Original Article
Modafinil for Excessive Sleepiness Associated with Shift-Work Sleep Disorder
N Engl J Med 2005; 353:476-486August 4, 2005
- Abstract
Background
Patients with shift-work sleep disorder chronically have excessive sleepiness during night work and insomnia when attempting to sleep during the day. We evaluated the use of modafinil for treating sleepiness in patients with this disorder.
Methods
In a three-month, double-blind trial, we randomly assigned 209 patients with shift-work sleep disorder to receive either 200 mg of modafinil or placebo before the start of each shift. Assessments were performed with the use of the nighttime Multiple Sleep Latency Test, the Clinical Global Impression of Change, the Psychomotor Vigilance Test, diaries of patients, and daytime polysomnography. After randomization, we conducted monthly assessments.
Results
Treatment with modafinil, as compared with placebo, resulted in a modest improvement from baseline in mean (±SEM) nighttime sleep latency (the interval between the time a person attempts to fall asleep and the onset of sleep) (1.7±0.4 vs. 0.3±0.3 minutes, respectively; P=0.002), and more patients had improvement in their clinical symptoms (74 percent vs. 36 percent, respectively; P<0.001). Patients who were receiving modafinil also had a reduction in the frequency and duration of lapses of attention during nighttime testing of their performance on the Psychomotor Vigilance Test (change from baseline, a reduction in lapse frequency of 2.6 vs. an increase of 3.8, respectively; P<0.001), and proportionally fewer patients reported having had accidents or near accidents while commuting home (29 percent vs. 54 percent, respectively; P<0.001). Despite these benefits, patients treated with modafinil continued to have excessive sleepiness and impaired performance at night. Modafinil did not adversely affect daytime sleep as compared with placebo. Headache was the most common adverse event.
Conclusions
Treatment with 200 mg of modafinil reduced the extreme sleepiness that we observed in patients with shift-work sleep disorder and resulted in a small but significant improvement in performance as compared with placebo. However, the residual sleepiness that was observed in the treated patients underscores the need for the development of interventions that are even more effective.
Media in This Article
Figure 1
Enrollment and Status of Patients in the Study.Figure 2
Efficacy Measures Used to Assess the Effects of Modafinil versus Placebo in Patients with Shift-Work Sleep Disorder.Article Activity
- Article
Nearly 6 million Americans work at night on a permanent or rotating basis.1 Night-shift work disrupts both sleep and waking because of the misalignment of circadian regulation and sleep–wake behavior.2,3 In about 5 to 10 percent of night-shift workers, the sleep–wake disturbance is severe enough to warrant diagnosis as shift-work sleep disorder,4-6 which is characterized by a level of excessive sleepiness during night work and insomnia when attempting to sleep in the daytime that is judged to be clinically significant.4,5 Persons with shift-work sleep disorder miss family and social activities more frequently and have higher rates of ulcers, sleepiness-related accidents, absenteeism, and depression than do night-shift workers without the disorder6 — conditions long known to affect a subgroup of shift workers.7 We conducted a study to evaluate the efficacy and safety of 200 mg of modafinil in patients with excessive sleepiness associated with chronic shift-work sleep disorder. This agent has shown efficacy in the treatment of narcolepsy and the residual excessive sleepiness in patients with obstructive sleep apnea.8-11
Methods
Patients
Adults between the ages of 18 and 60 years were eligible if they worked each month at least five night shifts for 12 hours or less, with 6 hours or more worked between 10 p.m. and 8 a.m. and at least three shifts occurring consecutively. Patients were diagnosed with shift-work sleep disorder in accordance with criteria stipulated in the International Classification of Sleep Disorders.5 Our diagnostic criteria included a primary symptom of excessive sleepiness on the night shift and insomnia during opportunities for daytime sleep and the absence of other primary sleep disorders, other medical conditions, and medications that might cause sleepiness. Patients had to have reported chronic excessive sleepiness (≥3 months) during night shifts; a Clinical Global Impression of Severity12 rating of moderately ill or worse for sleepiness on work nights, including the commute home from work; an average latency to sleep onset of 6 minutes or less during 20-minute nap opportunities at 2-hour intervals during the night, as measured by the Multiple Sleep Latency Test13,14; and a sleep efficiency of 87.5 percent or less as determined by daytime polysomnography. Participants provided written informed consent.
Study Design and Conduct
The three-month randomized, double-blind, placebo-controlled study was conducted in the United States between December 2001 and September 2002. At each of 28 centers, an institutional review board approved the informed-consent statement and protocol. The study included a screening visit to assess eligibility; a baseline visit on the night after the patient had worked three or more consecutive night shifts in order to establish pretreatment levels of alertness and performance, the severity of sleepiness, and results of daytime polysomnography; and a randomization visit for the administration of the study drug. Thereafter, patients were evaluated monthly during an overnight laboratory shift after having worked for three or more consecutive nights.
Patients were randomly assigned (in a 1:1 ratio) to receive 200 mg of modafinil (Provigil, Cephalon), formulated as 100-mg tablets, or an identical-appearing placebo, taken 30 to 60 minutes before the start of each night shift. Assessment of treatment adherence was performed at visits after the initial baseline visit.
Measures of Efficacy
Sleep latency during laboratory night shifts was measured by polysomnography at two-hour intervals, starting at 2 a.m., with the use of the Multiple Sleep Latency Test (see the Supplementary Appendix, available with the full text of this article at www.nejm.org).13,14 To assess alertness with the use of a performance measure, a 20-minute Psychomotor Vigilance Test15 was administered every two hours, starting at 1 a.m. The level of sleepiness as reported by patients was assessed hourly using the Karolinska Sleepiness Scale,16 which ranges from 1 (very alert) to 9 (very sleepy). The investigator-rated Clinical Global Impression of Change,12 the scoring of which ranges from 1 (very much improved) to 7 (very much worse), was used to assess changes from baseline in the severity of sleepiness during night shifts, including the commute to and from work. Patients also completed electronic diaries containing questions about sleepiness, sleep, and caffeine use during the night shift and the commute home.
There were two prespecified primary efficacy variables. The first was the rating on the Clinical Global Impression of Change test for sleepiness during the night shift, including the commute to and from work, at the final visit. This test assessed the extent to which treatment effects could be recognized by patients and physicians. The second prespecified primary efficacy variable was the change between baseline and the final visit (i.e., at the third month or at withdrawal from the study) in overall mean sleep latency on the basis of results of the nighttime Multiple Sleep Latency Test. This test has been validated as a measure of sleepiness during the day but not at night, so questions remain regarding which results on this test indicate pathological sleepiness during the night and what level of improvement at night is clinically meaningful. Therefore, as recommended,17 one of our secondary outcome measures — the frequency and duration of lapses of attention during performance on the Psychomotor Vigilance Test15 — served as a validated and objective measure of alertness at night.
Safety Assessments
Adverse events were monitored throughout the study. Blood pressure and heart rate were monitored, and clinical laboratory tests (including chemical and hematologic studies) were conducted at each visit. Physical examination and electrocardiography were performed at the screening visit and the final visit.
Other Assessments
Polysomnography was conducted for eight hours, starting at 10 a.m. after baseline and after final laboratory night shifts. Melatonin concentrations were measured from saliva samples.18
Statistical Analysis
A total of 204 patients were selected for enrollment in the study (see the Supplementary Appendix for calculations regarding the sample size). Randomization was performed with the use of a central randomization process and stratified by center with the use of permuted blocks of two. On the basis of the sample that was available for efficacy analysis, there was at least 80 percent power (with the use of post hoc power calculations) for the statistical inference on both prespecified primary end points (assuming an alpha level of 0.05).
Comparisons of continuous demographic variables between groups were conducted with the use of analysis of variance, with treatment as a factor. Discrete categorical demographic variables were compared with the use of the chi-square test or Fisher's exact test. Included in efficacy analyses were patients who had been randomly assigned to treatment and received at least one dose of study drug and who had had a baseline assessment and at least one assessment after baseline on either the Multiple Sleep Latency Test or the Clinical Global Impression of Change. For the final-visit efficacy analysis, data from the patients' last visit on or before the third month were used.
Comparisons between the groups were conducted on the change between the baseline visit and the final visit with regard to variables on the Multiple Sleep Latency Test, scores on the Karolinska Sleepiness Scale, polysomnographic measures, and data from patients' diaries related to sleepiness ratings, unintentional and intentional sleep episodes during the night shift, the consumption of caffeinated drinks, and sleep efficiencies. All of these variables were analyzed with the use of analysis of variance, with treatment and site as factors. Data from the Clinical Global Impression of Change test were evaluated with the use of a Cochran–Mantel–Haenszel chi-square test, with adjustment made for site and modified ridit scores used to account for ordered categories.
Comparisons were made with the use of a chi-square test or Fisher's exact test on data from diaries that were related to the percentage of patients reporting mistakes, near accidents, or accidents during the night shift; unintentional sleep episodes, accidents, or near accidents during the commute home; and rates of adverse events. Comparisons of performance on the Psychomotor Vigilance Test and of melatonin phase were performed with the use of the Wilcoxon nonparametric rank test. There were no interim analyses of the data. All reported P values are two-sided and not adjusted for multiple testing.
Six academic investigators and four representatives of the sponsor designed the study and analyzed the data. Drs. Czeisler, Walsh, Roth, and Dinges conceived of and designed the study in collaboration with representatives of the corporate sponsors, Drs. Hughes, Niebler, Arora, and Kingsbury. Data were fully accessible to all group members, with the study sponsor placing no limits on interpretation or publication. The study designers vouch for the completeness and accuracy of the analyses. All authors were involved with the preparation of the manuscript.
Results
Disposition and Baseline Characteristics of Patients
A total of 4533 shift workers were prescreened through telephone calls placed to a central agency; 2765 workers were referred to study sites. Of 609 patients undergoing laboratory testing, 400 were judged ineligible or withdrew (Figure 1Figure 1
Enrollment and Status of Patients in the Study. and Supplementary Appendix). Most commonly, ineligible patients did not meet inclusion criteria for polysomnography (107 patients) or sleep latency (53) or either withdrew their consent or were lost to follow-up (118). Of 209 patients who were randomly assigned to receive the study drug, 204 patients received the drug, and 153 patients completed the study. At baseline, there were no significant differences in demographic variables, shift-work type, sleepiness, performance, and results on polysomnography between the group that received modafinil and the one that received placebo (Table 1Table 1
Baseline Characteristics, Test Scores, and Severity of Sleepiness among Patients with Shift-Work Sleep Disorder Treated with Modafinil or Placebo.). The patients who completed the trial and those who did not had similar baseline values for the primary outcome variables (as measured by the Multiple Sleep Latency Test and the Clinical Global Impression of Severity test) and similar results on polysomnography. Patients were severely sleepy at baseline, with overall mean (±SD) sleep latencies of 2.0±1.8 minutes and 2.1±1.5 minutes for the placebo and modafinil groups, respectively.Efficacy Measures
Seventy-four percent of patients in the modafinil group were rated as at least minimally improved on the Clinical Global Impression of Change test at the final visit, as compared with 36 percent in the placebo group (P<0.001) (Figure 2AFigure 2
Efficacy Measures Used to Assess the Effects of Modafinil versus Placebo in Patients with Shift-Work Sleep Disorder., and Table 2 in the Supplementary Appendix). Overall mean (±SEM) sleep latency, as measured by the Multiple Sleep Latency Test, increased from 2.1 minutes at baseline to 3.8 minutes at the final visit with modafinil (change, 1.7±0.4 minutes; P<0.001) but not with placebo (2.04 at baseline vs. 2.37 at the final visit; change, 0.3±0.3; P=0.24) (Figure 2B). Sleep latency was significantly greater in the modafinil group than in the placebo group (P=0.002). This improvement in sleep latency with modafinil versus placebo was found at 2 a.m. (P=0.02) and 4 a.m. (P<0.001) (Figure 2C), but not at 6 a.m. (P=0.45) or 8 a.m. (P=0.17) (Figure 2D). A higher proportion of patients receiving modafinil had a positive change in the sleep-latency score from pretreatment to the final visit (Figure 1 in the Supplementary Appendix). Notwithstanding this improvement, sleep latencies during the night shift averaged less than six minutes, which is below the level considered normal during the daytime.Significant differences between the modafinil group and the placebo group were also found for performance on the Psychomotor Vigilance Test. The median number of lapses of attention in 20-minute tests during the night was 12.50 at baseline and 10.25 at the final visit for the modafinil group (median change from baseline, –2.6; P=0.012). In the placebo group, the median number of lapses per test bout was 16.13 at baseline and 23.75 at the final visit (median change from baseline, 3.8; P=0.008). The groups did not differ significantly at baseline (P=0.797), but they did differ significantly at the final visit (P=0.005), and the change in lapses of attention during performance of the Psychomotor Vigilance Test from baseline to the final visit was significant for modafinil versus placebo (P<0.001) (Figure 2E).
The duration of lapses showed a similar result, decreasing from baseline (780 msec) to the final visit (669 msec) for patients receiving modafinil and increasing from baseline (852 msec) to the final visit (1235 msec) for those receiving placebo. This resulted in a significant difference at the final visit (P=0.004) and in the change from baseline to the final visit in favor of modafinil versus placebo (P=0.019). Sleepiness levels on the Karolinska Sleepiness Scale were also significantly reduced for patients receiving modafinil (baseline mean, 7.3; final visit mean, 5.8; change, –1.5±0.2), as compared with placebo (baseline, 7.1; final visit, 6.7; change, –0.4±0.2) (P<0.001) (Figure 2F). In general, the results of efficacy measures at the final visit were observed at the first visit after baseline and sustained throughout subsequent visits (see the Supplementary Appendix).
Data Derived from Electronic Diaries
There were significant effects for three of the seven efficacy variables in the patients' diaries (Table 2Table 2
Variables for Patients with Shift-Work Sleep Disorder Treated with Modafinil or Placebo, as Derived from Diaries.). As compared with placebo, 200 mg of modafinil reduced the maximum level of sleepiness during night-shift work (P<0.001 for the change from baseline vs. placebo) and the level of sleepiness during the commute home (P=0.01), and 25 percent fewer patients receiving modafinil reported having had accidents or near accidents during the commute home (P<0.001). Modafinil treatment during night shifts had no statistically significant effects on unintentional or intentional sleep episodes, mistakes, accidents or near accidents, or caffeine consumption (Table 2). During days following nights off, there were no significant differences in caffeine use and sleep efficiency between the modafinil group and the placebo group (Table 2). The use of sleeping pills was not specifically monitored, although concomitant use of medications was queried at each visit. One of 96 patients in the modafinil group reported the use of a prescription hypnotic agent, whereas none of the 108 patients in the placebo group did. Five of the 96 patients in the modafinil group reported the use of over-the-counter sleep aids versus 1 of the 108 patients in the placebo group (P=0.102).Safety Outcomes
Headache was the most common adverse event associated with treatment in both groups (Table 3Table 3
Adverse Events in Patients Diagnosed with Shift-Work Sleep Disorder Treated with Modafinil or Placebo.). No serious adverse events were reported for patients in the modafinil group. More patients in the modafinil group than in the placebo group had insomnia (6 percent vs. 0 percent, respectively; P=0.01). Adverse events that were not serious but resulted in the inability to carry out usual activities were defined as severe. Eleven patients reported such events (six in the modafinil group and five in the placebo group) (see Table 3 of the Supplementary Appendix). No clinically meaningful differences in vital signs, clinical laboratory measures, physical examinations, or electrocardiographic findings were observed between treatment groups.Other Assessments
There were no significant differences between modafinil and placebo with respect to any measurement of daytime sleep, including sleep duration, latency, and efficiency and the proportion and distribution of sleep stages (Table 4Table 4
Daytime Polysomnographic Measures for Patients with Shift-Work Sleep Disorder Treated with Modafinil or Placebo.). Patients receiving modafinil did not differ significantly from those receiving placebo in the mean change in melatonin phase from baseline to the final visit (0.4 hour and –0.1 hour, respectively).Discussion
Circadian-rhythm sleep disorders have long been recognized as important disruptions of sleep–wake behaviors in a subgroup of people who are substantially more impaired than others with similar schedules.19-21 Such differential vulnerability regarding cognitive impairment that is induced by extended wakefulness at night is a stable characteristic of these persons.22,23 Estimates of the proportion of night-shift workers who meet the clinical criteria of both excessive sleepiness and daytime insomnia that we used to diagnose shift-work sleep disorder range from 5 to 10 percent.4-6,24 The burden of illness in persons with shift-work sleep disorder is substantial, as compared with shift workers without the disorder.6,7,24,25 Thus, shift-work sleep disorder is more than simply being tired on the night shift.
In this randomized, placebo-controlled study — the first such trial in the investigation of shift-work sleep disorder — improvements in alertness and performance were found with 200 mg of modafinil in measures of sleep latency, clinical-impression rating, sustained-attention performance, and patient-estimated sleepiness. Consistent with this profile were reductions in patient-estimated sleepiness on work nights and during the morning commute home. Despite these benefits, patients treated with modafinil continued to have high levels of sleepiness and impaired performance at night.
Although patients receiving 200 mg of modafinil continued to have lapses in performance on the Psychomotor Vigilance Test,26-29 there were twice as many lapses per night at the final visit in the placebo group as there were in the modafinil group, and the mean duration of these lapses in the modafinil group was nearly twice as long as that in the placebo group. It is likely that the effects of modafinil on sustained-attention performance derive, at least in part, from its effects on reducing the instability of wakefulness caused by brief episodes of sleep intruding into waking performance.15,30,31 Although lapses of attention were reduced, they remained at a high level in the treatment group. This suggests that although modafinil improves the measured levels of performance, it is far from what is needed for these patients to function at a normal level.
The results of this study also suggest that 200 mg of modafinil does not affect circadian adaptation to night-work schedules. Thus, the ability of modafinil to treat symptoms of excessive sleepiness in patients diagnosed with shift-work sleep disorder is a result of an improvement in wakefulness during the nocturnal work shift, similar to the improved alertness shown in other disorders of sleep and wakefulness,8-11 and not an improvement in the alignment between internal circadian rhythms and the work–sleep schedule.
Several considerations limit the interpretation and applicability of the findings. There remains a need for validated criteria and clinical instruments for assessing excessive sleepiness in shift-work sleep disorder. Although the Multiple Sleep Latency Test is sensitive to changes in sleepiness during nighttime hours32,33 and is recommended for assessing sleepiness at night in this population,5 it has not been specifically validated as a clinical instrument for measuring nighttime sleepiness, particularly in the absence of objectively monitored sleep in the laboratory on the day before testing. As recommended in the literature,17 we therefore used a validated performance measure — the Psychomotor Vigilance Test — to assess alertness at night, the results of which were consistent with the nighttime data from the Multiple Sleep Latency Test. Because patients worked in a variety of industries, actual work performance was not evaluated. We do not know how the laboratory sleep and performance variables that were used in the study may apply to actual on-the-job performance, although we do show concordance of results for measures of alertness, performance on the Psychomotor Vigilance Test, and diary data that collectively suggest a positive effect on personal and public safety. Although the study was open to both permanent and rotating night-shift workers with shift-work sleep disorder, the vast majority of study participants (90 percent) were permanent night-shift workers. Thus, it is not appropriate to generalize the findings of the study to patients who work on other types of shifts that include nighttime hours. The patients who met the criteria of having shift-work sleep disorder are only a subgroup of shift workers,7 a fact that limits the applicability of the findings to the broader shift-work population in whom the safety and efficacy of modafinil have not been evaluated. Our study was 12 weeks in duration; the effects of long-term modafinil use in this population are unknown.
In summary, we found that patients with shift-work sleep disorder had excessive sleepiness during night work, similar to that seen during the day in patients with narcolepsy. Even after treatment with modafinil, these patients still showed evidence of excessive sleepiness during the night shift. Although modafinil did not restore sleepiness to normal daytime levels, treatment was associated with improvements in symptoms of sleepiness, as well as objective measures of sleep propensity and performance. Modafinil is of some value in the clinical management of sleepiness associated with shift-work sleep disorder. Concern remains that even with treatment with 200 mg of modafinil, the excessive sleepiness observed in this underrecognized population requires the development of yet more effective therapies.
Supported by Cephalon, Frazer, Pa.
Drs. Czeisler and Dinges report having received consulting fees and speaker's fees from Cephalon and having received clinical trial research contracts, investigator-initiated research grants, and unrestricted research and education funds from Cephalon. Dr. Czeisler serves as the incumbent of an endowed professorship provided to Harvard University by Cephalon. Drs. Walsh, Roth, and Wright report having received consulting fees and speaker's fees from Cephalon and having received clinical trial research contracts and investigator-initiated research grants from Cephalon. Drs. Hughes, Kingsbury, Arora, and Niebler are employees of and report having an equity interest in Cephalon. Dr. Schwartz reports having received consulting fees and clinical trial research contracts from Cephalon and serving on the speakers bureau for Cephalon.
Drs. Walsh, Roth, and Hughes contributed equally to this article.
We are indebted to Mark Riotto, Angela Kaya, and Richard Malone for assistance in the preparation of the manuscript.
Source Information
From the Division of Sleep Medicine, Harvard Medical School, and the Division of Sleep Medicine, Department of Medicine, Brigham and Women's Hospital — both in Boston (C.A.C., K.P.W.); the Sleep Medicine Research Center, St. Luke's Hospital, Chesterfield, Mo. (J.K.W.); the Sleep Disorders and Research Center, Henry Ford Hospital, Detroit (T.R.); Cephalon, Frazer, Pa. (R.JH., L.K., S.A., G.E.N.); the Sleep and Chronobiology Laboratory, Department of Integrative Physiology, University of Colorado, Boulder (K.P.W.); Integris Southwest and Baptist Medical Centers, Oklahoma City (J.R.L.S.); and the Division of Sleep and Chronobiology, Department of Psychiatry and Center for Sleep and Respiratory Neurobiology, University of Pennsylvania School of Medicine, Philadelphia (D.F.D.).
Address reprint requests to Dr. Czeisler at Brigham and Women's Hospital, Harvard Medical School, 221 Longwood Ave., Suite 438, Boston, MA 02115, or at caczeisler@hms.harvard.edu.
Other members of the study group are listed in the Appendix.
Appendix
In addition to the authors, members of the U.S. Modafinil in Shift Work Sleep Disorder Study Group are as follows: J.E. Black, Stanford, Calif.; R.K. Bogan, Columbia, S.C.; M.H. Bonnet, Dayton, Ohio; M.A. Carskadon, Providence, R.I.; J.S. Cook, Danville, Ind.; B.C. Corser, Cincinnati; M.K. Erman, La Jolla, Calif.; N.T. Feldman, St. Petersburg, Fla.; J.M. Ferguson, Salt Lake City; Y. Furman, Los Angeles; S.C. Hardy, Charlotte, N.C.; J.R. Harsh, Hattiesburg, Miss.; M. Hirshkowitz, Houston; S.G. Hull, Overland Park, Kans.; V.K. Mahajan, Toledo, Ohio; G.V. Pegram, Jr., Birmingham, Ala.; J. Pinto, Las Vegas; G.S. Richardson, Detroit; R. Rosenberg, Atlanta; M.H. Rosenthal, San Diego, Calif.; M.H. Schmidt, Dublin, Ohio; P.K. Schweitzer, Chesterfield, Mo.; D. Seiden, Pembroke Pines, Fla.; D.R. Wagner, White Plains, N.Y.; C.C. Wells, Jr., Macon, Ga.; J.K. Wyatt, Chicago; and G.K. Zammit, New York.
- References
References
1
Beers TM . Flexible schedules and shift work: replacing the `9-to-5' workday? Monthly Labor Rev 2000;123:33-40
Web of Science2
Akerstedt T . Shift work and disturbed sleep/wakefulness. Occup Med (Lond) 2003;53:89-94
CrossRef | Web of Science | Medline3
Ohayon MM ,Lemoine P ,Arnaud-Briant V ,Dreyfus M . Prevalence and consequences of sleep disorders in a shift worker population. J Psychosom Res 2002;53:577-583
CrossRef | Web of Science | Medline4
Diagnostic and statistical manual of mental disorders, 4th ed. Washington, D.C.: American Psychiatric Association, 2000.
5
ICSD — international classification of sleep disorders: diagnostic and coding manual. 2nd ed. Westchester, Ill.: American Academy of Sleep Medicine, 2005.
6
Drake CL ,Roehrs T ,Richardson G ,Walsh JK ,Roth T . Shift work sleep disorder: prevalence and consequences beyond that of symptomatic day workers. Sleep 2004;27:1453-1462
Web of Science | Medline7
Knutsson A . Health disorders of shift workers. Occup Med (Lond) 2003;53:103-108
CrossRef | Web of Science | Medline8
US Modafinil in Narcolepsy Multicenter Study Group
Web of Science | Medline9
US Modafinil in Narcolepsy Multicenter Study Group
CrossRef | Web of Science | Medline10
Pack AI ,Black JE ,Schwartz JR ,Matheson JK . Modafinil as adjunct therapy for daytime sleepiness in obstructive sleep apnea. Am J Respir Crit Care Med 2001;164:1675-1681
Web of Science | Medline11
Black JE ,Hirshkowitz M . Modafinil for treatment of residual excessive sleepiness in nasal continuous positive airway pressure-treated obstructive sleep apnea/hypopnea syndrome. Sleep 2005;28:464-471
Web of Science | Medline12
Guy W. ECDEU assessment manual for psychopharmacology. Rockville, Md.: National Institute of Mental Health, 1976.
13
Carskadon MA ,Dement WC ,Mitler MM ,Roth T ,Westbrook PR ,Keenan S . Guidelines for the multiple sleep latency test (MSLT): a standard measure of sleepiness. Sleep 1986;9:519-524
Web of Science | Medline14
Carskadon MA ,Dement WC . Daytime sleepiness: quantification of a behavioral state. Neurosci Biobehav Rev 1987;11:307-317
CrossRef | Web of Science | Medline15
Dorrian J, Rogers NL, Dinges DF. Psychomotor vigilance performance: neurocognitive assay sensitive to sleep loss. In: Kushida CA, ed. Sleep deprivation: clinical issues, pharmacology and sleep loss effects. New York: Marcel Dekker, 2005:39-70.
16
Akerstedt T ,Torsvall L ,Gillberg M . Sleepiness and shift work: field studies. Sleep 1982;5:Suppl 2:S95-S106
Web of Science | Medline17
Mitler MM, Carskadon MA, Hirshkowitz M. Evaluating sleepiness. In: Kryger MH, Roth T, Dement WC, eds. Principles and practice of sleep medicine. 3rd ed. Philadelphia: W.B. Saunders, 2000:1251-7.
18
Wright KP Jr ,Hughes RJ ,Kronauer RE ,Dijk DJ ,Czeisler CA . Intrinsic near-24-h pacemaker period determines limits of circadian entrainment to a weak synchronizer in humans. Proc Natl Acad Sci U S A 2001;98:14027-14032
CrossRef | Web of Science | Medline19
Richardson GS ,Malin HV . Circadian rhythm sleep disorders: pathophysiology and treatment. J Clin Neurophysiol 1996;13:17-31
CrossRef | Web of Science | Medline20
Zisapel N . Circadian rhythm sleep disorders: pathophysiology and potential approaches to management. CNS Drugs 2001;15:311-328
CrossRef | Web of Science | Medline21
Mitler MM ,Miller JC ,Lipsitz JJ ,Walsh JK ,Wylie CD . The sleep of long-haul truck drivers. N Engl J Med 1997;337:755-761
Full Text | Web of Science | Medline22
Leproult R ,Colecchia EF ,Berardi AM ,Stickgold R ,Kosslyn SM ,Van Cauter E . Individual differences in subjective and objective alertness during sleep deprivation are stable and unrelated. Am J Physiol Regul Integr Comp Physiol 2003;284:R280-R290
Web of Science | Medline23
Van Dongen HPA ,Baynard MD ,Maislin G ,Dinges DF . Systemic inter-individual differences in neurobehavioral impairment from sleep loss: evidence of trait-like differential vulnerability. Sleep 2004;27:423-433
Web of Science | Medline24
Akerstedt T . Shift work and sleep disorders. Sleep 2005;28:9-11
Web of Science | Medline25
Axelsson J ,Akerstedt T ,Kecklund G ,Lowden A . Tolerance to shift work -- how does it relate to sleep and wakefulness? Int Arch Occup Environ Health 2004;77:121-129
CrossRef | Web of Science | Medline26
Van Dongen HP ,Maislin G ,Mullington JM ,Dinges DF . The cumulative cost of additional wakefulness: dose-response effects on neurobehavioral functions and sleep physiology from chronic sleep restriction and total sleep deprivation. Sleep 2003;26:117-126[Erratum, Sleep 2004;27:600.]
Web of Science | Medline27
Dinges DF ,Pack F ,Williams K , et al. Cumulative sleepiness, mood disturbance, and psychomotor vigilance performance decrements during a week of sleep restricted to 4-5 hours per night. Sleep 1997;20:267-277
Web of Science | Medline28
Powell NB ,Riley RW ,Schechtman KB ,Blumen MB ,Dinges DF ,Guilleminault C . A comparative model: reaction time performance in sleep-disordered breathing versus alcohol-impaired controls. Laryngoscope 1999;109:1648-1654
CrossRef | Web of Science | Medline29
Belenky G ,Wesensten NJ ,Thorne DR , et al. Patterns of performance degradation and restoration during sleep restriction and subsequent recovery: a sleep dose-response study. J Sleep Res 2003;12:1-12
CrossRef | Web of Science | Medline30
Doran SM ,Van Dongen HP ,Dinges DF . Sustained attention performance during sleep deprivation: evidence of state instability. Arch Ital Biol 2001;139:253-267
Web of Science | Medline31
Saper CB ,Chou TC ,Scammell TE . The sleep switch: hypothalamic control of sleep and wakefulness. Trends Neurosci 2001;24:726-731
CrossRef | Web of Science | Medline32
Walsh JK ,Muehlbach MJ ,Humm TM ,Dickins QS ,Sugerman JL ,Schweitzer PK . Effect of caffeine on physiological sleep tendency and ability to sustain wakefulness at night. Psychopharmacology (Berl) 1990;101:271-273
CrossRef | Web of Science | Medline33
Muehlbach MJ ,Walsh JK . The effects of caffeine on simulated night-shift work and subsequent daytime sleep. Sleep 1995;18:22-29
Web of Science | Medline
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CrossRef3
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CrossRef4
Bradley D. Shy, Ian Portelli, Lewis S. Nelson. (2011) Emergency medicine residents' use of psychostimulants and sedatives to aid in shift work. The American Journal of Emergency Medicine 29:9, 1034-1036.e1
CrossRef5
Milton K. Erman, David J. Seiden, Ronghua Yang, Ryan Dammerman. (2011) Efficacy and Tolerability of Armodafinil. Journal of Occupational and Environmental Medicine1
CrossRef6
Colin Sugden, Charlotte R. Housden, Rajesh Aggarwal, Barbara J. Sahakian, Ara Darzi. (2011) Effect of Pharmacological Enhancement on the Cognitive and Clinical Psychomotor Performance of Sleep-Deprived Doctors. Annals of Surgery1
CrossRef7
Ana Barion. (2011) Circadian Rhythm Sleep Disorders. Disease-a-Month 57:8, 423-437
CrossRef8
Thi-Lien Nguyen, Yu-Hua Tian, In-Jee You, Seok-Yong Lee, Choon-Gon Jang. (2011) Modafinil-induced conditioned place preference via dopaminergic system in mice. Synapse 65:8, 733-741
CrossRef9
CHRISTOPHER M. JUNG, JOSEPH M. RONDA, CHARLES A. CZEISLER, KENNETH P. WRIGHT JR. (2011) Comparison of sustained attention assessed by auditory and visual psychomotor vigilance tasks prior to and during sleep deprivation. Journal of Sleep Research 20:2, 348-355
CrossRef10
Sophie Lavault, Yves Dauvilliers, Xavier Drouot, Smaranda Leu-Semenescu, Jean-Louis Golmard, Michel Lecendreux, Patricia Franco, Isabelle Arnulf. (2011) Benefit and risk of modafinil in idiopathic hypersomnia vs. narcolepsy with cataplexy. Sleep Medicine 12:6, 550-556
CrossRef11
James K. Wyatt. (2011) Circadian Rhythm Sleep Disorders. Pediatric Clinics of North America 58:3, 621-635
CrossRef12
&NA;. (2011) Shift Work and Sleep. Journal of Occupational and Environmental Medicine 53, S1-S10
CrossRef13
Thomas J. Balkin, William J. Horrey, R. Curtis Graeber, Charles A. Czeisler, David F. Dinges. (2011) The challenges and opportunities of technological approaches to fatigue management
. Accident Analysis & Prevention 43:2, 565-572
CrossRef14
D. V. Tembe, A. Dhavale, H. Desai, D. N. Mane, S. K. Raut, G. Dhingra, U. Sardesai, S. Saoji, M. Rohra, V. G. Shinde, M. Padsalge, A. Paliwal, K. Abbasi, P. Devnani, S. Papinwar, S. Phadke, H. Mehta, V. Bhailume. (2011) Armodafinil versus Modafinil in Patients of Excessive Sleepiness Associated with Shift Work Sleep Disorder: A Randomized Double Blind Multicentric Clinical Trial. Neurology Research International 2011, 1-6
CrossRef15
Yia-Ping Liu, Che-Se Tung, Yu-Lung Lin, Chia-Hsin Chuang. (2011) Wake-promoting agent modafinil worsened attentional performance following REM sleep deprivation in a young-adult rat model of 5-choice serial reaction time task. Psychopharmacology 213:1, 155-166
CrossRef16
Mary B. O’Malley, Shelagh K. Gleeson, Ian D. Weir. 2011. Wake-Promoting Medications. , 527-541.
CrossRef17
Christopher L. Drake, Kenneth P. Wright. 2011. Shift Work, Shift-Work Disorder, and Jet Lag. , 784-798.
CrossRef18
Kathryn J. Reid, Lori L. McGee-Koch, Phyllis C. Zee. 2011. Cognition in circadian rhythm sleep disorders. , 3-20.
CrossRef19
Ehren R. Dodson, Phyllis C. Zee. (2010) Therapeutics for Circadian Rhythm Sleep Disorders. Sleep Medicine Clinics 5:4, 701-715
CrossRef20
Phyllis C. Zee, Cathy A. Goldstein. (2010) Treatment of Shift Work Disorder and Jet Lag. Current Treatment Options in Neurology 12:5, 396-411
CrossRef21
Scott Grady, Daniel Aeschbach, Kenneth P Wright, Charles A Czeisler. (2010) Effect of Modafinil on Impairments in Neurobehavioral Performance and Learning Associated with Extended Wakefulness and Circadian Misalignment. Neuropsychopharmacology 35:9, 1910-1920
CrossRef22
Warwick Black, Peter Hoey, Thomas Mayze. (2010) Modafinil use in patients with a primary psychiatric illness. Australian and New Zealand Journal of Psychiatry 44:6, 583-584
CrossRef23
Naveen Kanathur, John Harrington, Teofilo Lee-Chiong. (2010) Circadian Rhythm Sleep Disorders. Clinics in Chest Medicine 31:2, 319-325
CrossRef24
H. Mittendorf, J. Groth, M. Konermann, K. Freund, I. Fietze. (2010) Modafinil zur Behandlung exzessiver Schläfrigkeit bei Patienten mit Schichtarbeitersyndrom. Somnologie - Schlafforschung und Schlafmedizin 14:2, 123-128
CrossRef25
Robert L Sack. 2010. Insomnia in Circadian Rhythm Sleep Disorders: Shift Work/Jet Lag/DSP/ASP/Free-Running---Blindness. , 181-198.
CrossRef26
Ajna Hamidovic, Andrea Dlugos, Abraham A. Palmer, Harriet de Wit. (2010) Catechol-O-methyltransferase val158met genotype modulates sustained attention in both the drug-free state and in response to amphetamine. Psychiatric Genetics1
CrossRef27
Lia R. A. Bittencourt, Rogerio Santos-Silva, Marco T. Mello, Monica L. Andersen, Sergio Tufik. (2010) Chronobiological Disorders: Current and Prevalent Conditions. Journal of Occupational Rehabilitation 20:1, 21-32
CrossRef28
David E. Nichols. 2010. CNS Stimulants. .
CrossRef29
James K. Walsh, Lynette Salkeld, Lisa J. Knowles, Tim Tasker, Ian M. Hunneyball. (2010) Treatment of elderly primary insomnia patients with EVT 201 improves sleep initiation, sleep maintenance, and daytime sleepiness. Sleep Medicine 11:1, 23-30
CrossRef30
Di Lamb. (2010) Measuring Critical Care Air Support Teamsʼ Performance During Extended Periods of Duty. AACN Advanced Critical Care 21:3, 298-306
CrossRef31
Brian D. McBeth, Robert M. McNamara, Felix K. Ankel, Emily J. Mason, Louis J. Ling, Thomas J. Flottemesch, Brent R. Asplin. (2009) Modafinil and Zolpidem Use by Emergency Medicine Residents. Academic Emergency Medicine 16:12, 1311-1317
CrossRef32
D.H. Weissman, L.M. Warner, M.G. Woldorff. (2009) Momentary reductions of attention permit greater processing of irrelevant stimuli. NeuroImage 48:3, 609-615
CrossRef33
Charles A. Czeisler, James K. Walsh, Keith A. Wesnes, Thomas Roth, Sanjay Arora. (2009) Armodafinil for Treatment of Excessive Sleepiness Associated With Shift Work Disorder: A Randomized Controlled Study. Mayo Clinic Proceedings 84:11, 958-972
CrossRef34
S. Ian Gan, Mariana Jongh, Marshall M. Kaplan. (2009) Modafinil in the Treatment of Debilitating Fatigue in Primary Biliary Cirrhosis: A Clinical Experience. Digestive Diseases and Sciences 54:10, 2242-2246
CrossRef35
Mortimer Mamelak. (2009) Narcolepsy and depression and the neurobiology of gammahydroxybutyrate. Progress in Neurobiology 89:2, 193-219
CrossRef36
David Orlikowski, Sylvie Chevret, Maria Antonia Quera-Salva, Pascal Laforêt, Frédéric Lofaso, Annie Verschueren, Jean Pouget, Bruno Eymard, Djillali Annane. (2009) Modafinil for the treatment of hypersomnia associated with myotonic muscular dystrophy in adults: A multicenter, prospective, randomized, double-blind, placebo-controlled, 4-week trial. Clinical Therapeutics 31:8, 1765-1773
CrossRef37
Josephine Arendt. (2009) Managing jet lag: Some of the problems and possible new solutions. Sleep Medicine Reviews 13:4, 249-256
CrossRef38
Keith D. Lindor, M. Eric Gershwin, Raoul Poupon, Marshall Kaplan, Nora V. Bergasa, E. Jenny Heathcote. (2009) Primary biliary cirrhosis. Hepatology 50:1, 291-308
CrossRef39
Sadhna Kohli, Susan G. Fisher, Yolande Tra, M. Jacob Adams, Mark E. Mapstone, Keith A. Wesnes, Joseph A. Roscoe, Gary R. Morrow. (2009) The effect of modafinil on cognitive function in breast cancer survivors. Cancer 115:12, 2605-2616
CrossRef40
Elaine M. Fiocchi, Yin-Guo Lin, Lisa Aimone, John A. Gruner, Dorothy G. Flood. (2009) Armodafinil promotes wakefulness and activates Fos in rat brain. Pharmacology Biochemistry and Behavior 92:3, 549-557
CrossRef41
Bhavneesh SHARMA, Steven FEINSILVER. (2009) Circadian rhythm sleep disorders: An update. Sleep and Biological Rhythms 7:2, 113-124
CrossRef42
S Bodenmann, S Xu, UFO Luhmann, M Arand, W Berger, HH Jung, HP Landolt. (2009) Pharmacogenetics of Modafinil After Sleep Loss: Catechol-O-Methyltransferase Genotype Modulates Waking Functions But Not Recovery Sleep. Clinical Pharmacology & Therapeutics 85:3, 296-304
CrossRef43
Laura K. Barger, Steven W. Lockley, Shantha M. W. Rajaratnam, Christopher P. Landrigan. (2009) Neurobehavioral, health, and safety consequences associated with shift work in safety-sensitive professions. Current Neurology and Neuroscience Reports 9:2, 155-164
CrossRef44
András Szentkirályi, Csilla Z Madarász, Márta Novák. (2009) Sleep disorders: impact on daytime functioning and quality of life. Expert Review of Pharmacoeconomics & Outcomes Research 9:1, 49-64
CrossRef45
Mark W. Mahowald, Milton G. Ettinger. 2009. Circadian Rhythm Disorders. , 581-590.
CrossRef46
Max Hirshkowitz, Mary Wilcox Rose, Amir Sharafkhaneh. 2009. Neurotransmitters, Neurochemistry, and the Clinical Pharmacology of Sleep. , 67-79.
CrossRef47
MICHAEL A. CHRISTIE, JAMES T. MCKENNA, NINA P. CONNOLLY, ROBERT W. MCCARLEY, ROBERT E. STRECKER. (2008) 24 hours of sleep deprivation in the rat increases sleepiness and decreases vigilance: introduction of the rat-psychomotor vigilance task. Journal of Sleep Research 17:4, 376-384
CrossRef48
Richard C. Shelton, Rakesh Reddy. (2008) Adjunctive use of modafinil in bipolar patients: just another stimulant or not?. Current Psychiatry Reports 10:6, 520-524
CrossRef49
Giuseppe Aprile, Ornella Belvedere, Fabio Puglisi. (2008) From the podium to the patient: bringing the 2008 ASCO meeting to the clinic. Anti-Cancer Drugs 19:10, 941-956
CrossRef50
Phyllis C. Zee, Brandon S. Lu. (2008) Insomnia and Circadian Rhythm Sleep Disorders. Psychiatric Annals 38:9, 583-589
CrossRef51
P. Xu, H.-D. Li, B.-K. Zhang, Y.-W. Xiao, H.-Y. Yuan, Y.-G. Zhu. (2008) Pharmacokinetics and tolerability of modafinil tablets in Chinese subjects. Journal of Clinical Pharmacy and Therapeutics 33:4, 429-437
CrossRef52
Michael J Minzenberg, Cameron S Carter. (2008) Modafinil: A Review of Neurochemical Actions and Effects on Cognition. Neuropsychopharmacology 33:7, 1477-1502
CrossRef53
Julian Lim, David F. Dinges. (2008) Sleep Deprivation and Vigilant Attention. Annals of the New York Academy of Sciences 1129:1, 305-322
CrossRef54
Ari Shechter, Francine O. James, Diane B. Boivin. (2008) Circadian Rhythms and Shift Working Women. Sleep Medicine Clinics 3:1, 13-24
CrossRef55
Jacob M. Ballinger, Robert J. Comello, Beth Vealé. (2008) Stressors That Negatively Affect the Health of Radiology Professionals. Journal of Medical Imaging and Radiation Sciences 39:1, 11-15
CrossRef56
Amitabh Jha, Alan Weintraub, Amanda Allshouse, Clare Morey, Chris Cusick, John Kittelson, Cynthia Harrison-Felix, Gale Whiteneck, Don Gerber. (2008) A Randomized Trial of Modafinil for the Treatment of Fatigue and Excessive Daytime Sleepiness in Individuals with Chronic Traumatic Brain Injury. Journal of Head Trauma Rehabilitation 23:1, 52-63
CrossRef57
Martin Konermann, Hartmut Grüger, Ralf Warmuth. (2007) Modafinil zur Behandlung exzessiver Tagesschläfrigkeit trotz nCPAP-Therapie beim obstruktiven Schlafapnoe-Syndrom (OSAS) – Ergebnisse einer multizentrischen Beobachtungsstudie. Somnologie - Schlafforschung und Schlafmedizin 11:4, 291-298
CrossRef58
Claire C. Venker, James L. Goodwin, Denise J. Roe, Kristine L. Kaemingk, Shelagh Mulvaney, Stuart F. Quan. (2007) Normative psychomotor vigilance task performance in children ages 6 to 11—the Tucson Children’s Assessment of Sleep Apnea (TuCASA). Sleep and Breathing 11:4, 217-224
CrossRef59
Diane B. Boivin, Geneviève M. Tremblay, Francine O. James. (2007) Working on atypical schedules. Sleep Medicine 8:6, 578-589
CrossRef60
Ana Barion, Phyllis C. Zee. (2007) A clinical approach to circadian rhythm sleep disorders. Sleep Medicine 8:6, 566-577
CrossRef61
Antoine U. Viola, Simon N. Archer, Lynette M. James, John A. Groeger, June C.Y. Lo, Debra J. Skene, Malcolm von Schantz, Derk-Jan Dijk. (2007) PER3 Polymorphism Predicts Sleep Structure and Waking Performance. Current Biology 17:7, 613-618
CrossRef62
Kevin Birth. (2007) Time and the Biological Consequences of Globalization. Current Anthropology 48:2, 215-236
CrossRef63
Torbjörn Åkerstedt. (2007) Altered sleep/wake patterns and mental performance. Physiology & Behavior 90:2-3, 209-218
CrossRef64
D. E. J. JONES, J. L. NEWTON. (2007) An open study of modafinil for the treatment of daytime somnolence and fatigue in primary biliary cirrhosis. Alimentary Pharmacology & Therapeutics 25:4, 471-476
CrossRef65
B.A. Phillips. (2007) Modafinil for Excessive Sleepiness Associated With Shift-Work Sleep Disorder. Yearbook of Pulmonary Disease 2007, 303-305
CrossRef66
Elizabeth Coulthard, Victoria Singh-Curry, Masud Husain. (2006) Treatment of attention deficits in neurological disorders. Current Opinion in Neurology 19:6, 613-618
CrossRef67
Christopher D. Fahey, Phyllis C. Zee. (2006) Circadian Rhythm Sleep Disorders and Phototherapy. Psychiatric Clinics of North America 29:4, 989-1007
CrossRef68
Scott M. Leibowitz, Stephen N. Brooks, Jed E. Black. (2006) Excessive Daytime Sleepiness: Considerations for the Psychiatrist. Psychiatric Clinics of North America 29:4, 921-945
CrossRef69
Sandeep Vaishnavi, Kishore Gadde, Sayed Alamy, Wei Zhang, Kathryn Connor, Jonathan R.T. Davidson. (2006) Modafinil for Atypical Depression. Journal of Clinical Psychopharmacology 26:4, 373-378
CrossRef70
D H Weissman, K C Roberts, K M Visscher, M G Woldorff. (2006) The neural bases of momentary lapses in attention. Nature Neuroscience 9:7, 971-978
CrossRef71
David N Neubauer. (2006) Does modafinil safely and effectively treat shift-work sleep disorder?. Nature Clinical Practice Neurology 2:3, 134-135
CrossRef72
Jonathan R L Schwartz, Thomas Roth. (2006) Shift Work Sleep Disorder. Drugs 66:18, 2357-2370
CrossRef73
David F. Dinges, Sanjay Arora, Mona Darwish, Gwendolyn E. Niebler. (2006) Pharmacodynamic effects on alertness of single doses of armodafinil in healthy subjects during a nocturnal period of acute sleep loss*. Current Medical Research and Opinion 22:1, 159-167
CrossRef74
Basner, Robert C., . (2005) Shift-Work Sleep Disorder — The Glass Is More Than Half Empty. New England Journal of Medicine 353:5, 519-521
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