Hidden in the Epidemic: Opioid-Induced Adrenal Insufficiency

Miriam E. Tucker

April 30, 2019

LOS ANGELES — Opioid-induced adrenal insufficiency (OIAI) is a potentially serious and under-recognized danger from chronic opioid use that is likely to be on the rise given the current opioid epidemic, new research suggests.     

Findings from a retrospective case series of 40 patients with OIAI were presented April 27 in a poster here at the American Association of Clinical Endocrinologists (AACE) 2019 Annual Scientific & Clinical Congress by Taoran Li, MBBS, a research fellow at the Mayo Clinic, Rochester, Minnesota.

"Adrenal dysfunction secondary to chronic opioid use has been reported as early as 2000. However, only over the last several years do we note an increase in the number of studies systematically investigating OIAI," Li told Medscape Medical News, adding, "we believe there are deficiencies in awareness of OIAI, especially within non-endocrine providers."

"Easy to Miss," Check Basic Hormone Levels

Chronic opioid use can lead to adrenal insufficiency through central suppression of the hypothalamic-pituitary-adrenal axis. A recent review found that the estimated prevalence ranges from 9% to 29% of chronic opioid users. 

Li said he wants to raise clinician awareness of the endocrine dysfunctions secondary to chronic opioid use, noting, "As the clinical presentations of adrenal insufficiency are usually nonspecific and may overlap with other coexisting conditions, it is easy to miss."

As there are currently no gold standard diagnostic criteria for OIAI, he recommends checking basic hormone levels, including morning cortisol, adrenocorticotropic hormone (ACTH), and dehydroepiandrosterone sulfate (DHEAS) as screening tests in patients who take high doses of opioids clinically and referring them to an endocrinologist for further evaluation if any abnormal adrenal function is found.

And, if possible, patients with OIAI should discontinue or reduce their opioid usage levels, Li advised.

Asked to comment, Gregory Dodell, MD, assistant clinical professor of medicine, endocrinology, diabetes, and bone disease at the Icahn School of Medicine at Mount Sinai, New York City, agreed that the phenomenon is probably under-recognized.

"I haven't really seen it, but probably because we're not screening for it. If someone comes in with chronic pain on opioids you may have the sense that their symptoms are related to chronic pain or opioid use, not adrenal insufficiency. Maybe the standard should be checking random cortisol levels of anyone taking chronic opioids."

Dodell added, "If you can treat the adrenal insufficiency with corticosteroids that may help a lot of their symptoms and even mitigate the pain. I think if they have OIAI you would want to try to figure out another kind of pain regimen and maybe send them to a pain specialist."

Only 8% of OIAI Picked Up With Screening, Causes Significant Morbidity  

The series of 40 patients were all diagnosed in the endocrinology division of the Mayo Clinic between January 2006 and October 2018.

All patients had been taking opioids continuously or intermittently for 90 days or longer and were treated with glucocorticoid replacement therapy to avoid adrenal crisis. 

Only three (8%) cases of OIAI were detected with proactive screening. The rest had developed symptoms suggestive of adrenal insufficiency prior to OIAI diagnosis.

Of that 92%, more than half had symptoms suggesting adrenal insufficiency and low cortisol and had been referred by their primary care clinician or endocrinologist. The others were accidentally found to have low cortisol during hospitalization or evaluation for other disorders, Li told Medscape Medical News.

The 40 patients with OIAI were a mean age of 50.5 years and 72.5% were women. Most were taking opioids daily rather than as needed, with a median morphine milligram equivalent of 105 mg for a median duration of 96 months. 

The most commonly used opioid was oxycodone (n = 19), followed by hydrocodone (9), fentanyl patch (9), tramadol (6), morphine (5), and hydromorphone (5). Most were taking the opioid for musculoskeletal pain (21).

Presenting symptoms included fatigue (29), musculoskeletal pain (21), weight loss (17), headache (12), abdominal pain (8), and nausea (8). Patients reported having had symptoms suggestive of OIAI for a median of 12 months prior to diagnosis.  

Median morning cortisol was 3 mcg/dL (normal > 7 mcg/dL), ACTH was 9.7 pg/mL (normal > 10 pg/mL), DHEAS was 18.2 mcg/dL (normal > 50 mcg/dL), and peak cortisol using the cosyntropin stimulation test (CST) was 16 mcg/dL (normal > 18 mcg/dL).

The biochemical diagnosis of OIAI was made on the basis of low morning cortisol, baseline ACTH, and/or DHEAS in 59% and abnormal CST in 61%.

In addition to OIAI, seven men were diagnosed with opioid-induced hypogonadism. 

No patient presented in adrenal crisis, but one developed adrenal crisis after the OIAI diagnosis was made.

Of the 33 patients with follow-up, 14 (42%) had improvement in symptoms following hydrocortisone initiation and 20 (61%) tapered or discontinued opioids.

However, just 10 patients overall (30%) recovered from OIAI, and eight of the 20 (40%) who discontinued opioids recovered.

"Appropriate glucocorticoid treatment is vital to avoid adrenal crisis and can lead to improvement of symptoms," wrote Li and colleagues in their poster.

"Resolution of OIAI is possible following opioid cessation or reduction and should be recommended if possible," they conclude.

Li and Dodell have reported no relevant financial relationships.

AACE 2019. Presented April 27, 2019.

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