What are the short‑term and long‑term side effects of prednisone and how should they be managed?

Side Effects of Prednisone

Prednisone causes significant dose- and duration-dependent adverse effects that require systematic monitoring, with courses limited to ≤6 weeks whenever possible to minimize harm, particularly avoiding prolonged therapy >6 weeks which substantially increases risk of serious complications. 1, 2

Short-Term Side Effects (≤6 weeks)

Metabolic and Physical Changes

• Weight gain, fluid retention, and increased appetite occur within the first few weeks of therapy and are among the most common early side effects 2
• Hyperglycemia and worsening diabetes develop rapidly, particularly at doses >20 mg daily, requiring blood glucose monitoring even during short courses 1, 2
• Hypertension can develop or worsen quickly, necessitating regular blood pressure checks 1, 2
• Gastric irritation and increased peptic ulcer risk occur, especially when combined with NSAIDs 1, 3
• Facial rounding (moon face) can begin developing even during short-term use 2

Neuropsychiatric Effects

• Mood disturbances ranging from euphoria and hypomania to depression and psychosis occur in over 50% of patients, typically within the first few weeks 2, 4
• Insomnia, restlessness, and nervousness affect >30% of patients taking corticosteroids 2
• Sleep disturbances are particularly distressing and impact quality of life significantly 1

Rare but Serious Short-Term Complications

• Avascular necrosis can occur even with short courses, though uncommon 1
• Fatal varicella-zoster infections have been reported in immunocompetent patients receiving short-term systemic corticosteroids 1

Long-Term Side Effects (>6 weeks)

Musculoskeletal Complications

• Osteoporosis and fractures are among the most serious complications, with vertebral compression fractures occurring in up to 27% of patients requiring treatment withdrawal 2, 5
• Avascular necrosis of femoral and humeral heads develops even at moderate doses during prolonged therapy 2, 5
• Myopathy affecting proximal muscles, diaphragm, and intercostal muscles occurs in 32.5% of patients 4
• Bone formation markers decrease significantly even at doses as low as 5 mg daily in postmenopausal women 6

Metabolic and Endocrine Effects

• Redistribution of body fat with truncal obesity, moon facies, and buffalo hump occurs in 80% of patients after two years of therapy 2, 5
• New-onset or worsening diabetes mellitus develops commonly with prolonged use 2, 3
• Lipodystrophy is the most frequent adverse event (63% of patients) and is considered the most distressing by patients, particularly in women and younger patients 4
• Cosmetic changes including hirsutism, alopecia, and striae occur frequently 2

Ophthalmologic Complications

• Posterior subcapsular cataracts develop with prolonged use 1, 2, 5, 3
• Increased intraocular pressure and glaucoma can occur, requiring monitoring if therapy continues >6 weeks 2, 5, 3
• Regular ophthalmologic evaluation is essential for patients on long-term therapy 2

Infectious Complications

• Risk of opportunistic and non-opportunistic infections increases with dose, including pneumonia, skin infections, bacteremia, and sepsis 5, 3
• Tuberculosis reactivation may occur in patients with latent TB or tuberculin reactivity 3
• Hepatitis B reactivation can occur in carriers treated with immunosuppressive doses 3
• Systemic fungal infections may be exacerbated 3
• Strongyloides hyperinfection with potentially fatal gram-negative septicemia can occur in endemic areas 3

Cardiovascular Effects

• Long-term use at doses ≥5 mg daily is associated with higher cardiovascular event risk, including coronary artery disease and atrial fibrillation 2, 7

Gastrointestinal Effects

• Peptic ulcer formation and gastrointestinal perforation risk increases, particularly when combined with NSAIDs 1, 5, 3
• Pancreatitis and ulcerative esophagitis can occur 3

Dermatologic Effects

• Skin atrophy, telangiectasia, striae, purpura, and impaired wound healing develop with prolonged use 2, 3
• Acne and acneiform eruptions are common 3

Dose-Dependent Risk Stratification

Low-Dose Effects (≤10 mg/day)

• Even 5 mg daily suppresses bone formation markers and may adversely affect bone mass 6
• Doses >10 mg daily for >18 months lead to severe adverse effects in approximately 15% of patients 2

Moderate to High-Dose Effects (>10-20 mg/day)

• Doses >20 mg daily for >18 months significantly increase risk of severe complications 2
• Immunosuppressive effects become clinically significant at doses >20 mg daily, adversely affecting vaccine responses 2

Very High-Dose Effects (>20 mg/day)

• Risk of serious infections increases substantially 5, 3
• Pneumocystis jirovecii pneumonia prophylaxis should be provided for patients taking ≥20 mg for ≥4 weeks 5

Monitoring Requirements

Baseline Assessment

• Evaluate comorbidities that increase risk: hypertension, diabetes, cardiovascular disease, osteoporosis, peptic ulcer, glaucoma, chronic infections 1, 5
• Document baseline blood pressure, blood glucose, weight, and bone mineral density for anticipated long-term therapy 1, 5

Ongoing Monitoring

• Blood pressure and blood glucose should be monitored regularly, even during short courses 1, 2
• Weight monitoring to detect rapid fluid retention 2
• Mental health assessment for depression, fatigue, and mood disturbances while receiving corticosteroids 1
• Annual bone mineral density testing for patients on long-term therapy 5
• Regular ophthalmologic examinations for cataracts and glaucoma if therapy continues >6 weeks 2, 5

Risk Minimization Strategies

Duration and Dosing

• Limit courses to ≤6 weeks whenever possible, as the American Society of Hematology strongly recommends against prolonged courses (>6 weeks) due to increased risk of side effects 1
• Use the lowest effective dose for the shortest duration 2, 5
• Consider alternate-day therapy when appropriate to reduce adrenal suppression 2

Preventive Measures

• Calcium and vitamin D supplementation should be initiated for all patients anticipated to receive ≥5 mg prednisone for ≥3 months 5
• Bisphosphonates (alendronate or risedronate) should be prescribed if bone mineral density is below normal or osteoporosis is evident 5
• Consider steroid-sparing agents when long-term therapy is anticipated 2

Infection Prevention

• Update all vaccines before starting immunosuppressive therapy, including pneumococcal, influenza, hepatitis B, and live attenuated herpes zoster 5
• Avoid live vaccines in patients receiving immunosuppressive doses 3
• Pneumocystis prophylaxis for patients taking ≥20 mg for ≥4 weeks 5

Administration Recommendations

• Administer in the morning prior to 9 am to minimize adrenal suppression 3
• Take with food or milk to reduce gastric irritation 3
• Consider antacids between meals when large doses are given 3

High-Risk Populations

Elderly Patients

• Require more careful monitoring and often lower doses due to increased risk of complications 2

Patients with Comorbidities

• Diabetes, chronic liver disease, chronic kidney disease, or organ transplant patients have increased risk of infectious and metabolic complications 5

Women

• Female sex is associated with higher risk of glucocorticoid-related adverse events 1, 4
• Premenopausal women experience menstrual disorders in 39% of cases 4
• Lipodystrophy and skin disorders are more frequent in women 4

Children

• Growth suppression is a significant concern with long-term use 2

Common Pitfalls to Avoid

• Underestimating neuropsychiatric effects: Mood disturbances and sleep disruptions significantly impact quality of life and occur in over 50% of patients 1, 4
• Failing to limit duration: Continuing beyond 6 weeks substantially increases risk without additional benefit for most conditions 1
• Inadequate monitoring: Even short courses require blood pressure and glucose monitoring 1
• Abrupt discontinuation: Gradual tapering is essential to avoid adrenal insufficiency, which may persist up to 12 months after discontinuation 3
• Ignoring infection risk: Corticosteroids mask signs of infection and increase susceptibility to all pathogens 3