What is the appropriate next step in management for a 60‑year‑old man with persistent erectile dysfunction after adequate trials of sildenafil (Viagra) and tadalafil (Cialis)?

Management of PDE5 Inhibitor-Refractory Erectile Dysfunction

Before abandoning oral therapy, re-educate this patient on proper PDE5 inhibitor use and complete an adequate trial—defined as at least 5 separate attempts at maximum dose (sildenafil 100 mg or tadalafil 20 mg) with correct technique—because up to 30% of apparent non-responders convert to successful responders after addressing modifiable factors. 1, 2

Step 1: Verify an Adequate Trial Was Completed

Most "treatment failures" result from improper use rather than true medication inefficacy. 1, 3 Before proceeding to second-line therapies, systematically confirm:

Critical Elements of an Adequate Trial

• Minimum 5 separate attempts at maximum tolerated dose (not just 1–2 tries) 1, 2
• Sexual stimulation was present—PDE5 inhibitors require arousal to work and will not produce erections without it 1, 3
• Proper timing: sildenafil taken ~1 hour before activity, tadalafil allows up to 36 hours 1, 3
• Avoided large or fatty meals that delay absorption and reduce efficacy 1, 2
• Limited alcohol consumption—heavy drinking independently impairs erectile function 1, 2

A 2004 study of 60 men claiming sildenafil failure found that 77% had major suboptimal use: 30% didn't know sexual stimulation was necessary, 60% attempted fewer than 4 doses, and 45% never reached the 100 mg maximum dose. 4 After re-education and proper dosing, 58.5% achieved successful intercourse. 4

Step 2: Address All Modifiable Factors

Hormonal Assessment

• Check total testosterone, free testosterone, and SHBG 1
• Men with testosterone deficiency respond less robustly to PDE5 inhibitors alone 1, 3
• Combining tadalafil with testosterone replacement is more effective than either monotherapy in hypogonadal men (testosterone <300 ng/dL) 1, 3

Medication Review

• Identify drugs worsening ED: antihypertensives, antidepressants, opioids, hormone therapy 1
• Screen for CYP3A4 inhibitors (ritonavir, ketoconazole, erythromycin) that may require dose adjustment 3, 5
• Verify absolute absence of nitrate use in any form—this is a life-threatening contraindication 1, 3

Psychosocial Factors

• Screen for depression, anxiety, and relationship conflict—these significantly impact treatment response 1
• Involve the partner in counseling when possible, as relationship dynamics affect outcomes 2

Cardiovascular Fitness

• Confirm ability to walk 1 mile in 20 minutes or climb 2 flights of stairs without symptoms 1
• If unable, refer to cardiology before escalating therapy 1

Step 3: Switch to an Alternative PDE5 Inhibitor

If an adequate trial of both sildenafil and tadalafil has been completed at maximum dose with proper technique, try vardenafil before abandoning oral therapy. 1, 2

Rationale for Switching Agents

• Head-to-head trials show comparable efficacy (~69% response vs. 33% placebo for all three agents), but individual response variability means some men succeed with one agent after failing another 1, 6, 7
• Vardenafil demonstrates dose-dependent efficacy and an intermediate duration of action 1
• The three PDE5 inhibitors differ in pharmacokinetics despite sharing the same mechanism, which may explain differential individual responses 6, 7

Practical Approach

• Start vardenafil at standard dosing and titrate to maximum 1
• Complete at least 5 attempts at maximum dose before declaring failure 1, 2
• A 2006 crossover study found that 71% of men preferred tadalafil over sildenafil, citing longer duration and greater spontaneity, suggesting patient preference plays a role in adherence and perceived efficacy 8

Step 4: Consider Combination Strategies

Vacuum Erection Device (VED) Plus PDE5 Inhibitor

• Combining a VED with continued PDE5 inhibitor use may salvage some non-responders, though evidence is limited 2
• VEDs must include vacuum limiters to prevent penile injury from excessive negative pressure 2

Daily Low-Dose Tadalafil

• Tadalafil 2.5–5 mg once daily eliminates timing concerns and may benefit men who prefer spontaneous activity 1
• Daily dosing has been shown effective for long-term management in various contexts 2

Step 5: Proceed to Second-Line Therapies

Only after failure of at least two different PDE5 inhibitors at maximum dose with proper technique should you proceed to invasive options. 1, 2

Intraurethral Alprostadil (MUSE)

• Less invasive than injection therapy but lower efficacy than intracavernosal injections 1, 2
• First dose must be supervised in-office due to 3% risk of syncope 1, 2

Intracavernosal Injection Therapy (ICI)

• Most effective non-surgical option with up to 90% success rates 2
• Agents include alprostadil, papaverine, or phentolamine 1
• Highest risk of priapism—first dose must be administered under healthcare supervision 1, 2
• Requires patient education on self-injection technique and emergency management of prolonged erections 2

Vacuum Erection Device (VED) Monotherapy

• Initial efficacy of 90%, though drops to 50–64% at 2 years 2
• Best suited for older patients with infrequent intercourse 2
• No systemic side effects, making it appropriate for men with contraindications to pharmacotherapy 1

Low-Intensity Shockwave Therapy (LI-SWT)

• May benefit men with mild vasculogenic ED 2
• Some evidence in PDE5 inhibitor non-responders, though still considered investigational by some authorities 2

Penile Prosthesis Implantation

• Definitive surgical solution when all medical therapies fail or cause intolerable side effects 1, 2
• Modern devices have low failure and infection rates with high patient and partner satisfaction 2

Critical Pitfalls to Avoid

• Do not proceed to invasive therapies without confirming an adequate oral trial—many "failures" are actually improper use, inadequate dosing, or insufficient attempts 1, 2
• Do not overlook testosterone deficiency—hypogonadal men often fail PDE5 inhibitors until testosterone is replaced 2
• Do not prescribe intraurethral or intracavernosal therapy without in-office supervision of the first dose—this is a safety standard to prevent syncope and priapism 1, 2
• Do not assume all three PDE5 inhibitors will fail equally—individual pharmacokinetic differences justify sequential trials 1, 6