Melatonin therapy in shift workers with difficulty falling asleep: A randomized,double-blind,placebo-controlled crossover field study

Abstract

BACKGROUND: Disturbed sleep is common in shift work. It is hypothesized that administration of exogenous melatonin could reduce the sleep latency and improve the sleep quality.

OBJECTIVE: To evaluate the efficacy of 3 mg melatonin taken 30 min before night time sleep on shift workers with difficulty falling asleep.

METHODS: Pittsburgh Sleep Quality Index (PSQI) and Insomnia Severity Index (ISI) were applied to find out shift workers with difficulty falling asleep. A randomized, double-blind, placebo-controlled crossover study with periods of 3 night and washouts of 2 weeks comparing melatonin with placebo was performed. Night time sleep parameters obtained from somnowatch including total sleep time (TST), sleep onset latency (SOL), sleep efficiency (SE) and wakening after sleep onset (WASO) were analyzed.

RESULTS: Among 295 workers, 103 had difficulty falling asleep. Finally, from 50 randomly selected workers with difficulty falling asleep, 39 workers completed the study. Melatonin treatment significantly increased SE and decreased SOL in comparison with baseline and taking placebo. SE was increased from 82.1% at baseline to 85.5% after melatonin therapy. Also SOL was decreased from 0.27 h at baseline to 0.20 h after melatonin therapy. Effects of Melatonin administration on TST and WASO were not significant.

CONCLUSIONS: This study showed that melatonin therapy in shift workers with difficulty falling asleep significantly improved the sleep onset latency and sleep efficiency.

Keywords

Circadian rhythm somnowatch sleep onset latency sleep efficiency

1 Introduction

Nowadays, as a result of economical and occupational necessities, a number of people follow a work schedule that is outside of the usual hours of work [1]. Continuing disturbance of the circadian rhythm caused by shift working, adversely affects on physiological functions of the body. Investigations showed that diseases such as coronary heart disease [2] and diabetes [3] have been more reported among shift workers. The most prevalent complication of shift work is daytime sleepiness and night time insomnia [4] which consequent to increased risk of work and car accidents, memory and concentration difficulties, fatigue and anxiety [5].

Benzodiazepines are the most routine drugs for treating insomnia but they have multiple adverse effects such as alteration of sleep structure, memory impairment, poor concentration, dependency, abuse potential, withdrawal reaction at discontinuation and rebound insomnia [6]. In order to overcome some of the benzodiazepine adverse effects, more selective non-benzodiazepine compounds had been developed [7]. Zolpidem, the most widely used non-benzodiazepine hypnotic agent, has been shown to decrease the sleep onset latency but its usage had been reduced because of side effects such as memory impairment, dependency and tolerance. Also the stimulated sleep by zolpidem is electrophysiologically different with normal sleep pattern [8].

Melatonin is a hormone secreted by the pineal gland in response to darkness. In the last two decades, melatonin had been used for treatment of insomnia in adults and children [9]. In contrast to other hypnotic agents, melatonin has low toxicity [10] and decreased risk of dependency, withdrawal symptoms and hangover in morning after usage [11].

It is hypothesized that when endogenous secretion of melatonin is reduced, such as in shift workers [12], administration of exogenous melatonin could reduce the sleep latency and improves the sleep quality. There are conflicting studies on the efficiency of melatonin administration in shift workers. Several previous studies assessed the efficacy of melatonin therapy in shift workers [13 –20]. In two studies melatonin were delivered to shift workers before bed time [17, 18]. In a study for evaluation of the efficacy of melatonin on 86 shift work nurses for 1 night after their nightshift, a significant reduction in sleep onset latency was found [17]. In another study, 15 emergency physicians for 3 consecutive nights after nightshift duty were assessed and no beneficial effect of melatonin was seen on hours of sleep per night, sleep quality, sleep latency and early morning awakening [18]. We aimed to evaluate the efficacy of melatonin therapy on night time sleep in shift workers with difficulty falling asleep in a randomized, double-blind, placebo-controlled crossover study.

2 Subjects and methods

2.1 Study sample

A total of 295 workers from Tehran Refinary Oil Co. (Shahid Tond Gouyan) responded to a questionnaire package including demographic and occupational characteristics, Pittsburgh Sleep Quality Index (PSQI) and Insomnia Severity Index (ISI). All participants worked on rotating shift; one week day shift followed by one week night shift without days-off. Workers with at least one month of shift working were eligible for our study. The exclusion criteria were chronic hepatic, renal, cardiac and respiratory disease as well as taking sedative and hypnotic drugs. Also, the workers which affected to a disease during the study or desired to withdraw from the study were excluded.

To find the workers with difficulty falling asleep, we analyzed the response to ISI item 1a (Please rate the current (i.e., last 2 weeks) severity of your insomnia problem(s). a. difficulty falling asleep: none, mild, moderate, severe, very severe) and PSQI item 2 (How long (in minutes) has it taken you to fall asleep each night?). Workers who selected the choices of moderate, severe or very severe on ISI item 1a and had sleep onset latency of twenty minutes or more on PSQI item 2 were known to have difficulty falling asleep.

2.2 Methods

Fifty workers with difficulty falling asleep were randomly selected. Somnowatch (SOMNOmedics, Randersacker, Germany) was used to assess sleep/wake pattern of the workers. Somnowatch is a device commonly placed on the wrist in which an accelerometer monitors the occurrence and extent of movements. Wake/sleep parameters are derived from activity/inactivity analysis on collected data. For baseline evaluation, the workers after their nightshift (in day shift) were assessed by somnowatch for three days while they did not take any medicine. Then, they were randomly divided to two groups of 25 workers. After next nightshift (in day shift), group 1 took a 3 mg tablet of melatonin and group 2 took placebo about 30 minutes before usual sleep time for 3 nights assessing by somnowatch. Washout time of two week was considered. Then, two groups after nightshift (in day shift) were assessed by somnowatch for 3 nights; the workers in group 1 took placebo and the workers in group 2 took melatonin. The melatonin and placebo were identical in shape and color and were administered blindly both for workers and for other people involved in the study. Analysis of somnowatch data was done manually to determine the sleep parameters of workers’ night-time sleep.

2.3 Ethics

After explaining the goals, risks and benefits of the study and the participants’ right to withdraw from the study at any time, written informed consents were obtained from all workers. The ethical committee of Tehran University of medical sciences approved this study.

2.4 Statistics

PASW (Predictive Analytics SoftWare) version 18 was used for data analysis. Descriptive statistics are presented using mean (SD). Normality of data was analyzed by the Kolmogorov-Smirnov test. We used repeated measure ANOVA with post-hoc factor for comparison of changes between groups within different times according to the intervention. P value <0.05 was considered statistically significant.

3 Results

Among 295 workers, 103 selected the choices of moderate, severe or very severe on ISI item 1a and had sleep onset latency of twenty minutes or more on PSQI item 2. Finally, 50 workers with difficulty falling asleep were randomly selected. Eleven workers dropped out during the field study. Five workers did not complete the three phases of the study and data of 6 workers were excluded because they forgot to take melatonin or their somnowatch data was not suitable for analysis. All of the workers were men between the ages of 24–52 (mean age±SD = 32.9±8), with a mean body mass index of 24.5 kg/m² and a mean history of shift work of 74.1 months. No significant adverse effects were reported by the workers after melatonin administration.

In data analysis, we focused on total sleep time (TST), sleep onset latency (SOL), sleep efficiency (SE) and wakening after sleep onset (WASO) obtained from somnowatch. The results are shown in Table 1. In first night, melatonin administration caused a significant improvement in SE against to baseline but not significant difference in SE was found between subjects given placebo and those treated with melatonin. In average of 3 nights, melatonin treatment significantly improved SE in comparison with baseline and taking placebo. Also, SOL of workers treated with melatonin was significantly lower than both SOL of workers taking placebo and baseline SOL. Melatonin administration increased TST but the difference between subjects treated with melatonin and those taking placebo was not significant (p value: 0.056). Also, treatment with melatonin decreased WASO more than taking placebo, but there was not a significant difference between them (p value: 0.208). No significant difference was found on sleep parameters of workers in baseline and after taking placebo. Figures 1 to 4 show the effect of administration of melatonin and placebo on TST, SE, SOL and WASO in average of 3 nights,respectively.

4 Discussion

The first clinical evidence for the role of melatonin in biological rhythm and sleep regulation was described in 1958 [21]. This hormone has potent antioxi-dant action [22, 23], it has immune-enhancing activity [24] and protective affects against car-cinogenesis [25] and neurodegenerative processes [26]. According to these actions, melatonin may be used for treatment of insomnia [27], jet lag [28] and circadian rhythm disorders [29] as well as for malignances [30] and neurodegenerative disorders [31].

The focus of our analysis was a comparison of sleep parameters (sleep onset latency, sleep efficiency, total sleep time and wakening after sleep onset) in shift workers with difficulty falling sleep at baseline, after taking placebo and after melatonin therapy for 3 nights. Somnowatch was used for assessing sleep parameters. We found the significant improvement of SE and SOL after melatonin therapy against to baseline and placebo. Also a trend toward improvement of TST and WASO observed but there were no significant difference.

Brzezinski et al. [32] in a meta-analysis including 17 studies on healthy normal subjects and insomniacs found that melatonin significantly reduced sleep onset latency, increased sleep efficiency, and increased total sleep duration. They concluded that exogenous melatonin might have some use in treating insomnia, mostly for aged individuals with nocturnal melatonin deficiency or with an abnormal pattern of melatonin secretion. Buscemi et al. [33] in a meta-analysis reported that exogenous melatonin administration in primary sleep disorders resulted in significant decrease in sleep onset latency with greater extent in people with delayed sleep phase syndrome and not significant increase in sleep efficiency. Buscemi et al. [34] in another meta-analysis about efficacy of exogenous melatonin for secondary sleep disorders and sleep disorders accompanying sleep restriction such as jet lag or shift work showed that melatonin had no effect on sleep onset latency.

Shift workers with difficulty falling asleep were enrolled in this study. In our population, melatonin resulted in significant decrease in sleep onset latency and increase in sleep efficiency which is not in agreement with Buscemi et al. meta-analysis on shift workers. The discrepancy between findings might be due to different studied populations, the diagnostic criteria and treatment protocols (dosage of melatonin and time of taking before sleep) Our work as an effectiveness study found significant improvement in sleep onset latency and sleep efficiency after taking melatonin therefore melatonin may be a valuable treatment for shift workers with difficulty falling asleep and from a clinical standpoint we believe that shift workers with difficulty falling asleep benefit from taking melatonin. Further studies on the efficacy and safety of melatonin therapy for long-term use in large samples of shift workers are required to determine the advantages and disadvantages of melatonin in shift workers.

The main limitation of our study is that we could not perform polysomnography (the gold standard test for detecting sleep disorders) in favor of the assessment of sleep parameters, however the somnowatch was approved for detecting sleep/wake pattern.

5 Conclusions

Our study showed that melatonin therapy in shift workers with difficulty falling asleep significantly improved the sleep onset latency and sleep efficiency. No significant difference was found on total sleep time and wakening after sleep onset between melatonin and placebo.

Conflict of interest

The authors declare that they have no conflict of interest.

Footnotes

Acknowledgments

This study was supported by Tehran University of Medical Sciences and health services. The authors wish to extend their thanks and appreciation to Osvah Pharmaceutical Co, Dr. Farzaneh Chavoshi, Dr. Afshin Bolouri, Mahmoud Nikbakht, Farhad Taghizadeh, Vahid Yadollahi, Ghadir Heydari and Kaamel Mard.

References

McMenamin

. Time to work: Recent trends in shift work and flexible schedules. Monthly Lab Rev 2007;130:3–15.

Virkkunen

, Harma

, Kauppinen

, Tenkanen

. Shift work, occupational noise and physical workload with ensuing development of blood pressure and their joint effect on the risk of coronary heart disease. Scand J Work Environ Health 2007;33:425–34.

Zimberg

, Fernandes Junior

, Crispim

, Tufik

, de Mello

. Metabolic impact of shift work. Work 2012;41:4376–83.

Torbjörn

. Shift work and disturbed sleep/wakefulness. Occupational Medicine 2003;53:89–94.

Meltlaine

, leger

. Socioeconomic impact of insomnia in working populations. Industrial Health 2005;43:11–9.

Preston

, Ward

, Broks

, Traub

, Stahl

. Effects of lorazepam on memory, attention and sedation in man: Antagonism by Ro 15–Psychopharmacology 1989;97:222–7.

Terzano

, Rossi

, Palomba

, Smerieri

, Parrino

. New drugs for insomnia: Comparative tolerability of zopiclone, zolpidem and zaleplon. Drug Saf 2003;26:261–82.

Roth

, Soubrane

, Titeux

, Wash

. Efficacy and safety of zolpidem-MR: A double-blind, placebo-controlled study in adults with primary insomnia. Sleep Med 2006;7:397–406.

Claustrat

, Brun

, Chazot

. The basic physiology and pathophysiology of melatonin. Sleep Med Rev 2005;9:11–24.

10.

Lerner

, Nordlund

. Melatonin clinical pharmacology. J Neural Transm 1978;13:339–47.

11.

Kostoglou-Athanassiou

. Therapeutic applications of melatonin. Ther Adv Endocrinol Metab 2013;4(1):13–24.

12.

Reinhardt

ÉL

, Fernandes

, Markus

, Fischer

. Daily rhythm of salivary IL-1β, cortisol and melatonin in day and night workers. Work 2012;41:5788–90.

13.

Jorgensen

, Witting

. Does exogenous melatonin improve day sleep or night alertness in emergency physicians working night shifts? Ann Emerg Med 1998;31:699–704.

14.

Sack

, Lewy

. Melatonin as a chronobiotic: Treatment of circadian desynchrony in night workers and the blind. J Biol Rhythms 1997;12:595–603.

15.

James

, Tremea

, Jones

, Krohmer

. Can melatonin improve adaptation to night shift? Am J Emerg Med 1998;16:367–70.

16.

Bjorvatn

, Stangenes

, Øyane

, Forberg

, Lowden

, Holsten

, Åkerstedt

. Randomized placebo-controlled field study of the effects of bright light and melatonin in adaptation to night work. Scand J Work Environ Health 2007;33:204–14.

17.

Sadeghniiat-Haghighi

, Aminian

, Pouryaghoub

, Yazdi

. Efficacy and hypnotic effects of melatonin in shift-work nurses: Double-blind, placebo-controlled crossover trial. J Circadian Rhythms 2008;6:10.

18.

Wright

, Lawrence

, Wrenn

, Haynes

, Welch

, Schlack

. Randomized clinical trial of melatonin after night-shift work: Efficacy and neuropsychologic effects. Ann Emerg Med 1998;32:334–40.

19.

Yoon

, Song

. Role of morning melatonin administration and attenuation of sunlight exposure in improving adaptation of night-shift workers. Chronobiol Int 2002;19:903–13.

20.

Sharkey

, Fogg

, Eastman

. Effects of melatonin administration on daytime sleep after simulated night shift work. J Sleep Res 2001;10:181–92.

21.

Lerner

, Case

, Takahashi

, Lee

, Mori

. Isolation of melatonin, a pineal factor that lightens melanocytes. J Am Chem Soc 1958;80:2587.

22.

Tan

, Manchester

, Terron

, Flores

, Reiter

. One molecule, many derivatives: A never-ending interaction of melatonin with reactive oxygen and nitrogen species? J Pineal Res 2007;42:28–42.

23.

Galano

, Tan

, Reiter

. Melatonin as a natural ally against oxidative stress: A physicochemical examination. J Pineal Res 2011;51:1–16.

24.

Carrillo-Vico

, Reiter

, Lardone

, Herrera

, Fernández-Montesinos

, Guerrero

, Pozo

. The modulatory role of melatonin on immune responsiveness. Curr Opin Investig Drugs 2006;7:423–31.

25.

Bukowska

. Anticarcinogenic role of melatonin–potential mechanisms. Med Pr 2011;62:425–34.

26.

Ling

, Tian

, Wang

, Fu

, Wang

. Constant illumination induces Alzheimer-like damages with endoplasmic reticulum involvement and the protection of melatonin. J Alzheimers Dis 2009;16:287–300.

27.

Morin

, Jarvis

, Lynch

. Therapeutic options for sleep-maintenance and sleep-onset insomnia. Pharmacotherapy 2007;27:89–110.

28.

Sack

. Clinical practice. Jet lag. N Engl J Med 2010;362:440–7.

29.

Skene

, Arendt

. Human circadian rhythms: Physiological and therapeutic relevance of light and melatonin. Ann Clin Biochem 2006;43:344–53.

30.

Jung

, Ahmad

. Melatonin in cancer management: Progress and promise. Cancer Res 2006;66:9789–93.

31.

Olcese

, Cao

, Mori

, Mamcarz

, Maxwell

, Runfeldt

, Wang

, Zhang

, Lin

, Zhang

, Arendash

. Protection against cognitive deficits and markers of neurodegeneration by long-term oral administration of melatonin in a transgenic model of Alzheimer disease. J Pineal Res 2009;47:82–96.

32.

Brzezinski

, Vangel

, Wurtman

, Norrie

, Zhdanova

, Ben-Shushan

, Ford

. Effects of exogenous melatonin on sleep: A meta-analysis. Sleep Med Rev 2005;9:41–50.

33.

Buscemi

, Vandermeer

, Hooton

, Pandya

, Tjosvold

, Hartling

, Baker

, Klassen

, Vohra

. The efficacy and safety of exogenous melatonin for primary sleep disorders. A meta-analysis. J Gen Intern Med 2005;20:1151–8.

34.

Buscemi

, Vandermeer

, Hooton

, Pandya

, Tjosvold

, Hartling

, Vohra

, Klassen

, Baker

. Efficacy and safety of exogenous melatonin for secondary sleep disorders and sleep disorders accompanying sleep restriction: Meta-analysis. BMJ 2006;332:385–93.