What is the interaction between Duloxetine and Amitriptyline (Amitriptyline is a Tricyclic Antidepressant, TCA)?

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From the Guidelines

Duloxetine and amitriptyline should not be taken together without medical supervision due to the potential risk of serotonin syndrome, a life-threatening condition. The interaction between duloxetine, a serotonin-norepinephrine reuptake inhibitor (SNRI), and amitriptyline, a tricyclic antidepressant (TCA), can lead to increased levels of serotonin in the body, resulting in serotonin syndrome 1. Key points to consider when taking these medications together include:

  • Increased risk of serotonin syndrome, characterized by symptoms such as agitation, confusion, rapid heart rate, high blood pressure, dilated pupils, muscle rigidity, and hyperthermia
  • Potential for adverse effects, such as nausea, dizziness, and somnolence, which can be severe in older individuals
  • Importance of medical supervision and careful monitoring of dosages and potential interactions
  • Alternative treatment options, such as gabapentinoids, sodium channel blockers, and topical analgesics, which may be considered for the treatment of neuropathic pain 1. It is essential to inform your doctor about all medications you are taking and to never adjust dosages or stop taking either medication without medical guidance, as abrupt discontinuation can cause withdrawal symptoms 1. If you experience symptoms like confusion, hallucinations, seizures, extreme changes in blood pressure, fever, excessive sweating, shivering, racing heartbeat, muscle rigidity, or twitching after taking these medications, seek emergency medical attention immediately 1.

From the FDA Drug Label

Drugs Metabolized by CYP2D6 — Co-administration of duloxetine delayed-release capsules with drugs that are extensively metabolized by CYP2D6 and that have a narrow therapeutic index, including certain antidepressants (tricyclic antidepressants [TCAs], such as nortriptyline, amitriptyline, and imipramine), phenothiazines and Type 1C antiarrhythmics (e.g., propafenone, flecainide), should be approached with caution. Plasma TCA concentrations may need to be monitored and the dose of the TCA may need to be reduced if a TCA is co-administered with duloxetine delayed-release capsules

The interaction between Duloxetine and Amitriptyline (a Tricyclic Antidepressant, TCA) is that co-administration of these two drugs should be approached with caution.

  • Plasma TCA concentrations may need to be monitored.
  • The dose of the TCA may need to be reduced if a TCA is co-administered with duloxetine 2.

From the Research

Interaction between Duloxetine and Amitriptyline

  • The interaction between Duloxetine and Amitriptyline is not extensively studied in the provided evidence, but one case report suggests a potential adverse effect of combination therapy 3.
  • Duloxetine is a serotonin-norepinephrine reuptake inhibitor, and Amitriptyline is a Tricyclic Antidepressant (TCA) 4, 5.
  • The combination of Duloxetine and Amitriptyline may increase the risk of autonomic dysreflexia, a rare but potentially life-threatening condition 3.
  • There is limited information on the pharmacokinetic interactions between Duloxetine and Amitriptyline, but one potential mechanism is the inhibition of Duloxetine metabolism 3.
  • Patients receiving combination therapy with Duloxetine and Amitriptyline should be closely monitored for signs of autonomic dysreflexia, such as secondary hypertension 3.

References

Guideline

Guideline Directed Topic Overview

Dr.Oracle Medical Advisory Board & Editors, 2025

Research

Duloxetine: a balanced and selective norepinephrine- and serotonin-reuptake inhibitor.

American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists, 2005

Professional Medical Disclaimer

This information is intended for healthcare professionals. Any medical decision-making should rely on clinical judgment and independently verified information. The content provided herein does not replace professional discretion and should be considered supplementary to established clinical guidelines. Healthcare providers should verify all information against primary literature and current practice standards before application in patient care. Dr.Oracle assumes no liability for clinical decisions based on this content.

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