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. 2012 Oct 1;35(10):1395–1402. doi: 10.5665/sleep.2122

Repeated Melatonin Supplementation Improves Sleep in Hypertensive Patients Treated with Beta-Blockers: A Randomized Controlled Trial

Frank AJL Scheer 1,2,✉, Christopher J Morris 1,2, Joanna I Garcia 1, Carolina Smales 1, Erin E Kelly 1, Jenny Marks 1, Atul Malhotra 1,2, Steven A Shea 1,2,3
PMCID: PMC3443766  PMID: 23024438

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.

Citation:

Scheer FAJL; Morris CJ; Garcia JI; Smales C; Kelly EE; Marks J; Malhotra A; Shea SA. Repeated melatonin supplementation improves sleep in hypertensive patients treated with beta-blockers: a randomized controlled trial. SLEEP 2012;35(10):1395-1402.

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

Introduction

Approximately 22 million Americans use beta-adrenergic receptor antagonists, or beta-blockers.1 Despite their demonstrated benefit in various cardiovascular and non-cardiovascular diseases, beta-blockers have been associated with an incidence of adverse side effects including nighttime sleep disturbances and daytime fatigue.2–6 These side effects have mainly been ascribed to central nervous system and cardiac effects. However, beta-1-blockers not only reduce sympathetic outflow to the cardiovascular system but also block sympathetic signaling to the pineal gland, resulting in suppression of nighttime levels of the soporific hormone melatonin,7–10 which may help explain the insomnia associated with beta-blocker use.2,11,12 Thus, melatonin supplementation may potentially counteract the sleep disturbances associated with beta-blocker use.10,11 However, there has been no clinical trial to determine the efficacy of melatonin supplementation for improving sleep in patients treated chronically with a beta-blocker. Moreover, considerable data support adverse cardiometabolic effects of short sleep duration,13–16 leading to speculation that such outcomes could be improved in patients using beta-blockers by maintaining sleep duration. Thus, in the current study we tested the hypothesis that repeated melatonin supplementation (3 weeks) improves sleep in hypertensive patients chronically treated with beta-blockers. Changes in sleep were assessed by polysomnography (PSG) under standardized laboratory conditions.

METHODS

Patients

Sixteen patients completed the study (9 women; mean ± standard deviation [range]; age: 56.1 ± 6.1 yr [45–64 yr]; body mass index: 28.04 ± 3.86 kg/m2 [21.5–34.7 kg/m2]). These patients received a diagnosis of uncomplicated essential hypertension (blood pressure: 130/79 ± 15/9 mm Hg while on anti-hypertensive treatment) and were treated for at least 6 mo with beta-1-selective blockers (atenolol, 50 mg/day [n = 8], atenolol, 25 mg/day [n = 5], atenolol, 100 mg/day [n = 1], metoprolol, 50 mg/day [n = 1], and metoprolol, 100 mg/day [n = 1]). In addition to a beta-blocker, 4 patients took an angiotensin-converting enzyme inhibitor and/or thiazide diuretic before and throughout the study. Patients were not on any medication other than antihypertensive medication and were otherwise healthy as confirmed by extensive history, physical, psychologic, and laboratory examination. Sleeping problems were not part of the inclusion criteria. Patients underwent an overnight polysomnographic diagnostic test according to recommended criteria17 to exclude severe sleep apnea (apnea hypopnea index > 30/hr) and periodic limb movement during sleep (> 15/hr), as well as for patients to become accustomed to wearing the polysomnographic equipment before the start of the clinical trial. The average apnea-hypopnea index was 11/hr (range: 1-27/hr). One of the 16 patients was excluded from analysis because of a change in the dosing of prescription medication while enrolled in the study. Patients reported no shift work experience for at least 3 yr and not crossing more than two time zones in the 3 mo prior to the study. Toxicology screens at the time of both admissions confirmed that patients were free of any drugs (including caffeine, alcohol, and nicotine) apart from prescribed antihypertensive medications. Patients provided written informed consent, and the study was approved by the local Human Research Committee.

Study Design

The study had a randomized, double-blind, placebo-controlled, parallel design (Figure 1). Sequential randomization based on blocks of two was performed using dedicated software (http://www.randomization.com) by Brigham and Women’s Hospital pharmacy department to ensure that the randomization list was not known to the patients, investigators, and staff involved in the study and sleep scoring. Melatonin 2.5 mg capsule or matching placebo was taken orally 1 hr before bedtime each night for approximately 3 weeks (once nightly for a mean of 23 days; range, 20-28 days, the exact timing depending on the availability of laboratory suites, staff, and patients). The melatonin/placebo capsules were prepared by the Brigham and Women’s Hospital pharmacy department in compliance with Food and Drug Administration (FDA) Good Compounding Practice regulations and USP 795. Melatonin (2.5 mg; Regis Chemical Co. or Nature’s Bounty, Inc.) was added to microcrystalline cellulose, National Formulary, and encapsulated in gelatin capsules. The placebo for melatonin was prepared by filling matching gelatin capsules with microcrystalline cellulose. The Certificates of Analysis confirmed the melatonin and microcrystalline met the United States Pharmacopeial Convention standards for identity, purity, dose, and stability. This protocol, including the sources of melatonin, was approved by the FDA. A dose of 2.5 mg of melatonin was selected to achieve melatonin values at or above physiologic concentrations for approximately 8 hr, for the full duration of the sleep episode.18

Figure 1.

Figure 1

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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).

Study Protocol

The study protocol (Fig 1) consisted of the following five sequential parts: (1) 2-week baseline ambulatory monitoring (not depicted); (2) first 4-day in-laboratory monitoring; (3) 3-week ambulatory monitoring while taking the study drug; (4) second 4-day in-laboratory monitoring; and (5) 2-day poststudy drug ambulatory monitoring (not depicted). The drug or placebo was started during the in-laboratory segment (2) and stopped during the in-laboratory segment (4), as detailed below. To ensure stable rhythmicity of the circadian system immediately prior to both laboratory admissions, the patients maintained a self-selected and fixed sleep/wake cycle with 8 hr time in bed per night as verified by sleep/wake diaries, call-in times to a time-stamped voice recorder, and wrist actigraphy (Actiwatch; Minimitter, Bend, OR) during all ambutatory parts (for a minimum of 2 weeks prior to baseine and the full duration between both admissions).

During the 4-day in-laboratory admissions, patients stayed continuously in a private suite in the Clinical and Translational Research Center at Brigham and Women’s Hospital. The schedule in the laboratory consisted of 16 hr of scheduled wakefulness per day and 8 hr of scheduled bed rest per night at the same times as patients had maintained during the ambulatory parts in the week prior to both admissions. The light level was 90 lux for the wake episode of the first day of each in-laboratory admission (adaptation day) and 4 lux for the remaining three wake episodes to allow assessment of dim light melatonin concentrations (see Supplement). Light levels were 0 lux for all sleep episodes. Throughout each of the sleep episodes, the patients maintained a supine posture and received a urinal or bedpan as needed. During the wake episodes patients refrained from exercise, and spent most of their time seated, reading, watching movies, or engaged in the study procedures. Patients were not permitted to lie on the bed during the wake episodes. Meals were provided 1 hr 50 min (breakfast), 5 hr 25 min (lunch), 11 hr 25 min (dinner) and 13 hr 25 min (snack) after scheduled awakenings. A daily shower was scheduled at 2 hr 55 min after scheduled awakenings.

On the first in-laboratory admission, patients received a single-blind placebo capsule before sleep episodes 1 and 2, and a double-blind capsule (2.5 mg melatonin or placebo) before sleep episode 3 (Figure 1). After the first discharge from the laboratory, patients continued taking the double-blind capsule at home for 3 weeks until the second laboratory admission whereupon patients continued to take the double-blind capsule before sleep episodes 1 and 2, and received a single-blind placebo capsule before sleep episode 3. All melatonin or placebo capsules were taken 1 hr before the scheduled sleep episodes. Similarly, all patients took their beta-blocker 1 hr before bedtime for at least 2 weeks before and throughout the study. Study drug and prescribed beta-blocker use was verified by diaries and daily call-in times to a time-stamped voice recorder at home and by staff during the in-laboratory parts.

Measurements

Polysomnography

Sleep was recorded on the second and third night of each laboratory admission by PSG (Vitaport-3, Temec Instruments, Kerkrade, B.V., The Netherlands), including electroencephalography (EEG), left and right electrooculography (EOG), bipolar submental electromyography (EMG), and bipolar electrocardiography (ECG). EEG was recorded from C3, C4, O1, O2 (referenced to A1 or A2), with C3-A2 and C4-A1 used for sleep scoring. Sleep stages were scored in 30-s epochs,19 with scorer blinded to condition. Sleep efficiency was calculated as the total duration of sleep divided by the time in bed (8 hr).

Actigraphy

To estimate sleep quality at home, actigraphy data were collected throughout the ambulatory and in-laboratory portions of the study using an Actiwatch (Actiwatch-64 or the Actiwatch-L, Minimitter, Bend, OR). Patients wore this device on their nondominant wrist with integrated activity data recorded at 2-min intervals. Automatic sleep/wake scoring was performed with Actiwatch software (Actiware-Sleep 3.4; Minimitter Co. Inc.; sensitivity set at medium) between “bedtime” and “get-up time” derived from the sleep/wake diaries (at home) or between lights-off and lights-on (in-laboratory). Three sleep variables were objectively computed by this analysis: sleep onset latency, total sleep time, and sleep efficiency. Sleep onset latency was the calculated time between bedtime (from diary) and sleep onset (from actigraphy). Total sleep time was the calculated time asleep from actigraphy. Sleep efficiency was defined as the percentage of time asleep, as derived from actigraphy, while in bed, as derived from diary (at home), or while lights were off (in-laboratory).

Analysis

To determine the effect of 3-week melatonin supplementation on PSG, a generalized linear model was used with data collected at the end of 3 weeks of melatonin/placebo administration (second night of second laboratory admission) serving as outcome variables, treatment group as a fixed factor and baseline measurement (second night of first admission) as a covariate.20 To determine the effect of repeated melatonin supplementation on sleep as estimated by actigraphy, a generalized linear mixed model was used with averaged actigraphy data collected throughout each of the 3 weeks of melatonin/placebo administration serving as repeated outcome variables, treatment group as a fixed factor, and the averaged ambulatory baseline data as a covariate.20 All statistical procedures were performed via SPSS version 19 for Windows (IBM SPSS Statistics). Statistical significance was set at P < 0.05. Baseline-adjusted model estimated mean ± standard error data are presented.

RESULTS

Repeated melatonin supplementation (3 week) increased total sleep time by 37 min (placebo: 387 min vs. melatonin: 424 min; P = 0.046), increased sleep efficiency by 7.6% (80.5% vs. 88.1%; P = 0.046), and decreased latency to onset of Stage 1 sleep by 8 min (15 min vs. 7 min; P = 0.024) and latency to onset of Stage 2 sleep by 14 min (23 min vs. 9 min; P = 0.001) as assessed by PSG (Figure 2). Repeated melatonin supplementation significantly increased Stage 2 sleep by 41 min (230 vs. 272 min [note: numbers may not add up due to rounding]; P = 0.037). Melatonin did not significantly affect durations of Stage 1 sleep, slow wave sleep (Stages 3 and 4), rapid eye movement (REM) sleep (Figure 3), or the number and duration of awakenings.

Figure 2.

Figure 2

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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.

Figure 3

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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.

Melatonin also significantly improved actigraphy-estimated total sleep time (377 min vs. 390 min; P = 0.011) and sleep efficiency (78% vs. 81%; P = 0.010), but not actigraphy-estimated sleep onset latency, at home throughout the 3 weeks in between in-laboratory stays. The improvement of total sleep time and sleep efficiency was similar between the three separate weeks (Figure 4), suggesting that melatonin was effective in improving sleep from the first week to the last.

Figure 4.

Figure 4

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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).

This significant effect in the home was evident despite the fact that actigraphy underestimated the melatonin-induced changes in sleep as evident by comparing the actigraphy-estimates with PSG simultaneously in the laboratory, presumably due to misclassification of motion-free relaxed wakefulness as sleep when using actigraphy (see Figure S1).

In exploratory analysis, including the PSG assessments after single administration, 3-week administration, and after discontinuation of melatonin, there was a main effect of melatonin for the duration of Stage 2 sleep (lengthened), latency to Stage 1 sleep (shortened), and latency to Stage 2 sleep (shortened) (see Figure S2). In post-hoc analysis with Bonferroni correction, we found that latency to Stage 2 sleep remained significantly shortened after discontinuation of melatonin supplementation (P = 0.001), suggesting a carryover effect. In these post-hoc analyses we found no acute effect of melatonin on any PSG measure (i.e., no effect of a single dose of melatonin) and no sign of rebound sleep disturbance following discontinuation of melatonin (i.e., no worsening of any PSG measure compared with placebo).

Melatonin had no adverse effects on the patients’ general health complaints as determined through a questionnaire inquiring about the presence or absence of headache, insomnia, hyperactivity, irritability, nausea, “sleeping limbs,” dizziness, constipation, “shaky hands,” stomach cramp, drowsiness, sweating, hunger, weakness, and sore eyes, at the first laboratory admission (baseline) and the second laboratory admission (repeated use).

Of the 10 patients in whom we could assess the plasma melatonin concentrations hourly for 24 hr under the dim light conditions during baseline conditions (see Supplemental Material), 6 patients had melatonin values in the typical range, between approximately 40-100 pg/ml, and 4 patients had very low melatonin values (around or below 10 pg/ml), presumably in part due to inhibition of endogenous melatonin secretion by use of beta-blocker (see Figure S3, top panel). Even though the dose distribution is limited and the sample size is relatively low given the large interindividual differences in nighttime melatonin plasma concentrations even in young healthy control patients, the relationship between the peak nighttime melatonin concentrations at baseline and beta-blocker dose is consistent with a higher beta-blocker dose being more likely to lead to lower melatonin secretion, i.e., around or below 10 pg/ml (see Figure S4).

In the patients randomized to placebo, the four 24-hr dim light plasma melatonin profiles (baseline, acute, prolonged, and carryover) were very similar (see Figure S3, middle panel). In the patients randomized to melatonin supplementation, melatonin intake resulted in either supraphysiologic or physiologic nighttime plasma melatonin concentrations for the full 8-hr sleep episodes, with the profiles very similar after acute (single dose) and 3-week administration (see Figure S3, bottom panel). After discontinuation of melatonin administration, the melatonin profile phase and amplitude returned to baseline levels (see Figure S3, bottom panel).

DISCUSSION

To our knowledge, this is the first study to show effectiveness of repeated melatonin supplementation on PSG-recorded sleep in people chronically treated with beta-blockers. Our results show that 3 weeks of melatonin supplementation improved sleep quality in hypertensive patients chronically treated with beta-blockers. Melatonin supplementation decreased sleep onset latency and increased sleep maintenance. There was no sign of the development of tolerance to melatonin supplementation, and no sign of rebound sleep disturbance during withdrawal of melatonin supplementation.

Potential Clinical Relevance

These results of improved sleep with melatonin supplementation may have particular relevance to the millions of people around the world who chronically take beta-blockers.1 Beta-blockers are widely prescribed for a variety of cardiovascular disorders including hypertension, congestive heart failure, cardiac arrhythmias, angina pectoris, for cardioprotection after myocardial infarction, and for some non-cardiovascular disorders such as migraine, posttraumatic stress disorder, and generalized anxiety disorder.21 Beta-blockers are prescribed more than diuretics, angiotensin-converting enzyme inhibitors, or calcium channel blockers.1 Moreover, in Americans 60 yr of age and older, beta-blockers are the second most frequently used prescription drugs (second to cholesterol-lowering medications).1 In addition, the current findings may have relevance to thousands of patients with tetraplegia, because cervical spinal cord transection abolishes endogenous melatonin production, which may contribute to their reported sleeping problems.22,23 Furthermore, there is evidence for decreased nighttime melatonin levels in patients with coronary artery disease and non-dipper hypertensive patients (in whom blood pressure does not decrease at night), either due to or independent of beta-blocker use,24–26 in whom the effect of melatonin supplementation on sleep deserves further study. It has also been reported that melatonin supplementation can improve sleep in older individuals with insomnia and low endogenous melatonin concentrations.27,28 Finally, self-reported short sleep duration has been linked to increased risk for diabetes, obesity, and cardiovascular disease in epidemiologic studies and experimental sleep curtailment leads to decreased glucose tolerance and leptin values, and increased blood pressure and ghrelin values.13–16 Therefore, measures to improve sleep may not only have beneficial psychologic and cognitive effects, but also have potential for beneficial cardiovascular and metabolic health effects in some cases.

Mechanism

The suprachiasmatic nucleus (SCN) drives the circadian process of sleep regulation and contains high-affinity MT1 (Mel1b) and MT2 (Mel1b) receptors.29–31 Nighttime melatonin administration has been proposed to be able to influence sleep by three mechanisms: (1) long-term effects on the SCN via high-affinity melatonin receptors, amplifying or synchronizing the SCN neural activity rhythm and its output, resulting in a stronger nighttime sleep drive;32,33 (2) immediate/short-term effects on the SCN via high-affinity melatonin receptors, inhibiting SCN multiunit electrical activity to levels more typical of the biologic night and thereby increasing circadian sleep drive;32 and (3) immediate vasodilatory effects on proximal and distal skin via high-affinity melatonin receptors, leading to increased skin temperature and heat dissipation, which may increase sleep propensity.34 Our exploratory analysis showed that the latency to Stage 2 sleep was still significantly shortened after discontinuation of melatonin administration, i.e., when exogenous melatonin had cleared from the plasma, indicating a long-term effect of melatonin on sleep regulation. An amplification or phase advance of the output of the SCN that could outlast daily melatonin administration theoretically could explain such carryover effects of melatonin. However, the plasma melatonin profile was not amplified and not phase advanced, which does not support this hypothesis. The absence of a significant phase-shifting effect of 2.5 mg of melatonin given around the time of the dim light melatonin onset, as in our study, is consistent with the phase response curve to a similar dose of melatonin (3 mg) at that time.31 The absence of a significant acute effect of melatonin on sleep in our exploratory analyses in this population does not support the hypothesis that the effects on sleep were mediated through acute vasodilatory and thermoregulatory effects.

Comparison With Hypnotic Agents

Sleep disturbances in patients treated with beta-blockers presumably could be negated by use of prescribed hypnotic drugs, such as benzodiazepines. However, there are several side effects and limitations associated with many of these sleep aids35,36 that are not apparent with the use of melatonin supplementation. First, some hypnotic agents, including some benzodiazepines, have decreased effectiveness after chronic use (tolerance) and rebound insomnia after discontinuation, increasing the risk for dependence and abuse.37,38 Thus, although beta-blocker therapy for cardiovascular disorders is typically used for life, many sleep aids are not suitable for long-term use. In the current study, there was no sign of adverse side effects, tolerance (the effect after 3-week administration was not reduced as compared with single administration), or rebound insomnia with melatonin supplementation. Second, although benzodiazepines increase total sleep time, they often decrease slow wave and/or REM sleep,39 whereas melatonin increased total sleep time without decreasing slow wave and REM sleep in the current study. Third, there is a dose-dependent effect of hypnotic agents, ranging from anxiolytic to soporific, anesthesia, coma, and death, and an associated risk of drug overdose,40 benzodiazepine receptor agonists have been associated with memory and balance impairment,41 and a recent correlational report found a threefold increased mortality associated with prescribed hyponotic (mostly benzodiazepine) use,42 whereas melatonin appears relatively safe for the short-term use (weeks) for which there are good data, even at relatively high doses.43 Fourth, traditional hypnotic agents generally do not tackle the cause of sleeping problems if these are due to suppressed melatonin. Thus, based on these apparent potential benefits of melatonin over traditional hypnotic agents, larger-scale clinical trials are likely warranted to determine whether melatonin or melatonin agonists can be used as an alternative or add-on to hypnotic agents in treating sleeping problems in people treated with beta-blockers

Previous Studies Linking Beta-blockers, Melatonin, and Sleep

All beta-1-selective blockers investigated, including hydrophilic atenolol and moderately lipophilic metoprolol (both used in this study) and bisoprolol, suppress nighttime melatonin.2,–11,44 Because the pineal gland lies outside of the blood-brain barrier, both lipophilic and hydrophilic beta-blockers suppress melatonin production. Also, the nonselective beta-blocker propranolol (beta-1- plus beta-2-blocker) suppresses melatonin.2,10 The lack of a suppression of melatonin by the nonselective beta-blockers carvedilol (includes alpha-1-blocking activity) and nebivolol (has nitric oxide-mediated vasodilatory effects) has been hypothesized to be due to a compensatory increase in sympathetic activity following vasodilatation, and requires further investigation.45

Although it is clear that beta-1-selective blockers suppress melatonin levels and that melatonin administration during the daytime (when endogenous melatonin levels are low) improves sleep,46 there are few studies in the literature regarding the effects of beta-blockers on sleep at night and the role of melatonin suppression.

In studies based on self-reported measures of sleep in hypertensive patients, it was found that both 6 and 10 weeks of treatment with propranolol or ridazolol suppressed urinary 6-sulphatoxymelatonin levels by approximately 40-50% but had no effect on self-reported sleep complaints;47 that with 4 weeks of metoprolol there was a correlation between the magnitude of suppression of nighttime urinary melatonin excretion and the percentage of disturbed nights2; and in a randomized study of 149 patients over 6-12 mo revealed that replacement of beta-blockers (mostly atenolol) with angiotensin-converting enzyme inhibitors resulted in a decrease in sleep complaints.48 In one of the few studies investigating the effect of beta-blockers on PSG-assessed sleep in hypertensive patients, Danchin et al. reported a (nonsignificant) tendency for total sleep time to decrease by 34 min after a single dose of atenolol (100 mg) in a double-blind randomized crossover trial in 8 patients.5

To our knowledge, only one study has investigated the use of melatonin supplementation after beta-blocker use on PSG-assessed sleep. In that (acute) study, 100 mg atenolol in healthy volunteers led to decreases in urinary 6-sulphatoxymelatonin and total sleep time, whereas 5 mg of melatonin supplementation while on atenolol restored sleep to baseline levels without atenolol.11 The current study extends these observations to include a relevant patient population and demonstrates that repeated melatonin supplementation improves PSG-assessed sleep in hypertensive patients chronically treated with beta-blockers.

Interestingly, the anxiolytic property of beta-blockers has led people to test the effect of beta-blockers in the treatment of insomnia, with surprisingly disappointing results, including worsened sleep disturbances.49 This raises the question whether any anxiolytic effect of beta-blockers that might improve sleep is counteracted by the adverse melatonin-suppressing effects of beta-blockers. The potential clinical benefit of a combination of beta-blockers plus nighttime melatonin in the treatment of sleep disturbances, and in particular anxiety-related insomnia, warrants further investigation.

Limitations and Future Directions

The main limitations of the current study include the small sample size, and the fact that we could not determine the effect of the chronic beta-blocker use on melatonin production and sleep quality because we had no recordings before the chronic beta-blocker therapy. Furthermore, we cannot determine the extent to which the observed beneficial effect on sleep quality of melatonin supplementation is specific to beta-blocker-induced melatonin suppression. Indeed, our previous work indicates that even in hypertensive patients without any beta-blocker therapy, repeated nighttime melatonin supplementation improves actigraphy-estimated sleep quality.50 Larger studies are needed to determine which patient populations treated with beta-blockers may benefit most from melatonin supplementation. Such studies should assess both hard cardiovascular endpoints as well as patient-reported outcomes to determine the full effect of melatonin supplementation to beta-blocker treatment.

Contributors

Conceived and designed the experiments: Drs. Scheer and Shea. Performed the experiments: Drs. Scheer, Morris, Garcia, Smales, Kelly, Marks, and Malhotra. Analyzed the data: Drs. Scheer and Morris. Wrote the paper: Drs. Scheer, Morris, Malhotra, and Shea.

DISCLOSURE STATEMENT

This was not an industry supported study. Dr. Shea serves on the Board of Directors of the American Academy of Sleep Medicine. The other authors have indicated no financial conflicts of interest.

ACKNOWLEDGMENTS

The authors thank the patients for their participation in the study and the staff of Brigham and Women’s Hospital’s Center for Clinical Investigation for their contributions in carrying out the study protocol. The authors also thank Wei Wang for statistical advice and Patricia Kelly for pharmaceutical advice. This research was supported by Pickwick Fellowship by the National Sleep Foundation, NIH-R21 AT002713 and NIH-P30 HL101299 to Dr. Scheer and NCRR GCRC M01 RR02635 and UL1 RR025758, Harvard Clinical and Translational Science Center; National Space Biomedical Research Institute through NASA NCC 9-58 in support of Dr. Morris; NIH-K24 HL 093218 in support of Dr. Malhotra; NIH-K24 HL076446 in support of Dr. Shea.

Footnotes

A commentary on this article appears in this issue on page 1319.

SUPPLEMENTAL MATERIAL

Actigraphy Underestimated the Effect of Melatonin on Sleep: A Comparison With Polysomnographically Assessed Sleep

The magnitude of effect of melatonin on sleep at home as estimated by actigraphy was smaller than the magnitude of effect of melatonin on sleep in the laboratory as determined by polysomnography (PSG). This difference could be due to 3 factors: (1) difference in measurement technique (PSG vs. actigraphy); (2) difference in measurement location (laboratory [PSG] vs. home [actigraphy]); and/or (3) difference in duration of supplementation (throughout the 3 wk of taking the study drug [actigraphy] or after 3 wk of taking the study drug [PSG]). To test whether it was caused by a difference in measurement technique (1), while keeping the other factors (2) and (3) constant, we assessed actigraphy-estimated sleep on the same nights in the laboratory as when PSG was recorded.

These analyses indicate that the smaller effect of melatonin on sleep as estimated by actigraphy as compared to that measured by PSG was primarily due to the measurement technique (3.3% difference in sleep efficiency; comparing middle gray bar with right red bar; Figure S1) and less by location (factor 2) or duration (factor 3) of supplementation (combined 1.4% difference; comparing left gray bar with middle gray bar; Figure S1). Thus, it is likely that the actigraphy-estimated effect of melatonin on sleep also underestimated the true effect of melatonin while patients were sleeping at home. Actigraphy is considered less reliable for detecting disturbed sleep and especially less useful for assessing sleep latency which may explain this underestimation.1

Figure S1

Actigraphy underestimates the effect of melatonin on sleep efficiency. The magnitude of effect of melatonin on sleep efficiency as estimated by actigraphy at home (left gray bar) was smaller than that as determined by polysomnography (PSG) in the laboratory (right red bar). This difference was mainly due to an underestimation of the magnitude of effect by actigraphy as compared with the assessment by the golden standard, PSG. First, as measured under the same laboratory conditions and on the same recording night, the effect of melatonin on sleep efficiency as estimated by actigraphy was 3.3 % less than as measured by PSG (comparing middle gray bar and right red bar). Second, the difference in magnitude of effect of melatonin on sleep efficiency due to a combined difference in duration (as an average throughout 3 wk of supplementation vs. one night at the end of 3 wk of supplementation) and location (home vs. laboratory) was much smaller, i.e., 1.4 % (comparing left and middle gray bars).

graphic file with name aasm.35.10.1395s1.jpg

No Development of Tolerance After Repeated Melatonin Use and No Rebound Insomnia After Discontinuation of Melatonin

For the exploratory analysis, to determine the acute effect of melatonin and the carry-over effect of melatonin, a generalized linear mixed model was used with data collected after single administration (acute; the third sleep episode during the first admission starting 1 hr after the first administration of the study drug), after repeated administration, and after discontinuation (carryover; the third sleep episode on the second admission starting 25 hr after discontinuation of the 3-wk administration of the study drug) of melatonin/placebo serving as the outcome variables, treatment group, and measurement time as fixed factors, and baseline measurement as a covariate.2

These analyses showed a significant main effect of melatonin, shortening the latency to onset of Stage 2 sleep (P = 0.030). Post-hoc analysis with Bonferroni correction showed that melatonin significantly shortened the latency to onset of Stage 2 sleep after 3-wk use (24 vs. 10 min; P = 0.044) and also after discontinuation of melatonin (carryover effect; 37 vs. 13 min; P = 0.001), without significant effect after acute melatonin administration (after one dose) (Figure S2). In addition, there was a significant main effect of melatonin shortening latency to onset of Stage 1 sleep (P = 0.027), without significant effect in post-hoc analysis. Finally, there was a significant main effect of melatonin increasing Stage 2 sleep (P = 0.044), without significant effect in post-hoc analysis. None of the other PSG sleep variables showed a significant main effect of melatonin.

Melatonin Had No Effect on Subjective Sleep Quality

While in the laboratory, patients completed a post-sleep questionnaire within the first 15 min after each scheduled awakening, including the questions “how sound did you sleep last night” (5 categories from “very sound” to “very restless”) and “how good would you rate your sleep to have been last night” (5 categories from “very good” to “very bad”). Melatonin had no significant effect on either measure.

Melatonin Supplementation Resulted in Plasma Melatonin Levels At or Above Endogenous Nighttime Levels Throughout Sleeping Episodes

An intravenous catheter (20 g 1.25 inch in forearm) was inserted in the patients’ dominant arm on study day 2 of both laboratory admissions and blood was sampled via 12-ft tubing every 60 min beginning 8 hr after scheduled awakening on the second study day and continued until discharge on the fourth day of each laboratory stay. Plasma melatonin levels were assayed via radioimmunoassay I125 (Pharmasan Laboratories, Osceola, WI, USA). The sensitivity was 0.7 pg/ml and the interassay coefficient of variation was 13.2% and 8.4% at a mean concentration of 17.3 and 69 pg/ml, respectively. Due to subject characteristics (e.g., artificial body parts increasing risk of infection or intolerance precluding intravenous insertion) and technical difficulties, we could only analyze 24-hr melatonin profiles of 10 patients (4 of whom were randomized to the melatonin group).

Figure S2

Acute, prolonged, and carryover effects of melatonin on PSG-assessed sleep quality. In exploratory analysis, including the PSG assessments after single administration, 3-wk administration, and after discontinuation of melatonin, there was a main group effect for Stage 2 sleep (P = 0.030), latency to Stage 1 sleep (P = 0.027), and latency to Stage 2 sleep (P = 0.044). In post-hoc analysis, acute melatonin supplementation (after 1 dose) had no significant effect on any PSG measure. On the night after discontinuation of melatonin (i.e., the sleep opportunity starting 25 hr after the last dose), there was no worsening of any PSG measure (no sign of rebound insomnia). In fact, the latency to Stage 2 sleep remained significantly shortened for at least one night after discontinuation of melatonin (P = 0.001; top panel; Carry-over). Asterisk indicates significance of melatonin effect for post- hoc analysis.

graphic file with name aasm.35.10.1395s2.jpg

On the baseline day while on placebo (second day of first admission to the laboratory) there were large interindividual differences in nighttime plasma melatonin values: 6 patients had melatonin values in the typical range, between approximately 40-100 pg/ml, and 4 patients had very low melatonin values (≤ 10 pg/ml) (Figure S3, top panel). Because we had no assessments of melatonin profiles before the patients were prescribed their chronic beta-blocker therapy and because there is large interindividual variability even among healthy and unmedicated people, we could not determine the extent to which beta-blockers suppressed melatonin concentrations. Indeed, it has been proposed that the individual decline in melatonin production capacity, e.g., with aging, disease or medication use, may better correspond to sleep disruption than absolute melatonin concentrations.3,4 In those patients randomized to melatonin supplementation, melatonin plasma concentrations rose to a level more than an order of magnitude higher than during baseline conditions, stayed at or above nighttime levels for the full 8-hr sleep episode, and declined to levels below 20 pg/ml approximately 4 hr after scheduled awakening. This pattern was similar for both the acute administration and with repeated administration (Figure S3, bottom panel). The endogenous melatonin profile observed the day after discontinuation of melatonin supplementation, after exogenous melatonin had completely disappeared from the circulation and no longer obscured the endogenous melatonin profile, showed that repeated melatonin administration had not resulted in an amplification of the endogenous melatonin profile amplitude, and had not resulted in an advance of the dim light melatonin onset or dim light melatonin offset.

Figure S3

Plasma melatonin profiles. In the 10 volunteers in whom we could collect blood, 24-hr baseline melatonin profiles are depicted (top panel). In the placebo group, the melatonin profiles were very consistent across the four separate 24-hr windows (middle panel; log scale). In the melatonin group, plasma melatonin concentrations were increased by more than 20-fold in the first few hours after melatonin administration, and remained at superphysiologic or physiologic nighttime concentrations for the full 8-hr sleep episodes (bottom panel; log scale). Interestingly, melatonin profiles after a single melatonin dose (acute) and after 3 wk of daily melatonin dosing (prolonged) were comparable, and melatonin profiles at baseline and on the night following the last dose (carryover) were comparable. All melatonin samples were collected in dim light conditions (≤ 4 lux). Gray bar, 8-hr scheduled sleep episode in complete darkness in a supine posture at rest.

graphic file with name aasm.35.10.1395s3.jpg

Relationship Between Beta-blocker Dose and Peak Nighttime Melatonin Concentration

Although the dose distribution was limited and the sample size was relatively low, the individual peak nighttime melatonin concentrations were consistent with a higher beta-blocker dose being more likely to lead to lower melatonin secretion (Figure S4).

Figure S4

Relationship between beta-blocker dose and peak nighttime melatonin concentrations. For the 10 volunteers in whom we could collect blood, the relationship between their daily beta-blocker dose and the peak nighttime melatonin concentration at baseline is shown. Atenolol-equivalent beta-blocker dose was determined based on the approximation that twice the dose of metoprolol is required to achieve the same effectiveness as with atenolol (e.g., 100 mg metoprolol has an atenolol-equivalent dose of 50 mg).5

graphic file with name aasm.35.10.1395s4.jpg

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Figure S1

Actigraphy underestimates the effect of melatonin on sleep efficiency. The magnitude of effect of melatonin on sleep efficiency as estimated by actigraphy at home (left gray bar) was smaller than that as determined by polysomnography (PSG) in the laboratory (right red bar). This difference was mainly due to an underestimation of the magnitude of effect by actigraphy as compared with the assessment by the golden standard, PSG. First, as measured under the same laboratory conditions and on the same recording night, the effect of melatonin on sleep efficiency as estimated by actigraphy was 3.3 % less than as measured by PSG (comparing middle gray bar and right red bar). Second, the difference in magnitude of effect of melatonin on sleep efficiency due to a combined difference in duration (as an average throughout 3 wk of supplementation vs. one night at the end of 3 wk of supplementation) and location (home vs. laboratory) was much smaller, i.e., 1.4 % (comparing left and middle gray bars).

graphic file with name aasm.35.10.1395s1.jpg

Figure S2

Acute, prolonged, and carryover effects of melatonin on PSG-assessed sleep quality. In exploratory analysis, including the PSG assessments after single administration, 3-wk administration, and after discontinuation of melatonin, there was a main group effect for Stage 2 sleep (P = 0.030), latency to Stage 1 sleep (P = 0.027), and latency to Stage 2 sleep (P = 0.044). In post-hoc analysis, acute melatonin supplementation (after 1 dose) had no significant effect on any PSG measure. On the night after discontinuation of melatonin (i.e., the sleep opportunity starting 25 hr after the last dose), there was no worsening of any PSG measure (no sign of rebound insomnia). In fact, the latency to Stage 2 sleep remained significantly shortened for at least one night after discontinuation of melatonin (P = 0.001; top panel; Carry-over). Asterisk indicates significance of melatonin effect for post- hoc analysis.

graphic file with name aasm.35.10.1395s2.jpg

Figure S3

Plasma melatonin profiles. In the 10 volunteers in whom we could collect blood, 24-hr baseline melatonin profiles are depicted (top panel). In the placebo group, the melatonin profiles were very consistent across the four separate 24-hr windows (middle panel; log scale). In the melatonin group, plasma melatonin concentrations were increased by more than 20-fold in the first few hours after melatonin administration, and remained at superphysiologic or physiologic nighttime concentrations for the full 8-hr sleep episodes (bottom panel; log scale). Interestingly, melatonin profiles after a single melatonin dose (acute) and after 3 wk of daily melatonin dosing (prolonged) were comparable, and melatonin profiles at baseline and on the night following the last dose (carryover) were comparable. All melatonin samples were collected in dim light conditions (≤ 4 lux). Gray bar, 8-hr scheduled sleep episode in complete darkness in a supine posture at rest.

graphic file with name aasm.35.10.1395s3.jpg

Figure S4

Relationship between beta-blocker dose and peak nighttime melatonin concentrations. For the 10 volunteers in whom we could collect blood, the relationship between their daily beta-blocker dose and the peak nighttime melatonin concentration at baseline is shown. Atenolol-equivalent beta-blocker dose was determined based on the approximation that twice the dose of metoprolol is required to achieve the same effectiveness as with atenolol (e.g., 100 mg metoprolol has an atenolol-equivalent dose of 50 mg).5

graphic file with name aasm.35.10.1395s4.jpg

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