What medicines cannot be taken with hydrocodone?

October 15, 2025 •

3 min read

In 2021, nearly 14% of overdose deaths involving opioids also involved benzodiazepines. Knowing what medicines cannot be taken with hydrocodone is critical, as combining it with other substances can lead to severe side effects, including slowed breathing and death.

Quick Summary

Hydrocodone, an opioid pain reliever, should not be taken with alcohol, benzodiazepines, other CNS depressants, MAOIs, or certain antidepressants due to a high risk of severe sedation, respiratory depression, coma, and death.

Key Points

CNS Depressants: Combining hydrocodone with alcohol, benzodiazepines, muscle relaxants, or other opioids significantly increases the risk of fatal respiratory depression.
Boxed Warning: The FDA has a boxed warning for combining opioids and benzodiazepines due to the risk of profound sedation, coma, and death.
Metabolism Interference: CYP3A4 inhibitors (like ketoconazole) can dangerously increase hydrocodone levels, while CYP3A4 inducers (like St. John's Wort) can reduce its effectiveness.
Serotonin Syndrome: Mixing hydrocodone with MAOIs, SSRIs, or SNRIs can lead to a life-threatening condition called serotonin syndrome.
MAOIs: Hydrocodone should not be used within 14 days of taking a Monoamine Oxidase Inhibitor (MAOI) due to the risk of severe, unpredictable side effects.
Alcohol: No amount of alcohol is safe with hydrocodone; the combination can cause a fatal overdose and, if acetaminophen is present, severe liver damage.
Full Disclosure: Always inform your healthcare provider about all medications, supplements, and substances you take to avoid dangerous interactions.

Hydrocodone is a potent semi-synthetic opioid prescribed for moderate to severe pain. It works by interacting with opioid receptors in the brain and spinal cord, which reduces pain perception. As a central nervous system (CNS) depressant, hydrocodone slows brain activity, including vital functions like breathing. Combining it with other CNS depressants can be extremely dangerous and even fatal, making it essential to know which substances to avoid.

The Danger of Combining CNS Depressants

CNS depressants slow brain activity, and their sedative effects are amplified when combined with hydrocodone. This can result in significant drowsiness, dangerously slow breathing (respiratory depression), coma, and death. The FDA has issued a boxed warning about the risks of combining opioids like hydrocodone with benzodiazepines and other CNS depressants.

Benzodiazepines: A High-Risk Combination

Benzodiazepines, used for anxiety, insomnia, or seizures, are CNS depressants with a dangerous interaction profile with opioids. This combination greatly increases the risk of a fatal overdose.

Examples of Benzodiazepines: Alprazolam (Xanax), Clonazepam (Klonopin), Diazepam (Valium), and Lorazepam (Ativan).

Alcohol: A Common but Deadly Mix

No amount of alcohol is safe with hydrocodone. Alcohol is a CNS depressant. Mixing alcohol and hydrocodone enhances the effects of both, increasing the risk of overdose and respiratory depression. If the hydrocodone product contains acetaminophen, combining it with alcohol can cause severe liver damage.

Other CNS Depressants to Avoid

Other medications that depress the central nervous system also pose a risk with hydrocodone.

Other Opioids: Combining hydrocodone with other opioids like morphine or oxycodone significantly raises the overdose risk.
Muscle Relaxants: Drugs such as cyclobenzaprine (Flexeril) can increase sedation and respiratory depression.
Sleep Medications (Z-drugs): Medications like zolpidem (Ambien) can cause excessive sleepiness and increase overdose risk.
Antihistamines: Sedating antihistamines like diphenhydramine (Benadryl) can intensify drowsiness and respiratory side effects.

Interactions Affecting Hydrocodone Metabolism

Hydrocodone is metabolized in the liver by enzymes like CYP3A4 and CYP2D6. Some medications can interfere with these enzymes, changing hydrocodone levels in the body, which can be dangerous.

CYP3A4 Inhibitors

These drugs block the CYP3A4 enzyme, slowing hydrocodone metabolism. This can lead to increased hydrocodone levels, raising the risk of fatal overdose and prolonged opioid effects.

Examples: Certain macrolide antibiotics (e.g., erythromycin), azole antifungals (e.g., ketoconazole), and some HIV medications (e.g., ritonavir).

CYP3A4 Inducers

These drugs increase CYP3A4 activity, speeding up hydrocodone clearance. This can reduce effectiveness and potentially cause withdrawal symptoms in dependent individuals.

Examples: Certain seizure medications (e.g., carbamazepine), rifampin, and St. John's wort.

Serotonin Syndrome Risk

Taking hydrocodone with medications that increase serotonin levels can cause serotonin syndrome, a rare but life-threatening condition. Symptoms include agitation, confusion, rapid heart rate, and high blood pressure.

MAOIs and Antidepressants

Monoamine Oxidase Inhibitors (MAOIs): This older class of antidepressants carries a high risk. Do not take hydrocodone if you have used an MAOI within the last 14 days. The combination can cause serotonin syndrome or opioid toxicity.
SSRIs and SNRIs: Selective serotonin reuptake inhibitors (SSRIs) like fluoxetine and serotonin-norepinephrine reuptake inhibitors (SNRIs) like duloxetine can increase serotonin levels and interact with hydrocodone.

Comparison Table of Key Hydrocodone Interactions


Interacting Drug Class	Examples	Potential Risk	Citation(s)
CNS Depressants	Alcohol, Benzodiazepines (Xanax, Valium), Muscle Relaxants (Flexeril), other Opioids	Profound sedation, respiratory depression, coma, death
MAO Inhibitors	Phenelzine (Nardil), Selegiline (Emsam)	Serotonin syndrome, dangerously high blood pressure, respiratory depression
CYP3A4 Inhibitors	Ketoconazole, Erythromycin, Ritonavir	Increased hydrocodone levels, risk of fatal overdose
CYP3A4 Inducers	Carbamazepine (Tegretol), Rifampin, St. John's Wort	Decreased hydrocodone effectiveness, potential for withdrawal
Serotonergic Drugs	SSRIs (Prozac), SNRIs (Cymbalta), Triptans	Serotonin Syndrome
Opioid Antagonists	Naltrexone (Vivitrol)	Blocks opioid effects, can cause sudden withdrawal symptoms

Conclusion

Safe hydrocodone use requires careful management and open communication with your healthcare provider. Numerous prescription and over-the-counter medications, and even herbal supplements, can interact with hydrocodone, leading to severe and life-threatening outcomes. The most critical interactions involve other CNS depressants like alcohol and benzodiazepines, which have an FDA-mandated boxed warning due to the high risk of fatal overdose. Always provide your doctor and pharmacist with a complete list of all substances you are taking to prevent dangerous drug interactions.

Disclaimer: This article is for informational purposes only and does not constitute medical advice. Always consult with a qualified healthcare professional before starting or stopping any medication. For more information on safe opioid use, visit the FDA website.

Frequently Asked Questions

No, this is a very dangerous combination. Both are central nervous system depressants, and taking them together significantly increases the risk of severe drowsiness, slowed or difficult breathing, coma, and death. The FDA has a specific boxed warning against this combination.

No, it is not safe to drink any amount of alcohol while taking hydrocodone. Alcohol is a CNS depressant and will amplify the sedative and respiratory-depressing effects of hydrocodone, which can be fatal. If the hydrocodone product also contains acetaminophen, the combination can cause severe liver damage.

Taking hydrocodone with serotonergic antidepressants like Zoloft (an SSRI) can increase your risk of developing serotonin syndrome, a potentially life-threatening condition caused by too much serotonin in the brain. Symptoms include agitation, confusion, and rapid heart rate.

You must be very cautious. Many over-the-counter cold and cough medicines contain ingredients like antihistamines (e.g., diphenhydramine) or alcohol, which are CNS depressants and can dangerously increase sedation when mixed with hydrocodone. Always check the ingredients and consult a pharmacist.

CYP3A4 inhibitors are drugs that block an enzyme in your liver responsible for breaking down hydrocodone. When this enzyme is blocked, hydrocodone levels in your blood can rise to dangerous, potentially fatal levels, increasing the risk of overdose. Examples include certain antibiotics like erythromycin and antifungals like ketoconazole.

Combining hydrocodone with a Monoamine Oxidase Inhibitor (MAOI) is not recommended and can be very dangerous. This interaction can lead to serotonin syndrome or opioid toxicity, with symptoms like high blood pressure, seizures, and respiratory failure. You should not take hydrocodone if you have taken an MAOI within the last 14 days.

Yes, St. John's Wort is a CYP3A4 inducer, which means it can speed up the breakdown of hydrocodone in your body. This can make your hydrocodone less effective and may even lead to withdrawal symptoms if your body is dependent on the opioid.