Metyrapone 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
Metyrapone
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 acetaminophen (Tylenol), combined with codeine. Your body normally clears acetaminophen by attaching it to a sugar (a process called glucuronidation) so it can leave the body. Metyrapone can slow that clearing step down, so acetaminophen may hang around a little longer than usual.
In theory, this could raise the chance of acetaminophen building up and stressing the liver, especially with repeated doses. The good news is this is rated a minor interaction, and your care team can manage it easily, often by keeping your acetaminophen dose on the lower side or picking a pain reliever without acetaminophen. Please check with your pharmacist or doctor before making any changes.
Effect: Metyrapone may reduce acetaminophen clearance via inhibition of acetaminophen glucuronide formation, increasing acetaminophen exposure and, theoretically, hepatotoxicity risk. The codeine component is not implicated.
- Direction: increased acetaminophen exposure (reduced elimination).
- Onset: delayed.
- Evidence: probable; based on a single-dose acetaminophen elimination study.
- Severity: minor.
- Management: Use caution; consider lower acetaminophen doses or a non-acetaminophen analgesic. Watch cumulative daily acetaminophen and monitor hepatic function if prolonged/high-dose use is anticipated.
What happens
An increased risk of acetaminophen toxicity
Interaction Deep Dive
Research has examined how a single acetaminophen dose is cleared in patients who are also taking metyrapone1. When the two were given together, the total elimination of acetaminophen was reduced, an effect that may stem from suppressed formation of acetaminophen glucuronide. Based on these findings, metyrapone may increase the toxicity of acetaminophen.
Why it happens (mechanism)
Inhibition of acetaminophen glucuronide formation
How to manage this interaction
Keep taking both medications as prescribed unless your care team tells you otherwise. This is a minor interaction that can be managed.
- Your team may keep your acetaminophen dose on the lower side while you are on metyrapone.
- Alternatively, they may choose a pain reliever that does not contain acetaminophen.
- Watch your total daily acetaminophen from all sources, since many products contain it.
Ask your pharmacist or prescriber which option is best for you, and tell them if you have any liver concerns or drink alcohol regularly.
Management is individual — confirm any change with your pharmacist or prescriber.
Literature reports
1 report — tap to read
a) A study enrolled eight healthy male volunteers to assess how metyrapone affects the elimination rate of acetaminophen and the apparent rate at which acetaminophen metabolites are formed. The principal elimination pathways for acetaminophen include two capacity-limited processes that produce acetaminophen sulfate and acetaminophen glucuronide. Metyrapone inhibits cytochrome P-450-mediated oxidation, which is a minor elimination route for acetaminophen. In the setting of an acetaminophen overdose, the two capacity-limited pathways become saturated, and a greater proportion of the drug becomes available for cytochrome P-450 oxidation. In this randomized, crossover study, participants received a single oral dose of acetaminophen 1 gram on two separate occasions. On one of these occasions, participants also received metyrapone 750 mg one hour before and three hours after the acetaminophen dose. Metyrapone raised the half-life of acetaminophen by 46% (from 2.4 hours to 3.5 hours). The proportion of the acetaminophen dose recovered as the glucuronide metabolite fell by 31% when metyrapone was present, whereas the proportions recovered as the sulfate and mercapturic acid conjugates rose by 53% and 127%, respectively. These findings indicate that metyrapone might increase acetaminophen toxicity because it inhibits glucuronide conjugation more potently than it inhibits oxidation 1.
Common questions
Can I take Metyrapone and Acetaminophen And Codeine together?
Metyrapone can slow how your body clears acetaminophen, so your care team may keep the acetaminophen dose low or use a non-acetaminophen pain reliever. This is a minor, manageable interaction. Always confirm with your pharmacist or prescriber before making any change.
How serious is the Metyrapone and Acetaminophen And Codeine interaction?
It is rated minor. Usually limited clinical impact.
How quickly could this interaction happen?
The documented onset is "delayed". Effects tend to build up gradually over days to weeks.
How is the Metyrapone and Acetaminophen And Codeine interaction managed?
Keep taking both medications as prescribed unless your care team tells you otherwise. This is a minor interaction that can be managed. Your team may keep your acetaminophen dose on the lower side while you are on metyrapone. Alternatively, they may choose a pain reliever that does not contain acetaminophen. Watch your total daily acetaminophen from all sources, since many products contain it. Ask… Management is individual — always follow your own care team's guidance.
How strong is the evidence for this interaction?
The evidence is graded "probable". Good supporting evidence, though not definitively proven.
Questions for your pharmacist
- Does my dose of Metyrapone 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 anything you'd monitor while I'm on both?
References (1)
- Galinsky RE, Nelson EB, & Rollins DE: Pharmacokinetic consequences and toxicologic implications of metyrapone-induced alterations of acetaminophen elimination in man. Eur J Clin Pharmacol 1987; 33:391-396. PubMed
Keep reading about Acetaminophen And Codeine
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