Buprenorphine and Methdilazine: 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
Methdilazine
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.
You've been prescribed buprenorphine (an opioid used for pain or opioid use disorder) and methdilazine (an older antihistamine that can make you drowsy). Both of these can slow down your brain and your breathing. When you take them together, those calming effects can stack on top of each other. That can lead to heavy sedation, very slow or shallow breathing, and in serious cases it can become life-threatening.
The good news is that your care team can manage this safely. Don't stop either medicine on your own. Just let your doctor or pharmacist know you're taking both so they can watch you closely and pick the safest plan for you.
Effect: Additive CNS and respiratory depression from combining buprenorphine (partial opioid agonist) with methdilazine (a sedating phenothiazine antihistamine). Risk includes profound sedation, respiratory depression, coma, and death.
- Mechanism: Pharmacodynamic (additive CNS depression), not a metabolic/prodrug interaction.
- Direction: Increased combined depressant effect.
- Evidence: Probable; supported by epidemiologic MAT overdose data.
- Onset: Unspecified.
- Management: Use lowest effective doses, avoid unnecessary concomitant use, consider non-sedating alternatives for allergy/itch/insomnia, and monitor for respiratory depression. Do not withhold MAT solely due to this interaction.
What happens
An increased risk of respiratory depression and CNS depression
Interaction Deep Dive
Using buprenorphine together with a CNS depressant can produce additive CNS depression, thereby heightening 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 at a higher level of care or to taper. In other circumstances, slowly weaning a patient off a prescribed CNS depressant, or reducing it to the smallest effective dose, may be warranted. When concurrent use cannot be avoided, exercise careful monitoring and management; alternative treatments for anxiety or insomnia may be worth considering2. A Swedish epidemiological study found that patients undergoing methadone- or buprenorphine-based medication-assisted treatment (MAT) in combination with benzodiazepines or other CNS depressants (for example, agents used for insomnia) face a greater risk of death. Analysis of aggregate 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 overdose death associated 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
This combination can add up to dangerous sedation and slowed breathing, so your care team will handle it carefully.
- Keep taking both as prescribed unless your prescriber tells you otherwise. Do not stop buprenorphine on your own.
- Your team may use the lowest effective dose, adjust and individualize your doses, or watch you more closely.
- They may consider a non-sedating alternative to methdilazine for allergy or itching.
- Get help right away for very slow or shallow breathing, extreme drowsiness, confusion, or trouble waking up.
- Tell every prescriber and your pharmacist you take both drugs.
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 undergoing methadone- or buprenorphine-based medication-assisted treatment (MAT) together with benzodiazepines or other CNS depressants (for example, agents used for insomnia) have an increased risk of death. During the interval from July 1, 2005 to December 31, 2012, the study examined 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 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 MAT plus benzodiazepine treatment; however, these data were not deemed statistically significant. Although the results indicated an elevated risk of fatal overdose, non-overdose mortality, and all-cause mortality during periods when MAT was coadministered with non-benzodiazepines, only the fatal overdose and all-cause mortality data 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 perform a comparison between the benzodiazepine cohort and the non-benzodiazepine cohort because they did not adjust for the indication of use for the drugs 3.
b) A study based on aggregate nationwide death certificate data from 2010 to 2014 reported 3495 drug overdose deaths in 2014. Methadone and other CNS depressants were often cited as contributors to these deaths. Concurrent ALPRAZolam use appeared 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 involving buprenorphine. Among 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 greater than the number of buprenorphine-involved deaths, though 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 remains unknown 3.
Common questions
Can I take Buprenorphine and Methdilazine together?
Buprenorphine plus methdilazine can cause additive drowsiness and dangerously slowed breathing, so use the lowest doses possible and let your care team monitor you. Never stop either medicine on your own; talk with your pharmacist or doctor. Always confirm with your pharmacist or prescriber before making any change.
How serious is the Buprenorphine and Methdilazine 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 Methdilazine interaction managed?
This combination can add up to dangerous sedation and slowed breathing, so your care team will handle it carefully. Keep taking both as prescribed unless your prescriber tells you otherwise. Do not stop buprenorphine on your own. Your team may use the lowest effective dose, adjust and individualize your doses, or watch you more closely. They may consider a non-sedating alternative to methdilazine… 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 Buprenorphine or Methdilazine 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 Methdilazine
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