Acetaminophen And Codeine and Clorazepate: 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
Clorazepate
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 pain medicine contains codeine, an opioid, and clorazepate (Tranxene) is a benzodiazepine used for anxiety. Both of these calm down the brain and slow your breathing. When you take them together, those calming effects can stack up. That can lead to being very drowsy, breathing too slowly, low blood pressure, and in serious cases it can become dangerous.
This does not mean you can never use both, but it is something to take seriously. Please don't start, stop, or change either medicine on your own. Talk with your pharmacist or doctor so they can make sure the doses and timing are right for you and watch you closely.
Mechanism: additive CNS and respiratory depression from combining an opioid (codeine) with a benzodiazepine (clorazepate). Neither relevant effect here depends on prodrug activation for the risk; the concern is pharmacodynamic overlap.
Direction/effect: increased risk of hypotension, respiratory depression, profound sedation, coma, and death.
- Severity: major; evidence: theoretical/class-based; onset: unspecified.
- Management: reserve co-prescribing for when alternatives are inadequate; use lowest effective doses and shortest duration; monitor closely for sedation and respiratory depression; consider prescribing naloxone.
Note codeine is a CYP2D6 prodrug (variable analgesic response), but the sedation/respiratory risk is additive regardless.
What happens
An increased risk of hypotension, respiratory depression, profound sedation, coma, and death
Interaction Deep Dive
Concomitant use of codeine with benzodiazepines can increase the risk of hypotension, respiratory depression, profound sedation, coma and death. Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation. If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose134.
Why it happens (mechanism)
Additive CNS depression
How to manage this interaction
Your care team can manage this combination safely with a few steps:
- They typically use the lowest effective dose of each for the shortest time needed.
- They may monitor you more closely for heavy sedation, slow or shallow breathing, and low blood pressure.
- They may consider prescribing naloxone to keep on hand for emergencies.
What you can do: keep taking both exactly as prescribed, and avoid alcohol or other sedating medicines unless cleared first. Ask your pharmacist or prescriber before making any change, and get help right away if you feel unusually drowsy or short of breath.
Management is individual — confirm any change with your pharmacist or prescriber.
Literature reports
4 reports — tap to read
a) In one study, the rate of emergency department visits related to nonmedical use occurring between 2004 and 2011 that involved opioid analgesics and benzodiazepines rose significantly from 11 to 34.2 per 100,000. Drug overdose deaths attributable to both drug classes at prescribed and greater than prescribed doses also rose significantly from 0.6 to 1.7 per 100,000, and overdose deaths attributable to benzodiazepines rose 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 in patients receiving opioid analgesics who had a history of a benzodiazepine prescription, and rose by 3.86 fold in 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 daily doses of benzodiazepines increased 2.
d) Observational studies have shown that using opioid analgesics together with benzodiazepines raises the risk of drug-related mortality 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 together with opioid analgesics 34.
Common questions
Can I take Acetaminophen And Codeine and Clorazepate together?
Codeine and clorazepate both slow the brain and breathing, so together they raise the risk of heavy sedation, slow breathing, and low blood pressure. Take them only as prescribed at the lowest doses, watch for excessive drowsiness or breathing trouble, and check with your pharmacist or doctor. Always confirm with your pharmacist or prescriber before making any change.
How serious is the Acetaminophen And Codeine and Clorazepate 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 Clorazepate interaction managed?
Your care team can manage this combination safely with a few steps: They typically use the lowest effective dose of each for the shortest time needed. They may monitor you more closely for heavy sedation, slow or shallow breathing, and low blood pressure. They may consider prescribing naloxone to keep on hand for emergencies. What you can do: keep taking both exactly as prescribed, and avoid alcoh… 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 Clorazepate 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
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