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  • Writer's pictureDr. Harold Pierre

Opioid-Induced Adrenal Insufficiency in Patients Taking Chronic Opioids for Pain and Addiction

Updated: Nov 29, 2023

Opioid Induced Adrenal Insufficiency (Adrenal Fatigue)

Medicine concept. On a blue background, a wooden figure of a man and a plate with the inscription. Adrenal Insufficiency

Chronic pain impacts over 50 million Americans. Many rely on prescription opioid medications like morphine, oxycodone, and fentanyl to manage their pain. But long-term opioid use has serious risks. One under-recognized danger from chronic opioid use is its effects on hormone production.

Opioids can disrupt signals between the brain, pituitary gland, and adrenal glands. This suppresses production of cortisol and other vital hormones. Over months or years, this “opioid-induced adrenal insufficiency” can cause fatigue, illness, depression, and even death from adrenal crisis.

Unfortunately, many doctors overlook testing for this potentially dangerous condition. They mistake its vague symptoms for opioid side effects or worsening pain. But diagnosing and treating adrenal insufficiency may greatly improve well-being for those dependent on opioids. There are also steps patients can take to reduce their risk.

Understanding the Adrenal Glands

The adrenal glands are endocrine organs that are shaped like two small triangles that sit atop the kidneys. Each weighs only around 5 grams, but they play a huge role in the body’s stress response, metabolism, immunity, and more.

The outer layer of the adrenals, the cortex, produces three main types of hormones:

  • Glucocorticoids like cortisol help regulate blood sugar, pressure, inflammation, and the body’s response to stress.

  • Mineralocorticoids like aldosterone control salt and water balance in the bloodstream and tissues.

  • Androgens like DHEA provide a backup source of sex hormones.

Meanwhile, the adrenal medulla at the center makes catecholamines like adrenaline. These launch the “fight or flight” response to stress.

All the adrenal hormones work together to maintain equilibrium and prime the body to handle threats to its stability. But various diseases and drugs can throw this delicate balance out of whack.

The Danger from Chronic Opioid Use on Adrenal Hormone Production

The adrenals don’t regulate hormone output on their own. Like other glands, they rely on direction from the brain. The hypothalamus makes “releasing hormones” that tell the pituitary what to do. And the pituitary passes along signals to trigger secretion by target glands.

This hypothalamic-pituitary-adrenal (HPA) axis acts like a relay race. Each step hands off the baton to keep adrenal hormones flowing. But opioids disrupt this hormone highway at multiple points:

Opioids suppress the HPA axis by inhibiting signals from the hypothalamus and blocking ACTH from the pituitary.

  • In the hypothalamus, they inhibit production of CRH, the hormone that starts the cascade.

  • In the pituitary, they block the release of ACTH in response to CRH.

  • In the adrenals, they bind to opioid receptors directly, reducing cortisol synthesis.

The end result is lowered production of cortisol and other critical hormones.

Symptoms of Adrenal Insufficiency

“Adrenal insufficiency” is the medical term when the adrenals don’t make enough cortisol and other hormones. There are two types:

  • Primary insufficiency: The adrenals themselves are damaged by autoimmune disease, infection, surgery, etc. This is relatively rare.

  • Secondary/tertiary insufficiency: A problem with the pituitary or hypothalamus disrupts signals to the adrenals. This is the type caused by opioids.

Without sufficient cortisol, the body loses its ability to manage stress, regulate blood sugar, fight inflammation, and mount an immune response. This makes people with untreated adrenal insufficiency prone to adrenal crises - potentially deadly episodes of low blood pressure, vomiting, collapse, and shock.

But even before a crisis strikes, vague symptoms plague people whose adrenals aren’t working right. These may include:

  • Fatigue, lack of energy.

  • Nausea, abdominal pain, vomiting.

  • Dizziness, especially upon standing.

  • Weight loss, poor appetite.

  • Depression, mood changes.

  • Muscle aches, joint pain.

  • Salt craving.

  • Lower sex drive.

Nonspecific complaints like these are easy to misattribute to other causes. Doctors often overlook the possibility of adrenal issues in chronic pain patients. But ignoring the warning signs can have grave consequences.

That’s why testing adrenal function is crucial when opioid side effects don’t improve. Sadly, up to 90% of patients with opioid-induced adrenal insufficiency go undiagnosed.

Prevalence of Opioid-Induced Adrenal Insufficiency

Studies estimate anywhere from 9% to 30% of chronic opioid users may suffer from HPA axis suppression. Among specific groups, rates may be even higher:

  • Up to 35% of patients on prescription opioids long term.

  • Over 50% of those abusing IV heroin.

  • 15% to 20% of methadone maintenance patients.

Yet despite these numbers, poor awareness means only a fraction of cases are properly identified and treated. This leaves many to suffer the effects of under-treated adrenal insufficiency.

Dangers of Low Cortisol and Adrenal Crisis

Adrenal fatigue word cloud

In an adrenal crisis, the patient may experience:

  • Severe fatigue.

  • Confusion, delirium.

  • Abdominal pain.

  • Vomiting, diarrhea.

  • Fever.

  • Low blood pressure, shock.

  • Loss of consciousness.

Unless treated urgently with IV saline and steroids, adrenal crisis can lead to coma and death. Patients with unrecognized adrenal insufficiency face this risk whenever seriously ill or injured. Surgery, severe infections, trauma, or medications that deplete cortisol may all trigger a crisis.

Clearly, undiscovered impairment of adrenal function is no trivial matter. But the good news is that timely diagnosis and treatment can restore quality of life and help avoid crises.

Diagnosis of Adrenal Insufficiency in Patients

Diagnosing adrenal problems involves blood and sometimes urine tests. Key hormone levels to check are:

  • Morning cortisol - This should be at its highest early in the day. A low reading suggests inadequate output.

  • ACTH - Low levels mean the pituitary isn’t properly signaling the adrenals.

  • DHEAS - This shows adrenal androgen production over time.

If these screening tests are suspicious, a cosyntropin stimulation test can confirm impaired function. The patient gets an injection of synthetic consyntropin (ACTH). Cortisol levels are measured before and after to see if the adrenals respond appropriately.

There are no universal cutoff values to diagnose adrenal insufficiency. But the pattern of low cortisol plus low ACTH and DHEAS indicates the adrenals are not getting the support they need.

Of course, testing has limitations. Opioids acutely lower cortisol after a dose. So results can vary depending on timing. That’s why checking multiple hormones provides more insight.

Symptoms and risk factors are also important. Patients on higher opioid doses for longer periods have an elevated risk of adrenal suppression. But even those on low doses for a short time should be monitored.

Functional Testing Options

Salivary hormone testing is another more precise way of testing. Salivary adrenal and hormone testing provides an easy, convenient, and accurate way to assess free biologically active hormones levels across the full circadian rhythm. This allows for more personalized and precise treatment.

Salivary Testing for Adrenals

  • Measures cortisol and DHEA levels.

  • Four point testing at 8am, noon, 4pm, 10pm shows full daily pattern.

  • Graphs make it easy to see highs and lows.

  • Saliva shows biologically available levels.

  • Saliva measures the free, biologically active fraction of hormones like cortisol and DHEA. This is more clinically relevant than total levels.

Thyroid testing should also be done for a complete evaluation. The thyroid testing options:

  • TSH, free T3, free T4, reverse T3, and antibodies.

  • TSH should be under 2.

  • Free T3 and T4 should be midrange.

  • High reverse T3 indicates hypothyroidism.

T3 vs T4

  • T4 must convert to T3 to be used.

  • T3 is much stronger than T4.

  • Most people need both T3 and T4.

  • Conversion requires selenium - test levels.

Medical Management of Adrenal Insufficiency

Patients on long-term opioid therapy should be screened. If blood tests confirm inadequate adrenal reserve, doctors can prescribe hormone replacements to pick up the slack. These may include:

  • Hydrocortisone or cortisone tablets to replace cortisol throughout the day.

  • Prednisone for more potent anti-inflammatory effects.

  • Fludrocortisone to provide missing aldosterone.

  • DHEA supplements sometimes used for adrenal androgen deficiency.

Along with medication, patients should take these steps to support their adrenals:

  • Have emergency injections on hand in case of illness or crisis.

  • Increase medication doses when unwell or under major stress.

  • Seek urgent care for vomiting, diarrhea, dehydration, fever, or low blood pressure.

  • Wear a medical alert bracelet describing adrenal insufficiency.

However, exogenous steroids cannot fully mimic normal fluctuations and feedback loops. The best solution is to treat the underlying cause.

Recovering Adrenal Function After Opioid Cessation

Panoramic shot of handsome bi-racial man sleeping in bed in morning copy

In most cases, recovery of normal HPA axis activity requires reducing or eliminating opioid doses. This allows the inhibitory effects on the hypothalamus and pituitary to resolve.

Studies show the majority of diagnosed patients regain adrenal sufficiency within weeks to months of opioid cessation. However, the recovery timeframe is unpredictable. It depends on factors like:

  • Duration of opioid therapy.

  • Level of adrenal suppression.

  • Patient age and health status.

  • Whether opioids are tapered versus stopped abruptly.

During and after opioid discontinuation, doctors monitor adrenal hormones. If levels normalize, they gradually withdraw corticosteroid medications. But some long-term users may require ongoing treatment.

For those who cannot reduce opioid dosing, careful symptom monitoring and steroid adjustments are key. However, they likely remain at increased risk for periodic crises due to adrenal impairment.

Protecting Adrenal Function During Opioid Therapy

The best way to prevent opioid-induced adrenal insufficiency is to avoid long-term opioid use if at all possible. Always weigh the hormone-related risks against potential benefits before starting chronic opioid therapy.

For patients who do require ongoing opioid treatment, several strategies may reduce harm:

  • Take the lowest effective opioid dose. Higher doses increase adrenal suppression risk, but even low doses carry some risk for sensitive individuals.

  • Have cortisol levels checked periodically. Routine screening can catch early suppression before it causes symptoms.

  • Use extended-release opioids if possible. Long-acting opioids may impact hormone levels less severely compared to short-acting versions.

  • Consider opioid rotation. Switching between different opioids may allow the adrenals time to recover.

  • Watch carefully for side effects. Report symptoms like weakness and nausea promptly so adrenal function can be assessed.

  • Increase medication and fluids when ill. Prevent crises by mimicking the body’s normal stress response.

  • Carry emergency steroid injections. Be prepared to treat adrenal crisis if vomiting, collapse, or low blood pressure occur.

While more research on risk factors and prevention is still needed, these common-sense measures can help mitigate harm. Patients and providers together can work to ensure the benefits of opioids outweigh the risks.

The Bottom Line on Opioids and Adrenal Health

Chronic opioid use often prescribed for pain disrupts hormone production, potentially resulting in adrenal insufficiency. The resulting cortisol deficiency impairs stress handling, immunity, stamina, blood pressure control, and more.

In severe cases, under-treated adrenal insufficiency may lead to catastrophic adrenal crises. But even mild dysfunction significantly undermines wellness. Chronic opioid use may lead to the development of adrenal insufficiency. That's why testing for and treating impaired adrenal function is critical in patients treated with long-term opioids.

The best solution is to stop opioids if medically appropriate. This allows the body to regain normal hormone rhythms. But for patients dependent on ongoing opioid therapy, steroids, stress prevention, and emergency preparation help reduce the dangers of unrecognized adrenal impairment.

While more research would aid management, simply recognizing this serious issue is the first step. The second step is for you to use this information to talk to your doctor. Patients and doctors must partner to detect hormonal side effects early. Catching opioid-induced adrenal dysfunction quickly provides the opportunity to correct it before permanent health consequences result.

Coluzzi, F.; Pergolizzi, J.; LeQuang, J.A.K.; Sciacchitano, S.; Scerpa, M.S.; Rocco, M. (2023). A Closer Look at Opioid-Induced Adrenal Insufficiency: A Narrative Review. Int. J. Mol. Sci., 24(5), 4575.

Das, G. (2014). Chronic Heroin Dependence Leading to Adrenal Insufficiency. Case Reports in Endocrinology, 2014, Article ID 461816, 2 pages.

Rhodin, A.; Stridsberg, M.; Gordh, T. (2010). Opioid Endocrinopathy: A Clinical Problem in Patients With Chronic Pain and Long-term Oral Opioid Treatment. Clin J Pain, 26, 374–380.

Li, T.; Cunningham, J.L.; Gilliam, W.P.; Loukianova, L.; Donegan, D.M.; Bancos, I. (2020). Prevalence of Opioid-Induced Adrenal Insufficiency in Patients Taking Chronic Opioids. J Clin Endocrinol Metab, 105(10), e3766–e3775. doi: 10.1210/clinem/dgaa499.

About the author:

Dr. Harold Pierre is a board-certified anesthesiologist and addiction medicine specialist with over 20 years of experience. He is certified by the American Board of Anesthesiology and the American Board of Preventive Medicine.

This website is provided for educational and informational purposes only and does not constitute providing medical advice or professional services. The information provided should not be used for diagnosing or treating a health problem or disease, and those seeking personal medical advice should consult with a licensed physician or another qualified medical professional. Never disregard professional medical advice or delay in seeking it because of something you have read on this website.

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