Skip to main content

Advertisement

SpringerLink
Log in

Treatment of Excessive Daytime Sleepiness in Patients with Narcolepsy

  • Sleep Disorders (A Iranzo, Section Editor)
  • Published:
Current Treatment Options in Neurology Aims and scope Submit manuscript

A Correction to this article was published on 28 November 2019

This article has been updated

Abstract

Purpose of review

The aim of this review is to discuss and summarize the main therapeutic strategies for the management of excessive daytime sleepiness (EDS) in patients with narcolepsy. An overview of novel therapies and potential future options are covered as well.

Recent findings

First line treatments for EDS in narcolepsy patients include modafinil/armodafinil and sodium oxybate. Other options with a stimulant effect, such as methylphenidate and amphetamines are considered if the former do not control the symptoms. More recently, pitolisant (H3 receptor inverse agonist) was approved by the European Medicines Agency, and solriamfetol (dopamine and norepinephrine reuptake inhibitor) by the Food and Drug Administration, for the treatment of EDS in adult narcolepsy patients. Sodium oxybate was recently approved for EDS management in paediatric patients from the age of seven. Further studies involving the paediatric population are warranted to have solid evidence in the management of children with narcolepsy. Ongoing research of new molecules is based on several mechanisms of action (histamine antagonists/inverse agonists, GABA receptor modulators), and potential future strategies involve immunologic treatment and hypocretin-based therapies.

Summary

Additionally to the wakefulness-promoting agents and stimulants classically used, other pharmacologic options have been recently approved for the treatment of EDS in Europe (pitolisant) and the US (solriamfetol). Emerging treatments are under development; newly developed wakefulness-promoting agents act via different mechanisms of action, whereas other forms of therapy are focused in the underlying hypocretin deficiency that characterizes narcolepsy type 1.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Change history

  • 28 November 2019

    The correct spelling of the author should be listed as Laura Pérez-Carbonell, MD as shown above.

References and Recommended Reading

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

  1. Scammell TE. Narcolepsy. N Engl J Med. 2015;373(27):2654–62.

    Article  CAS  PubMed  Google Scholar 

  2. American Academy of Sleep Medicine. Systematic and imperious classification for the diagnosis of sleep disorders in its latest edition. In: International classification of sleep disorders. 3rd edition. In: diagnostic and coding manual. Westchester, IL: American Academy of Sleep Medicine; 2014. Systematic and imperious classification for the diagnosis of sleep disorders in its latest edition.

  3. Andlauer O, Moore H 4th, Hong SC, et al. Predictors of hypocretin (orexin) deficiency in narcolepsy without cataplexy. Sleep. 2012;35:1247–55F.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Barateau L, Lopez R, Dauvilliers Y. Treatment options for narcolepsy. CNS Drugs. 2016;30(5):369–79.

    Article  CAS  PubMed  Google Scholar 

  5. Dauvilliers Y, Barateau L. Narcolepsy and other central Hypersomnias. Continuum (Minneap Minn. 2017;23(4, Sleep Neurology):989–1004.

    Google Scholar 

  6. Thorpy MJ, Dauvilliers Y. Clinical and practical considerations in the pharmacologic management of narcolepsy. Sleep Med. 2015;16(1):9–18 Comprehensive and practical review of available treatments in narcolepsy.

    Article  PubMed  Google Scholar 

  7. Thakrar C, Patel K, D'ancona G, Kent BD, Nesbitt A, Selsick H, et al. Effectiveness and side-effect profile of stimulant therapy as monotherapy and in combination in the central hypersomnias in clinical practice. J Sleep Res. 2018;27(4):e12627.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Schwartz JR. Modafinil in the treatment of excessive sleepiness. Drug Des Devel Ther. 2009;2:71–85.

    PubMed  PubMed Central  Google Scholar 

  9. Billiard M, Besset A, Montplaisir J, Laffont F, Goldenberg F, Weill JS, et al. Modafinil: a double-blind multicentric study. Sleep. 1994;17(8 Suppl):S107–12.

    Article  CAS  PubMed  Google Scholar 

  10. Broughton RJ, Fleming JA, George CF, Hill JD, Kryger MH, Moldofsky H, et al. Randomized, double-blind, placebo-controlled crossover trial of modafinil in the treatment of excessive daytime sleepiness in narcolepsy. Neurology. 1997;49(2):444–51.

    Article  CAS  PubMed  Google Scholar 

  11. Randomized trial of modafinil for the treatment of pathological somnolence in narcolepsy. US Modafinil in Narcolepsy Multicenter Study Group. Ann Neurol. 1998;43(1):88–97.

    Article  Google Scholar 

  12. Randomized trial of modafinil as a treatment for the excessive daytime somnolence of narcolepsy: US Modafinil in Narcolepsy Multicenter Study Group. Neurology. 2000;54(5):1166–75.

    Article  Google Scholar 

  13. Darwish M, Kirby M, Hellriegel ET, Robertson P Jr. Armodafinil and modafinil have substantially different pharmacokinetic profiles despite having the same terminal half-lives: analysis of data from three randomized, single-dose, pharmacokinetic studies. Clin Drug Investig. 2009;29(9):613–23.

    Article  CAS  PubMed  Google Scholar 

  14. US Xyrem Multicenter Study Group. A randomized, double blind, placebo-controlled multicenter trial comparing the effects of three doses of orally administered sodium oxybate with placebo for the treatment of narcolepsy. Sleep. 2002;25(1):42–9.

    Google Scholar 

  15. US Xyrem Multicenter Study Group. A 12-month, open-label, multicenter extension trial of orally administered sodium oxybate for the treatment of narcolepsy. Sleep. 2003;26(1):31–5.

    Google Scholar 

  16. Mamelak M, Black J, Montplaisir J, Ristanovic R. A pilot study on the effects of sodium oxybate on sleep architecture and daytime alertness in narcolepsy. Sleep. 2004;27(7):1327–34.

    Article  PubMed  Google Scholar 

  17. Xyrem International Study Group. A double-blind, placebo-controlled study demonstrates sodium oxybate is effective for the treatment of excessive daytime sleepiness in narcolepsy. J Clin Sleep Med. 2005;1(4):391–7.

    Google Scholar 

  18. Boscolo-Berto R, Viel G, Montagnese S, Raduazzo DI, Ferrara SD, Dauvilliers Y. Narcolepsy and effectiveness of gamma-hydroxybutyrate (GHB): a systematic review and meta-analysis of randomized controlled trials. Sleep Med Rev. 2012;16(5):431–43.

    Article  PubMed  Google Scholar 

  19. Black J, Houghton WC. Sodium oxybate improves excessive daytime sleepiness in narcolepsy. Sleep. 2006;29(7):939–46.

    Article  PubMed  Google Scholar 

  20. Wang YG, Swick TJ, Carter LP, Thorpy MJ, Benowitz NL. Safety overview of postmarketing and clinical experience of sodium oxybate (Xyrem): abuse, misuse, dependence, and diversion. J Clin Sleep Med. 2009;5(4):365–71. Review.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Mitler MM, Shafor R, Hajdukovich R, Timms RM, Browman CP. Treatment of narcolepsy: objective studies on methylphenidate, pemoline, and protriptyline. Sleep. 1986;9(1 Pt 2):260–4.

    Article  CAS  PubMed  Google Scholar 

  22. Billiard M, Bassetti C, Dauvilliers Y, Dolenc-Groselj L, Lammers GJ, Mayer G, et al. EFNS task force. EFNS guidelines on management of narcolepsy. Eur J Neurol. 2006;13(10):1035–48.

    Article  CAS  PubMed  Google Scholar 

  23. Barateau L, Lopez R, Dauvilliers Y. Management of Narcolepsy. Curr Treat Options Neurol. 2016;18(10):43.

    Article  PubMed  Google Scholar 

  24. Shindler J, Schachter M, Brincat S, Parkes JD. Amphetamine, mazindol, and fencamfamin in narcolepsy. Br Med J (Clin Res Ed). 1985 Apr 20;290(6476):1167–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Mitler MM, Hajdukovic R, Erman M, Koziol JA. Narcolepsy. J Clin Neurophysiol. 1990;7(1):93–118.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Mitler MM, Hajdukovic R, Erman MK. Treatment of narcolepsy with methamphetamine. Sleep. 1993;16(4):306–17.

    Article  CAS  PubMed  Google Scholar 

  27. Barateau L, Jaussent I, Lopez R, Boutrel B, Leu-Semenescu S, Arnulf I, et al. Smoking, alcohol, drug use, abuse and dependence in narcolepsy and idiopathic hypersomnia: a case-control study. Sleep. 2016 Mar 1;39(3):573–80.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Syed YY. Pitolisant: first global approval. Drugs. 2016;76(13):1313–8.

    Article  CAS  PubMed  Google Scholar 

  29. Dauvilliers Y, Bassetti C, Lammers GJ, et al.; HARMONY I study group. Pitolisant versus placebo or modafinil in patients with narcolepsy: a double-blind, randomised trial. Lancet Neurol. 2013;12(11):1068–75. Pivotal study demonstrating efficacy and safety of pitolisant for the treatment of daytime sleepiness in adult patients with narcolepsy.

    Article  CAS  PubMed  Google Scholar 

  30. Kollb-Sielecka M, Demolis P, Emmerich J, Markey G, Salmonson T, Haas M. The European medicines agency review of pitolisant for treatment of narcolepsy: summary of the scientific assessment by the Committee for Medicinal Products for human use. Sleep Med. 2017;33:125–9.

    Article  PubMed  Google Scholar 

  31. Szakacs Z, Dauvilliers Y, Mikhaylov V, et al. Safety and efficacy of pitolisant on cataplexy in patients with narcolepsy: a randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2017;16(3):200–7.

    Article  CAS  PubMed  Google Scholar 

  32. https://www.ema.europa.eu/en/documents/product-information/wakix-epar-product-information_en.pdf.

  33. •• Szabo ST, Thorpy MJ, Mayer G, Peever JH, Kilduff TS. Neurobiological and immunogenetic aspects of narcolepsy: implications for pharmacotherapy. Sleep Med Rev. 2019;43:23–36 Excellent review of underlying pathophysiological mechanisms of narcolepsy and potential therapeutic targets.

    Article  PubMed  Google Scholar 

  34. Bogan RK, Feldman N, Emsellem HA, Rosenberg R, Lu Y, Bream G, et al. Effect of oral JZP-110(ADX-N05) treatment on wakefulness and sleepiness in adults with narcolepsy. Sleep Med. 2015;16(9):1102–8.

    Article  PubMed  Google Scholar 

  35. Ruoff C, Swick TJ, Doekel R, Emsellem HA, Feldman NT, Rosenberg R, et al. Effect of Oral JZP-110(ADX-N05) on wakefulness and sleepiness in adults with narcolepsy: a phase 2b study. Sleep. 2016;39(7):1379–87.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Thorpy MJ, Shapiro C, Mayer G, Corser BC, Emsellem H, Plazzi G, et al. A randomized study of solriamfetol for excessive sleepiness in narcolepsy. Ann Neurol. 2019;85(3):359–70. Recent study demonstrating efficacy and safety of this novel treatment in the management of daytime sleepiness in adult patients with narcolepsy.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/211230s000lbl.pdf.

  38. Nittur N, Konofal E, Dauvilliers Y, Franco P, Leu-Semenescu S, Cock VCD, et al. Mazindol in narcolepsy and idiopathic and symptomatic hypersomnia refractory to stimulants: a long-term chart review. Sleep Med. 2013;14(1):30–6.

    Article  PubMed  Google Scholar 

  39. Mayer G, Ewert Meier K, Hephata K. Selegeline hydrochloride treatment in narcolepsy. A double-blind, placebo-controlled study. Clin Neuropharmacol. 1995;18(4):306–19.

    Article  CAS  PubMed  Google Scholar 

  40. Trotti LM, Saini P, Koola C, LaBarbera V, Bliwise DL, Rye DB. Flumazenil for the treatment of refractory Hypersomnolence: clinical experience with 153 patients. J Clin Sleep Med. 2016;12(10):1389–94.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Trotti LM, Saini P, Bliwise DL, Freeman AA, Jenkins A, Rye DB. Clarithromycin in γ-aminobutyric acid-related hypersomnolence: a randomized, crossover trial. Ann Neurol. 2015;78(3):454–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Rogers AE, Aldrich MS, Lin X. A comparison of three different sleep schedules for reducing daytime sleepiness in narcolepsy. Sleep. 2001;24(4):385–91.

    Article  CAS  PubMed  Google Scholar 

  43. Marín Agudelo HA, Jiménez Correa U, Carlos Sierra J, Pandi-Perumal SR, Schenck CH. Cognitive behavioral treatment for narcolepsy: can it complement pharmacotherapy? Sleep Sci. 2014;7(1):30–42.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Morgenthaler TI, Kapur VK, Brown T, Swick TJ, Alessi C, Aurora RN, et al. Standards of practice Committee of the American Academy of sleep medicine. Practice parameters for the treatment of narcolepsy and other hypersomnias of central origin. Sleep. 2007;30(12):1705–11. Review.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Nevsimalova S. The diagnosis and treatment of pediatric narcolepsy. Curr Neurol Neurosci Rep. 2014;14(8):469.

    Article  PubMed  Google Scholar 

  46. Wise MS. Childhood narcolepsy. Neurology. 1998 Feb;50(2 Suppl 1):S37–42. Review.

    Article  CAS  PubMed  Google Scholar 

  47. Postiglione E, Antelmi E, Pizza F, Lecendreux M, Dauvilliers Y, Plazzi G. The clinical spectrum of childhood narcolepsy. Sleep Med Rev. 2018;38:70–85.

    Article  PubMed  Google Scholar 

  48. Lecendreux M. Pharmacological management of narcolepsy and cataplexy in pediatric patients. Paediatr Drugs. 2014;16(5):363–72.

    Article  PubMed  Google Scholar 

  49. Lecendreux M, Bruni O, Franco P, Gringras P, Konofal E, Nevsimalova S, et al. Clinical experience suggests that modafinil is an effective and safe treatment for paediatric narcolepsy. J Sleep Res. 2012;21(4):481–3.

    Article  PubMed  Google Scholar 

  50. Assess the Safety and Effectiveness of PROVIGIL Treatment in Children and Adolescents With Excessive Sleepiness. NCT00214968. 2005. Available from: https://clinicaltrials.gov/ [Last accessed 28 July 2019].

  51. Plazzi G, Ruoff C, Lecendreux M, Dauvilliers Y, Rosen CL, Black J, et al. Treatment of paediatric narcolepsy with sodium oxybate: a double-blind, placebo-controlled, randomised-withdrawal multicentre study and open-label investigation. Lancet Child Adolesc Health. 2018;2(7):483–94. Recent study that has confirmed the efficacy and safety of sodium oxybate in paediatric patients with narcolepsy from the age of seven.

    Article  Google Scholar 

  52. Efficacy and Safety of Pitolisant in Pediatric Narcoleptic Patients With or Without Cataplexy, Double-blind Study Followed by a Prolonged Open-label Period. NCT02611687. 2015. Available from: https://clinicaltrials.gov/ [Last accessed 29 July 2019].

  53. Thorpy M, Zhao CG, Dauvilliers Y. Management of narcolepsy during pregnancy. Sleep Med. 2013;14(4):367–76.

    Article  PubMed  Google Scholar 

  54. Abad VC, Guilleminault C. New developments in the management of narcolepsy. Nat Sci Sleep. 2017;9:39–57.

    Article  PubMed  PubMed Central  Google Scholar 

  55. Phase II randomized, double-blind, double-dummy, placebo and comparator-controlled, parallel group, multi-center study to investigate the safety and efficacy of a single dose of JNJ-17216498 administered to subjects with narcolepsy. NCT00424931. 2014. Available from: https://clinicaltrials.gov/ [Last accessed 28 July 2019].

  56. A randomized, placebo-controlled, double-blind, fixed-dose, multiple cohort, multiple crossover, dose-finding study of oral BTD-001 in adults with idiopathic hypersomnia (IH) or Narcolepsy type 2. NCT02512588. 2017. Available from: https://clinicaltrials.gov/ [Last accessed 28 July 2019].

  57. Huang YS, Guilleminault C. Narcolepsy: action of two γ-aminobutyric acid type B agonists, baclofen and sodium oxybate. Pediatr Neurol. 2009;41(1):9–16.

    Article  PubMed  Google Scholar 

  58. Black SW, Morairty SR, Chen TM. At al. GABAB agonism promotes sleep and reduces cataplexy in murine narcolepsy. J Neurosci. 2014;34(19):6485–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. The effect of caffeine on the narcoleptic patients randomized controlled clinical trial. NCT02832336. 2016. Available from: https://clinicaltrials.gov/ [Last accessed 28 July 2019].

  60. Sodium Oxybate for Treatment of Excessive Daytime Sleepiness and Cataplexy in Narcolepsy. NCT02720744. 2016. Available from: https://clinicaltrials.gov/ [Last accessed 28 July 2019].

  61. Safety and Efficacy of THN102 on Sleepiness in Narcoleptic Patients. NCT02821715. 2017. Available from: https://clinicaltrials.gov/ [Last accessed 28 July 2019].

  62. Takenoshita S, Sakai N, Chiba Y, Matsumura M, Yamaguchi M, Nishino S. An overview of hypocretin based therapy in narcolepsy. Expert Opin Investig Drugs. 2018;27(4):389–406.

    Article  CAS  PubMed  Google Scholar 

  63. Nepovimova E, Janockova J, Misik J, Kubik S, Stuchlik A, Vales K, et al. Orexin supplementation in narcolepsy treatment: a review. Med Res Rev. 2019;39(3):961–75.

    Article  PubMed  CAS  Google Scholar 

  64. Bhattarai J, Sumerall S. Current and future treatment options for narcolepsy: a review. Sleep Sci. 2017;10(1):19–27.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Sleep Disorders Centre, Guy’s and St Thomas’ NHS Foundation Trust, 18-20 Newcomen St, London, SE1 1UL, UK

    Laura Pérez-Carbonell MD

Authors
  1. Laura Pérez-Carbonell MD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Laura Pérez-Carbonell MD.

Ethics declarations

Conflict of Interest

Laura Pérez-Carbonell declares no potential conflicts of interest.

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.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

The original version of this article was revised: The correct spelling of the author should be listed as Laura Pérez-Carbonell, MD as shown above.

This article is part of the Topical Collection on Sleep Disorders

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Pérez-Carbonell, L. Treatment of Excessive Daytime Sleepiness in Patients with Narcolepsy. Curr Treat Options Neurol 21, 57 (2019). https://doi.org/10.1007/s11940-019-0595-9

Download citation

  • Published:

  • DOI: https://doi.org/10.1007/s11940-019-0595-9

Keywords

Search

Navigation