What is the recommended treatment approach for men with erectile dysfunction who have not responded to first-line treatments such as oral phosphodiesterase type 5 (PDE5) inhibitors?

Intracavernosal Injection Therapy for Erectile Dysfunction

Direct Recommendation

For men with erectile dysfunction who have failed an adequate trial of oral PDE5 inhibitors (at least 5 attempts at maximum dose with proper technique), intracavernosal injection therapy with alprostadil is the most effective non-surgical second-line treatment and should be offered as the next therapeutic option. 1, 2

Defining Treatment Failure Before Proceeding to Injections

Before declaring PDE5 inhibitor failure and moving to intracavernosal therapy, verify the following modifiable factors have been addressed:

• Complete at least 5 separate attempts at maximum tolerated PDE5 inhibitor dose with proper sexual stimulation, correct timing, and absence of heavy alcohol use 1, 3
• Verify adequate sexual stimulation is occurring—PDE5 inhibitors require sexual arousal to work 3
• Check testosterone levels (total testosterone, free testosterone, SHBG)—men with testosterone deficiency respond less robustly to PDE5 inhibitors alone, and combining testosterone therapy with PDE5 inhibitors may be more effective than dose escalation 3
• Assess for heavy alcohol use—this impairs erectile function independent of medication 3
• Evaluate timing relative to meals—taking medication with large or fatty meals reduces efficacy 3
• Screen for relationship issues—psychological factors significantly impact response 3
• Review medications that worsen ED—antihypertensives, antidepressants, opioids, hormone therapy 3
• Consider trying a different PDE5 inhibitor before proceeding to injections, as some patients respond to one agent but not another 1

Intracavernosal Injection Therapy: Efficacy and Safety

Effectiveness Profile

• Intracavernosal injection therapy is the most effective non-surgical treatment for ED, with response rates of 73-88% in clinical trials 1, 2, 4
• Alprostadil (prostaglandin E1) is the most widely used and FDA-approved agent for intracavernosal injection as monotherapy 1, 5, 2
• In controlled trials, 73-74% of men achieved erections sufficient for sexual intercourse with alprostadil injections compared to 7-13% with placebo 5
• Mean duration of erection is approximately 56-59 minutes following alprostadil injection 5
• Intracavernosal alprostadil should be offered as second-line therapy after PDE5 inhibitor failure 2, 4

Critical Safety Requirements

The initial trial dose MUST be administered under healthcare provider supervision due to the risk of syncope, prolonged erection, and to ensure proper injection technique 1, 5

• Healthcare provider presence is essential to instruct patients on proper technique, determine effective dose, and monitor for side effects, especially prolonged erection 1
• Proper patient education minimizes frustration and decreases the probability of untoward side effects, including improper injection and treatment failure 1
• Periodic follow-up decreases the occurrence of improper injection and treatment failure 1

Contraindications to Intracavernosal Therapy

Men with the following conditions should NOT use intracavernosal injections:

• Conditions predisposing to priapism: sickle cell anemia or trait, leukemia, multiple myeloma 5
• Penile implants or severe penile curvature 5
• Men advised not to engage in sexual activity 5
• Bleeding disorders or anticoagulation therapy require special caution—apply firm pressure for 5 minutes post-injection to prevent bruising 5

Adverse Events and Management

Priapism is the most serious risk with intracavernosal injection therapy:

• Erections lasting more than 6 hours can cause serious permanent damage to penile tissue and result in permanent impotence 5
• Patients must seek immediate medical attention if erection persists beyond 6 hours 5
• Priapism risk is highest with intracavernosal therapy compared to all other ED treatments 1

Common side effects include:

• Mild to moderate penile pain during or after injection is the most common side effect 5, 2
• Small amount of bleeding at injection site—apply firm pressure for 5 minutes to prevent bruising 5
• Penile fibrosis, nodules, or curvature can develop with repeated use—patients should report any redness, lumps, swelling, tenderness, or curvature 5
• Unlike alprostadil, VIP/phentolamine combination (Invicorp) is associated with very low incidence of penile pain and virtually negligible risk of priapism 6

Dosing and Administration

• Alprostadil doses typically range from 1-40 mcg, with mean optimum doses of 13.8-25.9 mcg depending on ED severity 5
• Patients should not use intracavernosal injections more than 3 times per week, with at least 24 hours between injections 5
• Injection should be administered just prior to foreplay, producing erection in 5-20 minutes 5
• Patients should be able to adjust dose within specific bounds determined by the healthcare provider to match individual response 1
• Effective training and periodic follow-up decrease treatment failure rates 1

Alternative Second-Line Options

If intracavernosal injections are declined or contraindicated, consider:

• Vacuum erection devices (VED)—effective alternative with no systemic side effects 1
• Intraurethral alprostadil suppositories—less effective than intracavernosal route (significantly lower efficacy in postmarketing studies compared to controlled trials), but less invasive 1, 2, 4
• Combination of intraurethral alprostadil with penile constriction device or oral PDE5 inhibitors shows increased efficacy over alprostadil alone 1

Combination Therapy Considerations

• Co-administration of oral PDE5 inhibitors and intracavernosal injection therapy has not been adequately evaluated and should be approached with caution 1
• There is no FDA-approved injectable treatment using multiple medications (bimix, trimix), and there are no data on the efficacy and safety of these combinations 5
• Combination VIP/phentolamine (Invicorp) offers complementary mechanisms: VIP affects veno-occlusive mechanism while phentolamine increases arterial blood flow, with effectiveness ≥80% and very low pain/priapism risk 6

Surgical Options for Refractory Cases

Penile prosthesis implantation should be offered to patients not responding to conventional medical therapy or reporting adverse effects with intracavernosal injections 1

• Surgical interventions represent third-line therapy after failure of both oral and injectable treatments 1
• Referral to urologist is appropriate for evaluation of surgical options 1

Psychosocial Counseling Integration

• Men are best served by combination of psychosocial counseling with intracavernosal therapy, particularly for partnered men where counseling should be directed at the couple 1
• Individual or couples counseling should be offered for those wishing to improve relationship or intimacy issues 1
• Shared decision making with the patient (and partner) is strongly recommended when selecting between treatment modalities 2

Critical Safety Warning

Intracavernosal injections offer no protection from sexually transmitted diseases including HIV—small amounts of bleeding at injection site can increase risk of transmission of blood-borne diseases between partners 5