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Double-blind, cross-over study comparing prostaglandin E1 and papaverine in patients with vasculogenic impotence
DOUBLE-BLIND, CROSS-OVER STUDY COMPARING PROSTAGLANDIN E1 AND PAPAVERINE IN PATIENTS WITH VASCULOGENIC IMPOTENCE* S. KATTAN, M.D. J. E COLLINS, M.D. D. MOHR, M.Sc. From the Division of Urology, Ottawa Civic Hospital, University of Ottawa, Ottawa, Canada
ABSTRACT--Intracorporeal injection of vasoactive agents is the patients with organic impotence. However, some patients with poorly to injections of papaverine or papaverine/phentolamine. Th mine if patients with vasculogenic impotence who failed to respono prostaglandin E1 and thus be salvaged from possible prosthetic su~ vasculogenic impotence were administered intracorporeal prostagh real papaverine (60 mg) randomized in a double-blind fashion a Forty-six percent of patients receiving prostaglandin E1 produced with 14 percent of patients with a similar response to papaverine results was highly significant by the McNemar test. The number of. drugs. Prostaglandin E1 might be considered the intracorporeal a significant vasculogenic impotence.
Intracorporeal injections, since introduced by Brindley1 and Virag et al. ,2 have become an accepted treatment for many patients with organic impotence. While more than 90 percent of patients with psychogenic and neurogenic impotence respond to papaverine 3 and papaverine/phentolamine,4 many patients with vasculogenic impotence fail to produce an adequate erection with intraeorporeal injections of vasoactive agents. 5 Patients who fail to respond to intracorporeal pharmacotherapy may be treated with a vacuum erection device,~ vacuum erection device augmenting intracorporeal injections,r or more frequently a penile prosthesis. Prostaglandin E1 is a naturally occurring substance important in the inflammatory response. Intraeorporeal injection of prostaglandin E1 in humans was introduced by Ischii et *Supported by the Mary A. Collins Fund and the John Duncan Fund, Division of Urology, Ottawa Civic Hospital.
516
al. in 1986s as a impotence. SoJ prostaglandin paverine° or p~ treatment of etiologies. Imp prostagandin patients with group has beel intraeorporeal a randomized comparing intJ glandin E1 and culogenic impl who fail to re spond to prosta from possible Material and Meth The study consisted of 54 r~ +_ 7.41 years (mean + stan~
UROLOGY / JUNE 1991 / VOLUME
~ ~i~
TABLE I.
Evaluation
of Response
Duration of Response
~ i i none I ~ partial - inadequate
IPaE 1 2o uQI I'PG ,
50 patients (4 drop out) ~IPAP
minutes
FIGURE 1.
normal
Results A total of 54 patients were admitted to the study; 4 patients dropped out after the first inUROLOGY / JUNE 1991 / VOLUME XXXVII, NUMBER 6
IPAP 60 "~1 1 week
b?ptimal - adequate
~ e r r e d from an Erectile Dysfunction Unit. Rtiology of their impotence was believed to be ~rirnarily vasculogenic based on an assessment I ~ history and physical examination, hormonal Bsays, penile plethysmography, penile biotheBbmetry, and intracorporeal injection of pa~ w e r m e . The sample size of 54 patients was a:s.ed on an estimate of a 60 percent success rate ~ i n g papaverine and an 85 percent success rate ~ i n g prostaglandin El. Using a false-positive ~ t e of 5 percent and a false-negative rate of 20 rcent, we wanted to be 80 percent certain of ecting this 25 percent superior success rate sing prostaglandin E l . These patients were idmitted to a double-blind, randomized, crossiver study comparing an intracorporeal injeciti0n of 20/zg of prostaglandin E 1 with an intra!Corporeal injection of 60 mg of papaverine (Fig. 1). Both drugs were prepared by the pharmacy in identical 2 mL vials. A 27-gauge needle was used to inject the drugs in the proximal lateral portion of either corpus cavernosum. Response was assessed by one observer (Table I) The primary end point was the quality of erectile response. After each study period, the erectile response was assessed and a comparison was made between the two study periods, preServing the unique feature of the cross-over trial. Similarly, the presence of any adverse drug effects was also evaluated after each study period. To reduce the potential carry-over effects, a washout period equivalent to the halflife of the drug was used. To assess the differences in erectile responses between papaverine and prostaglandin E l , the McNemar chi-square analysis with Yates correction for continuity was used. A similar analysis was used to assess adverse drug effects; 95 percent confidence intervals were also calculated. All probability values less or equal to 0.05 were Considered statistically significant.
60 mQI
2o ,,QI
Study schema.
52%
1
12%
34%
(1) No response to PGE -1 or Pap (2) (3) (4)
Response to PGE -1 Response to PGE -1 and Pap Response to Pap FIGURE 2. Detailed response to prostaglandin E1 and papaverine.
jection and were not included in the analysis of results. There were no statistical differences between the age of patients who received papaverine or prostaglandin E1 first (mean _+ standard deviation = 54.07 _+ 7.44 and 57.12 + 7.38, respectively). Overall, there was a 14 percent success rate of complete or partial erectile response observed with papaverine. However, a 46 percent success rate was observed with prostaglandin E l . This result indicated a statistically significant difference in erectile response between papaverine and prostaglandin E1 (X~ = 12.50, df = 1, p < 0.002). This superiority in prostaglandin E1 response ranged from (95 % confidence intervals) 22.2 percent to 41.8 percent. The relative differences in responses between papaverine and prostaglandin E1 was 37 percent. Therefore, for every 100 patients who did not have a complete or partial 517
response with papaverine, 37 patients could be expected to have a complete or partial response with prostaglandin El. Thirty-four percent of patients responded to prostaglandin E1 alone and 2 percent responded only to papaverine; 52 percent of patients did not respond to either drug (Fig. 2). Forty-four percent of patients receiving papaverine and 45 percent of patients receiving prostaglandin E1 complained of mild pain at the site of injection. This discomfort lasted less than ten minutes and was felt to be insignificant by all patients. In 3 patients slight dizziness and headache developed, 2 with papaverine and 1 with p r o s t a g l a n d i n E l . Priapism did not develop in any patient. Assessment of adverse drug effects indicated no statistical differences between drugs. Comment This study confirms the activity of prostaglandin E1 in the intracorporeal treatment of vasculogenic impotence. A high percentage (52 % ) did not respond to either drug. The overall response to prostaglandin E1 was low at 46 percent. Both these results might be expected in this selected patient group known to be refractory to vasoactive agents, xl Other factors such as inclusion of patients with veno-occlusive disease and a lack of a dose response study for prostaglandin E 1 might have been contributing factors. 12 However, there was a significant difference in response between the two drugs. This indicates that while both are smooth muscle dilators, their mechanisms of action might differ. Minor transient penile discomfort with injection was experienced by some patients but was believed to be insignificant. In summary, many patients with significant vasculogenic impotence are refractory to intracorporeal pharmacotherapy. However, in this randomized, double-blind, cross-over study, significantly more patients responded to intracorporeal prostaglandin E 1 than to papaverine.
518
This improved response, combined with thep~ tential flexibility of a linear dose responseili ~'~~ te~__ apparent low incidence of priapism,i3 2~
minor injection discomfort indicate th.t taglandin E1 may be the intraeorporeal a'gei~s~i of cho}ce for patients with significant vas~oi!I gemc impotence. Ottaw~ ACKNOWLEDGMENT. To of Research, O t t a w a Civi assistance. Rc 1. Brindley GS: Cavernos for investigating and treatin 143:332 (1983). 2. Virag R, Frydman D, I nons injection of papaverir method in erectile failure, A 3. Bodner DR, et al: The tion of vasoactive medicatic cord injury, J Urol 138:310 4. Sidi AA, Cameron JS: cavernous drug-induced ere erectile dysfunction: experie: (1986). 5. Szasz G, Stevenson R¥ duction of penile erection by blind comparison of phenox) tolamine versus saline, Arch 6. Nadig PW, Ware JC, al produce and maintain an (1986). 7. Mamar JL, DeBenedic vacuum constrictor device to an intracavernons injection, 8. Ischii N, et al: Studies ( therapeutic trial with prost~ Nippon Hinyokika Gakkia 7 9. Reiss H: Use of prostag tions, Urology 33:14 (1989) 10. Waldhanser M, and ! fects of prostaglandin E1 in J Urol 140:525 (1988). 11. Stacld W, Hasun R, a: jection of prostaglandin E1 (1988). 12. Rafter J, Rosciszewsld corporal venous leakage in il 13. Lee LM, Stevenson R versus phentolamine/papave tence: a double-blind comp;
UROLOGY
/
JUNE 1991
/
VOLUME XXXVII,
ABSTRACT--Intracorporeal injection of vasoactive agents is the patients with organic impotence. However, some patients with poorly to injections of papaverine or papaverine/phentolamine. Th mine if patients with vasculogenic impotence who failed to respono prostaglandin E1 and thus be salvaged from possible prosthetic su~ vasculogenic impotence were administered intracorporeal prostagh real papaverine (60 mg) randomized in a double-blind fashion a Forty-six percent of patients receiving prostaglandin E1 produced with 14 percent of patients with a similar response to papaverine results was highly significant by the McNemar test. The number of. drugs. Prostaglandin E1 might be considered the intracorporeal a significant vasculogenic impotence.
Intracorporeal injections, since introduced by Brindley1 and Virag et al. ,2 have become an accepted treatment for many patients with organic impotence. While more than 90 percent of patients with psychogenic and neurogenic impotence respond to papaverine 3 and papaverine/phentolamine,4 many patients with vasculogenic impotence fail to produce an adequate erection with intraeorporeal injections of vasoactive agents. 5 Patients who fail to respond to intracorporeal pharmacotherapy may be treated with a vacuum erection device,~ vacuum erection device augmenting intracorporeal injections,r or more frequently a penile prosthesis. Prostaglandin E1 is a naturally occurring substance important in the inflammatory response. Intraeorporeal injection of prostaglandin E1 in humans was introduced by Ischii et *Supported by the Mary A. Collins Fund and the John Duncan Fund, Division of Urology, Ottawa Civic Hospital.
516
al. in 1986s as a impotence. SoJ prostaglandin paverine° or p~ treatment of etiologies. Imp prostagandin patients with group has beel intraeorporeal a randomized comparing intJ glandin E1 and culogenic impl who fail to re spond to prosta from possible Material and Meth The study consisted of 54 r~ +_ 7.41 years (mean + stan~
UROLOGY / JUNE 1991 / VOLUME
~ ~i~
TABLE I.
Evaluation
of Response
Duration of Response
~ i i none I ~ partial - inadequate
IPaE 1 2o uQI I'PG ,
50 patients (4 drop out) ~IPAP
minutes
FIGURE 1.
normal
Results A total of 54 patients were admitted to the study; 4 patients dropped out after the first inUROLOGY / JUNE 1991 / VOLUME XXXVII, NUMBER 6
IPAP 60 "~1 1 week
b?ptimal - adequate
~ e r r e d from an Erectile Dysfunction Unit. Rtiology of their impotence was believed to be ~rirnarily vasculogenic based on an assessment I ~ history and physical examination, hormonal Bsays, penile plethysmography, penile biotheBbmetry, and intracorporeal injection of pa~ w e r m e . The sample size of 54 patients was a:s.ed on an estimate of a 60 percent success rate ~ i n g papaverine and an 85 percent success rate ~ i n g prostaglandin El. Using a false-positive ~ t e of 5 percent and a false-negative rate of 20 rcent, we wanted to be 80 percent certain of ecting this 25 percent superior success rate sing prostaglandin E l . These patients were idmitted to a double-blind, randomized, crossiver study comparing an intracorporeal injeciti0n of 20/zg of prostaglandin E 1 with an intra!Corporeal injection of 60 mg of papaverine (Fig. 1). Both drugs were prepared by the pharmacy in identical 2 mL vials. A 27-gauge needle was used to inject the drugs in the proximal lateral portion of either corpus cavernosum. Response was assessed by one observer (Table I) The primary end point was the quality of erectile response. After each study period, the erectile response was assessed and a comparison was made between the two study periods, preServing the unique feature of the cross-over trial. Similarly, the presence of any adverse drug effects was also evaluated after each study period. To reduce the potential carry-over effects, a washout period equivalent to the halflife of the drug was used. To assess the differences in erectile responses between papaverine and prostaglandin E l , the McNemar chi-square analysis with Yates correction for continuity was used. A similar analysis was used to assess adverse drug effects; 95 percent confidence intervals were also calculated. All probability values less or equal to 0.05 were Considered statistically significant.
60 mQI
2o ,,QI
Study schema.
52%
1
12%
34%
(1) No response to PGE -1 or Pap (2) (3) (4)
Response to PGE -1 Response to PGE -1 and Pap Response to Pap FIGURE 2. Detailed response to prostaglandin E1 and papaverine.
jection and were not included in the analysis of results. There were no statistical differences between the age of patients who received papaverine or prostaglandin E1 first (mean _+ standard deviation = 54.07 _+ 7.44 and 57.12 + 7.38, respectively). Overall, there was a 14 percent success rate of complete or partial erectile response observed with papaverine. However, a 46 percent success rate was observed with prostaglandin E l . This result indicated a statistically significant difference in erectile response between papaverine and prostaglandin E1 (X~ = 12.50, df = 1, p < 0.002). This superiority in prostaglandin E1 response ranged from (95 % confidence intervals) 22.2 percent to 41.8 percent. The relative differences in responses between papaverine and prostaglandin E1 was 37 percent. Therefore, for every 100 patients who did not have a complete or partial 517
response with papaverine, 37 patients could be expected to have a complete or partial response with prostaglandin El. Thirty-four percent of patients responded to prostaglandin E1 alone and 2 percent responded only to papaverine; 52 percent of patients did not respond to either drug (Fig. 2). Forty-four percent of patients receiving papaverine and 45 percent of patients receiving prostaglandin E1 complained of mild pain at the site of injection. This discomfort lasted less than ten minutes and was felt to be insignificant by all patients. In 3 patients slight dizziness and headache developed, 2 with papaverine and 1 with p r o s t a g l a n d i n E l . Priapism did not develop in any patient. Assessment of adverse drug effects indicated no statistical differences between drugs. Comment This study confirms the activity of prostaglandin E1 in the intracorporeal treatment of vasculogenic impotence. A high percentage (52 % ) did not respond to either drug. The overall response to prostaglandin E1 was low at 46 percent. Both these results might be expected in this selected patient group known to be refractory to vasoactive agents, xl Other factors such as inclusion of patients with veno-occlusive disease and a lack of a dose response study for prostaglandin E 1 might have been contributing factors. 12 However, there was a significant difference in response between the two drugs. This indicates that while both are smooth muscle dilators, their mechanisms of action might differ. Minor transient penile discomfort with injection was experienced by some patients but was believed to be insignificant. In summary, many patients with significant vasculogenic impotence are refractory to intracorporeal pharmacotherapy. However, in this randomized, double-blind, cross-over study, significantly more patients responded to intracorporeal prostaglandin E 1 than to papaverine.
518
This improved response, combined with thep~ tential flexibility of a linear dose responseili ~'~~ te~__ apparent low incidence of priapism,i3 2~
minor injection discomfort indicate th.t taglandin E1 may be the intraeorporeal a'gei~s~i of cho}ce for patients with significant vas~oi!I gemc impotence. Ottaw~ ACKNOWLEDGMENT. To of Research, O t t a w a Civi assistance. Rc 1. Brindley GS: Cavernos for investigating and treatin 143:332 (1983). 2. Virag R, Frydman D, I nons injection of papaverir method in erectile failure, A 3. Bodner DR, et al: The tion of vasoactive medicatic cord injury, J Urol 138:310 4. Sidi AA, Cameron JS: cavernous drug-induced ere erectile dysfunction: experie: (1986). 5. Szasz G, Stevenson R¥ duction of penile erection by blind comparison of phenox) tolamine versus saline, Arch 6. Nadig PW, Ware JC, al produce and maintain an (1986). 7. Mamar JL, DeBenedic vacuum constrictor device to an intracavernons injection, 8. Ischii N, et al: Studies ( therapeutic trial with prost~ Nippon Hinyokika Gakkia 7 9. Reiss H: Use of prostag tions, Urology 33:14 (1989) 10. Waldhanser M, and ! fects of prostaglandin E1 in J Urol 140:525 (1988). 11. Stacld W, Hasun R, a: jection of prostaglandin E1 (1988). 12. Rafter J, Rosciszewsld corporal venous leakage in il 13. Lee LM, Stevenson R versus phentolamine/papave tence: a double-blind comp;
UROLOGY
/
JUNE 1991
/
VOLUME XXXVII,