CNS Drugs

, Volume 32, Issue 2, pp 149–159 | Cite as

Use of α2δ Ligands for Restless Legs Syndrome/Willis Ekbom Disease

  • Michele A. Faulkner
Review Article


Restless legs syndrome is a common neurological condition affecting a substantial portion of the population. It can be an idiopathic disorder, or one that is secondary to another cause. Given that the underlying pathophysiology of restless legs syndrome is not well understood, several drug classes have been studied for symptom control. While dopamine agonists have long been the mainstay of first-line treatment for restless legs syndrome, recently, the α2δ ligands have been increasingly used. These agents have proven both efficacious and safe in a number of clinical trials. Additionally, compared with the dopamine agonists, they have been associated with less augmentation, a phenomenon whereby symptoms emerge earlier in the day, become more severe, and may spread to areas of the body previously unaffected. Newer clinical guidelines for restless legs syndrome are increasingly recommending the α2δ ligands as a logical first-choice medication for patients needing drug therapy for symptom control.


Compliance with Ethical Standards


No funding was received for the preparation of this article.

Conflict of interest

Michele A. Faulkner has no conflicts of interest directly relevant to the content of this article.


  1. 1.
    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;88:977–86.CrossRefPubMedGoogle Scholar
  2. 2.
    Hening W, Walters AS, Allen RP, et al. 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(3):237–46.CrossRefPubMedGoogle Scholar
  3. 3.
    Winkelmann J, Schadrack J, Wetter TC, et al. Opioid and dopamine antagonist drug challenges in untreated restless legs syndrome patients. Sleep Med. 2001;2:57–61.CrossRefPubMedGoogle Scholar
  4. 4.
    Picchietti DL, Picchietti MA. Restless legs syndrome: what have we learned from prevalence studies and how will incidence studies further clinical knowledge? J Clin Sleep Med. 2012;8:119–24.Google Scholar
  5. 5.
    Allen RP, Earley CJ. Restless legs syndrome: a review of clinical and pathophysiologic features. J Clin Neurophysiol. 2001;18:128–47.CrossRefPubMedGoogle Scholar
  6. 6.
    Leschziner G, Gringras P. Restless legs syndrome. BMJ. 2013;344:e3056.CrossRefGoogle Scholar
  7. 7.
    Ferini-Strambi L, Marelli S. Pharmacotherapy for restless legs syndrome. Expert Opin Pharmacother. 2014;15(8):1127–38.CrossRefPubMedGoogle Scholar
  8. 8.
    Trenkwalder C, Paulus W. Restless legs syndrome: pathophysiology, clinical presentation and management. Nat Rev Neurol. 2010;6:337–46.CrossRefPubMedGoogle Scholar
  9. 9.
    Ondo WG. Restless legs syndrome: pathophysiology and treatment. Curr Treat Options Neurol. 2014;16(11):317.CrossRefPubMedGoogle Scholar
  10. 10.
    Michaud M, Paquet J, Lavigne G, et al. Circadian rhythm of restless legs syndrome symptoms: relationship with salivary melatonin, core body temperature and subjective vigilance. Ann Neurol. 2004;55:372–80.CrossRefPubMedGoogle Scholar
  11. 11.
    International Restless Legs Syndrome Study Group. 2012 revised IRLSSG diagnostic criteria for RLS. Accessed 28 Jan 2018.
  12. 12.
    Allen RP, Picchietti D, Hening WA, et al. Restless legs syndrome: diagnostic criteria, special considerations, and epidemiology. Sleep Med. 2003;4:101–19.CrossRefPubMedGoogle Scholar
  13. 13.
    Comella CL. Treatment of restless legs syndrome. Neurotherapeutics. 2014;11:177–87.CrossRefPubMedGoogle Scholar
  14. 14.
    Allen RP, Bhamal M, Calloway M. Prevalence and disease burden of primary restless legs syndrome: result of a general population survey in the United States. Mov Disord. 2011;26:114–20.CrossRefPubMedGoogle Scholar
  15. 15.
    Freeman AA, Rye DV. The molecular basis of restless legs syndrome. Curr Opin Neurobiol. 2013;23:895–900.CrossRefPubMedGoogle Scholar
  16. 16.
    Tunς T, Karadağ YS, Doğulu F, Inan LE. Predisposing factors of restless legs syndrome in pregnancy. Mov Disord. 2007;22(5):627–31.CrossRefGoogle Scholar
  17. 17.
    Winkelmann J, Wetter TC, Collado-Seidel V, et al. Clinical characteristics and frequency of the hereditary restless legs syndrome in a population of 300 patients. Sleep. 2000;23:597–602.CrossRefPubMedGoogle Scholar
  18. 18.
    Whittom S, Dauvilliers Y, Pennestri MH, et al. Age-at-onset in restless legs syndrome: a clinical and polysomnographic study. Sleep Med. 2007;9:54–9.CrossRefPubMedGoogle Scholar
  19. 19.
    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;43:70–5.CrossRefPubMedGoogle Scholar
  20. 20.
    Hoque R, Chesson AL. 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(1):79–83.PubMedCentralPubMedGoogle Scholar
  21. 21.
    Aggarwal S, Dodd S, Berk M. Restless leg syndrome associated with olanzapine: a case series. Curr Drug Saf. 2010;5(2):129–31.CrossRefPubMedGoogle Scholar
  22. 22.
    Bolaños-Vergaray J, Obaya JC, Gonzalez R, et al. Restless legs syndrome due to aripiprazole. Eur J Clin Pharmacol. 2011;67(5):539–40.CrossRefPubMedGoogle Scholar
  23. 23.
    Wetter TC, Brunner J, Bronisch T. Restless legs syndrome probably induced by risperidone treatment. Pharmacopsychiatry. 2002;35(3):109–11.CrossRefPubMedGoogle Scholar
  24. 24.
    Neafsey PJ. Role of medications in the etiology and treatment restless leg syndrome. Home Healthc Nurse. 2005;23(4):207–9.CrossRefPubMedGoogle Scholar
  25. 25.
    Akpinar S. Restless legs syndrome treatment with dopaminergic drugs. Clin Neuropharmacol. 1987;10(1):69–79.CrossRefPubMedGoogle Scholar
  26. 26.
    Sethi KD. Restless legs syndrome sees the light of day. Lancet Neurol. 2008;7(7):564–5.CrossRefPubMedGoogle Scholar
  27. 27.
    Connor JR, Boyer PJ, Menzies SL, et al. Neuropathological examination suggests impaired brain iron acquisition in restless legs syndrome. Neurology. 2003;61(3):304–9.CrossRefPubMedGoogle Scholar
  28. 28.
    Oboshi Y, Ouchi Y, Yagi S, et al. In vivo mesolimbic D2/3 receptor binding predicts posttherapeutic clinical responses in restless legs syndrome: a positron emission tomography study. J Cereb Blood Flow Metab. 2012;32(4):654–62.PubMedCentralCrossRefPubMedGoogle Scholar
  29. 29.
    Connor JR, Wang XS, Allen RP, et al. Altered dopaminergic profile in the putamen and substantia nigra in restless leg syndrome. Brain. 2009;132:2403–12.PubMedCentralCrossRefPubMedGoogle Scholar
  30. 30.
    Sun ER, Chen CA, Ho G, et al. Iron and the restless legs syndrome. Sleep. 1998;21(4):3717.CrossRefGoogle Scholar
  31. 31.
    Allen RP, Barker PB, Wehrl F, et al. MRI measurement of brain iron in patients with restless legs syndrome. Neurology. 2001;56:263–5.CrossRefPubMedGoogle Scholar
  32. 32.
    Earley CJ, Barker P, Horska A, et al. MRI-determined regional brain iron concentrations in early and late-onset restless legs syndrome. Sleep Med. 2006;7:458–61.CrossRefPubMedGoogle Scholar
  33. 33.
    Allen R. Dopamine and iron in the pathophysiology of restless legs syndrome (RLS). Sleep Med. 2004;5(4):3850–91.CrossRefGoogle Scholar
  34. 34.
    Connor JR, Wang XS, Patton M, et al. Decreased transferrin receptor expression by neuromelanin cells in restless legs syndrome. Neurology. 2004;62(9):1562–7.CrossRefGoogle Scholar
  35. 35.
    Natarajan R. Review of periodic limb movement and restless leg syndrome. J Postgrad Med. 2010;56:157–62.CrossRefPubMedGoogle Scholar
  36. 36.
    Beard JL, Connor JR. Iron status and neural functioning. Annu Rev Nutr. 2003;23:41–58.CrossRefPubMedGoogle Scholar
  37. 37.
    Garcia-Borreguero D, Kohnen R, Silber MH, 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;14:675–84.CrossRefPubMedGoogle Scholar
  38. 38.
    Ondo WG. Methadone for refractory restless legs syndrome. Mov Disord. 2005;20:345–8.CrossRefPubMedGoogle Scholar
  39. 39.
    Ondo WG. Intravenous iron dextran for severe refractory restless legs syndrome. Sleep Med. 2010;11:494–6.CrossRefPubMedGoogle Scholar
  40. 40.
    Winkelman JW, Schoerning L, Platt S, Jensen JE. Restless legs syndrome and central nervous system gamma-aminobutyric acid: preliminary associations with periodic limb movements in sleep and restless leg syndrome symptom severity. Sleep Med. 2014;15:1225–30.CrossRefPubMedGoogle Scholar
  41. 41.
    Walters AS. Review of receptor agonist and antagonist studies relevant to the opiate system in restless legs syndrome. Sleep Med. 2002;3:301–4.CrossRefPubMedGoogle Scholar
  42. 42.
    Walter AS, Ondo WG, Zhu W, et al. Does the endogenous opiate system play a role in the restless legs syndrome? A pilot post-mortem study. J Neurol Sci. 2009;15:62–5.CrossRefGoogle Scholar
  43. 43.
    Allen RP, Barker PB, Horská A, et al. Thalamic glutamate/glutamine in restless legs syndrome: increased and related to disturbed sleep. Neurology. 2013;80(22):2028–34.PubMedCentralCrossRefPubMedGoogle Scholar
  44. 44.
    Winkelman JW, Armstrong MJ, Allen RP, et al. Practice guideline summary: treatment of restless legs syndrome in adults: report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology. Neurology. 2016;87:2585–93.PubMedCentralCrossRefPubMedGoogle Scholar
  45. 45.
    Stiasny-Kolster K, KohnenR Moller JC, et al. Validation of “l-dopa test” for diagnosis of restless legs syndrome. Mov Disord. 2006;21:1333–9.CrossRefPubMedGoogle Scholar
  46. 46.
    Manconi M, Ferri R, Zucconi M, et al. Pramipexole versus ropinirole: polysomnographic acute effects in restless legs syndrome. Mov Disord. 2011;26:892–5.CrossRefPubMedGoogle Scholar
  47. 47.
    Liu GJ, Wu L, Wang SL, et al. Incidence of augmentation in primary restless legs syndrome patients may not be that high: evidence from a systematic review and meta-analysis. Medicine. 2016;95(2):e2504.PubMedCentralCrossRefPubMedGoogle Scholar
  48. 48.
    Allen RP, Chen C, Garcia-Borreguero D, et al. Comparison of pregabalin with pramipexole for restless legs syndrome. N Engl J Med. 2014;370:621–31.CrossRefPubMedGoogle Scholar
  49. 49.
    Bogan RK, Bornemann MA, Kushida CA, et al. Long-term maintenance treatment of restless legs syndrome with gabapentin enacarbil: a randomized controlled study. Mayo Clin Proc. 2010;85:512–21.PubMedCentralCrossRefPubMedGoogle Scholar
  50. 50.
    Garcia-Borreguero D, Allen RP, Kohnen R, et al. Diagnostic standards for dopaminergic augmentation of restless legs syndrome: report from World Association of Sleep Medicine-International Restless Legs Syndrome Study Group consensus conference at the Max Planck Institute. Sleep Med. 2007;8:20–30.Google Scholar
  51. 51.
    Maestri M, Fulda S, Ferini-Strambi L, et al. Polysomnographic record and successful management of augmentation in restless legs syndrome/Willis–Ekbom disease. Sleep Med. 2014;15:570–5.CrossRefPubMedGoogle Scholar
  52. 52.
    Allen RP, Becker M, Bogan R, et al. Ropinirole decreases periodic leg movements and improves sleep parameters in patients with restless legs syndrome. Sleep. 2004;27:907–14.CrossRefPubMedGoogle Scholar
  53. 53.
    Allen RP, Earley CJ. Augmentation of the restless legs syndrome with carbidopa/levodopa. Sleep. 1996;19:205–13.CrossRefPubMedGoogle Scholar
  54. 54.
    Chen JF, Aloyo VJ, Weiss B. Continuous treatment with the D2 dopamine receptor agonist quinpirole decreases D2 dopamine receptors, D2 dopamine receptor messenger RNA and proenkephalin messenger RNA, and increases mu opioid receptors in mouse striatum. Neuroscience. 1993;54:669–80.CrossRefPubMedGoogle Scholar
  55. 55.
    Garcia-Borreguero D, Egatz R. Changes in dopamine receptor sensitivity during restless legs syndrome augmentation. Sleep Med. 2005;6(Suppl. 2):67S.Google Scholar
  56. 56.
    Paulus W, Trenkwalder C. Less is more: pathophysiology of dopaminergic-therapy-related augmentation in restless legs syndrome. Lancet Neurol. 2006;5:878–86.CrossRefPubMedGoogle Scholar
  57. 57.
    Wijemanne S, Jankovic J. Restless legs syndrome: clinical presentation diagnosis and treatment. Sleep Med. 2015;16:678–90.CrossRefPubMedGoogle Scholar
  58. 58.
    White HS, Rho JM. Mechanisms of action of antiepileptic drugs. West Islip: Professional Communications; 2010.Google Scholar
  59. 59.
    Frampton JE. Oxycodone/naloxone PR: a review in severe refractory restless legs syndrome. CNS Drugs. 2015;29:511–8.CrossRefPubMedGoogle Scholar
  60. 60.
    Trenkwalder C, Benes H, Grote L, et al. Prolonged release oxycodone-naloxone for treatment of severe restless legs syndrome after failure of previous treatment: a double-blind, randomized, placebo-controlled trial with an open-label extension. Lancet Neurol. 2013;12(12):1141–50.CrossRefPubMedGoogle Scholar
  61. 61.
    Earley CH. Restless legs syndrome. N Engl J Med. 2003;348:2103–9.CrossRefPubMedGoogle Scholar
  62. 62.
    Ondo WG. Methadone for refractory restless legs syndrome. Mov Disord. 2005;20(3):345–8.CrossRefPubMedGoogle Scholar
  63. 63.
    Walters AS, Wagner MI, Hening WA, et al. Successful treatment of the idiopathic restless legs syndrome in a randomized double-blind trial of oxycodone versus placebo. Sleep. 1993;16(4):327–32.CrossRefPubMedGoogle Scholar
  64. 64.
    Dooley DJ, Taylor CP, Donevan S, et al. Ca2+ channel alpha2delta ligands: novel modulators of neurotransmission. Trends Pharmacol Sci. 2007;28(2):75–82.CrossRefPubMedGoogle Scholar
  65. 65.
    Davies A, Hendrich J, Van Minh AT, et al. Functional biology of the alpha(2)delta subunits of voltage-gated calcium channels. Trends Pharmacol Sci. 2007;28(5):220–8.CrossRefPubMedGoogle Scholar
  66. 66.
    Steward BH, Kugler AR, Thompson PR, et al. A saturable transport mechanism in the intestinal absorption of gabapentin is the underlying cause of the lack of proportionality between increasing dose and blood levels in plasma. Pharm Res. 1993;10(2):276–81.CrossRefGoogle Scholar
  67. 67.
    Lal R, Sukbuntherng J, Luo W, et al. Pharmacokinetics and tolerability of single escalating doses of gabapentin enacarbil: a randomized-sequence, double-blind, placebo controlled crossover study in healthy volunteers. Clin Ther. 2009;31:1776–86.CrossRefPubMedGoogle Scholar
  68. 68.
    Gidal BE, Radulovic LL, Kruger S, et al. Inter- and intra-subject variability in gabapentin absorption and absolute bioavailability. Epilepsy Res. 2000;40(2–3):123–7.CrossRefPubMedGoogle Scholar
  69. 69.
    Bockbrader HN, Wesche D, Miller R, et al. A comparison of the pharmacokinetics and pharmacodynamics of pregabalin and gabapentin. Clin Pharmacokinet. 2010;49:661–9.CrossRefPubMedGoogle Scholar
  70. 70.
    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;59:1573–9.CrossRefPubMedGoogle Scholar
  71. 71.
    Mellick GA, Miellick LB. Management of restless legs syndrome with gabapentin (Neurontin). Sleep. 1996;19(3):224–6.CrossRefPubMedGoogle Scholar
  72. 72.
    Adler CH. Treatment of restless legs syndrome with gabapentin. Clin Neuropharmacol. 1997;20(2):148–51.CrossRefPubMedGoogle Scholar
  73. 73.
    Hassan HIC, Brennan F, Collett G, et al. Efficacy and safety of gabapentin for uremic pruritis and restless legs syndrome in conservatively managed patients with chronic kidney disease. J Pain Symptom Manag. 2015;49:782–9.CrossRefGoogle Scholar
  74. 74.
    Kumar V, Ambekar N, Singh A, et al. Successful treatment of antipsychotic-induced restless legs syndrome with gabapentin [letter]. Asian J Psychiatr. 2014;9:89–90.CrossRefPubMedGoogle Scholar
  75. 75.
    Bockbrader HN, Wesche D, Miller R, et al. A comparison of the pharmacokinetics and pharmacodynamics of pregabalin and gabapentin. Clin Pharmacokinet. 2010;49(10):661–9.CrossRefPubMedGoogle Scholar
  76. 76.
    Garcia-Borreguero D, Patrick J, DuBrava S, et al. Pregabalin versus pramipexole: effects on sleep disturbance in restless legs syndrome. Sleep. 2014;37:635–43.PubMedCentralCrossRefPubMedGoogle Scholar
  77. 77.
    Garcia-Borreguero D, Larrosa O, Williams AM, et al. Treatment of restless legs syndrome with pregabalin. Neurology. 2010;74:1897–904.CrossRefPubMedGoogle Scholar
  78. 78.
    Allen R, Chen C, Soaita A, 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.CrossRefPubMedGoogle Scholar
  79. 79.
    Sommer M, Bachmann CG, Liebetanz KM, et al. Pregabalin in restless legs syndrome with and without neuropathic pain. Acta Neurol Scand. 2007;115:347–50.CrossRefPubMedGoogle Scholar
  80. 80.
    Cundy KC, Branch R, Chernov-Rogan T, et al. XP13512 [(+/−)-1-9[alpha-isobutanoyloxyethoxy)carbonyl] aminomethyl)-1-cyclohexane acetic acid], a novel gabapentin prodrug: I. Design, synthesis, enzymatic conversion to gabapentin, and transport by intestinal solute transporters. J Pharmacol Exp Ther. 2004;311(1):315–23.CrossRefPubMedGoogle Scholar
  81. 81.
    Cundy KC, Sastry S, Luo W, et al. Clinical pharmacokinetics of XP13512, a novel transported prodrug of gabapentin. J Clin Pharmacol. 2008;48(12):1378–88.CrossRefPubMedGoogle Scholar
  82. 82.
    Lal R, Sukbuntherng J, Luo W, et al. The effects of food with varying fat content on the clinical pharmacokinetics of gabapentin after oral administration of gabapentin enacarbil. Int J Clin Pharamcol Ther. 2010;48(2):120–8.CrossRefGoogle Scholar
  83. 83.
    Kushida CA, Walters AS, Becker P, 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(2):159–68.PubMedCentralCrossRefPubMedGoogle Scholar
  84. 84.
    Walters AS, Ondo WG, Kushida CA, et al. Gabapentin enacarbil in restless legs syndrome: a phase 2b 2-week, randomized, double-blind placebo-controlled trial. Clin Neuropharmacol. 2009;32(6):311–20.CrossRefPubMedGoogle Scholar
  85. 85.
    Kushida CA, Becker PM, Ellenbogen AL, et al. Randomized, double-blind, placebo-controlled study of XP13512/GSK1838262 in patients with RLS. Neurology. 2009;72(5):439–46.CrossRefPubMedGoogle Scholar
  86. 86.
    Bogan RK, Bornemann MA, Kushida CA, et al. Long-term maintenance treatment of restless legs syndrome with gabapentin enacarbil: a randomized controlled study. Mayo Clin Proc. 2010;72(5):439–46.Google Scholar
  87. 87.
    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(3):282–92.PubMedCentralPubMedGoogle Scholar
  88. 88.
    Ellenbogen AL, Thein SG, Winslow DH, et al. A 52-week study of gabapentin enacarbil in restless legs syndrome. Clin Neuropharmacol. 2011;34(1):8–16.CrossRefPubMedGoogle Scholar
  89. 89.
    Winkelman JW, Bogan RK, Schmidt MH, et al. Rancomized polysomnography study of gabapentin enacarbil in subjects with restless legs syndrome. Mov Disord. 2011;26(11):2065–72.CrossRefPubMedGoogle Scholar
  90. 90.
    Kume A. Gabapentin enacarbil for the treatment of moderate to severe primary restless legs syndrome (Willis–Ekbom disease): 600 or 1,200 mg dose? Neuropsychiatr Dis Treat. 2014;10:249–62.PubMedCentralCrossRefPubMedGoogle Scholar
  91. 91.
    Razazian N, Azimi H, Heidarnegadian J, et al. Gabapentin versus levodopa-c for the treatment of restless legs syndrome in hemodialysis patients: a randomized clinical trial. Saudi J Kidney Dis Transpl. 2015;26(2):271–8.CrossRefPubMedGoogle Scholar
  92. 92.
    Sun Y, van Valkenhoef G, Morel T. A mixed treatment comparison of gabapentin enacarbil, pramipexole, ropinirole and rotigotine in moderate-to-severe restless legs syndrome. Cur Med Res Opin. 2014;30(11):2267–78.CrossRefGoogle Scholar
  93. 93.
    Hornyak M, Scholz H, Kohnen R. What treatment works best for restless legs syndrome? Meta-analyses of dopaminergic and non-dopaminergic medications. Sleep Med Rev. 2014;18:153–64.CrossRefPubMedGoogle Scholar
  94. 94.
    Griffin E, Brown JN. Pregabalin for the treatment of restless legs syndrome. Ann Pharmacother. 2016;50(7):586–91.CrossRefPubMedGoogle Scholar
  95. 95.
    Bonnet U, Scherbaum N. How addictive are gabapentin and pregabalin? A systematic review. Eur Neuropsychopharmacol. 2017;27(12):1185–215.CrossRefPubMedGoogle Scholar
  96. 96.
    Avidan AY, Lee D, Park M, et al. The effect of gabapentin enacarbil on quality of life and mood outcomes in a pooled population of adult patients with moderate-to-severe primary restless legs syndrome. CNS Drugs. 2016;30:305–16.CrossRefPubMedGoogle Scholar
  97. 97.
    Abetz L, Allen R, Follet A, et al. Evaluating the quality of life of patients with restless legs syndrome. Clin Ther. 2004;26:925–35.CrossRefPubMedGoogle Scholar
  98. 98.
    Winkelman JW, Gagnon A, Clair AG. Sensory symptoms in restless legs syndrome: the enigma of pain. Sleep Med. 2013;14:934–42.CrossRefPubMedGoogle Scholar
  99. 99.
    Lopes LA, Lins Cde M, Adeodato VG, et al. Restless legs syndrome and quality of sleep in type 2 diabetes. Diabetes Care. 2005;28:2633–6.CrossRefPubMedGoogle Scholar
  100. 100.
    Baldwin DS, Ajel K, Mastrakis VG, et al. Pregabalin for the treatment of generalized anxiety disorder: an update. Neuropsychiatr Dis Treat. 2013;9:883–92.PubMedCentralCrossRefPubMedGoogle Scholar
  101. 101.
    Raja M, Bentivoglio AR. Impulsive and compulsive behaviors during dopamine replacement treatment in Parkinson’s disease and other disorders. Curr Drug Saf. 2012;7(1):63–75.CrossRefPubMedGoogle Scholar
  102. 102.
    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 for the IRLSSG, EURLSSG, and the RLS Foundation. Sleep Med. 2016;21:1–11.CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Schools of Pharmacy and MedicineCreighton UniversityOmahaUSA

Personalised recommendations