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Database of Abstracts of Reviews of Effects (DARE): Quality-assessed Reviews [Internet]. York (UK): Centre for Reviews and Dissemination (UK); 1995-.

Database of Abstracts of Reviews of Effects (DARE): Quality-assessed Reviews [Internet].

Effect of melatonin on nocturnal blood pressure: meta-analysis of randomized controlled trials

E Grossman, M Laudon, and N Zisapel.

Review published: 2011.

CRD summary

This review found that controlled-release melatonin treatment may have improved blood pressure control in patients with nocturnal hypertension. Some methodological flaws mean that the reliability of the authors' conclusions is unclear.

Authors' objectives

To assess the effect of melatonin on nocturnal blood pressure and to analyse the data by type of melatonin formulation.


PubMed was searched for relevant studies in English from January 1980 to December 2010; search terms were reported. The reference lists of retrieved studies were checked for additional studies.

Study selection

Randomised controlled trials of patients with nocturnal hypertension in which melatonin was compared to placebo were eligible for inclusion. Eligible trials had to have Jadad scores of at least 3, and report nocturnal systolic and diastolic blood pressure measured by 24-hour ambulatory blood pressure monitoring. Open-label studies and studies that evaluated melatonin agonists were excluded from the review.

Included patients presented with coronary artery disease, type 1 diabetes mellitus and hypertension; some patients were normotensive. Mean age of the patients ranged from 16 to 63 years; one study enrolled only adolescents. Where reported, baseline systolic blood pressure ranged from 117 to 137mmHg and diastolic blood pressure ranged from 65 to 72mmHg. The melatonin doses administered were 5mg for the fast-release formulation and 2.5 to 3mg for the controlled-release formulation. Outcomes evaluated were blood pressure parameters and adverse events associated with treatment. The duration of the trials ranged from seven to 90 days.

The authors did not state how many reviewers performed study selection.

Assessment of study quality

Methodological quality was assessed with the Jadad five-point scale in terms of randomisation, blinding and treatment of withdrawals and drop-outs.

Two independent reviewers assessed study quality.

Data extraction

Data were extracted to calculate mean differences (MD) and 95% confidence intervals (CI) for the blood pressure outcomes.

The authors did not state how many reviewers performed the data extraction.

Methods of synthesis

Weighted mean differences (WMD) and 95% confidence intervals for the estimates were calculated using a random-effects model.

Results of the review

Seven RCTs (221 participants) were included in the review; three parallel studies and four crossover studies. The mean quality score was 3.8 out of 5 (range 3 to 5).

There were non-significant decreases in systolic and diastolic blood pressure associated with melatonin treatment compared to placebo observed across the seven studies. There were no statistically significant changes in systolic or diastolic blood pressure observed with the use of fast-release melatonin.

The use of controlled-release melatonin was associated with statistically significant decreases in systolic blood pressure (WMD -6.1mmHg, 95% CI -10.69 to -1.50) and diastolic blood pressure (WMD -3.51mmHg, 95% CI -6.14 to -0.86).

There were no serious adverse events reported across the seven trials. Headache, drowsiness, weakness and nightmares were reported in three studies.

Authors' conclusions

The addition of controlled-release melatonin at night to stable antihypertensive treatment may have improved control of nocturnal hypertension and may have reduced cardiovascular risk in high-risk patients with nocturnal hypertension.

CRD commentary

The review addressed a clear question and criteria for the inclusion of studies in the review were clearly defined and reproducible. Only one appropriate database was included in the review and there were no attempts to identify unpublished studies. This meant the search was limited, and there was potential for publication bias. In addition, the restriction of the review to studies published in English meant there was risk of language bias. Steps were taken to minimise errors and bias for the assessment of methodological quality, but were not reported for study selection or data extraction. There was no evaluation of statistical heterogeneity in the results across the trials, which made it difficult to assess if the combination of the results in a meta-analysis was appropriate. Some clinical heterogeneity in the included populations was present, particularly with the inclusion of normotensive populations in the review alongside patients with hypertension. Few studies were eligible for inclusion and the included studies were all small.

High potential for missed studies, small numbers of patients included in the review and the lack of information on study quality means that the reliability of the authors' conclusions is not known.

Implications of the review for practice and research

Practice: The authors stated that add-on melatonin therapy did not present risks of significant adverse events or detrimental drug interactions with other medications used to treat hypertension.

Research: The authors stated that future trials with longer duration of follow-up were needed to determine the long term safety of melatonin treatment in patients with nocturnal hypertension. In addition, larger trials with long-term administration of controlled-release melatonin were required to determine the beneficial effects of controlled-release melatonin in patients with nocturnal hypertension.


Neurin Pharmaceuticals Ltd., manufacturer of Circadin.

Bibliographic details

Grossman E, Laudon M, Zisapel N. Effect of melatonin on nocturnal blood pressure: meta-analysis of randomized controlled trials. Vascular Health and Risk Management 2011; 7: 577-584. [PMC free article: PMC3180511] [PubMed: 21966222]

Indexing Status

Subject indexing assigned by NLM


Adult; Aged; Antihypertensive Agents /adverse effects /therapeutic use; Blood Pressure /drug effects; Circadian Rhythm; Delayed-Action Preparations; Drug Therapy, Combination; Evidence-Based Medicine; Female; Humans; Hypertension /drug therapy /physiopathology; Male; Melatonin /adverse effects /therapeutic use; Middle Aged; Randomized Controlled Trials as Topic; Treatment Outcome; Young Adult



Database entry date


Record Status

This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn.

CRD has determined that this article meets the DARE scientific quality criteria for a systematic review.

Copyright © 2014 University of York.

PMID: 21966222