Acetaminophen And Codeine and Trazodone: Interaction Details
AI-assisted, pharmacist-reviewed · AI content regenerated Jul 11, 2026 · Source data updated Jun 30, 2026 · Sources: FDA labeling, DDInter 2.0, cited literature
Acetaminophen And Codeine
Trazodone
How we grade severity & evidence
Severity levels
- Contraindicated: These should generally not be used together.
- Major: Potentially serious — often needs a change or close monitoring.
- Moderate: Can be significant — usually manageable with monitoring.
- Minor: Usually limited clinical impact.
Evidence grades
- Established: Well documented — supported by controlled studies or strong clinical data.
- Probable: Good supporting evidence, though not definitively proven.
- Suspected: Some evidence suggests this interaction, but it is not well established.
- Possible: Limited or conflicting evidence; the interaction may occur.
- Theoretical: Predicted from the drugs' pharmacology; not yet confirmed in people.
Ratings come from the documented interaction literature and are reviewed by a pharmacist. They describe the documented risk of the combination, not what will necessarily happen to you — your dose, timing, and health picture all matter.
Your two medicines can add up in a couple of ways. Trazodone is used for mood and sleep, and the codeine in your pain medicine is an opioid. Both can make you sleepy, so together they may cause stronger drowsiness, slowed thinking, or slowed breathing.
Both also raise brain levels of a chemical called serotonin. Rarely, too much serotonin can cause a reaction called serotonin syndrome, with agitation, a racing heart, sweating, shaking, or fever. This is uncommon and is mostly a theoretical concern, but it is worth knowing. The good news is your care team can manage this by watching you closely, especially when either medicine is started.
Effect: Additive CNS depression and a theoretical increased risk of serotonin syndrome.
Mechanism: Both agents are serotonergic (trazodone via 5-HT modulation; codeine, an opioid prodrug activated by CYP2D6 to morphine, has weak serotonergic activity). Both are CNS depressants, producing additive sedation. Acetaminophen is not implicated.
- Direction: Additive PD interaction, not PK.
- Evidence: Theoretical; onset unspecified.
- Management: Monitor for serotonin syndrome (mental status changes, autonomic instability, neuromuscular findings) and for excess sedation/respiratory depression, particularly at initiation or dose increase. Discontinue serotonergic agents and provide supportive care if serotonin syndrome develops.
What happens
An increased risk of serotonin syndrome and an increased risk of CNS depression
Interaction Deep Dive
As a serotonergic agent, traZODone is recognized for producing sedation. When it is taken together with a different serotonergic medication that also causes CNS depression, the two may amplify each other's sedative actions, provoke serotonin syndrome, or do both. The manifestations of serotonin syndrome, which can be life-threatening, may encompass altered mental status (for example, agitation, hallucinations, delirium, coma), autonomic instability (for example, tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular findings (for example, tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and gastrointestinal effects like nausea, vomiting, or diarrhea. Should the two drugs need to be given together, watch every patient for serotonin syndrome, particularly at the start of therapy. Inform patients about the heightened likelihood of serotonin syndrome and of the additional sedation. Treatment with traZODone and any accompanying serotonergic drug should be stopped right away if serotonin syndrome symptoms develop, and supportive care should be started12. Advise patients that traZODone can heighten their reaction to CNS depressants1.
Why it happens (mechanism)
Additive serotonergic effects; additive CNS depression
How to manage this interaction
You can usually take both when your prescriber intends it, but stay alert to how you feel.
- Keep taking both as prescribed unless your prescriber tells you otherwise.
- Expect possible added drowsiness. Avoid driving until you know how the combination affects you, and be cautious with alcohol.
- Your care team may monitor you more closely, especially when starting or increasing either drug, and doses may be adjusted and individualized.
- Seek help right away if you notice agitation, confusion, fever, sweating, a racing heart, shaking, muscle stiffness, or hard-to-wake sleepiness.
Ask your pharmacist to review all your medicines for other sedating or serotonergic drugs.
Management is individual — confirm any change with your pharmacist or prescriber.
Common questions
Can I take Acetaminophen And Codeine and Trazodone together?
Taking codeine (with acetaminophen) and trazodone together can add up to more drowsiness and, rarely, serotonin syndrome. Keep taking both as prescribed, watch for excess sleepiness or agitation/racing heart/fever, and get medical help if those occur. Always confirm with your pharmacist or prescriber before making any change.
How serious is the Acetaminophen And Codeine and Trazodone interaction?
It is rated major. Potentially serious — often needs a change or close monitoring.
How quickly could this interaction happen?
The documented onset is "unspecified". The timing of this interaction is not well characterized.
How is the Acetaminophen And Codeine and Trazodone interaction managed?
You can usually take both when your prescriber intends it, but stay alert to how you feel. Keep taking both as prescribed unless your prescriber tells you otherwise. Expect possible added drowsiness. Avoid driving until you know how the combination affects you, and be cautious with alcohol. Your care team may monitor you more closely, especially when starting or increasing either drug, and doses m… Management is individual — always follow your own care team's guidance.
How strong is the evidence for this interaction?
The evidence is graded "theoretical". Predicted from the drugs' pharmacology; not yet confirmed in people.
From our Q&A
Real reader questions about these medications, each personally answered by our pharmacist:
Questions for your pharmacist
- Does my dose of Acetaminophen And Codeine or Trazodone need adjusting while I take them together?
- What symptoms should prompt me to call you or my prescriber right away?
- Does the timing of my doses matter for this combination?
- Is there a safer alternative to one of these medications for me?
References (2)
Keep reading about Acetaminophen And Codeine
Keep reading about Trazodone
These medications also interact with supplements
Prescription drugs aren't the whole picture — herbal and dietary supplements can interact with them too. From the evidence-graded Natural Medicines database:
major · moderate · minor — check everything you take with our drug–supplement interaction checker.
Check another combination
Our instant two-drug interaction checker is almost here.
Still have questions about this combination?
Every question gets a real answer from a licensed pharmacist — free, and usually within a day.
Ask the pharmacist