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9 Articles in Volume 14, Issue #6
Migraine Treatment From A to Z
Alternative Medicine in Chronic Migraine 2014: What Clinicians Need to Know
Hormone Abnormalities in Uncontrolled Chronic Pain Patients: Use of Hormone Profiles
Interpreting Negative Urine Drug Test Results
Case Challenge: Chronic Opioid Use Causing Adrenal Insufficiency
Editor's Memo: Toxic Insurance Plans
Guest Editor's Memo: The Forgotten Patients: Those Who Benefit From Opioid Treatment
Ask the Expert: Multiple Benzo Prescriptions
Ask the Expert: Burning Foot Syndrome

Case Challenge: Chronic Opioid Use Causing Adrenal Insufficiency

Sickle cell anemia patient develops opioid-induced endocrinopathy while on chronic opioid therapy.



A 24-year-old African American female with a history of sickle cell disease was admitted to the hospital for severe pain in her arms and legs bilaterally, which was typical of her previous episodes of sickle cell crisis. Since the age of 12, the patient has had more than 20 sickle cell attacks a year. She has been typically hospitalized for 5 to 14 days during each attack.
To manage her symptoms, she was treated with opioids, fluids, and, in rare cases of infection, with antibiotics. Given the severity of her disease, her primary care physician started her on a course of extended-release morphine sulfate (45 mg twice a day) when she was 21. During this hospital admission, the patient had atypical symptoms that included hypotension, nausea, and vomiting. In addition, she stated that she had not menstruated in 3 months.

Physical Examination

Her initial vital signs on admission to the hematology floor were: blood pressure, 91/54 mmHg; pulse, 98 beats per minute; respiratory rate, 18 breaths per minute; afebrile; and oxygen saturation of 99%. She was in mild distress due to pain. Her lungs were clear to auscultation, her abdomen was soft and nontender, and her heart had a regular rate and rhythm. She had tenderness to palpation in all 4 extremities. An initial work up included a complete blood count (CBC), complete metabolic panel (CMP), chest x-ray, urinalysis, and blood cultures.

The results of the patient’s CBC displayed a white blood cell count of 11,000 cells/mcL, hemoglobin of 8.2 g/dL, hematocrit of 24%, and platelet (thrombocyte) count of 484,000/mcL. Her CMP and chest x-ray were unremarkable. Blood glucose was 84 mg/dL. Blood cultures were negative after 2 days, and urinalysis was unremarkable.

Prior Treatment

During the patient’s sickle cell crises, she typically receives intravenous hydromorphone (1 mg every 2 h) until the pain subsides over a course of 5 to 7 days and she is typically sent home with oral hydromorphone for 1 to 2 weeks. The patient reports that the extended-release morphine sulfate 45 mg twice a day shortens her hospital stay. The patient reports that prior to starting morphine sulfate, she would be in the hospital for approximately 2 weeks during each sickle cell crisis.

Hospital Course

During her latest hospitalization, the patient was given fluids, antiemetics, and analgesics. Despite receiving fluid for 2 days, she continued to have persistent hypotension and vomiting.

Given the patient’s low blood pressure, an adrenal insufficiency work up was ordered. A morning cortisol level was taken, and came back at 4.2 mcg/dL (normal 5-23 mcg/dL); the adrenalcorticotrophic hormone (ACTH) level was 11 pg/mL (normal 9-52 pg/mL), and she had a normal response to a consyntropin stimulation test. A brain MRI was performed, which was unremarkable and displayed a normal pituitary gland. Given this data, a diagnosis of secondary adrenal insufficiency was made. Other causes of secondary adrenal insufficiency were ruled out, at which point the cause was attributed to chronic use of opioids—morphine sulfate and hydromorphone.


The patient was started on intravenous hydrocortisone (100 mg every 6 h) and her symptoms resolved. She was able to be discharged and was prescribed oral hydrocortisone (20 mg in morning and 10 mg at night). In addition, she was given hydromorphone 1 mg to take as needed and morphine sulfate 15 mg twice a day. Within 3 months of treatment, her menstrual cycle returned. Six months later, she was successfully weaned off the long-acting opioids. She continued having sickle cell crises during this time and was treated with intravenous fluids and short-acting opioids during her attacks.


Opioid endocrinopathy (OE) has been documented as early as the 18th century by Charles Alexander Bruce, an English explorer who was the father of the tea industry in India; Bruce stated that opium is causing the “feeble opium-smokers of Assam” to be “more effeminate than women.”1 With the increased use of opioids for chronic pain, the incidence of opioid endocrinopathy is rising. However, it remains relatively unknown among physicians. OE is a dysfunction in the hypothalamic-pituitary tracts affecting the sex and adrenal hormones. OE can produce a myriad of symptoms (Table 1). The symptoms can be subtle, which makes it difficult to diagnose without screening and diagnostic testing.

The hypothalamic-pituitary-gonadal tract is responsible for producing sex hormones in humans. The hypothalamus releases gonadotropin-releasing hormone (GnRH), which targets the pituitary gland, releasing luteinizing hormone (LH) and follicle-stimulating hormone (FSH). LH and FSH stimulate the testes and ovaries to produce testosterone and estrogen, respectively. Opioids bind to receptors on the hypothalamus and pituitary, inhibiting the release of GnRH and LH (Figure 1).2,3

As a result, hypogonadism can be seen in both males and females—producing the symptoms described in Table 1. One study has shown that naloxone, an opiate antagonist, was found to increase LH and increase testosterone days later.3 In rat studies, opioids have a direct effect on the testes, causing decreased levels of testosterone and testicular interstitial fluid.4

The hypothalamic-pituitary-adrenal (HPA) axis also is affected by opioids as demonstrated by this case. Opioids inhibit the release of corticotrophin-
releasing hormone from the hypothalamus, preventing the release of ACTH from the anterior pituitary gland.2 As a result, cortisol—a hormone responsible for homeostasis of the stress response, blood sugar, and blood pressure—is decreased. Also, the HPA axis is responsible for producing dehydro-
epiandrosterone (DHEA), a precursor for estrogen and testosterone. Opioids typically do not affect cortisol levels, although there have been case reports and studies showing that opioids suppress cortisol.5-10

Current Case

The case presented is that of a young woman with sickle cell anemia who was on chronic opioids. She was found to have opioid-induced endocrinopathy that affected her hypothalamic pituitary adrenal tract and caused a decrease in cortisol. Her primary care physician prescribed extended-release morphine sulfate to manage the pain of her numerous sickle cell attacks (20 per year).

Her HPA axis was disturbed as a result of her being on 90 mg of morphine equivalents along with intermittent hydromorphone over a 3-year period. Her cortisol level was suppressed, which affected her ability to respond to fluids given for hypotension. The patient’s amenorrhea could be caused by either suppression of the HPG tract or the inability of the HPA tract to produce DHEA. We did not get any hormonal testing, such as a LH, FSH, estradiol, testosterone, or DHEA sulfate level, because she had a great response to treatment.

There is little research and no guidelines related to hormonal testing in women with opioid-induced endocrinopathy. Given the patient’s diagnosis of adrenal insufficiency, we decided to treat her with hydrocortisone. We were not certain hydrocortisone would correct the patient’s amenorrhea, but it did. The other option we were considering was hormonal replacement therapy if hydrocortisone did not correct her amenorrhea. Her blood pressure responded rapidly to hydrocortisone and we weaned her off the extended-release morphine sulfate. She continued to be treated with hydrocortisone when she was discharged. Over the next 6 months, her menstruation returned while she was taking hydrocortisone. After 4 months of compliance, she discontinued the hydrocortisone on her own because she experienced weight gain and malaise. Her AM cortisol level was 9.9 mcg/dL (normal) 6 months after hospitalization. She continued to remain off long-acting opioids and had 3 sickle cell attacks with shorter stays in the hospital. Her opioid requirement was notably lower during the latest sickle cell attacks. A possible explanation for the need for the lower dose of opioids could be the cortisol’s ability to effectively bind opioids and maintain the blood-brain barrier.11 It has been recommended that cortisol level should be monitored every 90 to 120 days in patients with low or high cortisol levels.5 We are continuing to follow the patient’s cortisol level every 4 months.


This is case of a woman taking long-term opioid therapy that adversely affected the HPA axis. There are no published guidelines for treatment of hypogonadism and hypoadrenalism caused by opioid-induced endocrinopathy. Opioid-induced adrenal insufficiency should be clinically suspected in patients taking 100 mg of morphine equivalence for longer than 1 year if clinical symptoms and signs are present.12 Clinical judgment should be used for diagnostic work up and treatment. Treatment approaches can include switching opioids, weaning opioids if possible, interventional pain techniques, and, if these fail, steroid and hormonal supplements should be given to patients after explaining risks and benefits.

Last updated on: February 29, 2016
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