Although PDE5 inhibitors are remarkably effective for erectile dysfunction (ED), not all men are candidates for this therapy. 

The reasons vary, including contraindications, underlying heart disease, lack of efficacy, nitroglycerin or guanylate cyclase use, and severe retinal conditions, such as macular degeneration or retinitis pigmentosa. These patients may be eligible for treatment with second-line (2L) therapies or regenerative therapy. 

Verify nonresponse

The Princeton IV consensus guidelines on PDE5 inhibitors and cardiac health provide useful recommendations for patient management.

Kloner RA, Burnett AL, Miner M, et al. Princeton IV consensus guidelines: PDE5 inhibitors and cardiac health. J Sex Med. 2023.

In patients prescribed PDE5 inhibitors, before embarking on 2L treatment, it’s important to make sure that the patient is truly unresponsive to the drug. 

Specifically, it’s important to check whether patients are properly taking PDE5 inhibitors. Discuss whether there is adequate sexual stimulation necessary for successful use. Does the patient need testosterone replacement secondary to hypogonadism?

Importantly, patients’ erectile function may also benefit from treatment of their comorbidities, as well as switching to another PDE5 inhibitor or combining long- and short-acting PDE5 inhibitors.

2L therapies

When patients are unresponsive to or intolerant of PDE5 inhibitors, various 2L therapies are available, as outlined in the Princeton IV consensus guidelines.

Intracavernosal therapy

These vasoactive medications are self-administered into the corpora cavernosa. PGE1 and/or papaverine with or without phentolamine are the principal agents used. Patients with poor vision, poor manual dexterity, and at risk of priapism should use these medications with caution.

These injections are contraindicated in men taking monoamine oxidase inhibitors. Penetration hardness rates can exceed 80%, with the medication taking effect in a few minutes and erections exceeding an hour or more.

Intraurethral vasoactive agents

These PGE1-containing pellets are self-placed as a small urethral suppository. About 40% of patients are responsive, with a low risk of priapism. 

Vacuum devices

These manual or battery-operated pumps work by creating negative pressure around the penis and drawing blood into the corpora cavernosa. They are effective between 60% and 90% of the time. Adverse effects include pain, bruising, numbness, and color changes.

Penile implants

This surgery is a final choice in patients who are unresponsive to other treatments, including in those with Peyronie disease or other anatomical abnormalities. Urologists place either a semi-rigid or inflatable prosthesis in the corpora cavernosa. 

Topical treatments

These effective, noninvasive, easily administered, swift-acting, and well-tolerated options are applied directly to the glans and elicit a cooling-warming effect. 

Alprostadil

This synthetic analog of prostaglandin E1 (PGE1) functions by many mechanisms. It binds as an agonist to prostaglandin receptors (eg, EP2), which then activates adenylate cyclase, leading to accumulation of 3'5'-cAMP (cyclic adenosine monophosphate). This cascade results in smooth muscle relaxation and vasodilation—effects that are applicable to treating ED.

Alprostadil is an approved 2L treatment for erectile dysfunction, as discussed in an article in StatPearls.

Jain A, Iqbal OA. Alprostadil. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; updated July 17, 2023.

Another option is using alprostadil in combination with other medications.

Experimental therapies

Regenerative medicine entails the development of therapies that can regenerate or replace damaged/diseased tissues and organs. 

According to the Princeton IV consensus guidelines, “Regarding future implications, restorative therapies for ED have shown promising results in preclinical and clinical studies.” Stem cells, platelet-rich plasma (PRP), and low-intensity extracorporeal shock wave therapy (Li-ESWT) have been studied, although none have been approved by the FDA for ED. 

“The American Urological Association considers Li-ESWT and stem cell therapy to be investigational and PRP to be experimental,” the guidelines state. “The European Association of Urology determined that there is weak evidence supporting Li-ESWT in patients with mild ED as a first-line therapy and insufficient evidence to recommend stem cell or PRP. Overall, the field of restorative therapy for ED is rapidly evolving, and ongoing research is needed to determine the safety, efficacy, and accessibility of these therapies for patients with ED.”

Stem cells

Adipose-derived stem cells and bone marrow–derived stem cells are the main types of stem cells used with ED. Their action is hypothesized to involve neovascularization, anti-inflammatory effects, neuroprotection by the paracrine effects of the injected stem cells, anti-inflammatory effects, tissue regeneration, and neuroprotection.

PRP

Several growth factors and cytokines within PRP, which heal and regenerate, are the basis for its use in ED. Growth factor release, immune modulation, anti-inflammatory effects, recruitment of stem cells, and neovascularization could all play a role.

One small study involving 30 patients with mild to moderate ED showed some improvement in IIEF scores, whereas a more recent randomized, prospective placebo-controlled study showed no effects.

Li-ESWT

Experts suggest that Li-ESWT works by  enhanced endothelial function, neovascularization, anti-inflammatory effects, neural regeneration, and activation of penile tissue–resident stem cells. Results of a recent meta-analysis (n=1,064) demonstrated improvements in IIEF and Erectile Hardness scores, although the degree of improvement in IIEF was not clinically meaningful.