Pharmacology Update

Modafinil for the Treatment of Narcolepsy

By William T. Elliott, MD, FACP and James Chan, PharmD, PhD

Cephalon inc. has received approval to market modafinil (Provigil), the first nonamphetamine drug approved by the FDA for the treatment of excessive daytime sleepiness associated with narcolepsy. Narcolepsy is a disorder that afflicts about 125,000 Americans and is characterized by inability to stay awake or alert in the daytime, sleep attacks, disrupted nocturnal sleep, and cataplexy. Prior treatment for this disorder has consisted primarily of amphetamine type drugs—agents that are commonly associated with side effects and eventual development of tolerance.

While it is known that modafinil is not an amphetamine, the exact mechanism of action of the drug is not known. It apparently does not appear to bind to receptors associated with sleep/wake regulation, such as norepinephrine, serotonin, dopamine, GABA, melatonin, or benzodiazepine.1

Indications

Modafinil is indicated to improve wakefulness in patients with excessive daytime sleepiness associated with narcolepsy.

Dosage

The recommended dose of modafinil is 200 mg as a single dose in the morning. There is no consistent evidence that doses greater than 200 mg confer any additional benefit.1 Patients with severe hepatic impairment should reduce the dose by half.1 In the elderly population, consideration should be given to use the lowest effective dose.

Modafinil is supplied as 100 mg and 200 mg tablets. The drug is placed into DEA Schedule IV.

Potential Advantages

The major advantage of modafinil over other drugs, such as amphetamines and methylphenidate, used for narcolepsy is its apparent lower abuse potential. Modafinil is Schedule IV while amphetamine and methylphenidate are Schedule II. In clinical trials (9 weeks with open label up to 40 weeks), modafinil reduced daytime sleepiness, was generally well tolerated, did not affect sleep, and tolerance did not appear to be problematic.1,2,3 The improvement in average sleep latencies was about 58% based on Maintenance of Wakefulness Test (MWT).

Potential Disadvantages

While modafinil does not appear to have the same abuse potential as amphetamine, it may produce effects similar to other CNS stimulants such as euphoric effects and alteration in mood and/or perception. In addition, monkey studies suggest that modafinil is reinforcing in a manner similar to cocaine.1 Cocaine is one of the most strongly reinforcing self-administered drugs. A clinical study suggested that modafinil produced psychoactive and euphoric effects and feelings consistent with methylphenidate. Patients should be observed for signs of misuse or abuse.1

Albeit rare, chest pain, palpitations, dyspnea, and transient ischemic T-wave changes have been observed in association with mitral valve prolapse or left ventricular hypertrophy. Modafinil is not recommended in patients with a history of left ventricular or ischemic ECG changes, chest pain, arrhythmia, or significant manifestations of mitral valve prolapse in association with CNS stimulants.1

In vitro studies suggest that modafinil has the potential to inhibit cytochrome P450 2C19, suppress the expression of 2C9, and slightly induce 1A2, 2B6, and 3A4. If coadministration of modafinil and drugs that are substrates for one or more of these isoenzymes is clinically indicated, the patient should be monitored for potential toxicity or reduced effectiveness.

In clinical trials, common side effects of modafinil relative to placebo include headache (50% vs 40%), nausea (13% vs 4%), and diarrhea (8% vs 4%).1 Five percent of patients discontinue therapy in these trials.

Comments

Modafinil is the first nonamphetamine or non-methylphenidate drug approved for the treatment of excessive daytime sleepiness associated with narcolepsy. Effectiveness was established in two U.S. multicenter, placebo-controlled, double-blind, nine-week trials in more than 550 patients. The primary measures of efficacy were sleep latency as assessed by the MWT and the change in the patient’s overall disease status, determined by evaluators, as measured by the Clinical Global Impression of Change (CGI-C). MWT assesses the ability of the subject to remain awake without using extraordinary measures.

It measures latency (in minutes) to sleep onset averaged over four test sessions at two-hour intervals. Modafinil improved average sleep latency from 5.07 to 5.35 for placebo to 8.18 to 8.28 for the 200 mg dose. For CGI-C, 58% to 64% of patients improved compared to 37% to 38% for placebo. There are currently no comparative trials between modafinil and current agents such as amphetamine or methylphenidate, and, therefore, comparative efficacy cannot be assessed. A survey of several agents used to treat narcolepsy suggests that modafinil may be less effective than dextroamphetamine or methylphenidate based on MWT.4

The wholesale cost of modafinil is about $7 per day for a 200 mg dose.

Clinical Implications

Narcolepsy is a neurologic disorder of unknown cause characterized by excessive somnolence, cataplexy, sleep paralysis, disrupted nocturnal sleep, and hypnagogic hallucinations.5 It affects 2-10 individuals per 10,000 and has a gradual onset between the ages of 15 and 35. Sleep paralysis is a paralysis of voluntary muscles that occurs at the entry into or emergence from sleep.6 Hypnagogic hallucinations are visual hallucinations with auditory and tactile components that occur during onset and emergence from sleep.

Cataplexy is a sudden loss of muscle tone (often dropping of the jaw) triggered by strong emotions such as laughter.6 The symptoms of this condition have serious personal, social, and economic implications as the ability of the individual to function in normal daily activity can be significantly compromised. Excessive daytime sleepiness is generally the most prominent symptom of narcolepsy. Current pharmacologic treatment includes dextroamphetamine, methylphenidate, and pemoline. These drugs have potential for the development of tolerance and unwanted side effects. Modafinil offers an alternative with milder side effects and may have a lower abuse potential. Long-term safety and efficacy remains to be established. As with other stimulants, it does not affect cataplexy, which is generally managed with tricyclic antidepressants.5,6 Modafinil is only FDA-approved for use in narcolepsy. Efficacy and safety in improving vigilance in healthy sleep- derived individuals has not been established. Results from a trial of modafinil in sleep apnea patients are expected early next year.

References

1. Provigil Product Information. Cephalon, Inc. December 1998.

2. US Modafinil in Narcolepsy Multicenter Study Group. Ann Neurol 1998;43(1):88-97.

3. Broughton RJ, et al. Neurology 1997;49(2):441-451.

4. Mitler MM, et al. Sleep 1991;14(3):218-220.

5. Adams RD, Maurice V, Ropper AH. Sleep and its Abnormalities. In: Principles of Neurology. 6th ed. McGraw-Hill; 1997:380-402.

6. Fry JM. Sleep Disorders. In: Merritt’s Textbook of Neurology. 9th ed. William & Wilkens; 1995:875-881.