Duloxetine and Tramadol Interaction

How This Interaction Works (Mechanism)

Duloxetine inhibits both serotonin and norepinephrine reuptake (SNRI), while tramadol also inhibits serotonin reuptake and weakly activates mu-opioid receptors through its active metabolite. The combined serotonergic effect creates risk of serotonin syndrome. Additionally, duloxetine is a potent CYP2D6 inhibitor, blocking tramadol's conversion to its active analgesic metabolite (M1). This means the combination is both more dangerous (serotonin toxicity) and less effective (reduced pain relief).

Source: Cymbalta (Duloxetine) Prescribing Information, Eli Lilly, 2025

Sources and standards behind this page

Drug coverage in the United States is governed by published rules rather than by any one insurer's summary, and the sources below are the primary ones. They are linked so a reader can check a claim without taking this page's word for it.

• FDA Orange Book publishes the therapeutic-equivalence ratings that decide whether a generic may be substituted for a brand-name drug.
• FDA generic drug facts sets out what "generic equivalent" means and what a manufacturer must prove.
• CMS prescription drug coverage defines the rules a Medicare drug plan formulary must follow and how it may change mid-year.
• Medicare.gov drug coverage (Part D) states what a Part D plan is required to offer a member.
• CMS prescription drug appeals documents the coverage-determination and exception process when a drug is denied.
• Medicare Plan Compare is the official tool for checking what a specific plan charges for a specific drug at a specific pharmacy.
• Drugs@FDA is the federal database of approved drug products, which establishes whether a covered product exists and in what form.
• DailyMed carries the current FDA labeling for every marketed drug product, including approved strengths and forms.
• MedlinePlus drug information is the National Library of Medicine's consumer reference for what a medication is and how it is used.
• FTC report on pharmacy benefit managers documents how the middlemen between an insurer and a pharmacy shape what a plan actually covers.
• National Library of Medicine maintains the drug and health databases the sources above draw on.

This page describes how coverage and formularies work. It is not medical advice, and a reader's own plan documents and prescriber decide what applies to them.