A 60-year-old woman with metastatic breast cancer using morphine extended release 30 mg twice daily and as-needed oxycodone for cancer-related pain presents with fever, dyspnea, and productive cough for 2 days. She also notes several weeks of fatigue, nausea, weight loss, and orthostatic lightheadedness. She is found to have pneumonia and is admitted for intravenous antibiotics. She remains borderline hypotensive after intravenous fluids and the hospitalist suspects opioid-induced adrenal insufficiency (OIAI).
How is OIAI diagnosed and managed?
Brief overview of issue
In the United States, 5.4% of the population is currently using long-term opioids.1 Patients using high doses of opioids for greater than 3 months are 40%-50% more likely to be hospitalized than those on a lower dose or no opioids.2 Hospitalists frequently encounter common opioid side effects such as constipation, nausea, and drowsiness, but may be less familiar with their effects on the endocrine system. Chronic, high-dose opioids can suppress the hypothalamic-pituitary-adrenal (HPA) axis and cause secondary, or central, adrenal insufficiency (AI).1
Recognition of OIAI is critical given the current opioid epidemic and life-threatening consequences of AI in systemically ill patients. While high-dose opioids may acutely suppress the HPA axis,3 OIAI is more commonly associated with long-term opioid use.4 The prevalence of OIAI among patients receiving long-term opioids ranges from 8.3% to 29%. This range reflects variations in opioid dose, duration of use, and different methods of assessing the HPA axis.1,4 When screening for HPA axis suppression in subjects taking chronic opioids, Lamprecht and colleagues found a prevalence of 22.5%.5 In comparison, Gibb and colleagues found the prevalence of secondary AI to be 8.3% in patients enrolled in a chronic pain clinic.6 Despite the high prevalence on biochemical screening, the clinical significance of OIAI is less clear. Clinical AI and adrenal crisis among patients on opioids are less frequent and mostly limited to case reports.7,8 In one retrospective cohort, one in 40 patients with OIAI presented with adrenal crisis during a hospitalization for viral gastroenteritis.9
With this prevalence, one would expect to diagnose OIAI more commonly in hospitalized patients. A concerning possibility is that this diagnosis is underrecognized because of either a lack of knowledge of the disease or the clinical overlap between the nonspecific symptoms of AI and other diagnoses. In patients reporting symptoms suggestive of OIAI, the diagnosis was delayed by a median of 12 months.9 The challenge for the hospitalist is to consider OIAI, even among patients with common infections such as pneumonia, viral gastroenteritis, or endocarditis who present with these nonspecific symptoms, while also avoiding unnecessary testing and treatment with glucocorticoids.
Overview of the data
Opiates and opioids exert their physiologic effect through activation of the mu, kappa, and delta receptors. These receptors are located throughout the body, including the hypothalamus and pituitary gland.4 Activation of these receptors results in tonic inhibition of the HPA axis and results in central AI.4 Central AI is characterized by a low a.m. cortisol, low adrenocorticotropic hormone (ACTH), and low dehydroepiandrosterone sulfate (DHEAS) levels.1,4 The low ACTH is indicative of central etiology. This effect of opioids is likely dose dependent with patients using more than 60 morphine-equivalent daily dose at greater risk.1,5
Unexplained or unresolved fatigue, musculoskeletal pain, nausea, vomiting, anorexia, abdominal pain, and orthostatic hypotension in a patient on chronic opioids should prompt consideration of OIAI.9 Once suspected, an 8 a.m. cortisol, ACTH level, and DHEAS level should be ordered. Because of the diurnal variation of cortisol levels, 8 a.m. values are best validated for diagnosis.10 While cutoffs differ, an 8 a.m. cortisol less than 5 mcg/dL combined with ACTH less than 10 pmol/L, and DHEAS less than 50 mcg/dL are highly suggestive of OIAI. Low or indeterminate baseline a.m. cortisol levels warrant confirmatory testing.4,10 While the insulin tolerance test is considered the gold standard, the high dose (250 mcg) cosyntropin stimulation test (CST) is the more commonly used test to diagnose and confirm AI. A CST peak response greater than 18-20 mcg/dL suggests an intact HPA axis (see Figure 1).10 This testing will diagnose central AI, but is not specific for OIAI. Other causes of central AI such as exogenous steroid use, pituitary pathology, and head trauma should be considered before attributing AI to opioids (see Table 1).4
The abnormal CST in central AI is from chronic ACTH deficiency and lack of adrenal stimulation resulting in adrenal atrophy. Adrenal atrophy leaves the adrenal glands incapable of responding to exogenous ACTH. This process takes several weeks; therefore, those with ACTH suppression caused by recent high-dose opioid use or subacute pituitary injury may have an indeterminate or normal cortisol response to high-dose exogenous ACTH.4 Even in the setting of a normal CST, there may remain uncertainty in the diagnosis of OIAI. When evaluating for central AI, the sensitivity and negative likelihood ratio of the CST are only 0.64 and 0.39, respectively.4 In the same cohort of 40 patients with OIAI, 11 patients had a normal CST.9 The low-dose (1 mcg) CST may increase the sensitivity, but the use of this test is limited because of technical challenges.1 Endocrinology consultation can assist when the initial diagnostic and clinical presentation is unclear.
To manage a patient on opioid therapy who has laboratory data consistent with central AI, the clinician must weigh the severity of symptoms, probability of opioid weaning, and risks associated with glucocorticoid treatment. Patients presenting with acute adrenal crisis, hypotension, or critical illness should be managed with intravenous steroid replacement per existing guideline recommendations.10,11
Patients with mild symptoms of nausea, vomiting, or orthostatic symptoms that resolve with treatment of their admitting diagnosis but who have evidence of an abnormal HPA axis should be considered for weaning opioid therapy. Evidence suggests that OIAI is reversible with reduction and cessation of chronic opioid use.4,9 These patients may not need chronic steroid replacement; however, they should receive education on the symptoms of AI and potentially rescue steroids for home use in the setting of severe illness. Patients with OIAI admitted for surgical procedures should be managed in accordance with existing guidelines for perioperative stress dosing of glucocorticoids for AI.
Those with persisting symptoms of OIAI and an abnormal HPA axis require endocrinology consultation and glucocorticoid replacement. There is limited evidence that suggests low dose steroid replacement in patients with OIAI can improve subjective perception of bodily pain, activity level, and mood in chronic opioid users.9 Li and colleagues found that 16 of 23 patients experienced improvement of symptoms on glucocorticoids, and 15 were able to discontinue opioids completely.9 The authors speculated that the improvement in fatigue and musculoskeletal pain after steroid replacement is what allowed for successful opioid weaning. Seven of 10 of these patients with available follow-up had recovery of the HPA axis during the follow-up period.9 In central AI, doses as low as 10-20 mg/day of hydrocortisone have been used.10,11 Hospitalists should educate patients on recognizing symptoms of AI, as this low dose may not be sufficient to prevent adrenal crisis.
All patients with evidence of abnormalities in the HPA axis should receive a Medic-Alert bracelet to inform other providers of the possibility of adrenal crisis should a major trauma or critical illness render them unconscious.4,10 Since OIAI is a form of central AI, mineralocorticoid replacement is not generally necessary.11 Endocrinology follow-up can help wean steroids as the HPA axis recovers after weaning opioid therapy. Recognizing and diagnosing OIAI can identify patients with untreated symptoms who are at risk for adrenal crisis, improve communication with patients on benefits of weaning opioids, and provide valuable patient education and safe transition of care.