Ian Eardley, Department of Urology, St James University Hospital, Beckett Street, Leeds, West Yorkshire LS9 7TF, UK, Tel.: +44 113206 6994
Aims To determine the onset and duration of action of sildenafil in patients with erectile dysfunction (ED).
Methods Two randomised, double-blind, placebo-controlled, two-way crossover studies were conducted in men with ED of no known organic cause. Study I: The time to onset of erections after sildenafil (50 mg) or placebo dosing following visual sexual stimulation (VSS) was assessed in 17 patients. Patients not achieving >60% penile rigidity by 70 min postdose as measured by a RigiScan® monitoring device were assigned an onset time of 70 min. Study II: The duration of grade 3 (hard enough for penetration) and grade 4 (fully hard) erections, determined by self-assessment during 60 min of VSS starting 2 and 4 h after sildenafil (100 mg) or placebo dosing, was measured in 16 patients.
Results Study I: The median time (range) to onset of erections was 27 min (in a range of 12–70) after receiving sildenafil 50 mg. In the sildenafil group, 71% of patients experienced onset of erections within 30 min of dosing, and 82% responded within 45 min. Of the patients who achieved >60% penile rigidity after sildenafil, 86% had done so by 30 min after dosing. Study II: When VSS began 2 h postdose, the median duration of grade 3 or 4 erections was 19.5 min (0–55) for sildenafil vs 0 min (0–23) for placebo. When VSS began 4 h postdose, the median duration was 5 min (0–45) for sildenafil compared with 0 min for placebo (0–27).
Conclusions Sildenafil is an effective oral treatment for ED that produces a penetrative erection as early as 12 min and for most patients, within 30 min after dosing, and a duration of action lasting at least 4 h.
The ability to achieve penile erection is dependent on several factors, including relaxation of corpus cavernosal smooth muscle, increased vascular blood inflow and restricted venous outflow in the penis . The physiological mechanism is mediated via a nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) pathway [2–4]. During stimulation, nonadrenergic-noncholinergic neurones and vascular endothelial cells release NO, which activates guanylate cyclase, thereby increasing the level of cGMP in the corpus cavernosum .
Sildenafil citrate (Viagra®, Pfizer) is a selective inhibitor of cGMP-specific phosphodiesterase type 5 (PDE5), a PDE isozyme found in high concentration within the corpus cavernosum . By inhibiting the breakdown of cGMP, sildenafil enhances the natural NO-cGMP mechanism of penile erection following sexual stimulation. Clinical studies have demonstrated that for men with erectile dysfunction (ED) of organic, psychogenic and mixed organic/psychogenic aetiologies, sildenafil is associated with significant improvement in the ability to achieve and maintain erections [5–11].
Pharmacokinetic studies have supported the suitability of single oral doses of sildenafil for an as-needed and on-demand treatment for ED. In healthy volunteers, sildenafil doses are absorbed rapidly, with maximum plasma concentrations achieved within a median time of 1 h (range, 0.5–2 h) after dosing . The terminal half-life of sildenafil is 3–5 h; therefore, the drug's therapeutic response is expected to be sustained for at least 3 h following a dose of 100 mg. The two studies reported here were conducted to determine the time to onset (Study I) and duration of penile erection of sufficient rigidity for penetrative sexual intercourse (Study I and II), and duration of action (Study II) following a single oral dose of sildenafil in patients with ED. Patients with ED of no known organic cause were chosen because they represent a significant portion of patients with ED, and they exhibit high response rates to treatment.
Patients aged 35–70 years with a clinical diagnosis of ED of no known organic cause (as evidenced by the presence of nocturnal erections, erections of penetrative rigidity under any circumstance or a positive response to an intracavernosal prostaglandin E1 dose of ≤ 20 µg or a papaverine dose of ≤ 40 mg) of at least 6 months' duration were included in the studies. Major exclusion criteria included a history of serious medical conditions (diabetes or untreated hypogonadism, significant arterial disease, migraine headaches and alcohol or substance abuse) or current treatment with nitrates, antidepressants, tranquillisers or anticoagulants. Other therapies for ED (e.g. intracavernosal injections) had to be discontinued 2 weeks before the start of the study. Before enrolment, patients underwent a physical examination, a 12-lead electrocardiogram and standard laboratory tests. They were also required to provide written informed consent.
Both studies used a randomized, double-blind, placebo-controlled, two-way crossover design. In the first study, fasted patients received a single oral 50-mg dose of sildenafil, the recommended therapeutic starting dose, or matching placebo, followed by a 7-day washout period, after which they received a single dose of the alternate study drug. Visual sexual stimulation (VSS) began 10 min after dosing with study medication and lasted for 60 min. For VSS, subjects were given a free choice from a selection of sexually explicit magazines and videos and were to view similar materials on each occasion. To ensure immediate sexual stimulation, videos were to be set by the investigator to start with a sexually explicit scene. Penile rigidity at the base of the penis was measured using the RigiScan® monitoring device (Dacomed Corporation) , and data were recorded continuously from 15 min before dosing to 70 min after dosing. Rigidity measurements made using the RigiScan® were shown to be reproducible over a 3-night span in healthy volunteers .
In the second study, fasted patients received four treatments and underwent four assessments. The study consisted of two parts; each part was divided into two treatment periods in which the patients received a single oral 100-mg dose of sildenafil, the maximum recommended therapeutic dose, or placebo. VSS, which lasted for 60 min, commenced 2 h after dosing with study drug during the treatment periods in part one and 4 h after dosing with study drug during the treatment periods in part two.
Patients who had either at least one erection with >60% rigidity or a grade 3 or 4 erection were defined as responders. The time to onset of erections with >60% rigidity (considered hard enough for penetrative sexual intercourse) at the base of the penis was calculated from the RigiScan® data . The patients were asked to record all erections during VSS and to grade the degree of hardness on a scale of 1–4: grade 1=an increase in penis size but not hardness; grade 2=hard but not hard enough for penetration; grade 3=hard enough for penetration but not completely hard; grade 4=completely hard. Patients in Study I who did not achieve an erection with >60% rigidity at the base of the penis at 70 min after dosing were assigned a default onset time of 70 min and a default value of 0 for duration of erection in the calculation of means and medians of these parameters. The total duration of erections recorded during RigiScan® monitoring or from the patients' self-assessments during 60 min of VSS was determined in both studies.
Median values for assessments of time to onset and duration of erections were calculated. Means were also calculated for those assessments in which data were normally distributed. Patients' self-assessments of total mean durations of grade 3 and 4 erections were analysed using an analysis of variance (anova) model appropriate for a two-treatment, two-period crossover design (Study I). The duration of grade 3 or 4 erections (Study 2) was analysed using an anova model, with terms for sequence, patient, period and treatment. The proportion of responders was calculated for the sildenafil and placebo treatment groups and was analysed (Study II) using the Mainland-Gart test for treatment effect.
A total of 17 patients entered Study I. The mean age was 52 years (range 37–70 years), and the mean duration of ED was 3.1 years (range 0.5–19.0 years) for the patients in Study I. Of these 17 patients, three had a vasectomy, one had a unilateral orchidectomy, one had prostatitis and one had varicosities. Seven patients had received previous treatments for ED: four received prostaglandin, two yohimbine and one an investigational drug. One patient in Study I discontinued the study after completing treatment and was lost to follow-up.
Sixteen patients, none of whom had participated in Study I, entered Study II. The mean age was 57 years (range 35–68 years), and the mean duration of ED was 1.9 years (range 0.3–8.0 years) for the patients in Study II. Of the 16 patients, seven had a vasectomy, one had an undescended right testicle, one had redundant prepuce, one had a scrotal cyst and one had hyperplasia of the prostate. None of the patients had received previous treatment for ED. Due to malfunction in the RigiScan® equipment while downloading penile plethysmography data, the 2-h post placebo dosing data for one patient in Study II was not available for assessment of efficacy.
Onset and duration of action—Study I
The onset of all erections occurred only after the start of VSS. The proportion of responders (patients with >60% penile rigidity) was 82% (14 of 17 patients) after sildenafil treatment and 53% (9 of 17 patients) after placebo treatment. Eight of 17 patients (47%) responded to both sildenafil and placebo. A grade 3 or 4 erection was reported by 12 of 17 (71%) patients receiving sildenafil compared with 6 of 17 (35%) patients receiving placebo.
The overall median time to onset of erections with >60% rigidity for the 17 patients was 27 min (range 12–70 min) after receiving sildenafil (50 mg) and 50 min (range 15–70 min) after receiving placebo (Figure 1). Analysis of data from the sildenafil-treated patients showed that the onset of erection occurred within 30 min postdose in 12 patients (71%) and between 31 and 44 min in two patients (12%); three patients (18%) did not achieve an erection with >60% rigidity within 70 min of dosing. Of the 14 patients who responded to sildenafil, 12 (86%) achieved an erection with >60% penile rigidity within 30 min postdose, and the other two responders did so by 37 min postdose. In comparison, for the group of placebo-treated patients, the onset of erection occurred within 30 min postdose in seven patients (41%), between 31 and 44 min in one patient (6%) and between 45 and 70 min in one patient (6%); eight patients (47%) did not respond to treatment. Of the nine placebo responders, seven (78%) responded within 30 min postdose, one (6%) within 31–44 min postdose and one (6%) within 45–70 min postdose.
Sildenafil also significantly increased the duration of erections with >60% penile rigidity, compared with placebo. The anova showed a statistically significant treatment effect (P=0.006) and the ratio of geometric means (sildenafil : placebo) was 3.74 (95% confidence interval: 1.57, 8.94), suggesting that sildenafil increased the duration of rigidity by three- to fourfold, compared with placebo. The median total duration of erections with >60% rigidity, as determined by RigiScan® monitoring during the 70 min after dosing, was 8.5 min (range 0–48 min) for the sildenafil recipients, compared with 0 min (range 0–16 min) for the placebo recipients. Among the 14 sildenafil responders, the median duration of erections was 11.8 min (range 0.5–47.5 min). Among the nine placebo responders, the median duration of erections was 7.5 min (range 1.0–16.0 min).
Results of the patients' self-assessments of the median duration of grade 3 or 4 erections were similar to those derived from the RigiScan® data. Among all patients treated with sildenafil, the median duration of grade 3 or 4 erections was 10.0 min (range 0–60 min) and the adjusted mean was 15.8 min, compared with a median of 0 min (range 0–20 min) and an adjusted mean of 2.4 min for patients treated with placebo (anova, P<0.001 for treatment effect).
Duration of action—Study II
Treatment with a single 100-mg dose of sildenafil was associated with significantly greater mean duration of grade 3 or 4 erections compared with single-dose placebo treatment regardless of whether VSS commenced 2 (anova, P<0.001) or 4 h (anova, P<0.01) after dosing. The median and mean durations of grade 3 or 4 erections for the treatment groups as a whole and for the responder subsets are shown in Figure 2.
When VSS commenced 2 h after dosing, the median total duration of grade 3 or 4 erections for patients receiving sildenafil was 19.5 min (range 0–55 min), and the mean duration (±s.e. mean) was 19.4±4.1 min. In contrast, the median duration for patients receiving placebo was 0 min (range 0–23 min), and the mean duration was 3.9±2.1 min (P<0.001; Figure 2a, c). The proportion of treatment responders was 75% (12 patients) for those receiving sildenafil and 31% (five patients) for those receiving placebo (P<0.05). Among the sildenafil responders, the median total duration of grade 3 or 4 erections was 24.0 min (range 0–55 min), and the mean was 23.8±4.2 min, whereas the median duration for placebo responders was 0 min (range 0–23 min), and the mean was 4.8±2.5 min (P<0.001).
When VSS commenced 4 h after dosing, the median total duration of grade 3 or 4 erections in patients receiving sildenafil was 5.0 min (range 0–45 min), and the overall mean was 13.9±4.0 min, whereas in patients receiving placebo, the median total duration was 0 min (range 0–27 min), and the mean was 2.9±1.9 min (P<0.01; Figure 2b, 2d). The proportion of treatment responders was significantly greater among patients receiving sildenafil (13 of 16 patients, 81%) compared with patients receiving placebo (five of 16 patients, 31%; P<0.05). For the sildenafil responders, the median total duration of grade 3 or 4 erections was 10 min (range 2–45 min), and the mean was 17.2±4 min. For the placebo responders, the median total duration of grade 3 or 4 erections was 0 min (range 0–27 min) and the mean was 3.6±2 min (P<0.01).
Desirable characteristics of an oral treatment for ED include pharmacokinetic properties that allow a prompt onset of clinical effect and several hours of clinical activity after administration of a single dose, in addition to reliable efficacy and a favourable safety profile at recommended doses. The results of the present studies demonstrate that in men with ED of no known organic cause, treatment with 50- or 100-mg oral doses of sildenafil facilitated the achievement of erections in the presence of VSS that were rigid enough for penetrative sexual intercourse. Furthermore, the onset of action was achieved within a median time of 27 min after sildenafil dosing. Such erections were achieved as quickly as 12 min and, for most patients (71%), within 30 min. This finding reflects the time to peak plasma concentration of sildenafil after oral dosing (30–120 min)  and is consistent with the results of other clinical trials [5–11].
Erections also were achieved when VSS was delayed for 2 or 4 h after patients received 100-mg doses of sildenafil. Patients were able to maintain erections for a mean duration of 19 min (2 h after dosing) and 14 min (4 h after dosing). These data suggest that sufficient sildenafil remains systemically available to allow for adequate erections 4 h postdose and are consistent with a sildenafil half-life of 3–5 h . This is an appropriate period of therapeutic activity that is realistic and convenient for most couples.
In Study I, more than one-half (53%, 9/17) of the study patients responded (>60% penile rigidity) to placebo. Furthermore, among the nine patients who responded to placebo, seven (78%) did so within 30 min after dosing, similar to the proportion of sildenafil responders (86%, 12/14) who responded during the same time interval. In addition, a high percentage of patients responded to both sildenafil and placebo in Study I (47%) and in the first part of Study II when VSS started 2 h after dosing (42%). These findings suggest that a large proportion of the patients enrolled in these two studies appeared to have had a significant psychogenic component to their ED. In clinical practice, it would be worthwhile to perform nocturnal penile tumescence and rigidity testing  in patients presenting with ED of no organic cause and a history suggestive of psychogenic causes. An objective evaluation of psychogenic factors leading to ED may serve to direct the patient to the appropriate therapy, such as psychological treatment with or without pharmacological treatment.
Although this report supplies specific and detailed information related to the onset and duration of action of sildenafil, several limitations are inherent in the study design. The use of 60 min of continuous VSS may have confounded the results as, on its own, prolonged continuous VSS may produce some effects. Without suitable controls, the contribution of this variable to treatment outcome is not known. Even though the number of patients is small, reasonable means and medians were generated. Although direct comparisons between the two different sildenafil doses from the two studies are not possible, we felt it was important to investigate the onset of the recommended starting dose (50 mg) and the duration of the recommended highest dose (100 mg) . The lowest recommended dose of sildenafil (25 mg) is generally reserved for special populations (e.g. elderly or those with hepatic or renal impairment) or those patients who experience side-effects at a higher dose .
Thus, the findings presented have great relevance to clinical practice and suggest that the majority of patients with ED of no known organic cause can expect to have erections rigid enough for penetrative sexual intercourse within 30 min and as late as 4 h after taking sildenafil. In conclusion, oral sildenafil at recommended doses has a rapid onset of action and is effective for several hours after dosing, allowing couples to engage in sexual activity within a natural time frame.