Propoxyphene and Amitriptyline: Interaction Details
AI-assisted, pharmacist-reviewed · AI content regenerated Jul 11, 2026 · Source data updated Jul 2, 2026 · Sources: FDA labeling, DDInter 2.0, cited literature
Amitriptyline
Propoxyphene
No brand names on record
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.
Amitriptyline (Elavil) and propoxyphene both act on serotonin, one of your body's chemical messengers. When two medicines raise serotonin at the same time, there's a small chance the level gets too high, which can cause a reaction called serotonin syndrome. Signs include feeling agitated or confused, a fast heartbeat, sweating, shivering, muscle twitching or stiffness, and a fever.
The good news is that this concern is mostly theoretical, and many people take medicines like these safely. Please don't stop either one on your own. Your care team can watch you closely and adjust things if needed. If you feel any of those symptoms, contact your doctor or pharmacist right away.
Mechanism: Additive serotonergic effect. Amitriptyline inhibits serotonin (and norepinephrine) reuptake; propoxyphene also has serotonergic activity. Combined use can raise the risk of serotonin syndrome.
- Direction: Additive PD effect (increased serotonergic tone), not a metabolic PK interaction.
- Severity: Major. Evidence: Theoretical. Onset: Unspecified.
- Monitor for: Neuromuscular signs (hyperreflexia, clonus, tremor, rigidity), autonomic instability (hyperthermia, tachycardia, diaphoresis, mydriasis), and mental status changes (agitation, delirium).
- Management: Use with caution; monitor if coadministered. If serotonin syndrome develops, discontinue offending agents and provide supportive care.
What happens
An increased risk of serotonin syndrome (hypertension, hyperthermia, myoclonus, mental status changes)
Interaction Deep Dive
Amitriptyline, which acts as a serotonin reuptake inhibitor2, and propoxyphene both have an impact on serotonergic neurotransmitter systems. Because their serotonergic effects are additive and may heighten the risk of serotonin syndrome, caution is advised when the two are taken together. When amitriptyline and propoxyphene are administered concurrently, it may be appropriate to watch for the signs and symptoms of serotonin syndrome throughout therapy. These symptoms encompass neuromuscular disturbances (for example, hyperreflexia, tremor, muscle rigidity, clonus, peripheral hypertonicity, and shivering), autonomic hyperactivity (for example, tachycardia, mydriasis, diaphoresis, and diarrhea), and alterations in mental status (for example, agitation and delirium). Serotonin syndrome has the potential to be life-threatening. Should it occur, the causative agents should be stopped and supportive care along with any other necessary treatment provided 1.
Why it happens (mechanism)
Additive serotonergic effect
How to manage this interaction
If your care team has you on both amitriptyline and propoxyphene, keep taking them as prescribed unless told otherwise.
- Your team may choose to monitor you more closely for signs of serotonin syndrome while you take both.
- Doses may need to be adjusted and individualized by your prescriber based on how you respond.
- Watch for agitation, confusion, fast heartbeat, sweating, shivering, muscle twitching or stiffness, or fever, and report these promptly.
Ask your pharmacist or doctor before adding any other serotonin-affecting medicine, and check in if you have questions about your combination.
Management is individual — confirm any change with your pharmacist or prescriber.
Common questions
Can I take Propoxyphene and Amitriptyline together?
Taking amitriptyline and propoxyphene together can slightly raise the theoretical risk of serotonin syndrome. Keep taking both as prescribed, watch for symptoms like agitation, fast heartbeat, sweating, or muscle twitching, and contact your care team right away if they occur. Always confirm with your pharmacist or prescriber before making any change.
How serious is the Propoxyphene and Amitriptyline 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 Propoxyphene and Amitriptyline interaction managed?
If your care team has you on both amitriptyline and propoxyphene, keep taking them as prescribed unless told otherwise. Your team may choose to monitor you more closely for signs of serotonin syndrome while you take both. Doses may need to be adjusted and individualized by your prescriber based on how you respond. Watch for agitation, confusion, fast heartbeat, sweating, shivering, muscle twitchin… 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 Propoxyphene or Amitriptyline 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 Amitriptyline
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.
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