Promethazine 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
Promethazine
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 (like Belbuca or Suboxone) is an opioid, and promethazine (Phenergan) is used for nausea and allergies. Taken together, they can add up in ways that matter. Both can make you very drowsy and slow your breathing, and both can affect your heart's rhythm (called the QT interval). They can also slow your gut, which can lead to bad constipation.
The good news is that your care team knows how to handle this. If you need both, they may use the lowest dose that works and watch you more closely. Please don't stop or change either medicine on your own. Just talk with your pharmacist or doctor, and call for help right away if you feel unusually sleepy, confused, or short of breath.
Additive pharmacodynamic interaction (not CYP-mediated; neither agent is relevant as a prodrug here). Concurrent buprenorphine and promethazine increases risk of:
- QT prolongation (additive; consider baseline/follow-up ECG and electrolytes)
- CNS and respiratory depression (additive sedation, hypoventilation, risk of coma/death)
- Paralytic ileus / severe constipation and urinary retention (additive anticholinergic and opioid effects on GI/GU motility)
Severity major; evidence probable; onset unspecified. Management: avoid concurrent use where possible; if necessary, use lowest effective doses, monitor sedation, respiratory rate, bowel/bladder function, and QTc. Consider naloxone co-prescription and non-sedating alternatives. Do not withhold MAT.
What happens
An increased risk of QT interval prolongation, an increased risk of CNS and respiratory depression and an increased risk of paralytic ileus
Interaction Deep Dive
Do not use buprenorphine together with agents that can prolong the QT interval. Combining these medications also heightens 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 implement a taper. In other cases, slowly weaning a patient off a prescribed CNS depressant, or reducing to the smallest effective dose, may be the right approach. Should concurrent use be required, watch for urinary retention, severe constipation, sedation, and respiratory depression; think about alternative therapies for managing anxiety or insomnia and give strong consideration to prescribing naloxone as an emergency measure for opioid overdose1. 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 an elevated risk of death. Based on an analysis of pooled nationwide death certificate data spanning 2010 to 2014, most overdose deaths involving buprenorphine and methadone also involved the concurrent use of a CNS depressant. Whether the risk of overdose death associated with concomitant CNS depressant drugs varied between buprenorphine and methadone is not known 2.
Why it happens (mechanism)
Additive QT interval prolongation; additive CNS depression; additive effects on gastric motility
How to manage this interaction
Keep taking both medicines exactly as prescribed unless your care team tells you otherwise. This combination is manageable when handled carefully.
Your care team may:
- Use the lowest effective dose of each, individualized to you
- Monitor you more closely for heavy sedation, slowed breathing, severe constipation, or trouble urinating
- Check your heart rhythm (ECG) if appropriate
- Consider a non-sedating option for nausea or allergy
- Possibly prescribe naloxone for emergencies
Tell your pharmacist or prescriber about all your medicines. Seek help right away for extreme drowsiness, confusion, or breathing problems.
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 receiving methadone- or buprenorphine-based medication-assisted treatment (MAT) together with benzodiazepines or other CNS depressants (for example, medications used to treat insomnia) have an increased risk of death. From July 1, 2005 to December 31, 2012, investigators compared the risk of fatal overdose, non-overdose related mortality, and all-cause mortality during periods when CNS depressants were prescribed against periods without CNS depressant therapy in MAT prescribed 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 regarded as statistically significant. Although the results indicated a heightened risk of fatal overdose, non-overdose mortality, and all-cause mortality during periods when MAT and non-benzodiazepines were coadministered, 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. No comparison between the benzodiazepine cohort and the non-benzodiazepine cohort was performed because the authors did not adjust for the indication of use for the drugs 2.
b) Based on a study of pooled nationwide death certificate data from 2010 to 2014, 3495 drug overdose deaths were reported in 2014. Methadone and other CNS depressants were commonly identified as contributors in 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 reported 322 drug overdose deaths in 2014 that involved 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 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 unknown 2.
Common questions
Can I take Promethazine and Buprenorphine together?
Combining buprenorphine and promethazine adds up to more sedation, slowed breathing, heart-rhythm risk, and severe constipation, so use both only under close medical supervision at the lowest effective doses. Never stop or change either drug on your own; talk with your pharmacist or doctor. Always confirm with your pharmacist or prescriber before making any change.
How serious is the Promethazine 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 Promethazine and Buprenorphine interaction managed?
Keep taking both medicines exactly as prescribed unless your care team tells you otherwise. This combination is manageable when handled carefully. Your care team may: Use the lowest effective dose of each, individualized to you Monitor you more closely for heavy sedation, slowed breathing, severe constipation, or trouble urinating Check your heart rhythm (ECG) if appropriate Consider a non-sedatin… 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 Promethazine 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 (2)
- 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 Promethazine
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