Sleep Basics: OTC Antihistamines

Many over-the-counter (OTC) medications used for insomnia have primary effects on the H1 receptor. At this receptor, these medications serve as an antagonist; hence the name antihistamine. The H1 receptor is primarily implicated in allergic reactions, so blockade of this receptor decreases the allergic response. Histamine receptors in the central nervous system also have a role in wakefulness; blocking them causes sedation. Studies report that nearly 25 percent of patients with sleep disturbances use OTC sleep aids such as antihistamines, and 5 percent use them at least several nights a week.

Routine use of OTC antihistamines such as diphenhydramine (Benadryl) and doxylamine (Unisom SleepTabs and Nyquil) for insomnia is controversial. I know that on inpatient psychiatric hospitals, these medications are frequently used for sleep because 1) they are relatively safe and 2) they are not addictive. However, the evidence supporting the use of these medications for long-term treatment of insomnia is lacking.  Additionally, many OTC antihistamines (especially Benadryl and doxylamine) have effects at cholinergic receptors leading to uncomfortable side effects such as dry mouth, blurred vision, constipation, urinary retention, and more importantly cognitive impairment and possibly delirium 1.

Recent literature has explored the long term implications of use of anticholinergics (one of the more common being OTC antihistamines). A large prospective cohort study demonstrated that greater cumulative use of anticholinergic medicine in people >65 is associated with an increased risk of dementia 2. To quote from the study:

Higher cumulative anticholinergic medication use is associated with an increased risk for dementia. Efforts to increase awareness among health professionals and older adults about this potential medication-related risk are important to minimize anticholinergic use over time 2.

 

In cases where use of a medication is controversial; its important to be an informed consumer. Benadryl or Doxylamine? What dose is effective? Is Tylenol PM different than Benadryl? Is Nyquil? Is it okay to take these medications if you’re >65?

With regard to insomnia, diphenhydramine has been studied more thoroughly and is noted with short-term use to lead to improvements on self-reported sleep efficiency and the Insomnia Severity Index, and a decrease in participant-reported number of awakenings 3. Unfortunately, most studies fail to observe significant changes on the polysomnogram for sleep-onset, sleep efficiency, and total sleep time 3. Thus, although you may feel like you’re sleeping better, the data doesn’t show this. Furthermore, long-term use of OTC antihistamines may be futile. In fact, studies demonstrate that diphenhydramine may lose its sleep-promoting effects after just 3 days. Furthermore, when dosed at 50mg versus 25mg (i.e. 2 Benadryl vs 1) participants had significant psychomotor impairment and a decreased level of wakefulness the next morning 3.

The studies on doxylamine are few and far between. Similar to diphenhydramine, studies show improvement with self-reported sleep but not with the polysomnogram 3. The main drawback to doxylamine? It has a longer half-life than Benadryl, and thus is likely to cause more morning impairment than a comparable dose of Benadryl.

Diphenhydramine Doxylamine
Brand Name Benadryl, ZZQuil, Tylenol PM, All Unisom products except SleepTabs Nyquil, Unisom Sleep Tabs
Half-Life 3-9 hours (usually reported as 8) 10 hours
Dosing 25-50mg 12.5-25mg

My recommendation? If you’re having insomnia and you want a quick fix, go with 25mg of diphenhydramine each night for a short period of time (I’d recommend no more than 1 week). If you’re over 65, be extremely judicious with your use of OTC antihistamines. Likely due to their anticholinergic effects, long-term use is associated with an increased risk of dementia. Short-term use is probably okay, but if you continue to have sleepdisturbances after 1 week of use, ask your doctor for a better, more evidence based, long term solution.

  1. New Developments in Insomnia
  2. Anticholinergics and Dementia
  3. H1 Blockers for Insomnia

Sleep Basics: Melatonin

Melatonin is a hormone produced by the pineal gland from the precursor, serotonin. During daylight hours, serotonin is stored and is unavailable for use. As darkness sets in, an enzyme is activated which converts serotonin to melatonin. Through its changing concentration (high at night and low during the day), melatonin plays a significant role in the human circadian rhythm.

After synthesis, melatonin is released into the blood stream and cerebrospinal fluid, where it acts on receptors found in many different targets in the human body including the suprachiasmatic nucleus (SCN) in the hypothalamus. In the SCN, melatonin inhibits the firing of certain neurons, which may contribute to it’s sleep-promoting effects.

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Melatonin is produced by the pineal gland (red) and acts on the suprachiasmatic nucleus (green). Image here.

A few things we know about melatonin:

  1. Melatonin secretion starts when human infants are 3-4 months of age. This is the same time infants begin sleeping through the night.
  2. Nocturnal melatonin production decreases over the human lifespan. Peak concentrations in 70 year olds are only 25% of the peak concentrations in younger adults and may contribute to sleep difficulties in older adults. (Fun fact: this decrease may be related to the calcification of the pineal gland with time. Calcification = decreased synthetic capability = less melatonin).
  3. Certain substances (i.e. caffeine and ethanol) can lead to decreases in melatonin concentrations. (Recommendations on caffeine and ethanol intake can be found here).
  4. Very dim light (i.e. 100-200 lux) such as that from the darkest of overcast days or from light-emitting devices (i.e. iPhones) can suppress melatonin production and can lead to feeling less sleepy before bed, increased time to fall asleep, and increased grogginess the next morning 1.

As an over-the-counter supplement, melatonin has an indication for treatment of age-associated insomnia (such as elderly people with decreased melatonin production), jet lag, and shift work. Its primary efficacy is for sleep-initiation and has not been show to have significant effects on sleep-maintenance or early morning awakening 2.

We know that melatonin receptors are highly sensitive to desensitization and that supraphysiologic doses of melatonin may lead to this. As such, optimal dosing of melatonin has not been clearly established. Anecdotally, I have had neurologists and psychiatrists recommend a starting dose of 3mg (such as from this preparation), however from my reading and literature review it seems that lower doses may be preferable. UpToDate, a widely trusted medical resource, recommends starting doses as low as 0.3mg, whereas the European Food Safety Authority recommends that “in order to obtain the claimed effect, 1 mg of melatonin should be consumed close to bedtime”3.

The take home? Melatonin is relativey safe, has few to no addictive properties, and has an indication for sleep-onset insomnia. If you have trouble falling asleep, it is reasonable to try a melatonin supplement with a starting dose of 1 mg. LabDoor provides rankings of the top 10 melatonin supplements, and as I have heard from other physicians, the Nature Made brand ranks near the top for product purity and ingredient safety. What do I take? I buy the 3mg Nature Made brand, break it in half, take it 30 minutes before bedtime, and it helps me fall asleep.