Phenobarbital 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
Phenobarbital
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.
Taking buprenorphine (a pain or opioid-treatment medicine) together with phenobarbital (a seizure and sedative medicine) pulls in two directions at once. Both can slow your breathing and make you very sleepy, so combining them raises the risk of heavy sedation, low blood pressure, and dangerously slow breathing.
At the same time, phenobarbital speeds up how fast your body breaks down buprenorphine, which can make the buprenorphine work less well. Both drugs can also affect your heart's rhythm (the QT interval). This is a serious combination, but your care team can manage it by watching you closely and adjusting doses. Please talk with your doctor or pharmacist before changing anything.
Direction/mechanism: Dual concern. (1) Additive CNS and respiratory depression plus additive QTc prolongation (pharmacodynamic). (2) Phenobarbital induces CYP3A4, increasing buprenorphine clearance and reducing buprenorphine exposure/efficacy (risk of withdrawal or inadequate analgesia).
- Severity: Major; evidence probable; onset unspecified (induction develops over days to weeks).
- Monitor: Respiratory depression, sedation, hypotension, opioid withdrawal, and QTc/ECG.
- Manage: Reserve concurrent use for when alternatives are inadequate. Individualize/adjust buprenorphine dose. On phenobarbital discontinuation, buprenorphine levels rise, raising respiratory-depression risk, so consider a formulation permitting precise titration.
What happens
An increased risk of QT interval prolongation, an increased risk of CNS depression, reduced buprenorphine exposure and reduced efficacy of buprenorphine
Interaction Deep Dive
Taking buprenorphine together with PHENobarbital, or with its prodrug primidone, can cause hypotension, respiratory depression, and severe sedation, which may progress to coma or death. This combination can additionally reduce buprenorphine's effectiveness. When the two must be used together, watch for indications of respiratory depression or opioid withdrawal and weigh the need for dose changes. When PHENobarbital or primidone is stopped, buprenorphine plasma concentrations will rise, and this may amplify or extend both the therapeutic and adverse effects of buprenorphine, including the danger of serious respiratory depression2. If dosing cannot be modified once PHENobarbital is no longer present, switch the patient back to a buprenorphine formulation that allows finer dose titration 1. Prescribing these agents concurrently should be limited to patients for whom other treatment options are insufficient. In addition, using PHENobarbital (an agent that prolongs the QTc interval) alongside other QTc-prolonging agents such as buprenorphine can produce a larger increase in the QTc interval along with the adverse reactions tied to QTc interval prolongation. Where the combination cannot be avoided, monitor patients for a heightened risk of QTc interval prolongation 3.
Why it happens (mechanism)
Additive QT interval prolongation; additive CNS depression; induction of CYP3A4-mediated metabolism of buprenorphine
How to manage this interaction
This combination is used only when other options are not enough, so keep taking both exactly as prescribed unless your prescriber tells you otherwise.
- Your care team may adjust and individualize your buprenorphine dose and monitor you more closely, including watching your breathing, sedation, blood pressure, and heart rhythm (ECG).
- Watch for very slow or shallow breathing, extreme drowsiness, confusion, or feeling faint, and get help right away if these occur.
- Also tell your team if you feel withdrawal or less pain relief, since phenobarbital can lower buprenorphine's effect.
- If phenobarbital is ever stopped, your buprenorphine dose may need re-checking.
Management is individual — confirm any change with your pharmacist or prescriber.
Literature reports
1 report — tap to read
a) The impact of a concurrently administered CYP3A4 inducer on buprenorphine exposure in patients receiving subQ buprenorphine has not been investigated; nevertheless, these interactions have been demonstrated in studies employing transmucosal buprenorphine. Buprenorphine's effects may vary according to the route of administration 1.
Common questions
Can I take Phenobarbital and Buprenorphine together?
Buprenorphine plus phenobarbital is a major interaction: it adds up sedation, breathing, and heart-rhythm risks while also lowering buprenorphine's effectiveness. Keep taking both as prescribed and let your doctor or pharmacist monitor and adjust your doses. Always confirm with your pharmacist or prescriber before making any change.
How serious is the Phenobarbital 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 Phenobarbital and Buprenorphine interaction managed?
This combination is used only when other options are not enough, so keep taking both exactly as prescribed unless your prescriber tells you otherwise. Your care team may adjust and individualize your buprenorphine dose and monitor you more closely, including watching your breathing, sedation, blood pressure, and heart rhythm (ECG). Watch for very slow or shallow breathing, extreme drowsiness, conf… 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 Phenobarbital 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: ZUBSOLV(R) sublingual tablets, buprenorphine naloxone sublingual tablets. Orexo US Inc (per FDA), Morristown, NJ, 2023. DailyMed
- Product Information: SEZABY(TM) intravenous injection, phenobarbital sodium intravenous injection. Sun Pharmaceutical Industries Inc (per manufacturer), Cranbury, NJ, 2022. DailyMed
Keep reading about Buprenorphine
Keep reading about Phenobarbital
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