Elsevier LogoRare Diseases

    ThisiscontentfromClinicalKey

    Narcolepsy

    Sign up for your free ClinicalKey trial today!  Your first step in getting the right answers when you need them.

    Start Free Trial
    Jul.30.2025

    Narcolepsy

    Synopsis

    Key Points

    • Narcolepsy is an incurable sleep disorder characterized by excessive daytime sleepiness that may be associated with cataplexy, hypnagogic hallucination, or sleep paralysis
    • Diagnostic criteria for type 1 narcolepsy include: r1
      • Periods of excessive sleepiness that occur daily
      • Cataplexy and multiple sleep latency test showing mean sleep latency of 8 minutes or less and 2 or more periods of sleep-onset rapid eye movement or 1 sleep-onset rapid eye movement within 15 minutes of sleep onset on nocturnal polysomnography
        • Or orexin A level in cerebrospinal fluid of 110 pg/mL or less or less than one-third of mean values in controls
      • Signs and symptoms not explained by another sleep or mental disorder, or drug or substance use or withdrawal
    • Diagnostic criteria for type 2 narcolepsy include: r1
      • Periods of excessive sleepiness that occur daily for at least 3 months
      • Mean sleep latency of 8 minutes or less and 2 or more periods of sleep-onset rapid eye movement. 1 sleep-onset rapid eye movement within 15 minutes of sleep onset on nocturnal polysomnography may replace 1 of the sleep-onset rapid eye movements on the multiple sleep latency test
      • Cataplexy is not present
      • Orexin A level, if obtained, greater than 110 pg/mL or greater than one-third of mean values in controls
      • Signs and symptoms not explained by another sleep or mental disorder, or drug or substance use or withdrawal
    • Treatment of excessive daytime sleepiness includes improved sleep hygiene and use of short 15-minute naps during the day
    • Most patients require drug therapy that may be used in combination including central nervous system stimulants (eg, modafinil, armodafinil, solriamfetol, methylphenidate, amphetamines), oxybates (sodium or mixed), and pitolisant
    • Antidepressants (eg, venlafaxine, fluoxetine, clomipramine) can decrease the incidence of cataplexy and are also used to suppress severe hypnagogic hallucinations and sleep paralysis
    • There is no cure for narcolepsy; however, symptoms can be improved with drug therapy and good sleep hygiene r2

    Pitfalls

    • Historically overdiagnosed owing to a dependence on the multiple sleep latency test, which has high false-positive and false-negative rates for diagnosis r3
      • Consider both clinical history and other tests (eg, orexin A) to reliably diagnose

    Terminology

    Clinical Clarification

    • Narcolepsy is a sleep disorder characterized by excessive daytime sleepiness and, depending upon the subtype, can be associated with the following: r4
      • Cataplexy
      • Mean sleep latency of 8 minutes or less
      • Rapid eye movement sleep latency (time from start of sleep to onset of rapid eye movement) of 15 minutes or less
      • Orexin A (hypocretin-1) deficiency in cerebrospinal fluid
      • Hypnagogic or hypnopompic hallucinations, or sleep paralysis

    Classification

    • Type 1 narcolepsy (60%-70% of cases)r3
      • Presence of cataplexy (transient loss of motor tone triggered by emotions; generally bilateral and brief, lasting less than 2 minutes) r5
      • Associated with cerebrospinal fluid orexin A deficiencyr5(less than 10% of patients with cataplexy have orexin A levels within reference range)r6
    • Type 2 narcolepsy (unknown prevalence)
      • Absence of cataplexy r5
      • Associated with cerebrospinal fluid orexin A levels within reference range (only 10%-15% of patients have low orexin A levels) r5
      • As clinical history changes or cerebrospinal fluid orexin A level is measured, patients initially categorized with type 2 narcolepsy may instead be diagnosed with type 1 r7
    • Secondary narcolepsy due to medical condition (often present with cataplexy) r3
      • Prader-Willi syndrome
      • Niemann-Pick disease, type C
      • Multiple sclerosis
      • Hypothalamic lesion
      • Post–head trauma
      • Postencephalitis
    • Unspecified narcolepsy r8

    Diagnosis

    Clinical Presentation

    History

    • Daily excessive daytime sleepiness (eg, Epworth Sleepiness Scale greater than 10) that can be associated with: r4r5r9c1
      • Frequent short naps (5-15 minutes) during daytime, usually refreshing and associated with dreams r5c2
      • Sudden, brief sleep episodes (ie, sleep attacks) during stimulating situations (eg, driving, walking, talking) c3
        • Sleep attacks are generally longer in children, up to 2 to 3 hours r10
      • Nocturnal insomnia r3c4
    • Presence of cataplexy r4r5c5
      • Characterized by transient loss of motor tone triggered by strong emotions (eg, joy, amusement)
        • May affect all muscles (except diaphragm and extraocular muscles) or be segmental, affecting the face, speech muscles, or limbs
        • Generally bilateral; consciousness is preserved
        • Unique features such as sticking out the tongue, eyelid weakness, and abnormal facial expressions can be seen in children
      • Duration of seconds to minutes
      • Specific to type 1 narcolepsy
      • Occurs in 60% to 70% of patients r3
    • Presence of hypnagogic or hypnopompic hallucinations r5c6c7c8c9
      • Vivid sensory images that occur at sleep onset (hypnagogic) or awakening (hypnopompic)
      • Hallucinations can be visual, auditory, or tactile
      • Occur in 30% to 60% of type 1 narcolepsy patients and 15% of type 2 narcolepsy patients r5
    • Sleep paralysis r5c10c11
      • Transient inability to move or speak at sleep onset
      • Lasts seconds to minutes
      • Occurs in 50% of type 1 narcolepsy patients r5
        • Sleep paralysis prevalence is unknown in type 2 narcolepsy patients
    • Sleep diary and use of smartwatch (ie, actigraphy) can provide further data regarding sleep duration and sleep-wake times r11

    Physical examination

    • Physical examination of patients with suspected narcolepsy is unremarkable and no objective findings assist in diagnosing the disorder; however, during cataplectic episodes, deep tendon reflexes are diminished or absent r5c12c13

    Causes and Risk Factors

    Causes c14

    • Environmental exposures (eg, bacterial or viral infections) in patients with genetic predisposition can activate CD4+ and CD8+ T cells leading to destruction of orexin A neurons in the brain, particularly the lateral hypothalamus, in patients with type 1 narcolepsy r4r5
      • Orexin A is a neuropeptide involved in regulation of wakefulness, arousal, and appetite
      • Orexin A in cerebrospinal fluid level of 110 pg/mL or less, or less than one-third of control values, is common in patients with type 1 narcolepsy r4r12c15
    • Mechanism underlying type 2 narcolepsy is unknown r4

    Risk factors and/or associations

    Age
    • Although onset ranges from early childhood to age 60 years, it peaks in patients aged 15 to 36 years r3c16
    Genetics
    • Family history of narcolepsy c17
      • Increased relative risk (10- to 40-fold) of type 1 narcolepsy is found in first-degree relatives of narcolepsy patients r5
      • HLA-DQB1*06:02 haplotype is associated with development of narcolepsy r3r4c18
        • 98% of patients with narcolepsy with type 1 narcolepsy possess this haplotype r4r5c19
        • 40% to 50% of patients with type 2 narcolepsy have this haplotype r4r5
        • 25% of the general population possesses this haplotype r5

    Diagnostic Procedures

    Primary diagnostic tools

    • Diagnosis is based on the clinical manifestation of excessive daytime sleepiness, a polysomnogram followed by multiple sleep latency test, and presence or absence of cataplexy r4r12c20c21c22c23
      • Diagnosis of type 1 narcolepsy can be confirmed with low cerebrospinal fluid orexin A measurement
    • HLA typing can be obtained for further supportive evidence (when present) for narcolepsy, and it is particularly useful in children owing to its relative noninvasiveness; however, HLA results are no longer included in diagnostic criteria
    • Historically overdiagnosed owing to a dependence on the multiple sleep latency test, which has high false-positive (and false-negative) rates for diagnosis r3
      • Consider both clinical history and other tests (eg, orexin A test) to reliably diagnose

    Laboratory

    • Cerebrospinal fluid orexin A level of 110 pg/mL or less, or below one-third of control values, is indicative of type 1 narcolepsy r13c24
    • Obtain HLA typing, particularly in children
      • Positive finding of HLA-DQB1*06:02 haplotype is supportive of a narcolepsy diagnosis, but it is not diagnostic because it lacks specificity r3c25

    Functional testing

    • Polysomnographyr14 and multiple sleep latency testr15c26c27
      • Indicated for all adult patients and children aged 6 years and olderr10 with signs and symptoms suggestive of narcolepsy according to clinical presentation r5
        • Discontinue any sedating or stimulatory medications 2 weeks before the test to avoid inaccurate results (ie, washout) r15
        • Demonstrate a regular sleep-wake cycle by maintaining a sleep diary or by using actigraphy (measurement of activity and rest by a small, worn sensor) during that time r5
        • At least 6 hours of nocturnal sleep are necessary before performing the test r15
      • Overnight polysomnogram (of at least 6 hours) helps to exclude other causes of night sleep disruption (eg, sleep apnea, periodic limb movement disorder) r5
      • Next day multiple sleep latency test can measure the ability to sleep reflected by sleep latency during 20-minute nap opportunities (5 nap opportunities at 2-hour intervals), including the following 2 parameters: r15
        • Mean sleep latency: arithmetic mean of all naps or nap opportunities
        • Number of sleep-onset rapid eye movement periods during naps
      • Continuous 24-hour polysomnogram is performed in toddlers and children younger than 6 years r10
      • Results
        • Sleep latency of 8 minutes or less and 2 or more sleep-onset rapid eye movement periods are diagnostic of narcolepsy r5
          • Diagnostic specificity of multiple sleep latency test is 60%; when 2 or more sleep-onset rapid eye movement periods are present, diagnostic specificity increases to 95%
        • High false-positive and false-negative rates for diagnosis r3
          • Among patients without narcolepsy, 6% of males and 1.5% of females have test results that are diagnostic for this condition r3
          • 6% of patients with sleep-disordered breathing and 4% of patients with other sleep disorders test positive on the multiple sleep latency test r3
          • Some patients with orexin A deficiency and diagnosis of type 1 narcolepsy have normal multiple sleep latency test results r3
          • Underlies the importance of interpreting multiple sleep latency test results within the clinical context

    Procedures

    Lumbar puncture r5
    Indication
    • For diagnostic clarity when the multiple sleep latency test is not available or feasible, measure orexin A level using radioimmunoassay (recommended, but not required)
    Interpretation of results
    • Orexin A level of 110 pg/mL or less, or less than one-third of mean values in normal controls, is indicative of type 1 narcolepsy r16

    Differential Diagnosis

    Most common

    • Disorders with excessive daytime sleepiness
      • Idiopathic hypersomnia r17c28
        • Like narcolepsy, patient complains of excessive sleep
          • 10 or more hours of nighttime sleep plus daytime naps (total sleep time typically does not exceed 12 hours on weekdays, but may be as long as 19 hours on weekends or holidays) r17
          • For a diagnosis of idiopathic hypersomnia, symptoms have to be present for 3 months or longer r17
        • Differentiate from narcolepsy by:
          • Lack of restive naps during the day
          • Prolonged sleep
          • Diagnosis established through a series of sleep studies
            • Overnight polysomnogram
              • Differentiates idiopathic hypersomnia from narcolepsy and other sleep disturbances (eg, obstructive sleep apnea, periodic legs movement disorder)
            • Multiple sleep latency test r15
              • Less than 2 sleep-onset rapid eye movement periods r17
              • Mean sleep latency of 8 minutes or less
      • Sleep apnea c29
        • 1 or more pauses in breathing or shallow breaths during sleep
          • Breathing pauses can last from a few seconds to minutes and may occur 30 times or more per hour
          • Typically, normal breathing resumes, sometimes with a loud snort or choking sound
          • Sleep quality is poor, which results in excessive daytime sleepiness with frequent episodes of falling asleep, similar to narcolepsy
        • Differentiate from narcolepsy by history of pause in breathing during sleep, detected by polysomnography with apnea-hypopnea index of 5 or more (ie, number of apnea or hypopnea episodes per hour) r18
      • Advanced sleep phase syndrome c30
        • Circadian rhythm disorder defined by a stable sleep schedule that is several hours earlier than the desired sleep schedule, to the degree that the patient experiences significant difficulty keeping to a desired sleep schedule
        • Patients with advanced sleep phase syndrome are sleepy; they retire to bed early in the evening and wake up early in the morning. Sleep attacks are not reported
        • Differentiate by history of very early awakening associated with early bedtime and, if needed, polysomnography to exclude narcolepsy r19
      • Delayed sleep phase syndrome c31
        • Most prevalent circadian rhythm disorder; defined by delayed onset of sleep beyond the conventional bedtime, associated with difficulty in awakening at the desired time
        • Results in daytime sleepiness due to sleep deprivation; sleep attacks are not reported
        • Differentiate by history of late bedtime associated with difficulty arising at a desired (typically more conventional) time and, if needed, polysomnography to exclude narcolepsy
      • Depression with excessive daytime sleepiness c32d1
        • Disruption or irregularity in the circadian sleep-wake cycle resulting in excessive sleepiness or wakefulness at inappropriate times of day or night
        • Sleep attacks are not reported
        • Occurs in patients with depressive disorders and usually responds well to treatment of depression
        • Differentiate by history of depression and response to treatment of depression; if needed, perform multiple sleep latency test to exclude narcolepsy r5
      • Restless legs syndrome or periodic limb movement during sleep with subsequent excessive sleepiness c33
        • Irresistible urge to move the legs to avoid uncomfortable sensations, resulting in sleep disruption
        • Most patients with restless legs syndrome also have periodic limb movement during sleep, which results in nighttime awakening and daytime sleepiness
        • Sleep attacks are not reported
        • Differentiate from narcolepsy by history of restless legs when trying to sleep or periodic limb movements that disrupt sleep and multiple sleep latency test to exclude narcolepsy r5
    • Disorders with cataplexy
      • Cataplexy-like episodes in sleepy or nonsleepy patients (without narcolepsy) c34
        • Differentiate by involvement of only the lower limbs, triggered by positive and negative emotions r5
      • Cataplexy-like episodes in psychiatric patients c35
        • Differentiate by: r5
          • Prolonged duration
          • Unusual triggers and circumstances
          • Psychiatric history

    Treatment

    Goals

    • Minimize or eliminate excessive daytime sleepiness r4r8r11
    • Minimize or eliminate cataplectic episodes r4r8r11

    Disposition

    Recommendations for specialist referral

    • Refer to pediatric neurologist when narcolepsy is suspected in children, especially those younger than 6 years, owing to the difficulty in making the diagnosis
    • Neurologic consultation is recommended when the diagnosis is unclear and assistance is needed for medication management

    Treatment Options

    First step in treating narcolepsy is to provide guidance about appropriate sleep hygiene r3

    Some patients may prefer to manage without medication and may be able to adjust nap schedules that allow reasonable control r3

    • Limit naps to approximately 15 minutes
    • In prepubertal and pubertal children, at least 2 naps (lunchtime and between 4 PM and 5 PM) are recommended r10

    Most patients are managed with drug therapy r4r8r11r20r21

    • To address excessive daytime sleepiness, first line drugs include modafinil, armodafinil, pitolisant, solriamfetol, and sodium oxybate, while methylphenidate and amphetamines are considered second and third line, respectively
      • Stimulant medications (eg, modafinil, armodafinil) decrease daytime sleepiness and improve symptoms in a large majority of patients r4r21
    • Oxybates and pitolisant are used to manage cataplexy
    • Use of antidepressants to treat cataplexy is based on expert consensus. Doses are lower than those used to treat depression
    • Central nervous system stimulants
      • Those frequently used include: r22
        • Modafinil
          • First line treatment for patients with excessive daytime sleepiness of mild to moderate degree
          • May also be used in combination with amphetamines if needed to control daytime sleepiness r3
        • Armodafinil
          • Indicated to improve wakefulness in adult patients with excessive daytime sleepiness
        • Solriamfetol r23
          • Indicated to improve wakefulness in adult patients with excessive daytime sleepiness
        • Methylphenidate r24
          • Indicated in patients with daytime sleepiness when modafinil or armodafinil is insufficient
          • Given in daily divided doses
            • Therapy is initiated with immediate-release formulation until an effective daily dose is determined, then total daily dose is converted to a sustained-release formulation
          • Use caution when prescribing to patients with history of drug dependence or cardiac diseases r24c36c37
        • Amphetamines r24
          • Indicated in patients with daytime sleepiness when other medications are ineffective
      • Tolerance can develop with use of stimulant medications; switching between drugs or scheduling drug holidays can be effective in avoiding tolerance r3
    • γ-Aminobutyric acid receptor agonist
      • Sodium oxybate r22
        • Central nervous system depressant
        • Treatment for cataplexy or excessive daytime sleepiness in children 7 years and older and adults with narcolepsy
          • May take 8 to 12 weeks to have optimal effect r22
        • Highly effectiver25, although stimulants may still be required to treat daytime sleepiness r3
        • In 2020, the FDA approved a lower-sodium version that includes a combination of oxybates (calcium, magnesium, potassium, and sodium) to treat cataplexy or excessive daytime sleepiness in children and adults associated with narcolepsy r26
          • Lower-sodium oxybate contains 92% less sodium than sodium oxybate r27
        • Only available through a restricted distribution program owing to the need to monitor for abuse or misuse and respiratory depression that may be increased by interacting substances (eg, sedatives) r27
          • Enrollment in a REMS (risk evaluation and mitigation strategy) program is required by the FDA to dispense sodium oxybate (Xyrem) and mixed oxybates (Xywav) r27
        • Use with caution in patients who have compromised respiratory function, including obstructive sleep apnea
    • Pitolisant
      • First-in-class antagonist/inverse agonist of the histamine-3 receptor r28
      • FDA-approved for treatment of excessive daytime sleepiness or cataplexy in adults with narcolepsy and for treatment of excessive daytime sleepiness in children 6 years and older with narcolepsy r29
        • First medication not categorized as a controlled substance that is FDA-approved for treatment of symptoms of narcolepsy
    • Antidepressants r20
      • Effective to decrease the incidence of cataplexy; also used to suppress hypnagogic hallucinations and sleep paralysis if severe
        • Venlafaxine, fluoxetine, clomipramine
        • Antidepressants may increase the risk of suicidal thoughts and behaviors in children; therefore, monitor for changes in behavior r30

    The American Academy of Sleep Medicine suggests that modafinil and sodium oxybate can be used for treatment of narcolepsy in pediatric patients r8

    A 2021 guideline from the European Academy of Neurology, the European Sleep Research Society, and the European Narcolepsy Networkr21 is available. The American Academy of Sleep Medicine also published a clinical practice guideline r8 in 2021 that included recommendations on the treatment of narcolepsy

    Potential future therapy includes orexin receptor agonists r4r31

    Drug therapy

    • Central nervous system stimulants c38
      • Wake-promoting agent
        • Modafinil r22c39
          • Modafinil Oral tablet; Children† and Adolescents 2 to 16 years†: 50 to 400 mg/day PO in 1 to 2 divided doses.
          • Modafinil Oral tablet; Adolescents 17 years: 200 mg PO once daily.
          • Modafinil Oral tablet; Adults: 200 mg PO once daily.
        • Armodafinil c40
          • Armodafinil Oral tablet; Adults: 150 to 250 mg PO once daily.
      • Dopamine and norepinephrine reuptake inhibitor
        • Solriamfetol r23r32c41
          • Solriamfetol Oral tablet; Adults: 75 mg PO once daily, initially. May increase the dose to 150 mg/day after at least 3 days based on clinical response and tolerability. Max: 150 mg/day.
      • Methylphenidate derivatives
        • Methylphenidate c42
          • Methylphenidate Hydrochloride Oral tablet; Children and Adolescents 6 to 17 years: 5 mg PO twice daily, initially. May increase the dose by 5 to 10 mg/day at weekly intervals based on clinical response and tolerability. Max: 60 mg/day.
          • Methylphenidate Hydrochloride Oral tablet; Adults: 20 to 60 mg/day PO in 2 to 3 divided doses. Adjust dose based on clinical response and tolerability. Usual dose: 20 to 30 mg/day. Max: 60 mg/day.
      • Amphetamines derivatives c43
        • Amphetamine-dextroamphetamine c44
          • Amphetamine Aspartate, Amphetamine Sulfate, Dextroamphetamine Saccharate, Dextroamphetamine Sulfate Oral tablet; Children 6 to 11 years: 5 mg/day PO in 1 to 3 divided doses, initially. May increase the dose by 5 mg/day at weekly intervals based on clinical response and tolerability. Max: 60 mg/day.
          • Amphetamine Aspartate, Amphetamine Sulfate, Dextroamphetamine Saccharate, Dextroamphetamine Sulfate Oral tablet; Children and Adolescents 12 to 17 years: 10 mg/day PO in 1 to 3 divided doses, initially. May increase the dose by 10 mg/day at weekly intervals based on clinical response and tolerability. Max: 60 mg/day.
          • Amphetamine Aspartate, Amphetamine Sulfate, Dextroamphetamine Saccharate, Dextroamphetamine Sulfate Oral tablet; Adults: 5 to 60 mg/day PO in 2 or 3 divided doses.
        • Dextroamphetamine c45
          • Dextroamphetamine Sulfate Oral tablet; Children 6 to 11 years: 5 mg/day PO in 1 to 3 divided doses, initially. May increase the dose by 5 mg/day at weekly intervals based on clinical response and tolerability. Max: 60 mg/day.
          • Dextroamphetamine Sulfate Oral tablet; Children and Adolescents 12 to 17 years: 10 mg/day PO in 1 to 3 divided doses, initially. May increase the dose by 10 mg/day at weekly intervals based on clinical response and tolerability. Max: 60 mg/day.
          • Dextroamphetamine Sulfate Oral tablet; Adults: 5 to 60 mg/day PO in 2 or 3 divided doses. Adjust dose based on clinical response and tolerability. Max: 60 mg/day.
    • γ-Aminobutyric acid receptor agonist c46
      • Sodium oxybate r22r33c47
        • Immediate-release
          • Sodium Oxybate (Gamma Hydroxybutyrate Or Ghb) Oral solution; Children and Adolescents 7 to 17 years weighing 20 to 29 kg: 2 g/night or less PO in 2 divided doses, initially. May increase the dose by 1 g/night or less at weekly intervals based on clinical response and tolerability. Max: 6 g/night.
          • Sodium Oxybate (Gamma Hydroxybutyrate Or Ghb) Oral solution; Children and Adolescents 7 to 17 years weighing 30 to 44 kg: 3 g/night or less PO in 2 divided doses, initially. May increase the dose by 1 g/night or less at weekly intervals based on clinical response and tolerability. Max: 7.5 g/night.
          • Sodium Oxybate (Gamma Hydroxybutyrate Or Ghb) Oral solution; Children and Adolescents 7 to 17 years weighing 45 kg or more: 4.5 g/night or less PO in 2 divided doses, initially. May increase the dose by 1.5 g/night or less at weekly intervals based on clinical response and tolerability. Max: 9 g/night.
          • Sodium Oxybate (Gamma Hydroxybutyrate Or Ghb) Oral solution; Adults: 4.5 g/night PO in 2 divided doses, initially. May increase the dose by 1.5 g/night at weekly intervals based on clinical response and tolerability. Usual dose: 6 to 9 g/night. Max: 9 g/night.
        • Extended-release
          • Sodium Oxybate (Gamma Hydroxybutyrate Or Ghb) Oral suspension, extended release; Children and Adolescents 7 to 17 years weighing 20 to 29 kg: Use immediate-release sodium oxybate to initiate treatment; may transition to extended-release sodium oxybate when dose is 4.5 g/night or more. 4.5 to 6 g PO once nightly. Adjust dose by 1.5 g/night at weekly intervals based on clinical response and tolerability. Max: 6 g/night.
          • Sodium Oxybate (Gamma Hydroxybutyrate Or Ghb) Oral suspension, extended release; Children and Adolescents 7 to 17 years weighing 30 to 44 kg: Use immediate-release sodium oxybate to initiate treatment; may transition to extended-release sodium oxybate when dose is 4.5 g/night or more. 4.5 to 7.5 g PO once nightly. Adjust dose by 1.5 g/night at weekly intervals based on clinical response and tolerability. Max: 7.5 g/night.
          • Sodium Oxybate (Gamma Hydroxybutyrate Or Ghb) Oral suspension, extended release; Children and Adolescents 7 to 17 years weighing 45 kg or more: 4.5 g PO once nightly, initially. May increase the dose by 1.5 g/night at weekly intervals based on clinical response and tolerability. Max: 9 g/night.
          • Sodium Oxybate (Gamma Hydroxybutyrate Or Ghb) Oral suspension, extended release; Adults: 4.5 g PO once nightly, initially. May increase the dose by 1.5 g/night at weekly intervals based on clinical response and tolerability. Usual dose: 6 to 9 g/night. Max: 9 g/night.
      • Mixed oxybates (ie, calcium, magnesium, potassium, and sodium oxybate)
        • Calcium Oxybate, Magnesium Oxybate, Potassium Oxybate, Sodium Oxybate (Gamma Hydroxybutyrate Or Ghb) Oral solution; Children and Adolescents 7 to 17 years weighing 20 to 29 kg: 2 g/night or less PO in 2 divided doses, initially. May increase the dose by 1 g/night or less at weekly intervals based on clinical response and tolerability. Max: 6 g/night.
        • Calcium Oxybate, Magnesium Oxybate, Potassium Oxybate, Sodium Oxybate (Gamma Hydroxybutyrate Or Ghb) Oral solution; Children and Adolescents 7 to 17 years weighing 30 to 44 kg: 3 g/night or less PO in 2 divided doses, initially. May increase the dose by 1 g/night or less at weekly intervals based on clinical response and tolerability. Max: 7.5 g/night.
        • Calcium Oxybate, Magnesium Oxybate, Potassium Oxybate, Sodium Oxybate (Gamma Hydroxybutyrate Or Ghb) Oral solution; Children and Adolescents 7 to 17 years weighing 45 kg or more: 4.5 g/night or less PO in 2 divided doses, initially. May increase the dose by 1.5 g/night or less at weekly intervals based on clinical response and tolerability. Max: 9 g/night.
        • Calcium Oxybate, Magnesium Oxybate, Potassium Oxybate, Sodium Oxybate (Gamma Hydroxybutyrate Or Ghb) Oral solution; Adults: 4.5 g/night PO in 2 divided doses, initially. May increase the dose by 1.5 g/night at weekly intervals based on clinical response and tolerability. Usual dose: 6 to 9 g/night. Max: 9 g/night.
    • Histamine-3 receptor antagonist/inverse agonist
      • Pitolisant r28r34c48
        • For treatment of excessive daytime sleepiness
          • Pitolisant Oral tablet; Children and Adolescents 6 to 17 years weighing less than 40 kg: 4.45 mg PO once daily for 1 week, then 8.9 mg PO once daily for 1 week, then 17.8 mg PO once daily. Adjust dose based on tolerability. Max: 17.8 mg/day. Coadministration of certain drugs may need to be avoided, or dosage adjustments may be necessary; review drug interactions.
          • Pitolisant Oral tablet; Children and Adolescents 6 to 17 years weighing less than 40 kg who are CYP2D6 poor metabolizers: 4.45 mg PO once daily for 1 week, then 8.9 mg PO once daily. Adjust dose based on tolerability. Max: 8.9 mg/day. Coadministration of certain drugs may need to be avoided, or dosage adjustments may be necessary; review drug interactions.
          • Pitolisant Oral tablet; Children and Adolescents 6 to 17 years weighing 40 kg or more: 4.45 mg PO once daily for 1 week, then 8.9 mg PO once daily for 1 week, then 17.8 mg PO once daily for 1 week, and then 35.6 mg PO once daily. Adjust dose based on tolerability. Max: 35.6 mg/day. Coadministration of certain drugs may need to be avoided, or dosage adjustments may be necessary; review drug interactions.
          • Pitolisant Oral tablet; Children and Adolescents 6 to 17 years weighing 40 kg or more who are CYP2D6 poor metabolizers: 4.45 mg PO once daily for 1 week, then 8.9 mg PO once daily for 1 week, then 17.8 mg PO once daily. Adjust dose based on tolerability. Max: 17.8 mg/day. Coadministration of certain drugs may need to be avoided, or dosage adjustments may be necessary; review drug interactions.
          • Pitolisant Oral tablet; Adults: 8.9 mg PO once daily for 1 week, then 17.8 mg PO once daily for 1 week, and then 35.6 mg PO once daily. Adjust dose based on tolerability. Max: 35.6 mg/day. Coadministration of certain drugs may need to be avoided, or dosage adjustments may be necessary; review drug interactions.
          • Pitolisant Oral tablet; Adults who are CYP2D6 poor metabolizers: 8.9 mg PO once daily for 1 week, then 17.8 mg PO once daily. Adjust dose based on tolerability. Max: 17.8 mg/day. Coadministration of certain drugs may need to be avoided, or dosage adjustments may be necessary; review drug interactions.
        • For treatment of cataplexy
          • Pitolisant Oral tablet; Adults: 8.9 mg PO once daily for 1 week, then 17.8 mg PO once daily for 1 week, and then 35.6 mg PO once daily. Adjust dose based on tolerability. Max: 35.6 mg/day. Coadministration of certain drugs may need to be avoided, or dosage adjustments may be necessary; review drug interactions.
          • Pitolisant Oral tablet; Adults who are CYP2D6 poor metabolizers: 8.9 mg PO once daily for 1 week, then 17.8 mg PO once daily. Adjust dose based on tolerability. Max: 17.8 mg/day. Coadministration of certain drugs may need to be avoided, or dosage adjustments may be necessary; review drug interactions.
    • Antidepressants
      • Serotonin norepinephrine reuptake inhibitor
        • Venlafaxine r35c49c50c51
          • Venlafaxine Hydrochloride Oral tablet; Children and Adolescents 6 to 17 years: 37.5 mg PO once daily, initially. May increase the dose based on clinical response and tolerability. Max: 150 mg/day in 2 divided doses.
          • Venlafaxine Hydrochloride Oral tablet; Adults: 37.5 mg PO once daily, initially. May increase the dose based on clinical response and tolerability. Max: 225 mg/day PO in 2 divided doses.
      • Selective serotonin reuptake inhibitor
        • Fluoxetine r35c52c53c54
          • Fluoxetine Hydrochloride Oral tablet [Depression/Mood Disorders]; Children and Adolescents 6 to 17 years: 10 to 30 mg PO once daily.
          • Fluoxetine Hydrochloride Oral tablet [Depression/Mood Disorders]; Adults: 10 to 20 mg PO once daily, initially. May increase the dose based on clinical response and tolerability. Max: 60 mg/day.
      • Tricyclic antidepressant
        • Clomipramine r35c55c56c57
          • Clomipramine Hydrochloride Oral capsule; Children and Adolescents 10 to 17 years: 10 to 25 mg PO once daily, initially. May increase the dose based on clinical response and tolerability. Max. 150 mg/day.
          • Clomipramine Hydrochloride Oral capsule; Adults: 10 to 25 mg PO once daily, initially. May increase the dose based on clinical response and tolerability. Max: 200 mg/day PO in 1 or 2 divided doses.

    Nondrug and supportive care

    • Counsel patients to improve sleep hygiene r3c58
      • Maintain regular sleep schedule to get adequate sleep (most patients require 7-9 hoursr36)
      • Sleep environment conducive to sleep (eg, quiet, dark room, avoid screen time before sleep)
      • Schedule regular naps throughout the day to improve alertness r21
      • Allow 1-hour period before bedtime for relaxation r36
    • Avoid stimuli (eg, alcohol, heavy meals) that promote sleep attacks r20c59c60
    • Avoid stimulants (eg, caffeine, nicotine) 6 hours before bedtime r36c61
    • Engage in regular exercise to promote wakefulness (but not close to bedtime) r20c62
    • Psychological support (eg, cognitive behavioral therapy) can also be considered to address psychiatric symptoms (eg, depression, anxiety, impaired work and school performance, social impacts) r7

    Comorbidities

    • Sleep disorders, such as sleep apnea r21
      • Should be treated as in non-narcoleptic patients

    Special populations

    • Females of childbearing age
      • When pitolisant, modafinil, or armodafinil are used by a female individual using hormonal contraception, use of additional contraception is recommended and for 1 month after pharmacotherapy for narcolepsy has ended r7
    • Pregnant and/or breastfeeding patients
      • Consider potential risks of medical therapy for narcolepsy along with potential benefits. No teratogenicity has been shown, but none of the drugs typically used for narcolepsy have been specifically studied r2
        • If a patient being treated becomes pregnant, can reassure them about the absence of teratogenic effects associated with central nervous system stimulants, antidepressants, or sodium oxybate. May withdraw medications during pregnancy as further caution
          • For those maintained on medical therapy during pregnancy, consideration is given to temporarily discontinue some or all of the drugs used near delivery due to their possible effects on the newborn (eg, sedation, withdrawal)
        • For patients who want to become pregnant, either stop medication before pregnancy occurs or monitor closely for pregnancy and stop medical therapy with first positive pregnancy test
        • Pregnancy exposure registries are available for some medications (eg, pitolisant)
        • All medications employed in narcolepsy pass into breast milk in varying amounts; however, risk to the breastfed infant is largely unknown

    Monitoring

    • Regular monitoring is required to determine the effectiveness of therapy and identify any adverse effects
      • Monitor sleepiness and subjective response to medication using an objective measure, such as the Epworth Sleepiness Scale r35c63
      • Once stabilized on a stimulant or other medication, monitor for sleep disturbances, cardiovascular (eg, hypertension) or metabolic abnormalities, and mood changes c64
    • Because there is a risk of respiratory depression for those being treated with sodium oxybate, patients prescribed this medication must be monitored for obstructive sleep apnea or must adhere to nasal CPAP device therapy r37
      • If obstructive sleep apnea is not present initially, monitor with nocturnal oximetry for its development: c65
        • Every 2 years for all patients treated with sodium oxybate
        • Annually for obese patients (with BMI greater than 30)
        • After a 6.8-kg weight gain
        • After an increase in snoring (as indicated by the visual analog snoring severity scale)
        • After initiating a new sedating medication (which may worsen obstructive sleep apnea)

    Complications and Prognosis

    Complications

    • Increased incidence of motor vehicle accidents owing to daytime sleepiness c66
    • Difficulty with professional and interpersonal relationships owing to daytime sleepiness c67c68

    Prognosis

    • There is no cure for narcolepsy; however, symptoms can improve approximately 80% with drug therapy and good sleep hygiene r2
      • Patient must make adjustments to manage wakefulness and sleepiness and maintain regularity in sleep-wake patterns r2
      • Follow medication closely

    Screening and Prevention

    Screening c69

    Prevention c70

    American Academy of Sleep Medicine: International Classification of Sleep Disorders. 3rd ed, Text Revision (ICSD-3-TR). American Academy of Sleep Medicine; 2023.Mignot EJ: A practical guide to the therapy of narcolepsy and hypersomnia syndromes. Neurotherapeutics. 9(4):739-52, 201223065655Leschziner G: Narcolepsy: a clinical review. Pract Neurol. 14(5):323-31, 201424830461Barateau L et al: Narcolepsies, update in 2023. Rev Neurol (Paris). 179(7):727-40, 202337634997Iranzo A: Current diagnostic criteria for adult narcolepsy. In: Baumann CR et al, eds: Narcolepsy Pathophysiology, Diagnosis, and Treatment. Springer; 2011:369-81Thorpy MJ: Classification of sleep disorders. Neurotherapeutics. 9(4):687-701, 201222976557Morse AM et al: Narcolepsy: beyond the classic pentad. CNS Drugs. 39(Suppl 1):9-22, 202540111737Maski K et al: Treatment of central disorders of hypersomnolence: an American Academy of Sleep Medicine clinical practice guideline. J Clin Sleep Med. 17(9):1881-93, 202134743789Krahn LE et al: Quality measures for the care of patients with narcolepsy. J Clin Sleep Med. 11(3):335, 201525700880Nevsimalova S: The diagnosis and treatment of pediatric narcolepsy. Curr Neurol Neurosci Rep. 14(8):469, 201424954623Dye TJ: Clinical evaluation and management of narcolepsy in children and adolescents. Semin Pediatr Neurol. 48:101089, 202338065636Sateia MJ: International classification of sleep disorders-third edition: highlights and modifications. Chest. 146(5):1387-94, 201425367475Heier MS et al: CSF hypocretin-1 levels and clinical profiles in narcolepsy and idiopathic CNS hypersomnia in Norway. Sleep. 30(8):969-73, 200717702265Kushida CA et al: Practice parameters for the indications for polysomnography and related procedures: an update for 2005. Sleep. 28(4):499-521, 200516171294Krahn LE et al: Recommended protocols for the Multiple Sleep Latency Test and Maintenance of Wakefulness Test in adults: guidance from the American Academy of Sleep Medicine. J Clin Sleep Med. 17(12):2489-98, 202134423768Mignot E et al: The role of cerebrospinal fluid hypocretin measurement in the diagnosis of narcolepsy and other hypersomnias. Arch Neurol. 59(10):1553-62, 200212374492Dauvilliers Y et al: Idiopathic hypersomnia. In: Kryger M et al, eds: Principles and Practice of Sleep Medicine. 7th ed. PA: Elsevier; 2022:1048-1056Greenberg H et al: Obstructive sleep apnea. In: Kryger M et al, eds: Principles and Practice of Sleep Medicine. 7th ed. Elsevier; 2022:1244-1259Tsai SC: The history and physical examination of the sleep patient. In: Kirsch DB, ed: Sleep Medicine in Neurology. John Wiley & Sons; 2014:8-20Madala RR et al: Approach to a patient with narcolepsy. In: Kirsch DB, ed: Sleep Medicine in Neurology. John Wiley & Sons; 2014:43-50Bassetti CLA et al: European guideline and expert statements on the management of narcolepsy in adults and children. Eur J Neurol. 28(9):2815-30, 202134173695Billiard M et al: Management of narcolepsy in adults. In: Gilhus NE et al, eds: European Handbook of Neurological Management. 2nd ed. Blackwell Publishing; 2011:513-28Wang J et al: Efficacy and safety of solriamfetol for excessive sleepiness in narcolepsy and obstructive sleep apnea: findings from randomized controlled trials. Sleep Med. 79:40-7, 202133472129Wise MS et al: Treatment of narcolepsy and other hypersomnias of central origin. Sleep. 30(12):1712-27, 200718246981Xu XM et al: Gamma-hydroxybutyrate (GHB) for narcolepsy in adults: an updated systematic review and meta-analysis. Sleep Med. 64:62-70, 201931671326Jazz Pharmaceuticals Announces US FDA Approval of Xywav (calcium, magnesium, potassium, and sodium oxybates) Oral Solution for Cataplexy or Excessive Daytime Sleepiness Associated with Narcolepsy. Published July 22, 2020. Accessed May 16, 2025. https://investor.jazzpharma.com/news-releases/news-release-details/jazz-pharmaceuticals-announces-us-fda-approval-xywavtm-calciumhttps://investor.jazzpharma.com/news-releases/news-release-details/jazz-pharmaceuticals-announces-us-fda-approval-xywavtm-calciumXYWAV and XYREM Risk Evaluation and Mitigation Strategy program. Jazz Pharmaceuticals website. Published 2025. Accessed May 16, 2025. https://www.xywavxyremrems.com/https://www.xywavxyremrems.com/Lamb YN: Pitolisant: a review in narcolepsy with or without cataplexy. CNS Drugs. 34(2):207-18, 202031997137Guevarra JT et al: Pitolisant to Treat Excessive Daytime Sleepiness and Cataplexy in Adults with Narcolepsy: Rationale and Clinical Utility. Nat Sci Sleep. 12:709-719, 202033117007Walter HJ et al: Clinical practice guideline for the assessment and treatment of children and adolescents with major and persistent depressive disorders. J Am Acad Child Adolesc Psychiatry. 62(5):479-502, 202336273673Thomaz TG et al: Treatment of narcolepsy type 1 with orexin: a systematic review. Cureus. 16(12):e76692, 202439898129Thorpy MJ et al: A randomized study of solriamfetol for excessive sleepiness in narcolepsy. Ann Neurol. 85(3):359-70, 201930694576Abad VC: An evaluation of sodium oxybate as a treatment option for narcolepsy. Expert Opin Pharmacother. 20(10):1189-99, 201931136215Scammell TE: Narcolepsy. N Engl J Med. 373(27):2654-62, 201526716917Adenuga O et al: Treatment of disorders of hypersomnolence. Curr Treat Options Neurol. 16(9):302, 201425080137Feldman NT: Clinical perspective: monitoring sodium oxybate-treated narcolepsy patients for the development of sleep-disordered breathing. Sleep Breath. 14(1):77-9, 201019626356
    Small Elsevier Logo

    Cookies are used by this site. To decline or learn more, visit our cookie notice.


    Copyright © 2025 Elsevier, its licensors, and contributors. All rights are reserved, including those for text and data mining, AI training, and similar technologies.

    Small Elsevier Logo
    RELX Group