Modafinil for Narcolepsy
ABSTRACT & COMMENTARY
Synopsis: If its relatively low side effects continue, modafinil appears to be the first non-toxic drug that can improve the disturbing symptoms of narcolepsy.
Source: U.S. Modafinil in Narcolepsy Study Group. Ann Neurol 1998;43:88-97.
Narcolepsy affects approximately 100,000 persons in the United States, with a sizable fraction of the sufferers experiencing repeated, semi-disabling, excessive daytime sleepiness. A measurably fewer number suffer from cataplexy, fractioned nocturnal sleep, hypnagogic hallucinations, and sleep paralysis. The illness is usually inherited and associated with one of several HLA DRZ or DQB1 haplotype groups plus other factors. Haplotype specificity, however, does not guarantee expression of the disorder. Disabling daytime sleepiness provides narcolepsy's dominant dysfunction, for which amphetamines bring only modest improvement, often with considerable unwanted side effects. Investigators have suggested that the disease results from insufficient CNS dopamine release plus an increase in muscarinic acetylcholine receptors generating hypersensitivity to acetylcholine.
Against this therapeutically unfavorable backdrop, a new wake-provoking stimulus called modafinil, 2 ([diphenylmethyl] sulfinyl) acetamide has been introduced. Modafinil stimulates CNS targets known to respond to amphetamine and methylphenidate. Effects in animals indicate that modafinil increases wakefulness but induces little amphetamine-like excitation of motor function.
To test the value of modafinil, 283 persons aged 18-68 years were randomized into three cohorts: placebo (n = 92), 200 mg daily (n = 96), and 400 mg daily (n = 95). This report provides preliminary results, and a successive open-label trial is in progress. Participants graded the patient's post-therapy dozing response as: 1) never, 2) slight chance, 3) moderate, or 4) high. All categories were applied during times of relatively inactive behavior. Objective evaluations included Sleep Latency Testing (SLT) and Maintenance of Wakeful Test (MWT). Severity of disease was evaluated by a clinician's Clinical Global Impression (CGI). Nocturnal polysomnography was applied before each assessment. Mean age of the cohort was 42 years, and sex numbered 43 men and 51 women in each cohort. Mean length of disease amounted to 22 years; 95% had daytime sleep attacks, 88% had cataplexy, 71% had interrupted nighttime sleep, 69% hallucinated, and 64% experienced sleep paralysis. Results were appraised at three, six, and nine weeks following onset of the trial.
Self-reported sleepiness (ESS) events were similar at onset and, in the placebo group, at nine weeks. Otherwise, at week nine both modafinil cohorts showed less sleepiness than controls (P < 0.001), with the 400 mg group significantly better than the 200 mg group (P < 0.001). Sleep latency was similar between the two modafinil groups but was significantly better than controls (P < 0.001). Maintenance of wakefulness was better than control in both modafinil groups (P < 0.001) but not different between the two groups. Also, more subjects in the modafinil groups remained awake longer than in the control group. Blinded clinical assessment rated modafinil-taking patients as measurably improved compared to the controls.
Complications were relatively low: one of the 200 mg dose cohort withdrew, as did 11 (12%) of the 400 mg group. The only symptom significantly higher than placebo was headache.
A subsequent open-label trial continues beyond the above blind control studies. In that trial, clinical global impression showed 84% improvement by week two of taking modafinil with the number rising to 91% by week 40. Both times had significance at the P < 0.001 level. The authors indicate that "adverse experiences were mostly mild to moderate." In the open trial, however, 25% of patients withdrew because of side effects or lack of efficacy.
COMMENT BY FRED PLUM, MD
If its relatively low side effects continue, modafinil appears to be the first non-toxic drug that can improve the disturbing symptoms of narcolepsy. The drug clinically appears to reduce daytime sleepiness, and the result of latency tests supported that conclusion. The general clinical appraisal of the participating neurologists also concluded that wakefulness improved in the treated group. At this writing, the reporting participating neurologists estimate that overall efficacy of modafinil against narcolepsy amounts to about 55%, with Pemoline providing about an equal help but with amphetamine or methylphenidate each improving symptoms by about 80%. The latter level, however, produces a relatively high incidence of unwanted symptoms. As the authors conclude, "modafinil is a pharmacologically and clinically promising compound for treating pathological daytime somnolence." (Dr. Plum is Neurologist-in-Chief, New York Hospital-Cornell Medical Center.)
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