Alprostadil, Nitroglycerine, Aminophylline, Isosorbide Dinitrate, and Co-dergocrine

Efficacy. Although the use of topical alprostadil was associated with improvements in erection and a higher sexual intercourse success rate relative to placebo, the magnitude of this improvement might be small (about 10 percent) and limited to men with mild to moderate ED. Patients who used nitroglycerine plaster before planned intercourse did not have improved erections in comparison with those who used placebo. Nitroglycerine ointment produced only a small improvement in erections. Fewer patients who used nitroglycerine ointment or placebo improved compared with those who took minoxidil. Results for topical aminophylline plusisosorbide dinitrate and co-dergocrine were contradictory, improved erections being found in only one of two trials.

Harms. Adverse events, including local pain, was statistically significantly more frequently in patients treated with topicalalprostadil compared with those treated with placebo. Patients who used nitroglycerine plaster before planned intercourse experienced a higher frequency of pain and headaches than those who used placebo. The use of nitroglycerine ointment was associated with increased pain and hypotension.

Hormonal Treatments

Testosterone

Efficacy. The effectiveness of testosterone regarding to improve erectile function and sexual intercourse satisfaction was inconsistent compared with placebo. Differences in patient inclusion criteria (e.g. not all trials were comprised of exclusively of ED patients), methods of evaluation, interventions (e.g. mono versus combination treatment, cream, patch, gel, injections), outcome definitions, and use of subjective measures (e.g. IIEF, SEP), could explain some of the discrepancies in results across the studies evaluating the efficacy of testosterone. The intramuscular administration of testosterone was shown to have improved erectile function compared with placebo in only one of four small trials. The “patch” testosterone did not improve sexual function compared with placebo. However, in men with poor response to previous use of sildenafil, testosterone patch plus sildenafil significantly improved the sexual intercourse success rate and satisfaction compared with placebo and sildenafil alone. Gel testosterone (50 mg and 100 mg doses) was found to have increased sexual intercourse frequency compared with placebo. The 100 mg dose of gel testosterone also significantly improved sexual intercourse frequency versus patch testosterone. The use of combination cream of testosterone, isosorbide dinitrate, and co-dergocrine was associated with an increased rate of successful sexual intercourse and improved erections compared with placebo or cream testosterone alone. The application of dihydrotestosterone gel was related to an increased rate of successful sexual intercourse compared with that of placebo.

Although there is insufficient head-to-head data, the gel formulation of testosterone may be a more effective treatment compared with other formulations of testosterone.

Harms. Patients receiving testosterone patch had a higher rate of having application site skin reactions than those with placebo. The use of gel testosterone did not show a dose-related increase in adverse events. The use of combination cream containing testosterone, isosorbide dinitrate, and co-dergocrine was associated with an increased risk of mild headaches compared with placebo or cream testosterone alone. The short-term followup precluded ascertainment of the incidence of prostate cancer. In one trial,³¹⁷ two patients who had been treated with patch testosterone, developed prostate cancer.

Other Treatments (Off-label use)

For summary of trials refer to Evidence Table F-10 (Appendix F).

Phentolamine

Efficacy. The results indicated either numerical or statistically significant improvements in erectile function (i.e., percent of successful intercourse attempts, base/tip rigidity >60 percent for ≥ 10 minutes) were associated with the use of phentolaminerelative to placebo. There was no between-group difference for tumescence activity units.³³³ With insufficient data, statistical test results, and a small number of studies, the trial results are inconclusive regarding the efficacy of phentolamine relative to placebo.

Harms. Due to the lack of sufficient amount of harms data it is not clear if patients taking oral phentolamine are at higher risk of developing adverse events.

Trazodone

Efficacy. Evidence regarding efficacy of trazodone relative to placebo to treat ED was insufficient (i.e., only 5 smaller-scale trials) and inconsistent. In general, the use of trazodone was not associated with improved erectile function compared with placebo.^{336,337, 339, 341} Note that in one trial,³⁴⁴ patients on trazodone experienced statistically significant improvement in erectile response (i.e., at least 3 successful intercourses within 30 days of treatment) compared with those on placebo, ketanserin, or mianserin. Since this trial was not double blind, it is hard to judge if the observed differences were truly due to the treatment administered or to other extraneous factors. The current American Urological Association Practice Guidelines Committee (AUA PGC) does not recommend the use of trazodone in the treatment of ED.¹⁴

Harms. Limited evidence suggests that the use of trazodone may be associated with an increased risk of adverse events (priapism, sedation, headache) and higher rates of withdrawal due to adverse events compared with placebo.

Cabergoline

Efficacy. The limited amount of evidence suggests that the use of cabergoline was associated with numerically or statistically significantly improved mean scores of IIEF “EF” domain and IIEF-Q3/Q4 compared with placebo. Additional evidence from trials using different doses is needed to corroborate or disprove these findings.

Harms. In general, treatment with cabergoline was well tolerated. Nevertheless, there were higher frequencies of adverse events and withdrawals due to adverse events in the active treatment groups than in the placebo groups.

Pentoxifylline

Efficacy. The results of the trials were inconsistent, one³⁴⁰ indicated statistically significant improvements in peak systolic velocity; and the other trial³⁴³ yielded no difference in the frequency of morning erections, nocturnal penile tumescence, or penile rigidity in patients receiving pentoxifylline compared with those on placebo. Another trial³⁴⁵ demonstrated an increased number of successful coital episodes for the active treatment group of patients. However no formal statistical test results were presented to substantiate the findings. Given the above-mentioned limitations, more evidence is needed to draw more definitive conclusions regarding the relative efficacy of pentoxifylline.

Harms. No harms data were reported for two trials.^{343, 345} Some of the reported treatment-related adverse events in one trial³⁴⁰were nausea and headache. The harms profile of pentoxifylline in treating ED remains unclear.

Miscellaneous Agents

Efficacy. Overall, the limited amount of evidence suggested that naltrexone, tianeptine, tetrahydrobiopterin, and dehydroepiandrosterone may be more efficacious than placebo in improving early morning erections, proportion of patients with successful intercourse attempts, duration of rigidity (>60 percent), and mean total IIEF domain-specific scores, respectively.^{342,348, 352, 353} The evidence regarding the efficacy of moclobemide, isoxsuprine, angiotensin-converting enzyme (ACE), and myoinositol/folic acid was less conclusive.^{334, 335, 346, 351} The degree of erectile response was not statistically significantly different for isoxsuprine or ACE relative to placebo.^{335, 346} Although moxonidine was shown to be more effective in increasing deep penile diameter and artery velocities compared with metoprolol, this result may have been biased because this trial did not employ double blind techniques to adequately mask the treatment modality.³⁴⁷ More trials using a double-blind design are needed to corroborate these findings.

Harms. The limited amount of evidence suggested that the number of patients with adverse events was greater in the treatment groups than in the placebo groups. No definitive conclusions can be made at this time.