What not to take opioids with: A guide to dangerous drug interactions

October 11, 2025 •

4 min read

According to the Centers for Disease Control and Prevention (CDC), the combined use of opioids with other substances is extremely dangerous and can lead to serious adverse effects, including overdose and death. Understanding what not to take opioids with is crucial for anyone using these powerful medications, whether for short-term pain relief or long-term management.

Quick Summary

This article details the significant health risks of combining opioids with other substances. It explores the dangers of combining opioids with central nervous system depressants like benzodiazepines, muscle relaxants, and alcohol, as well as interactions with certain antidepressants and other medications. It highlights the potential for severe respiratory depression, overdose, and even fatality, emphasizing the importance of informing healthcare providers about all medications and substances being used.

Key Points

Avoid CNS Depressants: Never combine opioids with central nervous system depressants like benzodiazepines, alcohol, or sedatives, as this can cause fatal respiratory depression.
Dangerous Drug Pairs: The combination of opioids with alcohol, benzodiazepines (e.g., Xanax, Valium), muscle relaxants (e.g., Soma, Flexeril), and sleep aids (e.g., Ambien) is particularly hazardous.
Serotonin Syndrome Risk: Be aware of the risk of serotonin syndrome when taking opioids like tramadol with antidepressants (e.g., SSRIs, MAOIs) or migraine medications.
Inform Your Doctor: Always provide your healthcare provider with a complete list of all medications, supplements, and substances you use to prevent dangerous drug interactions.
Recognize Overdose Symptoms: Know the signs of an overdose, such as slowed breathing, constricted pupils, and unresponsiveness, and seek immediate emergency help if observed.
Consider Naloxone: Patients at high risk for opioid overdose, such as those also taking CNS depressants, should be offered naloxone, a life-saving reversal medication.

The Dangers of Combining Opioids and Central Nervous System Depressants

One of the most life-threatening combinations involves opioids and other central nervous system (CNS) depressants. Both classes of drugs slow down the brain and body's functions, including breathing and heart rate. When taken together, their depressant effects are dangerously amplified, a phenomenon known as additive or synergistic effects. This can lead to profound sedation, respiratory depression, coma, and death. The U.S. Food and Drug Administration (FDA) has issued its strongest warning, a boxed warning, on the labels of prescription opioids and benzodiazepines to highlight this risk.

Benzodiazepines (Benzos)

Benzodiazepines are prescribed for anxiety, insomnia, and seizures and include common brand names like Xanax, Valium, and Klonopin. Combining these with opioids is particularly hazardous. Studies have shown that patients receiving both types of medications have a significantly higher risk of drug overdose death. In fact, one study found that the risk of fatal overdose was more than seven times higher for those combining benzodiazepines and opioids compared to those using opioids alone.

Alcohol

Alcohol is another potent CNS depressant that should never be combined with opioids. Like benzodiazepines, alcohol significantly increases the risk of extreme sleepiness, slowed breathing, and overdose. This is because both substances slow down brain activity, and when used together, the effect is multiplied. According to the CDC, over half of Americans who misuse prescription opioids also engage in binge drinking, underscoring the severity of this common and dangerous practice.

Muscle Relaxants

Muscle relaxers, such as cyclobenzaprine (Flexeril) and carisoprodol (Soma), also carry a risk of increased sedation when taken with opioids. While some combinations of specific muscle relaxants and opioids may be safer than others, combining them without a doctor's explicit instruction is extremely risky and can lead to over-sedation and injury. Research indicates that certain muscle relaxants, when used with opioids, are associated with higher injury rates due to impaired motor control.

Other Sedatives and Hypnotics

Medications prescribed for sleep problems, such as zolpidem (Ambien), also have a high potential for dangerous interactions with opioids. These hypnotics cause drowsiness, and when combined with the sedative effects of opioids, they can dramatically increase the risk of severe respiratory depression and overdose.

Opioids and Other Drug Interactions

Beyond CNS depressants, opioids can interact with other classes of medications, leading to different but equally dangerous outcomes. These interactions highlight the importance of informing your healthcare provider of all medications, supplements, and substances you are taking.

Serotonergic Drugs

Certain opioids, like tramadol, enhance serotonin activity in the brain. Taking them with other serotonergic medications, such as antidepressants (including SSRIs and MAOIs) and migraine medicines, can cause a life-threatening condition called serotonin syndrome. Symptoms can range from agitation and rapid heart rate to hallucinations and loss of coordination. Healthcare providers must be vigilant in monitoring patients for these symptoms, particularly during initial treatment or dose changes.

Cytochrome P450 (CYP450) Inhibitors and Inducers

Opioids are metabolized in the liver by the cytochrome P450 enzyme system. Other medications can either inhibit or induce these enzymes, altering the effectiveness and safety of opioids.

CYP450 Inhibitors: Medications like certain antibiotics (e.g., clarithromycin) and antifungals (e.g., ketoconazole) can slow down the metabolism of opioids. This can lead to a buildup of the opioid in the body, increasing the risk of respiratory depression and overdose.
CYP450 Inducers: Conversely, medications like anti-seizure drugs (e.g., carbamazepine) can speed up opioid metabolism. This can reduce the opioid's effectiveness and, in some cases, cause withdrawal symptoms.

Comparison of Dangerous Opioid Combinations


Substance	Primary Risk	Mechanism	Signs of Overdose/Adverse Reaction
Alcohol	Respiratory Depression, Overdose	Synergistic CNS depressant effect	Extreme sleepiness, slow breathing, unresponsiveness
Benzodiazepines	Respiratory Depression, Overdose	Synergistic CNS depressant effect	Profound sedation, coma, slowed or difficult breathing
Muscle Relaxants	Respiratory Depression, Injury	Additive CNS depressant and sedative effects	Over-sedation, impaired coordination, coma
Serotonergic Drugs	Serotonin Syndrome	Enhanced serotonin levels in the brain	Agitation, hallucinations, rapid heart rate, confusion
Other Opioids	Respiratory Depression, Overdose	Additive CNS depression	Exacerbated sedation and breathing problems, pinpoint pupils

Navigating Opioid Therapy Safely

To minimize risks, patients must be completely transparent with their healthcare providers about all medications and substances they are using. This includes prescription drugs, over-the-counter medications, supplements, and any recreational substances, including marijuana. Patients should also use a single pharmacy whenever possible, as this allows pharmacists to identify potential drug interactions. Always follow the prescribed dosage and instructions, and never increase a dose without consulting a healthcare professional. Carrying a list of all your current medications is a useful practice. In case of a suspected overdose, calling 911 immediately is critical. The FDA also recommends that patients at risk of overdose, including those on concomitant CNS depressants, be offered naloxone, an opioid overdose reversal medication.

Conclusion

Using opioids responsibly is essential for both effective pain management and patient safety. Knowing what not to take opioids with—particularly CNS depressants like benzodiazepines, alcohol, muscle relaxants, and other sedatives—is a key part of this responsibility. The potential for fatal respiratory depression is a serious and well-documented risk that can be mitigated through careful communication with healthcare providers and strict adherence to medication guidelines. Additionally, vigilance regarding less common but dangerous interactions with serotonergic drugs and CYP450 inhibitors is necessary for comprehensive safety. A proactive and honest approach to medication management is the best defense against harmful drug interactions.

Frequently Asked Questions

Combining opioids and alcohol is dangerous because both are central nervous system (CNS) depressants that slow down brain and respiratory functions. When taken together, their effects are amplified, dramatically increasing the risk of extreme sedation, respiratory depression, coma, and overdose.

No, you should not take an opioid with a benzodiazepine like Xanax unless specifically instructed by a healthcare provider who has carefully weighed the risks and benefits. The FDA mandates a boxed warning for this combination due to the high risk of severe sedation, respiratory depression, and death.

Mixing opioids with muscle relaxers can lead to increased sedation and a higher risk of respiratory depression and injury. Both classes of drugs affect the central nervous system, and their combined sedative effects are dangerous and potentially life-threatening.

Yes, some antidepressants, including SSRIs and MAOIs, can interact with certain opioids (like tramadol) to cause serotonin syndrome. This is a potentially fatal condition resulting from dangerously high serotonin levels in the brain.

CYP450 inhibitors are drugs that slow down the liver's metabolism of other medications. When taken with opioids, these inhibitors can cause the opioid to build up in the body, increasing the risk of overdose. Examples include certain antibiotics and antifungals.

You should consult with a healthcare provider or pharmacist before combining opioids with any over-the-counter medications. Some over-the-counter drugs, like certain antihistamines and cold medicines, can have sedating effects that dangerously interact with opioids.

Yes, certain opioid combinations, especially those involving other CNS depressants, can lower the seizure threshold and potentially trigger seizures. Serotonin syndrome, a risk with some opioid combinations, can also cause neurological symptoms like hyperreflexia and muscle twitching.

It is crucial to inform all your healthcare providers about all your medications to prevent dangerous interactions. Different doctors may prescribe medications unaware of what others have prescribed, and a complete medical history helps them make safer treatment decisions and monitor for potential risks.