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Four-Drug Intracavernous Therapy for Impotence Due to Corporeal Veno-Occlusive Dysfunction
0022-534 7/93/1495-1291$03.00/0 Vol. 149, 1291-1295, May 1993
THE JOURNAL OF UROLOGY Copyright© 1993 by AMERICAN UROLOGICAL ASSOCIATION, INC.
Printed in U.S.A.
FOUR-DRUG INTRACAVERNOUS THERAPY FOR IMPOTENCE DUE TO CORPOREAL VENO-OCCLUSIVE DYSFUNCTION FRANCESCO MONTORSI, GIORGIO GUAZZONI, FRANCO BERGAMASCHI, LUIGI FERINISTRAMBI, LUIGI BARBIERI AND PATRIZIO RIGATTI From the Departments of Biomedical Sciences, Urology and Neurology, Scientific Institute H. San Raffaele, University of Milan School of Medicine, Milan, Italy
ABSTRACT
Although veno-occlusive dysfunction is a frequent cause of impotence, a definitive therapeutic strategy has not yet been clearly defined. A total of 56 patients with corporeal veno-occlusive dysfunction diagnosed by dynamic infusion cavernosometry-cavernosography (flow to maintain erection greater than 10 ml. per minute and rate of corporeal pressure decrease after interruption of intracavernous infusion greater than 50 mm. Hg for 30 seconds) not considered suitable candidates for surgery underwent self-injection therapy. A vasoactive mixture composed of 12.1 mg./ml. papaverine hydrochloride, 10.1 µgm./ml. prostaglandin El, 1.01 mg./ml. phentolamine mesylate and 0.15 mg./ml. atropine sulfate was used. After dose titration of the drug mixture 54 patients (95%) were able to obtain sustained rigid erections that guaranteed satisfactory sexual activity. Mean (plus or minus standard error of mean) volume of injected mixture was 0.42 ± 0.09 ml. (range 0.25 to 0.90 ml.). Four patients (7%) reported transient hypotension that did not recur after the application of a penile rubber band before injection. At a mean followup of 16 months 6 patients (11 %) discontinued use of injections, 37 (69%) were satisfied and using the mixture, and 11 (20%) maintained rigid erections using a lower than initial dose. No major complications were encountered. The association of drugs with different mechanisms of action caused a synergism that potentiated the therapeutic activity and reduced side effects by decreasing the total drug dose. KEY WORDS: impotence, papaverine, phentolamine, atropine, alprostadil
Dysfunction of the corporeal veno-occlusive mechanism is a major cause of male impotence. 1• 2 Quantitative and qualitative assessment of corporeal veno-occlusive dysfunction can be accurately obtained by cavernosometry and cavernosography performed after intracavernous vasoactive stimulation. 3 • 4 Choice of therapy is based on the results of pharmacocavernosometry and cavernosography, concomitant neurovascular risk factors, and clinical characteristics and expectations of the patient. Presently, venous surgery, 5 • 6 vacuum device 7 and penile implants8 are the main therapeutic options for impotence due to cavernous veno-occlusive dysfunction. lntracavernous injections of vasoactive drugs have also been used for treatment but the results have often been reported as unsatisfactory. 9 •10 However, recent studies have emphasized the enhanced effectiveness of the combination of multiple vasoactive drugs in intracavernous therapy of vasculogenic impotence. 11- 15 This pharmacological association is based upon the synergism between drugs that exert their actions through different mechanisms to increase the overall therapeutic activity while reducing the total dose of the drug and related side effects. 11 We report our experience with intracavernous injections of a 4-drug vasoactive mixture composed of papaverine hydrochloride, phentolamine mesylate, prostaglandin El and atropine sulfate in patients with corporeal veno-occlusive dysfunction who were not suitable candidates for venous surgery and elected to undergo self-injection therapy. MATERIALS AND METHODS
Patients included in this study were evaluated at our impotence clinic from January 1990 to June 1991. At our institution the diagnostic evaluation for impotent patients consists of careful history and physical examination, laboratory analysis (serum glucose, cholesterol, triglycerides and hormonal profile), Accepted for publication December 11, 1992. Read at annual meeting of Western Section, American Urological Association, Maui, Hawaii, October 21-30, 1992.
biothesiometry, polysomnographic recordings of nocturnal erections during a 3-night period, duplex or color Doppler sonography of the penile arteries and dynamic infusion cavernosometry-cavernosography. Selective internal pudendal angiography is performed only in select cases. The operative technique of dynamic infusion cavernosometry-cavernosography is that detailed by Padma-Nathan 16 with minor modifications. Briefly, 5 ml. 1% lidocaine are administered via a 25 gauge needle to the subcutaneous area overlying the dorsal subcoronal area. After distal dorsal penile anesthesia has been established, a 21 gauge butterfly is introduced intracavernosally. Heparinized saline is used to flush the butterfly angiocatheter to assure correct needle placement. The butterfly angiocatheter is used to administer 45 mg. papaverine hydrochloride and 2.5 mg. phentolamine mesylate. In the first phase of the procedure corporeal body pressure and circumference response to the aforementioned vasoactive mixture were measured. The length of time required to reach equilibrium corporeal body pressures was recorded. The second phase involved infusion of heparinized saline to a control suprasystolic corporeal body pressure and subsequent recording of the rate of decrease with time of the corporeal body pressure from this control value. A corporeal body pressure of 150 mm. Hg with an observation period of 30 seconds was used. To record the pressure loss value a second 21 gauge butterfly angiocatheter previously flushed with heparinized saline was percutaneously inserted into the opposite corporeal body. The butterfly angiocatheter was used to administer intracavernosal heparinized saline by an infusion pump. A maximum flow rate of approximately 120 ml. per minute was used. The flow rate necessary to maintain serial intracavernous pressures of 60, 90, 120 and 150 mm. Hg was recorded. The rate of decrease of corporeal body pressure after termination of infusion was recorded twice and the mean value was determined. Additional repeat studies were performed with perineal compression.
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The third and final phase involved intracavernosal infusion of an iodinated contrast agent at a control corporeal body pressure arbitrarily chosen as 90 mm. Hg, since this is the physiological corporeal body pressure at the equilibrium steady state. The presence of veins draining the corporeal body during penile rigidity could then be recorded fluoroscopically. At the end of the study aspiration of approximately 50 ml. corporeal contents was performed to aid in the elimination of the contrast agent from the erectile tissue. Maintenance flow rates higher than 10 ml. per minute at a minimum of 3 pressure levels and a decrease of more than 50 mm. Hg from 150 for 30 seconds were considered indicative of abnormal corporeal veno-occlusive function. Cavernosography indicated the precise location of the draining veins. Of 131 impotent patients evaluated during the 18-month period of this study 84 (64 % ) demonstrated an alteration of the corporeal veno-occlusive mechanism. In 58 of these patients (44%) associated alteration of cavernosal artery inflow was detected by duplex and color Doppler sonography. Selection of therapy for patients with corporeal veno-occlusive dysfunction included venous surgery (20 cases), vacuum device (8 cases) and intracavernous pharmacotherapy (56 cases). Patients considered for intracavernous self-injections were a mean of 58.5 years old and reported a mean duration of symptoms of 3.2 years. Overall mean (plus or minus standard error of mean) maintenance flow rate in these patients was 15.9 ± 1.8 ml. per minute, while the mean (plus or minus standard error of mean) decrease rate from an intracavernous pressure of 150 mm. Hg was 68.5 ± 6.2 mm. Hg. Venous leaks were detected by cavernosography at the deep dorsal vein in 36 patients, cavernosal veins in 20, crural veins in 22, corpus spongiosum in 6 and glans penis in 6. In 22 cases the leak was from a single anatomical site while in 34 it was from multiple venous channels. Neurovascular risk factors observed in this group of patients included smoking (35 patients), hypertension (8), diabetes mellitus (12), hypercholesterolemia (18) and alcoholism (1). Contraindications to intracavernosal injection therapy included history of hemoglobinopathy, bleeding diathesis, Peyronie's disease or idiopathic priapism. Patients on oral anticoagulation therapy also were excluded. After inclusion in the self-injection protocol the patients gave informed consent, which acknowledged the investigational nature of multidrug intracavernous therapy and which had been approved by the Ethics Committee at our hospital. A 4-drug vasoactive mixture was used. The solution for vasoactive stimulation was prepared by mixing 240 mg. papaverine hydrochloride, 200 µgm. prostaglandin El, 20 mg. phentolamine mesylate and 3 mg. atropine sulfate with a total of 19.8 ml. of vasoactive solution. The concentrations obtained were 12.1 mg./ml. papaverine hydrochloride, 10.1 µgm./ml. prostaglandin El, 1.01 mg./ml. phentolamine mesylate and 0.15 mg./ml. atropine sulphate. Patients were placed in the sitting position on an examination couch during each injection and kept in position for 30 minutes. Systemic blood pressure was recorded as a baseline in the event of syncope and to note hypertension. The right side (lateral aspect) of the penis was cleansed with an alcohol swab. An automatic self-injection system was used in the dose titration phase and at home. All patients received an initial injection of 0.1 ml. of the 4-drug mixture by a physician using a 27 gauge needle that was inserted by a quick jab up to the hilt of the needle such that the tip of the needle was in the center of the right corpus cavernosum. Immediately after injection the base of the penis was squeezed firmly between the right thumb and index finger, while the accessible portion of the penis was massaged for up to 5 minutes by squeezing it laterally along the length of the shaft between the left thumb, and index and middle fingers, thus distributing the drug throughout the pendulous shaft. Patients were then left alone to watch an erotic video to optimize sexual stimulation.
The erectile response was assessed by the physician and patient. The dose of mixture was considered adequate when a rigid erection was obtained and lasted for at least 30 minutes. If the first injection did not produce a satisfactory erection, the patient was reinjected after 3 days and the dose was increased by 0.1 ml. of the mixture. The titration process in 0.1 ml. of mixture proceeded until an adequate erection was obtained or a maximum dose of 1.0 ml. was used. If a rigid erection persisted for longer than 1 hour 20 ml. of cavernous blood were aspirated and 20 to 40 µgm. epinephrine were administered intracorporeally to obtain complete detumescence. Appropriate electrocardiographic and blood pressure monitoring was used during this procedure. Patients were contacted by telephone the next day to verify persistence of detumescence. After the proper dose of the vasoactive mixture was determined the patient was taught the auto-injection technique and was observed while self-administering the mixture in the clinic. Patients could then purchase the vasoactive mixture from the hospital pharmacy. Each vial containing 19.8 ml. of solution cost $150. Patients were instructed to limit vasoactive mixture use to twice a week, with no more than 1 injection in any 24hour period. They were also taught to inject alternatively the right and left cavernous body. Patients were then warned to return immediately to the emergency room if erection persisted for longer than 3 hours. They were also told to refrigerate the mixture and to examine the solution for changes in color or the formation of a precipitate. A 3-month expiration date was clearly printed on the vial, which was based on known time limits of effectiveness and sterility of prostaglandin El.17 Patients were advised not to use the mixture after it had expired. Patients were reevaluated once a month for the first 2 months and subsequently every 3 months. At each followup visit injection frequency, duration and consistency of erections, and patient satisfaction were recorded. The penis was carefully examined for nodules, hematomas or areas of induration. Liver function tests, including alkaline phosphatase, lactic dehydrogenase, serum glutamic oxaloacetic transaminase and total bilirubin, were assessed every 6 months. Penile ultrasonography was performed to verify any clinical finding on digital palpation of the penis. Eleven patients had been previously assessed for impotence at other centers and had failed to respond to intracavernosal injection therapy with papaverine or a papaverinephentolamine combination. Two patients had been placed on therapy with intracorporeal prostaglandin El but had stopped self-injection due to severe penile pain. RESULTS
During the dose titration phase injection of the vasoactive mixture was unsuccessful in causing a rigid erection lasting for at least 30 minutes in only 2 cases. These patients had massive leaks from the crural veins, deep dorsal vein and corpus spongiosum, and subsequently underwent implantation of penile prostheses. A total of 54 patients elected to begin treatment with intracavernous self-injection of the 4-drug mixture during our study. Mean duration of mixture use was 16.3 months (range 12 to 18 months). Mean frequency of drug use was 1.8 times per week. At the end of the preliminary dose titration phase the mean (plus or minus standard error of mean) dose to produce a sustained rigid erection was 0.42 ± 0.09 ml., and the mean (plus or minus standard error of mean) latency time between injection and erection was 7.5 ± 1.1 minutes. Presently, 37 patients (69%) are using the injections at the initial dose and enjoying satisfactory sexual activity, while 11 (20%) obtain a rigid erection with a lower dose (mean plus or minus standard error of mean 0.31 ± 0.07 ml.). None of the patients reported complete restoration of natural erections. Four patients (7%) reported dizziness and transient hypotension after injections on some occasions, which were resolved by applying a rubber band at the root of the penis before injecting the drug mixture. Six patients (11 %) discontinued the use of
INTRACAVERNOUS THERAPY FOR IMPOTENCE
injections because of significant intercurrent illness in 2 and lack of a sexual partner in 5. Overall, intracorporeal injection of the 4-drug mixture was successful in 89% of the impotent patients with hemodynamically significant corporeal veno-occlusive dysfunction. None of the patients experienced pain with the injection. At followup neither penile plaques nor clinically significant hematomas were encountered. A small palpable subcutaneous nodule was noted in 2 patients (4%), and a reduction in frequency of injections was suggested. Small and transient hematomas at the injection sites were reported by 15 patients (28%). There was no report of penile curvature after starting self-injection therapy, and no patient experienced prolonged (longer than 3 hours) erection during self-injection at home. However, in 2 cases (4%) 1 of the titration doses caused an erection that was still rigid after 2 hours and was reversed with intracorporeal epinephrine. Liver function tests performed during followup showed no significant alterations. DISCUSSION
Penile erection is a psychoneurovascular phenomenon that involves activation of the penile vascular system either by cerebral or local sensory stimuli with subsequent increase of arterial inflow via the paired cavernosal arteries, sinusoidal relaxation and filling of the corporeal bodies from this increase in arterial inflow, and a decrease in the outflow from or trapping of blood within the corpora causing tumescence and rigidity. 18 Scanning electron microscopic studies have demonstrated that the subtunical venules are compressed between the sinusoidal walls and the tunica albuginea, thus restricting venous flow to a minimum during erection. 19 In addition, the uneven stretching of the layers of the tunica albuginea also contributes to closure of the emissary veins. An active venous occlusive mechanism mediated by neuropeptide Y has also been described. 20 The reduction of venous outflow by the mechanical compression of subtunical venules is known as the corporeal venoocclusive mechanism. 21 Corporeal veno-occlusive dysfunction may occur due to insufficient relaxation of the trabecular smooth muscle or to a structural alteration in the fibroelastic components of the trabeculae. In patients with corporeal venoocclusive dysfunction an adequate perfusion pressure may not be able to balance the unrestricted venous outflow to ensure complete penile rigidity. Pathophysiology of corporeal veno-occlusive dysfunction may explain the poor results reported in these cases with intracavernous pharmacotherapy. 9 • 10 To achieve penile rigidity locally administered vasoactive drugs must cause maximal distention of the corporeal tissue, which in cases of corporeal veno-occlusive dysfunction can be hampered by the early clearance of these drugs from the corpora cavernosa due to increased outflow. In cases of concomitant arterial disease the effect of intracavernous vasoactive injections can be further reduced. In these cases an alternative therapeutic approach is based on the use of drugs with different mechanisms of actions possibly exerting a synergistic effect, Papaverine hydrochloride is an opium alkaloid that acts on a post-receptor level via the inhibition of phosphodiesterase, leading to an accumulation of cyclic adenosine monophosphate, which attenuates the alreceptor mediated contraction of the smooth muscle cell, possibly by interfering with the calcium ion mobilization. This drug facilitates erection by relaxation of smooth muscles in the sinusoids and by dilation of helicine arteries. 22 Phentolamine mesylate is an a-1 and a-2-adrenergic receptor blocking agent that dilates arterial vessels and abolishes sympathetic inhibition of erection. 23 Prostaglandin El has a blocking properties mediated through a membrane receptor, 24 and relaxes the cavernous and arteriolar smooth muscle 25 while causing restriction of venous outflow. The use of atropine sulfate in pharmacological erection programs was first reported by Virag et al. 11 • 26 • 27 It is now known that atropine sulfate in low doses (lo-s M.)
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blocks muscarinic receptors, thereby diminishing cholinergic inhibition of the adrenergic and cholinergic excitation of the nonadrenergic, noncholinergic neuroeffector systems controlling neurogenic corporeal smooth muscle relaxation. However, in large pharmacological doses (10- 3 M.) atropine causes release of the endothelium derived relaxing factor, 28 which has recently been identified as a neurotransmitter involved in penile erection. 21 The association of several agents acting on different phases of the erectile cycle proved successful in treating patients who responded insufficiently to papaverine alone and to papaverine combined with a blockers. 11- 15• 28 • 29 This finding was confirmed by our study in which the 4-drug mixture was able to guarantee a rigid erection in 11 patients with corporeal veno-occlusive dysfunction who had not responded to the papaverine-phentolamine combination. Almost all patients in our series modified the mixture dose after using the same vial for approximately 80 to 90 days, which was probably due to a reduction in the therapeutic effect of prostaglandin El with time, despite the use of a refrigerator to preserve drug function. 10•13• 17 The increase of mixture dose ranged from 0.5 to 1.0 ml. However, some patients reported the successful use of the mixture 6 months after the purchase of the vial. When multiple drugs are associated the final dose can be decreased, thus reducing the side effects. 11 • 13• 29 In our patients the typical side effects of every single drug, that is cavernous fibrosis, penile induration, priapism, pain at the injection site and elevation of liver enzymes, were not observed. At the time of writing this report we observed no evidence of systemic or local toxicity specifically related to the 4-drug mixture used in our study. To our knowledge, specific combination related toxicity has not been reported previously in the literature. Although our study is related to a short period of observation, we believe that it confirms that the reduction of the total drug dose delivered to the cavernous tissue is a key factor in avoiding toxic adverse effects. Of our patients 89% were satisfied and had rigid erections with self-injection therapy. Our success rate is noteworthy, since it was obtained in a population of patients usually considered as poor responders to conventional intracavernous therapy. Moreover, it should be emphasized that patients selected for intracavernous therapy were not considered for venous surgery since they presented with risk factors for erectile dysfunction usually associated with poor surgical outcome. 5 • 6• 30 Of our patients 20% were able to reduce the dose of the mixture with time, and almost 50% reported some amelioration of natural erections. However, no patient referred to total restoration of complete natural erections. The improvement of natural erectile activity was probably due to the positive effect of self-injections on anxiety and inhibitory emotional reactions that are often associated with organic impotence. 31 Our experience of a sustained rigid erection after intracavernosal vasoactive injection might seem to contradict the diagnosis of corporeal veno-occlusive dysfunction made at dynamic infusion cavernosometry-cavernosography but several parameters were used to define the dysfunction including maintenance flow rates and corporeal pressure decay. 16• 32 The cutoff values used in our study were similar to values reported by others. 32•33 Moreover, the vasoactive agents in the doses used in our patients were definitely within the range usually reported in most of the studies detailing the technique of pharmacocavernosometry-cavernosography testing. 32• 33 Thus, the diagnosis of corporeal veno-occlusive dysfunction was in agreement with commonly accepted diagnostic standards. However, Vickers et al reported "abnormal" dynamic infusion cavernosometry-cavernosography data in 6 impotent patients who spontaneously recovered normal erectile function that was then confirmed by home sleep tumescence and rigidity monitoring. 34 It should be noted that polysomnographic recording of nocturnal erections was also performed on all of our patients and always revealed
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organic impotence. Color Doppler sonography also showed concomitant deterioration of cavernosal artery function in twothirds of our patients. Thus, it seems reasonable to rule out the possibility of false-positive results of dynamic infusion cavernosometry-cavernosography in our study. In our patients sustained rigid erections were provoked by intracavernosal injection of the 4-drug mixture, and sexual stimulation as the pharmacological synergism exerted by the association of drugs with different mechanisms of action caused the stretching of corporeal tissue to its ultimate physiological limit. In other words, this mixture produced a supra-normal stimulation of the corporeal smooth muscle, which would not have been able to react normally to physiological erectogenic stimuli alone. We are aware that the dilemma of any study performed in the erect state, especially in the diagnostic evaluation of the corporeal veno-occlusive mechanism, that is the presence of contracted corporeal smooth muscle secondary to anxiety or inadequate doses of intracavernosal vasoactive agents, remains unresolved. 35 Saenz de Tejada et al demonstrated in an animal model that in the presence of complete smooth muscle relaxation venous outflow resistance was maximal at intracavernosal pressures as low as 30 mm. Hg. 36 The flow to maintain various intracavernosal pressures was minimal and a linear relationship was found between flow to maintain and intracavernosal pressures in a range of 30 to 150 mm. Hg. On the contrary, in the presence of smooth muscle contraction a nonlinear relationship exists between the maintenance flow and the intracavernosal pressures in the pressure range of 30 to 150 mm. Hg. When applying these principles to humans, 35 if the flow to maintain intracavernosal pressure values at 30, 60, 90, 120 and 150 mm. Hg are elevated, especially if they are not linearly related to increasing intracavernosal pressures, one may interpret the results as being abnormal secondary to incomplete smooth muscle relaxation. In this case additional vasoactive agents should be administered. After achieving a new steady state equilibrium the flow to maintain various intracavernosal pressures as well as pressure decay values should be repeated and compared with the pressures and values previously obtained. A linear response of flow to maintain various intracavernosal pressures should be observed, implying that complete smooth muscle relaxation has been achieved. In these conditions corporeal veno-occlusive dysfunction is identified when flow rates to maintain various intracavernosal pressures are greater than 3 ml. per minute. 36 This effect may occur when the collagen/ elastin erectile tissue stiffness is high, such as in aging, diabetes mellitus, atherosclerosis, Peyronie's disease and trauma. 35 The use of an automatic self-injection system made therapy much easier to perform and more easily accepted by the patients. In the system described our vasoactive mixture was contained in a pre-filled cartridge in a dose usually sufficient for 8 to 10 injections. Only the needle had to be changed at each injection. After interviewing our patients during followup we believe that the automatic injection system probably contributed to limit our dropout rate, which was considerably less than usually reported in the literature. 37 We conclude that intracavernous multi-drug pharmacotherapy has a role in the treatment of impotence due to the impairment of the corporeal veno-occlusive mechanism, alone or associated with alteration of penile arterial inflow. This new approach represents a safe and effective therapeutic option for those patients who are not suitable candidates for reconstructive vascular surgery. Prof. Karine Winter Beatty reviewed the linguistic style of the manuscript. REFERENCES
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34. Vickers, M. A., Jr., Benson, C., Dluhy, R. and Ball, R. A.: The current cavernosometric criteria for corporovenous dysfunction are too strict. J. Urol., 14 7: 614, 1992. 35. Goldstein, I. and Krane, R. J.: Diagnosis and therapy of erectile dysfunction. In: Campbell's Urology, 6th ed. Edited by P. C. Walsh, A. B. Retik, T. A. Stamey and E. D. Vaughan. Philadelphia: W. B. Saunders Co., vol. 3, sect. XIV, chapt. 84, pp. 30333072, 1992. 36. Saenz de Tejada, I., Moroukian, P., Tessier, J., Kim, J. J., Goldstein, I. and Frohrib, D.: Trabecular smooth muscle modulates the capacitor function of the penis. Studies on a rabbit model. Amer. J. Physiol., 260: H1590, 1991. 37. Althof, S. E., Turner, L. A., Levine, S. B., Risen, C., Kursh, E., Bodner, D. and Resnick, M.: Why do so many people drop out from auto-injection therapy for impotence? J. Sex. Marital Ther., 15: 121, 1989.
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FOUR-DRUG INTRACAVERNOUS THERAPY FOR IMPOTENCE DUE TO CORPOREAL VENO-OCCLUSIVE DYSFUNCTION FRANCESCO MONTORSI, GIORGIO GUAZZONI, FRANCO BERGAMASCHI, LUIGI FERINISTRAMBI, LUIGI BARBIERI AND PATRIZIO RIGATTI From the Departments of Biomedical Sciences, Urology and Neurology, Scientific Institute H. San Raffaele, University of Milan School of Medicine, Milan, Italy
ABSTRACT
Although veno-occlusive dysfunction is a frequent cause of impotence, a definitive therapeutic strategy has not yet been clearly defined. A total of 56 patients with corporeal veno-occlusive dysfunction diagnosed by dynamic infusion cavernosometry-cavernosography (flow to maintain erection greater than 10 ml. per minute and rate of corporeal pressure decrease after interruption of intracavernous infusion greater than 50 mm. Hg for 30 seconds) not considered suitable candidates for surgery underwent self-injection therapy. A vasoactive mixture composed of 12.1 mg./ml. papaverine hydrochloride, 10.1 µgm./ml. prostaglandin El, 1.01 mg./ml. phentolamine mesylate and 0.15 mg./ml. atropine sulfate was used. After dose titration of the drug mixture 54 patients (95%) were able to obtain sustained rigid erections that guaranteed satisfactory sexual activity. Mean (plus or minus standard error of mean) volume of injected mixture was 0.42 ± 0.09 ml. (range 0.25 to 0.90 ml.). Four patients (7%) reported transient hypotension that did not recur after the application of a penile rubber band before injection. At a mean followup of 16 months 6 patients (11 %) discontinued use of injections, 37 (69%) were satisfied and using the mixture, and 11 (20%) maintained rigid erections using a lower than initial dose. No major complications were encountered. The association of drugs with different mechanisms of action caused a synergism that potentiated the therapeutic activity and reduced side effects by decreasing the total drug dose. KEY WORDS: impotence, papaverine, phentolamine, atropine, alprostadil
Dysfunction of the corporeal veno-occlusive mechanism is a major cause of male impotence. 1• 2 Quantitative and qualitative assessment of corporeal veno-occlusive dysfunction can be accurately obtained by cavernosometry and cavernosography performed after intracavernous vasoactive stimulation. 3 • 4 Choice of therapy is based on the results of pharmacocavernosometry and cavernosography, concomitant neurovascular risk factors, and clinical characteristics and expectations of the patient. Presently, venous surgery, 5 • 6 vacuum device 7 and penile implants8 are the main therapeutic options for impotence due to cavernous veno-occlusive dysfunction. lntracavernous injections of vasoactive drugs have also been used for treatment but the results have often been reported as unsatisfactory. 9 •10 However, recent studies have emphasized the enhanced effectiveness of the combination of multiple vasoactive drugs in intracavernous therapy of vasculogenic impotence. 11- 15 This pharmacological association is based upon the synergism between drugs that exert their actions through different mechanisms to increase the overall therapeutic activity while reducing the total dose of the drug and related side effects. 11 We report our experience with intracavernous injections of a 4-drug vasoactive mixture composed of papaverine hydrochloride, phentolamine mesylate, prostaglandin El and atropine sulfate in patients with corporeal veno-occlusive dysfunction who were not suitable candidates for venous surgery and elected to undergo self-injection therapy. MATERIALS AND METHODS
Patients included in this study were evaluated at our impotence clinic from January 1990 to June 1991. At our institution the diagnostic evaluation for impotent patients consists of careful history and physical examination, laboratory analysis (serum glucose, cholesterol, triglycerides and hormonal profile), Accepted for publication December 11, 1992. Read at annual meeting of Western Section, American Urological Association, Maui, Hawaii, October 21-30, 1992.
biothesiometry, polysomnographic recordings of nocturnal erections during a 3-night period, duplex or color Doppler sonography of the penile arteries and dynamic infusion cavernosometry-cavernosography. Selective internal pudendal angiography is performed only in select cases. The operative technique of dynamic infusion cavernosometry-cavernosography is that detailed by Padma-Nathan 16 with minor modifications. Briefly, 5 ml. 1% lidocaine are administered via a 25 gauge needle to the subcutaneous area overlying the dorsal subcoronal area. After distal dorsal penile anesthesia has been established, a 21 gauge butterfly is introduced intracavernosally. Heparinized saline is used to flush the butterfly angiocatheter to assure correct needle placement. The butterfly angiocatheter is used to administer 45 mg. papaverine hydrochloride and 2.5 mg. phentolamine mesylate. In the first phase of the procedure corporeal body pressure and circumference response to the aforementioned vasoactive mixture were measured. The length of time required to reach equilibrium corporeal body pressures was recorded. The second phase involved infusion of heparinized saline to a control suprasystolic corporeal body pressure and subsequent recording of the rate of decrease with time of the corporeal body pressure from this control value. A corporeal body pressure of 150 mm. Hg with an observation period of 30 seconds was used. To record the pressure loss value a second 21 gauge butterfly angiocatheter previously flushed with heparinized saline was percutaneously inserted into the opposite corporeal body. The butterfly angiocatheter was used to administer intracavernosal heparinized saline by an infusion pump. A maximum flow rate of approximately 120 ml. per minute was used. The flow rate necessary to maintain serial intracavernous pressures of 60, 90, 120 and 150 mm. Hg was recorded. The rate of decrease of corporeal body pressure after termination of infusion was recorded twice and the mean value was determined. Additional repeat studies were performed with perineal compression.
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The third and final phase involved intracavernosal infusion of an iodinated contrast agent at a control corporeal body pressure arbitrarily chosen as 90 mm. Hg, since this is the physiological corporeal body pressure at the equilibrium steady state. The presence of veins draining the corporeal body during penile rigidity could then be recorded fluoroscopically. At the end of the study aspiration of approximately 50 ml. corporeal contents was performed to aid in the elimination of the contrast agent from the erectile tissue. Maintenance flow rates higher than 10 ml. per minute at a minimum of 3 pressure levels and a decrease of more than 50 mm. Hg from 150 for 30 seconds were considered indicative of abnormal corporeal veno-occlusive function. Cavernosography indicated the precise location of the draining veins. Of 131 impotent patients evaluated during the 18-month period of this study 84 (64 % ) demonstrated an alteration of the corporeal veno-occlusive mechanism. In 58 of these patients (44%) associated alteration of cavernosal artery inflow was detected by duplex and color Doppler sonography. Selection of therapy for patients with corporeal veno-occlusive dysfunction included venous surgery (20 cases), vacuum device (8 cases) and intracavernous pharmacotherapy (56 cases). Patients considered for intracavernous self-injections were a mean of 58.5 years old and reported a mean duration of symptoms of 3.2 years. Overall mean (plus or minus standard error of mean) maintenance flow rate in these patients was 15.9 ± 1.8 ml. per minute, while the mean (plus or minus standard error of mean) decrease rate from an intracavernous pressure of 150 mm. Hg was 68.5 ± 6.2 mm. Hg. Venous leaks were detected by cavernosography at the deep dorsal vein in 36 patients, cavernosal veins in 20, crural veins in 22, corpus spongiosum in 6 and glans penis in 6. In 22 cases the leak was from a single anatomical site while in 34 it was from multiple venous channels. Neurovascular risk factors observed in this group of patients included smoking (35 patients), hypertension (8), diabetes mellitus (12), hypercholesterolemia (18) and alcoholism (1). Contraindications to intracavernosal injection therapy included history of hemoglobinopathy, bleeding diathesis, Peyronie's disease or idiopathic priapism. Patients on oral anticoagulation therapy also were excluded. After inclusion in the self-injection protocol the patients gave informed consent, which acknowledged the investigational nature of multidrug intracavernous therapy and which had been approved by the Ethics Committee at our hospital. A 4-drug vasoactive mixture was used. The solution for vasoactive stimulation was prepared by mixing 240 mg. papaverine hydrochloride, 200 µgm. prostaglandin El, 20 mg. phentolamine mesylate and 3 mg. atropine sulfate with a total of 19.8 ml. of vasoactive solution. The concentrations obtained were 12.1 mg./ml. papaverine hydrochloride, 10.1 µgm./ml. prostaglandin El, 1.01 mg./ml. phentolamine mesylate and 0.15 mg./ml. atropine sulphate. Patients were placed in the sitting position on an examination couch during each injection and kept in position for 30 minutes. Systemic blood pressure was recorded as a baseline in the event of syncope and to note hypertension. The right side (lateral aspect) of the penis was cleansed with an alcohol swab. An automatic self-injection system was used in the dose titration phase and at home. All patients received an initial injection of 0.1 ml. of the 4-drug mixture by a physician using a 27 gauge needle that was inserted by a quick jab up to the hilt of the needle such that the tip of the needle was in the center of the right corpus cavernosum. Immediately after injection the base of the penis was squeezed firmly between the right thumb and index finger, while the accessible portion of the penis was massaged for up to 5 minutes by squeezing it laterally along the length of the shaft between the left thumb, and index and middle fingers, thus distributing the drug throughout the pendulous shaft. Patients were then left alone to watch an erotic video to optimize sexual stimulation.
The erectile response was assessed by the physician and patient. The dose of mixture was considered adequate when a rigid erection was obtained and lasted for at least 30 minutes. If the first injection did not produce a satisfactory erection, the patient was reinjected after 3 days and the dose was increased by 0.1 ml. of the mixture. The titration process in 0.1 ml. of mixture proceeded until an adequate erection was obtained or a maximum dose of 1.0 ml. was used. If a rigid erection persisted for longer than 1 hour 20 ml. of cavernous blood were aspirated and 20 to 40 µgm. epinephrine were administered intracorporeally to obtain complete detumescence. Appropriate electrocardiographic and blood pressure monitoring was used during this procedure. Patients were contacted by telephone the next day to verify persistence of detumescence. After the proper dose of the vasoactive mixture was determined the patient was taught the auto-injection technique and was observed while self-administering the mixture in the clinic. Patients could then purchase the vasoactive mixture from the hospital pharmacy. Each vial containing 19.8 ml. of solution cost $150. Patients were instructed to limit vasoactive mixture use to twice a week, with no more than 1 injection in any 24hour period. They were also taught to inject alternatively the right and left cavernous body. Patients were then warned to return immediately to the emergency room if erection persisted for longer than 3 hours. They were also told to refrigerate the mixture and to examine the solution for changes in color or the formation of a precipitate. A 3-month expiration date was clearly printed on the vial, which was based on known time limits of effectiveness and sterility of prostaglandin El.17 Patients were advised not to use the mixture after it had expired. Patients were reevaluated once a month for the first 2 months and subsequently every 3 months. At each followup visit injection frequency, duration and consistency of erections, and patient satisfaction were recorded. The penis was carefully examined for nodules, hematomas or areas of induration. Liver function tests, including alkaline phosphatase, lactic dehydrogenase, serum glutamic oxaloacetic transaminase and total bilirubin, were assessed every 6 months. Penile ultrasonography was performed to verify any clinical finding on digital palpation of the penis. Eleven patients had been previously assessed for impotence at other centers and had failed to respond to intracavernosal injection therapy with papaverine or a papaverinephentolamine combination. Two patients had been placed on therapy with intracorporeal prostaglandin El but had stopped self-injection due to severe penile pain. RESULTS
During the dose titration phase injection of the vasoactive mixture was unsuccessful in causing a rigid erection lasting for at least 30 minutes in only 2 cases. These patients had massive leaks from the crural veins, deep dorsal vein and corpus spongiosum, and subsequently underwent implantation of penile prostheses. A total of 54 patients elected to begin treatment with intracavernous self-injection of the 4-drug mixture during our study. Mean duration of mixture use was 16.3 months (range 12 to 18 months). Mean frequency of drug use was 1.8 times per week. At the end of the preliminary dose titration phase the mean (plus or minus standard error of mean) dose to produce a sustained rigid erection was 0.42 ± 0.09 ml., and the mean (plus or minus standard error of mean) latency time between injection and erection was 7.5 ± 1.1 minutes. Presently, 37 patients (69%) are using the injections at the initial dose and enjoying satisfactory sexual activity, while 11 (20%) obtain a rigid erection with a lower dose (mean plus or minus standard error of mean 0.31 ± 0.07 ml.). None of the patients reported complete restoration of natural erections. Four patients (7%) reported dizziness and transient hypotension after injections on some occasions, which were resolved by applying a rubber band at the root of the penis before injecting the drug mixture. Six patients (11 %) discontinued the use of
INTRACAVERNOUS THERAPY FOR IMPOTENCE
injections because of significant intercurrent illness in 2 and lack of a sexual partner in 5. Overall, intracorporeal injection of the 4-drug mixture was successful in 89% of the impotent patients with hemodynamically significant corporeal veno-occlusive dysfunction. None of the patients experienced pain with the injection. At followup neither penile plaques nor clinically significant hematomas were encountered. A small palpable subcutaneous nodule was noted in 2 patients (4%), and a reduction in frequency of injections was suggested. Small and transient hematomas at the injection sites were reported by 15 patients (28%). There was no report of penile curvature after starting self-injection therapy, and no patient experienced prolonged (longer than 3 hours) erection during self-injection at home. However, in 2 cases (4%) 1 of the titration doses caused an erection that was still rigid after 2 hours and was reversed with intracorporeal epinephrine. Liver function tests performed during followup showed no significant alterations. DISCUSSION
Penile erection is a psychoneurovascular phenomenon that involves activation of the penile vascular system either by cerebral or local sensory stimuli with subsequent increase of arterial inflow via the paired cavernosal arteries, sinusoidal relaxation and filling of the corporeal bodies from this increase in arterial inflow, and a decrease in the outflow from or trapping of blood within the corpora causing tumescence and rigidity. 18 Scanning electron microscopic studies have demonstrated that the subtunical venules are compressed between the sinusoidal walls and the tunica albuginea, thus restricting venous flow to a minimum during erection. 19 In addition, the uneven stretching of the layers of the tunica albuginea also contributes to closure of the emissary veins. An active venous occlusive mechanism mediated by neuropeptide Y has also been described. 20 The reduction of venous outflow by the mechanical compression of subtunical venules is known as the corporeal venoocclusive mechanism. 21 Corporeal veno-occlusive dysfunction may occur due to insufficient relaxation of the trabecular smooth muscle or to a structural alteration in the fibroelastic components of the trabeculae. In patients with corporeal venoocclusive dysfunction an adequate perfusion pressure may not be able to balance the unrestricted venous outflow to ensure complete penile rigidity. Pathophysiology of corporeal veno-occlusive dysfunction may explain the poor results reported in these cases with intracavernous pharmacotherapy. 9 • 10 To achieve penile rigidity locally administered vasoactive drugs must cause maximal distention of the corporeal tissue, which in cases of corporeal veno-occlusive dysfunction can be hampered by the early clearance of these drugs from the corpora cavernosa due to increased outflow. In cases of concomitant arterial disease the effect of intracavernous vasoactive injections can be further reduced. In these cases an alternative therapeutic approach is based on the use of drugs with different mechanisms of actions possibly exerting a synergistic effect, Papaverine hydrochloride is an opium alkaloid that acts on a post-receptor level via the inhibition of phosphodiesterase, leading to an accumulation of cyclic adenosine monophosphate, which attenuates the alreceptor mediated contraction of the smooth muscle cell, possibly by interfering with the calcium ion mobilization. This drug facilitates erection by relaxation of smooth muscles in the sinusoids and by dilation of helicine arteries. 22 Phentolamine mesylate is an a-1 and a-2-adrenergic receptor blocking agent that dilates arterial vessels and abolishes sympathetic inhibition of erection. 23 Prostaglandin El has a blocking properties mediated through a membrane receptor, 24 and relaxes the cavernous and arteriolar smooth muscle 25 while causing restriction of venous outflow. The use of atropine sulfate in pharmacological erection programs was first reported by Virag et al. 11 • 26 • 27 It is now known that atropine sulfate in low doses (lo-s M.)
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blocks muscarinic receptors, thereby diminishing cholinergic inhibition of the adrenergic and cholinergic excitation of the nonadrenergic, noncholinergic neuroeffector systems controlling neurogenic corporeal smooth muscle relaxation. However, in large pharmacological doses (10- 3 M.) atropine causes release of the endothelium derived relaxing factor, 28 which has recently been identified as a neurotransmitter involved in penile erection. 21 The association of several agents acting on different phases of the erectile cycle proved successful in treating patients who responded insufficiently to papaverine alone and to papaverine combined with a blockers. 11- 15• 28 • 29 This finding was confirmed by our study in which the 4-drug mixture was able to guarantee a rigid erection in 11 patients with corporeal veno-occlusive dysfunction who had not responded to the papaverine-phentolamine combination. Almost all patients in our series modified the mixture dose after using the same vial for approximately 80 to 90 days, which was probably due to a reduction in the therapeutic effect of prostaglandin El with time, despite the use of a refrigerator to preserve drug function. 10•13• 17 The increase of mixture dose ranged from 0.5 to 1.0 ml. However, some patients reported the successful use of the mixture 6 months after the purchase of the vial. When multiple drugs are associated the final dose can be decreased, thus reducing the side effects. 11 • 13• 29 In our patients the typical side effects of every single drug, that is cavernous fibrosis, penile induration, priapism, pain at the injection site and elevation of liver enzymes, were not observed. At the time of writing this report we observed no evidence of systemic or local toxicity specifically related to the 4-drug mixture used in our study. To our knowledge, specific combination related toxicity has not been reported previously in the literature. Although our study is related to a short period of observation, we believe that it confirms that the reduction of the total drug dose delivered to the cavernous tissue is a key factor in avoiding toxic adverse effects. Of our patients 89% were satisfied and had rigid erections with self-injection therapy. Our success rate is noteworthy, since it was obtained in a population of patients usually considered as poor responders to conventional intracavernous therapy. Moreover, it should be emphasized that patients selected for intracavernous therapy were not considered for venous surgery since they presented with risk factors for erectile dysfunction usually associated with poor surgical outcome. 5 • 6• 30 Of our patients 20% were able to reduce the dose of the mixture with time, and almost 50% reported some amelioration of natural erections. However, no patient referred to total restoration of complete natural erections. The improvement of natural erectile activity was probably due to the positive effect of self-injections on anxiety and inhibitory emotional reactions that are often associated with organic impotence. 31 Our experience of a sustained rigid erection after intracavernosal vasoactive injection might seem to contradict the diagnosis of corporeal veno-occlusive dysfunction made at dynamic infusion cavernosometry-cavernosography but several parameters were used to define the dysfunction including maintenance flow rates and corporeal pressure decay. 16• 32 The cutoff values used in our study were similar to values reported by others. 32•33 Moreover, the vasoactive agents in the doses used in our patients were definitely within the range usually reported in most of the studies detailing the technique of pharmacocavernosometry-cavernosography testing. 32• 33 Thus, the diagnosis of corporeal veno-occlusive dysfunction was in agreement with commonly accepted diagnostic standards. However, Vickers et al reported "abnormal" dynamic infusion cavernosometry-cavernosography data in 6 impotent patients who spontaneously recovered normal erectile function that was then confirmed by home sleep tumescence and rigidity monitoring. 34 It should be noted that polysomnographic recording of nocturnal erections was also performed on all of our patients and always revealed
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organic impotence. Color Doppler sonography also showed concomitant deterioration of cavernosal artery function in twothirds of our patients. Thus, it seems reasonable to rule out the possibility of false-positive results of dynamic infusion cavernosometry-cavernosography in our study. In our patients sustained rigid erections were provoked by intracavernosal injection of the 4-drug mixture, and sexual stimulation as the pharmacological synergism exerted by the association of drugs with different mechanisms of action caused the stretching of corporeal tissue to its ultimate physiological limit. In other words, this mixture produced a supra-normal stimulation of the corporeal smooth muscle, which would not have been able to react normally to physiological erectogenic stimuli alone. We are aware that the dilemma of any study performed in the erect state, especially in the diagnostic evaluation of the corporeal veno-occlusive mechanism, that is the presence of contracted corporeal smooth muscle secondary to anxiety or inadequate doses of intracavernosal vasoactive agents, remains unresolved. 35 Saenz de Tejada et al demonstrated in an animal model that in the presence of complete smooth muscle relaxation venous outflow resistance was maximal at intracavernosal pressures as low as 30 mm. Hg. 36 The flow to maintain various intracavernosal pressures was minimal and a linear relationship was found between flow to maintain and intracavernosal pressures in a range of 30 to 150 mm. Hg. On the contrary, in the presence of smooth muscle contraction a nonlinear relationship exists between the maintenance flow and the intracavernosal pressures in the pressure range of 30 to 150 mm. Hg. When applying these principles to humans, 35 if the flow to maintain intracavernosal pressure values at 30, 60, 90, 120 and 150 mm. Hg are elevated, especially if they are not linearly related to increasing intracavernosal pressures, one may interpret the results as being abnormal secondary to incomplete smooth muscle relaxation. In this case additional vasoactive agents should be administered. After achieving a new steady state equilibrium the flow to maintain various intracavernosal pressures as well as pressure decay values should be repeated and compared with the pressures and values previously obtained. A linear response of flow to maintain various intracavernosal pressures should be observed, implying that complete smooth muscle relaxation has been achieved. In these conditions corporeal veno-occlusive dysfunction is identified when flow rates to maintain various intracavernosal pressures are greater than 3 ml. per minute. 36 This effect may occur when the collagen/ elastin erectile tissue stiffness is high, such as in aging, diabetes mellitus, atherosclerosis, Peyronie's disease and trauma. 35 The use of an automatic self-injection system made therapy much easier to perform and more easily accepted by the patients. In the system described our vasoactive mixture was contained in a pre-filled cartridge in a dose usually sufficient for 8 to 10 injections. Only the needle had to be changed at each injection. After interviewing our patients during followup we believe that the automatic injection system probably contributed to limit our dropout rate, which was considerably less than usually reported in the literature. 37 We conclude that intracavernous multi-drug pharmacotherapy has a role in the treatment of impotence due to the impairment of the corporeal veno-occlusive mechanism, alone or associated with alteration of penile arterial inflow. This new approach represents a safe and effective therapeutic option for those patients who are not suitable candidates for reconstructive vascular surgery. Prof. Karine Winter Beatty reviewed the linguistic style of the manuscript. REFERENCES
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34. Vickers, M. A., Jr., Benson, C., Dluhy, R. and Ball, R. A.: The current cavernosometric criteria for corporovenous dysfunction are too strict. J. Urol., 14 7: 614, 1992. 35. Goldstein, I. and Krane, R. J.: Diagnosis and therapy of erectile dysfunction. In: Campbell's Urology, 6th ed. Edited by P. C. Walsh, A. B. Retik, T. A. Stamey and E. D. Vaughan. Philadelphia: W. B. Saunders Co., vol. 3, sect. XIV, chapt. 84, pp. 30333072, 1992. 36. Saenz de Tejada, I., Moroukian, P., Tessier, J., Kim, J. J., Goldstein, I. and Frohrib, D.: Trabecular smooth muscle modulates the capacitor function of the penis. Studies on a rabbit model. Amer. J. Physiol., 260: H1590, 1991. 37. Althof, S. E., Turner, L. A., Levine, S. B., Risen, C., Kursh, E., Bodner, D. and Resnick, M.: Why do so many people drop out from auto-injection therapy for impotence? J. Sex. Marital Ther., 15: 121, 1989.