7 Hydrocodone Interactions to Watch For

Hydrocodone extended-release (Hysingla ER) is an opioid medication that treats severe, chronic pain. It’s available as a long-acting tablet and capsule.

Hydrocodone is not a first-choice medication for pain. In fact, opioids are usually used only when non-opioid medications don’t work. This is because opioids are controlled substances with several risks, including dependence and misuse. They can also cause other side effects and drug interactions. Here, we’ll focus on seven hydrocodone interactions, including alcohol and benzodiazepines. Knowing about these interactions can help you minimize the risks of hydrocodone.

1. Alcohol

You should not drink alcohol if you take hydrocodone. In fact, the FDA has issued a boxed warning about combining opioids and alcohol. A boxed warning is the most serious warning the FDA can assign to a medication.

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Using alcohol and hydrocodone together increases the risk of several side effects. This includes drowsiness, confusion, and dizziness. It may also increase your risk of liver damage and substance use disorder. And importantly, combining alcohol and hydrocodone can increase your risk of overdose.

To put it simply, no amount of alcohol is safe to drink with hydrocodone. Be honest with your healthcare professional about how much alcohol you drink. They’ll likely recommend avoiding hydrocodone if you want to continue drinking alcohol.

2. Benzodiazepines and other medications that slow down the brain

There are many groups of medications that slow down the brain. Taking one of these medications along with hydrocodone may cause unwanted side effects. Some of the medications to look out for include:

• Benzodiazepines, such as lorazepam (Ativan) and diazepam (Valium)

• “Z-drugs,” such as zolpidem (Ambien) and eszopiclone (Lunesta)

• Muscle relaxers, such as cyclobenzaprine (Amrix) and tizanidine (Zanaflex)

• Opioids, such as oxycodone (OxyContin) and buprenorphine / naloxone (Suboxone)

• Antihistamines, such as diphenhydramine (Benadryl) and hydroxyzine (Vistaril)

• Antipsychotics, such as olanzapine (Zyprexa) and quetiapine (Seroquel)

Like hydrocodone, these medications affect the brain and may cause tiredness and dizziness. Combining these medications with hydrocodone can also slow your breathing, increasing your overdose risk. This is especially true for combining hydrocodone and benzodiazepines. In fact, all opioids and benzodiazepines have a boxed warning for the risk of overdose when combined.

Before starting hydrocodone, give your healthcare team a list of prescription and over-the-counter (OTC) medications you take. Include supplements as well. They will advise you if your medications can cause hydrocodone interactions.

If you’re prescribed an opioid, it’s a good idea to carry naloxone (Narcan, Zimhi). This is a fast-acting medication that can reverse the effects of an opioid overdose. The sooner it’s administered after an overdose, the better. It’s available OTC, but you may be able to get it for free in some states.

3. Medications that affect hydrocodone levels

Hydrocodone is metabolized (broken down) by the liver. Medications that affect this process may increase or decrease hydrocodone levels in the body.

Medications that block hydrocodone metabolism can increase hydrocodone levels. This makes you more likely to experience side effects. Examples include:

• Amiodarone (Pacerone)

• Haloperidol (Haldol)

• Cimetidine (Tagamet HB)

• Some antibiotics, such as ciprofloxacin (Cipro) and clarithromycin (Biaxin XL)

• Azole antifungals, like fluconazole (Diflucan) and ketoconazole

• Certain opioids, like codeine and tramadol (ConZip, Qdolo)

Other medications can speed up hydrocodone metabolism. This may decrease hydrocodone levels in the blood, making it less effective. Examples include:

• Some seizure medications, such as carbamazepine (Tegretol, Carbatrol), phenobarbital, and phenytoin (Dilantin, Phenytek)

• Certain herbal products, such as St. John’s wort

• Rifampin (Rifadin)

Ask your healthcare professional and pharmacist if your medications affect hydrocodone levels. They can tell you if you need to make any changes to your medication regimen.

4. Medications that increase serotonin

Antidepressants that increase serotonin can also interact with hydrocodone. Serotonin is a chemical messenger in the brain that’s best known for its effect on mood. Examples of medications that may increase serotonin include:

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

• SSRIs (selective serotonin reuptake inhibitors), such as fluoxetine (Prozac)

• SNRIs (serotonin and norepinephrine reuptake inhibitors), such as duloxetine (Cymbalta)

• TCAs (tricyclic antidepressants), such as amitriptyline

• Other antidepressants, such as buspirone (Buspar)

• Other opioids, such as tramadol

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

Hydrocodone may interact with these medications and increase the serotonin in the brain. This is dangerous because too much serotonin can cause serotonin syndrome. Mild symptoms may include sweating, tremors, and diarrhea. Serious symptoms may include seizures, hallucinations, and loss of consciousness.

Serotonin syndrome is rare. But your risk goes up when you take multiple medications that increase serotonin. So talk to your healthcare professional about whether you’re at risk. If you notice any symptoms of serotonin syndrome, contact your healthcare professional immediately. If you experience severe symptoms, call 911 or go to the emergency room.

5. Diuretic medications

Diuretics (also known as water pills) are medications that treat several health conditions. Examples include high blood pressure and heart failure. They work by helping you pee more fluid. Examples of diuretics include hydrochlorothiazide (Microzide) and furosemide (Lasix).

Hydrocodone can have the opposite effect of a diuretic. It releases a hormone that causes you to hold on to fluid. This can counteract the effect of diuretics and increase blood pressure and fluid buildup.

If you’re taking a diuretic and hydrocodone, tell your healthcare professional. They may want you to monitor your fluid status and blood pressure more closely. They might do this by checking your weight and the amount of times you pee per day. You might also be asked to check your blood pressure at home more regularly. In some cases, your healthcare professional may adjust the dose of your diuretic.

6. Naltrexone

Naltrexone (Vivitrol) is an opioid blocker, meaning it blocks the effects of opioids. It’s used to treat alcohol use disorder and opioid use disorder. Using naltrexone while taking hydrocodone can cause opioid withdrawal symptoms. Examples include nausea, diarrhea, and heart palpitations.

Opioid withdrawal isn’t usually life-threatening. Still, you should not take opioids if you’ve been prescribed naltrexone. In fact, you should avoid opioids for 7 to 10 days before starting naltrexone. This helps make sure that opioids are out of your system.

Additionally, if you’re taking naltrexone for opioid use disorder and you relapse to opioids, your body may be more sensitive to their effects. This means that lower opioid doses than what you’ve tolerated in the past could lead to an overdose.

If you take naltrexone, tell all your healthcare professionals that you’re taking it. They can help you avoid opioids like hydrocodone.

7. Anticholinergic medications

Anticholinergic medications treat a variety of conditions, including Parkinson’s disease, irritable bowel syndrome, and overactive bladder. Examples of anticholinergic medications include dicyclomine (Bentyl), oxybutynin (Ditropan), and diphenhydramine.

Anticholinergics have several side effects, including constipation, dry mouth, and decreased sweating. They can also cause difficulty peeing. Hydrocodone is also known to cause constipation and, more rarely, difficulty peeing. Combining hydrocodone with an anticholinergic medication may worsen these side effects.

If your healthcare professional prescribes hydrocodone, tell them if you’re taking any anticholinergic medications. If you are, you’ll want to watch for constipation or trouble peeing. If you experience these symptoms, ask your healthcare professional what to do.

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Written by:

Caleb Hoppe, PharmD

Caleb has more than 5 years of pharmacy practice experience in multiple settings, including retail pharmacy, hospital pharmacy, and academia (Indiana Pharmacy Teaching Certificate to be obtained in 2024). Caleb has been active in many pharmacy organizations and has been president of local chapters.

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:

Austin Ulrich, PharmD, BCACP

Austin Ulrich, PharmD, BCACP, is a board-certified ambulatory care clinical pharmacist. In his early career, he provided direct patient care in a variety of settings, including hospital and community pharmacies, and in a primary care clinic as a clinical pharmacist.

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