Modafinil is a unique and relatively benign CNS stimulant that can effectively promote wakefulness in patients with excessive daytime somnolence

 Modafinil has been attracting attention recently in the sleep-medicine field because its properties include the ability to promote wakefulness. This makes modafinil a potentially important tool for treating the excessive diurnal somnolence (EDS) that can accompany sleep disorders such as narcolepsy, sleep apnea, idiopathic hypersomnolence, and other medical conditions characterized by poor sleep quality and/or quantity.

In Europe, modafinil has been used since at least 1988 to treat narcolepsy and idiopathic hypersomnolence. Following two large, multicenter trials,1,2 modafinil was approved by the US Food and Drug Administration in December 1998.

The mode of action of modafinil is still a bit of a mystery. Although modafinil promotes wakefulness, it is not chemically or pharmacologically related to conventional, promoting-wakefulness stimulants of the central nervous system (CNS), such as amphetamine or methylphenidate. Modafinil has none of the dopaminergic activity associated with stimulants to which patients are tolerance prone, and it is listed as a schedule-IV substance having a relatively low potential for abuse. It is very site specific, acting in different brain regions (the hypothalamus and the subcortical areas involved in the regulation of waking and sleep) than other CNS stimulants. Its wakefulness-promoting action requires a functioning a1-adrenergic system.1

Modafinil has four major clinical advantages over other wakefulness-promoting drugs.

  • None of the serious adverse CNS effects associated with methylphenidate and amphetamine (tachycardia, hypertension, dizziness, insomnia, and psychotic episodes) are seen. The most common side effects of modafinil are headache (13%), nervousness (8%), and nausea (5%).3
  • No known serious drug interactions occur, and there are no required dietary restrictions.
  • No known risk exists of dependence, withdrawal symptoms, or abuse at therapeutic doses.3,4
  • No rebound sleepiness has been observed.

EDS in Narcolepsy
Narcolepsy affects 0.02% to 0.05% of the US population and 5% of sleep-center patients.5,6 The four cardinal symptoms of narcolepsy are EDS, cataplexy, sleep paralysis, and hypnagogic hallucinations. All four of these symptoms are the clinical expressions of erosion of the boundaries between the states of waking, rapid–eye-movement (REM) sleep, and non-REM sleep. The cause of narcolepsy is not fully known. Patients with narcolepsy have a higher prevalence of a specific gene type than the general population; however, the presence of this subtype is not necessary, or specific, for the diagnosis of narcolepsy. It is now believed by some investigators that narcolepsy is caused by an autoimmune disorder or triggered by an unknown environmental exposure or event. An exciting recent discovery is identification of hypocretin/orexin, which may be the neurotransmitter primarily implicated as the cause of narcolepsy. Animal models suggest that the absence of hypocretin results in narcolepsy. A preliminary study7 in humans has confirmed the animal-study findings.

In practical terms, EDS is probably the toughest problem for many narcoleptics. Unmanageable somnolence causes academic, employment, financial, and psychosocial difficulties, and can have devastating effects on the quality of life. Effective, safe, and tolerable treatment of EDS is a high priority in narcolepsy.

Thus, it is no surprise that modafinil, despite its relatively recent development, is now a first-line treatment for EDS in the most recent (2000) update of the American Academy of Sleep Medicine’s narcolepsy practice parameters.5

The efficacy of modafinil has been studied in two large US trials1,2 (which were placebo controlled, double blinded, and randomized and employed parallel groups). A total of 554 patients in 39 sleep centers received either 200 mg or 400 mg of modafinil or placebo for 9 weeks. Modafinil improved wakefulness by 50% to 75%, as measured by three standardized, validated sleepiness tests: the Multiple Sleep-Latency Test (MSLT), which objectively measures the time required to fall asleep; the Maintenance of Wakefulness Test (MWT), which objectively measures ability to remain awake; and the Epworth Sleepiness Scale (ESS), a self-rating measure of sleepiness.

A 40-week extension of these two studies assessed the long-term efficacy of modafinil.3 About 75% of the 341 subjects had moderate-to-severe narcolepsy, and about half of them reported near-normal ESS scores after 40 weeks of modafinil therapy. The subjects’ disease severity was more than 80% improved, as measured by the Clinical Global Impression of Change, a standard illness-assessment tool used by clinicians. No signs of drug tolerance were observed.

A separate study analyzed quality-of-life data during this long-term trial. The investigators used the Medical Outcomes Study (Short Form 36), a validated, self-administered health survey, to which they added several narcolepsy-specific scales.8 All quality-of-life scores improved and were sustained through the 40-month period. Among the patients taking 400 mg of modafinil, the most dramatic increases from a baseline of zero are shown in the table.

Comparison (placebo vs 400 mg modafinil) in health-related quality of life
changes from baseline to 40-week endpoint. Adjusted for baseline scores.
Adapted from Sleep.8

Idiopathic Hypersomnolence
Idiopathic hypersomnolence is a disabling condition (or conditions) characterized by severe EDS in the absence of narcolepsy or other sleep disorders. Nocturnal sleep is often long and undisturbed, and morning awakening is frequently accompanied by sleep drunkenness. In these patients (who can be poorly responsive to treatment), the dosage and effectiveness of amphetamine and methylphenidate may be limited by their adverse cardiovascular effects. Modafinil has been used successfully to treat this disorder.9 One sleep-research group10 notes that, in hypersomnolent subjects who have been taking conventional CNS stimulants, gradual withdrawal is important. Otherwise, the subject may have trouble accepting modafinil. In contrast, subjects who have not undergone prior drug treatment generally accept modafinil rather readily.10

EDS in Sleep Apnea
EDS is a standard symptom of sleep-disordered breathing. Nasal continuous positive airway pressure (CPAP), the treatment of choice for obstructive sleep apnea, can effectively eliminate EDS, along with the apnea episodes and their cardiovascular consequences. In some cases, however, significant EDS remains, for reasons still not understood. Conventional CNS stimulants are not ideal for treating EDS in sleep apnea because of their interference with sleep and the danger of cardiovascular events in this at-risk population.

Two recent studies11,12 have looked at the effectiveness of modafinil in treating residual EDS in sleep apnea. Kingshott et al11 performed a randomized, double-blind, placebo-controlled crossover study of 44 CPAP patients who took 400 mg of modafinil or a placebo. They found a significant improvement in alertness, as measured by the MWT, but no significant effect on sleepiness, as measured by the MSLT or the ESS, and no effect on cognitive function or quality of life. These modest results may reflect the small sample size or the relative abilities of the MWT, MSLT, and ESS to measure sleepiness. The investigators wondered whether the benefits of modafinil were worth its side effects (reported in 74% of their subjects).

A study of 157 CPAP patients by Pack et al12 found that the ESS score returned to normal (less than 10) in more than half of CPAP patients taking modafinil, compared with one quarter of those taking a placebo. Patients reported subjective improvements in sleepiness during the first week, and these were maintained throughout the study. Pack’s group concluded that modafinil appears to be useful for compliant CPAP users who display residual EDS.

They also raised two cautionary flags with respect to modafinil use among CPAP patients. Continued compliance with CPAP should be monitored after prescribing modafinil, lest patients conclude that improved alertness means that they are cured of the primary disorder, sleep apnea. In fact, the Kingshott group reported precisely this problem; despite emphasis on compliance, mean CPAP use decreased 12 minutes among patients who were taking modafinil.11 Modafinil should never be prescribed as primary treatment for sleep apnea12 because, of course, it has no effect on apnea, oxygen saturation, arousal, or cardiovascular sequelae.

Conventional CNS stimulants (amphetamine and methylphenidate) used to treat attention deficit hyperactivity disorder (ADHD) have unwanted side effects, in addition to further disturbing sleep that is already suboptimal. Modafinil has shown promise in several small, preliminary studies13,14 of adults and of children 5 to 15 years old who have ADHD. For children, modafinil has the important advantage of being a once-daily medication with a long duration.

A recent two-center study15 concluded that modafinil was safe and effective in treating debilitating fatigue in multiple sclerosis. The 9-week, single-blind, placebo-controlled study of 72 patients found that 200 mg per day produced a significant improvement in self-rated fatigue and ESS scores.

As in narcolepsy, dopamine imbalance is implicated in Parkinson disease. Thus, several small group and case studies16,17 have begun assessing the effectiveness of modafinil in improving EDS in Parkinson disease. Preliminary results are promising: diminished sleepiness and no adverse effects upon motor activity.

The benign, wakefulness-promoting profile of modafinil suggests its utility in circumstances in which alertness and a clear head are crucial (for example, transportation, public-safety, and military activities). Aeronautical and defense research groups18-20 are comparing modafinil with amphetamines in terms of relative effects on mood, fatigue, cognitive performance, and recovery from sleep deprivation. In safety and effectiveness, modafinil seems preferable to amphetamines for counteracting sleep deprivation and maintaining alertness; however, a group testing modafinil in helicopter pilots noted that “additional studies aimed at reducing side effects (nausea, vertigo, and dizziness) are needed before it should be used in aviators.”20

Modafinil is a unique and relatively benign CNS stimulant that can effectively promote wakefulness in patients with EDS. 5 It causes fewer adverse effects than conventional CNS stimulants and carries a lower risk of tolerance.

Daniel Loube, MD, is associate director; Ralph Pascualy, MD, is director; Jennie Sy is clinical coordinator; and Sally Soest is medical writer, all at the Swedish Medical Center, Seattle.

1. US Modafinil in Narcolepsy Study Group. Randomized trial of modafinil as a treatment for the excessive daytime somnolence of narcolepsy. Neurology. 2000;54:1166-1174.
2. US Modafinil in Narcolepsy Study Group. Randomized trial of modafinil for the treatment of pathological somnolence in narcolepsy. Ann Neurol. 1998;43:88-97.
3. Mitler MM, Harsh J, Hirshkowitz M, et al. Long-term efficacy and safety of modafinil (Provigil) for the treatment of excessive daytime sleepiness associated with narcolepsy. Sleep Medicine. 2000;1:231-243.
4. Jasinski DR. An evaluation of the abuse potential of modafinil using methylphenidate as a reference. Journal of Psychopharmacology. 2000;14:53-60.
5. Standards of Practice Committee. Practice parameters for the treatment of narcolepsy: an update for 2000. Sleep. 2001;24:451-466.
6. Thorpy M. Current concepts in the etiology, diagnosis and treatment of narcolepsy. Sleep Medicine. 2001;2:5-17.
7. Nishino S, Ripley B, Overeem S, et al. Hypocretin (orexin) deficiency in human narcolepsy. Lancet. 2000;355:39-40.
8. Beusterien KM, Rogers AE, Walsleben JA, et al. Health-related quality of life effects of modafinil for treatment of narcolepsy. Sleep. 1999;22:757-765.
9. Bastuji H, Jouvet M. Successful treatment of idiopathic hypersomnia and narcolepsy with modafinil. Prog Neuropsychopharmacol Biol Psychiatry. 1988;12:695-700.
10. Guilleminault C, Aftab FA, Karadeniz D, et al. Problems associated with switch to modafinil—a novel alerting agent in narcolepsy. Eur J Neurol. 2000;7:381-384.
11. Kingshott RN, Vennelle M, Coleman EL, et al. Randomized, double-blind, placebo-controlled crossover trial of modafinil in the treatment of residual excessive daytime sleepiness in the sleep apnea/hypopnea syndrome. Am J Respir Crit Care Med. 2001;163:918-923.
12. Pack AI, Black JE, Schwartz JRL, Matheson JK. Modafinil as adjunct therapy for daytime sleepiness in obstructive sleep apnea. Am J Respir Crit Care Med. 2001;164:1675-1681.
13. Taylor FB, Russo J. Efficacy of modafinil compared to dextroamphetamine for the treatment of attention deficit hyperactivity disorder in adults. J Child Adolesc Psychopharmacol. 2000;10:311-320.
14. Rugino TA, Copley TC. Effects of modafinil in children with attention-deficit/hyperactivity disorder: an open-label study. J Am Acad Child Adolesc Psychiatry. 2001;40:230-235.
15. Rammohan KW, Rosenberg JH, Lynn DJ, et al. Efficacy and safety of modafinil (Provigil) for the treatment of fatigue in multiple sclerosis: a two-centre phase 2 study. J Neurol Neurosurg Psychiatry. 2002;72:179-183.
16. Happe S, Pirker W, Sauter C, et al. Successful treatment of excessive daytime sleepiness in Parkinson’s disease with modafinil. J Neurol. 2001;248:632-634.
17. Rabinstein A, Shulman LM, Weiner WJ. Modafinil for the treatment of excessive daytime sleepiness in Parkinson’s disease: a case report. Parkinsonism and Related Disorders. 2001;7:287-288.
18. Pigeau R, Naitoh P, Buguet A, et al. Modafinil, d-amphetamine and placebo during 64 hours of sustained mental work. I. Effects on mood, fatigue, cognitive performance and body temperature. J Sleep Res. 1995;4:212-228.
19. Buguet A, Montmayeur A, Pigeau R, Naitoh P. Modafinil, d-amphetamine and placebo during 64 hours of sustained mental work. II. Effects on two nights of recovery sleep. J Sleep Res. 1995;4:229-241.
20. Caldwell JA Jr, Caldwell JL, Smythe NK III, Hall KK. A double-blind, placebo-controlled investigation of the efficacy of modafinil for sustaining the alertness and performance of aviators: a helicopter simulator study. Psychopharmacology. 2000;150:272-282.