Samidorphan and Acetaminophen And Codeine: 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
Samidorphan
No brand names on record
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.
These two medicines work against each other. Codeine is an opioid pain reliever. Samidorphan is an opioid blocker, meaning it sits on the same spots in your body that opioids use and blocks them. If you take both, the codeine can stop working, so your pain may not be controlled.
Even more important, if your body is already used to an opioid, samidorphan can trigger sudden, uncomfortable withdrawal (sweating, chills, cramps, nausea, and feeling very unwell). Because of this, the two are not meant to be used together. Please do not change anything on your own. Talk with your doctor or pharmacist so they can plan the safest option for you.
Contraindicated combination. Samidorphan is a mu-opioid receptor antagonist; codeine (and its active metabolite morphine, formed via CYP2D6) is a receptor agonist. Competitive binding at opioid receptors produces a pharmacodynamic interaction: reduced analgesic efficacy and, in opioid-dependent patients, precipitated acute withdrawal.
- Direction: reduced opioid effect; risk of withdrawal.
- Evidence: theoretical/mechanistic, but labeled contraindication.
- Management: avoid co-use. Ensure a 7-day opioid-free interval (short-acting) or 14 days (long-acting) before starting samidorphan. In emergencies needing opioids, discontinue samidorphan and administer opioid by trained staff with cardiopulmonary monitoring. For planned procedures, stop samidorphan at least 5 days beforehand.
What happens
Decreased opioid efficacy and precipitation of opioid withdrawal
Interaction Deep Dive
Because samidorphan, an opioid antagonist, raises the likelihood of triggering acute opioid withdrawal in opioid-dependent patients, giving it together with an opioid or to individuals in acute opioid withdrawal is contraindicated. Before samidorphan is started, patients should have gone at least 7 days without short-acting opioids since their last dose, and at least 14 days without long-acting opioids. Should an emergency arise in which a patient receiving samidorphan needs opioids for anesthesia or analgesia, stop the samidorphan. Administration of the opioid should be carried out by appropriately trained personnel, with the patient monitored appropriately in a location equipped and staffed for cardiopulmonary resuscitation. When the situation is not an emergency and a samidorphan-treated patient is anticipated to need opioid therapy (for example, analgesia during or following an elective surgical procedure), discontinue samidorphan no fewer than 5 days ahead of the opioid treatment1.
Why it happens (mechanism)
Competitive binding at opioid receptors
How to manage this interaction
These drugs should not be taken together. Because samidorphan blocks opioids like codeine, your care team will avoid using them at the same time and will plan any switch carefully.
- Before starting samidorphan, there should be an opioid-free gap (about 7 days after short-acting opioids, 14 days after long-acting ones).
- If you need opioid pain relief for surgery, samidorphan is usually stopped at least 5 days ahead.
- In an emergency needing opioids, this is handled in a monitored medical setting.
What you should do: Do not stop or start either drug on your own. Tell every prescriber and your pharmacist that you take (or recently took) codeine, and ask them to coordinate timing.
Management is individual — confirm any change with your pharmacist or prescriber.
Common questions
Can I take Samidorphan and Acetaminophen And Codeine together?
Codeine and samidorphan work against each other, so combining them can wipe out pain relief and trigger opioid withdrawal. They should not be used together; let your doctor or pharmacist manage the timing and any switch. Always confirm with your pharmacist or prescriber before making any change.
How serious is the Samidorphan and Acetaminophen And Codeine 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 Samidorphan and Acetaminophen And Codeine interaction managed?
These drugs should not be taken together. Because samidorphan blocks opioids like codeine, your care team will avoid using them at the same time and will plan any switch carefully. Before starting samidorphan, there should be an opioid-free gap (about 7 days after short-acting opioids, 14 days after long-acting ones). If you need opioid pain relief for surgery, samidorphan is usually stopped at le… 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 Samidorphan 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 (1)
- Product Information: LYBALVI(TM) oral tablets, olanzapine samidorphan oral tablets. Alkermes Inc (per manufacturer), Waltham, MA, 2021. DailyMed
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