How to Check for Drug Interactions That Increase Overdose Risk

Every year, over 107,000 people in the U.S. die from drug overdoses. Most of these aren’t accidents caused by taking too much of one drug-they happen because of drug interactions. Mixing even common medications with other substances can turn a routine dose into a life-threatening event. The most dangerous combinations involve opioids, benzodiazepines, alcohol, and street drugs laced with fentanyl. But here’s the good news: 90% of these deaths are preventable if you know what to look for and how to check.

Why Some Drug Mixes Are Deadly

Not all drug interactions are the same. Some cause nausea or dizziness. Others can shut down your breathing. The deadliest combinations target the central nervous system (CNS), slowing or stopping your ability to breathe. Opioids like oxycodone, hydrocodone, or fentanyl already depress breathing. Add benzodiazepines like Xanax or Valium, or alcohol, and the effect multiplies. A 2022 study in JAMA Internal Medicine found that combining opioids with benzodiazepines increases the risk of fatal overdose by more than 10 times. Alcohol doesn’t just add to the problem-it makes it worse. Research from the NIH shows opioid-alcohol combos increase respiratory depression by 67%.

Even more dangerous are substances you don’t think of as medications. Street drugs like cocaine, meth, or what you believe is heroin are often cut with fentanyl or other synthetic opioids. You might take one pill thinking it’s just pain relief, but if it’s laced with fentanyl and you’ve also had a drink or taken a sleep aid, your body has no chance. A 2023 harm reduction focus group shared: “I overdosed using what I thought was heroin but was fentanyl-laced cocaine-no app could have warned me.”

How Healthcare Providers Check for Risk

Doctors and pharmacists don’t just guess. They use proven tools. The CDC’s Opioid Risk Tool (ORT) is a 5-question screen that takes less than two minutes. It’s been shown to catch 95% of people at high risk for misuse. But the real key isn’t just the tool-it’s the questions they ask. Instead of saying, “Are you taking other medications?” they’re trained to ask, “Do you ever take medicines not prescribed to you?” That small change increases honest answers by 52%, according to a 2022 study in Addiction.

Pharmacists use the Beers Criteria, updated every two years by the American Geriatrics Society, to spot dangerous combinations in older adults. For example, mixing opioids with certain muscle relaxants or sleep aids can be deadly for someone over 65. The CDC’s 2022 guidelines now require all patients prescribed opioids to be screened for concurrent use of benzodiazepines, alcohol, and other CNS depressants. If a patient says they’re not taking anything else, providers often follow up with a urine drug test-because 58% of patients underreport benzodiazepine use, according to Pain Medicine.

Digital Tools: What They Can and Can’t Do

There are apps and websites that check drug interactions. The FDA’s Drug Interaction Checker, updated monthly, covers over 1,200 prescription and over-the-counter drugs. MedlinePlus from the National Library of Medicine tracks 10,000+ medications. These are great for checking if your painkiller clashes with your blood pressure med. But they have a huge blind spot: they don’t include street drugs, illicit substances, or drugs you got from a friend.

A 2022 BMJ study found that digital tools catch 89% of dangerous prescription interactions-but only 37% of actual drug use is captured by prescription records. Why? People share pills. They buy drugs off the street. They use substances they don’t call “medications.” That’s why 63% of dangerous interactions happen outside the system. Digital tools are helpful, but they’re not enough on their own.

What You Can Do: The Overdose Risk Self-Check

If you’re not seeing a doctor regularly-or if you’re using substances outside of prescriptions-you still have options. The National Harm Reduction Coalition offers a free, evidence-based Overdose Risk Self-Check tool. It’s available in 12 languages and asks 10 simple questions:

• Have you used any drugs in the last week that weren’t prescribed to you?
• Do you mix opioids with alcohol, benzodiazepines, sleep aids, or muscle relaxants?
• Have you stopped using opioids for more than a few days and then started again?
• Do you inject drugs instead of swallowing them?
• Do you have asthma, COPD, or another breathing condition?
• Have you used drugs like Xanax, Valium, or sleeping pills recently?
• Do you use drugs alone?
• Have you been told you have a high tolerance, or do you feel like you need more to get the same effect?
• Do you know what’s actually in the drugs you’re using?
• Have you ever passed out or had trouble breathing after using drugs?

Answering “yes” to one or more doesn’t mean you’re doomed. It means you need to take action. Carry naloxone. Don’t use alone. Talk to someone. The tool has been validated with 88% accuracy against clinical risk models.

Street Names Matter-And So Do You

One of the biggest gaps in prevention is language. If someone says, “I took Molly,” a digital tool won’t flag it. But “Molly” could mean MDMA-which increases the toxicity of cocaine by 200%-or it could be fake fentanyl. NIDA’s 2023 DrugFacts report says 73% of dangerous interactions involve drugs with multiple street names. If you’re asking someone about their use, don’t say, “Are you taking Xanax?” Say, “Have you ever taken anything to help you sleep or calm down? Like downers, benzos, or anything blue or white?”

People respond better when you don’t sound like a cop or a judge. A Reddit user in r/OpiatesRecovery wrote: “My pharmacist asked, ‘Do you ever take medicines not prescribed for you?’ I said yes-I’d been taking Xanax with my oxycodone. She gave me naloxone and a safety plan. That saved my life.”

What to Do If You’re at Risk

If you’re taking opioids, even for pain, and you also use alcohol, benzodiazepines, sleep aids, or street drugs:

• Carry naloxone. It reverses opioid overdoses and is available without a prescription in all 50 states.
• Don’t use alone. If you do, text someone before you start and ask them to check on you.
• Test your drugs. Some harm reduction sites offer fentanyl test strips for free. A single strip can tell you if your powder or pill contains fentanyl.
• Ask your doctor or pharmacist for a medication review. Bring every pill, capsule, or supplement you take-even vitamins or herbal teas.
• If you’ve been abstinent for more than a few days, your tolerance drops by 30-50%. Starting back at your old dose can kill you.

What’s Changing in 2026

The FDA updated its Drug Interaction Checker in February 2024 to include data on 47 fentanyl analogs and 12 new synthetic opioids found in U.S. drug supplies. SAMHSA now requires all federally funded harm reduction programs to screen for illicit substances using the updated Overdose Risk Assessment Protocol. And 38 states now legally require doctors to check for drug interactions before prescribing opioids.

But the biggest shift isn’t technological-it’s cultural. More hospitals are training staff to ask about non-prescribed use without judgment. In 2019, only 22% of U.S. hospitals asked about street drugs. By 2023, that number jumped to 63%. That’s because they’ve learned: people don’t lie because they’re dishonest. They lie because they’re scared.

Final Thought: Prevention Is Simple, But Not Easy

You don’t need a PhD to prevent an overdose. You need to ask the right questions, listen without judgment, and act. Whether you’re a patient, a caregiver, a friend, or someone who uses drugs, your awareness saves lives. The tools exist. The data is clear. The question isn’t whether we can stop these deaths-it’s whether we’re willing to talk about them.