Oxycodone rarely causes trouble on its own when it is taken as prescribed. Most of the serious problems people run into come from what it is combined with: a sleeping pill, a few beers, a five-day antibiotic, an herbal supplement. This page is a reference list of the oxycodone drug interactions patients and caregivers ask about most, arranged A to Z so you can find a name fast and know what to ask your prescriber or pharmacist.
Each entry has four lines: what it is, the interaction, a severity label, and what to do, with links to longer articles where we have them.
How to Read This List
Every entry carries one of three labels. They reflect the prescribing information and FDA safety communications. They are general categories, not personal advice. Your prescriber may deliberately combine two “Avoid” medicines with a monitoring plan, and a “Usually OK” pair can be a bad idea for someone with kidney disease, sleep apnea or advanced age.
- Avoid: The combination carries a high risk of life-threatening harm or makes oxycodone stop working. Only a prescriber who knows about both should decide otherwise.
- Use only with close monitoring: The two can be used together, but only when your prescriber knows about it, may adjust doses, and you watch for specific warning signs.
- Usually OK with care: Commonly used together; there is still a limit, side effect or warning sign to know.
One more tag, Rescue, appears only once: naloxone. It is not a risky combination; it is the antidote.
Six Ways Oxycodone Interactions Happen
Almost every entry fits one of six mechanisms, which helps you spot risky pairs not listed here. The categories come from the drug interactions section of the FDA-approved Roxicodone prescribing information.
| Mechanism | What happens | Common examples | Main risk |
|---|---|---|---|
| 1. Added CNS depression | Both substances slow the brain and breathing; effects stack | Benzodiazepines, alcohol, gabapentin, pregabalin, sleep medicines, muscle relaxants, sedating antihistamines | Extreme sleepiness, slow or stopped breathing, coma, death |
| 2. CYP3A4 changes | Inhibitors block the liver enzyme that clears oxycodone, so levels rise. Inducers speed it up, so levels fall; stopping an inducer makes levels climb again | Inhibitors: azole antifungals, clarithromycin, erythromycin, ritonavir and some other HIV drugs, grapefruit. Inducers: rifampin, carbamazepine, phenytoin, St John’s wort | Inhibitors: overdose-type effects. Inducers: poor pain control or withdrawal, then overdose risk when the inducer stops |
| 3. Serotonin and MAOI effects | Too much serotonin activity; MAOIs also cause unpredictable blood pressure and breathing effects | SSRIs, SNRIs, tricyclics, triptans, tramadol, linezolid, phenelzine | Serotonin syndrome (agitation, fever, sweating, stiff or twitching muscles); MAOI reactions |
| 4. Opioid receptor blockers and partial agonists | The other drug grabs the same receptor and pushes oxycodone off or blocks it | Buprenorphine, butorphanol, nalbuphine, pentazocine, naltrexone | Sudden withdrawal and loss of pain relief |
| 5. Anticholinergic effects | Both slow the bladder and gut | Diphenhydramine, amitriptyline, oxybutynin, some older bladder and stomach medicines | Urinary retention, severe constipation, paralytic ileus |
| 6. Diuretic effects | Opioids can trigger release of antidiuretic hormone, blunting a water pill | Furosemide, hydrochlorothiazide | Water pill works less well; fluid buildup in heart or kidney patients |
Mechanism 2 can strike days after a change. Our explainer on how the body breaks down oxycodone walks through the liver enzymes involved.
Two FDA warnings worth knowing. On August 31, 2016, the FDA required its strongest warning, a boxed warning, on opioid pain and cough medicines and on benzodiazepines after finding that using them together was causing serious breathing problems and deaths (FDA Drug Safety Communication, 2016). On December 19, 2019, the FDA warned that gabapentin and pregabalin can cause serious breathing problems in people who also take opioids or other sedating drugs, who have lung disease such as COPD, or who are older (FDA Drug Safety Communication, 2019).
Oxycodone Interactions From A to Z
Brand names are examples. A missing medicine is not automatically safe; ask your pharmacist.
Acetaminophen (Tylenol)
- What it is: An OTC pain reliever, also in Percocet and many cold products.
- Interaction: No dangerous chemical interaction; the risk is accidentally doubling up on acetaminophen, which can damage the liver.
- Severity: Usually OK with care.
- What to do: Check whether your oxycodone product already contains acetaminophen, and ask your pharmacist for your personal daily limit. See taking Tylenol with oxycodone and our acetaminophen and oxycodone dosing overview.
Alcohol
- What it is: Any drink, plus alcohol in some liquid cold medicines.
- Interaction: Added CNS depression. The Roxicodone label names alcohol alongside benzodiazepines in its boxed warning.
- Severity: Avoid.
- What to do: Skip alcohol while taking oxycodone, including “just one” at night. More detail in oxycodone and alcohol risks.
Alprazolam and Other Benzodiazepines
- What it is: Anxiety, panic and sleep medicines such as alprazolam (Xanax), diazepam (Valium), lorazepam (Ativan) and clonazepam (Klonopin).
- Interaction: Added CNS depression, covered by the 2016 FDA boxed warning. A study the FDA cited found about ten times the overdose death rate versus opioids alone.
- Severity: Avoid, unless one prescriber knowingly manages both with the lowest doses and shortest duration.
- What to do: Never add a leftover or borrowed benzodiazepine. Read whether oxycodone and Valium can be taken together, and our overview of anti-anxiety medication options.
Amitriptyline and Other Tricyclic Antidepressants
- What it is: Older antidepressants often used in low doses for nerve pain and sleep.
- Interaction: Sedation, serotonergic and anticholinergic overlap.
- Severity: Use only with close monitoring.
- What to do: Report heavy drowsiness or trouble urinating.
Antihistamines (Diphenhydramine, Doxylamine, Promethazine)
- What it is: Sedating allergy and sleep ingredients found in Benadryl, “PM” pain relievers, NyQuil-type products, Unisom, and prescription promethazine (Phenergan).
- Interaction: Added CNS depression plus anticholinergic effects. Promethazine is especially sedating.
- Severity: Use only with close monitoring.
- What to do: Read “Active ingredients” on every cold, allergy and sleep box. Ask about non-sedating options. A related pairing is covered in NyQuil with tramadol.
Aspirin
- What it is: An NSAID for pain and, in low doses, heart protection.
- Interaction: No major direct interaction; stomach bleeding is the concern when stacked with other NSAIDs.
- Severity: Usually OK with care.
- What to do: Do not stop a prescribed heart aspirin on your own, and avoid adding other NSAIDs without asking. See aspirin with oxycodone.
Baclofen
- What it is: A muscle relaxant for spasticity.
- Interaction: Added CNS depression. The label notes muscle relaxants can deepen breathing suppression.
- Severity: Use only with close monitoring.
- What to do: Ask whether either dose should be lower, and avoid driving until you know the combined effect. The same reasoning applies to tramadol and baclofen together.
Buprenorphine (Suboxone) and Mixed Agonist/Antagonists
- What it is: Buprenorphine treats opioid use disorder and some pain. Butorphanol, nalbuphine and pentazocine are related pain drugs.
- Interaction: They bind tightly to opioid receptors, which can blunt oxycodone’s pain relief or trigger sudden withdrawal.
- Severity: Avoid, unless a clinician is deliberately managing a transition or surgery plan.
- What to do: If you are on buprenorphine and need pain treatment, tell every clinician first. Background in buprenorphine vs Suboxone.
Cannabis (Marijuana, THC Edibles)
- What it is: Smoked, vaped or edible THC.
- Interaction: Added sedation and impaired coordination. Edibles kick in late, which makes stacking easy.
- Severity: Use only with close monitoring.
- What to do: Be honest with your prescriber, even where cannabis is legal. Never drive on the combination.
Carbamazepine
- What it is: A seizure and nerve pain medicine (Tegretol).
- Interaction: CYP3A4 inducer. Oxycodone may work less well; if carbamazepine is stopped, oxycodone levels can rise. It is also sedating.
- Severity: Use only with close monitoring.
- What to do: Tell your pain prescriber before carbamazepine is started, changed or stopped.
Clarithromycin and Erythromycin
- What it is: Macrolide antibiotics for chest infections, strep and H. pylori.
- Interaction: CYP3A4 inhibitors that can raise oxycodone levels within days.
- Severity: Use only with close monitoring.
- What to do: If urgent care prescribes one, mention oxycodone; ask whether another antibiotic would work. Watch for new drowsiness during the course.
Cyclobenzaprine
- What it is: A common muscle relaxant (Flexeril) for back and neck strain.
- Interaction: Sedation plus serotonergic and anticholinergic activity, since it is chemically related to tricyclics.
- Severity: Use only with close monitoring.
- What to do: Ask whether both are needed at the same time of day, and do not combine with alcohol or sleep aids.
Diuretics (Water Pills)
- What it is: Furosemide (Lasix), hydrochlorothiazide and similar drugs for blood pressure, heart failure and swelling.
- Interaction: Opioids can make diuretics less effective. Combined dizziness on standing is also common.
- Severity: Usually OK with care.
- What to do: Heart failure patients should report sudden weight gain or swelling.
Fluconazole
- What it is: An antifungal (Diflucan) used for yeast infections, sometimes as a single dose.
- Interaction: CYP3A4 inhibitor; can raise oxycodone levels, especially with longer courses.
- Severity: Use only with close monitoring.
- What to do: Tell the prescriber of either drug about the other. Full details in fluconazole and oxycodone interactions.
Gabapentin
- What it is: A nerve pain and seizure medicine (Neurontin, Gralise, Horizant).
- Interaction: Added CNS and breathing depression, the subject of the 2019 FDA warning.
- Severity: Use only with close monitoring.
- What to do: This pair is often prescribed on purpose. Know the warning signs, start low as directed, and take extra care if you are older or have COPD. Compare with gabapentin and hydrocodone, a closely related combination.
Grapefruit and Grapefruit Juice
- What it is: The fruit and its juice; Seville oranges and pomelos too.
- Interaction: Inhibits CYP3A4 in the gut and can raise oxycodone exposure. MedlinePlus advises talking to your doctor about grapefruit while on oxycodone.
- Severity: Avoid regular use unless your prescriber says otherwise.
- What to do: Switch to orange or apple juice. Other food questions are covered in foods to avoid while taking oxycodone; morning coffee is a separate, milder question addressed in coffee and oxycodone.
Ibuprofen and Naproxen (NSAIDs)
- What it is: Anti-inflammatory pain relievers (Advil, Motrin, Aleve).
- Interaction: No dangerous direct interaction, and often combined on purpose to reduce opioid needs. NSAID risks (stomach, kidneys, blood pressure) still apply.
- Severity: Usually OK with care.
- What to do: Use one NSAID at a time, take with food, and ask first if you have kidney disease or ulcers. See ibuprofen with oxycodone and naproxen with oxycodone.
Itraconazole, Ketoconazole and Voriconazole
- What it is: Prescription antifungals for serious or stubborn infections.
- Interaction: Strong CYP3A4 inhibitors; among the most powerful level-raisers on this list.
- Severity: Use only with close monitoring.
- What to do: Expect your prescriber to consider a lower oxycodone dose or a different antifungal. Watch for sleepiness or slow breathing.
Kratom
- What it is: A plant product whose compounds act on opioid receptors.
- Interaction: Opioid-like effects stack on top of oxycodone. The FDA warns consumers not to use kratom and notes that reported deaths usually involved other drugs as well.
- Severity: Avoid.
- What to do: Do not combine. If you have been using kratom, tell your prescriber so they can plan safely.
Linezolid and MAO Inhibitors
- What it is: MAOI antidepressants (phenelzine, tranylcypromine, isocarboxazid), selegiline, the antibiotic linezolid, and methylene blue.
- Interaction: Serotonin syndrome and unpredictable opioid toxicity. The label advises against oxycodone during or within 14 days of an MAOI.
- Severity: Avoid.
- What to do: Mention any MAOI from the past two weeks before starting oxycodone.
Methadone
- What it is: A long-acting opioid used for pain and for opioid use disorder.
- Interaction: Two full opioids together add up. Methadone lingers for days.
- Severity: Avoid, unless directly coordinated by your methadone clinic and pain prescriber.
- What to do: Give your clinic and pain team permission to talk to each other. For context, see Suboxone vs methadone.
Naloxone (Narcan)
- What it is: The opioid overdose reversal medicine. Narcan 4 mg nasal spray was approved for over-the-counter sale on March 29, 2023.
- Interaction: It knocks oxycodone off its receptors. In someone who takes opioids daily this can cause abrupt withdrawal, which is unpleasant but far safer than an untreated overdose.
- Severity: Rescue.
- What to do: Keep it at home, show family where it is, and call 911 after using it.
Naltrexone (Vivitrol, Contrave)
- What it is: An opioid blocker used for alcohol and opioid use disorder, and an ingredient in the weight-loss pill Contrave.
- Interaction: Blocks oxycodone’s effect and can trigger withdrawal. Trying to override the block with more oxycodone can lead to overdose.
- Severity: Avoid.
- What to do: If surgery or an injury is planned, tell the care team you take naltrexone (including the monthly shot) so they can plan pain control.
Ondansetron (Zofran)
- What it is: An anti-nausea medicine often given alongside oxycodone after surgery.
- Interaction: Opioid labels list 5-HT3 blockers such as ondansetron among serotonergic drugs. Problems are uncommon.
- Severity: Usually OK with care.
- What to do: Know the serotonin syndrome signs listed below, especially if you also take an antidepressant.
Phenytoin
- What it is: A long-standing seizure medicine (Dilantin).
- Interaction: CYP3A4 inducer, similar to carbamazepine: lower oxycodone levels while on it, higher levels if it is stopped.
- Severity: Use only with close monitoring.
- What to do: Never stop phenytoin abruptly (seizure risk), and tell your pain prescriber about any change.
Pregabalin (Lyrica)
- What it is: A nerve pain and fibromyalgia medicine closely related to gabapentin.
- Interaction: Added CNS and breathing depression; included in the 2019 FDA warning.
- Severity: Use only with close monitoring.
- What to do: Same precautions as gabapentin. Our comparison of gabapentin vs Lyrica explains how the two differ.
Rifampin
- What it is: An antibiotic for tuberculosis, given for months.
- Interaction: A strong CYP3A4 inducer that can sharply lower oxycodone levels.
- Severity: Use only with close monitoring.
- What to do: If pain control drops, call your prescriber. The higher-risk moment is when rifampin finishes and levels rebound.
Ritonavir (Including Paxlovid)
- What it is: An HIV “booster” and half of the COVID-19 treatment Paxlovid. Cobicistat behaves similarly.
- Interaction: A strong CYP3A4 inhibitor that can substantially raise oxycodone levels, even during a five-day course.
- Severity: Use only with close monitoring.
- What to do: Before filling Paxlovid, tell the prescriber and pharmacist about oxycodone. They may adjust the plan; do not change your dose on your own.
Sertraline and Other SSRIs/SNRIs
- What it is: Common antidepressants: sertraline (Zoloft), fluoxetine, escitalopram, paroxetine, duloxetine, venlafaxine.
- Interaction: Serotonergic; the oxycodone label carries a serotonin syndrome warning for this group. Fluoxetine and paroxetine also inhibit CYP2D6.
- Severity: Usually OK with care.
- What to do: Keep taking your antidepressant as prescribed and learn the warning signs. If low mood is new or worsening on oxycodone, read whether oxycodone can cause depression and raise it with your prescriber.
St John’s Wort
- What it is: An herbal mood supplement sold over the counter.
- Interaction: Double hit: a CYP3A4 inducer (lower levels, then a rebound when stopped) and serotonergic. MedlinePlus says not to start it during oxycodone treatment without talking to your provider.
- Severity: Avoid.
- What to do: If you already take it, ask before stopping or continuing. Other supplements are covered in vitamins and oxycodone.
Sumatriptan and Other Triptans
- What it is: Migraine treatments (Imitrex, rizatriptan, zolmitriptan).
- Interaction: Serotonergic; the risk rises if an SSRI or SNRI is also in the mix.
- Severity: Usually OK with care.
- What to do: Tell your prescriber how often you use one.
Tramadol
- What it is: A prescription opioid pain reliever (Ultram) that also boosts serotonin.
- Interaction: Two opioids at once (added breathing depression) plus serotonin syndrome and seizure risk.
- Severity: Avoid, unless one prescriber has planned it.
- What to do: Do not use leftover tramadol. How the two compare is covered in oxycodone vs tramadol.
Trazodone
- What it is: An antidepressant very often prescribed at low doses for sleep.
- Interaction: Sedating and serotonergic. It can also cause dizziness on standing.
- Severity: Use only with close monitoring.
- What to do: Ask whether the trazodone dose should be reviewed while you are on oxycodone.
Valerian, Melatonin and Other Sleep Supplements
- What it is: Valerian, kava and melatonin.
- Interaction: Valerian and kava can add sedation. Melatonin is milder, but evidence on combining it with opioids is limited.
- Severity: Use only with close monitoring (valerian, kava); usually OK with care (melatonin).
- What to do: List “natural” sleep products for your pharmacist.
Zolpidem and Other Z-Drugs
- What it is: Prescription sleep medicines: zolpidem (Ambien), eszopiclone (Lunesta), zaleplon.
- Interaction: Added CNS and breathing depression, plus a risk of sleepwalking or confusion at night.
- Severity: Use only with close monitoring.
- What to do: Ask whether you need both on the same night.
Letters skipped: E, H, J, Q, U, W, X and Y have no common, high-impact oxycodone interactions worth a separate entry, and E’s erythromycin sits with clarithromycin above. Hydroxyzine behaves like the sedating antihistamines.
Quick-Look Summary Table
| Substance | Interaction type | Severity |
|---|---|---|
| Acetaminophen | Duplicate ingredient / liver | Usually OK with care |
| Alcohol | CNS depression | Avoid |
| Benzodiazepines (alprazolam, diazepam) | CNS depression (boxed warning) | Avoid |
| Amitriptyline / tricyclics | CNS, serotonergic, anticholinergic | Close monitoring |
| Sedating antihistamines, promethazine | CNS, anticholinergic | Close monitoring |
| Aspirin | Bleeding (with other NSAIDs) | Usually OK with care |
| Baclofen | CNS depression | Close monitoring |
| Buprenorphine, butorphanol, nalbuphine, pentazocine | Receptor blocking / withdrawal | Avoid |
| Cannabis | CNS depression | Close monitoring |
| Carbamazepine | CYP3A4 inducer | Close monitoring |
| Clarithromycin, erythromycin | CYP3A4 inhibitor | Close monitoring |
| Cyclobenzaprine | CNS, serotonergic | Close monitoring |
| Diuretics | Reduced diuretic effect | Usually OK with care |
| Fluconazole | CYP3A4 inhibitor | Close monitoring |
| Gabapentin | CNS depression (2019 warning) | Close monitoring |
| Grapefruit | CYP3A4 inhibitor | Avoid |
| Ibuprofen, naproxen | NSAID side effects | Usually OK with care |
| Itraconazole, ketoconazole, voriconazole | Strong CYP3A4 inhibitor | Close monitoring |
| Kratom | Opioid-like stacking | Avoid |
| Linezolid, MAOIs | Serotonin / MAOI reaction | Avoid |
| Methadone | Opioid stacking | Avoid |
| Naloxone | Reversal agent | Rescue |
| Naltrexone | Receptor blocking / withdrawal | Avoid |
| Ondansetron | Serotonergic | Usually OK with care |
| Phenytoin | CYP3A4 inducer | Close monitoring |
| Pregabalin | CNS depression (2019 warning) | Close monitoring |
| Rifampin | Strong CYP3A4 inducer | Close monitoring |
| Ritonavir / Paxlovid | Strong CYP3A4 inhibitor | Close monitoring |
| SSRIs / SNRIs | Serotonergic | Usually OK with care |
| St John’s wort | Inducer + serotonergic | Avoid |
| Triptans | Serotonergic | Usually OK with care |
| Tramadol | Opioid stacking + serotonergic | Avoid |
| Trazodone | CNS, serotonergic | Close monitoring |
| Valerian, kava / melatonin | CNS depression | Close monitoring / Usually OK with care |
| Zolpidem and Z-drugs | CNS depression | Close monitoring |
How to Protect Yourself From Interactions
Most dangerous interactions happen through gaps: a dentist unaware of your sleeping pill, an urgent care antibiotic, an unmentioned supplement. Four habits close most of them.
- Use a single pharmacy. Its software flags clashes even between doctors who never talk to each other.
- Keep an updated medicine list. Include prescriptions, over-the-counter products, vitamins, herbal supplements, cannabis and alcohol. Bring it to every appointment, including dental visits.
- Ask before any OTC product. Cold, sleep and allergy products hide sedatives.
- Keep naloxone at home. MedlinePlus recommends asking about a rescue medicine and teaching household members to recognize an overdose. Store it where people can find it fast, separate from the locked spot where you keep oxycodone (see how to store oxycodone safely).
Older adults clear drugs more slowly and fall more easily, so pairs that are routine at 45 can be risky at 80; see oxycodone in elderly patients for more. COPD and sleep apnea also leave less breathing reserve.
Emergency Signs: When an Interaction Becomes an Emergency
The CDC’s naloxone guidance lists the overdose signs below. Call 911 right away for any of them:
- Cannot be woken up, or keeps nodding off mid-sentence
- Slow, shallow or irregular breathing, or gurgling and snoring sounds
- Blue or gray lips or fingernails
- Tiny “pinpoint” pupils
- Limp body or unusual confusion
If you see these, give naloxone if you have it, call 911, keep the person on their side, and stay with them. A second dose can be given after 2 to 3 minutes if breathing does not improve. For a broader list of warning signs, see signs your oxycodone dose is too high.
Serotonin syndrome looks different: agitation, hallucinations, fever, heavy sweating, fast heartbeat, shivering, stiff or twitching muscles, or loss of coordination, usually within hours of starting or raising a serotonergic drug. Seek emergency care. For urgent questions that are not emergencies, call Poison Help at 1-800-222-1222, any time, free. If you are in emotional crisis, call or text 988.
Frequently Asked Questions About Oxycodone Drug Interactions
Can I take Paxlovid for COVID-19 while I am on oxycodone?
Possibly, but not without telling the prescriber first. Paxlovid contains ritonavir, a strong CYP3A4 inhibitor that can push oxycodone levels much higher during the five-day course and for a few days afterward. The prescriber may adjust the plan or choose another treatment.
Is it safe to take Benadryl or a nighttime cold medicine with oxycodone?
Diphenhydramine and doxylamine, the sleepy ingredients in Benadryl and most “night” cold products, add sedation and can make it harder to pass urine or move your bowels. Some liquid cold medicines also contain alcohol. Ask your pharmacist for a non-sedating option.
How long after stopping an MAOI can I take oxycodone?
The Roxicodone prescribing information does not recommend oxycodone during MAOI treatment or within 14 days of stopping one. Linezolid falls under the same caution; mention any recent use before the first dose.
Why would finishing an antibiotic or changing a seizure medicine change how my oxycodone feels?
Drugs such as rifampin, carbamazepine and phenytoin speed up the liver enzyme that clears oxycodone, so the same dose does less. When they are stopped, the enzyme slows back down over days to weeks and oxycodone levels climb, sometimes into the overdose range. Either change is a reason to call your prescriber.
Is one glass of wine with dinner really a problem on oxycodone?
The label puts alcohol in the same boxed warning as benzodiazepines, and there is no officially safe amount. A drink that seems harmless one night can hit harder the next. The safest choice is no alcohol while you take oxycodone.
Can naloxone hurt someone who takes oxycodone every day?
Naloxone will not cause an overdose or poison anyone. In a person who uses opioids daily it can bring on sudden withdrawal, which is distressing but not usually dangerous. Because naloxone can wear off before oxycodone does, always call 911 and stay with the person after giving it.
Can I rely on an online interaction checker instead of asking my pharmacist?
Online checkers are a useful first look, but they cannot weigh your age, organ function, dose or other conditions. Use a checker to prepare questions, then let your pharmacist or prescriber make the call.