What are the next steps for a patient with erectile dysfunction (ED) if sildenafil (phosphodiesterase type 5 (PDE5) inhibitor) is not effective?

What to Do If Sildenafil Isn't Helping

Before declaring sildenafil a failure, ensure the patient has completed an adequate trial: at least 5 separate attempts at the maximum dose (100 mg) with proper timing, adequate sexual stimulation, and correction of modifiable factors. 1

Step 1: Verify an Adequate Trial Was Conducted

Many apparent "treatment failures" are actually inadequate trials. Address these common pitfalls first:

Dosing and Administration Issues

• Confirm dose titration to maximum: Start at 50 mg, increase to 100 mg if inadequate response 1
• Verify proper timing: Take approximately 1 hour before sexual activity, not with large meals (delays absorption) 2, 3
• Ensure adequate sexual stimulation: Sildenafil requires sexual arousal to work—it does not produce spontaneous erections 2, 3
• Confirm at least 5 attempts at maximum dose before declaring failure 1

Modifiable Risk Factors to Address

• Check testosterone levels: Total testosterone <300 ng/dL indicates hypogonadism; combination therapy with testosterone is more effective than sildenafil alone 4, 2
• Assess alcohol consumption: Heavy alcohol use impairs erectile function and reduces PDE5i efficacy 2
• Review concurrent medications: CYP3A4 inhibitors (ritonavir, ketoconazole, erythromycin, cimetidine) may require dose adjustment 2, 5
• Evaluate relationship factors: Partner communication issues and performance anxiety reduce treatment success 1

Step 2: Switch to a Different PDE5 Inhibitor

If sildenafil fails after an adequate trial, try a different PDE5 inhibitor before abandoning oral therapy entirely. 1

Alternative PDE5 Inhibitors

• Tadalafil: Effective for up to 36 hours, allowing spontaneous sexual activity; daily dosing (2.5-5 mg) eliminates timing concerns entirely 4
• Vardenafil or avanafil: Similar efficacy to sildenafil but different pharmacokinetic profiles may benefit some patients 1
• Note: All PDE5 inhibitors have similar efficacy in the general ED population (69% success vs 33% placebo), but individual response varies 4, 6

Special Considerations

• Men with diabetes or post-prostatectomy have more severe baseline ED and respond less robustly to all PDE5 inhibitors 1, 4
• Tadalafil does not show dose-dependent improvement between 5-20 mg, unlike sildenafil which has clear dose-response 4

Step 3: Consider Combination Therapy

Testosterone Replacement (if deficient)

• Check total testosterone, free testosterone, and SHBG in all men with PDE5i failure 4
• If testosterone <300 ng/dL: Add testosterone replacement therapy—combination is more effective than either alone 1, 4, 2
• Contraindication: Do not use testosterone in prostate cancer patients on active surveillance or androgen deprivation therapy 1

Psychosexual Counseling

• Refer to sex therapist or couples counselor for men with predominantly psychogenic ED or relationship issues 1
• Psychotherapy as adjunct to medical treatment improves outcomes by reducing performance anxiety and improving partner communication 1

Step 4: Escalate to Second-Line Therapies

If oral therapy fails after adequate trials of multiple PDE5 inhibitors and correction of modifiable factors, proceed to more invasive but highly effective options. 1

Intracavernosal Injection Therapy

• Alprostadil (prostaglandin E1): Most effective non-surgical treatment for ED 1
• Requires in-office training for proper injection technique 1
• Risk of priapism: Highest among ED treatments but manageable with proper dosing 1

Intraurethral Alprostadil Suppositories

• Less invasive than injection but also less effective 1
• First dose must be supervised due to 3% risk of syncope 1
• Consider combination with vacuum device to enhance efficacy 1

Vacuum Erection Devices (VEDs)

• Non-pharmacologic option with high efficacy when used correctly 1
• Can be combined with intraurethral alprostadil for improved results 1

Step 5: Penile Prosthesis (Last Resort)

If all first-line and second-line therapies fail, penile prosthesis implantation is definitive treatment. 1, 7

Critical Safety Reminders

Absolute Contraindications

• Concurrent nitrate use: Any form (organic nitrates, glyceryl trinitrate, isosorbide) causes potentially fatal hypotension 2, 5
• Emergency nitrate protocol: Wait 24 hours after sildenafil (48 hours after tadalafil) before administering nitrates under close supervision 1, 4

Cardiovascular Risk Stratification

• High-risk patients should defer ED treatment until cardiac condition stabilized: unstable angina, uncontrolled hypertension, recent MI/stroke, NYHA Class II-IV heart failure 4
• Assess exercise tolerance: Patient should be able to walk 1 mile in 20 minutes or climb 2 flights of stairs without symptoms 4, 2

Common Pitfalls to Avoid

• Do not declare failure without addressing modifiable factors first (testosterone, alcohol, timing, stimulation, relationship issues) 1, 2
• Do not assume all PDE5 inhibitors will fail if one fails—individual response varies despite similar class efficacy 1
• Do not overlook end-organ dysfunction: Progressive endothelial dysfunction and diminished cavernosal smooth muscle content cause true treatment failure 7
• Do not skip cardiovascular assessment: ED is a risk marker for cardiovascular disease as strong as smoking or family history of MI 1