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Can benadryl cause headaches: Common and Rare Side Effects for Benadryl Allergy-Sinus-Headache oral

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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.

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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.   

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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.


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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 210th Street, Bronx, NY, 10467, [email protected], (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

Variable Metoclopramide + diphenhydramine Metoclopramide + placebo
Female, n/N(%) 88/104 (85%) 92/104 (89%)
Age in years, mean (SD) 34 (11) 36 (10)
Used medication for headache prior to ED visit, n/N(%) 66/104 (64%) 67/103 (65%)
Visual Aura1, n/N(%) 29/104 (28%) 39/104 (38%)
Sensory Aura2, n/N(%) 5/104 (5%) 15/104 (14%)
Duration of headache in hours, median (IQR) 72 (24, 96) 48 (16, 72)
Baseline pain on 0–10 scale, median (IQR) 9 (8, 10) 9 (8, 10)
Number of functionally impairing headaches over previous 90 days, median (IQR) 3 (1, 5) 3 (2, 5)
Allergic symptoms3, n/N (%) 15/104 (14%) 14/104 (14%)

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

Variable Metoclopramide + diphenhydramine Metoclopramide + placebo Difference (95%CI)
Improvement in 0–10 NRS pain score between baseline and one hour 5.1 (n=104) 4.8 (n=101)* 0.3 (−0.6, 1.1)
Required rescue medication in ED 31/104 (30%) 40/104 (38%) 9% (−4, 21%)
Sustained headache freedom1 17/101 (17%) 14/102 (14%) 3% (−7, 13%)
Want same med again2 84/99 (85%) 77/102 (76%) 9% (−2, 20%)
Functional impairment at one hour
 Unable to perform usual activities3
27/103 (26%)* 30/98 (31%)* 4% (−8, 17%)

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

Adverse event Metoclopramide + diphenhydramine n/N (%) Metoclopramide + placebo n/N (%) Difference (95%CI)
Very restless after receiving study meds* 8/99 (8%) 7/102 (7%) 1% (−6, 8%)
Required rescue dose of diphenhydramine to treat symptoms of acute akathisia 5/104 (5%) 8/103 (8%) 3% (−4, 10%)
Very drowsy after receiving study meds* 17/99 (17%) 14/102 (14%) 3% (−7, 13%)

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

Variable Metoclopramide + diphenhydramine Metoclopramide + placebo Difference (95%CI)
Improvement in 0–10 pain score between baseline and one hour 3.8 (n=15) 3.7 (n=12)* 0.1 (−2.1, 2.3)
Requirement of Rescue medication 6/15 (40%) 3/14 (21%) 19% (−14, 51%)
Sustained headache freedom1 3/15 (20%) 1/13 (8%) 12% (−13, 37%)
Want same med again2 14/15 (93%) 7/13 (54%) 39% (10, 69%)

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 years20,21. 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, 25th and 75th 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

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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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