Narcolepsy
Highlights
Drug Warning
In October 2007, the FDA added new safety information to the prescribing label of modafinil (Provigil). The new information warns that:
- Rare but serious skin reactions, such as Stevens-Johnson Syndrome, have been reported with modafinil use. Patients should stop taking modafinil at the first signs of any rash, and immediately contact their doctors.
- Psychiatric side effects, such as anxiety, mania, hallucinations, and suicidal thinking, have been reported. Doctors should be cautious about prescribing modafinil to patients with a history of psychosis, depression, or mania.
- Modafinil is approved only for adults and should not be given to children.
Drug Treatments for Narcolepsy
The two main drug treatments for narcolepsy are:
- Modafinil (Provigil) for excessive daytime sleepiness
- Sodium oxybate (Xyrem) for cataplexy (sudden muscle weakness)
Behavioral Strategies for Managing Narcolepsy
- Scheduled naps can help combat narcolepsy-associated sleepiness and improve alertness, according to 2007 practice parameters from the American Academy of Sleep Medicine. Patients with narcolepsy should try to take three or more short naps on a regular basis during the day.
- To improve nighttime sleep quality and reduce fatigue, avoid heavy meals before bedtime and limit alcohol and caffeine use.
Introduction
The word narcolepsy comes from two Greek words roughly translated as "seized by numbness." The two primary symptoms in narcolepsy reflect this phrase:
- Excessive daytime sleepiness, with frequent daily sleep attacks or a need to take several naps during the day.
- Temporary and sudden muscle weakness (called cataplexy), usually brought on by strong emotions.
Some, but not all, patients experience other symptoms:
- Microsleep episodes, in which the patient behaves automatically but without conscious awareness
- A sense of paralysis that occurs between wakefulness and sleep (called atonia)
- Dreamlike states between waking and sleeping (called hypnagogic hallucinations)
Rapid eye movement (REM) sleep is abnormal in narcolepsy. In fact, narcolepsy is sometimes defined as the loss of boundaries between wakefulness, nonREM sleep, and REM sleep. REM sleep is the active, dreaming phase of sleep.
Excessive Sleepiness. All people with narcolepsy experience excessive sleepiness during the day with episodes of falling asleep rapidly and inappropriately, even when fully involved in an activity. It is sometime described as an irresistible daytime need for naps, which will generally refresh the patient. These events may be characterized by the following behaviors:
- Patients often have periods of drowsiness every 3 or 4 hours that usually end in short naps.
- Patients may sleep for a few minutes, particularly if they are in an awkward position or for a few hours if they are lying down.
- Patients often underestimate the duration of their drowsy periods and may not recall clearly their behavior during that time.
Cataplexy. Cataplexy is an abrupt loss of muscle tone or strength that results in an inability to move and always occurs during wakefulness. Symptoms of excessive daytime sleepiness are often present for years before symptoms of cataplexy develop. Around two thirds of patients with narcolepsy have symptoms of cataplexy. Cataplexy occurs in about two-thirds of narcolepsy patients. The following events may be triggers:
- Sudden emotion, usually anger or laughter (the most common trigger)
- Following a heavy meal
- During periods of stress
Muscle reflexes are completely absent during a cataplectic attack. Cataplectic attacks can be very minimal and appear as passing weakness or affecting only the eyelids and face. They may, on the other hand, be so severe that they weaken the whole body. In the most severe form of cataplexy, attacks can recur repeatedly for hours or days. Abrupt withdrawal from certain drugs used to treat narcolepsy, notably clomipramine, can trigger this uncommon but troublesome occurrence.
Cataplexy may have the following characteristics:
- Most attacks last less than 30 seconds and can be missed by even skilled observers. However, in severe cases, a person may fall and remain paralyzed for as long as several minutes.
- Typically the patient's head will suddenly fall forward, the jaw becomes slack, and the knees will buckle.
- Speech may become suddenly loud or broken and stutter-like.
Atonia. Atonia is a sense of paralysis that occurs between wakefulness and sleep, usually upon waking or sometimes at the onset of sleep. The person is conscious but cannot speak, move (cannot even open the eyes), or breathe deeply. Atonia rarely lasts beyond 20 minutes, but when it first occurs, this experience can be terrifying, particularly if the patient also develops hallucinations.
Hypnagogic Hallucinations. Hypnagogic hallucinations are dreams that intrude on wakefulness, which can cause visual, auditory, or touchable sensations. They occur between waking and sleeping, usually at the onset of sleep, and can also occur about 30 seconds after a cataplectic attack.
- Visual hallucinations have been described as a "film running through the head" or as a waking dream with strong emotional content. Images can be intrusive. More commonly they may involve seeing colored forms that shift in size and shape.
- Auditory hallucinations may include random sounds or elaborate melodies.
- A person may also hallucinate feelings of rubbing or light touches, even levitation.
Such symptoms may also appear in other sleep disorders and are probably related to extreme sleepiness. In general, cataplexy must also be present for a clear diagnosis of narcolepsy. Some experts believe, however, that some patients with narcolepsy may experience hypnagogic hallucinations and daytime sleepiness and not cataplexy.
Microsleep and Automatic Behavior. In some cases, patients have so-called microsleep episodes, in which they behave automatically without conscious awareness. Such automatic behavior may not be recognized as part of a disorder by either patients or the people around them. Some examples include:
- People with narcolepsy can be driving or walking competently but end up in a location different from the intended one.
- A narcolepsy patient can be carrying on a conversation and jump from one unrelated topic to another or just trail off and stop talking altogether.
- The patient may suddenly perform bizarre actions, such as putting socks in the refrigerator.
- Patients may have severe forgetfulness.
- Their movements may suddenly become slow or clumsy.
- In some cases, their behavior may resemble some forms of epileptic seizures.
Disturbed Sleep. Nighttime sleep is often disturbed in narcolepsy, but it is usually mild to moderate and does not account for the daytime sleepiness experienced by people with narcolepsy.
Periodic Limb Movement Disorder. Many patients with narcolepsy experience periodic limb movement disorder, also called PLMD (formerly known as nocturnal myoclonus). In PLMD, the leg muscles involuntarily contract every 20 - 40 seconds during sleep, occasionally arousing the patient. The patient is usually unaware of the cause of the interruption.
Most people need about 8 hours of sleep each day. Individual adults differ in the amount of sleep they need to feel well rested, however. (Infants may sleep as many as 16 hours a day.)
The daily cycle of life, which includes sleeping and waking, is called a circadian (meaning "about a day") rhythm, commonly referred to as the biologic clock. Hundreds of bodily functions follow biologic clocks, but sleeping and waking comprise the most prominent circadian rhythm. The sleeping and waking cycle is about 24 hours. (If confined to windowless apartments, with no clocks or other time cues, sleeping and waking as their bodies dictate, humans typically live on slightly longer than 24-hour cycles.) It usually takes the following daily patterns:
- Humans are designed for daytime activity and nighttime rest.
- Additionally, there is a natural peak in sleepiness at mid-day, the traditional siesta time.
In addition, daily rhythms intermesh with other factors that may interfere or change individual patterns:
- The fraction-of-a-second-firing of nerve cells in the brain may be faster or slower in different individuals.
- The monthly menstrual cycle in women can shift the pattern.
- Light signals coming through the eyes reset the circadian cycles each day, so changes in season or various exposures to light and dark can unsettle the pattern. The importance of sunlight as a cue for circadian rhythms is dramatized by the problems experienced by people who are totally blind. They commonly suffer trouble sleeping and other rhythm disruptions.
The response to light signals in the brain is an important key factor in sleep:
- Light signals travel to a tiny cluster of nerves in the hypothalamus in the center of the brain, the body's master clock, which is called the suprachiasmatic nucleus (SCN).
- This nerve cluster takes its name from its location, which is just above (supra) the optic chiasm, a major junction for nerves transmitting information about light from the eyes.
- The approach of dusk each day prompts the SCN to signal the nearby pineal gland (named so because it resembles a pinecone) to produce the hormone melatonin.
- Melatonin is thought to act as the body's time-setting hormone. The longer a person is in darkness, the longer the duration of melatonin secretion. Secretion can be diminished by staying in bright light. Melatonin also appears to trigger the need to sleep.
Sleep consists of two distinct states that alternate in cycles and reflect differing levels of brain nerve cell activity.
Non-Rapid Eye Movement Sleep (NonREM). NonREM sleep is also termed quiet sleep. NonREM is further subdivided into three stages of progression:
- Stage 1 (light sleep)
- Stage 2 (so-called true sleep)
- Stage 3 to 4 (deep "slow-wave" or delta sleep)
With each descending stage, awakening becomes more difficult. It is not known what governs NonREM sleep in the brain. A balance between certain hormones, particularly growth and stress hormones, may be important for deep sleep.
Rapid Eye-Movement Sleep (REM). REM sleep is termed active sleep. Most vivid dreams occur in REM sleep. REM-sleep brain activity is comparable to that in waking, but the muscles are virtually paralyzed, possibly preventing people from acting out their dreams. In fact, except for vital organs like lungs and heart, the only muscles not paralyzed during REM are the eye muscles. REM sleep may be critical for learning and for day-to-day mood regulation. When people are sleep-deprived, their brains must work harder than when they are well rested.
Click the icon to see an image of sleep patterns.
The REM/NonREM Cycle. The cycle between quiet (nonREM) and active (REM) sleep generally follows this pattern:
- After about 90 minutes of nonREM sleep, eyes move rapidly behind closed lids, giving rise to REM sleep.
- As sleep progresses the nonREM/REM cycle repeats.
- With each cycle, nonREM sleep becomes progressively lighter, and REM sleep becomes progressively longer, lasting from a few minutes early in sleep to perhaps an hour at the end of the sleep episode.
Causes
Narcolepsy is a neurological sleep disorder. It is not caused by mental illness or psychological problems. It is most likely the end result of a number of genetic abnormalities that affect specific biologic factors in the brain, coupled with an environmental trigger such as a virus.
Researchers are attempting to come up with a unifying theory involving genetic factors, autoimmunity, and deficiencies in hypocretin, a brain peptide that is important in regulating sleep. Most of the research conducted on narcolepsy uses dogs that have genetic factors that cause narcolepsy, but such studies are helping researchers find the biologic bases to this strange and distressing condition.
Hypocretin. Hypocretin (also called orexin) is a peptide that modulates activity in the hypothalamus (the region in the brain associated with sleep, well-being, and appetite). Hypocretin specifically has properties that promote wakefulness and inhibits REM sleep. Hypocretin may also have other actions that affect feeding behavior and increase activity in the autonomic (sympathetic) nervous system and systems that regulate motor control. Deficiencies in this peptide have been observed in most patients with narcolepsy who also have cataplexy. Deficiencies might set off the following chemical responses that may produce sleep attacks:
- Lower levels of histamine, a chemical that promotes wakefulness
- Low levels of epinephrine (commonly known as adrenaline), a hormone important in alertness and arousal
- Increase in acetylcholine, which affects REM sleep
- Changes in the enzyme monoamine oxidase, which is believed to be important in preventing arousal
- Changes in dopamine, an important neurotransmitter (chemical messenger in the brain) that helps regulate sleep
- Lower levels of leptin, a hormone associated with obesity when levels decline (people with narcolepsy tend to be overweight)
- Higher-than-normal secretion of growth-hormone during the day, which may play a role in sudden falling-asleep episodes
Narcolepsy has a genetic component and tends to run in families. Experts estimate that around 8 - 10% of people with narcolepsy have a close relative who has the disorder. The risk for narcolepsy among first-degree relatives (parents or sibling) is 1 - 2%.
However, most experts agree that genetics are not the only factor involved in narcolepsy. Narcolepsy most likely involves a combination of genetics and one or more environmental triggers, such as infection, trauma, hormonal changes, immune system problems, or stress. Researchers are looking for specific genetic mutations that may make individuals susceptible to this disorder.
It has been theorized that narcolepsy may be an autoimmune disease, in which the immune system may be tricked into perceiving its own proteins to be antigens. (Antigens are foreign substances targeted for attack by immune factors in the body.)
Important autoimmune diseases include multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, and type 1 diabetes. In such diseases, the immune system overproduces potent factors called cytokines, which cause inflammation and injury in the susceptible cells and tissues affected by the disease. Most autoimmune diseases also tend to afflict those with particular genetically determined molecules of the immune system called human leukocyte antigens (HLAs).
Some research suggests that an immune attack in narcolepsy may occur against cells containing the brain peptide hypocretin (orexin), resulting in deficiencies that are now believed to be major components of the narcolepsy process. HLAs, particularly a subgroup known as (HLA)DQB1-0602, have been strongly associated with narcolepsy and low levels of hypocretin. Narcolepsy patients who carry this HLA group tend to have a specific syndrome of symptoms that include cataplexy and periodic limb movement disorder. However, 20 - 40% of people without narcolepsy carry these HLA types.
Risk Factors
Narcolepsy affects around 1 in 2,000 people. Experts estimate that around 135,000 - 200,000 Americans have narcolepsy, but the number may be higher. Only about 25% of people who have narcolepsy are actually diagnosed with the disorder. Patients are often mistakenly diagnosed with other conditions, such as psychiatric or emotional problems. Many patients wait decades before receiving a proper diagnosis.
Narcolepsy symptoms usually first appear in adolescence or young adulthood. However, narcolepsy can begin at any age. Growing evidence suggests that the disorder may emerge in early childhood in many patients. People who develop it at a young age often have a family history of the disease and a severe condition, suggesting that genetic factors are important in this group.
Complications
Narcolepsy is a life-long problem, but it is not progressive. Symptoms may even lessen over time, but they never completely disappear. In one study comparing older adults (over 65 years old) and younger adults, the older group had less cataplexy, although there was no difference in excessive daytime sleepiness. In fact, another study suggested that sleep disturbances at night often worsen as a person ages.
Perhaps the most serious consequence of narcolepsy is the high risk for accidents. In one survey, almost 75% of patients with narcolepsy reported falling asleep while driving, and 56% reported nearly having accidents. Other common narcolepsy-related accidents include burns from touching hot objects, cuts from sharp objects, and breaking things.
Some studies report that people with narcolepsy have problems with memory, thinking, and attention. Whether these problems are more likely to be due to tiredness and episodes of sleepiness than to brain abnormalities is not clear.
The patient suffers emotional and social difficulties from the uncontrollable sleep episodes and cataplexy. Studies have reported rates of depression in people with narcolepsy ranging from 30 - 57%. (In the general population, the prevalence of depression is 8%.) Studies have shown severe emotional and social dysfunction in all areas, including work, relationships, and leisure activities. Men with narcolepsy frequently suffer from sexual problems. Some experts believe that the psychological and social effects are more serious than those caused by epilepsy (for which narcolepsy can be mistaken).
Obesity. Evidence suggests that people with narcolepsy are at high risk for obesity compared to the general population. This could be a consequence of low activity level, but research also indicates that deficiencies in the brain peptide hypocretin may play a role in both narcolepsy and eating behaviors, which could increase the risk for obesity.
Diagnosis
Although narcolepsy is a physical disorder, doctors are still very likely to misdiagnose patients as having psychological problems. For most patients, narcolepsy is not diagnosed for up to 10 - 15 years after their symptoms first began. To determine specific sleep disorders, the doctor will take a medical and family history and should be told of any medications being taken. The symptoms of narcolepsy are sometimes undeniable if the patient reports all of the major symptoms:
- Excessive daytime sleepiness with a tendency for frequent naps. (These frequent naps should occur every day for at least 6 months to serve as a diagnosis of narcolepsy.) Narcolepsy is usually diagnosed in adolescence and young adulthood when falling asleep suddenly in school brings the problem to attention.
- Cataplexy (abrupt loss of muscle tone or weakness that causes a person to stop all motor activity).
- Hypnagogic hallucinations (vivid visual or auditory phenomena) experienced at the onset of sleep.
- Sleep paralysis (an inability to move on first awakening).
Diagnosis based only on symptoms, however, is often problematic for various reasons:
- Patients often seek medical help for single symptoms (sleep paralysis or hypnagogic hallucinations) that might be associated with other disorders, particularly epilepsy.
- Symptoms are sometimes not dramatically apparent for years, even to the patient or a skilled observer. In one study, the average number of years between onset of symptoms and diagnosis was 14. Another study conducted in a sleep clinic reported that more than half of patients were diagnosed when they were over 40 and had not realized they had narcolepsy until they experienced a bout of cataplexy.
In some cases, the patient may need to consult a sleep specialist or go to an accredited sleep disorder center for accurate diagnosis of a sleep disorder. Patients should carefully investigate centers to make sure that they offer full sleep studies. Patients who visit a sleep center undergo an in-depth analysis, usually supervised by a multidisciplinary team of consultants who can provide both physical and psychiatric evaluations.
A doctor may administer certain questionnaires on sleeping habits.
The Epworth Sleepiness Scale. The Epworth Sleepiness Scale (ESS) uses a simple questionnaire to measure excessive sleepiness and differentiate it from normal daytime sleepiness.
Situation | Chance of Dozing 0 = no chance of dozing 1 = slight chance of dozing 2 = moderate chance of dozing 3 = high chance of dozing |
Sitting and reading | (Indicate a score of 0 - 3) |
Watching TV | (Indicate a score of 0 - 3) |
Sitting inactive in a public place (a theater or a meeting) | (Indicate a score of 0 - 3) |
As a passenger in a car for an hour without a break | (Indicate a score of 0 - 3) |
Lying down to rest in the afternoon when circumstances permit | (Indicate a score of 0 - 3) |
Sitting and talking to someone | (Indicate a score of 0 - 3) |
Sitting quietly after a lunch without alcohol | (Indicate a score of 0 - 3) |
In a car, while stopped for a few minutes in traffic | (Indicate a score of 0 - 3) |
Score Results | 1 - 6: Getting enough sleep 4 - 8: Tends to be sleepy but is average 9 - 15: Very sleepy and should seek medical advice Over 16: Dangerously sleepy |
The multiple sleep latency test (MSLT) uses a machine that measures the time it takes to fall asleep lying in a quiet room during the day. The patient takes 4 or 5 scheduled naps 2 hours apart. People with healthy sleep habits fall asleep in about 10 - 20 minutes. In patients with narcolepsy, polysomnography plus MSLT will show a much shorter duration of time (less than 8 minutes) from wakefulness into sleep. At least 2 of the naps are REM-onset (the active sleep phase associated dreaming). The test has limitations, however. There is no clear definition of exactly which abnormal results would indicate narcolepsy. It is most useful for measuring the severity of the problem. The Epworth Sleepiness Scale may be more accurate in differentiating narcolepsy from normal daytime sleepiness.
An overnight sleep study, called polysomnography, can be a valuable means for determining the basic cause of sleepiness. The patient arrives at the sleep center about 2 hours before bedtime without having made any changes in daily habits. The patient will be monitored by a variety of devices while sleeping:
- Electroencephalogram, or EEG (monitors the electrical activity of the brain)
- Electrocardiogram or ECG (monitors the heart)
- Electromyogram (monitors the movements of muscles)
- Electrooculogram (monitors eye movements)
These instruments record activity as the patient passes, or fails to pass, through the various sleep stages. One study using polysomnography reported that both healthy patients and those with narcolepsy perform equally during the first 5 - 10 minutes of the test, but after that, patients with narcolepsy show evidence of drowsiness and even indications of sleep. In general, however, polysomnography is most useful for ruling out other disorders, such as sleep apnea, in people with narcolepsy.
Ruling out Other Sleep Disorders. Other sleep disorders can share some or all of the symptoms of narcolepsy:
- Patients with obstructive sleep apnea also experience sleep disturbance and excessive daytime fatigue.
- Idiopathic hypersomnia is a less well-defined syndrome in which patients have excessive daytime sleepiness without evidence of cataplexy. Patients have a hard time becoming fully awake despite an adequate amount of sleep time.
- Chronic sleep deprivation
- Secondary narcolepsy, resulting from head trauma, tumors, vascular malformations in the brain, multiple sclerosis, or Parkinson's disease
Ruling out Psychologic Disorders. In one study, 40% of patients who actually had narcolepsy had been diagnosed incorrectly with some psychological or psychiatric problem. Certainly, patients with narcolepsy have emotional difficulties because of the condition, and it is often difficult, particularly for a nonspecialist, to detect the physical problem. Even worse, hypnagogic hallucinations may result in diagnoses of schizophrenia or bipolar disorder, which are treated with potent antipsychotic drugs that have severe side effects and are useless for narcolepsy.
Ruling out Epilepsy. Narcolepsy can easily be mistaken for epilepsy, a group of disorders that cause seizures. Case studies have reported a misdiagnosis of epilepsy in patients who were actually experiencing cataplexy and sleep paralysis.
Other Causes of Persistent Fatigue. A number of conditions can cause persistent fatigue and should be ruled, including:
- Obstructive sleep apnea. This is a major sleep disorder that causes fatigue and afternoon sleepiness and must be ruled out before a diagnosis of narcolepsy can be established. (A person may also suffer sleep apnea and narcolepsy at the same time.)
- Chronic fatigue syndrome
- Head trauma
- Infectious mononucleosis
- Guillain-Barre syndrome
- Hepatitis
- Atypical pneumonia, particularly those involving echoviruses
These conditions may also worsen sleep paralysis in narcolepsy. Narcolepsy sleep paralysis usually occurs at the onset of sleep and is chronic.
Neuroimaging techniques may be used in a research setting to confirm sleep physiological theories in humans and to discover new information about the neurobiological aspects of sleep, dreams, and memory. Few neuroimaging studies have focused on patients with sleep disorders such as narcolepsy.
Treatment
Lifestyle treatment of narcolepsy includes taking three or more scheduled sleep-times/naps throughout the day. Patients should also avoid heavy meals and alcohol, which can interfere with sleep.
People with mild narcolepsy symptoms who do not need medication may be able to maintain alertness with sleep scheduling. The role of scheduled naps for patients who are responding to medications for narcolepsy remains unclear.
Medications for narcolepsy target the major symptoms of sleepiness and cataplexy. Stimulant drugs are used to manage excessive daytime sleepiness while antidepressants and other compounds address cataplectic symptoms. The FDA has approved two drugs specifically for the treatment of narcolepsy. They are now the first-line treatments:
- Modafinil (Provigil): For excessive daytime sleepiness
- Sodium oxybate (Xyrem): For cataplexy
Modafinil. Modafinil (Provigil) is a drug used to treat the excessive sleepiness associated with narcolepsy and other sleep disorders. It has largely replaced methylphenidate (Ritalin) and other stimulants for treatment of narcolepsy sleepiness. Patients who switch to modafinil from stimulants such as methylphenidate have few problems if they gradually taper off the stimulant dose.
Modafinil helps patients with narcolepsy stay awake during the day. While only some experience normal wake times, patients taking modafinil often have up to a 50% improvement in the ability to stay awake, as well as a 25% reduction in the number of involuntary sleep episodes.
Some of modafinil's additional benefits include what it does not do:
- Modafinil does not appear to affect natural hormones important in sleep, including cortisol (the major stress hormone), melatonin, and growth hormone. Therefore, studies suggest that it does not interfere with voluntary naps during the day or with the quantity or quality of nighttime sleep.
- It does not cause anxiety to the degree that the standard stimulants do.
- It does not cause a rebound effect as stimulants do. In other words, people who take modafinil do not usually "crash" when the drug wears off.
- It has less potential for abuse than stimulant drugs. However, modafinil can still be habit-forming. Patients may need to gradually lower the dose before stopping treatment.
Side effects may include:
- Headache (the most commonly reported side effect)
- Nausea
- Diarrhea
- Dry mouth
- Nasal and throat congestion
- Nervousness and anxiety
- Dizziness
- Back pain
- Difficulty sleeping
- Decreases in the effects of hormonal methods of birth control, including the pill. (Women of childbearing age who take modafinil should switch to another form of birth control.)
- Anxiety, mania, hallucinations, suicidal ideation, and other psychiatric side effects may occur. Caution should be exercised when giving modafinil to patients with a history of psychosis, depression, or mania.
- Rare, but serious, skin reactions such as Stevens-Johnson syndrome have been reported with modafinil use. Patients should immediately stop taking modafinil if a rash occurs, and contact their doctors right away.
- Modafinil is approved only for adults.
A newer drug, armodafinil (NuVigil), which is nearly identical to modafinil, is also approved for treatment of narcolepsy-associated excessive sleepiness. In clinical trials comparing it with placebo, armodafinil improved wakefulness, memory, attention, and fatigue in patients with narcolepsy.
Stimulants. Medications that act as stimulants are standard treatments for narcolepsy. They include:
- Methylphenidate (Ritalin)
- Dextroamphetamine (Dexedrine)
- Methamphetamine (Desoxyn)
Methylphenidate and dextroamphetamine last for 2 - 5 hours and used to be the standard drugs for excessive daytime sleepiness. These drugs are useful for people who can manage wakefulness with a night's sleep and scheduled naps. They can improve mood, mental acuity, and other aspects of mental functioning. However, the evidence to support their benefit for patients with narcolepsy is not a strong as with modafinil.
Stimulants can have unpleasant side effects, including:
- Weight loss
- Dizziness
- Nausea
- Changes in blood pressure and rapid heartbeat
- Headache
People with heart disease, hyperthyroidism, glaucoma, anxiety disorder, and high blood pressure should avoid stimulants, or take them only with a doctor's supervision.
These drugs become ineffective if used continuously, and patients are advised to take a drug holiday one day a week or to withdraw gradually and resume treatment at a lower dose. Patients should not engage in activities that require being awake (such as driving) during withdrawal.
Sodium oxybate (Xyrem). Sodium oxybate (Xyrem), also referred to as gamma hydroxybutyrate (GHB), helps reduce the frequency of cataplexy attacks and improve daytime sleepiness. It takes about 4 weeks for significant benefits, which reach their peak at about 8 weeks. Food intake can affect it, so patients are advised to take it at a regular time after the evening meal.
The FDA has placed tight restrictions on the use of this drug. Although the drug appears to be effective and safe when used for narcolepsy, it has a history of illegal and "date-rape" use, with street names such as "Grievous Bodily Harm" or "Liquid Ecstasy." (The last term is not the same as "Ecstasy," another street drug with different effects.) In high doses, it can cause dependence over time.
Very serious side effects -- including seizures, coma, respiratory arrest, and death -- have been reported in people who abused GHB. Trials of Xyrem, however, have not reported these effects with the doses used in treatment for cataplexy.
Antidepressants. Antidepressant drugs are not approved for treatment of cataplexy, but they are commonly used to manage this condition. Unfortunately, there have been few studies conducted on antidepressant treatment of cataplexy, and there are little data on which type of antidepressant work bests. A 2005 review of antidepressants for narcolepsy noted the lack of good quality evidence to support their use and urged for more clinical trials.
Antidepressants used for cataplexy, hallucinations, sleep paralysis, and management of REM symptoms include:
- Tricyclic antidepressants: Protriptyline (Vivactil), clomipramine (Anafranil), imipramine (Janimine, Tofranil), and desipramine (Norpramin, Pertofran)
- Selective serotonin reuptake inhibitors (SSRIs): Fluoxetine (Prozac), paroxetine (Paxil), and sertraline (Zoloft)
- Newer antidepressants: Venlafaxine (Effexor)
Tricyclics were the first antidepressants used for cataplexy; they were also one of the first treatments for cataplexy. They can be helpful for some patients but have many unpleasant side effects, including dry mouth, constipation, and weight gain. Tricyclics can also lower blood pressure and cause disturbances in heart rhythm.
SSRIs have fewer side effects than tricyclics but may not work as well for cataplexy control. The most common side effects include nausea, drowsiness or insomnia, headache, weight gain, and sexual dysfunction.
Venlafaxine (Effexor) is a selective serotonin and norepinephrine reuptake inhibitor (SSNRI) that has shown promising results for treatment of cataplexy. Some patients with narcolepsy, and their doctors, report that venlafaxine seems to work best of all the antidepressants. [For more information, see In-Depth Report #8: Depression.]
Monoamine Oxidase Inhibitors (MAOIs). Selegiline (Eldepryl, Movergan), also known as deprenyl, is an MAOI that blocks monoamine oxidase B, an enzyme that degrades dopamine. MAOIs may play a role in narcolepsy, but how much benefit this group of drugs provides is not well proven.
Selegiline has significant side effects:
- It interacts with nearly every antidepressant. Patients suffering from depression should discuss all treatment options with their doctor.
- People taking any monoamine oxidase inhibitor are at risk for high blood pressure if they consume tyramine-containing foods or beverages, including aged cheeses, most red wines, vermouth, dried meats and fish, canned figs, fava beans, and concentrated yeast products.
[For more information, see In-Depth Reports #8: Depression and #51: Parkinson's disease for more complete discussion of MAOIs.]
Resources
- www.aasmnet.org -- American Academy of Sleep Medicine
- www.sleepfoundation.org -- National Sleep Foundation
- www.narcolepsynetwork.org -- Narcolepsy Network
- www.med.stanford.edu/school/psychiatry/narcolepsy -- Stanford Center For Narcolepsy
- www.nhlbi.nih.gov/sleep -- National Center on Sleep Disorders Research
- www.ninds.nih.gov -- National Institute on Neurological Disorders and Stroke
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Reviewed By: Harvey Simon, MD, Editor-in-Chief, Associate Professor of Medicine, Harvard Medical School; Physician, Massachusetts General Hospital. Also reviewed by David Zieve, MD, MHA, Medical Director, A.D.A.M., Inc.
