Over-the-Counter Sleep Aids

Many people take non-prescription (‘over-the-counter’) sleep aids, with a market of over $400 million annually in the U.S. Most commonly these are antihistamines, usually diphenhydramine but also doxylamine. Since these medicines don’t require a prescription, many people assume that they are both milder and safer. In the case of antihistamines, this is not a good assumption: they have a variety of side effects, particularly in the elderly, and it’s worthwhile understanding them before taking, in the same way one should with a prescription medicine. Many are the same as melatonin side effects. Diphenhydramine was first marketed in the 1940’s, and subsequently has been used for a variety of purposes besides sleep, including allergies, inflammation, movement disorders and nausea. It is sold under various brand names by itself as well as in combination with the pain medicine acetaminophen in what are known as the ‘PM’ drugs.1

Diphenhydramine (like Benadryl) and Other Antihistamine Over-the-Counter Sleep Aids

Diphenhydramine and other antihistamine non-prescription ‘over-the-counter’ OTC sleep aids act in the brain primarily by interfering with the action of the neurotransmitter histamine, quieting this wake-promoting system.  They also block the action of the neurotransmitter acetylcholine, which leads to some of the side effects we will talk about later. Diphenhydramine is one of the first generation antihistamines. Later ones such as loratadine, which enter the brain to a lesser degree, in general produce less sedation, and are primarily used for allergies rather than for sleep.

The Effects of Diphenhydramine and Other Over-the-Counter Sleep Aids (like Tylenol PM, ZZZquil, Unisom, Advil PM)

Taken in the daytime, diphenhydramine and other non-prescription over-the-counter OTC sleep aids produce well-documented sleepiness, which decreases over the course of a few days. There is little information about whether taking it at night produces morning sleepiness. One study found that the next morning, healthy subjects did not report being more sleepy, but brain scan studies (‘positron emission tomography, or PET’) showed significant continued effects on histamine receptors. Since a person is often unaware of the sedating effects of a medicine the next day, the possibility that there is impairment seems likely but has not been well examined. Some persons develop what are known as paradoxical reactions, in which they become anxious and agitated. 2 In addition to binding at histamine receptors, diphenhydramine also blocks acetylcholine receptors, resulting in dry mouth, blurred vision, increased heart rate, difficulty urinating, memory problems and confusion (‘anticholinergic symptoms’). Long-term use of diphenhydramine has been associated with cognitive impairment in older persons, and in some cases it has been associated with severe confusional states. It is included in the ‘Beers List’ of medicines to be avoided in the elderly.   One study which tracked over 3000 persons over seven years found an association between long-term antihistamine use and the later development of dementia. This risk was related to how long a person had taken the medication: those who took antihistamines for over three years were about 50 percent more likely to develop dementia than those who took them for less than three months.3

Do Diphenhydramine and Other Over-the-Counter Sleep Aids (like Tylenol PM, ZZZquil, Unisom, Advil PM) yield better sleep?

It is clear that diphenhydramine is sedating when taken in the daytime, but whether this translates into improved sleep when taken at night is less clear. In perhaps the largest study, comparing it with a mixture of valerian and hops and with placebo, sleep recording measures of sleep onset and total sleep time were unchanged; patient reports of sleep efficiency (the percentage of bed time spent asleep) improved, without changes in reported sleep onset or total sleep. One study found that diphenhydramine actually increased the amount of movement at night, and no reported benefits. About half of patients describe withdrawal sleep disturbance.4

In choosing whether to use diphenhydramine, among things to consider is that it is available over-the-counter and is not dependence-producing. It is considered in pregnancy category B, which means that animal studies have not shown harm to the fetus but that it has not been carefully tested in humans. On the other hand, as we described above, studies of its benefits for sleep have had very mixed results, and one even suggested that it might make a person more restless at night. It can produce anticholinergic side effects, and is worrisome in the elderly in whom it can cause confusional states. There is also the concern about long-term use and the later development of dementia. There are many uses for diphenhydramine in medicine, primarily in treating allergies, but the overall balance for benefits and risk as a sleep aid suggests that it has limited utility. Non-prescription over-the-counter OTC sleep aids are not recommended as a treatment for chronic insomnia in the most recent guidelines of the American Academy of Sleep Medicine.

Author: Wallace B. Mendelson MD

Dr. Mendelson’s most recent books include ‘Understanding Antidepressants’  and ‘Understanding Sleeping Pills’ (from which this article is excerpted), both available on Amazon.


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