Buprenorphine and Ramelteon: Interaction Details
AI-assisted, pharmacist-reviewed · AI content regenerated Jul 11, 2026 · Source data updated Jul 2, 2026 · Sources: FDA labeling, DDInter 2.0, cited literature
Buprenorphine
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.
Buprenorphine is a strong pain and opioid-treatment medicine, and ramelteon (Rozerem) is a sleep medicine. Both can slow down your brain and body a little. When taken together, those calming effects can add up. In some people this can lead to too much drowsiness or, in more serious cases, slowed breathing.
This does not mean you cannot take both, but it is something your care team watches closely. The good news is this is very manageable. Please do not stop or change either medicine on your own. Talk with your pharmacist or doctor so they can pick the safest plan for you and let you know what warning signs to watch for.
Interaction: Additive CNS depression when buprenorphine (partial opioid agonist) is combined with ramelteon (melatonin receptor agonist hypnotic). This is a pharmacodynamic interaction, not enzyme- or prodrug-mediated; neither direction reverses.
- Effect: Increased risk of profound sedation and respiratory depression; rare reports of coma and death with buprenorphine plus CNS depressants.
- Severity/evidence: Major; probable substantiation. Onset unspecified.
- Management: Use lowest effective doses, avoid unnecessary concomitant CNS depressants, consider alternative insomnia options, and monitor for respiratory depression and excess sedation.
Do not withhold MAT solely due to this interaction.
What happens
An increased risk of respiratory depression and CNS depression
Interaction Deep Dive
When buprenorphine is given together with a CNS depressant, the CNS depressant effects can be additive, raising the likelihood of respiratory depression, deep sedation, coma, and death. Discontinuing CNS depressants is favored rather than using them concurrently. Depending on the situation, it may be suitable to monitor the patient in a higher level of care or to pursue a taper. In other situations, slowly weaning a patient from a prescribed CNS depressant or reducing to the smallest effective dose may be warranted. Should concurrent use be required, exercise careful monitoring and management, and weigh alternative therapies for anxiety or insomnia2. A Swedish epidemiological investigation found that patients on methadone- or buprenorphine-based medication-assisted treatment (MAT) who also took benzodiazepines or other CNS depressants (for instance, medications used for insomnia) faced a heightened risk of death. An analysis of pooled nationwide death certificate records spanning 2010 to 2014 showed that most overdose deaths involving buprenorphine and methadone also involved concurrent CNS depressant use. Whether the risk of fatal overdose with concomitant CNS depressant drugs varied between buprenorphine and methadone remains unknown 3.
Why it happens (mechanism)
Additive CNS depression
How to manage this interaction
Your care team can manage this safely. Typical steps include:
- Using the lowest effective dose of the sleep medicine, tailored and individualized by your team.
- Considering alternative options for insomnia if appropriate.
- Closer monitoring for excess drowsiness or slowed breathing, especially when starting or changing doses.
What you should do:
- Keep taking both medicines exactly as prescribed unless told otherwise.
- Ask your pharmacist or prescriber about warning signs and the safest plan for you.
- Seek help right away for very slow or shallow breathing, extreme sleepiness, or trouble waking.
Management is individual — confirm any change with your pharmacist or prescriber.
Literature reports
2 reports — tap to read
a) A Swedish epidemiological study found that patients on methadone- or buprenorphine-based medication-assisted treatment (MAT) who also took benzodiazepines or other CNS depressants (for example, medications for insomnia) had an increased risk of death. From July 1, 2005 through December 31, 2012, investigators examined the risk of fatal overdose, non-overdose related mortality, and all-cause mortality during periods when CNS depressants were prescribed compared with periods without such therapy in MAT-treated patients (aged 18 to 50). The findings showed a raised risk of all-cause mortality (adjusted hazard ratio (HR) 1.44; 95% CI, 0.93 to 2.23) and non-overdose related mortality (HR 1.74; 95% CI 1.00 to 3.01) with combined MAT and benzodiazepine treatment; however, these data were not deemed statistically significant. Although the results also showed an increased risk of fatal overdose, non-overdose mortality, and all-cause mortality during periods when MAT was combined with non-benzodiazepines, only the fatal overdose and all-cause mortality figures reached statistical significance; HR 2.34 (95% CI, 1.37 to 3.99) and HR 1.33 (95% CI, 1.12 to 2.45), respectively. The authors did not compare the benzodiazepine cohort with the non-benzodiazepine cohort because they did not adjust for the indication of use for the drugs 3.
b) A study of pooled nationwide death certificate data from 2010 to 2014 recorded 3495 drug overdose deaths in 2014. Methadone and other CNS depressants were commonly cited as contributing to those deaths. Concurrent ALPRAZolam use was noted in 18.1% of cases, followed by oxyCODONE (10.1%), cocaine (9.6%), heroin (9%), and diazePAM (6.6%). The FDA documented 322 drug overdose deaths in 2014 that involved buprenorphine. Of these 322 deaths, 32.9% involved ALPRAZolam, 17.4% involved clonazePAM, 11.2% involved diazePAM, 11.2% involved heroin, and 9.9% involved fentaNYL. The absolute number of methadone-involved deaths was 10 times that of buprenorphine-involved deaths, though confounding factors and differences in drug utilization were not taken into account. Whether the risk of overdose death with concurrent CNS depressant drugs differed between buprenorphine and methadone is not known 3.
Common questions
Can I take Buprenorphine and Ramelteon together?
Combining buprenorphine and ramelteon can add up to too much sedation and slowed breathing, so use the lowest effective dose and stay in close contact with your care team. Do not stop either medicine on your own. Always confirm with your pharmacist or prescriber before making any change.
How serious is the Buprenorphine and Ramelteon 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 Buprenorphine and Ramelteon interaction managed?
Your care team can manage this safely. Typical steps include: Using the lowest effective dose of the sleep medicine, tailored and individualized by your team. Considering alternative options for insomnia if appropriate. Closer monitoring for excess drowsiness or slowed breathing, especially when starting or changing doses. What you should do: Keep taking both medicines exactly as prescribed unless… 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.
From our Q&A
Real reader questions about these medications, each personally answered by our pharmacist:
Questions for your pharmacist
- Does my dose of Buprenorphine or Ramelteon 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 (3)
- Product Information: BRIXADI(TM) subcutaneous extended-release injection, buprenorphine subcutaneous extended-release injection. Braeburn Inc (per FDA), Plymouth Meeting, PA, 2023. DailyMed
- Product Information: SUBUTEX(R) sublingual tablets, buprenorphine sublingual tablets. Indivior Inc (per FDA), North Chesterfield, VA, 2021. DailyMed
- US Food and Drug Administration (FDA): Drug Safety Communications: FDA urges caution about withholding opioid addiction medications from patients taking benzodiazepines or CNS depressants: careful medication management can reduce risks. US Food and Drug Administration (FDA). Silver Spring, MD. 2017.
Keep reading about Buprenorphine
Keep reading about Ramelteon
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