Correspondence Johns Hopkins University, School of Medicine, 4940 Eastern Avenue, Box 151, Baltimore, MD 21224, USA

Email neubauer@jhmi.edu

Original article

Czeisler CA et al. (2005) Modafinil for excessive sleepiness associated with shift-work sleep disorder. N Engl J Med 353: 476–486   PubMed

Synopsis

Background

Shift-work sleep disorder affects approximately 5–10% of night-shift workers, and involves excessive sleepiness during night shifts and insomnia when trying to sleep during the daytime. Modafinil is an effective treatment for narcolepsy and excessive sleepiness caused by obstructive sleep apnea, but its efficacy for the treatment of shift-work sleep disorder is not known.

Objective

To evaluate the efficacy and safety of modafinil as a treatment for excessive sleepiness in patients with shift-work sleep disorder.

Design and intervention

In this double-blind, multicenter trial, 204 patients aged 18–60 years diagnosed with shift-work sleep disorder were randomly assigned and treated with modafinil 200 mg (n = 96) or placebo (n = 108) taken 30–60 min before the start of each night shift for 3 months. Monthly overnight patient evaluations were carried out after three or more consecutive night shifts—the Multiple Sleep Latency Test was used in combination with polysomnography to measure SLEEP LATENCY at 2-h intervals commencing at 2 am, and alertness was assessed using a 20-min Psychomotor Vigilance Test carried out every 2 h commencing at 1 am. The CLINICAL GLOBAL IMPRESSION OF CHANGE TEST was used to assess changes in the severity of night-shift sleepiness. Pre-treatment baseline values for patients were determined using the same testing methods. Safety monitoring was carried out throughout the study; this included clinical laboratory testing.

Outcome measures

Primary outcomes were the Clinical Global Impression of Change rating at the final study visit, and the change from baseline to the final visit in overall mean sleep latency. A secondary outcome was performance on the Psychomotor Vigilance Test.

Results

At the final visit, of the patients included in the efficacy analysis, 66/89 patients (74%) in the treatment group and 37/104 patients (36%) in the placebo group were rated as minimally, much, or very much improved on the Clinical Global Impression of Change test (P <0.001). The overall mean sleep latency for patients in the modafinil group was 2.1 min at baseline, increasing to 3.8 min at the final visit (P <0.001), and for patients receiving placebo, it was 2.04 min at baseline and 2.37 min at the final visit (P = 0.24). Sleep latency was significantly higher in the treatment arm than in the placebo group (P = 0.002). In the modafinil group, the median number of attention lapses during night-time testing was 12.50 at baseline, and 10.25 at the final visit (P = 0.012), and in the placebo group it was 16.13 at baseline and 23.75 at the final visit (P = 0.008). There was a significant difference in the degree of change in attention lapses from baseline to the final visit between the two groups (P <0.001). No serious adverse events were recorded for patients receiving modafinil.

Conclusion

Treatment with modafinil 200 mg is safe, and results in a small but significant reduction in sleepiness associated with shift-work sleep disorder.

Commentary

Czeisler and colleagues have focused welcome attention on the serious effects shift workers might experience owing to diminished alertness and vigilance when working a night shift and driving home the following morning. For many people who work through the night, excessive sleepiness during the shift and subsequent morning is predictable because of their inability to achieve sufficient sleep during off-work hours, and from the influence of the endogenous circadian system, which promotes night-time sleepiness.¹ Most people experience some difficulty with rotating shifts or permanent night-work schedules, but some appear to experience greater impairment than others.^{2, 3} Overall, shift-work-associated impairment remains a significant public health problem because of the risk of mistakes and accidents, and possible long-term metabolic sequelae.⁴

This 3-month, placebo-controlled study asks whether modafinil (200 mg) given before the night shift results in less sleepiness and improved psychomotor performance in a population of shift workers complaining of problematic sleepiness while working at night. The data showed a statistically significant improvement in sleepiness and vigilance. The clinical significance is limited, however: the modafinil-treated subjects still experienced worrisome levels of sleepiness and psychomotor impairment. Ironically, the modafinil-treated subjects were still sufficiently sleepy to meet the entrance criteria to participate in the study. Although the treated subjects did report fewer accidents and near-accidents on the morning drive home, the rates were still high. Perhaps this is not surprising, as the sleepiness, as measured by the Multiple Sleep Latency Test, was distinguishable from placebo at the 2 am and 4 am tests, but not at the 6 am and 8 am nap opportunities.

The authors conclude that the residual sleepiness and associated impairment in the treated subjects highlight the need for continued research to develop more effective interventions for shift workers. Nevertheless, the relatively large scale of this project, the confirmation of baseline sleepiness and psychomotor impairment, and the evidence of some improvement in the modafinil group, together represent a valuable contribution to investigation of this serious public health problem.

Several important questions are raised by this research. What physiological vulnerabilities contribute to the greater sleepiness and impairment in the subjects labeled with shift-work sleep disorder, and would these symptoms be evident in any conditions associated with sleep loss or significant changes in the timing of sleep and waking? What is the boundary between a normal and a pathological reaction to working during a night shift? What specific neural mechanisms mediating alertness might represent pharmacological targets for safe and effective medications? Should medications be prescribed to individuals for lifestyle or work schedule indications that may not represent medical disorders?

No medication, including modafinil, has demonstrated efficacy in promoting a normal degree of night-shift alertness and vigilance among shift workers complaining of baseline sleepiness while working at night. Currently, it would be inadvisable to give workers a false sense of security that they can function at work with full alertness and drive home safely after a pre-shift medication dose. Although this study showed that the modafinil-treated subjects and controls could be differentiated with regard to some outcomes, the treated subjects still demonstrated a worrisome degree of sleepiness and attention impairment.

Acknowledgments

The synopsis was written by Christine Kyme, Assistant Editor, Nature Clinical Practice.

References

1. Akerstedt T (1995) Work hours, sleepiness and the underlying mechanisms. J Sleep Res 4: 15–22 | PubMed | ISI |
2. American Academy of Sleep Medicine (2005) International Classification of Sleep Disorders: Diagnostic and Coding Manual, edn 2. Westchester, Illinois: American Academy of Sleep Medicine
3. Drake CL et al. (2004) Shift work sleep disorder: prevalence and consequences beyond that of symptomatic day workers. Sleep 27: 1453–1462 | PubMed | ISI |
4. Akerstedt T et al. (2005) Impaired alertness and performance driving home from the night shift: a driving simulator study. J Sleep Res 14: 17–20 | Article | PubMed | ISI |

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Subject areas under which this article appears: Sleep