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Treatment of narcolepsy in adults

Treatment of narcolepsy in adults
Author:
Thomas E Scammell, MD
Section Editor:
Ruth Benca, MD, PhD
Deputy Editor:
April F Eichler, MD, MPH
Literature review current through: Feb 2022. | This topic last updated: Jan 30, 2022.

INTRODUCTION — Narcolepsy is a central disorder of hypersomnolence characterized by excessive daytime sleepiness in all patients, along with additional symptoms that may include cataplexy (in narcolepsy type 1), disrupted nighttime sleep, sleep paralysis, and hypnogogic and hypnopompic hallucinations.

Management of narcolepsy is symptomatic, and there are no disease-modifying therapies yet available. In many patients with narcolepsy, sleepiness and cataplexy substantially interfere with daily life, impacting school, work, relationships, and social life. Most patients require pharmacologic therapy, and many feel more alert with daytime naps.

Treatment of narcolepsy of adults is reviewed here. The diagnosis and neurobiology of narcolepsy and the treatment of narcolepsy in children are discussed separately. (See "Clinical features and diagnosis of narcolepsy in adults" and "Clinical features and diagnosis of narcolepsy in children".)

GENERAL MEASURES IN ALL PATIENTS

Napping and sleep hygiene — Daytime naps are the mainstay of nonpharmacologic therapy for narcolepsy. Many patients feel more alert with daytime naps, although most will require pharmacotherapy in addition.

One or two well-timed, 20-minute naps will often improve sleepiness, though some patients only benefit from long naps [1]. Specifically, a short nap around 1 PM or 2 PM is often helpful as it can improve alertness for one to three hours, reducing the need for stimulants in the afternoon. If it can be arranged, a brief nap at work or school is often helpful.

Sleep deprivation may worsen narcolepsy symptoms, and therefore patients should be counseled to maintain a regular and adequate sleep schedule [2]. (See "Insufficient sleep: Evaluation and management".)

Comorbid sleep disorders — Patients with narcolepsy often have concomitant obstructive sleep apnea, periodic limb movements of sleep, fragmented sleep, and/or rapid eye movement (REM) sleep behavior disorder that can contribute to their daytime sleepiness. It is often helpful to treat these disorders first and then to focus on improving the sleepiness that is caused by the narcolepsy.

Avoidance of certain drugs — Certain medications and substances should be avoided by patients with narcolepsy due to their potential to worsen symptoms.

Drugs that can worsen daytime sleepiness include benzodiazepines, opiates, antipsychotics, antiseizure medications, and alcohol. (See "Excessive daytime sleepiness due to medical disorders and medications".)

Other medications such as theophylline or excessive caffeine can cause insomnia, which can worsen daytime sleepiness.

Prazosin and other alpha-1 antagonists can worsen cataplexy.

Psychosocial support — Patients with narcolepsy face various psychosocial and work-related challenges throughout their lives; as a result, they may have difficulty meeting economic and social responsibilities [3]. They also have the additional burden of coping with misperceptions about the causes and the involuntary nature of their symptoms.

Common misconceptions, even among medical caregivers, are that sleep attacks and cataplexy (emotionally triggered muscle paralysis resulting in partial or complete collapse) are manifestations of poor motivation, denial, or avoidance. Thus, patients often benefit from participation in support groups that focus on coping skills and identification of community resources to assist with administrative and medical issues.

Health maintenance

Psychiatric – Patients with narcolepsy are at increased risk for psychiatric comorbidities, particularly depression and anxiety [4]. Patients should be screened for depression at least every one to two years, and those who screen positive should be referred for appropriate evaluation and treatment. (See "Screening for depression in adults" and "Unipolar depression in adults: Assessment and diagnosis".)

We recommend the Patient Health Questionnaire-2 (PHQ-2), as it is quick, adequately sensitive, and scores on other screening instruments such as the Patient Health Questionnaire-9 (PHQ-9) may be falsely elevated by questions related to fatigue, trouble concentrating, and fragmented sleep. The PHQ-2 is very simple and consists of two questions:

During the last month, have you often been bothered by feeling down, depressed, or hopeless?

During the last month, have you often been bothered by having little interest or pleasure in doing things?

Cardiovascular – Cardiovascular risk factor assessment and modification is an important component of health maintenance in patients with narcolepsy. (See "Atherosclerotic cardiovascular disease risk assessment for primary prevention in adults: Our approach" and "Overview of preventive care in adults", section on 'Cardiovascular disease prevention'.)

Narcolepsy is associated with higher than expected rates of hypertension, which may be related only in part to stimulants or other medications. In a study that assessed 24-hour ambulatory blood pressure in 160 consecutive adults with narcolepsy type 1 (median age 32 to 41 years), rates of hypertension were 41 percent in untreated patients and 58 percent in patients taking stimulant medications [5]. Patients with narcolepsy also have increased rates of obesity and diabetes.

Obesity – Overweight and obesity are common in narcolepsy. This is likely related to orexin deficiency, but whether the obesity is due to low basal metabolism, reduced physical activity, or increased caloric intake remains unclear [6-8]. Substantial weight gain of 20 to 30 pounds is not unusual around the onset of narcolepsy in children, even without obvious changes in food intake, so reduced metabolism seems likely. We recommend regular exercise, limiting calories, and meeting with a dietician to work on a specific weight loss plan if needed. (See "Obesity in adults: Overview of management".)

Driving safety — People with narcolepsy have a three- to fourfold increased risk of having a car crash, and over one-third have had an accident due to sleepiness [9-13]. Long highway drives can be especially difficult, as many people with narcolepsy find it difficult to sustain vigilance under monotonous conditions.

Small studies suggest that modafinil improves driving performance in patients with narcolepsy or idiopathic hypersomnia [14,15], but overall, there is little research on whether narcolepsy medications improve driving safety and how to determine whether a patient is safe to drive.

We recommend that clinicians have an honest discussion with patients about their driving ability. As sleepiness can be difficult for the patient to recognize, feedback from caregivers and friends can be helpful. If a patient reports persistent sleepiness or has had an accident due to sleepiness, we perform a maintenance of wakefulness test (MWT) to determine whether the individual can stay awake even under boring circumstances [16]. This test cannot guarantee that an individual will remain alert when driving, but the results can still be helpful for optimizing medications and to assist in patient counseling. (See "Quantifying sleepiness", section on 'Maintenance of wakefulness test (MWT)'.)

Most narcolepsy patients are safe to drive, though sometimes with limits. As an example, some individuals may be safe driving around town for 30 minutes but not on a four-hour, monotonous highway drive. Some may choose to take medications before driving, to break up longer drives with scheduled naps, or to take turns driving with a friend or colleague. Others may choose not to drive after a meal or after dark. Patients with narcolepsy should not work as commercial drivers.

Additional information on driving and risks associated with sleep disorders can be found elsewhere. (See "Drowsy driving: Risks, evaluation, and management".)

APPROACH TO PHARMACOTHERAPY

Goals of therapy — The goals of therapy are to achieve "normal" alertness during conventional waking hours or to maximize alertness at important times of the day (eg, during work, school, or while driving). With some medications, such as modafinil or amphetamines, the benefits are apparent within a few days, whereas oxybates require several weeks of treatment to achieve full effects.

All patients with narcolepsy have some degree of daytime sleepiness. Although a few manage this successfully with only an afternoon nap, most patients require a medication that promotes wakefulness. Such agents improve performance as measured by reaction time and simulated driving tasks, but patients' ability to stay awake rarely exceeds 70 to 80 percent of normal [17-25].

We aim for monotherapy by choosing and optimizing a single drug first. If symptoms are inadequately controlled on a single medication, a second agent is added and titrated to effect. Ideally, the first medication can later be reduced or eliminated, depending on symptom control and tolerability. Still, many patients respond best to a combination of medications, such as long-acting methylphenidate once or twice each day plus short-acting methylphenidate at times of day when sleepiness is most problematic, or a wake-promoting medication plus another medication to suppress cataplexy (algorithm 1).

Medication selection — Selection of initial and subsequent pharmacotherapy should be individualized based on factors that include symptom severity and type, patient age and comorbidities, and medication efficacy, side effects, and cost. Although multiple medications have been shown to be more effective than placebo in randomized trials, very few comparative studies have been performed [26-28].

Our approach in patients with narcolepsy is therefore based primarily on clinical experience and expert opinion, with the following general principles:

Excessive daytime sleepiness is usually the most prominent disabling symptom. About one-third of people with narcolepsy have cataplexy that is substantial enough to warrant treatment. Although hypnogogic hallucinations and sleep paralysis usually do not require treatment, these symptoms are often improved by medications that suppress cataplexy.

Among wake-promoting medications, few head-to-head studies have been performed. In the author's experience, oxybates and solriamfetol appear to have the largest clinical effects at usual doses. Moderate to high doses of either amphetamines or methylphenidate have intermediate effects, and modafinil, armodafinil, and pitolisant tend to have more modest effects.

Some medications for narcolepsy treat both sleepiness and cataplexy (eg, oxybates, pitolisant), some treat only cataplexy (eg, venlafaxine, fluoxetine), and some have no effect on cataplexy (eg, modafinil, armodafinil, solriamfetol).

Risks and side effects vary roughly inversely with wake-promoting strength. For this reason, oxybates are typically reserved for second-line use unless symptoms are severe and disabling.

Patients with mild to moderate sleepiness — For patients with mild to moderate sleepiness (with or without cataplexy), first-line wake-promoting agents include modafinil, armodafinil, pitolisant, and solriamfetol. All four drugs are more effective than placebo for sleepiness, and all have relatively few side effects, though no comparative trials have been performed.

Among the four drugs, we suggest starting with modafinil in most patients, based largely on cumulative experience with the drug and tolerability. Armodafinil is very similar to modafinil and can be substituted for modafinil for reasons of cost/formulary constraints. Pitolisant and solriamfetol are newer drugs with good safety and efficacy profiles in short-term trials. (See 'Modafinil' below and 'Armodafinil' below and 'Pitolisant' below and 'Solriamfetol' below.)

For patients with inadequate control of mild to moderate sleepiness on modafinil or armodafinil monotherapy, we add either pitolisant or solriamfetol and titrate to effect, then consider tapering off the first agent. Unlike solriamfetol, pitolisant has anti-cataplexy effects and is therefore often a good choice for patients with both sleepiness and cataplexy.

We consider methylphenidate and amphetamines to be second-line wake-promoting agents in adults with narcolepsy because they generally have more sympathomimetic side effects than the other choices. They are most commonly used as second-line add-on agents for patients with sleepiness, or occasionally as first-line agents if the cost of modafinil or armodafinil is too high. (See 'Methylphenidate' below and 'Amphetamines' below.)

Patients with severe/disabling sleepiness — For patients with severe sleepiness, modafinil and other first-line agents are less likely to be sufficient as monotherapy. In addition, severe sleepiness is usually accompanied by more severe nighttime sleep disruption. For these reasons, we suggest adding or switching to oxybates in patients with severe sleepiness who fail one or more first-line wake-promoting medications. Alternatively, some clinicians suggest starting with oxybates in such patients, although from a practical standpoint, insurance coverage for oxybates may require a trial of modafinil first.

Oxybates (sodium oxybate or mixed oxybate salts) have a different mechanism of action than other narcolepsy medications and act primarily through consolidating nighttime sleep. Although risks and side effects, as well as cost, may be higher with oxybates, they can offer the best chance of optimal symptom control with monotherapy. For patients with a good response to oxybates, other wake-promoting medications may be able to be tapered. (See 'Oxybates' below.)

Not all patients are candidates for oxybates, however, either due to the high cost, inability to adhere to safety requirements, or a comorbidity or concurrent medication that increases risk (eg, untreated obstructive sleep apnea, substance abuse, chronic opioids, poorly controlled depression). In our experience, alternatives with the best chance of achieving adequate control of severe sleepiness as monotherapy are solriamfetol and high doses of either methylphenidate or amphetamines. Modafinil/armodafinil and pitolisant can also be tried in combination with other wake-promoting agents (eg, solriamfetol, methylphenidate, amphetamines). (See 'Administration of medications' below.)

Patients with residual cataplexy — Treatment of residual cataplexy in patients on first-line therapy for sleepiness is individualized depending on the medication chosen for first-line therapy and the presence or absence of residual sleepiness.

For patients with mild to moderate sleepiness who respond well to a first-line wake-promoting agent but have disruptive cataplexy, we suggest adding venlafaxine. Fluoxetine, duloxetine, and the tricyclic antidepressants also have anti-cataplexy effects. An alternative to antidepressants is to add or switch to pitolisant. For more severe cataplexy, we add or switch to oxybates. (See 'Antidepressants for cataplexy' below and 'Pitolisant' below and 'Oxybates' below.)

Patients with disrupted sleep — Disrupted nighttime sleep is common in patients with narcolepsy, but daytime symptoms are generally targeted first. For those with persistent difficulties with sleep initiation or maintenance, treatment depends on severity. Most patients with severely disrupted nighttime sleep also have severe daytime sleepiness, and in these patients, oxybates are useful for both symptoms.

For patients with milder insomnia complaints but who nonetheless require pharmacotherapy, we prefer a short-acting benzodiazepine receptor agonist such as zolpidem. Other similar medications for insomnia are also reasonable, with the exception of dual orexin receptor antagonists, which are contraindicated in patients with narcolepsy. (See "Pharmacotherapy for insomnia in adults".)

Follow-up and monitoring — Once therapy has been optimized, the severity of residual sleepiness should be reassessed with the Epworth Sleepiness Scale (calculator 1). The maintenance of wakefulness test (MWT) should be considered for narcolepsy patients who operate heavy machinery or have other responsibilities in which dozing off would be especially risky. Persistently sleepy patients should be counseled to avoid potentially dangerous activities, such as driving. (See "Quantifying sleepiness".)

Most medications that promote wakefulness have overlapping mechanisms of action and cardiovascular effects. We therefore recommend monitoring heart rate and blood pressure at each clinic visit, especially as cardiovascular risk factors are common in narcolepsy [5].

Special populations

Children and adolescents — Management of narcolepsy in children and adolescents is reviewed separately. (See "Management and prognosis of narcolepsy in children".)

Pregnancy and lactation — Management of narcolepsy during pregnancy can be challenging. The risks of medication exposure to the fetus, which are often incompletely known, are weighed against risks of uncontrolled sleepiness that could result from discontinuation of symptomatic medications.

Decisions should therefore take into account multiple factors, including the potential harms of medications to the fetus, the stage of pregnancy, the severity of a patient's narcolepsy, and the availability and usefulness of nonpharmacologic therapies for symptom mitigation. It is always prudent to avoid medications in the first trimester, when organogenesis begins and information on teratogenicity is absent or minimal. Still, drug exposure after the first trimester can have effects on fetal growth and behavior, since brain development is ongoing.

Based on an international survey of clinicians experienced in managing narcolepsy, most clinicians generally recommend discontinuing medications (or at least avoiding polypharmacy) during pregnancy unless the benefits of the medications outweigh the potential risk to the fetus [29,30]. A survey of 123 women with narcolepsy who reported one or more pregnancies found that 79 percent discontinued medications during pregnancy, and while over half discussed this with their doctor, most felt the counseling regarding the risks and benefits of medications during pregnancy was inadequate [31].

Nonpharmacological options for symptom management during pregnancy include improving alertness with more daytime naps, optimizing nighttime sleep, and managing sleep disorders that can arise during pregnancy (eg, sleep apnea, restless legs syndrome). Patients can also consider working reduced hours and using public transportation instead of driving. These same approaches can help in the postpartum period, when many women with narcolepsy report that their sleepiness interferes with infant care [30]. (See "Obstructive sleep apnea in pregnancy" and "Restless legs syndrome during pregnancy and lactation".)

Data are limited on risks to the fetus of various medications used for symptomatic treatment of narcolepsy [29].

Methylphenidate/amphetamines – Several studies examining the use of methylphenidate or amphetamines for attention deficit hyperactivity disorder during pregnancy have found either no association or only a small increase (less than 1.5-fold) in the relative risk of congenital malformations, placental abruption, growth restriction, and preterm birth among exposed infants and mothers [32-36]. Still, it is possible that exposure to amphetamines in utero may lead to lasting effects on the child's behavior [37]. Illicit use of amphetamines increases the risk of prematurity and intrauterine growth restriction. (See "Infants with prenatal substance use exposure", section on 'Amphetamines'.)

Modafinil/armodafinil – A pregnancy registry reported an elevated rate of major congenital anomalies (17 percent) and cardiac anomalies (4 percent) among women in the United States exposed to modafinil and/or armodafinil (some took additional drugs) [38,39]. Based on these and other data, Health Canada updated product labeling in 2019 to include a warning that modafinil is contraindicated in women who are pregnant or may become pregnant [39]. Subsequent registry data from other countries have reported conflicting results, and more studies are needed [40,41].

Antidepressants – The risks of antidepressants during pregnancy appear low and are discussed elsewhere. (See "Antenatal use of antidepressants and risk of teratogenicity and adverse pregnancy outcomes: Selective serotonin reuptake inhibitors (SSRIs)" and "Antenatal use of antidepressants and risks of teratogenicity and adverse pregnancy outcomes: Drugs other than selective serotonin reuptake inhibitors".)

As with pregnancy, most clinicians recommend discontinuing medications during the months of breastfeeding as all medications used for narcolepsy can be excreted in milk [42,43]. The LactMed database contains the most updated information on levels of drugs in breast milk and infant blood and the possible adverse effects in the nursing infant. The UpToDate drug database also contains information under breastfeeding considerations. (See "Breastfeeding infants: Safety of exposure to antipsychotics, lithium, stimulants, and medications for substance use disorders".)

Perioperative and inpatient care — Patients with narcolepsy may have increased symptoms during hospitalization due to discontinuation of their narcolepsy medications and may be at risk for slower recovery after anesthesia. Best practices for care of inpatients are reviewed separately. (See "Sleep disorders in hospitalized adults: Evaluation and management", section on 'Other sleep disorders'.)

ADMINISTRATION OF MEDICATIONS — Dosing, side effects, and supporting evidence for various medications are reviewed below and in the table (table 1). The approach to selection of medications as monotherapy or in combination is reviewed above and in the algorithm (algorithm 1). (See 'Medication selection' above.)

Modafinil — Modafinil is a first-line pharmacologic therapy for narcolepsy because it provides good control of sleepiness, is generally well tolerated, and illicit use is rare. The mechanism of action of modafinil is not well understood, but it probably increases dopaminergic signaling by blocking dopamine reuptake in a manner distinct from amphetamines (figure 1) [44-46].

Dosing – The usual starting dose of modafinil is 200 mg each morning (table 1). It can be titrated up to 300 or 400 mg per day depending on response and tolerability. Once-daily dosing in the morning typically promotes wakefulness into the early evening without disrupting nighttime sleep. Patients with persistent afternoon sleepiness may benefit from divided dosing with 200 mg in the morning and 200 mg in the early afternoon (table 1) [19,47,48].

Side effects – Side effects are uncommon but include headache, nausea, dry mouth, anorexia, and diarrhea. Modafinil may have fewer sympathomimetic effects than amphetamines and is often a good choice for older patients. Still, modafinil may increase blood pressure (especially at high doses), and it should be used cautiously in people with a history of arrhythmias or heart disease [49-52]. Rarely, modafinil can cause a serious rash, including Stevens-Johnson syndrome.

The drug is hepatically metabolized and induces several cytochrome P450 enzymes, thus decreasing the effectiveness of hormonal contraceptives and perhaps other medications; women of childbearing age who use modafinil should use an alternative method of contraception.

Efficacy – Supporting evidence for the use of modafinil in narcolepsy includes a trial in which 283 patients with narcolepsy were randomly assigned to receive 200 mg/day of modafinil, 400 mg/day of modafinil, or placebo [19]. After nine weeks, patients treated with modafinil at either dose had significant improvements in their maintenance of wakefulness test (MWT) and Epworth Sleepiness Scale measurements, without evidence of tolerance to the drug. Similar results were found in a second trial involving 271 patients with narcolepsy [47]. In a small trial that included 13 patients with narcolepsy, patients randomly assigned to modafinil had improved driving performance compared with patients receiving placebo [14].

Armodafinil — Armodafinil is the active R enantiomer of modafinil, and the two drugs appear to have very similar clinical effects. Like modafinil, armodafinil improves sleepiness, is generally well tolerated, and illicit use is rare.

Dosing – The usual starting dose is 150 mg each morning (table 1). Effective doses generally range from 150 to 250 mg each morning. Patients with persistent afternoon sleepiness may benefit from divided dosing (eg, 125 mg in the morning and 125 mg in the early afternoon).

Side effects Side effects and precautions are the same as for modafinil. (See 'Modafinil' above.)

Efficacy – Supporting evidence includes one 12-week, placebo-controlled trial in 196 patients with narcolepsy and a smaller 12-month, open-label, flexible dosing study [18,53]. In the randomized trial, both doses studied (150 mg/day and 250 mg/day) were superior to placebo on outcomes of subjective sleepiness, sleep latency on the MWT, and disease severity [18].

Methylphenidate — Methylphenidate is a relatively potent wake-promoting drug at moderate to high doses. It is considered a second-line wake-promoting agent due to sympathomimetic side effects, which can be more problematic than with other agents, such as modafinil.

Although primarily considered a wake-promoting agent, in our experience, methylphenidate can partially reduce cataplexy, hypnagogic hallucinations, and sleep paralysis as well (eg, by 10 to 20 percent) [17,54].

Dosing – A typical starting dose of methylphenidate is 10 mg twice per day, with the second dose given no later than about 3 PM. We typically use an immediate-release formulation initially for titration. The dose can be increased in 5 to 10 mg increments every one to two weeks based on response and tolerability, up to a maximum of 60 mg per day (table 1).

Once a stable dose has been reached, patients can be converted to an extended-release formulation for convenience. Although the extended-release formulation is intended to be taken once daily, many patients with narcolepsy find that the clinical effect wears off in four to six hours; such patients may use a second dose of either immediate or extended release in the early afternoon (no later than about 2 PM for extended release).

Side effects – Common side effects of methylphenidate include reduced appetite, nausea, headache, palpitations, and insomnia. Typical doses of methylphenidate increase systolic blood pressure about 5 mmHg [55], which may have long-term consequences. In addition, regulatory authorities reviewed several cases of sudden death in patients taking methylphenidate and issued a warning regarding serious cardiovascular events in children and adults [56,57]. Some of these deaths were associated with hypertrophic obstructive cardiomyopathy, while others may have been related to arrhythmias.

Patients taking high doses of methylphenidate for daytime sleepiness can develop psychosis, anorexia, or require psychiatric hospitalization. Methylphenidate and other stimulants can also lower the threshold for seizures. The potential for methylphenidate dependency exists.

Patients prescribed methylphenidate should be carefully informed about these risks, and their blood pressure, pulse, and weight should be monitored regularly. (See 'Follow-up and monitoring' above.)

EfficacyMethylphenidate has not been studied in randomized trials in patients with narcolepsy, despite widespread clinical use and experience with the drug. A 2021 American Academy of Sleep Medicine (AASM) systematic review identified three observational studies of methylphenidate in a total of 130 patients with narcolepsy [26]. Studies generally reported improvements in sleepiness and disease severity, but the quality of the evidence was rated as very low due to imprecision.

Amphetamines — Like methylphenidate, the amphetamines are considered second-line agents because their sympathomimetic side effects can be problematic. Dextroamphetamine, dextroamphetamine-amphetamine, and lisdexamfetamine are the most commonly prescribed amphetamines for narcolepsy.

Amphetamines can be potent wakefulness-promoting drugs, although some patients require relatively high doses. Like methylphenidate, amphetamines can partially reduce cataplexy, hypnagogic hallucinations, and sleep paralysis as well (eg, by 10 to 20 percent) [17,54].

Dosing – A typical starting dose of dextroamphetamine is 5 mg twice daily, with the last dose given no later than about 3 PM (table 1). The total daily dose can be increased in 10 mg increments every one to two weeks based on response and tolerability, up to a maximum of 60 mg per day. Dosing for other amphetamines can be found in the table (table 1).

We usually start with immediate-release formulations and then convert to an extended-release formulation for convenience once a stable daily dose has been reached. Although extended-release formulations are intended to be taken once daily, many patients with narcolepsy find that the clinical effect wears off in four to six hours; such patients may use a second dose of either immediate or extended release in the early afternoon. The immediate-release formulations are also helpful to promote wakefulness during the later part of the day if sleepiness is a critical challenge, such as during a late afternoon drive home.

Side effects – Common side effects of amphetamines include reduced appetite, nausea, headache, palpitations, and insomnia. Like methylphenidate, amphetamines are associated with increased risk of cardiovascular events (eg, hypertension, sudden death) and psychiatric events (eg, psychosis, anorexia, addiction) [56,58]. Patients prescribed amphetamines should be carefully informed about these risks and monitored regularly. Many states and countries require clinicians to use a prescription monitoring program when prescribing amphetamines. (See "Prescription drug misuse: Epidemiology, prevention, identification, and management", section on 'Prescription monitoring programs'.)

Efficacy – Supportive evidence for amphetamines in narcolepsy includes one small, randomized trial (12 patients) and observational studies in an additional 80 patients [26]. In the trial, both levo-amphetamine (20 to 60 mg) and dextroamphetamine (10 to 45 mg) reduced the number of sleep attacks but did not affect the rate of cataplexy [59].

Solriamfetol — Solriamfetol is an oral selective dopamine and norepinephrine reuptake inhibitor with wake-promoting effects. Solriamfetol was approved by the US Food and Drug Administration (FDA) in 2019. Side effects are similar to modafinil, and it may become a reasonable first-line choice for treating sleepiness in narcolepsy as clinical experience with the drug evolves.

Dosing – The starting dose of solriamfetol is 75 mg orally once daily in the morning. The dose can be increased as tolerated after a minimum of three days to 150 mg daily, which is the maximum dose approved by the FDA. Tablets are scored and can be cut in half.

Dose reductions are required for renal insufficiency, and the drug should not be used in patients with end-stage kidney disease. Concurrent use of monoamine oxidase inhibitors and noradrenergic drugs is contraindicated.

Side effects – The most common side effects are headache, nausea, decreased appetite, and anxiety. In the largest randomized trial, rates of discontinuation for adverse effects for solriamfetol 150 mg, 300 mg, and placebo were 5.1, 8.5, and 1.7 percent, respectively [23]. Small, dose-dependent increases in mean blood pressure and heart rate were observed in the 12-week study [23]. Insomnia was uncommon (5 percent in the 300 mg dose group, 7 percent with long-term therapy) [23,60].

EfficacySolriamfetol was studied in a randomized trial of 236 adults with narcolepsy who were randomly assigned to one of three doses of solriamfetol (75, 150, or 300 mg daily) or placebo [23,61]. At 12 weeks, sleep latency on the MWT improved more in the 150 and 300 mg dose groups than in the placebo group (mean change from baseline 9.8, 12.3, and 2.1 minutes, respectively) [23]. Epworth Sleepiness Scale and global impression scores improved in all three dose groups compared with placebo. Responses were maximal or near-maximal by one week and were sustained across the 12-week treatment period [23], as well as in an open-label follow-up for up to a year [60].

Solriamfetol has not been compared to or studied in combination with modafinil, methylphenidate, or amphetamines.

Oxybates — Gamma hydroxybutyrate (GHB), which is clinically available as sodium oxybate or as mixed oxybate salts (lower-sodium oxybate), is a metabolite of gamma amino butyric acid (GABA) with potent anti-cataplexy effects. It may act through GABA-B receptors, but its precise mechanism of action in patients with narcolepsy is unknown [62,63].

Oxybates improve daytime sleepiness and markedly reduce cataplexy; therefore, they are a good choice for patients with severe sleepiness and/or cataplexy [20,64-70]. The reduction in symptoms develops over several weeks of treatment so doses should be adjusted slowly [66,71].

Initial dose – Both sodium oxybate and oxybate salts are given as a liquid at bedtime, with a second dose 2.5 to 4 hours later; this second dose is necessary as the half-life is only two to three hours (table 1). An appropriate initial dose for most patients is 3 g, twice per night. A lower starting dose (2.25 g, twice per night) can be used if there are concerns about the potential for excessive sleepiness or other side effects. Patients may initially need to set an alarm clock to remind them to take the second dose, but after a few weeks, many learn to wake around the correct time.

The mixed salt oral solution (oxybate salts), comprised of calcium, magnesium, potassium, and sodium oxybates, was approved by the US FDA in July 2020 [72]. The active moiety is the same as that of sodium oxybate (ie, GHB), and dosing is the same; the only difference is that oxybate salts have 90 percent less sodium content. This mixed salt formulation may be preferred in many patients to lower daily sodium load, particularly given the high prevalence of comorbid hypertension in patients with narcolepsy.

Titration – The benefits of oxybates are often apparent in the first few days, but it can take three months or more to achieve the full response [73]; therefore, the dose should be increased slowly if troublesome sleepiness or cataplexy persists. We typically increase in 1.5 g increments (0.75 g per dose) every two to four weeks, if needed, up to a maximum of 4.5 g twice per night. In a 12-week, open-label study of 202 patients with narcolepsy type 1 who were either treatment-naïve or had been previously exposed but not titrated to adequate clinical effect, the majority of patients were much improved (79 percent) or somewhat improved (11 percent) at their final dose level [69]. The two most common final doses were 6 g/night (40 percent) and 7.5 g/night (33 percent).

Side effects and precautions – Side effects of oxybates are dose-dependent and are more common than with most other medications for narcolepsy. Oxybates rapidly produce deep sedation, so household safety should be discussed (ability to respond to smoke alarms, care for children, etc). Additional adverse effects include nausea and dizziness, weight loss, urinary incontinence, mood swings, and worsening of depression, sleepwalking, and psychosis [70,71,74]. In a retrospective study that included 59 adults with narcolepsy who were newly started on sodium oxybate, mean weight loss was approximately 3 kg in men and 7 kg in women over a mean follow-up of two years, and proportionate changes can be seen in children [75,76].

Over-dosage can result in respiratory depression, coma, and death [77,78]. Coadministration with alcohol and central nervous system depressants such as benzodiazepines and opioids increases risk for impaired consciousness and respiratory depression. Due to these risks, combined use with alcohol, sedatives, or hypnotics is specifically contraindicated in United States licensing information [79,80].

GHB gained notoriety as a "date rape" drug and has potential for abuse [81,82]. Thus, access to oxybates is restricted in the United States, and prescribers and patients are required to register with the Risk Evaluation and Mitigation Strategies (REMS) program.

Efficacy – Evidence to support use of oxybates in adults with narcolepsy includes a multicenter trial of 228 adults with narcolepsy type 1 who had symptoms despite standard therapies and were withdrawn from anticataplectic therapy in a lead-in phase [21,83-85]. At eight weeks, the median percent reduction in weekly cataplexy episodes from baseline was higher with sodium oxybate than placebo (85, 65, 57, and 20 percent lower for sodium oxybate 9 g, 6 g, 4.5 g, and placebo, respectively).

Oxybates can also decrease daytime sleepiness, perhaps by improving the quality of nighttime sleep [20,66-68,83,86]. In one observational study, sodium oxybate was associated with a 30 percent decrease in subjective sleepiness, assessed by the Epworth Sleepiness Scale [66]. Similarly, another observational study demonstrated improved sleepiness with sodium oxybate, as assessed by the MWT [67].

Pitolisant — Pitolisant is an oral histamine H3 receptor inverse agonist that improves daytime sleepiness and reduces cataplexy in adults with narcolepsy [22,87]. Like modafinil, pitolisant appears to have relatively modest strength as a wake-promoting agent and should be considered for patients who do not adequately respond to or tolerate other medications.

Pitolisant can also reduce cataplexy and is a good alternative to oxybates in patients whose cataplexy does not respond adequately to an antidepressant such as venlafaxine.

Dosing – The suggested starting dose of pitolisant is 8.9 mg once daily and increased to 17.8 mg after one week if well tolerated [88]. The maximum recommended dose is 35.6 mg once daily. The median time to peak plasma concentration is 3.5 hours, and the median half-life is 20 hours.

Pitolisant is metabolized by cytochrome P450 (CYP) 2D6 and CYP3A4 and excreted in the urine. Potential drug interactions need to be considered before prescribing pitolisant in combination with strong CYP2D6 inhibitors (eg, paroxetine, fluoxetine), as the combination can double pitolisant levels. Dose reductions are required in patients with either renal or hepatic impairment, and the drug should not be used in patients with end-stage kidney disease or severe hepatic impairment.

Side effectsPitolisant is generally well tolerated. The most common side effects are headache, insomnia, nausea, and anxiety. Rare cases of allergy and anaphylaxis have been reported [89].

Pitolisant is associated with dose-dependent prolongation of the QT interval; the prescribing information recommends monitoring of the QT interval in patients with renal or hepatic impairment and avoidance of the drug in combination with drugs that also increase the QT interval [88]. Like modafinil, pitolisant may decrease the effectiveness of hormonal contraception via weak CYP3A4 induction.

Efficacy – In a randomized trial of 95 patients with narcolepsy, pitolisant 8.9 to 35.6 mg reduced the Epworth Sleepiness Scale score by 5.8 points compared with a reduction of 3.4 points with placebo [22]. This effect size is similar to that seen with modafinil. MWT scores and frequency of hallucinations were also improved compared with placebo.

In a randomized trial of 106 adults with narcolepsy type 1, pitolisant (4.5 to 35.6 mg/day) was more effective than placebo at reducing weekly cataplexy rate (75 versus 35 percent relative reduction from baseline rates of seven to nine episodes per week) [90].

Antidepressants for cataplexy — Cataplexy is thought to be a rapid eye movement (REM) sleep-like state in which the paralysis of REM sleep intrudes into wakefulness. Brainstem circuits that generate REM sleep are strongly inhibited by norepinephrine and serotonin. Thus, antidepressants that increase noradrenergic and serotonergic signaling suppress REM sleep and reduce cataplexy [91]. They are not considered treatments for sleepiness.

Among antidepressants, venlafaxine is the most widely used for cataplexy in patients with narcolepsy. Reasonable alternatives are fluoxetine and duloxetine [92,93]. Older tricyclic antidepressants such as protriptyline or clomipramine can be very effective, but anticholinergic side effects limit their utility as daily medications.

Venlafaxine – Robust clinical experience supports the efficacy of venlafaxine to reduce cataplexy substantially with relatively few side effects, although data from clinical trials are lacking [94]. We use the extended-release formulation beginning at a dose of 37.5 each morning. The usual effective dose of venlafaxine for cataplexy ranges from 37.5 to 150 mg (table 1). A reduction in cataplexy should be obvious within a few days. In our clinical experience, both fluoxetine and duloxetine are also effective and are reasonable alternatives to venlafaxine.

Tricyclic antidepressants – For many years, cataplexy was treated with tricyclic antidepressants such as protriptyline or clomipramine, which decrease the reuptake of aminergic neurotransmitters. These drugs are very effective, but many patients are bothered by anticholinergic side effects, including dry mouth and constipation [95]. Nonetheless, they are quite effective for suppressing cataplexy, and low doses can be effectively used on an as-needed basis just before social events likely to trigger cataplexy such as a party or wedding.

Abrupt withdrawal from any of these antidepressants can trigger status cataplecticus: severe, nearly continuous rebound cataplexy that can last several hours.

OUTCOMES AND PROGNOSIS — Narcolepsy impacts daily life in many ways, and optimizing therapy should address more than just simple measures of sleepiness and cataplexy. (See 'Health maintenance' above.)

Quality of life — The chronic sleepiness of narcolepsy can make it hard to socialize, drive safely, study in school, and stay awake in meetings at work. In addition, cataplexy can be quite embarrassing, and many patients try to suppress their emotions and avoid parties, weddings, or other events likely to trigger their cataplexy. One study of Danish patients showed that people with onset of narcolepsy in childhood or adolescence achieved lower educational levels and had lower earnings as adults [96].

Little research has focused on addressing these psychosocial challenges, but these should be considered as part of disease management. In addition, narcolepsy support groups, cognitive behavioral therapy, and other forms of counseling should be helpful (Narcolepsy Network, Wake Up Narcolepsy, Project Sleep) [97,98].

Natural history — Narcolepsy with cataplexy (type 1 narcolepsy) is considered a lifelong condition, as it is almost certainly caused by autoimmune destruction of the orexin-producing neurons of the lateral hypothalamus [99,100]. However, rare patients with low cerebrospinal fluid (CSF) orexin levels may show improvement or even complete resolution of their sleepiness and cataplexy, perhaps due to neural compensation unrelated to orexins [101,102].

By contrast, narcolepsy without cataplexy (type 2 narcolepsy) is probably not due to loss of the orexin neurons, and it is unclear if the disorder is stable over time. From the time of diagnosis, about 40 percent of narcolepsy without cataplexy patients show resolution of their sleepiness over the next five years [99]. In another study, 4 out of 15 patients with narcolepsy without cataplexy had a normal multiple sleep latency test (MSLT) about four years later [100]. It remains unclear if this apparent improvement is due to true resolution of type 2 narcolepsy, inconsistent sleep study protocols, or changes in comorbidities such as depression.

Excess mortality — As narcolepsy is associated with an increased incidence of motor vehicle accidents, hypertension, obesity, and sleep apnea, one would expect increased mortality from cardiovascular disease and other complications. Some studies have reported 1.3- to 1.5-fold increased mortality in young and older people with narcolepsy [96,103,104], but these data should be viewed cautiously, as subjects were identified using billing diagnoses, and some may have had sleepiness of another cause.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Parasomnias, hypersomnias, and circadian rhythm disorders".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topics (see "Patient education: Narcolepsy (The Basics)" and "Patient education: Daytime sleepiness (The Basics)")

SUMMARY AND RECOMMENDATIONS

Overview – Narcolepsy is a lifelong disorder characterized by excessive daytime sleepiness, cataplexy in some patients, and disrupted nighttime sleep. Treatment is symptomatic, aimed at improving alertness and restoring function during waking hours. (See 'Introduction' above and 'Outcomes and prognosis' above.)

Importance of adequate sleep – Daytime naps and a regular, adequate sleep schedule are the mainstays of nonpharmacologic therapy. For occasional patients with mild symptoms, a well-timed, short nap in the early afternoon and avoidance of sleep deprivation at night may be sufficient for adequate function. (See 'Napping and sleep hygiene' above.)

Comorbidities – Comorbid sleep disorders such as obstructive sleep apnea should be diagnosed and treated to ensure optimal nighttime sleep. Psychiatric comorbidity is common, especially depression and anxiety. Psychosocial support and regular screening for depression are important components of care. (See 'Comorbid sleep disorders' above and 'Psychosocial support' above.)

Health maintenance – Patients with narcolepsy have an increased risk for obesity and cardiovascular disease. Heart rate and blood pressure should be monitored at each clinic visit and hypertension treated appropriately. (See 'Health maintenance' above.)

Pharmacotherapy – Most patients with narcolepsy require medication to promote wakefulness. Multiple effective medications are now available to improve alertness (table 1), but few comparative studies have been performed. Selection is individualized based on factors that include symptom severity, comorbidities, and medication efficacy, side effects, and cost (algorithm 1). (See 'Goals of therapy' above and 'Medication selection' above.)

Mild to moderate sleepiness – For patients with mild to moderate sleepiness, we suggest an initial trial of modafinil (Grade 2C). Reasonable first-line alternatives are armodafinil, pitolisant, and solriamfetol. Our preference for modafinil is based largely on cumulative experience with the drug and tolerability. (See 'Patients with mild to moderate sleepiness' above.)

Severe/disabling sleepiness – For patients with severe and disabling sleepiness with or without cataplexy, we suggest treatment with oxybates rather than other wake-promoting medications (Grade 2C). Although risks and side effects, as well as cost, may be higher with oxybates, they can offer the best chance of optimal symptom control with monotherapy for patients with severe symptoms. (See 'Patients with severe/disabling sleepiness' above.)

Alternatives in patients who are not candidates for oxybates include solriamfetol, moderate to high doses of methylphenidate or amphetamines, and medication combinations (algorithm 1).

Residual cataplexy – For patients with mild to moderate sleepiness who respond well to a first-line wake-promoting agent but have disruptive cataplexy, we suggest adding a serotonergic antidepressant with anti-cataplexy effects, such as venlafaxine (Grade 2C). An alternative to antidepressants is to add or switch to pitolisant. For more severe cataplexy, which is usually accompanied by severe sleepiness, we add or switch to oxybates. (See 'Patients with residual cataplexy' above.)

Driving safety – People with narcolepsy have a three- to fourfold increased risk of having a car accident, and over one-third have had an accident due to sleepiness. Clinicians should discuss these risks openly with patients and talk about strategies to mitigate risk. (See 'Driving safety' above.)

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  100. Trotti LM, Staab BA, Rye DB. Test-retest reliability of the multiple sleep latency test in narcolepsy without cataplexy and idiopathic hypersomnia. J Clin Sleep Med 2013; 9:789.
  101. Büchele F, Baumann CR, Poryazova R, et al. Remitting narcolepsy? Longitudinal observations in a hypocretin-deficient cohort. Sleep 2018; 41.
  102. Vellieux G, Frija-Masson J, Rouvel-Tallec A, et al. Narcolepsy Type 1: A Remitting Disease? An Unusual Case Report. Nat Sci Sleep 2021; 13:1669.
  103. Ohayon MM, Black J, Lai C, et al. Increased mortality in narcolepsy. Sleep 2014; 37:439.
  104. Jennum P, Thorstensen EW, Pickering L, et al. Morbidity and mortality of middle-aged and elderly narcoleptics. Sleep Med 2017; 36:23.
Topic 7681 Version 48.0

References

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