Sildenafil: what it is, how it works and what the evidence says

Few medicines carry so much fame and so little real understanding as sildenafil. People talk about it as if it were a switch: you take it and something happens. The pharmacology is rather more elegant and rather less magical: sildenafil does not create an erection, it stops the chemical signal that sustains one from breaking down too soon. Without sexual stimulation there is no signal to sustain, and therefore no effect. That nuance explains nearly everything else: why it works in some cases and not others, why it is not an aphrodisiac and why it does not resolve the cause of erectile dysfunction. In Spain it is a prescription-only medicine. We are not going to tell you what to take or how much: we are going to tell you what is known.

What sildenafil actually is

Sildenafil is a selective and potent inhibitor of phosphodiesterase type 5, an enzyme found in abundance in the smooth muscle of the corpus cavernosum of the penis. To understand what it does, you first need to understand how an erection works chemically.

In response to sexual stimulation, the nerve endings and the endothelium release nitric oxide. That nitric oxide triggers the production of cyclic GMP (cGMP), a messenger molecule that relaxes the smooth muscle of the penile arteries and the corpora cavernosa. As they relax, blood flows in, the corpora cavernosa fill and compress venous drainage: that is an erection. PDE5 is the enzyme responsible for breaking down that cGMP and returning the tissue to its resting state.

Sildenafil blocks PDE5. In other words, it switches nothing on: it allows the cGMP that has already been produced to last longer and act more strongly. That is why the Summary of Product Characteristics is explicit about something many people do not know: sexual stimulation is needed for there to be any effect. If no nitric oxide is released, there is no cGMP to protect, and the drug does nothing. It amplifies an existing signal, it does not generate one.

The selectivity is not absolute, and that is where the effects people notice come from. Relative inhibition of PDE6, present in the retina, explains the transient visual disturbances that some people describe as a bluish tinge to their vision, chromatopsia or photophobia. Inhibition of PDE1 explains facial flushing. These effects are consistent with the mechanism, not surprises.

And one point worth holding on to: sildenafil is a symptomatic treatment, not a cure. It acts while it is present in the body and does not change the underlying cause of erectile dysfunction.

What it showed in the trials

The pivotal trial in erectile dysfunction was published in the New England Journal of Medicine in 1998, by Goldstein and the Sildenafil Study Group. It is worth looking at exactly what was measured, because that is the key to interpreting the result.

The primary endpoints were questions 3 and 4 of the International Index of Erectile Function (IIEF): how often the patient achieved penetration and how often he maintained the erection through to completion of intercourse. Added to that was the global efficacy question, in which the patient simply answers whether the treatment has improved his erections. In other words, no laboratory variable or blood flow parameter was measured: what was measured was whether sex worked, according to the patient himself.

The result was a success rate in intercourse attempts far higher than with placebo. The placebo effect in erectile dysfunction is far from negligible, which is why a design with a control arm matters so much: a good part of what is attributed to any product for erections is explained by expectation, and here the difference against placebo was clear.

That said, efficacy is not uniform across all populations. The response tends to be lower in settings such as diabetes or after radical prostatectomy, where the vascular or nerve damage runs deeper. There are specific Cochrane reviews on PDE5 inhibitors in erectile dysfunction associated with diabetes for precisely that reason: it is a population that behaves differently.

Sildenafil compared with the other PDE5 inhibitors

It is the most frequently asked question and the answer is less exciting than people expect. The European Association of Urology guidelines on sexual and reproductive health are clear: there is no solid evidence that any one PDE5 inhibitor is superior in efficacy to another. The choice is based on duration of action, tolerability and patient preference.

Several are marketed in Spain. Sildenafil, as Viagra (Pfizer) and numerous EFG generics in 25, 50 and 100 mg presentations. Tadalafil (Cialis and generics), whose most relevant difference is a long half-life of around 17.5 hours, which allows a daily 2.5 to 5 mg regimen as well as on-demand use. Vardenafil (Levitra). And avanafil (Spedra), authorised by the EMA in 2013. It is worth noting that the marketing status of specific presentations changes over time and some presentations are suspended: the current information is available in the AEMPS CIMA database.

All of them are prescription-only medicines in Spain. Which one fits a particular case, and whether any of them does, is an individual clinical judgement that depends on the person's medical conditions, their medication and their preferences: not something to be decided by reading an article.

The other indication: pulmonary arterial hypertension

Many people are surprised to discover that the same active ingredient is sold under a different brand, at a different dose and for a different purpose. Sildenafil is authorised for pulmonary arterial hypertension at a dose of 20 mg three times a day, marketed as Revatio and generics. The logic is the same: PDE5 is also present in the pulmonary vasculature, and inhibiting it produces vasodilation in that territory.

The pivotal trial in this indication was SUPER-1, published by Galiè and colleagues in the New England Journal of Medicine in 2005, which showed an improvement in the distance covered in the 6-minute walk test, a standard functional measure in this disease. There is also a landmark Cochrane systematic review on PDE5 inhibitors in pulmonary hypertension (Barnes H et al., 2019).

The fact that it is the same drug does not mean the two are interchangeable: the doses, regimens and clinical contexts are different, with specialist follow-up in the case of pulmonary hypertension.

Contraindications and precautions: the part you cannot skip

This is where the information really matters, because there is one combination that can be serious.

The absolute contraindication is use with nitrates or nitric oxide donors in any form. That includes the nitroglycerin taken by people with angina and also poppers (amyl nitrite), used recreationally. The reason is mechanical: if the nitrate supplies nitric oxide and sildenafil prevents the resulting cGMP from being broken down, the vasodilation adds up and severe hypotension can follow. It is also contraindicated with riociguat.

The Summary of Product Characteristics also sets out other situations to bear in mind:

• Caution with alpha-blockers, because of the risk of orthostatic hypotension.
• Not recommended after a recent myocardial infarction or stroke.
• Not recommended in hypotension, with readings below 90/50 mmHg.
• Not recommended in severe hepatic impairment.
• Not recommended in hereditary degenerative retinal disorders, such as retinitis pigmentosa.

As for adverse effects, the common ones are headache, facial flushing, dyspepsia, nasal congestion and visual disturbances. The patient information leaflet also lists rare but relevant effects: NAION (non-arteritic anterior ischaemic optic neuropathy), sudden hearing loss and priapism. On that last one it is worth being specific: an erection lasting more than 4 hours is a medical emergency and needs immediate attention.

One relevant note outside the male indication: the Dutch arm of the STRIDER trial, which was studying sildenafil in pregnant women for fetal growth restriction, was stopped early in 2018 because of an excess of pulmonary hypertension in the newborns. It is a good reminder that a mechanism that works in one context can be harmful in another.

Myths worth dismantling

Sildenafil drags a considerable mythology behind it. It is worth separating what is known from what gets repeated.

It is not an aphrodisiac

It does not act on libido. It does not increase desire, it does not create arousal and it does not produce an automatic erection in the absence of sexual stimulation. That follows directly from its mechanism: with no nitric oxide released, there is nothing to amplify. When the main problem is lack of desire rather than the erection, the clinical approach is different, and in men it is worth exploring causes such as hypogonadism; you can read about the real symptoms of low testosterone and when to worry.

It does not change anatomy or resolve the cause

It does not change the size or structure of the penis, and it does not correct the underlying erectile dysfunction: it is a symptomatic treatment, used on demand in its classic indication. Once you stop taking it, the underlying situation is exactly as it was.

It does not cause blindness

The associated visual disturbances are transient and are explained by relative inhibition of retinal PDE6. NAION appears in the patient information leaflet as a rare effect, but causality has not been established.

It does not cause physical addiction

No physical dependence has been described. Psychological dependence can develop, in the sense that someone may come to feel incapable of having sex without the drug, particularly where there is an element of performance anxiety. That is a different phenomenon and it is dealt with differently.

There is no evidence that it improves performance in people without erectile dysfunction

The authorised indication is erectile dysfunction (and pulmonary arterial hypertension in the case of Revatio). Using it to improve sexual performance in men without erectile dysfunction is neither authorised nor supported by evidence.

The Alzheimer's and melanoma stories

On the hypothesis that sildenafil might prevent Alzheimer's: there have been signals from observational studies since 2021, with no clinical trial to confirm it. It is a hypothesis, not a finding. On melanoma: the signal comes from observational studies and has been attributed to confounding factors; causality has not been established. In both cases, the honest answer is that we do not know.

What erectile dysfunction says about your health

This is probably the most important message in the article and the one that gets least airtime. Erectile dysfunction is considered an early marker of cardiovascular disease, with an estimated window of between 2 and 5 years before coronary events according to the Princeton III consensus recommendations (Nehra A et al., Mayo Clinic Proceedings, 2012) and the EAU guideline.

The reason is anatomical: the penile arteries have a smaller calibre than the coronary arteries, so diffuse endothelial deterioration produces symptoms there before it does in the heart. Vasculogenic causes are the most common in men over 40, and they appear in association with diabetes, hypertension, dyslipidaemia, smoking, obesity, metabolic syndrome and hypogonadism. Medications also play a part (antihypertensives, SSRIs, antiandrogens), as do pelvic surgery and radical prostatectomy, and the psychogenic component, which rarely acts alone.

The practical consequence is that treating the erection alone and not looking at the rest is a missed opportunity. Many of those associated conditions can be tackled and are picked up with blood tests and a decent history: for example, the disturbance in glucose metabolism that precedes diabetes, which we explain in our guide to what prediabetes is and how it is managed, or obstructive sleep apnoea and how it is managed, which frequently overlaps with metabolic syndrome.

How things stand in Spain

In Spain sildenafil is a prescription-only medicine and is not dispensed without a prescription. That marks a difference with the United Kingdom, where since 2018 there has been a sildenafil 50 mg presentation reclassified by the MHRA for pharmacy sale without a prescription. It is a fact that causes confusion, because the idea circulates that in Europe you can buy it freely: here you cannot.

Medicines for erectile dysfunction are excluded from National Health System funding, so the cost is borne entirely by the patient. Nor is there any sildenafil approved in Spain for female sexual dysfunction, despite what some products advertised online suggest.

That gap between demand and prescription is exactly the territory of illegal and counterfeit products, about which the AEMPS issues alerts regularly. Buying without a prescription a drug with absolute contraindications such as the one involving nitrates is not just skipping a formality: it means doing without the one person who could have checked whether that combination affects you.

In summary

Sildenafil is a well-characterised drug, with an understandable mechanism and efficacy demonstrated against placebo since 1998, but also with contraindications that allow no shortcuts and with an implication almost nobody draws: erectile dysfunction is usually the visible sign of something vascular or metabolic that has been there for some time. Treating the symptom without looking deeper is doing half the job. Part of that deeper picture may be hormonal: when a lack of desire or difficulty with erections goes hand in hand with hypogonadism, what does exist in Spain today is male hormonal health treatment, with a prior assessment, a prescription from a registered doctor when appropriate and ongoing follow-up. If you suspect this is your case, you can check whether you are eligible.