Current Treatment Options in Neurology (2010) 12:396–411
Treatment of Shift Work
Disorder and Jet Lag
Phyllis C. Zee, MD, PhD
Cathy A. Goldstein, MD*
*710 North Lake Shore Drive, 5th Floor, Chicago, IL 60611, USA
Published online: 20 July 2010
* Springer Science+Business Media, LLC 2010
With the growth of the 24-hour global marketplace, a substantial proportion of workers
are engaged in nontraditional work schedules and frequent jet travel across multiple
time zones. Thus, shift work disorder and jet lag are prevalent in our 24/7 society
and have been associated with significant health and safety repercussions. In both dis-
orders, treatment strategies are based on promoting good sleep hygiene, improving
circadian alignment, and targeting specific symptoms.
Treatment of shift work must be tailored to the type of shift. For a night worker, cir-
cadian alignment can be achieved with bright light exposure during the shift and
avoidance of bright light (with dark or amber sunglasses) toward the latter portion
of the work period and during the morning commute home. If insomnia and/or exces-
sive sleepiness are prominent complaints despite behavioral approaches and adequate
opportunity for sleep, melatonin may be administered prior to the day sleep period to
improve sleep, and alertness during work can be augmented by caffeine and wake-
For jet lag, circadian adaptation is suggested only for travel greater than 48 h,
with travel east more challenging than travel west. Although advancing sleep and
wake times and circadian timing for eastward travel with evening melatonin and
morning bright light several days prior to departure can help avoid jet lag at the
new destination, this approach may be impractical for many people, Therefore,
strategies for treatment at the destination, such as avoidance of early morning light
and exposure to late-morning and afternoon light alone or in conjunction with bedtime
melatonin, can accelerate re-entrainment following eastward travel. For westward
travel, a circadian delay can be achieved after arrival with afternoon and early-evening
light with bedtime melatonin.
Good sleep hygiene practices, together with the application of circadian principles, can
traditional efficacy outcomes such as sleep and performance as well as novel biomarkers
Humans have an endogenous circadian rhythm
slightly longer than 24 h. The International Classifi-
cation of Sleep Disorders describes nine circadian
rhythm disorders defined by a persistent or recurrent
pattern of sleep disturbance resulting from either
alterations of the circadian timekeeping system or
misalignment between the endogenous circadian
rhythm and exogenous factors that affect the timing
and duration of sleep . Shift work disorder and
jet lag are two circadian rhythm disorders that occur
due to the alteration of the external environment
relative to the internal circadian timing system
Shift work disorder
As of 1991, 20% of the United States workforce partic-
ipated in some type of shift work . Of these, more
than 30% of night workers and 25% of rotating shift
workers meet criteria for shift work sleep disorder
. In Europe, only 24% of the workforce keeps con-
ventional working hours, and 18.8% have a work
schedule that involves night shift work . Shift work
disorder is characterized by both insomnia and exces-
sive sleepiness associated with the work period occur-
ring during the usual time for sleep . The diagnosis
requires that symptoms are of at least 1 month’s dura-
tion and circadian misalignment must be demonstrat-
ed with a sleep diary or actigraphy . Insomnia and
excessive sleepiness are thought to be primarily due
to a misalignment between the scheduled sleep/wake
cycle and the circadian propensity for sleep and alert-
ness. Typically, the patient is attempting to sleep when
the circadian signal for alertness is high and working at
a time when the circadian alertness levels are low .
In addition to circadian factors, sleep is often short-
ened in shift workers because of problems with the en-
vironment for sleep and because domestic and social
responsibilities encroach on the worker’s nonconven-
tional sleep time . Therefore, sleep loss, in addition
to circadian misalignment, contributes to decreased
alertness during night work . Sleepiness in shift
workers can be profound: one third of night workers
admit to nodding off once a week during work, and
one half report falling asleep while commuting .
In addition to sleepiness, circadian misalignments in
performance have also contributed to serious acci-
dents, including the incidents at Three Mile Island
and Chernobyl and the Exxon Valdez disaster . Shift
workers with shift work disorder are at higher risk for
cardiovascular disease, ulcers, depression, and absen-
teeism than shift workers without shift work disorder
. Because of both public safety concerns and conse-
quences to the patient, treatment of shift work disor-
der is imperative.
Jet lag disorder
Jet lag disorder is defined as symptoms of insomnia
and/or excessive daytime sleepiness resulting from
travel across at least two time zones . It is also asso-
ciated with compromised daytime function, general
malaise, or somatic complaints (eg, gastrointestinal
symptoms) occurring within 1 to 2 days of travel .
Unlike travel fatigue, jet lag symptoms do not resolve
with an adequate sleep period upon arrival and may
occur even when unfavorable air travel conditions
(cramped space, etc.) are minimized . Because the
intrinsic clock cannot adjust to the change in time
zones as rapidly as we can traverse them with jet travel,
there is a resultant discord between the timing of sleep
as generated by the endogenous circadian rhythm and
the sleep/wake times necessary in the new time zone
[8••]. Eastward travel often results in sleep-onset in-
somnia as the endogenous circadian rhythm (as set
by the location of origin) is not conducive to sleep
at the new, earlier time at the destination; the circadi-
an rhythm must advance. In westward travel, difficul-
ties in remaining asleep are a more prominent
problem, as the circadian alerting signal occurs during
the desired sleep period at the new destination; the cir-
cadian rhythm must delay . In either case, sleepi-
ness results from both circadian misalignment and
truncated sleep duration. In jet travel, it has been
demonstrated that the endogenous circadian rhythm
resets approximately 92 min later each day after a
flight westward and approximately 57 min earlier
each day after a flight eastward. Therefore it is more
difficult to align the intrinsic rhythm with the external
clock in eastward travel . Alignment may occur in
the opposite direction (referred to as antidromic re-
entrainment) when traveling across more than eight
time zones . In addition to the direction of travel
Shift Work Disorder and Jet LagZee and Goldstein
and sleep loss, other factors that may influence the
severity of jet lag include the number of time zones
crossed, exposure to and the magnitude of local
circadian time cues (eg, alteration of light during
various times of the year), and individual variance
. Thirty million US citizens traveled overseas in
2009, but the exact incidence of jet lag is unknown
. Although jet lag is usually benign and transient,
it may become recurrent and problematic in those who
travel frequently and may result in occupational hazard.
To understand the therapeutic strategies used in
treating shift work disorder and jet lag, one must ap-
preciate how circadian and homeostatic processes
interact to regulate sleep and wakefulness. The mas-
ter clock regulating the endogenous circadian
rhythm is located in the suprachiasmatic nucleus
(SCN) located in the anterior hypothalamus .
The cycle of sleep and wake is the most prominent
circadian rhythm, with the highest propensity for
sleep occurring near the nadir of core body temper-
ature (occurring approximately 2 to 3 h before the
usual wake time) .
This circadian process interacts closely with the ho-
meostatic drive for sleep. SCN neurons are active dur-
ing the subjective day and are stimulated by light. As
the homeostatic drive for sleep accumulates with
wakefulness, SCN activity increases to maintain alert-
ness and then decreases in the evening, prior to sleep
time , facilitating sleep. Interestingly, pineal melato-
nin begins to rise about 2 h before sleep onset . As
the homeostatic drive dissipates during sleep, SCN ac-
tivity remains low. It has been postulated that melato-
nin helps to maintain sleep by its ability to inhibit the
firing rate of the SCN neurons .
Light is the strongest cue synchronizing the circa-
dian clock to the external environment . After light
is received by melanopsin-containing retinal gangli-
on cells, photic information is transmitted via the ret-
inohypothalamic tract to the suprachiasmatic nucleus
. Light in the evening (before the core body tem-
perature minimum is reached) delays the circadian
rhythm, and light given in the morning (after the core
body temperature minimum is reached) advances the
circadian rhythm. The phase-response curve to light
demonstrates that the magnitude of phase shift is
greatest when light would usually be absent (during
Melatonin is a hormone regulated by the SCN and
secreted by the pineal gland. Melatonin levels begin to
rise 1 to 3 h before the habitual sleep time and peak
just prior to the core body temperature nadir . In
contrast to light, melatonin given in the evening shifts
the circadian rhythm to an earlier time, and melatonin
given in the morning shifts it to a later time. The
phase-response curve to melatonin shows the largest
magnitude of change occurring at the time when endog-
enous secretion is the lowest (during the day).
The treatment of shift work disorder and jet lag is multifaceted and
includes strategies to achieve and maintain some degree of circa-
dian alignment (Fig. 1), improve sleep (using hypnotics, melatonin,
and behavioral approaches), and facilitate alertness (using light,
wake-promoting agents and sleep scheduling) (Table 1). In addi-
tion, good general sleep hygiene is an integral part of managing
both disorders. Measures include: regular sleep and wake times,
routine exercise (but not within three hours of bedtime), abstaining
from caffeine, nicotine, heavy meals, alcohol, and stressful or
stimulating activities near bedtime, and creating an environment
conducive for sleep .
Treating shift work disorder
Diet and lifestyle
Scheduled sleep times
By dissipating the homeostatic drive for sleep, napping is an effective
strategy to counteract sleepiness in shift workers. Napping prior to night
Figure 1. In an individual with normal circadian phase, dim-light melatonin onset occurs 7 h prior to core body temperature
minimum, which is about 2 to 3 h before the usual wake time. The timing of the peak of melatonin secretion and core body
temperature minimum are associated with a high circadian propensity for sleep and occur within the sleep period during
normal conditions. A, In a night-work/day-sleep cycle, circadian sleep-promoting factors occur before the sleep period, so the
goal is a phase delay to align the endogenous clock with the external environment with appropriately timed light, avoidance of
light, and melatonin. B, With jet travel over six time zones east, the circadian propensity for sleep (as set by the origin of
travel) falls after the desired sleep period at the local time in the destination. A phase advance with appropriately timed light
and/or melatonin can accelerate circadian alignment. (Adapted from Kwon and Zee ).
Shift Work Disorder and Jet LagZee and Goldstein
shift work has been associated with decreased accidents and improved
alertness and performance. Beneficial effects of napping before night
work were further augmented with caffeine administration [13, Class III;
14, Class I].
Naps of 20 to 50 min duration during shift work have produced
improvements in reaction time and have restored performance to that
seen at the beginning of the shift. In addition, napping early in the night
shift improves objective measures of alertness [15, 16; Class II]. If the
nap duration is greater than 30 min, some degree of sleep inertia may
occur [15, Class II].
No disruption of the main sleep period occurred secondary to the nap
[16, Class II; 17, Class IV]. Planned napping is considered a standard of
care in the treatment of shift work disorder by the American Academy of
Sleep Medicine (AASM) .
The AASM recommends melatonin prior to day sleep as a treatment
guideline for shift work disorder . Exogenous melatonin has effects
of both resetting the circadian clock and acting as a direct hypnotic .
In a randomized, controlled trial of 32 individuals undergoing
simulated night work with attempted sleep occurring in the afternoon
and evening, melatonin at doses of 3 mg or 0.5 mg or a placebo was
given prior to the nonconventional sleep period. Both doses of melato-
nin resulted in a significant phase advancement (3 h for 0.5 mg and 3.9 h
for 3 mg), compared with placebo [18, Class I]. In addition to shift work
simulation, the clock resetting effects of melatonin have also been
demonstrated in some night workers during field studies [19, Class I].
The addition of melatonin did not augment circadian adaptation in
the setting of a treatment strategy using bright light therapy during the
night shift and light avoidance in the morning [20, Class II].
Melatonin (1.8–6 mg), given prior to day sleep, has been shown to
improve total sleep duration in both simulated night shifts and studies
of night workers [21, Class I; 22, Class III; 23, Class II].
No improvements in nighttime alertness have been seen with the use
of melatonin [21, Class I; 24, 25, Class II].
Table 1. Treatment of shift work disorder
Timed light exposure
Administration of melatonin prior to day sleep
Hypnotic medication to promote day sleep
Modafinil to enhance alertness
Caffeine to enhance alertness
Strength of recommendation
aStandard—Generally accepted patient care strategy reflecting a high degree of clinical certainty.
bGuideline—Patient care strategy reflecting a moderate degree of certainty.
cOption—Uncertain clinical use.
(Adapted from Morgenthaler et al. .)
No field studies or simulated studies of early morning shift work
using melatonin are currently available. However due to the known
efficacy of exogenous evening melatonin in advancing circadian rhythms,
melatonin may be a rational treatment option for shift work requiring an
early rise time. Further studies are needed.
The AASM suggests caffeine as a treatment option to enhance alertness
during night work .
It is well known that caffeine can be an effective countermeasure
for sleepiness during experimentally induced sleep deprivation,
making it a feasible option for treatment in shift work disorder and jet
In a double-blind, randomized, placebo-controlled trial of 15
individuals performing simulated night work, coffee (2 mg/kg dose of
caffeine) was given immediately prior to and during the first portion of
the night shift. There was significant improvement in sleepiness as
measured by the multiple sleep latency test, and participants rated
themselves as 25% more alert. There was no residual effect on daytime
sleep as measured by polysomnography [26, Class I].
A recent meta-analysis found that caffeine (compared with placebo)
improved shift workers’ performance in multiple domains of neuropsy-
chiatric testing, including memory and attention .
Benzodiazepines and benzodiazepine receptor agonists
Hypnotic medications have been evaluated for shift work disorder, spe-
cifically for the treatment of insomnia occurring as a result of attempting
sleep during the period of high circadian alerting signal.
Triazolam (0.25–0.5 mg) and temazepam (20 mg) have been shown
to be effective in increasing daytime sleep duration with both subjective
and objective measures. No improvements in nighttime alertness (by self
report or by mean sleep latency testing) have been demonstrated with
either medication, however [28, 29, Class I; 30, Class III; 31, Class II].
Two field studies of shift workers using zopiclone also showed sub-
jective improvements in sleep quality and duration, but there was no
evidence of improvement in work performance [32, Class I; 33, Class II].
In a study of seven individuals undergoing simulated rotating shifts,
those receiving zolpidem had improved subjective sleep quality, but
their mood was worsened during the following work period, compared
with placebo .
In the AASM practice parameters, the use of hypnotic medication is a
treatment guideline to facilitate day sleep in night workers. These agents
should be administered with great caution when used for insomnia
during the nonconventional sleep period, however, because of the
potential for unfavorable effects on nighttime performance and
alertness . Further studies are needed to determine the efficacy
Shift Work Disorder and Jet Lag Zee and Goldstein
of benzodiazepines and benzodiazepine receptor agonists in shift work
Benzodiazepine and benzodiazepine receptor agonist medications are not
approved by the US Food and Drug Administration (FDA) for the specific
purposes of treating shift work disorder or jet lag. However, for short-term
insomnia, temazepam (7.5–30 mg) or zolpidem (5–10 mg) may be used at
bedtime [35, 36]. Zopiclone is not available in the United States.
Temazepam and zolpidem should be used with care in elderly and de-
bilitated patients, and alcohol should not be used with either. With
temazepam, slow tapering of the medication should be performed prior
to discontinuation because of a risk of seizure with abrupt cessation.
Zolpidem is a pregnancy category C medication. Pregnancy is an absolute
contraindication to temazepam use because of its class X designation [35, 36].
Main drug interactions
Central nervous system depressants may have an additive effect with tema-
zepam and zolpidem. Oral contraceptive pills may increase the clearance of
temazepam, and probenecid may decrease its clearance [35, 36].
Main side effects
The most frequently reported adverse effects of zolpidem are daytime
drowsiness, headache, and dizziness. Amnesia may occur with benzodiaze-
pine and benzodiazepine receptor agonist medications, and non–rapid eye
movement (NREM) parasomnias such as sleep walking or sleep eating also
may occur. The most common adverse effects of temazepam are headache,
drowsiness, ataxia, dizziness, confusion, depression, syncope, fatigue, verti-
go, and tremor. Patients should be monitored for physiologic dependence
on temazepam [35, 36].
Both zolpidem and temazepam are less than $20 for a 30-day supply,
making them cost-effective treatment options.
Because night shift work occurs during a time of high propensity for
sleep, wake-promoting medications have been investigated to improve
alertness in shift workers.
In one study, methamphetamine improved mood and performance
during the night shift in simulated laboratory workers [37, Class II].
However, because of the minimal evidence supporting its use and its
potential for abuse, this medication is not indicated in the treatment of
shift work disorder .
In a randomized double-blind controlled trial, modafinil (200 mg)
was given 30 to 60 min before the start of night shift work, resulting
in objective improvement in sleepiness and improved performance on
psychomotor vigilance testing. In addition, there were 25% fewer
accidents and near-accidents in the modafinil group than in the pla-
cebo group (PG0.001). Despite these functional improvements and
the attenuation of sleepiness, a pathologic level of sleepiness similar
to that of narcolepsy (mean sleep latency, 3.8 min) persisted in night
shift workers [38, Class I].
Armodafinil is the R isomer of modafinil and has a longer half life
(15 h) than the S isomer of modafinil (3–4 h). In a 12-week randomized
controlled trial of 254 night shift and rotating shift workers with shift
work disorder, 150 mg of armodafinil was given 30 to 60 min prior to
beginning the night shift. Armodafinil resulted in a significant increase in
meansleep latencycompared withplacebo (3min vs0.4minrespectively).
By self-report, armodafinil reduced sleepiness during work and on the
morning commute. Significant improvement in performance on standard-
daytime sleep parameters occurred with armodafinil [39•, Class I].
Modafinil and armodafinil are effective in promoting alertness during
night shift work and are FDA-approved for the treatment of shift work
Modafinil (200 mg) or armodafinil (150 mg) taken approximately 1 h prior
to shift work.
Patients with cardiac signs or symptoms occurring in the setting of stimulant
medication should not take modafinil or armodafinil. Caution should be
exercised in prescribing these medications for patients with a known history
of psychosis, unstable angina, or recent myocardial infarction, and those
with seizures. Both drugs are FDA pregnancy category C [40, 41].
Main drug interactions
Modafinil and armodafinil may decrease the effectiveness of oral contra-
ceptive pills and other drugs metabolized by the CYP3A4 isoenzyme, and
drugs inducing the CYP3A4 enzyme may increase the metabolism of mod-
afinil and armodafinil [40, 41].
Main side effects
Rare but life-threatening rashes have occurred with modafinil therapy .
Headache, nausea/vomiting, anxiety, nervousness, and insomnia were the
most common adverse reactions occurring in clinical trials of modafinil .
Headache, nausea/vomiting, dizziness, and insomnia were the most com-
mon adverse reactions occurring in clinical trials of armodafinil . Some
individuals taking armodafinil had a small elevation in blood pressure .
The retail price for a 30-day supply is $475.95 for modafinil (Provigil;
Cephalon, Frazer, PA) and $304.97 for armodafinil (Nuvigil; Cephalon,
Timed bright light exposure
Timed light exposure can be employed for its circadian phase shifting
effects as well as its beneficial effects on alertness and cognitive perfor-
mance . The AASM suggests the use of timed light during the work
period and restriction of morning light in night shift workers as a treat-
ment guideline .
In field studies of shift workers, light regimens of 2350 to 12,000 lux
for durations of 20 minutes (with multiple exposures) to 6 h have shown
improvements in psychomotor performance, subjective alertness, and
self-rated mood [43, 44, 45, Class III].
Bright light exposure and the avoidance of light have been used to
promote circadian shifts to move the core body temperature nadir from
the work period to the sleep period. Studies using this treatment strategy
have been performed in both night work simulation and in field testing
of actual night workers . Bright light of 6000 to 12,000 lux during at
least half of a 12-hour night shift resulted in a significant phase shift in
50% of shift workers receiving the treatment, compared with controls
Shift Work Disorder and Jet LagZee and Goldstein
receiving ambient light [44, Class III]. The largest phase shifts and
improvements in subjective sleep quality have occurred in groups using
both interventions: bright light during the night shift combined with
light avoidance (using dark sunglasses or goggles) the following morning
[23, 46; Class II].
Despite the benefits in performance and alertness produced by aligning
the circadian rhythm to night work, many patients may be reluctant to do
so, as they want to realign their phase to a conventional diurnal waking
using a goal “compromise position” with the core body temperature nadir
near 10:00, which puts the highest circadian propensity for sleep early but
within the sleep period on work days and late but within the sleep period
appropriate for days off. This compromise position was achieved with
bright light, light avoidance, and scheduled sleep times (08:30 to 15:30 on
off. The subjects aligning to the “compromise position” had mood, fatigue,
and performance ratings that were markedly superior to controls and were
similar to those of subjects completely entrained to a night-wake, day-sleep
schedule. This partial entrainment strategy may be an effective strategy for
permanent night workers to improve function on both work days and days
off [47•, Class II].
Although no standard protocol for bright light therapy exists, studies have
been performed with both intermittent and sustained exposures of 2350 to
12,000 lux. Ultraviolet wavelength light should be filtered . Light therapy
treatment is not regulated by the FDA.
Patients with retinopathies should not receive treatment with bright light
therapy. Great care should be taken in those using medications causing
photosensitization and patients with bipolar disorder .
Hypomania, irritability, nausea, headache, blurred vision, eye strain, pho-
tophobia, and sleep disturbances are the most frequently reported adverse
reactions. Side effects are uncommon, may depend on dose and timing, and
may resolve over time .
Light boxes range in price from about $200 to $500. As a one-time investment,
this may be a cost-effective option.
Treating jet lag
Diet and lifestyle
Scheduled sleep times
In jet lag, sleep scheduling is used as an adjunct to light in shifting the
For travel of greater than 48 h, travelers could attempt to shift their
circadian rhythm prior to departure. In a study to determine how
much bedtimes could be shifted (while using bright light therapy) in
preparation for eastward travel, subjects advancing bedtimes by 2 h
per day experienced greater sleep-onset insomnia than those advancing by
treatment. Therefore, advancing bedtime by 1 h per day in combination
with light therapy may be a useful intervention in the anticipation of east-
ward travel [49, Class II]. This sleep schedule advance prior to travel east is
recommended as a treatment option by the AASM .
However, for travel less than 48 h, those maintaining the sleep/wake
times of the location of origin reported decreased sleepiness and better
global jet lag ratings than those adopting the sleep/wake times of the
destination location during a study of travel over nine time zones [50,
Class II]. The AASM suggests keeping home sleep and wake times during
travel of 2 days or less as a treatment option .
Exposure to and avoidance of natural light
Bright light therapy has demonstrated significant augmentation of phase
shifts in simulated studies of eastward travel. (See the discussion of
timed light exposure below.) However, although this phase shift may
attenuate circadian misalignment, bright light therapy may be inconve-
nient during travel, making the exposure to and avoidance of natural
light (using dark sunglasses) a more feasible treatment for jet lag.
During westward travel, the goal is to delay the circadian rhythm, so
light exposure should be sought during what would be evening in the
location of departure and avoided during what would be morning in the
location of departure. For eastward travel, to initiate a phase advance,
light should be avoided during what would be evening in the location of
departure, and light exposure should occur during what would be
This strategy is best illustrated by example. If a traveler lives in
Chicago and usually sleeps from 11 PM to 7 AM, his core body temperature
minimum (assumingnormalcircadianphase)wouldlikelybecloseto4 AM
(11 PM Hawaii time). If he departs from Chicago at 0900 and lands in
light and avoid bright light in the morning. Conversely, if he travels from
Chicago to Paris (where his core body temperature minimum would be at
11 AM), departing at 1800 and arriving at 1100 (local time), he should seek
plenty of afternoon light and avoid morning light prior to 11 AM. This
example also demonstrates that some degree of phase shifting prior to
eastward travel may be beneficial to move the core body temperature
minimum to the dark period, preventing light exposure during the wrong
portion of the phase-response curve .
In multiple studies for jet lag, melatonin has shown benefits likely due to
both its phase shifting and sedating effects.
Of nine double-blind, placebo-controlled field studies evaluating the
effects of melatonin on subjective measures of jet lag, seven studies
showed more favorable ratings of symptoms with melatonin than with
placebo. These studies used 0.5 mg to 8 mg (most commonly 5 mg) of
melatonin for travel of up to 12 time zones [8••].
Objectively, melatonin has demonstrated increased total sleep time
and decreased waking after sleep onset (as measured by actigraphy),
compared with placebo [53, Class I].
Shift Work Disorder and Jet LagZee and Goldstein
Melatonin has also shown acceleration of phase shift during travel, as
measured by cortisol and melatonin rhythms [54, 55, 56].
Appropriately timed melatonin use, to improve both sleep and
waking symptoms, is considered a standard treatment for jet lag by the
Caffeine has been evaluated in jet lag in two studies, both with 27
subjects traveling eastward over seven time zones. Slow-release caffeine
(300 mg) given at 0800 the first 5 days after arrival improved objective
measures of daytime sleepiness and accelerated circadian entrainment, as
measured by cortisol rhythms. Caffeine did result in greater subjective
and objective sleep disruption than placebo [54, 57; Class II].
related to jet lag .
Benzodiazepine and benzodiazepine receptor agonists
The benzodiazepines temazepam, midazolam, and triazolam have been
evaluated for the treatment of jet lag in four studies. In eastward travel,
temazepam and midazolam showed improvement in subjective sleep
quality and objective sleep measures by actigraphy, but no benefits were
noted in westward travel [8••].
Zolpidem (10 mg) has demonstrated improved sleep quality and dura-
tion, as well as improvement in jet lag symptoms, after eastward travel, but
adverse effects (including nausea, vomiting, amnesia, and somnambulism)
Zopiclone has also shown increased sleep duration (as measured by
in comparison with melatonin, and there is no evidence that this hypnotic
improves symptoms of jet lag [53, Class I; 60, Class II].
The AASM does suggest benzodiazepine receptor agonist hypnotic
However, more research is needed regarding the effect of these agents on
waking jet lag symptoms, and patients must be educated about potential
side effects .
Timed light exposure
In jet lag, light therapy has been used with the goal of shifting circadian
or continuous bright light therapy in the first 3.5 h after awakening (com-
bined with advancing sleep schedules), subjects in the bright light group
control group. In addition, those receiving continuous light did not have a
worsening in their jet lag score with advancing bedtimes, as did those
receiving intermittent or no bright light [61, Class II].
In a field study of westward travel (Zurich to New York), light was
used to delay the circadian rhythm after arrival. Although a greater
phase delay occurred with bright light therapy, there was no difference
in jet lag scale, psychomotor performance, or mood [62, Class II].
Morning bright light therapy (in combination with advancement of
the sleep schedule) before travel east is recommended as a treatment
option by the AASM.
Emerging therapies for shift work disorder and jet lag
The homeostatic drive for sleep is dissipated by sleep occurring during the
initial portion of the sleep period. During the night, this is counteracted by
the circadian propensity for sleep, partly due to the inhibitory effects of
melatonin on the SCN . Because night workers are sleeping during the
“wrong” circadian time, they lack this mechanism for sleep maintenance.
When 2.1 mg of melatonin (compared with placebo) was given
transdermally 1 h before an 8-hour daytime sleep opportunity, waking
after sleep onset and in the latter third of the sleep period decreased,
sleep efficiency increased, and total sleep time increased. Although
melatonin levels remained elevated after the sleep period, subjective
alertness and visual attention were not affected, as measured by the
Karolinska Sleepiness Scale and psychomotor vigilance testing .
A sustained-release method of delivering melatonin may be an
effective option for sleep-maintenance insomnia in those with a
nonconventional day sleep schedule, but more studies are needed.
Melatonin receptor agonists
Melatonin has produced marked improvement in jet lag symptoms and
mixed effects in the treatment of shift work disorder. Because melatonin
varies in potency and quality and is not regulated by the FDA, a mela-
tonin receptor agonist may be a promising treatment for shift work
disorder and jet lag.
Ramelteon is an MT1and MT2receptor agonist. In a study to de-
termine the ability of ramelteon to realign the circadian rhythm after
an imposed 5-hour advance of sleep-wake times in 75 healthy adults,
ramelteon was given 30 min prior to the new bedtime. A significant
circadian shift to an earlier time occurred in patients receiving 1 mg,
2 mg, or 4 mg of ramelteon, compared with placebo. Headache and
nausea were the most commonly experienced adverse reactions and
were mild in severity [64, Class I].
In a recent randomized, double-blind, placebo-controlled trial, 109
individuals with a history of jet lag were given 1 mg, 4 mg, or 8 mg of
ramelteon or placebo at their usual bedtime after arrival following
eastward travel of five time zones. On all nights following travel, with a
1-mg dose of ramelteon, there was a significant reduction of latency to
Shift Work Disorder and Jet LagZee and Goldstein
persistent sleep (-10.6 min, P=0.03) as compared with placebo. When
further examining two subsets of the study (those exposed to natural
light and those kept in dim light conditions), the group exposed to
natural bright light and taking a placebo experienced sleep-promoting
effects similar to the effects on those in dim light who received 1 mg of
ramelteon. Therefore, ramelteon could be a treatment option during
travel when bright light is less accessible (eg, during the winter). There
were no significant differences between the ramelteon group the placebo
group in sleepiness scales during waking hours. At the 4-mg dose,
significant improvements in subjective daytime function, alertness,
concentration, sleep quality, and ease of awakening were seen. Adverse
effects were similar across all groups [65•, Class I].
Tasimelteon is another MT1and MT2receptor agonist. In a phase 3,
double-blind, randomized placebo-controlled trial, 411 individuals un-
derwent a 5-hour advance of sleep-wake times and received tasimelteon
at the new bedtime. Compared with placebo, all doses of tasimelteon
were followed by decreased latency to persistent sleep onset, decreased
waking after sleep onset, increased total sleep time, and increased sleep
efficiency. Results of neurocognitive testing the day after treatment were
no different with tasimelteon or placebo [66, Class I].
Agomelatine (also an MT1and MT2receptor agonist, as well as a
serotonin agonist) has been shown in a double-blind, placebo-controlled
trial to significantly phase-advance body temperature profiles .
treatingshift workdisorder resulting fromearly morningshifts as wellas jet
lag resulting from eastward travel.
Although approved for shift work disorder, armodafinil does not cur-
rently have an indication in jet lag.
In a recent double-blind, randomized, placebo-controlled study to
determine the efficacy of armodafinil in jet lag, 427 individuals traveled
or placebo daily at 7 AM local time after arrival. Those receiving 150 mg of
armodafinil had significant improvements in objective measures of sleepi-
ness (mean sleep latency on the Multiple Sleep Latency Test of 11.7 min vs
4.8 min with placebo, PG0.001) and less severe symptoms of jet lag [68•,
Armodafinil may be an effective agent for combating daytime sleep-
iness associated with jet lag.
Dr. Zee has received consulting fees from Takeda, Cephalon, Philips, Sanofi-aventis, and Merck; hon-
oraria from Sanofi-aventis; and a sleep fellowship education grant fromTakeda.She also has beenpaid to
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