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Shift-Work Sleep Disorder — The Glass Is More Than Half Empty
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     As many as 20 percent of workers in industrialized nations are shift workers — in other words, people who work either at night or on rotating shifts.1 Shift-work sleep disorder, defined as a primary complaint of insomnia or excessive sleepiness temporally associated with a work period that occurs during the habitual sleep phase,2 has been diagnosed in as many as 10 percent of shift workers.3 Shift workers overall appear to be at increased risk for peptic ulcer disease, coronary heart disease, insulin resistance, and the metabolic syndrome,4,5 as well as for sleep deprivation, depression, sleepiness-related accidents, and curtailed family and social activities.3,4 People who receive the diagnosis of shift-work sleep disorder appear to have a higher morbidity rate than do those without such a diagnosis.3 A high proportion of shift workers are employed in the health care and transportation industries.

    Therefore, a large-scale, well-designed investigation of treatment for sleepiness related to shift work commands considerable attention. Such a study, by Czeisler and colleagues, who are members of the U.S. Modafinil in Shift Work Sleep Disorder Study Group, appears in this issue of the Journal.6 The investigators present a double-blind, placebo-controlled study involving 204 subjects with shift-work sleep disorder who were randomly assigned to either a three-month trial of the wakefulness-promoting drug modafinil at 200 mg daily or placebo; 153 subjects completed the study. Subjects received the study medication before each night shift. It is important to note that the study design allowed for the exclusion of other primary sleep disorders, such as obstructive sleep apnea. The major findings were that modafinil was associated with significant improvements in laboratory measurements of nighttime sleepiness and vigilance, as compared with placebo, and that there was an increased likelihood that subjects taking modafinil would have clinical improvement.

    However, enthusiasm for these results should be tempered by putting into perspective what the current research is specifically designed to assess and what it actually finds. It is, basically, a narrowly focused investigation that concerns itself with whether a specific wakefulness-promoting agent, modafinil, is able to improve nocturnal alertness and vigilance in objectively sleepy shift workers during laboratory testing. Modafinil, recently approved by the Food and Drug Administration for the treatment of excessive sleepiness associated with shift-work sleep disorder, probably enhances wakefulness by interactions of adrenergic and dopaminergic systems.7 At a 200-mg daily dose during the course of four consecutive simulated night shifts among non–shift-worker volunteers, the drug has attenuated sleepiness and neurobehavioral deficits occurring during the hours of the simulated night shifts.8

    However, promotion of wakefulness and vigilance, as well as inhibition of sleep, is subserved by multiple neuromodulator and neurotransmitter systems,7 and it is reasonable to postulate that other wakefulness-promoting agents would show similar efficacy in a comparison with placebo, modafinil, or both in shift workers. Improvements in performance and vigilance during the morning hours following more than 40 continuous hours of being awake among normal adults has been found to be similar for modafinil and 600 mg of caffeine,9 and low-dose caffeine has improved cognitive performance and the ability to remain awake when compared with placebo among healthy adults during extended enforced time awake and circadian desynchrony.10 In the current study, modafinil did not induce measurable effects on circadian rhythm. Taken together, neither these data nor any other published studies provide evidence to indicate that modafinil is uniquely suited to be used as an enhancer of wakefulness and vigilance in humans subjected to nighttime shift work.

    The current study was not designed to investigate the effects of modafinil among subjects who would be defined as having shift-work sleep disorder on the basis of symptoms2 3; rather, the investigators selected a small group of subjects with shift-work sleep disorder who had both objectively measured severe nighttime sleepiness and decreased daytime sleep efficiency. In a similar vein, by design, this study does not address many of the major morbidities associated with shift work, nor does it allow an understanding of the potential effects of wakefulness-promoting agents as part of a larger strategy for treating disorders related to shift work. Such a strategy could rationally include behavioral and pharmacologic treatment of the characteristic shortened diurnal sleep times among shift workers, healthy-lifestyle training, provision of breaks,10 a more fluid scheduling of shifts,11,12 shift-work naps, manipulation of circadian rhythms, and assessment for and treatment of concomitant sleep disorders that may be contributing to morbidity among some shift workers.13

    Furthermore, safety risks associated with shift-work sleep disorder have been shown to accrue over the increasing length of shifts, as well as length of time working these shifts, whereas such risks can decrease almost linearly over the course of a single night shift.14 These clinically significant aspects of night-shift work in relation to potential interactions with a wakefulness-promoting pharmacologic agent were not addressed by the current study design. It is simplistic to consider that a pill alone could sufficiently modify the effects of this disorder.

    How may the efficacy and safety data offered by this study be interpreted? Shift workers receiving modafinil improved from falling asleep within an average of 2.1 minutes during four nocturnal nap opportunities to falling asleep within an average of 3.8 minutes, whereas there was no statistically significant change among the placebo users. The subjects receiving modafinil also showed significant improvements during nighttime vigilance testing, including reduced attention lapses, as compared with their baseline scores. Subjects receiving placebo had worsened performance on this testing. However, limited reliability and validity data exist for sleepiness and vigilance testing in these circumstances, and similar concerns exist regarding the Clinical Global Impression of Change metric used for this investigation; it remains unclear to what extent this format is a valid, disease-specific scale for use in clinical trials among shift workers.15 Thus, there is no reliable way to know how the improvements found with modafinil during laboratory testing are potentially significant clinical improvements in health, safety, or productivity among shift workers. The results documented here with the modafinil regimen, however, suggest that these workers would still be considered greatly impaired regarding vigilance and wakefulness during the nights they would need to remain awake and alert, as is pointed out by the investigators. Furthermore, although modafinil was associated with self-reports of fewer accidents or near accidents than was placebo, these data were not clearly corroborated, and no productivity or safety data were collected on the job during the time the study was in progress.

    Regarding the safety of the drug itself, no adequately powered, randomized, controlled study has documented long-term efficacy or safety of this medication among shift workers, who may have substantial cardiovascular disease.8 It is of concern, however, that modafinil in this study was associated with increased insomnia, as compared with placebo, thus apparently worsening one of the defining criteria of shift-work sleep disorder even as it improved nighttime sleepiness and vigilance.

    What, then, can one conclude from the current study, in the context of other studies regarding health disorders associated with shift work? Reduction of sleepiness and improvement of vigilance are clearly a major therapeutic imperative for shift workers, but the investigators' own most robust conclusion from this study appears to be that "modafinil is of some value in the clinical management of sleepiness associated with shift-work sleep disorder."6 Modafinil has a reasonable safety profile to date, and it may well be that it will be shown to be an effective and safe adjunct to comprehensive treatment strategies for shift-work sleep disorder. But the current study does not adequately assess the clinical value of this particular drug in shift-work sleep disorder, nor does it justify writing more prescriptions for modafinil. Rather, it serves as a wake-up call for the design and implementation of further scientific studies to address in a cohesive manner the serious health and safety issues that surround us by virtue of our having become, to a large extent, a shift-working society.

    Source Information

    From the Columbia University College of Physicians and Surgeons, New York.

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