Acetaminophen And Codeine and Metaxalone: 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
Metaxalone
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 can slow down your body and brain. The codeine in your pain pill is an opioid, and metaxalone (Skelaxin) is a muscle relaxer. Taken together, they can add up and make you very drowsy, slow your breathing, or cause deep sleepiness. There is also a possible chance of a rare reaction called serotonin syndrome, which can cause shakiness, a fast heartbeat, sweating, or confusion.
The good news is that your care team can manage this. They may use the lowest dose for the shortest time and watch you closely. If you feel unusually sleepy, hard to wake, or short of breath, get help right away. Talk with your pharmacist or doctor before making any changes.
Effect: Additive CNS and respiratory depression, plus a theoretical risk of serotonin syndrome when metaxalone is combined with acetaminophen/codeine.
- Mechanism: Additive CNS/respiratory depression from opioid plus muscle relaxant; possible additive serotonergic activity (metaxalone has been associated with serotonin syndrome at therapeutic doses).
- Direction/magnitude: Enhanced sedation, hypoventilation, profound sedation, coma, death; magnitude not quantified.
- Onset: Unspecified. Evidence: Theoretical.
- Management: Reserve concurrent use for when alternatives are inadequate; use lowest effective dose and shortest duration. Monitor for sedation, respiratory depression, urinary retention, constipation, and serotonergic signs. Strongly consider prescribing naloxone.
What happens
Increased risk of serotonin syndrome, an increased risk of respiratory depression and an increased risk of CNS depression
Interaction Deep Dive
When metaxalone (at doses within the standard therapeutic range) is taken together with serotonergic agents, serotonin syndrome has been documented3. Beyond this, giving muscle relaxants alongside opioids can produce cumulative CNS depression, raising the likelihood of respiratory depression, deep sedation, coma, and death. Such combined prescribing should be limited to patients for whom other therapeutic choices prove insufficient. Should concurrent use be required, employ the smallest effective dose over the shortest possible period. Watch for sedation, respiratory depression, urinary retention, and severe constipation, and give serious consideration to prescribing naloxone as an emergency measure for opioid overdose12.
Why it happens (mechanism)
Additive serotonergic effects; additive CNS depression
How to manage this interaction
Keep taking both medicines as prescribed unless your care team tells you otherwise. This combination can be used when needed, but it is handled carefully.
- Your team may use the lowest effective dose for the shortest time.
- They may monitor you more closely for heavy sedation, slowed breathing, trouble urinating, or severe constipation.
- Your prescriber may consider giving you naloxone as an emergency backup.
- Tell your pharmacist or doctor about any other sedating medicines, alcohol, or serotonin-affecting drugs you use.
Seek urgent help for extreme drowsiness, confusion, fast heartbeat, or breathing that becomes slow or shallow.
Management is individual — confirm any change with your pharmacist or prescriber.
Common questions
Can I take Acetaminophen And Codeine and Metaxalone together?
Taking acetaminophen/codeine with metaxalone can add up to cause heavy sedation and slowed breathing, and rarely serotonin syndrome. Use only when needed at the lowest dose, watch for extreme drowsiness or breathing trouble, and talk with your pharmacist or doctor. Always confirm with your pharmacist or prescriber before making any change.
How serious is the Acetaminophen And Codeine and Metaxalone 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 Metaxalone interaction managed?
Keep taking both medicines as prescribed unless your care team tells you otherwise. This combination can be used when needed, but it is handled carefully. Your team may use the lowest effective dose for the shortest time. They may monitor you more closely for heavy sedation, slowed breathing, trouble urinating, or severe constipation. Your prescriber may consider giving you naloxone as an emergenc… 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 Acetaminophen And Codeine or Metaxalone 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: Oxycodone HCl acetaminophen oral tablets, oxycodone HCl acetaminophen oral tablets. Mayne Pharma (per DailyMed), Greenville, NC, 2021.
- Product Information: CARISOPRODOL, ASPIRIN, CODEINE PHOSPHATE oral tablets, carisoprodol, aspirin, codeine phosphate oral tablets. Ingenus Pharmaceuticals LLC (per DailyMed), Orlando, FL, 2021. DailyMed
- Product Information: SKELAXIN(R) oral tablets, metaxalone oral tablets. King Pharmaceuticals, Inc. (per FDA), Bristol, TN, 2018. DailyMed
Keep reading about Acetaminophen And Codeine
Keep reading about Metaxalone
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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