What is Prednisone (corticosteroid) withdrawal syndrome?

Prednisone Withdrawal Syndrome

Prednisone withdrawal syndrome occurs when patients experience symptoms resembling adrenal insufficiency despite adequate cortisol levels, typically following abrupt discontinuation or rapid tapering of corticosteroid therapy, and requires gradual dose reduction to prevent this potentially serious complication. 1

Definition and Clinical Presentation

• Prednisone withdrawal syndrome manifests as a constellation of symptoms that can mimic the underlying disease being treated or present as signs of adrenal insufficiency when corticosteroids are rapidly reduced or stopped 2
• Common symptoms include weakness, fatigue, loss of appetite, weight loss, nausea, vomiting, diarrhea, abdominal pain, myalgia, arthralgia, and malaise 2, 3
• The syndrome can occur even when laboratory tests show acceptable cortisol levels, suggesting mechanisms beyond simple adrenal suppression 3
• Psychiatric symptoms may also occur, ranging from emotional lability and mood swings to severe depression 1

Pathophysiology

• The primary mechanism involves hypothalamic-pituitary-adrenal (HPA) axis suppression due to exogenous corticosteroid use, which can persist for up to 12 months after discontinuation of therapy 2, 1
• Development of tolerance to glucocorticoids may play a role, with mediators including interleukin-6, corticotrophin-releasing hormone, vasopressin, and central noradrenergic and dopaminergic systems 3
• Adaptive changes in receptor sensitivity and density occur during prolonged corticosteroid use, contributing to withdrawal symptoms when the medication is reduced 4

Risk Factors

• Duration of corticosteroid therapy is the strongest predictor of withdrawal syndrome, with longer use (especially beyond 3 weeks) significantly increasing risk 5
• Higher doses of corticosteroids (particularly >10 mg prednisone daily) increase the likelihood and severity of withdrawal symptoms 6
• Type of corticosteroid matters - dexamethasone appears to cause more severe withdrawal symptoms than prednisone (75% vs 51.4% of patients) 7
• Individual susceptibility varies, with some patients developing dependency patterns that can persist for years 8

Prevention and Management

• Gradual tapering of corticosteroids is essential to prevent withdrawal syndrome, with dose reductions of approximately 2.5 mg per month until the lowest effective dose is reached 2
• For patients on long-term therapy who have relapsed after previous withdrawal attempts, two main strategies are recommended:
  1. Low-dose prednisone maintenance: Using the lowest dose possible (median 7.5 mg daily) to prevent symptoms and maintain serum aminotransferase levels below 5-fold normal 2
  2. Indefinite azathioprine maintenance: Substituting azathioprine (2 mg/kg daily) for prednisone after induction of remission, then gradually withdrawing prednisone 2
• All patients receiving corticosteroids should receive calcium (800-1000 mg/day) and vitamin D (800 IU/day) supplementation to prevent osteoporosis 2
• Close monitoring during and after tapering is essential, with laboratory tests performed frequently during withdrawal and for at least 3 months after termination of therapy 2

Special Considerations

• In situations of stress during the withdrawal period or up to 12 months after discontinuation, hormone therapy may need to be reinstituted or increased 1
• Patients with multiple relapses after withdrawal have higher risks of disease progression and adverse outcomes, warranting more careful management 2
• Children may require more individualized tapering schedules, as they often need longer treatment periods and have higher relapse rates (60-80%) after drug withdrawal 2
• Patients should be warned not to discontinue corticosteroids abruptly and to seek medical advice immediately during acute illness, fever, or other signs of infection 1

Distinguishing from Disease Flares

• A key clinical challenge is distinguishing withdrawal symptoms from recurrence of the underlying disease, as they can present similarly 5
• In inflammatory conditions, monitoring specific disease markers (such as serum aminotransferase levels in autoimmune hepatitis) can help differentiate between withdrawal syndrome and disease relapse 2
• The timing of symptom onset in relation to dose reduction can provide clues - withdrawal symptoms typically emerge within days of dose reduction 7

Long-term Outcomes

• Prednisone withdrawal syndrome is generally self-limiting, with a median duration of approximately 10 months (range 6-10 months) 3
• Most patients respond well to a temporary increase in glucocorticoid dose followed by a more gradual tapering schedule 3
• With proper management, side effects associated with earlier conventional treatments improve or disappear in 85% of patients maintained on appropriate withdrawal protocols 2