Doxylamine 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
Doxylamine
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 that can slow your breathing and make you sleepy. Doxylamine is a sedating antihistamine found in many sleep aids like Unisom or ZzzQuil, and it also makes you drowsy. When you take them together, those calming effects can stack on top of each other. That can lead to too much sedation, slowed breathing, and in serious cases much worse.
The good news is your care team can manage this. If they decide you need both, they will use the lowest doses for the shortest time and watch you closely. Please talk with your pharmacist or doctor before combining them, and don't stop anything on your own.
Additive CNS and respiratory depression from combining codeine (opioid) with doxylamine (sedating H1 antihistamine).
- Mechanism: additive CNS depression; both agents independently cause sedation and blunt respiratory drive. This is a pharmacodynamic, not pharmacokinetic, interaction.
- Direction/effect: increased risk of hypotension, profound sedation, respiratory depression, coma, death.
- Evidence: theoretical; severity major. Onset unspecified.
- Management: avoid combination where possible. If required, use lowest effective dose and shortest duration, consider reducing either agent, monitor closely for sedation/respiratory depression, and consider prescribing naloxone.
Note: codeine is a prodrug (CYP2D6 to morphine), but this interaction is additive pharmacodynamic, not metabolic.
What happens
An increased risk of respiratory and CNS depression
Interaction Deep Dive
Avoid concomitant use of opioid cough medication formulations and CNS depressants. Concomitant use of opioid analgesics with benzodiazepines has been associated with increased rates of emergency department visits and fatal overdose2. Concomitant use of codeine with CNS depressants can increase the risk of hypotension, respiratory depression, profound sedation, coma and death. Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation. If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose 341.
Why it happens (mechanism)
Additive CNS depression
How to manage this interaction
Both medicines cause drowsiness, so your care team will focus on limiting that combined effect.
- Keep taking both exactly as prescribed unless your prescriber tells you otherwise, and don't stop on your own.
- Your team may use the lowest dose for the shortest time, or lower the dose of one medicine, and monitor you more closely for heavy sedation or slowed breathing.
- In some cases they may prescribe naloxone as an emergency backup.
- Tell your pharmacist or doctor about any over-the-counter sleep aids (many contain doxylamine), and get help right away for extreme drowsiness or trouble breathing.
Management is individual — confirm any change with your pharmacist or prescriber.
Literature reports
4 reports — tap to read
a) One study found that emergency department visits related to nonmedical use that occurred between 2004 and 2011 and involved opioid analgesics together with benzodiazepines rose significantly from 11 to 34.2 per 100,000. Drug overdose deaths attributable to prescribed and above-prescribed doses of both drug classes likewise increased significantly from 0.6 to 1.7 per 100,000, and overdose deaths attributable to benzodiazepines rose significantly from 18% to 31% 2.
b) In a prospective cohort study, the rate of overdose deaths involving the dispensing of both opioid analgesics and benzodiazepines was 10 times greater than that with the dispensing of opioid analgesics alone (7 vs 0.7 per 10,000 person years) 2.
c) In a cohort study using data from 2004 to 2009, the risk of fatal overdose increased significantly by 2.33 fold among patients taking opioid analgesics who had a history of a benzodiazepine prescription, and by 3.86 fold among those with a current benzodiazepine prescription, compared with patients taking opioid analgesics who had no history of a benzodiazepine prescription. The risk of drug overdose deaths rose as the daily doses of benzodiazepines increased 2.
d) Observational studies have shown that using opioid analgesics and benzodiazepines together increases the risk of drug-related mortality relative to using opioid analgesics alone. Given comparable pharmacological properties, it is reasonable to anticipate a similar risk when other CNS depressant drugs are used concurrently with opioid analgesics 34.
Common questions
Can I take Doxylamine and Acetaminophen And Codeine together?
Codeine and doxylamine both cause sedation and can slow breathing, so combining them raises the risk of over-sedation. Check with your pharmacist or doctor before using both, especially any OTC sleep aids. Always confirm with your pharmacist or prescriber before making any change.
How serious is the Doxylamine and Acetaminophen And Codeine 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 Doxylamine and Acetaminophen And Codeine interaction managed?
Both medicines cause drowsiness, so your care team will focus on limiting that combined effect. Keep taking both exactly as prescribed unless your prescriber tells you otherwise, and don't stop on your own. Your team may use the lowest dose for the shortest time, or lower the dose of one medicine, and monitor you more closely for heavy sedation or slowed breathing. In some cases they may prescribe… 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 Doxylamine 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 (4)
- Product Information: CARISOPRODOL, ASPIRIN, CODEINE PHOSPHATE oral tablets, carisoprodol, aspirin, codeine phosphate oral tablets. Ingenus Pharmaceuticals LLC (per DailyMed), Orlando, FL, 2021. DailyMed
- US Food and Drug Administration (FDA): Drug Safety Communications: FDA warns about serious risks and death when combining opioid pain or cough medicines with benzodiazepines; requires its strongest warning. US Food and Drug Administration (FDA). Silver Spring, MD. 2016.
- Product Information: Codeine sulfate oral solution, codeine sulfate oral solution. Hikma Pharmaceuticals USA Inc(per FDA), Berkeley Heights, NJ, 2023. DailyMed
- Product Information: Codeine sulfate oral tablets, codeine sulfate oral tablets. Hikma Pharmaceuticals USA Inc. (per FDA), Berkeley Heights, NJ, 2023. DailyMed
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