1. health and fitness
2. disorders
3. sleep disorders

Treatment of patients
with shift work sleep disorder
Gonzalo A. Salgado, MD
Fredric Jaffe, DO
hift workers with shift work sleep disorder
(SWSD) are at high risk for various comorbidities.
Because of these consequences to the patient,
as well as public safety concerns related to workers
with SWSD, effective treatment for patients with this
condition is imperative. The 2 cardinal symptoms of
SWSD—excessive sleepiness and insomnia—are thought
to be caused by misalignment between the scheduled
sleep-wake periods and the circadian propensity for
sleep alertness.1 Patients typically attempt to sleep
when their circadian signals for alertness are high, and
they work when their circadian alertness levels are low.
S
Dialogue and Diagnosis // March 2012
27
The management of SWSD requires
an individualized and comprehensive
approach, incorporating various strategies targeted at either the underlying
misalignment or at the 2 defining
symptoms of the disorder. Other objectives of treatment are to improve the
patient’s cognitive function and performance and safety on the job. In the
present article, we review the physiologic mechanisms of the circadian
rhythm and various alternatives for
treating patients with SWSD including
the level of recommendation based on
the American Academy of Sleep Medicine (AASM) guidelines for the treatment of circadian rhythm disorders
(Table 1).2
Normal circadian
physiology
To better understand how available interventions correct circadian misalignment, it is necessary to understand the
normal mechanisms of circadian
rhythm physiology.
A circadian pacemaker, also referred to as the “biological clock,”
controls the daily patterns in neuroendocrine function and behavior,
such as the sleep-wake cycle and fluc-
tuations in many physiologic processes. This central pacemaker—located in
the suprachiasmatic nucleus (SCN),
within the hypothalamus of human
beings and other mammals—functions on a cycle of approximately 24.2
hours.3 Because the cycle of the SCN
pacemaker is slightly longer than the
24-hour biological clock, it eventually
will not fit into the 24-hour day if the
two systems are not entrained or synchronized. Natural zeitgebers (German for “time givers” or “synchronizers”) help the circadian rhythm stay
within a 24-hour window and not
shift out of phase. These zeitgebers are
light, melatonin, and social or physical activities.4 Of these agents, light
and melatonin are recognized as having the greatest influence on determining the entrainment of endogenous circadian rhythms.
Light stimulates the neurons in the
SCN via the retinohypothalamic tract.4
The timing of light exposure ultimately determines effects on the entrainment of circadian rhythms. Exposure
to light in the evening causes a delay
in the circadian rhythm, with the consequences of postponement of the rest
period and a late awakening time.
Exposure to light in the morning causes an advance of the circadian rhythm,
resulting in early initiation of sleep and
early awakening.
Melatonin is a hormone secreted
by the pineal gland under regulation
of the SCN. Melatonin levels start to
increase 1 to 3 hours before an individual’s usual sleep time.5 This melatonin secretion essentially blocks the
circadian signals for wakefulness from
the SCN. Opposite to the effects of
light exposure, exogenous melatonin
administration in the evening shifts
the circadian rhythm to an earlier
time (ie, advances the circadian
rhythm), and melatonin administration in the morning shifts the circadian rhythm to a later time (ie, delays
the circadian rhythm).
The circadian system interacts
with the homeostatic drive for sleep,
which naturally generates pressure
for sleep after several successive hours
of wakefulness. As the homeostatic
drive for sleep accumulates, the SCN
activity increases to maintain alertness. In the evening, with decreased
light exposure and secretion of melatonin, the SCN activity decreases to
facilitate sleep.
Table 1
AASM Levels of Recommendations
Strength of
Recommendation
Standard
Definition
Generally accepted patient-care
strategy that reflects a high
degree of clinical certainty
Guideline
Patient-care strategy that reflects a
moderate degree of clinical certainty
Option
Patient-care strategy that
reflects uncertain clinical use
Table 1. Adapted from Morgenthaler TI, Lee-Chiong T, Alessi C, et al.2
28
Dialogue and Diagnosis // March 2012
Nonpharmacologic
treatment
dian rhythm.14 Thus, an exercise program might help in the adaptation of
Change in work pattern
shift workers to their sleep-wake schedThe symptoms of SWSD are directly ule. Further research is needed to idenlinked to the out-of-phase shift-work tify the timing and type of exercise that
schedule, and they usually resolve after would have the best impact on SWSD.
the patient returns to daytime work.
However, returning to daytime work is Scheduled naps
impractical for many individuals. In Napping is considered an effective
most cases, occupational and societal strategy to counteract sleepiness in
constraints prevent the implementa- shift workers. Naps have been shown
tion of this option.
to decrease accidents15 and to improve
For workers on night shifts, more performance in shift workers, as measthan 4 consecutive 12-hour night ured by the Maintenance of Wakefulshifts should be avoided because of a ness Test and the Psychomotor Vigidocumented increased risk of accidents lance Task, particularly when used
and injuries.6 There is also evidence of with caffeine administration.16 Benefidecreased cognitive performance and cial effects, such as improvements in
increased sleepiness in this group of sleepiness and performance in vigiworkers.7,8 Individuals on rotating lance and neurobehavioral testing, can
shift schedules should be encouraged be seen when planned naps take place
to rotate in a clockwise, rather than before or during night-shift work.17,18
counterclockwise, manner (ie, mornIt is important to note that no studing to evening to night, rather than ies have evaluated outcomes of napping
night to evening to morning), because in patients with SWSD. Besides this limthis pattern follows the natural pattern itation, implementation of napping
of delaying the sleep period.9
might be difficult in the workplace, because appropriate facilities may not be
Sleep hygiene
available and napping might be considMeasures for improving sleep hygiene ered unprofessional or ethically unacare recommended not only for patients ceptable in some work settings. Neverwith SWSD, but also for all shift work- theless, the AASM considers scheduled
ers. Patients should be advised on how or planned naps a standard treatment of
to create a proper environment for patients with SWSD.2
sleep in terms of levels of darkness,
noise, and temperature, together with Light exposure
how to mentally and physically pre- The interaction between light exposure
pare for sleep (eg, avoidance of large and the endogenous circadian rhythm
meals, caffeinated drinks, smoking, and forms the basis for light therapy as a
alcohol prior to sleep). There is also evi- therapeutic option for patients with
dence to support a continuous 7-hour SWSD. Several studies have evaluated
to 8-hour sleep episode to promote bet- the effects of scheduled light exposure
ter sleep, as opposed to fragmented during the work period and its impact
sleep periods,10,11 because fragmenta- on the patient’s circadian physiologic
tion of sleep can affect sleep architec- mechanisms, degree of sleepiness, and
ture and accumulated sleep debt.12
mood. The outcomes of some studies
Exercise has been shown to be bene- indicate that light exposure causes
ficial in promoting sleep and improv- physiologic adjustment of phase shift,
ing perceived sleep quality13 and in resulting in improved alertness and
facilitating phase shifting of the circa- mood.19,20 Other studies suggest that
Dialogue and Diagnosis // March 2012
workers’ performance is improved only
when light exposure is combined with
caffeine intake during the night shift.21
Despite potential benefits produced
by realigning circadian rhythms to
night work, many workers might refuse to take such steps, preferring to
preserve their natural phase and to
keep a conventional diurnal waking
schedule during their off-days. A strategy of “partial realignment,” resulting
in a new circadian sleep-wake cycle
that is considered appropriate for both
workdays and off-days, has achieved
positive results in healthy volunteers
under simulated conditions.22 This
strategy seems promising, but it requires further validation in real-world
conditions and in patients with SWSD.
A variety of light regimens (different
light intensities and timing) have been
evaluated in studies; these studies have
been conducted mostly with simulated
night shifts in the laboratory, which result in limitations when interpreting
the results. To our knowledge, no light-
29
exposure studies have been conducted
in the field, and none of the studies
have specifically consisted of patients
with SWSD.
The AASM recommends the use of
light exposure during the nighttime
work period, as well as restriction of
morning light (with the use of sunglasses or goggles) as a guideline in
night-shift workers.2
Pharmacologic
treatment
Stimulants
Caffeine is a commonly used agent to
promote wakefulness among shift
workers.23,24,25 A recent Cochrane Review study showed that caffeine could
reduce the number of errors and improve cognitive performance in shift
workers, compared to no intervention.
However, no statistically significant
difference in effect was found when
caffeine was compared with other interventions, such as other wakefulness-promoting agents (modafinil),
planned naps, and light exposure.26
The most appropriate dose and timing
of caffeine intake for shift workers still
needs to be determined by research
studies. It should be kept in mind that
the potential for hyperstimulation,
toxic effects, and development of tolerance might limit the long-term efficacy of caffeine in the management of
SWSD. The AASM recommends its use
only as an option.2
Similarly, although there is evidence
of the effectiveness of methamphetamines at improving performance and
mood in individuals undergoing simulated night-shift work,27 these agents
cannot be recommended for management of SWSD given their potential for
abuse and adverse cardiovascular effects.
associated with excessive daytime
sleepiness, including narcolepsy and
idiopathic hypersomnia. These agents
are the only medications approved by
the U.S. Food and Drug Administration (FDA) for promotion of wakefulness in patients with SWSD.28
Evidence of the efficacy of modafinil
was described in a report of a randomized controlled trial using this drug at a
dose of 200 mg, with improvement in
wakefulness and ability to sustain attention in patients with SWSD. These improvements were measured using patient-reported diaries and changes on
the Multiple Sleep Latency Test.29 Importantly, these effects were not sustained throughout the night despite the
15-hour half-life of modafinil. A subsequent study by the same research group,
using armodafinil at a dose of 150 mg
for 12 weeks, showed improved levels of
wakefulness, long-term memory, and attention, as well as an improved overall
clinical condition.30 Both modafinil and
armodafinil are recommended by the
AASM as a guideline to enhance alertness during night shift work.2
To date, there have been no studies
directly comparing the efficacy and
Wakefulness-promoting agents
safety of modafinil and armodafinil.
Modafinil and armodafinil are wake- Given the pharmacokinetic profile of
fulness-promoting agents used in the armodafinil, with once-daily dosing
treatment of patients with conditions and longer duration of action than
30
modafinil, this drug might be a more
appropriate and convenient choice for
patients with SWSD. Headache and
nausea were the most common adverse effects observed in patients who
participated in the clinical trials of
modafinil and armodafinil. Caution
should be taken when prescribing
these drugs to patients who have histories of angina, recent myocardial infarction, or seizures.
Melatonin
Several studies have been conducted—
both in simulated and in real-world
shift-work conditions—evaluate melatonin administration before daytime
sleep. These studies have shown mixed
results. Although some melatonin studies have demonstrated decreased sleep latency and increased sleep duration,31-33
others have failed to demonstrate any
subjective or objective benefits.34 Regardless, the AASM recommends the
use of melatonin as a guideline in the
treatment of patients with SWSD.2
Greater benefits might be obtained
from melatonin administration when
used as part of a phase-advancing program in individuals with SWSD. Because different melatonin formulations vary in potency and quality (as a
result of lack of FDA regulation), a
melatonin receptor agonist, such as
Dialogue and Diagnosis // March 2012
Benzodiazepine receptor agonists
are reported to cause the adverse effects
of headache, dizziness, and drowsiness.
Amnesia and nonrapid-eye-movement
parasomnias, such as sleepwalking and
sleep-related eating syndrome, have
also been reported with the use of benManagement of insomnia
The use of sleep-promoting agents zodiazepine receptor agonists.
prior to required sleep periods has been
evaluated in a number of studies. Ben- Comorbid conditions
zodiazepines, such as triazolam and Patients presenting with SWSD should
temazepam,36-38 and benzodiazepine receive a comprehensive evaluation to
receptor agonists, such as zolpidem identify and address any comorbid
and zopiclone,39-41 can increase sleep conditions, including other sleep disorduration during daytime and improve ders (eg, obstructive sleep apnea),
wakefulness during night-shift work. mood disorders, and medical problems
All these agents have been evaluated in that might contribute to symptoms.
simulated conditions, but zopiclone, at
a dose of 7.5 mg taken before the re- Final notes
quired sleep period, has also been eval- The treatment of patients with SWSD
uated in volunteers working 12-hour requires an individualized and compreshifts.41 In that study, zopiclone was hensive approach, including the diaggiven prior to daytime sleep (after nosis and management of comorbid
night shift-work) and prior to night- sleep disorders, patient education, and
time sleep (on days off). It was found behavioral interventions to optimize
to improve sleep at night but not dur- sleep and wakefulness at the appropriing required daytime sleep periods. It ate times.
Unfortunately, few studies have
has been suggested that hypnotic
agents, such as zopiclone, may be less been conducted among actual patients
efficacious when administered out of with SWSD in real-world conditions.
Thus, it is unknown whether results
phase with the usual sleep period.
ramelteon, might be a more promising agent for treating patients with
SWSD, since it is known to be more
effective than regular melatonin in
advancing the circadian shift.35
achieved with patients in simulated
conditions or with healthy shift workers in real-world conditions can be
generalized to actual clinical situations.
In addition, the majority of available
evidence and strategies have focused
on the night-shift worker. Further studies involving patients with SWSD and
workers with different work schedules,
such as rotating shifts or early-morning
shifts, are necessary.
Effective interventions for managing
SWSD include sleep and wake hygiene,
planned napping, adjustments to dietary habits, an exercise program, appropriately timed light exposure, and
work-hour limitations. These nonpharmacologic treatments usually need
to be combined with medications.
Melatonin could be used to facilitate
circadian adaptation, and modafinil or
armodafinil could improve persistent
excessive sleepiness.
References
1. American Academy of Sleep Medicine:
The International Classification of Sleep
Disorders: Diagnostic & Coding Manual.
2nd ed. Westchester, IL: American
Academy of Sleep Medicine; 2005.
2. Morgenthaler TI, Lee-Chiong T,
Alessi C, et al; Standards of Practice
Committee of the American Academy
of Sleep Medicine. Practice parameters
for the clinical evaluation and treatment
of circadian rhythm sleep disorders:
an American Academy of Sleep Medicine
report [published correction appears
in Sleep. 2008;31(7):table of contents].
Sleep. 2007;30(11):1445-1458.
3. Wever RA. Light effects on human
circadian rhythms: a review of recent
Andechts experiments. J Biol Rhythms.
1989;4(2):161-185.
4. Dodson ER, Zee PC. Therapeutic
for circadian rhythm sleep disorders.
Sleep Med Clin. 2010;5(4):701-715.
5. Zawilska JB, Skene DJ, Arendt J.
Physiology and pharmacology
of melatonin in relation to biological
rhythms. Pharmacol Rep. 2009;61(3):383-410.
6. Folkard S, Tucker P. Shift work, safety
and productivity. Occup Med (Lond).
2003;53(2):95-101.
(continued)
Dialogue and Diagnosis // March 2012
31
Dialogue
Diagnosis
and
20. Crowley SJ, Lee C, Tseng CY, Fogg LF,
Eastman CI. Complete or partial circadian
re-entrainment improves performance,
alertness, and mood during night-shift work.
Sleep. 2004;27(6):1077-1087.
34. Wright SW, Lawrence LM, Wrenn KD,
Haynes ML, Welch LW, Schlack HM.
Randomized clinical trial of melatonin after
night-shift work: efficacy and neuropsychologic
effects. Ann Emerg Med. 1998;32(3 pt 1):334-340.
7. Dula DJ, Dula NL, Hamrick C, Wood GC.
The effect of working serial night shifts on the
cognitive functioning of emergency physicians.
Ann Emerg Med. 2001;38(2):152-155.
21. Babkoff H, French J, Whitmore J,
Sutherlin R. Single-dose bright light and/or
caffeine effect on nocturnal performance.
Aviat Space Environ Med. 2002;73(4):341-350.
35. Richardson GS, Zee PC, Wang-Weigand S,
Rodriguez L, Peng K. Circadian phase-shifting
effects of repeated remelteon administration in
healthy adults. J Clin Sleep Med. 2008;4(5):456-461.
8. Son M, Kong JO, Koh SB, Kim J, Harma M.
Effects of long working hours and the night
shift on severe sleepiness among workers with
12-hour shift systems for 5 to 7 consecutive
days in the automobile factories of Korea
[published online ahead of print October 8,
2008]. J Sleep Res. 2008;17(4):385-394.
22. Smith MR, Fogg LF, Eastman CI.
Practical intervention to promote circadian
adaptation to permanent night shift work:
study 4. J Biol Rhythms. 2009;24(2):161-172.
36. Walsh JK, Sugerman JL, Muehlbach MJ,
Schweitzer PK. Physiological sleep tendency
on a simulated night shift: adaptation and
effects of triazolam. Sleep. 1988;11(3):251-264.
23. Jay SM, Petrilli RM, Ferguson SA, et al.
Major physical and psychological harms of
methamphetamine use. Drug Alcohol Rev.
2008;27:253-262.
37. Walsh JK, Schweitzer PK, Anch AM,
Muehlbach MJ, Jenkins NA, Dickins QS.
Sleepiness/alertness on a simulated night
shift following sleep at home with triazolam.
Sleep. 1991;14(2):140-146.
9. Lavie P, Tzischinsky O, Epstein R,
Zomer J. Sleep-wake cycle in shift workers on
a “clockwise” and “counter-clockwise” rotation
system. Isr J Med Sci. 1992;28(8-9):636-644.
10. Banks S, Dinges DF. Behavioral and
physiologic consequences of sleep restriction.
J Clin Sleep Med. 2007;3(5):519-528.
11. 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(4):267-277.
12. 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(2):117-126.
13. Youngstedt SD. Effects of exercise on sleep.
Clin Sports Med. 2005;24(2):355-365.
14. Youngstedt SD, Kripke DE, Elliott JA, et al.
Exercise phase-response curves in young and
older adults. Soc Res Biol Rhythms. 2002,8:110.
15. Gabarino S, Mascialino B, Penco MA,
et al. Professional shift-work drivers who
adopt prophylactic naps can reduce the risk
of car accidents during night work. Sleep.
2004;27(7):1295-1302.
16. Schweitzer PK, Randazzo AC, Stone K, Erman
M, Walsh JK. Laboratory and field studies of naps
and caffeine as practical countermeasures for
sleep-wake problems associated with night work.
Sleep. 2006;29(1):39-50.
17. Sallinen M, Harma M, Akerstedt T,
Rosa R, Lillqvist O. Promoting alertness with
a short nap during a night shift. J Sleep Res.
1998;7(4):240-247.
24. Muehlbach MJ, Walsh JK. The effects
of caffeine on simulated night-shift work
and subsequent daytime sleep. Sleep.
1995;18(1):22-29.
38. Bonnet MH, Dexter JR, Gillin JC, et al.
The use of triazolam in phase-advanced sleep.
Neuropsychopharmacology. 1988;1(3):225-234.
25. 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. 1990;101(2):271-273.
39. Casagrande M, Ferrara M, Curcio G,
Porcu S. Assessing nighttime vigilance through
a three-letter cancellation task (3-LCT): effects
of daytime sleep with temazepam or placebo.
Physiol Behav. 1999;68(1-2):251-256.
26. Ker K, Edwards PJ, Felix LM, Blackhall K,
Roberts I. Caffeine for the prevention of injuries
and errors in shift workers. Cochrane Database
Syst Rev. 2010;12(5):CD008508.
40. Hart CL, Ward AS, Haney M, Foltin RW.
Zolpidem-related effects on performance
and mood during simulated night-shift work.
Exp Clin Psychopharmacol. 2003;11(4):259-268.
27. Hart CL, Ward AS, Haney M, Nasser J,
Foltin RW. Methamphetamine attenuates
disruptions in performance and mood
during simulated night-shift work
[published online ahead of print May 7, 2003].
Psychopharmacology (Berl). 2003;169(1):42-51.
41. Moon CA, Hindmarch I, Holland RL. The
effect of zopiclone 7.5 mg on the sleep, mood
and performance of shift workers. Int Clin
Psychopharmacol. 1990;5(suppl 2):79-83. D&D
28. Nuvigil (armodafinil) tablets [prescribing
information]. Frazer, PA: Cephalon, Inc; 2010.
29. Czeisler CA, Walsh JK, Roth T, et al;
U.S. Modafinil in Shift Work Sleep Disorder
Study Group. Modafinil for excessive sleepiness
associated with shift-work sleep disorder.
N Engl J Med. 2005;353(5):476-486.
30. Czeisler CA, Walsh JK, Wesnes KA, Arora S,
Roth T. Armodafinil for treatment of excessive
sleepiness associated with shift-work disorder:
a randomized controlled study. Mayo Clin Proc.
2009;84(11):958-972.
31. Sharkey KM, Eastman CI. Melatonin
phase shifts human circadian rhythms in a
placebo-controlled simulated night-work study.
Am J Physiol Regul Integr Comp Physiol.
2002;282(2):R454-R463.
18. Purnell MT, Feyer AM, Herbison GP. The
impact of a nap opportunity during the night
shift on the performance and alertness of 21-h
shift workers. J Sleep Res. 2002;11(3):219-227.
32. Wyatt JK, Dijk DJ, Ritz-de Cecco A, Ronda
JM, Czeisler CA. Sleep-facilitating effect of
exogenous melatonin in healthy young men
and women is circadian-phase dependent.
Sleep. 2006;29(5):609-618.
19. Horowitz TS, Cade BE, Wolfe JM, Czeisler
CA. Efficacy of bright light and sleep/darkness
scheduling in alleviating circadian maladaptation
to night work. Am J Physiol Endocrinol Metab.
2001;281(2):E384-E391.
33. Yoon IY, Song BG. Role of monitoring
melatonin administration and attenuation
of sunlight exposure in improving
adaptation of night-shift workers.
Chronobiol Int. 2002;19(5):903-913.
Gonzalo A. Salgado, MD, is a Fellow
in sleep medicine in the Department
of Pulmonary and Critical Care
Medicine at Temple University
Hospital in Philadelphia, Penn. He
can be reached at Gonzalo.Salgado
@tuhs.temple.edu.
Fredric Jaffe, DO, is assistant
professor of medicine at Temple
University Hospital, Philadelphia,
Penn. He is board certified in sleep
medicine, pulmonary medicine,
critical care, and internal medicine.
He also serves as the medical
director of pulmonary function testing and pulmonary rehabilitation at
Temple Hospital. He can be reached
at Fredric.jaffe@ tuhs.temple.edu.