Esketamine 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
Esketamine
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 an opioid, and esketamine (Spravato) works on your brain too. When you take them together, their calming effects can stack up. That can make you very sleepy, foggy, or even slow your breathing more than is safe.
The good news is your care team knows about this. Because Spravato is given in a monitored clinic setting, staff can watch you closely for drowsiness and breathing changes. Please don't stop or change either medicine on your own. Just make sure both your prescriber and pharmacist know you take both so they can keep you safe.
Mechanism: Additive CNS and respiratory depression. Neither agent's effect here depends on metabolic activation; this is a pharmacodynamic (PD) interaction, not a PK one.
- Direction: Increased sedation, respiratory depression, risk of profound sedation, coma, and death.
- Severity/evidence: Major; probable substantiation (epidemiologic overdose data with buprenorphine plus CNS depressants).
- Onset: Unspecified; concern is acute during co-exposure.
- Management: Use lowest effective doses; monitor respiratory status and sedation during and after esketamine dosing (already administered under REMS observation). Do not withhold MAT solely due to this interaction.
What happens
An increased risk of respiratory depression and CNS depression
Interaction Deep Dive
Using buprenorphine together with a CNS depressant can produce additive CNS depression, thereby raising the likelihood of respiratory depression, profound sedation, coma, and death. Discontinuing the CNS depressant is preferable to taking the two agents together. Depending on the situation, it may be suitable to observe the patient within a higher level of care or to pursue a taper. In other situations, it may be appropriate to slowly wean a patient off a prescribed CNS depressant or to reduce it to the lowest dose that remains effective. When combined use cannot be avoided, exercise caution in monitoring and management, and weigh alternative treatments for anxiety or insomnia2. A Swedish epidemiological study found that patients on methadone- or buprenorphine-based medication-assisted treatment (MAT) who also took benzodiazepines or other CNS depressants (for instance, agents used to treat insomnia) had a heightened risk of death. Analysis of aggregate nationwide death certificate data spanning 2010 to 2014 showed that most overdose deaths involving buprenorphine and methadone also involved concurrent CNS depressant use. Whether the risk of overdose death associated with concurrent CNS depressant drugs varied between buprenorphine and methadone remains unknown 3.
Why it happens (mechanism)
Additive CNS depression
How to manage this interaction
Keep taking both as prescribed unless your care team tells you otherwise. This combination can be used safely with the right precautions.
- Esketamine (Spravato) is given in a certified clinic where staff monitor you for sedation and breathing after each dose, which helps manage this risk.
- Your team may use the lowest effective doses and watch you more closely.
- Tell your prescriber and pharmacist about every sedating medicine, alcohol, or sleep/anxiety product you use.
- Get help right away for severe drowsiness, confusion, or slowed or shallow breathing.
Access to buprenorphine treatment should not be denied just because of this interaction.
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 on methadone- or buprenorphine-based medication-assisted treatment (MAT) who also took benzodiazepines or other CNS depressants (for example, medications used to treat insomnia) had a higher 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 during periods when CNS depressants were prescribed compared with periods when no CNS depressant therapy was given, among MAT patients aged 18 to 50. The findings showed an increased 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 raised risk of fatal overdose, non-overdose mortality, and all-cause mortality during periods of coadministration of MAT and non-benzodiazepines, 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. The authors did not compare the benzodiazepine cohort with the non-benzodiazepine cohort because they did not adjust for the indication for which the drugs were used 3.
b) According to a study of pooled nationwide death certificate data spanning 2010 to 2014, 3495 drug overdose deaths were recorded in 2014. Methadone along with other CNS depressants were commonly cited as contributing to those deaths. Concurrent ALPRAZolam use appeared in 18.1% of cases, followed by oxyCODONE (10.1%), cocaine (9.6%), heroin (9%), and diazePAM (6.6%). The FDA documented 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 count of deaths involving methadone was 10 times greater than the count involving buprenorphine, though confounding factors and differences in drug utilization were not taken into account. Whether the risk of overdose death associated with concurrent CNS depressant drugs differed between buprenorphine and methadone is not known 3.
Common questions
Can I take Esketamine and Buprenorphine together?
Buprenorphine and esketamine can add up to cause dangerous sedation and slowed breathing, so use the lowest effective doses and stay under your care team's monitoring. Do not stop either drug on your own; keep your prescriber and pharmacist informed. Always confirm with your pharmacist or prescriber before making any change.
How serious is the Esketamine 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 Esketamine and Buprenorphine interaction managed?
Keep taking both as prescribed unless your care team tells you otherwise. This combination can be used safely with the right precautions. Esketamine (Spravato) is given in a certified clinic where staff monitor you for sedation and breathing after each dose, which helps manage this risk. Your team may use the lowest effective doses and watch you more closely. Tell your prescriber and pharmacist ab… 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 Esketamine 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: 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 Esketamine
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