Abstract

BACKGROUND: Chronic opioid use may lead to adrenal insufficiency due to central suppression of the hypothalamic-pituitary-adrenal axis. Opioid induced adrenal insufficiency (OIAI) is likely under-recognized and its prevalence is unclear. OBJECTIVE: To determine the prevalence of OIAI in patients taking opioids for chronic pain and to identify predictors of OIAI. METHODS: A prospective study of patients admitted to the Pain Rehabilitation Center (PRC) at an academic medical center completed between 2016 and 2018. Inclusion criteria were: 1) age ≥18 years, 2) intermittent or continuous opioid use of at least 90 days, 3) am cortisol measurement on admission. Exclusion criteria were: 1) known pituitary or adrenal dysfunction, 2) exogenous glucocorticoid use within 3 months. Each patient’s opioid daily dose was converted into a morphine mg equivalent (MME). All patients had a functional 5-minute walk test and measurements of quality of life on admission to the PRC. Diagnosis of OIAI was based on the endocrine evaluation. RESULTS: One hundred sixty-two patients (median age of 53.5 years (range 21-84), 67% women, 95 % Caucasian) met inclusion criteria. Patients used opioids daily (141, 87%) or as needed (21, 13.0%) at a median MME of 30 mg (3-840), median duration of 60 months (3-360). In addition to morning cortisol (CORT), 112 (69.1%) patients had measurements of corticotropin (ACTH) and 106 (65.4%) - dehydroepiandrosterone sulfate (DHEAS). CORT was directly correlated with both DHEAS (p=0.04) and ACTH (p<0.0001). Overall, low concentrations of CORT (<7mcg/dl), ACTH (<10pg/mL) and DHEAS (<25mcg/dL) were observed in 17%, 14% and 21% of patients, respectively. Patients with either low CORT or ACTH had a lower performance on the 5-minute walk test (1080 feet (range 175-1899) vs 1261 feet (361-2008), p=0.04). No significant differences were found on measures of quality of life. OIAI was confirmed through endocrine evaluation in 8 (5%) patients (7 women, median age 53 years (48-76)). At the time of admission, patients with OIAI had median CORT of 5 mcg/dl (1-9.9), ACTH of 11.5pg/mL (5-15), and DHEAS of 17mcg/dL (15-22). MME of patients with OIAI was higher than patients without OIAI (median 110 (20-392) vs. 30 (1-840), p=0.01). No patient taking opioid at <MME of 20 mg/day developed OIAI (sensitivity of 100% for MME>20 mg), however specificity of MME cutoff >20 mg to predict OIAI development was only 34%. After opioid discontinuation, 3/8 patients recovered adrenal function when reassessed at 14 months (5-14). CONCLUSION: The prevalence of OIAI based on the endocrine evaluation was 5%, with MME being the only predictor for OIAI development. Patients on MMED of 20 mg and above should be monitored for OIAI. Abnormalities in the hypothalamic-pituitary-adrenal axis were frequent, affecting 14-21% of patients taking opioids, possibly contributing to patients’ symptoms, physical performance and well-being.

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