- Email: [email protected]
Intracavernous Injection of Prostagland in E1 in combination With Papaverine: Enhanced Effectiveness in Comparison With Papaverine Plus Phentolamine and Prostaglandin E1 Alone
0022-5347/91/1451-0056$02.00/0
THEJOURNAL OF UROLOGY Copyright 0 1991 by AMERICANUROLOGICAL ASSOCIATION,INC.
Vol. 145, 56-59 January 1991 Printed in U.S.A.
INTRACAVERNOUS INJECTION OF PROSTAGLANDIN E l IN COMBINATION WITH PAPAVERINE: ENHANCED EFFECTIVENESS IN COMPARISON WITH PAPAVERINE PLUS PHENTOLAMINE AND PROSTAGLANDIN E l ALONE ANDREAS FLBTH A N D PAUL SCHRAMEK From the Department of Urology, Allgemeine Poliklinik der Stadt Wien, Vienna, Austria
ABSTRACT
W e compared t h e erectile response t o intracavernous injection of a combination of papaverine a n d prostaglandin E l with t h a t of a combination of papaverine a n d phentolamine (49 patients), a n d prostaglandin E l alone (38). T h e degree of erection achieved was significantly better with papaverine p l u s prostaglandin E l t h a n with papaverine plus phentolamine a n d t h e duration of erection was less, although t h e incidence of prolonged erections (greater t h a n 5 hours) w a s similar with b o t h combinations. Papaverine with prostaglandin E l likewise resulted in a significantly better degree of erection t h a n prostaglandin E l alone (prolonged erections occurred only after t h e drug combination). All erections subsided spontaneously a n d none required medical intervention througho u t t h e study. P a i n was noted only after injection of prostaglandin El. T h e incidence was clearly lower (7 of 3 8 versus 1 3 of 38) after t h e injection of only 5 pg. prostaglandin E l i n combination with papaverine (although t h e difference i s n o t statistically significant). Subjectively, t h e side effects caused by t h e d r u g combination were described a s m u c h less dramatic b y t h e patients t h a n after prostaglandin E l alone. T h e combination of papaverine a n d prostaglandin E l shows a clearly synergistic effect a n d might suitably replace papaverine plus phentolamine o r prostaglandin E l alone in p a t i e n t s w h o d o n o t respond well o r suffer side effects after high single doses. KEYWORDS: penis, impotence, prostaglandins E, papaverine of vasoactive substances. As an initial test dose we routinely use 10 pg. prostaglandin E l (in 0.5 ml. 4% glucose) or 7.5 mg. papaverine plus 0.25 mg. phentolamine in 0.5 ml. saline. In our experience these dosages showed equivalent effectivness in a large number of patients.14 In this study both standard substances were to be compared with a combination of 7.5 mg. papaverine and 5 pg. prostaglandin E l in 0.5 ml. saline. Patients were randomly assigned to 1 of the 2 groups. The order of injections in each group also was randomized with a minimum interval of 2 days between the 2 injections. The grade of erection was determined by palpation and inspection of the penis by the same observer (A. F.) in all patients according to a scale from 1 to 5 (1-no erection, 2-slight tumescence, 3-full tumescence without rigidity, 4-incomplete rigidity and 5-full rigidity) as proposed by other^.',^^,^^ The latent period between injection and erection, duration of the erection and side effects (with emphasis on subjective side effects) were also recorded. Arterial blood flow was evaluated by duplex ultrasound (Diasonics DRF 400) and an average flow velocity of 20 to 25 cm. ~ .lack ~~ per second was assumed as the lower limit of n ~ r m a l . ' A of increase in vascular diameter as well as decreased pulsations of the penile vessels after injection of the vasoactive substance were additional criteria in establishing the diagnosis of arterial insufficiency. Pharmacodynamic cavernosography was performed if erections could not be achieved by increased dosage of the drugs injected and the arteries were considered normal in duplex sonography. The diagnosis of venous insufficiency was based on a leakage of diluted contrast medium from the corpora cavernosa after injection of a combination 45 mg. papaverine and 1.5 mg. phentolaminel5 or 60 pg. prostaglandin E l . All patients in the study also were evaluated by a neurologist and a psychiatrist, if indicated. Papauerine plus phentolamine versus papaverine plus prostaglandin E l . Data from 49 patients were available for evaluation (mean patient age 51 & 12.5 years). The predominant diagnostic findings wire significantly reduced arterial flow in
The intracavernous injection of papaverine has been widely used for diagnostic and therapeutic purposes. When combined with the @-blockerphentolamine the dosage can be significantly decreased. The incidence of priapism after the papaverine plus phentolamine combination (7.5 and 0.25 mg., respectively) has been 2.5% in our experience (4 of 160 patients), and can be kept in this range by carefully selecting patients and using a low dose at the initial test injection. Fibrosis of the corpus cavernosum as well as a n increase in liver enzymes have been described after repeated intracorporeal injections of papaverine alone and in combination with phentolamine.' Although the l ~ ~a~clear dose-dependence has definitive cause is e q u i ~ o c a and not been established, t h e formation of nodules and fibrosis frequently is preceded by the injection of high single doses of papa~erine.~.' There also is evidence that the injection of papaverine alone causes fibrosis more frequently than the combination with other d r ~ g s . ~ The intracavernous injection of prostaglandin E l effectively induces erections for diagnostic or therapeutic purpose^.^-^ Prostaglandin E l relaxes intracorporeal smooth muscle and antagonizes the action of noradrenalins-dual effects that might explain the high efficiency in inducing erections, although exact dose equivalents with other substances have not Pain occurring after prostaglandin E l yet been e~tablished.~,' has been a major problem in our experience. This problem also has been encountered by others, with an incidence of 16 to 40%6,9-11 and a clear dose d e p e n d e n ~ y . ' ~ ' ~ ~ ' ~ With this in mind we investigated a possible synergism between papaverine and prostaglandin E l in the hope of effectively diagnosing and treating erectile failure with the fewest side effects. MATERIALS AND METHODS
Our standard evaluation procedure includes a complete history and physical examination, and the intracorporeal injection Accepted for publication J u l y 27, 1990. 56
'
INTRACAVERNBUS INJECTION G P PROSTAGLANDIN E l AND PAPAYERYNE
14 patients, mild or borderline arterial disease in 18 and venous leakage in 8 (table 1). Dysfunction was predominantly neurogenic in 3 patients and psychogenic in 6. Eight patients suffered from diabetes mellitus. Prostaglandin El versus papaverine plus prostaglandin E l . Data from 38 patients could be evaluated (mean patient age 52.7 f 11.6 years). Twenty patients had a predominant decrease in arterial flow, 6 presented with mild arterial disease and 5 with venous leakage (table 1). Three patients suffered from significant neurological problems and 4 showed a clear psychogenic component. In this group 1 patient was a diabetic. Many patients showed multiple pathogenetic factors. The most prominent factor was used to assign the individuals to the different diagnostic groups (table 1). The Wilcoxon signed rank test was used to compare the grades of erection, Student's t test was used for the comparison of latency times and the duration of erections, and McNemar's test was used for side effects. Results are expressed as the mean f standard deviation. RESULTS
With the combination of papaverine and phentolamine in 49 patients 12 (24.5%) showed no response or slight tumescence only (grades 1and 2), 9 (18.4%)had tumescence without rigidity (grade 3) and 28 (57%) achieved erections of grades 4 and 5 (table 2). The mean latency time between injection and erection was 8.6 f 3.8 minutes and the mean duration of erection was 178.5 133.29 minutes in patients with erections of grades 4 and 5. Prolonged erections (greater than 5 hours) were observed in 4 patients. No side effects were noted in this group. After the injection of papaverine plus prostaglandin E l only 6 of the 49 patients (12.2%) did not react or showed only slight tumescence, 5 (10.2%) had tumescence without rigidity and 38 (77.5%) achieved erections of grades 4 and 5 (table 2). The mean latency period between injection and erection was 8.2 f 5.1 minutes. Mean duration was 148.6 + 131.07 minutes with erections of more than grade 3. Prolonged erections were observed in 4 patients with psychogenic, neurogenic or minimally arteriogenic disease. Side effects were reported by 8 patients (16.3%), including some discomfort at the injection site in 5 (10.2%) and moderate pain during the erection in 3 (6.1%). There was no apparent correlation between the occurrence of side effects and the cause of erectile dysfunction. The erectile response was significantly greater for the combination of papaverine and prostaglandin E l (p <0.01). Latency times showed no significant difference (p = 0.5) but erections induced with papaverine plus prostaglandin E l had significantly shorter duration (p = 0.027). The distribution of erection times is illustrated better by a percentile plot (part A of figure), which demonstrates that the result of statistics must be interpreted with care. Although the over-all difference in erection times is statistically significant, the number of prolonged erections was similar in both groups. All prolonged erections subsided spontaneously and did not require medical intervention. In the 8 patients who reported pain after papaverine plus prostaglandin E l the sensation was not limited to the injection site but extended t o the suprapubic area and was described as
+
burning, dull or a feeling of pressure. None of the patients described the pain as significant, as had been reported in a previous study of prostaglandin E l alone.7 After the injection of 10 pg. prostaglandin E l 3 of the 38 patients (7.9%) showed slight tumescence only, 12 (31.6%) exhibited tumescence without rigidity and 23 (60.5%) achieved an erection with incomplete or complete rigidity (grades 4 and 5). The mean latency time between injection and the onset of erection was 7.3 + 3.4 minutes and the mean duration of erection was 109.3 + 61 minutes (maximum 210 minutes). A total of 13 patients (34.2%) complained of moderate to severe pain and burning after injection and throughout the erection. In these 38 patients the combination of papaverine and prostaglandin E l induced an erection of grade 4 or 5 in 28 (73.6%).The mean latency time was 8.3 & 4.8 minutes and the mean duration was 124.3 + 111.3 minutes. Prolonged erections (greater than 5 hours) occurred in 4 patients with psychogenic, neurogenic or minimally arteriogenic disease. Mild to moderate pain was noted in 7 patients (18.4%). The combination of 7.5 mg. papaverine and 5 pg. prostaglandin E l showed a significantly higher potential to induce erections (p = 0.03) than 10 pg. prostaglandin E l alone. The latency period was not significantly different (p = 0.45). No prolonged erections occurred after prostaglandin E l alone (part B of figure) and the duration of erection was significantly lower in this group (p = 0.045). The drug combination caused prolonged erections in 4 patients but these subsided spontaneously. The incidence of side effects (13 versus 7 or 38) was not statistically different (p = 0.08) but the pain after the drug combination was described by the patients in significantly less dramatic terms than after prostaglandin E l alone. The randomization of the order of injections did not have an influence on the results in either study group. The degree of erection achieved after injection and the incidence of side effects were equally distributed no matter which substance was injected first. DISCUSSION
The combination of papaverine and phentolaminels is widely used for diagnostic and therapeutic intracorporeal injections in impotent patients. The apparent synergism of smooth muscle relaxant and an al-blocking agent allows for a significant decrease in the respective single doses. The main concern about the administration of papaverine is based on the observation of fibrosis at the tunica albuginea as well as inside the corpora after injection of papaverine alone or in combination with other sub~tances.',~ A clear dose-dependence has not been established, although most investigators report single doses of 20 mg. papaverine or more. The incidence seems to be higher with papaverine a10ne.~Other clinical reports do not confirm significant fibrotic changes.' Given this uncertainty, a further decrease in the dose needed to induce erection and injection in combination with another drug seems to be advisable. The intracavernous injection of prostaglandin E l has also been widely accepted as a standard procedure in the diagnosis and treatment of erectile dysfunction. It effectively induces erections and appears to have a lower potential to cause priap-
TABLE1. Diagnostic findings Papaverine/Phentolamine Versus Papaverine/ Prostaglandin E l No. Pts. (%) Total No. pts. Severe arterial restriction Moderate arterial restriction Venous leak Neurogenic Predominantly psychogenic Diabetes mellitus *Some patients with multiple pathogenetic factors in both groups.
57
Prostaglandin E l Versus Papaverine/Prostaglandin E l No. Pts. (%)
58
FLOTH AND SCHRAMEK
TABLE2. Grade of erection after injection Grade of Erection
Papaverine Plus Phentolamine* No. Pts. (%)
Papaverine Plus Prostaglandin E l * No. Pts. (%)
Prostaglandin E l t No. Pts. (%)
1-2 (tumescence) 3 (no rigidity) 4-5 (sufficient rigidity)
12 (24.5) 9 (18.4) 28 (57.1)
6 (12.2) 5 (10.2) 38 (77.5)
3 (7.9) 12 (31.6) 23 (60.5)
Papaverine Plus Prostaglandin E l t No. Pts. (%) 2 (5.3) 8 (21.0)
28 (73.7)
* Total 49 patients. + Total 38 patients.
Papaverine Phentolamine
Papaverine Prostaglandin E l
Prostaglandin E l
Papaverine Prostaglandin E l
A, percentile plot illustrates similar incidence of prolonged erections after papaverine/phentolamine and papaverine/prostaglandin E l , although there is significant difference in mean duration of erections in both study groups. Ordinate shows duration of erection in minutes. B, percentile plot shows clear difference in incidence of prolonged erections after injection of prostaglandin E l alone or in combination with papaverine. Notches represent 95% confidence bands about median. Outliers are indicated by black dots.
ism t h a n other drugs used for t h e same purpose. T h e most frequently reported side effect is pain, with a n incidence of 16 to 40%fi,g-11,1"a n d a clear dose dependency.gslVhe threshold for t h e induction of pain a s a side effect appears t o be a single dose between 5 a n d 10 fig. I n our experience 5 fig. are not always sufficient t o allow for a differential diagnosis with t h e least number of diagnostic injections possible. I n our selfinjection program this a m o u n t was frequently not sufficient t o achieve a n adequate erection. Since several patients chose t o discontinue t h e diagnostic process or t h e self-injection program after experiencing t h e side effects of a n injection of 1 5 t o 20 fig. prostaglandin E l , w e decided t o investigate t h e possible synergism of prostaglandin E l a n d papaverine. T h e combination of different mechanisms of action is a possible explanation for t h e synergistic behavior. Papaverine acts o n a post-receptor level via t h e inhibition of phosphodiesterase (the consequent increase in cyclic adenosine monophosphate attenuates t h e al-receptor-mediated contraction of t h e smooth muscle cell, possibly by interfering with t h e calcium ion-mobilization),lg whereas prostaglandin E l acts via a membrane-receptor. Furthermore, t h e a-blocking properties of prostaglandin E l seem t o be a t least a s effective as phentolamine, if not more so.'' I n our series side effects were still noted with t h e combination of papaverine a n d prostaglandin E l b u t i n contrast t o a previous report7 they were m u c h less frequent a n d severe. None of t h e patients withdrew f r o m t h e study. W e conclude t h a t a combination of 7.5 mg. papaverine and 5 fig. prostaglandin E l i s significantly more effective t h a n 7.5
mg. papaverine with 0.25 mg. phentolamine or 10 fig. prostaglandin E l alone, a n d t h a t t h e effect of papaverine a n d prostaglandin E l is clearly synergistic. T h i s drug combination can also replace prostaglandin E l alone, especially i n patients with significant side effects or with a weak response t o prostaglandin E l t h a t may be caused by a low receptor density. REFERENCES
1. Levine, S. B., Althof, S. E., Turner, L. A,, Risen, C. B., Bodner, D.
2. 3.
4.
5. 6. 7. 8.
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. Sidi, A. A,, Becher, E. F, and Cherwitz, D. L.: Light microscopic analysis of penile tissues after vasoactive intracavernous pbarmacotherapy (VIP). J. Urol., 141: 273A, abstract 415, 1989. Abozeid, M., Juenemann, K.-P., Luo, J.-A,, Lue, T. F., Yen, T.-S. B. and Tanagho, E. A,: Chronic papaverine treatment: the effects of repeated injections on the simian erectile response and penile tissue. J. Urol., 138: 1263, 1987. Fuchs, M. E. and Brawer, M. K.: Papaverine-induced fibrosis of the corpus cavernosum. J. Urol., 141: 125, 1989. Tullii, R. E., Degni, M. and Pinto, A. F. C.: Fibrosis of the cavernous bodies following intracavernous auto-injection of vasoactive drugs. Int. J. Impotence Res., 1: 49, 1989. Stackl, W., Hasun, R. and Marberger, M.: Intracavernous injection of prostaglandin E l in impotent men. J. Urol., 140: 66, 1988. Waldhauser, M. and Schramek, P.: Efficiency and side effects of prostaglandin E l in the treatment of erectile dysfunction. J . Urol., 140: 525, 1988. 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.
INTRACAVZRWOUS INJECTION OF PROSTAGLANDIN E l AND PAPAVEXINE
9. Sarosdy, M. F., Hudnall, C. H., Erickson, D. R., Hardin, T. C. and Novicki, D. E.: A prospective double-blind trial of intracorporeal papaverine versus prostaglandin E l in the treatment of impotence. J. Urol., 141: 551, 1989. 10. Hwang, T. I.-S., Yang, C.-R., Wang, S.-J., Chang, C.-L., Tzai, T.S., Chang, C.-H. and Wu, H.-C.: Impotence evaluated by the use of prostaglandin E l . J. Urol., 141: 1357, 1989. 11. Lue, T. F.: Editorial comment. J. Urol., 141: 325, 1989. 12. Schramek, P. and Waldhauser, M.: Dose-dependent effect and sideeffect of prostaglandin E l in erectile dysfunction. Brit. J. Clin. Pharm., 28: 567, 1989. 13. Lee, L. M., Stevenson, R. W. D. and Szasz, 6 . : Prostaglandin E l versus phentolamine/papaverine for the treatment of erectile impotence: a double-blind comparison. J. Urol., 141: 549, 1989. 14. Floth, A. and Schramek, P.: Unpublished data.
59
15. Stief, C. G., Bahren, W., Gall, H. and Scherb, W.: Functional evaluation of penile hemodynamics. J. Urol., 139: 734, 1988. 16. Lue, T.: Personal communication. 17. Shabsigh, R., Fishman, I. J., Quesada, E. T., Seale-Hawkins, C. K. and Dunn, J . K.: Evaluation of vasculogenic erectile impotence using penile duplex ultrasonography. J . Urol., 142: 1469, 1989. 18. Zorgniotti, A. W. and Lefleur, R. S.: Auto-injection of the corpus cavernosum with a vasoactive drug combination for vasculogenic impotence. J. Urol., 133: 39, 1985. 19. Christ, G. J., Valcic, M., Maayani, S. and Melman, A,: Kinetic studies of contraction in human erectile tissue (HET) and rabbit aortic rings in vitro: modulation by papaverine and the dihydropyridine analog nifedipine. Int. J. Impotence Res., 1: 1, 1989. 20. Langer, S. Z.: Presynaptic regulation of the release of catecholamines. Pharmacol. Rev., 32: 337, 1981.
THEJOURNAL OF UROLOGY Copyright 0 1991 by AMERICANUROLOGICAL ASSOCIATION,INC.
Vol. 145, 56-59 January 1991 Printed in U.S.A.
INTRACAVERNOUS INJECTION OF PROSTAGLANDIN E l IN COMBINATION WITH PAPAVERINE: ENHANCED EFFECTIVENESS IN COMPARISON WITH PAPAVERINE PLUS PHENTOLAMINE AND PROSTAGLANDIN E l ALONE ANDREAS FLBTH A N D PAUL SCHRAMEK From the Department of Urology, Allgemeine Poliklinik der Stadt Wien, Vienna, Austria
ABSTRACT
W e compared t h e erectile response t o intracavernous injection of a combination of papaverine a n d prostaglandin E l with t h a t of a combination of papaverine a n d phentolamine (49 patients), a n d prostaglandin E l alone (38). T h e degree of erection achieved was significantly better with papaverine p l u s prostaglandin E l t h a n with papaverine plus phentolamine a n d t h e duration of erection was less, although t h e incidence of prolonged erections (greater t h a n 5 hours) w a s similar with b o t h combinations. Papaverine with prostaglandin E l likewise resulted in a significantly better degree of erection t h a n prostaglandin E l alone (prolonged erections occurred only after t h e drug combination). All erections subsided spontaneously a n d none required medical intervention througho u t t h e study. P a i n was noted only after injection of prostaglandin El. T h e incidence was clearly lower (7 of 3 8 versus 1 3 of 38) after t h e injection of only 5 pg. prostaglandin E l i n combination with papaverine (although t h e difference i s n o t statistically significant). Subjectively, t h e side effects caused by t h e d r u g combination were described a s m u c h less dramatic b y t h e patients t h a n after prostaglandin E l alone. T h e combination of papaverine a n d prostaglandin E l shows a clearly synergistic effect a n d might suitably replace papaverine plus phentolamine o r prostaglandin E l alone in p a t i e n t s w h o d o n o t respond well o r suffer side effects after high single doses. KEYWORDS: penis, impotence, prostaglandins E, papaverine of vasoactive substances. As an initial test dose we routinely use 10 pg. prostaglandin E l (in 0.5 ml. 4% glucose) or 7.5 mg. papaverine plus 0.25 mg. phentolamine in 0.5 ml. saline. In our experience these dosages showed equivalent effectivness in a large number of patients.14 In this study both standard substances were to be compared with a combination of 7.5 mg. papaverine and 5 pg. prostaglandin E l in 0.5 ml. saline. Patients were randomly assigned to 1 of the 2 groups. The order of injections in each group also was randomized with a minimum interval of 2 days between the 2 injections. The grade of erection was determined by palpation and inspection of the penis by the same observer (A. F.) in all patients according to a scale from 1 to 5 (1-no erection, 2-slight tumescence, 3-full tumescence without rigidity, 4-incomplete rigidity and 5-full rigidity) as proposed by other^.',^^,^^ The latent period between injection and erection, duration of the erection and side effects (with emphasis on subjective side effects) were also recorded. Arterial blood flow was evaluated by duplex ultrasound (Diasonics DRF 400) and an average flow velocity of 20 to 25 cm. ~ .lack ~~ per second was assumed as the lower limit of n ~ r m a l . ' A of increase in vascular diameter as well as decreased pulsations of the penile vessels after injection of the vasoactive substance were additional criteria in establishing the diagnosis of arterial insufficiency. Pharmacodynamic cavernosography was performed if erections could not be achieved by increased dosage of the drugs injected and the arteries were considered normal in duplex sonography. The diagnosis of venous insufficiency was based on a leakage of diluted contrast medium from the corpora cavernosa after injection of a combination 45 mg. papaverine and 1.5 mg. phentolaminel5 or 60 pg. prostaglandin E l . All patients in the study also were evaluated by a neurologist and a psychiatrist, if indicated. Papauerine plus phentolamine versus papaverine plus prostaglandin E l . Data from 49 patients were available for evaluation (mean patient age 51 & 12.5 years). The predominant diagnostic findings wire significantly reduced arterial flow in
The intracavernous injection of papaverine has been widely used for diagnostic and therapeutic purposes. When combined with the @-blockerphentolamine the dosage can be significantly decreased. The incidence of priapism after the papaverine plus phentolamine combination (7.5 and 0.25 mg., respectively) has been 2.5% in our experience (4 of 160 patients), and can be kept in this range by carefully selecting patients and using a low dose at the initial test injection. Fibrosis of the corpus cavernosum as well as a n increase in liver enzymes have been described after repeated intracorporeal injections of papaverine alone and in combination with phentolamine.' Although the l ~ ~a~clear dose-dependence has definitive cause is e q u i ~ o c a and not been established, t h e formation of nodules and fibrosis frequently is preceded by the injection of high single doses of papa~erine.~.' There also is evidence that the injection of papaverine alone causes fibrosis more frequently than the combination with other d r ~ g s . ~ The intracavernous injection of prostaglandin E l effectively induces erections for diagnostic or therapeutic purpose^.^-^ Prostaglandin E l relaxes intracorporeal smooth muscle and antagonizes the action of noradrenalins-dual effects that might explain the high efficiency in inducing erections, although exact dose equivalents with other substances have not Pain occurring after prostaglandin E l yet been e~tablished.~,' has been a major problem in our experience. This problem also has been encountered by others, with an incidence of 16 to 40%6,9-11 and a clear dose d e p e n d e n ~ y . ' ~ ' ~ ~ ' ~ With this in mind we investigated a possible synergism between papaverine and prostaglandin E l in the hope of effectively diagnosing and treating erectile failure with the fewest side effects. MATERIALS AND METHODS
Our standard evaluation procedure includes a complete history and physical examination, and the intracorporeal injection Accepted for publication J u l y 27, 1990. 56
'
INTRACAVERNBUS INJECTION G P PROSTAGLANDIN E l AND PAPAYERYNE
14 patients, mild or borderline arterial disease in 18 and venous leakage in 8 (table 1). Dysfunction was predominantly neurogenic in 3 patients and psychogenic in 6. Eight patients suffered from diabetes mellitus. Prostaglandin El versus papaverine plus prostaglandin E l . Data from 38 patients could be evaluated (mean patient age 52.7 f 11.6 years). Twenty patients had a predominant decrease in arterial flow, 6 presented with mild arterial disease and 5 with venous leakage (table 1). Three patients suffered from significant neurological problems and 4 showed a clear psychogenic component. In this group 1 patient was a diabetic. Many patients showed multiple pathogenetic factors. The most prominent factor was used to assign the individuals to the different diagnostic groups (table 1). The Wilcoxon signed rank test was used to compare the grades of erection, Student's t test was used for the comparison of latency times and the duration of erections, and McNemar's test was used for side effects. Results are expressed as the mean f standard deviation. RESULTS
With the combination of papaverine and phentolamine in 49 patients 12 (24.5%) showed no response or slight tumescence only (grades 1and 2), 9 (18.4%)had tumescence without rigidity (grade 3) and 28 (57%) achieved erections of grades 4 and 5 (table 2). The mean latency time between injection and erection was 8.6 f 3.8 minutes and the mean duration of erection was 178.5 133.29 minutes in patients with erections of grades 4 and 5. Prolonged erections (greater than 5 hours) were observed in 4 patients. No side effects were noted in this group. After the injection of papaverine plus prostaglandin E l only 6 of the 49 patients (12.2%) did not react or showed only slight tumescence, 5 (10.2%) had tumescence without rigidity and 38 (77.5%) achieved erections of grades 4 and 5 (table 2). The mean latency period between injection and erection was 8.2 f 5.1 minutes. Mean duration was 148.6 + 131.07 minutes with erections of more than grade 3. Prolonged erections were observed in 4 patients with psychogenic, neurogenic or minimally arteriogenic disease. Side effects were reported by 8 patients (16.3%), including some discomfort at the injection site in 5 (10.2%) and moderate pain during the erection in 3 (6.1%). There was no apparent correlation between the occurrence of side effects and the cause of erectile dysfunction. The erectile response was significantly greater for the combination of papaverine and prostaglandin E l (p <0.01). Latency times showed no significant difference (p = 0.5) but erections induced with papaverine plus prostaglandin E l had significantly shorter duration (p = 0.027). The distribution of erection times is illustrated better by a percentile plot (part A of figure), which demonstrates that the result of statistics must be interpreted with care. Although the over-all difference in erection times is statistically significant, the number of prolonged erections was similar in both groups. All prolonged erections subsided spontaneously and did not require medical intervention. In the 8 patients who reported pain after papaverine plus prostaglandin E l the sensation was not limited to the injection site but extended t o the suprapubic area and was described as
+
burning, dull or a feeling of pressure. None of the patients described the pain as significant, as had been reported in a previous study of prostaglandin E l alone.7 After the injection of 10 pg. prostaglandin E l 3 of the 38 patients (7.9%) showed slight tumescence only, 12 (31.6%) exhibited tumescence without rigidity and 23 (60.5%) achieved an erection with incomplete or complete rigidity (grades 4 and 5). The mean latency time between injection and the onset of erection was 7.3 + 3.4 minutes and the mean duration of erection was 109.3 + 61 minutes (maximum 210 minutes). A total of 13 patients (34.2%) complained of moderate to severe pain and burning after injection and throughout the erection. In these 38 patients the combination of papaverine and prostaglandin E l induced an erection of grade 4 or 5 in 28 (73.6%).The mean latency time was 8.3 & 4.8 minutes and the mean duration was 124.3 + 111.3 minutes. Prolonged erections (greater than 5 hours) occurred in 4 patients with psychogenic, neurogenic or minimally arteriogenic disease. Mild to moderate pain was noted in 7 patients (18.4%). The combination of 7.5 mg. papaverine and 5 pg. prostaglandin E l showed a significantly higher potential to induce erections (p = 0.03) than 10 pg. prostaglandin E l alone. The latency period was not significantly different (p = 0.45). No prolonged erections occurred after prostaglandin E l alone (part B of figure) and the duration of erection was significantly lower in this group (p = 0.045). The drug combination caused prolonged erections in 4 patients but these subsided spontaneously. The incidence of side effects (13 versus 7 or 38) was not statistically different (p = 0.08) but the pain after the drug combination was described by the patients in significantly less dramatic terms than after prostaglandin E l alone. The randomization of the order of injections did not have an influence on the results in either study group. The degree of erection achieved after injection and the incidence of side effects were equally distributed no matter which substance was injected first. DISCUSSION
The combination of papaverine and phentolaminels is widely used for diagnostic and therapeutic intracorporeal injections in impotent patients. The apparent synergism of smooth muscle relaxant and an al-blocking agent allows for a significant decrease in the respective single doses. The main concern about the administration of papaverine is based on the observation of fibrosis at the tunica albuginea as well as inside the corpora after injection of papaverine alone or in combination with other sub~tances.',~ A clear dose-dependence has not been established, although most investigators report single doses of 20 mg. papaverine or more. The incidence seems to be higher with papaverine a10ne.~Other clinical reports do not confirm significant fibrotic changes.' Given this uncertainty, a further decrease in the dose needed to induce erection and injection in combination with another drug seems to be advisable. The intracavernous injection of prostaglandin E l has also been widely accepted as a standard procedure in the diagnosis and treatment of erectile dysfunction. It effectively induces erections and appears to have a lower potential to cause priap-
TABLE1. Diagnostic findings Papaverine/Phentolamine Versus Papaverine/ Prostaglandin E l No. Pts. (%) Total No. pts. Severe arterial restriction Moderate arterial restriction Venous leak Neurogenic Predominantly psychogenic Diabetes mellitus *Some patients with multiple pathogenetic factors in both groups.
57
Prostaglandin E l Versus Papaverine/Prostaglandin E l No. Pts. (%)
58
FLOTH AND SCHRAMEK
TABLE2. Grade of erection after injection Grade of Erection
Papaverine Plus Phentolamine* No. Pts. (%)
Papaverine Plus Prostaglandin E l * No. Pts. (%)
Prostaglandin E l t No. Pts. (%)
1-2 (tumescence) 3 (no rigidity) 4-5 (sufficient rigidity)
12 (24.5) 9 (18.4) 28 (57.1)
6 (12.2) 5 (10.2) 38 (77.5)
3 (7.9) 12 (31.6) 23 (60.5)
Papaverine Plus Prostaglandin E l t No. Pts. (%) 2 (5.3) 8 (21.0)
28 (73.7)
* Total 49 patients. + Total 38 patients.
Papaverine Phentolamine
Papaverine Prostaglandin E l
Prostaglandin E l
Papaverine Prostaglandin E l
A, percentile plot illustrates similar incidence of prolonged erections after papaverine/phentolamine and papaverine/prostaglandin E l , although there is significant difference in mean duration of erections in both study groups. Ordinate shows duration of erection in minutes. B, percentile plot shows clear difference in incidence of prolonged erections after injection of prostaglandin E l alone or in combination with papaverine. Notches represent 95% confidence bands about median. Outliers are indicated by black dots.
ism t h a n other drugs used for t h e same purpose. T h e most frequently reported side effect is pain, with a n incidence of 16 to 40%fi,g-11,1"a n d a clear dose dependency.gslVhe threshold for t h e induction of pain a s a side effect appears t o be a single dose between 5 a n d 10 fig. I n our experience 5 fig. are not always sufficient t o allow for a differential diagnosis with t h e least number of diagnostic injections possible. I n our selfinjection program this a m o u n t was frequently not sufficient t o achieve a n adequate erection. Since several patients chose t o discontinue t h e diagnostic process or t h e self-injection program after experiencing t h e side effects of a n injection of 1 5 t o 20 fig. prostaglandin E l , w e decided t o investigate t h e possible synergism of prostaglandin E l a n d papaverine. T h e combination of different mechanisms of action is a possible explanation for t h e synergistic behavior. Papaverine acts o n a post-receptor level via t h e inhibition of phosphodiesterase (the consequent increase in cyclic adenosine monophosphate attenuates t h e al-receptor-mediated contraction of t h e smooth muscle cell, possibly by interfering with t h e calcium ion-mobilization),lg whereas prostaglandin E l acts via a membrane-receptor. Furthermore, t h e a-blocking properties of prostaglandin E l seem t o be a t least a s effective as phentolamine, if not more so.'' I n our series side effects were still noted with t h e combination of papaverine a n d prostaglandin E l b u t i n contrast t o a previous report7 they were m u c h less frequent a n d severe. None of t h e patients withdrew f r o m t h e study. W e conclude t h a t a combination of 7.5 mg. papaverine and 5 fig. prostaglandin E l i s significantly more effective t h a n 7.5
mg. papaverine with 0.25 mg. phentolamine or 10 fig. prostaglandin E l alone, a n d t h a t t h e effect of papaverine a n d prostaglandin E l is clearly synergistic. T h i s drug combination can also replace prostaglandin E l alone, especially i n patients with significant side effects or with a weak response t o prostaglandin E l t h a t may be caused by a low receptor density. REFERENCES
1. Levine, S. B., Althof, S. E., Turner, L. A,, Risen, C. B., Bodner, D.
2. 3.
4.
5. 6. 7. 8.
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. Sidi, A. A,, Becher, E. F, and Cherwitz, D. L.: Light microscopic analysis of penile tissues after vasoactive intracavernous pbarmacotherapy (VIP). J. Urol., 141: 273A, abstract 415, 1989. Abozeid, M., Juenemann, K.-P., Luo, J.-A,, Lue, T. F., Yen, T.-S. B. and Tanagho, E. A,: Chronic papaverine treatment: the effects of repeated injections on the simian erectile response and penile tissue. J. Urol., 138: 1263, 1987. Fuchs, M. E. and Brawer, M. K.: Papaverine-induced fibrosis of the corpus cavernosum. J. Urol., 141: 125, 1989. Tullii, R. E., Degni, M. and Pinto, A. F. C.: Fibrosis of the cavernous bodies following intracavernous auto-injection of vasoactive drugs. Int. J. Impotence Res., 1: 49, 1989. Stackl, W., Hasun, R. and Marberger, M.: Intracavernous injection of prostaglandin E l in impotent men. J. Urol., 140: 66, 1988. Waldhauser, M. and Schramek, P.: Efficiency and side effects of prostaglandin E l in the treatment of erectile dysfunction. J . Urol., 140: 525, 1988. 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.
INTRACAVZRWOUS INJECTION OF PROSTAGLANDIN E l AND PAPAVEXINE
9. Sarosdy, M. F., Hudnall, C. H., Erickson, D. R., Hardin, T. C. and Novicki, D. E.: A prospective double-blind trial of intracorporeal papaverine versus prostaglandin E l in the treatment of impotence. J. Urol., 141: 551, 1989. 10. Hwang, T. I.-S., Yang, C.-R., Wang, S.-J., Chang, C.-L., Tzai, T.S., Chang, C.-H. and Wu, H.-C.: Impotence evaluated by the use of prostaglandin E l . J. Urol., 141: 1357, 1989. 11. Lue, T. F.: Editorial comment. J. Urol., 141: 325, 1989. 12. Schramek, P. and Waldhauser, M.: Dose-dependent effect and sideeffect of prostaglandin E l in erectile dysfunction. Brit. J. Clin. Pharm., 28: 567, 1989. 13. Lee, L. M., Stevenson, R. W. D. and Szasz, 6 . : Prostaglandin E l versus phentolamine/papaverine for the treatment of erectile impotence: a double-blind comparison. J. Urol., 141: 549, 1989. 14. Floth, A. and Schramek, P.: Unpublished data.
59
15. Stief, C. G., Bahren, W., Gall, H. and Scherb, W.: Functional evaluation of penile hemodynamics. J. Urol., 139: 734, 1988. 16. Lue, T.: Personal communication. 17. Shabsigh, R., Fishman, I. J., Quesada, E. T., Seale-Hawkins, C. K. and Dunn, J . K.: Evaluation of vasculogenic erectile impotence using penile duplex ultrasonography. J . Urol., 142: 1469, 1989. 18. Zorgniotti, A. W. and Lefleur, R. S.: Auto-injection of the corpus cavernosum with a vasoactive drug combination for vasculogenic impotence. J. Urol., 133: 39, 1985. 19. Christ, G. J., Valcic, M., Maayani, S. and Melman, A,: Kinetic studies of contraction in human erectile tissue (HET) and rabbit aortic rings in vitro: modulation by papaverine and the dihydropyridine analog nifedipine. Int. J. Impotence Res., 1: 1, 1989. 20. Langer, S. Z.: Presynaptic regulation of the release of catecholamines. Pharmacol. Rev., 32: 337, 1981.