Acetaminophen And Codeine and Zaleplon: 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
Zaleplon
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 both slow down your brain and breathing, and taking them together makes that effect stronger. The codeine in your pain pill is an opioid, and zaleplon is a sleep medicine. Each one on its own can make you drowsy. Together, they can cause heavy sedation, very slow or shallow breathing, low blood pressure, and in serious cases, breathing that stops.
The good news is that your care team can manage this. If you have been given both, don't stop either one on your own. Instead, talk with your pharmacist or doctor so they can review your doses, watch you more closely, and make a safe plan for you.
Mechanism: additive CNS and respiratory depression from combining an opioid (codeine) with a nonbenzodiazepine sedative-hypnotic (zaleplon). Neither is a prodrug concern here that changes direction; the risk is pharmacodynamic, not PK-based.
- Effect: increased risk of profound sedation, hypotension, respiratory depression, coma, and death.
- Evidence: theoretical for this specific pair; extrapolated from documented opioid plus CNS depressant harms.
- Onset: unspecified.
- Management: reserve for patients lacking alternatives; use lowest effective dose and shortest duration; consider reducing the dose of one agent; monitor sedation and respiratory status; consider prescribing naloxone.
What happens
An increased risk of respiratory and CNS depression
Interaction Deep Dive
Do not combine opioid cough preparations with CNS depressants. Taking opioid analgesics together with benzodiazepines has been linked to higher rates of both emergency department visits and fatal overdose2. When codeine is used alongside CNS depressants, the likelihood of hypotension, respiratory depression, profound sedation, coma, and death rises. Prescribing these agents together should be limited to patients whose alternative treatment options prove inadequate. Keep both doses and treatment durations at the lowest level necessary. Monitor patients carefully for indications of sedation and respiratory depression. Should combined use be justified, consider prescribing naloxone to allow emergency management of opioid overdose 341.
Why it happens (mechanism)
Additive CNS depression
How to manage this interaction
Keep taking both exactly as prescribed unless your care team tells you otherwise. This combination is usually reserved for when other options aren't enough, so raise it with your pharmacist or prescriber.
- Your team may use the lowest dose and shortest duration of one or both drugs and may adjust and individualize your dose.
- They may monitor you more closely for heavy sedation and slowed breathing.
- Ask whether naloxone (an emergency opioid rescue medicine) is right for you to have on hand.
- Get help right away for severe drowsiness, confusion, or slow/shallow breathing.
Management is individual — confirm any change with your pharmacist or prescriber.
Literature reports
4 reports — tap to read
a) In one study, emergency department visits related to nonmedical use that took place between 2004 and 2011 and involved both opioid analgesics and benzodiazepines rose significantly from 11 to 34.2 per 100,000. Drug overdose deaths attributed to prescribed and above-prescribed doses of both drug classes likewise rose 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 associated with dispensing both opioid analgesics and benzodiazepines was 10 times greater than with dispensing of opioid analgesics on their own (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 rose significantly by 2.33 fold among patients taking opioid analgesics who had a prior benzodiazepine prescription and rose 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 grew as the daily doses of benzodiazepines increased 2.
d) Observational studies have shown that using opioid analgesics together with benzodiazepines raises 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 together with opioid analgesics 34.
Common questions
Can I take Acetaminophen And Codeine and Zaleplon together?
Combining codeine with zaleplon adds up to dangerous sedation and slowed breathing, so use both only under close medical supervision at the lowest effective doses. Talk to your pharmacist or doctor before changing anything, and ask about keeping naloxone available. Always confirm with your pharmacist or prescriber before making any change.
How serious is the Acetaminophen And Codeine and Zaleplon 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 Acetaminophen And Codeine and Zaleplon interaction managed?
Keep taking both exactly as prescribed unless your care team tells you otherwise. This combination is usually reserved for when other options aren't enough, so raise it with your pharmacist or prescriber. Your team may use the lowest dose and shortest duration of one or both drugs and may adjust and individualize your dose. They may monitor you more closely for heavy sedation and slowed breathing.… 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 Acetaminophen And Codeine or Zaleplon 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
Keep reading about Acetaminophen And Codeine
Keep reading about Zaleplon
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