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Intracavernosal prostaglandin E1 self vs office injection therapy in patients with erectile dysfunction

Abstract

We have investigated the reliability of intracavernosal prostaglandin E1 (PGE1) office vs self-injection therapy in patients with erectile dysfunction (ED). A total of 298 male patients with ED were enrolled in this study. In all patients, intracavernosal titration of the PGE1 dose was performed. A total of 106 patients were enrolled in the self-injection program, and 192 patients were enrolled in the office injection program. There were significant differences between number of injections and amount of PGE1 per month, total number of injections, and total amount of PGE1 on office and self-injection programs (P<0.05 for each). There was a significant increase in the dropout rate in the office injection group compared with the self-injection group (P<0.05). There was an increase in penile fibrosis in the self-injection program compared with the office program (P<0.05). A self-injection program is reliable. Office injection program can be reserved for a subset of ED patients with special preferences.

Introduction

Since its initial description by Virag1 in 1982, intracavernosal injection (ICI) therapy has become widely accepted for the treatment of erectile dysfunction (ED). Prostaglandin E1 (PGE1) (alprostadil) was introduced for ICI by Adaikan et al.2 and Ishii et al.,3 in 1986. Since that time, the publications of its efficacy and demonstrated safety in larger population groups have paved the way for worldwide acceptance of alprostadil in both office use and self-injection therapy.4

PGE1 is a potent smooth-muscle relaxant, which induces relaxation of isolated human penile erectile tissue and cavernous arteries.5 The convincing efficacy of alprostadil is attributed to several pharmacological properties of the drug: stimulation of the adenylate cyclase with intracellular accumulation of cAMP and subsequent intracellular calcium decrease; direct stimulation of the maxi potassium-channels resulting in hyperpolarization; inhibition of the noradrenalin release via presynaptic alpha1 adrenoceptors, resulting in a decrease of sympathetic tone; and suppression of angiotensin II secretion.6, 7 Each of these different pharmacological effects contributes to cavernous smooth muscle relaxation.

The high efficacy and low side effect rates – with priapism <1% and fibrosis about 1% – prompted the Clinical Guidelines Panel on ED of the American Urological Association to recommend that alprostadil monotherapy should be preferred to other vasoactive drugs in self-injection therapy.

Despite the availability of oral agents as first line therapy, ICI still has its place in the field of ED treatment. Earlier, after the institution of PDE5 inhibitors for ED, a good portion of the patients were hesitant to use those oral agents due to phobias about cardiovascular effects and a preference for using local medicines rather than those with a general mode of action.8, 9 Therefore, our opportunity was unique: to investigate the reliability of intracavernosal PGE1 office vs self injection therapy in patients with ED in the era of available effective oral agents. Although numerous studies had investigated the efficacy and reliability of PGE1 as a self-administered pharmacotherapy, very few studies had compared reliability, dropout rates and efficacy of self vs office injection programs. In addition, in a subset of patients with ED, some are unable to or dislike injecting themselves. These factors prompted us to conduct the current study to assess the reliability of intracavernosal PGE1 office vs self injection therapy in patients with ED.

Subjects and methods

Research design

This was a prospective, office based study. Male patients with a clinical diagnosis of ED visiting the Andrology clinic were candidates for study. From July 2001 to July 2004, 298 male patients who had not used ICI before, and preferred this method as a treatment modality for their ED, were enrolled in this study. Patients were assessed for ED using IIEF. The erectile function domain consists of questions 1–5 and question 15 for assessing the global erectile function. Scoring of the IIEF domain of erectile function allowed classification of each patient as having no (26–30), mild (17–25), moderate (11–16) or severe (0–10) ED. At the same time they were assessed for ED, all patients were also interviewed for socio-demographic and medical histories. Socio-demographic data included age, education, occupation, marital status and smoking habits. Whenever useful, information provided by the patients was checked with the medical records. All patients underwent routine laboratory investigations, plus total testosterone and prolactin assessment.

Intracavernosal pharmacotesting and titration of the PGE1 dose was performed for all patients. In this study we used Prostin VRTM ‘Alprostadil’ by Upjohn after being diluted to a concentration level of 20 μg/ml. After determination of the suitable dose, patients were informed about the two available ICI programs. Patients were assigned to either the self or office injection program, according to their preference in addition to the physician assessment of their manual and mental ability to do self-injection properly at home. A total of 106 patients were enrolled in the self-injection program and 192 patients were enrolled in the office injection program. Results of patients who had at least one injection/week were used for analysis. Patients who stopped treatment before 3 months or irregularly used the treatment during the follow-up period were excluded.

All patients were assessed at the beginning of the study and every 3 months thereafter for erectile function using erectile function domain of the IIEF and for any adverse symptoms or signs related to the use of PGE1 injections. They also were quizzed about and examined for any penile pain, curvatures, deformities and any forms of swelling or fibrosis in the penis by only one physician.

Analysis of data

The data was analyzed using the Statistical Package of Social Science (SPSS.11.0) software program. An unpaired t-test was used to assess the significance of the difference between patients on office and self-injection programs for each of the measured variables. Patients' characteristics according to ED severity were compared using χ2 test.

Results

Mean age±s.d. was 58.1±9.4. Of the patients, 90.3% were currently married with one wife. Regarding the level of education, 85.2% of the patients listed secondary school or less. Of the patients, 45% was retired or not currently working. In total, 10.4% had mild, 40.3% had moderate and 49.3% had severe ED. Of the study population, 62.1% had had an ED complaint for less than 5 years, and 84.6% had had a gradual onset of their complaint. The majority of the patients (91.3%) had either a progressive or stationary course, while the minority reported a regressive course and improvement of the condition (Tables 1 and 2).

Table 1 Demographic characteristics of the study population
Table 2 Characteristics of erectile dysfunction in the study population

There were significant differences between the mean age of patients, duration of treatment, number of injections per month, total number of injections, amount of PGE1 per month and total amount of PGE1 on office and self-injection programs (P<0.05 for each). There was no significant difference between the two programs with regard to the dose of PGE1 per injection (P>0.05) (Table 3). A significant increase in the dropout rate in the office injection group in comparison to the self-injection group was observed at different time points of the follow-up period (P<0.05) (Figure 1). There was a significant decrease in ED severity in both self and office injection programs after 1 year of injections, compared to the pretreatment severity (P<0.05 for each). There was no significant difference between the pretreatment severity of ED in the office group compared to self-injection programs. Also, there was no significant difference between the post-treatment severity of ED in the two groups (P>0.05 for each). No significant differences in the presence of pain or priapism were found between the office and self injection programs (P>0.05 for each). However, there was an increase in both penile nodules and fibrosis in the self-injection program compared with the office program (P<0.05) (Table 4). Six patients in this study had experienced priapism. They all were conservatively treated using intracavernosal washing with normal saline 0.9% and ICI of vasoactive agent.

Table 3 Comparison of treatment parameters in office and self-injection programs
Figure 1
figure1

Comparison of dropout rate in office and self-injection programs. *P=<0.05. *χ2; significance level at P<0.05; percentages are calculated for a total of 192 for patients on office injection and a total of 106 for patients on self-injection programs.

Table 4 Assessment of complications in office and self-injection programs after 1 year

Minor hematoma had occurred in nine patients in the self-injection program in the first 3 months and had resolved spontaneously. No cases of infection or elevated liver enzymes were detected in the study population.

There was no significant difference between improvement of natural erection or satisfaction rate after 1 year between patients in both programs (P>0.05 for each). However, there was a significant decrease in the dose of PGE1 used per injection after 1 year in the office program compared with the self-injection program (P<0.05) (Table 5).

Table 5 Assessment of improvement of natural erection and satisfaction rate in office and self-injection programs after 1 year

Discussion

ICI therapy has an important role in the treatment of ED. Despite the advent of new oral agents as first line therapy, ICI still has its place in the field of ED treatments. ICI is a relatively safe, effective and durable strategy for managing ED of various etiologies. Although it is currently regarded as second line therapy, ICI has a reported efficacy rate of 70–90%.10, 11, 12 In the current study, ICI of PGE1 proved to be effective, and the severity of ED complaints was significantly diminished after 1 year of treatment in self- and office injection programs.

Irrespective of the type of vasoactive agent, all published reports of ICI revealed high dropout rates up to 40–50% in at least 1 year follow-up.13 In the current study, the dropout rate was significantly higher in office (80%) compared with self-injection (30%) programs after 1 year. This high dropout rate is at least partly due to the needle phobia, which prohibits many patients from using this method. In addition, the necessity of preplanned intercourse according to the opening hours of the clinic contributed to the high dropout rate in those patients in the office injection program. In our community, we had a unique opportunity to have a large number of patients who preferred to have office injection rather than self-injection. The mean reason was that most of the patients were afraid to inject themselves, and some of them did not like their wives to know about their ED treatment. Although there were significant differences between the mean age of patients, duration of treatment, number of injections per month, total number of injections, amount of PGE1 per month and total amount of PGE1 on office and self-injection programs, there was a comparable satisfaction rate in both programs.

In many studies, improvement in natural or spontaneous erections has been reported to occur in patients with ED who use ICI of papaverine, phentolamine and/or PGE1 for erection induction,9, 14, 15, 16, 17, 18 with 9.2% (range 2–37%) achieving natural erections and no longer requiring any injections. In a large series, improvement of spontaneous erections in 65% of patients who were on a long-term program of ICI was reported.9 Additionally, 29.2% (range 1–50%) reported a reduction in the frequency or dose of injections needed to achieve satisfactory sexual function.14

In the current study, we demonstrated that 7.1 and 14.2% of the patients had reported an improvement of natural erections and a reduction in the dose of injections needed for satisfactory erection, respectively. No significant difference in improvement of natural erections was found between the office and self-injection programs. However, there was a significant decrease in the dose of injections needed for satisfactory erections in the office compared to the self-injection program. Several mechanisms have been reported to account for the improvement in erectile function with ICI therapy: psychological effect as relief of performance anxiety;19 improved cavernous hemodynamic responses resulting from mechanical dilatation of cavernous arteries and/or mechanical stretching of cavernous and tunical tissues;16 angiogenesis and neovascularization of cavernous tissue induced by prostaglandin injection;15 improved oxygenation and hypertrophy of the cavernous tissues during induced erections,20, 21 resulting in a reduction in collagenization and fibrosis, which ultimately produced more efficient responses to sexual stimulation; and finally, normal episodic fluctuations in erectile function related to variations in stress, general health, medications and partner factors.14

Penile fibrosis refers to fibrotic changes in the subcutaneous tissues, the tunica albuginea or intracavernosal sinusoids of the penis. The fact that PGE1 is probably metabolized by the penile tissue and is less acidic than papaverine would at least theoretically suggest that it would result in fewer complications than those commonly seen with papaverine and alpha-1 blockers.20 Hu et al.22 first described penile curvature and fibrosis in patients using ICI therapy. PGE1 became the vasoactive agent of choice for ICI therapy because of its high efficacious rate, and because the risk of priapism and penile fibrosis was reported to be much lower.23, 24 The overall incidence of penile fibrosis post-PGE1 injection therapy is extremely variable; it ranges from no cases reported in some studies up to 15% in other studies.25, 26

In the current study, there were no significant differences in the presence of pain or priapism between office and self-injection programs. However, there was an increase in penile nodules and fibrosis in the self-injection program compared with the office program. The explanation for a higher rate of penile fibrosis in the self-injection rather than the office injection program could be attributed to increased duration of treatment, a higher number of injections per month and total number of injections, a higher amount of PGE1 per month and total amount of PGE1. Furthermore, the standardized technique and the continued titration in the office program could contribute to the diminution of the needed dose of PGE1 and ultimately a decrease in the rate of fibrosis. However, due to the small number of patients with penile fibrosis in this study, we cannot ascertain the difference in that complication between the two programs.

Chen et al.26 reported that there was no significant increase in penile fibrosis related to the number of injections, injection frequency, dose per injection or total dose of PGE1. Other studies have shown that age, total number of injections and total amount of PGE1 are significantly different between patients who developed penile fibrosis and patients who did not.27 The procedure of injection itself was found to produce mild inflammation changes in the superficial and deep dermis and the corpus cavernosum,28 and an increase in the albuginea wall thickness.29 In an experimental study, it has been demonstrated that surgical trauma to the tunica albuginea can induce the production of TGF-B and produce a chronic inflammatory process. However, it did not produce overt tunical fibrosis.30

The presence of fibrosis at locations where needles had not been inserted in the dorsal aspect of the penis has been reported. This implies that the fibrosis that occurs might not have been directly related to the needle trauma. The total number of injections and the total amount of PGE1 used over the whole treatment period appear to indicate a cumulative influence of PGE1 in the development of penile fibrosis. It is possible that penile fibrosis commences as a vasculitis in the subtunical tissues and continues as a chronic inflammation leading to perivascular fibrosis and dense plaque formation.30, 31 The natural history of penile fibrosis needs to be better elucidated in those patients. In impotent men, whether they are using ICI or not, penile fibrosis is much more common than in the general population.30, 31 Therefore, for medical and legal purposes, it is important that the penis should be routinely examined for any fibrotic changes before the therapy is initiated. Patients must be specifically warned of the risk of penile fibrosis. In some studies, fibrosis is constant or probably increases with time. However, others have reported a decrease or even a complete resolving of the fibrosis.32, 33

Resolving of penile fibrosis could be due to discontinuation of self-injection therapy or improvement of the individual injection technique. However, the exact role of drug-related and technique-related fibrotic side effects remains unclear.32, 33 It is therefore mandatory to properly instruct the patients on the self-injection program about the technique and its pitfalls. The use of ultra-thin needles (27–30 gauge) and frequent alteration of the injection site may provide appropriate precautions for the diminution of local side effects.

We investigated a clinically relevant issue: the reliability of intracavernosal office vs self-injection of PGE1 in patients with ED. Potential methodological limitations of our study are the relatively short follow-up period, and the high dropout rate in the office injection program. However, the reasonable number of patients enrolled in this study and the standard instruments we used make our findings reliable and predictive for patients on both office and self-injection programs. The prospective nature of the study enabled us to define the relevant issues to be investigated and compared in both programs.

To our knowledge, this is the largest study to evaluate the reliability of intracavernosal PGE1 office vs self-injection therapy in patients with ED in this community.

Conclusions

In the present study, the intracavernosal self-injection program was more reliable than an office-based program. It is still the ‘gold standard’ in the pharmacological treatment of ED. An office-based injection therapy program can be reserved for a subset of ED patients with special preferences.

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El-Sakka, A. Intracavernosal prostaglandin E1 self vs office injection therapy in patients with erectile dysfunction. Int J Impot Res 18, 180–185 (2006). https://doi.org/10.1038/sj.ijir.3901388

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Keywords

  • erectile dysfunction
  • prostaglandin E1
  • intracavernosal injection

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