Suboxone and Adrenal Insufficiency
Suboxone (buprenorphine/naloxone) can cause adrenal insufficiency through suppression of the hypothalamic-pituitary-adrenal (HPA) axis, and patients with pre-existing adrenal insufficiency taking Suboxone should maintain their standard glucocorticoid replacement doses without routine increases, though they must remain vigilant for signs of adrenal crisis. 1, 2
Mechanism of Opioid-Induced Adrenal Insufficiency
Buprenorphine, like other opioids, inhibits the secretion of adrenocorticotropic hormone (ACTH) and cortisol, which can lead to clinically significant adrenal suppression, particularly with chronic use exceeding one month. 1
The FDA drug label explicitly states that "cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use," with presentation including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. 1
Opioid-induced adrenal insufficiency (OIAI) occurs in up to 29% of chronic opioid users through HPA axis suppression, representing a significant but underrecognized complication. 3, 4
Clinical Evidence Specific to Buprenorphine
A documented case report from 2024 identified Suboxone (buprenorphine/naloxone) as the culprit of newly diagnosed adrenal insufficiency in a 33-year-old male patient, confirming that buprenorphine specifically can cause this endocrinopathy. 2
In a retrospective study of 40 patients with OIAI, the minimum daily morphine milligram equivalent (MME) dose associated with adrenal insufficiency was 60 mg, with a median dose of 105 mg and median duration of 60 months. 5
Patients with OIAI reported fatigue (73%), musculoskeletal pain (53%), and weight loss (53%) for a median of 12 months prior to diagnosis, and only 7.5% were identified through proactive case detection, highlighting the need for high clinical suspicion. 5
Management in Patients with Pre-Existing Adrenal Insufficiency
Standard Replacement Dosing Remains Unchanged
Patients with established adrenal insufficiency taking Suboxone should continue their standard physiologic replacement doses of hydrocortisone (15-25 mg daily in divided doses) or equivalent glucocorticoid without routine dose increases. 6, 7
There is no evidence that buprenorphine increases glucocorticoid metabolism or clearance that would necessitate higher replacement doses in patients already on adequate replacement therapy. 1
Critical Monitoring Requirements
Monitor closely for symptoms suggesting inadequate replacement or impending adrenal crisis: worsening fatigue, orthostatic hypotension, weight loss, nausea, vomiting, or hypoglycemia. 1, 5
Check serum sodium and potassium levels periodically, as hyponatremia is common in adrenal insufficiency and may worsen with opioid use. 6
Patients must be educated on stress dosing protocols: doubling the usual hydrocortisone dose during minor illness and using emergency injectable hydrocortisone (100 mg IM/IV) for vomiting, severe illness, or inability to take oral medication. 6, 7
Stress Dosing Protocols Remain Standard
For major surgery, administer hydrocortisone 100 mg IV at induction, followed by 100 mg every 6 hours until the patient can take oral medications, then double the oral dose for 24-48 hours before tapering to baseline. 6
For minor surgery or dental procedures, give 100 mg hydrocortisone IM just before anesthesia, then double the oral dose for 24 hours. 6
During labor and vaginal delivery, administer 100 mg hydrocortisone IM at onset of active labor, then double the oral dose for 24-48 hours postpartum. 6
Diagnostic Considerations for New-Onset OIAI
If adrenal insufficiency is suspected in a patient taking Suboxone without prior diagnosis, confirm with morning cortisol (<5 μg/dL is diagnostic, >15 μg/dL excludes it) and ACTH levels, or perform cosyntropin stimulation testing (peak cortisol <500 nmol/L or <18 μg/dL is diagnostic). 6, 8
Traditional diagnostic assays have not been extensively validated in the OIAI population, and interpretation may be complicated by ongoing opioid use. 8
Treatment of Newly Diagnosed OIAI
If adrenal insufficiency is diagnosed in a patient taking Suboxone, treat immediately with physiologic replacement doses of hydrocortisone and attempt to wean the opioid to allow HPA axis recovery. 1, 5
In the study of 40 OIAI patients, 70% experienced symptom improvement with glucocorticoid replacement, and among those who tapered or discontinued opioids, 70% recovered adrenal function. 5
Continue corticosteroid treatment until adrenal function recovers, which typically requires periodic retesting (every 3 months) after opioid cessation or dose reduction. 1, 8
Critical Safety Considerations
All patients with adrenal insufficiency taking Suboxone should wear medical alert identification, carry a steroid emergency card, and have access to emergency injectable hydrocortisone. 6, 7
Adrenal crisis occurs at a rate of 6-8 per 100 patient-years in those with adrenal insufficiency and carries significant mortality risk (2.19-fold increase for men, 2.86-fold for women). 7, 9
Never reduce or withdraw steroid supplementation while a patient is febrile or acutely ill, as persistent pyrexia may be attributed to infection but could represent inadequate glucocorticoid coverage. 6
Common Pitfalls to Avoid
Do not assume that opioid-induced symptoms (fatigue, nausea, musculoskeletal pain) exclude adrenal insufficiency—these symptoms overlap significantly and require biochemical evaluation. 8, 5
Avoid attributing all symptoms to the underlying pain disorder or opioid side effects without considering OIAI, as only 7.5% of cases are identified proactively. 5
Do not discontinue fludrocortisone in patients with primary adrenal insufficiency, as hydrocortisone alone does not provide adequate mineralocorticoid activity at physiologic doses. 6, 9
Healthcare providers, particularly non-endocrinologists, demonstrate significant knowledge gaps regarding opioid-induced endocrinopathies, with only 19% reporting comfort with opioid side effects and 68% of non-endocrine providers identifying adrenal insufficiency as a known complication. 3