Dr. Rogers is research associate and Dr. Dinges is professor of psychology in psychiatry at the Unit for Experimental Psychiatry in the Division of Sleep and Chronobiology at the University of Pennsylvania School of Medicine in Philadelphia.

Acknowledgments: This work was supported in part by NIH grant NR04281, NASA Cooperative Agreement NCC 9-58 with the National Space Biomedical Research Institute, and AFOSR grant 49620-95-1-0388. Reprinted from TEN. 2001;3(9):58-64. 



In today’s global society with work schedules placed across the 24-hour day, shiftwork, particularly night shiftwork, is becoming increasingly common. Despite the almost universal acceptance of the necessity of night shiftwork, the full impact of these schedules on workers is still not fully appreciated. Both short- and long-term effects of night shiftwork have been described, in retrospective, epidemiological, and laboratory and field studies investigating sleep deprivation. Increases in certain disorders, including cardiovascular disease and reproductive problems, have been reported as long-term consequences of shiftwork. In the short term, individuals required to work at night and sleep during the day experience disruption in their circadian systems, due to misalignment with the external environment and time cues, as well as chronic sleep restriction. Potential treatments for this circadian disruption include strategies to promote synchrony and rapid adaptation between the internal body clock and external environment (eg, melatonin, bright-light therapy) and wakefulness during the night shift (eg, napping, wake-promoting compounds).


The Circadian System

Circadian rhythms are biological rhythms that are endogenously produced by an organism, characterized by repetitive oscillations having a frequency of one cycle approximately every 24 hours,1 and sustained in constant environmental conditions (for a review see Czeisler and Khalsa2). In humans the endogenous circadian pacemaker, or biological clock, is located in the suprachiasmatic nuclei (SCN), which are situated in the anterior hypothalamus (for a review see Weaver3). The circadian system oversees the timing of a range of physiological processes, including those controlled by the endocrine, thermoregulatory, immune, cardiovascular, respiratory, gastrointestinal, renal, and sleep-wake systems.

Environmental time cues that are able to entrain the biological clock are termed zeitgebers; the most salient zeitgeber in many animals including humans is the light-dark cycle.2 In addition to entraining the circadian system to maintain an appropriate phase relationship with the environment, zeitgebers are able to shift the timing of the biological clock and, consequently, the circadian rhythms of the functions under its control.

Markers of the Circadian System


Melatonin is an indoleamine produced in the pineal gland. The production of melatonin is under the control of sympathetic innervation of the pineal gland. At night, in the absence of light, melatonin synthesis in the pineal gland is stimulated by signals from neurons originating in the SCN (for a review see Arendt4). The SCN receive light information from the eyes, and send information via the spinal cord to paraventricular nuclei and superior cervical ganglia, which terminate near the pineal gland. During the daylight hours, melatonin synthesis is inhibited due to suppression of activity in the sympathetic neurons coming from the SCN. Onset of melatonin secretion typically occurs between 10pm and 12am.

It is important to note, however, that while the circadian rhythm of melatonin secretion is regulated by the SCN, and thus is strongly influenced by the light-dark cycle, in the absence of a light-dark cycle (ie, in dark:dark), circadian rhythmicity of melatonin secretion is conserved. Additionally, exposure to a new light-dark cycle (eg, during night shiftwork) does not immediately shift the secretory profile of melatonin to a new light-dark cycle phase. Rather, this process is gradual, and hence may take a number of days to weeks to be completed. Although melatonin secretion occurs across the sleep period and has been proposed as a trigger for sleep,5,6 studies have demonstrated that melatonin secretion occurs irrespective of sleep-wake status, even in the absence of nocturnal sleep.7 Consequently, changes in circadian timing can alter the timing of melatonin secretion, independent of sleep-wake state or sleep deprivation.

Melatonin may function as a timekeeper for the circadian system, keeping the pacemaker informed about changes in day length and time of day. In addition, as a circadian-mediated humoral factor circulating in the bloodstream, melatonin may be responsible for relaying information from the circadian pacemaker to the physiological systems that are regulated by the biological clock. Therefore, melatonin may play a role in coordinating various circadian rhythms within the body.

Core Body Temperature

Another robust marker of the circadian system is core body temperature. In a normally entrained person, core body temperature increases gradually throughout the day, and decreases at night, continuing across the sleep period, reaching a nadir in the early hours of the morning (between 4am and 6am). Core body temperature typically begins rising prior to nocturnal sleep offset and continues to increase across the day.

Circadian Disruption

Circadian disruption occurs as a result of misalignment in the timing of circadian rhythms in relation to either the external light-dark cycle or to each other. Circadian disruption is evident in transmeridian travelers, and contributes significantly to the group of maladies collectively referred to as “jet lag,” which is experienced annually by millions of people who fly across time zones. In addition, night-shift workers experience a disruption of the circadian system. The difference between jet lag and night-shift work is that in the former, zeitgebers are available to help the circadian system re-entrain to a new rest-activity phase, while in night-shift work, zeitgebers reinforce the endogenous circadian phase that is out of symmetry with the rest-activity phase required by the night shift. As a result, jet lag is typically transient, lasting 1–14 days, depending on the number of time zones crossed, while circadian disruption from night work can last much longer.

Indeed, as will be explained below, many night-shift workers never fully adjust their endogenous phase to align with the requirement to be awake and alert at night. Circadian realignment can be experimentally induced by using appropriately timed exposure to bright light, by administering melatonin, or by altering the timing or duration of the light-dark cycle. However, to be effective, these interventions must be administered at the appropriate circadian phase, and hence, a reasonable estimate of phase position must be obtained. Consequently, this may limit their utility in some situations.


Shiftwork is defined as any work conducted outside the standard Monday–Friday, 8am–6pm work day. Recent estimates suggest that approximately 15% to 20% of the workforce in industrialized countries can be considered shiftworkers.8-10 There are several detrimental effects associated with working irregular shifts. Epidemiological studies show a high occurrence of several chronic disorders, including cardiovascular complaints and reproductive difficulties, in shiftwork populations. More immediate effects are also evident. These include decreased sleep quantity and quality, decreased neurobehavioral functioning, and increased fatigue, sleepiness, irritability, and illness. These effects are due to a number of factors, including circadian disruption.

Chronic Health Problems

Several researchers have investigated the long-term effects of shiftwork and health. Koller11 described a dose-response relationship between number of shiftwork years and risk for cardiovascular disease in 270 oil refinery workers. Later, Knutsson and colleagues12 reported an association between an increased risk for ischemic heart disease and shiftwork in 504 male blue-collar workers from a paper and pulp manufacturing plant in Sweden. This finding was reported to be independent of both age and cigarette smoking. Knutsson and colleagues13 then reported an increased risk of myocardial infarction in men and women shiftworkers, relative to controls. Again, this finding was independent of age and cigarette smoking, and was also not related to job strain or job educational level. In contrast, Tenkanen and colleagues14 reported an increased risk of coronary heart disease (CHD) in 1,806 Finnish shiftworkers that was significantly associated with smoking and obesity. A similar association was not evident in day workers. The authors suggest that shiftwork may be a trigger for CHD in individuals who have other lifestyle factors that place them at increased risk for CHD.

Shiftwork and health in female workers have also been investigated. Japanese15,16 and French studies17 reported an increased incidence of irregular menstrual cycles in women involved in shiftwork. In addition, shiftwork has been associated with reduced fertility, as assessed by the number of menstrual cycles required for a planned pregnancy to occur.15,18-20

Several studies have reported a relationship between the frequency of spontaneous abortions and shiftwork. Bisanti and colleagues19 reported that night work and three-shift schedules may be related to an increased incidence in spontaneous abortions in a group of Swedish midwives. Further, a number of studies have reported an increased incidence of spontaneous abortion in women working nonstandard work hours.15,21-25 Three of these studies stated that spontaneous abortion was associated with some variety of rotating schedule.22,23,25

In a Canadian study, Fortier and colleagues26 reported an increased risk of preterm births in mothers employed in regular evening or night work. This elevated risk appeared in women who continued with irregular shiftwork following week 23 of their pregnancies. Xu and colleagues27 reported an association between preterm births and mothers involved in rotating shiftwork in Chinese textile workers, and McDonald and colleagues28 reported an inconsistent association between preterm births and shiftwork in Canadian workers. In contrast, Saurel-Cubizolles and Kaminski29 reported no relationship between preterm births and shiftwork in a group of French shiftworking mothers.

Circadian Misalignment

When working during the night and sleeping during the day, shiftworkers are attempting to be active during their inactive phase and vice versa. The circadian systems of shiftworkers generally do not adapt well to the change in working time, usually due to the short duration of the night-shift period and the time taken for the body to adapt. Consequently, shiftworkers can be considered to be in a state of almost constant circadian misalignment. This point is illustrated in a study by Sack and colleagues,30 who monitored melatonin secretion across the 24-hour day in a group of night-shift workers who had been on a shift for 2–5 nights prior to the study. In eight of the nine shiftworkers studied, melatonin secretion occurred at an innappropriate time versus that in normally entrained subjects. The time of melatonin onset for these workers ranged between the hours of 10:28pm and 12:30am. A study of subjects in Antarctica revealed that, in the absence of sunlight, potential synchronizers such as social contact and mealtimes were unable to entrain circadian rhythms.31

Although circadian re-entrainment may be difficult to achieve under many conditions of night work, it may not be impossible. Barnes and colleagues32 examined adaptation to a 2-week night-shift period in oil rig workers, using 6-sulphatoxy melatonin (aMT.6S) excretion as a circadian marker. Urine samples were taken at 2- to 3-hour intervals during wake hours and one sample was collected across the sleep period, in both winter and summer. Adaptation of the aMT.6S rhythm to the new work and sleep schedule occurred within a week during both summer and winter. This phase shift was achieved via a phase delay of the aMT.6S acrophase. The authors suggest that possible entraining mechanisms include forced reversal of work and sleep schedules, timing of meals, and exposure to artificial lighting and sunlight, particularly during the summer.

Potential Treatments for Circadian Misalignment


Appropriately timed exposure to bright light can act as an artificial zeitgeber, and hence, has been suggested as a treatment for circadian disruption. One of the most widely studied areas of the application of light for this purpose is in shiftworkers. This has been accomplished in the field using shiftworkers, and in the laboratory, where normal subjects are placed on “shiftwork schedules.” For example, in a laboratory-based study, Dawson and Campbell33 placed subjects on a day-sleep/night-wake schedule, and investigated the effects of bright-light exposure on sleep, circadian phase (core body temperature), and alertness. Two groups of subjects completed three consecutive sessions of night work, followed by daytime sleep. Both groups of subjects were maintained in dim light, with one group (treatment group) receiving a 4-hour light pulse from 12am–4am on the first night. In both groups, the timing of the temperature nadir was phase-delayed after the night shifts, relative to baseline. Compared with the control group, the light-treatment group achieved a significantly greater delay (355±43 versus 143±60 minutes). Coincident with these changes in the timing of the temperature rhythm, improved sleep efficiency and increased alertness levels were reported for the treatment group. Such findings suggest that appropriately timed bright-light administration to night workers accelerates circadian adaptation to a new sleep-wake schedule, with coincident improvements in sleep and alertness.

Eastman34 reported similar findings following light exposure during a 12-hour shift of the sleep-wake cycle, for a longer period of time (≥8 night shifts). In nearly 90% of subjects, the core temperature rhythm was shifted following appropriately timed bright-light exposure during the first 4 days of the schedule. Light was also administered on the following days, to maintain the new phase position. In all subjects, the average daily shift in temperature was approximately 2 hours. In the subjects who produced a phase delay, there was complete adaptation of the temperature curve to the new sleep-wake schedule by day 7.

While these bright-light-induced phase shifts appear positive, they are not dissimilar to those reported in shiftworkers with no active intervention.32 Barnes and colleagues32 reported that the timing of the aMT.6S rhythm in oil rig workers had entrained to a 12-hour phase shift in their sleep-wake cycle within 7 days. This adaptation period is similar to that reported above by Eastman for the core temperature rhythm following exposure to bright light.34 Barnes and colleagues suggest that the entrainment of the circadian system to the new sleep-wake schedule was likely due in part to exposure to both artificial and natural light.

Therefore, in real life, workers may be able to adjust their circadian systems relatively rapidly without having to use specific bright-light treatments. Alternatively, it may be that an interaction between a number of time markers (eg, meals or forced reversal of work and sleep times, and light exposure) facilitates circadian adaptation.

Gallo and Eastman35 studied the effects of bright-light exposure on circadian adaptation during rapidly rotating changes in the sleep-wake schedule. Sleep times were progressively delayed across 5 days by a total of 10 hours, maintained at this time for 5 days, and then progressively returned to the initial timing.

The timing of the temperature rhythm did not shift equally in all subjects. Some subjects demonstrated a greater phase shift, and their core temperature rhythm approached synchronization to their new sleep-wake schedule. Other subjects did not shift their temperature rhythm to such an extent, and one subject even appeared to free run. These data demonstrate a high degree of intersubject variability in bright-light-induced resynchronization of the core temperature circadian rhythm following large phase shifts.

The authors suggested that the type of illumination used might be a reason why the temperature rhythm did not fully adapt to the new sleep-wake schedules. It is important for subjects to face the light source and be at an optimal distance from it for maximum light intensity to reach the pacemaker.36 While this may be a factor in the results obtained, it may also represent a more real-life situation. Typically, shiftworkers would not be exposed to optimal intensity of light for the correct duration at the appropriate time. Therefore, the results of this study may illustrate what is likely to occur in the real world, and not just in the laboratory.

The magnitude of the acute effects of light on melatonin suppression and temperature elevation can vary depending on the intensity of the light administered.37 Similarly, it is possible that the magnitude of the delayed (phase-shifting) effects of light may also be affected by light intensity. Martin and Eastman38 compared the phase-shifting effects of three different light intensities: low (<250 lux), medium (~1,250 lux), and high (~5,700 lux) for 3 hours/day light intensities for 5 out of 6 nights of work with daytime sleep.38 Following exposure to the high-intensity light, temperature rhythms in all subjects were delayed, such that the nadir occurred during the day-sleep period (ie, full adaptation). This effect was also observed in most (85%) of the subjects exposed to medium-light intensity. In contrast, fewer subjects (42%) exposed to low-light intensity had a temperature rhythm shift of this amount. Therefore, it appears that both timing of light exposure and intensity are important.

Exogenous Melatonin Administration

Exogenous melatonin administration has been proposed to treat persons with circadian disruption disorders, eg, shiftworkers, and with delayed sleep phase syndrome.39,40 Attenburrow and colleagues41 administered melatonin to a group of healthy subjects at 5pm, and reported a significant phase advance in endogenous melatonin rhythm.41 This advance was evident after 7 days of melatonin administration, with no effect after a single day of administration.

In a laboratory-based study, Dawson and colleagues42 compared the effectiveness of light and melatonin in producing phase shifts in subjects on an enforced shiftwork schedule. Following light treatment, a significant phase delay (8.8 hours) was evident. In contrast, the delay following melatonin administration was approximately half (4.7 hours). This delay was not significantly different from that found in the placebo condition (4.2 hours).

Sack and colleagues43 have suggested that lack of response to melatonin may be due to timing of administrations (split dose: two administrations). When comparing the time of administration with the phase response curve for melatonin,44,45 Dawson and colleagues42 apparently administered one dose of melatonin on the advance portion of the phase response curve and the other during the delay portion. Therefore, Sack and colleagues43 concluded that any phase-shifting effect may have been cancelled out.

Folkard and colleagues46 compared the effects of melatonin and placebo on sleep and alertness in a group of night shiftworkers. Subjects took the treatments at bedtime (during the diurnal portion of the circadian cycle). Melatonin increased self-reported sleep quality and duration, relative to placebo and baseline. There was no effect of melatonin on sleep-onset latencies. Melatonin also reportedly increased early-morning alertness. Hypothetically, this increase may have been due to a phase shift in the alertness rhythm, but the authors conclude that this would be unlikely. It may be that increased sleep duration and sleep quality increased alertness levels.

Sack and colleagues47 also noted that shiftworkers demonstrated a high degree of variability in their ability to phase shift, both with and without melatonin treatment. Some subjects shifted after taking placebo, but not after taking melatonin. Other subjects demonstrated an equivalent delay following administration of placebo and melatonin, while a small number of subjects did not shift following either treatment.

This high degree of intersubject variability highlights the difficulties in assessing the effectiveness of melatonin treatment. Much experimental evidence appears to suggest that, in order for melatonin to be effective, regimens that are personalized with regard to timing, dose, and route of administration, are required.

Several studies have reported that exogenous melatonin administration at doses of ≥5 mg produces significant decrements in neurobehavioral performance.48-56 This finding is particularly important if melatonin is to be administered as a chronobiotic rather than a soporific agent. Under these circumstances, it is possible that melatonin would be administered at a time other than directly prior to bedtime, when activities such as driving or operating machinery may be undertaken.

Several research groups have reported the absence of hangover effects following a night’s sleep when melatonin was taken.51,54-56 Taken together, these findings suggest that, if melatonin were administered as a soporific agent, it would be unlikely to produce unwanted neurobehavioral effects. However, if melatonin were administered as a chronobiotic agent during the day, eg, in shiftworkers and transmeridian travelers, these adverse performance effects could be problematic.

In addition, treatment with melatonin and bright-light administration are aimed at improving the adaptation of circadian rhythms to a new sleep-wake schedule, via manipulation of the circadian system. While some of these methods have demonstrated efficacy, the time required for reversal of the phase misalignment is often greater than the time of exposure to the new schedule. Consequently, these treatments are unlikely to be successful in the management of circadian maladjustment in shiftworkers who do not remain on new sleep-wake schedules for substantial periods of time (eg, 2 weeks or more).

Wake-Promoting Compounds

Treatment regimens for shiftwork have begun to move toward more immediate-acting therapies, such as wake-promoting compounds and napping strategies.


A number of studies have examined caffeine’s effectiveness in night-shift workers in promoting neurobehavioral functioning and alertness during sleep deprivation. Rosenthal and colleagues57 reported significant alerting effects of caffeine 75 mg and 150 mg following both a normal (8 hours) and a restricted (5 hours) night’s sleep. Penetar and colleagues58 showed significant alerting effects of caffeine 150 mg, 300 mg, and 600 mg using subjective and objective measures of alertness during a 49-hour period of sustained wakefulness.58 Kamimori and colleagues59 had similar findings after administering low (2.1 mg/kg), medium (4.3 mg/kg), or high (8.6 mg/kg) doses of caffeine during 49 hours of sustained wakefulness.

In subjects deprived of sleep for 45.5 hours, Wright and colleagues60 reported that caffeine 200 mg, administered at 8pm and 2am, enhanced neurobehavioral performance. They used a battery of performance tasks, including reaction time, vigilance and memory tasks, and alertness, assessed using the Maintenance of Wakefulness Test. Caffeine coupled with bright-light exposure, from 8pm–8am, produced the greatest improvement in neurobehavioral performance and alertness, relative to a control condition (dim light plus placebo). The greatest improvement in alertness and performance was observed during the early morning hours, around the time of the circadian nadir.

Lagarde and colleagues61 assessed the efficacy of three doses (150 mg, 300 mg, and 600 mg) of slow-release caffeine on wakefulness and performance, using questionnaires, the multiple sleep latency test (MSLT), and performance tasks including attention, grammatical reasoning, tracking, and memory, across 32 hours of sleep deprivation. Significant increases in MSLT sleep-onset times and decreased subjective sleepiness were reported for the three caffeine doses. This finding is consistent with increased nocturnal sleep latencies noted by Sicard and colleagues62 following administration of 600-mg caffeine using a slow-release formulation. In addition, there was an increase in performance on some neurobehavioral measures relative to placebo, which lasted for 13 hours after administration.


Dinges and colleagues63 investigated the effects of 2-hour naps during 56 hours of sustained operations. The naps took place at the circadian peak and trough, following 6, 18, 30, 42, and 54 hours of wakefulness. Neurobehavioral performance and subjective mood were assessed throughout. There was a significant improvement in neurobehavioral performance following the naps, but no effect on subjective measures of mood. The benefit of naps on neurobehavioral performance may not be apparent immediately if the nap occurs prior to an accumulation of sleep loss, ie, a prophylactic nap. In contrast, it appears that the duration of the effect may be limited (up to 12 hours) if the nap occurs following a period of sleep loss.

Therefore, despite a reported benefit on performance following all the nap periods, the timing of a nap relative to the amount of sleep loss appears to be an important determinant of a nap’s effect on neurobehavioral functioning. Hence, it would appear that prophylactic naps, despite having both lower sleep quantity and quality versus naps occurring later in the deprivation period, provide significant benefits in neurobehavioral functioning for many hours following waking.

Naps Plus Caffeine

A small number of studies have examined the combined effects of caffeine and naps on alertness and neurobehavioral functioning. Bonnet and Arand64 reported a greater improvement in alertness and performance following a 4-hour afternoon nap combined with nocturnal caffeine administration relative to four 1-hour naps across the night. They also reported positive effects on neurobehavioral functioning and alertness during 24 hours of sleep deprivation when prophylactic naps were used in conjunction with caffeine administration.65

Dinges and colleagues66-68 investigated the effects of 88 hours of total sleep deprivation, with and without two 2-hour naps in 24 hours, and with and without sustained low-dose caffeine (0.3 mg/kg/hour) for 66 hours. Caffeine, without naps, reduced the frequency of psychomotor vigilance task (PVT) lapses for up to 22 hours following the first administration (at 22 hours of sleep deprivation), compared with the placebo/no-nap condition. The positive effects of caffeine on neurobehavioral functioning lasted for approximately 22 hours, coinciding with the rising slope of the plasma caffeine pharmacokinetic curve. The greatest benefits in neurobehavioral functioning were evident in the subjects who received caffeine combined with naps. In addition, in these subjects, caffeine was apparently able to significantly attenuate the effects of sleep inertia on neurobehavioral functioning following the 2-hour naps.68


Modafinil is currently approved for use in the management of excessive sleepiness in patients with narcolepsy, a central nervous system disorder characterized by excessive daytime sleepiness, and other symptoms.69 In addition, recent studies have examined modafinil’s wake-promoting effects during sleep deprivation and simulated shiftwork settings.

While its exact mechanism of action has yet to be fully described, modafinil appears to be a novel wake-promoting agent that is chemically and pharmacologically distinct from other central nervous system psychostimulants (eg, amphetamine) and lacks their more serious adverse effects (eg, locomotor agitation). In a randomized, double-blind, crossover study comparing the subjective effects of modafinil (300 mg) to dextroamphetamine (15 mg), caffeine (300 mg), and placebo, the subjective effects of modafinil were similar to those of caffeine, and markedly different from those of dextroamphetamine.70

A number of studies have investigated modafinil’s effectiveness in maintaining alertness in the face of excessive sleepiness due to pathological disorders (eg, narcolepsy) and sleep deprivation (eg, as experienced by shiftworkers). In rested, nonsleep-deprived subjects, morning administration of modafinil 200 mg was reported to enhance vigilance recorded by an electroencephalogram, daytime sleep latency, concentration, complex reactions, subjective alertness, and performance on search and memory tests.71

Two recent studies investigated the effects of modafinil during 64-hour total sleep deprivation.72,73 Pigeau and colleagues73 compared modafinil 300 mg to dextroamphetamine 20 mg or placebo in a double-blind, crossover trial. Both modafinil and dextroamphetamine decreased subjective fatigue and sleepiness and improved reaction time, logical reasoning, and short-term memory performance.73 Although modafinil generally improved all aspects of performance in this study, the drug has also been associated with mild adverse effects on the efficiency of communication74 and subjective estimates of cognitive capability.75

Sleep polysomnography before and after drug administration and sleep deprivation demonstrated that modafinil was associated with fewer sleep disturbances compared to amphetamine.76 Modafinil-treated subjects were better able to sleep than those given amphetamine, and their sleep closely resembled that of subjects in the placebo group. Additionally, the amount of recovery sleep required following 64 hours of sustained wakefulness appeared to be less in those subjects receiving modafinil. This finding is consistent with results from animal work by Edgar and Seidel77 showing that, unlike other psychostimulants, modafinil reduces rebound sleepiness and could reduce the requirement for recovery sleep.

Modafinil’s effect on sleepiness associated with four 24-hour periods of simulated night shiftwork was assessed recently in a controlled laboratory environment.78 During night shifts, subjects were randomized to receive either modafinil 200 mg or placebo. Placebo-treated subjects reported increased subjective feelings of sleepiness and demonstrated significantly attenuated performance on the PVT. In contrast, subjects receiving modafinil reported significantly higher subjective alertness, with a coincident improvement in performance on the PVT. In addition, modafinil did not significantly disrupt daytime sleep periods.

Modafinil’s positive effects on neurobehavioral functioning do not appear to be associated with changes in circadian physiology (Process C)79 or in circadian-mediated hormones (melatonin, cortisol, growth hormone). Rather, its effects appear to involve changes in waking and sleeping processes that reflect the homeostatic drive for sleep (Process S).79 This is evidenced by the fact that modafinil not only reverses physiological, behavioral, and subjective sleepiness, but it does so without disrupting recovery sleep following sleep deprivation. It actually appears to attenuate the need for slow-wave sleep and prolonged recovery sleep following deprivation.76


Shiftwork produces a range of effects on a number of physiological systems, in both the short and long term. Epidemiological studies report decreased health in shiftworkers, including increased cardiovascular complaints and reproductive dysfunctions in night workers. In addition, immediate effects on sleep and neurobehavioral functioning may be evident after only 1 night of shiftwork. Potential treatments for deficits in neurobehavioral functioning include those directed at improving adaptation of the circadian system to new sleep-wake schedules (eg, melatonin and bright light), and more acutely, at improving alertness and neurobehavioral performance directly (eg, naps and caffeine). PP


1.    Czeisler CA, Duffy JF, Shanahan TL, et al. Stability, precision, and near-24-hour period of the human circadian pacemaker. Science. 1999;284:2177-2181.
2.    Czeisler CA, Khalsa SBS. The human circadian timing system and sleep-wake regulation. In: Kryger MH, Roth T, Dement WC, eds. Principles and Practice of Sleep Medicine. 3rd ed. Philadelphia, Pa: W.B. Saunders Company; 2000:353-376.
3.    Weaver DR. The suprachiasmatic nucleus: a 25-year retrospective. J Biol Rhythms. 1998;13:100-112.
4.    Arendt J. Melatonin and the pineal gland: influence on mammalian seasonal and circadian physiology. Rev Reprod. 1998;3:13-22.
5.    Myers BL, Badia P. Changes in circadian rhythms and sleep quality with aging: mechanisms and interventions. Neurosci Biobehav Rev. 1995;19:553-571.
6.    Dawson D, Encel N. Melatonin and sleep in humans. J Pineal Res. 1993;15:1-12.
7.    Morris M, Lack L, Barrett J. The effect of sleep/wake state on nocturnal melatonin excretion. J Pineal Res. 1990;9:133-138.
8.    Australian Bureau of Statistics. Working Arrangements Australia; 1993. Report no. Cat. 63420.
9.    U.S. Congress Office of Technology Assessment. Biological Rhythms: Implications for the Worker; 1991. Report no. OTA-BA-463.
10.    Wedderburn A. Bulletin of European Studies on Time. Dublin, Ireland: European Foundation for the Improvement of Living and Working Conditions; 1993.
11.    Koller M. Health risks related to shiftwork. Int Arch Occup Environ Health. 1983;53:59-75.
12.    Knutsson A, Akerstedt T, Jonsson BG, Orth-Gomer K. Increased risk of ischaemic heart disease in shift workers. Lancet. 1986;2(8498):89-92.
13.    Knutsson A, Hallquist J, Reuterwall C, Theorell T, Akerstedt T. Shiftwork and myocardial infarction: a case-control study. Occup Environ Med. 1999;56:46-50.
14.    Tenkanen L, Sjoblom T, Harma M. Joint effect of shift work and adverse life-style factors on the risk of coronary heart disease. Scand J Work Environ Health. 1998;24:351-357.
15.    Uehata T, Sasakawa N. The fatigue and maternity disturbances of night workwomen. J Hum Ergol. 1982;11(suppl):465-474.
16.    Miyauchi F, Nanjo K, Otsuka K. Effects of night shift on plasma concentrations of melatonin, LH, FSH and prolactin, and menstrual irregularity. Japanese J Ind Health. 1992;34:545-550.
17.    Messing K, Saurel-Cubizolles MJ, Bourgine M, Kaminski M. Menstrual-cycle characteristics and work conditions of workers in poultry slaughterhouses and canneries. Scand J Work Environ Health. 1992;18:302-309.
18.    Ahlborg G Jr., Axelsson G, Bodin L. Shift work, nitrous oxide exposure and subfertility among Swedish midwives. Int J Epidemiol. 1996;25:783-790.
19.    Axelsson G, Ahlborg G, Bodin L. Shift work, nitrous oxide exposure, and spontaneous abortion among Swedish midwives. Occup Environ Med. 1996;53:374-378.
20.    Bisanti L, Olsen J, Basso O, Thonneau P, Karmaus W. Shift work and subfecundity: a European multicenter study. European Study Group on Infertility and Subfecundity. J Occup Environ Med. 1996;38:352-358.
21.    Axelsson G, Lutz C, Rylander R. Exposure to solvents and outcome of pregnancy in university laboratory employees. Br J Ind Med. 1984;41:305-312.
22.    Axelsson G, Rylander R. Outcome of pregnancy in women engaged in laboratory work at a petrochemical plant. Am J Ind Med. 1989;16:539-545.
23.    Hemminki K, Kyyronen P, Lindbohm ML. Spontaneous abortions and malformations in the offspring of nurses exposed to anaesthetic gases, cytostatic drugs, and other potential hazards in hospitals, based on registered information of outcome. J Epidemiol Commun Health. 1985;39:141-147.
24.    Infante-Rivard C, David M, Gauthier R, Rivard GE. Pregnancy loss and work schedule during pregnancy. Epidemiology. 1993;4:73-75.
25.    McDonald AD, McDonald JC, Armstrong B, et al. Fetal death and work in pregnancy. Br J Indust Med. 1988;45:148-157.
26.    Fortier I, Marcoux S, Brisson J. Maternal work during pregnancy and the risks of delivering a small-for-gestational-age or preterm infant. Scand J Work, Environ Health. 1995;21:412-418.
27.    Xu X, Ding M, Li B, Christiani DC. Association of rotating shiftwork with preterm births and low birth weight among never smoking women textile workers in China. Occup Environ Med. 1994;51:470-474.
28.    McDonald AD, McDonald JC, Armstrong B, et al. Prematurity and work in pregnancy. Br J Ind Med. 1988;45:56-62.
29.    Saurel-Cubizolles MJ, Kaminski M. Pregnant women’s working conditions and their changes during pregnancy: a national study in France. Br J Ind Med. 1987;44:236-243.
30.    Sack RL, Blood ML, Lewy AJ. Melatonin rhythms in night shift workers. Sleep. 1992;15:434-441.
31.    Kennaway DJ, Van Dorp CF. Free-running rhythms of melatonin, cortisol, electrolytes, and sleep in humans in Antarctica. Am J Physiol. 1991;260 (6 Pt 2):R1137-R1144.
32.    Barnes RG, Deacon SJ, Forbes MJ, Arendt J. Adaptation of the 6-sulphatoxymelatonin rhythm in shiftworkers on offshore oil installations during a 2-week 12-h night shift. Neurosci Lett. 1998;241:9-12.
33.    Dawson D, Campbell SS. Timed exposure to bright light improves sleep and alertness during simulated night shifts. Sleep. 1991;14:511-516.
34.    Eastman CI. High-intensity light for circadian adaptation to a 12-h shift of the sleep schedule. Am J Physiol. 1992;263(2 Pt 2):R428-R436.
35.    Gallo LC, Eastman CI. Circadian rhythms during gradually delaying and advancing sleep and light schedules. Physiol Behav. 1993;53:119-126.
36.    Dawson D, Campbell SS. Bright light treatment: are we keeping our subjects in the dark? Sleep. 1990;13:267-271.
37.    Trinder J, Armstrong SM, O’Brien C, Luke D, Martin MJ. Inhibition of melatonin secretion onset by low levels of illumination. J Sleep Res. 1996;5:77-82.
38.    Martin SK, Eastman CI. Medium-intensity light produces circadian rhythm adaptation to simulated night-shift work. Sleep. 1998;21:154-165.
39.    Arendt J, Deacon S. Treatment of circadian rhythm disorders—melatonin. Chronobiol Int. 1997;14:185-204.
40.    Arendt J. Jet-lag and shift work: (2). Therapeutic use of melatonin. J R Soc Med. 1999;92:402-405.
41.    Attenburrow ME, Dowling BA, Sargent PA, Sharpley AL, Cowen PJ. Melatonin phase advances circadian rhythm. Psychopharmacology. 1995;121:503-505.
42.    Dawson D, Encel N, Lushington K. Improving adaptation to simulated night shift: timed exposure to bright light versus daytime melatonin administration. Sleep. 1995;18:11-21.
43.    Sack RL, Hughes RJ, Edgar DM, Lewy AJ. Sleep-promoting effects of melatonin: at what dose, in whom, under what conditions, and by what mechanisms? Sleep. 1997;20:908-915.
44.    Lewy AJ, Ahmed S, Jackson JM, Sack RL. Melatonin shifts human circadian rhythms according to a phase-response curve. Chronobiol Int. 1992;9:380-392.
45.    Lewy AJ, Bauer VK, Ahmed S, Thomas KH, Cutler NL, Singer CM, et al. The human phase response curve (PRC) to melatonin is about 12 hours out of phase with the PRC to light. Chronobiol Int. 1998;15:71-83.
46.    Folkard S, Arendt J, Clark M. Can melatonin improve shift workers’ tolerance of the night shift? Some preliminary findings. Chronobiol Int. 1993;10:315-320.
47.    Sack RL, Lewy AJ. Melatonin as a chronobiotic: treatment of circadian desynchrony in night workers and the blind. J Biol Rhythms. 1997;12:595-603.
48.    Rogers NL, Phan O, Kennaway DJ, Dawson D. Effect of daytime oral melatonin administration on neurobehavioral performance in humans.
J Pineal Res. 1998;25:47-53.
49.    Lieberman HR, Waldhauser F, Garfield G, Lynch HJ, Wurtman RJ. Effects of melatonin on human mood and performance. Brain Res. 1984;323:201-207.
50.    Wynn VT, Arendt J. Effect of melatonin on the human electrocardiogram and simple reaction time responses. J Pineal Res. 1988;5:427-435.
51.    Waldhauser F, Saletu B, Trinchard-Lugan I. Sleep laboratory investigations on hypnotic properties of melatonin. Psychopharmacology. 1990;100:222-226.
52.    Dollins AB, Lynch HJ, Wurtman RJ, Deng MH, Kischka KU, Gleason RE, et al. Effect of pharmacological daytime doses of melatonin on human mood and performance. Psychopharmacology. 1993;112:490-496.
53.    Dollins AB, Zhdanova IV, Wurtman RJ, Lynch HJ, Deng MH. Effect of inducing nocturnal serum melatonin concentrations in daytime on sleep, mood, body temperature, and performance. Proc Nat Acad Sci U S A. 1994;91:1824-1828.
54.    Deacon S, Arendt J. Melatonin-induced temperature suppression and its acute phase-shifting effects correlate in a dose-dependent manner in humans. Brain Res. 1995;688:77-85.
55.    Zhdanova IV, Wurtman RJ, Lynch HJ, et al. Sleep-inducing effects of low doses of melatonin ingested in the evening. Clin Pharmacol Ther. 1995;57:552-558.
56.    Zhdanova IV, Wurtman RJ, Morabito C, Piotrovska VR, Lynch HJ. Effects of low oral doses of melatonin, given 2-4 hours before habitual bedtime, on sleep in normal young humans. Sleep. 1996;19:423-431.
57.    Rosenthal L, Roehrs T, Zwyghuizen-Doorenbos A, Plath D, Roth T. Alerting effects of caffeine after normal and restricted sleep. Neuropsychopharmacology. 1991;4:103-108.
58.    Penetar D, McCann U, Thorne D, et al. Caffeine reversal of sleep deprivation effects on alertness and mood. Psychopharmacology. 1993;112:359-365.
59.    Kamimori GH, Penetar DM, Headley DB, Thorne DR, Otterstetter R, Belenky G. Effect of three caffeine doses on plasma catecholamines and alertness during prolonged wakefulness. Eur J Clin Pharmacol. 2000;56:537-544.
60.    Wright KP Jr, Badia P, Myers BL, Plenzler SC. Combination of bright light and caffeine as a countermeasure for impaired alertness and performance during extended sleep deprivation.
J Sleep Res. 1997;6:26-35.
61.    Lagarde D, Batejat D, Sicaed B, Trocherie CD, Enslen M, Chauffard F. Slow-release caffeine: a new response to the effects of a limited sleep deprivation. Sleep. 2000;23:651-661.
62.    Sicard BA, Perault MC, Enslen M, Chauffard F, Vandel B, Tachon P. The effects of 600 mg of slow release caffeine on mood and alertness. Aviat Space Environ Med. 1996;67:859-862.
63.    Dinges DF, Whitehouse WG, Carota Orne E, Orne MT. The benefits of a nap during prolonged work and wakefulness. Work Stress. 1988;2:139-153.
64.    Bonnet MH, Arand DL. Impact of naps and caffeine on extended nocturnal performance. Physiol Behav. 1994;56:103-109.
65.    Bonnet MH, Arand DL. The use of prophylactic naps and caffeine to maintain performance during a continuous operation. Ergonomics. 1994;37:1009-1020.
66.    Dinges DF, Doran SM, Mullington J, et al. Neurobehavioral effects of 66 hr of sustained low-dose caffeine during 88 hr of total sleep deprivation. Sleep. 2000;23(suppl 1):A20-A21.
67.    Rogers NL, Price NJ, Szuba MP, Van Dongen HP, Dinges DF. Effect of sustained caffeine on core body temperature during 88 hours of sustained wakefulness. Sleep. 2001;24(suppl 1). In press.
68.    Van Dongen HP, Doran SM, Mullington JM, et al. Sustained low-dose caffeine administration reduces sleep inertia after nap sleep during 88h extended wakefulness. Sleep. 2000;23(suppl 1):A120-A121.
69.    Lafon LL. Application Dossier Modafinil. France; 1998.
70.    Warot D, Corruble E, Payan C, Weil JS, Puech AJ. Subjective effects of modafinil, a new central adrenergic stimulant in healthy volunteers: a comparison with amphetamine, caffeine and placebo. Eur Psychiatry. 1993;8:201-208.
71.    Lyons TJ, French J. Modafinil: the unique properties of a new stimulant. Aviat Space Environ Med. 1991;62:432-435.
72.    Baranski JV, Cian C, Esquivie D, Pigeau RA, Raphel C. Modafinil during 64 hr of sleep deprivation: dose-related effects on fatigue, alertness, and cognitive performance. Milit Psychol. 1998;10:173-193.
73.    Pigeau R, Naitoh P, Buguet A, et al. Modafinil, d-amphetamine and placebo during 64 hours of sustained mental work. I. Effects on mood, fatigue, cognitive performance and body temperature. J Sleep Res. 1995;4:212-228.
74.    Bard EG, Sotillo C, Anderson AH, Thompson HS, Taylor MM. The DICEM map task corpus: Spontaneous dialogue under sleep deprivation and drug treatment. Speech Commun. 1996;20:71-84.
75.    Baranski JV, Pigeau RA. Self-monitoring cognitive performance during sleep deprivation: effects of modafinil, d-amphetamine and placebo. J Sleep Res. 1997;6:84-91.
76.    Buguet A, Montmayeur A, Pigeau R, Naitoh P. Modafinil, d-amphetamine and placebo during 64 hours of sustained mental work. II. Effects on two nights of recovery sleep. J Sleep Res. 1995;4:229-241.
77.    Edgar DM, Seidel WF. Modafinil induces wakefulness without intensifying motor activity or subsequent rebound hypersomnolence in the rat. J Pharmacol Exp Ther. 1997;283:757-769.
78.    Hughes RJ, Van Dongen HPA, Dinges DF, et al. Modafinil improves alertness and performance during simulated night work. Sleep. 2001;24(suppl 1):A200.
79.    Borbely AA. A two process model of sleep regulation. Hum Neurobiology. 1982;1:195-204.