Ramelteon 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
Ramelteon
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 can slow you down. The codeine in your pain medicine is an opioid, and Rozerem (ramelteon) is a sleep medicine. Each one can make you drowsy and can slow your breathing. When they are taken together, those effects can add up, so you may feel more sleepy than expected, and in some cases breathing can become dangerously slow.
Please don't stop either medicine on your own. This combination can be managed. Talk with your pharmacist or doctor so they can decide if both are truly needed, use the lowest doses, and watch you closely. Get help right away if you feel very hard to wake up or your breathing seems slow.
Effect: Additive CNS and respiratory depression when acetaminophen/codeine is combined with ramelteon.
Mechanism: Pharmacodynamic additive CNS depression. Codeine is an opioid (a CYP2D6-activated prodrug for its analgesic morphine metabolite, but the relevant concern here is opioid-mediated sedation and respiratory drive suppression); ramelteon is a melatonin-receptor agonist hypnotic. No PK interaction is implicated.
- Direction: Increased sedation, hypotension, respiratory depression risk.
- Onset: Unspecified; expect within dosing window.
- Evidence: Theoretical; severity rated major by analogy to opioid plus CNS depressant data.
- Management: Reserve for when alternatives are inadequate; use 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
Do not combine opioid cough preparations with agents that depress the CNS. When opioid analgesics are taken together with benzodiazepines, higher rates of emergency department visits and fatal overdose have been reported2. Taking codeine alongside CNS depressants raises the likelihood of hypotension, respiratory depression, profound sedation, coma, and death. Prescribing these medications together should be limited to patients in whom other treatment options prove inadequate. Keep both the doses and the treatment durations at the lowest level necessary. Monitor patients carefully for indications of sedation and respiratory depression. Should combined use be justified, consider providing naloxone for emergency management of opioid overdose341.
Why it happens (mechanism)
Additive CNS depression
How to manage this interaction
The good news: your care team can manage this combination safely.
- Keep taking both exactly as prescribed unless your prescriber tells you otherwise.
- Your team may reserve using both together only when other options aren't enough, and may use the lowest dose of the codeine product or the ramelteon for the shortest time needed.
- They may monitor you more closely for heavy sedation or slowed breathing, and the doses can be adjusted and individualized for you.
- Ask whether having naloxone (an opioid rescue medicine) on hand is right for you.
Call your pharmacist or doctor if you feel unusually drowsy, confused, or short of breath.
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 took place between 2004 and 2011 and involved both opioid analgesics and benzodiazepines rose significantly from 11 to 34.2 per 100,000. Deaths from drug overdose 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 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 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, compared with those taking opioid analgesics who had no history of a benzodiazepine prescription. The risk of drug overdose deaths grew as daily benzodiazepine doses increased 2.
d) Observational studies have shown that using opioid analgesics and benzodiazepines together increases 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 together with opioid analgesics 34.
Common questions
Can I take Ramelteon and Acetaminophen And Codeine together?
Codeine (an opioid) and ramelteon can both depress the brain and breathing, so combined they raise the risk of heavy sedation and slowed breathing. Use only if truly needed, at the lowest dose, and be watched closely by your care team. Always confirm with your pharmacist or prescriber before making any change.
How serious is the Ramelteon 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 Ramelteon and Acetaminophen And Codeine interaction managed?
The good news: your care team can manage this combination safely. Keep taking both exactly as prescribed unless your prescriber tells you otherwise. Your team may reserve using both together only when other options aren't enough, and may use the lowest dose of the codeine product or the ramelteon for the shortest time needed. They may monitor you more closely for heavy sedation or 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.
From our Q&A
Real reader questions about these medications, each personally answered by our pharmacist:
Questions for your pharmacist
- Does my dose of Ramelteon 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 Ramelteon
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