The Biochemical Diagnosis of Adrenal Insufficiency With Modern Cortisol Assays

Reappraisal in the Setting of Opioid Exposure and Hospitalization

Caitlin Colling; Lisa Nachtigall; Beverly M. K. Biller; Karen K. Miller


Clin Endocrinol. 2022;96(1):21-29. 

In This Article

Abstract and Introduction


Objective: We aimed to (1) examine the diagnosis of opioid-induced adrenal insufficiency, and (2) investigate the diagnostic value of a morning cortisol <83 nmol/L (3 μg/dl) for the diagnosis of adrenal insufficiency, using newer more specific cortisol assays and cut-offs.

Design: Retrospective study (5/2015–10/2020).

Participants: Cohort 1 (N = 75): adults who underwent cosyntropin stimulation testing and opioid exposure for >30 days. Cohort 2 (N = 854): adults, with or without opioid exposure, who had a morning cortisol level measured the same day as stimulation testing.

Measurements: Peak cortisol during cosyntropin stimulation testing. Sensitivity and specificity of morning serum cortisol for adrenal insufficiency.

Results: The prevalence of adrenal insufficiency in patients with chronic opioid exposure who underwent cosyntropin stimulation testing was 4.0% using a cortisol cutoff of <405 nmol/L (14.7 μg/dl) versus 19% using the traditional cutoff of <500 nmol/L (18.1 μg/dl). For hospitalized patients with and without opioid-exposure, 14 of 22 (64%) patients with morning cortisol levels of <83 nmol/L (3 μg/dl) passed cosyntropin stimulation testing. A morning cortisol level of <348 nmol/L (12.6 μg/dl) had 100% sensitivity (95% confidence interval: 84.5%–100%) for the diagnosis of adrenal insufficiency.

Conclusion: Applying a cutoff of <405 nmol/L (14.7 μg/dl), opioid-induced adrenal insufficiency is rare. Nearly 1 out of 6 patients would be reclassified as having adrenal insufficiency applying the guideline-recommended cutoff of <500 nmol/L (18.1 μg/dl). Serum morning cortisol <83 nmol/L (3 μg/dl) is not a valid diagnostic test for adrenal insufficiency in hospitalized patients, whether or not receiving opioids.


Opioids are among the most commonly prescribed medications, and opioid use disorder is a major public health problem affecting two million people in the United States, with an estimated 10.3 million Americans misusing prescription opioids in 2018.[1–3] In addition to the risk of overdose and increased risk of viral, bacterial and fungal infections,[4–6] opioid use has been estimated to cause adrenal insufficiency in 8%–29% of chronically exposed patients.[7–10]

The interaction between morphine and the hypothalamic–pituitary–adrenal (HPA) axis has been recognized since the 1920s.[11] Subsequent studies identified a suppressive effect of opioids and endorphins on adrenocorticotropin (ACTH), CRH, AVP and cortisol.[12–14] However, little is known about risk factors for development of adrenal insufficiency in patients on long-term opioids. A study of 40 patients with noncancer pain treated with opioids identified an association between higher median morphine-equivalent daily dose (MEDD) and risk for adrenal insufficiency,[15] but this was not reproduced in a later study of 102 patients with noncancer pain that found an association only between cumulative opioid exposure and adrenal insufficiency.[7]

Complicating the diagnosis of adrenal insufficiency is accumulating evidence that assay-specific cortisol cutoffs should be used for the diagnosis to reflect the increased specificity of modern cortisol assays. In a study comparing a polyclonal antibody competitive immunoassay, monoclonal antibody immunoassay, competitive binding immunoenzymatic assay and liquid chromatography–tandem mass spectrometry (LC-MS/MS), 60-min post-cosyntropin cortisol cutoffs between 375 and 405 nmol/L (13.7–14.7 μg/dl) were recommended, depending on the assay.[16]

Moreover, the optimal approach to diagnosis of adrenal insufficiency in patients receiving opioids is unknown. Opioids have been shown to disrupt cortisol circadian rhythm and acutely suppress cortisol levels. For example, in healthy patients, plasma cortisol levels are reduced within 60 min of intravenous morphine exposure, and patients with heroin addiction have been shown to have abnormal circadian rhythms.[17,18] Relying on a morning cortisol level for the diagnosis of adrenal insufficiency requires an intact circadian rhythm with the expected peak daily cortisol 30–120 min after awakening.[19] It is unknown whether the acute effects of opioids on cortisol levels or a disrupted circadian rhythm alter the validity of a serum morning cortisol in the diagnosis of adrenal insufficiency. Therefore, although Endocrine Society guidelines, co-sponsored by the European Society of Endocrinology, recommend measuring a morning cortisol level as the first-line test for diagnosing adrenal insufficiency, with cosyntropin stimulation testing indicated only in patients with indeterminant morning cortisol levels,[20] it is unclear whether this is a valid strategy in patients receiving opioids.

Determining whether patients prescribed chronic opioids are at high risk for adrenal insufficiency is essential for understanding when to screen patients. This is especially true in a group of patients that is prone to experience overlapping signs and symptoms with adrenal insufficiency due to the side effects of opioids themselves and underlying conditions for which opioids are prescribed. In addition, determining whether recommended diagnostic approaches are valid in this group of patients is critical to preventing under- and over-prescribing of glucocorticoids. We therefore investigated the prevalence of adrenal insufficiency in patients receiving chronic opioids using an assay-specific cortisol cutoff (cohort one) and evaluated the diagnostic utility of morning serum cortisol in a separate cohort of patients (who had been exposed or had not been exposed to opioids) who both underwent cosyntropin stimulation testing and had a morning cortisol level collected (cohort two).