Does ZMA actually help you sleep

Does melatonin help with insomnia?

question

Sleep disorders are a very common reason for treatment in general practitioners. The usually prescribed benzodiazepines or Z-substances (zolpidem, zopiclone, zaleplon) should - if at all - only be given for a short period, especially not for elderly patients. Represents melatonin (Circadin®) is an effective and safe alternative?

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answer

The data on the general treatment of sleep disorders with melatonin are inconsistent and inadequate. There is evidence that melatonin shortens the time it takes to fall asleep in the elderly and improves the quality of sleep. Here, however, large, high-quality, randomized controlled long-term studies are required in order to be able to make valid recommendations. The best data are available on the prevention and treatment of jet lag. A cautious recommendation can be made here. However, sustained-release melatonin should not be used. Certain patient groups may also benefit from taking melatonin. However, there is currently insufficient data on this.

Department of General Medicine and Family Medicine, Center for Public Health, Medical University of Vienna, Austria DOI 10.3238 / zfa.2019.0103-0105

background

Sleep disorders are a frequent reason for advice in general practitioners' practices. According to the DAK Health Report 2017, up to 80% of the working population in Germany suffer from more or less pronounced sleep disorders [1]. One in ten employees has severe insomnia. Half of those affected resort to self-medication, around 40% can be prescribed sleeping pills - very often on a private prescription, so that this does not appear in the routine data of the health insurance companies. In many cases, benzodiazepines and the so-called Z-substances (zolpidem, zopiclone, zaleplon) are prescribed, which have a considerable potential for dependence and are often prescribed for years [1].

Melatonin is repeatedly touted as a natural "sleep hormone" as an alternative. Melatonin is formed from serotonin in the epiphysis (pineal gland) of the diencephalon. The synthesis is inhibited by light and reaches its maximum around 3 a.m. Melatonin is an important clock for the day-night or wake-sleep rhythm. In particular, the deep sleep phase seems to be triggered by melatonin [2]. It has long been controversial whether melatonin has a place in the therapy of sleep disorders, and if so, in what dosage and form it should be administered. Melatonin has been approved as a prescription drug in the European Union since 2007. In some non-European countries it is also freely sold as a dietary supplement.

The question arises as to the existing study evidence on the effectiveness and safety of melatonin in the treatment of sleep disorders.

We conducted a non-systematic search for current intervention studies and systematic reviews in PubMed / Medline and the Cochrane Database of Systematic Reviews.

Results

Cochrane Database

Various Cochrane reviews deal with melatonin, but rather special situations are considered. A general Cochrane review on the pharmacological treatment of sleep disorders is only available as a protocol [3].

A current Cochrane review examines the effectiveness of melatonin as a sleep-promoting drug in patients in the intensive care unit [4]. In their extensive systematic research, the Cochrane authors identified only four randomized controlled studies with a total of 151 participants in which melatonin was tested against placebo (three studies) or “usual care” (one study). In three studies, the duration and quality of sleep were assessed through subjective assessments by nurses and relatives. There was no difference between the melatonin and placebo groups. One study used the Richards-Campbell Sleep Questionnaire (RCSQ) and the scores were the same in both groups. Two studies assessed the subjects' sleep using polysomnography, EEG and bispectral index (a measure that is calculated from various EEG parameters). In one of the two studies there was no difference in polysomnography and EEG, but a slight advantage for melatonin in the bispectral index with regard to sleep quality. A meta-analysis could not be carried out due to the great heterogeneity of the study. No significant adverse effects were observed with melatonin. The Cochrane authors conclude from the available data that there is no robust evidence for the effectiveness of melatonin in promoting sleep in patients in the intensive care unit.

In another Cochrane review, various pharmacological interventions to end benzodiazepine abuse were investigated [5]. Four randomized controlled trials of melatonin versus placebo were also included. Only one of the four studies reported a positive effect for melatonin. The meta-analysis showed a non-significant tendency that melatonin increased the chance of discontinuing benzodiazepines (RR 1.20, 95% CI 0.73–1.96). However, this “positive” tendency is exclusively due to the one positive study. There was also a positive trend with regard to the “insomnia” outcome. Two studies use the Pittsburgh Sleep Quality Index (PSQI) to assess sleep, and one study uses a VAS (visual analog scale) of 1-10. Both one of the two studies with PSQI and the VAS study show a significantly positive result for melatonin. In the meta-analysis, however, the significance is lost. With regard to adverse drug reactions, no difference can be seen between melatonin and placebo.

The Cochrane authors conclude that the currently available study evidence is insufficient to provide reliable information on the effectiveness of melatonin as a replacement for benzodiazepines.

An older Cochrane review deals with the effectiveness of melatonin for the prevention and treatment of jet lag [6]. The authors identified nine randomized controlled trials of sufficient quality that compared melatonin with placebo. There was a clear advantage for melatonin in a global jetlag score (0–100) (standard mean difference –19.52, 95% CI –28.13 to –10.92) on flights from west to east over 5 –6 time zones. The effect was somewhat lower on flights in the opposite direction (-17.27, 95% CI -27.28 to -7.26). The risk of having a jetlag score> 60 decreased by half (RR 0.5, 95% CI 0.25-0.74, number needed to treat = 2). It was taken at bedtime (between 10 p.m. and midnight) at the destination for several days in a dose between 0.5 and 5 mg without delay. There was a dose-dependent increase in effectiveness up to 5 mg. Higher dosages brought no further benefit. The 2 mg delayed dose was less effective. There were no major side effects in any of the studies. The Cochrane authors conclude from the available studies that the occasional intake of melatonin can be recommended to prevent jet lag. However, they note that there is no data on long-term safety.

Another Cochrane review examined the effect of melatonin on improving sleep during shift work [7 [. Nine studies were identified that examined the effects of melatonin in a randomized controlled manner compared to placebo. The length of daytime sleep after a night shift was increased by an average of 24 minutes with melatonin (95% CI 9.8–38.9), the night sleep following a shift change by 17 minutes (95% CI 3.71–30.22) . No dose dependency of the effect could be found at doses between 1 and 10 mg. The sleep time was not shortened. The authors conclude that the current study situation suggests a slight benefit from melatonin. The study quality is rated as low, however, and the lack of long-term data on safety is criticized.

PubMed / Medline

Overall, only a few randomized controlled trials of sufficient size for the general population could be identified. A moderately large (n = 281) randomized controlled study from 2010 found a significantly shorter time to fall asleep with melatonin (2 mg, delayed release, compared to placebo) only in older study participants (65–80 years) [8]. The effect persisted over the entire study period of six months without developing tolerance.

A systematic review with meta-analysis from 2017 identified twelve randomized controlled trials [9]. Essentially, there was a shortening of the time to fall asleep. However, the authors call for further larger randomized controlled trials to support the validity of the available evidence.

Individual studies examine the effects of melatonin in special patient groups. A recent study was specifically devoted to the sleep disorders of tumor patients. This randomized controlled study showed clear advantages for melatonin (3 mg, non-retarded, taken at 7 p.m.) on the Athens Insomnia Scale. However, the study only included 50 patients who were treated for 14 days. Adverse effects were not reported.

Another small (n = 16) randomized controlled study showed an increase in the duration of sleep (36 min) and a shortening of the time to fall asleep (–14 min) in patients with hypertension on beta-blocker therapy [10].

There are numerous similar, small and qualitatively questionable studies for a wide variety of patient groups (Alzheimer's, ADHD, autism, etc.). What is missing, however, is a high-quality, really large randomized controlled trial in the general population.

Conclusion

The only proof of the effectiveness of melatonin that was sufficiently valid for a recommendation was provided for the prevention and treatment of jet lag. An attempt at therapy in sensitive people appears to be justified here, especially since long-term use with a possible safety risk is not to be expected here either. Evidence from studies suggests a positive effect in older people with sleep disorders. Here, however, larger, high-quality randomized controlled studies are required, especially to document the safety of long-term use. Certain patient groups may benefit from melatonin medication. However, the study situation is far from sufficient here to make a general recommendation. It is also not clear whether the dosage of 2 mg with delayed release available in Germany and Austria actually achieves the optimal effects. This does not seem to be the case with jetlag in particular.

literature

1. Storm A. Health Report 2017. DAK, www.dak.de/dak/download/gesundheitsreport-2017-1885298.pdf (last accessed on February 12, 2019)

2. Claustrat B, Leston J. Melatonin: Physiological effects in humans. Neurosurgery 2015; 61: 77-84

3. De Crescenzo F, Foti F, Ciabattini M, et al. Comparative efficacy and acceptability of pharmacological treatments for insomnia in adults: a systematic review and network meta-analysis. Cochrane Database of Systematic Reviews 2016: 9. CD012364

4. Lewis SR, Pritchard MW, Schofield-Robinson OJ, Alderson P, Smith AF. Melatonin for the promotion of sleep in adults in the intensive care unit. Cochrane Database of Systematic Reviews 2018: 5. CD012455.pub2

5. Baandrup L, Ebdrup BH, Rasmussen JØ, Lindschou J, Gluud C, Glenthøj BY. Pharmacological interventions for benzodiazepine discontinuation in chronic benzodiazepine users. Cochrane Database of Systematic Reviews 2018: 3.CD011481.pub2

6. Herxheimer A, Petrie KJ. Melatonin for the prevention and treatment of jet lag. Cochrane Database of Systematic Reviews 2002: 2. CD001520

7. Liira J, Verbeek JH, Costa G, et al. Pharmacological interventions for sleepiness and sleep disturbances caused by shift work. Cochrane Database of Systematic Reviews 2014: 8. CD009776.pub2

8. Wade AG, Ford I, Crawford G, et al. Nightly treatment of primary insomnia with prolonged release melatonin for 6 months: a randomized placebo controlled trial on age and endogenous melatonin as predictors of efficacy and safety. BMC Med 2010; 8:51

9. Auld F, Maschauer EL, Morrison I, Skene DJ, Riha RL. Evidence for the efficacy of melatonin in the treatment of primary adult sleep disorders. Sleep Med Rev 2017; 34: 10-22

10. Scheer FAJL, Morris CJ, Garcia JI, et al. Repeated melatonin supplementation improves sleep in hypertensive patients treated with beta-blockers: a randomized controlled trial. Sleep 2012; 35: 1395-402


(As of March 12, 2019)