Treatment with armodafinil, 150 mg, significantly reduced sleep propensity and subjective ratings of sleepiness and improved aspects of attention and memory in patients with SWD during usual night shift hours. These differences were associated with significantly greater improvement in the severity of patients' overall clinical condition compared with those who received placebo. Armodafinil increased nighttime mean sleep latency to greater than 5 minutes, although a proportion of individuals remained sleepy; patients who fall asleep in 5 minutes or less are often considered severely sleepy.26
This improvement was demonstrated at the first laboratory night shift and was sustained throughout the 12-week study. The findings confirm our hypothesis that armodafinil would significantly increase mean sleep latency and improve the overall clinical condition in patients with excessive sleepiness associated with SWD.
In a previous study in a similar population, modafinil, 200 mg, significantly improved overall mean nighttime sleep latency as measured by the MSLT by a mean of 1.7 minutes, with statistically significant increases in sleep latency vs placebo at the 2 and 4 am
In the current study, armodafinil, 150 mg, significantly improved the overall mean nighttime sleep latency as measured by
the MSLT by a mean of 3.1 minutes at the final visit, with statistically significant increases in sleep latency at all 5 MSLT sessions from midnight to 8 am
. A direct comparison study is necessary to compare the efficacy and safety of these agents.
The MSLT has also been used to assess sleepiness in other disorders for which excessive sleepiness is a cardinal symptom—narcolepsy and obstructive sleep apnea (OSA). The improvement in the mean sleep latency for patients with narcolepsy who received modafinil, 200 mg/d, for 9 weeks in a placebo-controlled clinical study was approximately 1.8 minutes vs baseline.27
A meta-analysis revealed that the summary estimate of improvement in mean sleep latency for patients with OSA who were successfully treated with nasal continuous positive airway pressure (nCPAP) was 0.74 minutes.28
Both modafinil and nCPAP are recognized as standard treatments for individuals with excessive sleepiness associated with narcolepsy29
respectively, and the effects of these interventions on mean sleep latency have been shown to be associated with significantly improved health-related quality of life.31,32
Moreover, nCPAP treatment significantly reduces the elevated risk of motor vehicle crashes in patients with nontreated OSA.33,34
These findings suggest that an improvement in objective sleep latency comparable with that shown in the current study is sufficient to ameliorate the burden of illness and may be considered clinically relevant; our conclusion is similar to that reached in the meta-analysis mentioned herein, which showed a less than 1-minute mean improvement in objective sleep latency from nCPAP therapy in patients with OSA.28
Considering the nonlinear relationship between MSLT scores and sleepiness, a given numerical improvement in mean sleep latency at the low end of the scale is more clinically relevant than the same numerical improvement at the high end of the scale.35
The proportion of patients in the placebo group who were rated by the investigator as at least minimally improved on the CGI-C, the other coprimary outcome measure, was higher than what was anticipated and observed in a previous study16
of modafinil in patients with excessive sleepiness associated with SWD, for reasons that are not understood.
Excessive sleepiness impairs performance on various tasks, including those involving psychomotor performance or cognitive functions such as attention and memory.36-41
In the current study, attention was comprehensively enhanced as assessed by the CDR system with administration of armodafinil: the ability to both focus and sustain attention was improved compared with placebo, as shown by improvements in both speed and accuracy measures from an attention task (simple reaction time). Furthermore, armodafinil significantly improved long-term memory (quality of episodic secondary memory) and speed of memory compared with placebo, with significant improvements in the accuracy of delayed word recall. This improvement in accuracy was accompanied by an improvement in speed.
In the armodafinil group, reductions in patients' subjective ratings of sleepiness throughout the laboratory night shift were consistent with their ratings during actual work shifts and during the commute home. Furthermore, treatment with armodafinil was associated with significant reductions in reports of intended and unintended sleep episodes and mistakes, near misses, or accidents during the night shift. A similar magnitude of improvement was demonstrated for the commute home, although this effect was not statistically significant compared with placebo. Long-term, prospective studies of the impact of armodafinil on work performance and safety in patients with SWD are necessary to confirm the effects observed in the current 3-month trial.
Before treatment, our patients with SWD were severely sleepy, as shown by mean nocturnal sleep latencies of approximately 2 minutes, which are comparable to the latencies observed in patients with narcolepsy during the daytime.27
Patients with reports of excessive sleepiness associated with SWD are at substantially greater risk of impaired physical and mental well-being and performance.4
These risks constitute a public health concern. Untreated OSA and narcolepsy and working more than 24 consecutive hours42
can increase the risk of motor vehicle crashes.43,44
Patients diagnosed as having OSA are at a 2- to 7-fold greater risk of motor vehicle crashes,33
a risk that can be mitigated with appropriate treatment.33,34,45,46
Data from the health care field, which represented the largest segment of patients in the current study and is the largest and fastest growing industry in the United States, show that extended work shifts lasting more than 24 consecutive hours are also associated with increased risk of attentional failures, degraded performance, and increased risk of occupational accidents and serious fatigue-related medical errors and adverse events, resulting in patient injury and even death.42,47-50
Although the shift durations in these studies differ from those in the current study, SWD can increase the risk of attentional failures and degrade employee performance. To mitigate these risks, health care employers should implement fatigue management programs that include screening programs for the diagnosis and treatment of employees with SWD and other disorders of sleep and wakefulness.
Armodafinil was well tolerated and did not adversely affect scheduled daytime sleep. No clinically important effects on laboratory values, vital signs, polysomnograms, or electrocardiograms were seen. The current study did not find a statistically significant difference for armodafinil vs placebo in mean vital signs; increases in heart rate and blood pressure have been reported in other randomized, double-blind studies of the medication, although not consistently.51,52
Our study has several considerations that may limit the interpretation of data. Most patients enrolled were permanent night shift workers. This may limit the generalizability of these results to individuals working alternative shift schedules. This study was performed in SWD patients with both excessive sleepiness and insomnia, who may represent a more severely affected group; therefore, additional studies may be necessary to quantify the effects in a patient population with less severe SWD. The study did not include patients with SWD associated with starting work in the early morning. Although the prevalence of SWD is unknown in this population, approximately 3 times as many individuals work shifts that start in the early morning than night shifts. Further studies are necessary to determine whether these results are generalizable to those who start work in the early morning.
Although the effects of armodafinil were statistically significant and clinically relevant, a proportion of patients remained sleepy on objective assessment at the end of treatment. This finding suggests that armodafinil, 150 mg, is not equally effective in all patients and highlights the importance of ensuring that use of pharmacotherapy to enhance wakefulness is part of a comprehensive program that includes diagnostic screening for sleep disorders, education, and behavioral treatment interventions designed to optimize sleep and wakefulness. Recommended for industries such as the health care field, a comprehensive approach for SWD should address sleep and wake hygiene, strategic napping, appropriate time off between work periods, diet, exercise, appropriately timed light exposure to facilitate circadian adaptation, and work hour limits. Diagnosis and treatment of comorbid sleep disorders, such as OSA, narcolepsy, and restless legs syndrome, are important components of any comprehensive program for SWD.