US Pharm. 2012;37(2):Epub.

Approximately 20% of the U.S. workforce performs shift work.¹ Shift work involves a nonstandard work schedule, such as early-morning (starting 4-7 am), extended, rotating, evening, or night shifts.² Individuals in service industries (e.g., health care, transportation) are most likely to work nonstandard shifts.³ While all shift workers are at risk for developing sleep disturbances, approximately 32% of those who work night shifts meet the minimum requirement for shift work disorder (SWD).² According to the second edition of the International Classification of Sleep Disorders (ICSD-2), SWD is a circadian-rhythm sleep disorder (CRSD) characterized by the “presence of excessive sleepiness and/or insomnia for at least 1 month, in association with a shift-work schedule.”⁴ The ICSD-2 identifies the key feature of CRSDs as a “persistent or recurrent pattern of sleep disturbance due primarily to alterations in the circadian timekeeping system or a misalignment between the endogenous circadian rhythm and exogenous factors that affect the timing and duration of sleep.”⁴ Because individuals who work night shifts tend to return to conventional sleep schedules on their days off, they are in a state of continuous circadian misalignment.⁵ This may contribute to the greater prevalence of SWD in this population of shift workers.

SWD is associated with sleep disturbances and impaired performance and alertness during waking hours. Studies of the consequences of SWD are lacking; however, many studies have been conducted to evaluate the consequences of shift work. These studies indicate that shift work is associated with significant health, social, and economic problems. Associations between shift work and cancer, coronary artery disease, and gastrointestinal disturbances have been established.² Shift workers may decline social invitations or repeatedly miss family activities because of excessive sleepiness (ES) or insomnia. Shift work has been linked to increased workplace injuries and accidents and decreased productivity during night shifts. Employers may be impacted economically by the increased absenteeism and higher turnover occurring among shift workers.³ Because SWD is often underrecognized,³ there is an opportunity for pharmacists to help identify patients with SWD and contribute to the management of the disorder.

IDENTIFYING PATIENTS WITH SWD

The defining symptoms of SWD are insomnia and ES. Patients experiencing these symptoms may also present with “fatigue, difficulty concentrating, reduced work performance, headache, irritability or depressed mood, and a feeling of being un-refreshed after sleeping.”⁶ These symptoms can also occur with other CRSDs, as well as with mood disorders.⁶ Additionally, some antipsychotic medications used to treat mood disorders can result in excessive sedation.⁵ A pharmacist encountering a patient with these symptoms should review the patient’s medical profile to determine whether other disorders or medications could be responsible for ES. The patient should be questioned about risk factors for SWD, including night shift work, job dissatisfaction, exposure to daylight or bright light in the early morning (for night shift workers), and preference for waking in the early morning (i.e., being a “morning person”). Lifestyle factors may trigger SWD in individuals who are predisposed to sleep-wake disorders. For example, shift workers may be unable to get adequate rest because other people in the home have conventional sleep schedules, or because social obligations require them to be awake during the day.⁶

Patients who complain of ES should be asked about other symptoms they experience while sleeping to determine whether other CRSDs, such as obstructive sleep apnea (OSA) or restless legs syndrome (RLS), might be the cause. For example, patients who snore, have choking episodes during sleep, or wake with a sore throat may have OSA. Patients who jerk their legs involuntarily while sleeping or feel discomfort in their legs may have RLS. Patients without these additional symptoms should be counseled about sleep hygiene.⁶ Referral to a physician for further evaluation should be considered, as proper diagnosis of SWD can occur only with a thorough physical examination and medical history.³ However, the pharmacist can help identify SWD risk factors and counsel patients about good sleep hygiene. Recommendations for achieving an appropriate environment for restorative sleep are listed in TABLE 1. Pharmacists can also make recommendations concerning nonpharmacologic and nonprescription remedies and counsel patients about prescription medications once they have begun therapy.

MANAGING SWD

Nonpharmacologic Therapy

In addition to good sleep hygiene, naps and timed light exposure are the main nonpharmacologic treatments for SWD. According to the American Academy of Sleep Medicine (AASM) practice parameter guidelines, napping before and/or during shifts has been shown to improve reaction time, reduce accidents, and increase alertness and vigilance.¹ Timed light exposure administered at different intensities and at various times throughout the shift has been found to decrease sleepiness and improve alertness during the night shift.

The effect of the combination of napping and bright light pulses on driver sleepiness at the wheel was assessed in a pilot study.⁷ The study took place over two similar 24-hour work periods separated by 3 weeks. There were three subjects in each shift, and each subject drove the same car during the study period. Ambulatory polysomnography and the Stanford Sleepiness Scale (SSS) were used to assess sleepiness at the wheel. During the first study period (baseline), subjects were told to manage their rest in their usual manner. During the second study period, subjects took two 20-minute naps lying on a bed in a dark room and then were exposed to bright light pulses (Philips Bright Light = 5,000 lux) for 10 minutes. Compared with baseline, subjects demonstrated significant reductions in sleepiness at the wheel (as measured by polysomnography), but not in average SSS score.

Pharmacologic Therapy

According to the AASM, pharmacologic therapy for SWD aims to promote daytime sleep and enhance alertness (i.e., promote wakefulness) during the night shift. Melatonin and hypnotic medications are among the therapeutic options used to promote daytime sleep, while wakefulness-promoting agents (e.g., modafinil, armodafinil) and stimulants (e.g., methamphetamine, caffeine) may be used to enhance alertness.¹

Melatonin: This endogenous hormone linked to circadian rhythm is a popular supplement used to promote daytime sleep. Melatonin administered between nighttime work and daytime sleep improved daytime sleep quality and duration in some studies, but did not improve alertness at night.¹

A meta-analysis of studies evaluating the efficacy and safety of melatonin for the treatment of secondary sleep disorders and sleep disorders associated with sleep restriction (e.g., jet lag, SWD) was conducted.⁸ Studies were included in the efficacy evaluation if they were randomized, controlled trials comparing melatonin with placebo and if common sleep parameters such as sleep-onset latency (amount of time it takes to fall asleep after lying down) were assessed. The studies involved 427 participants and melatonin dosages of 0.5 mg to 10 mg daily. Combined results from trials in which sleep latency was evaluated favored melatonin, but the results were not statistically significant. Headache, dizziness, nausea, and drowsiness, the most commonly reported adverse events, did not differ significantly between the melatonin and placebo groups. Other studies suggest that melatonin may be more useful on a short-term basis for helping patients adjust to night shift work, rather than as a chronic therapeutic option for SWD.²

Hypnotics: Hypnotic agents available in the U.S., such as triazolam, temazepam, and zolpidem, have generally improved the duration and quality of daytime sleep.² However, the effects on objective measures of nighttime alertness have been inconsistent.¹ These agents have been tested in simulated work environments and in shift workers, but none has been evaluated in patients diagnosed with SWD.² According to the AASM, hypnotic medications may be used to promote daytime sleep in night shift workers. However, it is recommended that clinicians consider the risks of carryover sedation and worsening of coexisting sleep conditions (e.g., OSA) when they are considering the use of hypnotics to promote daytime sleep.¹

Stimulants: Methamphetamine and other stimulants have demonstrated efficacy in enhancing alertness in shift workers.² However, these agents may not be optimal for chronic management of SWD because they can induce rebound insomnia, have cardiovascular adverse effects, and carry a high potential for abuse. Because of its affordability and availability, caffeine is one of the most common stimulants used to enhance performance during waking hours. Caffeine has been shown to increase sleep latency as measured by the Multiple Sleep Latency Test (MSLT), but these effects were not maintained throughout the night.³

Wakefulness-Promoting Agents: Modafinil (Provigil) and armodafinil (Nuvigil), the R-enantiomer of modafinil, are the only medications specifically indicated to improve wakefulness in patients with ES associated with SWD.^9,10 While their exact mechanism of action is unknown, wakefulness-promoting agents appear to be more selective than stimulants. Stimulants use direct dopaminergic pathways to cause widespread activation of the central nervous system, whereas wakefulness-promoting agents appear to act selectively in the hypothalamus by inhibiting sleep-promoting centers and/or stimulating wake-promoting centers.

Modafinil and armodafinil do not bind directly to dopamine receptors, but they affect the dopaminergic system by inhibiting the dopamine transporter.¹¹ Modafinil and armodafinil are metabolized through the CYP450 isoenzymes. They may induce the CYP3A4 isoenzyme, resulting in lower concentrations of CYP3A4 substrates (e.g., oral contraceptives, triazolam, and cyclosporine). They may also inhibit CYP2C19, resulting in higher concentrations and a need for dosage adjustments in drugs such as omeprazole, diazepam, and phenytoin.¹² Potent inducers of CYP3A4 (e.g., carbamazepine, phenobarbital, rifampin) may reduce plasma levels of modafinil and armodafinil. In patients with ES associated with SWD, the recommended dose is 200 mg/day for modafinil and 150 mg/day for armodafinil given 1 hour before meals. Both agents are Schedule IV drugs because they are considered to have some potential for abuse.^9,10

Modafinil was evaluated in 209 patients with ES associated with chronic SWD in a 12-week, double-blind, multicenter study.¹³ Patients reported excessive sleepiness for more than 3 months and met ICSD criteria for SWD (a primary complaint of ES on the night shift and insomnia when attempting to sleep during the day). The primary efficacy measures were the change from baseline to final visit in the Clinical Global Impression of Change (CGI-C) test, which measures the change in symptom severity, and sleep latency as assessed by the MSLT. Nighttime performance was assessed using the Psychomotor Vigilance Test, which measures the frequency and duration of lapses of attention during performance. Patients were randomized to receive modafinil 200 mg or placebo 30 to 60 minutes before the start of each night shift. Compared with placebo patients, more patients receiving modafinil had improvements in their clinical symptoms as measured by the CGI-C at the final visit (74% vs. 36%, P <.001). Sleep latency and nighttime performance also improved; however, residual sleepiness was noted in some patients at the end of the study. Headache was the most common side effect reported in both treatment groups, but insomnia was more commonly reported in the modafinil group. Modafinil 200 mg or 300 mg was shown to be well tolerated in a safety analysis that used aggregate data from studies in patients with ES associated with SWD, OSA, or narcolepsy.¹⁴ In another study, modafinil 300 mg improved functioning and health-related quality of life in patients experiencing ES associated with SWD.¹⁵

Armodafinil was evaluated for the treatment of ES in 254 adults with SWD in a 12-week randomized, placebo-controlled trial.¹⁶ Patients meeting ICSD diagnostic criteria for SWD were given armodafinil 150 mg or placebo 30 to 60 minutes before the night shift. Patients receiving armodafinil experienced significantly improved wakefulness throughout the night shift, as demonstrated by prolonged sleep latency. Armodafinil-treated patients also improved in overall clinical condition, long-term memory, and attention. Headache, nausea, nasopharyngitis, and anxiety were reported by 5% or more of patients taking armodafinil and more frequently versus patients taking placebo. Similar results were seen when 108 patients from this study were subsequently enrolled in a 12-month open-label, flexible-dose extension study to evaluate the long-term safety and tolerability of armodafinil at doses up to 250 mg.¹⁷ Armodafinil continued to be effective and was well tolerated during the study period. Pharmacokinetic comparisons have shown that armodafinil administered at doses similar to those for modafinil demonstrated higher plasma concentrations later in the day. Theoretically, this would result in improved wakefulness throughout the day in patients with ES.^18,19 However, the only published comparative clinical trial showed similar efficacy and safety profiles between armodafinil 150 mg and modafinil 200 mg.²⁰

CONCLUSION

SWD is an underrecognized illness with serious implications for the social, health, and economic status of patients. Pharmacists can play a role in identifying patients at risk for SWD and counseling them about good sleep hygiene and nonpharmacologic treatment options. Effective pharmacologic options exist for the management of SWD. By counseling patients about proper dosing and administration, potential drug interactions, and common adverse events, the pharmacist can be instrumental in optimizing these therapies.

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