmer, C, Berkels, R, Gwarek, M, Lübbert, H. The in vitro receptor profile of rotigotine: a new agent for the treatment of Parkinson’s disease. Naunyn Schmiedebergs Arch Pharmacol. 2009; 379(1): 7386.
16. Winkelmann, J, Schormair, B, Lichtner, P, et al. Genome-wide association study of restless legs syndrome identifies common variants in three genomic regions. Nat Genet. 2007; 39(8): 10001006.
17. Kemlink, D, Polo, O, Frauscher, B, et al. Replication of restless legs syndrome loci in three European populations. J Med Genet. 2009; 46(5): 315318.
18. Michaud, M, Soucy, J-P, 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(2): 164170.
19. Connor, JR, Wang, X-S, Allen, RP, et al. Altered dopaminergic profile in the putamen and substantia nigra in restless leg syndrome. Brain. 2009; 132(9): 24032412.
20. 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(3): c155c160.
21. Azar, S, Hatefi, R, Talebi, M. Evaluation of effect of renal transplantation in treatment of restless legs syndrome. Transplant Proc. 2007; 39(4): 11321133.
22. Kim, J-M, Kwon, H-M, Lim, CS, Kim, YS, Lee, S-J, Nam, H. Restless legs syndrome in patients on hemodialysis: symptom severity and risk factors. J Clin Neurol. 2008; 4(4): 153157.
23. Kawauchi, A, Inoue, Y, Hashimoto, T, et al. Restless legs syndrome in hemodialysis patients: health-related quality of life and laboratory data analysis. Clin Nephrol. 2006; 66(6): 440446.
24. Silber, MH, Becker, PM, Earley, C, et al. Willis-Ekbom Disease Foundation revised consensus statement on the management of restless legs syndrome. Mayo Clin Proc. 2013; 88(9): 977986.
25. 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(1): 7480.
26. 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; 14: 194.
27. Kaye, CM, Nicholls, B. Clinical pharmacokinetics of ropinirole. Clinical Pharmacokinet. 2000; 39(4): 243254.
28. Montplaisir, J, Karrasch, J, Haan, J, Volc, D. Ropinirole is effective in the long‐term management of restless legs syndrome: A randomized controlled trial. Mov Disord. 2006; 21(10): 16271635.
29. Pellecchia, MT, Vitale, C, Sabatini, M, et al. Ropinirole as a treatment of restless legs syndrome in patients on chronic hemodialysis: an open randomized crossover trial versus levodopa sustained release. Clinical Neuropharmacol. 2004; 27(4): 178181.
30. Antonini, A, Calandrella, D. Pharmacokinetic evaluation of pramipexole. Expert Opin Drug Metab Toxicol. 2011; 7(10): 13071314.
31. Dauvilliers, Y, Benes, H, Partinen, M, et al. Rotigotine in hemodialysis-associated restless legs syndrome: a randomized controlled trial. Am J Kidney Dis. 2016; 68(3): 434443.
32. Williams, A-M, Garcia-Borreguero, D. Management of restless legs syndrome augmentation. Curr Treat Options Neurol. 2009; 11(5): 327332.
33. Paulus, W, Trenkwalder, C. Less is more: pathophysiology of dopaminergic-therapy-related augmentation in restless legs syndrome. Lancet Neurol. 2006; 5(10): 878886.
34. Ferini-Strambi, L. Restless legs syndrome augmentation and pramipexole treatment. Sleep Med. 2002; 3(Suppl): S23S25.
35. Winkelman, JW, Johnston, L. Augmentation and tolerance with long-term pramipexole treatment of restless legs syndrome (RLS). Sleep Med. 2004; 5(1): 914.
36. Quilici, S, Abrams, K, Nicolas, A, et al. Meta-analysis of the efficacy and tolerability of pramipexole versus ropinirole in the treatment of restless legs syndrome. Sleep Med. 2008; 9(7): 715726.
37. Miranda, M, Kagi, M, Fabres, L, et al. Pramipexole for the treatment of uremic restless legs in patients undergoing hemodialysis. Neurology. 2004; 62(5): 831832.
38. Oertel, W, Beneš, H, Bodenschatz, R, et al. Efficacy of cabergoline in restless legs syndrome: a placebo-controlled study with polysomnography (CATOR). Neurology. 2006; 67(6): 10401046.
39. Nutt, JG, Woodward, WR, Anderson, JL. The effect of carbidopa on the pharmacokinetics of intravenously administered levodopa: the mechanism of action in the treatment of parkinsonism. Ann Neurol. 1985; 18(5): 537543.
40. Akpinar, L. Restless legs syndrome treatment with dopaminergic drugs. Clin Neuropharmacol. 1987; 10(1): 6979.
41. Saletu, M, Anderer, P, Högl, B, et al. Acute double-blind, placebo-controlled sleep laboratory and clinical follow-up studies with a combination treatment of rr-L-dopa and sr-L-dopa in restless legs syndrome. J Neural Transm. 2003; 110(6): 611626.
42. Allen, RP, Earley, CJ. Augmentation of the restless legs syndrome with carbidopa/levodopa. Sleep. 1996; 19(3): 205213.
43. Högl, B, García-Borreguero, D, Kohnen, R, 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(2): 230237.
44. Trenkwalder, C, Stiasny, K, Pollmächer, T, et al. L-dopa therapy of uremic and idiopathic restless legs syndrome: a double-blind, crossover trial. Sleep. 1995; 18(8): 681688.
45. Walker, SL, Fine, A, Kryger, MH. L-DOPA/carbidopa for nocturnal movement disorders in uremia. Sleep. 1996; 19(3): 214218.
46. Bockbrader, HN, Wesche, D, Miller, R, Chapel, S, Janiczek, N, Burger, P. A comparison of the pharmacokinetics and pharmacodynamics of pregabalin and gabapentin. Clin Pharmacokinet. 2010; 49(10): 661669.
47. Happe, S, Sauter, C, Klösch, G, Saletu, B, Zeitlhofer, J. Gabapentin versus ropinirole in the treatment of idiopathic restless legs syndrome. Neuropsychobiology. 2003; 48(2): 8286.
48. Hassan, HIC, Brennan, F, Collett, G, Josland, EA, Brown, MA. Efficacy and safety of gabapentin for uremic pruritus and restless legs syndrome in conservatively managed patients with chronic kidney disease. J Pain Symptom Manage. 2015; 49(4): 782789.
49. Thorp, ML, Morris, CD, Bagby, SP. A crossover study of gabapentin in treatment of restless legs syndrome among hemodialysis patients. Am J Kidney Dis. 2001; 38(1): 104108.
50. Micozkadıoglu, H, Ozdemir, FN, 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(4): 393397.
51. Joy, MS. Clonazepam: benzodiazepine therapy for the restless legs syndrome. ANNA J. 1997; 24(6): 686689.
52. Saletu, M, Anderer, P, Saletu-Zyhlarz, G, et al. Restless legs syndrome (RLS) and periodic limb movement disorder (PLMD): acute placebo-controlled sleep laboratory studies with clonazepam. Eur Neuropsychopharmacol. 2001; 11(2): 153161.
53. Read, D, Feest, T, Nassim, M. Clonazepam: effective treatment for restless legs syndrome in uraemia. Br Med J (Clin Res Ed). 1981; 283(6296): 885886.
54. Von Spiczak, S, Whone, AL, Hammers, A, et al. The role of opioids in restless legs syndrome: an [11C] diprenorphine PET study. Brain. 2005; 128(4): 906917.
55. Kaplan, PW, Allen, RP, Buchholz, DW, Walters, JK. A double-blind, placebo-controlled study of the treatment of periodic limb movements in sleep using carbidopa/levodopa and propoxyphene. Sleep. 1993; 16(8): 717723.
56. Walters, AS, Winkelmann, J, Trenkwalder, C, et al. Long‐term follow‐up on restless legs syndrome patients treated with opioids. Mov Disord. 2001; 16(6): 11051109.
57. Earley, CJ, Heckler, D, Allen, RP. Repeated IV doses of iron provides effective supplemental treatment of restless legs syndrome. Sleep Med. 2005; 6(4): 301305.
58. Grote, L, Leissner, L, Hedner, J, Ulfberg, J. A randomized, double‐blind, placebo controlled, multi‐center study of intravenous iron sucrose and placebo in the treatment of restless legs syndrome. Mov Disord. 2009; 24(10): 14451452.
59. Giannaki, CD, Hadjigeorgiou, GM, Karatzaferi, C, Pantzaris, MC, Stefanidis, I, Sakkas, GK. Epidemiology, impact, and treatment options of restless legs syndrome in end-stage renal disease patients: an evidence-based review. Kidney Int. 2014; 85(6): 12751282.
60. Winkelmann, J, Stautner, A, Samtleben, W, Trenkwalder, C. Long‐term course of restless legs syndrome in dialysis patients after kidney transplantation. Mov Disord. 2002; 17(5): 10721076.



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