ERECTILE RESPONSE PROFILES OF MEN USING PDE5 INHIBITORS COMBINED WITH INTRACAVERNOSAL INJECTIONS AS PART OF A PENILE REGABILITATION PROGRAM AFTER RADICAL PROSTATECTOMY

Abstract

BACKGROUND:

PDE5 inhibitor (PDE5i) labeling states that these agents should not be used in conjunction with other erectogenic medications for fear of priapism occurring.

AIM:

We explored the risk of priapism and prolonged erections in men in our post-radical prostatectomy (RP) penile injection program who were using regular PDE5i and intracavernosal injections (ICI) as part of their rehabilitation program.

METHODS:

Study cohort included men on penile injection therapy who (i) were taking tadalafil 5mg daily or taking sildenafil 25mg on non-injection days (ii) had a RP (iii) were using their respective PDE5i regularly at the time of penile injection training and (iv) complied with the program instructions regarding penile injection use. Demographics, comorbidity details, PDE5i dose and utilization as well as injection dose and utilization data were collected. All patients underwent in-office injection training and used trimix (papaverine/phentolamine/PGE1) as the intracavernosal medication.

OUTCOMES:

Priapism was defined as a patient self-reported penetration hardness erection ≥4 hours in duration, while prolonged erection was defined as a penetration hardness erection lasting ≥2 hours.

RESULTS:

112 tadalafil (T) users and 364 sildenafil (S) users were compared. Mean age and duration post-RP were 62±14 years and 5.2±12 months respectively, no difference between T and S groups. Mean trimix dose was: T 24±24 units; S 31±37 units, p<0.05. Priapism occurred in: T 2/112 (1.7%); S 5/364 (1.4%), p=0.47. Excluding those men experiencing priapism on any occasion, those with any reported penetration hardness erection lasting ≥2 hours: T 7/112 (6.3%); S 12/364 (3.3%), p<0.01. 53% of these prolonged erections occurred within the first 6 injections at home (no difference between T and S groups).

CLINICAL IMPLICATIONS:

We emphasize the need for continued monitoring and education on proper injection techniques to minimize the risk of adverse events ICI and PDE5i combination therapy.

STRENGHTS & LIMITATIONS:

This study has a relatively large patient population with a considerable follow-up time. Additionally, the rigorous training, education, and monitoring of the participants, as well as the use of formal definitions for priapism and prolonged erections, enhances the accuracy and reliability of the results. However, there are some limitations: social desirability, confounding factors, and recall bias.

CONCLUSION:

There is no significant difference in the incidence of priapism in an intracavernosal injection program in which men combine ICI with tadalafil or sildenafil. However, tadalafil patients had a higher rate of prolonged erections, which was found to occur mostly early during the titration phase.

INTRODUCTION

While tadalafil, sildenafil, vardenafil, avanafil belong to the same phosphodiesterase 5 inhibitor (PDE5i) class of drugs, they have distinct pharmacokinetic and pharmacodynamic properties. Of the more commonly used PDE5i, tadalafil has the longest half-life compared to the other agents, which allows for a more sustained erectogenic effect estimated to be up to 36h, while sildenafil/vardenafil can sustain a erectogenic effect for approximately 8–10h.(1, 2) Tadalafil 5mg daily reaches a peak serum level of approximately 8mg after 5 days and remains at erectogenic serum levels at all times.(3) Regarding their safety, their labeling warns their use in combination with other erectogenic medications due to an increased risk of priapism. The risk of priapism associated with these medications is largely unknown, but all PDE5i have good safety profiles with only rare reports of priapism. (4) For example, only 1 case of priapism has been reported with tadalafil and 2 reports with sildenafil.(5–7) A post marketing safety surveillance study conducted by Lilly found the risk of tadalafil-associated priapism to be less than 1 in 10,000.(4)

Introduced in early 1980s, intracavernosal injection (ICI) therapy had been the gold standard treatment for erectile dysfunction (ED) until the advent of oral PDE5i in the late 1990s. Nowadays, ICI is considered a second-line treatment for ED and has a important role in penile rehabilitation programs for men who have undergone radical prostatectomy (RP) who fail to achieve a desirable erection hardness with PDE5i. Trimix is one of the most commonly used medication combinations for intracavernosal injections, at least in the United States (understanding that this combination is not available everywhere in the world), and consists of a mixture of papaverine, phentolamine and prostaglandin E1 (PGE1).(8) Regarding safety, trimix has been reported to cause priapism in the range of 0.5–5% of patients. (8–10).

Priapism, an erection lasting over four hours, is a rare but serious adverse event. This adverse event requires rapid diagnosis and management, otherwise it can have irreversible sequelae, especially cavernosal smooth muscle fibrosis. (11) These irreversible changes lead to profound erectile dysfunction.

The actual risk of prolonged erections and priapism with the concomitant use of the two class of medications is largely unknown. The aim of this study is to compare the incidence of priapism and prolonged erections in two patient populations: those using daily tadalafil combined with ICI versus those using daily sildenafil combined with ICI.

METHODS

Study Population:

The study cohort was composed of men who were undergoing penile injection therapy after RP who were (i) taking either tadalafil 5mg daily or (ii) taking sildenafil 25mg on non-injection days, (iii) tadalafil patients that had been using tadalafil 5mg daily for at least one week prior to ICI training begun and (iv) followed all ICI program instructions. For all patients in the study, demographic information, details on comorbidities, nerve sparing status, PDE5i dose and utilization, as well as injection dose and utilization data were collected. Institutional Review Board approval was obtained under the number 16–459.

Intracavernosal Injection Therapy:

Patients were part of an institutional penile rehabilitation program and were either using daily tadalafil (5mg) or daily sildenafil (25mg), combined with intracavernosal medication (trimix). The trimix mixture was: papaverine (30mg/ml), phentolamine (1mg/ml) and PGE1 (10mcg/ml). Two in office training sessions occurred led by nursing staff and dosing was adjusted by telephone/written communication to ensure penetration hardness erections lasted no longer than 90 minutes.

Definitions:

Priapism was defined as a self-reported penetration hardness erection lasting ≥4 hours, while prolonged erection was defined as a penetration hardness erection lasting ≥2 hours. Patients were instructed to take pseudoephedrine 120mg by mouth if they had a penetration hardness erection lasting 2 hours, to call us at 3 hours and to be in the emergency room at 4 hours.

Statistics:

A p value less than 0.05 was considered statistically significant. A two-tailed student’s t-test was used for comparison (SPSS, IBM Corp., Armonk, N.Y., USA).

RESULTS

Patient Population:

This consisted of 476 men after RP. Five surgeons did the operations. 85% of men had bilateral nerve sparing and 92% of patients had organ confined cancer. The participants had a mean age of 62±14 years and a mean duration post-radical prostatectomy (RP) of 5.2±12 months. There was no difference in duration post-RP between groups; mean duration at time of program enrollment was 4.5±6 months. 84% patients had bilateral nerve sparing, 10% had unilateral nerve sparing and 6% have had no nerve sparing. There were no significant differences in nerve sparing status, comorbidity profile and pathological status between the two groups. None of the patients analyzed had any adjuvant therapy during the course of the study. Of note, there was no difference in pre-RP erectile function (EF), based on patient report, between groups, with a mean of 84% of all patients being capable of penetrative sexual relations at baseline.

112 men were taking tadalafil (T) and 364 men were taking sildenafil (S). Mean follow up was 39±13 months. There was no significant difference in age or duration post-RP between the T and S groups. In terms of the trimix dose, the T group had a mean dose of 24±24 units while the S group had a higher mean dose of 31±37 units (p<0.05).

Erection Data:

The incidence of priapism was 2/112 (1.7%) in the T group and 5/364 (1.4%) in the S group, with no significant difference between the two groups (p=0.47). Excluding men who experienced priapism, the incidence of reported penetration hardness erection lasting ≥2 hours was significantly higher in the T group (7/112, 6.3%) compared to the S group (12/364, 3.3%), with a significant difference (p<0.01). Of these prolonged erections, 53% occurred within the first 6 injections at home, with no significant difference in this between the T and S groups.

DISCUSSION

Erectogenic pharmacotherapy is utilized either alone or in combination with PDE5i as part of penile rehabilitation programs after RP, with the aim of achieving cavernosal oxygenation and endothelial protection. (12) Phosphodiesterase type 5 (PDE5) inhibitors, such as tadalafil and sildenafil, are the most commonly used medications and form the cornerstone of penile rehabilitation therapy.(13) In our program, patients who do not respond adequately (penetration hardness erection) to oral medications, ICI therapy will be started. After RP, at our institution, 85% of men fail to respond to a maximum dose PDE5i with a penetration hardness erection in the first 6 months after RP.

It is acknowledged that PDE5i have an excellent safety profile, with rarely reported cases of priapism in the literature.(5–7) However, there are concerns regarding the increased risk of priapism when these medications are combined with other erectogenic therapies, such as intracavernosal injections. Despite these warnings, the safety of combined therapy, as well as the relative risk of priapism and prolonged erections associated with tadalafil and sildenafil, is largely unknown. The purpose of this study was to evaluate the actual risk of priapism and prolonged erections in these patient populations. To the best of our knowledge, this is the first report to compare sildenafil to tadalafil in combination with ICI regarding prolonged erection and priapism rates.

Our findings showed that there was no significant difference in the incidence of priapism between the T and S groups, despite different duration of erectogenicity of each drug. Our priapism rates also are relatively low (1.4% S group, 1.7% T group), which is consistent with previous reported rates of priapism with the use of ICI therapy. (8–10) However, the T group had a higher incidence of prolonged erections compared to the S group, and this difference was statistically significant. Most of these prolonged erections occurred within the first 6 injections at home, emphasizing the need for continued monitoring and education on proper injection techniques to minimize the risk of adverse events. The S group had a higher mean trimix dose compared to the T group, this finding emphasizes the importance of individualized dosing to optimize efficacy and minimize adverse events in this population.

Several studies have assessed the combination of intraurethral alprostadil (MUSE) with PDE5 inhibitors (PDE5i). The most common adverse effects observed in these studies were urethral burning, throbbing, headache, and a glans hypersensitivity compared to PDE5i or MUSE used alone. None of the studies reported cases of priapism or prolonged erection. (14–16) Furthermore, the combination therapy of PDE5i and intracavernosal injections (ICI) was reviewed by Dhir et al (17), who expressed concerns about an elevated risk of prolonged erections and priapism when using both medications together. However, despite these concerns, studies have not demonstrated an increased risk of adverse effects, including priapism, in patients using combination therapy.(17) In another study by Gutierrez et al. (2005), the use of intracavernosal alprostadil with PDE5i was investigated, and no instances of prolonged erections were reported among their patients.(18)

The current study adds valuable information to the literature on the use of PDE5 inhibitors in combination with penile injection therapy for post-radical prostatectomy erectile dysfunction. One of the strengths of this study is the relatively large patient population (476 men) with a considerable follow-up time. Additionally, the rigorous training, education, and monitoring of the participants, as well as the use of formal definitions for priapism and prolonged erections, enhances the accuracy and reliability of the results. Despite the strengths of the study, there are some limitations to consider: social desirability and confounding factors such as differences in baseline characteristics, concomitant medications, or health status may have affected the results and of course recall bias in determining erection duration.

CONCLUSION

There is no significant difference in the incidence of priapism in an intracavernosal injection program in which men combine ICI with tadalafil or sildenafil. However, tadalafil patients had a higher rate of prolonged erections, which was found to occur mostly early during the titration phase.

Table 1.

Erectile Response Data

	Sildenafil (S)	Tadalafil (C)
N	364	112
Mean Trimix Dose (Units)	31±37	24±24	p=0.02
Prolonged Erection	3.3% (12)	6.3% (7)	p<0.01
Priaprism	1.4% (5)	1.7% (2)	p=0.47