9 Opioid Interactions to Know About

Opioids are prescription medications used to treat pain. They’re typically prescribed when nonopioid medications haven't provided pain relief. Examples of opioids include oxycodone (Roxicodone, Oxycontin), hydrocodone / acetaminophen, and tramadol (ConZip, Qdolo). 

Opioids are controlled substances, which means they have the ability to cause dependence and misuse. They also have several other possible side effects and drug interactions to know about. Most opioid interactions occur with medications that have similar side effects to opioids. But some are related to the way the body metabolizes (breaks down) medications.

Here, we will review nine potential opioid interactions to be aware of.

1. Gabapentin

Gabapentin (Neurontin) is FDA approved to treat seizures and nerve pain from shingles. It’s also prescribed for off-label uses, such as nerve pain from diabetes and anxiety.

In some cases, such as after certain surgeries, gabapentin and opioids may be prescribed together to reduce total opioid use. But this combination does come with risks, and for many people, these risks may outweigh the benefits. For example, combining gabapentin and opioids can increase the risk of drowsiness, slowed breathing, and overdose.

Some research shows that taking opioids with gabapentin nearly doubles the risk of opioid overdose compared to taking opioids alone. So if you take gabapentin, your prescriber may want you to avoid opioids. If you’re experiencing pain that isn’t relieved by nonopioid medications and doesn’t improve over time, they can talk to you about your options.

EXPERT PICKS: WHAT TO READ NEXT

• Opioid side effects: Opioids have several common side effects to consider, including constipation, drowsiness, and nausea.

• Opioid alternatives: There are several nonopioid pain relievers that help with mild-to-moderate pain. And many of them can be found over the counter. 

• Checking for opioid interactions: The best way to check for potential opioid interactions is to give your prescriber and pharmacist a list of all of your medications, including any over-the-counter products.

2. Benzodiazepines, such as alprazolam

Benzodiazepines and opioids have some similar side effects, including drowsiness and dizziness. Commonly benzodiazepines include alprazolam (Xanax), clonazepam (Klonopin), and lorazepam (Ativan).

Taking benzodiazepines with opioids increases the risk of drowsiness and dizziness. In turn, this can increase the risk of falls and injuries, which is especially dangerous for older adults. The combination can also increase the risk of overdose and death. In fact, opioids and benzodiazepines both carry a boxed warning about the risk of overdose when these medications are combined. A boxed warning is the most serious warning the FDA assigns a medication.

Some research shows that up to 50% of opioid overdose deaths also involve benzodiazepines. Another study found the rate of overdose-related death in people taking opioids and benzodiazepines was 10 times higher than in people taking opioids alone. This is why it’s best to avoid combining benzodiazepines and opioids, unless your prescriber has determined the benefits outweigh the risks. 

Read more like this

Explore these related articles, suggested for readers like you.

The 15 Most Addictive Prescription Medications

Opioid Withdrawal Symptoms: What Are They And How Long Do They Last?

12 Tramadol Interactions You Should Know About

7 Oxycodone Side Effects to Know About

View more

3. Alcohol

Combining alcohol and opioids can lead to an increased risk of drowsiness, dizziness, and confusion. You may also be at an increased risk of serious risks such as opioid use disorder (OUD), heart problems, and overdose.

You should avoid drinking alcohol if you’re prescribed an opioid. If you feel you’re unable to stop drinking, talk to your prescriber. They can talk to you about other medication options and, if needed, resources that can help you address how much you’re drinking.

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. 

4. Other medications that slow the brain, such as zolpidem

There are several other medications that slow brain function in similar ways to opioids. Examples of these medications include:

• Muscle relaxers, such as cyclobenzaprine (Amrix) 

• Barbiturates, such as phenobarbital

• Sleep medications, such as zolpidem (Ambien)

• Some over-the-counter medications like diphenhydramine (Benadryl)

These medications can have some similar side effects to opioids, such as drowsiness and dizziness. If taking one of these medications with an opioid is unavoidable, your prescriber may reduce the dosage or frequency of the medications. 

Since many medications have similar side effects to opioids, make sure your healthcare team has a list of all the medications you take, including prescription and over-the-counter (OTC) products. This will help them check for potential opioid interactions.

5. Medications that increase serotonin, such as escitalopram

Some opioids can increase levels of a chemical in the body called serotonin. In rare cases, this can lead to serotonin syndrome, a potentially dangerous health condition in which too much serotonin builds up in the blood.

In 2016, the FDA released a warning about the risk of serotonin syndrome when opioids are combined with other medications that increase serotonin levels. One of the opioids that’s most likely to increase serotonin is tramadol. Other medications that can increase serotonin include:

• Monoamine oxidase inhibitors (MAOIs), such as selegiline (Zelapar, Emsam)

• Selective serotonin reuptake inhibitors (SSRIs), such as escitalopram (Lexapro)

• Serotonin-norepinephrine reuptake inhibitors (SNRIs), such as venlafaxine

• Migraine medications, such as sumatriptan (Imitrex, Onzetra)

• St. John’s wort

• Trazodone

Although still rare, serotonin syndrome is more likely to occur if you take multiple or high dosages of medications that increase serotonin. Symptoms of serotonin syndrome may include a fever, sweating, and confusion. Severe cases can be fatal.

In some cases, you may need to avoid taking these medications with opioids For example, MAOIs and certain opioids shouldn’t be taken within 2 weeks of each other. In other cases, your prescriber may just ask you to watch out for symptoms of serotonin syndrome. 

6. Naltrexone

Naltrexone (Vivitrol) is FDA approved to treat alcohol use disorder and OUD. Taking naltrexone with opioids can lead to opioid withdrawal. While opioid withdrawal isn’t usually life-threatening, it can be extremely uncomfortable. 

Symptoms of opioid withdrawal include:

• Nausea and vomiting

• Runny nose

• Sweating

• Muscle aches

• Trouble sleeping

To prevent opioid withdrawal symptoms, experts usually recommend avoiding opioids for 7 to 10 days before starting treatment with naltrexone. 

If you’re taking naltrexone to treat OUD, contact your healthcare team if you experience a relapse with opioids. After taking naltrexone, you’ll likely be more sensitive to the effects of opioids. And you may not be able to tolerate opioid dosages that you once could, putting you at greater risk of an opioid overdose.

Good to know: Naltrexone is not the same as naloxone (Narcan, Zimhi). While they’re both “opioid antagonists”, the medications are used differently. Naloxone quickly reverses the effects of an opioid overdose, while naltrexone does not. It’s best to keep naloxone on you at all times if you or a loved one takes an opioid. There are several ways to access naloxone, including getting it OTC.

7. Substances that affect opioid metabolism, such as grapefruit juice

Drug metabolism refers to how the body metabolizes and removes medications. This process often involves enzymes (proteins) in the liver. Certain substances can affect the metabolism of opioids by affecting these liver enzymes.

For example, medications such as ritonavir (Norvir) and fluconazole (Diflucan), as well as grapefruit juice, can block specific liver enzymes, leading to higher levels of certain opioids in the body. This can increase the risk of side effects from the opioids. 

On the other hand, some medications can speed up opioid metabolism by increasing levels of certain liver enzymes, leading to lower opioid levels. This may make opioids less effective. Examples of medications that can have this effect include carbamazepine (Tegretol, Carbatrol), phenytoin (Dilantin, Phenytek), and St. John’s wort.

8. Diuretics, such as hydrochlorothiazide

Diuretics are a group of medications that remove fluid from the body and lower blood pressure. They’re used to treat several health conditions, including heart failure and high blood pressure. Examples of diuretics include furosemide (Lasix) and hydrochlorothiazide (Microzide).

Opioids may lower the effectiveness of diuretics. This is because opioids can cause the body to release more antidiuretic hormone, counteracting the effects of diuretics.

So if you’re taking a diuretic and an opioid, your healthcare team may recommend checking your blood pressure at home more often. They may also ask you to watch for signs of fluid buildup, such as peeing less than usual, having swollen ankles and feet, or having high blood pressure readings.

9. Anticholinergic medications, such as scopolamine

Anticholinergic medications treat a variety of conditions, including Parkinson’s disease and overactive bladder. Some common examples of anticholinergic medications are oxybutynin (Ditropan XL), glycopyrrolate (Robinul), and scopolamine (Transderm Scop). 

Anticholinergics have similar side effects to opioids, such as constipation, trouble peeing (urinary retention), and confusion. Taking opioids with anticholinergics can make these side effects worse. This is especially risky for older adults. 

Before starting treatment with an opioid, ask your pharmacist if any of your medications fall under the category of anticholinergics or have anticholinergic effects.

Do opioids interact with cannabis?

Opioids and cannabis can both cause side effects like dizziness and drowsiness. Taking them together can worsen these effects. 

Though cannabis is sometimes used to manage chronic pain, it’s not an FDA-approved medication. Avoid combining opioids and cannabis unless you’ve discussed it with a healthcare professional. 

Why trust our experts?

Written by:

Nicole E. Cieri-Hutcherson, PharmD, BCPS, NCMP

Nicole E. Cieri-Hutcherson, PharmD, BCPS, NCMP, has over a decade of experience as a pharmacist, professor, and researcher. She was a full-time clinical professor in the pharmacy practice department at D’Youville School of Pharmacy before subsequently joining the faculty of the pharmacy practice department at the University at Buffalo School of Pharmacy and Pharmaceutical Sciences.

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:

Bailey E. Eason, PharmD, MS, BCPS

Bailey Eason has been licensed for 6 years and has held licenses in three states (North Carolina, Virginia, and Illinois). She has held positions as a health-system pharmacy administration resident, operating room pharmacy manager, pharmacy manager of clinical operations: surgery, neurology and controlled substances, and most recently as program director  of drug diversion for a large academic health system.

Our editorial standards

Meet our experts