New Light Shed on the Hormone of Darkness
Abstract & Commentary
By Barbara A. Phillips, MD, MSPH. Professor of Medicine, University of Kentucky; Director, Sleep Disorders Center, Samaritan Hospital, Lexington. Dr. Phillips serves on the speakers bureau for PotomaCME.
Synopsis: Nightly melatonin improved objective and subjective sleep quality in a small number of patients who were taking beta-blockers for hypertension.
Source:Scheer FA, et al. Repeated melatonin supplementation improves sleep in hypertensive patients treated with beta-blockers: A randomized controlled trial. Sleep 2012;35:1395-1402.
This small, randomized, placebo-controlled trial was done to test the hypothesis that melatonin can improve sleep quality in patients who are taking beta-blockers. The rationale for this is that beta-blockers are associated with insomnia and fatigue and also suppress secretion of melatonin.1-2 This study included 16 patients (nine women, mean age 56 years, mean body mass index 28 kg/m2), of which 15 had analyzable data. All patients had been diagnosed with essential hypertension, and had been taking either atenolol or metoprolol for at least 6 months. Four of these patients were also taking an angiotensin-converting enzyme inhibitor and/or thiazide diuretic. These patients were not on any other medications and were otherwise healthy. Sleeping complaints were not part of the inclusion criteria. Patients were randomized to take either melatonin 2.5 mg or matching placebo an hour before bedtime each night for approximately 3 weeks. Participants underwent home monitoring of sleep (with motion-detecting actigraphy) for 2 weeks, then began taking the study drug for about 3 weeks while undergoing sleep monitoring at home. Then they returned to the sleep lab for 4 more days of in-laboratory monitoring while continuing to take the medication and stopped the drug before the second night of in-laboratory testing. Finally, they were monitored at home for 2 days. During the 4-day in-laboratory admissions, patients stayed continuously in private suites with controlled light levels and schedules. They refrained from exercise, and spent most of their time seated, reading, watching movies, or engaged in the study procedures. Sleep studies were done during the in-laboratory stays at the beginning and end of study drug treatment.
Based on the in-laboratory sleep studies, melatonin increased total sleep time by 37 minutes, increased sleep efficiency by 7.6%, and decreased sleep latency by 8 minutes. All of these changes were statistically significant compared with placebo. Most of the increased sleep was stage N2 non-REM sleep. Based on the in-home monitoring, melatonin also significantly improved total sleep time and sleep efficiency (78% vs 81%), but decreased sleep onset latency, at home throughout the 3 weeks in between in-laboratory stays. The improvement in total sleep time and sleep efficiency was similar across all 3 separate weeks of at-home monitoring, suggesting that melatonin was effective in improving sleep from the first week to the last. In post-hoc analyses of the in-laboratory sleep studies, there was no acute effect of melatonin on sleep after a single dose and no sign of rebound sleep disturbance following discontinuation of melatonin. Melatonin had no adverse effects on the patients' general health complaints. Ten patients had plasma melatonin concentrations measured, and four of these had very low levels; these tended to be in those on higher doses. In the patients randomized to melatonin supplementation, melatonin intake resulted in either supraphysiologic or physiologic nighttime plasma melatonin concentrations; after discontinuation, the melatonin levels returned to baseline.
Commentary
Insomnia is a prevalent and distressing condition, and it is notoriously refractory to treatment. It is also a very heterogeneous condition; patients who have sleep complaints associated with depression are different from those who are taking multiple sleep-disrupting drugs who are different from shift-workers. While there is considerable debate about whether insomnia carries a health risk, emerging evidence indicates that chronic use of sleeping pills almost certainly does.3-6 This is not to say that we should ignore insomnia, but rather that we should attempt to address underlying issues whenever possible (sometimes it's not!) rather than "treating" insomnia with chronic hypnotic prescription. Insomnia treatment should be carefully tailored to the afflicted individual. (Often, the optimum treatment is beyond the expertise of the primary care practitioner or even the sleep specialist, since management of mood disturbance and/or cognitive behavioral therapy are frequently the optimum approaches).
The current study is an important demonstration of tailoring the treatment to the underlying cause of insomnia (although it should be noted that the patients in this study did not actually have insomnia). In the accompanying editorial,7 Burgess notes that about 2% of U.S. adults are already using exogenous melatonin as a sleep aid, which suggests that it must do something. Supplemental melatonin has the greatest effect when endogenous melatonin levels are low, such as during the daytime or in elderly insomniacs with low endogenous melatonin levels.
Beta-blockers suppress endogenous melatonin secretion and worsen sleep in normal humans, and administration of exogenous melatonin can restore sleep to baseline levels.8 Burgess also notes that the 2.5 mg dose used in this study is very close to the commonly available 3 mg dose, but notes that choosing the over-the-counter melatonin from a manufacturer who participates in the USP Verified Program is more likely to result in consistent quality and bioactivity.
The findings of this small study are potentially quite important given the prevalence of insomnia and the number of people who take beta-blockers. The authors note that beta-blockers are prescribed for hypertension, congestive heart failure, cardiac arrhythmias, angina, cardioprotection after myocardial infarction, and migraine. Indeed, in Americans 60 years of age and older (a group with a high prevalence of sleep complaints), beta-blockers are the second most frequently used prescription drugs.9
Given the low risk, lack of abuse potential, absence of rebound insomnia with discontinuation of the drug, and ready availability of melatonin, it seems reasonable to me to recommend USP-verified melatonin, 3 mg, an hour before bedtime in insomniacs who are taking beta-blockers. That's a lot of people. It is extremely unlikely to hurt, and it just might help.
References
1. Cowen PJ, et al. Treatment with beta-adrenoceptor blockers reduces plasma melatonin concentration. Br J Clin Pharmacol 1985;19:258-260.
2. Kostis JB, et al. CNS side effects of centrally-active antihypertensive agents: A prospective, placebo-controlled study of sleep, mood state, and cognitive and sexual function in hypertensive males. Psychopharmacology (Berl) 1990;102:163-170.
3. Moloney ME, et al. The medicalization of sleeplessness: A public health concern. Am J Public Health 2011; 101:1429-1433.
4. Kao C-H, et al. Relationship of zolpidem and cancer risk: A Taiwanese population-based cohort study. Mayo Clin Proc 2012;87:430-436.
5. Kripke DF, et al. Hypnotics' association with mortality or cancer: A matched cohort study. BMJ Open 2012;2: e000850.
6. Phillips BA. Insomnia, hypnotic drug use, and patient well-being: First, do no harm. Mayo Clin Proc 2012;87: 417-418.
7. Burgess HJ. Melatonin: An adjunctive treatment for cardiometabolic disease? Sleep 2012;35:1319-1329.
8. Arendt J, et al. Immunoassay of 6-hydroxymelatonin sulfate in human plasma and urine: Abolition of the urinary 24-hour rhythm with atenolol. J Clin Endocrinol Metab 1985;60:1166-1173.
9. Gu Q, et al. Prescription drug use continues to increase: U.S. prescription drug data for 2007-2008. Hyattsville, MD: National Center for Health Statistics; 2010.
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