ED patients who do not respond to PDE5I may benefit from topical alprostadil–PDE5i combo

For men with erectile dysfunction (ED) who show a lack of response to oral phosphodiesterase type 5 inhibitors (PDE5Is), combination therapy with topical alprostadil plus PDE5Is seems favourable, producing greater improvements in sexual function without compromising safety compared with topical alprostadil alone, as shown in a study.

In a cohort of 170 ED patients (mean age 59.2 years), those who received the combination (n=98) showed a significant increase in their mean International Index of Erectile Function (IIEF-5) score at 3 months after treatment (from 12.4 at baseline to 17.1; p<0.001). In contrast, the IIEF-5 score remained unchanged in patients who received topical alprostadil monotherapy (n=72; from 12.2 to 12.7; p=0.148). [Int J Impot Res 2022;34:164-171]

The number of patients who responded positively to the Sexual Encounter Profile (SEP) question 2 (whether the erection was hard enough to penetrate) rose from 57 at baseline to 78 after 3 months of combination treatment (p<0.001), whereas no significant difference was found in the monotherapy group (from 48 to 49; p=0.894). Just the same, the number of affirmative responses to SEP question 3 (whether the erection was maintained for completion) increased after treatment in both groups (from 1 to 50 and from 0 to 10, respectively; p<0.001 for both).

Finally, more patients in the combination than in the monotherapy group said that their treatment had improved their erections (65.3 percent vs 24.6 percent; p<0.001) and that this led to an improvement in their ability to engage in sexual activity (53.7 percent vs 18.8 percent; p<0.001).

In terms of safety, adverse events (AEs) occurred in 59 (34.7 percent) patients. These AEs were mild, self-limited, and did not result in treatment discontinuation. None of the patients developed an episode of priapism, and there was no significant between-group difference in the incidence of AEs, except for facial flushing that was reported only in the combination group.

Managing nonresponse to PDE5Is

“The oral PDE5Is are the first-line therapy for ED, and they [have been] described as an effective, safe, and easy-to-administer treatment. Nonetheless, a [considerable] number of patients discontinue the PDE5Is [mostly because] of failure of therapy,” according to the study authors. [J Sex Med 2010;7:524-540; J Sex Med 2009;6:3111-3124]

“In particular, PDE5Is fail in 35–40 percent of patients… The reasons for the ineffectiveness of oral therapy can include inappropriate source of supply of the drug, inadequate waiting time before sexual intercourse, lack of sexual stimulation, uncooperative partner, insufficient dose, severity of ED, concomitant comorbidities, curable causes not treated, and other drugs taken simultaneously,” they pointed out. [Sex Med Rev 2019;7:430-441; BMJ 2006;332:589-592]

That being said, nonresponse to treatment can be managed with an appropriate patient education, dose optimization, change of oral agent (eg, another PDE5I or daily intake), treatment of concomitant comorbidities, psychosexual therapy, and testosterone replacement in hypogonadic patients. [Urology 2014;83:1334-1338]

When all else fails, patients have alprostadil, a synthetic form of prostaglandin E1, as a second-line therapeutic option. It is available as an intracavernous, intraurethral, or topical formulation. The drug acts directly on the cavernous smooth muscle, binding and activating the prostaglandin receptor. It causes an increase in cyclic adenosine monophosphate, a reduction in intracellular calcium, and ultimately the relaxation of the cavernous muscle, so erection can be achieved without sexual stimulation. [Urologia 2015;82:84-92; Pharm Rev 2011;63:811-859]

Synergistic interaction

Due to the different pharmacodynamic mechanisms and a potential synergistic action, alprostadil and PDE5I have been explored as a combination treatment to give to ED patients with nonresponse to oral PDE5I alone. Nonetheless, only a few studies assessed combination therapy including topical alprostadil, which has the advantage of noninvasive administration that reduces local side effects when compared with the intracavernous formulation, authors pointed out. [Res Rep Urol 2016;8:123-131]

Despite the limitations of the present study, including the short follow-up time and the relatively small sample size, the findings are encouraging and show that the combination therapy can significantly improve sexual function, especially in younger patients, the authors said.

“Further randomized placebo-controlled studies, with large sample size and long follow-up, are needed to confirm our results,” they added.