Open Access

Efficacy and hypnotic effects of melatonin in shift-work nurses: double-blind, placebo-controlled crossover trial

Journal of Circadian Rhythms20086:10

https://doi.org/10.1186/1740-3391-6-10

Received: 20 September 2008

Accepted: 29 October 2008

Published: 29 October 2008

Abstract

Background

Night work is associated with disturbed sleep and wakefulness, particularly in relation to the night shift. Circadian rhythm sleep disorders are characterized by complaints of insomnia and excessive daytime sleepiness that are primarily due to alterations in the internal circadian timing system or a misalignment between the timing of sleep and the 24-h social and physical environment.

Methods

We evaluated the effect of oral intake of 5 mg melatonin taken 30 minutes before night time sleep on insomnia parameters as well as subjective sleep onset latency, number of awakenings, and duration of sleep. A double-blind, randomized, placebo-controlled crossover study with periods of 1 night and washouts of 4 days comparing melatonin with placebo tablets was conducted. We tried to improve night-time sleep during recovery from night work. Participants were 86 shift-worker nurses aged 24 to 46 years. Each participant completed a questionnaire immediately after awakening.

Results

Sleep onset latency was significantly reduced while subjects were taking melatonin as compared with both placebo and baseline. There was no evidence that melatonin altered total sleep time (as compared with baseline total sleep time). No adverse effects of melatonin were noted during the treatment period.

Conclusion

Melatonin may be an effective treatment for shift workers with difficulty falling asleep.

Background

There is substantial evidence that the prevalence of sleep disorders is an important occupational health problem, especially among health care professionals on night or on rotating work shifts [110]. An important aspect of the work environment of nurses is that they are required to work at any point in the 24 hour day [11]. Night work is associated with disturbed sleep and impaired alertness. The impact of sleep is the result of the circadian interference with sleep during daylight hours and circadian suppression of pineal gland by light at night [12].

The definition of insomnia is a complaint of disturbed sleep, manifested as difficulties in sleep initiation, sleep maintenance, early morning awakenings, or nonrestorative sleep. Many sources also add the presence of associated daytime impairments, such as fatigue, irritability, decreased memory and concentration, and pervasive malaise affecting many aspects of daytime functioning [13]. In a recent study, 32% of night-shift workers reported symptoms of insomnia or excessive daytime sleepiness, whereas these symptoms were reported in only 18% of day workers from the same sample population [14]. Several studies have reported that sleep problems are more common among health care personnel on rotating work shifts [15]. The quality of sleep has been found to be altered in hospital nurses working on rotating shift schedules, especially those working morning and night shifts as well as in hospital nurses working shifts when compared with day nurses [16].

The pineal hormone melatonin regulates a variety of physiological processes, including circadian, cardiovascular, reproductive, and neuroendocrine functions [1719]. However, it is the hypnotic effects of melatonin that are considered an integral component of its physiological role in sleep modulation [20, 21]. Administration of melatonin facilitates sleep onset and improves the quality of sleep [2224]. Administration of melatonin can also produce phase shifts in circadian rhythms, and has been used to treat the symptoms of circadian maladaptation associated with shift work [2527]. There is currently a great deal of interest in whether properly timed melatonin administration can facilitate circadian phase shifting in these situations [28].

Normally, production of melatonin by the pineal gland is stimulated by darkness and inhibited by light [29]. Hajak et al [30] reported lower levels in blood melatonin in patients with insomnia than in healthy controls, and Haimov et al [31] found lower levels of urinary 6-sulphatoxymelatonin in elderly patients with insomnia than in healthy elderly subjects. Surprisingly, only a few studies have explored the beneficial effect of melatonin administration on night shift workers in an actual workplace setting [26]. The purpose of this study was to compare the efficacy of melatonin (5 mg) and placebo in the treatment of shift workers with insomnia.

Methods

Study Design

We conducted a double-blind, placebo-controlled, randomized crossover trial among healthy, non-smoking, non-pregnant shift worker nurses at Imam Hospital (Tehran, Iran). Each subject signed an informed consent document after the procedures had been fully explained. All subjects were asked to sign the consent form, confirming that they understood the goals, risks, and potential benefits of the study and their right to withdraw from the study at any time. The Ethical Committee of Tehran University approved the study.

Consenting participants were randomized to one of two sequences: placebo followed by melatonin or melatonin followed by placebo. The randomization list was completed using a random number generator. The treatment phase of each sequence consisted of taking a 5 mg tablet of melatonin about 30 minutes before habitual nighttime sleep. The placebo phase consisted of taking an identical looking placebo on the same schedule. Both melatonin and placebo were taken on the first night after night work. All participants had 3 visits to the hospital. At the first visit, eligibility was checked, participants gave informed consent, and baseline insomnia parameters were assessed by using seven questions [32]. Participants were asked to scale their difficulties in falling asleep, staying asleep and waking up too early with scores from 1 (no problem) to 5 (very severe problem). They were also asked to specify their sleep quality (satisfaction with their sleep) using scores from 1 (very satisfied) to 5 (very unsatisfied) and were asked to answer the following three questions about their habitual night time sleep: 1) How long does it take you to fall asleep? 2) How many times do you wake up during the night? 3) How many hours do you sleep?

All the participants who reported sleep problems in the baseline questionnaire were included in the study. In the first visit, one placebo or one melatonin was given to the nurses. They were asked to use it at home on the first night after shift work, about 30 minutes before their intended sleep. On the following morning, upon awakening, each participant answered the questionnaire. In the second visit, after the 4 days of washout and receiving their completed questionnaire, patients entered into another study period, conducted as in the first. In the third visit, the last completed questionnaire was received from nurses.

Data Analysis

We used SPSS 11.5 for Windows for statistical analysis. When the Kolmogorov-Smirnov test confirmed normality, parametric tests were conducted. One-way analysis of variance was used to determine the statistical significance of subjective scores of insomnia from each phase of the trial. Statistically significant results detected by analysis of variance (p < 0.05) were further analyzed by using Tukey post hoc paired comparisons. Results in the text are expressed as mean +/- standard deviation.

Results

Eigthy-six out of 118 participants completed the study. Eleven subjects dropped out during the first treatment phase because they could not attend the scheduled tablet taking, whereas one did not complete the second treatment phase because of an acute illness unrelated to the study protocol. Twenty participants did not report sleeping problems in the baseline questionnaire. Table 1 presents a description of the 86 subjects who completed the study. Females accounted for 80.2% of the participants, and the mean age was 30.05 years (range: 24–46 years). Subjective parameters of sleep obtained from the baseline questionnaire are shown in Table 1.
Table 1

Demographic and subjective sleep data of subjects (N = 86)

 

Mean (SD) or percentage (n)

Sex

80.2% female (69)

Age

30.05 (5.2)

Mean BMI in kg/m2

26.7 (3.1)

Subjective sleep onset latency in min

37.5 (41.3)

Subjective number of awakenings

5.2 (2.1)

Subjective duration of sleep in min

450.5 (82.3)

Differences in sleep data at baseline, while taking placebo, and while taking melatonin are shown in Tables 2 and 3. Subjective sleep onset latency (SOL) was 37.5 +/- 41.3 minutes at the baseline. There was evidence of an effect of melatonin treatment on SOL. Specifically, the mean SOL for subjects being treated with melatonin was significantly lower than the mean SOL for subjects given placebo. Furthermore, means for both the subjects given melatonin and those given placebo were significantly different from the baseline mean (see Table 2). Although melatonin treatment did not significantly alter other insomnia variable compared with baseline values, there was a significant improvement in sleep quality with melatonin treatment (see Table 3).
Table 2

Subjective sleep parameters during a randomized, double-blind, placebo-controlled crossover study of shift work nurses: results at baseline and after 1 night melatonin or placebo treatment (N = 86)

  

Mean

SD

P(vs.baseline a )

P(vs.placebo a )

Fb

Pb

Sleep onset latency

Melatonin

21.5

17.7

< 0.05

< 0.05

6.3

0.01

 

Placebo

49.7

30.3

< 0.05

   
 

Baseline

37.5

41.3

    

Total sleep time

Melatonin

392.1

52.4

> 0.05

> 0.05

0.49

NS

 

Placebo

372

49.4

> 0.05

   
 

Baseline

450.5

82.3

    

Number of awakenings

Melatonin

5.1

1.9

> 0.05

> 0.05

0.64

NS

 

Placebo

5.1

1.9

> 0.05

   
 

Baseline

5.2

2.1

    

a p values for Tukey post hoc analysis.

b Overall test for differences

Table 3

Subjective assessment of insomnia: results at baseline and after 1 night of melatonin or placebo treatment (N = 86)

  

Mean

SD

P(vs.baseline a )

P(vs.placebo a )

Fb

Pb

Difficulty falling asleep

Melatonin

1.63

0.61

< 0.05

< 0.05

4.5

0.01

 

Placebo

2.53

0.62

> 0.05

   
 

Baseline

2.67

0.80

    

Difficulty staying asleep

Melatonin

2.32

0.83

> 0.05

> 0.05

0.71

NS

 

Placebo

2.31

0.69

> 0.05

   
 

Baseline

2.48

1.11

    

Problem waking up too early

Melatonin

2.26

0.81

> 0.05

> 0.05

0.42

NS

 

Placebo

2.40

0.74

> 0.05

   
 

Baseline

2.39

1.29

    

Sleep quality

Melatonin

2.58

0.76

< 0.05

< 0.05

1.2

0.02

 

Placebo

2.69

0.67

> 0.05

   
 

Baseline

3.16

0.92

    

a p values for Tukey post hoc analysis.

b Overall test for differences

Discussion

In 86 shift-work nurses with insomnia disorders, administration of 5 mg of melatonin about 30 minutes before a night time sleep significantly decreased sleep onset latency (SOL) and increased sleep quality as compared with placebo. We observed a significant improvement in falling asleep induced by 5 mg of melatonin (16 min) as compared to baseline, which supports the well known capacity of this hormone to change biological rhythms [3336].

Placebo was not equal to baseline for SOL. A general meta-analysis of placebo effects pointed to a nonsignificant beneficial effect on sleep latency (a 10-min decrease in subjective estimates of sleep latency) in five clinical trials [37]. Melatonin did not alter the other sleep parameters that we measured. These findings are in accordance with those of earlier open trials using smaller numbers of subjects [38, 39].

The focus of our analysis was a comparison of assessment of insomnia parameters (sleep onset, sleep maintenance, sleep quality) in nurses with shift working at baseline, after a one-night melatonin treatment, and after a one-night placebo treatment. Our study revealed no major impact of melatonin on difficulty staying asleep or waking up too early. Our results agree with a previous investigation suggesting that patients with primary insomnia have a pathophysiologic disturbance that is not reversed by melatonin [40]. No adverse effects of melatonin were noted during the treatment.

The fact that we observed a reduction in SOL but no change in sleep duration after melatonin administration has at least two possible explanations: either 1) melatonin caused a small (16 min) phase advance of the circadian system or 2) random variation obscured a correspondingly small lengthening of total sleep time. Our data do not provide the basis for favoring either one or the other of these alternatives.

A limitation of this study is that we were unable to perform polysomnography or actigraphy to evaluate sleep parameters objectively. Our results based on subjective self-reports were, however, very encouraging. Regarding the high prevalence of insomnia in shift workers, more studies about melatonin effect on different kinds of insomnia parameters (difficulty falling asleep, difficulty staying asleep, problem waking up too early, and sleep quality) causing by shift working is recommended.

Conclusion

Melatonin may be an effective treatment for shift workers with difficulty falling asleep.

Declarations

Acknowledgements

This study was supported by Tehran University of Medical Sciences (TUMS). The authors gratefully acknowledge (i) the efforts of Dr. Ramin Mehrdad who helped with data analysis and interpretation, (ii) the time and effort generously provided by all participants, (iii) the assistance with data collection provided by staff and students at Imam and Baharloo Hospital/Tehran University of Medical Sciences.

Authors’ Affiliations

(1)
Baharloo Hospital, Tehran University of Medical Sciences

References

  1. Coffey L, Skipper J, Jung F: Nurses and shift work: effects onjob performance and job-related stress. J Adv Nurs 1988, 13:245–254.View ArticlePubMedGoogle Scholar
  2. Estryn-Behar M, Kaminski M, Peigne E, Bonnet N, Vaichere E, Gozian C, Azoulay S, Giorgi M: Stress at work and mental health status among female hospital workers. Br J Ind Med 1990, 47:20–28.PubMedGoogle Scholar
  3. Skipper J, Jung F, Coffey L: Nurses and shiftwork: effects on physical health and mental depression. J Adv Nurs 1990, 15:835–842.View ArticlePubMedGoogle Scholar
  4. Golde D, Rogacz S, Bock N, Torstenson T, Baum T, Speizer F, Czeisler C: Rotating shift work, sleep and accidents related to sleepiness in hospital nurses. Am J Public Health 1992, 82:1011–1014.View ArticleGoogle Scholar
  5. Kandolin I: Burnout of female and male nurses in shiftwork. Ergonomics 1993, 36:141–147.View ArticlePubMedGoogle Scholar
  6. Menna-Baretto L, Benedito-Silva A: Individual differences in night and continously-rotating shiftwork: seeking anticipatory rather than compensatory strategy. Ergonomics 1993, 36:135–140.View ArticleGoogle Scholar
  7. Neidhammer I, Lert F, Marne M-J: Effects of shift work on sleep among French nurses. A longitudinal study. J Occup Med 1994, 36:667–674.Google Scholar
  8. Barton J, Spelten E, Totterdell P, Smith L, Folkard S: Is there an optimum number of night shifts? Relationship between sleep, health and wellbein. Work Stress 1995, 9:109–123.View ArticlePubMedGoogle Scholar
  9. Efinger J, Nelson L, Starr J: Understanding circadian rhythms. a holistic approach to nurses and shiftwork. Holist Nurs 1995, 13:306–322.View ArticleGoogle Scholar
  10. Hakola T, Harma M, Laitinen J: Circadian adjustment of men and women to night work. Scand J Work, Environ Health 1996,22(2):133–138.Google Scholar
  11. Fitzpatrick JM, While AE, Roberts JD: Shift work and its impact upon nurse performance: current knowledge and research issues. J Adv Nurs 1999, 29:18–27.View ArticlePubMedGoogle Scholar
  12. Lowden A, Akerstedt T, Wibom R: Suppression of sleepiness and melatonin by bright light exposure during breaks in night work. J Sleep Res 2004, 13:37–43.View ArticlePubMedGoogle Scholar
  13. National Institutes of Health: State-of-the-Science Conference Statement on Manifestations and Management of Chronic Insomnia in Adults. Sleep 2005, 28:1049–1057.Google Scholar
  14. Drake CL, Roehrs T, Richardson G, Walsh JK, Roth T: work sleep disorder: prevalence and consequences beyond that of symptomatic day workers. Sleep 2004, 27:1453–1462.PubMedGoogle Scholar
  15. Menna-Baretto L, Benedito-Silva A: Individual differences in night and continuously-rotating shiftwork: seeking anticipatory rather than compensatory strategy. Ergonomics 1993, 36:135–140.View ArticleGoogle Scholar
  16. Herdis Sveinsdottir: Self-assessed quality of sleep, occupational health, working environment, illness experience and job satisfaction of female nurses working different combination of shifts. Scand J Caring Sci 2006, 20:229–237.View ArticleGoogle Scholar
  17. Vanecek J: Cellular mechanisms of melatonin action. Physiol Rev 1998, 78:687–721.PubMedGoogle Scholar
  18. Borjigin J, Li X, Snyder SH: The pineal gland and melatonin: molecular and pharmacologic regulation. Annu Rev Pharmacol Toxicol 1999, 39:53–65.View ArticlePubMedGoogle Scholar
  19. Reiter RJ: Oxidative damage in the central nervous system: protection by melatonin. Prog Neurobiol 1998, 56:359–384.View ArticlePubMedGoogle Scholar
  20. Naguib M, Baker MT, Spadoni G, Gregerson MS: The hypnotic and analgesic effects of 2-bromomelatonin. Anesth Analg 2003, 97:763–768.View ArticlePubMedGoogle Scholar
  21. Naguib M, Hammond DL, Schmid IP: Pharmacological effects of intravenous melatonin: comparative studies with thiopental and propofol. Br J Anaesth 2003, 90:504–507.View ArticlePubMedGoogle Scholar
  22. Wurtman RJ, Zhdanova I: Improvement of sleep quality by melatonin. Lancet 1995,346(8988):1491.View ArticlePubMedGoogle Scholar
  23. Tzischinsky O, Lavie P: Melatonin possesses time-dependent hypnotic effects. Sleep 1994, 17:638–645.PubMedGoogle Scholar
  24. Petrie K, Conaglen JV, Thompson L, Chamberlain K: Effect of melatonin on jet lag after long houl flights. BMJ 1989, 298:705–707.View ArticlePubMedGoogle Scholar
  25. Folkard S, Arendt J, Clark M: Can melatonin improve shift workers' tolerance of the night shift? Some preliminary findings. Chronobiol Int 1993, 10:315–320.View ArticlePubMedGoogle Scholar
  26. James M, Tremea MO, Jones JS, Krohmer JR: Can melatonin improve adaptation to night shift? Am J Emerg Med 1998, 16:367–370.View ArticlePubMedGoogle Scholar
  27. Jorgensen KM, Witting MD: Does exogenous melatonin improve day sleep or night alertness in emergency physicians working night shifts? Ann Emerg Med 1998, 31:699–704.View ArticlePubMedGoogle Scholar
  28. Shapiro CM, et al.: Working the shifting: a self-health guide. Jolijoco Publications 1997, 40–44.Google Scholar
  29. Does melatonin help to cure insomnia? [http://neurology.health-cares.net/insomnia-melatonin.php]
  30. Hajak G, Rodenbeck A, Staedt J, Bandelow B, Hueter G, Rüther E: Nocturnal plasma melatonin levels in patients suffering from chronic primary insomnia. J Pineal Res 1995, 19:116–122.View ArticlePubMedGoogle Scholar
  31. Haimov I, Laudon M, Zisapel N, Souroujon M, Nof D, Shlitner A, et al.: Sleep disorders and melatonin rhythms in elderly people. BMJ 1994, 309:167.PubMedGoogle Scholar
  32. Morin CM: Insomnia: Psychological Assessment and Management New York, NY: Guilford Press 1993.Google Scholar
  33. Sack RL, Hughes RJ, Edgar DM, Lewy AJ: Sleep-promoting effects of melatonin: at what dose, in whom, under what conditions, and by what mechanisms? Sleep 1997, 20:908–915.PubMedGoogle Scholar
  34. Sack RL, Blood ML, Lewy AJ: Melatonin administration to night shift workers: an update [letter]. J Sleep Res 1995, 24:539.Google Scholar
  35. Sack RL, Lewy AJ, Blood ML: Melatonin administration to blind people: phase advances and entrainment. J Biol Rhythms 1991, 6:249–261.View ArticlePubMedGoogle Scholar
  36. Lewy AJ, Ahmed S, Jackson JML, Sack RL: Melatonin shifts circadian rhythms according to phase-response curve. Chronobiol Int 1992, 9:380–392.View ArticlePubMedGoogle Scholar
  37. Hrobjartsson A, Gotzsche PC: Is the placebo powerless? An analysis of clinical trials comparing placebo with no treatment. N Engl J Med 2001, 344:1594–1602.View ArticlePubMedGoogle Scholar
  38. Alvarez B, Dahlitz MJ, Vignau J, Parkes JD: The delayed sleep phase syndrome: clinical and investigative findings in 14 subjects. J Neurol Neurosurg Psychiatry 1992, 55:665–670.View ArticlePubMedGoogle Scholar
  39. Tzischinsky O, Dagan Y, Lavie P: The effects of melatonin on the timing of sleep in patients with delayed sleep phase syndrome. Melatonin and the pineal gland: from basic science to clinical application (Edited by: Touitou Y, Arendt J, Pevet P). Amsterdam: Elsevier Excerpta Medica 1993, 351–354.Google Scholar
  40. Almeida Montes LG, Ontiveros Uribe MP, Cortes Sotres J, Heinze Martine G: Treatment of primary insomnia with melatonin: a double-blind, placebo-controlled, crossover study. J Psychiatry Neurosci 2003, 28:191–196.PubMedGoogle Scholar

Copyright

© Sadeghniiat-Haghighi et al. 2008

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Advertisement