Acetaminophen And Codeine and Hydromorphone: 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
Hydromorphone
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.
Both of these medicines are opioid pain relievers. Your acetaminophen with codeine also contains codeine, and hydromorphone (Dilaudid) is another strong opioid. When you take two opioids together, their calming effects on the brain and breathing add up. That can cause heavy drowsiness, slowed or shallow breathing, low blood pressure, and in rare cases a reaction called serotonin syndrome (restlessness, sweating, shaking, fast heartbeat).
The good news is your care team knows how to handle this. They can use the lowest dose for the shortest time and watch you closely, especially when starting or changing doses. Please don't stop or adjust either medicine on your own. Just talk with your pharmacist or doctor about the best plan.
Additive CNS and respiratory depression from combining two opioids (codeine plus hydromorphone), with a theoretical additive serotonergic risk.
- Mechanism: additive opioid-mediated CNS/respiratory depression; additive serotonergic effects (pharmacodynamic, not PK).
- Direction/effect: increased sedation, respiratory depression, hypotension; potential serotonin syndrome.
- Evidence: theoretical; severity rated major; onset unspecified.
- Management: reserve concomitant use for when alternatives are inadequate; use lowest effective dose and shortest duration; consider lowering the dose of one agent; monitor for sedation, respiratory depression, and serotonin syndrome, especially at initiation/titration. Discontinue if serotonin syndrome suspected. Consider prescribing naloxone and counsel patient/caregivers.
What happens
Increased risk of respiratory and CNS depression and an increased risk of serotonin syndrome
Interaction Deep Dive
Concomitant use of opioids, such as HYDROmorphone, with serotonergic CNS depressant drugs may result in increased risk of serotonergic syndrome, profound sedation, hypotension, respiratory depression, coma death. Reserve the concomitant use of HYDROmorphone and CNS depressants to patients for whom alternatives are inadequate. If concomitant use is necessary, use the lowest dose and shortest duration necessary to achieve treatment goals. Consider using a lower dose of HYDROmorphone or the CNS depressant and closely monitor for sedation, respiratory depression, and signs and symptoms of serotonin syndrome. If concomitant use is needed, carefully observe the patient, particularly during treatment initiation and dose adjustments for serotonin syndrome. Discontinue HYDROmorphone if serotonin syndrome is suspected123. Consider prescribing naloxone for the emergency treatment of opioid overdose. Inform and educate the patients and caregivers on the signs and symptoms of respiratory depression (including sedation) 2.
Why it happens (mechanism)
Additive CNS depression; additive serotonergic effects
How to manage this interaction
Both medicines are opioids, so their effects on breathing and alertness stack up. Your care team can manage this safely.
- Keep taking both exactly as prescribed unless your prescriber tells you otherwise. Do not double up or add extra doses.
- Your team may use the lowest dose for the shortest time and may lower one of the doses, tailored to you.
- Expect closer monitoring, especially when starting or changing a dose.
- Ask whether having naloxone at home makes sense for you.
- Get help right away for very slow or shallow breathing, extreme sleepiness, confusion, sweating, shaking, or a racing heartbeat.
Management is individual — confirm any change with your pharmacist or prescriber.
Literature reports
2 reports — tap to read
a) Instances of serotonin syndrome, a condition that can be life-threatening, have been documented when opioids are used together with serotonergic drugs 32.
b) Observational studies have shown that taking opioid analgesics along with benzodiazepines raises the risk of drug-related death compared with taking opioid analgesics by themselves. Given their comparable pharmacological properties, it is reasonable to anticipate a similar risk when other CNS depressant drugs are used together with opioid analgesics 23.
Common questions
Can I take Acetaminophen And Codeine and Hydromorphone together?
Taking codeine and hydromorphone together adds up their sedative and breathing-slowing effects and carries a small serotonin risk, so use only under close medical supervision at the lowest effective dose. Never adjust either medicine on your own; talk with your pharmacist or prescriber and ask about naloxone. Always confirm with your pharmacist or prescriber before making any change.
How serious is the Acetaminophen And Codeine and Hydromorphone 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 Hydromorphone interaction managed?
Both medicines are opioids, so their effects on breathing and alertness stack up. Your care team can manage this safely. Keep taking both exactly as prescribed unless your prescriber tells you otherwise. Do not double up or add extra doses. Your team may use the lowest dose for the shortest time and may lower one of the doses, tailored to you. Expect closer monitoring, especially when starting or… 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.
Questions for your pharmacist
- Does my dose of Acetaminophen And Codeine or Hydromorphone 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 (3)
- Product Information: EXALGO(R) oral extended-release tablets, hydromorphone HCl oral extended-release tablets. SpecGx LLC (per FDA), Webster Groves, MO, 2019. DailyMed
- Product Information: DILAUDID(R) oral tablets, oral solution, hydromorphone HCl oral tablets, oral solution. Rhodes Pharmaceuticals LP (per FDA), Wilson, NC, 2023. DailyMed
- Product Information: DILAUDID(R) intravenous injection, intramuscular injection, subcutaneous injection, hydromorphone HCl intravenous injection, intramuscular injection, subcutaneous injection. Fresenius Kabi. (per FDA), Lake Zurich, IL, 2023. DailyMed
Keep reading about Acetaminophen And Codeine
Keep reading about Hydromorphone
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