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Because of varied problems with currently available stimulants--ineffectiveness, side-effects, tolerance, risk of drug abuse--the authors consider there is need for new stimulant medication to counteract excessive daytime sleepiness (EDS). Modafinil, which may act by increasing tonic (sustained) activity of central alpha-adrenergic receptors(those which recognize and respond to norepinephrine or epinephrine as a transmitter), may represent an improvement over amphetamines and methylphenidatein that its actions don't seem to involve another transmitter, dopamine, its peripheral sympathomimetic effects (like sweating and increased heart rate and blood pressure) are minimal, and its subjective effects don't include the kind of euphoria which is typical of amphetamine.
Although not yet available in the U>S>, in other countries more than 1,000 patients have been exposed to modafinil, some of whom have taken it for over 7 years.
This study was designed to generate well-controlled data on the short-term efficacy of 200 and 400 mg/day doses of modafinil in the treatment of EDS associated with narcolepsy. It was supported by a grant from Draxis Health of Mississauga, Ontario, presumably the Canadian manufacturer of the drug.
Patients had moderate to severe EDS and satisfied International Classification of Sleep Disorders diagnostic criteria for narcolepsy. All had at least one Multiple Sleep Latency Test (MSLT) except for a few who had definite cataplexy to confirm the diagnosis. Patients were excluded in cases of chronic amphetamine treatment for the past two months, EDS related to sleep apnea or periodic limb movement disorder, or alcohol; clinical depression and variouis other psychiatric and medical diseases and treatments that might contribute to EDS. Nine centers in Canada enrolled a total of 75 subjects.
All subjects underwent initial polysomnography. Prior stimulants were continued up to the first day of the study, when study medications were substituted: either placebo, modafinil 200 mg, or modafinil 400 mg, administered in identical-appearing capsules in twice-daily doses (morning and noon). Each patient spent two weeks on each treatment, with the patients randomized among the six possible sequences of treatments. Outcome measures were respresented by the Maintenance of Wakefulness Test (MWT), preceded by overnight polysomnography at the end of each treatment period, and the mean number of sleep episodes and periods of severe sleepiness reported in patient diaries. Subjects also completed the Epworth Sleepiness Scale (ESS). Also, every two hours between MWT naps a 10-minute fourpchoice reaction time test (FCRTT) was given to measure daytime performance. At the end of each two-week treatment period both patient and doctor compared the results of that treatment with the patient's condition prior to the study on a six-level scale from marked effect to much worse. At the end of the six weeks both patient and doctor ranked the three treatment periods in order of preference and compare them with any prior treatment experience.
To measure the effect of treatment on mood states, the Profile of Mood States self-completed questionnaire was administered for the second week of each treatment period, as well as before the morning dose and three hours after the morning dose administered in the laboratory during the day of the MWT.
Of the 75 subjects enrolled, 71 completed the three weeks. They were mostly middle-aged (ave=43 years SD=16), Caucasian (92%), and female (63%). Diagnoses of narcolepsy were made an average of 16 years (SD=13) after the onset of EDS. Their mean MSLT latencies were short at 3.5 minutes (SD=2.5), with frequent sleep onset REM periods to further confirm the diagnosis. Treatment with anticataleptic medications like protriptyline was continued in 28 patients (37%).
On the MWT, both doses of modafinil increased the sleep latency, compared to placebo, by 40% (200 mg) and 54% (400 mg). More MWTs ended without any sleep at all on modafinil than on placebo (19% and 23% vs. 9% on placebo). Modafinil reduced self-reported sleep episodes by 24% and severe sleepiness by 26%, without difference between the two doses. On the ESS, both doses of modafinil reduced the sleepiness score without difference between doses; on this scale, the items must sensitive to change were those involving falling asleep reading and watching TV. The FCRTT showed little evidence of improved performance on reaction time.
The preferred treatment interval for 84% of patients was one of the modafinil periods, more (50%) preferring the higher than the lower (34%) dose and only 16% preferring the placebo. Of 29 patients who had been on methylphenidate prior to the study, 23 had a marked preference for modafinil.
The POMS used to measure the second week of each treatment period showed little differences between groups; the immediate effects of modafinil on mood did not seem to differ from placebo. No significant drug effects were detected on blood pressure or heart rate, and no serious adverse effects occured although three patients dropped out due to "side effects", two on placebo with rash and palpitations, and one on high-dose modafinil with nausea, headache, and anxiety. Complaints of side-effects were more frequent with high-dose modafinil (44%) than with low-dose modafinil (33%) or placebo (23%). High-dose modafinil appeared to cause more nausea and nervousness than the other treatments.
The authors concluded that modafinil had a therapeutic effect on EDS in narcolepsy at both doses, though with evidence of stronger effects at the higher dose. The drug did not appear to have any serious side-effects or any conspicuous effects on mood. Nor did it appear to alter nocturnal sleep as measured by the PSG. In these respects it seemed to have advantages over other stimulants now used to treated EDS in narcolepsy. Likewise, some of the other adverse effects attributed to amphetamines--such as vasculitis--would not show up in a (relatively) small sample of subjects studied for a brief period of time on the drug. What appears to be needed are head-to-head comparisons of modafinil with at least a couple of alternative stimulants in a parallel-group design where precuations are taken to avoid accepting patients who have had time to grow tolerant to any drug they might receive during the study. Furthermore, such a study should continue for a matter of months, not weeks, at the minimum. More formal testing of drugs for abuse potential is available and should be conducted with modafinil in comparison with other stimulants.The frequent coadministration of anticataleptic drugs in sleep apneics demands the study of the several varieties
of anticataleptic drugs in current use for possible interactions with modafinil. It is, for example, well known that methylphenidate is capable of drastically raising blood levels of the tricyclics with greatly augmented side-effects, but this was discovered only accidentally after many years of use for both types of drug.
Almost every new sleeping medication and antianxiety medication that comes on the market claims freedom from the need for concern over dependency, abuse, and withdrawal effects, but many turn out in retrospect to have about as much risk of these as any other. If modafinil does prove to be a stimulant without such risks, it would be a great boon to the entire field of sleep medicine, since EDS is not limited to narcolepsy and often persists while adjustments are made in treatment for sleep apnea or PLMS, and even thereafter. However, the stimulants are used with such sparing concern as highly controlled substances, that few patients other than those with well-proven narcolepsy will have access to these drugs for symptomatic relief of their persistent somnolence. A new stimulant truly free of such risks could enjoy much more liberal use in a much wider range of sleep disorders where somnolence may present an ongoing problem, even with the best of specific treatment.
Regular viewers of this website may recall an article previously reviewed (see Article #14) on the use of modafinil for EDS in sleep apneics. That was a small, preliminary study, and I mentioned the probability that the drug had received much more thorough research for EDS in narcolepsy. This article represents one such piece of well-controlled research. It is designed in a fairly standard way for such short-term trials, and seems to clearly demonstrate a therapeutic effect for modafinil on EDS in a substantial number of subjects, without indication of drastic side-effects. Apparently it has somewhat different mechanisms of action from drugs like amphetamine and methylphenidate, which would encourage one to hope for differences in clinical effect that might be used to advantage with some patients.
However, before we jump to conclusions about the superior effects of this new drug, we should observe several points of caution. First of all, narcolepsy is a chronic disease while this was a short-term treatment trial--a point of immediate incongruence between the way the drug is studied and the way it would be used. This is all the more important since other stimulants have shown an unfortunate tendency to develop tolerance with prolonged use and work less well or require higher doses with time. This study offers no evidence bearing on this aspect of modafinil. Patients seemed to prefer modafinil to other drugs they had tried, particularly methylphenidate, but may well have been on that drug long enough to develop tolerance and lessened response, whereas modafinil by virtue of representing a treatment "new" to them would have maximal impact. The authors seem to use the lack of change on the POMS scale as an indicator of low abuse potential but it is not quite the same as a test for potential addictiveness. It might be relevant to ask whether still higher doses of modafinil could yield a "high." In any case, abuse could really only be ascertained with longer-term treatment and less strict controls over drug supply.
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