Sources: Padma-Nathan H, et al. Treatment of men with erectile dysfunction with transurethral alprostadil. N Engl J Med 1997;336:1-7; Linet OI, et al. Efficacy and safety of intracavernous alprostadil in men with erectile dysfunction. N Engl J Med 1996;334:873-877.
Erectile dysfunction is a common complication of stroke, epilepsy, multiple sclerosis, spinal cord injury, peripheral neuropathy, depression, and aging. Often, psychogenic factors and vascular insufficiency coexist. A variety of treatments are available and include: behavioral, psychotherapeutic, medical, intracavernous injection, penile prostheses, and surgery. The recent article by Padma-Nathan et al discusses a new approach to the problem using transurethral suppositories. Those results are compared here with the 1996 study by Linet et al using intracavernous injection.
Intracavernous injections are the first-line approach to impotence of neurogenic, vasculogenic, and mixed origin. There are two main types of treatment: alprostadil (Caverject), a synthetic prostaglandin E1, and papaverine in combination with phentolamine, an alpha adrenergic blocker (Regitine). Both of these preparations cause relaxation of smooth muscle and vasodilation. After intracavernous injection, the drug increases arterial inflow through vasodilation and decreases venous outflow by relaxing the corporal smooth muscle that occludes draining venules.
Padma-Nathan and colleagues studied transurethral alprostadil as a novel alternative to intracavernous injection method of application. A total of 1511 men with vasculogenic, neurogenic, or mixed erectile dysfunction were enrolled in a double-blind, placebo-controlled study looking at dose-response and dose-efficacy. Of the 1511, 996 men (65.9%) reported erection with doses ranging from 100 g to 1000 g. Mean onset of erection time was 10 minutes and duration 70 minutes. In a separate study of home efficacy, 294 of 461 men (64%) had satisfactory intercourse compared to 43 of 500 men (18.6%) using placebo (P < 0.001). The efficacy was similar regardless of age or the cause of erectile dysfunction. Adverse effects included mild pain (32.7%), minor urethral trauma (5.1%), and dizziness (1.9%). None reported either prolonged erection or priapism, and none reported fibrosis or hematoma. The authors suggest that preliminary dose titration and administration technique be performed in the physician’s office under supervision. The transure-thral suppository seems to offer similar efficacy to intracavernous injection but with fewer adverse effects. At this time, the two methods have not been compared directly.
Serving as a background to the above, Linet et al conducted three separate multi- institutional prospective studies of intracavernous injection, examining dose-response, dose-finding, and dose-efficacy. The cohort included 1180 men with erectile dysfunction due to vasculogenic, neurogenic, psychogenic, and mixed factors. A linear dose-response curve was observed in 296 men tested with 2.5, 5, 10, and 20 g doses. The mean duration of erection ranged from 12 to 44 minutes. Erection was defined as 70% or greater rigidity on the Rigiscan Ambulatory Rigidity and Tumescence System. A total of 201 men participated in the dose-finding study. The range of effective doses for 90% of subjects was from 5 g to 20 g. Men with neurogenic erectile dysfunction required smaller doses of alprostadil than those with vasculogenic dysfunction. As with the Padma-Nathan et al study, Linet et al recommend establishing individualization of optimal dose in the physician’s office, starting with 2-3 g followed by small increments. Of the 13,762 injections with optimal treatment, 11,924 (87%) resulted in satisfactory sexual activity. Adverse effects included mild pain in about half the men but only after having about 10% of injections; only 6% discontinued treatment because of pain. Complaints included: prolonged erection (5%), priapism (1%), fibrosis (2%), hematoma/ ecchymosis (8%), and complaints of hypotension, dizziness, and diaphoresis (1%).
Many past trials have compared alprostadil to papaverine alone or in combination but without strict investigational design. Most found similar (70-80%) efficacy of achieving intercourse. The big difference is with regard to adverse effects. Alprostadil appears to be more painful, but papaverine causes unwanted side effects such as priapism, fibrosis, and elevation in liver enzymes.
COMMENTARY
For the moment, at least, alprostadil delivered transurethrally or intracavernously appears to be the most reliable approach to recently developed impotence. Medical treatment including yohimbine and hormonal supplementation with parenteral testosterone has not proven effective. Testosterone is indicated for hypogonadal disorders. The aim is to restore potency and libido by restoring normal serum levels of testosterone. Indiscriminate use in patients with normal baseline serum testosterone is ill advised, since it stimulates prostatic adenocarcinoma. Testosterone has the reputation of increasing libido, which may serve only to further frustrate patients who remain unable to achieve erection.
What is unexplainable at this point is the fact that although effective strategies exist for treating impotence, surprisingly studies report up to a 50% dropout rate among effectively treated patients. Hirsh and colleagues (Paraplegia 1994;32:661-664) report that four out of seven patients with multiple sclerosis ceased using intracavernous alprostadil despite restoration of erectile function. The reason they provided was "loss of interest." The effective treatment of impotence should start with clear and open discussion of the problem and a team approach involving the cooperation of a neurologist, urologist, and psychiatrist. jr
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