Intracavernous Pharmacotherapy for Impotence: Selection of Appropriate Agent and Dose

0022-534 7/93/1495-1288$03.00/0 Vol. 149, 1288-1290, May 1993

THE JOURNAL OF UROLOGY Copyright© 1993 by AMERICAN UROLOGICAL ASSOCIATION, INC.

Printed in U.S.A.

INTRACA VERNOUS PHARMACOTHERAPY FOR IMPOTENCE: SELECTION OF APPROPRIATE AGENT AND DOSE BURKHARD VON HEYDEN, CRAIG F. DONATUCCI, NORBERT KAULA AND TOM. F. LUE* From the Department of Urology, University of California School of Medicine, San Francisco, California

ABSTRACT

We performed a retrospective analysis of 101 impotent patients using intracavernous selfinjections as primary therapy for vasculogenic impotence. A total of 70 patients used an average of 5.58 µg. prostaglandin El (95% confidence interval 4.83 to 6.34 µg.) as a single agent, and 31 injected 0.40 mi. (95% confidence interval 0.342 to 0.457 ml.) of a combination of papaverine (12 mg./ml.), phentolamine (1 mg./ml.) and prostaglandin El (9 µg./ml.). We describe the procedure to establish the dosage for home use and discuss the implications of the low dosages relative to previous reports. KEY WORDS: prostaglandins, alprostadil, papaverine, phentolamine, penile erection

The introduction of intracavernous vasoactive agents has revolutionized the diagnosis and treatment of impotence. The widespread applicability of these drugs to current diagnostic regimens requires familiarity on the part of the urologist, and the broad acceptance of therapeutic self-injection programs demands that all practitioners in the field be facile in the use of these drugs. Papaverine hydrochloride and phentolamine were the first agents used for self-injection therapy, with reports of success ranging from 60 to 80% in the literature. 1 However, with accumulated experience it has become apparent that repetitive intracavernous injections of papaverine may result in corporeal fibrosis. Levine et al have shown that the acidic vehicle in which the papaverine is suspended may be responsible for this fibrosis. 2 To obviate the problems ofpapaverine injection, Ishii 3 and Stackl 4 et al independently presented the first reports of the efficacy of prostaglandin El as an intracorporeal agent. This single agent produced erection in a greater percentage of patients than papaverine hydrochloride alone or combined with phentolamine. The average reported dose in the literature ranges from 10 to 40 µg. Unfortunately, self-injection of prostaglandin El has been associated with pain in approximately 20% of the patients and this has limited its acceptance. 5 Bennett et al have recently reported the results of a selfinjection program using combination therapy. 6 This approach is attractive because a lesser amount is injected and the undesirable effects of each agent can be minimized. Clearly, the adverse effects of each drug necessitate the use of the smallest possible amount for self-injection. In our experience patients who use prostaglandin El for self-injection appear to require a much smaller dose than previously reported. Therefore, we reviewed retrospectively our self-injection program to determine our method for establishing patient dose and to identify those aspects of our program that permitted the use of significantly lower amounts of prostaglandin El. PATIENTS AND METHODS

We performed a retrospective analysis of 101 consecutive new patients who began to use intracavernous injections as the primary therapy for vasculogenic impotence at our erectile dysfunction clinic between July 1, 1990 and July 1, 1991. The distribution of risk factors established by medical history included coronary artery disease in 25 patients, hypertension in 22, diabetes mellitus in 13, smoking in 18, hypercholesterolemia in 6, transurethral prostatic resection in 5 and radical pelvic Accepted for publication August 21, 1992. Supported by Deutsche Forschungsgemeinschaft Grant HE1830/1-l. * Requests for reprints: Department of Urology, University of California, San Francisco, California 94143-0738.

surgery in 3. Patient age ranged from 22 to 80 years, with a median age of 59 years (mean 58.62). The duration of erectile dysfunction ranged from 2 months to 20 years, with a median of 3 years (mean 4.07). Initial evaluation of these patients was the same as that of all impotent patients at our institution. A detailed history was obtained regarding the nature and duration of erectile dysfunction. Physical examination with provocation of the bulbocavernosus reflex was performed. Hormonal profile, including prolactin and testosterone levels, was obtained and psychological assessment was determined with a standardized symptom questionnaire. Patients with suspected psychogenic impotence underwent nocturnal penile tumescence monitoring. If psychogenic impotence was confirmed they were referred for appropriate psychotherapy and excluded from further consideration. We used the combined intracavernous injection and selfstimulation test 7 as an initial diagnostic procedure and, more importantly, to determine the potential suitability of the patient for home injection therapy. Combined intracavernous injection and self-stimulation testing was performed in conjunction with high resolution duplex ultrasonography of the penis (Diasonics, SP A 1000). The patient was placed in a supine position. All patients received a test dose of 10 µg. prostaglandin El injected into the right corpus cavernosum followed by duplex ultrasonography 5 minutes later. The diameter of each cavernous artery was measured, the vessels were examined for arterial wall thickness (sclerosis) and quality of pulsations, and the peak flow velocity in both arteries was determined. Approximately 10 minutes after injection, or at completion of duplex ultrasonography, the initial quality of erection was estimated on a graded scale (1-soft, 2-firm and 3-rigid) by 1 of us (C. F. D. or T. F. L.). The patient was then placed in a sitting position with a rubber band around the base of the penis and asked to perform genital self-stimulation, short of ejaculation, for 5 minutes in a private setting, and the quality of erection was again estimated. Finally, the patient was asked to sit quietly for 5 more minutes after which the character of the erection was then graded. Patients maintaining erectile rigidity were presumed to have an intact veno-occlusive mechanism, while patients who lost substantial rigidity within 5 minutes of stimulation were presumed to have significant venous leakage. 7 If the erection achieved after 10 µg. prostaglandin El proved to be insufficient, we used a diagnostic booster injection of intracavernous drugs to determine if an increase in agent would produce rigid erection. This diagnostic booster saved the patient a second visit and allowed us to determine better the initial dosage for self-injection therapy. A combination of papaverine (12 mg./ml.), phentolamine (1 mg./ml.) and prosta-

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lNTRACAVERNOUS PHARMACOTHERAPY FOR IMPOTENCE

glandin El (9 µg./ml.) was administered at an initial dosage of 0.3 ml. Patients with a significant erectile response after combined intracavernous injection and self-stimulation testing were observed for the duration of erection. If erection exceeded 60 minutes an intracavernous injection of 250 µg./ml. phenylephrine hydrochloride was given every 5 minutes until detumescence. Patients who wished to begin a self-injection program returned for 2 further visits, at which time the dosage of the intracavernous agent was individualized. Patients with an adequate erection after prostaglandin El alone received this drug. In our practice 15 µg. per injection is the upper limit of single agent therapy. Patients not responding to prostaglandin El as a single agent, who had a submaximal response to the diagnostic booster injection or who experienced significant pain with prostaglandin El began self-injection with combination therapy. The initial dosage was 0.3 ml. with a maximal dosage of 0.6 ml. Patients were provided a handout detailing the technique of self-injection at the initial visit, were "walked through" selfinjection at the second visit and were observed for proper technique at the third office visit. Self-stimulation was performed after each injection and the response was noted to allow for further modification of dose at the next visit. When patients were ready to begin self-injection therapy the office dose was decreased slightly (10%) to arrive at the proper initial home dosage. This method corrected for the better response anticipated in a relaxed and more natural atmosphere, thus decreasing the chance of prolonged erection. Statistical analysis was performed with JMP software, SAS Institute. RESULTS

Two groups of patients were established depending upon which drug was eventually chosen for self-injection. Prostaglandin El was used in 70 patients, with 31 injecting the combination. The average dose injected by patients using prostaglandin El was 5.58 µg. (95% confidence interval 4.83 to 6.34 µg.). Patients using the combination injected an average dose of 0.40 ml. (95% confidence interval 0.342 to 0.457 ml., 0.40 ml. of the combination equals 4.8 mg. papaverine, 0.4 mg. phentolamine and 3.6 µg. prostaglandin El). No relationship between age and dosage injected could be discerned in either group, although both groups demonstrated a tendency towards greater dose requirements with increasing age. The increase in cavernous artery diameter (inner) after injection was measured in all patients. The response was similar in both groups: the increase after prostaglandin El was 82.6% on the right side and 77.5% on the left side, and the increase after the combination was 88.9% on the right side and 80.0% on the left side (p <0.005 on both sides). Mean peak flow rate was 24.7 cm. per second (95% confidence interval 22.7 to 26.7). Although this was not significant, we found a tendency toward lower velocity with increasing age. Self-stimulation improved erection in the majority of the patients. Of the 101 patients 19 achieved a rigid erection on injection of the initial test dose of 10 µg. prostaglandin El alone, 59 improved the character of the erection with genital self-stimulation and 7 remained unchanged. No data were available in 16 patients. Approximately 90% of the patients were able to begin home self-injection therapy after 2 instructional visits. DISCUSSION

Intracavernous vasoactive agents have an essential role in the diagnosis and treatment of impotence. Functional evaluation of the penile arteries depends on changes in the morphology of the cavernous arterial system, as well as measurement of the blood flow velocity within these arteries after induction of erection with a pharmacological agent. The mean peak flow velocity of 25 cm. per second after prostaglandin El or the

1289

combination seen in our rrn,w,~n,,nr1s, •Nell with our previously reported data. 8 Lopez et al recently proposed a penile blood flow index to incorporate all parameters from duplex ultrasonography into 1 value. 9 According to them patients with index values of less than 285 are suffering from predominantly arteriogenic impotence. When applied to our patients the mean penile blood flow index was 240 (95% confidence interval 212 to 269), indicating arterial insufficiency as the most common cause. The main side effect of prostaglandin El is painful erection reported in 9 to 75% of the patients. 10• 11 Approximately 15% of our patients using prostaglandin El for home injection therapy have reported pain. Prolonged erection (in 0.1 %10 ) and priapism (in 2.6% 12 ) are rarely seen. Although papaverine has not caused pain on injection, prolonged erection has been reported in 2.4 to 9.5% of the patients. 10 The use of papaverine as a single agent should be avoided in most instances because of its low efficacy (35. 7%) and the high risk of cavernous fibrosis. 10 Phentolamine alone does not result in sufficient erection. Therefore, it is widely used in combination with papaverine. 10 • 13 • 14 Priapism with this combination has been recorded in 4 % of the patients 13 and corporeal fibrosis is a documented long-term adverse effect. 15 Bennett et al have introduced the use of a triple combination of prostaglandin El, papaverine and phentolamine, relying on the synergistic effect of each drug while diminishing individual adverse effects. 6 In our laboratory, in vivo primate and canine studies have suggested that prostaglandin El and papaverine increase the concentration of intracellular cyclic adenosine monophosphate, which results in relaxation of the cavernous smooth muscle. Prostaglandin El promotes the action of adenylate cyclase, while papaverine inhibits phosphodiesterase from breaking down cyclic adenosine monophosphate. Phentolamine blocks a-mediated smooth muscle contraction, preventing detumescence. With the combination we noted few side effects, only occasional pain at the moment of injection and a rare hematoma. Duplex ultrasonography parameters increased significantly after injection of intracavernous agents. We did not routinely measure all parameters after a diagnostic booster injection in our patients. Muelemann et al recently presented data suggesting that post-injection cavernous blood flow is independent of agents and dosages used. 16 Diagnostic booster injections are used to determine more quickly if a patient is a candidate for self-injection therapy. In our study only patients responding to booster injection were begun on home therapy. In 29 boosters done recently 18 patients (62%) were saved for autoinjection therapy alone, while 11 needed additional therapy (10 injection plus an external vacuum device and 1 penile vein ligation). Three patients required injection of phenylephrine 1 hour after the booster for detumescence (unpublished data). There have been no instances of prolonged erection or priapism with this diagnostic regimen. The dosages used by our patients for self-injection were 25 to 50% less than the average dose reported by most other groups (see table). 4 • 6 • 10- 14• 17- 22 Presumably, adverse effects can be diminished by injection of the smallest effective amount. Our prior data indicate that sexual/tactile self-stimulation improves an erection significantly (74 % of the patients) 7 and that the anxiety provoking setting (doctor's office versus home) may also decrease erectile quality. Failure to consider these factors when formulating a dosage for home use may lead to administration of an inappropriately large amount of medication with resultant prolonged erection. The duration of induced erections reported in the literature varies widely and may reflect the use of inappropriately high doses. Prostaglandin El alone resulted in erections of a mean duration of 40 minutes to 3.5 hours, 11 • 12• 14• 17• 18• 23 and the combination of papaverine and phentolamine resulted in a mean

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VON HEYDEN AND ASSOCIATES

Comparison of dosages for pharmacotherapy of impotence Combination Reference

Stack! et al' Bennett et al 6 Juenemann 10 Waldhauser and Schramek 11 Schramek et al 12 Sidi et al 13 Stief and Wetterauer 14 Hwang et al1 7 Schramek and W aldhauser 18 Ishii et a!1 9 Sarosdy et a!2° Floth and Schramek 21 Earle et al2 2 Present data

Prostaglandin El (µg.) Test Dose

Final Dose

20

10- 20

20

5- 40

5- 40

5- 40

20 5, 10 20 10 10 5 10

Papaverine (mg.)

Phentolamine (mg.)

Prostaglandin El (µg.)

Papaverine (mg.)

0.15 0.25- 1.5 0.25

3.75- 12.5 12.l

0.12- 0.4 0.4

3.6

0.30

Prostaglandin El (µg.)

Final Dose

Test Dose 4.41 3.75- 45 7.5

Phentolamine (mg.)

1.47

4.41 3.75- 45 7.5

0.15 0.25- 1.5 0.25

3.75- 12.5 12.1

0.12-0.4 0.4

4.10- 5.48

0.34- 0.55

1.47

20 5, 10 20 10 5-60 5

1- 15

duration of 165 minutes.11 Schramek and Waldhauser demonstrated that the duration could be lessened from 120 to 40 minutes by decreasing the prostaglandin El dose from 10 to 5 µg. 18 We believe that an erection longer than 30 to 60 minutes carries an increased risk of priapism. By diminishing the dose of intracavernous agent necessary for home injection, the combined intracavernous injection and self-stimulation test markedly decreases this risk. Although occasionally a patient may find a request for genital self-stimulation to be embarrassing, in our experience most patients cooperate fully once the rationale for self-stimulation is explained to them. That rationale is to initiate and maintain a natural erection adequate for sexual satisfaction without adverse effects. This is the preferred outcome of our self-injection program.

11. 12. 13.

14. 15.

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1. Junemann, K.-P. and Alken, P .: Pharmacotherapy of erectile dysfunction: a review. Int. J. Impotence Res., 1: 71, 1989. 2. Levine, S. B., Althof, S. E., Turner, L. A., Risen, C. B., Bodner, D. R., Kursh, E. D. and Resnick, M. I.: Side effects of self-administration of intracavernous papaverine and phentolamine for the treatment of impotence. J . Urol., 141 : 54, 1989. 3. Ishii, N., Watanabe, H., Irisawa, C. , Kikuchi, Y., Kawamura, S., Suzuki, K., Chiba, R., Tokiwa, M. and Shiiai, M.: Studies on male sexual impotence. Report 18. Therapeutic trial with prostaglandin El for organic impotence. Jap. J. Urol., 77: 954, 1986. 4. Stack!, W., Hasun, R. and Marberger, M. : Intracavernous injection of prostaglandin El in impotent men. J. Urol., 140: 66, 1988. 5. Lue, T . F.: Impotence: a patient's goal-directed approach to treatment. World J . Urol., 8: 67, 1990. 6. Bennett, A. H., Carpenter, A. J . and Barada, J. H.: An improved vasoactive drug combination for a pharmacological erection program. J . Urol., 146: 1564, 1991. 7. Donatucci, C. F. and Lue, T. F.: The combined intracavernous injection and stimulation test: diagnostic accuracy. J . Urol., 148: 61, 1992. 8. Lue, T. F., Mueller, S. C., Jow, Y. R. and Hwang, T. I.: Functional evaluation of penile arteries with duplex ultrasound in vasodilator-induced erection. Urol. Clin. N. Amer., 16: 799, 1989. 9. Lopez, J. A., Espeland, M. A. and Jarow, J. P.: Interpretation and quantification of penile blood flow studies using duplex ultrasonography. J . Urol., 146: 1271, 1991. 10. Juenemann, K. P.: Pharmacotherapy of impotence: where are we going? In: World Book on Impotence Research: Basic and Clin-

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