Buprenorphine and Primidone: 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
Primidone
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.
These two medicines can pull in a few directions at once, so this pairing needs care. Primidone is turned into phenobarbital in your body, and phenobarbital speeds up how fast you clear buprenorphine. That can make your buprenorphine work less well, which for some people can feel like it is wearing off or triggering withdrawal.
At the same time, both drugs can slow your breathing and make you very sleepy, and both can affect your heart's rhythm (the QT interval). If primidone is ever stopped, your buprenorphine level can climb again. The good news is your care team can manage this by adjusting your dose and watching you more closely. Please do not change either medicine on your own, just talk with your pharmacist or doctor.
Direction: Primidone is metabolized to phenobarbital, a potent CYP3A4 inducer, increasing buprenorphine clearance and reducing buprenorphine exposure/efficacy (risk of withdrawal, inadequate analgesia). Both agents also contribute additive CNS/respiratory depression and additive QTc prolongation.
- Severity: Major; evidence probable.
- Monitor: sedation, respiratory rate, hypotension, opioid withdrawal, and ECG/QTc in at-risk patients.
- Manage: reserve for patients without adequate alternatives; individualize buprenorphine dosing. On primidone/phenobarbital discontinuation, buprenorphine levels rise, raising respiratory depression risk, so anticipate downward adjustment. Consider a buprenorphine formulation allowing 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 marked sedation, with the potential to progress to coma or death. Buprenorphine's efficacy may also be reduced. When these agents must be given together, watch for indications of respiratory depression or opioid withdrawal and weigh dose modifications. Once PHENobarbital or primidone is stopped, buprenorphine plasma levels will rise, potentially heightening or extending both the therapeutic and adverse effects of buprenorphine, including the danger of serious respiratory depression2. When dosing cannot be adjusted after PHENobarbital is removed, switch the patient back to a buprenorphine formulation that allows finer dose titration 1. Prescribing these medications concurrently should be limited to patients whose alternative treatment options are insufficient. In addition, using PHENobarbital (an agent that prolongs the QTc interval) alongside other QTc-prolonging agents such as buprenorphine may produce a larger increase in the QTc interval and adverse reactions linked to QTc interval prolongation. If concurrent use is unavoidable, monitor patients for an elevated 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
Keep taking both exactly as prescribed unless your care team tells you otherwise. This combination is usually reserved for when other options are not enough.
- Your buprenorphine dose may need to be adjusted and individualized by your care team, since primidone can lower how well it works.
- Your team may monitor you more closely for very slow or shallow breathing, deep drowsiness, low blood pressure, or signs of opioid withdrawal.
- If primidone is ever stopped, buprenorphine levels can rise, so tell your team before any changes.
- Ask about ECG/heart rhythm monitoring, since both drugs can affect the QT interval.
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 individuals receiving subcutaneous buprenorphine has not been investigated; nevertheless, such interactions have been documented in studies employing transmucosal buprenorphine. The effects of buprenorphine may vary according to the route of administration 1.
Common questions
Can I take Buprenorphine and Primidone together?
Primidone (via phenobarbital) can weaken buprenorphine while both drugs together raise the risk of dangerous sedation, slowed breathing, and QT prolongation; use only when necessary and let your care team adjust doses and monitor you closely. Always confirm with your pharmacist or prescriber before making any change.
How serious is the Buprenorphine and Primidone 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 Primidone interaction managed?
Keep taking both exactly as prescribed unless your care team tells you otherwise. This combination is usually reserved for when other options are not enough. Your buprenorphine dose may need to be adjusted and individualized by your care team, since primidone can lower how well it works. Your team may monitor you more closely for very slow or shallow breathing, deep drowsiness, low blood pressure,… 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 Primidone 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 Primidone
These medications also interact with supplements
Prescription drugs aren't the whole picture — herbal and dietary supplements can interact with them too. From the evidence-graded Natural Medicines database:
major · moderate · minor — check everything you take with our drug–supplement interaction checker.
Check another combination
Our instant two-drug interaction checker is almost here.
Still have questions about this combination?
Every question gets a real answer from a licensed pharmacist — free, and usually within a day.
Ask the pharmacist