Eszopiclone 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
Eszopiclone
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.
Both of these medicines slow down your brain and body. Codeine (an opioid pain reliever, combined here with acetaminophen) can cause drowsiness and slow your breathing. Eszopiclone (Lunesta) is a sleep medicine that also relaxes and sedates you. Taken together, those calming effects can stack up.
That means more than usual sleepiness, confusion, very slow breathing, or being hard to wake. That is why doctors are cautious about using both at the same time. The good news is your care team can manage this. If you have been prescribed both, don't stop either on your own. Instead, talk with your pharmacist or doctor so they can use the lowest doses needed and watch you closely.
Effect: Additive CNS and respiratory depression when acetaminophen/codeine is combined with eszopiclone.
Mechanism: Pharmacodynamic additive CNS depression (opioid plus non-benzodiazepine sedative-hypnotic). Codeine is a prodrug activated via CYP2D6 to morphine, but this interaction is PD, not PK, so metabolizer status does not alter the additive sedation risk.
- Direction/magnitude: Increased sedation, hypotension, respiratory depression; magnitude not quantified.
- Onset: Unspecified.
- Evidence: Theoretical, but class-level opioid + CNS depressant data show higher ED visits and fatal overdose.
- Management: Reserve co-use for when alternatives are inadequate; lowest effective dose and shortest duration; monitor for sedation/respiratory depression; consider naloxone.
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
If both medicines have been prescribed to you, keep taking them as directed and do not stop or change either one on your own. This combination is used only when other options are not enough.
- Your care team may prescribe the lowest dose of each for the shortest time needed.
- They may lower the dose of the codeine product or the eszopiclone and monitor you more closely for heavy sedation or slowed breathing.
- Your prescriber may also consider providing naloxone as an emergency backup.
Call your doctor or pharmacist right away if you notice unusual drowsiness, confusion, or slow or shallow breathing.
Management is individual — confirm any change with your pharmacist or prescriber.
Literature reports
4 reports — tap to read
a) One study found that the rate of emergency department visits linked to nonmedical use and involving both opioid analgesics and benzodiazepines rose significantly from 11 to 34.2 per 100,000 between 2004 and 2011. Drug overdose deaths attributable to prescribed and higher than 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 of both opioid analgesics and benzodiazepines was 10 times greater than that associated with dispensing of opioid analgesics alone (7 versus 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 history of a benzodiazepine prescription, and rose by 3.86 fold among those with a current benzodiazepine prescription, when compared with patients taking opioid analgesics who had no history of a benzodiazepine prescription. The risk of drug overdose deaths increased as the daily doses of benzodiazepines increased 2.
d) Observational studies have shown that using opioid analgesics and benzodiazepines together raises the risk of drug-related mortality compared with using opioid analgesics alone. Given their 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 Eszopiclone and Acetaminophen And Codeine together?
Combining acetaminophen/codeine with eszopiclone can dangerously add up their sedating effects and slow breathing, so use both together only when necessary, at the lowest doses, with close monitoring from your care team. Always confirm with your pharmacist or prescriber before making any change.
How serious is the Eszopiclone 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 Eszopiclone and Acetaminophen And Codeine interaction managed?
If both medicines have been prescribed to you, keep taking them as directed and do not stop or change either one on your own. This combination is used only when other options are not enough. Your care team may prescribe the lowest dose of each for the shortest time needed. They may lower the dose of the codeine product or the eszopiclone and monitor you more closely for heavy sedation or slowed br… 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 Eszopiclone 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
Keep reading about Acetaminophen And Codeine
Keep reading about Eszopiclone
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