ENDO 2019: 101st Annual Meeting of the Endocrine Society:

Six Clinical Insights for Better Management of Adrenal Insufficiency

With James W. Findling, MD

James W. Findling, MD­, currently a visiting professor at Rush Medical Center in Chicago, Illinois, presented a series of patient cases in a Meet-the-Professor session at the 101st annual meeting of the Endocrine Society in New Orleans, Louisiana, as a way to elucidate common considerations to keep in mind when facing a patient with adrenal insufficiency (AI).1

The onset of secondary adrenal insufficiency, marked by hypocortisolemia, often arises in response to long-term treatment with exogenous glucocorticoids or extended exposure to opioids,1 according to Dr. Findling, or may develop due in response to conditions affecting the hypothalamic-pituitary-axis (HPA).

Adrenal insufficiency when not well managed can lead to adrenal crisis, and death.

There are no professional treatment guidelines to inform clinicians as to the best approaches for managing these patients. Certainly, it is beneficial for clinicians to be prepared to lessen the risks that patients will reach adrenal crisis when AI is not adequately treated. In recognition of this clinical opportunity,  Dr. Findling  identified several key strategies that have informed his practice and which provided the basis for this presentations, offering  one caveat—the list is ever-evolving to reflect his clinical experiences with his patients.1

In an exclusive interview with EndocrineWeb, Dr. Findling focused on an underrecognized and unappreciated manifestation of the ongoing opioid crisis—the potential development of secondary adrenal insufficiency. Since the symptoms of opioid-induced AI are similar to and overlap with chronic pain syndrome, making the diagnosis particularly challenging.


Know the Signs of Opioid-Induced Secondary Adrenal Insufficiency 

“Opioids are a major cause of suboptimal cortisol levels when taken in high doses after protracted use,” said Dr. Findling. The limited data suggest a prevalence of opioid-induced AI, ranging from 9% to 29% among patients on chronic opioids.2As such, this needs to be considered particularly if a patient presents with signs or symptoms of cortisone deficiency, namely weight loss, myalgia, fatigue, and low blood pressure. He suggested that the HPA function be assessed in these patients by obtaining a morning cortisol level and/or an ACTH stimulation testing, as appropriate

Making judgments about how to treat those patients is also challenging. He said: “In asymptomatic patients, I would not screen for adrenal insufficiency but certainly for any patient with symptoms, this needs to be considered.”

“Low cortisol levels and adrenal insufficiency is an underappreciated problem in many patients, which is due largely to exogenous steroids or opioids,” said Dr. Findling.

Assessing Patients on Steroids, Taking/Using Opioids 

“Any patient who has been exposed to corticosteroid therapy or opioids for a month or longer should probably be assessed for pituitary function followed by appropriate tapering to discontinuation to allow time for their HPA to recover,” he said.

This is easy to undertake—the first step is to obtain a morning cortisol level with a stimulation test (ie, standard adrenocorticotropic hormone (ACTH) test or cosyntropin stimulation).

“Given that many opioid-treated males will have low testosterone, this should be assessed, and if needed, given treatment,” said Dr. Findling, “but these same patients often have low cortisol levels as well, and in the right clinical circumstances that need to be evaluated.”

“I, for example, see a lot of opioid-treated patients on referral, and my personal approach is to treat only the patients who present with symptoms. Whether these patients need hydrocortisone in the morning will depend on their morning cortisol levels,” he said.

Adrenal Insufficiency Is Easily Reversable 

Fortunately, patients with opioid-induced adrenal insufficiency are able to recover rapidly once they are weaned off the drugs. Therefore, a patient who is responsive to being tapered off the narcotics will see their HPA access recover promptly, which is in steep contrast to patients who develop AI following extended treatment with exogenous glucocorticoids.

The HPA in these patients may take months to improve; this is particularly true of patients taking inhaled steroids in addition to oral steroids since the inhaled steroids have a significant effect in suppressing the HPA function..

These patients—unless the inhaled steroids are stopped—may experience long-term adrenal insufficiency that may require adrenal support, particularly during times of sickness or stress.  

Again, it is important to realize that low cortisol levels or frank adrenal insufficiency is common, particularly in patients who are taking steroids as well as in individuals who are taking opioids for a chronic pain condition, or using illicit opioids like fentanyl, heroin, or illegally obtained drugs like oxycodone and hydrocodone, he said.

Key Strategies for Clinicians and their Patients with Adrenal Insufficiency

Other insights shared by Dr. Findling to facilitate diagnosis and management of AI included:1

Aim for optimal dosing for adrenal insufficiency. At present, patients with adrenal insufficiency typically receive conventional glucocorticoid replacement therapy,2 which requires multiple daily injections; this may leave them in a pro-inflammatory state.

Consider providing a treatment schedule that more closely mimics their normal circadian rhythm, allowing for better disease response. For example, “around lunchtime, cortisol naturally rises, so I recommend a second dose at midday to avoid confounding sleep patterns,” said Dr. Findling.

Also, it is good practice to take a sleep history in order to anticipate cortisol peaks and to gain awareness of sleep apnea. Similarly, know when they are planning to travel; I find, for example, that my patients do best when advised to take their morning hydrocortisone to match the morning time at their destination.

Review Sick Day management: Every patient, every visit, at every opportunity.  “Patients should be taught to self-administer an injectable glucocorticoid in order to protect them from an adrenal crisis when they are unable to consume oral hydrocortisone due to nausea and vomiting.  Patients may never use this rescue dose but I tell them it’s like wearing a seatbelt—you use it and haven’t needed it but the one time you might need it, you want to be using it. If the patients are capable of taking oral hydrocortisone, I recommend the 3 X 3 rule for illness: triple your daily dose for the first three days or until you are feeling better. 

Adrenal Crisis is a bigger problem then you think. Adrenal insufficiency should be diagnosed and managed by an endocrinologist to assure that patients are carefully managed. Approximately 5-10% of patients with adrenal insufficiency experience an adrenal crisis each year and 0.5% of patients die. Reviewing sick day management at each visit is important.

Know the Differences in New Diagnostic Assays (LC-MS/MS). The newer, more specific cortisol assays have a tendency to produce lower peak cortisol in response to stimulation with cosyntropin (approximately 14-15 µg/dL [400 nmol/L]) that produces an overestimation of adrenal dysfunction.3  

Plasma ACTH should not be utilized to assess the efficacy of glucocorticoid therapy.

Be Wary of Adrenal Fatigue Products. Ask your patients about their use of any and all supplements, and be prepared to caution against the use of over-the-counter “adrenal support” hormone products to self-treat for a non-existent condition. Studie s have shown that all of these over the counter adrenal support compounds contain thyroid hormone (T3) and may contain potent synthetic glucocorticoids.

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