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A Prospective Double-Blind Trial of Intracorporeal Papaverine Versus Prostaglandin E1 in the Treatment of Impotence
0022-534 7/89 /1413-0551$02.00/0 Vol. 141, March
THE JOURNAL OF UROLOGY
Copyright© 1989 by The Williams & Wilkins Co.
Printed in U.S.A.
A PROSPECTIVE DOUBLE-BLIND TRIAL OF INTRACORPOREAL PAPAVERINE VERSUS PROSTAGLANDIN El IN THE TREATMENT OF IMPOTENCE MICHAEL F. SAROSDY,* CLAYTON H. HUDNALL, DEBORAH R. ERICKSON, THOMAS C. HARDIN AND DONALD E. NOVICKI From the Division of Urology and Department of Pharmacology, The University of Texas Health Science Center, San Antonio, Texas
ABSTRACT
A randomized prospective, double-blind clinical trial was performed comparing intracorporeal injections ofpapaverine (30 mg. per ml.) with prostaglandin El (10 mcg. per ml.) as pharmacological treatment of impotence. A total of 15 men completed the study, receiving papaverine and prostaglandin El in a crossover design. Over-all, 9 of 15 evaluable patients had a full erection with either 1 or both drugs: 3 secondary to papaverine only, 2 to prostaglandin El only, and 4 to both drugs. No major complications were observed. We conclude that intracorporeal prostaglandin El may be used successfully to stimulate pharmacological erections and that it might be useful in patients not responding to intracorporeal papaverine. (J. Ural., 141: 551-553, 1989) lntracorporeal pharmacotherapy for erectile impotence has gained widespread acceptance since its introduction by Virag and associates, 1 and Brindley. 2 While a combination of papaverine hydrochloride and phentolamine mesylate is used most commonly, a wide variety of pharmacological agents have been identified that are capable of producing erections in selected impotent men.'1 Although papaverine hydrochloride and phentolamine mesylate work well in the majority of patients, side effects of the combination include priapism and corporeal fibrosis. Therefore, evaluation of other agents that might avoid these complications is desirable. Prostaglandin El is a naturally occurring compound important to the inflammatory response of human tissues. After an initial report of prostaglandin El-induced changes in human erectile tissues observed in vitro,4 Ishii and associates reported a noncomparative series of 88 patients treated with prostaglandin El in which no cases of priapism were observed. 5 We evaluate the efficacy of prostaglandin El compared to papaverine hydrochloride when used as single agents in a controlled trial of intracorporeal pharmacological treatment of impotence. MATERIALS AND METHODS
Patients. Patients presenting with a chief complaint of impotence were evaluated for suitability and invited to participate in the study. Those who agreed underwent a complete history and physical examination, including penile and brachia! blood pressures, as well as nocturnal penile tumescence monitoring for 2 or 3 consecutive nights. Laboratory evaluation included a complete blood count, thyroid function tests, serum glucose and measurements of serum testosterone, and luteinizing and follicle-stimulating hormones. Patients with uncontrolled diabetes, thyroid disease and psychogenic impotence were excluded. Informed consent was obtained according to Federal and institutional guidelines. Medications. Papaverine injections were prepared using 30 mg./ml. papaverine hydrochloride with 0.5 per cent chlorobutanol as preservative. On each study day either 30 mg. (1 ml.) or 60 mg. (2 ml.) were drawn into a 3 ml. plastic syringe, labeled to· indicate only study drug and delivered to a blinded investigator who administered the injection and evaluated response. Accepted for publication August 17, 1988. * Requests for reprints: Division of Urology, 7703 Floyd Curl Drive, San Antonio, Texas 78284-7845. 551
Prostaglandin El (500 mcg./ml.) was diluted with sterile normal saline to yield a concentration of 10 mcg./ml. Diluted solutions were stored at 4C and unused dilutions were discarded after 14 days. Prostaglandin El injections were similarly prepared from this dilution for each study day as described previously, resulting in doses of either 10 mcg. (1 ml.) or 20 mcg. (2 ml.). The same investigator prepared all dilutions and syringes. Randomization was performed with the closed-envelope technique in blocks of 8. The randomization code was not broken until all patients had completed the trial. Drug administration. Drugs were administered by direct corporeal injection with a 25 gauge needle and a 3 cc syringe. Manual compression of the injection site was maintained for 5 minutes after the injection. Patients were monitored for injection site hematoma, pain, swelling and hypotension. Study design. Each patient was randomized to receive either papaverine or prostaglandin El at the .respective lower initial dose in blinded fashion (see figure). Tumescence was graded as none, partial or full and the duration of any full erection was recorded. Partial erections were defined as some degree of tumescence without rigidity, while full erections were those with tumescence and rigidity adequate for vaginal penetration. If no erection occurred the higher dose of the same drug was administered 1 week later. After the higher dose was given or if a full erection occurred with the starting dose, the patient was switched over to the other drug and received the starting dose of it and, if necessary, the higher dose also. Thus, all patients received up to 2 doses of prostaglandin El and papaverine during 2 to 4 weeks, with the investigator blinded to the identity of the drugs. RESULTS
Of 16 patients enrolled in the study 1 withdrew after receiving only 1 injection, leaving 15 evaluable patients. Based upon history and physical examination the causes of erectile dysfunction were classified as secondary to diabetes mellitus in 5 patients, neurogenic lesions in 6 and undetermined in 4. Patient age ranged from 36 to 70 years, with a mean age of 63 years. The penile-to-brachia! blood pressure ratio (index) ranged from 0.56 to 0.96, with a mean of 0.81. All patients had inadequate erection by nocturnal penile tumescence monitoring. Of the 15 patients 9 (66 per cent) had a full erection during the course of the study: 4 with both drugs, 3 with papaverine
552
SAROSDY AND ASSOCIATES
only and 2 with prostaglandin El only (see table). Thus, all patients had either a partial or full erection with prostaglandin El, including 2 (patients 3 and 7) who had no response to either dose of papaverine. The durations of the full erections were comparable and no case of priapism was observed with either drug. None of the response differences was statistically significant by chi-square analysis. DISCUSSION
Our study confirms the activity of prostaglandin El in the intracavernous pharmacological treatment of impotence. Of particular note, patients who responded to prostaglandin El were not identical to the group who responded to papaverine hydrochloride at the doses used in our study. While 4 patients achieved a complete erection with both drugs, 2 had a complete erection with prostaglandin El only and 3 others with papaverine hydrochloride only. Although the different responses may be due to the doses used in the study, it is possible that the
~--~/ s ···············-... Papav er i ne
30 mg
\ F--+- Papaverine /
/
60 mg
j Randomize j
"-...-'-PG-E--1~/S ........ ··-. · · · - Papaverine / 10 mcg
30 mg
"-
F-
5
~
S
F.,..rp_a_p-av_e_r_i-ne-,/ 60 mg \.
/
._____, "'r
Patients were randomized to receive study drugs blindly. With success to injection 1 (S, complete erection) patients crossed to drug 2 without receiving higher dose of drug 1. If patient failed injection 1 (F), same drug at twice dose was given 1 week later and then he was crossed to drug 2. PGE-1, prostaglandin El.
mechanism of action may be sufficiently different so that some patients not responding to 1 drug might respond to anoth.er. The over-all total response rate in our study was slightly low at 66 per cent. This relatively low percentage may have been due to several factors. Foremost, patients were entered into the study without cavernosography to rule out venous leak:age. 6 Patients with venous leaks have been shown to respond poorly to pharmacotherapy and some of our patients may have suffered from that process. Also, phentolamine, regularly used to augment the response to papaverine hydrochloride, was not used in our study with either drug. Thus, any potential augmentation of response associated with phentolamine was not determined. The stability of prostaglandin El after dilution is not known. While no association was observed between response to prostaglandin El injection and age of dilution, we cannot rule out a reduction in response to prostaglandin El secondary to instability of the diluted drug. Finally, since this was not a doseresponse study the optimal dosage of prostaglandin El remains to be determined relative to the duration of response as well as side effects. Some of our patients responded to 1 drug but did not respond to both drugs. This also may be secondary to the dosages of prostaglandin El used or because papaverine was used as a single agent without phentolamine. Another possibility is that while both drugs appear to cause relaxation of intracorporeal smooth muscle, the sites of relaxation or the mechanisms of action might be different. Such differences might allow successful pharmacotherapy of impotence with prostaglandin El in patients not responding satisfactorily to papaverine, with or without phentolamine. Major side effects were not observed in this study. Priapism did not occur with either drug, although Padma-Nathan and associates have reported it in as many as 16 per cent of patients treated with the combination of papaverine and phentolamine. 3 Despite the relatively small numbers our results support the uncontrolled study by Ishii and associates in which no case of priapism was seen among 88 patients. 5 Pain at the injection
Etiologies, penile brachia[ indexes and responses to injection Response Pt. No.
Etiology
Penile Brachia! Index
Papaverine 30mg.
Neurological
0.65
2
Diabetic
0.75
3
Unknown
0.83
4
Neurological
0.88
5
Diabetic
0.82
6
Neurological
0.91
7
Neurological
0.96
8
Unknown
0.75
9
Neurological
0.95
10
Diabetic
0.66
11
Unknown
0.94
12
Diabetic
t
13
Diabetic
t
14
Unknown
15
Neurological
* Adequate for penetration regardless of duration.
t Penile blood pressure not detectable.
0.88
t
Partial tumescence Partial tumescence
Prostaglandin El 60mg.
Full tumescence* Partial tumescence
None
None
Partial tumescence Partial tumescence Full tumescence*
Full tumescence* Partial tumescence
None
None
Partial tumescence Partial tumescence Partial tumescence Partial tumescence Partial tumescence Full tumescence* Partial tumescence Partial tumescence
Full tumescence* Full tumescence* Full tumescence* Partial tumescence Partial tumescence
Partial tumescence Partial tumescence
10 mcg. Full tumescence* Partial tumescence Partial tumescence Partial tumescence Partial tumescence Full tumescence* Partial tumescence Full tumescence* Partial tumescence Partial tumescence Partial tumescence Partial tumescence Partial tumescence Partial tumescence Partial tumescence
20 mcg.
Partial tumescence Partial tumescence Full tumescence* Partial tumescence
Full tumescence*
Partial tumescence Partial tumescence Full tumescence* Partial tumescence Partial tumescence Partial tumescence Partial tumescence
INTRACORPOREAL PHARMACOTHERAPY OF IMPOTENCE WITH PROSTAGLANDIN El
site was the only minor complication, occurring in 5 of 15 patients (33 per cent) with prostaglandin El. Injection site pain resolved within 3 minutes in all instances and was not noted with any papaverine injections. A theoretical advantage to the use of prostaglandin El is that it appears to be metabolized locally in the corporeal tissues.4 Systemic side effects of papaverine plus phentolamine include elevated liver enzymes, seen in 4.5 per cent of the patients reported on by Padma-Nathan and associates." While these reversed with cessation of therapy, such systemic side effects might be avoided by the use of an agent metabolized locally rather than systemically. In summary, this randomized, prospective, double-blinded study of prostaglandin El confirms that this compound has the ability to treat impotence and suggests that it may work through a different mechanism than papaverine hydrochloride. Since prostaglandin El is a naturally occurring substance, further evaluation appears to be warranted to determine if it may be associated with a lower complication rate than papaverine or the papaverine plus phentolamine combination.
553
REFERENCES
1. Virag, R., Frydman, D., Legman, Mand Virag, H.: Intracavernous injection of papaverine as a diagnostic and therapeutic method in erectile failure. Angiology, 35: 79, 1984. 2. Brindley, G. S.: Cavernosal alpha-blockade: a new technique for investigating and treating erectile impotence. Brit. J. Psychiat., 143: 332, 1983. 3. Padma-Nathan, H., Goldstein, I., Payton, T. and Krane, R. J.: Intracavernosal pharmacotherapy: the pharmacologic erection program. World J. Urol., 5: 160, 1987. 4. Hedlund, H. and Andersson, K.-E.: Contraction and relaxation induced by some prostanoids in isolated human penile erectile tissue and cavernous artery. J. Urol., 134: 1245, 1985. 5. Ishii, N., Watanabe, H., Irisawa, C. and Kikuchi, Y.: Therapeutic trial with prostaglandin El for organic impotence. Abstract presented at Second World Meeting on Impotence, Prague, Czechoslovakia, June 17-20, 1986. 6. Virag, R.: Arterial and venous hemodynamics in male impotence. In: Management of Male Impotence. Edited by A. H. Bennett. Baltimore: The Williams & Wilkins Co., chapt. 7, pp. 108-126, 1982.
THE JOURNAL OF UROLOGY
Copyright© 1989 by The Williams & Wilkins Co.
Printed in U.S.A.
A PROSPECTIVE DOUBLE-BLIND TRIAL OF INTRACORPOREAL PAPAVERINE VERSUS PROSTAGLANDIN El IN THE TREATMENT OF IMPOTENCE MICHAEL F. SAROSDY,* CLAYTON H. HUDNALL, DEBORAH R. ERICKSON, THOMAS C. HARDIN AND DONALD E. NOVICKI From the Division of Urology and Department of Pharmacology, The University of Texas Health Science Center, San Antonio, Texas
ABSTRACT
A randomized prospective, double-blind clinical trial was performed comparing intracorporeal injections ofpapaverine (30 mg. per ml.) with prostaglandin El (10 mcg. per ml.) as pharmacological treatment of impotence. A total of 15 men completed the study, receiving papaverine and prostaglandin El in a crossover design. Over-all, 9 of 15 evaluable patients had a full erection with either 1 or both drugs: 3 secondary to papaverine only, 2 to prostaglandin El only, and 4 to both drugs. No major complications were observed. We conclude that intracorporeal prostaglandin El may be used successfully to stimulate pharmacological erections and that it might be useful in patients not responding to intracorporeal papaverine. (J. Ural., 141: 551-553, 1989) lntracorporeal pharmacotherapy for erectile impotence has gained widespread acceptance since its introduction by Virag and associates, 1 and Brindley. 2 While a combination of papaverine hydrochloride and phentolamine mesylate is used most commonly, a wide variety of pharmacological agents have been identified that are capable of producing erections in selected impotent men.'1 Although papaverine hydrochloride and phentolamine mesylate work well in the majority of patients, side effects of the combination include priapism and corporeal fibrosis. Therefore, evaluation of other agents that might avoid these complications is desirable. Prostaglandin El is a naturally occurring compound important to the inflammatory response of human tissues. After an initial report of prostaglandin El-induced changes in human erectile tissues observed in vitro,4 Ishii and associates reported a noncomparative series of 88 patients treated with prostaglandin El in which no cases of priapism were observed. 5 We evaluate the efficacy of prostaglandin El compared to papaverine hydrochloride when used as single agents in a controlled trial of intracorporeal pharmacological treatment of impotence. MATERIALS AND METHODS
Patients. Patients presenting with a chief complaint of impotence were evaluated for suitability and invited to participate in the study. Those who agreed underwent a complete history and physical examination, including penile and brachia! blood pressures, as well as nocturnal penile tumescence monitoring for 2 or 3 consecutive nights. Laboratory evaluation included a complete blood count, thyroid function tests, serum glucose and measurements of serum testosterone, and luteinizing and follicle-stimulating hormones. Patients with uncontrolled diabetes, thyroid disease and psychogenic impotence were excluded. Informed consent was obtained according to Federal and institutional guidelines. Medications. Papaverine injections were prepared using 30 mg./ml. papaverine hydrochloride with 0.5 per cent chlorobutanol as preservative. On each study day either 30 mg. (1 ml.) or 60 mg. (2 ml.) were drawn into a 3 ml. plastic syringe, labeled to· indicate only study drug and delivered to a blinded investigator who administered the injection and evaluated response. Accepted for publication August 17, 1988. * Requests for reprints: Division of Urology, 7703 Floyd Curl Drive, San Antonio, Texas 78284-7845. 551
Prostaglandin El (500 mcg./ml.) was diluted with sterile normal saline to yield a concentration of 10 mcg./ml. Diluted solutions were stored at 4C and unused dilutions were discarded after 14 days. Prostaglandin El injections were similarly prepared from this dilution for each study day as described previously, resulting in doses of either 10 mcg. (1 ml.) or 20 mcg. (2 ml.). The same investigator prepared all dilutions and syringes. Randomization was performed with the closed-envelope technique in blocks of 8. The randomization code was not broken until all patients had completed the trial. Drug administration. Drugs were administered by direct corporeal injection with a 25 gauge needle and a 3 cc syringe. Manual compression of the injection site was maintained for 5 minutes after the injection. Patients were monitored for injection site hematoma, pain, swelling and hypotension. Study design. Each patient was randomized to receive either papaverine or prostaglandin El at the .respective lower initial dose in blinded fashion (see figure). Tumescence was graded as none, partial or full and the duration of any full erection was recorded. Partial erections were defined as some degree of tumescence without rigidity, while full erections were those with tumescence and rigidity adequate for vaginal penetration. If no erection occurred the higher dose of the same drug was administered 1 week later. After the higher dose was given or if a full erection occurred with the starting dose, the patient was switched over to the other drug and received the starting dose of it and, if necessary, the higher dose also. Thus, all patients received up to 2 doses of prostaglandin El and papaverine during 2 to 4 weeks, with the investigator blinded to the identity of the drugs. RESULTS
Of 16 patients enrolled in the study 1 withdrew after receiving only 1 injection, leaving 15 evaluable patients. Based upon history and physical examination the causes of erectile dysfunction were classified as secondary to diabetes mellitus in 5 patients, neurogenic lesions in 6 and undetermined in 4. Patient age ranged from 36 to 70 years, with a mean age of 63 years. The penile-to-brachia! blood pressure ratio (index) ranged from 0.56 to 0.96, with a mean of 0.81. All patients had inadequate erection by nocturnal penile tumescence monitoring. Of the 15 patients 9 (66 per cent) had a full erection during the course of the study: 4 with both drugs, 3 with papaverine
552
SAROSDY AND ASSOCIATES
only and 2 with prostaglandin El only (see table). Thus, all patients had either a partial or full erection with prostaglandin El, including 2 (patients 3 and 7) who had no response to either dose of papaverine. The durations of the full erections were comparable and no case of priapism was observed with either drug. None of the response differences was statistically significant by chi-square analysis. DISCUSSION
Our study confirms the activity of prostaglandin El in the intracavernous pharmacological treatment of impotence. Of particular note, patients who responded to prostaglandin El were not identical to the group who responded to papaverine hydrochloride at the doses used in our study. While 4 patients achieved a complete erection with both drugs, 2 had a complete erection with prostaglandin El only and 3 others with papaverine hydrochloride only. Although the different responses may be due to the doses used in the study, it is possible that the
~--~/ s ···············-... Papav er i ne
30 mg
\ F--+- Papaverine /
/
60 mg
j Randomize j
"-...-'-PG-E--1~/S ........ ··-. · · · - Papaverine / 10 mcg
30 mg
"-
F-
5
~
S
F.,..rp_a_p-av_e_r_i-ne-,/ 60 mg \.
/
._____, "'r
Patients were randomized to receive study drugs blindly. With success to injection 1 (S, complete erection) patients crossed to drug 2 without receiving higher dose of drug 1. If patient failed injection 1 (F), same drug at twice dose was given 1 week later and then he was crossed to drug 2. PGE-1, prostaglandin El.
mechanism of action may be sufficiently different so that some patients not responding to 1 drug might respond to anoth.er. The over-all total response rate in our study was slightly low at 66 per cent. This relatively low percentage may have been due to several factors. Foremost, patients were entered into the study without cavernosography to rule out venous leak:age. 6 Patients with venous leaks have been shown to respond poorly to pharmacotherapy and some of our patients may have suffered from that process. Also, phentolamine, regularly used to augment the response to papaverine hydrochloride, was not used in our study with either drug. Thus, any potential augmentation of response associated with phentolamine was not determined. The stability of prostaglandin El after dilution is not known. While no association was observed between response to prostaglandin El injection and age of dilution, we cannot rule out a reduction in response to prostaglandin El secondary to instability of the diluted drug. Finally, since this was not a doseresponse study the optimal dosage of prostaglandin El remains to be determined relative to the duration of response as well as side effects. Some of our patients responded to 1 drug but did not respond to both drugs. This also may be secondary to the dosages of prostaglandin El used or because papaverine was used as a single agent without phentolamine. Another possibility is that while both drugs appear to cause relaxation of intracorporeal smooth muscle, the sites of relaxation or the mechanisms of action might be different. Such differences might allow successful pharmacotherapy of impotence with prostaglandin El in patients not responding satisfactorily to papaverine, with or without phentolamine. Major side effects were not observed in this study. Priapism did not occur with either drug, although Padma-Nathan and associates have reported it in as many as 16 per cent of patients treated with the combination of papaverine and phentolamine. 3 Despite the relatively small numbers our results support the uncontrolled study by Ishii and associates in which no case of priapism was seen among 88 patients. 5 Pain at the injection
Etiologies, penile brachia[ indexes and responses to injection Response Pt. No.
Etiology
Penile Brachia! Index
Papaverine 30mg.
Neurological
0.65
2
Diabetic
0.75
3
Unknown
0.83
4
Neurological
0.88
5
Diabetic
0.82
6
Neurological
0.91
7
Neurological
0.96
8
Unknown
0.75
9
Neurological
0.95
10
Diabetic
0.66
11
Unknown
0.94
12
Diabetic
t
13
Diabetic
t
14
Unknown
15
Neurological
* Adequate for penetration regardless of duration.
t Penile blood pressure not detectable.
0.88
t
Partial tumescence Partial tumescence
Prostaglandin El 60mg.
Full tumescence* Partial tumescence
None
None
Partial tumescence Partial tumescence Full tumescence*
Full tumescence* Partial tumescence
None
None
Partial tumescence Partial tumescence Partial tumescence Partial tumescence Partial tumescence Full tumescence* Partial tumescence Partial tumescence
Full tumescence* Full tumescence* Full tumescence* Partial tumescence Partial tumescence
Partial tumescence Partial tumescence
10 mcg. Full tumescence* Partial tumescence Partial tumescence Partial tumescence Partial tumescence Full tumescence* Partial tumescence Full tumescence* Partial tumescence Partial tumescence Partial tumescence Partial tumescence Partial tumescence Partial tumescence Partial tumescence
20 mcg.
Partial tumescence Partial tumescence Full tumescence* Partial tumescence
Full tumescence*
Partial tumescence Partial tumescence Full tumescence* Partial tumescence Partial tumescence Partial tumescence Partial tumescence
INTRACORPOREAL PHARMACOTHERAPY OF IMPOTENCE WITH PROSTAGLANDIN El
site was the only minor complication, occurring in 5 of 15 patients (33 per cent) with prostaglandin El. Injection site pain resolved within 3 minutes in all instances and was not noted with any papaverine injections. A theoretical advantage to the use of prostaglandin El is that it appears to be metabolized locally in the corporeal tissues.4 Systemic side effects of papaverine plus phentolamine include elevated liver enzymes, seen in 4.5 per cent of the patients reported on by Padma-Nathan and associates." While these reversed with cessation of therapy, such systemic side effects might be avoided by the use of an agent metabolized locally rather than systemically. In summary, this randomized, prospective, double-blinded study of prostaglandin El confirms that this compound has the ability to treat impotence and suggests that it may work through a different mechanism than papaverine hydrochloride. Since prostaglandin El is a naturally occurring substance, further evaluation appears to be warranted to determine if it may be associated with a lower complication rate than papaverine or the papaverine plus phentolamine combination.
553
REFERENCES
1. Virag, R., Frydman, D., Legman, Mand Virag, H.: Intracavernous injection of papaverine as a diagnostic and therapeutic method in erectile failure. Angiology, 35: 79, 1984. 2. Brindley, G. S.: Cavernosal alpha-blockade: a new technique for investigating and treating erectile impotence. Brit. J. Psychiat., 143: 332, 1983. 3. Padma-Nathan, H., Goldstein, I., Payton, T. and Krane, R. J.: Intracavernosal pharmacotherapy: the pharmacologic erection program. World J. Urol., 5: 160, 1987. 4. Hedlund, H. and Andersson, K.-E.: Contraction and relaxation induced by some prostanoids in isolated human penile erectile tissue and cavernous artery. J. Urol., 134: 1245, 1985. 5. Ishii, N., Watanabe, H., Irisawa, C. and Kikuchi, Y.: Therapeutic trial with prostaglandin El for organic impotence. Abstract presented at Second World Meeting on Impotence, Prague, Czechoslovakia, June 17-20, 1986. 6. Virag, R.: Arterial and venous hemodynamics in male impotence. In: Management of Male Impotence. Edited by A. H. Bennett. Baltimore: The Williams & Wilkins Co., chapt. 7, pp. 108-126, 1982.