Introduction

Narcolepsy is a chronic neurologic condition with implications for co-occurring psychiatric symptoms or disease states. Per the American Psychiatric Association Diagnostic and Statistical Manual of Mental Health Disorders, fifth edition, text revision, narcolepsy is described as recurrent episodes of an irrepressible need to sleep, lapses into sleep, or naps that occur within the same day at least 3 times per week over 3 months.¹ There are 2 primary classifications of narcolepsy, narcolepsy type 1 (NT1) and narcolepsy type 2 (NT2).^1,2 The hallmark symptom is excessive daytime sleepiness (EDS), but only patients with NT1 experience cataplexy.^1,2 Cataplexy is a brief, sudden loss of muscle tone.^1,3 Patients with both NT1 or NT2 can experience sleep attacks, sleep-related hallucinations, disturbed nighttime sleep, and sleep paralysis.

In the United States, the incidence of narcolepsy is between 0.02% and 0.18%.³ The diagnosis peaks in teenage years with a second peak in the mid 30s.^2,3 Screening typically begins in a clinic with the administration of the Epworth Sleepiness Scale (ESS) on which scores greater than 10 indicate the need for additional evaluation.¹ A formal diagnosis requires an overnight polysomnogram combined with a multiple sleep latency test.¹ These tests rule out other sleep disorders and may be combined with an assessment of cerebrospinal fluid (CSF) hypocretin levels.^1,2 CSF hypocretin measurement is considered by experts to be a sufficient test for NT1 in which hypocretin levels are often low; however, it is not often obtained in clinical practice because few laboratories are equipped to perform this test and because of the procedure’s invasive nature.⁴

Many patients report functional impairment from narcolepsy symptoms, including social isolation and school or work challenges. To improve function, patients are encouraged to follow sleep hygiene, including a regular sleep schedule and scheduled naps.²

As of 2025, the FDA has approved 11 unique agents for narcolepsy, including 1 medication with 3 different formulations. Current medications used to manage narcolepsy include select antidepressants, controlled substances, and medications that must be obtained through restricted access programs (Table).^5-18 There are few comparator trials evaluating efficacy for EDS and no head-to-head studies evaluating pharmacotherapy for cataplexy, leading to an uncertainty with regimen selection. For the management of EDS, the American Academy of Sleep Medicine (AASM) guidelines strongly support use of modafinil, pitolisant, sodium oxybate, and solriamfetol.⁵ Other medications are conditionally recommended for EDS, including methylphenidate, dextroamphetamine, and armodafinil, generally as a result of low-to-moderate quality of evidence. For cataplexy, pitolisant and sodium oxybate are strongly recommended, wheras dextroamphetamine has a conditional recommendation. In practice, venlafaxine or clomipramine may be used for cataplexy, but their role is not well addressed in the AASM guidelines.

TABLEAgents used in the treatment of narcolepsy^5-18

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Narcolepsy management requires an intentional and individualized approach tailored to a patient’s specific symptoms, unique situations, and co-occurring conditions. Although it is generally known which agents treat specific symptoms, comparative efficacy is largely undetermined. Patients who initially respond to a certain medication may lose symptom control over time. Additionally, though narcolepsy is a lifelong condition, most guidance focuses on initial treatment upon diagnosis and when new symptoms arise. There is little guidance regarding long-term management, including treatment adaptation over time. This article highlights and reviews key considerations in medication selection and subsequently modifying a regimen for a patient with narcolepsy. The need for a real-world, practical overview is imperative given the lack of medication preference in the AASM guideline, clinical use of medications not addressed by the guidelines, and unique clinical presentations for each patient.

Case 1: Initiation of Pharmacotherapy for New Diagnosis of Narcolepsy NT 1

A 19-year-old female presented to the clinic 1 week previously with a several-year history of increasing severe daytime sleepiness and episodes of head bobbing and eyelid drooping with laughter. She reported episodes of lightheadedness and hypotension. Sleepiness interferes with school and social activities. In the clinic, the head bobbing and eyelid drooping are determined to be an atypical presentation of cataplexy. A sleep test revealed a mean sleep latency of 2.1 minutes with 3 sleep onset rapid eye movement periods. She returns today to discuss results and to begin a treatment plan.

Few medications are effective for cataplexy, which limits monotherapy options for NT1. Clinical decision making heavily favors following guidelines when initiating therapy. Sodium oxybate is a strong choice for the pharmacotherapy of EDS and cataplexy and carries a strong recommendation for both symptoms in the AASM guidelines.⁵ Efficacy was demonstrated in clinical trials and is seen in clinical practice in ‘real-world’ patients. Oxybate selection should be based on individual patient criteria with considerations for differences in formulations. A twice-nightly immediate-release formulation (SXB) has been available for more than 2 decades. In recent years, 2 newer formulations have been approved to address limitations of the original oxybate. The mixed-salt oxybate product (calcium/magnesium/potassium/sodium oxybate) (LXB) was developed to provide a formulation with 92% less sodium; once-nightly sodium oxybate (ON-SXB) was introduced to reduce dose burden for patients.^12,13 SXB contains a significant amount of sodium content that patients with sodium-sensitive conditions may not tolerate. In contrast, patients with hypotension may benefit from the sodium load of either SXB or ON-SXB. SXB and LXB are twice-nightly regimens that require patients to set an alarm and wake up to take the second dose.^11,13 Approximately 70% of patients miss this second dose.¹⁹ Survey data indicates an overwhelming preference (>90%) for ON-SXB with most patients reporting more symptomatic control compared with SXB.¹⁹

Patient access and affordability must be considered, and patients can benefit from the proactive and intentional planning to address these issues. Only SXB is available as a generic product, but all oxybate formulations could be cost-prohibitive. Without insurance, the annual cost of generic SXB can exceed $275,000, and all proprietary oxybate formulations exceed $285,000.²⁰ Financial support and savings programs are available for all oxybate formulations, and this can reduce out-of-pocket costs for patients with commercial insurance coverage. Additionally, oxybates may only be dispensed by specific certified pharmacies due to the medications’ Risk Evaluation and Mitigation Strategy requirements, which may be a logistical barrier, making it difficult for some patients to obtain the medication.

In practice, clinicians often initiate SXB to evaluate efficacy, dosing requirements, and tolerance before transitioning to a different formulation. The selection of an oxybate formulation has several facets, and clinicians must use clinical experience and understanding of pharmaceutical principles. Sodium content must be considered in patients with concomitant sodium-sensitive conditions. ON-SXB is appropriate for patients who frequently sleep though the second dose of SXB or who find that awakening during the night results in increased daytime sleepiness. Prescribing information guidance on transitioning from SXB to a newer oxybate is based on studies in which up to 62% of patients were oxybate naïve.²¹ Based on clinical experience, most patients transition from SXB to a newer formulation with a 1-to-1 total daily dose. The RESTORE study transitioned patients to ON-SXB based on the closest total nightly dose of twice-nightly SXB.¹⁹ Oxybate formulations have pharmacokinetic (PK) differences. In fasting, LXB takes approximately 28 minutes longer to reach maximum plasma concentrations, and median maximum plasma concentrations are 28.37 mcg/mL lower than SXB.²² Based on clinical experience, despite these differences, patients do not require adjustments in dosing or timing when taking LXB to have the same response as they would to SXB. The major PK difference shown to affect patients is the extended duration from ON-SXB. Between 60% and 70% of patients on twice-nightly SXB or LXB miss their second dose occasionally and more than 92% get out of bed following the second dose, a practice shown to result in falls or other injuries.¹⁹ In the RESTORE study, approximately 94% of patients who transitioned to ON-SXB preferred the once-nightly formulation, 63% reported more symptom control, and 91% felt more adherent.¹⁹

The only other medication with strong support in the AASM guidelines to treat both EDS and cataplexy is pitolisant. Whereas dextroamphetamine carries a conditional recommendation, it is less effective.⁵ Like sodium oxybate, pitolisant dispensing is restricted to a limited number of specialty pharmacies.¹⁴ However, pitolisant has an advantage as the only medication currently recommended by the AASM guidelines that is not a controlled substance. It is important to understand that there are no comparator studies for cataplexy pharmacotherapy and only 1 for EDS, in which pitolisant is shown to be noninferior to modafinil in an 8-week double-blind, randomized controlled trial of 95 adults with narcolepsy.²³ At 8 weeks, ESS score reductions were noninferior with pitolisant versus modafinil (-5.8 versus -6.9; p = 0.25).

Certain antidepressants may provide another pharmacotherapy option for cataplexy though supporting studies are limited. The guidelines indicate that there was not sufficient evidence to recommend for or against the use of venlafaxine for cataplexy, but a joint guideline from the European Academy of Neurology, European Sleep Research Society, and the European Narcolepsy Network (European guidelines) considers venlafaxine an appropriate option if used with a wake promoting agent (WPA).⁶ Two meta-analyses of placebo-controlled trials suggest solriamfetol may have the greatest magnitude of effect among the WPAs on EDS, whereas LXB is associated with the fewest adverse effects (AEs).^24,25 The lack of comparator data reinforces the need for narcolepsy pharmacotherapy to be tailored and individualized based on pharmaceutical properties and patient-specific variables. Patients should be made aware that regimens require modifications over time based on their specific needs and medication response.

The patient in this case was started on SXB to allow for monotherapy to treat both EDS and cataplexy. Based on clinical experience, it is efficacious in managing the symptoms of NT1 and considered a first-line agent.^3,5,6 For many patients, SXB controls symptoms better than other available medications that treat EDS or cataplexy independently.¹⁹ Lack of cataplexy rebound with abrupt withdrawal is another benefit of oxybate therapy. The only other monotherapy option for NT1 is pitolisant. The AASM guidelines give both medications a strong recommendation, but the European guidelines give pitolisant a weak recommendation for EDS and make no recommendation on cataplexy based on available data when written in 2021.^5,6 Clinical experience with pitolisant and newer data have led to it being utilized as initial management in treatment-naïve patients. Any oxybate formulation or pitolisant would have been reasonable for this patient. All medications have AEs that may be use-limiting in some patients. With oxybates, starting at lowest dose and increasing total daily dose by 1.5 g every week can mitigate most AEs.²⁶ The patient was titrated to a dose of SXB 4.5 g twice nightly and tolerated it well. Cases such as this are routinely encountered in clinical practice and decisions described are central to patient discussions. Patients managed with oxybates follow-up in the clinic at least every 3 months and more frequently when symptoms are unstable or AEs occur.

Case 1 Continued: Drug Interaction Management in Narcolepsy

The patient in case 1 is now 24 years old. She has continued to take SXB 4.5 g twice nightly for 5 years. Approximately 2 years ago, she started college and began experiencing more EDS and cataplexy occurrences. Pitolisant was added to her regimen, and her symptoms have remained stable. She presented after a visit with her gynecologist the previous week. The patient wanted to change her method of contraception from a diaphragm to an intrauterine device (IUD) containing levonorgestrel, but the gynecologist had concerns about placing the IUD given her current narcolepsy regimen. The patient also reported recently being prescribed quetiapine by another physician for symptoms of depression but was not told why quetiapine was specifically selected.

Narcolepsy is a complex condition, and evolutions in symptoms, lifestyle situations, and co-occurring conditions influence the individualized management approach. Many patients ultimately require multiple medications to manage narcolepsy even when a medication that is usually effective across a wide range of symptoms, such as an oxybate, is used.²¹ Based on clinical experience, a decline in symptom control or increase in symptom frequency or severity can occur during major life changes. In this case, the patient began college at which it is common for the change in daily routine and increased stress to worsen EDS or increase cataplexy occurrences. Most patients with narcolepsy have co-occurring conditions for which pharmacotherapy is warranted.^1,26 Narcolepsy and its therapeutic options can both affect and be affected by numerous co-occurring conditions and medications. For this reason, it is essential to evaluate drug and drug-disease interactions in all patients.

Pitolisant, modafinil, and armodafinil all reduce the effect of hormonal contraceptives via induction of CYP3A4.^7,8,14 This interaction includes any hormone-based contraceptive, including certain IUDs. Patients taking modafinil, armodafinil, and pitolisant should be made aware of the interaction even if they are not currently taking or expressing interest in contraception. According to survey data, more than half of all female patients with narcolepsy report that they were not adequately educated on pregnancy, contraception, or aware of this key interaction.²⁷ Even if a patient’s narcolepsy regimen can be modified to discontinue interacting medications, hormonal contraception should still not be initiated for at least 1 month because the reduced effectiveness of hormonal contraception persists for 21 to 30 days after the last dose is taken.^7,8,14 If hormonal contraception is absolutely necessary, use of an oxybate or solriamfetol with venlafaxine may be viable options through the patient’s childbearing years.^2,11,15 Based on clinical experience, a nonhormonal contraceptive is preferred in patients taking an interacting medication. IUDs made of copper or other material with a mechanical mechanism of action may also be considered. Other barrier methods remain an option for contraception and should be discussed.

Depressive symptoms and the diagnosis of depression occur in more than half of patients with narcolepsy and a complex bidirectional relationship exists between the 2 conditions.^{1,2,21,22,28-30} Depression is also one of the most common reasons for nonadherence to narcolepsy pharmacotherapy.³¹ Symptoms of depression can arise from lifestyle impairments related to narcolepsy, insufficiently treated EDS, and medication-related AEs.²⁸ The intentional selection of an antidepressant, when needed, is vitally important. In general, antidepressant selection can and should follow guideline-directed management in the same manner as would occur for a patient who does not have narcolepsy. According to clinical experience, practical considerations, such as interactions, should direct individual regimen selection. Several antidepressants interact with stimulants and WPAs. Concurrent use of central nervous system (CNS) depressants, such as quetiapine, are contraindicated with oxybates due to the ability to potentiate the oxybates’ CNS-depressant effects.^11-13 According to expert opinion, concurrent medications with sedating properties should generally be avoided to prevent negative effects on EDS control. The European guideline’s recommendation of venlafaxine or clomipramine for cataplexy makes these 2 agents compelling options when coexisting depressive symptoms require medication.⁶ There may be some pharmacologic overlap between serotonin and norepinephrine reuptake inhibitors and solriamfetol, a dopamine and norepinephrine reuptake inhibitor, and some variables such as sleep latency may differ among patients taking solriamfetol who have depression compared with those who do not have depression.²⁸ Though uncommon, oxybates can cause or exacerbate depressive symptoms.^11-13,32 In clinical settings, this exacerbation is usually observed soon after oxybate initiation, dose titration, or when used with modafinil. The patient in case 1 has tolerated SXB for 5 years at the highest dose. Based on expert opinion, SXB is unlikely to be causing or contributing to her depressive symptoms. However, overdose with an oxybate can be lethal, and clinicians should not automatically dismiss drug-induced depression as a differential diagnosis even when the possibility is minute. When mild depression symptoms are determined to be oxybate-related, clinical experience supports continuing oxybate use in certain patients in which the benefit of oxybate use is strong. The clinician must determine if the oxybate can be safely used and ensure depression is effectively managed. These patients should be monitored carefully and frequently for both narcolepsy-related symptoms and manifestations of depression.

The patient in case 1 experienced multiple changes to her clinical status in a short time. She was initiated on quetiapine, which is inconsistent with guidelines and standard of care and potentially dangerous when used with SXB because of the CNS depressant effects. Her depressive symptoms were reevaluated. Quetiapine was discontinued, and venlafaxine was initiated. Three months after beginning venlafaxine, she reported improvement in her depressive symptoms. Because she had experienced effective symptom control for 2 years with SXB and pitolisant, her narcolepsy regimen was continued, and a copper IUD was inserted by her gynecologist as a method of contraception. Education on medication use should pregnancy occur or be desired was integrated into her monitoring plan at each future clinic visit.

Case 2: Treatment of Narcolepsy and Co-Occurring Migraine Headaches

A 27-year-old with NT2 and a 10-year history of mild migraine headaches presented with complaints of increasing headache frequency. The patient was initially treated for narcolepsy with dextroamphetamine but had unacceptable blood pressure elevations. Therapy was changed to armodafinil, which initially resulted in improvement in EDS with no adverse effect on blood pressure. The patient’s migraines prior to armodafinil initiation had been mild but increased in frequency after starting armodafinil and now occur 3 to 4 days a week, interfering with work. The patient had previously been treated for migraines with nortriptyline, which increased the degree of EDS and led to only modest improvement of headaches. Both the migraines and medication AEs were described by the patient as intolerable.

More than a third of patients with migraines experience EDS.³³ When EDS occurs without cataplexy or other clear symptoms of narcolepsy the etiology of sleepiness must be determined prior to establishing a narcolepsy diagnosis. It is not uncommon for narcolepsy to coexist with other etiologies of EDS and sleep and migraines are known to be interconnected and reciprocal.^34,35 In addition to EDS, narcolepsy can trigger migraines.³⁵ It has been suggested that orexin plays a role, but the exact mechanism and direction of the association is not fully understood.³⁵ The combined effect of narcolepsy and untreated or undermanaged migraines on EDS can lead to significant negative effects on quality of life, increased risk of accidents, and impaired activities of daily living.³³ Therefore, optimal management of one condition is a key factor in the management of the other condition.

When managing a patient with coexisting narcolepsy and migraines, the negative effect of medications on either condition should be minimized. Increased headache frequency and/or severity is reported with most narcolepsy pharmacotherapy in clinical studies, but in clinical practice, prevalence is higher with specific agents. Headaches are a relatively common AE of armodafinil and modafinil and may also occur with simulants but to a lesser extent.⁹ In case 2, discontinuation of armodafinil is warranted given severe headaches. From both neurological and sleep medicine expert perspectives, headaches are commonly seen with armodafinil and modafinil, but severe headaches are infrequent. Unfortunately, when headaches are severe, resolution or adequate clinical control of the headaches is rare without stopping the causative medication.

In comparison, headache is a relatively uncommon AE of solriamfetol.¹⁵ Based on clinical experience, solriamfetol may be a reasonable option in patients without cataplexy. According to clinical experience, headache is also less common with pitolisant and oxybates and could be considered if EDS persists on solriamfetol. In patients who require an oxybate, formulation and patient-specific factors are crucial considerations. Headaches are more prevalent in older adults compared with younger adults taking an oxybate.^11,12 Headache occurrence decreases with transition from SXB to LXB, most likely due to the differences in sodium content of the 2 formulations.²¹

The patient in this case was treated with an amphetamine but experienced more than a 20-mmHg increase in systolic blood pressure. Hypertension and tachycardia are clinically important AEs of stimulant medication, which are more frequently encountered in patients with dysautonomia. When clinically encountered, the stimulant should be discontinued and an alternative agent initiated. Armodafinil was changed to solriamfetol because of headache incidence. Furthermore, it is a strong choice for patients of childbearing potential given the lack of effect on hormonally based contraceptive medications.

Case 3: Narcolepsy Management in Pregnancy

A 29-year-old female with NT2 is currently successfully treated with solriamfetol. She wants to become pregnant. She is otherwise healthy except for generalized anxiety disorder, which was previously worsened by stimulant therapy. The patient has transitioned to cognitive behavioral therapy for anxiety and scheduled naps for EDS after opting to discontinue citalopram and solriamfetol in anticipation of becoming pregnant. She works a day-shift job as a data analyst. Her work commute is 30 minutes and includes both city and highway driving.

When managing narcolepsy in a patient who is pregnant or plans to become pregnant, collaboration with the patient’s obstetrician is essential.³⁶ Concern for the embryo or developing fetus is common; more than 82% of patients who become pregnant discontinue narcolepsy pharmacotherapy for this reason.²⁷ Although the full effect between narcolepsy and fetal development has not been investigated, literature reports a range of teratogenicity from 0% to 14%, primarily with modafinil.^27,36,37 Most data is retrospective and involves confounders for pregnancy outcomes. Though the risk for teratogenic effects from narcolepsy medications in therapeutic doses is thought to be overestimated and primarily based on theoretical concerns, the actual effects of these medications on fetal development are relatively unknown.^2,36 When pregnancy is planned or desired, medications used for narcolepsy should be discontinued prior to conception whenever possible; the decision to continue pharmacotherapy while pursuing pregnancy should be an informed collaborative decision between the patient and pertinent health care providers.² If pregnancy is unplanned, the medication(s) should be discontinued as soon as possible. In both situations, compensatory plans should be enacted, including scheduled napping. Ideally, medications should be avoided throughout pregnancy and, if selected, until breastfeeding is complete. Patients with severe EDS or cataplexy often require medication during pregnancy to avoid personal injury or injury to the fetus related to falls or accidents.

Some patients notice their EDS improves during pregnancy, especially in the second and third trimesters. This may be due to changes in hormone levels. Other patients may report worsening EDS. According to clinical experience, extended sleep time and a structured nap schedule can help but may not fully alleviate symptoms.²⁷ It is essential that patients understand driving and other activities requiring alertness must be avoided during medication discontinuation until the effect of medication removal on EDS is known.²⁷ When driving resumes, patients should be instructed to pull over to the side of the road any time sleepiness occurs. If sleepiness becomes severe or unpredictable, driving should cease. Patients may be able to request accommodation from employers for additional nap time or discuss hybrid or remote work. In practice, caffeine is the least desirable nonpharmacologic strategy; data on its efficacy for EDS is weak and outweighed by concerns for low birth weight and spontaneous abortion.²⁷

If a patient is unable to manage narcolepsy symptoms to a tolerable degree, medication therapy may be considered in the second and third trimesters with lower risk to the developing fetus. Pregnancy outcomes have not been shown to differ between no pharmacotherapy, monotherapy, or polytherapy.²⁷ Care must be coordinated with the obstetrician prior to delivery to avoid newborn withdrawal effects. In clinical practice, stimulants are the most commonly used option in pregnancy; whereas use during the third trimester can result in neonate withdrawal symptoms, there does not appear to be an association with congenital or cardiovascular defects.^9,27,38 Data on modafinil use and embryo or fetal harm is conflicting, and as a result, modafinil is often discontinued in pregnant patients during the first 10 weeks from the last menstrual period.^37,39 There is little data to guide treatment of narcolepsy in general, and much less data for cases with co-occurring conditions and reproductive health concerns. SXB is present in breastmilk and exposes infants to elevated levels of gamma-hydroxybutyric acid.^2,11-13 Methylphenidate has low concentrations in breast milk with less than 1% of the maternal dose transmitting and does not appear to pose significant risk to the nursing infant or cause a reduction in breast milk volume.⁴⁰ Overall, other medications used for narcolepsy should be avoided when breastfeeding. When medication is required, formula feeds or banked breast milk should be utilized for the newborn.

Managing a patient in preparation for pregnancy, during pregnancy, and throughout breastfeeding are common clinical scenarios. The questions that arise are complex and often include significant changes in behavioral patterns and activities. The patient in case 3 stopped citalopram and began using cognitive behavioral therapy with acceptable results. Scheduled napping helped with residual sleepiness. When the degree of sleepiness became unacceptable, methylphenidate was initiated. The risk of this approach is that anxiety may worsen, requiring a resumption of pharmacotherapy. Methylphenidate was carefully managed and minimized prior to delivery to avoid newborn withdrawal effects.

Conclusion

Narcolepsy is a significant cause of EDS.^5,6,26 It routinely appears and/or is diagnosed in adolescence and early adulthood, and individual patient characteristics commonly determine medication selection and management. Unfortunately, there is little data to guide treatment in general and much less data in smaller, more focused topics, such as co-occurring conditions and reproductive health. A practical understanding of medication-specific characteristics and pharmaceutical properties provides the strongest foundation on which to base pharmacotherapy decisions.