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Oxycodone interactions to avoid

Other opiate agonist mediciations can intensify or worsen the depressive effects of oxycodone
Kristi Torres writer headshot
By | Feb. 1, 2024
Rx pill bottle and Rx prescription pad: Oxycodone interactions

Key takeaways

  • Oxycodone and other class II opiates carry a warning from the U.S. Food and Drug Administration (FDA) due to the potential for addiction, abuse, and misuse of oxycodone and similar drugs. Patients with a history of addiction or drug abuse may not be candidates for opioid pain therapy.

  • You should be very cautious when combining oxycodone with other opiates, sedatives, or sleep medications, as the combined depression of the central nervous system can be dangerous, especially concerning the respiratory system.

  • Some commonly used drugs can increase blood levels of oxycodone, prolonging or worsening side effects. These include erythromycin (antibiotic), ketoconazole (antifungal), and ritonavir (antiviral).

  • Some drugs can cause oxycodone to be metabolized faster and, therefore, be less effective. These include Carbamazepine (antiseizure), phenytoin (antiseizure), or rifampin (antimicrobial for tuberculosis).

  • If you suspect you are having an interaction between oxycodone and another drug you are taking, speak to our prescriber immediately. Make sure family or friends know you are taking oxycodone and are aware of the signs and symptoms of an oxycodone interaction. If you become over-sedated or have trouble breathing, they should take you to seek emergency care immediately. In some cases, it may be advisable to keep Narcan on hand to reverse high opiate drug levels.

In this article:

Oxycodone is a prescription-only narcotic pain medication that belongs to a class of drugs known as opiates. Oxycodone is intended for acute severe or persistent severe pain for which other treatments have been inadequate. Oxycodone can be a first-choice opiate in opiate-naive patients. It has been used off-label for diabetic neuropathy and restless leg syndrome. Oxycodone is available in many forms and brand names, including immediate-release tablets and capsules (Roxicodone), extended-release tablets (OxyContin), and a concentrated oral solution.

Oxycodone can interact with a variety of other types of medications, including other opioids, sleeping medications, antidepressants, and sedatives. It may also interact with headache treatments, medications for nausea and vomiting, or even over-the-counter cold medications. It’s essential to be aware of interactions with oxycodone if you begin therapy. Some interactions can lead to over-sedation, making it difficult to function in your daily activities. These interactions have the potential to cause life-threatening respiratory depression in some cases. Speak to your prescriber and pharmacist before taking oxycodone.

Oxycodone drug interactions

Oxycodone interactions can be described in three primary forms: 

  1. The interacting drug causes similar CNS depressive effects to oxycodone, and the additive effects can be dangerous.
  2. The interacting drug causes an increase in oxycodone levels, leaving a patient prone to exacerbated or dangerous side effects.
  3. The interacting drug causes oxycodone to be metabolized faster than intended, which may render it less effective in pain relief.

Milder side effects of opiates include drowsiness, nausea, and constipation. These will also be more severe with some drug interactions. Do not take oxycodone if you are pregnant or breastfeeding without explicit consent from your healthcare provider.

Below are some of the most common interacting classes or types of medications. You should speak to your healthcare professional for the most comprehensive list of potential interactions.

Other opioid analgesics

Oxycodone is an opioid, and other opiate agonist medications can potentiate or make worse the depressive effects of the involved drugs. This can lead to profound respiratory depression and difficulty breathing marked sedation, and, in some rare cases, coma. Patients with a history of addiction or abuse of opiates should have counseling to this effect if opiate treatment is necessary. Buprenorphine products may be a better choice for these patients. Drugs purchased from non-licensed sources could be laced with opiates without the knowledge of the user, and this can be very dangerous. Patients should not take more than one opiate at a time without direct oversight by a qualified physician.

Examples: Dilaudid (hydromorphone), Vicodin (hydrocodone/ acetaminophen), MS Contin (morphine), Duragesic (fentanyl), Opana (oxymorphone), Vicoprofen (hydrocodone/ ibuprofen), methadone, codeine

Benzodiazepines

Benzodiazepines are a class of medications used most commonly for anxiety and sedation. They cause marked CNS depression, much like opiates. The combined effects of CNS depression from opiates and benzodiazepines can also lead to respiratory depression, increased sedation, or even coma. Benzodiazepines are also a class of controlled substances that are abused or misused at times, and addiction is a possibility. Combining oxycodone and benzodiazepines should be done with extreme caution and under the direct supervision of a healthcare provider.

Examples: Ativan (lorazepam), Klonopin (clonazepam), Valium (diazepam), Xanax (alprazolam)

Seizure medications

Some seizure medications are 3A4 inducers. This leads to oxycodone being metabolized more quickly than expected, and this could lead to subtherapeutic levels of oxycodone and insufficient pain relief. If a patient is oxycodone dependent, this could also lead to symptoms of withdrawal, such as anxiety, restlessness, nausea, vomiting, stomach cramps, and sweating. If one of these seizure medications becomes necessary, you may need to titrate the oxycodone dose in small increments with monitoring to avoid withdrawal symptoms.

Examples: Tegretol (carbamazepine), Dilantin (phenytoin)

Macrolide antibiotics

Macrolide antibiotics are CYP3A4 inhibitors. Oxycodone depends upon 3A4 to be metabolized and excreted from the body as designed. When 3A4 is inhibited, oxycodone levels begin to increase in the blood, and therefore, side effects, such as sedation, dizziness, or even difficulty breathing, can be exacerbated. There are likely other antibiotic class choices for many infection types that will not interfere with opiate metabolism, and it is probably safest to choose a different antibiotic. If a macrolide is the only appropriate antibiotic, your prescriber should consider lowering your oxycodone dose while on the macrolide.

Examples: Ery-Tab (Erythromycin), Biaxin (clarithromycin)

Azole antifungals

Azole antifungals are also 3A4 inhibitors. Similarly, they can lead to an increase in oxycodone levels. Unfortunately, there aren’t many alternatives to azole antifungals when they are needed for fungal infections. Prescribers should consider lowering the dose of oxycodone while on azole therapy. 

Examples: Ketodan (ketoconazole), Sporanox (itraconazole)

Serotonergic drugs

Oxycodone and other opioid medications can affect serotonin levels in the central nervous system. There are a variety of other drugs which interact with the serotonin receptors in the CNS as well. Combining opiates with these drugs has the potential to lead to serotonin syndrome, a result of too much free serotonin in the CNS. Serotonin syndrome can lead to agitation, insomnia, confusion, rapid heart rate, high blood pressure, and muscle twitching. While it may not happen to everyone, if the combination of oxycodone with a serotonin drug is necessary, the patient should know what symptoms to monitor for. A few different classes of serotonergic drugs may interact this way, and some examples are listed below.

Examples of serotonergic drug classes:

Monoamine oxidase inhibitors (MAOIs)

MAOIs are serotonergic drugs that can lead to serotonin syndrome, as referenced above. More importantly, the enzyme inhibition caused by MAOIs can lead to toxic levels of oxycodone and fatal respiratory syndrome. You should stop an MAOI for 14 days before initiating oxycodone or any opiate drug.

Examples: Nardil (phenelzine), Zyvox (linezolid)

This list of potential interactions is not intended to be all-inclusive. There are many other interactions documented with oxycodone. Some include muscle relaxers like cyclobenzaprine, diuretics, and anticholinergic drugs. Consult your pharmacist for a complete list of detailed interactions.

Oxycodone food interactions

Prescribers and pharmacists have historically recommended that you take oxycodone and similar opiates with food. This is thought to help alleviate the stomach upset that can result from opiate intake. Some data suggest taking oxycodone with a high-fat meal can increase the bioavailability and plasma concentration of oxycodone following ingestion. However, despite this effect, efficacy and adverse events were similar to those who took it on an empty stomach.

Oxycodone and grapefruit

Grapefruit is a strong CYP3A4 inhibitor. As with other drugs that inhibit 3A4, this can lead to increased blood levels of oxycodone. Adverse effects such as sedation and breathing problems can be increased and prolonged by this. It is best to avoid consuming grapefruit or grapefruit juice when taking oxycodone.

Other oxycodone interactions

There are a few other considerations when taking oxycodone and avoiding interactions that can affect oxycodone efficacy and absorption. Prescription drugs aren’t the only substances that can interact with oxycodone. Alcohol and other supplements can affect oxycodone, and your body functions as well.

Oxycodone and alcohol 

While taking oxycodone, one should avoid alcohol consumption. Alcohol causes CNS depression, and the additive effect of oxycodone can be lethal. A person’s alcohol consumption should be considered before prescribing oxycodone. Abuse or misuse of alcohol could be indicative of that tendency with drugs such as oxycodone. Dangerous respiratory depression can occur. If this combination is suspected, it would be prudent to keep Naloxone (naltrexone) on hand.

Oxycodone and disease/CBD/illicit drugs/vitamins/herbal supplements/etc. 

Cannabis and its derivatives are known to cause CNS depression, and like with other CNS depressants, the effect of oxycodone is addictive. Marked sedation can occur, as well as respiratory depression. It is prudent to use the lowest effective dose of oxycodone if it is the only treatment option for a patient who uses cannabis.

How to minimize oxycodone interactions

Before taking oxycodone, provide a complete list of medications and supplements you are taking to your prescriber. It is vital to note any medications that may cause serious side effects, such as drowsiness or slow breathing. Take oxycodone only when needed or as prescribed and at the lowest effective dose. It is important to try other interventions that may help with pain and decrease the needed oxycodone dose. For acute pain, take the oxycodone only for as long as required or until the pain subsides enough to be treated with non-opiate options. Due to the need for routine dosing in chronic pain, work with your provider for the lowest effective dose to minimize side effects.

If you are on other CNS depressants, you should keep Narcan available at all times and make sure those around you know how to use it and what the symptoms of an opioid overdose are. Narcan can reverse the effects of an opioid overdose and sustain life until medical help can be obtained.

When to talk to a healthcare provider about oxycodone interactions

If you notice a change in the way oxycodone is working or the intensity of the side effects, speak to your healthcare provider immediately. Before starting any new therapy, make sure the prescriber is aware that you are taking oxycodone. Your pharmacist can screen for any potential interactions as well. If you feel that oxycodone isn’t working as well as it used to, or you feel that the adverse events have increased in intensity, speak to your healthcare professional immediately.