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By Aaron H. Burstein, PharmD
As much as 7% of the american labor force works rotating shifts or exclusively night shifts.1 One difficulty in working such shifts is the transition back to a regular sleep/wake cycle. Melatonin has been advocated as an antioxidant to slow aging, an adjunct to cancer chemotherapy, a contraceptive, and a promoter of sleep, especially for jet lag, another type of shift in sleep schedule.
Pharmacology and Mechanism of Action
Melatonin is an endogenous hormone synthesized within the pineal gland through a series of metabolic conversions. (See Figure 1.) The cascade is stimulated by release of norepinephrine in response to lack of light and is inhibited by retinal exposure to light.2
It is unclear how melatonin affects sleep. Melatonin secretion is typically synchronized to a 24-hour light/dark cycle. Secretion begins at approximately 10 pm and reaches highest concentrations (90 pg/ml) between 2 am and 4 am. Secretions subsequently decrease to less than 10 pg/ml during daylight hours. Because of its relatively short half-life (30-60 min), melatonin’s effects on sleep are unlikely to be exclusively the result of direct hypnotic action. Melatonin-induced mild hypothermia (0.5-1º F decrease) may be responsible for induction of sleep.2,3
During periods of night-shift work, the circadian pattern of melatonin secretion is advanced, resulting in maximum secretion during daylight and facilitation of daytime sleep.4 The altered pattern of secretion may result in a decrease in nighttime sleep duration and an increase in number of daytime naps when the worker is not working nights. It has been suggested that melatonin use prior to retiring for nighttime sleep may reset the pattern and facilitate sleep in individuals experiencing insomnia due to varying work schedules.
Literature evaluating melatonin use for shift-work insomnia is limited to four relatively small studies. All were randomized, double-blind, placebo-controlled, crossover studies.1,5-7 (See Table 1 for a summary of clinical trials.) These studies evaluate melatonin’s ability to facilitate daytime sleep in subjects working night shifts5-7 or nighttime sleep upon completion of a block of night shifts.1 Additionally, one study evaluated efficacy in a simulated night-shift model,8 and another, available only in abstract, examined degree of phase shift in endogenous melatonin production during a week of night shifts with daily melatonin administration prior to daytime sleep.9 The three largest and highest quality trials are described below.
|Table 1-Clinical trials of melatonin in shift-work|
|James5||24||6 mg oral||No differences in sleep parameters||I||Minor|
|Wrightz1||15||5 mg oral||No differences in sleep parameters||I||Major|
|Jorgenson6||20||10 mg SL§||No significant differences in sleep parameters||II||Major|
|Folkard7||17||5 mg oral||Increased subjective sleep quality||II||Major|
| = Level of Evidence|
|§ = sublingual|
Jorgensen and colleagues evaluated melatonin’s ability to improve daytime sleep and/or nighttime alertness in 20 emergency physicians.6 During a block of night shifts, subjects received 10 mg sublingual melatonin (Source Naturals Products) or placebo each morning in a randomized crossover manner. Each treatment was evaluated during one block of night shifts. Subjects maintained sleep logs during daytime sleep and completed the Stanford Sleepiness Scale three times during the night. At the conclusion of a block of night shifts, VAS measures of impression of day sleep and night alertness were completed. Only 18 subjects were evaluable; two were excluded because of alcohol or sedative medication ingestion. Exogenous melatonin failed to significantly improve VAS measures of daytime sleep and night-work alertness. While there were trends toward longer duration, shorter sleep latency, fewer premature awakenings, and a small difference between amounts of desired and actual sleep, no statistically significant differences were detected. Melatonin was associated with a statistically significant improvement in alertness at the end of a night shift compared to placebo. The authors concluded that melatonin may offer a modest benefit. However, data do not clearly support such a statement. Limitations include a homogenous population (89% male, mean age 32 years, range 25-40 years), insufficient description of inclusion/exclusion criteria, lack of statistical power, and evaluation of each treatment over a single block of nights. Level II, major limitations
Wright and colleagues evaluated effects of melatonin on cognitive function, manual dexterity, mood, length of sleep, and/or quality of sleep in 15 emergency physicians following a block of two night shifts.1 Beginning the evening following the last night shift worked, subjects were randomized to receive 5 mg oral melatonin (Nature’s Vision) or placebo 30 min before retiring. Assessments included Karolinska Sleep Scale, VAS assessment of tiredness in the morning and evening of day one and in the morning of treatment days two and three, VAS for global assessment of recovery from the night-shift work, and characteristics of sleep (time to fall asleep, hours slept, awakening frequency). No differences between groups were found for any measurements. According to the authors, melatonin appeared to be of limited value in aiding recovery of emergency physicians from night-shift work. Limitations include inconsistency of the primary outcome measure with the stated objective; sample size calculation was based on a primary outcome measure of global assessment of recovery rather than on changes in the outcome measures stated by investigators. This small study also had insufficient description of study participants (concurrent medications, disease states) and evaluated each treatment only once rather than repeatedly over multiple blocks of night shifts. Level I, major limitations
Generally well tolerated, melatonin’s most common side effects include sedation, headache, mild hypothermia (decrease in temperature of 0.5-1º F), and next day tiredness.1-3,5,6 Other infrequently reported side effects include depression, tachycardia, pruritis, nightmares, and increased seizure activity in neurologically impaired pediatric patients.2,3
Information regarding melatonin use in pregnancy and lactation is lacking. Women attempting to conceive should avoid melatonin as it may have contraceptive potential at high doses.10 Melatonin should be used cautiously and/or avoided in patients with autoimmune diseases and allergies (potential for immune system stimulation),11 cardiovascular disease (potential for coronary artery vasoconstriction in animal models),12 depression (exacerbation of dysphoria),13 and neurologic conditions including epilepsy.14 Patients with hepatic impairment should use with caution because of potential for impaired clearance by the cytochrome p450 (CYP) system.2
Limited human data are available characterizing drug interactions with melatonin. Results from in vitro studies suggest an inhibitory effect of melatonin on CYP activity, especially 1A2, 2C, and 3A.15-17 Melatonin is primarily metabolized by CYP1A2; it is unclear if melatonin has enzyme-inducing potential.
Administration with fluvoxamine, a known inhibitor of CYP1A2 and CYP2C19, resulted in great increases in melatonin concentration.18 Clearance may be reduced in patients taking concurrent chlorpromazine.2 Animal studies have shown melatonin enhances anxiolytic effects of benzodiazepines through binding with GABA receptor sites,2 and may potentiate neuromuscular blockade induced by agents such as succinylcholine.2
Formulation and Dosage
Suggested melatonin doses for use in sleep disorders range from 0.3-10 mg administered approximately 30-60 min before retiring. The optimal effective dose, if any, is not known.
Synthetic melatonin is available in capsule, liquid, and sublingual, immediate-release, and controlled-release tablet formulations. There are theoretical advantages to different forms that involve higher immediate levels for sleep induction vs. sustaining higher levels that mimic physiological secretion patterns; an optimum dosage form is not known. Although tablet content usually seems consistent,19 studies have found various quality problems with at least nine different brands of tablets.20
These melatonin studies do not show benefit for improving daytime sleep, nighttime work performance, or transition back to nighttime sleep; however, concerns exist with the small patient experience reported. Future studies should enroll more subjects, establish a dose response, and improve trial methodologies.
Current evidence does not support a recommendation for melatonin use by shift workers. Patients considering melatonin should be informed of the lack of evidence to support this particular indication. Patients also should be counseled about the potential for adverse effects and drug interactions. Grade B
Dr. Burstein is a Pharmacokineticist in the Clinical Center, Pharmacy Department of the National Institutes of Health. The views presented in this article are those of the author and do not necessarily represent the policy of the National Institutes of Health (NIH), the NIH Clinical Center, or the Food and Drug Administration.
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16. Niwatananun K, et al. The inhibitory effect of melatonin on hepatic drug metabolism in rats and pigs. Abstract presented at: The University of Maryland School of Pharmacy Research Day; April 1999; Baltimore, MD.
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18. Härtter S, et al. Increased bioavailability of oral melatonin after fluvoxamine coadministration. Clin Pharmacol Ther 2000;67:1-6.
19. Aboul-Enein HY, et al. Capillary GC-MS determination of melatonin in several pharmaceutical tablet formulations. Biomed Chromatogr 1999;13:24-26.
20. Hahm J, et al. Comparison of melatonin products against USP’s nutritional supplements standards and other criteria. J Am Pharm Assoc 1999;39:27-31.