Buprenorphine and Diphenoxylate: 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
Diphenoxylate
No brand names on recordBuprenorphine
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 down your brain and breathing. Buprenorphine is a strong opioid used for pain or opioid dependence, and diphenoxylate is an opioid-type medicine used to slow down diarrhea. Taking them together can add up, so you may feel very drowsy, breathe too slowly, or in serious cases become hard to wake.
There is also a smaller chance of a reaction called serotonin syndrome, which can cause shakiness, a fast heartbeat, sweating, and confusion. This sounds scary, but your care team can manage it by adjusting your doses and watching you closely. Please don't stop either drug on your own. Talk with your pharmacist or doctor about the safest plan.
Effect: Additive CNS and respiratory depression, plus an increased risk of serotonin syndrome, when buprenorphine is combined with diphenoxylate (a serotonergic opioid CNS depressant).
Mechanism: Pharmacodynamic, not PK. Additive mu-opioid CNS/respiratory depressant effects and additive serotonergic activity.
- Severity: Major; evidence: probable; onset: unspecified.
- Management: Avoid concomitant use where possible; cessation of the other CNS depressant is preferred. If continued, use lowest effective doses, taper where appropriate, and monitor for sedation, hypoventilation, and serotonin syndrome, especially at initiation and dose changes.
- Discontinue buprenorphine if serotonin syndrome is suspected; consider alternatives.
What happens
An increased risk of serotonin syndrome and an increased risk of respiratory and CNS depression
Interaction Deep Dive
When buprenorphine is given together with a serotonergic CNS depressant, the combined effect can produce additive CNS depression, raising the likelihood of serotonin syndrome as well as respiratory depression, profound sedation, coma, and death. Discontinuing the other CNS depressant is favored rather than using the two together. Depending on the situation, it may be suitable to monitor the patient at a higher level of care or to implement a taper. In other circumstances, slowly weaning a patient off a prescribed benzodiazepine or other CNS depressant, or reducing it to the lowest effective dose, may be appropriate. Should concurrent use be required, watch for sedation, respiratory depression, and the signs and symptoms of serotonin syndrome. Observe the patient closely, especially when starting therapy and when the dose of the serotonergic agent is being adjusted. If serotonin syndrome is suspected, stop buprenorphine; consider alternative treatments for anxiety or insomnia21.
Why it happens (mechanism)
Additive serotonergic effects; additive CNS and respiratory depression
How to manage this interaction
The safest option is often to avoid using these two together, so your care team may prefer stopping or tapering one of them rather than continuing both. When they must be combined, your doses may be adjusted and individualized, often to the lowest effective dose, and your team may monitor you more closely, especially when starting or changing a dose.
- Keep taking both as prescribed unless your prescriber tells you otherwise.
- Watch for heavy drowsiness, slow or shallow breathing, or trouble waking, and get help right away.
- Report shakiness, sweating, fast heartbeat, or confusion (possible serotonin syndrome).
- Ask your pharmacist or prescriber if a safer alternative fits your situation.
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 (e.g., agents used for insomnia) have an increased risk of death. From July 1, 2005 to December 31, 2012, investigators examined the risk of fatal overdose, non-overdose related mortality, and all-cause mortality by comparing periods of prescribed CNS depressants to periods without CNS depressant therapy among 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, these data were not deemed statistically significant. Although results indicated 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 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. 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 3.
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 cited 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 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 taken into account. Whether the risk of overdose death with concomitant CNS depressant drugs differed between buprenorphine and methadone is unknown 3.
Common questions
Can I take Buprenorphine and Diphenoxylate together?
Combining buprenorphine and diphenoxylate can dangerously add up their sedating and breathing-slowing effects and slightly raise the risk of serotonin syndrome, so use them together only under your care team's guidance with close monitoring. Always confirm with your pharmacist or prescriber before making any change.
How serious is the Buprenorphine and Diphenoxylate 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 Diphenoxylate interaction managed?
The safest option is often to avoid using these two together, so your care team may prefer stopping or tapering one of them rather than continuing both. When they must be combined, your doses may be adjusted and individualized, often to the lowest effective dose, and your team may monitor you more closely, especially when starting or changing a dose. Keep taking both as prescribed unless your pres… 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 Diphenoxylate 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 Diphenoxylate
Keep reading about Buprenorphine
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