9 Hydrocodone / Acetaminophen (Norco) Interactions to Watch For

You may have heard of Norco, Lortab, and Vicodin. These brand-name medications all contain the opioid hydrocodone and the nonopioid pain reliever acetaminophen (Tylenol). Though none of these brand-name pills are available anymore, generic hydrocodone / acetaminophen is still on the market.

Hydrocodone / acetaminophen is prescribed to treat pain that can’t be managed by nonopioid medications. It’s metabolized (broken down) by the liver. Several other medications and supplements can affect this process. Hydrocodone / acetaminophen can also interact with other medications and substances that have similar side effects, such as drowsiness and dizziness.

Here, we’ll review nine hydrocodone / acetaminophen interactions to consider.

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If you or a loved one takes hydrocodone / acetaminophen, it’s a good idea to carry naloxone (Narcan, Zimhi) or nalmefene (Opvee, Zurnai) with you at all times. These medications can help treat an opioid overdose quickly.

1. Medications that contain opioids or acetaminophen, such as Percocet

Taking too many opioids, or too much acetaminophen, can have serious health consequences. High opioid doses can put you at a greater risk for side effects, like drowsiness, dizziness, and nausea. More seriously, taking too many opioids can lead to slowed breathing, overdose, and death. Taking too much acetaminophen can lead to acetaminophen overdose and liver damage.

Many combination medications contain opioids, including oxycodone / acetaminophen (Percocet) and codeine / acetaminophen (Tylenol #3). Several combination medications also contain acetaminophen, including:

• Headache medications, such as Excedrin Migraine (acetaminophen / aspirin / caffeine)

• Cough and cold products, such as Dayquil Cold and Flu (acetaminophen / dextromethorphan / phenylephrine)

• Menstrual cramp medications, such as Midol Complete (acetaminophen / caffeine / pyrilamine)

Several acetaminophen-containing medications are available over the counter (OTC). So make sure you’re reading the labels of OTC products you take. You can also give your pharmacist a list of your prescription and OTC medications. They can check whether you take other medications that contain an opioid or acetaminophen.

Keep in mind that the maximum daily dose of acetaminophen is 4,000 mg. However, you may need a lower dose, depending on your health history. If you’re taking medications that contain acetaminophen, your pharmacist can help you calculate your daily dose.

2. Alcohol

No amount of alcohol is safe to drink with hydrocodone / acetaminophen. Combining alcohol and hydrocodone / acetaminophen can cause increased drowsiness, dizziness, and falls. This combination also increases your risk of overdose and death.

EXPERT PICKS: WHAT TO READ NEXT

• Possible hydrocodone / acetaminophen side effects: Find out what side effects to watch for if you’re taking hydrocodone / acetaminophen.

• Can you drink alcohol while taking opioids? No amount of alcohol is safe to use with opioids. Here’s why.

• Why should you avoid combining opioids and benzodiazepines? Taking opioids and benzodiazepines together is a particularly risky interaction. It can increase the risk of misuse and overdose.

There’s also a risk of combining alcohol and acetaminophen when either is used in excess. This is because drinking too much alcohol and taking too much acetaminophen can both harm the liver.

If you’re prescribed hydrocodone / acetaminophen, be honest with your prescriber about whether you drink alcohol. This way, they can determine if hydrocodone / acetaminophen is a safe medication for you.

3. Benzodiazepines, such as alprazolam

Benzodiazepines treat several health conditions, including trouble sleeping (insomnia) and anxiety. Examples of benzodiazepines include alprazolam (Xanax), clonazepam (Klonopin), and diazepam (Valium).

Benzodiazepines and opioids have some common risks. For instance, taking them together increases your risk of drowsiness and dizziness. This can lead to falls, injuries, and accidents. This is especially risky for older adults who have a greater risk of severe health consequences from injuries.

Combining opioids and benzodiazepines can also increase your risk of misuse and overdose, which can be life-threatening. This is why they’re both classified as controlled substances. For these reasons, it’s best to avoid combining opioids and benzodiazepines unless your prescriber tells you otherwise.

4. Muscle relaxers, such as carisoprodol

Muscle relaxers are a group of medications that treat muscle spasms. They’re typically used for short periods of time. Examples include cyclobenzaprine (Amrix) and carisoprodol (Soma). 

Muscle relaxers have some similar side effects to hydrocodone / acetaminophen, including drowsiness and dizziness. So if you’ve been prescribed a muscle relaxer and hydrocodone / acetaminophen for pain, speak to your prescriber. It may be best for you to try one or the other, rather than starting both at the same time.

5. Sleep medications, such as zolpidem

Prescription sleep medications, also known as “Z-drugs,” can interact with hydrocodone / acetaminophen. Examples of Z-drugs include zolpidem (Ambien) and eszopiclone (Lunesta). As you’d expect, this group of medications can cause drowsiness. 

When combined with opioids like hydrocodone / acetaminophen, Z-drugs can cause excessive sleepiness. Z-drugs are also controlled substances, and taking them with opioids increases your risk of overdose.

Examples of other medications that may be used for sleep problems are trazodone, diphenhydramine (ZzzQuil, Benadryl), and amitriptyline. Combining these medications with opioids can increase sedation and daytime drowsiness. 

Speak to your prescriber before taking any sleep medications with hydrocodone / acetaminophen. And keep in mind that sleep medications aren’t the only medications that cause drowsiness. Several other medications can, too. So make sure you give your healthcare team a list of the medications you take so they can check for interactions.

6. Medications that increase serotonin, such as fluoxetine

Antidepressants such as fluoxetine (Prozac) and amitriptyline increase serotonin levels in the brain. Taking hydrocodone / acetaminophen may also increase serotonin.

If you combine antidepressants with hydrocodone / acetaminophen, your risk of serotonin syndrome increases. This is a rare condition that happens when your serotonin levels are too high. Symptoms may include sweating, confusion, and high blood pressure. Hallucinations and seizures may also occur in severe cases.

Monoamine oxidase inhibitors (MAOIs), another group of antidepressants, are particularly risky when taken with hydrocodone / acetaminophen. Examples include selegiline (Zelapar, Emsam) and phenelzine (Nardil). You need to wait at least 2 weeks after your last MAOI dose before taking hydrocodone / acetaminophen.

Other medications that can increase serotonin include:

• Other opioids, such as tramadol (ConZip, Qdolo)

• Triptans, such as sumatriptan (Imitrex)

• St. John’s wort

Ask your healthcare team to check whether you take medications that increase serotonin. They can let you know if you need to make any changes to your medication regimen or simply watch for symptoms.

7. Antifungals, antibiotics, and antivirals, such as ciprofloxacin

Both hydrocodone and acetaminophen are metabolized by the liver. Medications that block certain liver proteins can increase hydrocodone / acetaminophen levels. Examples include:

• Antibiotics, such as clarithromycin and ciprofloxacin (Cipro)

• Antifungals, such as fluconazole (Diflucan) and ketoconazole

• Antivirals containing ritonavir, such as Paxlovid (nirmatrelvir / ritonavir) and Kaletra (lopinavir / ritonavir)

Increased hydrocodone / acetaminophen levels can put you at risk of side effects, including severe drowsiness and dizziness. Slowed breathing and overdose are also possible.

On the other hand, antibiotics such as rifampin (Rifadin), can cause hydrocodone / acetaminophen blood levels to go down. This means that your normal dose of hydrocodone / acetaminophen might not give you enough pain relief.

Keeping up with which medications affect hydrocodone / acetaminophen levels is complicated. Make sure your prescriber has an up-to-date medication list so they can screen for drug interactions.

8. Seizure medications, such as carbamazepine

Some seizure medications have many drug interactions. This includes carbamazepine (Tegretol), phenytoin (Dilantin, Phenytek), and phenobarbital. These seizure medications can decrease the amount of hydrocodone / acetaminophen in your blood.

Lower hydrocodone / acetaminophen levels mean you may have to take more hydrocodone / acetaminophen to get the same effect. But don’t change your hydrocodone / acetaminophen dose on your own. And don’t stop taking your seizure medication because it may cause your seizures to worsen.

9. Warfarin

Warfarin (Jantoven) is an anticoagulant (blood thinner). It prevents your body from forming blood clots. Although the risk is low, taking hydrocodone / acetaminophen with warfarin can increase the risk of bleeding. This is because acetaminophen can increase warfarin’s effects.

If you’re prescribed hydrocodone / acetaminophen, make sure your prescriber knows if you’re taking warfarin. They may check your international normalized ratio (INR) more often. This is a test that measures how well your blood is clotting. Your INR helps your prescriber determine whether you’re on the right warfarin dose.

If you notice signs of abnormal bleeding, such as blood in your urine or stool, call your prescriber right away. However, if you have bleeding that can’t be stopped, or you feel confused or extremely weak, seek emergency care right away.

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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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