Sildenafil: two decades of benefits or risks?

Abstract

Sildenafil is a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE-5). A patent was registered for this drug in 1990, which expired in 2010. Since expiration, the drug has been marketed under various trade names or as generic drugs. Numerous clinical trials have been conducted addressing the effectiveness of the drug for erectile dysfunction (ED) and its safety regarding the presence or absence of specific comorbidities. After over 20 years in the market, we need to ask: has the scientific community reached a general consensus as to the overall efficacy and safety of the drug? Can we firmly state that the benefits of the drug outweigh its risks? This review suggests that sildenafil is an effective and easily manageable treatment for erectile dysfunction, both in the absence and in the presence of comorbidities. After two decades of the emergence of sildenafil as a drug of choice for the treatment of ED (and the numerous studies and clinical trials undertaken during this time span), it is now possible to state that the benefits of the drug do outweigh the risks, and represent an significant improvement in the quality of life in men with ED.

• Adverse events
• efficacy
• erectile dysfunction
• safety
• sildenafil

Introduction

Erectile dysfunction (ED) is defined as the inability to achieve or maintain an sufficient erection for satisfactory sexual performance [1]. ED is experienced at least once by the majority of men who reach the age of 45 years old, and projections for 2025 show a prevalence of 322 million with ED. The largest projected increases are for the developing world, i.e. Africa, Asia and South America [2]. In these regions prevalence of ED is high in men of all ages and increases markedly in the elderly. Studies have demonstrated that ED may be the first expression of endothelial damage in men with vascular risk factors, and ED has been associated with the appearance of hypertension, dyslipidemia and atherosclerosis [3].

In 1989, researchers of the pharmaceutical company Pfizer, aiming to treat patients with angina, synthesized a molecule, later named sildenafil. In 1991, they started clinical trials with the drug in healthy individuals and in patients with cardiovascular disorders. Clinical results of efficacy in patients with angina were clearly weak. However, some subjects reported the occurrence of erection as an adverse event. The studies then changed their focus, with investigations turning to assessing the use of sildenafil in ED management. In 1998, the Food and Drug Administration (FDA) approved sildenafil for ED treatment [4]. The discovery of the molecule, which became widely known by its brand name (Viagra®), was a milestone in the pharmaceutical industry and, since its launch, other new substances such as vardenafil and tadalafil have been added to ED management [5].

The resulting exponential increased access to and use of this drug after patent expiration (as generic drugs or under various brands) call for a critical analysis of the numerous studies on the effectiveness and safety of sildenafil in the presence or absence of associated comorbidities. In this sense, we conducted a systematic literature review in an attempt to answer emerging questions such increases pose: what would a closer inspection of the overall cost-benefit of using sildenafil for ED reveal in these two decades of existence? Do the risks outweigh the benefits or do the benefits outweigh the risks?

Methods

We evaluated clinical trials correlating the efficacy and safety of sildenafil in ED treatment in men using PUBMED as our database. The key words used in the search were: sildenafil, erectile dysfunction, efficacy, safety and adverse events. The search was limited to clinical trials in humans, written in English, from full texts available in the database. The collected articles are from 1990 to 2013. All texts included in the review were assessed and compiled.

Results and discussion

Erectile dysfunction

Sexual stimulation triggers the release of nitric oxide in the cavernous smooth muscle of the penis. Nitric oxide is then released, which in turn activates the guanylyl cyclase enzyme, which induces an increase in cyclic guanosine monophosphate (cGMP) levels. cGMP produces a relaxation of the cavernous smooth muscle, allowing the blood to flow into the penis, keeping it erect. Once the stimulus is stopped, or after ejaculation, a 5-hydrolase phosphodiesterase (PDE-5) is released, reducing the levels of cGMP and the blood flow in the corpus cavernosum [4].

Early release of PDE-5, and consequently ED, has been attributed to psychogenic, endocrine, neurological or vascular cause factors. Vascular etiology is the most common one and can be triggered by oxidative stress deriving from a number of contributors to endothelial dysfunction, such as hypertension, diabetes, dyslipidemia, tobacco and obesity, as summarized in Figure 1. An imbalance in the release of vasodilator substances in the cavernous bodies endothelium is then produced, along with a reduction in nitric oxide bioavailability [6] (Figure 1).

Figure 1. Causes of erectile dysfunction (adapted from Guay [6]).

Treatment of erectile dysfunction

Earlier treatments included vacuum constriction devices, intracavernous self-injections of vasoactive agents (alprostadil, prostaglandin E1) [7] and transurethral insertion of alprostadil [8], in addition to the deployment of penile prostheses or venous/arterial surgery, all of which were widely used in the management of ED. Currently, the treatment is carried out using PDE-5 inhibitors. The main drugs of this category are sildenafil, vardenafil and tadalafil.

Sildenafil, vardenafil and tadalafil are indicated for oral treatment of ED, but are contraindicated in patients using organic nitrates, since nitrates have a hypotensive effect, which is potentiated by the use of PDE-5 inhibitors. Additionally, vardenafil is not recommended for patients taking type 1 A (such as quinidine or procainamide) or type 3 antiarrhythmics (such as sotalol or amiodarone) [9].

These PDE-5 inhibitors differ in onset of action, with vardenafil being the fastest (26 min) [11] followed by sildenafil (27 min) [10] and the slower tadalafil (45 min) [12]. The duration of action is also different: 4 h for sildenafil [10], 10 h for vardenafil [13], and 36 h for tadalafil [14].

In response to sexual stimuli, nonadrenergic, noncholinergic nerves and endothelial cells of the arterioles in the penis release nitric oxide, which induces smooth muscle relaxation via stimulation of guanylate cyclase and the production of cGMP. Subsequently, cGMP is hydrolyzed by cGMP-especific enzyme, the predominant isoenzyme in the corpus cavernosum. An increase in cGMP resulting from inhibition of PDE-5 by sildenafil causes a reduction in intracellular calcium that leads to relaxation of the smooth cells [15]. The substance does not trigger a directly relaxing effect on the isolated corpus cavernous from humans, but potentially increases the relaxing effect of nitric oxide on this local, as observed in Figure 2. Therefore, sexual stimulation is required for sildenafil to produce its pharmacological effects [16] (Figure 2).

Figure 2. Action mechanism of sildenafil. eNOS – endothelial nitric oxide synthase; NO – nitric oxide; GTP – guanosine-5'-triphosphate; cGMP – cyclic guanosine monophosphate; GMP – guanosine monophosphate; PDE 5 – phosphodiesterase type 5; Ptn – protein; PKG – protein kinase G.

Efficacy of the oral use of sildenafil

In studies carried out in the context of absence of comorbidities, we observed that, for men with different ED etiologies, oral sildenafil administration was both effective in handling ED and well-tolerated by patients, presenting high rates of success, without any life–threatening adverse effects [15, 17–21]. The oral use of sildenafil has been effective and well-tolerated both for short- and long-term treatment, maintaining the desired action [22].

In a study with increasing doses (25, 50 or 100 mg) carried out with men over 18 years old, sildenafil was found to be safe, in addition to presenting beneficial effects across all erectile function and life quality indexes [23]. Moreover, in elderly subjects, sildenafil proved to be effective and well = tolerated even among those over 70 years old. The rate of improvement in the erectile function in young men, however, is higher than in elderly [24].

Several clinical trials, in different geographical regions, have indicated that sildenafil is an effective, well-tolerated treatment for ED in Egypt, South Africa [25], Colombia, Equator, Venezuela [26], Argentina [27], Singapore [28,29], Malaysia [29], Philippines [29] and Taiwan [30]. Similar results were found in Afro-Americans and Hispanic-Americans [31], Brazilians, Mexicans [32] and Koreans [33], indicating no difference in the profile of efficacy of sildenafil between Western or Eastern peoples. Sildenafil can also trigger significant improvement in self-esteem, trust, and satisfaction in the relationships of men with ED [34]. The level of satisfaction of sexual partners was also assessed in placebo-controlled studies, and compared with the patients’ assessment, and satisfaction levels of the partners and patients were found to be consistently higher than those in placebo group [20,35].

Cardiovascular diseases

ED has been frequently associated with the presence of cardiovascular diseases and risk factors, such as hypertension, congestive heart failure, dyslipidemia and stable coronary arterial disease [36–41]. In this sense, both sildenafil and vardenafil were effective for and well-tolerated by men with diabetes in ED treatment [40].

ED is frequent in men taking antihypertensive drugs for blood pressure control, and sildenafil was effective in the management of this disorder, without significant changes in blood pressure measurement [36–38]. In fact, a survey in Spain with hypertensive patients has shown that sildenafil has an outstanding response to ED treatment [39].

Congestive heart failure (CHF) is an increasingly common cardiovascular disease and the ED highly frequent among them (75%). Sildenafil has been shown to be effective and well-tolerated in the management of ED in men with mild to moderate CHF, and its use was not associated with additional risks for this population [41]. Sildenafil is well-tolerated in heart failure patients and it does not decrease blood pressure. It can be safely added to standard heart failure therapy [42].

Diabetes mellitus

Diabetes mellitus is an important risk factor for ED, and it is associated with an early onset of this disorder. In fact, Rendell et al. [43], Safarinejad [44] and Price et al. [45], in controlled placebo studies, have demonstrated that sildenafil is effective in the treatment of ED in diabetic patients. However, Safarinejad [44] has argued that sildenafil is less effective in diabetic patients than in individuals without comorbidities, but was well-tolerated with side effects being inexpressive and transient [46].

Spinal cord injury

Sildenafil has also been shown to be a safe and effective drug for patients with traumatic spinal cord injury, particularly for those with incomplete injury [47–50], despite the time of injury [51]. Patients’ acceptance and satisfaction with the use of sildenafil is high [52] as the drug brings significant remarkable improvement in orgasm and ejaculation [53]. In a study comparing the use of oral sildenafil, intracavernous injection and vacuum constriction devices, 90% of patients reported improved erections while using sildenafil, i.e., the use of oral medication was considered the most effective and widely accepted by the population in the study [54].

Sildenafil, vadernafil and tadalafil are all effective and well-tolerated in the treatment of ED in patients with spinal cord injury. It should be noted that therapeutic success is absent if there is a complete disorder of the neurogenic impulse transmission [52].

Obstructive sleep apnea

Obstructive sleep apnea has been associated with the ED [55]. While sildenafil has been found to be effective in the handling of this dysfunction, such efficiency is further increased when apnea is controlled with specific techniques, such as the application of continuous positive airway pressure (CPAP). Though both treatments are safe and well-tolerated, it should be stressed that dissatisfaction rates in the management of ED in these cases vary from 33 to 50%, indicating the need for new therapeutic agents and a more effective treatment of the disease [55,56].

Multiple sclerosis

Multiple sclerosis is an autoimmune disease which can affect youngsters and middle-aged adults, who have a high likelihood of presenting ED. The change in the erectile function may be due to the neurological dysfunction of the underlying disease, to psychological factors, or to an adverse event of the drugs used in the autoimmune disease treatment. A controlled-placebo study has found that sildenafil has little effect on the ED in patients with multiple sclerosis, and should not be recommended as a choice of treatment for ED in these patients [57]. However, a study carried out by Fowler [58] has demonstrated that sildenafil is effective and well-tolerated in men with multiple sclerosis and resulted in significant improvement in erection quality and in quality of life of MS patients. Further studies are therefore needed to clarify the efficacy of oral sildenafil in ED in patients with multiple sclerosis.

Prostate cancer

ED incidence is high in patients who undergo radical prostatectomy or who are referred to three-dimensional radiotherapy due to prostate cancer [59,60]. Sildenafil has proved to be a safe and satisfactory treatment to ED in both situations. The dose-dependent effect and the adverse events increased with the increase in the dose. The regular use of sildenafil during radiation treatment for prostate cancer may improve short-term sexual function for patients using the medication [59,60].

Depression

The use of selective serotonin reuptake inhibitor in depression treatment such as fluoxetine can initiate ED in patients during the use of medication. Fava et al. [61] have assessed sildenafil efficacy in such patients and found a significant improvement in erectile function and in sexual satisfaction in men with ED associated with the use of serotonin reuptake inhibitors. Since the study conducted by Fava et al. [61] is the only one addressing the issue in our database, further research should be undertaken to confirm these findings. Sildenafil may be a beneficial treatment for antidepressant-induced sexual dysfunction, but there was no significant improvement in the quality-of-life of the patients [62].

Parkinson’s disease

The increased prevalence of ED in patients with Parkinson’s disease indicates that the inability to achieve or keep an erection is indeed a problem affecting these patients. The use of sildenafil, orally, is effective and significantly improves the erectile function and the quality of their sexual life [63,64]. In a study undertaken by Raffaele [64], 25 out of 33 patients, i.e., 75%, presented a clear improvement in the depressive symptoms after their ED was addressed and treated with sildenafil. Another study, conducted by Hussain [63] has reported that 9 out of 10 patients with Parkinson’s disease reversed the course of ED with the use of sildenafil.

Renal dysfunction

ED is common in men with renal dysfunction, but it is not always improved after kidney transplant. Mahon et al. [65] have shown that sildenafil brings a substantial improvement of ED in patients in peritoneal dialysis, with a success rate, at least, as high as the ones reported in other groups of patients.

Interactions between immunosuppressive drugs were not reported, and there were no significant adverse effects of sildenafil on the transplant function [66]. Another study has also shown that sildenafil seems to be an efficient and safe ED treatment for patients with acute renal failure who need hemodialysis [67].

Traumatic stress

Combat-related post-traumatic stress disorder can initiate a psychogenic ED in returning veterans. A controlled placebo study with non-smoking, non-comorbid veterans found that sildenafil was not better than placebo in the erectile disorder treatment. Additional randomized clinical trials are needed to deepen our understanding of the role of the drug in the treatment of this disorder. The existing studies seem to indicate that sildenafil is not effective in the treatment of psychogenic ED associated with combat-related post-traumatic stress disorder. Further studies are required to offer affected veterans other alternatives for ED recovery [68].

Adverse events, contra-indication and risks resulting from the oral use of sildenafil

According to the Second Princeton Consensus Guidelines, sildenafil is contraindicated in patients taking organic nitrates (nitroglycerin, isosorbide dinitrate, isosorbide mononitrate, amyl nitrate or nitrate). The past use of nitrates (>2 weeks) is not considered a contraindication. Similar results were thereafter observed for tadalafil and vardenafil [9,69]. Vardenafil is also not recommended in patients taking type 1 A (such as quinidine or procainamide) or type 3 antiarrhythmics (such as sotalol or amiodarone) [9].

Recreational use of inhibitors of PDE-5 by young people has been reported in the literature and does not cover a significant portion of the youth population; however, there seems to be a correlation between risky sexual behavior and misuse of the substance, particularly among young people [70]. The concomitant use of sildenafil, tadalafil and vardenafil with illicit drugs, such as cocaine, methamphetamine, marijuana, MDMA, ectasy, alkyl nitrates (poppers) and ketamine in the young population is associated with risky sexual behaviors, increasing the exposure of such young people to sexually transmitted diseases as human immunodeficiency virus infection/acquired immunodeficiency syndrome [71].

Regardless of ED etiology, the adverse events most commonly reported in clinical trials for men, in general, were headaches [15,21,22,27,28,30–33,58], flushing [21,22,25,27,28,30–33], dyspepsia [15,21,22,25]), dizziness [28,30], changes in color vision [33], visual disturbance [28], insomnia [28], myalgia [28], backache [28] and pelvic musculoskeletal pain [15]. The adverse events reported in the clinical studies were mild and temporary.

In elderly patients, the most commonly reported adverse events were flushing and dyspepsia [24]. In studies which dealt with the presence of comorbidities, the main adverse events found in patients using antihypertensive drugs were facial redness [36,37], headache [36,37], dyspepsia [37], tachycardia, rhinitis [36], dizziness, dyspnea and nausea [36]. In patients with CHF, the most frequent symptoms were temporary headache, flushing, respiratory tract infection and asthenia, revealing a low incidence of effects related to cardiovascular events [41]. In men with stable coronary artery disease, the adverse events included temporary headache, hypertension, flushing and dyspepsia. There were no major cardiovascular effects related to the drug [72].

In clinical trials in patients with comorbidities coexisting with ED, headache was present in most of the studies assessed, with a mild and temporary character [44,45,52,55–57,60,61,63–65,67]. Manifestations of flushing affected diabetic patients [44,45], radical post-prostatectomy patients [60] and renal patients [67]. In a lower frequency, dyspnea, rhinitis, nasal congestion, muscular aches and cardiovascular effects occurred in diabetic patients [43–45]. In patients with ED due to spinal cord injury, dizziness was also reported by some patients as an adverse event of sildenafil [52].

Besides headache, the adverse events reported by the patients who used simultaneously sildenafil and serotonin reuptake inhibitors were dyspepsia, anxiety and abnormal vision [61]. The most frequent adverse events reported by post-prostatectomy patients were temporary headache, facial redness and dyspepsia. There were no reports of priapism, cardiovascular events or death [60].

Conclusion

The introduction of sildenafil enabled different groups of patients to have their erectile function restored. Among them, the elderly, diabetics, individuals who suffered from incomplete spinal cord injury, patients with Parkinson’s disease, or users of serotonin reuptake inhibitors patients with cardiovascular disorders, patients with obstructive sleep apnea, patients with renal disorders, post-prostatectomy patients or post-radiotherapy of prostate cancer.

Thus, this review suggests that sildenafil is an effective and well-controlled treatment for ED in patients, both in the absence and in the presence of comorbidities, and the most common adverse events reported in the clinical trials are headache, flushing and dyspepsia. However, it was observed that in ED treatment associated with diabetes mellitus, the efficacy of sildenafil is lower and the cardiovascular events are higher than those previously reported in non-diabetic patients. Moreover, although the ED management is efficient in men with obstructive sleep apnea, the rates of the patient dissatisfaction with the treatment were high.

After two decades of the emergence of sildenafil, we may state that the benefits of the drug outweigh the risks. Bearing in mind the contraindications of the drug, sildenafil does represent a breakthrough in the treatment of ED. This overall safe and effective substance has enabled men, who not long ago were doomed to impotence, to restore their sexual functioning and self-esteem, and improve their quality of life. However, the efficacy of sildenafil in the ED treatment in men with multiple sclerosis is still questionable and controversial, and additional clinical trials are needed to clarify the real efficacy of the drug in the management of ED in MS patients.

Declaration of interest

The authors declare that they not have conflict of interest.