Opioids and Benzodiazepines: The Deadly Breathing Risk When Taken Together

When opioids and benzodiazepines are taken together, the risk of stopping breathing doesn’t just go up-it explodes. This isn’t a theoretical concern. It’s happening every day in homes, clinics, and emergency rooms across the country. The FDA issued its first official warning in 2016, and by 2019, they strengthened it with a Boxed Warning-the highest level of alert-for both drug classes. Why? Because the numbers don’t lie: people who take both drugs are ten times more likely to die from an overdose than those taking opioids alone.

How These Drugs Kill Together

Opioids like oxycodone, fentanyl, and hydrocodone work by binding to mu-opioid receptors in the brainstem, the area that controls automatic breathing. Benzodiazepines like alprazolam, lorazepam, and diazepam boost the effect of GABA, a calming neurotransmitter that slows down nerve activity-including the signals that tell your lungs to breathe. Individually, each drug can cause drowsiness and shallow breathing. Together, they don’t just add up-they multiply.

Studies show that when these drugs are combined, oxygen levels in the blood drop dramatically. One human trial found that 85% of participants taking both drugs had oxygen saturation fall below 90%, compared to only 45% taking opioids alone. That’s not just sleepy-it’s life-threatening. The brain’s ability to respond to rising carbon dioxide levels, which normally triggers deeper breathing, becomes severely blunted. Even people who’ve been on opioids for years and think they’ve built up tolerance aren’t protected. Their bodies haven’t adapted to benzodiazepines’ effect on breathing.

There’s another hidden danger: drug metabolism. Some opioids, including fentanyl and methadone, are broken down by the liver enzyme CYP3A4. Benzodiazepines like alprazolam and ketoconazole can block this enzyme. That means the opioid stays in the body longer, building up to toxic levels even if the dose hasn’t changed. A person might be taking their usual pain pill, add a sleeping pill, and suddenly find themselves in respiratory arrest-without realizing why.

Who’s Most at Risk?

It’s not just people using drugs recreationally. Many of those at highest risk are patients prescribed both medications by doctors. Older adults are especially vulnerable. The American Geriatrics Society lists this combination as potentially inappropriate for seniors in their Beers Criteria, citing increased fall risk and respiratory depression. People with sleep apnea, COPD, or other lung conditions face even greater danger. The combination can turn mild snoring into full-blown airway collapse.

Even patients on opioid replacement therapy for addiction-like those on methadone or buprenorphine-are at risk. Their tolerance to opioids doesn’t extend to benzodiazepines. A 2021 review in the Annals of Palliative Medicine found that clinicians often mistakenly assume these patients can handle higher sedative doses, leading to fatal miscalculations.

Emergency room data shows that 16% of opioid-related overdose deaths in 2020 involved benzodiazepines. That’s roughly 30% of all opioid overdoses. The CDC reported that the death rate from this combination rose from 0.6 per 100,000 in 1999 to 8.8 per 100,000 in 2017. While it’s dipped slightly since, it’s still far above historical levels.

What Happens During an Overdose?

The signs don’t always look like a typical overdose. There’s no screaming, no thrashing. Often, it’s quiet. The person becomes extremely drowsy, slurs their words, or can’t stay awake. Their breathing slows to just a few breaths per minute-shallow, irregular, and ineffective. Lips or fingertips turn blue. They may nod off and not wake up. In many cases, family members find them unresponsive hours later, thinking they were just sleeping deeply.

What makes this so dangerous is how easily it can be missed. A person might seem fine during a doctor’s visit. Their oxygen levels might look okay on a pulse oximeter. But that device doesn’t detect the slow, silent decline that happens during sleep. That’s when the combination becomes lethal. The brain stops responding to rising CO2. The airway collapses. Breathing stops. And there’s no alarm.

Doctors Are Being Warned-But It’s Still Happening

The FDA, CDC, and major medical societies all agree: avoid prescribing these drugs together unless absolutely necessary. The CDC’s 2022 opioid prescribing guidelines say to avoid benzodiazepines with opioids whenever possible. The FDA says if you must prescribe both, start with the lowest possible dose of the benzodiazepine and monitor closely.

Yet, a 2021 study in JAMA Network Open found that 15% of Medicare Part D patients on long-term opioids were also getting benzodiazepines. In 4.3% of cases, it was a high-risk combo-extended-release opioids with long-acting benzos. That’s tens of thousands of people still being exposed to this deadly mix.

Some healthcare systems are fighting back. Electronic health records now include automated alerts that pop up when a prescriber tries to write both scripts. One study showed these alerts reduced dangerous co-prescribing by 27.3%. But alerts aren’t foolproof. If a doctor clicks past them, the system can’t stop the prescription.

What Should You Do If You’re Taking Both?

If you’re on both medications, don’t stop suddenly. Withdrawal from benzodiazepines can trigger seizures. Opioid withdrawal is brutal-sweating, vomiting, anxiety, rapid heartbeat. Abruptly quitting either one can be dangerous. But continuing both? That’s a death sentence waiting to happen.

Here’s what to do:

1. Call your doctor. Don’t wait for your next appointment. Tell them you’re concerned about the risks.
2. Ask if there’s a safer alternative. For anxiety, consider therapy, SSRIs, or non-benzodiazepine sleep aids. For pain, explore physical therapy, nerve blocks, or non-opioid medications like gabapentin or acetaminophen.
3. If you must continue both, never take them together without supervision. Avoid alcohol, sleep aids, or any other sedatives.
4. Have naloxone on hand. It won’t reverse benzodiazepine effects, but it can help if opioids are part of the overdose. Make sure someone you live with knows how to use it.
5. Use a pulse oximeter at home if you’re at high risk. If your oxygen drops below 92% for more than a few minutes, seek help immediately.

The Bottom Line

This isn’t about being careful. It’s about avoiding the combination entirely. The science is clear. The deaths are real. The warnings have been out for years. Yet people are still dying because they didn’t know, or because they were told it was safe.

If you’re prescribed both, ask: Is this truly necessary? Is there another way? And if you’re a caregiver, watch for signs: Is your loved one harder to wake? Are they unusually confused or slow to respond? Don’t assume they’re just tired. It could be the beginning of the end.

One drug can be managed. Two together? That’s a recipe for disaster. The system has failed too many people already. Don’t let it fail you.