Benzodiazepines and opioids together: the boxed warning on every benzodiazepine label
The alprazolam label opens with a boxed warning: taken with opioids, benzodiazepines "may result in profound sedation, respiratory depression, coma, and death." The two drugs slow breathing through different receptors, and the effects add.
Reasonable evidence with real limitations. how we score evidence
Caveat on this rating: A label warning states a risk the regulator considers established; it does not give the size of the risk. The size is in the Sun 2017 BMJ analysis in this wave (about twice the odds of an overdose visit with concurrent use), which is observational and cannot prove the combination caused the overdoses.
The strongest warning the FDA can require sits at the top of every benzodiazepine label, and its first bullet is about a combination.
Significant findings
The XANAX XR prescribing information (Viatris, June 2026) opens: "Concomitant use of benzodiazepines and opioids may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of these drugs for patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients for signs and symptoms of respiratory depression and sedation."
The label explains why the two add up rather than cancel: "The concomitant use of benzodiazepines and opioids increases the risk of respiratory depression because of actions at different receptor sites in the CNS that control respiration. Benzodiazepines interact at gamma-aminobutyric acid (GABAA) sites and opioids interact primarily at mu receptors." And it states the evidence base: "Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioids alone."
The same boxed warning names alcohol and other sedatives: "Abuse and misuse of benzodiazepines commonly involve concomitant use of other medications, alcohol, and/or illicit substances, which is associated with an increased frequency of serious adverse outcomes." Alprazolam is also contraindicated with strong CYP3A inhibitors such as ketoconazole and itraconazole, because they raise its blood level, and the dose is halved when ritonavir is started.
Worth asking
If you take a benzodiazepine and are prescribed an opioid for pain, or a cough medicine containing one, the question for whoever prescribes the second drug is whether they know about the first. The label puts the responsibility on the prescriber to limit doses and durations and to watch for slowed breathing; the person who can make sure both prescribers know is you. Do not stop a benzodiazepine on your own: the same label carries a warning about withdrawal, which can be severe, and any change belongs in a conversation with the prescriber.
Source
XANAX XR (alprazolam) extended-release tablets: FDA-approved prescribing information, Boxed Warning, Warnings and Precautions 5.1, Drug Interactions 7.1 — Viatris Specialty LLC; US Food and Drug Administration (2026)
Regulator or national health body
How this was scored
- Study design
- Regulatory safety determination
- Funding
- Industry funded
- Published in
- Regulator or national health body
- Sample size
- not recorded
- Preregistered
- not recorded
- Conflicts disclosed
- not recorded
- Independent of proponent
- not recorded
- Retracted
- No
Read the full scoring rubric, including what it can't tell you.
Published September 21, 2026.
Questions
How strong is the evidence behind this?
veisund rates this source "moderate evidence". Reasonable evidence with real limitations. It scores 57 out of 100 on our published rubric. One caveat travels with that badge: A label warning states a risk the regulator considers established; it does not give the size of the risk. The size is in the Sun 2017 BMJ analysis in this wave (about twice the odds of an overdose visit with concurrent use), which is observational and cannot prove the combination caused the overdoses. The score is calculated from recorded facts about the source — study design, funding, publication venue, sample size, preregistration — not typed in by an editor.
What is the source for this?
XANAX XR (alprazolam) extended-release tablets: FDA-approved prescribing information, Boxed Warning, Warnings and Precautions 5.1, Drug Interactions 7.1 — Viatris Specialty LLC; US Food and Drug Administration (2026). Published in: Regulator or national health body. The full source is linked on this page so you can read it yourself.
Who paid for this research, and does that matter?
Study design: Regulatory safety determination. Funding: Industry funded. Independence from the proponent is not recorded. Industry sponsorship is one of the most reliably measured biases in medicine, which is why funding carries real weight in the score rather than sitting in a footnote.
Is this medical advice?
This is information to bring to your prescriber, not medical advice and not a reason to change anything on your own. Nothing here is an instruction to stop or reduce a medication. If you are in crisis, call or text 988.
This is information to bring to your prescriber, not medical advice and not a reason to change anything on your own. Nothing here is an instruction to stop or reduce a medication. If you are in crisis, call or text 988.