Doxylamine hangover reddit

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Can't sleep? You're not alone. Some 70 million Americans have chronic sleep problems, according to the Centers for Disease Control and Prevention. And it's about far more than feeling tired all the time. Sleep deprivation is a contributor to a host of medical issues ranging from obesity to mental illness to "poor quality of life and well-being."

That explains the explosive market for prescription drugs that help you sleep. Driven by sales of Lunesta, the prescription sleep aid market hit $1.48 billion in 2013, according to IMS Health.

Prescription sleeping pills may be popular, but they can be dicey—the tales of side effects for drugs like Ambien and Halcion are legendary. This has led many to explore herbs, natural remedies, and over-the-counter products that, in theory, have fewer ill effects. But do they work?

I asked Dr. Shanon Makekau, medical director of the sleep laboratory at the Hawaii Permanente Medical Group, about supplements like valerian root, melatonin, and tryptophan, and whether they have any legitimate medical value. She's pragmatic. "The bottom line is that the available alternatives are not really rooted in science," she says. "The studies that are out there, particularly on valerian and chamomile, are limited and small in number, and the results are inconclusive. That being said, I generally tell my patients that if they find a sleep aid anecdotally to be helpful and not harmful, I don't see anything wrong with it."

Given some patients' concern with prescription drugs, Makekau understands the desire for alternatives, but stresses caution. "There are effective prescription medications," she notes, "but they are associated with negative side effects. But people need to know that even things over the counter can be harmful." She points to kava (related to severe liver damage) and l-tryptophan (associated with a rare and fatal muscle-jellifying disease called Eosinophilia-myalgia syndrome) as drugs to treat with special caution.

Still, Makekau says most alternative sleep aids are thought to be safe, though they have little scientific backing. The exception is melatonin, which data suggest helps workers who must switch between day and night shifts, and for managing jet lag. "But the effect is very small in comparison to a prescription sleep aid," she says, "and there's no long-term safety data."

"We don't know how these things work, and there's no evidence that the effect will predictable or repeatable from person to person," she says. "If you're looking for something that's not prescription-based, have a conversation with your physician up front. The key is finding something that's safe and doesn't interact with any other medications you're taking."

Snoozeville

Given that individuals tend to react differently to these supplements, I wondered how I would fare in a test group of one. I've long had trouble sleeping—rousing a lot during the night and waking much too early. I'm not interested in prescription sleep aids or over-the-counter drugs like diphenhydramine (Benadryl and Sominex) or doxylamine (Unisom), which can lead to tolerance issues if taken regularly. However, the thought of taking a chamomile capsule after dinner didn't seem so bad. So I rounded up eight alternative sleep aids—five single-supplement products and three "cocktails" of a variety of supplements—and took them semi-randomly over the course of about six weeks. The cocktail supplement market is vast, but if you check ingredient labels you'll find that the three I chose are fairly representative.

Clinicians and drug companies alike generally consider three categories when determining the effectiveness of a sleep aid: how much it shortens the time needed to fall asleep, how much it increases the total amount of sleep experienced, and the severity of drowsiness—the "hangover effect"—experienced the next day.

The quality and depth of sleep can be measured with sleep monitoring equipment; I used a Withings Aura to measure the amount of REM sleep I was getting each night. I then used this information in combination with a daily sleep log (which I highly recommend even if you aren't experimenting with sleep aids) that I kept throughout the experiment, never taking the same sleep aid for two consecutive nights, and taking nothing at all for many nights to ensure my system was "clean" for the next go-round. In my sleep log, each night I gave the prior night's sleep a "quality rating" from 1 (nonstop insomnia) to 10 (perfect sleep). As a sort of master measurement of the night, I multiplied this rating by the total amount of sleep I achieved in hours, so a total "sleep score" of 80 points—8 hours of level 10 sleep—would be perfect.

It can't be noted strenuously enough that this is a thoroughly unscientific test and my experiences should not be seen as representative of how anyone else may respond to these supplements, or as a benchmark for their effectiveness. Rather, my intent is to investigate how widely variable sleep aids like these can be outside of the lab while offering my own anecdotal evidence about what worked as a baseline for further investigation.

As well, remember that many things can impact how you sleep. What you eat, what you drink, evening exercise, late-night brain stimulation (like watching TV or playing games), pets in the room, temperature, ambient noise and light, and who knows what else can each have a severe impact on how well you sleep. Supplements are only one piece of the puzzle, but the question is whether they can genuinely help to overcome those other elements.

Still, consider those elements before thinking about a supplement. "Look at your overall sleep habits and your environment before you engage with a sleep aid," Makekau says. "Make sleep a priority, get exercise during the day, and avoid things like alcohol and caffeine."

The Players

I investigated five single-product supplements. Prices are approximate based on larger capacity bottles.

Melatonin (4¢/dose). The big name in alternative sleep aids, this is a hormone that builds in the body as it gets darker outside.
Valerian Root (8¢/dose). A flowering herb that has sedative effects. The root is powdered and put into a capsule.
Chamomile (10¢/dose). The same stuff that's in herbal tea. The flowers of this plant are used for a wide variety of ailments, including indigestion and anxiety.
Lemon balm (18¢/dose). Also known as Melissa. It's part of the mint family (not the lemon family) and finds a home in aromatherapy and culinary uses. Tea made from lemon balm is used as a mild sedative.
L-tryptophan (45¢/dose). An amino acid and a precursor to serotonin and melatonin in the brain. Famously thought to be in high concentrations in turkey (but not really), it's also used to improve mood.

The three "cocktails" I sampled included these products:

Somnis (30¢/dose). A mix of L-tryptophan, melatonin, and gamma aminobutyric acid (GABA).
Serenity ($1.33/dose). Valerian root, passion flower extract, magnolia bark, jujube, chamomile, L-theanine, 5-HTP, melatonin, and something called BioPerine (a black pepper extract), plus a smattering of vitamins.
Luna (73¢/dose). L-theanine, valerian root, chamomile, passion flower, lemon balm, hops flower, L-taurine, and melatonin, plus magnesium.

The Results

After weeks of testing, my personal results were far from what I expected. The biggest surprise was that, based on my sleep log and the Aura data, I found I'd been sleeping better than I thought, even when I didn't take anything. With no supplement, I was getting a baseline of 6.85 hours of sleep at an average 6.6 quality rating for a total sleep score of 46 points. Not bad, and the Aura reported 1.46 hours of REM sleep each night, which was also surprisingly good.

When looking at the overall amount of sleep I got while using a single supplement, L-tryptophan came out on top. On nights I took L-tryptophan, I got 7.53 hours of sleep, significantly above any other alternative. The downside was the quality of that sleep, which I rated at only a 6.5, for an average sleep score of 49 points. That's all pretty good, but the whole jellied muscles business put me off a bit, so ultimately I'm not sure it's a great option for sustained use.

How about sleep quality? Looking at all the single-product supplements, chamomile gave me the soundest night's sleep—so deep one night that my wife reported she was unable to rouse me during a snoring jag. I gave those nights an average quality rating of 7.3, and the 7.18 average hours of sleep I got was also noticeably higher than the no-meds nights. The net sleep score of 52 points earned chamomile the top spot among the single-supplement products.

Surprisingly, none of the other three supplements were effective for me, and all netted lower total sleep times and lower quality ratings than using nothing at all.

Melatonin was the big surprise. Some of my worst nights I experienced during testing were ones in which I'd taken this drug. After melatonin, I tossed and turned in bed, waking repeatedly throughout the night—once close to a dozen times. The next morning I invariably experienced a severe hangover effect, groggy for hours.

Valerian was not much better. On this drug I experienced wild dreams, lots of waking, and extreme next-morning fatigue. The valerian pills also smelled awful, like pungent, wet cardboard, a problem not to be underestimated when you have to choke it down at bedtime. But the absolute worst was lemon balm. The first night I tried it I woke repeatedly with an unbearably full bladder. Three lengthy trips to the bathroom later, lemon balm's apparent diuretic effect started causing significant concern. I discontinued it soon after for fear of kidney damage or worse.

The three cocktails performed better than most of the individual supplements, but only Serenity and Luna did significantly better at giving me extra time asleep, and only Serenity offered any improvement in sleep quality. In fact, Serenity provided some of my best numbers across the board—7.26 hours of total sleep, 1.80 hours of REM sleep (vs. 1.46 hours with no supplement), a 7.7 sleep quality rating, and a total sleep score of 56. The only problem is that, as with valerian, Serenity smells so hideous it is physically difficult to choke down. At $1.33 per dose, it's by far the most expensive solution I tested.

Luna had similar total sleep numbers to Serenity, but provided less REM and only a 6.4 quality rating for a net sleep score of 46, the same as sleeping without a supplement. Somnis's 6.88 total sleep hours made it an also ran—largely thanks to one night where I spent more than two hours trying to get to sleep—with a total sleep score of 43.

What happens now? While I'll probably keep both Serenity and chamomile in my arsenal in case of insomnia—and to attempt to help with jet lag when traveling internationally—I'm not planning to take any of these supplements on a regular basis, as it seems, in the end, I sleep well enough without them. Just remember that if you decide to try any of these for yourself, your mileage will, without a doubt, vary.

Chart: Sleep supplements by the numbers

Supplement

Sleep (hrs)

Quality Rating

Sleep score

None

6.85

6.6

46

Serenity

7.26

7.7

56

Chamomile

7.18

7.3

52

L-tryptophan

7.53

6.5

49

Luna

7.26

6.3

46

Somnis

6.88

6.3

43

Valerian root

6.80

5.0

34

Melatonin

5.67

3.7

21

Lemon balm

6.70

3.0

20

Sours: https://www.wired.com/2015/04/sleep-aids/

If you’re having trouble sleeping, medicines shouldn’t be your first option. Exercise regularly, cut back on coffee (and other caffeinated drinks) after midday, eat less in the evening, ease up on “screen time” before, and in, bed, practise meditation and try to have a quiet, dark bedroom dedicated mostly to sleep.

But what if you’ve tried everything and are still struggling with sleep? Many people will want to turn to a medicine for help. Navigating the various options for effectiveness, safety and the potential to become habit-forming can be difficult.

Long-term regular use of medicines to promote sleep should be avoided, as initial effectiveness declines rapidly over a few weeks and dependence and adverse effects become problematic. But in the short short term, sleep medications do have their place. Unfortunately they are often over-used, especially in older people.


Read more: Why getting enough sleep should be on your list of New Year's resolutions


Benzodiazepines

Benzodiazepines are drugs such as Valium, also used to treat anxiety. They are the most commonly prescribed sleeping pills.

Their effects, which include some muscle relaxing properties, are achieved by enhancing the effect of GABA, an inhibitory neurotransmitter operating throughout the brain. Rarely, some people experience the opposite and become over-excited and more anxious.

As benzodiazepines depress brain function (they depress the central nervous system), their effects add to other central nervous system depressants including alcohol, sedating antihistamines and opioid analgesics such as oxycodone (Endone). This can be very dangerous, and when combined can lead to respiratory failure, coma and even death.

Physiological and psychological dependence on the drug can develop after only a few days in some people, or weeks in most. Unfortunately, far too many people are dependent.


Read more: Weekly Dose: Valium, the 'safer choice' that led to dependence and addiction


Importantly, the effectiveness for inducing sleep wears off after a few weeks. It can be very hard to stop taking benzodiazepines as insomnia and often anxiety returns. The duration of “withdrawal” is related to the length of time these are taken.

Stopping suddenly after long-term use can be dangerous, with violent withdrawal reactions possible, including epileptic seizures. Ceasing these medicines needs to be managed by your doctor. Essentially, a gradual reduction in dose is needed with support and counselling to assist with the temporary increase in insomnia and perhaps anxiety.

Side effects include a “dulling” of cognitive function, memory impairment and the increased risk for accidents, especially unsteadiness and falls in older people.

Benzodiazepines should only be used for two to four weeks, or intermittently, and only in addition to good sleep hygiene (that is, practising the measures listed in the first paragraph).

Temazepam (brand names Normison, Temaze, Temtabs) and lorazepam (brand name Ativan) are reasonable choices from the many benzodiazepines available. That’s because they have a faster onset and short duration of effect so as to avoid a “hangover” the next day.


Read more: Health Check: how to soothe yourself to sleep


Z-drugs (hypnotics)

Zopiclone (brand names Imovane and Imrest) and zolpidem (brand name Stilnox) are similar in their pharmacology and effects to the benzodiazepines. These prescription-only medicines also enhance the actions of GABA to depress brain activity and have the same hazards related to excessive sedation and dependence.

Bizarre behaviours and symptoms, for example hallucinations and sleep-walking that can be dangerous, are more likely than with benzodiazepines.

Antihistamines

Older antihistamine medicines, now known as sedating antihistamines, induce drowsiness through their central nervous system-depressing properties. These are available over the counter from pharmacies. Common examples include diphenhydramine (brand name Unisom Sleep Gels), doxylamine (brand name Restavit) and promethazine (branded Phenergan).

Especially in those with allergies such as hay fever disturbing their sleep, these may be a reasonable short-term option. Dependence on these medications to sleep is a hazard.

These medicines have side effects including dry mouth, blurred vision, constipation, confusion, dizziness and urinary retention in men with prostrate problems. All side-effects are worse in older people.

By contrast, over-the-counter antihistamines commonly used to treat hay fever (such as brand names Telfast, Zyrtec and Claratyne) are non-sedating, and therefore not likely to make you drowsy.

Analgesics

Any opioid-containing medicine, all now requiring a prescription, will induce drowsiness (depending on the dose) because they also depress our central nervous system. Codeine (in Panadeine, Panadeine Forte or Nurofen Plus), tramadol, tapentadol, morphine or oxycodone will make us sleepy, but they’re not recommended to treat insomnia.

These powerful medicines are best reserved for judicious use in pain relief, given the severe hazards of dependence and overdose. Older people are more sensitive to the central nervous system-depressing effects and also to constipation.


Read more: Health Check: five ways to get a better night's sleep


Melatonin

Our sleep-wake cycle is dependent on the hormone melatonin released cyclically from a gland in our brain. Melatonin administered orally helps induce sleep in some people, but is not as effective as other sedatives.

However, a recent Australian study tested melatonin in people with sleep problems caused by delayed melatonin release in their brains. These people have trouble falling asleep and waking at times appropriate for proper functioning.

Taken one hour prior to bed time, melatonin (0.5mg) accompanied by a behavioural intervention (such as learning how to meditate) helped the participants get to sleep and improved common accompanying impairments such as low mood, anxiety and difficulty concentrating.

You need a prescription for melatonin in Australia. It’s best to avoid alcohol as it interferes with sleep, thereby reducing any effect of melatonin. It is worth trying as it is generally well tolerated, although some people experience back pain. It may work in other types of sleep disturbances, not due to delayed release of melatonin. A dose of 2mg, controlled release one to two hours before bedtime is most commonly used.

Antipsychotics

Antipsychotic medicines (such as quetiapine) have been increasingly used to treat insomnia.

Typically used at a lower dose, quetiapine can induce sleep but carries a significant burden of possible harmful effects. These include a fast heart rate, agitation, low blood pressure and unsteadiness. These make quetiapine not appropriate for treating common sleep problems.

Antidepressants

Antidepressants are typically prescribed at a low dose for insomnia, but the supporting evidence of efficacy (despite the wide use) is low quality and there is the risk of adverse effects such as confusion, dry mouth and blurred vision.

Herbal and complementary medicines

Herbal remedies such as valerian, lavender, passiflora, chamomile, hops and catnip are widely promoted to promote “sleep health”. Research to support their efficacy is limited.


Read more: Is it possible to catch up on sleep? We asked five experts


Many newer and emerging medicines are being tested for insomnia, so in the future more options should be available.

For now it’s important to remember none of the options listed above is without side effects, and most will cause dependence if used long term, meaning falling asleep without them will be even harder than it was before.

Improve your sleep hygiene, and if that hasn’t worked for you, speak with your doctor about what’s keeping you up at night. She’ll be able to prescribe the best type of medication for you to use in the short term.

Sours: https://theconversation.com/i-cant-sleep-what-drugs-can-i-safely-take-102343
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Doxylamine in Unisom and Nyquil Not Recommended for Insomnia Treatment

Doxylamine is a sleep aid found in over-the-counter products such as Unisom and Nyquil. It's sometimes taken to treat insomnia.

Like the related medication diphenhydramine, doxylamine does not require a prescription. That doesn't mean it doesn't come with potential side effects, though. Before taking doxylamine, you should learn how well it works and what problems it can cause.

Uses

Doxylamine is an antihistamine, meaning that it treats allergies. It's also used for nighttime cold symptoms. Causing drowsiness is considered a side effect, but it can be a useful one for some people who need help getting to sleep or staying asleep. It shouldn't be used for more than two weeks to treat insomnia.

Like many sleeping pills, doxylamine affects neurotransmittersspecialized chemical messengers that send signals between brain and nerve cells (neurons). More specifically, it blocks receptors that allow the neurotransmitter histamine to affect a neuron. This causes you to get sleepy.

Doxylamine works centrally (within the central nervous system) and elsewhere in the body to sedate you.

Before Taking

As an over-the-counter medication, the risks are thought to be slightly lower than with prescription medications that require more careful monitoring. No routine tests are recommended with its use.

Ultimately, doxylamine is not the best option if you are considering taking sleeping pills; there are a number of other choices that are better suited to aiding sleep. Doxylamine doesn't promote sleep in the same way as prescription hypnotic medications, such as benzodiazepine and non-benzodiazepine medications.

To take a medication for its side effect—in this case, sleepiness—is not recommended.

Doxylamine is non-habit forming medication. However, you can develop tolerance to it and take more than needed.

Precautions and Contraindications

Doxylamine is contraindicated for various groups.

Age Restrictions

Children under 12 years of age should not use doxylamine 25 milligrams (mg). Children under 6 and elderly patients shouldn't use it without a healthcare provider's advice.

Breastfeeding

According to a National Institutes of Health publication, small, occasional doses shouldn't cause problems with breastfed babies. However, larger doses or long-term use may cause drowsiness, irritability, and colicky symptoms in babies. It may also lower your milk supply.

Medical Conditions

People with many conditions should be cautious about doxylamine as it may cause problems or drug interactions. These conditions include:

  • Glaucoma
  • Hyperthyroidism
  • Heart disease
  • High blood pressure (hypertension)
  • Asthma
  • Chronic obstructive pulmonary disease (COPD)
  • Pneumonia
  • Peptic ulcer disease
  • Prostate enlargement
  • Liver disease
  • Bowel or bladder obstruction

If you're concerned about whether you may have problems using doxylamine, you should first consult with your healthcare provider.

Negative drug interactions are also a risk, especially with other medications that affect the brain, so be sure to review your medications with your healthcare provider or pharmacist before starting to use doxylamine.

Side Effects

The list of potential side effects for any drug can be quite long, and doxylamine is no exception. Although you likely wouldn't experience most side effects, and may not have any at all, some that occur commonly with doxylamine include:

  • Dizziness
  • Loss of coordination
  • Headache
  • Stomach pain
  • Dry mouth or nose
  • Constipation
  • Difficulty urinating
  • Blurred or double vision

Potential Serious Reactions

While they're rare, serious side effects can result from the use of doxylamine, including:

  • Severe allergic reaction, including difficulty breathing (anaphylaxis)
  • Low blood cell counts (agranulocytosis, anemia, thrombocytopenia, and leukopenia)
  • Abnormal heart rhythms or altered heart rate
  • Seizures
  • Toxic psychosis
  • Inner ear problems (acute labyrinthitis)
  • Hallucinations
  • Confusion or delirium
  • Low blood pressure

Insomnia Healthcare Provider Discussion Guide

Get our printable guide for your next healthcare provider's appointment to help you ask the right questions.

Download PDF

A Word From Verywell

If you experience any difficulties when taking this drug, you should be in close contact with your primary health provider. If you wish to pursue preferred treatments for insomnia, you should likewise make an appointment and discuss the better prescription options that are available.

Effective treatment may include medications, learning better sleep habits, or cognitive behavioral therapy for insomnia (CBTI).

Frequently Asked Questions

  • No. Unisom is intended as a temporary sleep aid and should not be taken for more than two weeks. If you need ongoing help falling asleep, speak to your healthcare provider. 

    Learn More:What Causes Insomnia?

  • Yes. The doxylamine succinate in Unisom taken with vitamin B6 can treat morning sickness during pregnancy. Talk to your healthcare provider before taking the combination to be sure it’s right for you.

    Learn More:Using Doxylamine Safely in Pregnancy

  • Doxylamine may increase the risk for dementia. This is due to its anticholinergic properties, which means it blocks neurotransmitters that transmit messages along the nervous system. According to researchers, anticholinergics are associated with cognitive decline.

    Learn More:Warning Signs of Dementia

Thanks for your feedback!

Verywell Health uses only high-quality sources, including peer-reviewed studies, to support the facts within our articles. Read our editorial process to learn more about how we fact-check and keep our content accurate, reliable, and trustworthy.

  1. Krystal AD, Richelson E, Roth T. Review of the histamine system and the clinical effects of Hi antagonists: basis for a noew model for understanding the effects of insomnia medications. Sleep Med Rev. 2013;17(4):263-272. doi:10.1016/j.smrv.2012.08.001

  2. Drugs and Lactation Database. Doxylamine. Bethesda, MD: National Library of Medicine (US). Updated December 3, 2018.

  3. MedlinePlus. Doxylamine. Updated February 18, 2020.

  4. Unisom. Frequently Asked Questions.

  5. Koren G, Clark S, Hankins GDV, et al. Maternal safety of the delayed-release doxylamine and pyridoxine combination for nausea and vomiting of pregnancy; a randomized placebo controlled trial. BMC Pregnancy and Childbirth. 2015;15(1):59.

  6. Coupland CAC, Hill T, Dening T, Morriss R, Moore M, Hippisley-Cox J. Anticholinergic drug exposure and the risk of dementia: a nested case-control study. JAMA Intern Med. 2019;179(8):1084. doi:10.1001/jamainternmed.2019.0677

Additional Reading
  • "Doxylamine." Epocrates Rx Pro. Version 16.3, 2016. Epocrates, Inc. San Mateo, California.
Sours: https://www.verywellhealth.com/doxylamine-and-insomnia-3015179

Doxylamine

First-generation antihistamine used as a short-term sedative and hypnotic (sleep aid)

Skeletal formula of the doxylamine molecule
Ball-and-stick model of the doxylamine molecule
Trade namesUnisom, Vicks Formula 44 (in combination with Dextromethorphan), others
AHFS/Drugs.comMonograph
MedlinePlusa682537
Pregnancy
category
Routes of
administration
By mouth
ATC code
Legal status
  • AU: S3 (Pharmacist only)
  • US: OTC
BioavailabilityOral: 24.7%[1]
Intranasal: 70.8%[1]
MetabolismHepatic (CYP2D6, CYP1A2, CYP2C9)[2]
Elimination half-life10–12 hours[2]
ExcretionUrine (60%), feces (40%)[3]

IUPAC name

  • (RS)-N,N-dimethyl-2-(1-phenyl-1-pyridin-2-yl-ethoxy)-ethanamine

CAS Number
PubChemCID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard(EPA)
ECHA InfoCard100.006.742Edit this at Wikidata
FormulaC17H22N2O
Molar mass270.369 g·mol−1
3D model (JSmol)

SMILES

  • n1ccccc1C(c1ccccc1)(C)OCCN(C)C

InChI

  • InChI=1S/C17H22N2O/c1-17(20-14-13-19(2)3,15-9-5-4-6-10-15)16-11-7-8-12-18-16/h4-12H,13-14H2,1-3H3 checkY
  • Key:HCFDWZZGGLSKEP-UHFFFAOYSA-N checkY
  (verify)

Doxylamine is a first-generation antihistamine used as a short-term sedative and hypnotic (sleep aid) or in combination formulations to provide night-time allergy and cold relief. It provides a calmative effect in preparations containing the analgesics paracetamol (acetaminophen) and codeine. It is prescribed in combination with vitamin B6 (pyridoxine) to prevent morning sickness in pregnant women. Its fetalsafety rating is "A" (no evidence of risk).[4]

It was first described in 1948.[5]

Medical uses[edit]

Doxylamine is an antihistamine used to treat sneezing, runny nose, watery eyes, hives, skin rash, itching, and other cold or allergy symptoms. It is also used as a short-term treatment for sleep problems (insomnia).[6]

It is used in the combination drugpyridoxine/doxylamine to treat nausea and vomiting of pregnancy.[7][8]

As of 2004, doxylamine and diphenhydramine were the agents most commonly used to treat short-term insomnia.[9] As of 2008, antihistamines were not recommended by the American Academy of Sleep Medicine for treatment of chronic insomnia "due to the relative lack of efficacy and safety data".[10]

Doses of doxylamine that have been used for sleep range from 5 to 50 mg, with 25 mg being the typical dose.[11][12][13]

[edit]

Doxylamine succinate is a potent anticholinergic and has a side-effect profile common to such drugs, including dry mouth, ataxia, urinary retention, drowsiness, memory problems, inability to concentrate, hallucinations, psychosis, and a marked increased sensitivity to external stimuli.[citation needed]

Because of its relatively long elimination half-life (10–12 hours), doxylamine is associated with daytime/next-day drowsiness, grogginess, dry mouth, and tiredness when used as a hypnotic.[14] The shorter elimination half-life of diphenhydramine (4–8 hours) may give it an advantage over doxylamine in this regard.[15]

Unlike with diphenhydramine, case reports of coma and rhabdomyolysis have been reported with doxylamine.[2]

Toxicity[edit]

Doxylamine succinate is generally safe for administration to healthy adults. The median lethal dose (LD50) is estimated to be ~500 mg/kg in humans.[16] Symptoms of overdose may include dry mouth, dilated pupils, insomnia, night terrors, euphoria, hallucinations, seizures, rhabdomyolysis, and death.[17] Fatalities have been reported from doxylamine overdose. These have been characterized by coma, tonic-clonic (or grand mal) seizures and cardiorespiratory arrest. Children appear to be at a high risk for cardiorespiratory arrest. A toxic dose for children of more than 1.8 mg/kg has been reported. A 3-year-old child died 18 hours after ingesting 1000 mg doxylamine succinate.[3] Rarely, an overdose results in rhabdomyolysis and acute kidney injury.[18]

Studies of doxylamine's carcinogenicity in mice and rats have produced positive results for both liver and thyroid cancer, especially in the mouse.[19] The carcinogenicity of the drug in humans is not well studied, and the IARC lists the drug as "not classifiable as to its carcinogenicity to humans".[20]

Pharmacology[edit]

Pharmacodynamics[edit]

SiteKi (nM)SpeciesRef
SERT>10,000Human[22]
NET>10,000Human[22]
DAT>10,000Human[22]
5-HT2A>10,000Human[22]
5-HT2C>10,000Human[22]
α1B>10,000Human[22]
α2A>10,000Human[22]
α2B>10,000Human[22]
α2C>10,000Human[22]
H142Human[22]
H2NDNDND
H3>10,000Human[22]
H4NDNDND
M1490Human[22]
M22,100Human[22]
M3650Human[22]
M4380Human[22]
M5180Human[22]
Values are Ki (nM), unless otherwise noted. The smaller the value, the more strongly the drug binds to the site.

Doxylamine acts primarily as an antagonist or inverse agonist of the histamineH1 receptor.[23][22] This action is responsible for its antihistamine and sedative properties.[23][22] To a lesser extent, doxylamine acts as an antagonist of the muscarinic acetylcholine receptors,[23][22] an action responsible for its anticholinergic and (at high doses) deliriant effects.[23][22]

Pharmacokinetics[edit]

The bioavailability of doxylamine is 24.7% for oral administration and 70.8% for intranasal administration.[1] The Tmax of doxylamine is 1.5 to 2.5 hours.[2] Its elimination half-life is 10 to 12 hours (range 7 to 13 hours).[2][24] Doxylamine is metabolized in the liver primarily by the cytochrome P450enzymesCYP2D6, CYP1A2, and CYP2C9.[2][25] The main metabolites are N-desmethyldoxylamine, N,N-didesmethyldoxylamine, and doxylamine N-oxide.[26] Doxylamine is eliminated 60% in the urine and 40% in feces.[3]

Doxylamine concentrations after a single 25 mg oral dose of doxylamine in healthy volunteers.[24]

History[edit]

Doxylamine is a first-generation antihistamine sleep aid with weak hypnotic and calming effects first reported in 1949.[27][third-party source needed]

Society and culture[edit]

Formulations[edit]

Doxylamine is primarily used as the succinic acidsalt, doxylamine succinate.

  • It is the sedating ingredient of NyQuil (generally in combination with dextromethorphan and acetaminophen).
  • In Commonwealth countries, such as Australia, Canada, South Africa, and the United Kingdom, doxylamine is available prepared with paracetamol (acetaminophen) and codeine under the brand name Dolased, Propain Plus, Syndol, or Mersyndol, as treatment for tension headache and other types of pain.
  • Doxylamine succinate is used in general over-the-counter sleep-aids branded as Somnil (South Africa), Dozile, Donormyl, Lidène (France, Russian Federation), Dormidina (Spain, Portugal), Restavit, Unisom-2, Sominar (Thailand), and Sleep Aid (generic, Australia).
  • In the United States:
    • doxylamine succinate is the active ingredient in many over-the-counter sleep-aids branded under various names.
    • doxylamine succinate and pyridoxine (Vitamin B6) are the ingredients of Diclegis, approved by the FDA in April 2013 becoming the only drug approved for morning sickness[28] with a class A safety rating for pregnancy (no evidence of risk).
  • In Canada:
    • doxylamine succinate and pyridoxine (vitamin B6) are the ingredients of Diclectin, which is used to prevent morning sickness.
    • It is also available in combination with vitamin B6 and folic acid under the brand name Evanorm (marketed by Ion Healthcare).
  • In India
    • Doxylamine preparations are available typically in combination with Pyridoxine that may also contain folic acid. Doxylamine usage is thus restricted for pregnant women.

References[edit]

  1. ^ abcPelser A, Müller DG, du Plessis J, du Preez JL, Goosen C (2002). "Comparative pharmacokinetics of single doses of doxylamine succinate following intranasal, oral and intravenous administration in rats". Biopharm Drug Dispos. 23 (6): 239–44. doi:10.1002/bdd.314. PMID 12214324. S2CID 32126626.
  2. ^ abcdefMeir H. Kryger; Thomas Roth; William C. Dement (1 November 2010). Principles and Practice of Sleep Medicine E-Book. Elsevier Health Sciences. pp. 925–. ISBN .
  3. ^ abc"New Zealand Datasheet: Doxylamine Succinate"(PDF). Medsafe, New Zealand Medicines and Medical Devices Safety Authority. 16 July 2008. Archived from the original on 22 March 2016.
  4. ^Briggs, Gerald G.; Freeman, Roger K.; Yaffe, Sumner J. (2008). Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk. Obstetric Medicine. 2. Lippincott Williams & Wilkins. p. 89. doi:10.1258/om.2009.090002. ISBN . PMC 4989726.
  5. ^Fischer, Jnos; Ganellin, C. Robin (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 546. ISBN .
  6. ^"Doxylamine: MedlinePlus Drug Information".
  7. ^Madjunkova, S; Maltepe, C; Koren, G (June 2014). "The delayed-release combination of doxylamine and pyridoxine (Diclegis®/Diclectin®) for the treatment of nausea and vomiting of pregnancy". Paediatric Drugs. 16 (3): 199–211. doi:10.1007/s40272-014-0065-5. PMC 4030125. PMID 24574047.
  8. ^Cada, DJ; Demaris, K; Levien, TL; Baker, DE (October 2013). "Doxylamine succinate/pyridoxine hydrochloride". Hospital Pharmacy. 48 (9): 762–6. doi:10.1310/hpj4809-762. PMC 3857125. PMID 24421551.
  9. ^Ringdahl, EN; Pereira, SL; Delzell JE, Jr (2004). "Treatment of primary insomnia". The Journal of the American Board of Family Practice. 17 (3): 212–9. doi:10.3122/jabfm.17.3.212. PMID 15226287.
  10. ^Schutte-Rodin, S; Broch, L; Buysse, D; Dorsey, C; Sateia, M (15 October 2008). "Clinical guideline for the evaluation and management of chronic insomnia in adults"(PDF). Journal of Clinical Sleep Medicine. 4 (5): 487–504. doi:10.5664/jcsm.27286. PMC 2576317. PMID 18853708.
  11. ^Perry, Paul J. (2007). Psychotropic Drug Handbook. ISBN .
  12. ^Dupuis G, Vaugeois JM (February 2020). "Les effets anti-H1 intéressants dans les insomnies de maintien : réflexion sur les intérêts comparés de la doxylamine et de la doxépine" [The interesting anti-H1 effects in maintenance insomnia: A reflection on the comparative advantages of doxylamine and doxepin]. Encephale (in French). 46 (1): 80–82. doi:10.1016/j.encep.2019.01.006. PMID 30879783.
  13. ^Lie JD, Tu KN, Shen DD, Wong BM (November 2015). "Pharmacological Treatment of Insomnia". P T. 40 (11): 759–71. PMC 4634348. PMID 26609210.
  14. ^Alon Y. Avidan (29 June 2017). Review of Sleep Medicine E-Book. Elsevier Health Sciences. pp. 394–. ISBN .
  15. ^Paul Professor Rutter; David Newby (11 September 2015). Community Pharmacy ANZ – eBook: Symptoms, Diagnosis and Treatment. Elsevier Health Sciences. pp. 99–. ISBN .
  16. ^DOXYLAMINE SUCCINATE. hazard.com.
  17. ^Syed, Husnain; Sumit Som; Nazia Khan; Wael Faltas (17 March 2009). "Doxylamine toxicity: seizure, rhabdomyolysis and false positive urine drug screen for methadone". BMJ Case Reports. 2009 (90): 845. doi:10.1136/bcr.09.2008.0879. PMC 3028279. PMID 21686586.
  18. ^Leybishkis, B.; Fasseas, P.; Ryan, K. F. (2001). "Doxylamine overdose as a potential cause of rhabdomyolysis". American Journal of the Medical Sciences. 322 (1): 48–9. doi:10.1097/00000441-200107000-00009. PMID 11465247.
  19. ^Doxylamine succinate (CAS 562-10-7). berkeley.edu.
  20. ^DOXYLAMINE SUCCINATE. International Agency for Research on Cancer (IARC) – Summaries & Evaluations.
  21. ^Roth, BL; Driscol, J. "PDSP Ki Database". Psychoactive Drug Screening Program (PDSP). University of North Carolina at Chapel Hill and the United States National Institute of Mental Health. Retrieved 14 August 2017.
  22. ^ abcdefghijklmnopqrstKrystal AD, Richelson E, Roth T (2013). "Review of the histamine system and the clinical effects of H1 antagonists: basis for a new model for understanding the effects of insomnia medications". Sleep Med Rev. 17 (4): 263–72. doi:10.1016/j.smrv.2012.08.001. PMID 23357028.
  23. ^ abcdVande Griend JP, Anderson SL (2012). "Histamine-1 receptor antagonism for treatment of insomnia". J Am Pharm Assoc (2003). 52 (6): e210–9. doi:10.1331/JAPhA.2012.12051. PMID 23229983.
  24. ^ abAllison M, Hale C (June 2018). "A Phase I Study of the Pharmacokinetics and Pharmacodynamics of Intranasal Doxylamine in Subjects with Chronic Intermittent Sleep Impairment". Drugs R D. 18 (2): 129–136. doi:10.1007/s40268-018-0232-1. PMC 5995792. PMID 29671128.
  25. ^Krystal AD (August 2009). "A compendium of placebo-controlled trials of the risks/benefits of pharmacological treatments for insomnia: the empirical basis for U.S. clinical practice". Sleep Med Rev. 13 (4): 265–74. doi:10.1016/j.smrv.2008.08.001. PMID 19153052.
  26. ^Holder, C. L.; Korfmacher, W. A.; Slikker Jr, W.; Thompson Jr, H. C.; Gosnell, A. B. (1985). "Mass spectral characterization of doxylamine and its rhesus monkey urinary metabolites". Biomedical Mass Spectrometry. 12 (4): 151–158. doi:10.1002/bms.1200120403. PMID 2861861.
  27. ^Sperber, Nathan.; Papa, Domenick.; Schwenk, Erwin.; Sherlock, Margaret. (1949). "Pyridyl-Substituted Alkamine Ethers as Antihistaminic Agents". Journal of the American Chemical Society. 71 (3): 887–890. doi:10.1021/ja01171a034. PMID 18113525.
  28. ^Slaughter, Shelley R.; Hearns-Stokes, Rhonda; van der Vlugt, Theresa; Joffe, Hylton V. (2014). "FDA Approval of Doxylamine–Pyridoxine Therapy for Use in Pregnancy". New England Journal of Medicine. 370 (12): 1081–1083. doi:10.1056/NEJMp1316042. PMID 24645939.

Medical uses

Insomnia pharmacotherapies

GABAARPAMs
  • Benzodiazepines:Brotizolam
  • Cinolazepam
  • Climazolam
  • Clorazepate
  • Doxefazepam
  • Estazolam
  • Etizolam
  • Flunitrazepam
  • Flurazepam
  • Flutoprazepam
  • Haloxazolam
  • Loprazolam
  • Lormetazepam
  • Midazolam
  • Nimetazepam
  • Nitrazepam
  • Quazepam
  • Temazepam
  • Triazolam; Nonbenzodiazepines/Z-drugs:Eszopiclone
  • Zaleplon
  • Zolpidem
  • Zopiclone; Others:Alcohols (e.g., ethchlorvynol, amylene hydrate, ethanol)
  • Barbiturates (e.g., amobarbital, pentobarbital, phenobarbital, secobarbital)
  • Bromides (e.g., potassium bromide, sodium bromide)
  • Carbamates (e.g., meprobamate)
  • Chloral hydrate
  • Clomethiazole
  • Kava
  • Paraldehyde
  • Piperidinediones (e.g., glutethimide)
  • Quinazolinones (e.g., methaqualone)
  • Sulfonmethane
  • Valerian
Antihistamines
(H1Rinverse agonists)
OXRantagonists
MTRagonists
Miscellaneous
  • Antipsychotics (e.g., quetiapine, olanzapine, chlorpromazine)
  • Ashwagandha
  • Benzoctamine
  • Cannabinoids (e.g., cannabis, dronabinol (THC), nabilone)
  • Chamomile
  • Fenadiazole
  • Gabapentinoids (e.g., gabapentin, pregabalin, phenibut)
  • Hops
  • Lavender
  • Menthyl isovalerate
  • Niaprazine
  • Opioids (e.g., hydrocodone, oxycodone, morphine)
  • Passion flower
  • Scopolamine
  • Serotonin precursors (tryptophan, 5-HTP)
  • Sodium oxybate (GHB)
  • Sympatholytics (e.g., clonidine, guanfacine)
  • TCAs (e.g., amitriptyline, doxepin, trimipramine)
  • TeCAs (e.g., mirtazapine)
  • Theanine
  • Trazodone
  • Valnoctamide

Hallucinogens

Psychedelics
(5-HT2A
agonists)
Benzofurans
Lyserg‐
amides
Phenethyl‐
amines
Piperazines
Tryptamines
alpha-alkyltryptamines
x-DALT
x-DET
x-DiPT
x-DMT
  • 4,5-DHP-DMT
  • 2,N,N-TMT
  • 4-AcO-DMT
  • 4-HO-5-MeO-DMT
  • 4,N,N-TMT
  • 4-Propionyloxy-DMT
  • 5,6-diBr-DMT
  • 5-AcO-DMT
  • 5-Bromo-DMT
  • 5-MeO-2,N,N-TMT
  • 5-MeO-4,N,N-TMT
  • 5-MeO-α,N,N-TMT
  • 5-MeO-DMT
  • 5-N,N-TMT
  • 7,N,N-TMT
  • α,N,N-TMT
  • (Bufotenin) 5-HO-DMT
  • DMT
  • Norbaeocystin
  • (Psilocin) 4-HO-DMT
  • (Psilocybin) 4-PO-DMT
x-DPT
Ibogaine-related
x-MET
Sours: https://en.wikipedia.org/wiki/Doxylamine

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