Acetaminophen And Codeine and Midazolam: Interaction Details
AI-assisted, pharmacist-reviewed · AI content regenerated Jul 11, 2026 · Source data updated Jul 1, 2026 · Sources: FDA labeling, DDInter 2.0, cited literature
Acetaminophen And Codeine
Midazolam
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.
These two medicines both slow down your brain and body. Codeine is an opioid pain reliever (combined here with acetaminophen, which is Tylenol), and midazolam is a benzodiazepine sedative. When you take them together, their calming effects add up. That can make you very sleepy, drop your blood pressure, and most importantly slow your breathing. In serious cases this can be dangerous.
The good news is that your care team can manage this. Doctors sometimes use both on purpose, but they keep the doses low and watch you closely. If you feel unusually drowsy, dizzy, confused, or short of breath, let your doctor or pharmacist know right away.
Mechanism: additive CNS and respiratory depression from an opioid (codeine, with acetaminophen) plus a benzodiazepine (midazolam). Neither agent's activity depends on the other for this pharmacodynamic effect; the concern is additive PD, not a PK interaction.
- Effect: increased risk of hypotension, respiratory depression, profound sedation, coma, and death.
- Severity/evidence: major; theoretical/class-based. Onset unspecified.
- Management: reserve concurrent use for when alternatives are inadequate; use lowest effective doses and shortest duration; monitor closely for sedation and respiratory depression; consider prescribing naloxone.
What happens
An increased risk of hypotension, respiratory depression, profound sedation, coma, and death
Interaction Deep Dive
When codeine is taken alongside benzodiazepines, the likelihood of hypotension, respiratory depression, deep sedation, coma, and death may rise. Prescribing both agents together should be limited to patients for whom other treatment choices prove insufficient. Keep doses and treatment length to the smallest amount necessary. Monitor patients carefully for indications of sedation and respiratory depression. Should combined use be justified, consider prescribing naloxone for emergency management of opioid overdose134.
Why it happens (mechanism)
Additive CNS depression
How to manage this interaction
Keep taking both exactly as prescribed unless your care team tells you otherwise. This combination is used only when needed, and your team manages it deliberately.
- Doses may be kept low and the treatment as short as possible, individualized by your care team.
- Your team may monitor you more closely for heavy drowsiness, slow or shallow breathing, and low blood pressure.
- In some cases your prescriber may provide naloxone as a safety measure.
- Avoid alcohol and other sedating substances, and tell your pharmacist or doctor about new drowsiness, dizziness, or trouble breathing.
Management is individual — confirm any change with your pharmacist or prescriber.
Literature reports
4 reports — tap to read
a) In a study, emergency department visits related to nonmedical use that took place between 2004 and 2011 and involved opioid analgesics together with benzodiazepines rose significantly from 11 to 34.2 per 100,000. Drug overdose deaths attributable to prescribed and above-prescribed doses of both drug classes likewise increased significantly from 0.6 to 1.7 per 100,000, and overdose deaths caused by benzodiazepines increased significantly from 18% to 31% 2.
b) In a prospective cohort study, the rate of overdose deaths involving the dispensing of both opioid analgesics and benzodiazepines was 10 times greater than that seen with dispensing of opioid analgesics alone (7 vs 0.7 per 10,000 person years) 2.
c) In a cohort study using data from 2004 to 2009, the risk of fatal overdose rose significantly by 2.33 fold among patients taking opioid analgesics who had a history of a benzodiazepine prescription and rose by 3.86 fold among those with a current benzodiazepine prescription, compared with patients taking opioid analgesics who had no history of a benzodiazepine prescription. The risk of drug overdose deaths grew as the daily doses of benzodiazepines increased 2.
d) Observational studies have shown that using opioid analgesics and benzodiazepines together raises the risk of drug-related mortality when compared with using opioid analgesics alone. Given their comparable pharmacological properties, it is reasonable to anticipate a similar risk when other CNS depressant drugs are used concurrently with opioid analgesics 34.
Common questions
Can I take Acetaminophen And Codeine and Midazolam together?
Taking codeine (with acetaminophen) and midazolam together adds up their sedating effects and can dangerously slow breathing, so this pairing is used only when necessary, at the lowest doses, with close monitoring by your care team. Always confirm with your pharmacist or prescriber before making any change.
How serious is the Acetaminophen And Codeine and Midazolam 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 Midazolam interaction managed?
Keep taking both exactly as prescribed unless your care team tells you otherwise. This combination is used only when needed, and your team manages it deliberately. Doses may be kept low and the treatment as short as possible, individualized by your care team. Your team may monitor you more closely for heavy drowsiness, slow or shallow breathing, and low blood pressure. In some cases your prescribe… 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 Midazolam 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 (4)
- Product Information: CARISOPRODOL, ASPIRIN, CODEINE PHOSPHATE oral tablets, carisoprodol, aspirin, codeine phosphate oral tablets. Ingenus Pharmaceuticals LLC (per DailyMed), Orlando, FL, 2021. DailyMed
- US Food and Drug Administration (FDA): Drug Safety Communications: FDA warns about serious risks and death when combining opioid pain or cough medicines with benzodiazepines; requires its strongest warning. US Food and Drug Administration (FDA). Silver Spring, MD. 2016.
- Product Information: Codeine sulfate oral solution, codeine sulfate oral solution. Hikma Pharmaceuticals USA Inc(per FDA), Berkeley Heights, NJ, 2023. DailyMed
- Product Information: Codeine sulfate oral tablets, codeine sulfate oral tablets. Hikma Pharmaceuticals USA Inc. (per FDA), Berkeley Heights, NJ, 2023. DailyMed
Keep reading about Acetaminophen And Codeine
Keep reading about Midazolam
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