Diphenhydramine interactions to avoid

Diphenhydramine is a first-generation antihistamine. Diphenhydramine has branded equivalents under the brand name of Benadryl Allergy and Banophen, as well as many other names alone or in combination with other active ingredients. Diphenhydramine blocks H1 histamine receptors and belongs to the ethanolamine class of antihistamines. This class has significant antimuscarinic activity in users and causes marked sedation in most people. Diphenhydramine is used for multiple purposes: treatment of allergic reactions, hay fever, symptoms of allergies, prevention of allergic reactions, motion sickness, vertigo, insomnia, and to reduce Parkinson’s symptoms. It is available in oral, topical, and injectable dosage forms.

Diphenhydramine interacts with other medications, both prescription and over-the-counter. Some interactions cause a more pronounced antimuscarinic effect or sedation and can be very dangerous. Cannabis or THC products can be dangerous with diphenhydramine as well. These interactions can severely affect cognitive function, and it’s important to understand what precautions to take while taking diphenhydramine.

RELATED: Don’t take these medicines with Benadryl

Key takeaways:

• Diphenhydramine is contraindicated with monoamine oxidase inhibitors (MAOIs). MAOI drugs enhance the anticholinergic and sedative effect to a dangerous extent and should never be used with diphenhydramine.
• Diphenhydramine interactions can impair cognitive function and have a negative impact on activities of daily living. Sedation and delayed reactions make it unsafe to drive or supervise the actions of others. Antimuscarinic symptoms are also worse when interacting drugs are given, and these include dilated pupils and blurry vision, decreased secretions, urinary retention, and a fast heart rate (tachycardia). These can be dangerous if unaddressed and not corrected.
• For some drugs, diphenhydramine may mask other symptoms or signs we need to be aware of. For example, gentamicin can cause ototoxicity, and we would generally know that by tinnitus, dizziness, and vertigo. If diphenhydramine is being given simultaneously, it may mask these symptoms and make it hard for us to detect ototoxicity.
• Some medical conditions are not suitable for use of diphenhydramine. Patients with glaucoma should not take diphenhydramine as it could worsen the symptoms.
• Speak to a prescriber or pharmacist before adding diphenhydramine to any drug regimen. They can help review for any interactions with other drugs being taken. It is vital to disclose over-the-counter (OTC), cannabis, and alcohol use so providers can help in making an informed decision. Be sure to read the labels of over-the-counter sleep aids and cold medications to look for the presence of diphenhydramine before taking more.

Diphenhydramine-drug interactions

Diphenhydramine is contraindicated in patients taking MAOIs and those who have a history of an allergic reaction to diphenhydramine or any of its components. Diphenhydramine should be used cautiously in patients taking other medications with sedating or antimuscarinic effects. These include some pain medications, other allergy medications, alcohol, and cannabis.

Monoamine oxidase inhibitors

Monoamine oxidase inhibitors are an older class of drugs initially used for depression but more recently used for neurological disorders. They interact with many classes of drugs, and for that reason, many prescribers will avoid MAOIs unless they are necessary. As mentioned before, MAOIs enhance the anticholinergic and sedative effects of diphenhydramine. This can lead to impaired cognitive function and many physical effects, which can have dangerous consequences. These include constipation, blurry vision, and trouble urinating. If these are not recognized, they can lead to more serious things like bowel blockage or kidney problems. MAOI drug use with diphenhydramine is contraindicated. This means one should not be taking both drugs at the same time. If taking this combination, speak to a healthcare provider immediately.

Examples of MAOI drugs include:

• Marplan (isocarboxazid)
• Nardil (phenelzine)
• Eldepryl (selegiline)
• Mellaril (thioridazine)
• Parnate (tranylcypromine)

Other antihistamine allergy medications

There are different classes of antihistamine allergy medications. These medications all block at the H1 receptor, but where the H1 receptor is located plays a factor in the effects of the drug. 

First-generation H1 antihistamines

First-generation H1 receptor blockers cross the blood-brain barrier and affect H1 receptors in the central nervous system (CNS). They cause CNS depression, and this is responsible for the sedation and other serious side effects. Their duration of action in the body is relatively short-lived, lasting 4 to 6 hours. Two first-generation antihistamines should not be taken together. The effects of this combination would be similar to that of taking diphenhydramine with an MAOI. This includes constipation, blurred vision, and trouble urinating.

First-generation H1 antihistamines include:

• Chlor Trimeton (chlorpheniramine)
• Hydroxyzine
• Doxylamine

Second-generation H1 antihistamines

Second-generation antihistamines block the H1 receptors in the body’s periphery, and they are selective to the peripheral receptors over those in the brain. For that reason, they do not cause many of the CNS depression adverse effects like drowsiness, dizziness, and mental impairment. These drugs last longer, typically 12 to 24 hours, but also do not start working as quickly as the first-generation antihistamines. If someone has a severe allergic reaction, a second-generation antihistamine alone won’t work quickly to reverse the symptoms. However, they are an excellent alternative for everyday minor symptoms like itchy and watery eyes, sneezing, and runny nose because they do not tend to cause sedation like the first generation. There may be situations where the combination of a first-generation and a second-generation antihistamine is warranted, but only a healthcare professional can advise. Generally speaking, one should avoid combining antihistamines unless explicitly told to do so by a medical professional.

Second-generation H1 antihistamines include:

• Zyrtec (cetirizine)
• Claritin (loratadine)
• Allegra (fexofenadine)
• Xyzal (levocetirizine)
• Clarinex (desloratadine)

RELATED: What are the best non-drowsy allergy medicines?

Narcotic pain medications

Narcotic pain medications are typically reserved for moderate to severe pain. Utilization should be limited to as short of a duration as possible to achieve adequate pain relief. Narcotic pain medications cause CNS depression similar to first-generation antihistamines but via the opioid receptors. The combined effect can be dangerous. Patients taking both diphenhydramine and a narcotic pain medication can experience drowsiness, dizziness, fatigue, and impaired mental functioning. It would not be safe to drive, operate machinery, or be responsible for the care of others while taking this combination of drugs. Depending on the situation, the prescriber may determine that taking these two types of medications together is necessary. If they do, it is important to pay attention to these warnings. It is important to remember that codeine and hydrocodone are not just used as pain medications; they are often found in prescription cough preparations that a person could be taking for allergy symptoms. Always be aware of the contents of cough and cold products.

If pain medication is needed while on diphenhydramine, speak to a healthcare provider about other treatment options like Tylenol (acetaminophen) or Advil (ibuprofen).

Examples of narcotic pain medications include:

• Vicodin (hydrocodone/ acetaminophen)
• Tylenol #3 (acetaminophen/ codeine)
• Ultram (tramadol)
• Roxicodone (oxycodone)

Diphenhydramine-food interactions

Diphenhydramine does not have any well-documented cases of interactions with food. It is not metabolized in the same enzyme pathway as grapefruit and, therefore, is safe to take with grapefruit consumption.

Diphenhydramine and alcohol

Alcohol is a CNS depressant like diphenhydramine, and when used together, this effect is magnified. Patients may experience extreme sedation and impairment. If diphenhydramine treatment is necessary, avoid alcohol consumption while taking it.

Diphenhydramine and cannabis

Cannabis causes sedation, impairs psychomotor skills, and increases heart rate and blood pressure. These should sound like familiar effects because these effects stem from diphenhydramine use. The combined effects can be dangerous, and the concurrent use of these two substances should be avoided when at all possible.

Diphenhydramine and other CNS drugs

Diphenhydramine can have a compounding effect when used with other drugs that have activity within the central nervous system. Antidepressants and anxiety medications can cause some level of CNS depression, and this effect can be compounded with diphenhydramine. While it is generally safe to use diphenhydramine with these drugs on an occasional basis, some drug classes, like benzodiazepines, may cause too much sedation in combination with diphenhydramine and be considered unsafe. Benzodiazepines include drugs like Ativan (lorazepam), Valium (diazepam), and Xanax (alprazolam).

Supplements like melatonin are sedating as well, and their combined use with diphenhydramine should be monitored and limited.

How to minimize diphenhydramine interactions

Before starting diphenhydramine, speak to the prescribing doctor or pharmacist. They have access to one’s prescription drug list and make sure to tell them of anything else being taken. It helps to keep a comprehensive drug list of prescription and non-prescription items with you at all times. Generally speaking, avoid other medications that may cause drowsiness, dizziness, or impaired functions. Spacing the other drug away from diphenhydramine may help as well. Most of the effects of diphenhydramine wear off after about 6 hours. The effects of other medications may last longer, and a pharmacist can help to decide on timing.

Speak to a healthcare provider about taking diphenhydramine while pregnant or breastfeeding, as there may be effects on the developing child. Diphenhydramine does cross into the breast milk and can have adverse events for the young child.

Remember, diphenhydramine comes in products by MANY names, and you don’t want to double up, so read the labels carefully. It can be in medications labeled as sleep aids, allergy medications, and cough and cold preparations. 

Some other branded products containing diphenhydramine include:

• Alka-Seltzer plus Allergy
• Diphenhist
• Nytol
• Pediacare Children’s Allergy
• Theraflu Multi Symptom
• Sominex
• Unisom

This list is not all-inclusive. The best thing one can do if unsure is to speak with the pharmacist or healthcare provider first for more drug information and medical advice.

When to talk to a healthcare provider about diphenhydramine interactions

This article does not cover all possible drug interactions with diphenhydramine. A pharmacist or doctor can provide a complete list too. Because some interactions can be very serious, speak to a healthcare provider first before combining diphenhydramine with other medications. The 25 mg oral dose is available over the counter, but some dosage forms and strengths are prescription only. Regardless, talk with the pharmacist if taking medications that cause sleepiness or other symptoms like dry mouth or difficulty urination. Make sure to mention if you are being treated for high blood pressure. Taking more than one drug that causes these effects can be harmful to one’s health.