612972018 “Treatment of narcolepsy in adults ~ UpToDate Official reprint from UpToDate® www,uptodate.com ©2018 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Wolters Kluwer Treatment of narcolepsy in adults ‘Author: Thomas € Scammell, MD Section Editor: Ruth Benca, MD, PhD Deputy Editor: April F Eichler, MD, MPH All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: May 2018. | This topic last updated: Feb 07, 2018. INTRODUCTION — Nearly half of patients with narcolepsy report that their sleepiness and cataplexy substantially interfere with their daily lives, including school, work, marriage, or social life [1,2]. The mainstays of therapy are brief daytime naps and pharmacologic therapy (3]. Itis important to realize that patients with narcolepsy often have concomitant obstructive sleep apnea, periodic limb movements of sleep, fragmented sleep, andior rapid eye movement (REM) sleep behavior disorder that contribute to their daytime sleepiness. itis often helpful to treat these disorders first and then to focus on improving the sleepiness that is caused by the narcolepsy. This topic assumes that coexisting sleep disorders have been treated and reviews the treatment of narcolepsy and its symptoms. 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 "Narcolepsy in children".) NONPHARMACOLOGIC THERAPY — There are several nonpharmacologic interventions that may benefit the patient with narcolepsy. These provide some benefit, but most patients also require medications that reduce sleepiness and cataplexy. Avoidance of certain drugs — Some drugs should be avoided by patients with narcolepsy. Drugs that can worsen daytime sleepiness inciude benzodiazepines, opiates, antipsychotics, and alcohol. (See "Excessive daytime sleepin medical disorders and medications".) Other medications such as theophylline or excessive caffeine can cause insomnia, which can worsen daytime sleepiness. In addition, prazosin and other alpha-1 antagonists can worsen cataplexy. Napping and sleep hygiene — Behavioral interventions are often helpful for optimal control of narcolepsy. One or two well-limed, 20-minute naps will often improve sleepiness for one to three hours though some patients only benefit from long naps [4]. {fit 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 [5]. (See “Insufficient sleey. Evaluation and management’) 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 [6]. They also have the additional burden of coping with misperceptions about the causes and the involuntary nature of their symptoms, hitoa:wnmwsuptodate.comoontentsireatmentof-narcel 12 -n-aduls/pnn?asarchenarcolepeySsZO\reatmantSsource=search_resulasolectcTile=t.. 1/10,sr2srz018 “Treatment of narcolepsy in adults - UpToDate ‘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 — Patients with narcolepsy are at increased risk for psychiatric comorbidities, particularly depression and anxiety. 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 inadults" and "Unipolar depression in adults: Assessment and diagnosis’.) We recommend the Patient Health Questionnaire-2 (PHQ-2), as itis 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? Narcolepsy is also 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 §8 percent in patients taking stimulant medications [7]. Patients with narcolepsy also have increased rates of obesity and diabetes. Cardiovascular risk factor assessment and modification is therefore an important component of health maintenance in patients with narcolepsy. (See "Preventive care in adults. Recommendations”, section on ‘Cardiovascular disease’ and “Cardiovascular disease risk assessment for primary prevention: Our approach’.) PHARMACOLOGIC THERAPY Daytime sleepiness — 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 [8]. Such agents improve performance (measured by reaction time and simulated driving tasks), but their ability to stay awake rarely exceeds 70 to 80 percent of normal [8-10]. The goals of therapy are to obtain "normal" alertness during conventional waking hours or to maximize alertness at important times of the day (eg, during work, school, or while driving). Once therapy has been optimized, the severity of residual sleepiness should be assessed with the Epworth Sleepiness Score or the Maintenance of Wakefulness Test, and persistently sleepy patients should be counseled to avoid potentially dangerous activities, such as driving. (See "Quantifying sleepiness") Modafinil — Modafinil has become a first line pharmacologic therapy because it provides good control of sleepiness, is generally well tolerated, and ilicit use is rare. A non-amphetamine "wakefulness promoting agent,” its mechanism of action is not well understood, but it probably increases dopaminergic signaling (figure 1) [11: 43). Armodafinil is the active R enantiomer of modafinil and has very similar effects. One trial randomly assigned 283 patients with narcolepsy to receive 200 mg/day of modafinil, 400 mg/day of modafinil, or placebo [14]. After nine weeks, patients treated with modafinil at either dose had significant improvements in their Maintenance of Wakefuiness Test and Epworth Sleepiness Scale measurements, without evidence of tolerance to the drug. Similar results were found in a second clinical trial involving 271 patients with narcolepsy [15]. In a small tral that included 13 patients with narcolepsy, patients randomly assigned to modafinil had improved driving performance compared with patients receiving placebo [16]. nips: hew.uptodate.comicontentsitreatment-of-narcolepsy n-aduks/print?searchenarcolepsy%:20traalmentRsource=search resuléselectedTitest... 2/10erzsre018 Treatment of narcalepay in adits - UpToDate Modafini given once in the morning typically promotes wakefulness into the early evening without disrupting nighttime sleep. tt is generally started at a dose of 200 mg each morning and then titrated up to 300 or 400 mg as needed. Patients with persistent aftemoon sleepiness may benefit from divided dosing with 200 mg in the morning and 200 mg in the early afternoon (jable 1) {14.15.17}, Doses of asmodafinil generally range from 150 to 250 mg each morning. Side effects are uncommon but include headache, nausea. dry mouth, anorexia, and diarrhea, Modatin) may have fewer sympathomimetic effects than amphetamines and is often a good choice for older patients. Stil, 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 [18-21]. Rarely, modafinil can cause a serious rash, including Stevens- Johnson syndrome. Modafini! reaches peak bioavailability in about two hours. The drug is hepatically metabolized and induces several cytochrome P450 enzymes, thus decreasing the effectiveness of oral contraceptives and perhaps other medications; women of childbearing age who use modafinil should use an alternative method of contraception. Methylphenidate — Methylphenidate is a central nervous system stimulant and a potent wakefulness- promoting drug. Although effective, its sympathomimetic side effects can be problematic. The initial dose of methylphenidate (10 mg) is typically administered twice per day, with the last dose given no later than about 3:00 PM. Therapy is often initiated with immediate release formulations and then converted to a sustained release formulation once a stable daily dose has been reached. Methylphenidate dosages are shown in the table (table 4). Typical doses of increase systolic blood pressure about 5 mmHg [22]. 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 [23,24]. ‘Some of these deaths were associated with hypertrophic obstructive cardiomyopathy, while others may have been related to arrhythmias. Patients taking high doses for daytime sleepiness also can develop psychosis, anorexia, or require psychiatric hospitalization [25]. 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. (phe Amphetamines — Like methyiph .. amphetamines are central nervous system stimulants. Amphetamines may be the most potent wakefulness-promoting drugs, although some patients require relatively high doses. Dext 1no, mixed amphetamine salts (Adderall), and |i \e are among the most commonly prescribed. The amphetamines are considered second-line agents because their sympathomimetic side effects can be problematic. By increasing aminergic signaling, these drugs can also reduce cataplexy, hypnagogic hallucinations, and sleep paralysis (2.26.21). A typical starting dose of dextroamphetamine is § mg twice daily, with the last dose given no later than about 3:00 PM (table 4). Therapy is usually initiated with immediate release formulations and then converted to a sustained release formulation once a stable daily dose has been reached. mpneta Amphetamines can produce adverse effects similar to those seen with me"tyiphenidate. These include cardiovascular events (eg, hypertension, sudden death) and psychiatric events (eg, psychosis, anorexia, addiction) [23,25]. 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 "Pr ent? .seation on ‘Pre: tps sivinw uptodate conveantentsiraatment-a-narcolapsysn-adulsipeat?sea/chonarcolepsy*:2Otreament8source=soarch tesuk&selectedTile=1... 3/10