Midazolam and Buprenorphine: 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
Midazolam
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.
Buprenorphine (used for pain or for treating opioid use disorder) and midazolam (a benzodiazepine sedative) both slow down your brain and body. When you take them together, those calming effects can stack up. This can lead to heavy drowsiness, very slow or shallow breathing, and in serious cases it can be life-threatening.
This does not mean you can't safely take both. The important thing is that your care team knows you're on both so they can plan the safest approach. Please don't start, stop, or change either medicine on your own. Talk with your pharmacist or doctor, and get help right away if you feel very sleepy, confused, or short of breath.
Effect: Additive CNS and respiratory depression. Both agents are CNS depressants (buprenorphine is a partial mu-opioid agonist; midazolam a benzodiazepine), so the mechanism is pharmacodynamic (additive), not primarily PK. Risk includes profound sedation, respiratory depression, coma, and death.
- Direction: Increased combined CNS depressant effect.
- Evidence: Probable; epidemiologic data link concomitant benzodiazepine/CNS depressant use with higher overdose mortality in MAT patients.
- Severity: Major. Onset unspecified.
Management: Avoid concurrent use when possible; consider tapering the benzodiazepine or using the lowest effective dose. If co-use is necessary, monitor mental status and respiratory function closely. Do not withhold MAT solely due to CNS depressant use.
What happens
An increased risk of CNS depression and respiratory depression
Interaction Deep Dive
When buprenorphine is given together with a benzodiazepine, the CNS depressant effects can be additive, raising the likelihood of respiratory depression, deep sedation, coma, and death. Discontinuing benzodiazepines or other CNS depressants is favored rather than using them alongside buprenorphine. Depending on the situation, it may be suitable to observe the patient in a setting offering a higher level of care, or to implement a taper. In other circumstances, slowly weaning a patient off a prescribed benzodiazepine or other CNS depressant, or reducing to the smallest effective dose, may be the right approach. Should concurrent use be unavoidable, watch for respiratory depression and proceed with caution1. 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, agents used for insomnia) faced a heightened risk of death. Analysis of pooled nationwide death certificate data spanning 2010 to 2014 showed that most overdose deaths involving buprenorphine and methadone also involved the concurrent use of a CNS depressant. Whether the risk of fatal overdose from concomitant CNS depressant drugs varied between buprenorphine and methadone remains unknown 3.
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 manageable, but it does need attention.
- Your team may prefer reducing or gradually tapering the midazolam, or using the lowest effective dose.
- They may consider alternative treatments for anxiety or sleep that don't add sedation.
- They may monitor you more closely, sometimes in a higher level of care, watching for excess sedation and slowed breathing.
Tell your pharmacist or prescriber about all sedating medicines, alcohol, or sleep aids you use. Seek help right away for extreme drowsiness, confusion, or trouble breathing. Importantly, needing a sedative should never be a reason you are denied buprenorphine treatment.
Management is individual — confirm any change with your pharmacist or prescriber.
Literature reports
2 reports — tap to read
a) A Swedish epidemiological study reported that patients receiving methadone- or buprenorphine-based medication-assisted treatment (MAT) together with benzodiazepines or other CNS depressants (for example, drugs used to treat insomnia) have an increased risk of death. Between July 1, 2005 and December 31, 2012, investigators analyzed the risk of fatal overdose, non-overdose related mortality, and all-cause mortality by comparing periods when CNS depressants were prescribed to periods without CNS depressant therapy in MAT prescribed patients (aged 18 to 50). The findings showed an elevated 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 MAT and benzodiazepine treatment; however, these data were not considered statistically significant. Although the results showed an elevated risk of fatal overdose, non-overdose mortality, and all-cause mortality during periods of coadministration of MAT and non-benzodiazepines, only the data for fatal overdose and all-cause mortality were considered statistically significant; HR 2.34 (95% CI, 1.37 to 3.99) and HR 1.33 (95% CI, 1.12 to 2.45), respectively. A comparison between the benzodiazepine cohort and the non-benzodiazepine cohort was not performed because the authors did not adjust for the indication of use for the drugs 3.
b) According to a study of aggregate nationwide death certificate data from 2010 to 2014, 3495 drug overdose deaths were reported in 2014. Methadone and other CNS depressants were frequently cited as contributors to those deaths. Concurrent alprazolam use was reported in 18.1% of cases, followed by oxycodone (10.1%), cocaine (9.6%), heroin (9%), and diazepam (6.6%). The FDA reported 322 drug overdose deaths in 2014 involving 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 the number of buprenorphine-involved deaths, although confounding factors and differences in drug utilization were not taken into account. Whether the risk of overdose death with concomitant CNS depressant drugs differed between buprenorphine and methadone is unknown 3.
Common questions
Can I take Midazolam and Buprenorphine together?
Combining buprenorphine and midazolam adds up their sedating effects and can dangerously slow breathing, so use both only under close medical supervision and never adjust either on your own. Always confirm with your pharmacist or prescriber before making any change.
How serious is the Midazolam and Buprenorphine 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 Midazolam and Buprenorphine interaction managed?
Keep taking both exactly as prescribed unless your care team tells you otherwise. This combination is manageable, but it does need attention. Your team may prefer reducing or gradually tapering the midazolam, or using the lowest effective dose. They may consider alternative treatments for anxiety or sleep that don't add sedation. They may monitor you more closely, sometimes in a higher level of ca… 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.
Questions for your pharmacist
- Does my dose of Midazolam or Buprenorphine 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 Midazolam
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