COMMENTARY

Opioid-Induced Adrenal Insufficiency for the Hospitalist

John M. Cunningham, MD, Anna Maria Muñoa, MD, and Kimberly A. Indovina, MD

October 27, 2021

Case

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

Dr John Cunningham

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

Dr Anna Maria Muñoa

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

Dr Kimberly Indovina

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

Figure 1: Diagnostic Pathway of OIAI

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.

Table 1: Causes of Central Adrenal Insufficiency

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.

Table 2: Management of Adrenal Insufficiency

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.

Application of the Data to the Original Case

To make the diagnosis of OIAI, 8 a.m. cortisol, ACTH, and DHEAS should be obtained. Her cortisol was less than 5 mcg/dL, ACTH was 6 pmol/L and DHEAS was 30 mcg/dL. A high dose CST was performed with 30-minute and 60-minute cortisol values of 6 mcg/dL and 9 mcg/dL, respectively. The abnormal CST and low ACTH indicate central AI. She should undergo testing for other etiologies of central AI, such as a brain MRI and pituitary hormone testing, before confirming the diagnosis of OIAI.

The insufficient adrenal response to ACTH in the setting of infection and hypotension should prompt glucocorticoid replacement. Tapering opioids could result in recovery of the HPA axis, though may not be realistic in this patient with chronic cancer-related pain. If the patient is at high risk for adverse effects of glucocorticoids, repeat testing of the HPA axis in the outpatient setting can assess if the patient truly needs steroid replacement daily rather than only during physiologic stress. The patient should be given a Medic-Alert bracelet and instructions on symptoms of AI and stress dosing upon discharge.

Bottom Line

OIAI is underrecognized because of central adrenal insufficiency. Knowing its clinical characteristics, diagnostic pathways, and treatment options aids in recognition and management.

Cunningham, Munoa, and Indovina are based in the division of hospital medicine at Denver Health and Hospital Authority.

References

1. Donegan D. Opioid induced adrenal insufficiency: What is new? Curr Opin Endocrinol Diabetes Obes. 2019 Jun;26(3):133-8. doi: 10.1097/MED.0000000000000474.

2. Liang Y and Turner BJ. Opioid risk measure for hospitalization. J Hosp Med. 2015 July;10(7):425-31. doi: 10.1002/jhm.2350.

3. Policola C et al. Adrenal insufficiency in acute oral opiate therapy. Endocrinol Diabetes Metab Case Rep. 2014;2014:130071. doi: 10.1530/EDM-13-0071.

4. Donegan D and Bancos I. Opioid-induced adrenal insufficiency. Mayo Clin Proc. 2018 July;93(7):937-44. doi: 10.1016/j.mayocp.2018.04.010.

5. Lamprecht A et al. Secondary adrenal insufficiency and pituitary dysfunction in oral/transdermal opioid users with non-cancer pain. Eur J Endocrinol. 2018 Dec 1;179(6):353-62. doi: 10.1530/EJE-18-0530.

6. Gibb FW et al. Adrenal insufficiency in patients on long-term opioid analgesia. Clin Endocrinol (Oxf). 2016 June;85(6):831-5. doi:10.1111/cen.13125.

7. Abs R et al. Endocrine consequences of long-term intrathecal administration of opioids. J Clin Endocrinol Metab. 2000 June;85(6):2215-22. doi: 10.1210/jcem.85.6.6615.

8. Tabet EJ et al. Opioid-induced hypoadrenalism resulting in fasting hypoglycaemia. BMJ Case Rep. 2019 Dec 11;12(12):e230551. doi: 10.1136/bcr-2019-230551.

9. Li T et al. Clinical presentation and outcomes of opioid induced adrenal insufficiency. Endocr Pract. 2020 Nov;26(11):1291-1297. doi: 10.4158/EP-2020-0297.

10. Grossman AB. Clinical Review: The diagnosis and management of central hypoadrenalism. J Clin Endocrinol Metab. 2010 Nov;95(11):4855-63. doi: 10.1210/jc.2010-0982.

11. Charmandari E et al. Adrenal insufficiency. Lancet. 2014 June 21;383(9935):2152-67. doi: 10.1016/S0140-6736(13)61684-0.

Key Points

  • Opioids can cause central adrenal insufficiency because of tonic suppression of the HPA axis. This effect is likely dose dependent, and reversible upon tapering or withdrawal of opioids.

  • The prevalence of biochemical OIAI in chronic opioid users of 8%-29% clinical AI is less frequent but may be underrecognized in hospitalized patients leading to delayed diagnosis.

  • Diagnosis of central adrenal insufficiency is based upon low 8 a.m. cortisol and ACTH levels and/or an abnormal CST. OIAI is the likely etiology in patients on chronic opioids for whom other causes of central adrenal insufficiency have been ruled out.

  • Management with glucocorticoid replacement is variable depending on clinical presentation, severity of HPA axis suppression, and ability to wean opioid therapy. Patient education regarding symptoms of AI and stress dosing is essential.

Additional Reading

Grossman AB. Clinical Review: The diagnosis and management of central hypoadrenalism. J Clin Endocrinol Metab. 2010 Nov;95(11):4855-63. doi: 10.1210/jc.2010-0982.

Donegan D and Bancos I. Opioid-induced adrenal insufficiency. Mayo Clin Proc. 2018 July;93(7):937-44. doi: 10.1016/j.mayocp.2018.04.010.

Li T et al. Clinical presentation and outcomes of opioid induced adrenal insufficiency. Endocr Pract. 2020 Nov;26(11):1291-7. doi: 10.4158/EP-2020-0297.

Quiz

A 55-year-old man with chronic back pain, for which he takes a total of 90 mg of oral morphine daily, is admitted for pyelonephritis with fever, nausea, vomiting, dysuria, and abdominal pain. He is febrile and tachycardic on presentation, but his vitals quickly normalize after hydration and antibiotics. About 48 hours into his hospitalization his fevers, dysuria, and abdominal pain have resolved, but he has persistent nausea and headaches. On further questioning, he also reports weight loss and fatigue over the past 3 weeks. He is found to have a morning cortisol level less than 5 mcg/dL, as well as low levels of ACTH and DHEAS. OIAI is suspected.

Which of the following is true about management?

A. Glucocorticoid replacement therapy with oral hydrocortisone should be considered to improve his symptoms.

B. Tapering off opioids is unlikely to resolve his adrenal insufficiency.

C. Stress dose steroids should be started immediately with high-dose intravenous hydrocortisone.

D. Given high clinical suspicion for OIAI, further testing for other etiologies of central adrenal insufficiency is not recommended.

Explanation of Correct Answer

The correct answer is A. This patient’s ongoing nonspecific symptoms that have persisted despite treatment of his acute pyelonephritis are likely caused by adrenal insufficiency. In a symptomatic patient with OIAI, treatment with oral hydrocortisone should be considered to control symptoms and facilitate tapering opioids. Tapering and stopping opioids often leads to recovery of the HPA axis and resolution of the OIAI. Tapering opioids should be considered a mainstay of therapy for OIAI when clinically appropriate, as in this patient with chronic benign pain. Stress dose steroids are not indicated in the absence of critical illness, adrenal crisis, or major surgery. OIAI is a diagnosis of exclusion, and patients should undergo workup for other causes of secondary adrenal insufficiency.

This article originally appeared on The Hospitalist, an official publication of the Society of Hospital Medicine.

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