Treatment of Central Nervous System Hypersomnias
Jeffrey H. Lin
Clete A. Kushida
The overall management strategy of central nervous system (CNS) hypersomnias involves a multifaceted approach combining generalized measures to promote optimal sleep conditions, pharmacologic therapy to target disease-specific manifestations, and close follow-up by sleep professionals to assess symptom progression. Increased awareness for this group of disorders has prompted greater eff orts to educate the public and to develop optimal treatments. Generalized measures, such as practicing adequate sleep hygiene, strategically timed naps, (1), and regular follow-ups, are becoming more accepted by patients and the community. Over the last few years, exciting advances in research have introduced new agents that can help in treating CNS hypersomnias (2,3). This chapter will review the current treatment regimens.
GENERAL MEASURES
Identify and Treat Non-CNS Causes of Hypersomnia
Before addressing issues surrounding CNS hypersomnias, it is important to identify and treat non-CNS causes of hypersomnia. These include circadian rhythm sleep disorders, sleep-related breathing disorders, sleep-related movement disorders, sleepiness associated with insomnia, and medication-induced sleepiness (4,5). Detailed descriptions of each disease process will be discussed in other parts of this handbook.
Sleep Hygiene
Once non-CNS causes of hypersomnia are addressed, the next step is to establish adequate sleep hygiene. Although not intended as a stand-alone therapy, there is a positive set of sleep-related behaviors that complement the entire treatment regimen (6). The three major categories are as follows: (i) creating a homeostatic need for sleep and reinforcing the circadian drive, (ii) making the sleep environment conducive to sleep, and (iii) performing activities that will support good sleep (7). Each patient should receive individualized counseling because home, academic, and occupational situations may vary dramatically among patients. Here are a few examples of the guidelines (8):
Avoid stimulants such as caffeine and nicotine 6 hours before bedtime.
Avoid alcohol 4 hours before bedtime.
Exercise regularly, but not within 2 hours before bedtime.
Allow at least a 1-hour period to unwind before bedtime.
Keep the bedroom environment quiet, dark, and comfortable.
Maintain a regular sleep schedule.
Strategically Timed Naps
Strategically timed naps have been shown to improve alertness while not adversely affecting sleep latency the following night (9). Some patients with CNS hypersomnias benefit from planned daytime naps. In patients with narcolepsy, two 15-minute naps coupled with regularly scheduled nocturnal sleep significantly reduced daytime
sleepiness and the amount of unscheduled daytime sleep. This was especially beneficial to patients with profound sleepiness despite appropriate pharmacologic treatment (10). The recommended schedule for napping involves one nap after lunch and another nap at 5:30 PM (8). This can be specifically tailored for the individual based on school and work limitations but should be scheduled at the same time each day and for the same amount of time. Naps more than 30 minutes should be avoided due to the effects of sleep inertia (11). The data are less clear in patients with other types of CNS hypersomnias, but scheduled naps may still be a good nonpharmacologic therapy option.
sleepiness and the amount of unscheduled daytime sleep. This was especially beneficial to patients with profound sleepiness despite appropriate pharmacologic treatment (10). The recommended schedule for napping involves one nap after lunch and another nap at 5:30 PM (8). This can be specifically tailored for the individual based on school and work limitations but should be scheduled at the same time each day and for the same amount of time. Naps more than 30 minutes should be avoided due to the effects of sleep inertia (11). The data are less clear in patients with other types of CNS hypersomnias, but scheduled naps may still be a good nonpharmacologic therapy option.
Education of Patients, Family, and Friends
Even with the current advances in treatment for CNS hypersomnias, many patients continue to suffer symptoms of excessive sleepiness (12, 13 and 14). Patients may be labeled as unmotivated, disinterested, or lazy, which may adversely affect life at home, in school, and in the workplace. Therefore, it is important to provide resources for patients, family, and friends to better understand the signs and symptoms of this disorder, which can promote acceptance of the disease manifestations. Then, supervisors and educators may be more willing to make adjustments, such as scheduled naps and avoidance of changes in work hours. Organizations such as The Narcolepsy Network (http://www.narcolepsynetwork.org/), American Academy of Sleep Medicine (http://www.aasmnet.org), and National Sleep Foundation (http://www.sleepfoundation.org/) provide helpful information about educational materials, frequently asked questions, support groups, and patient stories.
Caffeine
Caffeine, a xanthine derivative, is used by 85% of Americans to combat morning inertia (15). It has been studied and used to improve psychomotor vigilance in sleep-deprived subjects (15,16). Caffeine’s stimulating effects come via inhibition of the adenosine A1 receptor (17). It was shown that 600 mg of caffeine, which is the amount in a 16-oz cup of Starbuck’s coffee, produced similar performance results in sleep-deprived subjects taking 400 mg of modafinil (8). Common side effects include nervousness, insomnia, nausea, and diarrhea. There are no studies evaluating the effectiveness of caffeine in promoting wakefulness in narcolepsy, but it is likely that most patients with CNS hypersomnia are using caffeine as an adjunct treatment. The current recommendation is to avoid daily caffeine intake over 4 mg/kg due to its side effects.
PHARMACOLOGIC TREATMENT OPTIONS (Table 10.1)
Traditional Stimulants
Amphetamines
Amphetamine was first synthesized in 1887 (18), but was not used to treat hypersomnia until 1935 (19). It has a chemical structure similar to endogenous catecholamines, including epinephrine (EP), norepinephrine (NE), and dopamine (DA) (20). Amphetamine enters the nerve terminals via the plasma membrane through its lipophilic properties. Once in place, it interacts with DA and NE transporter molecules (DAT/NET) to increase the concentration of these catecholamines by inhibiting uptake (21). In addition, amphetamine interacts with vesicular monoamine transporter 2 (VMAT2) to enhance release of DA, NE, and serotonin (5-HT) (22). Randomized controlled trials have been conducted to show the ability of amphetamine to reduce sleepiness in patients with narcolepsy (23).
Amphetamine is a racemic compound that contains equal portions of the optical isomers levo (L)-amphetamine and dextro (D)-amphetamine (24). Damphetamine has a more potent effect on promoting wakefulness, and this characteristic has led to formulation of medications such as Adderall and its generic equivalent, which has D-amphetamine in a 3:1 ratio compared to Lamphetamine. Normal dosing is 5 to 60 mg daily given once or twice daily (25). The usual adult starting dose is 10 mg daily. If unsuccessful in 1 week, then increase the frequency to twice daily before increasing the dosage amount. The extended-release formulation of amphetamine/D-amphetamine is currently not FDA approved for narcolepsy, but it may be a consideration starting at 10 mg daily and increasing the amount by 5 to 10 mg every week if ineffective, to a maximum of 60 mg daily.
TABLE 10.1 Medications Used to Treat CNS Hypersomnias | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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There are also medications in the market, including Dexedrine and ProCentra, which contain only D-amphetamine. The normal dosing is 5 to 60 mg daily, given in 2 to 3 divided doses for the immediate-release formulation. The initial starting dose for adults is 5 mg twice daily (upon awakening and at noon), with peak serum concentration 2 to 3 hours after ingestion. If symptoms do not improve after 1 week, the titration should be individualized based on the timing of hypersomnia. For some patients, late afternoon sleepiness is the most troubling, so they may benefit from a third dose around that time. On the other hand, some patients prefer increasing the morning or noon dose. Late evening doses should be avoided due to the increased risk of nighttime insomnia.
Side effects for amphetamines are common and reported in 73% of patients in a case series by Parkes et al. (26). Irritability, headache, palpitations, and jitteriness top the list. Others include anorexia, weight loss, behavior changes, and seizures. A black box warning states that amphetamines have a high potential for abuse, and administration for a prolonged period of time may lead to drug dependence and must be avoided. Misuses of amphetamines may cause sudden death and serious cardiovascular adverse events. This category of medication is therefore labeled as a Schedule II medication, requiring a triplicate written prescription with no refills or verbal authorizations permitted (25).
Adding a methyl group to the amine of amphetamine results in the synthesis of methamphetamine, prescribed under the brand name Desoxyn. This medication was approved in 1994 by the FDA for the treatment of narcolepsy (27). Even though this indication has since been removed, methamphetamine has been shown to reduce sleepiness and errors in narcoleptic patients while in driving simulation. Initial dose tested ranged from 5 to 60 mg daily (28). With the elimination half-life between 4 to 5 hours, the doses may be divided. Methamphetamine carries the same side effect profile and black box warning as the other amphetamines.
Methylphenidate
Methylphenidate is a piperazine derivative of amphetamine, which was introduced in 1959 as a milder alternative to amphetamine (29). Today, this medication comes in different brand names including Ritalin, Methylin, Metadate, and Concerta. There are also immediate-release and extended-release formulations, although the latter is not currently FDA approved for the treatment of narcolepsy. Randomized controlled trials and clinical series have tested patients with a definite diagnosis of narcolepsy and in those who report a history of sleepiness. Methylphenidate doses used in these studies range from 10 mg to 300 mg, although the average is less than 60 mg daily (23,29,30). All of these studies show a dose response effect on decreasing sleepiness in study populations. The current recommendation is to start with 10 mg daily, given in 2 to 3 divided doses, preferably 30 to 45 minutes before a meal to improve absorption. If necessary, titration may be done on a weekly basis to a maximum cumulative daily dose of 60 mg.
Methylphenidate carries a similar side effect profile to amphetamines, which include anorexia, headaches, xerostomia, insomnia, tachyarrhythmia, and anxiety. Rare but serious adverse effects include aggressive behavior, myocardial infarction, and drug dependence. Because methylphenidate is an amphetamine-like
compound, it is also under Schedule II restrictions. There is a black box warning regarding use in emotionally unstable patients, such as those with a history of drug dependence or alcoholism. Chronic abuse can lead to tolerance and psychic dependence with varying degrees of abnormal behavior including psychotic episodes. Careful supervision during drug withdrawal is advised, because severe depression and the effects of chronic overactivity can be unmasked (25).
compound, it is also under Schedule II restrictions. There is a black box warning regarding use in emotionally unstable patients, such as those with a history of drug dependence or alcoholism. Chronic abuse can lead to tolerance and psychic dependence with varying degrees of abnormal behavior including psychotic episodes. Careful supervision during drug withdrawal is advised, because severe depression and the effects of chronic overactivity can be unmasked (25).
Mazindol
Mazindol is a sympathomimetic amine similar to amphetamine that blocks DA and NE reuptake by binding the DAT and NET. It is most often used as an anorexigen and marketed as Mazanor and Sanorex, but it has been shown to be effective in treating both sleepiness and cataplexy (31, 32 and 33), both short term and long term (34), in patients with narcolepsy. The dosage range tested was 0.5 to 8 mg daily. The recommended dose is 2 mg twice daily and titration based upon symptom control. It has a lower abuse potential compared to amphetamines. Adverse effects include nausea, nervousness, constipation, and urinary retention (25).
Pemoline
Pemoline is another amphetamine-like stimulant that may act through dopaminergic mechanisms. Initial studies showed that the medication appears to be a milder stimulant with lower potential for abuse compared to other amphetamines (35). Hypersomnia is not an FDA-labeled indication for this medication. Moreover, reports of pemoline-associated hepatotoxicity and death have significantly reduced its routine use (36).
Nonamphetamine Wakefulness-Promoting Agents
Modafinil (Provigil)
Modafinil, a primary metabolite of adrafinil, is a medication specifically developed for the treatment of narcolepsy. It was synthesized in France in the 1970s and has been available in Europe since 1986 (37). Modafinil’s exact mechanism of action has been much debated. Although it is not an amphetamine, studies have shown that modafinil does have selective affinity for the DAT (38). Later studies revealed that modafinil may interact with both NE and DA reuptake through novel mechanisms (39). Most recently, there is new information suggesting involvement of the central histaminergic systems in promoting wakefulness with modafinil (40).
There have been several studies showing the efficacy of modafinil in the treatment of hypersomnia due to narcolepsy (41, 42 and 43) and idiopathic hypersomnia (41)
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