Treatment of patients with shift work sleep disorder

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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.

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Patients typically attempt to sleep

when their circadian signals for alertness are high, and

they work when their circadian alertness levels are low.

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The management of SWSD requires an individualized and comprehensive approach, incorporating various strate-gies targeted at either the underlying misalignment or at the 2 defining symptoms of the disorder. Other objec-tives of treatment are to improve the patient’s cognitive function and per-formance and safety on the job. In the present article, we review the physio-logic 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 Medi-cine (AASM) guidelines for the treat-ment of circadian rhythm disorders (Table 1).2

Normal circadian

physiology

To better understand how available in-terventions correct circadian misalign-ment, it is necessary to understand the normal mechanisms of circadian rhythm physiology.

A circadian pacemaker, also re-ferred to as the “biological clock,” controls the daily patterns in neu-roendocrine function and behavior, such as the sleep-wake cycle and

fluc-tuations in many physiologic process-es. This central pacemaker—located in the suprachiasmatic nucleus (SCN), within the hypothalamus of human beings and other mammals—func-tions on a cycle of approximately 24.2 hours.3Because 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 syn-chronized. Natural zeitgebers (Ger-man for “time givers” or “synchroniz-ers”) help the circadian rhythm stay within a 24-hour window and not shift out of phase. These zeitgebers are light, melatonin, and social or physi-cal activities.4 Of these agents, light

and melatonin are recognized as hav-ing the greatest influence on deter-mining the entrainment of endoge-nous circadian rhythms.

Light stimulates the neurons in the SCN via the retinohypothalamic tract.4

The timing of light exposure ultimate-ly determines effects on the entrain-ment of circadian rhythms. Exposure to light in the evening causes a delay in the circadian rhythm, with the con-sequences of postponement of the rest period and a late awakening time.

Exposure to light in the morning caus-es 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 indi-vidual’s usual sleep time.5This

mela-tonin 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 administra-tion in the morning shifts the circadi-an 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 alert-ness. In the evening, with decreased light exposure and secretion of mela-tonin, the SCN activity decreases to facilitate sleep.

Table 1

AASM Levels of Recommendations

Strength of

Recommendation

Definition

Standard

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

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Nonpharmacologic

treatment

Change in work pattern

The symptoms of SWSD are directly linked to the out-of-phase shift-work schedule, and they usually resolve after the patient returns to daytime work. However, returning to daytime work is impractical for many individuals. In most cases, occupational and societal constraints prevent the implementa-tion of this opimplementa-tion.

For workers on night shifts, more than 4 consecutive 12-hour night shifts should be avoided because of a documented increased risk of accidents and injuries.6There is also evidence of

decreased cognitive performance and increased sleepiness in this group of workers.7,8 Individuals on rotating

shift schedules should be encouraged to rotate in a clockwise, rather than counterclockwise, manner (ie, morn-ing to evenmorn-ing to night, rather than night to evening to morning), because this pattern follows the natural pattern of delaying the sleep period.9

Sleep hygiene

Measures for improving sleep hygiene are recommended not only for patients with SWSD, but also for all shift work-ers. Patients should be advised on how to create a proper environment for sleep in terms of levels of darkness, noise, and temperature, together with how to mentally and physically pre-pare for sleep (eg, avoidance of large meals, caffeinated drinks, smoking, and alcohol prior to sleep). There is also evi-dence to support a continuous 7-hour to 8-hour sleep episode to promote bet-ter sleep, as opposed to fragmented sleep periods,10,11 because

fragmenta-tion of sleep can affect sleep architec-ture and accumulated sleep debt.12

Exercise has been shown to be bene-ficial in promoting sleep and improv-ing perceived sleep quality13 and in

facilitating phase shifting of the circa

-dian rhythm.14Thus, an exercise

pro-gram might help in the adaptation of shift workers to their sleep-wake sched-ule. Further research is needed to iden-tify the timing and type of exercise that would have the best impact on SWSD.

Scheduled naps

Napping is considered an effective strategy to counteract sleepiness in shift workers. Naps have been shown to decrease accidents15and to improve

performance in shift workers, as meas-ured by the Maintenance of Wakeful-ness Test and the Psychomotor Vigi-lance Task, particularly when used with caffeine administration.16

Benefi-cial effects, such as improvements in sleepiness and performance in vigi-lance and neurobehavioral testing, can be seen when planned naps take place before or during night-shift work.17,18

It is important to note that no stud-ies have evaluated outcomes of napping in patients with SWSD. Besides this lim-itation, implementation of napping might be difficult in the workplace, be-cause appropriate facilities may not be available and napping might be consid-ered unprofessional or ethically unac-ceptable in some work settings. Never-theless, the AASM considers scheduled or planned naps a standard treatment of patients with SWSD.2

Light exposure

The interaction between light exposure and the endogenous circadian rhythm forms the basis for light therapy as a therapeutic option for patients with SWSD. Several studies have evaluated the effects of scheduled light exposure during the work period and its impact on the patient’s circadian physiologic mechanisms, degree of sleepiness, and mood. The outcomes of some studies indicate that light exposure causes physiologic adjustment of phase shift, resulting in improved alertness and mood.19,20Other studies suggest that

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 re-fuse to take such steps, preferring to preserve their natural phase and to keep a conventional diurnal waking schedule during their off-days. A strate-gy 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 re-quires 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 re-sult in limitations when interpreting the results. To our knowledge, no

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light-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 sun-glasses 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.23,24,25A recent Cochrane

Re-view study showed that caffeine could reduce the number of errors and im-prove cognitive performance in shift workers, compared to no intervention. However, no statistically significant difference in effect was found when caffeine was compared with other in-terventions, such as other wakeful-ness-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 tol-erance might limit the long-term effi-cacy 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 methampheta-mines at improving performance and mood in individuals undergoing simu-lated night-shift work,27 these agents

cannot be recommended for manage-ment of SWSD given their potential for abuse and adverse cardiovascular effects.

Wakefulness-promoting agents

Modafinil and armodafinil are wake-fulness-promoting agents used in the treatment of patients with conditions

associated with excessive daytime sleepiness, including narcolepsy and idiopathic hypersomnia. These agents are the only medications approved by the U.S. Food and Drug Administra-tion (FDA) for promoAdministra-tion of wakeful-ness in patients with SWSD.28

Evidence of the efficacy of modafinil was described in a report of a random-ized controlled trial using this drug at a dose of 200 mg, with improvement in wakefulness and ability to sustain atten-tion in patients with SWSD. These im-provements were measured using pa-tient-reported diaries and changes on the Multiple Sleep Latency Test.29

Im-portantly, these effects were not sus-tained throughout the night despite the 15-hour half-life of modafinil. A subse-quent 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 at-tention, as well as an improved overall clinical condition.30Both modafinil and

armodafinil are recommended by the AASM as a guideline to enhance alert-ness during night shift work.2

To date, there have been no studies directly comparing the efficacy and safety of modafinil and armodafinil. Given the pharmacokinetic profile of armodafinil, with once-daily dosing and longer duration of action than

modafinil, this drug might be a more appropriate and convenient choice for patients with SWSD. Headache and nausea were the most common ad-verse 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 histo-ries of angina, recent myocardial in-farction, or seizures.

Melatonin

Several studies have been conducted— both in simulated and in real-world shift-work conditions—evaluate mela-tonin administration before daytime sleep. These studies have shown mixed results. Although some melatonin stud-ies have demonstrated decreased sleep la-tency and increased sleep duration,31-33

others have failed to demonstrate any subjective or objective benefits.34

Re-gardless, 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 pro-gram in individuals with SWSD. Be-cause different melatonin formula-tions vary in potency and quality (as a result of lack of FDA regulation), a melatonin receptor agonist, such as

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ramelteon, might be a more promis-ing agent for treatpromis-ing patients with SWSD, since it is known to be more effective than regular melatonin in advancing the circadian shift.35

Management of insomnia

The use of sleep-promoting agents prior to required sleep periods has been evaluated in a number of studies. Ben-zodiazepines, such as triazolam and temazepam,36-38 and benzodiazepine

receptor agonists, such as zolpidem and zopiclone,39-41can increase sleep

duration during daytime and improve wakefulness during night-shift work. All these agents have been evaluated in simulated conditions, but zopiclone, at a dose of 7.5 mg taken before the re-quired sleep period, has also been eval-uated in volunteers working 12-hour shifts.41In that study, zopiclone was

given prior to daytime sleep (after night shift-work) and prior to night-time sleep (on days off). It was found to improve sleep at night but not dur-ing required daytime sleep periods. It has been suggested that hypnotic agents, such as zopiclone, may be less efficacious when administered out of phase with the usual sleep period.

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 ben-zodiazepine receptor agonists.

Comorbid conditions

Patients presenting with SWSD should receive a comprehensive evaluation to identify and address any comorbid conditions, including other sleep disor-ders (eg, obstructive sleep apnea), mood disorders, and medical problems that might contribute to symptoms.

Final notes

The treatment of patients with SWSD requires an individualized and compre-hensive approach, including the diag-nosis and management of comorbid sleep disorders, patient education, and behavioral interventions to optimize sleep and wakefulness at the appropri-ate times.

Unfortunately, few studies have been conducted among actual patients with SWSD in real-world conditions. Thus, it is unknown whether results

achieved with patients in simulated conditions or with healthy shift work-ers 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 stud-ies 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 di-etary habits, an exercise program, ap-propriately timed light exposure, and work-hour limitations. These non-pharmacologic 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.

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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 test -ing and pulmonary rehabilitation at Temple Hospital. He can be reached at Fredric.jaffe@ tuhs.temple.edu.

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