MAJOR — Use With Caution
FDA warning on both labels. Fluoxetine is especially problematic because it also inhibits CYP2D6, affecting tramadol metabolism. Avoid combination.
Evidence level: STRONG
Fluoxetine (Prozac) with tramadol is a particularly risky combination. Prozac blocks the enzyme that processes tramadol AND both drugs increase serotonin, creating a high risk for the dangerous condition serotonin syndrome.
Dual serotonin syndrome risk: fluoxetine is a strong CYP2D6 inhibitor AND SSRI. It both increases tramadol serotonergic effects and blocks conversion to active metabolite (O-desmethyltramadol). FDA label warns about serotonin syndrome.
Do not take Prozac with tramadol without doctor supervision. Because Prozac stays in your body for weeks after stopping (long half-life), the risk persists even after discontinuation.
Some opioids (tramadol, fentanyl, meperidine) have serotonergic activity and can cause serotonin syndrome with SSRIs. Take each at their prescribed times. Watch for agitation, rapid heartbeat, muscle rigidity, or confusion. Codeine and morphine are generally lower risk.
Higher risk with: high doses, multiple serotonergic agents, older age, recent dose changes, CYP2D6 poor metabolizer status, liver impairment.
Agitation, hallucinations, rapid heartbeat, fever, muscle stiffness, twitching, loss of coordination, nausea, vomiting, diarrhea
Ask about the long washout period for fluoxetine (5-6 weeks). Discuss non-serotonergic pain alternatives. Know that fluoxetine active metabolite norfluoxetine has a very long half-life.
Discuss this combination with your prescriber. They may adjust timing, dosing, or switch to an alternative with fewer interaction risks. Never stop an antidepressant abruptly — taper under medical guidance.
Fluoxetine (Prozac) with tramadol is a particularly risky combination. Prozac blocks the enzyme that processes tramadol AND both drugs increase serotonin, creating a high risk for the dangerous condition serotonin syndrome.
Some opioids (tramadol, fentanyl, meperidine) have serotonergic activity and can cause serotonin syndrome with SSRIs. Take each at their prescribed times. Watch for agitation, rapid heartbeat, muscle rigidity, or confusion. Codeine and morphine are generally lower risk.
Agitation, hallucinations, rapid heartbeat, fever, muscle stiffness, twitching, loss of coordination, nausea, vomiting, diarrhea
Discuss this combination with your prescriber. They may adjust timing, dosing, or switch to an alternative with fewer interaction risks. Never stop an antidepressant abruptly — taper under medical guidance.
Ask about the long washout period for fluoxetine (5-6 weeks). Discuss non-serotonergic pain alternatives. Know that fluoxetine active metabolite norfluoxetine has a very long half-life.
Or browse the full interaction database (121,000+ pairs).