Chlorzoxazone and Acetaminophen And Codeine: 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
Chlorzoxazone
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 chlorzoxazone is a muscle relaxant. Both can slow down your brain and body, making you very sleepy. When you take them together, those calming effects can stack up. In some cases this can cause very deep sedation, slowed breathing, low blood pressure, and in rare, serious situations it can become life-threatening.
This does not mean you can't use both, but it is something your care team watches closely. The good news is this is very manageable. Your doctor or pharmacist can pick the lowest doses that still help, keep the treatment short, and check on how you're doing. Please talk with them before making any changes on your own.
Effect: Additive CNS and respiratory depression when codeine (opioid agonist) is combined with chlorzoxazone (centrally acting skeletal muscle relaxant/CNS depressant).
- Mechanism: Additive CNS depression; possible enhanced neuromuscular effects. Pharmacodynamic, not pharmacokinetic.
- Direction: Increased sedation, hypotension, respiratory depression, risk of coma/death. Codeine is a CYP2D6 prodrug, but this interaction is PD-based, so activation status does not change the direction here.
- Evidence/onset: Theoretical; onset unspecified.
- Management: Reserve for patients lacking adequate alternatives; use lowest effective dose and shortest duration; consider reducing codeine and/or chlorzoxazone; monitor for sedation/respiratory depression; consider prescribing naloxone.
What happens
Increased risk of profound sedation, respiratory depression, coma and death
Interaction Deep Dive
Concomitant use of codeine with drugs that are skeletal muscle relaxants and CNS depressants can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death. Reserve the concomitant use of codeine 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 codeine or the CNS depressant and closely monitor for sedation and respiratory depression. Inform patients and caregivers of this potential interaction and educate them on the signs and symptoms of respiratory depression (including sedation). Respiratory depression may be greater than otherwise expected with concomitant skeletal muscle relaxant and hence decrease the dosage of codeine and/or the muscle relaxant as necessary. If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose12.
Why it happens (mechanism)
Enhanced neuromuscular blockade; additive CNS depression
How to manage this interaction
Both drugs can be used together when needed, but the goal is the smallest effective amount for the shortest time. Here is what typically happens and what you can do:
- Your care team may lower the dose of the codeine product, the chlorzoxazone, or both, and individualize it for you.
- They may monitor you more closely for heavy sedation or slowed breathing.
- Keep taking both exactly as prescribed unless your prescriber tells you otherwise.
- Your doctor may also consider prescribing naloxone as a safety measure.
Call your pharmacist or prescriber if you notice unusual drowsiness, confusion, or slow or shallow breathing.
Management is individual — confirm any change with your pharmacist or prescriber.
Literature reports
1 report — tap to read
a) Observational research has shown that using opioid analgesics together with benzodiazepines raises the risk of drug-related death when compared with using opioid analgesics by themselves. Given the comparable pharmacological characteristics, it is reasonable to anticipate a similar risk when other CNS depressant medications are combined with opioid analgesics 12.
Common questions
Can I take Chlorzoxazone and Acetaminophen And Codeine together?
Combining codeine with the muscle relaxant chlorzoxazone can add up to dangerous sedation and slowed breathing, so use the lowest doses for the shortest time and let your care team monitor you. Always confirm with your pharmacist or prescriber before making any change.
How serious is the Chlorzoxazone and Acetaminophen And Codeine 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 Chlorzoxazone and Acetaminophen And Codeine interaction managed?
Both drugs can be used together when needed, but the goal is the smallest effective amount for the shortest time. Here is what typically happens and what you can do: Your care team may lower the dose of the codeine product, the chlorzoxazone, or both, and individualize it for you. They may monitor you more closely for heavy sedation or slowed breathing. Keep taking both exactly as prescribed unles… 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 Chlorzoxazone or Acetaminophen And Codeine 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)
- 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 Chlorzoxazone
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