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 multiplies. This isn’t a hypothetical warning. It’s a documented, deadly reality that has killed thousands in the U.S. alone. In 2020, nearly one in six opioid-related overdose deaths involved benzodiazepines. That’s not a coincidence. It’s pharmacology in action-and it’s terrifying.

Why This Combination Stops Breathing

Opioids like oxycodone, hydrocodone, and fentanyl slow breathing by targeting mu-opioid receptors in the brainstem. That’s where your body controls automatic functions like inhaling and exhaling. Benzodiazepines like alprazolam, lorazepam, and diazepam work differently-they boost GABA, a calming neurotransmitter that suppresses brain activity, including the signals that tell you to breathe.

When you take them together, these two drugs don’t just add up. They amplify each other. Studies show that people taking both drugs experience far worse drops in blood oxygen than those taking either alone. One clinical trial found that 85% of patients on both drugs had oxygen levels fall below 90%, compared to just 45% on opioids by themselves. That’s not a small difference. It’s the gap between feeling drowsy and slipping into respiratory arrest.

The danger doesn’t stop at brainstem depression. Both drugs also relax the muscles in your upper airway. That means even if your brain is still trying to breathe, your throat can collapse. You end up with obstructive apneas-long pauses where no air moves in or out. This is especially risky at night, when people are asleep and can’t wake themselves up. Many overdose deaths happen quietly, in bed, with no one around to notice the slow, silent stoppage of breath.

How Much More Dangerous Is It?

The numbers don’t lie. Patients taking both opioids and benzodiazepines are ten times more likely to die from an overdose than those taking opioids alone. The CDC confirmed this in 2022, and their research grant to UC Davis was specifically aimed at understanding why this combination is so lethal.

Even people who’ve been on opioids for years aren’t safe. Chronic opioid users develop tolerance to the sedative effects-but not to the respiratory depression caused by benzodiazepines. That means someone who can handle 80 mg of oxycodone daily might still overdose on 1 mg of alprazolam if they’ve never taken it before. Their body doesn’t recognize the threat. And that’s when the system fails.

The risk climbs even higher with certain drugs. Fentanyl, methadone, and oxycodone are metabolized by the CYP3A4 liver enzyme. Benzodiazepines like alprazolam block that same enzyme. So instead of clearing the opioid from your system, your body lets it build up. One dose of alprazolam can turn a normal opioid dose into a toxic one. That’s not an accident. It’s a chemical trap.

Who’s Most at Risk?

Older adults are especially vulnerable. The American Geriatrics Society lists this combination as potentially inappropriate for patients over 65. Why? Because aging slows metabolism, reduces lung capacity, and increases sensitivity to sedatives. A dose that’s safe for a 30-year-old can be deadly for a 75-year-old. Falls, confusion, and coma become far more likely.

People with sleep apnea are another high-risk group. Their airways are already prone to collapse. Adding opioids and benzodiazepines makes that collapse more frequent and more severe. Many of these patients are prescribed opioids for chronic pain and benzodiazepines for anxiety or insomnia-two very common conditions. The overlap is dangerous, and often overlooked.

Even people who don’t use these drugs recreationally are at risk. A 2021 study found that 15% of Medicare Part D beneficiaries on long-term opioids were also prescribed benzodiazepines. That’s over a million older Americans. And 4.3% of them were on high-risk combinations-extended-release opioids with long-acting benzos. These are the patients doctors are supposed to protect. Too often, they’re being put in harm’s way.

What Doctors Are Supposed to Do

The FDA has been clear since 2016-and more forcefully in 2019-that this combination should be avoided unless absolutely necessary. Their guidelines say: if you must prescribe both, start with the lowest possible dose of the benzodiazepine. Monitor breathing and sedation closely. Never combine opioid cough syrups with benzodiazepines. And never assume tolerance protects you.

The CDC’s 2022 prescribing guidelines say the same thing: avoid benzodiazepines with opioids whenever possible. That’s not a suggestion. It’s a standard of care. Many hospitals now use electronic alerts in their systems to flag these dangerous prescriptions. One study showed these alerts reduced inappropriate co-prescribing by nearly 28%.

For patients already on both drugs, stopping suddenly is just as dangerous as continuing. Benzodiazepine withdrawal can trigger seizures. Opioid withdrawal brings intense flu-like symptoms, anxiety, and insomnia. The safest path is a slow, supervised taper-often one drug at a time, with medical support. This isn’t something to try at home.

What Patients and Families Need to Know

If you’re on an opioid for pain and your doctor prescribes a benzodiazepine for anxiety, sleep, or muscle spasms, ask: Is this absolutely necessary? Are there alternatives? Can you try non-drug therapies like CBT for anxiety? Physical therapy for pain? Sleep hygiene for insomnia?

If you’re already taking both, watch for these signs: extreme drowsiness, slurred speech, confusion, slow or shallow breathing, or difficulty staying awake. If you or someone you care for shows these symptoms, especially after a dose change or new medication, seek help immediately. Don’t wait. Don’t assume it’s just "feeling tired." Keep naloxone on hand. It won’t reverse benzodiazepine effects, but it can block the opioid component and buy critical time. Make sure family members or caregivers know how to use it. Keep it in the same place as your medications-not tucked away in a drawer.

Talk to your pharmacist. They see your full medication list. They can spot interactions your doctor might miss. Don’t assume your doctor knows everything you’re taking. Many people use over-the-counter sleep aids or alcohol with their prescriptions. Those add to the risk too.

What’s Changing Now

The tide is turning. More prescribers are aware. More systems are alerting. More research is being funded. The CDC’s 2022 grant to UC Davis is part of a larger push to identify which patients might safely benefit from this combination-and which ones are walking into a trap.

In hospice and palliative care, where pain and distress are severe and life expectancy is short, the risks may be weighed differently. But even there, dosing is carefully controlled. This isn’t about blanket bans. It’s about informed, cautious decisions.

The future lies in safer alternatives. New non-opioid pain treatments, better non-benzodiazepine sleep aids, and targeted therapies for anxiety are all in development. But until then, the message is simple: don’t mix these drugs. Not even once. Not even a little. The risk isn’t worth it.

What to Do If You’re Already on Both

If you’re currently taking opioids and benzodiazepines together, don’t panic. But don’t ignore it either. Schedule a visit with your doctor. Bring your full medication list-including supplements, alcohol, and over-the-counter sleep aids. Ask:

• Can I safely stop one of these drugs?
• Is there a non-addictive alternative for my pain or anxiety?
• Can we start tapering one slowly, under supervision?
• Should I have naloxone on hand?

Keep a journal. Note your energy levels, breathing patterns, and sleep quality. Bring it to your appointment. Real data helps your doctor make better decisions.

And if you ever feel dangerously sleepy, or someone you love is struggling to stay awake after taking their meds-call 911. Don’t wait. Don’t hope it passes. This isn’t a normal side effect. It’s a medical emergency.