Acetaminophen And Codeine and Methylene Blue: 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
Methylene Blue
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, along with acetaminophen (Tylenol). Methylene blue acts like a type of drug called an MAOI. When these two are combined, they can affect serotonin, a brain chemical, and raise the risk of a serious reaction called serotonin syndrome (things like agitation, fever, a fast heartbeat, and shaking). Because both drugs can also slow down your brain and breathing, using them together can make you dangerously sleepy or make breathing too slow.
This combination is considered not safe to use together. Please don't change anything on your own, but do talk with your pharmacist or doctor. Your care team can plan safer options.
Contraindicated combination. Methylene blue is a potent MAOI; combined with codeine (a serotonergic opioid) it raises the risk of serotonin syndrome plus additive CNS and respiratory depression.
- Mechanism: additive serotonergic activity via MAO inhibition, plus additive CNS depression.
- Evidence: theoretical, but severity classed as contraindicated.
- Management: discontinue methylene blue 14 days before starting codeine. If urgent analgesia is needed, select an alternative opioid (oxycodone, hydrocodone, oxymorphone, buprenorphine), use IR test doses, titrate carefully while monitoring BP and CNS/respiratory status.
- If IV methylene blue is required, use the lowest dose and monitor CNS effects for up to 4 hours.
What happens
Increased risk of serotonin syndrome and an increased risk of respiratory and CNS depression
Interaction Deep Dive
Codeine must not be given together with methylene blue, which acts as both an MAOI and a CNS depressant, so this combination is contraindicated. Methylene blue is to be stopped 14 days prior to beginning codeine. When opioid therapy cannot be delayed, select a different opioid (for example, oxyCODONE, HYDROcodone, oxyMORphone, or buprenorphine), begin with test doses using an immediate-release formulation, and titrate the dose cautiously while keeping watch on blood pressure as well as any signs and symptoms of respiratory and CNS depression1. Should intravenous methylene blue be needed, administer the smallest feasible dose and observe for CNS effects for as long as 4 hours following the dose 2.
Why it happens (mechanism)
Additive serotonergic effects; additive CNS depression
How to manage this interaction
This pairing is flagged as contraindicated, so your care team will usually avoid using them together.
- Methylene blue is typically stopped 14 days before codeine is started.
- If pain relief is urgently needed, your team may choose a different opioid (such as oxycodone, hydrocodone, oxymorphone, or buprenorphine), starting low and adjusting the dose while watching your blood pressure, alertness, and breathing.
- If IV methylene blue must be given, the lowest dose is used with monitoring for several hours afterward.
Keep taking medicines exactly as prescribed and tell your pharmacist or doctor if both were ordered so they can tailor a safe plan.
Management is individual — confirm any change with your pharmacist or prescriber.
Common questions
Can I take Acetaminophen And Codeine and Methylene Blue together?
Codeine (in your acetaminophen-codeine product) and methylene blue should not be used together because of the risk of serotonin syndrome and dangerous slowing of breathing and alertness. Do not change anything yourself; contact your pharmacist or doctor so they can arrange a safer option. Always confirm with your pharmacist or prescriber before making any change.
How serious is the Acetaminophen And Codeine and Methylene Blue interaction?
It is rated contraindicated. These should generally not be used together.
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 Methylene Blue interaction managed?
This pairing is flagged as contraindicated, so your care team will usually avoid using them together. Methylene blue is typically stopped 14 days before codeine is started. If pain relief is urgently needed, your team may choose a different opioid (such as oxycodone, hydrocodone, oxymorphone, or buprenorphine), starting low and adjusting the dose while watching your blood pressure, alertness, and… 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 Methylene Blue 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: CARISOPRODOL, ASPIRIN, CODEINE PHOSPHATE oral tablets, carisoprodol, aspirin, codeine phosphate oral tablets. Ingenus Pharmaceuticals LLC (per DailyMed), Orlando, FL, 2021. DailyMed
- Product Information: PROVAYBLUE(R) intravenous injection, methylene blue intravenous injection. American Regent, Inc. (per FDA), Shirley, NY, 2023. DailyMed
Keep reading about Acetaminophen And Codeine
Keep reading about Methylene Blue
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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