Like many people here in Nashville, I go to bed early but wake up at 3 AM. I return to sleep at 3:45 AM and begin my day’s work at 6 AM- only slightly rested. I have taken melatonin from my pharmacy. It did not help! Why? I wish the world were simple. There are many reasons I wake at 3 AM.
My patients here at our suboxone clinic in Nashville are far too polite to tell me that I overcomplicate everything. When I see a bird, I don’t immediately enjoy its beauty. I immediately begin thinking.
“ Most common: Northern Cardinal. Next most common: Carolina Wren. Consider: Morning Dove. Consider: Blue Jay. Never forget: Asian Koel. Never forget: African Grey Parrot”
I apologize to you in advance. This thinking process was built into my genes early in internal medicine training, reinforced by recurrent certification examinations, and used daily. This is what it means to be a card-carrying internist. We internists are a tribe. I live in daily fear that if I do not think about the possibility of an African Grey Parrot, I will be kicked out of the tribe. Woe is me.
Think about awakening at 3 AM the way I think about birds. There are many reasons why I may be awakening at 3 AM. The most common reason is the logical place to start, but it is not the end of differential diagnosis. In this blog, we are not exploring the differential diagnosis of insomnia. We are thinking together about melatonin.
By William Conway, MD, FACP, FASAM
Internal Medicine, Diabetes & Metabolic Health, Longevity
Nashville Concierge Medicines
The Blog Series
My patients mention insomnia-occasionally as a major concern, but usually in passing, with an unspoken acceptance of awakening every night as a permanent condition of their lives. Many of them have taken Melatonin purchased from a food store, pharmacy, or gas station. They too stopped it. There was no benefit.
Sleep is fundamental to a good life. Something as important as sleep should be simple. It is not. A medical specialty is devoted to sleep. Sleep specialists are often very busy, so you may have to wait a long time for an appointment. To introduce you to sleep problems, consider the following series of four blogs.
- Melatonin
- Sleep in Opioid Use Disorder
- Buprenorphine and Sleep
- Diagnosis and Treatment of Insomnia with Buprenorphine
In this blog, we are talking about what is most common, most treatable, and most easily understood in my patients. I do understand that you are much more complicated. I do understand that there may be many underlying causes for your insomnia- we internists call that by the fancy name of “differential diagnosis.” If you want, I can overcomplicate anything, give you a boring esoteric lecture, and leave you wondering why you even asked-and if this visit will ever come to an end.
Today, together, we are going to be practical. You will leave my visit with a recommendation that may benefit you, at a price you can afford, and that is easy to follow.
Hormones
Hormones are important. When hormones are too high or too low, you may feel it-even if you get used to always feeling bad. You do not have to take my word for it. Just go to YouTube for the stories. Or spend a small fortune on a contemporary practitioner subtly promising results that appeal to your deepest vision of who you want to be or look like. Claims about hormones are everywhere. Most of the hormone claims you see on TikTok or YouTube are, at best, truly “interesting.” In any event, hormones are important.
Melatonin: The Hormone of Darkness.[i]
A hormone is a signal with a complicated but important function in the body’s work. Melatonin is one of the signals that tell the body that biological night has arrived. Secreted primarily by the brain’s pineal gland, melatonin coordinates the body’s circadian timing. It can facilitate sleep. Melatonin is the hormone of darkness.
Throughout most of the night, natural melatonin remains elevated. Natural melatonin is not a brief spike. Its levels rise in the evening, remain elevated for hours, and decline in the morning.
The body has a built-in 24-hour clock. Melatonin is the downstream hormonal signal of the 24-hour clock, not the clock itself. Melatonin is the hormone of darkness.
Melatonin production often declines with age. There is much variation between individuals. Some older adults have much less nighttime melatonin than when they were younger. This age-related change is one reason prolonged- released melatonin has been studied in older adults: lower endogenous melatonin by itself has not been shown to predict treatment response[ii].
The Evidence behind Extended-Release Melatonin- It’s Message and Limits
Consumer choice is supreme in melatonin: gummies, liquids, capsules, and tablets are all available in doses ranging from less than 1 mg to more than 10 mg. The dose matters.
What is poorly advertised is another question: “ Should I choose immediate release or extended release? Studies of specific extended-release and sustained-release formulations show a later peak, lower peak concentration, and more sustained melatonin exposure than immediate release. These are pharmacokinetic studies. By themselves, they do not prove better sleep maintenance
For clarification of magnitude, Lemoine et al. primarily reported improvements in subjective sleep quality and morning alertness in ages fifty-five and older. [iii] Wade et al. report a placebo-adjusted reduction in sleep latency after three weeks of study in the 65–80-year-old subgroup, with a 14.5-minute reduction in sleep latency maintained during longer- term treatment. These patients were not selected because they demonstrated a melatonin deficiency. These findings do not generalize to younger adults. Evidence in younger adults is much more limited.
For relevant context, the Lemoine and Wade trials had ties to Neurim Pharmaceuticals, the maker of Cicadin, a commercial 2 mg prolonged-release product… These relationships do not invalidate studies.
These efficacy trials used a specific standardized 2 mg prolonged-release product. Please note that an over-the-counter product labeled “extended release” does not automatically have the same release profile or clinical effect.
Translating medical evidence is an art form. Your question is “ Do I need to go to sleep or do I need to stay asleep?” The question frames the problem. The question does not identify the underlying cause of insomnia.
Why Short-Acting Melatonin May Not Address Sleep-Maintenance Insomnia
Immediate-release melatonin works best to help you fall asleep. Its rapid rise can reinforce the body’s biological understanding that bedtime has arrived. For those patients whose sole problem is falling asleep (sleep-onset insomnia) , immediate-release melatonin may be appropriate.
In scientific terms, the pharmacokinetic profile of immediate-release melatonin better supports an early melatonin signal for sleep. This may be important, but its benefit for sustaining sleep is modest and inconsistent.
Why Long-Acting Melatonin May Be a Better Choice?
The logic of the drug (pharmacological rationale) is clear. Your decision is less clear. You must be more cautious. Long-acting melatonin is designed to provide more melatonin on a sustained basis throughout the night. However, this does not guarantee that you will remain asleep all night after taking an over-the-counter extended-release melatonin.
The bottom line-executive summary- is clear: Long-Acting Melatonin is designed to support sleep throughout most of the night, not just the beginning of sleep. . Lemoine et al, found that adults age 55 and older receiving 2 mg prolonged-release melatonin demonstrated improvements in sleep quality and morning alertness compared to placebo.[iv]
In Lemoine’s randomized trial, discontinuation of 2 mg prolonged-release melatonin did not produce the withdrawal pattern associated with traditional sedative-hypnotic drugs. Longer-term research by Wade et al. has suggested favorable tolerability in older patients.[v] These studies have their limits. The Literature does not have hundreds of studies.
Longer-acting melatonin may be particularly logical for you for nighttime or early-morning awakening. It is not a powerful sedative hypnotic. Its duration may better match sleep maintenance than simply increasing immediate-release melatonin.
In the face of imperfect evidence, you have a choice. What matters in your decision for melatonin is the benefit you receive and whether you experience side effects.
Take-Home Messages?
Translated into practical terms with all the imperfections of clinical translation:
- Long-acting Melatonin is designed to maintain melatonin throughout more of the night.
- Long-acting melatonin does more than an early peak
- Adults in Lemoine et al. who received 2 mg prolonged melatonin saw benefits in sleep and morning alertness.
Insomnia in Opioid Use Disorder is Usually More Complicated Than One Medication
The following should be understood as fundamental principles.
- Insomnia requires diagnosis rather than automatic treatment with another medication.
- Buprenorphine and insomnia have a complicated relationship.
- Adding sedating medications adds risk.
Long-acting melatonin may offer an advantage because it carries a lower risk of dependence. As in all patient care, prudence and individualized judgment remain central. If you are struggling with sleep issues, reach out to us for a consultation here in Nashville.
[i] . Zisapel N. New perspectives on the role of melatonin in human sleep, circadian rhythms and their regulation. British Journal of Pharmacology. 2018;175(16):3190–3199. doi:10.1111/bph.14116.
[ii] ] 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 Medicine. 2010;8:51. doi:10.1186/1741-7015-8-51.
[iii] Lemoine P, Nir T, Laudon M, Zisapel N. Prolonged-release melatonin improves sleep quality and morning alertness in insomnia patients aged 55 years and older and has no withdrawal effects. Journal of Sleep Research. 2007;16(4):372–380. doi:10.1111/j.1365-2869.2007.00613.x.
[iv] Lemoine P, Nir T, Laudon M, Zisapel N. Prolonged-release melatonin improves sleep quality and morning alertness in insomnia patients aged 55 years and older and has no withdrawal effects. Journal of Sleep Research. 2007;16(4):372–380. doi:10.1111/j.1365-2869.2007.00613.x.
[v] 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 Medicine. 2010;8:51. doi:10.1186/1741-7015-8-51.
