Narcolepsy is a chronic sleep disorder characterized by severe and persistent daytime sleepiness. The International Classification of Sleep Disorders-Third Edition recognizes 2 types of narcolepsy: narcolepsy type 1 (NT1) and type 2 (NT2). NT1 is associated with the symptom of cataplexy, the sudden loss of muscle tone, which is estimated to affect up to 60% of patients with narcolepsy.1 NT2 presents with the same characteristics as NT1 but excludes cataplexy; however, cataplexy has been later observed in people initially diagnosed with NT2, resulting in its re-diagnosis as NT1.1,2

A relatively rare condition, narcolepsy affects children and adults of both sexes.3 However, the exact prevalence of this condition is challenging to determine due to underdiagnosis and delayed diagnosis.4 The prevalence estimates range from 20 to 67 people per 100,0005 to as many as 180 per 100,000.6 A health care claims database that includes 6703 individuals diagnosed with narcolepsy with and without cataplexy estimates an overall prevalence of 79.4 per 100,000 — 65.4 per 100,000 without cataplexy and 14.0 per 100,000 with cataplexy — with the prevalence increasing with age (Figure).7

Narcolepsy, with or without cataplexy, can have a substantial detrimental effect on well-being and quality of life. Because there is no cure for this condition, current treatments aim to improve wakefulness and reduce cataplexy attacks, sleep disruption, sleep paralysis, and sleep-related hallucinations.3 However, despite their efficacy, conventional treatments that have been used as the standard of care for excessive daytime sleepiness (modafinil, armodafinil, stimulants, and sodium oxybate) and cataplexy (sodium oxybate and venlafaxine) may not be tolerated by some patients. In contrast, for other patients their narcolepsy may become refractory to treatment or treatment may be contraindicated due to comorbidities or the use of concomitant medications.3
New treatment options have emerged from improved understanding of the underlying pathophysiologic mechanisms of narcolepsy, with treatments targeting the histamine 3 receptor and dopamine and norepinephrine reuptake recently being approved.

Optimal Treatment Starts With a Prompt and Accurate Diagnosis

The negative consequences of narcolepsy with or without cataplexy can be seen in various settings, including at schools, workplaces, and social settings. Narcolepsy also increases the risk for serious accidents and injuries. The associated significant health care resource utilization, the detrimental effect on employment, and stigma negatively affect the quality of life of individuals with narcolepsy.8 Effective treatment is critical to the management of this condition, starting with a prompt differential diagnosis, which often requires assessment at specialized sleep centers. Diagnostic evaluation includes sleep history, multiple sleep latency tests, polysomnography, cardiac and pulmonary evaluations, and assessment of muscle and eye movements.9
A diagnosis of NT1 includes excessive daytime sleepiness for at least 3 months that cannot be explained by another sleep disorder, medical or neurologic disorder, mental disorder, medication use, or substance use disorder and at least 1 of the following1,3:

  • Cataplexy and mean sleep latency of 8 minutes or less with at least 2 sleep-onset REM periods (SOREMPs) on multiple sleep latency tests (1 of which can be on the preceding night’s polysomnography), and/or
  • Cerebrospinal fluid hypocretin 1 levels less than 110 pg/mL or one-third of baseline normal levels and mean sleep latency for up to 8 minutes with 2 or more SOREMPs on multiple sleep latency tests.

Data suggest that a SOREMP within 15 minutes of nocturnal sleep onset, in the absence of another sleep disorder, is highly specific (but with low sensitivity) for cataplexy.10 Currently, few clinical practices offer hypocretin testing, although testing for orexin-A/hypocretin-1 in spinal fluid is available through Mayo Clinic Laboratories.11 The diagnosis of NT2 is more challenging due to the nonspecificity of symptoms, limitations of diagnostic tests, and the absence of useful biomarkers.12
The differential diagnosis of NT1 and NT2 can be particularly challenging because other conditions with similar symptomology of excessive daytime sleepiness, including Kleine-Levin syndrome and idiopathic hypersomnia, can be confused with narcolepsy. Comorbid diseases and medications that increase daytime sleepiness also add to the diagnostic challenges. Consequently, diagnostic delays between 10 and 20 years from symptom onset have been reported,3,4 and an estimated 50% of narcolepsy cases remain undiagnosed.13
Improving symptom recognition among health care professionals and a collaborative approach with specialists at sleep centers can improve the differential diagnosis and disease management.13,14

Improved Understanding of Narcolepsy Pathophysiology Guides Development of New Treatment Options

Sleep is a complex biological state controlled by circadian rhythm and brain neurochemicals, and influenced by behavioral and physiologic parameters.15 Understanding the complex neurochemical interplay involved in the wake/sleep cycle and its potential role in narcolepsy and cataplexy requires a review of the role of hypocretin/orexin and histamine. Hypocretin neurons widely project to multiple areas throughout the brain. Dense projection of hypocretin neurons occurs in the serotonergic raphe nuclei, histaminergic tuberomammillary nucleus, and noradrenergic locus coeruleus. In these locations, hypocretin receptors are expressed, which suggests their involvement in the regulation of wake and sleep states.16
The tuberomammillary nucleus, which is stimulated by hypocretin/orexin, is the sole neuronal source of histamine in the brain; it diffusely innervates the cortex, thalamus, and other wake-promoting brain regions.15
Histamine — through its receptors H1, H2, H3, and H4 — modulates processes including wakefulness, feeding, and learning and memory consolidation. Histamine has been recognized as being pivotal in regulating sleep and wakefulness through its interaction with the H1 and H3 receptors.17 H1 receptor agonists induce wakefulness, and H1 receptor antagonists promote sleep. H3 receptors regulate the synthesis and release of histamine; activation reduces the release of histamine, thereby promoting sleep, and blockade promotes wakefulness.3
Although the pathophysiology of cataplexy is not well understood, the same mechanism involved in REM sleep may play a role in cataplexy. When hypocretin-producing neurons stimulate brain areas that inhibit REM sleep, extensive loss of these neurons results in dissociated REM sleep, which may manifest as cataplexy.18 Modulation of the H3 receptors is also thought to affect cataplexy.3
Dysfunction of the hypocretin/orexin system has been implicated in the pathophysiology of narcolepsy with and without cataplexy.3 Deficiency of hypocretin signaling, possibly caused by selective loss of hypocretin-producing neurons in the hypothalamus, is thought to attenuate histamine levels. Overall, NT1 is associated with low levels of hypocretin-1, which is essential to control wakefulness.1
Results of a study suggest that differences in the degradation of the hypocretin peptide differentiate NT1 and NT2. Approximately 90% of individuals with NT1 and 10% to 20% of individuals with NT2 have abnormally low hypocretin-1 levels.16
New compounds have been evaluated that enhance histamine signaling, and clinical trials have shown that these medications reduce sleepiness and cataplexy in narcolepsy.19 Targeting the H3 receptor, along with other targets and compounds, has been explored to treat daytime sleepiness in narcolepsy with and without cataplexy.19
These findings have resulted in the identification of new agents, with several of them currently at various stages of clinical development (Table).

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Pitolisant20,21 and solriamfetol22,23 are the most recently approved treatments for excessive daytime sleepiness associated with narcolepsy (Table). Pitolisant is currently the only H3 receptor antagonist/inverse agonist approved for treating narcolepsy with or without cataplexy in adults in the US and Europe. The approval of pitolisant is based on a series of 4 phase 3 Harmony randomized clinical trials.1,20 The key advantage of pitolisant over conventional wake-promoting treatment options is the lack of effect on dopamine release in the nucleus accumbens and the low rates of treatment-emergent adverse events, both contributing to its tolerability. Clinical trials data suggest that pitolisant is likely to be used as first- or second-line treatment for narcolepsy with or without cataplexy and as an add-on treatment with other narcolepsy medications.1 However, the potential for drug-drug interactions with antidepressants (particularly if used off-label for the treatment of narcolepsy) must be considered.1

Pitolisant adverse effects
Adverse effects commonly reported with pitolisant include insomnia, nausea, and anxiety.

Solriamfetol is a dopamine and norepinephrine reuptake inhibitor; its approval is based on the phase 3 Treatment of Obstructive Sleep Apnea and Narcolepsy Excessive Sleepiness (TONES) clinical trials. Available data suggest that solriamfetol may have efficacy advantages in improving alertness over conventional agents for treating excessive daytime sleepiness. Although there is a lower potential for drug-drug interactions, currently available data suggest that solriamfetol does not significantly affect cataplexy when compared with pitolisant and sodium oxybate.

Solriamfetol adverse effects
Adverse effects commonly reported with solriamfetol include headache, nausea, decreased appetite, insomnia, and anxiety.

Although head-to-head clinical trials of approved agents are not available, insight into the comparative efficacy and safety of different treatments for narcolepsy has been obtained from a network meta-analysis of 14 comparative randomized controlled trials of medical treatments for narcolepsy.24 The treatments compared were sodium oxybate (6 and 9 g/d), modafinil (200-400 mg/d), and pitolisant (up to 20 and up to 40 mg/d). Of note, this study was conducted before the approval of pitolisant and solriamfetol. The study authors concluded that modafinil (200-400 mg/d), sodium oxybate 9 g/d, and pitolisant up to 40 mg/d had similar efficacy in reducing excessive daytime sleepiness. However, only sodium oxybate 9 g/d and pitolisant up to 40 mg/d had a comparable beneficial effect on cataplexy, with pitolisant demonstrating the best benefit:risk ratio.24

A Holistic Approach to Narcolepsy Management

Currently, there is no cure for narcolepsy, and management goals are focused on treatment to reduce symptoms, enhance quality of life, and improve patient safety. A holistic management approach involving behavioral modifications and pharmacotherapy is advocated for both NT1 and NT2.
Behavioral modifications may include intentionally incorporating short naps into the daily schedule and developing good sleep hygiene of a consistent sleep schedule and restful sleep environment. Good health habits that include a balanced diet, regular exercise, and avoiding alcohol and recreational drugs are also important, as is seeking guidance via support groups.
Pharmacotherapy, particularly for cataplexy, aims to improve wakefulness, reduce cataplexy attacks, and treat the symptoms of disturbed nocturnal sleep, sleep paralysis, and sleep-related hallucinations.  Current treatment options include modafinil, armodafinil, stimulants, sodium oxybate, venlafaxine, solriamfetol, and pitolisant.1,22 Until recently, sodium oxybate, was the only medication indicated as a first-line therapy for both excessive daytime sleepiness and cataplexy. Modafinil and armodafinil are options for patients who cannot tolerate sodium oxybate; however, some patients may experience side effects and interactions with other drugs, and there is risk for dependency and abuse with these agents.3
With various options now available, treatment selection remains challenging as there are no clear guideline recommendations on selection or strategy. The consequence is often suboptimal treatment and poor patient outcomes, as revealed in the Unite Narcolepsy survey, which was conducted in collaboration with a patient-focused drug development initiative.3 The survey indicated that, despite treatment for narcolepsy, 57.1% of people continued to experience daytime sleepiness or fatigue 3 or more times per day, and 3.9% reported no daytime sleepiness in response to treatment.3 Adverse events and costs contributed to low treatment adherence, with 12.9% of patients taking their medications 50% to 80% of the time.25
The diagnosis and management of narcolepsy with or without cataplexy in special populations, including children and women of childbearing potential, poses unique clinical challenges due to the lack of recognition of the condition and limited clinical studies.3
In children, excessive daytime sleepiness, cataplexy, and hallucinations during sleep may be poorly understood by parents and the child. In children, diagnosis and treatment are similar compared with adults; lifestyle modifications include a good sleeping and waking routine. Pharmacotherapy is used as needed, and in the absence of evidence-based treatment guidelines or consensus statements, treatment must be individualized for each child’s symptoms.3
In women of childbearing potential, medications were stopped at the time of conception, during pregnancy, and during breastfeeding due to limited studies on the potential effects of narcolepsy medications on the human fetus and neonate. The absence of treatment poses risks that may include compromised safety to both mother and fetus or infant, increased work absences, and potential for unemployment due to poor symptom control.3,26 Increased awareness and improved recognition by physicians of narcolepsy and cataplexy in all patients, particularly in children and women of childbearing age, can improve diagnosis and treatment. In addition, improved awareness by patients and family members and incorporating lifestyle modifications in its management can improve patient safety and quality of life.


1. Thorpy MJ. Recently approved and upcoming treatments for narcolepsy. CNS Drugs. 2020;34(1):9-27. doi:10.1007/s40263-019-00689-1
2. Barateau L, Dauvilliers Y. Recent advances in treatment for narcolepsy. Ther Adv Neurol Disord. 2019;12:1756286419875622. doi:10.1177/1756286419875622
3. Barker EC, Flygare J, Paruthi S, Sharkey KM. Living with narcolepsy: current management strategies, future prospects, and overlooked real-life concerns. Nat Sci Sleep. 2020;12:453-466. doi:10.2147/NSS.S162762
4. Taddei RN, Werth E, Poryazova R, Baumann CR, Valko PO. Diagnostic delay in narcolepsy type 1: combining the patients’ and the doctors’ perspectives. J Sleep Res. 2016;25(6):709-715. doi:10.1111/jsr.12420
5. Silber MH, Krahn LE, Olson EJ, Pankratz VS. The epidemiology of narcolepsy in Olmsted County, Minnesota: a population-based study. Sleep. 2002;25(2):197-202. doi:10.1093/sleep/25.2.197
6. Sleep Foundation. Narcolepsy. What it is, its causes, and the steps that can help manage it. Updated February 17, 2021. Accessed August 4, 2021.
7. Scheer D, Schwartz SW, Parr M, Zgibor J, Sanchez-Anguiano A, Rajaram L. Prevalence and incidence of narcolepsy in a US health care claims database, 2008-2010. Sleep. 2019;42(7):zsz091. doi:10.1093/sleep/zsz091
8. Flores NM, Villa KF, Black J, Chervin RD, Witt EA. The humanistic and economic burden of narcolepsy. J Clin Sleep Med. 2016;12(3):401-7. doi:10.5664/jcsm.5594
9. Golden EC, Lipford MC. Narcolepsy: diagnosis and management. Cleve Clin J Med. 2018;85(12):959-969. doi:10.3949/ccjm.85a.17086
10. Andlauer O, Moore H, Jouhier L, et al. Nocturnal rapid eye movement sleep latency for identifying patients with narcolepsy/hypocretin deficiency. JAMA Neurol. 2013;70(7):891-902. doi:10.1001/jamaneurol.2013.1589
11. Mayo Clinic Laboratories. Orexin-A/hypocretin-1 in spinal fluid. Accessed April 4, 2020.
12. Baumann CR, Mignot E, Lammers GJ, et al. Challenges in diagnosing narcolepsy without cataplexy: a consensus statement. Sleep. 2014;37(6):1035-1042. doi:10.5665/sleep.3756
13. Narcolepsy Link. Recognizing narcolepsy. Your role in facilitating a diagnosis of this chronic disorder. Accessed August 4, 2021.
14. Narcolepsy Link. Diagnosing narcolepsy. A practical reference guide for an underrecognized disorder. Accessed August 4, 2021.
15. Eban-Rothschild A, Appelbaum L, de Lecea L. Neuronal mechanisms for sleep/wake regulation and modulatory drive. Neuropsychopharmacol. 2018;43(5):937-952. doi:10.1038/npp.2017.294
16. Sakai N, Matsumura M, Lin L, Mignot E, Nishino S. HPLC analysis of CSF hypocretin-1 in type 1 and 2 narcolepsy. Sci Rep. 2019;9(1):477. doi:10.1038/s41598-018-36942-8
17. Thakkar MM. Histamine in the regulation of wakefulness. Sleep Med Rev. 2011;15(1):65-74. doi:10.1016/j.smrv.2010.06.004
18. Thompson MD, Sakurai T, Rainero I, Maj MC, Kukkonen JP. Orexin receptor multimerization versus functional interactions: neuropharmacological implications for opioid and cannabinoid signalling and pharmacogenetics. Pharmaceuticals (Basel). 2017 Oct 8;10(4):79. doi:10.3390/ph10040079
19. Scammell TE, Jackson AC, Franks NP, Wisden W, Dauvilliers Y. Histamine: neural circuits and new medications. Sleep. 2019;42(1):zsy183. doi:10.1093/sleep/zsy183
20. Wakix. Prescribing Information. Bioprojet Europe, Ltd; Updated March 2021. Accessed August 9, 2021.
21. European Medicines Agency. Wakix, pitolisant.  Authorized for use in the European Union. Accessed August 4, 2021.
22. Sunosi. Prescribing Information. Jazz Pharmaceuticals, Inc.; Updated March 2019. Accessed August 9, 2021.
23. European Medicines Agency. Sunosi solriamfetol. Authorized for use in the European Union. Accessed August 4, 2021.
24. Lehert P, Falissard B. Multiple treatment comparison in narcolepsy: a network meta-analysis. Sleep. 2018;41(12):zsy185. doi:10.1093/sleep/zsy185
25. Perez-Carbonell L, Lyons E, Gnoni V, et al. Adherence to wakefulness promoting medication in patients with narcolepsy. Sleep Med. 2020;70:50–54. doi:10.1016/j.sleep.2020.02.013
26. Miller MA, Mehta N, Clark-Bilodeau C, Bourjeily G. Sleep pharmacotherapy for common sleep disorders in pregnancy and lactation. Chest. 2020;157(1):184-197. doi:10.1016/j.chest.2019.09.026

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Reviewed August 2021