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Comparative Study of Papaverine Plus Phentolamine Versus Prostaglandin E1 in Erectile Dysfunction
oozzsslr7/97/1576-2132$03.W0 "Hll JOURNAL OF UROLOGY copyright @ 1997 by AMERICAN URouw7.1c~L ASSOCUTION.b c
Vol. 157.2132-2134, June 1997 Printed in U.S.A.
COMPARATIVE STUDY OF PAPAVERINE PLUS PHENTOLAMINE VERSUS PROSTAGLANDIN E l IN ERECTILE DYSFUNCTION A. BECHARA, A. CASABE, G. CHELIZ, S. ROMANO, H. REY
AND
N. FREDOTOVICH
From the Urology Division, Hospital Durand, Buenos Aires, Argentina
ABSTRACT
Purpose: We compared the efficacy and short-term adverse effects of 1 ml. 30 mg./ml. papaverine plus 0.5 mg./ml. phentolamine versus 1 ml. 30 pg./ml. prostaglandin E l in patients undergoing pharmacological erection testing. Materials and Methods: A total of 60 patients (mean age 58 years) with a history of sexual erectile dysfunction longer than 6 months was randomly classified into 6 groups to be tested 1 week apart with the 2 solutions and with placebo to evaluate erection response and short-term adverse effects. Results: Of the patients tested with papaverine plus phentolamine 54% responded with erections adequate for penetration, compared to 50% of those tested with prostaglandin E l (p >0.05). Prolonged erection occurred in 18%of patients tested with papaverine plus phentolamine and 15%of those tested with prostaglandin E l (p >0.05). Pain was reported by 15 and 35% of patients, respectively (p <0.05). Conclusions: One ml. 30 mg./ml. papaverine plus 0.5 mg./ml. phentolamine has the same efficacy and equal prolonged erection rate as 1 ml. 30 pg./ml. prostaglandin E l but the latter agent induces significantly more pain. KEYWORDS:impotence, prostaglandins E, papaverine, phentolamine, drug therapy
There is no doubt that the use of vasoactive drugs has signaled a pivotal point in the diagnosis and treatment of sexual erectile dysfunction. Historically, the first of these drugs to be used clinically was papaverine hydrochloride.1 Since then many other agents have been incorporated into daily practice, which alone or jointly induce a better erectile response with a lower rate of adverse effects."B Based on reviewed literature the efficacy of these drugs is approximately 35% for papaverine alone, 65% for papaverine plus phentolamine, 75% for prostaglandin El9 and 85% for the mixture of all 3 drugs.10 Many studies evaluating the efficacy and adverse effects of vasoactive drugs are available in the literature but relatively few compare the efficiency of 2 drugs mixed together with placebo control, with intra-subject evaluation and in an unselected population. Therefore, we compared randomly and in the same population the efficacy of a solution of prostaglandin E l versus papaverine plus phentolamine. MATERIALS AND METHODS
Between December 1992 and April 1993 the response to vasoactive drugs was evaluated in 60 patients 22 to 78 years old (mean age 58 years). The protocol was designed in a prospective, intra-subject, randomized, double-blind, placebo controlled fashion, and included patients with a history of sexual erectile dysfunction longer than 6 months. Patients with major neurological impairment secondary to spinal cord injury or radical pelvic surgery were excluded from the study, since the triggering of an erection as reflected in diagnostic procedures would hinder the interpretation. Patients who were or may have been treated with selfinjected vasoactive drugs or may have previously undergone Accepted for publication December 20, 1996. Editor'e Note: This article is the third of 5 published in this issue for which category 1 CME credits can be earned. Instructions for obtaining credits are given with the questions on pages 2318 and 2319.
a pharmacological erection test also were excluded from the study. Patients included in the protocol were randomly classified into 6 groups and given a weekly intracavernous injection of 30 mg. papaverine hydrochloride plus 0.5 mg. phentolamine mesylate in 1ml. solution, 30 pg. prostaglandin E l in 1 ml. solution or 1 ml. isotonic sodium chloride solution. Concentrations of the drugs used corresponded to the upper range of the habitual mean v a l ~ e . ~All. 3 ~ solutions ~ . ~ ~ were kept in the refrigerator for the duration of the study to minimize the temperature factor in results and to decrease the likelihood of the attending physician to identify the injected drug. For that reason 1examiner prepared each injection, which was delivered within a self-injector to the physician in charge of the study. To investigate the influence of sequential drug administration and to rule out the probable negative effect of the initial injection, 6 groups were constructed according t o the permutation order of the solutions used (factorial 3 = 6). Responses achieved up to 10, 20 and 30 minutes after injection were evaluated using manual and visual sexual stimulation.13-15 Erectile responses were classified as EO -without tumefaction, El-elongation alone, E2-moderate tumefaction, E3complete tumefaction without rigidity, E4-tumefaction without complete rigidity but allowing penetration and E5complete rigidity.9 Responses allowing penetration were considered positive (E4 and E5) and those failing to do so were regarded as negative (EO to E3). In addition to erectile response, the appearance of prolonged erection (a positive response lasting longer than 3 hours), pain and systemic effects was also considered. Pain unrelated to trauma caused by the injection needle was considered when it was liable to prevent or hinder use of vasoactive drugs in a sexual relationship. Long-term adverse effects were not evaluated, since only a pharmacological test was performed. All 60 patients studied were able to complete the protocol. Results were statistically analyzed by the multiple chisquare method.
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PAPAVERINE PLUS PHENTOLAMINE VERSUS PROSTAGLANDIN E l IN ERECTILE DYSFUNCTION RESULTS
2133
TABLE2. Prolonged erection and pain with papaverine plue
phentolamine vemw prostaglandin E l versus placebo in sex& Of the 60 patients 34 (54%)responded positively to papaverectile dysfunction erine plus phentolamine and 30 (50%)to prostaglandin El. The difference between these solutions for E4, E5 and E4 No.Pts. (56) Drug plus E5 responses was not significant (p >0.05,table 1). No PIOlonged Erection Pain difference was observed between the number of patients who PlWbo 0 0 responded positively, and the order in which the vasoactive Papaverine plue phentolamine 11 (18). 9 (16)t h g s and placebo were self-injeded (p >0.05). No patient h t a g l a n d i n El 9 (16)* 21 (36)t responded to placebo. The observed adverse effects were pro* p 20.05. longed erection in 9 of 60 patients (15%)given prostaglandin t p 4.05. E l and 11 (18%) given papaverine plus phentolamine (p >0.05),and pain was reported in 21 (35%)and 9 (15%)of 60 patients, respectively (p <0.05, table 2). No systemic effects to evaluate the possibilities of response to these drugs rewere noted. gardless of the pathological cause. Our results failed to show any significant differences between the 2 solutions with reDISCUSSION gard to erectile response and prolonged erections. However, The use of vasoactive drugs affords a valuable resource in pain was significantly greater with prostaglandin El. the diagnosis and treatment of sexual erectile dysfunction, Most investigators report a greater efficiency of prostaand has become widespread in the management of this af- glandin E l compared to papaverine plus phentolamine. fliction. Meanwhile, the search continues for a drug that Waldhauser and Schramek documented greater efficiency of proves to be more effective with milder adverse effects, is 20 pg. prostaglandin E l versus papaverine plus phentoleasy to administer and is accessible to most patients. Thus, amine (7.5 and 0.25 mg., respectively) in a double-bhd study from the introduction of papaverine to present clinical prac- of 12 impotent patients (11 versus 6, respectively).mLee et al tice a wide variety of drugs injected via the intracavernous compared the efficiency of 50 pg. prostaglandin E l versus 30 route to induce an adequate erectile response have been plus 1 mg. papaverine plus phentolamine, respectively, in 25 tested.”s organically impotent patients and all achieved erection with Papaverine hydrochloride, prostaglandin E l and phentol- penetration capacity.21 However, they based the better qualamine mesylate alone or jointly are the drugs most commonly ity of response to prostaglandin E l on the subjective apused in clinical practice. Papaverine and prostaglandin E l praisal of 9 patients from that group who reported having a favor an increase in the concentration of intracellular cyclic better quality of erection with prostaglandin E l than with adenosine monophosphate inducing relaxation of the smooth papaverine plus phentolamine. Earle et al also compared the muscle of the cavernous body and helicine arteries. Prosta- efficiency of 5 pg. prostaglandin E l versus 18 mg. papaverine glandin E l stimulates the enzyme adenylate cyclase, while alone in a home pharmacological erection program in 129 papaverine prevents metabolism of cyclic adenosine mono- patients who received each drug for 1 month, generaphosphate through phosphodiesterase inhibition. Phentol- better quality erections with prostaglandin E l than with amine mesylate is an a-adrenergic blocker that suppresses papaverine in 5546.22 Papaverine was more effective than the sympathetic inhibitory effect of eredion.11,l6 prostaglandin E l a t inducing rigid erections in only 17% of The association of 2 or more vasoactive drugs would seem the studied population. to provide greater efficiency with milder adverse effects, However, we found no statistically significant differences since based on the cascade hypothesis a synergic drug effect among the tested solutions, probably due to the fact that the due to the different mechanisms of action would presumably adopted design was more reliable and the population under act on the diverse local. neurolo&al and endothelial fac- study was different. Our results agree with those reported by turs.6.10 In a double-blind study Sgenfeld et al demonstrated Wetterauer, who in a prospective intra-individual comparithe greater efficiency of a triple mixture of papaverine, phen- son failed to observe a si&cant differencein drug response, kd-ne and Proitadan& E l versus -PaPaVenne PIUS although they suggested that prostaglandin E l is more effecphentolamine.17 We observed that the triple association was tivein patientswith venom leakage.12 results agree significantly more effective than prostaglandin E l alone in a with those of Boullier et al, who also found no statistically select population of nonresponders to high dose papaverine significant differences in a redspective analysis of the effiplus phentolamine (60 plus 1 mgJd., respedivelY).’8 Re- ciency and adverse effects up to 5 years with papaverine cently, Mulhall et al treated successfully 90%of patients who alone vemw prostaglandin ~1 for self-iqjdon therapy.= had become refractory to use of a triple association by adding is greater with the use Most investigators agree that another drug, forskolm, which is a natural alkaloid that of prostaglandin ~ 1 2 0 . 2 9 - 2 7and, furthermore, it is do= d e increases cyclic adenosine monophosphate l e ~ e l s . 1 ~ pendent.21.w Our increased pain index with prostaglandin we compared the association of papaverine and phentol- ~1 (35%)could be due to the high inj& dose (30 a*). amine to prostaglandin E l to evaluate the efficiency and However, Waldhauser and Schramek reported pain in 75% of Short-hrm adverse effecta The study design and features of patients injected 6 t h 20 p,g.,zo and @ r b r and b h e docthe population (patients with sexual erectile dysfunction -&& pain in 39%heated with 10 pg. prosalandin El.% longer than 6 months in duration who had not PreGouSlY our 35%rate of pain compares favorably with those reported undergone therapeutic or diagnostic procedures) allowed us previously.zi. 29 According to Jueneman in more than 7,000 pharmacological tests the incidence of prolonged erection was 9.5%with TABLE1. Positive response to papaverim plus phentolamim versus papaverine 5.3% with papave,.i,-,e phentolamine and prostaglandin E l versus placebo in sexual erectile dysfunction 2.4%with ~ o s t a g l a~n ~ 1me . fact that ~1 No. Erectile Response (%) is metabolized locally within the cavernous body could exD W E4 E5 ~4 + E5 plain the lower incidence of prolonged erection.so~sl In our population the rate of prolonged erection was high, PlaCet.0 0 0 0 reaching 18 and 15%for papaverine plus p h e n t o l d n e and Papavefine plus phentolamine 20 (33) 14 (23) 94 (66) prostaglandin El, respectively.This result prob&ly due hataglandin E l 16 (27) 14 (23) 30 (50) to the high in patients P N . 0 5 for papaverine plus phentolamine versus prostaglandin El and p cause, bearing in mind that potential patients with psyche <0.001 for prostaglandin E l versus placebo.
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PAPAWRINE PLUS PHENTOLAMINE VERSUS PROSTAGLANDIN E l IN ERECTILE DYSFUNCTION
W. F. Thon and C. G. Stief. New York: Springer-Verlag, chapt. 19, pp. 221-235, 1991. 13. Katlowitz, N. M., Albano, G. J., Morales, p. and Golimbu, M.: Potentiation of drug-induced erection with audiovisual sexual stimulation. Urology, 41: 431, 1993. 14. Vruggink, P., Debruyne, F. and Meuleman, E.: Enhanced pharmacological testing in erectile dysfunction. Int. J. Impotence Res., suppl. 1, p. D-47, 1994. 15. Donatucci, C. F. and Lue, T. F.: The combined intracavemous injection and stimulation test: diagnostic accuracy. J. Urol., 148:61, 1992. 16. Lue, T. F. and Tanagho, E. A,: Physiology of erection and pharmacological management of impotence. J. Urol., 137: 829, 1987. 17. Shenfeld, O., Hanani, A,, Shalhav, Y. and Goldwasser, B.: Papaverine-phentolamine and prostaglandin E l versus papaverine-phentolamine alone for intracorporeal injection CONCLUSIONS therapy: a clinical double-blind study. J. Urol., 154: 1017, According to available medical literature, we believe that 1995. for self-injection treatment of sexual erectile dysfunction 18. Bechara, A., CasaM, A., ChBliz, G., Romano, S.and Fredotovich, prostaglandin E l would be the drug of choice, since papavN.: Prostaglandin E l versus mixture of prostaglandin E l , erine induces a greater index of fibrosis in the long term.27.30 papaverine and phentolamine in nonresponders to high papaverine plus phentolamine doses. J . Urol., 155: 913, 1996. However, since prostaglandin E l is more expensive and causes more pain than papaverine, such factors could be 19. Mulhall, J., Traish, A., Gupta, S., Payton, T., Krane, R. J. and Goldstein, I.: Rescuing the failed injection patient with the use responsible for a greater percentage of dropouts from treatof forskolin. J. Urol., part 2, 155: 496A. abstract 743, 1996. ment programs.24.33According to our results a 1 ml. solution M. and Schramek, P.: Efficiency and side effects of of 30 mg./ml. papaverine plus 0.5 mg./ml. phentolamine has 20. Waldhauser, prostaglandin E l in the treatment of erectile dysfunction. the same efficiency to achieve an erection suitable for peneJ. Urol., 1 4 0 525, 1988. tration and has a prolonged erection rate similar to that with 21. Lee, L. M., Stevenson, R. W. D. and Szasz, G.: Prostaglandin E l 1 ml. 30 pg./ml. prostaglandin E l , the latter proving to be versus phentolamindpapaverine for the treatment of erectile significantly more painful. impotence: a double-blind comparison. J. Urol., 141: 549, 1989. 22. Earle, C. M., Keogh, E. J., Wisniewski, Z. S., Tulloch, A. G. S., Farmacia Roma provided the vasoactive drugs and Dr. Lord, D. J., Watters, G. R. and Glatthaar, C.: Prostaglandin E l Carlos Bantar performed the statistical analysis. therapy for impotence, comparison with papaverine. J. Urol., 143.57, 1990. 23. Boullier, J. A., Rauscher, J . A., Cummings, J . M. and Parra, REFERENCES R. 0.:Comparison of papaverine and prostaglandin E l (PGE1) single drug therapy for erectile dysfunction. J. Urol., part 2, 1. Virag, R.: Intracavernous injection of papaverine for erectile failure. Letter to the Editor. Lancet, 2: 938, 1982. 156 468A, abstract 631A, 1996. 2. Zorgniotti, A. W. and Lefleur, R. S.: Auto-injection of the corpus 24. Gerber, G. S. and Levine, L. A.: Pharmacological erection program using prostaglandin E l . J. Urol., 1 4 6 786, 1991. cavemosum with a vasoactive drug combination for vasculogenic impotence. J. Urol., 133 39, 1985. 25. Mahmoud, K Z., El Dakhli, M. M., Fahmi, I. M. and Abdel-Aziz, 3. Zorgniotti, A. W.: Corpus cavernosum blockade for impotence: A. A.: Comparative value of prostaglandin E l and papaverine practical aspects and results in 250 cases. J. Urol., part 2,135: in treatment of erectile failure: double-blind crossover study 306A, abstract 808, 1986. among Egyptian patients. J. Urol., 147: 623, 1992. 4. Ishii, N., Watanabe, H., Irisawa, C., Kikuchi, Y., Kawamura, S., 26. Lakin, M. M., Montague, D. K., VanderBrug Mendendorp, S., Suzuki, K., Chiba, R., Tokiwa, M. and Shirai, M.: IntracavernTesar, L. and Schover, L. R.: Intracavernous injection therapy: o w injection of prostaglandin E l for the treatment of erectile analysis ofresults and complications. J. Urol., 143: 1138,1990. impotence. J. Urol., 141: 323, 1989. 27. Jueneman, K.: Pharmacotherapy of impotence: where are we 5. Virag, R. and Shoukry, K: Long term follow-up on self intragoing? In: World Book of Impotence Research: Basic and Clincavernous injections (SICI) for impotence. J. Urol., part 2,141: ical. Edited by T. F. Lue. London: E. Smith Jordon & Co., Ltd., 288A, abstract 476, 1989. chapt. 13, pp. 181-188.1992, 6. Goldstein, I., Borges, F., Kauf€man, J., Moreno, J., Payton, T. 28. Stackl, W., Hasun, R. and Marberger, M.: Intracavernous injecand Krane, R. J.: Rescuing the failed papaverine/phentoltion of prostaglandin E l in impotent men. J. Urol., 1 4 0 66, amine erection: a proposed synergistic action of papaverine, 1988. phentolamine and prostaglandin E l . Int. J. Impotence bs., 29. Schramek, P., Dorninger, R., Waldhauser, M., Konecny, P. and suppl., 2:277, 1990. Porpaczy, P.: Prostaglandin E l in erectile dysfunction. Effi7. Montorsi, F., Guazzoni, G., Bergamaschi, F., Fernini-Strambi, ciency and incidence of priapism. Brit. J . Urol., 65: 68, 1990. L., Barbieri, L. and Rigatti, P.: Four-drug intracavernous ther- 30. Aboseif, S. R., Breza, J., Bosch, R. J. L. H., Benard, F., Stief, apy for impotence due to corporeal veno-occlusive dysfunction. C. G., Stackl, W., Lue, T. F. and Tanagho, E. A,: Local and J. Urol., part 2,149: 1291, 1993. systemic effects of chronic intracavernous injection of papav8. Bennett, A. H., Carpenter, A. J . and Barada, J . H.: An improved erine, prostaglandin E l , and saline in primates. J . Urol., 1 4 2 vasoactive drug combination for a pharmacological erection 403, 1989. program. J . Urol., 146: 1564, 1991. 31. Stief, C. G., Wetterauer, U., Popken, G. and Sommerkamp, H.: 9. Juenemann, K-P.: Pharmacotesting in erectile dysfunction. In: Experience with an intracavernous drug delivery system. Erectile Dysfunction. Edited by U. Jonas, W. F. Thon and C. G. J. Urol., part 2, 1 3 9 328A, abstract 664,1988. Stief. New York: Springer-Verlag, chapt. 9, pp. 104-114,1991. 32. Sidi, A. A., Cameron, J . S., Dykstra, D. D., Reinberg, Y. and 10. Goldstein, 1.: Comment. In: World Book of Impotence Research: Lange, P. H.: Vasoactive intracavernous pharmacotherapy for Basic and Clinical. Edited by T. F. Lue. London: Smith Jordon the treatment of erectile impotence in men with spinal cord & Co., Ltd., chapt. 13, pp. 194-197, 1992. injury. J. Urol., 138 539, 1987. 11. von Heyden, B., Donatucci, C. F., Kaula, N. and Lue, T. F.: 33. Abobakr, R. A., Mulhall, J., Goldstein, B., Leitzes, R., Woods, J., Intracavernous pharmacotherapy for impotence: selection of Payton, T., Krane, R. J. and Goldstein, I.: The prevalence and appropriate agent and dose. J. Urol., part 2, 149: 1288, 1993. causes of patient drop-out from long-term self-injection ther12. Wetterauer, U.: Intracavernous pharmacotherapy for erectile apy for impotence: survey results from 708 respondents. dysfunction. In: Erectile Dysfunction. Edited by U. Jonas, J . Urol., part 2, 156: 469A, abstract 632, 1996.
logical and/or neurological disorders respond better than those with a vascular origin of the dysfunction.32 Based on our results the efficiency of 1ml. 30 jg./ml. prostaglandin E l and 1 ml. 30 mg./ml. papaverine plus 0.5 mg./ml. phentolamine proved to be similar and, therefore, the choice will depend on the adverse effects and cost. Prostaglandin E l is more painful in a sigdicant percentage of patients and has a greater cost per dose (in our country approximately $18 for prostaglandin E l versus $2.6 for papaverine plus phentolamine), with a similar incidence of prolonged erection. This finding suggests that papaverine plus phentolamine would be the drugs of choice for a pharmacological erection test.
Vol. 157.2132-2134, June 1997 Printed in U.S.A.
COMPARATIVE STUDY OF PAPAVERINE PLUS PHENTOLAMINE VERSUS PROSTAGLANDIN E l IN ERECTILE DYSFUNCTION A. BECHARA, A. CASABE, G. CHELIZ, S. ROMANO, H. REY
AND
N. FREDOTOVICH
From the Urology Division, Hospital Durand, Buenos Aires, Argentina
ABSTRACT
Purpose: We compared the efficacy and short-term adverse effects of 1 ml. 30 mg./ml. papaverine plus 0.5 mg./ml. phentolamine versus 1 ml. 30 pg./ml. prostaglandin E l in patients undergoing pharmacological erection testing. Materials and Methods: A total of 60 patients (mean age 58 years) with a history of sexual erectile dysfunction longer than 6 months was randomly classified into 6 groups to be tested 1 week apart with the 2 solutions and with placebo to evaluate erection response and short-term adverse effects. Results: Of the patients tested with papaverine plus phentolamine 54% responded with erections adequate for penetration, compared to 50% of those tested with prostaglandin E l (p >0.05). Prolonged erection occurred in 18%of patients tested with papaverine plus phentolamine and 15%of those tested with prostaglandin E l (p >0.05). Pain was reported by 15 and 35% of patients, respectively (p <0.05). Conclusions: One ml. 30 mg./ml. papaverine plus 0.5 mg./ml. phentolamine has the same efficacy and equal prolonged erection rate as 1 ml. 30 pg./ml. prostaglandin E l but the latter agent induces significantly more pain. KEYWORDS:impotence, prostaglandins E, papaverine, phentolamine, drug therapy
There is no doubt that the use of vasoactive drugs has signaled a pivotal point in the diagnosis and treatment of sexual erectile dysfunction. Historically, the first of these drugs to be used clinically was papaverine hydrochloride.1 Since then many other agents have been incorporated into daily practice, which alone or jointly induce a better erectile response with a lower rate of adverse effects."B Based on reviewed literature the efficacy of these drugs is approximately 35% for papaverine alone, 65% for papaverine plus phentolamine, 75% for prostaglandin El9 and 85% for the mixture of all 3 drugs.10 Many studies evaluating the efficacy and adverse effects of vasoactive drugs are available in the literature but relatively few compare the efficiency of 2 drugs mixed together with placebo control, with intra-subject evaluation and in an unselected population. Therefore, we compared randomly and in the same population the efficacy of a solution of prostaglandin E l versus papaverine plus phentolamine. MATERIALS AND METHODS
Between December 1992 and April 1993 the response to vasoactive drugs was evaluated in 60 patients 22 to 78 years old (mean age 58 years). The protocol was designed in a prospective, intra-subject, randomized, double-blind, placebo controlled fashion, and included patients with a history of sexual erectile dysfunction longer than 6 months. Patients with major neurological impairment secondary to spinal cord injury or radical pelvic surgery were excluded from the study, since the triggering of an erection as reflected in diagnostic procedures would hinder the interpretation. Patients who were or may have been treated with selfinjected vasoactive drugs or may have previously undergone Accepted for publication December 20, 1996. Editor'e Note: This article is the third of 5 published in this issue for which category 1 CME credits can be earned. Instructions for obtaining credits are given with the questions on pages 2318 and 2319.
a pharmacological erection test also were excluded from the study. Patients included in the protocol were randomly classified into 6 groups and given a weekly intracavernous injection of 30 mg. papaverine hydrochloride plus 0.5 mg. phentolamine mesylate in 1ml. solution, 30 pg. prostaglandin E l in 1 ml. solution or 1 ml. isotonic sodium chloride solution. Concentrations of the drugs used corresponded to the upper range of the habitual mean v a l ~ e . ~All. 3 ~ solutions ~ . ~ ~ were kept in the refrigerator for the duration of the study to minimize the temperature factor in results and to decrease the likelihood of the attending physician to identify the injected drug. For that reason 1examiner prepared each injection, which was delivered within a self-injector to the physician in charge of the study. To investigate the influence of sequential drug administration and to rule out the probable negative effect of the initial injection, 6 groups were constructed according t o the permutation order of the solutions used (factorial 3 = 6). Responses achieved up to 10, 20 and 30 minutes after injection were evaluated using manual and visual sexual stimulation.13-15 Erectile responses were classified as EO -without tumefaction, El-elongation alone, E2-moderate tumefaction, E3complete tumefaction without rigidity, E4-tumefaction without complete rigidity but allowing penetration and E5complete rigidity.9 Responses allowing penetration were considered positive (E4 and E5) and those failing to do so were regarded as negative (EO to E3). In addition to erectile response, the appearance of prolonged erection (a positive response lasting longer than 3 hours), pain and systemic effects was also considered. Pain unrelated to trauma caused by the injection needle was considered when it was liable to prevent or hinder use of vasoactive drugs in a sexual relationship. Long-term adverse effects were not evaluated, since only a pharmacological test was performed. All 60 patients studied were able to complete the protocol. Results were statistically analyzed by the multiple chisquare method.
2132
PAPAVERINE PLUS PHENTOLAMINE VERSUS PROSTAGLANDIN E l IN ERECTILE DYSFUNCTION RESULTS
2133
TABLE2. Prolonged erection and pain with papaverine plue
phentolamine vemw prostaglandin E l versus placebo in sex& Of the 60 patients 34 (54%)responded positively to papaverectile dysfunction erine plus phentolamine and 30 (50%)to prostaglandin El. The difference between these solutions for E4, E5 and E4 No.Pts. (56) Drug plus E5 responses was not significant (p >0.05,table 1). No PIOlonged Erection Pain difference was observed between the number of patients who PlWbo 0 0 responded positively, and the order in which the vasoactive Papaverine plue phentolamine 11 (18). 9 (16)t h g s and placebo were self-injeded (p >0.05). No patient h t a g l a n d i n El 9 (16)* 21 (36)t responded to placebo. The observed adverse effects were pro* p 20.05. longed erection in 9 of 60 patients (15%)given prostaglandin t p 4.05. E l and 11 (18%) given papaverine plus phentolamine (p >0.05),and pain was reported in 21 (35%)and 9 (15%)of 60 patients, respectively (p <0.05, table 2). No systemic effects to evaluate the possibilities of response to these drugs rewere noted. gardless of the pathological cause. Our results failed to show any significant differences between the 2 solutions with reDISCUSSION gard to erectile response and prolonged erections. However, The use of vasoactive drugs affords a valuable resource in pain was significantly greater with prostaglandin El. the diagnosis and treatment of sexual erectile dysfunction, Most investigators report a greater efficiency of prostaand has become widespread in the management of this af- glandin E l compared to papaverine plus phentolamine. fliction. Meanwhile, the search continues for a drug that Waldhauser and Schramek documented greater efficiency of proves to be more effective with milder adverse effects, is 20 pg. prostaglandin E l versus papaverine plus phentoleasy to administer and is accessible to most patients. Thus, amine (7.5 and 0.25 mg., respectively) in a double-bhd study from the introduction of papaverine to present clinical prac- of 12 impotent patients (11 versus 6, respectively).mLee et al tice a wide variety of drugs injected via the intracavernous compared the efficiency of 50 pg. prostaglandin E l versus 30 route to induce an adequate erectile response have been plus 1 mg. papaverine plus phentolamine, respectively, in 25 tested.”s organically impotent patients and all achieved erection with Papaverine hydrochloride, prostaglandin E l and phentol- penetration capacity.21 However, they based the better qualamine mesylate alone or jointly are the drugs most commonly ity of response to prostaglandin E l on the subjective apused in clinical practice. Papaverine and prostaglandin E l praisal of 9 patients from that group who reported having a favor an increase in the concentration of intracellular cyclic better quality of erection with prostaglandin E l than with adenosine monophosphate inducing relaxation of the smooth papaverine plus phentolamine. Earle et al also compared the muscle of the cavernous body and helicine arteries. Prosta- efficiency of 5 pg. prostaglandin E l versus 18 mg. papaverine glandin E l stimulates the enzyme adenylate cyclase, while alone in a home pharmacological erection program in 129 papaverine prevents metabolism of cyclic adenosine mono- patients who received each drug for 1 month, generaphosphate through phosphodiesterase inhibition. Phentol- better quality erections with prostaglandin E l than with amine mesylate is an a-adrenergic blocker that suppresses papaverine in 5546.22 Papaverine was more effective than the sympathetic inhibitory effect of eredion.11,l6 prostaglandin E l a t inducing rigid erections in only 17% of The association of 2 or more vasoactive drugs would seem the studied population. to provide greater efficiency with milder adverse effects, However, we found no statistically significant differences since based on the cascade hypothesis a synergic drug effect among the tested solutions, probably due to the fact that the due to the different mechanisms of action would presumably adopted design was more reliable and the population under act on the diverse local. neurolo&al and endothelial fac- study was different. Our results agree with those reported by turs.6.10 In a double-blind study Sgenfeld et al demonstrated Wetterauer, who in a prospective intra-individual comparithe greater efficiency of a triple mixture of papaverine, phen- son failed to observe a si&cant differencein drug response, kd-ne and Proitadan& E l versus -PaPaVenne PIUS although they suggested that prostaglandin E l is more effecphentolamine.17 We observed that the triple association was tivein patientswith venom leakage.12 results agree significantly more effective than prostaglandin E l alone in a with those of Boullier et al, who also found no statistically select population of nonresponders to high dose papaverine significant differences in a redspective analysis of the effiplus phentolamine (60 plus 1 mgJd., respedivelY).’8 Re- ciency and adverse effects up to 5 years with papaverine cently, Mulhall et al treated successfully 90%of patients who alone vemw prostaglandin ~1 for self-iqjdon therapy.= had become refractory to use of a triple association by adding is greater with the use Most investigators agree that another drug, forskolm, which is a natural alkaloid that of prostaglandin ~ 1 2 0 . 2 9 - 2 7and, furthermore, it is do= d e increases cyclic adenosine monophosphate l e ~ e l s . 1 ~ pendent.21.w Our increased pain index with prostaglandin we compared the association of papaverine and phentol- ~1 (35%)could be due to the high inj& dose (30 a*). amine to prostaglandin E l to evaluate the efficiency and However, Waldhauser and Schramek reported pain in 75% of Short-hrm adverse effecta The study design and features of patients injected 6 t h 20 p,g.,zo and @ r b r and b h e docthe population (patients with sexual erectile dysfunction -&& pain in 39%heated with 10 pg. prosalandin El.% longer than 6 months in duration who had not PreGouSlY our 35%rate of pain compares favorably with those reported undergone therapeutic or diagnostic procedures) allowed us previously.zi. 29 According to Jueneman in more than 7,000 pharmacological tests the incidence of prolonged erection was 9.5%with TABLE1. Positive response to papaverim plus phentolamim versus papaverine 5.3% with papave,.i,-,e phentolamine and prostaglandin E l versus placebo in sexual erectile dysfunction 2.4%with ~ o s t a g l a~n ~ 1me . fact that ~1 No. Erectile Response (%) is metabolized locally within the cavernous body could exD W E4 E5 ~4 + E5 plain the lower incidence of prolonged erection.so~sl In our population the rate of prolonged erection was high, PlaCet.0 0 0 0 reaching 18 and 15%for papaverine plus p h e n t o l d n e and Papavefine plus phentolamine 20 (33) 14 (23) 94 (66) prostaglandin El, respectively.This result prob&ly due hataglandin E l 16 (27) 14 (23) 30 (50) to the high in patients P N . 0 5 for papaverine plus phentolamine versus prostaglandin El and p cause, bearing in mind that potential patients with psyche <0.001 for prostaglandin E l versus placebo.
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PAPAWRINE PLUS PHENTOLAMINE VERSUS PROSTAGLANDIN E l IN ERECTILE DYSFUNCTION
W. F. Thon and C. G. Stief. New York: Springer-Verlag, chapt. 19, pp. 221-235, 1991. 13. Katlowitz, N. M., Albano, G. J., Morales, p. and Golimbu, M.: Potentiation of drug-induced erection with audiovisual sexual stimulation. Urology, 41: 431, 1993. 14. Vruggink, P., Debruyne, F. and Meuleman, E.: Enhanced pharmacological testing in erectile dysfunction. Int. J. Impotence Res., suppl. 1, p. D-47, 1994. 15. Donatucci, C. F. and Lue, T. F.: The combined intracavemous injection and stimulation test: diagnostic accuracy. J. Urol., 148:61, 1992. 16. Lue, T. F. and Tanagho, E. A,: Physiology of erection and pharmacological management of impotence. J. Urol., 137: 829, 1987. 17. Shenfeld, O., Hanani, A,, Shalhav, Y. and Goldwasser, B.: Papaverine-phentolamine and prostaglandin E l versus papaverine-phentolamine alone for intracorporeal injection CONCLUSIONS therapy: a clinical double-blind study. J. Urol., 154: 1017, According to available medical literature, we believe that 1995. for self-injection treatment of sexual erectile dysfunction 18. Bechara, A., CasaM, A., ChBliz, G., Romano, S.and Fredotovich, prostaglandin E l would be the drug of choice, since papavN.: Prostaglandin E l versus mixture of prostaglandin E l , erine induces a greater index of fibrosis in the long term.27.30 papaverine and phentolamine in nonresponders to high papaverine plus phentolamine doses. J . Urol., 155: 913, 1996. However, since prostaglandin E l is more expensive and causes more pain than papaverine, such factors could be 19. Mulhall, J., Traish, A., Gupta, S., Payton, T., Krane, R. J. and Goldstein, I.: Rescuing the failed injection patient with the use responsible for a greater percentage of dropouts from treatof forskolin. J. Urol., part 2, 155: 496A. abstract 743, 1996. ment programs.24.33According to our results a 1 ml. solution M. and Schramek, P.: Efficiency and side effects of of 30 mg./ml. papaverine plus 0.5 mg./ml. phentolamine has 20. Waldhauser, prostaglandin E l in the treatment of erectile dysfunction. the same efficiency to achieve an erection suitable for peneJ. Urol., 1 4 0 525, 1988. tration and has a prolonged erection rate similar to that with 21. Lee, L. M., Stevenson, R. W. D. and Szasz, G.: Prostaglandin E l 1 ml. 30 pg./ml. prostaglandin E l , the latter proving to be versus phentolamindpapaverine for the treatment of erectile significantly more painful. impotence: a double-blind comparison. J. Urol., 141: 549, 1989. 22. Earle, C. M., Keogh, E. J., Wisniewski, Z. S., Tulloch, A. G. S., Farmacia Roma provided the vasoactive drugs and Dr. Lord, D. J., Watters, G. R. and Glatthaar, C.: Prostaglandin E l Carlos Bantar performed the statistical analysis. therapy for impotence, comparison with papaverine. J. Urol., 143.57, 1990. 23. Boullier, J. A., Rauscher, J . A., Cummings, J . M. and Parra, REFERENCES R. 0.:Comparison of papaverine and prostaglandin E l (PGE1) single drug therapy for erectile dysfunction. J. Urol., part 2, 1. Virag, R.: Intracavernous injection of papaverine for erectile failure. Letter to the Editor. Lancet, 2: 938, 1982. 156 468A, abstract 631A, 1996. 2. Zorgniotti, A. W. and Lefleur, R. S.: Auto-injection of the corpus 24. Gerber, G. S. and Levine, L. A.: Pharmacological erection program using prostaglandin E l . J. Urol., 1 4 6 786, 1991. cavemosum with a vasoactive drug combination for vasculogenic impotence. J. Urol., 133 39, 1985. 25. Mahmoud, K Z., El Dakhli, M. M., Fahmi, I. M. and Abdel-Aziz, 3. Zorgniotti, A. W.: Corpus cavernosum blockade for impotence: A. A.: Comparative value of prostaglandin E l and papaverine practical aspects and results in 250 cases. J. Urol., part 2,135: in treatment of erectile failure: double-blind crossover study 306A, abstract 808, 1986. among Egyptian patients. J. Urol., 147: 623, 1992. 4. Ishii, N., Watanabe, H., Irisawa, C., Kikuchi, Y., Kawamura, S., 26. Lakin, M. M., Montague, D. K., VanderBrug Mendendorp, S., Suzuki, K., Chiba, R., Tokiwa, M. and Shirai, M.: IntracavernTesar, L. and Schover, L. R.: Intracavernous injection therapy: o w injection of prostaglandin E l for the treatment of erectile analysis ofresults and complications. J. Urol., 143: 1138,1990. impotence. J. Urol., 141: 323, 1989. 27. Jueneman, K.: Pharmacotherapy of impotence: where are we 5. Virag, R. and Shoukry, K: Long term follow-up on self intragoing? In: World Book of Impotence Research: Basic and Clincavernous injections (SICI) for impotence. J. Urol., part 2,141: ical. Edited by T. F. Lue. London: E. Smith Jordon & Co., Ltd., 288A, abstract 476, 1989. chapt. 13, pp. 181-188.1992, 6. Goldstein, I., Borges, F., Kauf€man, J., Moreno, J., Payton, T. 28. Stackl, W., Hasun, R. and Marberger, M.: Intracavernous injecand Krane, R. J.: Rescuing the failed papaverine/phentoltion of prostaglandin E l in impotent men. J. Urol., 1 4 0 66, amine erection: a proposed synergistic action of papaverine, 1988. phentolamine and prostaglandin E l . Int. J. Impotence bs., 29. Schramek, P., Dorninger, R., Waldhauser, M., Konecny, P. and suppl., 2:277, 1990. Porpaczy, P.: Prostaglandin E l in erectile dysfunction. Effi7. Montorsi, F., Guazzoni, G., Bergamaschi, F., Fernini-Strambi, ciency and incidence of priapism. Brit. J . Urol., 65: 68, 1990. L., Barbieri, L. and Rigatti, P.: Four-drug intracavernous ther- 30. Aboseif, S. R., Breza, J., Bosch, R. J. L. H., Benard, F., Stief, apy for impotence due to corporeal veno-occlusive dysfunction. C. G., Stackl, W., Lue, T. F. and Tanagho, E. A,: Local and J. Urol., part 2,149: 1291, 1993. systemic effects of chronic intracavernous injection of papav8. Bennett, A. H., Carpenter, A. J . and Barada, J . H.: An improved erine, prostaglandin E l , and saline in primates. J . Urol., 1 4 2 vasoactive drug combination for a pharmacological erection 403, 1989. program. J . Urol., 146: 1564, 1991. 31. Stief, C. G., Wetterauer, U., Popken, G. and Sommerkamp, H.: 9. Juenemann, K-P.: Pharmacotesting in erectile dysfunction. In: Experience with an intracavernous drug delivery system. Erectile Dysfunction. Edited by U. Jonas, W. F. Thon and C. G. J. Urol., part 2, 1 3 9 328A, abstract 664,1988. Stief. New York: Springer-Verlag, chapt. 9, pp. 104-114,1991. 32. Sidi, A. A., Cameron, J . S., Dykstra, D. D., Reinberg, Y. and 10. Goldstein, 1.: Comment. In: World Book of Impotence Research: Lange, P. H.: Vasoactive intracavernous pharmacotherapy for Basic and Clinical. Edited by T. F. Lue. London: Smith Jordon the treatment of erectile impotence in men with spinal cord & Co., Ltd., chapt. 13, pp. 194-197, 1992. injury. J. Urol., 138 539, 1987. 11. von Heyden, B., Donatucci, C. F., Kaula, N. and Lue, T. F.: 33. Abobakr, R. A., Mulhall, J., Goldstein, B., Leitzes, R., Woods, J., Intracavernous pharmacotherapy for impotence: selection of Payton, T., Krane, R. J. and Goldstein, I.: The prevalence and appropriate agent and dose. J. Urol., part 2, 149: 1288, 1993. causes of patient drop-out from long-term self-injection ther12. Wetterauer, U.: Intracavernous pharmacotherapy for erectile apy for impotence: survey results from 708 respondents. dysfunction. In: Erectile Dysfunction. Edited by U. Jonas, J . Urol., part 2, 156: 469A, abstract 632, 1996.
logical and/or neurological disorders respond better than those with a vascular origin of the dysfunction.32 Based on our results the efficiency of 1ml. 30 jg./ml. prostaglandin E l and 1 ml. 30 mg./ml. papaverine plus 0.5 mg./ml. phentolamine proved to be similar and, therefore, the choice will depend on the adverse effects and cost. Prostaglandin E l is more painful in a sigdicant percentage of patients and has a greater cost per dose (in our country approximately $18 for prostaglandin E l versus $2.6 for papaverine plus phentolamine), with a similar incidence of prolonged erection. This finding suggests that papaverine plus phentolamine would be the drugs of choice for a pharmacological erection test.