Repeated melatonin supplementation improves sleep in hypertensive patients treated with beta-blockers: a randomized controlled trial

Abstract

Study objectives: In the United States alone, approximately 22 million people take beta-blockers chronically. These medications suppress endogenous nighttime melatonin secretion, which may explain a reported side effect of insomnia. Therefore, we tested whether nightly melatonin supplementation improves sleep in hypertensive patients treated with beta-blockers.

Design: Randomized, double-blind, placebo-controlled, parallel-group design.

Setting: Clinical and Translational Research Center at Brigham and Women's Hospital, Boston.

Patients: Sixteen hypertensive patients (age 45-64 yr; 9 women) treated with the beta-blockers atenolol or metoprolol.

Interventions: Two 4-day in-laboratory admissions including polysomnographically recorded sleep. After the baseline assessment during the first admission, patients were randomized to 2.5 mg melatonin or placebo (nightly for 3 weeks), after which sleep was assessed again during the second 4-day admission. Baseline-adjusted values are reported. One patient was removed from analysis because of an unstable dose of prescription medication.

Measurements and results: In comparison with placebo, 3 weeks of melatonin supplementation significantly increased total sleep time (+36 min; P = 0.046), increased sleep efficiency (+7.6%; P = 0.046), and decreased sleep onset latency to Stage 2 (-14 min; P = 0.001) as assessed by polysomnography. Compared with placebo, melatonin significantly increased Stage 2 sleep (+41 min; P = 0.037) but did not significantly change the durations of other sleep stages. The sleep onset latency remained significantly shortened on the night after discontinuation of melatonin administration (-25 min; P = 0.001), suggesting a carryover effect.

Conclusion: n hypertensive patients treated with beta-blockers, 3 weeks of nightly melatonin supplementation significantly improved sleep quality, without apparent tolerance and without rebound sleep disturbance during withdrawal of melatonin supplementation (in fact, a positive carryover effect was demonstrated). These findings may assist in developing countermeasures against sleep disturbances associated with beta-blocker therapy.

Clinical trial information: his study is registered with ClinicalTrials.gov, identifier: NCT00238108; trial name: Melatonin Supplements for Improving Sleep in Individuals with Hypertension; URL: http://www.clinicaltrials.gov/ct2/show/NCT00238108.

Keywords: Actigraphy; adrenergic beta-antagonists; atenolol; autonomic nervous system; hypertension; hypnotics; melatonin; metoprolol; polysomnography; sleep.

Figure 1

Example of in-laboratory protocol for patient with habitual bedtime of midnight. Polysomnography (PSG) collected on the baseline night (second sleep episode of first admission) was compared with PSG collected on the night after 3-week melatonin/placebo administration (second sleep episode of second admission) as the main comparison to assess the effect of 3-week melatonin supplementation. Patients were kept in the laboratory for an extra night after first administration and the first night after discontinuation as a safety precaution and to address exploratory questions (see Supplemental Material). Filled circles, double-blind study drug (melatonin/placebo); open circles, single-blind placebo; black bars, sleep episodes in complete darkness; hatched bars, wakefulness in dim light for assessment of endogenous melatonin profile (approximately 4 lux); white bars, wakefulness in room light (approximately 90 lux).

Figure 2

Melatonin improves PSG-assessed sleep quality. Three-week melatonin supplementation significantly increased total sleep time and sleep efficiency (left panels), and significantly decreased latency to Stage 1 and Stage 2 sleep (right panels). P values, significance of melatonin effect; numbers underneath P values, magnitude of melatonin effect.

Figure 3

Melatonin increases Stage 2 sleep without effects on other sleep stages. Three-week melatonin supplementation significantly increased Stage 2 sleep, without significant change in slow wave sleep (Stage 3 and Stage 3), rapid eye movement (REM) sleep, and Stage 1 sleep. P values, significance of melatonin effect; numbers underneath P values, magnitude of melatonin effect.

Figure 4

Time course of the effect of melatonin on actigraphy-estimated sleep. Melatonin increased total sleep time and sleep efficiency as estimated by actigraphy similarly during the 1st, 2nd, and 3rd week of supplementation at home, i.e., without significant interaction with time. P values, significance of melatonin effect (group; melatonin vs. placebo) and interaction of group with week of supplementation (group × time).