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UNMET NEEDS IN NARCOLEPSY MANAGEMENT

Narcolepsy is a chronic neurologic disorder characterized by the brain’s abnormal regulation of the sleep-wake cycle.^1-3 It was first clearly defined in 1877, but, by 1924, only 35 cases of narcolepsy had been reported.⁴ Although recognition of narcolepsy has improved significantly in the past century, the disease remains rare. Narcolepsy is diagnosed in approximately 1 of every 2000 people in the United States (U.S.),⁵ but it is suspected that the actual number of people with narcolepsy is substantially higher, with estimates claiming that 75% of patients with narcolepsy are undiagnosed and untreated. Narcolepsy is most prevalent in Japanese populations and is least prevalent in Jewish and Arabic populations.⁴ 

The average time between symptom onset and diagnosis ranges from 8 to 22 years,^5-8 and narcolepsy is misdiagnosed in approximately 60% of patients.⁵ The excessive daytime sleepiness (EDS) that is prominent with narcolepsy is most commonly misattributed to depression, insomnia, sleep deprivation, or obstructive sleep apnea.⁹

The disease typically first presents in adolescence, though a small portion of disease onset occurs in children younger than 10 years old and in adults around 35 years old.⁴ The EDS that patients experience may make it difficult to focus during school or work, to drive, or to stay awake while watching a movie.¹⁰ EDS occurs even with adequate nighttime sleep; patients will awaken from nighttime sleep or a nap feeling refreshed only to experience severe sleepiness less than 2 hours later.

Narcolepsy confers a large disease burden that includes reductions in quality of life and functional status and increased direct and indirect costs associated with healthcare resource utilization, reduced productivity, and increased disability.^8,9,11 The inability to remain awake during daytime hours can complicate occupation options and employability.⁷ Lack of understanding of narcolepsy symptoms can result in authority figures characterizing patients as unmotivated, immature, or less capable than their peers, which negatively affects patient self-confidence and self-worth.⁹ The delay in time to diagnosis can have a notable impact on the disease burden, with those diagnosed before age 30 more likely to have better outcomes, less unemployment, and a better perception of health than people diagnosed later in life.⁸

UNDERSTANDING NARCOLEPSY AS A DISEASE

Two types of narcolepsy have been defined: both classifications are characterized by EDS, but they differ in terms of other associated symptoms. Patients with cataplexy and orexin deficiency are diagnosed with narcolepsy type 1 (NT1); those without cataplexy are diagnosed with narcolepsy type 2 (NT2). Table 1 describes the clinical features associated with both types of narcolepsy.^6,10

EDS and rapid eye movement (REM) sleep attacks occur throughout the day: they usually have a sudden onset but often last less than 20 minutes in duration.^3,10 EDS is commonly the initial and most debilitating symptom of narcolepsy.¹² Some patients experience automatic waking behaviors, such as driving to an unintended destination or doodling on a paper, that are associated with amnesia.⁶ These automatic behaviors occur more often in patients who try to resist sleep during periods of EDS.⁶ Children who resist sleep during EDS periods may appear hyperactive or restless.⁴

Cataplexy is a sudden bilateral loss of muscle tone with fully preserved consciousness provoked by a strong emotion; this loss of tone can be total or partial in the muscles affected.^3,11 Sudden positive emotions are more likely to cause cataplexy, but it can occur with negative emotions, as well. As a result, common activities such as tickling, coitus, and sports can trigger an attack.⁴ Cataplexy will usually start in the face and neck muscles and spread to the limbs and the trunk.¹⁰ Partial cataplexy can mimic a stroke with slurred speech, face and jaw sagging, and eyelid droop, but it is distinguished from stroke by the bilateral distribution.^6,10,11 The diagnosis of NT1 is complicated by the fact that cataplexy does not present until years after EDS in approximately 43% of patients; however, when present, it is confirmatory of a narcolepsy diagnosis, as cataplexy is not known to occur with any other disorder.^3,4,11 Notably, more adults than children experience cataplexy.³ Repeated, persistent episodes of cataplexy, called status cataplecticus, can occur with narcolepsy and are either spontaneous or caused by withdrawal of an anticataplectic medication.⁶

Approximately one-third to one-half of patients with narcolepsy have sleep paralysis and more than half of patients have vivid dreams manifesting as hallucinations during wake-sleep transitions.^3,6 Sleep paralysis is described as the inability to move limbs or speak and may be accompanied by a sense of suffocation.^4,6 Hypnagogic hallucinations occur at sleep onset while hypnopompic hallucinations occur during wakening.⁴ These hallucinations are typically visual and mainly associated with preserved insight regarding their reality. However, some hallucinations are severe enough to be misdiagnosed as schizophrenia or other psychiatric disorders.^4,6 Both sleep paralysis and hallucinations are significantly more common in NT1 than in NT2.³ Some patients may experience co-existing insomnia and obstructive sleep apnea.^3,4 However, EDS with narcolepsy does not appear to be impacted by these other sleep disorders.³

Narcolepsy has also been associated with less prominent features: weight gain and obesity are the most common, especially at disease onset.^4,11 Children seem to be more susceptible to weight gain, particularly during puberty.⁴ Disorders of cognition and attention occur in many patients; historically, they have been categorized as resulting from EDS, but the impact of orexin loss on the development of these symptoms is being evaluated.⁴ Less understood autonomic disturbances include digestive issues, fainting, night sweats, dry mouth, olfactory dysfunction, headache, and palpitations.⁴

NT1 is caused by a deficiency in orexin, which is also known as hypocretin, a chemical produced by the hypothalamus that plays an essential role in the sleep cycle by regulating REM sleep and maintaining alertness.^4-6,11 Orexin-producing neurons are most active during times when a person is awake, particularly during muscle use and during motivated and exploratory behaviors. A loss of this neuropeptide is thought to manifest as an inability to stay in wake or sleep states for a usual length of time and a fast transition into and out of REM sleep.^4,11 Subsequently, patients experience short periods of sleep and wakefulness, REM sleep atonia while awake, and dreaming (which may be hallucinations) during sleep-wake and wake-sleep transitions.⁴

Autoimmune, infectious, environmental, post-traumatic, and genetic origins have all been proposed as potential causes of decreased hypocretin levels and selective loss of approximately 90% of the orexin neurons in the lateral hypothalamus.⁴ Patients with NT1 may also have at least 50% more histamine neurons than normal in the tuberomammillary nucleus, which is suggested to be compensatory for the orexin deficit.^4,12 Like orexin, histamine release and neuron activity is highest during wakefulness.⁴

Compared to NT1, less is understood about the pathophysiology of NT2. Animal studies have demonstrated that a partial loss of orexin neurons leads to narcolepsy, but, in NT2, orexin levels in the cerebrospinal fluid (CSF) are normal and cataplexy is not evident.⁴

The human leukocyte antigen (HLA) DQB1*0602 haplotype, previously thought to be only associated with cataplexy, is expressed in up to 98% of patients with NT1 and up to 53% of patients with NT2.^3,4,6,11 The allele is associated with shorter REM sleep latencies and is under evaluation as a potential biomarker for narcolepsy.^3,4 One study showed that 30% of NT2 patients with low hypocretin levels in the CSF were positive for HLA-DQB1*0602 and one-third of these patients went on to develop cataplexy 4 to 26 years after EDS onset.³ It is important to understand that this allele is expressed in up to 38% of the general population and only 1 in 1000 carriers go on to develop narcolepsy.^4,6 Other studies have identified associations between genetic polymorphisms and narcolepsy, but the clinical utility of these findings remains unclear. Less than 2% of persons with narcolepsy have a family member who also suffers from the disease and only 25% of monozygotic twin pairs have been shown to be concordant for narcolepsy.⁴

A temporal association between pulmonary infections and narcolepsy onset has been observed since the 1920s⁴: infections from streptococcal bacteria and influenza A H1N1 have been implicated most often.^4,6 The results of an immunologic study indicated that molecular mimicry of the influenza hemagglutinin protein may trigger an autoimmune process that targets orexin neurons.⁴ Additionally, autoantibodies and autoreactive inflammatory mediators have been identified in patients with narcolepsy.⁴ This supports the theory that an autoimmune process causes, or at least contributes to, the development of narcolepsy.⁴ Unfortunately, many of these markers also occur in patients without narcolepsy and the translation of these findings into clinical or therapeutic utilities remains unclear.

Narcolepsy diagnosis and screening tools

Two sets of diagnostic criteria exist for narcolepsy: the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) and the International Classification of Sleep Disorders, Third Edition (ICSD-3).^11,13 A comparison of the criteria is shown in Table 2.^11,13 Both criteria require EDS for at least 3 months. EDS is formally diagnosed by a nocturnal sleep polysomnography (PSG) with a REM sleep latency of 15 minutes or less or a multiple sleep latency test (MSLT) with a mean sleep latency of 8 minutes or less and more than 2 sleep-onset REM periods. Diagnosis of NT1 must also involve either cataplexy or hypocretin deficiency, which is defined by CSF hypocretin-1immunoreactivity values (also known as orexin levels) that are 110 pg/mL or lower or less than one-third of levels observed in healthy patients.^11,13 The ICSD-3 does not require a minimum frequency of cataplexy, but the DSM-5 requires it to occur at least a few times per month.^11,13

NT2 has the same diagnostic criteria for EDS as NT1, but cataplexy is absent; additionally, in NT2, CSF hypocretin-1 concentration is more than 110 pg/mL or more than one-third of the levels observed in healthy patients, or it has not been measured. Finally, NT2 is diagnosed when EDS and MSLT findings cannot be explained by other etiologies.¹¹ Because cataplexy may not develop until years after EDS presentation, some patients may initially be diagnosed with NT2 and eventually require reclassification to NT1.¹¹

The most specific and sensitive test for NT1 is the measurement of orexin in the CSF: orexin is either undetectable or less than 110 pg/mL in 95% of patients with NT1.⁴ Levels are typically normal in NT2. However, up to 40% of patients without cataplexy do have low CSF orexin levels, thereby meeting the diagnostic requirements for NT1.^4,12

The MSLT used in the diagnosis of narcolepsy has a sensitivity and specificity that range from 70% to 80% for NT1; its sensitivity and specificity are both 100% for NT2.⁴ Medications that suppress REM sleep should be discontinued at least 1 week before the test, and medications with long half-lives must be discontinued at least 3 weeks in advance.¹⁰ A confirmatory urine toxicology test is collected the day the MSLT is performed to ensure the results will not be impacted by medications.⁶ The test is conducted the day following a nocturnal PSG. The patient is placed in a dark room conducive to sleep and given 4 nap opportunities (20 minutes each and spaced 2 hours apart).^3,6,10,14,15 A fifth nap is allowed if at least 1 sleep-onset REM period occurs in the first 4 naps. Interpretation of the MSLT is based on the time it takes the patient to fall asleep. A sleep latency of 15 to 20 minutes is considered excellent, 10 to 15 minutes is manageable, 5 to 10 minutes is troublesome, and 0 to 5 minutes is severe. A sleep latency of less than 8 minutes is required to meet the diagnosis of narcolepsy.^14,15 However, results of the MSLT can be influenced by age, sleep deprivation, medication, and shift work.⁴ MSLT results on follow-up tests consistent with narcolepsy are usually present with NT1, whereas they may improve with NT2.⁴

The maintenance of wakefulness test (MWT) is another method to evaluate EDS, but, unlike the MSLT, a preceding PSG is not required and patients do not have to discontinue any medications in order to complete the test.^14,15 Patients sit in a dimly lit room of comfortable temperature for 4 sessions, each lasting 20 to 40 minutes and separated by 2 hours. Patients are instructed to stay awake as long as possible. Not falling asleep is considered normal while sleep onset of less than 12 minutes can indicate EDS.

Several sleep scales can be used to evaluate the severity of EDS. The Epworth Sleepiness Scale (ESS) is a questionnaire in which patients indicate their likelihood of falling asleep during 8 common situations.^14,15 Scores range from 0 to 24 and patients with narcolepsy commonly score at least 18.^4,14,15 The ESS is nonspecific for narcolepsy and may detect hypersomnolence from other disorders.

The Swiss Narcolepsy Scale (SNS) is a self-administered screening questionnaire developed specifically to identify patients with narcolepsy.^4,16 It contains 5 questions that evaluate a patient’s ability to fall asleep, the likelihood of feeling unrefreshed on morning awakening, the frequency of noon naptimes, and experiences of weak knees/buckling of knees and sagging of jaw during strong emotions. A score of less than zero indicates narcolepsy.¹⁶ The SNS is 93% sensitive and 82% specific for NT1 and 63% sensitive and 70% specific for NT2.¹⁶

The Narcolepsy Severity Scale (NSS) is a relatively new scale developed by experts in narcolepsy specifically to evaluate the features of NT1.¹⁷ The NSS contains 15 items that evaluate symptom frequency and severity over the previous month and are scored by the patient using a Likert scale. Symptoms or features of narcolepsy evaluated in the NSS include EDS, cataplexy, sleep paralysis, hypnagogic and hypnopompic hallucinations, and fragmented nighttime sleep. The total sum of item scores ranges from 0 to 57, with higher scores indicating more frequent and severe symptoms. The NSS considers factors such as narcolepsy’s impacts on family and social relationships and ability to drive. It has primarily been used and evaluated in patients with NT1 and its utility in NT2 is not well defined. A summary of scales and tests used to diagnose or monitor narcolepsy is provided in Table 3.^{3,4,6,10,11,14-17}  

OVERVIEW OF NARCOLEPSY MEDICATIONS

Many types of medications are available to treat the features of narcolepsy. From stimulants to antidepressants, all of the medications used in the treatment of this disease offer benefits and risks. The choice among medications is based on patient-specific factors, and the optimal treatment choice may change over time, as symptoms evolve and tolerance may develop to the effects of some medications.

Older therapies

The treatment of narcolepsy has been hallmarked by stimulants. These medications are useful for maintaining wakefulness, but many other classes of agents are available to treat other symptoms related to narcolepsy.

Stimulants

Stimulants were among the first medications used to treat narcolepsy and they remain among the most effective agents for sleepiness. Amphetamines have been indicated for narcolepsy since 1935 and methylphenidate has been used for EDS since the 1950s.^18,19 Stimulants improve wakefulness by blocking the reuptake and increasing the release of monoamines, primarily dopamine but also norepinephrine and serotonin.⁶ The amphetamines are essentially derivatives of catecholamines made lipophilic enough to cross the blood-brain barrier.¹⁹ Methylphenidate has similar pharmacologic mechanisms to amphetamines, but it does not completely substitute for catecholamines at the dopamine transporter.²⁰ Only a few older studies support the efficacy of methylphenidate in EDS. However, methylphenidate’s effects are evident within days of starting therapy, even at low dosages.

Stimulant medications should be dosed in the morning and again at lunch. Some patients may require up to 4-times-daily dosing with immediate-release formulations.²¹ Long-acting formulations may be better tolerated and may also improve adherence compared to immediate-acting formulations.²⁰ However, studies have shown a benefit of combining short-acting stimulants (usually methylphenidate) with modafinil and sodium oxybate, particularly during periods when wakefulness is essential.²⁰

Methamphetamine is recommended as a second-line therapy for EDS.²² It has similar pharmacologic activity to amphetamines, but the addition of the methyl group increases brain penetration owing to enhanced lipophilicity.¹⁹ Caffeine as a stimulant is generally not helpful to overcome the degree of sleepiness associated with narcolepsy and is generally not used as a therapeutic option for EDS in this population.²⁰

Antidepressants

Certain antidepressants are used in the management of non-EDS symptoms of narcolepsy, including cataplexy, sleep paralysis, and hypnagogic hallucinations. Norepinephrine and serotonin suppress REM sleep and it is thought that the role of antidepressants in narcolepsy derives from their blockade of the reuptake of these neurotransmitters.¹⁰ However, the exact mechanism for their anticataplectic effects remains unclear.²³

Venlafaxine, a serotonin-norepinephrine reuptake inhibitor, is considered a first-line choice for cataplexy and its effects can be seen almost immediately after initiation. Doses are generally lower than those used in depression, and it has been shown to be effective in children as young as 6 years of age.¹⁹ Either the immediate-release tablets or the extended-release formulations (capsules or tablets) may be used. However, one study showed an increase in cataplexy episodes when immediate-release venlafaxine was changed to extended-release venlafaxine during a shortage of the immediate-release tablet.²⁴ Patients subsequently demonstrated an improvement in cataplexy control when the shortage of the immediate-release formulation was resolved and they could be switched back to extended-release products. Venlafaxine may also improve sleep-related hallucinations in narcolepsy.^4,22 It has been suggested that venlafaxine may have some stimulant effects (though not enough to be used as monotherapy) and this may provide an added benefit for patients with NT1.^19-21

The selective serotonin reuptake inhibitors (SSRIs) citalopram, escitalopram, sertraline, fluoxetine, and fluvoxamine have been used to treat cataplexy and co-existing depression and anxiety. They are also useful when a long duration of action is required.^18,19,25

Tricyclic antidepressants (TCAs) may be more effective than SSRIs in narcolepsy.^18,19,25 Within the class, clomipramine, desipramine, doxepin, imipramine, nortriptyline, and protriptyline have been studied in narcolepsy. Of these, clomipramine is the most often used and is thought to be the most potent suppressant of REM sleep.^4,20,25 Clomipramine may also be useful on an as-needed basis to prevent cataplexy when taken before an event that may provoke a strong emotion.¹⁰ However, TCAs are not prescribed as often as other therapies due to their adverse effects.⁶

Selegiline, a monoamine oxidase (MAO) B inhibitor, is a second-line option for EDS and cataplexy; it is one of only 2 drugs recommended for the treatment of both symptoms.^{18,19,22,26-28} Its effects in narcolepsy are thought to be due, in part, to its metabolism to L-amphetamine and L-methamphetamine.¹⁹ However, it is not thought to have the same potential for misuse or abuse as most of the other available medications for EDS and it is one of the few available that is not a controlled substance.^26-28 Selegiline’s anticataplectic effects are particularly impressive. Up to 89% of patients experience a reduction in cataplexy with its use.²⁶ Still, the use of selegiline in narcolepsy is uncommon due to its sympathomimetic adverse effects and numerous drug interactions.

One limitation to antidepressant use in narcolepsy is that patients can develop a tolerance to the medications and symptom control may lessen over time.^21,25 It is not well understood if switching to another agent within the same class will resume symptom control, but there may be efficacy with changing to another antidepressant class.^18,19,25 However, patients may eventually require the use of an alternative class as tolerance develops to antidepressants as a whole over time.

Targeted therapies for narcolepsy

Modafinil is one of 2 first-line therapies recommended by the narcolepsy guidelines for EDS and it is one of the most studied medications for sleepiness.^19,22 It is considered a stimulant, but it is structurally and chemically unrelated to other stimulants.²⁰ Modafinil is thought to reduce sleepiness by blocking the dopamine transporter and subsequently increasing extracellular dopamine concentrations.^6,10,18,19 It activates hypocretin, histamine, alpha-adrenergic, and glutamate receptors. Additionally, modafinil inhibits the presynaptic transport of norepinephrine, which reduces the activity of sleep-promoting neurons.

Modafinil is usually dosed twice daily, at awakening and in early afternoon. However, it can be dosed once daily in patients who have difficulty with adherence. Efficacy with EDS is normally seen within just a few days of starting therapy.⁴ Unfortunately, its stimulant effects are only potent enough to effectively manage EDS in approximately half of patients and, even when it is initially effective, some patients experience declining symptom control with long-term use.¹⁹ In addition to modafinil, some patients require short-acting stimulants (i.e., methylphenidate) for times when wakefulness is challenging or on an as-needed basis in urgent situations, such as driving.¹⁹

Although not recommended for use in children under the age of 16 years by the U.S. Food and Drug Administration (FDA), modafinil is used off-label by some physicians for EDS in pediatric patients.²¹ One small study evaluated the use of modafinil for EDS in 13 children aged 2 to 18 years old.²⁹ The medication was dosed in a similar manner to what is recommended for adults for an average of 15.6 months. Improvements in EDS and sleep latency were seen in all but 1 patient. One child had a pre-existing seizure disorder and another had a history of hallucinations prior to study enrollment. Both experienced worsening of these comorbidities but were able to be managed with pharmacotherapy and continued modafinil use without further complications. No other safety concerns were reported.

Armodafinil is the purified R-isomer of modafinil. It has a longer half-life and generally only requires once-daily dosing.⁶ In 2 studies, armodafinil showed improvement in EDS at each of the 12 monthly visits throughout the studies.^30,31 Because the potency of armodafinil is twice that of modafinil on a milligram-per-milligram basis, some patients may see improved symptom control with armodafinil.²⁰ Rebound hypersomnolence is not common with either modafinil or armodafinil and tapering either medication prior to discontinuation is not usually required.²¹

Sodium oxybate is the only available medication that is FDA approved and guideline recommended for EDS, cataplexy, fragmented sleep, sleep paralysis, and hypnagogic hallucinations.^19,22,32 It is also the only medication FDA approved for the treatment of narcolepsy in children. It is the sodium salt of γ-hydroxybutyrate.¹⁹ It activates γ-aminobutyric acid type B receptors and produces a deep, slow wave sleep and REM sleep and improves sleep continuity.^10,19 Sodium oxybate’s effects on cataplexy may be more pronounced than its effects on EDS, but the mechanism for reducing cataplexy is not well understood.²¹

The dosing of sodium oxybate is unique among narcolepsy treatments: it is administered in 2 liquid doses, the first at bedtime and the second 4 hours later.^10,32 Doses are titrated weekly to a maximum dose of 9 grams per night.^18,19,32 Dose reductions are necessary for patients taking concomitant valproic acid, those with liver impairment, and pediatric patients who weigh between 20 and 45 kg.³² Patients should be instructed to avoid eating at least 2 hours before the first dose to ensure optimal absorption.^18,19 Effects on cataplexy may be noticeable at lower doses, but effects on EDS are more evident with doses towards the higher end of the dosing range.²⁰

While sodium oxybate is one of the most effective medications for narcolepsy symptoms, it also has one of the longest onsets.³³ Median time to first response is approximately 37 days for EDS and 25 days for cataplexy.³³ However, maximal response may not be seen until 106 days for EDS and 213 days for cataplexy.³³ The full impact of the medication may not be seen until up to 3 months or more after initiation; some patients may require additional medications for symptom management during the interim period.^4,21 Unlike other medications, tolerance does not develop to the anticataplectic effects nor is there a risk of cataplexy rebound with sudden cessation of sodium oxybate.^20,34 Sodium oxybate is the only medication recommended by treatment guidelines as a potential first-line therapy for both EDS and cataplexy.²²

Theoretically, initiation of sodium oxybate could occur at any time after narcolepsy diagnosis. However, the abuse potential, side effect profile, and mandatory specialty pharmacy distribution often delays initiation of sodium oxybate until symptom control with other medications wanes or until monotherapy for multiple narcolepsy features is desired.

Some patients require multiple medications for effective symptom control. Combination therapy with sodium oxybate and either venlafaxine or stimulants has been shown to be beneficial in managing EDS or cataplexy.³⁵ A 2016 study demonstrated that the combination of sodium oxybate and modafinil resulted in significantly lower ESS scores at 8 weeks compared to monotherapy with either medication in patients with NT1 and NT2.³⁶ Combination therapy also resulted in significantly longer sleep latency on the MWT and a higher percentage of patients who rated their symptoms as “very much improved” or “much improved” on the Clinical Global Impression of Change scale. Other long-term studies with sodium oxybate showed that approximately 70% of patients were on combination therapy, suggesting that, while it is appropriate to start with sodium oxybate monotherapy, many patients will eventually require polypharmacy.³⁵

Novel and emerging therapies

The most recent guidelines for the treatment of narcolepsy were published by the American Academy of Sleep Medicine in 2007. The guidelines include only 10 medications that are currently available in the U.S.²² Since the guideline’s publication, there has been a rise in research related to therapies for narcolepsy, and, in 2019, the FDA approved 2 new medications for the condition, marking the first new approvals since that of sodium oxybate.

Solriamfetol is a second-generation phenylalanine-derived wake-promoting medication approved for EDS associated with narcolepsy or obstructive sleep apnea.^11,37 It selectively inhibits the reuptake of dopamine and norepinephrine.^4,21,37,38 This duel pharmacologic mechanism and lack of monoamine release makes it different than other wake-promoting agents.^38,39 Unlike stimulants, solriamfetol does not promote the release of norepinephrine or monoamines.^21,39 Its reuptake of neurotransmitters occurs at dopamine and norepinephrine transporters.

Solriamfetol is initially dosed at 75 mg once daily and can be increased to a maximum dose of 150 mg daily after at least 3 days. It has been studied in patients with compromised kidney function: it requires dose adjustments in patients with decreased kidney function and is not recommended in patients with end-stage renal disease.^37,40

Solriamfetol’s efficacy in narcolepsy has only been evaluated in 3 studies; an additional post-hoc analysis of 1 study has also been published.^38,39,41,42 Two phase II studies showed significantly greater improvements in sleep latency and ESS with solriamfetol than with placebo over 4 weeks; one of the phase II studies demonstrated continued superiority through week 12.^39,41,42

The TONES 2 study is the only published phase III study of solriamfetol specifically in narcolepsy.³⁸ Significantly, greater improvements in sleep latency, ESS scores, and Patient Global Impression of Change scores were seen with solriamfetol 150 mg and 300 mg over 12 weeks.³⁸ The onset of efficacy for EDS occurs within the first week of therapy and effects appear to last for at least 9 hours during the day.^38,39,41 No effect on cataplexy has been seen in any of the studies.^38,39,41 It should be noted that solriamfetol has not been compared to any other active treatment option in narcolepsy and its comparative efficacy to other medications is not established.

Pitolisant has the distinction of being the only non-controlled substance approved for the treatment of EDS.⁴³ It is an inverse agonist of the histamine 3 receptor that enhances histaminergic neuron activation in the brain.^12,43 Pitolisant also increases dopamine, acetylcholine, and norepinephrine in the brain.¹²

Pitolisant requires dose titration over a 3-week period, starting with 8.9 mg and doubling the dose as needed each week to a maximum of 35.6 mg once daily by week 3.⁴³ Full effects on narcolepsy may not be evident for several weeks after initiation.²¹

Pitolisant’s efficacy has been evaluated in 5 phase III studies.¹² Overall, pitolisant’s effects on EDS appear to be similar to those of modafinil. Though currently FDA approved for the treatment of EDS, pitolisant has demonstrated anticataplectic effects in some studies.^4,21 Three of the studies showed that 66% to 71% of patients had improvements in EDS and cataplexy.^4,21 The Harmony I and Harmony CTP studies each showed significant reductions in ESS, MWT, and cataplexy episodes with pitolisant compared to placebo over 8 weeks. Harmony I also showed non-inferiority of pitolisant compared to modafinil for EDS according to ESS scores.^4,21

The Harmony Ibis study had an essentially identical design to Harmony I, but it failed to show superiority of pitolisant over modafinil or placebo for EDS and did not demonstrate a significant reduction in cataplexy.^4,21 The maximum dose of pitolisant was limited to 18 mg daily and only 75% of patients were titrated to this dose. It is possible that pitolisant’s anticataplectic effects require titration to the maximum dose.

Pitolisant’s efficacy as add-on therapy to sodium oxybate for EDS was evaluated in the Harmony IV study. No significant differences were seen compared to placebo, but the study was only 8 weeks long and it is possible that the medication did not have time to achieve maximum effects. Pitolisant’s FDA approval was based on the Harmony I and Harmony Ibis studies, which may explain why the medication does not carry an indication for cataplexy.⁴³ It is also important to understand that all of the studies evaluating pitolisant to date have been relatively small, with the largest study (Harmony Ibis) only enrolling 163 patients.¹² Larger and longer studies are needed to understand the full extent of the efficacy of pitolisant for EDS and other narcolepsy-related features.

AXS-12 (reboxetine) is an investigational medication under evaluation for narcolepsy. It is a selective and potent inhibitor of norepinephrine reuptake.^44,45 A pilot study published in 2001 evaluated the stimulant and anticataplectic effects of reboxetine in 12 patients over 2 weeks.⁴⁴ Doses were initiated at 2 mg every morning and titrated every 2 days to a final dose of 6 mg at breakfast and 4 mg at lunch by day 9. After 1 week of treatment, there were significant improvements in sleepiness, sleep latency, and sleep-onset REM periods: 8 of the 12 subjects experienced at least 65% improvement in sleep latency and ESS. At the end of week 2, the ESS scores were significantly improved not only from baseline but compared to week 1, suggesting that reboxetine may resemble other narcolepsy medications with respect to requiring several weeks of therapy before achieving maximum effects. The pilot study also showed a significant reduction in cataplexy episodes; however, it should be noted that only 7 of the subjects had appreciable cataplexy at baseline and, of those, 5 had notable declines in cataplexy.

An abstract of a single case report describes reboxetine’s use in a 72-year-old female with NT1, severe and chronic kidney disease and liver insufficiency, and multiple bone fractures secondary to cataplexy episodes who was unable to tolerate other narcolepsy treatments.⁴⁶ The authors report significant improvements in both EDS and cataplexy, but data to quantify the full effect of the treatment are not available. A more recent murine study of reboxetine showed reductions in sleep and cataplexy attacks.²³ A phase II cross-over study involving approximately 20 patients evaluated the medication’s use versus placebo over 3 weeks: the study was completed in 2019 and publication of data is pending.⁴⁷

Weighing the safety and efficacy of narcolepsy treatments

Treatment for narcolepsy remains directed at symptom management and control. It is important that patients be provided realistic expectations about the impact of medications on their symptoms. For example, patients should know that residual sleepiness can occur despite optimized therapy.⁶ Medications should be dosed to provide maximum wakefulness during daytime activities, including school and/or work, while, at the same time, ensuring optimal safety.

Stimulants

Use of amphetamines and methylphenidate can cause cardiovascular effects, irritability, aggression, and insomnia.^6,9,21 For patients receiving these treatments, baseline electrocardiography should be obtained and monitoring for hypertension and arrhythmias should be conducted regularly.⁶ Anorexia and weight loss may also occur but to a lesser extent with methylphenidate.^6,18,19 If bothersome, patients should eat before or immediately after dosing when the impact on appetite is at its nadir. At high doses, stimulants are known to exacerbate or cause psychosis, particularly amphetamines and methamphetamine.^6,19 The psychosis usually disappears with the cessation of the medication.¹⁹

Abuse and addiction are risks with the use of any stimulant, but these rarely occur in patients with narcolepsy.⁶ Modafinil is a controlled substance, but, overall, it has less potential for abuse than stimulants. It is generally well tolerated at the doses used in narcolepsy. The most common adverse effects include headache, nausea, anxiety, and insomnia.^19,21 Most side effects resolve after approximately 3 weeks of treatment.²⁰ However, modafinil can cause a severe rash, including reports of delayed-onset Stevens-Johnson Syndrome.^19,21 This is a reason that modafinil is not normally recommended for use in children.^19,21

Antidepressants

One of the biggest challenges with antidepressants in narcolepsy involves medication cessation. Antidepressants require tapering for discontinuation.²⁵ Abrupt withdrawal can cause rebound cataplexy, or, in severe situations, status cataplecticus.^10,21,25 Rebound cataplexy may be seen within a day after treatment interruption and can persist for weeks, depending on the agent.^19,25 Longer times to peak rebound may be related to elimination half-life and/or the presence of active metabolites.²⁵ TCAs appear to have worse rebound potential than SSRIs, which may be reciprocally related to differences in anticataplectic potency between the 2 classes.²⁵ Despite its longer half-life, there are limited data to compare the risk of rebound cataplexy with fluoxetine and other SSRIs.²⁵ Because of this risk of rebound, adherence must be repeatedly and clearly stressed with the patient and evaluated by a clinician when treatment appears to be ineffective.¹⁹

Despite their strong efficacy, TCAs have a significant side-effect profile that includes anticholinergic effects, weight gain, sexual dysfunction, and cardiovascular effects; for this reason, TCAs are not used as often as venlafaxine and SSRIs in the treatment of narcolepsy.²¹ Common adverse effects with venlafaxine are headache, nausea, dizziness, increased blood pressure, and dry mouth²¹; SSRIs can cause similar effects and may also cause sexual difficulties. Selegiline, an MAO inhibitor, may treat more narcolepsy symptoms than other antidepressants, but its use is restricted and complicated by a risk of drug interactions and the propensity for sympathomimetic adverse effects.²¹

Sodium oxybate

Sodium oxybate is one of the most effective medications for narcolepsy, but it has myriad safety concerns.^{10,18,19,21,32} Use of positive airway pressure prior to initiation may help reduce any respiratory effects patients may experience.^19,20 Because of the potential for respiratory effects, patients should not drink alcohol while taking sodium oxybate. Nausea can occur with sodium oxybate, but it is usually mitigated by reducing the dose; if necessary, this side effect can be treated with an antiemetic.^19,21 Other adverse effects of sodium oxybate include enuresis and sleep walking, which can often be managed by lowering the dose.^19,20

Some patients experience new or worsened depression and anxiety with sodium oxybate. It has been demonstrated that discontinuing the medication, initiating an SSRI, and then reintroducing sodium oxybate can be an effective strategy for managing patients whose depression or anxiety is intolerable.¹⁹ Not all patients can stop therapy, and if the patient can tolerate continued therapy, it may be prudent to add an antidepressant to continued sodium oxybate treatment.

Sodium oxybate has a large sodium content. Initial doses of 4.5 grams per night contain 820 mg of sodium.³² If titrated to the maximum dose, patients receive 1640 mg of sodium from the medication alone. This may preclude its use in patients with uncontrolled hypertension, heart failure, or other edemas. A medication under investigation, JZP-258, is similar to sodium oxybate, but it contains 92% less sodium.^48,49

Some patients may express hesitation about using sodium oxybate due to its reputation for misuse, its association with stimulant and MDMA abuse, and its use as a date-rape drug.¹⁹ However, it is important to highlight that dependence is rare when used according to standard practices in narcolepsy.^19,20 To reduce abuse and prevent diversion, sodium oxybate is distributed through a restricted access program and a central pharmacy in the U.S.⁶: diversion occurs in only 1 in 5200 patients, abuse in 1 in 2600 patients, and dependence in 1 in 3250 patients.⁶

Sodium oxybate does have positive aspects to its safety profile. Use often results in weight loss and patients may return to pre-narcolepsy baseline weights.¹⁹ It is important to monitor this effect in patients who did not have significant weight gain associated with narcolepsy onset.

A long-term evaluation of sodium oxybate use for almost 3 years showed the medication to be well-tolerated, overall.³⁵ Nausea, headache, mood swings, and dizziness were the most common causes of drug discontinuation. Three patients, all over the age of 50 years and on dexamphetamine, experienced psychosis that resulted in sodium oxybate cessation. Adverse effects were more likely to occur early in therapy and with advancing age.³⁵ Still, it is important to discuss the risks versus benefits with all patients and to understand the complexity of sodium oxybate prescribing and dispensing.

Solriamfetol and pitolisant

Because solriamfetol and pitolisant are newer medications, there is significantly less knowledge about the potential long-term effects of these agents, but, so far, both appear to be well tolerated in clinical studies. Solriamfetol may cause insomnia, headache, nausea, decreased appetite, diarrhea, anxiety, dry mouth, and nasopharyngitis.^21,37,38,41 Minimal effects on blood pressure and heart rate have been seen.^37,38,41 Although daily doses of solriamfetol 150 mg and 300 mg were shown to be effective, the incidence of adverse effects in studies was higher with the 300-mg dose.^38,39,41 Consequently, the maximum recommended daily dose of solriamfetol is 150 mg.³⁷ Pitolisant may cause gastrointestinal upset, increased appetite, and weight gain, as well as headache, insomnia, and anxiety. It may also prolong the QT interval, so patients at risk for QT prolongation or those who are taking other medications that may increase the QT interval should use caution with pitolisant.⁴³

One randomized study of patients with a history of polysubstance abuse showed that solriamfetol had an abuse potential comparable to or lower than phentermine.⁵⁰ Unlike many of the other medications used to treat narcolepsy, pitolisant is not thought to have a potential for abuse or dependence.¹² As a result, it is the only FDA-approved option for EDS without the restrictions of controlled substance prescribing and monitoring. However, pitolisant was shown to increase memory performance in animal studies, and, therefore, diversion for the purpose of intellectual performance could be concerning.¹²

Narcolepsy treatment during pregnancy

Sodium oxybate may be one of the safest medications to take for narcolepsy during pregnancy: no fetal harm was associated with sodium oxybate in animal studies.^19,51 More early miscarriages in animals were seen in the embryo period with sodium oxybate and, therefore, it may be prudent to hold the medication in early pregnancy when possible and to reinitiate therapy during the fetal period.⁵¹ However, human studies have not been conducted to definitively determine what risk occurs during this period.

A small number of reported exposures to modafinil during pregnancy have not shown conclusive risks of birth defects.^51,52 However, preliminary data from the modafinil/armodafinil pregnancy registry suggest that there may be a risk of congenital malformations.⁵³ Pitolisant has shown teratogenicity in animal studies and should be avoided in pregnancy.^43,51 Female patients of childbearing potential must use effective contraception throughout pitolisant treatment and for at least 21 days after the medication is stopped.⁴³ The risks to a fetus are unknown with other anti-narcoleptic drugs, so, even with fetal harm being seen in animal or human studies, modafinil or sodium oxybate may be the most reassuring medications for patients who require continued therapy throughout their pregnancies.¹⁹

Choosing among treatment options

Many factors must be considered when choosing a treatment option for narcolepsy: patient symptoms, quality of life, work or school requirements, and co-existing conditions must all be addressed when assessing and monitoring narcolepsy management. Tables 4 and 5 summarize the indications, administration guidelines, and clinical effects of medications used in the treatment of narcolepsy.^{4,6,10,20,32,37,43}

THE PHARMACIST’S ROLE IN MANAGING NARCOLEPSY

Pharmacists can play an important role in assessing costs and assisting with insurance coverage of narcolepsy medications. Many of the medications used for narcolepsy are available in generic formulations and, therefore, may provide a low cost burden to the patient. However, all medications, except antidepressants, can require prior authorization for insurance coverage. Drugs that are still under proprietary patent, such as sodium oxybate, solriamfetol, and pitolisant, may also have additional criteria for use, including failing other therapies, in order to be covered by a managed care organization.

Management strategies for initiating narcolepsy treatment are generally patient specific and based on symptoms, comorbidities, goals, and other individual factors.⁸ Few pharmacoeconomic studies have been conducted with these medications in this patient population. On average, each patient with narcolepsy spends $3356 each year on medications alone.⁸ However, patients with narcolepsy incur indirect costs related to lost productivity that are significantly higher and direct medical costs that are almost twice as high as patients without narcolepsy; it is reasonable to extrapolate a much higher economic burden without appropriate pharmacotherapy.⁸

A generic product for sodium oxybate will not be available until 2023 and the cost for the medication currently exceeds $100,000 per year.^48,54 Despite the high acquisition cost, one analysis found that if patients treated with sodium oxybate have 18 fewer days of sickness or absenteeism compared to those treated with older therapies, the medication could be considered cost effective.⁵⁵ It remains unknown what financial impact pitolisant, solriamfetol, and other emerging therapies will have on narcolepsy management.

Pharmacists can also work to ensure optimal compliance and safe use of medications in narcolepsy. The dosing regimens of the medications differ considerably, and it is important that patients clearly understand the nuances associated with each medication in order to achieve optimal benefit and minimize potential rebound symptoms. Pharmacists can help patients identify dosing times that will simultaneously optimize benefits while minimizing adverse effects. For example, it may be best to time stimulant dosing around breakfast and lunch to minimize the impact on decreased appetite while patients on sodium oxybate need to pay attention to evening meal and snack times because the medication must be taken at least 2 hours after eating.^18,19

Many of the therapies for narcolepsy have important drug interactions that can be proactively addressed with the care team. Pitolisant induces cytochrome P450 (CYP) enzymes 3A4, 2B6, and 1A2,⁴³ and it inhibits CYP 2D6 and organic cation transporter 1 (OCT1).^12,43 TCAs theoretically inhibit histamine receptors and may reduce the efficacy of pitolisant; therefore, it is best to avoid combination therapy with these agents in narcoleptic patients.⁴³ If selegiline is used, pharmacists should closely monitor for drug interactions and reinforce the need to follow a low-tyramine diet, as it relates to the potential for adverse effects.²⁶ Use of antidepressants, triptans, and stimulants, particularly amphetamine, should be avoided in combination with selegiline due to the heightened risk of sympathomimetic effects.^18,19,26 Patients on valproic acid will require an approximately 20% lower dose of sodium oxybate, and all patients on sodium oxybate must be counseled to avoid alcohol and other sedative hypnotics.^18,32

One particularly problematic drug interaction in this patient population involves the increased metabolism of hormonal contraceptives by modafinil, armodafinil, and pitolisant.^6,21,51 Female patients of childbearing age who wish to use contraception while taking modafinil or armodafinil will need an oral contraceptive that contains progestin and at least 40 mcg of ethinyl estradiol.⁵¹ Patients may also use a hormonal intrauterine device, but they should be counseled that the duration of efficacy will be reduced by 1 year.⁵¹ Less is known about the full impact of pitolisant on contraception efficacy, but alternative birth control strategies should most likely be considered in females of childbearing age.^6,21,51

Sodium oxybate is a schedule III medication that is dispensed by specialty pharmacies.^21,32 The restricted distribution is directly related to the abuse potential of the medication.²¹ Though pharmacists in other settings may not fill the prescription, their knowledge about this unique medication can have a positive impact on patient adherence, drug efficacy, and the management of adverse effects. Food reduces the medication’s absorption and patients must be instructed to stop eating and drinking at least 2 hours before their first dose. Patients will need to set an alarm so that they can wake up and take their second dose in the middle of the night.^18,19,32 Because of sodium oxybate’s strong sedative effects, patients should be advised to prepare both doses prior to bedtime by mixing each with one-fourth cup of water. Pharmacists should also continuously emphasize the need to be mindful of sodium intake because an appreciable portion of the recommended daily sodium intake will come from the medication itself.

CONCLUSION

Despite advances in therapy, there is still no cure for narcolepsy. Treatment remains directed at symptom management. Cataplexy, hallucinations, and sleep paralysis may be alleviated with medication, but there will always be some degree of EDS, even with the most optimal pharmacotherapy regimen. Before starting narcolepsy therapy, it is important that families and patients have a clear understanding of the disease, its potential features and progression, and expectations about the efficacy and risks of the available medications.

Many of the therapies for narcolepsy have been on the market for many years, but ongoing research in this disease state has been fruitful. In 2019, 2 novel agents were approved for EDS, each with unique properties that facilitate their role in therapy. It is worth noting that, while these new medications are manufactured by different companies, the published studies for each agent were written by many of the same authors, thus reducing the bias of the data.

Overall, the treatment of narcolepsy is complicated by the potential for tolerance with many of the medications, a variety of adverse effects and drug interactions, concerns regarding symptom rebound, diversion and misuse potential, restrictive prescribing logistics, and high costs. Most of these challenges can be addressed with effective pharmaceutical care, and good communication among the pharmacist, the prescriber, and the patient can help minimize the impact of prescribing challenges and improve access to care.

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