Antihistamines – NHS

Antihistamines are medicines often used to relieve symptoms of allergies, such as hay fever, hives, conjunctivitis and reactions to insect bites or stings.

They’re also sometimes used to prevent motion sickness and as a short-term treatment for insomnia.

Most antihistamines can be bought from pharmacies and shops, but some are only available on prescription.

Types of antihistamine

There are many types of antihistamine.

They’re usually divided into 2 main groups:

They also come in several different forms – including tablets, capsules, liquids, syrups, creams, lotions, gels, eyedrops and nasal sprays.

Which type is best?

There’s not much evidence to suggest any particular antihistamine is better than any other at relieving allergy symptoms.

Some people find certain types work well for them and others do not. You may need to try several types to find one that works for you.

Non-drowsy antihistamines are generally the best option, as they’re less likely to make you feel sleepy. But types that make you feel sleepy may be better if your symptoms stop you sleeping.

Ask a pharmacist for advice if you’re unsure which medicine to try as not all antihistamines are suitable for everyone.

How to take antihistamines

Take your medicine as advised by the pharmacist or doctor, or as described in the leaflet that comes with it.

Before taking an antihistamine, you should know:

• how to take it – including whether it needs to be taken with water or food, or how to use it correctly (if eyedrops or a nasal spray)
• how much to take (the dose) – this can vary depending on things such as your age and weight
• when to take it – including how many times a day you can take it and when to take it (some types should be taken before bedtime)
• how long to take it for – some types can be used for a long time, but some are only recommended for a few days
• what to do if you miss a dose or take too much (overdose)

The advice varies depending on the exact medicine you’re taking. If you’re not sure how to take your medicine, ask a pharmacist.

Side effects of antihistamines

Like all medicines, antihistamines can cause side effects.

Side effects of antihistamines that make you drowsy can include:

• sleepiness (drowsiness) and reduced co-ordination, reaction speed and judgement – do not drive or use machinery after taking these antihistamines
• dry mouth
• blurred vision
• difficulty peeing

Side effects of non-drowsy antihistamines can include:

• headache
• dry mouth
• feeling sick
• drowsiness – although this is less common than with older types of antihistamines

Check the leaflet that comes with your medicine for a full list of possible side effects and advice about when to get medical help.

If you think your medicine has caused an unwanted side effect, you can report it through the Yellow Card Scheme.

Taking antihistamines with other medicines, food or alcohol

Speak to a pharmacist or GP before taking antihistamines if you’re already taking other medicines.

There may be a risk the medicines do not mix, which could stop either from working properly or increase the risk of side effects.

Examples of medicines that could cause problems if taken with antihistamines include some types of:

Try not to drink alcohol while taking an antihistamine, particularly if it’s a type that makes you drowsy, as it can increase the chances of it making you feel sleepy.

Food and other drinks do not affect most antihistamines, but check the leaflet that comes with your medicine to make sure.

Who can take antihistamines

Most people can safely take antihistamines.

But speak to a pharmacist or GP for advice if you:

Some antihistamines may not be suitable in these cases. A pharmacist or doctor can recommend one that’s best for you.

Always read the leaflet that comes with your medicine to check it’s safe for you before taking it or giving it to your child.

How antihistamines work

Antihistamines block the effects of a substance called histamine in your body.

Histamine is normally released when your body detects something harmful, such as an infection. It causes blood vessels to expand and the skin to swell, which helps protect the body.

But in people with allergies, the body mistakes something harmless – such as pollen, animal hair or house dust – for a threat and produces histamine. The histamine causes an allergic reaction with unpleasant symptoms including itchy, watering eyes, a running or blocked nose, sneezing and skin rashes.

Antihistamines help stop this happening if you take them before you come into contact with the substance you’re allergic to. Or they can reduce the severity of symptoms if you take them afterwards.

Find out more about your medicine

The leaflet that comes in the packet with your medicine will have detailed information about it, including how to take it and what side effects you might get.

If you no longer have the leaflet that came with your medicine, you can search for an online version of it using our medicines guide.

You may also find information on individual antihistamines on these websites:

Community content from HealthUnlocked

Page last reviewed: 28 February 2020
Next review due: 28 February 2023

Benadryl for Migraine – 19 Important Questions and Answers You Need to Know

This post may contain affiliate links. Migraine Strong, as an Amazon Affiliate, makes a small percentage from qualified sales made through affiliate links at no cost to you.

One of the most common questions people with migraine have is, “what can I take to get rid of this migraine attack that is over-the-counter.” Another inquiry is about what to do when their usual acute medication is inconsistent. They are often surprised by hearing that Benadryl for migraine is often helpful.

This can be music to their ears as many have easy access to this common, inexpensive medication that is in so many medicine cabinets. For some, it has been their so long they need to check the expiration date!

The goal of this article is to give you clear, concise information about how Benadryl may or may not be appropriate for you and your aching head.

To help make this article as practical as possible, I obtained many of the questions below from our peppy and eager-for-information private Facebook group.  If you are not already a member, please consider joining us.  

While Migraine Strong writes about the latest in migraine treatments, this is not medical advice. We are patient educators and all information you read should be discussed with your doctor.

How Benadryl works, in general:

Benadryl is a popular brand name for diphenhydramine. There are many other brand names as well as generic diphenhydramine available on the market.  Since Benadryl is a household name here in the US, I will use it interchangeably with its chemical name. Please note that in other countries, diphenhydramine many not be sold under the same brand name.

People reach for Benadryl primarily because it’s an effective first-generation antihistamine. Histamine is a naturally-occurring substance made by our bodies. It is necessary for our health and wellbeing, but it can get out of balance and cause trouble. Surges of histamine are the main culprit in allergic reactions. Benadryl is commonly suggested by pharmacists and doctors to suppress the histamine response and for relief of symptoms.

#AD

Diphenhydramine is both an antihistamine and anticholinergic drug

Benadryl’s effects are mainly from blocking two substances made by your body. It blocks histamine from attaching to cell receptors and causing changes in the cell that give us the negative symptoms we are trying to remedy. This is especially important during allergic reactions.

Histamine is a neurotransmitter that is excitatory. As you may already know, the migraine brain is already overly responsive to everyday stimulation, so having too much histamine may further exaggerate your symptoms.

Biochemically, Benadryl also acts to block the uptake of serotonin.  This can lead to sleepiness as well as other welcomed or unwelcomed side effects.

The other substance it blocks is acetylcholine thereby putting this medication in the anticholinergic category. This fact will be discussed later when we review a controversial topic surrounding Benadryl. When this medication blocks acetylcholine you get drying effects that are often helpful for relieving up runny noses and watery eyes but can also lead to dry mouth.

Diphenhydramine has a sedating effect for many because of the dual action of blocking histamine and acetylcholine. For some people it can also cause brain fog or the feeling of being “out of it” or hung-over.

Some popular nighttime pain relievers like Tylenol PM, Advil PM and Aleve PM are a combination of diphenhydramine and their name-brand pain reliever. It has been observed for a long time that combining Benadryl with analgesics boosts the pain-relieving effect.  More on this key fact later.

What does Benadryl do for migraine, specifically?

It has been known for a long time that many people with migraine have trouble with excessive histamine. Whether too much histamine is produced or too little is metabolized, we do not know but it is certainly part of the problem for many of us.

Taking Benadryl for headache and migraine can help in 3 possible ways-

1- The antihistamine action blocks circulating histamine from attaching to cells and causing negative effects like swelling of blood vessels. Also, histamine in the brain promotes wakefulness so blocking this perky chemical messenger may help calm our nervous system.

2- Benadryl provides a welcomed soothing effect for the brain through blocking acetylcholine in addition to histamine. For many of us, sleep or at the very least, rest, is a key part of recovering from an attack. Many people know that they must get at least a short sleep to finally end the attack.  Sometimes it’s Benadryl that comes to the rescue.

3- Benadryl can boost the effectiveness of some medications.  I’ve never gotten a good explanation of how it happens, but Benadryl has a known effect of boosting the effectiveness of some medications it is taken with. Drug makers know this as it’s paired with analgesics and cold medications for nighttime sleep. It is often suggested to couple Benadryl with other acute migraine medications to enhance the speed and effectiveness of the primary treatment. Since it can interact with some medications in a good way it can also interact in a bad way so a pharmacist or doctor should be consulted before you use Benadryl for headache and migraine relief.

Cyproheptadine – A popular migraine preventive for kids

Cyproheptadine (brand name Periactin) is considered a first-line preventive for some kids who need a migraine preventive. During one of the Migraine World Summits, Dr. Christopher Oakley, a pediatric neurologist specializing in headache disorders spoke about how effective it can be for his young migraine patients. I have heard it described as a more powerful Benadryl with some light Zoloft qualities. The description fits. Like Benadryl, it is a first-generation antihistamine, an anticholinergic (blocks acetylcholine) and also has a mild serotonin-blocking effects.

Frequently Asked Questions about Benadryl for headaches and migraine

1- I get agitated and feel terrible from Benadryl.  Why is that? 

There is very little published information about a known side effects that some people have to diphenhydramine and other first-generation antihistamines. While most people experience sedation from Benadryl, some people experience the opposite, “paradoxical” reaction. Some research suggests that this is due to genetics.

For some, it’s mild jumpiness and an acceptable trade-off for migraine relief whereas other people feel too agitated and jittery or “wired,” and prefer to not use the medication.

According to several sites, side effects of Benadryl may include: dry mucous membranes, mood changes (feeling agitated), drowsiness, constipation, increased heart rate, irregular heartbeat, dizziness, difficulty urinating and stomach upset.

If you think you are having negative side effects from diphenhydramine, call your pharmacist or doctor.

2- Why do I get crazy restless legs sometimes and not other times?

Restless Leg Syndrome (RLS) is known to be worsened in some people by taking Benadryl.  Personally, I have mild RLS but when I was pregnant it became awful certain times but was fine other times.

As people with migraine, we already know we are sensitive to even mild changes in the balance of neurotransmitters.  I urge you to read this article about restless leg syndrome.  My takeaway from it is that many things influence our neurotransmitter balance and sometimes it’s just “off” enough for that creep-crawly feeling to ruin our night. 

3- Benadryl for Vestibular Migraine (VM)- Does it help dizziness, disequilibrium, vertigo and other vestibular symptoms?

If you think the research on migraine is lacking, the research on subtypes of migraine is even worse. It’s no surprise that there aren’t any good studies looking at Benadryl for vestibular migraine.  However, there is some data that may be helpful as it has shaped recommendations from some prominent doctors specializing in the treatment of vestibular disorders including vestibular migraine.

Some of the information is from studies on motion sickness and antihistamines. As mentioned earlier, Benadryl effects acetylcholine. This substance is a known vestibular neurotransmitter (chemical messenger). Histamine may be a vestibular neurotransmitter and play a role in the vestibular system.  Limiting both substances by first-generation antihistamines like Benadryl may be helpful for some people with motion sickness.  The second-generation antihistamines like citerizine (Zyrtec), loratadine (Claritin) and fexofenadine  (Allegra) are not anticholinergic medications and do not cross the blood-brain barrier. They have not been shown to be effective for motion sickness.

Dr. Timothy Hain, a prominent expert in VM and other vestibular disorders, considers the first-generation antihistamines effective vestibular suppressants and potentially helpful for some of his patients. His article on drug management of vestibular migraine has excellent information. Anecdotally, in social media we do not see many people reporting success with antihistamines. Dr, Hain says they are ineffective when the symptoms already start so maybe this is why. Perhaps Benadryl for vestibular migraine would be helpful to preempt an anticipated attack.  

4- Why Does Benadryl work for migraine when other anti-histamines don’t work?

The common, over-the-counter antihistamines that are marketed for allergy fall into 2 categories.   Diphenhydramine is in the category of first-generation antihistamines.  Others in that category like Dramamine dimenhydrinate (Dramamine), meclizine (Bonine) and doxylamine succinate (NyQuil) may also be effective for migraine, headache and vestibular symptoms. These medications act centrally as they cross the blood-brain barrier and can be more helpful for migraine. As discussed previously, blocking histamine and acetylcholine in the nervous system seem to be what makes them helpful in migraine and other conditions.

The other category of antihistamines, called second-generation antihistamines, do not cross the blood-brain barrier and are not anticholinergics. Examples are citerizine (Zyrtec), fexofenadine (Allegra) and loratadine (Claritin). These can be very helpful for seasonal allergies.  Since they do not cross the blood-brain barrier they do not have the same possibly helpful effect as the first-generation antihistamines. They also do not have the same side effect profile.

5- Is Benadryl for migraine considered a preventive or acute treatment?

When doctors suggest using Benadryl for headache and migraine, it is typically done for acute treatment. There aren’t good studies to support using first-generation antihistamines as migraine preventives. Later, we will discuss the recent controversy about frequent use of diphenhydramine and similar medications.

We have a resource loaded with excellent information on migraine preventives if you think you are at the point of needing to talk to your doctor about them.

6- How about Benadryl for migraine nausea?

Published research literature suggests that diphenhydramine may be helpful for nausea caused by vestibular symptoms like vertigo and dizziness. There is speculation that that sedative effect of Benadryl may also help the migraine nausea.. 

7- Can Benadryl give you rebound?

Benadryl is not on the list of medications that contribute to the risk of rebound / medication-overuse headache. We have several resources to help our readers understand if they are in rebound and how they can help escape the difficult trap.

8- I’ve gotten intravenous Benadryl in cocktails at the hospital.  Why is that?

It has been known for a long time that IV fluids, Benadryl, an analgesic or triptan and an anti-emetic like Compazine can be an effective “cocktail” to break a bad attack. The Benadryl may be given for the reasons discussed earlier as well as to minimize side effects from the IV anti-emetic. Antiemetics are often very helpful in breaking a bad migraine attack (with or without nausea) but sometimes they have very unpleasant side effects.

9- When taking Benadryl for migraine, what should I know to help with the attack?

**As stated earlier, this is NOT medical advice and any medications you take should be discussed with your physician.  The following is based on personal experience and observation**

As you know, combining certain medications potentiates (boosts) the effect of the other.   This is why some drug labels say “do not take with ____.”  Some medications, when taken and metabolized together have a stronger effect than when they are taken separately.  Benadryl is known to do this with quite a few medications including analgesics like acetaminophen (Tylenol) and non-steroidal anti-inflammatories like ibuprofen (Advil), aspirin, and naproxen (Aleve).

It was suggested to me by more than one healthcare provider that to “give the migraine a bigger punch and knock it out,” I can combine my triptan with 1 or 2 Aleve tablets and Benadryl.  As far as how much Benadryl for migraine is effective, I was not told specifically. I take 1, 25mg tablet.

After years of reading about this topic including watching each year of the Migraine World Summit and scrolling through social media many hours each week, the above combination of three medications is often cited.  This is an example of the potentiating (boosting) effect of combining medications may be helpful. Is it right for you?  I do not know.   You MUST ask your doctor for specific medical advice. This article is not medical advice.

10- Can Benadryl be helpful on its own or does it have to be combined with other medications?

From all that I have read, it seems that Benadryl for headache and migraine (non-vestibular) is effective when it’s working synergistically with an analgesic and/or a triptan. See my answer above regarding how I take Benadryl for migraine.

11- What is the latest research on Benadryl and dementia?

As evidenced in threads in our Facebook group and others, concern about Benadryl and dementia is making many people pause before reaching for it. The fairly recent news has made me hesitate, too. So, I took a deep dive into this issue and and happy with what I have to share with you.

Why the fuss?

In 2015 a population study was done that concluded that higher cumulative use of strong anticholinergic medications is associated with an increased risk for dementia. This was not specifically a study of a medication or antihistamines. It was a look at dementia associated with the known side effect that anticholinergics have on clear thinking while taking them. Studies like this are excellent to bring attention to observed patterns and bring about further research.

Additional data in 2018 and 2019

In a study done in 2019, There were no significant increases in risk associated with antihistamines. The dementia was associated with other anticholinergic medications.

In the WebMD review of the 2019 study they specifically state, “There was no increased risk of dementia among patients who took other types of anticholinergic drugs such as antihistamines (Benadryl) and gastrointestinal drugs.” The article further states, “The researchers noted that this was an observational study, so it cannot prove that anticholinergic drugs help cause dementia. For example, it’s possible that the drugs were prescribed to dementia patients to help treat very early symptoms of the disease.” 

The risk-benefit analysis- What to do now?

The studies done in 2018 and 2019 are helpful for those of us who find Benadryl for headache and migraine helpful.   Quite honestly, I’m still a little spooked by the 2015 study as I don’t want to interfere with the flow of my acetylcholine any more than necessary. But, being debilitated by migraine and/or the consequences of poor sleep may be equally bad for my brain. It’s a conundrum.

So, what to do. A risk-benefit analysis. You look at the risks and the how likely the risks are to happen. And, you look at the benefits and how likely they are to happen.  Then you make a decision.  Sorry if this is too obvious, but I must state that it is very important to look at the risks of choosing to not treat a condition.

If we choose to not effectively treat an attack, what is the cost of not treating to our immediate health as well as our long-term health.  Personally, I consider the physical, mental, emotional and social cost of being moderately or severely impaired by each migraine attack. 

Since I also occasionally take Benadryl to help me sleep when away from home, I look at the toll that a sleepless night may have on me and those around me. My personal decision is to accept the possible risk for the upside of getting needed rest, feeling well and joyfully fully participating in my life. 

This decision process is important to go through in your own mind and again with your doctor.  Of all the literature that I read while researching this topic, this article written by a medical doctor for GoodRx about whether or not to take Benadryl was my favorite.  He discusses minimizing the medication and understanding other options.

12- What about long-term safety of regular use of Benadryl?

In spite of this medication being available since the 1940s, there is very little published data about the long-term effects of using it.  The dementia risks as well as tolerance to diphenhydramine have been discussed above.

All medications, even those deemed very safe for the general public, come with some risk as we are all genetically and behaviorally unique. 

13- If migraine responds to an allergy med, does that mean migraine is related to allergy?

Allergies can certainly trigger migraine attacks in some people.   Environmental allergies and food sensitivities causing an immune response can contribute to your migraine attack threshold.  For more about that, please read about The Bucket Theory

With that said, migraine is a complex neurological condition linked to genetics.  Your genes could make you more prone to imbalances in neurochemistry.  These imbalances may be helped by antihistamines and other medications.  But, that does not mean that the neurological condition is related to allergy.

14- Can you build up tolerance to Benadryl?

There is quite a lot of supporting evidence as well as anecdotal reporting of people building tolerance to Benadryl as well as other types of antihistamines.

15- What is the Benadryl for migraine dose?

The directions on the package should be followed.  My package at home says the dosage for people 12 years and above is 1-2, 25mg tablets.

16- Should it only be taken at night since it can make you drowsy?

Caution regarding drowsiness is given by the manufacturers. So it is best to see how your body reacts if you are taking Benadryl when you cannot rest or sleep. Of course, some people do not experience drowsiness at all and others may feel “wired” from it.  The paradoxical reaction was discussed above.

17- Can you take Benadryl for migraine during pregnancy and lactation?

According to the FDA, Benadryl is a Category B medication.  Anecdotally, many moms active in social media have been appreciative of having both Benadryl and Tylenol to use during their pregnancies. Taking any medication must be approved by your obstetrician. 

Regarding breastfeeding, Benadryl crosses into the breastmilk and can be consumed by the baby. According to this current publication from the NCBI:  “Small, occasional doses of diphenhydramine would not be expected to cause any adverse effects in breastfed infants. Larger doses or more prolonged use may cause effects in the infant or decrease the milk supply, particularly in combination with a sympathomimetic such as pseudoephedrine or before lactation is well established. Single bedtime doses after the last feeding of the day may be adequate for many women and will minimize any effects of the drug.”  ** I know it’s getting old, but I repeat- this is not medical advice.  Consult your doctor. **

18- Can Benadryl give you a migraine?

There is nothing in the literature nor have I heard many anecdotes of Benadryl triggering migraine. That does not mean that an individual cannot be triggered by this or any other medication. It’s also possible that the ingredients along with diphenhydramine can be the culprit. For instance, some people take Benadryl gelcaps made with gelatin.  Gelatin may be a problem for some of us. Fortunately, diphenhydramine is available in many forms.

19- How can I find substitute diphenhydramine outside of the US?

As stated earlier, there is inconsistency between brand names from country to country.  In this article we are discussing Benadryl for headache and migraine when the actual medication is diphenhydramine.   Outside of the United States make sure that what you are taking is diphenhydramine.  If it’s not available, ask your pharmacist or doctor about other first-generation antihistamines and do a quick internet search to find out more.

We have quite a few people from Australia in our Facebook group and they have saved a step for their fellow Aussies with a list of products containing diphenhydramine.   

Amazon and the Amazon logo are trademarks of Amazon.com, Inc, or its affiliates.

Antihistamine (Oral Route, Parenteral Route, Rectal Route) Side Effects

Side Effects

Drug information provided by: IBM Micromedex

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur:

Less common or rare

1. 
   Abdominal or stomach pain
2. 
   burning
3. 
   chills
4. 
   clay-colored stools or dark urine
5. 
   cough
6. 
   diarrhea
7. 
   difficulty swallowing
8. 
   dizziness
9. 
   fast or irregular heartbeat
10. 
    fever
11. 
    headache
12. 
    hives
13. 
    itching
14. 
    prickly sensations
15. 
    puffiness or swelling of the eyelids or around the eyes, face, lips or tongue
16. 
    redness of skin
17. 
    seizures
18. 
    shortness of breath
19. 
    skin rash
20. 
    swelling
21. 
    tightness in chest
22. 
    tingling
23. 
    unusual tiredness or weakness
24. 
    wheezing

Check with your doctor as soon as possible if any of the following side effects occur:

Less common or rare

1. 
   Sore throat
2. 
   unusual bleeding or bruising
3. 
   unusual tiredness or weakness

Symptoms of overdose

1. 
   Clumsiness or unsteadiness
2. 
   convulsions (seizures)
3. 
   drowsiness (severe)
4. 
   dryness of mouth, nose, or throat (severe)
5. 
   feeling faint
6. 
   flushing or redness of face
7. 
   hallucinations (seeing, hearing, or feeling things that are not there)
8. 
   shortness of breath or troubled breathing
9. 
   trouble in sleeping

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

More common

1. 
   Drowsiness
2. 
   dry mouth, nose, or throat
3. 
   gastrointestinal upset, stomach pain, or nausea
4. 
   headache
5. 
   increased appetite and weight gain
6. 
   thickening of mucus

Less common or rare

1. 
   Acid or sour stomach
2. 
   belching
3. 
   blurred vision or any change in vision
4. 
   body aches or pain
5. 
   clumsiness or unsteadiness
6. 
   confusion (not with diphenhydramine)
7. 
   congestion
8. 
   constipation
9. 
   cough
10. 
    diarrhea
11. 
    difficult or painful urination
12. 
    difficulty in moving
13. 
    difficult or painful menstruation
14. 
    dizziness (not with brompheniramine or hydroxyzine)
15. 
    drowsiness (with high doses of desloratadine and loratadine)
16. 
    dryness of mouth, nose, or throat
17. 
    early menstruation
18. 
    fast heartbeat
19. 
    fever
20. 
    heartburn
21. 
    hoarseness
22. 
    increased sensitivity of skin to sun
23. 
    increased sweating
24. 
    indigestion
25. 
    loss of appetite
26. 
    joint pain
27. 
    muscle aching or cramping
28. 
    muscle pains or stiffness
29. 
    nausea
30. 
    nightmares (not with azatadine, chlorpheniramine, cyproheptadine, desloratadine, hydroxyzine, or loratadine)
31. 
    ringing or buzzing in ears
32. 
    runny nose
33. 
    skin rash
34. 
    swollen joints
35. 
    stomach discomfort, upset or pain
36. 
    tender swollen glands in neck
37. 
    tremor
38. 
    unusual excitement, nervousness, restlessness, or irritability
39. 
    vomiting

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

Portions of this document last updated: Nov. 01, 2021

Copyright © 2021 IBM Watson Health. All rights reserved. Information is for End User’s use only and may not be sold, redistributed or otherwise used for commercial purposes.

.

Diphenhydramine as adjuvant therapy for acute migraine. An ED-based randomized clinical trial

Ann Emerg Med. Author manuscript; available in PMC 2017 Jan 1.

Published in final edited form as:

PMCID: PMC4695376

NIHMSID: NIHMS719422

, MD, MS,¹, MD,¹, MD,¹, PharmD,², MD,¹, PhD,¹ and , MD¹

Benjamin W Friedman

¹Department of Emergency Medicine, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY, USA

Lisa Cabral

¹Department of Emergency Medicine, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY, USA

Victoria Adewunmi

¹Department of Emergency Medicine, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY, USA

Clemencia Solorzano

²Pharmacy Department, Montefiore Medical Center, Bronx, NY, USA

David Esses

¹Department of Emergency Medicine, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY, USA

Polly E Bijur

¹Department of Emergency Medicine, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY, USA

E John Gallagher

¹Department of Emergency Medicine, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY, USA

¹Department of Emergency Medicine, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY, USA

²Pharmacy Department, Montefiore Medical Center, Bronx, NY, USA

Corresponding author: Benjamin W. Friedman, MD, MS, Department of Emergency Medicine, Montefiore Medical Center, Albert Einstein College of Medicine, 111 East 210^th Street, Bronx, NY, 10467, moc.liamg@dmnamdeirfwb, (718) 920-6626The publisher’s final edited version of this article is available at Ann Emerg MedSee other articles in PMC that cite the published article.

Abstract

Background

More than one million patients present to US emergency departments (ED) annually seeking care for acute migraine. Parenteral anti-histamines have long been used in combination with anti-dopaminergics such as metoclopramide to treat acute migraine in the ED. High quality data supporting this practice do not exist. We determined whether administration of diphenhydramine 50mg IV + metoclopramide 10mg IV resulted in greater rates of sustained headache relief than placebo+ metoclopramide 10mg IV.

Methods

This was a randomized, double-blind clinical trial comparing two active treatments for acute migraine in an ED. Eligible patients were adults younger than 65 years presenting with an acute moderate or severe headache meeting International Classification of Headache Disorders-2 migraine criteria. Patients were stratified based on presence or absence of allergic symptoms. The primary outcome was sustained headache relief, defined as achieving a headache level of mild or none within two hours of medication administration, and maintaining this level of relief without use of any additional headache medication for 48 hours. Secondary efficacy outcomes include mean improvement on a 0 to 10 verbal scale between baseline and one hour, the frequency with which subjects indicated they would want the same medication the next time they present to the ED with migraine, and the ED throughput time. Sample size calculation using a 2-sided alpha of 0.05, a beta of 0.20 and a 15% difference between study arms determined the need for 374 patients. An interim analysis was conducted when data were available for 200 subjects.

Results

420 patients were approached for participation. 208 eligible patients consented to participate and were randomized. At the planned interim analysis, the data safety monitoring committee recommended that the study be halted for futility. Baseline characteristics were comparable between the groups. 14% (29/208) of the sample reported allergic symptoms. Of patients randomized to diphenhydramine, 40% (40/100) reported sustained relief at 48 hours, as did 37% (38/103) of patients randomized to placebo (95%CI for difference of 3%: −10, 16%). One hour after medication administration, those randomized to diphenhydramine improved by a mean of 5.1 on the 0 to 10 scale versus 4.8 for those randomized to placebo (95%CI for difference of 0.3: −0.6, 1.1). 85% (84/99) of the patients in the diphenhydramine arm reported they would want the same medication combination during a subsequent ED visit, as did 76% (77/102) of those who received placebo (95%CI for difference of 9%: −2, 20%). Median ED length of stay was 122 minutes (IQR: 84, 180) in the diphenhydramine group and 139 minutes (IQR: 90, 235) in the placebo arm. Rates of side effects, including akathisia, were comparable between the groups.

Conclusions

Intravenous diphenhydramine, when administered as adjuvant therapy with metoclopramide, does not improve migraine outcomes.

Migraine, a recurrent disorder characterized by acute headaches, causes more than one million visits to US emergency departments (EDs) annually.¹ Parenteral anti-histamines including diphenhydramine and promethazine are commonly administered to migraine patients in the ED,¹ yet high quality data to support efficacy do not exist. Associations among migraine, histamine, and allergy have been reported². Elevated levels of serum histamine and IgE have been reported in patients with a history of migraine when compared to healthy controls.² Among patients with a history of migraine, there is greater elevation of histamine levels during an acute migraine than during the inter-ictal period. ² This tends to be more marked among migraine patients with a history of allergy or atopy than those without such a history.² Prevalence of migraine is higher among those patients with a history of allergic rhinitis than matched controls.^3,4 In patients with a history of migraine, an acute headache can be induced by histamine infusion, which can be blocked by co-administration of an antihistamine.⁵ These data are consistent with the hypothesis that histamine contributes to migraine pathogenesis, particularly among patients who are prone to allergy, and that centrally-acting anti-histamines may be a useful treatment for acute migraine.

Despite the very large number of migraine patients who present to EDs annually, there is substantial variability in treatment.¹ More than twenty different parenteral medications or combinations of medications are commonly used to treat acute migraine in this setting, yet the goal of sustained headache relief remains elusive. ^1,6 When anti-histamines are used to treat acute migraine in the ED, this is usually done as part of a two-drug combination, with the goals of increasing efficacy and decreasing adverse events such as akathisia.¹ However, there are no high quality data available to support or refute this practice. Therefore, we conducted a randomized trial to determine the efficacy of co-administering a centrally-acting anti-histamine with standard migraine therapy. Specifically, we wished to test the following hypothesis: In a population of patients presenting to an ED with acute migraine rated as moderate or severe intensity, diphenhydramine 50mg IV + metoclopramide 10mg IV results in greater rates of sustained headache relief than placebo +metoclopramide 10mg IV.

Methods

Study design and setting

This was a randomized, double-blind clinical trial comparing two active treatments for acute migraine. Patients were enrolled upon presentation to the ED, followed for up to two hours in the ED, and then contacted by telephone 48 hours later to determine headache status. This trial was registered at http://www.clinicaltrials.gov ({“type”:”clinical-trial”,”attrs”:{“text”:”NCT01825941″,”term_id”:”NCT01825941″}}NCT01825941). The Albert Einstein College of Medicine IRB provided ethical oversight.

This study was performed in the ED of Montefiore Medical Center, an urban ED that receives 100,000 adult visits annually. Salaried, full-time, bilingual (English and Spanish) technician-level research associates, who gather data for studies under the supervision of the principal investigators, staffed the ED 18–24 hours per day, seven days per week during the study period.

Selection of Participants

Eligible patients were adults younger than 65 years who presented with an acute moderate or severe headache meeting migraine criteria, as defined by the International Classification of Headache Disorders-2 (ICHD-2 1.1, migraine without aura)⁷. Patients who met criteria for Probable Migraine without Aura (ICHD-2 1.6.1) were also included, provided they had at least one similar headache previously. Status migrainosus, prolonged duration of headache (>72 hours), or early presentation (<4 hours) did not preclude participation. Patients were excluded if informed consent could not be obtained, the attending emergency physician suspected a secondary cause of headache or intended to obtain diagnostic imaging or a lumbar puncture, the maximum documented temperature prior to enrollment was ≥100.4 degrees F, for presence of a new objective neurologic abnormality, or allergy, intolerance, or contra-indication to the study medication. Because all investigational medications used in this study are classified as pregnancy category B and are commonly used for acute migraine in pregnant patients, and because there is a need for evidence-based treatment in pregnant patients, pregnancy did not exclude patients from participation in this study. We required the attending emergency physician’s permission to enroll their patient in this clinical trial.

Interventions

Patients were randomly allocated in a 1:1 ratio to one of the following two interventions:

1. Metoclopramide 10mg + diphenhydramine 50mg, infused intravenously over 15 minutes

2. Metoclopramide 10mg + saline placebo, infused intravenously over 15 minutes

To ensure a comparable number of atopic patients in each study arm, patients were stratified by symptoms of allergic nasal congestion as “allergic” or “not allergic”. Allergic symptoms were assessed using the Congestion Quantifier 5 instrument (Appendix).⁸ Patients were categorized as “allergic” if they scored >6 on this validated instrument.

Randomization was performed by the research pharmacist who generated two sequences (“allergic” and “not allergic”) in blocks of four using computer generated random number tables available at http://www.randomization.com. The pharmacist performed the randomization in a location removed from the ED and inaccessible to ED personnel. In an order determined by these random number tables, the pharmacist inserted medication into identical vials and placed these vials into sequentially numbered identical research bags. These research bags, which were maintained in a locked cabinet in the ED, were then used in a pre-specified order by the research team. Only the pharmacist knew an individual patient’s assignment. Every research bag contained two vials. The metoclopramide vial was as labeled by the manufacturer and contained 2cc of a 10mg/2cc solution of metoclopramide. The other vial was labeled as a research medication and contained 1ml of a clear solution, which consisted of either 50 milligrams of diphenhydramine or saline placebo. After a subject had been enrolled, the two vials from each research bag were placed in a 50cc bag of normal saline by a blinded nurse, which was administered as a slow intravenous drip over 15 minutes.

Methods of measurement

As a primary measure of headache intensity, we utilized a standardized ordinal headache intensity scale, in which subjects describe their headache as “severe”, “moderate”, “mild”, or “none”.⁹ Other measurement tools included a functional disability scale, in which subjects describe their headache-related disability as severe (“cannot get up from bed or stretcher”), moderate (“great deal of difficulty doing what I usually do and can only do very minor activities^”), mild (“little bit of difficulty doing what I usually do”), or none, and an 11-point verbal pain rating scale. ¹⁰ This latter scale asks subjects to assign their pain a number between 0 and 10, with 0 representing no pain and ten representing the worst pain imaginable. All of these measures are recommended for use in migraine research by the International Headache Society⁹.

After informed consent was obtained from the patient, a pain assessment was performed. The intravenous solution was then administered as an intravenous drip between time zero and fifteen minutes. Research associates ascertained the patient’s headache level every thirty minutes, and asked a more detailed series of questions regarding pain, functional limitations, and adverse events at one and two hours. If subjects requested more pain medication at or after one hour, they were administered additional medication at the discretion of the treating physician. A final pain assessment was performed by telephone 48 hours after randomization.

At the 48 hour phone call, we also assessed patient satisfaction with the investigational medication they received by asking them, “Would you wish to receive the same medication the next time you visit the ER with migraine?” This question allows patients to summarize succinctly the relative efficacy and tolerability of the medication.

Adverse effects were assessed one, two, and 48 hours after medication administration, using open-ended questions. Two specific, expected adverse effects, drowsiness and restlessness, were both assessed with three-item Likert questions. Acute akathisia, an unpleasant but self-limited reaction characterized by restlessness and anxiety, occurs commonly after administration of intravenous anti-dopaminergics such as metoclopramide. Although instruments have been developed to measure this phenomenon, we have found akathisia difficult to quantify using these instruments because the time of onset of akathisia is variable and typically aborts quickly and completely in response to intravenous therapeutics such as diphenhydramine.¹¹ Therefore, we attempted to capture this phenomenon through the use of other measures: 1) At the time of the 48 hour follow-up, we asked patients if they experienced “restlessness” at any time after receiving the medication. Those who reported that they were “very restless” were considered to have had akathisia. 2) Because diphenhydramine is the rescue medication of choice for akathisia in our ED, we recorded any off-protocol use of parenteral diphenhydramine in all study patients.

Outcome measures

The primary outcome was sustained headache relief. As per international criteria, this is defined as achieving a headache level of mild or none within two hours of medication administration, and maintaining that level of mild or none without the use of any additional headache medication for 48 consecutive hours post-treatment.⁹ Patients who received rescue medication were considered a primary outcome failure.

Secondary efficacy outcomes include the mean improvement in 0 to 10 pain scale between baseline and one hour, the frequency of use of additional anti-headache medication during the ED visit, the frequency of poor functional scores one hour after investigational medication administration, the ED throughput time, defined as time elapsed between medication administration and ED discharge, and the frequency with which subjects indicated they would wish to receive the same medication the next time they presented to the ED with migraine. The frequency of any adverse event was recorded, including the development of akathisia, and the frequency of drowsiness.

Primary Data Analysis

We collected and managed study data using REDCap electronic data capture tools hosted at Albert Einstein College of Medicine. All dichotomous outcomes were reported as frequencies with 95%CI. Absolute risk reduction and number needed to treat were also reported with 95%CI. Improvement in 0 to 10 pain score is reported as mean with 95%CI.

We used the following parameters to calculate the sample size: alpha of 0.05, beta of 0.20, a difference between the groups in the rate of sustained headache relief of 15% (48% in the placebo + metoclopramide arm estimated from prior studies,¹² and 63% in the diphenhydramine + metoclopramide arm). This difference of 15% is equivalent to a number needed to treat (NNT) of 6.67, which was chosen as a clinically relevant threshold by polling and averaging the responses of local clinical emergency physicians. Using these assumptions, we determined the need for 344 patients but intended to enroll 374 patients to account for patients lost to follow-up.

A planned interim analysis was conducted after we collected analyzable data on 200 patients. The purpose of the interim analysis was to determine if the study lacked conditional power. The following stopping rule, which was established prior to initiation of the trial, was implemented: If at the interim analysis, which was to take place slightly past the halfway point (200/374 patients), the absolute risk reduction was <7.5% (i.e., < 1/2 of the between-group difference in the sample size calculation), the study was to be halted. Because we did not intend to subject the interim data to a statistical analysis, the alpha of the final analysis was not adjusted.

Results

The study commenced in April, 2013 and continued for 21 months. An interim analysis was performed in December, 2014. At that time, the data monitoring committee recommended that the study be halted for futility. During the 21 study months, 420 patients were approached for participation and 208 were randomized (). Some attending physicians refused to allow their patients to be enrolled in this trial, usually because they felt uncomfortable administering metoclopramide without diphenhydramine (). Baseline characteristics were comparable between the groups (). Most participants reported severe headache at baseline, though more than 1/3 of our patients had not taken any medication for headache prior to ED presentation ().

CONSORT flow diagram

* One patient lost-to-follow-up received rescue medication in the ED. Therefore, we were able to count this participant as an outcome failure despite being unable to contact her at 48 hours.

Table 1

The primary outcome, sustained headache relief, was reported by 40/100 (40%, 95%CI: 31, 50%) patients randomized to diphenhydramine and 38/103 (37%, 95%CI: 28, 47%) of patients randomized to placebo (95%CI for difference of 3%: −10, 16%). Secondary outcomes are reported in . Despite rates of sustained headache freedom of less than 20% in both arms, more than 3/4rds of patients stated they would want to receive the same medication again (). Patients randomized to placebo had comparable ED throughput times (median 139 minutes, IQR: 90, 235 minutes) as those who received diphenhydramine (median 122 minutes, IQR: 84, 180 minutes) (p value by Mann-Whitney U was 0.53).

Table 2

Outcomes among all patients

Adverse events were comparable between the study arms (). Patients randomized to placebo did not report greater rates of restlessness nor were they more likely to require rescue doses of diphenhydramine. No patients reported unremitting muscle spasms or tremors.

Table 3

At baseline, fewer than 15% of our patients reported symptoms of allergy, as defined by a score of six or greater on the Congestion Quantifier instrument (). Among this subset, 7/15 (47%, 95%CI: 25, 70%) patients randomized to diphenhydramine reported sustained relief, as did 8/14 (57%, 95%CI: 33, 79%) patients randomized to placebo (95%CI for difference of 10%: −26, 47%). Among the allergic participants, more patients randomized to diphenhydramine reported satisfaction with the medication received, as reflected by desire to receive the same medication again for a recurrence of migraine ().

Table 4

Outcomes among patients deemed allergic

Limitations

This study was conducted in one urban ED serving a predominantly socio-economically depressed population. The impact of socio-economics on our study population is apparent in some of the data, such as the high frequency with which patients presented to the ED without having taken any medication for their migraine ().

When powering the study, we determined our hypothesized effect size by polling and averaging the responses of local emergency physicians as we were unable to identify an evidence-based minimum clinically significant decrease for our primary outcome (sustained headache relief). Therefore, an important assumption of our design may not reflect the widespread opinion of practicing emergency physicians. Specifically, we needed to observe an absolute 15% increase in the proportion of patients with headache relief at 48 hours; since other emergency physicians and patients might be satisfied with less efficacious treatments, the current trial only addresses adjuvant diphenhydramine lacking a large effect. As such, our findings may have less generalizability to some patients and clinicians. As with all clinical studies, individual physicians should interpret our data in context of which outcome and number needed to treat is most relevant for them and their individual patient—for example, some clinicians may see that 85% of participants who received diphenhydramine would want the same medication combination during a subsequent ED visit while only 76% of those who received placebo would want the same medication combination again. The changes in pain score from baseline to 1-hour are depicted by group and individually in the .

Outcome measures in the allergic sub-group were less encouraging about the potential for smaller, but plausibly important effects. Symptoms of allergy at baseline were relatively uncommon in this cohort. Fewer than 15% of all study participants were rated as allergic using a validated instrument. This limits our ability to comment on the efficacy of diphenhydramine within this population. Our data do not preclude the possibility of benefit, particularly because more patients who received diphenhydramine would want the same medication combination during a subsequent migraine attack. However, the point estimate of the primary outcome favored placebo, as did need for rescue medication. The improvement in 0 to 10 pain score between baseline and one hour was comparable.

Based on a stopping rule established before this study began, the study monitoring committee recommended halting the study after 208 patients were enrolled, slightly past the halfway point of the trial. It is possible that the findings in the first half of the sample were not representative and continued data collection would have revealed a clinically significant difference between groups but that is extremely unlikely given the large size of the interim sample and the small difference between groups.

Discussion

In this ED-based, double-blind, randomized clinical trial of treatment for acute migraine, we found that adding 50mg of intravenous diphenhydramine to metoclopramide 10mg did not improve outcomes when compared to metoclopramide alone. Diphenhydramine also did not decrease the rate of akathisia. Our results are generally in keeping with other ED-based acute migraine clinical trials, which have shown that although substantial initial relief is generally obtainable regardless of which parenteral intervention is used, sustained relief for 48 hours beyond the ED visit is more difficult to achieve.^12–17

Given the frequency with which anti-histamines are used to treat acute migraine, there is a surprising paucity of experimental data on this topic. Existing data comes from small clinical trials¹⁸ or non-experimental designs,¹⁹ which have reached different conclusions. To our knowledge, this is the first adequately powered randomized clinical trial to demonstrate that diphenhydramine does not improve outcomes in an unselected population of ED patients presenting with acute moderate to severe migraine.

Theories of an allergic basis of migraine date back nearly 100 years^20,21. Food allergy in particular has been linked to migraine and food elimination diets have purportedly cured migraine.²² Experimentally designed studies have reached differing conclusions, but suggest that targeted food elimination diets may be of mild to modest benefit for selected allergic migraine patients. ^23,24,25,26 Among our migraine patients with concomitant symptoms of allergic rhinitis, diphenhydramine did not appear to confer any benefit over metoclopramide alone.

Diphenhydramine is often given prophylactically to blunt extra-pyramidal side effects (mostly akathisia) of intravenous anti-dopaminergics. While this is an evidence-based strategy for patients given intravenous prochlorperazine,^10,27 existing data do not support the use of diphenhydramine in this role for patients given intravenous metoclopramide.^11,28 Similarly, in this study, the rate of akathisia was comparable regardless of whether patients received 50mg intravenous diphenhydramine or placebo. While only 8% of patients who received metoclopramide + placebo experienced akathisia, this is frequent enough that physicians should caution patients that this side effect may occur with this medication.

Other extra-pyramidal side effects were uncommon. As far as we could determine using structured telephone follow-up at 48 hours, there were no occurrences of other dystonic reactions or tardive dyskinesia in either study arm. Tardive dyskinesia in particular is a rare extra-pyramidal side effect, typically associated with longer exposure to anti-dopaminergic agents. Nonetheless, this study of only 208 patients is ill-suited to comment on the incidence of this rare irreversible motor disorder. To the best of our knowledge, tardive dyskinesia has never occurred after a single dose of intravenous metoclopramide.²⁹

We were somewhat surprised to discover that length of stay in the ED was not greater among those patients who received 50mg of intravenous diphenhydramine. Drowsiness is a known side effect of diphenhydramine. It is therefore unclear why study participants who received diphenhydramine did not have longer ED dwell times or report more functional impairment at two hours than those allocated to placebo. Our findings, however, are consistent with other studies of centrally-acting anti-dopaminergics combined with diphenhydramine, in which drowsiness or functional impairment at the time of ED discharge among those who received the centrally acting agents was no greater than among those who received sumatriptan, a medication not expected to cause drowsiness.^13,30

In conclusion, there is no reason to co-administer intravenous diphenhydramine with metoclopramide routinely for ED patients with acute migraine.

Acknowledgments

This publication was supported in part by the CTSA Grant UL1 TR001073, TL1 TR001072, KL2 TR001071 from the National Center for Advancing Translational Sciences (NCATS), a component of the National Institutes of Health (NIH).

Appendix. Congestion Quantifier 5 Instrument

⁸

During the past week, how often….

1. Did you have nasal stuffiness, blockage or congestion

2. Did you have to breathe through your mouth because you couldn’t breathe through your nose

3. Did you have difficulty completely clearing your nose even after repeated blowing

4. Did you awaken in the morning with nasal stuffiness, blockage, or congestion

5. How often was your sleep affected by nasal stuffiness, blockage, or congestion

None of the time=0

A little of the time=1

Some of the time=2

Most of the time=3

All of the time=4

Score of ≥6= positive

Figure

Group and individual change in pain scores following treatment with metoclopramide plus either placebo or diphenhydramine

The box plots show the median, 25^th and 75^th percentiles for the baseline pain score and the pain score measured one hour after treatment for each of the groups. The waterfall plots show the individual change in pain score for subjects in each group from baseline to one hour grouped by baseline pain score, (dots indicate no change, lines going above baseline indicate a worsening). The numbers above the waterfall plot are given to indicate every 10 patients.

Appendix Figure

Box and whiskers plot of the percent improvement in 0 to 10 pain score between baseline and one hour (Improvement in 0–10 score/Baseline score). 1.0 signifies complete improvement. 0 signifies no improvement. Negative score indicate worsening.

Appendix Figure

Line graph representing each participant’s experience at baseline and one hour later. The origin of the line depicts the 0 to 10 pain score at baseline. The terminus of the line depicts the 0 to 10 pain score at one hour. The graphs are sorted by baseline pain score. Thus, lines that rise unexpectedly depict participants whose pain worsened during the study period.

Footnotes

We will present this study at the American Headache Society national meeting in Washington DC on 6/20/2015

We have no conflicts of interest to report.

BWF, CS, DE, PEB, EJG conceived the study and designed the trial. BWF, DE supervised the conduct of the trial and data collection. BWF, LC, VA managed the data, including quality control. BWF analyzed the data; PEB chaired the data oversight committee. BWF drafted the manuscript, and all authors contributed substantially to its revision. BWF takes responsibility for the paper as a whole.

Publisher’s Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

References

1. Friedman BW, West J, Vinson DR, Minen MT, Restivo A, Gallagher EJ. Current management of migraine in US emergency departments: An analysis of the National Hospital Ambulatory Medical Care Survey. Cephalalgia. 2014 [PubMed] [Google Scholar]2. Gazerani P, Pourpak Z, Ahmadiani A, Hemmati A, Kazemnejad A. A Correlation between Migraine, Histamine and Immunoglobulin E. Iran J Allergy Asthma Immunol. 2003;2:17–24. [PubMed] [Google Scholar]3. Aamodt AH, Stovner LJ, Langhammer A, Hagen K, Zwart JA. Is headache related to asthma, hay fever, and chronic bronchitis? The Head-HUNT Study. Headache. 2007;47:204–12. [PubMed] [Google Scholar]4. Ku M, Silverman B, Prifti N, Ying W, Persaud Y, Schneider A. Prevalence of migraine headaches in patients with allergic rhinitis. Ann Allergy Asthma Immunol. 2006;97:226–30. [PubMed] [Google Scholar]6. Friedman BW, Bijur PE, Lipton RB. Standardizing emergency department-based migraine research: an analysis of commonly used clinical trial outcome measures. Acad Emerg Med. 2010;17:72–9. [PMC free article] [PubMed] [Google Scholar]7. Classification and diagnostic criteria for headache disorders, cranial neuralgias and facial pain. Headache Classification Committee of the International Headache Society. Cephalalgia. 1988;8(Suppl 7):1–96. [PubMed] [Google Scholar]8. Stull DE, Meltzer EO, Krouse JH, et al. The congestion quantifier five-item test for nasal congestion: refinement of the congestion quantifier seven-item test. American journal of rhinology & allergy. 2010;24:34–8. [PubMed] [Google Scholar]9. Tfelt-Hansen P, Block G, Dahlof C, et al. Guidelines for controlled trials of drugs in migraine: second edition. Cephalalgia. 2000;20:765–86. [PubMed] [Google Scholar]10. Vinson DR. Diphenhydramine in the treatment of akathisia induced by prochlorperazine. J Emerg Med. 2004;26:265–70. [PubMed] [Google Scholar]11. Friedman BW, Bender B, Davitt M, et al. A randomized trial of diphenhydramine as prophylaxis against metoclopramide-induced akathisia in nauseated emergency department patients. Ann Emerg Med. 2009;53:379–85. [PubMed] [Google Scholar]12. Friedman BW, Mulvey L, Esses D, et al. Metoclopramide for acute migraine: a dose-finding randomized clinical trial. Ann Emerg Med. 2011;57:475–82. e1. [PMC free article] [PubMed] [Google Scholar]13. Friedman BW, Corbo J, Lipton RB, et al. A trial of metoclopramide vs sumatriptan for the emergency department treatment of migraines. Neurology. 2005;64:463–8. [PubMed] [Google Scholar]14. Friedman BW, Esses D, Solorzano C, et al. A randomized controlled trial of prochlorperazine versus metoclopramide for treatment of acute migraine. Ann Emerg Med. 2008;52:399–406. [PubMed] [Google Scholar]15. Friedman BW, Garber L, Yoon A, et al. Randomized trial of IV valproate vs metoclopramide vs ketorolac for acute migraine. Neurology. 2014;82:976–83. [PubMed] [Google Scholar]16. Friedman BW, Greenwald P, Bania TC, et al. Randomized trial of IV dexamethasone for acute migraine in the emergency department. Neurology. 2007;69:2038–44. [PubMed] [Google Scholar]17. Friedman BW, Solorzano C, Esses D, et al. Treating headache recurrence after emergency department discharge: a randomized controlled trial of naproxen versus sumatriptan. Ann Emerg Med. 2010;56:7–17. [PMC free article] [PubMed] [Google Scholar]18. Tek D, Mellon M. The effectiveness of nalbuphine and hydroxyzine for the emergency treatment of severe headache. Ann Emerg Med. 1987;16:308–13. [PubMed] [Google Scholar]19. Swidan SZ, Lake AE, 3rd, Saper JR. Efficacy of intravenous diphenhydramine versus intravenous DHE-45 in the treatment of severe migraine headache. Curr Pain Headache Rep. 2005;9:65–70. [PubMed] [Google Scholar]23. Mitchell N, Hewitt CE, Jayakody S, et al. Randomised controlled trial of food elimination diet based on IgG antibodies for the prevention of migraine like headaches. Nutrition journal. 2011;10:85. [PMC free article] [PubMed] [Google Scholar]24. Alpay K, Ertas M, Orhan EK, Ustay DK, Lieners C, Baykan B. Diet restriction in migraine, based on IgG against foods: a clinical double-blind, randomised, cross-over trial. Cephalalgia. 2010;30:829–37. [PMC free article] [PubMed] [Google Scholar]25. Aydinlar EI, Dikmen PY, Tiftikci A, et al. IgG-based elimination diet in migraine plus irritable bowel syndrome. Headache. 2013;53:514–25. [PubMed] [Google Scholar]26. Mansfield LE, Vaughan TR, Waller SF, Haverly RW, Ting S. Food allergy and adult migraine: double-blind and mediator confirmation of an allergic etiology. Annals of allergy. 1985;55:126–9. [PubMed] [Google Scholar]27. Vinson DR, Drotts DL. Diphenhydramine for the prevention of akathisia induced by prochlorperazine: a randomized, controlled trial. Ann Emerg Med. 2001;37:125–31. [PubMed] [Google Scholar]28. Erdur B, Tura P, Aydin B, et al. A trial of midazolam vs diphenhydramine in prophylaxis of metoclopramide-induced akathisia. Am J Emerg Med. 2012;30:84–91. [PubMed] [Google Scholar]29. Friedman BW, Garber L, Gallagher EJ. Author response. Neurology. 2014;83:1389. [PubMed] [Google Scholar]30. Kostic MA, Gutierrez FJ, Rieg TS, Moore TS, Gendron RT. A prospective, randomized trial of intravenous prochlorperazine versus subcutaneous sumatriptan in acute migraine therapy in the emergency department. Ann Emerg Med. 2010;56:1–6. [PubMed] [Google Scholar]

Can Allergy Medications Harm Your Brain? | Cognitive Vitality

It’s allergy season and many of us will be reaching into the medicine cabinet for relief. But it is important to choose wisely, as some allergy medications can harm brain health and increase dementia risk.

Diphenhydramine (e.g., Benadryl®) is a first-generation antihistamine medication [1]. In addition to treating allergy and cold symptoms such as sneezing and watery eyes, it also blocks the actions of acetylcholine. This is a neurotransmitter that is important for brain functions including learning and memory. Diphenhydramine is classified as an anticholinergic drug, and a study of this class of drug found that increased use is associated with an up to 54% increased risk of dementia [2].

In the short-term, side effects of diphenhydramine can include dizziness, drowsiness, confusion, blurred vision, sedation, difficulty urinating, constipation, and low blood pressure [3]. Multiple high-quality human trials have shown that diphenhydramine impairs cognitive functions such as alertness [4], attention [5], memory [5][6][7], executive function [8], reaction time [7], and vigilance [5]. These studies also reported that diphenhydramine increased fatigue and sleepiness while decreasing motivation [5]. An observational study of older hospitalized patients reported that diphenhydramine treatment significantly increased risk for delirium symptoms, including inattention, disorganized speech, and altered consciousness [9]. Older adults with kidney or liver impairment are especially prone to these adverse effects [1]. In fact, diphenhydramine is listed as inappropriate on the Beer’s Criteria for Potentially Inappropriate Medication Use in Older Adults [10].

SAFER ALTERNATIVES

The good news is that newer antihistamines equal the effectiveness of diphenhydramine with few or no cognitive side effects. These medications were developed to minimize adverse events common to diphenhydramine and other older antihistamines [11][12].

• Desloratadine (e.g., Clarinex®) was tested against diphenhydramine in a study of 204 people. It had no significant effect on sleepiness, working memory, psychomotor speed, reasoning/computation, and divided attention [13]. Diphenhydramine, by contrast, caused impairment on all these measures.
• Loratadine (e.g., Claritin®) was compared to diphenhydramine in a study of 98 healthy people. The study found that loratadine fared the same as a placebo with regards to side effects while patients taking diphenhydramine reported fatigue, sleepiness, and low motivation, and demonstrated poorer cognitive performance [5].
• Fexofenadine (e.g., Allegra®) also fared better than diphenhydramine in several studies. In one trial of 42 people, a single dose of diphenhydramine significantly slowed response time, increased omission errors, and increased drowsiness compared with placebo [14]. Fexofenadine did not cause any significant changes. Another trial in 42 aviation personnel found that a single fexofenadine treatment resulted in faster reaction time, fewer omission and commission errors, and better delayed recall accuracy compared to diphenhydramine treatment [15].
• Cetirizine (e.g., Zyrtec®) was compared to new and old antihistamines. Clinical evidence confirmed that it is more likely to cause sedation than other newer medications options [11]. It does, however, have the fastest onset of action among the newer antihistamines.

If you’re older or have concerns about brain health, consider an allergy medication other than diphenhydramine. In addition to the medications above, topical nasal sprays and allergy shots are available by prescription and can also help alleviate symptoms. As always, it’s a good idea to discuss your options with a medical professional.

1. 1. Schroeck JL, Ford J, Conway EL et al. (2016) Review of Safety and Efficacy of Sleep Medicines in Older Adults. Clin There 38, 2340-2372.
2. Gray SL, Anderson ML, Dublin S et al. (2015) Cumulative use of strong anticholinergics and incident dementia: a prospective cohort study. JAMA Intern Med 175, 401-407.
3. Diphenhydramine. Drugs.com.
4. Kay GG, Schwartz HI, Wingertzahn MA et al. (2016) Next-day residual effects of gabapentin, diphenhydramine, and triazolam on simulated driving performance in healthy volunteers: a phase 3, randomized, double-blind, placebo-controlled, crossover trial. Hum Psychopharmacol 31, 217-226.
5. Kay GG, Berman B, Mockoviak SH et al. (1997) Initial and steady-state effects of diphenhydramine and loratadine on sedation, cognition, mood, and psychomotor performance. Arch Intern Med 157, 2350-2356.
6. Papassotiropoulos A, Gerhards C, Heck A et al. (2013) Human genome-guided identification of memory-modulating drugs. Proc Natl Acad Sci U S A 110, E4369-4374.
7. Katz IR, Sands LP, Bilker W et al. (1998) Identification of medications that cause cognitive impairment in older people: the case of oxybutynin chloride. J Am Geriatr Soc 46, 8-13.
8. Sands L, Katz IR, DiFilippo S et al. (1997) Identification of drug-related cognitive impairment in older individuals. Challenge studies with diphenhydramine. Am J Geriatr Psychiatry 5, 156-166.
9. Agostini JV, Leo-Summers LS, Inouye SK (2001) Cognitive and other adverse effects of diphenhydramine use in hospitalized older patients. Arch Intern Med 161, 2091-2097.
10. (2015) Potentially Inappropriate Medication Use in Older Adults 2015. HealthAging.org.
11. Spangler DL, Brunton S (2006) Efficacy and central nervous system impairment of newer-generation prescription antihistamines in seasonal allergic rhinitis. South Med J 99, 593-599.
12. Bender BG, Berning S, Dudden R et al. (2003) Sedation and performance impairment of diphenhydramine and second-generation antihistamines: a meta-analysis. J Allergy Clin Immunol 111, 770-776.
13. Wilken JA, Kane RL, Ellis AK et al. (2003) A comparison of the effect of diphenhydramine and desloratadine on vigilance and cognitive function during treatment of ragweed-induced allergic rhinitis. Ann Allergy Asthma Immunol 91, 375-385.
14. Mansfield L, Mendoza C, Flores J et al. (2003) Effects of fexofenadine, diphenhydramine, and placebo on performance of the test of variables of attention (TOVA). Ann Allergy Asthma Immunol 90, 554-559.
15. Bower EA, Moore JL, Moss M et al. (2003) The effects of single-dose fexofenadine, diphenhydramine, and placebo on cognitive performance in flight personnel. Aviat Space Environ Med 74, 145-152.

Yuko Hara, PhD, is Director of Aging and Alzheimer’s Prevention at the Alzheimer’s Drug Discovery Foundation. Dr. Hara was previously an Assistant Professor in Neuroscience at the Icahn School of Medicine at Mount Sinai, where she remains an adjunct faculty member. Her research focused on brain aging, specifically how estrogens and reproductive aging influence the aging brain’s synapses and mitochondria. She earned a doctorate in neurology and neuroscience at Weill Graduate School of Medical Sciences of Cornell University and a bachelor’s degree in biology from Cornell University, with additional study at Keio University in Japan. Dr. Hara has authored numerous peer-reviewed publications, including articles in PNAS and Journal of Neuroscience.

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The Risks, And The Complications

Diphenhydramine(DPH), familiar to most as Benadryl, is an over-the-counter first-generation antihistamine with antimuscarinic properties used primarily for the treatment of seasonal allergies. Its spectrum of use also extends to the treatment of mild insomnia, insect bites, and stings, rashes as well as several other conditions. Despite the broad spectrum of use, there is a long history of Diphenhydramine addiction. Throughout the latter half of the 20th century, multiple researchers suggested the potential of Benadryl addiction and some even described case reports of patients who fulfilled the Diagnostic and Statistical Manual of Psychiatry’s criteria for substance abuse. Furthermore, since DPH use is unrestricted and Benadryl abuse is so frequent, being able to recognize signs and symptoms of chronic Diphenhydramine addiction and acute Benadryl withdrawal can be of paramount importance to an individual’s health. Therefore, this article will delve into the most common indications for Diphenhydramine use, the information about its abuse, addiction, withdrawal, and most importantly, the steps to take towards a Benadryl addiction-free life.

It is noteworthy that Benadryl addiction and abuse are well documented in the medical community and warrant discussion.

What Is Diphenhydramine?

As previously mentioned, Diphenhydramine(DPH) is a first-generation H₁ antihistamine drug. Thus, there are two terms that require elucidation in order to truly understand what Diphenhydramine is. The first of those terms is “antihistamine”, and the second of them is “first-generation”.

Antihistamine Effects of DPH

Histamine is a molecule that is found in abundance within our bodies. It is mainly sequestered in mast cells primarily in the skin, the smooth muscle and mucosa of intestinal and respiratory  tracts, cardiac muscle, endothelium of blood vessels, and the central nervous system. Within these tissues, histamine plays a significant role in producing symptoms of allergic hypersensitivity through its actions at one of its 5 receptors, referred to as H₁-H₅. Diphenhydramine mediates its action by blocking the action of histamine at H₁ receptors, both in peripheral tissues and in the central nervous system.

The Major Antihistamine Effects of Diphenhydramine Prevents Histamine-Mediated:

• constriction of respiratory smooth muscle
• rapid vasodilation in blood vessels
• increased capillary permeability and subsequent edema
• sensations of itching, pain, and “flare” formation
• increase in heart rate and strength of contraction

DPH a “First-Generation” Antihistamine

The distinction of the first-generation antihistamine is given to various antihistamines. This distinction denotes the capability of some antihistamines, especially Diphenhydramine, to cross the blood-brain barrier and enter the central nervous system(CNS) avidly. Once in the CNS, they can bind to neuronal H₁ receptors and produce drowsiness and sedation as well as suppress medullary cough and vomiting/emesis centers.

Furthermore, it is worth mentioning that DPH acts not only on H₁ receptors but also on Muscarinic Receptors and Sodium Channels, which mediate its “alternative” therapeutic effects.

As these two terms have been elucidated, now the question of “what is Diphenhydramine” can be fully answered. Diphenhydramine is a first-generation H₁ antihistamine medication with concurrent antiemetic, anti-vertigo, and potent sedative/hypnotic properties.

What Is Benadryl Used For?

H₁ receptor blockers are the most commonly used over-the-counter drugs for the treatment of allergic conditions. However, its various effects, as mentioned above, can have other therapeutic potentials.

The Following Is a Brief Overview of the Indications of Its Use:

What Are the Brand and Generic Names For Diphenhydramine?

Diphenhydramine Hydrochloride(DPH) is the generic Benadryl. However, Benadryl ingredients in other forms of generic Benadryl can also include Diphenhydramine citrate, Diphenhydramine methylbromide, and Diphenhydramine salicylate.

DPH is available both as over-the-counter and prescription under numerous Generic and Brand Names. Some of these products include:

Over-the-counter Oral Diphenhydramine Preparations:

• 7 Select Allergy
• 7 Select Allergy Children
• 7 Select Night Time Sleep Aid
• Aleryl
• Alledryl
• Banophen
• Basic Care Allergy Relief
• Basic Care Nightime Sleep Aid
• Diphen
• Dibondrin
• Desentol
• Dipheyst
• Dimedrol
• Benadryl
• Benadryl Allergy
• Benylin Cough and Cold
• Circle K antihistamine
• Dormarex 2
• Genahist
• Histaxin
• Hyrexin
• Dermodrin
• Nytol Quickgels

Over-the-counter Topical Diphenhydramine Preparations:

• Sebrx Topical Analgesic
• Rite Aid Maximum Strength Itch Relief
• CVS Maximum Strength Itch Relief
• Select Brand Extra Strength Itch Stopping
• Benadryl Extra Strength Itch Stopping
• Benadryl Itch Stopping Gel
• Itch Relief
• The Itch Eraser
• After Bite Plus
• After Bite Outdoor
• After Bite Xtra
• After Sting

Over-the-Counter Mixture Diphenhydramine Preparations:

• 7 Select Ibuprofen PM
• 7 Select Night Time Severe Cold Cough and Flu
• 7 Select Pain Relief PM
• Acetadryl
• Acetaminophen PM
• Advil PM
• Aleve PM
• Benadryl Severe Allergy & Sinus Headache, Cold
• Theraflu Nighttime Severe Cold & Cough
• Sudafed Sinus Nighttime Plus Pain
• Delsym Cough + Cold Night-Time
• Tylenol PM
• Pain Relief PM Extra Strength
• Contac Day and Night Cold and Flu
• Respa C&C
• Diabetic Tussin Night Time Cold & Flu

What Are Diphenhydramine Formulations?

Diphenhydramine is available in different formulations for children and adults, basically in a gel, lotion, cream, spray, or oral formulations.

Diphenhydramine For Children

Generic and branded formulations are available in the form of a gel, lotion, cream, and spray. The dosage for children depends on their age and weight. It is not recommended to be used for children under the age of 2.

Diphenhydramine Formulations for Kids Include:

• Children’s Benadryl tablets are available in the form of flavored, chewable 12.5 mg tablets.
• Liquid formulation for children is also available, which has 12.5 mg diphenhydramine per 5 ml of the oral solution.
• Topical ointment, lotion, spray, or gel may be used as a topical solution for itching and skin rashes.

Diphenhydramine For Adults

For Adults, Diphenhydramine Oral Formulations Include:

• Benadryl tablets and capsules are available containing 25 mg of diphenhydramine.
• The liquid formulation may be used for flexible dosing according to the doctor’s advice.
• Topical forms are available in the form of ointment, cream, gel, spray, and lotion.
• Diphenhydramine is also available in the form of diphenhydramine HCI Injection, USP.

Is Benadryl Addictive: Data and Statistics

Regardless, systematic studies providing information about the statistics of Diphenhydramine addiction and abuse are lacking, as it is an over-the-counter drug whose sales are not controlled by the FDA. However, some regional studies performed by pharmacists found that 69% of them felt that sedating antihistamines, like Diphenhydramine, were subject to misuse by patients. Based on the aforementioned information, the possibility of Benadryl addiction can be considered as strong.

There Are Various Reasons for Benadryl Abuse:

• Its ease of accessibility as an over-the-counter drug makes it especially susceptible to overuse and abuse.
• Its potent sedative properties, which can be markedly amplified if used concomitantly with alcohol, also increase the likelihood of abuse and subsequent development of Diphenhydramine addiction for those who suffer from insomnia.
• Its short duration of action and propensity for the development of tolerance may lead patients to take increasing dosages of Benadryl at frequent intervals, which would meet the definition of Benadryl addiction.
• One other reason behind  Benadryl abuse and addiction may lie behind its ability to elevate mood, and increase energy levels. Its anticholinergic properties may be combined with other drugs and increase dopaminergic neurotransmission in the central nervous system. This may yield rewarding properties and drug-seeking behavior.

What Are The Risks Of Benadryl Abuse and Addiction?

The risk factors behind any substance abuse are commonly shared and include various issues in familial, social, occupational settings as well as previous history of mental health disorders or substance abuse (alcohol, opioids, etc,). With regard to the specific risks of Benadryl abuse and addiction, once again information is lacking. However, one specific group of individuals, namely patients suffering from schizophrenia, were among those who were likely to abuse DPH. This stems from the anticholinergic properties of DPH that can relieve the secondary negative symptoms of antipsychotic drugs.

Signs And Symptoms Of Benadryl Addiction

There are some common signs through which one can identify if someone is addicted to Diphenhydramine. Diphenhydramine is a habit-forming drug that can lead to its dependence.

Some of the Symptoms and Signs of Benadryl Addiction Are Listed Below:

• Unable to fall asleep without taking diphenhydramine
• Feeling anxious and confused when a dose of is skipped
• Agitation and mood swings
• Problems with concentration and focus
• Nightmares and Impatience
• Hallucinations
• Heart palpitations and low blood pressure
• Body jitters and shivering
• Difficulty in urinating

Side Effects Of Diphenhydramine Addiction

Adverse reactions of diphenhydramine addiction include the following physical conditions:

• Short-term memory impairment
• Anxiety
• Irritability
• Nausea
• Blurred vision
• Dizziness
• Constipation

Risks Of Diphenhydramine Overdose

DPH overdose can lead to inevitable severe repercussions to one’s health. According to the study about the dose-dependent toxicity of Diphenhydramine overdose, DPH overdose can lead to acute toxicity. Patients should immediately seek medical help in case of an overdose of Diphenhydramine.

Some of the Signs and Symptoms Associated With Dph Toxicity Include:

• Drowsiness, Reduced Attention, Unsteadiness, Dizziness,
• Dry mouth, blurred vision
• Fast heart-rate
• Muscle twitching, convulsions, headaches
• Confusion, Hallucinations
• Nausea and vomiting
• Urinary retention

Furthermore, it should be noted that consumption of alcohol together with Benadryl can worsen some of the side effects of DPH during an overdose.

To avoid Diphenhydramine HCL withdrawal symptoms, a person should understand how they need to stop using this medicine, especially after they have been using the drug for a more extended period.

Benadryl Withdrawal

When one has developed a dependency on Diphenhydramine or had an overdose recently, a sudden cessation can lead to a more significant severity of symptoms related to withdrawal. When Diphenhydramine withdrawal symptoms develop, the patient may experience a number of adverse health reactions.

Common Benadryl Withdrawal Effects

Each person may experience withdrawal side effects in their own way. For some, withdrawal symptoms may be mild and easy to overcome. Other individuals, however, may find that these symptoms are severe and they could have a significant impact on the person’s daily life and health. The specific withdrawal side effects a person may experience depends on how severe the individual’s addiction is.

Some Possible Side Effects During Diphenhydramine Withdrawal Period That May Occur In a Person Include:

• Difficulty sleeping at night
• Feeling restless and irritable
• Anxiety
• Tremors and muscular aching
• Nausea
• Diarrhea

Some individuals also tend to experience cold sweats while they are withdrawing from the drug. Other people may experience hot sweats instead. This can further contribute to insomnia that the individual is already suffering from due to withdrawal.

It should also be noted that many users may experience symptoms usually associated with a cold while they are going through the withdrawal stage after Benadryl cessation.

These withdrawal symptoms may occur with other types of antihistamines that cause similar side effects as Diphenhydramine as well. Thus, individuals seeking out alternative over-the-counter antihistamines may continue to experience addiction if they give up this drug for another one that can have a similar effect on their bodies.

How To Stop Taking Benadryl Safely?

As noted above Benadryl is prone to the development of withdrawal when doses are missed or stopped abruptly, so it is crucial to consider the half-life of diphenhydramine. Therefore, in those patients wishing to stop Benadryl use, a gradual taper in which the dose of used Benadryl is slowly decreased over a period of time can be used to avoid more significant diphenhydramine withdrawal symptoms.

The environment(Home vs. Rehab) in which cessation of Benadryl use can be carried out depends on the severity of the existent addiction. 

• For mild cases of Benadryl addiction, treatment may be carried out at home by gradually decreasing the dosage.
• For severe cases of Benadryl addiction, where a decrease in dosage will result in significant withdrawal symptoms, treatment may need to be carried out in a rehab facility. At the facility, the detoxification from DPH will be carried out using the same form of the gradual decrease in dosage and the patient will be managed symptomatically while recording the severity of withdrawal symptoms on a scale.

Furthermore, if the patient also has concomitant substance use disorder(alcohol, opiates, other prescription medications) or is being treated for other chronic conditions or mental illnesses, a hospital or a rehab setting will be more beneficial in the withdrawal process as the possibility for complications is higher.

Benadryl Addiction Treatment

Benadryl addiction not only affects users physically but emotionally and psychologically as well. Due to the symptoms associated with antihistamine withdrawal, including those individuals who developed a dependency on diphenhydramine, relapse is often possible. Furthermore, patients who are addicted to DPH, often have concomitant addictions to alcohol and other substances. Therefore, seeking professional help at a drug rehab might be an option that patients can consider if they are struggling to overcome their substance abuse disorders. Professional help provided in either an outpatient or inpatient setting can offer the patient a better understanding of their addiction and how they can effectively recover. How long does it take for Benadryl to wear off? It usually depends on how severe the individual’s addiction is. A customized program can be developed for a specific person’s case. During treatment, patients are also offered various therapies to help them regain control over their lives. These may include:

• Psychological therapies,
• Meetings
• Counseling
• Support groups
• Individual and group therapies

After patients have been fully recovered from addiction, they may be required to participate in after-care support programs to ensure that they do not relapse and continue on their road to sobriety.

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Page Sources

1. American Society of Health-System Pharmacists. (2015, August 15). Diphenhydramine: MedlinePlus Drug Information. Medlineplus.Gov. https://medlineplus.gov/druginfo/meds/a682539.html
2. Dicpinigaitis, P. V., Dhar, S., Johnson, A., Gayle, Y., Brew, J., & Caparros-Wanderley, W. (2015). Inhibition of cough reflex sensitivity by diphenhydramine during acute viral respiratory tract infection. International journal of clinical pharmacy, 37(3), 471–474. https://doi.org/10.1007/s11096-015-0081-8
3. Brunton, L., Knollmann, B., & Hilal-Dandan, R. (2017). Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 13th Edition (13th ed.). McGraw-Hill Education / Medical
4. Halpert, A. G., Olmstead, M. C., & Beninger, R. J. (2001, September). https://www.queensu.ca/psychology/sites/webpublish.queensu.ca.psycwww/files/files/Faculty/Richard%20Beninger/Beninger_prp_25.pdf
5. Katzung, B., & Trevor, A. (2020). Basic and Clinical Pharmacology 15e (15th ed.). McGraw-Hill Education / Medical
6. Radovanovic, D. (2000, September 19). Dose-dependent toxicity of diphenhydramine overdose. PubMed. https://pubmed.ncbi.nlm.nih.gov/11204550/
7. Saran, J. S., Barbano, R. L., Schult, R., Wiegand, T. J., & Selioutski, O. (2017). Chronic diphenhydramine abuse and withdrawal: A diagnostic challenge. Neurology. Clinical practice, 7(5), 439–441. https://doi.org/10.1212/CPJ.0000000000000304
8. Thomas, A. (2009, January 23). Diphenhydramine abuse and detoxification: a brief review and case report. PubMed. https://pubmed.ncbi.nlm.nih.gov/18308811/
9. Thomas, A., Nallur, D. G., Jones, N., & Deslandes, P. N. (2007). Diphenhydramine abuse and detoxification: a brief review and case report. Citeseerx.Ist.Psu.Edu. https://citeseerx.ist.psu.edu/viewdoc/download?doi=10.1.1.978.5190&rep=rep1&type=pdf
10. U.S. NATIONAL LIBRARY OF MEDICINE. (n.d.). BENADRYL- diphenhydramine hydrochloride tablet, film-coated. Dailymed.Nlm.Nih.Gov. Retrieved April 2021, from https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=702f9786-7ce9-43e4-921d-e1db09612127&audience=consumer

Published on: June 5th, 2019

Updated on: October 25th, 2021

After successful graduation from Boston University, MA, Sharon gained a Master’s degree in Public Health. Since then, Sharon devoted herself entirely to the medical niche. Sharon Levy is also a certified addiction recovery coach.

8 years of nursing experience in wide variety of behavioral and addition settings that include adult inpatient and outpatient mental health services with substance use disorders, and geriatric long-term care and hospice care.  He has a particular interest in psychopharmacology, nutritional psychiatry, and alternative treatment options involving particular vitamins, dietary supplements, and administering auricular acupuncture.

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Ask Dr. Lisa: Should I Stop Using Benadryl to Help Me Sleep?

In each edition of Ask Dr. Lisa, our medical sleep expert, Dr. Lisa Shives, answers questions from our visitors who need help sleeping better.  In this edition, Dr. Shives answers a question from a man who is using a common medication every night to help him get to sleep.

Joe Sperry asks:
I’ve been using Benadryl as a sleep aid for years. How unhealthy or serious of an issue is this? I’m 31 yrs 125 pds and I take 150 to 300mg a night, usually not all at once. I think I’m addicted but websites say it’s only psychosomatic?

Dr. Lisa says:
Benadryl, the brand name for the drug diphenhydramine, is one of a class of drugs called antihistamines that are designed to relieve symptoms of allergies and the common cold. It is not a sleep aid, although many people use it for that purpose. One of diphenhydramine’s side effects is sleepiness, but other side effects include dizziness, nausea, vomiting, loss of appetite, constipation, increased chest congestion, headache, muscle weakness, and nervousness.

 A number of things concern me about how you are using this drug. First, you are taking much more than you should, even if you’re using it for the purpose for which it’s intended. The maximum recommended dose is 50 mg every four to six hours. You say you are taking upwards of six times that amount, but you also say you don’t take it all at once. This makes me suspect that you’re waking up in the middle of the night and then taking another dose to get back to sleep.

 Additionally, I’m concerned that you’ve been taking this drug every day for years. I don’t have a problem with someone occasionally taking Benadryl as a sleep aid. However, even actual over-the-counter sleep aids shouldn’t be taken every night. Those who take diphenhydramine for extended periods of time may experience low blood pressure and heart palpitations. Some people have a paradoxical reaction to drugs, meaning the drug has the opposite effect, and this often the case with diphenhydramine. Also, if you continue to take the drug every night you may physically need more and more of it to receive the desired result. You may have already noticed this. Finally, there is also the potential of a psychological addiction, meaning that you’ve been using this crutch for so long that you no longer know how to go to sleep without it.

 My recommendation is that see your family physician or to discuss your sleep problems, your overall health and how to taper off the diphenhydramine. Given how much you are taking and for such a long time, I don’t recommend that you stop it cold turkey but should slowly decrease the amount over a 1-2 week period. Your doctor may recommend a visit to a sleep specialist who can help you get to the root of why you started taking diphenhydramine in the first place, and discuss how you can learn to sleep naturally.

90,000 Headache pills cause headaches

On the air of the Russia 1 channel, doctor Alexander Myasnikov said that some pain pills can only intensify it.

Answering the question of Natalia Demina, a TV viewer from Omsk, who complained of constant headaches and asked for help, Myasnikov spoke about the pharmaceutical phenomenon – some pain medications can, on the contrary, contribute to headaches.

Treatment of headaches is not an easy topic.Most often this is the so-called “tension headache” when the muscles, fascia and ligaments that cover the head begin to ache. With this type of pain it becomes easier during the massage, recalled Myasnikov and cited advice known from the TV series “17 Moments of Spring”, when Stirlitz advised Mueller: “Gruppenführer, put your left hand on the back of your head, some fingers, and your right hand on your forehead. And start massage, just close your eyes. ”

People who suffer from headaches take a large number of pills, the doctor reminded: “You know them well, these are ibuprofen, diclofenac, ketorophen, ketorolac and others.Their name is Legion. “However, it is the intake of a large number of painkillers – more than 15 tablets per month – on the contrary, can contribute to a drug-induced headache.

“Drugs violate the threshold of sensitivity. Receptors that perceive pain, not only do not” stall “, they, on the contrary, become supersensitive,” Myasnikov pointed out. First-generation antidepressants have to be prescribed to such patients, which reconfigure pain receptors back to a less sensitive form.

“Better than pills, fresh air, proper nutrition, proper weight and as many movements and good mood as possible help to cope with pain,” Myasnikov advised.

Earlier, the doctor talked about amnesia after a tick bite and meat allergy. And also compared the advice of doctors in 1919 and modern methods of treating COVID-19.

90,000 Off Shoulders: When is a Headache Especially Dangerous | Articles

Headaches are among the most common disorders of the nervous system.Adults and, unfortunately, children suffer from them. All over the world, according to WHO experts, headaches are underestimated, not recognized and treated on an appropriate scale. How to assess the severity of a headache, how dangerous it is in the heat and how to stop it – in the material of Izvestia.

Why did I have a headache

“I have a headache! ..” How often do we hear this or say to others ourselves. A person feels a headache when pain receptors are irritated, which are located in the dura mater, in the periosteum and in the vessels of the brain, soft tissues of the head, explains general practitioner Anna Fedorova.

One of the most common causes of headaches is stress. Pharmaceutical drugs relieve pain only for a while, but as soon as the effect decreases, the torment continues. Physiologically, headache can be associated with diseases of ENT organs, migraines, conditions after injuries, changes in intracranial or blood pressure. But almost always the pain is preceded by a situation of psycho-emotional stress.

Headache plays a protective role, signaling problems that have arisen.In some cases, pain indicates a particular danger. A signal can be intense sudden pain that first appeared (especially after 50 years), steadily intensifying over several weeks or with a change in posture (especially in the supine position), says a leading researcher at the N.N. L.I. Sverzhevsky, Professor of the Department of General Medical Practice of the RUDN University Mikhail Tardov. According to him, a headache, accompanied by neurological or mental symptoms, as well as a change in the nature and intensity of a headache familiar to a person, should cause alertness.

Photo: Depositphotos / ArturVerkhovetskiy

– If you are faced with one of the listed types of headache, you should definitely and without delay contact a neurologist, – advises Mikhail Tardov. – If we are talking about a “familiar” headache, then you should not endure it either: the body reacts to pain by releasing biologically active substances into the bloodstream, which cause vasospasm. In case of recurrence of some type of pain, it makes sense to choose a drug on your own or with the help of a neurologist – better not to combine it – and use it to stop the attack.

It is important to keep in mind, explains Dr. Tardov, that when more than 15 pain pills are taken per month, the analgesics themselves can begin to provoke pain attacks (the so-called abusal pain). In this case, the help of a neurologist is also needed.

– As for the appearance of a headache in the heat, this may serve as an indication of overheating and dehydration of the body, – says a leading researcher at the N.N. L.I. Sverzhevsky. “Both can be life threatening and require immediate action.Overheating in urban conditions can occur more quickly, causing great distress, since oxygen saturation in the city is significantly lower than in nature.

When children have pain

“A healthy child’s head shouldn’t hurt at all, either in preschool or adolescence,” says pediatrician Natalya Gritsenko.

However, if pain occurs, then their causes in children may be overwork of the nervous system, lack of daily walk, excessive TV and gadget watching (more than 4-6 hours), late bedtime and irrational daily routine with long preparation of lessons.Dark or bluish circles under the eyes are signs of chronic overwork of the nervous system! The optimal solution in this case is to optimize the daily routine.

First graders at their first lesson in a Moscow school

Photo: RIA Novosti / Konstantin Chalabov

– As a rule, small children cannot tell that they have pain. But if they are worried about a headache, then this can be seen by their behavior, – says the deputy chief physician for medical work of the Pediatric Medical University, head of the Department of Pediatrics named after Academician A.F. Tura Maria Revnova. – The kids start screaming, crying, grabbing their heads with their hands, scratching their faces, cannot find a position in the crib, fidget. If the headache persists for a long time, then it is imperative to visit a pediatric neurologist, make an encephalogram and other studies that are prescribed by the doctor.

“In adolescents, headaches can be associated with overwork,” continues Dr. Revnova. – It is necessary to ensure that the young man sleeps at night, does not strain his eyes with gadgets.In addition, intoxication with various substances has recently been widespread. Please note that e-cigarettes and vapes can lead to oxygen deprivation and, as a result, headaches.

What will help

As a rule, headache treatment should primarily focus on improving the emotional state. Stressful situations should be avoided whenever possible. To walk outside. Listen to soothing music. A good sleep in a dark room will also help.It is important to limit (and it is better to exclude altogether) the TV and the stress when working at the computer. Soothing herbs also help: lemon balm, lavender, mint (infusions, decoctions). Light exercise, swimming, yoga, meditation, general relaxing massage, neck and head massage will not be superfluous.

Photo: Izvestia / Konstantin Kokoshkin

Of course, it is best to immediately consult with your doctor. And, of course, to deal with the prevention of headache attacks.It is useful to pay attention to your lifestyle and water and drinking regime.

Can Benadryl cause panic attacks? (2021)

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4. Can older dogs have panic attacks?
5. Can hormonal changes cause panic attacks?
6. Can stress and anxiety cause chest pain?
7. Can anxiety awaken shortness of breath?
8. Can the thyroid gland cause panic attacks?
9. Can Benadryl cause depression and anxiety?
10. Can the thyroid gland cause anxiety and panic attacks?

Can anxiety cause coughing fits?

Ryan M
Date of Creation: Nov 09, 2021

Anxiety does not cause coughing fits if they are not of psychological origin.Sometimes anxiety can cause hyperventilation and shortness of breath, but none of these symptoms can trigger coughing fits.

lurker
Date of Creation: Nov 09, 2021

Can stress and anxiety cause esophageal spasms?

Ernest Friedman-Hill
Date of Creation: Nov 03, 2021

Achalasia is a nervous system problem in which the muscles of the esophagus and the lower esophageal sphincter (LES) do not work properly. Similar symptoms can also be triggered by anxiety or panic attacks.

MrYoshiji
Date Created: Nov 06, 2021

Is chest pain a concern?

shellter
Date of Creation: Nov 09, 2021

Anxiety and panic attacks can definitely cause chest pain. Some of the accompanying symptoms may include dizziness, shortness of breath, palpitations, tingling, and trembling. SOURCES: American College of Gastroenterology: Non-cardiac chest pain.

Louis Rhys
Date of Creation: Nov 11, 2021

Can older dogs have panic attacks?

Stefan Fenn
Date of creation: Nov 10, 2021

In older dogs, these panic attacks can occur for a variety of reasons.One that is often overlooked is that they drink more water due to kidney problems and are desperate to go outside to urinate. Giving your dog the antihistamine Benadryl is a shot in the dark.

Sergey Kalinichenko
Date of creation: Nov 10, 2021

Can hormonal changes cause panic attacks?

Delan Azabani
Date of Creation: Nov 11, 2021

A: Fluctuations in the body of estrogen and another key hormone, progesterone, can cause feelings of anxiety or depression.But frequent, anxiety attacks or panic attacks are not normal during menopause. Some women develop panic disorder during menopause.

Marko Ivkovic
Date of Creation: Nov 11, 2021

Can stress and anxiety cause chest pain?

Patryk
Date of Creation: Nov 09, 2021

Anxiety and panic attacks can definitely cause chest pain. Some of the accompanying symptoms may include dizziness, shortness of breath, palpitations, tingling, and trembling.SOURCES: American College of Gastroenterology: Non-cardiac chest pain.

John Leidegren
Date of creation: Nov 10, 2021

Can anxiety awaken shortness of breath?

aefxx
Date of Creation: Nov 04, 2021

Both anxiety and panic attacks can cause you to wake up gasping for breath. Seizures can occur during sleep without an obvious trigger. Both conditions can cause increased hypnagogic twitching.

Joshua Taylor
Date of Creation: Nov 07, 2021

Can the thyroid gland cause panic attacks?

James McMahon
Date of Creation: Nov 02, 2021

Hyperthyroidism is directly related to panic attacks.Panic attacks are usually considered a symptom of this type of thyroid disease. An overactive thyroid gland can cause changes in brain chemistry, which can lead to anxiety or panic attacks.

Daniel Roseman
Date of Creation: Nov 04, 2021

Can Benadryl cause depression and anxiety?

Tristan Havelick
Date Created: Nov 06, 2021

Depression is not a side effect that commonly occurs in people taking Benadryl.If you experience symptoms of depression while taking Benadryl, talk to your doctor.

fmw42
Date of Creation: Nov 08, 2021

Can the thyroid gland cause anxiety and panic attacks?

JayD
Date of Creation: Nov 05, 2021

An overactive thyroid gland can cause changes in brain chemistry, which can lead to anxiety or panic attacks.

Benjamin W.
Date Created: Nov 06, 2021

Benadryl: Side Effects and Precautions – Health

Benadryl (diphenhydramine) is a well-known antihistamine used to treat allergy symptoms including sneezing, runny nose, itching and watery eyes, as well as colds, dry coughs, sleeplessness

Content

Benadryl (diphenhydramine) is a well-known antihistamine used to treat allergy symptoms including sneezing, runny nose, itching and watery eyes, as well as colds, dry coughs, insomnia, and motion sickness.While Benadryl’s side effects are usually mild, some people may experience more severe side effects, making its use undesirable, especially during the day, or even unsafe.

General Side Effects

Sold over the counter without a prescription since 1946, Benadryl is now available as tablets, fast dissolving tablets or strips, capsules, liquid capsules, powder and liquid. Benadryl, a short-acting antihistamine, lasts four to six hours.

Usually considered an effective drug, but has side effects.

If these common side effects are serious or bothersome, talk to your doctor:

• Dry mouth, nose and throat
• Drowsiness
• Dizziness
• Nausea or vomiting
• Loss of appetite
• Constipation

chest

• Increased congestion
• Headache
• Excitability (especially in children)
• Nervousness

Benadryl can impair mental and motor function and your performance at work or school.It can also reduce a person’s ability to drive a vehicle or other potentially hazardous equipment.

Serious side effects

Call your doctor right away if you experience any of these more serious Benadryl side effects:

• Vision problems
• Difficulty urinating or painful urination

Although anyone can experience these side effects taking Benadryl, the drug should be used with particular caution by people taking certain medications and those who are in certain population groups.

Interactions

Benadryl may interact with medicines used to treat diseases, including:

• Medicines with anticholinergic effects, such as Paxil (paroxetine) and Desirel (trazodone)
• Medicines with a depressant effect on the central nervous system, such as Xanamax (alprazol ) and Klonopin (clonazepam)
• Opioid pain reliever hydrocodone

Do not mix alcohol with Benadryl, as this may worsen side effects and worsen drowsiness caused by this medication.

Special Considerations

The use of Benadryl in certain people may lead to increased side effects, risk of overdose and other problems. Be sure to check with your doctor before using this medication if you (or someone you care about) is in one of the following groups.

People with certain medical conditions

Benadryl helps relieve nasal congestion by drying out the nasal passages. While it can be helpful for allergies, the medication can also dehydrate the entire body.It can affect heart rate, blood pressure, breathing, and secretion.

With this in mind, people with certain health problems should not use Benadryl without medical supervision. An antihistamine can aggravate underlying health problems, including:

• Angle-closure glaucoma
• Constipation
• Urinary retention
• Asthma, emphysema or other lung conditions
• Severe liver disease
• Heart disease
• High blood pressure
• Seizures
• Overactive thyroid

Your doctor can best help you determine if Benadryl is safe for you.

Children

Benadryl and other first-generation antihistamines should be used with caution in children and preferably under the guidance of a physician. Benadryl should never be given to children with the intention of causing drowsiness.

Children may experience the same side effects as adults, or potentially experience unexpected side effects such as agitation, irritability, and insomnia.

Potential overdose is a serious problem in young children as it can lead to seizures and heart rate problems.

Signs of a Benadryl overdose include:

• Blurred vision
• Very dry eyes
• Enlarged pupils
• Dry mouth
• Tinnitus
• Dry red skin
• Nausea or vomiting

or

• Drowsiness
• Inability to urinate
• Low blood pressure
• Rapid heartbeat
• Unstable
• Nervousness
• Agitation, confusion, delirium or hallucinations
• Tremors
• Convulsions
• Depression

poisoning by calling 1-800-222-1222 or visit the Poison Services website for more information.Call 911 if the person passes out, has a seizure, has trouble breathing, or cannot be woken up.

Elderly

Benadryl is generally not recommended for adults 65 years of age or older, except for the treatment of an acute allergic reaction. Older people may suffer more from side effects than younger people.

General side effects such as drowsiness, dizziness and decreased reaction time may be more severe in older people, especially if they have other medical conditions, and can lead to falls or accidents.

Because of the dehydrating effect of Benadryl, it can cause dry mouth, constipation, blurred vision and urinary retention, which can increase the risk of urinary tract infections (UTIs) or affect kidney function.

In addition, first-generation antihistamines such as Benadryl may have anticholinergic effects, which can lead to cognitive impairment or confusion. There is growing evidence that chronic use of these drugs may be associated with long-term development of dementia.

Don’t take sleeping pills: why older people should avoid diphenhydramine

Pregnant and lactating women

Benadryl is a widely used antihistamine during pregnancy. However, it should not be considered the preferred antihistamine for daily use in pregnant or lactating women. Regardless of how often you plan to take it, the drug should only be used under medical supervision.

Large doses or overdose of Benadryl can lead to premature contractions during pregnancy.Caution should be exercised when prescribing Benadryl before childbirth, as side effects in a newborn may include agitation, irritability and seizures.

Like many medicines, Benadryl is excreted in breast milk and can be passed on to a nursing baby, causing temporary side effects such as irritability and colic.

Second-generation antihistamines such as Zyrtec (cetirizine) or Claritin (loratadine) have fewer side effects, are more effective and are safer for pregnant women and nursing children.

Safety of antihistamines during pregnancy

A word from Verywell

Benadryl is an effective antihistamine, however its side effects make it less desirable or contraindicated for some. Newer antihistamines such as Xyzal (levocetirizine), Zyrtec (cetirizine), Allegra (fexofenadine), Claritan (loratadine), and Clarinex (desloratadine) generally do not cause drowsiness and are generally preferred over Benadryl for long-term use.