Key takeaways:
Oxycodone (Roxicodone, OxyContin) is an opioid medication that treats pain. It’s a controlled substance, so it comes with serious risks.
Oxycodone can interact with sedatives such as alprazolam (Xanax) and lorazepam (Ativan), alcohol, and naltrexone. There are also several other oxycodone interactions to be aware of.
Talk to your healthcare team about oxycodone interactions. And be sure to give them your current medication list. This can help you avoid harmful interactions.
Oxycodone (Roxicodone, OxyContin) is an opioid medication. It’s FDA approved to treat pain when non-opioid pain medications haven’t worked or aren’t a good option.
Oxycodone and other opioids are controlled substances. Compared to non-controlled medications, they’re more likely to cause dependence and misuse. Controlled substances also have state-by-state restrictions on prescribing and refills.
The FDA and many other organizations have recommendations for how to safely prescribe and take opioids. This includes only prescribing opioids for people who really need them. It also includes prescribing the lowest dose and quantity of opioids when they’re needed.
Safe use of oxycodone also involves avoiding potentially harmful drug interactions.
Oxycodone interactions at a glance
Oxycodone can interact with several medications, dietary supplements, and certain foods. Some interactions with oxycodone to be aware of include:
Macrolide antibiotics
Azole antifungals
Certain antivirals
Certain antidepressants
Grapefruit and grapefruit juice
Seizure medications
Rifampin
St. John’s wort
Sedatives, such as benzodiazepines, antipsychotics, and general anesthetics
Muscle relaxers
Alcohol
Sleep medications
Monoamine oxidase inhibitors (MAOIs)
Triptans
Naltrexone and other mixed opioid agonist/antagonist medications
Diuretics (water pills)
Anticholinergic medications
Here, we’ll dig a little deeper into 10 oxycodone interactions you should know about.
1. Medications that affect oxycodone metabolism, such as fluoxetine
Your liver helps metabolize (break down) many medications, including oxycodone. The liver does this through liver proteins (enzymes). But many medications can affect how these enzymes work. Some medications block these enzymes, making them less active. Others boost the activity of these enzymes, making them more active.
If you take other medications that affect oxycodone’s metabolism, you may have higher or lower oxycodone levels in your body.
Medications that increase oxycodone levels
Higher oxycodone levels can increase the risk of oxycodone side effects, including overdose.
Common medications and substances that can increase oxycodone levels include:
Macrolide antibiotics, such as clarithromycin
Azole antifungals, such as ketoconazole
Medications that contain ritonavir (Norvir), such as Paxlovid (nirmatrelvir / ritonavir)
Some antidepressants, such as paroxetine (Paxil), fluoxetine (Prozac), and bupropion (Wellbutrin SR, Wellbutrin XL)
Grapefruit or grapefruit juice
Risk management: Along with drug interactions, oxycodone (Roxicodone, OxyContin) has possible side effects to know about.
Avoiding oxycodone and alcohol: Opioids and alcohol don’t mix, and here’s why.
Managing pain: If you want or need to avoid medications like oxycodone, there are several alternatives to opioids for pain that may help you.
Medications that lower oxycodone levels
Some substances and medications speed up oxycodone’s metabolism. This can lead to lower oxycodone levels, making it less effective. Examples include:
Anti-seizure medications, such as carbamazepine (Tegretol) and phenytoin (Dilantin, Phenytek)
Rifampin (Rifadin)
St. John’s wort
If you take any medications or supplements besides oxycodone, your pharmacist can help you find out whether they interact with oxycodone. Share a current medication list with your healthcare team so they can check for potential interactions. If a potential interaction is severe, your prescriber may recommend changing your medication regimen. But don’t make any changes without talking to your prescriber first.
2. Sedatives, such as alprazolam
Sedatives are medications that affect brain activity. These medications can cause drowsiness, forgetfulness, and coordination changes. These side effects become even more likely when you take multiple sedatives at the same time.
Benzodiazepines, such as lorazepam (Ativan) and alprazolam (Xanax), are a common group of sedatives. And oxycodone is a sedative-like medication. Combining benzodiazepines with oxycodone is dangerous and should be avoided. In severe cases, too many sedatives in the body can lead to serious side effects, such as coma and overdose. In fact, the FDA has assigned oxycodone a boxed warning for this risk. This is the most serious warning the FDA can place on a medication label.
Other common sedatives that are risky to combine with oxycodone include:
Other opioids, such as tramadol (ConZip)
Antipsychotic medications, such as quetiapine (Seroquel)
General anesthetics, such as propofol (Diprivan)
Gabapentin (Neurontin)
Make sure your prescriber or pharmacist knows about all the medications you take before starting oxycodone.
3. Muscle relaxers, such as cyclobenzaprine
Similar to benzodiazepines, muscle relaxers such as methocarbamol and cyclobenzaprine (Amrix) have sedative effects. They shouldn’t be combined with oxycodone because of the risk of serious side effects.
Your prescriber should help you avoid this interaction. They will likely recommend taking either a muscle relaxer or oxycodone to help with pain rather than both.
4. Alcohol
Although alcohol isn’t a medication, it can still have sedative effects. It’s dangerous to drink alcohol while you’re taking oxycodone for this reason. This combination can raise your risk of excessive sleepiness, dizziness, and overdose.
If you plan to drink alcohol while taking oxycodone, be honest with your prescriber. They’ll likely recommend you avoid oxycodone if you can’t stay away from drinking alcohol. And if you think you may be drinking too much, talk to your healthcare team. They can help you access resources to help limit your 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.
5. Sleep medications, such as Benadryl and Ambien
Medications that treat insomnia (difficulty sleeping) should generally be avoided with oxycodone. Combining the following medications with oxycodone also raises the risk of excessive sleepiness and overdose:
Zolpidem (Ambien, Edluar)
Eszopiclone (Lunesta)
Diphenhydramine (Benadryl, ZzzQuil, Unisom SleepGels)
Ramelteon (Rozerem)
Doxepin (Silenor)
Belsomra (suvorexant)
Dayvigo (lemborexant)
Some of these interactions with oxycodone may be more dangerous than others. But, combining any of these medications with oxycodone can be dangerous. So it may be best to avoid these combinations entirely.
6. Monoamine oxidase inhibitors, such as selegiline
Monoamine oxidase inhibitors (MAOIs) are a group of medications that treat health conditions such as Parkinson’s disease and depression. Examples of MAOIs include rasagiline (Azilect) and selegiline (Zelapar, Emsam).
The combination of oxycodone and MAOIs may increase the risk of serotonin syndrome and trouble breathing. Serotonin syndrome is a medical condition of too much serotonin. This is a chemical that helps regulate many body functions, like our mood and sleep. Mild symptoms include tremors, a fast heartbeat, and sweating. Severe symptoms include high fever, agitation, and high blood pressure. If you experience symptoms of serotonin syndrome, contact your prescriber immediately. If they feel severe, call 911 or go to the nearest ER.
Some opioids, such as tramadol, are more known to raise serotonin compared to oxycodone. To be safe, though, you should still avoid oxycodone within 14 days of taking an MAOI.
7. Other medications that raise serotonin levels, such as sertraline
Many medications besides MAOIs can raise serotonin levels. When taken with oxycodone, serotonin syndrome may be more likely to occur. It’s a good idea to use extra caution if you’re taking any of these medications with oxycodone:
Selective serotonin reuptake inhibitors (SSRIs), such as sertraline (Zoloft)
Serotonin and norepinephrine reuptake inhibitors (SNRIs) such as venlafaxine (Effexor XR)
Tricyclic antidepressants (TCAs), such as amitriptyline
Triptans, such as sumatriptan (Imitrex)
If you’re taking any of these medications, check with your prescriber before starting oxycodone. They may recommend another choice. Or, they might suggest you carefully watch for serotonin syndrome if you need to take both.
8. Naltrexone
Opioid antagonists are medications that block the effects of alcohol and opioids. Naltrexone (Vivitrol) is a common example. It treats alcohol use disorder and opioid use disorder.
If you’re currently taking naltrexone, you shouldn’t start oxycodone. Experts recommend avoiding opioids for 7 to 10 days before starting naltrexone. If you don’t, you may experience uncomfortable opioid withdrawal symptoms. They range from mild to severe and may include muscle pain, vomiting, and agitation.
This withdrawal effect can also happen if you take oxycodone with a similar medication like buprenorphine (Subutex).
Good to know: Naloxone (Narcan) is another opioid antagonist. It comes as an injection and nasal spray. It’s different from naltrexone, and the two shouldn’t be confused. Naloxone is a fast-acting medication that’s used when needed to reverse the effects of an opioid overdose.
9. Diuretics, such as hydrochlorothiazide
Diuretics (water pills) work by removing extra fluid from the body through your urine. This helps treat medical conditions like high blood pressure and heart failure. Examples of diuretics include furosemide (Lasix) and hydrochlorothiazide (Microzide).
Diuretics may be less effective when combined with oxycodone. This is because oxycodone may release a substance called antidiuretic hormone (ADH). ADH counteracts the effects of diuretics.
If you take oxycodone and a diuretic, watch for signs your heart condition may be worsening. Signs may include peeing less, swollen legs and feet, or higher blood pressure. Let your healthcare team know if you experience any of these symptoms.
10. Anticholinergic medications, such as dicyclomine
Anticholinergic medications are a broad group of medications that block the effects of acetylcholine in the body. Acetylcholine is a chemical that’s essential for brain and muscle function.
Anticholinergic medications can cause many side effects. These include dry mouth, trouble peeing, constipation, and more. Examples of anticholinergic medications include scopolamine (Transderm Scop), dicyclomine, and oxybutynin. Other medications, such as diphenhydramine and TCAs, also have anticholinergic effects.
Oxycodone and other opioids can cause anticholinergic side effects, too, especially in older adults. Before starting oxycodone, ask your pharmacist if any of your medications have anticholinergic effects. And watch for signs of worsening side effects like trouble peeing or constipation.
Frequently asked questions about oxycodone interactions
Yes, in most cases you can take nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen (Advil, Motrin) or naproxen (Aleve, Naprosyn) with oxycodone. There’s even a medication that’s a combination pill containing both oxycodone and ibuprofen. But keep in mind that NSAIDs aren’t right for everyone because of certain risks. So check with your healthcare team before taking an NSAID.
Yes, it’s safe to take oxycodone with acetaminophen (Tylenol). There aren’t any extra risks from combining these two medications. In fact, a medication called Percocet combines both oxycodone and acetaminophen.
While acetaminophen is safe for most people, it’s a good idea to check with your healthcare team before taking it with oxycodone.
Oxycodone most notably interacts with St. John’s wort. St. John’s wort is an OTC dietary supplement that's sometimes marketed to treat depression. Taking St. John’s wort with oxycodone can make your body break down oxycodone faster. When that happens, there’s less of the medication in your system, so it may not ease your pain as well as it should. Because of this, it’s best to avoid using St. John’s wort and oxycodone together. Separately, there’s also a risk of serotonin syndrome.
Yes, in most cases you can take nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen (Advil, Motrin) or naproxen (Aleve, Naprosyn) with oxycodone. There’s even a medication that’s a combination pill containing both oxycodone and ibuprofen. But keep in mind that NSAIDs aren’t right for everyone because of certain risks. So check with your healthcare team before taking an NSAID.
Yes, it’s safe to take oxycodone with acetaminophen (Tylenol). There aren’t any extra risks from combining these two medications. In fact, a medication called Percocet combines both oxycodone and acetaminophen.
While acetaminophen is safe for most people, it’s a good idea to check with your healthcare team before taking it with oxycodone.
Oxycodone most notably interacts with St. John’s wort. St. John’s wort is an OTC dietary supplement that's sometimes marketed to treat depression. Taking St. John’s wort with oxycodone can make your body break down oxycodone faster. When that happens, there’s less of the medication in your system, so it may not ease your pain as well as it should. Because of this, it’s best to avoid using St. John’s wort and oxycodone together. Separately, there’s also a risk of serotonin syndrome.
The bottom line
Oxycodone (Roxicodone, OxyContin) is an opioid pain medication. It’s a controlled substance and comes with many risks, including drug interactions. Oxycodone interactions could cause worsening side effects like drowsiness and constipation. They could also cause severe side effects, including trouble breathing and overdose.
Examples of oxycodone interactions to avoid include benzodiazepines such as alprazolam (Xanax), alcohol, and sleep medications such as zolpidem (Ambien). Other interactions are also possible, including cyclobenzaprine (Amrix), fluoxetine (Prozac), and Benadryl (diphenhydramine). Ask your pharmacist to screen for oxycodone interactions before you start taking it. Giving them your current medication list will allow them to do this.
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References
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Prostran, M., et al. (2023). Pharmacotherapy of pain in the older population: the place of opioids. Frontiers in Aging Neuroscience.
Sam, C., et al. (2023). Physiology, acetylcholine. StatPearls.
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