What are the first-line and second-line treatments for erectile dysfunction (ED)?

Erectile Dysfunction: First-Line and Second-Line Treatment

First-Line Treatment: PDE5 Inhibitors

Oral PDE5 inhibitors (sildenafil, tadalafil, vardenafil) are the first-line therapy for erectile dysfunction and should be prescribed unless contraindicated. 1

Efficacy and Selection

• PDE5 inhibitors demonstrate clinically significant improvements with 69% success rates compared to 35% with placebo 1
• All three FDA-approved agents have equivalent efficacy in the general ED population, so selection should be based on pharmacokinetic differences and patient lifestyle preferences rather than effectiveness 1
• Tadalafil offers a 36-hour window of opportunity due to its 17.5-hour half-life, making it ideal for men who prefer spontaneous sexual activity 1, 2
• Tadalafil has lower rates of flushing compared to other PDE5 inhibitors 1, 3
• Sildenafil and vardenafil have approximately 4-hour half-lives and require timing with sexual activity 4

Proper Dosing Strategy

• Start tadalafil at 10mg as needed, titrate to 20mg if necessary 1, 2
• An adequate trial requires at least 5 separate attempts at maximum dose before declaring treatment failure 1, 2
• For patients preferring spontaneity, tadalafil 2.5-5mg once daily eliminates the need to time medication with sexual activity 3
• Tadalafil does NOT show dose-dependent improvement between 5mg, 10mg, and 20mg, so dose selection should be based on tolerability rather than expecting better efficacy at higher doses 3

Critical Safety Screening Before Prescribing

• Never prescribe PDE5 inhibitors to patients taking nitrates—this combination causes potentially fatal hypotension 1, 2, 5
• Assess cardiovascular risk using Princeton Consensus Panel criteria before initiating treatment 1
• High-risk patients requiring deferral until stabilization include those with: 1
  • Unstable or refractory angina
  • Uncontrolled hypertension
  • Left ventricular dysfunction/CHF (NYHA class II or greater)
  • MI or stroke within previous 2 weeks
  • High-risk arrhythmias
  • Hypertrophic obstructive cardiomyopathy
  • Moderate-to-severe valvular disease
• Patients whose cardiovascular risk is indeterminate or who cannot perform moderate physical activity should be referred to cardiology before prescribing 3

Common Reasons for Treatment Failure

• Many apparent failures result from inadequate trials, improper timing, lack of sexual stimulation, or modifiable factors 3
• Before switching therapies, evaluate: 3
  • Hormonal abnormalities
  • Food or drug interactions
  • Timing and frequency of dosing
  • Adequacy of sexual stimulation
  • Heavy alcohol use
  • Relationship issues with partner
• Sexual stimulation is necessary for PDE5 inhibitors to be effective 3

Lifestyle Modifications

• Counsel all ED patients on risk factor modification regardless of pharmacologic treatment 1
• Recommend smoking cessation, weight loss if overweight, increasing physical activity, avoiding excess alcohol, and optimal management of diabetes, hypertension, and dyslipidemia 1

Hormonal Testing

• Do not routinely measure testosterone in all ED patients 1
• Measure testosterone when patients present with decreased libido, premature ejaculation, fatigue, testicular atrophy, or muscle atrophy 1
• For men with both ED and testosterone deficiency, combining tadalafil with testosterone therapy is more effective than tadalafil alone 3
• Testosterone therapy alone is not effective monotherapy for ED 3

Special Populations

• Men with diabetes have more severe ED at baseline and respond less robustly to PDE5 inhibitors 1, 3
• Post-prostatectomy patients show reduced response compared to the general population 1, 3
• For severe hepatic impairment, PDE5 inhibitors are generally not recommended 3
• In moderate hepatic impairment (Child-Pugh B), start vardenafil at 5mg with maximum dose of 10mg 6

Second-Line Therapies

If PDE5 inhibitors fail after an adequate trial (at least 5 attempts at maximum dose), proceed to second-line interventions. 1

Available Second-Line Options

• Intraurethral alprostadil suppositories 1
• Intracavernous vasoactive drug injection (alprostadil) 1, 7
• Vacuum constriction devices 1

Intracavernous Alprostadil Considerations

• Should produce an erection in 5 to 20 minutes lasting up to one hour 7
• Use no more than 3 times per week with at least 24 hours between injections 7
• Contraindicated in men with conditions causing prolonged erections (sickle cell anemia, leukemia, multiple myeloma) 7
• Erections lasting more than 6 hours require immediate medical attention to prevent permanent damage 7
• Common side effect is mild to moderate pain during injection 7

Third-Line Therapy

• Penile prosthesis implantation is the definitive third-line intervention for refractory ED 1

Additional Diagnostic Workup for Non-Responders

• Consider measuring free (rather than total) testosterone in patients who do not respond to PDE5 inhibitors 8
• Additional evaluations may include nocturnal penile tumescence, penile Doppler ultrasound, bulbo-cavernosus reflex, and psychological evaluation 8
• Cardiac risk factors should be evaluated and managed in all ED patients 8