The objective of drug treatment of narcolepsy is to alleviate the two most troublesome symptoms, sleep attacks and cataplexy. Although cataplexy is present in 80% of patients with narcolepsy, often only one symptom (either sleep attacks or cataplexy) interferes with overall functioning. Sleep attacks are generally treated with stimulants of the central nervous system (e.g. methylphenidate), and cataplexy is generally treated with REM-suppressing antidepressants (e.g., imipramine). There are also newer prospects in drug treatment such as modafinil, sodium oxybate and GHB. All these drugs are discussed in the sections below. When a specific drug is mentioned, it is presented in bold for easier recognition.
Sleep attacks and excessive daytime sleepiness are primarily treated with stimulants of the central nervous system, which can have the effects of increasing alertness, elevating mood, and preventing sleep. The stimulant agents most commonly prescribed are methylphenidate, dextroamphetamine and pemoline.
Methylphenidate, better known by the non-generic name Ritalin, is an appealing drug because of it produces effects promptly after the drug’s consumption and has a low incidence of side effects. One significant problem with methylphenidate is that the drug is only effective for a few hours, requiring more than one dose to be effective all day. Time-release methylphenidate is also now available which only requires once a day dosage.
Pemoline has behavioral effects similar to those of methylphenidate. Because of its 12-hour half-life, pemoline may be given once daily. It has a slower onset of action, and both its degree of stimulation and its side effects seem to be lower than those of methylphenidate and amphetamines. Occasionally pemoline initially worsens sleepiness for several hours after ingestion. Tolerance to pemoline usually does not develop. (Honda et al, 1980)
Mitler et al reported on the comparative effectiveness of methylphenidate and pemoline in patients with narcolepsy. Methylphenidate improved wakefulness but pemoline did not; however, pemoline improved performance ability more reliably than did methylphenidate. (Mitler et al, 1986)
Dextroamphetamine is often used and preferred by some. Drug dependence, amphetamine psychosis, and even paradoxical sleepiness (Dement et al, 1976) can occur.
Although many patients take stimulants with enduring benefit and without significant side effects, they can cause insomnia, hypertension, palpitations, and irritability. Tolerance to long-term stimulant therapy also may occur, necessitating an increase in dosage to achieve the same control of symptoms. (Van den Hoed et al, 1981) While tolerance may necessitate a higher dose to relieve symptoms, higher doses may result in increased side effects. Late afternoon or evening doses should be avoided so as not to interfere with nighttime sleep. (Mitler et al, 1986; Mitler et al, 1987) Because of the potential for side effects, changes in stimulant dosages should be made gradually and the effects experienced by the person taking the stimulant medication should be monitored by his or her doctor as well as a trusted friend or family member while changes in dosage are being made.
Stimulant drugs are unfortunately not effective in the treatment of cataplexy, hypnagogic hallucinations, and sleep paralysis; however, these symptoms are treatable using some of the same medications that are typically applied as antidepressants. There are two main classes of antidepressants that are used to treat narcoleptic symptoms: tricyclics and serotonin-selective reuptake inhibitors (SSRIs). Although these drugs are known to suppress REM sleep, their exact mechanism of action in alleviating cataplexy is unknown.
The tricyclic medication most commonly prescribed for narcolepsy is imipramine, but there are several other used tricyclics such as protriptyline and clomipramine. The effect of imipramine on REM sleep and on cataplexy is immediate. Usually imipramine can effectively control cataplexy, sleep paralysis, and hypnagogic hallucinations. Protriptyline has been reported to control both cataplexy and sleep attacks. Protriptyline has become popular because of its effectiveness in treating cataplexy; and because it does not cause drowsiness, it can be given during the daytime. It is usually better tolerated than stimulant drugs by the elderly.
Serotonin-selective reuptake inhibitors (SSRIs) include fluoxetine (better known as Prozac) and paroxetine (better known as Paxil). SSRIs may be preferable over tricyclics due to their lower likelihood of side effects
Dosages of these medications used to treat narcolepsy are generally lower than doses typically applied to treat depression, so the likelihood of experiencing negative side effects is relatively less; however, patients may experience dry mouth, sweating, constipation, and sexual dysfunction, which may lead a person to discontinue use of the medication. (Van den Hoed et al, 1981) Because of the potential for side effects, changes in antidepressant dosages should be made gradually and the effects experienced by the person taking the antidepressant medication should be monitored by his or her doctor as well as a trusted friend or family member while changes in dosage are being made.
Tricyclic antidepressants in particular have a number of potential side effects because, unlike SSRIs, they have an effect on the neurotransmitter acetylcholine. These potential side effects include anorexia, hypotension, abnormally rapid heart beat, and blurred vision. When tricyclics are suddenly withdrawn, there can be a marked increase in cataplexy.
When cataplexy and sleepiness symptoms are both severe, stimulants and antidepressants may be combined, but careful adjusting of the dosage and monitoring are mandatory in view of serious side effects. Methylphenidate can increase the effect of tricyclics by interfering with metabolism in the liver. Therefore, tricyclics with sedating properties such as imipramine should only be given in the evening so as not to interact with the effect of stimulant medications.
Modafinil (also known by the trade name Provigil) is a newer narcolepsy treatment drug that has been shown to reduce sleep attacks and excessive daytime sleepiness. Modafinil seems to affect the brain principally as a GABA release inhibitor. GABA is the main chemical in the brain that inhibits the activity of neurons. If modafinil inhibits the release of GABA, then modafinil is preventing the inhibition of neuronal activity, thereby effectively increasing the activity of neurons. Some properties that may make modafinil more appealing than other narcolepsy drugs for sleepiness are that it has little or no effect on nocturnal sleep, it only requires once a day dosage, and it has few adverse effects in general including its low abuse potential and the absence of rebound excessive sleepiness if a person stops taking modafinil. Because of modafinil’s low occurrence of side effects and low potential for abuse, many clinicians consider modafinil to be the drug of first choice for treating sleep attacks and excessive daytime sleepiness in newly diagnosed narcolepsy patients.