How to Check for Drug Interactions That Increase Overdose Risk

Every year, over 107,000 people in the U.S. die from drug overdoses. Many of these deaths aren’t caused by one drug alone-they happen when substances mix in ways that shut down breathing. The most dangerous combinations involve opioids with other central nervous system (CNS) depressants like benzodiazepines, alcohol, or even some sleep aids. These mixtures don’t just add up-they multiply the risk. A single pill of oxycodone might be manageable. Add a Xanax or a few drinks, and your breathing can stop without warning. The good news? Most of these deaths are preventable-if you know how to check for these interactions before it’s too late.

Why Some Drug Mixes Are Deadly

Not all drug interactions are the same. Some cause nausea or dizziness. Others can kill. The deadliest combinations slow down your brain’s ability to control breathing. Opioids like oxycodone, fentanyl, or heroin already do this. Add another depressant, and your body loses its last safety valve.

According to the CDC, 75% of opioid-related overdoses involve more than one substance. The most common deadly mixes:

• Opioids + benzodiazepines (like Xanax, Valium, Klonopin)
• Opioids + alcohol
• Opioids + sleep medications (like Ambien or Lunesta)
• Opioids + muscle relaxants (like cyclobenzaprine)
• Opioids + illicit drugs like fentanyl-laced cocaine or meth

A 2022 study in JAMA Internal Medicine found that people who took opioids and benzodiazepines together were 10.3 times more likely to die from an overdose than those who took opioids alone. Alcohol doesn’t just add to the risk-it triples it. And if you’ve been sober for even a few days, your tolerance drops by 30-50%. That means a dose you used to handle could now be fatal.

How Clinicians Check for Dangerous Interactions

Doctors and pharmacists use several tools to catch risky combinations before they’re prescribed. The most common is the CDC’s Opioid Risk Tool (ORT), a quick 5-question screen that takes less than two minutes. It doesn’t just ask about current meds-it looks at your history of substance use, mental health, and past prescriptions.

Pharmacists also use the Beers Criteria, updated every two years by the American Geriatrics Society. It flags 56 dangerous combinations specifically for older adults, who are more sensitive to CNS depression. For example, mixing an opioid with an antihistamine like diphenhydramine (Benadryl) can be deadly in seniors, even if both are taken as directed.

Digital tools like the FDA’s Drug Interaction Checker and MedlinePlus are updated monthly with data on over 1,200 prescription drugs. These are great for catching known interactions between legal medications. But they have a huge blind spot: street drugs, shared pills, or substances bought online. That’s where these tools fail-and where people die.

What Digital Tools Miss (And Why It Matters)

Most drug interaction checkers only list FDA-approved medications. They don’t include:

• Fentanyl analogs (like carfentanil or acetylfentanyl)
• Illicit benzodiazepines (like etizolam or clonazolam sold as “Xanax”)
• Stimulants laced with opioids (like cocaine or meth with fentanyl)
• Herbal supplements (like kava or kratom) that also depress breathing

A 2023 study found that 63% of dangerous interactions involve substances not listed in any digital database. People often don’t know what they’re taking. One user thought they were buying heroin. It was fentanyl-laced cocaine. No app could warn them.

Even when people take prescribed meds, they often don’t tell their doctor about everything. A 2021 study in Pain Medicine showed that 58% of patients on opioids didn’t admit to using benzodiazepines-even when it was clear from their urine test. Why? Fear. Shame. Not knowing it was dangerous.

How to Check for Interactions If You’re Not in a Clinic

You don’t need a doctor to protect yourself. Here’s how to do it yourself:

1. Make a full list of everything you’ve used in the last week-not just prescriptions. Include alcohol, marijuana, sleep aids, painkillers from a friend, herbal teas, and even cough syrup.
2. Use the National Harm Reduction Coalition’s free Overdose Risk Self-Check. It’s a 10-question tool validated by clinical research and available in 12 languages. It asks: “Have you used any of these in the last week?” and lists street names like “downers,” “blues,” “molly,” or “pink.”
3. Ask yourself: “Have I taken anything not prescribed to me?” This question, used by harm reduction workers, gets 52% more honest answers than “Are you taking other medications?”
4. Know the street names. “Molly” can mean MDMA, but it can also mean fake pills with fentanyl. “Xanax bars” might be counterfeit and contain etizolam. “Percs” could be fentanyl disguised as oxycodone.
5. Check your substances with a fentanyl test strip. Available for free from harm reduction sites, these strips cost less than a dollar and can tell you if your drugs contain fentanyl-even if you think you know what you’re taking.

What to Do If You Find a Dangerous Mix

If you discover you’re mixing risky substances, don’t panic. You’re not alone-and help is available.

• Don’t stop cold turkey. If you’ve been using opioids regularly, quitting suddenly can cause severe withdrawal and increase overdose risk if you relapse.
• Ask for naloxone. It’s a life-saving nasal spray that reverses opioid overdoses. You don’t need a prescription in most states. Pharmacies give it out free. Carry it with you.
• Talk to someone who won’t judge. Harm reduction centers, peer support groups, or even a trusted pharmacist can help you make a safer plan. You don’t have to quit to stay alive.
• Use one substance at a time. If you’re using opioids, avoid alcohol, benzodiazepines, and sleep aids completely. Even one drink can be dangerous.
• Never use alone. Overdoses happen fast. Someone nearby can call 911 and give naloxone.

Real Stories: What Works and What Doesn’t

One Reddit user, u/HarmReductionRN, shared that in 12 years of ER work, they saw 217 overdose cases where patients denied using benzodiazepines-until after naloxone was given. Then, 82% admitted to mixing them with opioids.

Another user on r/OpiatesRecovery said: “My pharmacist asked, ‘Do you ever take medicines not prescribed for you?’ That question saved my life. I told her I was taking my mom’s Xanax with my pain meds. She gave me naloxone and a referral.”

A SAMHSA case study tells of a man who overdosed after taking oxycodone with Valium. He survived because his doctor asked, “Do you ever use ‘downers’?” not “Are you on any other meds?” He’d never heard of Valium as a “downer.” Once he understood the term, he told the truth.

What’s Changing Now

In 2024, the FDA updated its Drug Interaction Checker to include 47 fentanyl analogs and 12 new synthetic opioids found in the U.S. drug supply. That’s progress.

Thirty-eight U.S. states now require doctors to check for drug interactions before prescribing opioids. But only 17% of syringe service programs have access to pharmacists who can do proper screening.

The biggest shift? More clinics are using harm reduction language. Instead of asking, “Are you taking other drugs?” they ask, “What do you use to feel better?” That small change makes people talk. And talking saves lives.

Final Thought: Prevention Starts With a Question

You don’t need to be a doctor to prevent an overdose. You just need to ask the right questions-of yourself, your friends, your family.

If you’re taking opioids, ask: “Have I mixed this with anything else?”

If you’re helping someone, ask: “What did you actually take?”

And always carry naloxone. It’s not just for addicts. It’s for anyone who takes pain meds, sleeps with a pill, or uses substances to cope. It’s the one thing that can turn a tragedy into a second chance.