Opioids and Adrenal Insufficiency: A Rare but Life-Threatening Side Effect You Need to Know

Most people know opioids can cause constipation, drowsiness, or addiction. But few know they can quietly shut down your body’s stress response - and that could kill you.

What Exactly Is Opioid-Induced Adrenal Insufficiency?

Opioid-induced adrenal insufficiency (OIAI) happens when long-term opioid use messes with your brain’s ability to tell your adrenal glands to make cortisol. Cortisol isn’t just a stress hormone - it’s your body’s emergency fuel. It keeps your blood pressure up, your blood sugar stable, and your immune system from going haywire during illness, injury, or infection.

Unlike adrenal damage from disease, OIAI isn’t about broken glands. It’s about broken signals. Opioids bind to receptors in your hypothalamus and pituitary, the command centers that normally say, “Release ACTH - now make cortisol!” When that signal gets blocked, cortisol production drops. And if you’re on high-dose opioids for months or years, your body forgets how to make enough on its own.

It’s not common - about 5% of people on chronic opioid therapy develop it, according to a 2023 study. But here’s the catch: it’s often missed. Symptoms like fatigue, nausea, low blood pressure, and dizziness look just like the pain condition you’re being treated for. So doctors don’t test for it. And that’s dangerous.

Who’s at Risk?

You don’t need to be on heroin or oxycodone daily to be at risk. The real red flag is dose and duration. If you’re taking more than 20 morphine milligram equivalents (MME) per day for longer than 90 days, your risk jumps significantly. A 2020 study found that 22.5% of long-term opioid users failed adrenal stimulation tests - compared to 0% of people not on opioids.

It doesn’t matter if you’re taking methadone for pain after surgery, fentanyl patches for cancer, or hydrocodone for chronic back pain. The suppression happens across the board. One case study followed a 25-year-old man on methadone after a car accident. He developed high calcium levels during recovery - a sign his body was in crisis. Turns out, his cortisol was barely detectable. Once his opioids were tapered, his adrenal function returned within weeks.

Higher doses mean higher risk. Patients taking over 100 MME per day are most likely to develop full-blown adrenal insufficiency. And the longer you’re on them, the more your body loses its natural rhythm. Cortisol naturally peaks in the morning. In OIAI, that peak vanishes.

How Is It Diagnosed?

There’s no blood test you can take at your local clinic. Diagnosis requires a special stimulation test - usually an ACTH stimulation test. You get a shot of synthetic ACTH, and your cortisol levels are measured before and 30 to 60 minutes later.

Normal response: cortisol jumps above 18 mcg/dL (500 nmol/L). If it stays below that, your adrenal glands aren’t responding - even if your baseline cortisol looks “okay.” Some newer studies suggest even lower thresholds may be needed, especially in chronic users.

Baseline morning cortisol alone isn’t enough. A level of 5 mcg/dL might seem low, but if you’re stressed or sick, your body might still be trying to compensate. That’s why the stimulation test is gold standard. Without it, OIAI slips through the cracks.

And here’s the problem: most pain specialists don’t order it. Endocrinologists rarely see these patients unless they’re already in crisis. So unless someone asks - or you bring it up - it won’t be tested.

What Are the Symptoms?

They’re sneaky. Fatigue. Dizziness. Nausea. Weight loss. Low blood pressure. Muscle weakness. These look like depression, chronic pain flares, or even just “getting older.”

But there’s a dangerous twist: if you get sick, injured, or have surgery - and your cortisol is already low - your body can’t respond. That’s when an Addisonian crisis hits. Blood pressure crashes. You go into shock. You can die within hours if you don’t get IV hydrocortisone and fluids.

One patient in a 2015 case report had a severe infection after surgery. His cortisol was so low, his body couldn’t fight it. He developed hypercalcemia - calcium levels so high they caused kidney damage. Only after starting glucocorticoid replacement did he stabilize. His opioid dose was lowered, and within months, his adrenal function returned.

That’s why OIAI isn’t just a lab curiosity. It’s a silent timer. You might feel fine until the moment you need your body to save itself - and it can’t.

Can It Be Reversed?

Yes. And that’s the good news.

Unlike permanent adrenal damage from autoimmune disease, OIAI is reversible. Once opioids are tapered slowly, the brain’s signaling system usually wakes up again. Studies show cortisol levels return to normal in weeks to months after stopping or reducing opioids.

But here’s the catch: you can’t just quit cold turkey. If you’re on high doses, sudden withdrawal can trigger adrenal crisis - because your body isn’t ready to make cortisol yet. That’s why tapering under medical supervision is non-negotiable.

During the taper, doctors often give low-dose hydrocortisone as a bridge. It’s temporary - just enough to keep you stable while your HPA axis relearns how to work. Once cortisol levels stabilize on their own, the replacement is stopped.

One study followed 12 patients who stopped opioids after years of use. All of them recovered adrenal function within 6 months. But two had adrenal crises during withdrawal because they weren’t monitored. That’s why this isn’t something to handle alone.

What Should You Do If You’re on Opioids?

If you’ve been on opioids for more than 90 days - especially at doses above 20 MME - ask your doctor this:

• Could my symptoms be linked to low cortisol?
• Should I get an ACTH stimulation test?
• What’s my current opioid dose in MME?

Don’t wait for a crisis. If you’re planning surgery, starting chemotherapy, or even just getting the flu, your body needs cortisol to handle the stress. If you’re on long-term opioids and your doctor hasn’t checked your adrenal function, it’s time to bring it up.

Also, keep a list of all your medications - including opioids - and carry it with you. In an emergency, paramedics and ER staff need to know you might be at risk for adrenal crisis. A simple note in your phone or wallet can save your life.

Why Isn’t This More Widely Known?

Because it’s been hiding in plain sight.

For decades, doctors knew opioids could suppress cortisol. But it was seen as a lab curiosity - not a clinical threat. With the opioid epidemic focused on overdose deaths, addiction, and diversion, the endocrine side effects got lost.

Plus, the symptoms are vague. Fatigue? Everyone’s tired. Nausea? Everyone gets sick. Low blood pressure? Maybe you didn’t drink enough water.

But the evidence is piling up. A 2024 review in Frontiers in Endocrinology called it an “underappreciated endocrinopathy.” A 2020 systematic review of over 16,000 patients confirmed the link. And yet, most guidelines still don’t recommend routine screening.

That’s changing. Some pain clinics in the U.S. now screen patients on long-term opioids. But it’s not standard. Until it is, patients are left vulnerable.

The Bigger Picture

Opioids aren’t going away. Millions of people rely on them for chronic pain. But we need to treat them like any other powerful drug - with awareness of all their risks.

Adrenal insufficiency is rare, but it’s serious. And it’s preventable. If you’re on opioids long-term, you deserve to know if your body can still respond to stress. No one should have to survive a heart attack or infection only to find out their body had no backup plan.

The fix isn’t more pills. It’s better questions. Better testing. Better communication between pain doctors and endocrinologists. And most of all - awareness.

If you’re on opioids, don’t assume you’re fine. Ask. Test. Protect yourself. Your adrenal glands can’t speak - but your life depends on them working.