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Narcolepsy

Description

An in-depth report on the causes, diagnosis, and treatment of narcolepsy.

Treatment

Lifestyle treatment of narcolepsy includes taking three or more scheduled sleep-times throughout the day. One study suggested that the best approach is a combination of scheduled nighttime sleep and two 15-minute naps (for example one before lunch and another before dinner). Patients should also avoid heavy meals and alcohol, which can interfere with sleep.

People with mild narcolepsy symptoms that do not require medication may be able to maintain alertness with sleep scheduling. In a 2001 study, scheduled sleep periods were also helpful for patients who were extremely sleepy in spite of medications. The benefits of scheduled naps, however, are not clear for patients whose condition responds to medication. In the same study, patients who took stimulants and were able to maintain alertness or were only moderately sleepy derived no additional benefit from the naps.

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

Drug Treatments for Sleepiness

Modafinil. Modafinil (Provigil) is a drug used to treat the excessive sleepiness associated with narcolepsy and other sleep disorders. (Modafinil does not treat cataplexy.) The FDA approved modafinil in 1998. Since that time, it has largely replaced methylphenidate (Ritalin) and other stimulants for treatment of narcolepsy sleepiness. Patients who switch to modafinil from stimulants such as methylphenidate experience few problems if they gradually taper off the stimulant dose.

Modafinil helps patients with narcolepsy stay awake during the day. In one study, patients who had not yet taken modafinil were able to stay awake only an average of 6 out of 20 minutes. After taking the medication, awake time increased to 12 - 14 of every 20 minutes, and some patients had normal wake times. In another study, modafinil increased the ability to stay awake by 50% and reduced the number of involuntary sleep episodes by about 25%.

Some of its 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. In one trial, no patients developed dependence on the drug after 9 weeks of daily use. 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 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.)

A new drug, armodafinil (NuVigil), which is related to modafinil, is being investigated 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 are 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. An older drug, pemoline (Cylert), is now prescribed less frequently due to its risks for liver damage.

Stimulants can have unpleasant side effects, including:

• Weight loss
• Dizziness
• Nausea
• Changes in blood pressure and rapid heartbeat
• Headache

There are some differences between these drugs:

• Methylphenidate, which is the standard drug for treating attention deficit hyperactivity disorder, is safer than dextroamphetamine. Small studies suggest that high doses may help avert cataplexy, although more research is needed to confirm this effect. Psychosis from overdose is very rare. Psychologic dependence can occur, but abuse has not been reported in children who have taken it for years.
• Dextroamphetamine has more severe side effects than methylphenidate. These include mood changes and jerky muscle movements. Prolonged use may cause serious depression. Overdose, which can occur at doses of only 100 to 500 mg, can cause psychosis and even death. This drug should not be used during pregnancy. There is also a risk for addiction and abuse.

Stimulants should be avoided or only taken under a doctor's guidance in people with heart disease, hyperthyroidism, glaucoma, anxiety disorder, and high blood pressure.

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.

Drug Treatments for Cataplexy

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.

In 2002, the FDA approved Xyrem for treatment of cataplexy associated with narcolepsy. However, the FDA placed tight restrictions on its use. 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 to be confused with "Ecstasy," another street drug with different effects.) In high doses, it can cause dependence over time. In addition, very serious side effects -- including seizures, coma, respiratory arrest, and death -- have been reported in people who abused it. Trials of Xyrem, however, have not reported these effects with the doses used in treatment for cataplexy. Patients still report side effects, although they tend to be mild. They include nausea, headache, dizziness, urine leakage, and sleepwalking.

Monoamine Oxidase Inhibitors (MAOIs). Selegiline (Eldepryl, Movergan), also known as deprenyl, is an MAOI that blocks monoamine oxidase B, an enzyme that degrades dopamine and may play a role in narcolepsy.

Adverse Effects. 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.

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 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 on antidepressants, see In-Depth Report #8: Depression.]

• Review Date: 7/13/2006
• Reviewed By: Harvey Simon, M.D., Editor-in-Chief, Associate Professor of Medicine, Harvard Medical School; Physician, Massachusetts General Hospital

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