What Medications Should You Not Take Tramadol With?

October 10, 2025 •

4 min read

In 2023, tramadol was the 36th most commonly prescribed medication in the United States, with over 16 million prescriptions filled [1.8.3]. Understanding what medications you should not take tramadol with is crucial for preventing potentially life-threatening side effects.

Quick Summary

A comprehensive overview of dangerous tramadol drug interactions. Key contraindications include MAOIs, SSRIs, benzodiazepines, and alcohol, which can lead to severe health risks.

Key Points

MAOIs are Contraindicated: Do not take tramadol with Monoamine Oxidase Inhibitors (MAOIs) or within 14 days of using one due to high risk of serotonin syndrome [1.5.3].
Serotonin Syndrome Risk: Combining tramadol with antidepressants like SSRIs, SNRIs, and TCAs, or migraine medications called triptans, can cause a life-threatening condition called serotonin syndrome [1.2.1, 1.4.5].
Respiratory Depression Hazard: Mixing tramadol with other Central Nervous System (CNS) depressants like benzodiazepines, alcohol, other opioids, and sleep aids can lead to slowed breathing, coma, and death [1.6.4, 1.7.1].
Alcohol is Unsafe: Alcohol should be completely avoided while taking tramadol as it dramatically increases the risk of sedation, overdose, and fatal respiratory depression [1.7.3, 1.7.5].
Metabolism Interactions: Certain drugs, like the antidepressant bupropion or the antifungal ketoconazole, can alter how the body processes tramadol, increasing the risk of side effects [1.2.1].
Consult a Professional: Always inform your healthcare provider about all medications, including over-the-counter drugs and supplements, to prevent dangerous interactions [1.3.5].
Know the Symptoms: Be aware of the signs of serotonin syndrome (agitation, rapid heart rate, muscle stiffness) and CNS depression (extreme sleepiness, slowed breathing) and seek immediate medical help if they occur [1.3.2, 1.7.1].

Tramadol is a synthetic opioid pain medication used to treat moderate to moderately severe pain [1.8.3]. Unlike some other opioids, it has a dual mechanism of action: it binds to μ-opioid receptors and also weakly inhibits the reuptake of serotonin and norepinephrine, two important neurotransmitters in the brain [1.4.5, 1.8.3]. This unique profile means it can interact with a wide range of other medications, leading to serious and sometimes fatal consequences. The two most critical risks associated with tramadol interactions are serotonin syndrome and central nervous system (CNS) depression, which can cause slowed or stopped breathing [1.3.2, 1.6.4].

The Dual Dangers: Serotonin Syndrome and CNS Depression

Understanding the primary risks is key to recognizing why certain medication combinations are so hazardous.

Serotonin Syndrome

Serotonin syndrome is a potentially fatal condition caused by excessive serotonin levels in the body [1.2.1]. Tramadol increases serotonin, and when combined with other drugs that do the same, the risk becomes significant [1.2.1, 1.4.5]. Symptoms can range from mild to severe and include agitation, confusion, rapid heart rate, high blood pressure, dilated pupils, muscle rigidity, heavy sweating, and fever [1.3.2, 1.4.5]. In severe cases, it can lead to seizures, high fever, irregular heartbeat, and unconsciousness [1.3.6].

CNS and Respiratory Depression

As an opioid, tramadol is a central nervous system (CNS) depressant, meaning it slows down brain activity, which includes the automatic drive to breathe [1.7.1, 1.7.3]. When combined with other CNS depressants like alcohol, benzodiazepines, or other opioids, this effect is amplified [1.6.4, 1.7.1]. This can lead to extreme drowsiness, sedation, respiratory depression (slowed or difficult breathing), coma, and death [1.6.4, 1.6.6]. The FDA has issued its strongest warning, a Boxed Warning, about the combined use of opioids and benzodiazepines due to these risks [1.6.4].

Medications and Substances to Avoid with Tramadol

It is essential to provide your healthcare provider with a complete list of all medications, supplements, and substances you use. The following classes of drugs are known to have significant interactions with tramadol.

Monoamine Oxidase Inhibitors (MAOIs)

This class of antidepressants is considered one of the most dangerous to combine with tramadol. The combination can lead to a high risk of serotonin syndrome and seizures [1.5.1, 1.5.3]. Because of this severe risk, tramadol is contraindicated for use with MAOIs or within 14 days of discontinuing an MAOI [1.3.2, 1.5.1].

Examples: Isocarboxazid (Marplan), Phenelzine (Nardil), Selegiline (Emsam, Zelapar), Tranylcypromine (Parnate), Linezolid (Zyvox) [1.2.1, 1.3.3].

SSRIs, SNRIs, and Tricyclic Antidepressants

These are some of the most commonly prescribed antidepressants, and they all work by increasing serotonin levels. Combining them with tramadol adds to this effect, increasing the risk of serotonin syndrome [1.2.1, 1.4.5].

SSRIs (Selective Serotonin Reuptake Inhibitors): Fluoxetine (Prozac), Sertraline (Zoloft), Paroxetine (Paxil), Citalopram (Celexa), Escitalopram (Lexapro) [1.2.1].
SNRIs (Serotonin-Norepinephrine Reuptake Inhibitors): Venlafaxine (Effexor XR), Duloxetine (Cymbalta), Desvenlafaxine (Pristiq) [1.2.1].
Tricyclic Antidepressants (TCAs): Amitriptyline, Nortriptyline (Pamelor), Imipramine (Tofranil) [1.2.1].

Benzodiazepines and Other Sedatives

This combination significantly increases the risk of life-threatening respiratory depression, extreme sedation, and coma [1.6.3, 1.6.4]. Both drug classes depress the central nervous system, and their combined effect can be fatal [1.6.6].

Benzodiazepines: Alprazolam (Xanax), Diazepam (Valium), Lorazepam (Ativan), Clonazepam (Klonopin) [1.2.1, 1.2.4].
Other Sedative-Hypnotics (Sleep Medications): Zolpidem (Ambien), Eszopiclone (Lunesta), Zaleplon (Sonata) [1.2.1].

Other Opioids

Taking tramadol with other opioid pain medications enhances the risk of respiratory depression, sedation, and overdose [1.2.1].

Examples: Hydrocodone (Vicodin), Oxycodone (OxyContin, Percocet), Codeine, Morphine [1.2.1, 1.5.6].

Alcohol

Alcohol is a potent CNS depressant. Combining it with tramadol can lead to dangerous levels of sedation, impaired coordination, memory loss, and life-threatening respiratory depression and overdose [1.7.1, 1.7.3, 1.7.5]. It is strongly advised to avoid alcohol completely while taking tramadol [1.3.5, 1.7.2].

Triptans (Migraine Medications)

Like tramadol, triptans work on serotonin pathways. Using them together elevates the risk of developing serotonin syndrome [1.2.1].

Examples: Sumatriptan (Imitrex), Rizatriptan (Maxalt), Zolmitriptan (Zomig) [1.2.1].

Medications Affecting Tramadol Metabolism

Some drugs interfere with the liver enzymes (specifically CYP2D6 and CYP3A4) responsible for breaking down tramadol [1.3.2].

Inhibitors (Increase Tramadol Levels): Certain drugs can block these enzymes, leading to higher levels of tramadol in the blood and an increased risk of side effects like seizures and serotonin syndrome. Examples include bupropion (Wellbutrin), quinidine, and certain antifungals like ketoconazole [1.2.1].
Inducers (Decrease Tramadol Effectiveness): Other drugs speed up these enzymes, clearing tramadol from the body too quickly and reducing its pain-relieving effects. Examples include carbamazepine (Tegretol) and rifampin [1.2.1].

Tramadol Interaction Comparison Table


Interacting Medication Class	Primary Risk(s)	Example Drugs
MAOIs	Serotonin Syndrome, Seizures	Phenelzine, Selegiline, Linezolid [1.5.1, 1.5.3]
SSRIs / SNRIs / TCAs	Serotonin Syndrome	Sertraline (Zoloft), Duloxetine (Cymbalta), Amitriptyline [1.2.1]
Benzodiazepines & Sedatives	Respiratory Depression, Extreme Sedation, Coma	Alprazolam (Xanax), Zolpidem (Ambien) [1.2.1, 1.6.4]
Alcohol	Respiratory Depression, Overdose, Severe Sedation	Beer, wine, liquor [1.7.1, 1.7.3]
Other Opioids	Respiratory Depression, Overdose	Oxycodone, Hydrocodone [1.2.1]
Triptans	Serotonin Syndrome	Sumatriptan (Imitrex), Rizatriptan (Maxalt) [1.2.1]
CYP450 Enzyme Modifiers	Increased side effects or decreased efficacy	Ketoconazole, Carbamazepine, Bupropion [1.2.1]

Conclusion: Prioritizing Your Safety

Due to its complex mechanism, tramadol carries a significant risk of interacting with many common medications and substances. The consequences, including serotonin syndrome and respiratory depression, can be severe and life-threatening. Always consult with your doctor or pharmacist before starting or stopping any medication while taking tramadol. Maintaining an open dialogue and providing a complete medical history is the most effective way to prevent dangerous drug interactions and ensure your treatment is both safe and effective.

For more information from an authoritative source, you can visit the FDA's page on drug interactions.

Frequently Asked Questions

Taking tramadol with SSRI antidepressants like Zoloft (sertraline) or Lexapro (escitalopram) significantly increases the risk of serotonin syndrome, a potentially life-threatening condition caused by excess serotonin in the brain. Symptoms include agitation, confusion, rapid heart rate, and muscle stiffness [1.2.1, 1.4.5].

No, you should not drink alcohol while taking tramadol. Both are central nervous system depressants, and mixing them can lead to dangerous side effects including extreme drowsiness, impaired coordination, slowed or stopped breathing, overdose, and death [1.7.1, 1.7.3].

No, it is extremely risky to take tramadol with benzodiazepines like Xanax (alprazolam) or Valium (diazepam). This combination can cause severe sedation, life-threatening respiratory depression, and coma. The FDA has issued its strongest warning against this combination [1.6.4, 1.2.1].

Tramadol should never be taken with Monoamine Oxidase Inhibitors (MAOIs) or within 14 days of stopping one [1.5.1]. It is also contraindicated in patients with significant respiratory depression, acute or severe bronchial asthma, or known or suspected gastrointestinal obstruction [1.2.3].

Taking ibuprofen (an NSAID) or acetaminophen (Tylenol) with tramadol is generally considered safe under medical guidance, and some prescription products combine tramadol and acetaminophen [1.5.4]. However, always consult your doctor to ensure the correct dosage and avoid risks like stomach bleeding from NSAIDs or liver damage from too much acetaminophen [1.5.4].

Signs of serotonin syndrome include mental status changes (like agitation, confusion, or delirium), autonomic hyperactivity (like fast heart rate, sweating, or flushing), and neuromuscular abnormalities (like muscle tremors, rigidity, or twitching) [1.3.2, 1.4.5].

Yes, St. John's Wort can interact with tramadol. Because St. John's Wort affects serotonin levels, combining it with tramadol increases the risk of developing serotonin syndrome [1.3.1, 1.3.2].