Topical vasodilatators Numerous topical vasodilatators have been tried in the management of erectile dysfunction (Crenshaw and Goldberg 1996, pp. 443-458). These include nitroglycerin 2% ointment, glyceryl trinitrate paste, and minoxidil gel rubbed onto glans penis (hair growth on glans penis is not a concern - there are no hair follicles on glans penis). All of these agents have produced better response than placebo in some studies. In an open, randomized crossover study of 28 males with spinal cord lesions, Renganathan et al. (1997) showed that intracavernous injections of papaverine were more effective than a transdermal nitroglycerine patch in treating erectile dysfunction. The response rate for nitroglycerine was 61%. However, Gramkow et al. (1999), in a double-blind, placebo-controlled crossover study of 18 men, was unable to demonstrate any effect of nitroglycerine by application of the Rigiscan Monitor™ under laboratory conditions. In this study, there was no statistically significant effect of transcutaneous nitroglycerine in comparison with placebo. Most of the studies with topical vasodilatators have been done outside the United States. Management of erectile dysfunction with topical vasodilatators has not gained approval from the FDA and is considered rather experimental.
Suppositories The intraurethral suppository of alprostadil (prostaglandin E1 - Muse™) is a minimally invasive pharmacological treatment of erectile dysfunction. Prostaglandin E1 is a naturally occurring compound that has both vasodilatating and relaxing effects on smooth muscles in the corpora cavernosa. It causes a highly dose-dependent pharmacological erection (without stimulation) and thus has a low rate of priapism. During treatment of erectile dysfunction, a small (3-mm) pellet of alprostadil is delivered into the distal end of the urethra by a tiny sterile applicator usually 5-10 minutes prior to intercourse. Erection occurs within 5-10 minutes as the drug is rapidly absorbed by the urethral mucosa and transported to the corpora cavernosa. Alprostadil suppositories are available in 125-, 250-, 500-, and 1,000-?g doses. Use of the suppositories should not exceed 2 per 24-hour period. The first application should be done under a physician’s supervision to determine the adequate dose (Mobley and Baum 1998). The most frequent side effects of alprostadil are minor urethral bleeding, pain, hypotension, and headaches. This treatment method has a fairly high initial satisfaction rate; however, a high discontinuation rate is found at 6-month follow-up (Seidman et al. 1999). The suppository technique also requires a certain degree of manual dexterity, as well as the partner’s cooperation. The compression ring may be used in patients who obtain an erection with alprostadil but are unable to maintain it for vaginal penetration.
Intracavernous penile injections The substance most frequently used in intracavernous injections is alprostadil (Caverject). The mechanism of action of alprostadil was described above. This highly effective nonsurgical method consists of an injection of a small dose of alprostadil (usually 10-20 ?g, although doses as high as 40 ?g can be used) into the penis with a small needle. Injections of alprostadil are indicated for the treatment of the mixed, idiopathic, and organic erectile dysfunctions that usually accompany neurogenic problems such as spinal cord injury. Intracavernous injections may serve as adjunct therapy to psychological intervention. Alprostadil is not indicated in severe veno-occlusive dysfunction or arterial insufficiency (Althof and Seftel 1995). Intracavernous alprostadil has been found to significantly improve the recovery rate of spontaneous erections after nerve-sparing radical retropubic prostatectomy (Montorsi et al. 1997). Intracorporeal prostaglandin E1 was found to be useful in patients who were unresponsive to intracorporeal papaverine (Sarosdy et al. 1989). In a 3-year follow-up study of 69 patients using intracavernous prostaglandin E1 (Kunelius and Lukkarinen 1999), the most common doses used at home were between 10 and 20 ?g. About half of the patients (46.4%) eventually discontinued the therapy. Most of the patients who discontinued prostaglandin E1 in this study suffered from erectile dysfunction of psychogenic origin. Intracavernous injections of prostaglandin E1 were found to be generally well tolerated and associated with only minor problems. There were no systemic side effects, and the infrequent local side effects included hematoma (10.1%), priapism (4.3%), and fibrosis in ultrasonography (5.8%). Other frequently noted reasons for discontinuation in various studies were complaints of ineffectiveness, penile scarring, penile pain, fear of injections, inconvenience, and lack of spontaneity. Lehmann et al. (1999) noted that patients discontinuing alprostadil were less motivated and less satisfied, considered the effort required to perform injection substantial, and had not achieved improved self-esteem. Interestingly, Sexton (1998), in a telephone survey of 180 patients, found that intracavernous injection served only as a palliative therapy for the majority of patients with erectile dysfunction. Many patients who discontinued intracavernous injections remained sexually active with other therapies, including vacuum erectile devices, prostheses, and vascular surgery.
Mobley and Baum (1998) provide very instructive guidelines for this treatment method. Patients who choose this method should be given a demonstration of the injection technique, and the first injection should be given under a physician’s supervision to determine the optimal dose. The dose is usually titrated to produce an erection that lasts 3-60 minutes. The first dose should be the lowest effective one, usually 10-20 ?g, and the patient should remain in the office until detumescence occurs. If detumescence occurs within 30-45 minutes, priapism is probably not going to occur with the same dose away from the office. Patients should be advised not to use the injections more than twice a week, to rotate the injection sites, and to compress the site after the injection for 1-2 minutes. Injections are given at the base of the penis at the 3 or 9 o’clock position, away from the neurovascular bundle and urethra, using a disposable 1-mL insulin syringe and a 26- to 30-gauge needle. Again, the compression ring may be used in patients who obtain an erection with alprostadil but are unable to maintain it for vaginal penetration. The antidotes for sustained erection from alprostadil are terbutaline 5 mg orally or pseudoephedrine hydrochloride. If the oral antidotes are ineffective and the erection lasts longer than 4 hours, the patient should be seen by a urologist immediately for an intracorporeal irrigation with phenylephrine hydrochloride.
Other substances, such as phentolamine, phenoxybenzamine, papaverine, vasoactive intestinal polypeptide, and combinations of papaverine with phentolamine and of prostaglandin E1 with papaverine have been used for intracorporeal injections. Shmueli et al. (1999) found a high erectile dysfunction treatment success rate with intracorporeal injections of combinations of papaverine with phentolamine; papaverine with phentolamine and alprostadil; and papaverine, phentolamine, alprostadil, and atropine sulfate. Roy et al. (1990) did not find intracavernous vasoactive intestinal polypeptide (VIP) very useful in the treatment of erectile dysfunction in a double-blind, placebo-controlled study. Even though there was a response in penile length and diameter, increases in penile rigidity were not clinically adequate for intromission.
Intracorporeal alprostadil seems to be the most effective and reliable penile injection therapy. Its long-term usefulness and tolerability need further assessment. Intracavernous injections therapies should always be combined with psychological counseling.
Oral medications The development of convenient oral medications for the treatment of erectile dysfunction has been the greatest achievement of the 1990s.
Trazodone The possibility of using trazodone in the treatment of erectile dysfunction has been entertained for more than a decade and is related to the discovery that priapism is associated with this antidepressant (approximately 1 in 6,000 men treated with trazodone). Lal et al. (1990) described the case of a physician who treated his own impotence with trazodone up to 350 mg once a week. The efficacy was confirmed in a comparison with placebo under a blind condition. However, trazodone was not found to be effective in patients with severe physiological erectile dysfunction in a double-blind, placebo-controlled study by Constabile and Spevak (1999). Montorsi et al. (1994) found the combination of trazodone with yohimbine a safe and effective first-line treatment for psychogenic impotence. It seems that trazodone could be occasionally useful in the treatment of psychogenic erectile dysfunction, especially when combined with yohimbine. However, the danger of priapism, a urological emergency, hampers its wider use by psychiatrists and primary care physicians.
Yohimbine (Yocon) Yohimbine, originally an herbal remedy from the bark of an African tree, is commonly indicated in the treatment of impotence, hypotension, and diabetic neuropathy. The prescription yohimbine hydrochloride is a synthetic salt. The folklore basis of yohimbine’s reputation as an aphrodisiac is that it causes blood rush to the penis, producing an erection (Crenshaw and Goldberg 1996, p. 427). Yohimbine’s mechanism of action includes an increase of sympathetic tone, ?2-adrenergic antagonism, inhibition of platelet aggregation, and blockade of the calcium channel. The agent’s purported mechanism of action in erectile dysfunction is restriction of the blood outflow from the penis. It may also have a central effect in the brain to increase sex drive. The efficacy of yohimbine in erectile dysfunction remains questionable. The drug has shown modest effectiveness in organic impotence in one of the earlier placebo-controlled studies (Morales et al. 1987). However, even the authors of this study labeled the response rate of organically impotent males to yohimbine as marginal at best. Four convergent meta-analyses of yohimbine effectiveness (Carey and Johnson 1996) found a consistent tendency for yohimbine, and other medications containing yohimbine, to enhance erectile functioning relative to placebo. On the other hand, results of one of the latest double-blind, placebo-controlled crossover studies with yohimbine dosages of up to 30 mg/day (Rowland et al. 1997) indicated that yohimbine had no effect on most aspects of sexual response in sexually functional men. The effect of yohimbine in men with erectile dysfunction was mixed. However, this study used a fairly small sample population. Interestingly, daily diaries indicated increased erectile response during masturbation but not intercourse.
Although most men do not respond to yohimbine, some do (Mobley and Baum 1998). It is a quite safe and inexpensive treatment modality that may be used as a first step (Morales et al. 1987). The usual dose of yohimbine is 5.4 mg three times a day, even though 5.4 mg administered as needed was used in sexual dysfunction associated with antidepressants (Hollander and McCarley 1992). The usual length of an adequate trial is 2-3 weeks, although Crenshaw and Goldberg (1996, p. 429) noted that the drug’s effects could take 6-8 weeks to appear. The side effects of yohimbine, such as anxiety, flushing, and dizziness, are usually mild. However, clinicians may need to exercise caution when prescribing yohimbine for anxious patients, because yohimbine has been used to provoke panic attacks in panic patients in the laboratory setting.
Yohimbine has been used in combination with numerous other agents, such as amylbarbitone, strychnine, testosterone, atropine, thioridazine, vitamin E, and trazodone (Montorsi et al. 1994).
Sildenafil (Viagra) The arrival of sildenafil citrate has truly revolutionized and transformed the treatment of erectile dysfunction. Sildenafil is a potent inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5. This enzyme metabolizes cGMP in the corpora cavernosa. Inhibition of phosphodiesterase type 5 leads to increased levels of cGMP in the corpora cavernosa. cGMP relaxes the smooth muscles of the corpora cavernosa, which in turn increases blood inflow to the penis, increases the pressure in the corpora cavernosa, and leads to erection. Because sildenafil potentiates the action of cGMP by decreasing its metabolism rather than stimulating its production, it should be effective only when cGMP production in the corpora cavernosa is increased by central or reflex sexual arousal and mediated by nitric oxide (Utiger 1998). Thus, sildenafil will be ineffective if there is no arousal, enhancing the role of the man’s partner. In contrast, administration of alprostadil can result in erection in the absence of arousal, thus minimizing the participation of the partner (Utiger 1998). In sum: Sexual stimulation releases nitric oxide, which induces formation of cGMP. cGMP relaxes smooth muscles in the corpora cavernosa, which leads to an increased flow of blood into the penis and an erection. Sildenafil, by the inhibition of the cGMP-degrading enzyme, potentiates the effect of sexual stimulation as it increases the level of cGMP
Sildenafil is rapidly absorbed and reaches peak serum levels in about 1 hour. The serum half-life is 3-5 hours. The effect of sildenafil is dose proportional. Sildenafil has been administered to healthy volunteers in doses of up to 200 mg without any observed alteration of heart rate, blood pressure, or laboratory test results.
Sildenafil is indicated in erectile dysfunction of various etiologies. It has been demonstrated to be an efficacious treatment of various forms of erectile dysfunction (Goldstein et al. 1998; Morales et al. 1998), including erectile dysfunction related to diabetes mellitus (Rendell et al. 1999), erectile dysfunction after radical prostatectomy (Zippe et al. 1998), erectile dysfunction caused by spinal injury (Derry et al. 1998), and numerous other conditions associated with erectile dysfunction, such as comorbid depression, hypertension, and ischemic heart disease. In some trials, its efficacy rates have reached 70%-80%.
Sildenafil has also been found useful in antidepressant-induced erectile dysfunction (caution: this is not an FDA-approved indication) and in one case of antipsychotic-induced sexual dysfunction (Segraves 1999). One study (Fava et al. 1998) and several case reports of the use of sildenafil in antidepressant-induced sexual dysfunction have been published (the case reports are summarized in Balon 1999a and Balon 1999b). Sildenafil has been used mostly in selective serotonin reuptake inhibitor (SSRI)-associated sexual dysfunction, but also mirtazapine-, nefazodone-, and phenelzine-induced sexual dysfunction. It has been frequently used as a first-line therapy in this indication, although its mechanism of action in this area remains unclear. Smooth-muscle relaxation induced by increased cGMP probably overrides the erectile dysregulation caused by the noradrenergic or other effects of antidepressants. The effective dose has been between 50 and 100 mg 1-2 hours prior to intercourse. The lowest dose used was 25 mg in phenelzine-associated erectile dysfunction. The side effects of sildenafil in this indication were infrequent and usually mild.
The following case example (reprinted with permission from Balon 1998) illustrates the use of sildenafil in antidepressant-induced erectile dysfunction.
Mr. A was a 39-year-old single male who had been treated for social phobia and alcohol abuse for many years. He experienced “a couple of panic attacks and during class in the eighth grade and severe anxiety with shaking during the speech class at tenth grade.” Since then, he has been severely anxious, trembling, shaking, short of breath and has experienced sweaty palms and heart pounding when in a social situation. He has tried to avoid performance situations, and the recognition that the fear had been unreasonable caused him a lot of distress. He also drank up to 20 beers over the weekend for many years.
He has been treated by several psychiatrists since the age of 26. He was on imipramine first, but discontinued it for various side effects, including erectile dysfunction. He tried fluoxetine and paroxetine, but could tolerate neither of these antidepressants because of erectile dysfunction. He also tried buspirone, which helped but caused a lot of lightheadedness, and alprazolam, which was not very effective. He reported no erectile problems when antidepressants were discontinued.
He was referred to me while he was on clonazepam (1 mg three times a day) and naltrexone hydrochloride (50 mg/day). At the time of his initial evaluation, he denied any side effects, including any sexual dysfunction. He also denied any alcohol or drug abuse, was clean and sober, and had been attending Alcoholics Anonymous for several months. He was physically healthy.
He was started on 50 mg/day of fluvoxamine. Fluvoxamine was gradually increased to 150 mg/day while naltrexone was gradually discontinued. Clonazepam remained unchanged. He continued to abstain from alcohol. He gradually improved, reporting that his anxiety “was down, the best I have ever been,” yet he complained of erectile dysfunction. He stated that his penis was very soft during attempts to have intercourse with his girlfriend. He stated, “I have had erectile problems on every antidepressant I have been on, starting with imipramine.”
Since he was healthy, and sildenafil, having been just introduced to the market, was not contraindicated, Mr. A was started on 50 mg sildenafil citrate prior to planned intercourse. Fluvoxamine (150 mg/day) and clonazepam (3 mg/day) remained unchanged. He reported that the 50 mg was not very effective. When the dose was increased to 100 mg about an hour before planned intercourse, he reported a significant improvement regularly. He stated, “My erection and the whole intercourse was like when I was 19 or before I started the antidepressant again.” He reported that on fluvoxamine prior to taking sildenafil his erection was at best a 5 on a scale of 1 to 10, while on sildenafil his erection was an unequivocally a 10. He stated, “Long time ago I had the tools and did not know what to do, and lately I knew what to do, but I did not have the tools. This pill (sildenafil) gives me both.” He reported having “a stuffy nose, a little headache, and sensitivity to light. Everything takes a blue tinge.” He decided on his own that he was going to request his insurance to pay for sildenafil, stating, “they should pay for this as my erectile dysfunction is due to medication which I have to take for my anxiety.”
Patients should be briefly counseled prior to starting sildenafil. They should be advised that sildenafil is not an aphrodisiac and that it helps with erectile dysfunction only. Routine laboratory tests and testosterone level should be checked, and brief physical examination may be indicated. Sildenafil should be taken about an hour prior to intercourse. The clinically effective dose range of sildenafil for various forms of erectile dysfunction is between 25 and 100 mg. The most prudent strategy is to start with a 50-mg dose and adjust the dose based on erectile response and side effects. If a patient does not reach erection after a trial with three 100-mg doses of sildenafil, a different treatment for erectile dysfunction should be tried. Onset of action may occur as soon as in 20 minutes, and the effect can last 8 hours or longer (Mobley and Baum 1998). Sildenafil should be used only once a day and should not be taken in combination with any other form of pharmacological treatment for erectile dysfunction. The usual dosage should not exceed 100 mg. The most frequent side effects of sildenafil are headaches, facial flushing, stuffy nose, sensitivity to light, and dyspepsia.
Sildenafil is absolutely contraindicated during concurrent use of nitrates and nitrate-containing medications - taking sildenafil with nitrates can cause malignant, fatal hypotension. The cardiovascular effects of sildenafil may be potentially hazardous in some conditions; thus, individualized cardiovascular assessment is required and a reduced initial dose of sildenafil suggested. Caution is warranted when prescribing sildenafil for active coronary ischemic inpatients who do not take nitrates; patients with congestive heart failure, borderline low blood pressure, and borderline low-volume status; patients on complicated multidrug antihypertensive regimens; and patients taking drugs that prolong sildenafil’s half-life, such as cimetidine, erythromycin, and other drugs inhibiting the P450 3A4 system.
The FDA has reported 128 nonviolent deaths in the United States among men who received prescriptions for sildenafil (Arora and Melilli 1999). Of these deaths, 34% occurred within 4-5 hours after sildenafil administration, and approximately 70% of the men who died had risk factors for cardiovascular or cerebrovascular disease. Thus, patients should be warned of the risks of taking sildenafil and nitrates concurrently, even if they have received a prescription for only one or the other. However, the FDA has repeatedly affirmed sildenafil’s safety when it is prescribed in accordance with the package labeling information.
Some have suggested that patients taking sildenafil should carry a medallion or tag with the information that they are taking sildenafil. Some have also suggested a Medic Alert membership, which provides the protection of a body-worn medical ID emblem backed by a 24-hour hotline that can transmit additional information, such as medications or the patient’s physician contact. The tag should contain the following: Caution with all medications, call for information, caution with antianginal medications and nitrates.
Sildenafil is quite expensive (about $10/pill), and many insurance companies do not cover payment for it. Some insurance companies may require documentation of the indication for use of sildenafil.
It should be noted that medication treatment of organically based erectile dysfunction still requires an understanding of the dysfunction in a broader psychosocial context (Wise 1999). Wise (1999) described two cases in which a couple’s marital relationship worsened after the husband refused to take sildenafil for erectile failure following radical prostatectomy. Successful treatment of erectile dysfunction may also disrupt a long-standing marital equilibrium. A man’s increased demands for sexual activity may not be matched by his partner’s desire or readiness, and substantial conflicts may arise. Sometimes a marital therapy process may be needed to help the couple readjust to this situation and establish a new marital contract regarding sexuality.
However, sildenafil could also have some positive psychosocial and public health consequences. The use of sildenafil might be helpful in some condom-phobic or -avoidant patients (prevention of human immunodeficiency virus [HIV] and other sexually transmitted diseases?). Sildenafil could also be used as an adjunct or augmenting device during traditional sex therapy (squeeze method, etc.) for premature ejaculation. Segraves (1999) recently described a case of sildenafil-augmented behavioral sex therapy. Sildenafil also probably improves the perception of the orgasmic quality through the firmer erection.
Apomorphine Apomorphine is still in the clinical trials stage and has not yet been approved by the FDA for the treatment of erectile dysfunction. It is a centrally acting dopamine agonist that has been used for inducing emesis and as an antiparkinsonian drug. It causes vasodilatation, and erection induced by apomorphine is mediated by sympathetic and parasympathetic nervous systems. Apomorphine is rapidly absorbed, with an erection occurring within 20-45 minutes in the presence of sexual stimulation (Seidman et al. 1999). Brachial subcutaneous injections of apomorphine hydrochloride have been reported to elicit penile erections in men with psychogenic impotence (Segraves et al. 1991). Placebo-controlled trials (e.g., Heaton et al. 1995) have demonstrated the efficacy of various doses of apomorphine - 2, 4, and 6 mg; the efficacy rates seem to be dose dependent, with 8 mg being the most efficacious. The most frequent side effect was nausea (dose related) and sweating.
Phentolamine (Vasomax) One of the more promising oral medications, which as of 1999 has still not been approved by the FDA, is phentolamine. This agent, an ?-adrenergic blocker with affinity for both ?1 and ?2 receptors, reduces sympathetic tone. It is a smooth-muscle relaxant that has been successfully used in the treatment of erectile dysfunction via intracorporeal injection. Phentolamine has been also used intravenously for monoamine oxidase inhibitor (MAOI)-induced hypertensive crisis and other indications. It has been investigated in numerous placebo-controlled trials both outside and within the United States (Becker et al. 1998; Gwinup 1988). The drug has been found to be effective in mild forms of erectile dysfunction. The effective doses ranged from 20 mg to 80 mg, and the response seemed to be dose dependent. Side effects included headache, flushing, and nasal congestion, all at less than 10% (Seidman et al. 1999). Phentolamine seems to be an efficacious and safe oral medication for the treatment of mild erectile dysfunction.
Hormonal treatment The National Institutes of Health Conference on Impotence (1992) concluded that androgen replacement therapy for erectile dysfunction is indicated only in erectile dysfunction associated with hypogonadism and/or abnormally low testosterone levels. Testosterone is not therapeutically effective in eugonadal men with erectile dysfunction and normal sexual desire. Even in young men with insufficient testosterone, hormone replacement therapy usually results in only marginal improvement in erectile function (Althof and Seftel 1995). Long-term androgen administration may cause prostatic growth and even prostatic cancer, unwanted cardiovascular effects, fluid retention, hepatotoxicity, hyperlipidemia, and sleep apnea. Testosterone is available in long-acting injectable preparations (testosterone cypionate and testosterone enanthate). Oral preparations are also available.
Biological treatment modalities have brought us an enormous improvement in the treatment of male erectile disorder. These modalities, especially sildenafil, somewhat arbitrarily blur the importance of the etiology of erectile dysfunction. However, determination of etiology (if possible) is always very important for treatment planning, especially in view of the fact that none of these therapies is totally safe and harmless. So far, we also lack solid long-term efficacy and safety studies of many of these treatments. Thus, an integrated and individualized approach to the erectile dysfunction in each patient is warranted.
Revision date: June 18, 2011
Last revised: by Andrew G. Epstein, M.D.