Zaleplon 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
Zaleplon
No brand names on record
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 (a pain and opioid-treatment medicine) and zaleplon (a sleep medicine) both slow down your brain and breathing. When you take them together, those calming effects can add up. That can make you very drowsy, slow your breathing too much, and in serious cases lead to dangerous or even life-threatening problems.
This is a well-recognized combination, so please don't stop either medicine on your own. The good news is your care team can manage this safely by choosing the right doses, sometimes suggesting a different sleep option, and watching you more closely. Let your pharmacist or doctor know you take both so they can keep you safe.
Effect: Additive CNS and respiratory depression from combining buprenorphine (partial opioid agonist) with zaleplon (a nonbenzodiazepine 'Z-drug' hypnotic). Both are pharmacodynamic CNS depressants; neither is a prodrug and this is a PD, not PK, interaction. Risk includes profound sedation, respiratory depression, coma, and death.
- Severity: Major; evidence: probable (epidemiologic overdose-mortality data).
- Onset: Unspecified.
- Management: Avoid concomitant use where possible; taper or use lowest effective dose. Do not withhold MAT. If combined, use lowest doses, monitor for respiratory depression/sedation, consider higher level of care, and consider alternative insomnia therapy.
What happens
An increased risk of respiratory depression and CNS depression
Interaction Deep Dive
When buprenorphine is given together with a CNS depressant, the CNS depressant effects can be additive, raising the likelihood of respiratory depression, deep sedation, coma, and death. Discontinuing CNS depressants is favored rather than using them at the same time. For certain patients, it may be suitable to observe them in a higher level of care or to taper. For others, it may be suitable to slowly wean the patient off a prescribed CNS depressant or reduce the dose to the lowest amount that remains effective. When concurrent use cannot be avoided, exercise caution in monitoring and management, and weigh alternative therapies for treating 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 example, medications used for insomnia) face a heightened 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 concurrent CNS depressant use. Whether the risk of overdose death from concomitant CNS depressant drugs was different for buprenorphine versus methadone is not known 3.
Why it happens (mechanism)
Additive CNS depression
How to manage this interaction
Both of these medicines calm the nervous system, so used together they can slow breathing and cause heavy sedation. Your care team can manage this, and importantly, needing a sleep aid should never mean you are denied buprenorphine treatment.
- Keep taking both as prescribed unless your prescriber tells you otherwise.
- Your team may lower the dose to the smallest effective amount, or discuss safely tapering the sleep medicine.
- They may suggest a different option for sleep or anxiety.
- They may monitor you more closely for excessive drowsiness or slow breathing.
Tell your pharmacist or doctor if you feel unusually sleepy, confused, or short of breath.
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 examined the risk of fatal overdose, non-overdose related mortality, and all-cause mortality in MAT-prescribed patients (aged 18 to 50), comparing periods during which CNS depressants were prescribed to periods without CNS depressant therapy. The findings indicated a higher 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 combined with 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 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 perform a comparison between the benzodiazepine cohort and the non-benzodiazepine cohort because they did not adjust for the indication of use for the drugs 3.
b) A study of pooled nationwide death certificate data spanning 2010 to 2014 reported 3495 drug overdose deaths in 2014. Methadone and other CNS depressants were commonly identified as contributors to those deaths. Concomitant 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 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 concurrent CNS depressant drugs differed between buprenorphine and methadone remains unknown 3.
Common questions
Can I take Zaleplon and Buprenorphine together?
Buprenorphine and zaleplon together can dangerously add up to slow breathing and heavy sedation, so use them together only under close medical guidance. Don't stop either on your own, and tell your care team you take both so they can adjust doses and monitor you. Always confirm with your pharmacist or prescriber before making any change.
How serious is the Zaleplon 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 Zaleplon and Buprenorphine interaction managed?
Both of these medicines calm the nervous system, so used together they can slow breathing and cause heavy sedation. Your care team can manage this, and importantly, needing a sleep aid should never mean you are denied buprenorphine treatment. Keep taking both as prescribed unless your prescriber tells you otherwise. Your team may lower the dose to the smallest effective amount, or discuss safely t… 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 Zaleplon 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 Zaleplon
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