Oxycodone is a powerful semi-synthetic opioid agonist prescribed to manage moderate to severe pain [1.7.1, 1.2.4]. It works by binding to opioid receptors in the central nervous system (CNS) to alter the perception of pain [1.7.1]. While effective, its use carries significant risks, including the potential for addiction, misuse, and life-threatening adverse effects, especially when combined with other substances [1.2.3, 1.2.4]. The U.S. Food and Drug Administration (FDA) has issued numerous warnings, including boxed warnings, about these dangers [1.3.3, 1.3.6]. A contraindication is a specific situation in which a drug should not be used because it may be harmful to the person [1.2.6]. Understanding which medications are contraindicated or have dangerous interactions with oxycodone is vital for safety.
Central Nervous System (CNS) Depressants
Combining oxycodone with other substances that depress the central nervous system is extremely dangerous. These interactions can potentiate the effects of each drug, leading to profound sedation, respiratory depression, coma, and death [1.2.5, 1.2.6]. The risk is so significant that the FDA requires boxed warnings on opioids and benzodiazepines detailing this danger [1.3.3].
Benzodiazepines
Benzodiazepines (sometimes called "benzos") are prescribed for anxiety, insomnia, and seizures [1.3.1]. Common examples include alprazolam (Xanax), diazepam (Valium), clonazepam (Klonopin), and lorazepam (Ativan) [1.3.2]. When taken with oxycodone, the combination can cause extreme sleepiness and severely slow or stop breathing [1.3.1, 1.3.3]. Studies have shown that the overdose death rate for patients receiving both opioids and benzodiazepines is significantly higher—up to 10 times higher in one study—than for those only receiving opioids [1.3.5]. Healthcare providers are urged to avoid prescribing these medications concurrently unless no other alternatives are available [1.3.3].
Alcohol
Alcohol is another potent CNS depressant. Mixing oxycodone with alcohol can lead to unpredictable and harmful effects, including a high risk of overdose [1.2.2]. This combination can severely slow breathing and heart rate, leading to loss of consciousness and death [1.2.2]. Patients taking oxycodone should be counseled to avoid all alcoholic beverages and medications that contain alcohol [1.6.1].
Other CNS Depressants
Other drug classes that act as CNS depressants should also be used with extreme caution or avoided entirely. These include:
- Muscle Relaxants: Medications like cyclobenzaprine (Flexeril) can increase sedation and the risk of respiratory depression when combined with oxycodone [1.4.1].
- Sleep Medications: Drugs such as zolpidem (Ambien) can amplify sedation and cognitive impairment, increasing the risk of accidents and overdose [1.4.1].
- Antipsychotics: Medications like quetiapine (Seroquel) can lead to extreme drowsiness and impaired motor coordination [1.4.1].
- Other Opioids: Using oxycodone with other opioid pain medicines or prescription cough medicines multiplies the depressant effects [1.2.3].
MAOIs and Serotonergic Drugs
Another critical area of contraindication involves medications that affect serotonin levels in the brain.
Monoamine Oxidase Inhibitors (MAOIs)
MAOIs are a class of antidepressants that can have a dangerous, potentially fatal interaction with opioids. You should not use oxycodone if you have used an MAO inhibitor within the past 14 days [1.2.3]. Examples of MAOIs include phenelzine (Nardil), tranylcypromine (Parnate), and isocarboxazid (Marplan) [1.2.3, 1.4.1]. The combination can lead to serotonin syndrome, a life-threatening condition characterized by high levels of serotonin in the brain [1.4.1, 1.4.3]. Symptoms include delirium, convulsions, respiratory failure, and coma [1.2.2].
Serotonin Syndrome Risk with Other Antidepressants
While MAOIs pose the highest risk, other antidepressants can also interact with oxycodone to cause serotonin syndrome [1.5.1]. This includes Selective Serotonin Reuptake Inhibitors (SSRIs) like sertraline (Zoloft) and fluoxetine (Prozac), as well as Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs) [1.4.1, 1.5.1]. Symptoms to watch for include agitation, hallucinations, rapid heart rate, fever, muscle twitching, and nausea [1.5.1]. While some sources indicate that oxycodone itself is not a Serotonin Reuptake Inhibitor (SRI) and therefore has a lower risk of causing serotonin toxicity compared to opioids like tramadol or pethidine, case reports of serotonin syndrome with oxycodone and SSRIs do exist, warranting close monitoring [1.4.4, 1.5.2, 1.5.4].
Opioid Antagonists
Opioid antagonists like naltrexone (Vivitrol) are absolutely contraindicated with oxycodone [1.6.1, 1.6.2]. Naltrexone works by blocking the effects of opioid medications [1.6.1]. Taking naltrexone while on oxycodone will not only render the pain medication ineffective but can also precipitate severe and sudden opioid withdrawal symptoms [1.6.2]. It is recommended to be free of opioids for 7 to 10 days before starting naltrexone [1.6.3]. Naloxone (Narcan) is another opioid antagonist used specifically for the emergency reversal of an opioid overdose [1.6.2].
Medications Affecting Drug Metabolism (CYP3A4/CYP2D6)
Oxycodone is primarily metabolized in the liver by enzymes known as CYP3A4 and CYP2D6 [1.7.1]. Medications that inhibit or induce these enzymes can dangerously alter the concentration of oxycodone in the blood.
- CYP3A4 Inhibitors: These drugs block the metabolism of oxycodone, leading to increased plasma concentrations. This can prolong the drug's effects and increase the risk of a potentially fatal respiratory depression [1.7.1]. Examples include certain macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), and protease inhibitors [1.7.1, 1.7.3]. Grapefruit juice is also a known CYP3A4 inhibitor [1.7.3].
- CYP3A4 Inducers: These drugs have the opposite effect, speeding up oxycodone's metabolism and reducing its effectiveness. This can lead to inadequate pain control or withdrawal symptoms [1.7.1]. Examples include rifampin, carbamazepine, and phenytoin [1.7.1].
| Drug Class | Examples | Primary Risk of Interaction with Oxycodone |
|---|---|---|
| Benzodiazepines | Alprazolam (Xanax), Diazepam (Valium) | Profound sedation, severe respiratory depression, coma, death [1.3.1, 1.3.5] |
| Alcohol | Beer, wine, spirits | High risk of overdose, slowed breathing and heart rate, death [1.2.2] |
| MAOIs | Phenelzine (Nardil), Tranylcypromine (Parnate) | Serotonin syndrome, delirium, convulsions, respiratory failure [1.2.2, 1.2.3] |
| Opioid Antagonists | Naltrexone (Vivitrol) | Blocks opioid effects, precipitates severe withdrawal symptoms [1.6.1, 1.6.2] |
| CYP3A4 Inhibitors | Ketoconazole, Erythromycin, Grapefruit Juice | Increased oxycodone levels, risk of fatal respiratory depression [1.7.1, 1.7.3] |
| Other CNS Depressants | Muscle Relaxants, Sleep Aids, Antipsychotics | Increased sedation, cognitive impairment, respiratory depression [1.4.1] |
Conclusion
Due to the serious risks involved, it is crucial for patients to provide their healthcare provider with a complete list of all medications they are taking, including prescription, over-the-counter, and herbal supplements [1.2.3, 1.3.5]. Combining oxycodone with contraindicated medications, particularly other CNS depressants like benzodiazepines and alcohol, can have fatal consequences [1.2.5]. Always follow the guidance of a healthcare professional and never mix medications without their explicit instruction. If you or someone you know experiences symptoms like slowed breathing, extreme drowsiness, or unresponsiveness after taking oxycodone, seek emergency medical help immediately [1.3.3].
For more information on opioid safety and drug interactions, you can visit the U.S. Food and Drug Administration (FDA) website.
