Reasons for discontinuing intracavernous injection therapy with prostaglandin E1 (alprostadil)

ADULT UROLOGY

REASONS FOR DISCONTINUING INTRACAVERNOUS INJECTION THERAPY WITH PROSTAGLANDIN E1 (ALPROSTADIL) ¨ CHLINGER, K. LEHMANN, R. CASELLA, A. BLO

AND

T. C. GASSER

ABSTRACT Objectives. To clarify the reasons why experience with self-injection therapy for erectile dysfunction shows high dropout rates. Methods. We studied 86 patients 36 to 76 years old who had been on home treatment for at least 3 months. Sixty-nine patients (80%) were continuing to use injections, and 17 (20%) had discontinued the treatment. Patients were evaluated by interview and clinical examination. Results. Patients still in the program used one injection every 2 weeks, and those who had given up treatment had used one injection in 3 weeks (P 5 0.31). They were in the program for 39 6 27 and 16 6 22 months (P 5 0.002), respectively, and had used 50 (95% confidence interval [CI] 21 to 91) versus 12 (95% CI 4 to 20) injections, respectively (P , 0.0001). Injections producing unsatisfactory penile rigidity, prolonged erections, hematoma at injection site, corporal fibrosis, secondary penile deviation, and mean estimated duration of a pharmacoinduced erection showed no significant differences. Patient satisfaction (P 5 0.02), estimated partner satisfaction (P 5 0.02), increase in self-esteem (P 5 0.01), and negligible effort in performing injections (P 5 0.001) all showed significantly better results for those still in the program. Conclusions. Reasons for dropout from self-injection therapy are not based on objective side effects and discomfort. Patients leaving the program are less motivated, less satisfied with the quality of pharmacoinduced sexuality, consider the effort to perform injections to be substantial, and have not achieved improved self-esteem. UROLOGY 53: 397–400, 1999. © 1999, Elsevier Science Inc. All rights reserved.

E

rectile dysfunction (ED) has been defined as the persistent inability to attain and maintain an erection adequate to permit satisfactory sexual intercourse.1 ED affects approximately 20 to 30 million men in the United States.1–3 Current treatments for ED include oral medications such as yohimbine and trazadone, vacuum devices, intracavernous self-injection therapy, vascular surgery, penile prosthesis implantation, and, more recently, transurethral delivery of alprostadil4 and the oral agent sildenafil.5 Since the observation in the early 1980s6 that intracavernous injection of papaverine may cause an erection, intracorporeal self-injection of vasoactive drugs has become the reference standard in the

diagnosis and treatment of organic ED. Numerous vasoactive agents are currently used for intracavernous self-injection therapy, including papaverine hydrochloride, phentolamine, and prostaglandin E1 (PGE1), alone or in combinations.7,8 There are only a few studies with long-term results from intracaverous injection therapy. They document large dropout rates associated with the treatment itself.9 –20 Most of these studies are based on questionnaires mailed to the patients. Personal interviews or clinical examinations were not routinely performed. We analyzed whether dropout rates from the self-injection program at our institution were related to the technique and/or quality of pharmacoinduced erections.

From the Urologic Clinic, University of Basel, Basel, Switzerland Reprint requests: Kurt Lehmann, M.D., Urologic Clinic, Department of Surgery, Spitalstrasse 21, CH-4031 Basel, Switzerland Submitted: May 26, 1998, accepted (with revisions): August 11, 1998

MATERIAL AND METHODS

© 1999, ELSEVIER SCIENCE INC. ALL RIGHTS RESERVED

We analyzed patients who had participated in the self-injection program for at least 3 months. The inclusion criteria for self-injection were informed consent; a stable relationship; erectile dysfunction with unsatisfactory sexual performance 0090-4295/99/$20.00 PII S0090-4295(98)00478-6 397

TABLE I. Subjective variables and assessment scales Patient’s Estimation

Assessment Scale

Overall satisfaction with pharmacoinduced erections Partner satisfaction as rated by patient himself Penile pain At injection site Within corpus cavernosum (drug-related discomfort) Change in self-esteem General improvement of sexuality

for a minimum of 6 months in duration; manual dexterity; and an organic, mixed, or in select cases a psychogenic cause of ED. Patients had been previously evaluated in a goal-directed approach21 and had been taught self-injection with PGE1 for home use. Usually, a minimum of three sessions was required for instruction in the technique of intracavernous self-injection. The instruction and follow-up evaluations were performed by a physician. We used syringes of 2-mL volume with 26-gauge needles. Patients were seen at least once per year. The interval between the control visits was dependent on the frequency at which individual patients used new syringes. We dispensed a maximum of 10 dosages per patient visit. Of 105 patients who met the inclusion criteria, 19 could not be contacted. The remaining 86 men (82%, mean age 58 6 10 years, range 36 to 76) were available for evaluation by interview and clinical examination. The causes of ED were organic in 60% of patients, mixed in 27%, and psychogenic in 13%, respectively. The distribution was not significantly different between the active and inactive groups (P 5 0.72). Sixty-nine patients (80%) were still active in the program, and 17 (20%) had discontinued. The self-injection program with PGE1 started in June 1987, with the latest inclusion in May 1995. The reevaluation for this study was performed from January up to July 1996. The evaluation protocol covered objective and subjective variables that were related to the technique and effectiveness of intracavernous injection therapy. Objective items were number of injections used, injections producing unsatisfactory rigidity, episodes with prolonged erections, hematoma at the injection site, corporal nodules and fibrosis with or without secondary penile deviation, and pain at the injection site or within the corpus cavernosum. Because patients were supplied with PGE1 from the hospital pharmacy only, we could calculate the number of injections used per individual. All other variables were based on patient reports. Subjective variables and their various assessment scales are shown in Table I. Furthermore, patients were asked whether they would recommend this treatment to a close friend.

STATISTICS Patients who were active in the program were compared with those who discontinued therapy by Student’s t test, Mann-Whitney U test, or Fisher’s exact test, as appropriate; P , 0.05 was considered statistically significant.

RESULTS Table II summarizes the results of the present study. The objective variables that were significantly different between the active and inactive groups were injections used and the treatment period. Patients still in the program had used a total of 4186 injections (1.5 injections per man per month) versus 144 injections for patients who dis398

1–6: 1 5 not at all; 6 5 very satisfied 1–6: 1 5 not at all; 6 5 very satisfied 1–6: 1 5 no pain; 6 5 extremely painful 1–6: 1 5 no pain; 6 5 extremely painful 0–2: 0 5 none; 1 5 some increase; 2 5 marked increase Yes/no

continued treatment (1.2 injections per man per month, P 5 0.31). All other variables showing a significant difference between the two groups were subjective variables: patient and partner satisfaction, better quality of sexuality, increase in self-esteem, and recommendation of this treatment to a close friend (Table II). Furthermore, the effort to prepare and inject PGE1 was substantial for those who became inactive (P 5 0.001). No significant differences were found with respect to penile pain, hematoma at injection site, priapism, erections lasting longer than desired for adequate sexuality, or quality of pharmacostimulated erections. One patient discontinued treatment because of recovery from ED and another because of loss of partner. No patient discontinued as a consequence of pain, prolonged erections, or priapism. Patients in the active group adjusted dosages of PGE1 as required much more frequently than patients who discontinued self-injection (Table III). COMMENT Intracavernous injections are a well accepted and efficacious treatment for ED, with an overall erectile response rate of over 70%.16 Dropout rates from self-injection programs range from 37% to 41%.16 The reasons for discontinuation are recurrent spontaneous erections, concomitant severe disease, loss of partner or severe problems in partner relationship, dissatisfaction with the method, or ineffectiveness of the drug. Patients and partners who continue self-injection therapy show satisfaction rates of nearly 90%.16 We evaluated 86 patients (82%) who were available from a total of 105 men. An important inclusion criterion was that after initial training, they had to be in the intracavernous injection program for at least 3 months. Therefore, those patients who were dissatisfied with the method or complained of ineffectiveness of the treatment were not included in this study population.15 The results show that success in treatment is independent of objective side-effects. Injections producing unsatisfactory penile rigidity and adverse effects, such as prolonged erections, hematoma at injection site, corUROLOGY 53 (2), 1999

TABLE II.

Summary of results Active [n 5 69 (80%)]

Inactive [n 5 17 (20%)]

P Value

58 6 10 38 (4–107) 50 (95% CI 21–91) 0.36 5 5

57 6 8 16 (3–64) 12 (95% CI 4–20) 0.27 4 3.5

0.65 0.0016* ,0.0001* 0.31 0.02* 0.02*

Variable Age (yr) Treatment period (mo) No. of injections used Injections/wk Patient satisfaction (1 5 none; 6 5 very satisfied) Partner satisfaction, patient’s view (1 5 none; 6 5 very satisfied) Better quality of sexuality Increase in self-esteem (0 5 none; 1 5 some; 2 5 marked) Recommend treatment to close friend Pain from injection (1 5 none; 6 5 intensive) Aching pain in corpus cavernosum from PGE1 (1 5 none; 6 5 intensive) Injection failures New scar tissue Duration of erections (min)† Improved spontaneous erections† Bleeding from injection site† Secondary penile deviation† Erections lasting longer than desired for adequate sexuality† Priapism (9 episodes in total)

63 2 65 1 1

(91%) (0–2) (94%) (1–5) (1–5)

5 1 7 2 2

26 1 53 23 8 7 34 8

(38%) (2%) (5–240) (33%) (12%) (10%) (50%) (12%)

2 1 30 3 1 1 3 0

(30%) (0–2) (41%) (1–4) (1–6)

0.001* 0.012* 0.01* 0.42 0.32

(12%) (6%) (8–150) (18%) (6%) (6%) (18%)

0.48 0.26 0.10 0.25 0.70 0.90 0.07 0.20

KEY: PGE1 5 prostaglandin E1. Data presented are mean value 6 SD, median (range), or number (%) of patients. * Significant difference. † Reported by patients; no objective data available.

TABLE III.

Dosages and injections used Active

Patients increasing dosage during treatment period Initially on 20 mg PGE1 Remained on low-dose (#10 mg PGE1) No. of injections #10 mg PGE1 #20 mg PGE1

20 (30%)* 29 (42%) 20 (28%) 1603 2583

Inactive 1 (6%)* 5 (29%) 11 (65%) 66 78

KEY: PGE1 5 prostaglandin E1. Data presented are number (%) of patients, unless otherwise indicated. * P 5 0.059, active vs. inactive group.

poral fibrosis, secondary penile deviation, and erections lasting longer than desired for adequate sexuality, showed no significant differences between the two groups. Neither prolonged erections (9%) nor secondary penile deviations (9%) required termination of treatment. Sixty-nine men still using intracavernous injection reported very high satisfaction rates. This may have been a consequence of the inclusion criterion of at least three successful months in the program. Furthermore, patients were encouraged to contact the treating urologist for any problem, and they used this service frequently. Patient self-report showed a beneficial impact on sexual function for both patient and partner22 and an increase in self-esteem. A common complaint in 50% of men on regular use of intracavernous injecUROLOGY 53 (2), 1999

tion was that erection persisted after successful intercourse. Patients who had discontinued therapy reported significantly lower satisfaction rates and lower increase in self-esteem. They felt inconvenienced by the need to inject themselves. For a subset of 55%, pharmacoinduced erections lasted too briefly and their self-esteem did not increase. An important reason for dropout may be a lower level of motivation. Only 1 patient from the dropout group (6%) tested the effectiveness of increasing dosages. In contrast to this patient, 20 men (29%) from the active group used increasing dosages, demonstrating their willingness to maximize the injection therapy (P 5 0.059). Another important reason for dropout may be the significantly lower partner satisfaction, which itself may have contributed to 399

low patient motivation and finally dropout from treatment. Preparation of the solution and self-injection introduce artificial effects into sexuality, including lack of spontaneity. An immediate erection from the injection occurs in the man. The partner may feel uninvolved because she has not participated in the inducement of erection. The majority of the patients who dropped out did so for reasons not related to the quality of erection that injections could provide. High dropout rates within 1 year of starting injection therapy are found even in those who respond with a rigid erection.20 After initial dropout, discontinuation does not progress at the same rate with long-term use of injection therapy: patients who continued for 2 years tended to do so to long term.12 Dropout rates may be lowered by use of autoinjectors in combination with improved potency of a drug mixture.18 The objective factors were not causative for dropout from treatment in the present series. A total of 26 patients (30%) reported a return of better overall quality of sexually stimulated erections (without injections). Only one of them withdrew from self-injection, probably an individual who overcame psychogenic anxiety.19 The very low dropout rate of patients with improved spontaneous erections in this series is a remarkable result. Pharmacoinduced erection may help men with usually “low” sexual performance to a new positive attitude, which is a strong argument to continue with injections. This effect may become particularly important with the new, less invasive delivery systems, such as intraurethral alprostadil or oral sildenafil.4,5 CONCLUSIONS Intracavernous injection therapy with alprostadil is an efficacious treatment for erectile dysfunction of organic and mixed etiologies. It has some mild side effects such as hematoma formation at the injection site or pain, but very few of them are serious and require termination of treatment. Objective side effects are only rarely causative for dropout in patients who continued beyond the initial 3 months. Patients who discontinue intracavernous injection improve little in self-esteem and also show low motivation to adjust dosages for testing the capacity of the treatment. ACKNOWLEDGMENT. To R. McGandy, M.D., for critical review of the manuscript. REFERENCES 1. NIH consensus conference: impotence. JAMA 270: 83– 90, 1993.

400

2. Feldman HA, Goldstein I, Hatzichristou DG, et al: Impotence and its medical and psychosocial correlates: results of the Massachusetts male aging study. J Urol 151: 54 – 61, 1994. 3. Krane RJ, Goldstein I, and Saenz de Tejada I: Impotence. N Engl J Med 321: 1648 –1659, 1989. 4. Padma-Nathan H, Hellstrom WJG, Kaiser FE, et al: Treatment of men with erectile dysfunction with transurethral alprostadil. N Engl J Med 336: 1–7, 1997. 5. Gingell CJ, Jardin A, Olsson AM, et al: UK-92480, a new oral treatment for erectile dysfunction: a double-blind, placebo-controlled once daily dose response study (abstract). J Urol 155 (suppl): 495A, 1996. 6. Virag R: Intracavernous injection of papaverine for erectile failure (letter). Lancet 2: 938, 1982. 7. Shenfeld O, Hanani J, Shalhav A, et al: Papaverinephentolamine and prostaglandin E1 versus papaverine-phentolamine alone for intracorporal injection therapy: a clinical double blind study. J Urol 154: 1017–1019, 1995. 8. Bennett AH, Carpenter AJ, and Barada JH: An improved vasoactive drug combination for a pharmacological erection program. J Urol 146: 1564 –1565, 1991. 9. Sidi AA, Camoeron J, Duffy L, et al: Intracavernous drug-induced erections in the management of male erectile dysfunction: experience with 100 patients. J Urol 135: 704 – 706, 1986. 10. Girdley FM, Bruskewitz RC, Feyzi J, et al: Intracavernous self injection for impotence: a long-term therapeutic option? Experience in 78 patients. J Urol 140: 972–974, 1988. 11. Hollander JB, Gonzalez J, and Norman T: Patient satisfaction with pharmacologic erection program. Urology 39: 439 – 441, 1992. 12. Sundaram CP, Thomas W, Pryor LE, et al: Long-term follow-up of patients receiving injection therapy for erectile dysfunction. Urology 49: 932–935, 1997. 13. Levine SB, Althof SE, Turner LA, et al: Side effects of self administration of intracavernous papaverine and phentolamine for the treatment of impotence. J Urol 141: 54 –57, 1989. 14. Lakin MM, Montague DK, Medendorp SV, et al: Intracavernous injection therapy: analysis of results and complications. J Urol 143: 1138 –1141, 1990. 15. Pagliarulo A, Ludovico GM, Cirillo-Marucco E, et al: Compliance to long term vasoactive intracavernous therapy. Int J Impot Res 8: 63– 64, 1996. 16. Porst H: The rationale for prostaglandin E1 in erectile failure: a survey of worldwide experience. J Urol 155: 802– 815, 1996. 17. Sidi AA, and Chen K-K: Clinical experience with vasoactive intracavernous pharmacotherapy for treatment of impotence. World J Urol 5: 156 –159, 1987. 18. Virag R, Shoukry K, Floresco J, et al: Intracavernous self-injection of vasoactive drugs in the treatment of impotence: 8 year experience with 615 cases. J Urol 145: 287–292, 1991. 19. McMahon CG: The return of spontaneous erections after self-injection of prostaglandin E1. Int J Impot Res 4: 179 –186, 1992. 20. Witjes WPJ, Meuleman EJH, Nijeholt GABL, et al: The efficacy and acceptance of intracavernous autoinjection therapy with the combination of papaverine/phentolamine. Int J Impot Res 4: 65–72, 1992. 21. Lue TF: Impotence: a patient’s goal-directed approach to treatment. World J Urol 8: 67–74, 1990. 22. Althof SE, Turner LA, Levine SB, et al: Through the eyes of women: the sexual and psychological responses of women to their partner’s treatment with self-injection or external vacuum therapy. J Urol 147: 1024 –1027, 1992.

UROLOGY 53 (2), 1999