8 Possible Fentanyl Interactions to Watch Out for

Fentanyl is a powerful, opioid medication that treats severe pain. Like other opioids, prescription fentanyl is a controlled substance, because it can cause dependence and addiction. But the risks of fentanyl — including overdose — are higher than they are for most other medications. This is especially true when fentanyl is used incorrectly or inappropriately.

Prescription fentanyl is only recommended when less potent opioids or other pain medications aren’t working well enough. It comes in multiple forms, including an extended-release patch, lozenges (Actiq), and dissolvable tablets (Fentora). 

If you’re prescribed fentanyl, carefully follow the directions for taking it. Additionally, you should know about possible fentanyl interactions, including those involving other medications and substances. Here, we’ll cover eight of the most important fentanyl interactions to know about.

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1. Medications that increase fentanyl levels

Fentanyl is metabolized (broken down) in the liver. Some medications block this process and, as a result, can cause increased levels of fentanyl in the blood. Examples of medications and substances that can increase fentanyl levels include:

• Erythromycin (Ery-Tab)

• Ketoconazole

• Ritonavir (Norvir)

• Grapefruit juice

Because fentanyl is so potent, even a tiny increase can be dangerous and lead to an overdose. Signs of fentanyl overdose include:

• Slowed breathing

• Vomiting

• Small “pinpoint” pupils

• Falling asleep or losing consciousness

Before taking fentanyl, talk to your healthcare provider and pharmacist about all of the medications you take. Also, let them know if you eat grapefruit or drink grapefruit juice, especially in large or frequent quantities. They’ll want to carefully review for potential fentanyl interactions.

Keep in mind: You should call 911 if you think you’re witnessing an opioid overdose. And you might consider keeping naloxone (Narcan) on hand. Administering this over-the-counter (OTC) medication can quickly reverse the effects of an opioid and treat an overdose before help arrives. To learn more, watch this short GoodRx video that shows you what to do if an overdose occurs.

2. Medications that lower fentanyl levels

Some medications make liver enzymes (proteins) more active. This can lead to lower levels of fentanyl in the blood. Phenytoin (Dilantin, Phenytek), carbamazepine (Carbatrol, Tegretol), and rifampin (Rifadin) are examples of medications that may lower fentanyl levels.

This interaction can make fentanyl less effective, potentially causing you to feel more pain or experience opioid withdrawal symptoms, including:

• Nausea and vomiting

• Increased heart rate

• Sweating

• Body aches

• Feeling moody or anxious

If you take any of these medications, your healthcare provider may adjust your fentanyl dose. And if you stop any medications while taking fentanyl, make sure to tell your provider. Your fentanyl dose might need to be adjusted again.

3. Medications that slow down brain function

Opioids cause a slowdown in brain activity. Many other medications can also slow down brain function, including: 

• Benzodiazepines like lorazepam (Ativan)

• Sleep medications like zolpidem (Ambien, Edluar, ZolpiMist) 

• Other opioids like oxycodone (Roxicodone, OxyContin) 

• Sedating OTC antihistamines like diphenhydramine (Benadryl) 

• Barbiturates like phenobarbital 

• Muscle relaxants like cyclobenzaprine (Amrix)

• Antidepressants like trazodone 

• Gabapentin (Neurontin)

Combining fentanyl with medications that slow down brain activity can increase your risk for excessive sedation and overdose. So it’s safest to avoid these medications when taking fentanyl. Just keep in mind that this isn’t a complete list.

4. Alcohol

Alcohol acts as a depressant in the body and can also slow down the brain. Combining fentanyl and alcohol can lead to brain fog, dizziness, and lack of coordination. In more serious cases, fentanyl and alcohol can slow down breathing and make an overdose more likely.

To put it simply, you should avoid drinking any alcohol if you take fentanyl. If you’re unable to avoid alcohol, have an honest conversation with your healthcare provider. They may recommend other methods for controlling your pain, beyond taking fentanyl.

5. Medications that increase serotonin

Serotonin is a naturally-occurring chemical in the body. It helps regulate your mood and other bodily functions. Opioids like fentanyl raise serotonin levels by a small amount. Taking fentanyl with other medications that increase serotonin could cause serotonin syndrome.

Examples of other medications that can increase serotonin levels include:

• Selective serotonin reuptake inhibitors (SSRIs) like fluoxetine (Prozac) and sertraline (Zoloft)

• Serotonin and norepinephrine reuptake inhibitors (SNRIs) like duloxetine (Cymbalta)

• Tricyclic antidepressants (TCAs) like nortriptyline

• Triptans like sumatriptan (Imitrex)

• Monoamine oxidase inhibitors (MAOIs) like linezolid (Zyvox) and selegiline (Zelapar, Emsam)

The risk of developing serotonin syndrome is very low, but it can happen. It usually occurs within a day of taking the medication(s) that caused it. Signs to watch out for include feeling sweaty or shaky and having a fast heartbeat. In rare cases, severe symptoms are possible. These include confusion, high fever, and muscle stiffness. Seek emergency care if you notice any of these symptoms.

MAOIs have the highest risk of causing serotonin syndrome. So they shouldn’t be combined with fentanyl, or even taken within 14 days (2 weeks) of taking fentanyl.

6. Diuretics

Fentanyl raises levels of a natural chemical in the body called antidiuretic hormone (ADH). This chemical prevents your body from getting rid of fluids effectively. But diuretics (water pills) work by helping the body get rid of fluids. So if you’re taking a diuretic and fentanyl, you might need a higher dose of your diuretic for it to have its intended effect. Otherwise, your body may hold onto fluid, causing your blood pressure to increase.

Hydrochlorothiazide and furosemide (Lasix) are two common examples of diuretics. If you’re taking a diuretic and fentanyl, and you notice you’re peeing less, let your healthcare provider know. They may recommend adjusting one or more of your medications.

7. Anticholinergic medications

Anticholinergics are medications that block the effects of acetylcholine. This chemical is involved in many bodily processes, like helping the bladder and intestinal muscles contract. Anticholinergics can prevent this from happening and lead to urinary retention and constipation. This makes urinary tract infections (UTIs) more likely. And if constipation is severe, serious intestinal blockage can occur. 

More than 600 medications, including fentanyl, have anticholinergic effects. Some examples are:

• Medications for lung conditions, such as Spiriva (tiotropium)  

• Overactive bladder medications like oxybutynin (Ditropan XL) 

• Medications for Parkinson’s disease, such as as benztropine 

• Sedating antihistamines like diphenhydramine

• Some antidepressants, including nortriptyline and amitriptyline

Taking too many anticholinergic medications can cause unwanted side effects. Before starting treatment with fentanyl, ask your pharmacist if any of your other medications have anticholinergic effects. If you take multiple anticholinergic medications, you’ll want to watch for side effects like trouble peeing and constipation.

8. Opioid blockers

Medications that block opioids are called opioid antagonists, or “opioid blockers.” If you take one of these medications with fentanyl, you’ll likely experience opioid withdrawal symptoms. 

One example of an opioid blocker is naltrexone (Vivitrol). Naltrexone is used to treat alcohol use disorder and opioid use disorder. Naltrexone and an opioid shouldn’t be taken together (or even within 7 to 10 days of each other)

Another example of an opioid blocker is Narcan. But you shouldn’t hesitate to administer Narcan if you think you’re witnessing an opioid overdose, even if you’re not sure. Narcan will cause withdrawal symptoms if opioids are involved, but the withdrawal isn’t life-threatening. Narcan can reverse an overdose, saving someone’s life.

When should I contact my healthcare provider about a fentanyl interaction?

Let your healthcare provider and pharmacist know about all the prescription medications and OTC products you take. They’ll help you check for fentanyl interactions. And giving them an updated medication list is the best way to do this. 

If you have any side effects while taking fentanyl, it could be a sign of an interaction. Let your provider know about any side effects, so you can discuss how to proceed. Keep in mind, though, that it’s not a good idea to stop taking fentanyl without talking to your provider first. This could lead to opioid withdrawal.

If you think someone around you is experiencing an opioid overdose, act fast. Call 911 and administer Narcan if you have it. 

If you or someone you know struggles with substance use, help is available. Call SAMHSA’s National Helpline at 1-800-662-4357 to learn about resources in your area.

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Written by:

Daphne Berryhill, RPh

Daphne Berryhill, RPh, has two decades of experience as a clinical pharmacist. She spent most of her career in the Chicago area practicing in-home infusion.

Edited by:

Amy B. Gragnolati, PharmD, BCPS

Amy Gragnolati, PharmD, BCPS, is a pharmacy editor for GoodRx. Amy currently holds her pharmacist license in Georgia and California.

Reviewed by:

Joshua Murdock, PharmD, BCBBS

Joshua Murdock, PharmD, BCBBS, is a licensed pharmacist in Arizona, Colorado, and Rhode Island. He has worked in the pharmacy industry for more than 10 years and currently serves as a pharmacy editor for GoodRx.

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