Introduction

Although sildenafil citrate has been very successful in treating erectile dysfunction (ED), intracorporeal (IC) penile injections with prostaglandin (PGE1) alone^1,2 or in combination with papaverine and phentolamine³ continue to be an important therapeutic option. While the use of an oral agent (sildenafil citrate) as a first line agent is optimal, this option in postprostatectomy patients depends on the presence of one or two neurovascular bundles.⁴ Patients who had non-nerve-sparing (non-NS) procedures and those who have failed oral therapy will require other options such as IC injections.^5,6,7

Dennis and McDougal⁸ were the first to document the use of IC (PGE 1) therapy in previously potent RP patients with success rates of 85%. A study by Rodriquez Vela et al⁹ in 1999 found that IC PGE1 injection provided adequate rigidity in 95% of their patients. Despite its high degree of effectiveness, patients often do not accept penile injections. Studies show that compliance rates are poor, ranging from 11 to 70%.^{1,3,5,6,10,11,12} Dropout rates in many series exceed 40%.¹³ Factors that compromise the success of therapy include: pain associated with the injection, difficulty in reproducing a successful injection, and penile fibrosis.¹⁴

Recent work by Montorsi et al, demonstrated that early postoperative IC injection limited the development of hypoxia-induced tissue damage and produced an overall improvement in the recovery of spontaneous erections. This study opened a new era of interest for the role of IC injections after RP.⁷ Since oral therapy demonstrated limited effect in the early postoperative period, IC injections can be used as adjuvant therapy for treatment of RP during the recovery of temporary neuropraxia.¹⁵

The literature contains no reports on the long-term effects and durability in patients using IC injections for ED following RP. Therefore, we conducted this study to evaluate the long-term efficacy and compliance of IC injection therapy in a postprostatectomy population and to detail the reasons for its discontinuation. We also sought to determine whether the efficacy of IC injections in postprostatectomy patients is affected by preservation of the neurovascular bundles during surgery or by the type of medication used for injections.

Materials and methods

Patients

We obtained and reviewed the surgical records of a single surgeon (April 1997 to October 2001) who performed radical prostatectomies on 450 sexually active patients with localized prostate cancer. With a mean follow-up of 9 months (6–12 months), 68% (306 /450) patients experienced severe ED with no patient able to achieve vaginal penetration. All 306 patients who sought treatment for ED were initially evaluated by an internist in our group who took a comprehensive sexual history, laboratory evaluation, and physical examination. At that time, the patients were offered standard ED treatments including vacuum constriction device (VCD), intracavernous (IC) injection, or medicated urethral system for erection (MUSE) and since 1998 oral therapy with sildenafil citrate was offered. Of the 306 patients, 102 chose IC injection therapy.

We retrospectively stratified these 102 patients according to the type of NS radical prostatectomy procedure they had undergone: bilateral NS (n=40), unilateral NS (n=19), and non-NS (n=43). The surgeon recorded the anatomic status of the neurovascular bundle at the time of surgery; no intraoperative function tests were performed. The type of NS procedure was confirmed by reviewing operative records.

Drug therapy

The IC regimens used in this study were PGE1 alone (10 or 20 g/ml in normal saline), high-dose triple therapy (20 g/ml PGE1+1 g/ml phentolamine+30 g/ml papaverine), or low-dose triple therapy (5.88 g/ml PGE1+0.59 g/ml phentolamine+ 17.65 g/ml papaverine). Patient training was conducted by an experienced nurse practitioner during two to three office visits and consisted of selection of an appropriate vasoactive agent, dose titration, patient education regarding sterile technique and hemostasis, and partner education. In some cases, the spouse or sexual partner performed the injections if the patient was unable or unwilling to do so. Patients were routinely instructed to change injection sites to prevent corporeal fibrosis and to change their drug regimen (dose and type of IC solution) to ensure effectiveness. All patients were followed at 6- to 9-month intervals.

Survey and data assessment

The patients' response to IC injections was assessed using the International Index of Erectile Function (IIEF-15) questionnaire.¹⁶

A second questionnaire was used to determine the sexual satisfaction of the patients' spouses/partners. The spouses/partners were specifically asked how often they were satisfied with intercourse and how often the patient was able to achieve and maintain an erection. This questionnaire was scored from 1 to 5: 1=never/occasionally; 2=less than half of the time; 3=sometimes/half of the time; 4=more than half of the time; and 5=almost always. Total spousal satisfaction was calculated from these questions and expressed as a percentage.⁴

Patients completed the IIEF-15 questionnaire in the office before (preoperative, baseline) and at mean interval of 9 months (6–12 months) after RP surgery during their follow-up visit. Both surveys were mailed to the 102 patients and their respective spouses/partners. At this time, we also performed a retrospective chart review to collect data on treatment effect, frequency of use, duration of erection following penile injections and side effects. All 102 patients answered IIEF-15 questionnaire and their spouses/partners completed the corresponding spousal questionnaires.

Data from the IIEF-15 questionnaire were condensed into the IIEF-5 questionnaire, which is an abridged five-item version of the IIEF-15 questionnaire, referred to as the Sexual Health Inventory of Men (SHIM). The SHIM is a validated, multidimensional, self-administered questionnaire that is a sensitive indicator of changes in erectile function. It is scored from 1 to 5: 1=never/occasionally; 2=less than half of the time; 3=sometimes/half of the time; 4=more than half of the time; and 5=almost always. The total IIEF-5 score was calculated by totaling the response to all five questions.^16,17

To be included in the study, participants must have completed the office training, completed the IIEF-15 questionnaire, and reported satisfactory home use. Men were excluded if they received preoperative or postoperative hormonal therapy, radiation therapy, or any concurrent form of therapy for ED.

Statistical analysis

The patients were retrospectively stratified according to the type of NS procedure they had undergone: bilateral NS, unilateral NS, or non-NS. The type of surgical procedure was determined by a chart review and confirmed by the questionnaire. Skewness and kurtosis were used to evaluate the distribution of the results. The Wilcoxon signed-rank test was used to compare baseline IIEF-5 (SHIM) scores before surgery, before treatment, and after IC injections therapy to determine changes in response. The ² test was used to compare categories (NS vs non-NS RP surgery, single therapy vs triple therapy (high- and low-dose). The number of patients discontinuing treatment for multiple reasons was calculated as a percentage of the total. The data are presented using mean, standard deviation, and percentages. A two-tailed significance level of P0.05 was used for all statistical tests, and all tests were performed with SAS version 8.0 software.

Results

The mean follow-up period for all the patients was 42.2 y, and the mean patient age was 60.46.3 y. Of the 102 patients, 40 had a bilateral NS procedure, 19 had a unilateral NS procedure, and 43 had a non-NS procedure. All of the patients had experienced ED for 9 months (6–12 months) after surgery before they started IC injection therapy. Of the 102 patients, 62 (61%) used PGE1 alone, 21 (20%) used low-dose triple therapy, and 19 (19%) used high-dose triple therapy. Overall, 68% (69/102) of the patients achieved and maintained erections sufficient for sexual intercourse; and 48% (49/102) of patients continued long-term therapy with a mean use of 3.71.9 y. The duration of erection following penile injection ranged from 9 to 12 min. The ability to achieve vaginal penetration (68%) directly correlated with the spousal satisfaction rate (65%).

Table 1 shows that for all SHIM (IIEF-5) domains, scores dropped after surgery but increased significantly after IC injection use. Furthermore, the total mean SHIM score after IC injections use was similar to the total presurgery mean score P0.05. There were no statistically significant differences in the IIEF-5 responses between the NS (n=63) and non-NS (n=39) groups (Table 2). The frequency of use in the compliant (49/102) subgroup (median, 25 and 75% interquartile range) was four (2, 8) times a month. In the compliant group, there was no significant difference in response for the type of IC solution used: PGE1 (n=29) or triple therapy (n=20).

Table 1 - SHIM (IIEF-5) scores (presurgery, pretreatment, and after IC use) from 102 men with ED caused by radical prostatectomy.

Full table

Table 2 - SHIM (IIEF-5) questionnaire responses stratified by type of surgery/treatment with injection.

Full table

In all, 52% (53/102) patients discontinued IC therapy after a mean use of 14.5 months for the following reasons: insufficient erections, 33% (18/53); preference for oral therapy, 32% (17/53); fear of injections, 11% (6/53); troublesome procedure, 11% (6/53); loss of partner, 8% (4/53); priapism, 1% (1/53); natural return of erections, 1% (1/53). When including patients who preferred oral therapy to IC injections, who had loss of partners, and return of normal erections, the compliance to IC injections was 70.6% (71/102).

The total mean SHIM (IIEF-5) score for the 18 patients who stopped using the IC injections because of a lack of efficacy (insufficient erections) was 10.52.65. These 18 patients did not differ from the compliant patients in the type of injection agent used. The type of IC injection solution did not influence the discontinuation rate. The SHIM (IIEF-5) scores and treatment discontinuation rates showed a distinct pattern. Patients with an IIEF-5 score 10 while on IC therapy were much more likely to discontinue treatment [90% (28/31)] than patients with post-therapy IIEF-5 scores 19 [35% (25/71)].

Discussion

In this study, we found that 69 (68%) of our 102 postprostatectomy patients were satisfied with IC injection therapy and that 49/102 (48%) chose to continue with the therapy long-term (mean, 3.5 y). However, including preference to oral therapy (n=17), loss of partner (n=4), and return of natural erections (n=1), the compliance to IC injections was 70.6% (71/102). The type of RP surgery (bilateral NS, unilateral NS, and non-NS) and type of regimen (single, high-dose triple therapy, or low-dose triple therapy) did not affect the efficacy of this therapy.

The latter finding is not consistent with the results of a prospective study performed by Bechara et al,¹⁸ who showed that the three-drug mixture is more effective than high-dose PGE1 alone in achieving erections suitable for penetration. However, our satisfaction and compliance rates are similar to those of Mulhall et al³ and Purvis et al.⁶ Using an institutional questionnaire, Mulhall et al found a good response in 75% of their patient group using PGE1, which included patients with ED of all etiologies.³ They reported an attrition rate of 31% over a 38-month period. Purvis found that 87% of their patient sample (which included patients with ED caused by a variety of etiologies) was fully or partially satisfied with IC injections. Their discontinuation rate in their study was 58% over 2 y.⁶

Cost, penile discomfort, and patient–partner problems were the major reasons for discontinuation in the Mulhall³ study. Lack of efficacy was the primary reason for discontinuation in one of seven (14.1%) patients. In the Purvis study, lack of spontaneity, penile discomfort, and cost of therapy were the main reasons for dissatisfaction. Inadequate rigidity or lack of efficacy was the primary reason for discontinuation in 18% of the patients.⁶ The primary reasons for discontinuation in our study were inadequate erections and a preference for oral treatment with sildenafil citrate. Like both Mulhall³ and Purvis,⁶ we found side effects to be an infrequent reason for discontinuing treatment.

When the response of IC injections is stratified according to the NS status, we found IC injections just as effective in non-NS patients vs patients who had NS procedures (P>0.05). Thus, IC injection therapy can be used as contemporary second-line management strategy for NS patients who fail oral therapy and a first option in patients with non-NS procedures.¹⁵ The presence or absence of the neurovascular bundles, which influences the relative amount of nitric oxide secretion significantly, influences a man's ability to achieve vaginal intercourse. With a neurologic injury, there is a decreased release of nitric oxide across the neuromuscular junction, limiting the amount of available cyclic guanosine monophosphate (cGMP).^19,20 The advantage of IC injection agents is that the ensuing smooth muscle relaxation is independent of endogenous vasoactive substance such as nitric oxide production, which is impaired by nerve damage. The degree of smooth muscle relaxation may be more complete with pharmacologically induced erections, so that a patient with a mild venous leak still may veno-occlude to the point of functional erection.^2,21

Our study showed that 32% (17/53) of the patients, who discontinued IC therapy (mean use 1.5 y) switched to sildenafil citrate with acceptable sexual satisfaction. The mean IIEF-5 score of these subgroups was 18.64.5. Thus, although injections may be more efficacious than sildenafil citrate, the discomfort and anxiety weigh heavily in the patient's preference for oral therapy.^15,22 Our study suggested that patients who are successfully managed with IC injection therapy should be offered the option of using oral therapy.

The compliant patients performed IC injections at a frequency of 4.8 times a month with efficacy scores similar to their presurgery scores. The regular follow-up and comprehensive training that was offered to the patients may have improved compliance. We feel that periodic follow-up combined with realistic expectations increase patient compliance and lowers the attrition rate. Further studies are required to determine if other injectable agents (forskalin, vasoactive intestinal peptide, and moxisylate), alone or in combination, can provide better efficacy and long-term compliance.^23,24,25

Although penile injection therapy is often not routinely advised in the early postoperative period because of penile discomfort, patient anxiety or lack of interest, there is some evidence that 'early rehabilitation' of the penis may be necessary to prevent corporeal fibrosis during the neuropraxia period following radical prostatectomy.⁷

In our experience, the neuropraxia may persist from 6 to 24 months.²⁶ This concept supports the study of Montorsi et al of 1997 who demonstrated that early postoperative IC injection limited the development of hypoxia-induced tissue damage and produced an overall improvement in the recovery of spontaneous erections.⁷ Since sildenafil citrate shows limited effect in the early postoperative period, the temporary use of IC injections during this time may become an important adjuvant treatment for postprostatectomy patients.²⁶ Further confirmatory studies are necessary to support this concept that early penile rehabilitation improves long-term penile function. The routine use of IC injection as adjuvant therapy immediately following radical prostatectomy may require the development of new vasoactive agents that produce less penile discomfort and pain.

Conclusions

IC injections can provide excellent efficacy and compliance in up to 70% of patients, when patients who switched to oral therapy, had loss of a partner, or experienced return of normal erections were included. Comprehensive patients and partner's education may contribute to high compliance rates. IC injections appeared to be just as effective in patients who underwent non-NS prostatectomy as those who had NS procedures. Thus, our study suggests that IC injections are an excellent salvage option in NS patients who fail oral therapy and a first option in patients with non-NS procedures. Whether IC injections can be used as adjuvant therapy in the neuropraxia period following radical prostatectomy may depend on the development of new injectable agents that do not produce pain.

References

1. Porst H. The rationale for prostaglandin E1 in erectile failure: a survey of worldwide experience. J Urol 1996; 155: 802–815.  | Article | PubMed | ISI | ChemPort |
2. Cawello W et al. Pharmacokineticks of prostaglandin E 1 and its main metabolites after intacavernous injection and short term infusion of prostaglandin E1 in patients with erectile dysfunction. J Urol 1997; 158: 1403–1407. | PubMed |
3. Mulhall JP et al. The causes of patient dropout from penile self-injection therapy for impotence. J Urol 1999; 162: 1291–1294. | Article | PubMed | ChemPort |
4. Zippe CD et al. Role of Viagra after radical prostatectomy. Urology 2000; 55: 241–245. | Article | PubMed | ISI | ChemPort |
5. Linet OI, Ogrinc FG. Efficacy and safety of intracavernosal alprostadil in men with erectile dysfunction. N Eng J Med 1996; 334: 873–877.
6. Purvis K, Egdetveit I, Christiansen E. Intracavernosal therapy for erectile failure—impact of treatment and reasons for dropout and dissatisfaction. Int J Impot Res 1999; 11: 287–299. | Article | PubMed | ChemPort |
7. Montorsi F et al. Recovery of spontaneous erectile function after nerve sparing radical retropubic prostatectomy with and without early intracavernous injections of alprostadil: results of a prospective, randomized trial. J Urol 1997; 158: 1408–1410. | Article | PubMed | ISI | ChemPort |
8. Dennis RL, McDougal WS. Pharmacological treatment of erectile dysfunction after radical prostatectomy. J Urol 1988; 139: 775–776. | PubMed |
9. Rodriguez VL et al. Erectile dysfunction after radical prostatectomy. Etiopathology and treatment. Actas Urol Esp 1997; 21: 909–921. | PubMed |
10. Irwin MB, Kata EJ. High attrition rate with intracavernous injection of prostaglandin E1 for impotency. Urology 1994; 43: 84–87.  | PubMed |
11. Vardi Y, Sprecher E, Gruenwald I. Logistic regression and survival analysis of 450 impotent patients treated with injection therapy: long-term dropout parameters. J Urol 2000; 163: 467–470. | PubMed |
12. Sexton WJ, Benedict JF, Jarow JP. Comparison of long-term outcomes of penile prosthesis and intracavernosal injection therapy. J Urol 1998; 159: 811–815. | Article | PubMed | ISI | ChemPort |
13. Lakin MM et al. Prostaglandin E1 injection therapy for post-prostatectomy impotence: an outcome analysis. J Urol 1996; 155: 639–643. | PubMed |
14. Evans C. Complications of intracavernosal therapy for impotence. In: Carson C, Kirby R, Goldstein I (eds). Textbook of Erectile Dysfunction. Isis Medical Media: Oxford, 1999, pp 365–370.
15. Ajay Nehra. Intracavernosal therapy: when oral agents fail. Cur Urol Rpt 2001; 2: 468–472.
16. Rosen RC et al. The International Index of Erectile Function (IIEF): a multidimensional scale for assessment of erectile dysfunction. Urology 1997; 49: 822. | Article | PubMed | ISI | ChemPort |
17. Rosen RC et al. Development and evaluation of an abridged 5-Item version of the International Index of Erectile Function (IIEF-5) as a diagnostic tool for erectile dysfunction. Int J Impot Res 1999; 11: 319–326. | Article | PubMed | ISI | ChemPort |
18. Bechara A et al. Prostaglandin E1versus mixture of prostaglandin E1, papavereine and phentolamine in non-responders to high papaverine plus phentolamine doses. J Urol 1996; 155: 913–914.  | Article | PubMed | ChemPort |
19. Burnett AL. Nitric oxide in the penis: physiology and pathology. J Urol 1997; 157: 320–324. | Article | PubMed | ISI | ChemPort |
20. Burnett AL. Nitric oxide regulation of penile erection: biology and therapeutic implications. J Androl 2002; 23: S20–S24. | PubMed | ISI | ChemPort |
21. Ajay Nehra, Irwin Goldstein. Sildenafil citrate after radical retropubic prostatectomy: con. Urology 1999; 54: 587–589. | PubMed |
22. De la Taille A, Delmas V, Amar E, Boccon-Gibod L. Reasons for dropout from short-and long-term self-injection therapy for impotence. Europ Urol 1999; 35: 312–317.
23. Mc Mohan CG. A pilot study of role of intracavernous injection of vasoactive intestinal peptide and phentolamine in the management of erectile failure. Int J Impot Res 1996; 8: 233–236. | PubMed |
24. Mullhall JP et al. Intracavernosal forskalin: role in management of vasculogenic impotence resistant to 3-agent pharmacotherapy. J Urol 1997; 158: 1752–1758. | PubMed |
25. Buvat J et al. Double blind multicenter study comparing alprostadil alpha-cyclodextrin with moxisylyte chlorohydratein chronic organic erectile dysfunction. J Urol 1998; 159: 116–119. | Article | PubMed | ISI | ChemPort |
26. Raina R et al. Management of erectile dysfunction following radical prostatectomy. Curr Urol Rpt 2001; 2: 495–503.