Diphenhydramine 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
Diphenhydramine
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.
Both of these medicines can slow you down. Buprenorphine is a strong opioid pain and addiction medicine that can slow your breathing and make you sleepy. Diphenhydramine (Benadryl) is an antihistamine that also causes drowsiness and dries you out. Taken together, they can add up, causing very deep sleepiness, dangerously slow breathing, and in rare cases coma. They can also gang up on your gut, causing bad constipation or trouble emptying your bladder.
Please don't stop either medicine on your own. Talk with your pharmacist or doctor, because your care team can manage this by adjusting doses, watching you more closely, or picking a safer allergy or sleep option.
Effect: Additive CNS and respiratory depression, plus additive reduction in GI/urinary motility (risk of severe constipation, urinary retention, paralytic ileus).
Mechanism: Pharmacodynamic additivity. Buprenorphine (partial mu-opioid agonist) plus diphenhydramine (sedating H1 antihistamine with anticholinergic activity) compound sedation, hypoventilation, and slowed gut motility. Not a PK/prodrug interaction; both drugs contribute their own PD effects.
Evidence/severity: Probable, rated major; onset unspecified.
- Use lowest effective doses; avoid combination where feasible.
- Consider non-sedating alternatives for allergy/insomnia.
- Monitor sedation, respiratory rate, bowel/bladder function.
Do not withhold MAT solely due to CNS depressant use.
What happens
An increased risk of respiratory and CNS depression and an increased risk of paralytic ileus
Interaction Deep Dive
When buprenorphine is given together with an anticholinergic CNS depressant, the combined effect may produce additive CNS depression and raise the likelihood of respiratory depression, deep sedation, coma, and death; it can also bring about urinary retention and/or severe constipation, potentially progressing to paralytic ileus. Discontinuing benzodiazepines or other CNS depressants is favored rather than using them together. In certain situations, a taper or observation within a higher level of care may be suitable. In other situations, it may be appropriate to slowly wean a patient off a prescribed benzodiazepine or other CNS depressant, or to reduce the dose to the lowest amount that remains effective. When combined use cannot be avoided, watch for urinary retention, severe constipation, sedation, and respiratory depression, and think about alternative approaches for managing anxiety or insomnia1. A Swedish epidemiological study found that patients on methadone- or buprenorphine-based medication-assisted treatment (MAT) who also took benzodiazepines or other CNS depressants face a heightened risk of death. Based on an analysis of pooled nationwide death certificate records spanning 2010 to 2014, most overdose deaths involving buprenorphine and methadone also involved concurrent CNS depressant use. Whether buprenorphine and methadone differ in the risk of overdose death when combined with CNS depressant drugs remains unknown 2.
Why it happens (mechanism)
Additive CNS depression; additive effects on gastric motility
How to manage this interaction
Keep taking both as prescribed unless your care team tells you otherwise. This combination is manageable with the right precautions.
Your care team may:
- Use the lowest effective dose of each medicine.
- Watch you more closely for heavy sedation, slow or shallow breathing, constipation, or trouble urinating.
- Suggest a non-drowsy alternative for allergies or sleep instead of diphenhydramine.
Get help right away if breathing becomes very slow, you can't wake easily, or you develop severe belly pain or bloating. Ask your pharmacist before adding any new sleep aid or allergy product, since many contain diphenhydramine.
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 during periods when CNS depressants were prescribed compared with 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 MAT and benzodiazepine treatment; however, this data was not deemed statistically significant. Although the results showed an increased 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 was regarded as 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 2.
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 often reported as culprits in 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, though confounding factors and differences in drug utilization were not accounted for. It remains unknown whether the risk of overdose death with concomitant CNS depressant drugs differed between buprenorphine and methadone 2.
Common questions
Can I take Diphenhydramine and Buprenorphine together?
Buprenorphine and diphenhydramine both cause sedation and can add up to dangerously slow breathing plus severe constipation or urinary retention. Don't stop either on your own, but tell your pharmacist or doctor so they can lower doses, monitor you, or swap to a non-drowsy allergy or sleep option. Always confirm with your pharmacist or prescriber before making any change.
How serious is the Diphenhydramine 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 Diphenhydramine and Buprenorphine interaction managed?
Keep taking both as prescribed unless your care team tells you otherwise. This combination is manageable with the right precautions. Your care team may: Use the lowest effective dose of each medicine. Watch you more closely for heavy sedation, slow or shallow breathing, constipation, or trouble urinating. Suggest a non-drowsy alternative for allergies or sleep instead of diphenhydramine. Get help… 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 Diphenhydramine 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 Diphenhydramine
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