Can you take DULoxetine and nortriptyline together? Understanding the Risks

October 8, 2025 •

3 min read

In the United States, antidepressant use is common, with studies showing a high prevalence of polypharmacy, or the use of multiple medications at once. This raises important questions about drug interactions, such as: can you take duloxetine and nortriptyline together?

Quick Summary

Combining duloxetine and nortriptyline is generally not recommended due to a major interaction risk. This combination significantly increases the danger of developing serotonin syndrome, a potentially life-threatening condition.

Key Points

Major Interaction: Combining duloxetine and nortriptyline is considered a major drug interaction that should generally be avoided.
Serotonin Syndrome Risk: The primary danger is a significantly increased risk of serotonin syndrome, a potentially fatal condition caused by excess serotonin.
Different Drug Classes: Duloxetine is a Serotonin-Norepinephrine Reuptake Inhibitor (SNRI), and nortriptyline is a Tricyclic Antidepressant (TCA). Both affect serotonin levels.
Requires Expert Supervision: The combination should only be considered in rare cases under the close supervision of a doctor who can monitor drug levels and watch for complications.
Patient Awareness is Crucial: Patients must be aware of the symptoms of serotonin syndrome (e.g., agitation, high fever, seizures) and seek immediate medical help if they occur.
Metabolic Interaction: Duloxetine can inhibit the metabolism of nortriptyline, leading to higher, potentially toxic levels of nortriptyline in the blood.
Full Disclosure is Key: Always inform your doctor about all medications, supplements (like St. John's Wort), and herbal products you are taking to prevent dangerous interactions.

Understanding the Medications: Duloxetine and Nortriptyline

Before exploring the interaction, it's essential to understand each medication individually. Both drugs are used to treat conditions like depression and nerve pain, but they belong to different classes and work in distinct ways.

What is Duloxetine?

Duloxetine is an antidepressant known as a serotonin-norepinephrine reuptake inhibitor (SNRI). It works by increasing the levels of two chemical messengers, serotonin and norepinephrine, in the brain. This helps regulate mood and block pain signals. The FDA has approved duloxetine for treating major depressive disorder, generalized anxiety disorder, painful diabetic neuropathy, and fibromyalgia.

What is Nortriptyline?

Nortriptyline belongs to an older class of antidepressants called tricyclic antidepressants (TCAs). Like duloxetine, it also works by inhibiting the reuptake of norepinephrine and serotonin, increasing their availability in the brain. It is approved to treat depression and is often used off-label for conditions like chronic nerve pain.

The Major Risk: Why Combining is Not Recommended

Healthcare providers generally avoid prescribing duloxetine and nortriptyline together due to the significant risk of a major drug interaction. This combination primarily increases the likelihood of developing serotonin syndrome, a serious condition caused by excessive serotonin activity in the nervous system. Since both duloxetine and nortriptyline increase serotonin levels, taking them concurrently can contribute to this risk.

What is Serotonin Syndrome?

Serotonin syndrome occurs when the body has an unsafe level of serotonin. Symptoms can appear within minutes or hours of taking a new medication or combining medications that affect serotonin.

Symptoms can range from mild to life-threatening:

Mild Symptoms: Shivering, diarrhea, headache, restlessness, nervousness, and tremor.
Moderate Symptoms: Agitation, muscle rigidity or twitching, heavy sweating, dilated pupils, confusion, and rapid heart rate.
Severe Symptoms: High fever (over 101.3°F or 38.5°C), seizures, irregular heartbeat, loss of consciousness, and coma.

Severe serotonin syndrome is a medical emergency. If you experience any of these symptoms while taking serotonergic medications, you should seek immediate medical attention.

Duloxetine vs. Nortriptyline: A Comparison

Both medications can be effective but have different profiles regarding uses, side effects, and dosing.


Feature	Duloxetine	Nortriptyline
Drug Class	Serotonin-Norepinephrine Reuptake Inhibitor (SNRI)	Tricyclic Antidepressant (TCA)
Approved Uses	Depression, anxiety, diabetic neuropathy, fibromyalgia, chronic pain	Depression
Common Off-Label Uses	Stress urinary incontinence	Nerve pain, migraine prevention, smoking cessation
Common Side Effects	Nausea, dry mouth, headache, drowsiness, insomnia, anxiety	Dry mouth, constipation, dizziness, drowsiness, weight gain
Dosing Frequency	Typically once daily	Often multiple times a day
Interaction Risk	Can increase nortriptyline levels in the blood, leading to toxicity	Risk of cardiac toxicity, especially in patients with heart conditions

Are There Ever Exceptions?

In rare cases, a specialist might prescribe this combination when other treatments have failed and benefits are deemed to outweigh risks. This requires extreme caution and close monitoring. Monitoring might include starting with low doses, checking nortriptyline levels, potentially reducing the nortriptyline dose, and educating the patient about serotonin syndrome signs.

Communicating With Your Healthcare Provider

Open communication with your doctor is vital. Inform them about all medications, including over-the-counter drugs, vitamins, and herbal supplements like St. John's Wort, which can increase serotonin levels. Never stop or adjust doses without consulting your provider.

Conclusion

Combining duloxetine and nortriptyline is generally not recommended due to a major risk of serotonin syndrome. While both treat depression and pain, they should not be combined except in specific circumstances under expert supervision. Always consult your healthcare provider for the safest treatment.

Disclaimer: This article is for informational purposes only and does not constitute medical advice. Always consult with a qualified healthcare professional before making any decisions about your health or medications.

Analgesic effect of duloxetine compared to nortryptiline in the management of patients with diabetic neuropathy

Frequently Asked Questions

The main risk is developing serotonin syndrome, a rare but potentially life-threatening condition caused by having too much serotonin in your body. Both medications increase serotonin, so taking them together elevates this risk significantly.

Symptoms can range from mild (shivering, diarrhea, tremor) to severe (high fever, agitation, muscle rigidity, seizures, and unconsciousness). Severe symptoms require immediate medical attention.

No. Duloxetine is a serotonin-norepinephrine reuptake inhibitor (SNRI), while nortriptyline is a tricyclic antidepressant (TCA). Although they are in different classes, both affect serotonin and norepinephrine levels in the brain.

In very rare and specific circumstances, a specialist may prescribe this combination, but only with extreme caution, low doses, and close monitoring for side effects and drug levels in the blood. It is not a standard treatment approach.

Yes, duloxetine can inhibit the liver enzyme (CYP2D6) responsible for breaking down nortriptyline. This can cause nortriptyline levels to rise in the bloodstream, increasing the risk of toxicity and side effects.

Talk to your doctor or pharmacist to ensure they are aware of the potential interaction. Discuss the risks, the plan for monitoring your health, and be sure you know the signs of serotonin syndrome to watch for.

Yes, treatment guidelines often recommend starting with a single agent like duloxetine or nortriptyline. If one is not effective, a doctor might switch to another medication or add a drug from a different class that doesn't carry the same interaction risk.