Naltrexone 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
Naltrexone
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 (it works together with acetaminophen). Naltrexone (ReVia) is a medicine that blocks opioids at the same spots in your body. Because it sits on those spots, it can push the codeine off and stop it from working.
If you are already taking an opioid and then take naltrexone, it can trigger sudden withdrawal, sometimes within minutes. That can mean sweating, cramps, nausea, and feeling very sick. This combination is not meant to be used together. Please talk with your pharmacist or doctor before starting or stopping either one so your care team can plan it safely.
Contraindicated combination. Naltrexone is a competitive opioid receptor antagonist. It displaces codeine (and its active metabolite morphine) at mu-opioid receptors, producing pharmacodynamic antagonism.
- Direction: reduced/abolished opioid analgesia; risk of precipitated withdrawal in opioid-dependent patients, onset within minutes.
- Evidence: probable; onset rapid.
- Note: Codeine is a prodrug (CYP2D6 to morphine), but the antagonism occurs at the receptor regardless of activation.
- Management: Avoid co-administration. Patients should be opioid-free 7 to 10 days before initiating naltrexone. A naloxone challenge test can confirm opioid-free status. Attempting to override the blockade with high opioid doses risks fatal overdose.
What happens
Precipitation of opioid withdrawal symptoms; decreased opioid effectiveness
Interaction Deep Dive
Giving naltrexone together with opioids is contraindicated12. In individuals who are opioid dependent, naltrexone counteracts the action of narcotic analgesics, producing withdrawal symptoms as soon as 5 minutes after it is taken6. Before beginning naltrexone or products that contain naltrexone (for instance bupropion/naltrexone), patients must remain free of opioids (traMADol included) for at least 7 to 10 days; those who were formerly on methadone or buprenorphine may need as long as 2 weeks42. The blockade, even when naltrexone is started correctly, can still be overridden by extremely high opiate doses, which creates a danger of fatal overdose among patients who try to overcome the blockade on their own1. As a combination product, morphine sulfate/naltrexone hydrochloride is indicated for the management of moderate to severe pain when used as directed3.
Why it happens (mechanism)
Competitive binding at opioid receptors
How to manage this interaction
These are not used together. This is a contraindicated pair, so the usual approach is to avoid combining them and to separate them in time.
- Do not start naltrexone while taking codeine-containing products. Patients generally need to be opioid-free for about 7 to 10 days first, and your care team decides the exact timing.
- Your prescriber may use a naloxone challenge test to confirm you are opioid-free before naltrexone.
- Never try to overcome the blockade with extra opioid doses, this can cause a dangerous overdose.
- Keep taking medicines exactly as prescribed and ask your pharmacist or doctor before any change so they can manage the switch safely.
Management is individual — confirm any change with your pharmacist or prescriber.
Literature reports
1 report — tap to read
a) A patient with painful peripheral neuropathy showed marked improvement after oral naltrexone was added. A 61-year-old man with diabetes reported pain and paresthesias in his feet, distal legs, and fingers. His finger stick glucose readings were around 250. He was receiving methadone 80 mg/day plus oxycodone 5 mg four times daily for breakthrough pain. One week before presentation, both drugs had been cut by 50% because of concerns regarding medication-seeking behavior. During the following months he had many dose changes, yet the pain kept recurring. He also reported nausea. Eight months after presentation, he was on methadone 60 mg four times daily along with methylphenidate 30 mg twice daily for opioid-induced sedation. "Ultra-low" dose naltrexone was started at 1 mcg twice daily. The patient noted improvement within 1 day. His pain lessened considerably and the chronic nausea resolved. The methadone dose was lowered to 50 mg four times daily while the methylphenidate dose was left unchanged. One month later the patient continued to have the same level of pain relief. The identical methadone dose and 50% of the short-acting opioid were used 5.
Common questions
Can I take Naltrexone and Acetaminophen And Codeine together?
Naltrexone blocks codeine, wiping out pain relief and possibly triggering sudden withdrawal, so the two should not be used together. Talk to your pharmacist or doctor before starting or stopping either one. Always confirm with your pharmacist or prescriber before making any change.
How serious is the Naltrexone 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 "rapid". Effects can appear quickly, often within about 24 hours of combining the drugs.
How is the Naltrexone and Acetaminophen And Codeine interaction managed?
These are not used together. This is a contraindicated pair, so the usual approach is to avoid combining them and to separate them in time. Do not start naltrexone while taking codeine-containing products. Patients generally need to be opioid-free for about 7 to 10 days first, and your care team decides the exact timing. Your prescriber may use a naloxone challenge test to confirm you are opioid-f… 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 Naltrexone 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 (6)
- Product Information: VIVITROL(R) intramuscular injection extended-release suspension, naltrexone intramuscular injection extended-release suspension. Alkermes, Inc. (per Manufacturer), Waltham, MA, 2013.
- Product Information: REVIA(R) oral tablets, naltrexone HCl oral tablets. Duramed Pharmaceuticals, Inc. (per FDA), Pomona, NY, 2013.
- Product Information: EMBEDA(R) oral extended-release capsules, morphine sulfate and naltrexone hcl oral extended-release capsules. King Pharmaceuticals, Inc. Bristol, TN, 2009. DailyMed
- Product Information: CONTRAVE(R) oral extended-release tablets, naltrexone HCl and bupropion HCl oral extended-release tablets. Orexigen Therapeutics, Inc. (per manufacturer), La Jolla, CA, 2014. DailyMed
- Cruciani RA, Lussier D, Miller-Saultz D, et al: Ultra-low dose oral naltrexone decreases side effects and potentiates the effect of methadone (letter). J Pain Symptom Manage 2003; 25(6):491-494. PubMed
- Tornabene VW: Narcotic withdrawal syndrome caused by naltrexone. Ann Intern Med 1974; 81:785-787. PubMed
Keep reading about Acetaminophen And Codeine
Keep reading about Naltrexone
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.
Check another combination
Our instant two-drug interaction checker is almost here.
Still have questions about this combination?
Every question gets a real answer from a licensed pharmacist — free, and usually within a day.
Ask the pharmacist