Re-evaluating Old and New Therapies for Narcolepsy

Recent research indicates that narcolepsy is a growing problem in the United States.1,2


Research into Type 1 narcolepsy with cataplexy has revealed that many patients have a deficiency in hypocretin, also known as orexin or Hcrt, a neuropeptide hormone produced in the lateral hypothalamus that stabilizes the sleep/wake cycle and promotes wakefulness.3,5,6 In patients with Type 1 narcolepsy associated with cataplexy, the number of Hcrt neurons in the hypothalamus are severely reduced thereby suppressing excitation of certain neurons that support differentiation of sleep/wake states.6 Decreased secretion of hypocretin not only reduces daytime alertness but also interferes with REM sleep, allowing for a blending of the sleep/wake states. This explains the appearance of sleep paralysis in conjunction with hallucinations and cataplexy, all at the point of waking or falling asleep.3

A second pathophysiologic mechanism in Type 1 narcolepsy is autoimmune with a genetic component. Up to 95% of patients with Type 1 narcolepsy have at least 1 HLA-DQB1*0602 allele. However, this allele is also present in 12% to 38% of the unaffected general population, limiting the current clinical utility of HLA typing.3

Clinical Signs of Narcolepsy1,3,7

Narcolepsy is characterized primarily by excessive daytime sleepiness (EDS) and dysregulation of rapid eye movement (REM) sleep. The disruption of REM sleep can result in symptoms of cataplexy during the day. This affects nighttime sleep quality and often manifests as sleep paralysis or hypnagogic and hypnopompic hallucinations. Although these latter symptoms are common, they are not required for a diagnosis of narcolepsy. Only EDS is required for diagnosis.

Primary Symptoms of Narcolepsy1,3,7

EDS: The inability to maintain a wakeful state throughout the day, with involuntary lapses into sleep during waking hours. Patients may refer to their EDS symptoms as fatigue, tiredness, or lack of energy, which are features of many conditions. Clinicians should evaluate patients to uncover possible causes of their reported inability to stay awake during the day.7

Cataplexy: This involuntary sudden loss of muscle tone while awake occurs in approximately three quarters of patients with narcolepsy. Cataplexy is transitory, often beginning in facial muscles as slackening of the jaw and drooping of the head. More pronounced episodes may involve the lower limbs and trunk, causing the individual to collapse while remaining conscious. These symptoms usually occur in parallel with the emergence of EDS but may also appear later in the disease course. An estimated 60% of patients with Type 1 narcolepsy1 and 10% of patients with Type 2 narcolepsy6  experience cataplectic episodes, which are triggered by expressions of emotion.6

Hallucinations: Visual distortions or false perceptions occurring either upon awakening or just before sleep and usually with the patient’s comprehension that they are not real.1,3

Sleep paralysis: An inability to move or speak, lasting for seconds to minutes and most often occurring upon waking or just before falling asleep.1,3

What differentiates Type 1 from Type 2 narcolepsy?
Type 1 has the additional symptom of cataplexy or cerebrospinal fluid hypocretin 1 levels less than 110 pg/mL.

Diagnostic Criteria

Two types of narcolepsy have been identified. Both Type 1 and Type 2 require the presence of the following symptoms and signs:

•       EDS for 3 months or longer that is not explained by other potential causes such as medical and/or psychological conditions, substance overuse, or effects of prescribed medications.
•       Mean sleep latency (MSL) of 8 minutes with 2 or more sleep-onset REM periods shown by results of the MSL Test (MSLT; described below in Assessment Tools for Diagnosis).

These symptoms alone are sufficient for a diagnosis of Type 2 narcolepsy. Cataplexy is only present in Type 1 narcolepsy. Alternatively, cerebrospinal fluid hypocretin-1 levels of 110 pg/mL or lower may substitute for cataplexy in the diagnosis of Type 1 narcolepsy.3

Differential Diagnosis

Idiopathic hypersomnia: A condition that is also characterized by significant daytime sleepiness. The main diagnostic measurement differentiating it from narcolepsy is up to 2 sleep-onset REM sleep periods shown on the MSLT. Unlike patients with narcolepsy, patients with idiopathic hypersomnia usually do not experience fragmented sleep, nocturnal arousals occur less frequently, and daytime naps do not help to restore alertness.3

Kleine-Levin syndrome: A hypersomnia disorder that is less common than narcolepsy. It is characterized by intermittent bouts of sleepiness lasting days to weeks. It is accompanied by cognitive changes and behavioral symptoms such as hyperphagia and hypersexuality.3

Assessment Tools for Diagnosis3,7

Several tools can be used to evaluate and diagnose narcolepsy:

•        Epworth Sleepiness Scale: Administered in the office, this self-rating tool scores the patient’s perception (from 0 to 3) of the chances of falling asleep in 8 different situations. A rating of 0 indicates the patient would never doze and 3 indicates a high change of dozing. Scores below 10 are normal, whereas scores of 10 and above indicate EDS.
•        Pediatric Daytime Sleepiness Scale: Similar to Epworth Sleepiness Scale, this instrument is tailored for the evaluation of children.
•        Actigraphy: A monitoring bracelet that the patient wears for a period of 1 to 2 weeks to measure sleep/wake patterns, sleep duration, bedtimes, and wake times. The patient is asked to complete a sleep log for the duration of the monitoring period to measure subjective observations of these parameters. In order for clinicians to obtain accurate results from actigraphy, all medications with alerting or sedating properties (including antidepressants) should be tapered off 2 to 4 weeks prior to testing.
•        Polysomnography: An overnight test conducted at a monitored sleep study lab. It employs electroencephalogram and electromyography testing to monitor sleep parameters and body movements throughout a single night of sleep. This full-measure test is used to rule out causes of EDS other than narcolepsy.
•        MSLT: Administered subsequent to polysomnography, the MSLT measures sleep and REM latency during 4 to 5 nap opportunities (each 2 hours apart) over the course of a full day. The MSLT is administered 2 hours after waking from an overnight polysomnogram. An average sleep latency of less than 8 minutes is diagnostic for narcolepsy.
•        Maintenance of Wakefulness Test: A test given over 4 periods and lasts 40 minutes each. During the test, the patient is asked to sit without being exposed to any stimulating activity. This test may be used with medication to measure the effects of selected treatments on wakefulness. Notably, the Maintenance of Wakefulness Test is used by the Federal Aviation Administration and other organizations to ensure that its employees are able to remain awake when necessary.
• A cerebrospinal fluid hypocretin-1 level at or below 110 pg/mL is occasionally used instead of the MSLT to diagnose Type 1 narcolepsy.

Current Approved Therapies

Only a few therapies are currently approved by the US Food and Drug Administration (FDA) for the treatment of narcolepsy. Multiple classes of drugs may be used to target either EDS or cataplexy (see Table).

•     Modafinil and armodafinil are first-line choices for the treatment of EDS.1,3 These wakefulness-promoting agents carry a low potential for abuse and are associated with relatively mild adverse effects.3
•       Methylphenidate and amphetamines are often prescribed to manage daytime sleepiness, but they are associated with cardiovascular effects and, rarely, abuse.3
•       Sodium oxybate and antidepressants such as venlafaxine and fluoxetine are commonly prescribed for cataplexy.3
•       Pitolisant was recently approved by the FDA for the treatment of narcolepsy. Meta-analyses showed that pitolisant was superior to modafinil for the treatment of cataplexy in patients who had a high burden of narcolepsy symptoms and was noninferior for the treatment of EDS in Type 1 narcolepsy. 5,8 Both drugs were equally effective treatments for Type 2 narcolepsy.8
•       Solriamfetol, another agent newly approved by the FDA, has shown efficacy for EDS and has acceptable tolerability. Indirect comparisons indicate that improvements in wakefulness seen with solriamfetol may be greater than those achieved with modafinil or armodafinil.1

Nonpharmacologic Treatments

In addition to medications, nonpharmacologic approaches such as counseling and psychosocial guidance are recommended. Scheduled naps lasting 15 to 20 minutes have been shown to improve daytime alertness, and good sleep hygiene improves the quality of nighttime sleep.3 Patients should also be counseled on the effects of caffeine, alcohol, and other substances on sleep and wakefulness. 


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. Acquavella J, Mehra R, Bron M, Suomi JM-H, Hess GP. Prevalence of narcolepsy and other sleep disorders and frequency of diagnostic tests from 2013-2016 in insured patients actively seeking care. J Clin Sleep Med. 2020;16(8):1255-1263. doi:10.5664/jcsm.8482
3. Golden EC, Lipford MC. Narcolepsy: diagnosis and management. Cleve Clin J Med. 2018;85(12):959-969. doi:10.3949/ccjm.85a.17086
4. Thorpy MJ, Krieger AC. Delayed diagnosis of narcolepsy: characterization and impact. Sleep Med. 2014;15(5):502-507. doi:10.1016/j.sleep.2014.01.015
5. Monderer R, Ahmed IM, Thorpy M. Evaluation of the sleepy patient: differential diagnosis. Sleep Med Clin. 2020;15(2):155-166. doi:10.1016/j.jsmc.2020.02.004
6. Fabara SP, Ortiz JF, Anas Sohail A, et al. Efficacy of pitolisant on the treatment of narcolepsy: a systematic review. Cureus. 2021;13(7):e16095. doi: 10.7759/cureus.16095
7. 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. doi:10.1016/j.smrv.2018.09.006
8. Lehert P, Szoeke C. Comparison of modafinil and pitolisant in narcolepsy: a non-inferiority meta-analytical approach. Drugs Context. 2020;9:2020-6-2. doi:10.7573/dic.2020-6-2
9. Mignot EJ. A practical guide to the therapy of narcolepsy and hypersomnia syndromes. Neurotherapeutics. 2012;9(4):739-52. doi: 10.1007/s13311-012-0150-9

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Reviewed March 2022