Codeine and CYP2D6 Ultrarapid Metabolizers: Why Some People Overdose on Normal Doses

Imagine taking a standard dose of codeine for a headache or after surgery-something millions of people have done without issue. But for a small group, that same dose can be deadly. It’s not about taking too much. It’s not about addiction. It’s about your genes.

How Codeine Turns Into a Silent Killer

Codeine isn’t active on its own. Your body has to turn it into morphine to feel any pain relief. That conversion happens thanks to an enzyme called CYP2D6. Most people have one or two copies of the gene that makes this enzyme. They convert codeine slowly and safely. But some people have extra copies-three, four, even five. These are called CYP2D6 ultrarapid metabolizers. For them, codeine turns into morphine so fast that it floods the bloodstream.

That flood doesn’t just make pain go away. It shuts down breathing. In fact, the U.S. Food and Drug Administration (FDA) reviewed 64 cases where codeine led to serious harm or death. Of those, 24 were fatal. Twenty-one of those deaths happened in children under 12. Post-surgery pain? A simple cough syrup? Both became death traps for kids with this genetic quirk.

The Numbers Don’t Lie

CYP2D6 ultrarapid metabolizers convert codeine into morphine 3.5 to 4.5 times faster than normal. That means a 10 mg dose can produce blood morphine levels that rival someone who just took 50 mg of pure morphine. The FDA found that in 13 out of 15 cases where blood levels were measured, morphine was far above the safe range. One 15-month-old child died after a standard dose following tonsil surgery. Autopsy confirmed: ultrarapid metabolizer. Toxic morphine levels. No chance to react.

It’s not rare. In Europe and North America, about 3% to 7% of people are ultrarapid metabolizers. In North Africa and Ethiopia, it’s as high as 29%. That’s nearly one in three people. And yet, most doctors still prescribe codeine without asking about genetics. Why? Because until recently, testing wasn’t common. Now, it’s available-but still not routine.

Who’s at Risk? And Who’s Not

Your CYP2D6 status is fixed from birth. It doesn’t change. There are four categories:

• Ultrarapid metabolizers: Activity score >2.25. High morphine production. High overdose risk.
• Normal metabolizers: 1.25-2.25. Safe with standard doses.
• Intermediate metabolizers: 0.25-1.0. May not get enough pain relief.
• Poor metabolizers: 0. No conversion. Codeine does nothing.

The problem? You can’t tell by looking. A person who feels nothing from codeine might be a poor metabolizer. Someone who gets dangerously sleepy might be an ultrarapid one. Symptoms of overdose include extreme drowsiness, trouble waking up, shallow breathing, bluish lips, and unresponsiveness. These signs often appear within hours of taking the drug.

Why This Isn’t Just a Pediatric Problem

The FDA’s 2013 warning focused on children because most deaths occurred in kids after tonsillectomies. But adults are at risk too. In Australia, researchers found that nearly 3% of adults are ultrarapid metabolizers-and they’re more likely to develop codeine use disorder. Why? Because they get a stronger high. That’s not addiction. That’s biology.

And here’s the twist: some people with this gene might have been taking codeine for years without knowing the danger. One study showed that 7 out of 10 children who died after codeine had this genetic profile. Only 3 were normal metabolizers. That’s not luck. That’s a ticking time bomb.

What Should You Do Instead?

The Clinical Pharmacogenetics Implementation Consortium (CPIC) says it clearly: Do not use codeine or tramadol in ultrarapid metabolizers. The same goes for children under 12-regardless of genetics. The American Academy of Pediatrics and New Zealand’s Medsafe agree.

So what’s safe? Opioids that don’t rely on CYP2D6:

• Morphine (direct-acting, no conversion needed)
• Hydromorphone
• Fentanyl
• Non-opioid options like acetaminophen or ibuprofen

Hydrocodone and oxycodone? They’re sometimes used-but they’re partially metabolized by CYP2D6 too. That means they’re not completely safe either. For ultrarapid metabolizers, the safest bet is to avoid all CYP2D6-dependent drugs.

Can You Get Tested?

Yes. Genetic tests for CYP2D6 are available through hospitals and private labs. Turnaround time? Usually 3 to 14 days. Cost? $200 to $500. Insurance often requires prior approval. In New Zealand, testing is available but not yet standard practice. Most GPs don’t order it unless there’s a red flag-like a family history of bad reactions to codeine.

Some hospitals are starting pre-emptive testing-running the gene panel before prescribing anything. Vanderbilt University is testing a point-of-care system that could give results in two hours. If it works, it could change everything. Imagine walking into a clinic, getting a quick cheek swab, and walking out with a safe painkiller prescription-all in one visit.

Why Isn’t Everyone Tested Already?

Because healthcare moves slowly. Electronic records don’t automatically flag high-risk patients. Doctors aren’t trained in pharmacogenetics. And until recently, testing was expensive and slow. The FDA’s 2013 warning led to a 50% drop in pediatric codeine prescriptions in the U.S. But in many places, codeine is still sold over the counter in cough syrups. In New Zealand, Medsafe issued a similar warning in 2013-but people still ask for it.

There’s also a false sense of safety. Codeine has been around for over a century. It’s cheap. It’s familiar. But familiarity doesn’t mean safe. For ultrarapid metabolizers, it’s a trap.

The Bigger Picture

This isn’t just about codeine. It’s about the future of medicine. We’re moving from one-size-fits-all to personalized care. Your genes aren’t just about ancestry. They’re about how your body handles drugs. That’s why pharmacogenomics is becoming part of standard care in cancer treatment, mental health, and now pain management.

Dr. Mary Relling of St. Jude Children’s Research Hospital predicts codeine will become a drug of historical interest within the next decade. She’s not alone. As testing gets cheaper and faster, prescribing without genetic data will seem as outdated as bloodletting.

What to Do Now

If you or someone you care for has ever had a bad reaction to codeine-extreme sleepiness, trouble breathing, no pain relief-ask about genetic testing. If you’re planning surgery, especially for a child, ask your doctor: Is codeine really the best choice? Push for alternatives. If you’re a parent, don’t give codeine to a child under 12. Period. Even if it’s prescribed.

The science is clear. The warnings are loud. The deaths are real. You don’t need to wait for a tragedy to act. Your genes are already telling you what’s safe. You just have to listen.