When the Pills Don't Work: What's Really Going On

There's a question I get asked more often than you'd think, usually in that slightly awkward way where someone's trying to sound casual but you can tell they've been thinking about it for weeks: "What if it just... doesn't work?"

They're talking about sildenafil or tadalafil. They took the pill. Nothing happened. Or something happened, but not what they expected. And now they're wondering if it's them, if it's the medication, if they need a higher dose, a different drug, or if they should just give up entirely.

The answer is rarely simple. Because when these medications don't work - and sometimes they don't - it's usually not because the medication failed. It's because something else is going on. Something mechanical, hormonal, psychological, vascular, or neurological. Sometimes it's obvious. Sometimes it takes a while to figure out.

Why PDE5 Inhibitors Fail: The Physiology of Non-Response

Let me be clear about what sildenafil and tadalafil can and cannot do. They block phosphodiesterase-5 (PDE5), the enzyme that breaks down cyclic GMP - the chemical messenger that relaxes smooth muscle in the penis and allows blood to flow in. That's it. That's all they do.

They don't create arousal. They don't fix damaged blood vessels. They don't restore testosterone. They don't override nerve damage. They just make cyclic GMP last longer, which means if everything else in the erection cascade is working - arousal, nitric oxide release, intact blood vessels, functioning nerves - then the erection will be firmer and last longer.

But if something upstream is broken, blocking PDE5 won't help. You can't compensate for absent arousal, severely damaged arteries, or profound nerve dysfunction with a pill that only works at the very end of the process.

That's the first thing people misunderstand. These aren't magic pills. They're amplifiers. If the signal isn't there to begin with, there's nothing to amplify.

Vascular Disease: When the Pipes Are Blocked

The most common reason these medications fail is vascular disease. Erections depend on blood flow. If the arteries supplying the penis are narrowed or blocked - atherosclerosis, essentially the same process that causes heart attacks and strokes - then no amount of PDE5 inhibition will force blood through a vessel that's too narrow to carry it.

This is why erectile dysfunction is sometimes called the canary in the coal mine for cardiovascular disease. The penile arteries are smaller than the coronary arteries, so they tend to get blocked earlier. A man with erectile dysfunction that doesn't respond to treatment might have early atherosclerosis. It's not just about sex. It's about survival.

I've seen this play out more times than I can count. Someone comes in frustrated that tadalafil isn't working. We do a workup. Elevated cholesterol. High blood pressure they didn't know they had. Pre-diabetes. Sometimes we find significant coronary artery disease. The erectile dysfunction wasn't the problem. It was the warning sign.

If the arteries are severely narrowed, the medication won't work because there's simply not enough blood flow to generate an erection, no matter how long cyclic GMP stays active. In those cases, the treatment isn't a higher dose of sildenafil. It's lifestyle modification - diet, exercise, smoking cessation - and sometimes revascularisation procedures. You have to fix the pipes before the pump will work.

Hormonal Issues: When Testosterone Is Low

Testosterone doesn't directly cause erections, but it modulates sexual desire, arousal, and the responsiveness of the tissues involved. If testosterone is very low - hypogonadism - then even if the vascular system is intact, the drive to initiate the erection cascade is diminished.

PDE5 inhibitors don't fix low testosterone. They can't restore libido if it's hormonally suppressed. I've had people tell me they took tadalafil and got a decent erection, but they didn't care. No interest. No arousal. That's often a clue that we need to check testosterone levels.

Normal testosterone in men varies, but generally we're looking at levels above 10-12 nmol/L (roughly 300 ng/dL in US units). If it's significantly below that, and symptoms align - low libido, fatigue, mood changes - then addressing the testosterone deficiency first often makes PDE5 inhibitors more effective.

Testosterone replacement isn't something you do lightly. It has risks - cardiovascular effects, prostate considerations, effects on fertility - but when it's genuinely low and causing symptoms, replacing it can restore not just erectile function but quality of life more broadly.

Nerve Damage: When the Signals Don't Travel

Erections require intact nerve pathways. The signal from arousal travels down through the spinal cord and out to the penis via the cavernous nerves. If those nerves are damaged - diabetes, prostate surgery, spinal cord injury, multiple sclerosis - then the signal never arrives.

This is one of the hardest forms of erectile dysfunction to treat. PDE5 inhibitors work downstream of nerve function, so if the nerve signal isn't getting through, blocking PDE5 won't help much. Some people with nerve damage still get partial benefit, especially if the damage is incomplete. But if the nerves are fully severed or severely compromised, medications alone won't restore function.

Diabetic neuropathy is a classic example. Over time, high blood sugar damages small nerves throughout the body. The autonomic nerves that control erections are particularly vulnerable. Early on, PDE5 inhibitors might work. But as neuropathy progresses, they become less effective. The solution isn't a higher dose - it's better glucose control to prevent further nerve damage, and sometimes alternative treatments like intracavernosal injections or vacuum devices.

Prostate surgery is another. Even with nerve-sparing techniques, some degree of nerve trauma is almost inevitable. Recovery can take months to years. During that time, PDE5 inhibitors may help partially, but they won't fully restore function until the nerves regenerate - if they do.

Psychological Factors: When the Mind Gets in the Way

I don't think people realise how much psychology affects physiology. Arousal isn't just a light switch. It's a complex interplay between sensory input, emotional state, past experiences, expectations, and stress. If someone is anxious, depressed, distracted, or under enormous pressure, arousal doesn't happen easily.

PDE5 inhibitors don't fix anxiety. They don't reverse depression. They don't resolve relationship conflicts. What they do is make the mechanics more reliable once arousal does occur. But if arousal itself is blocked by psychological factors, the medication won't work.

I've seen this pattern repeatedly. Someone takes sildenafil. It doesn't work. They take a higher dose. Still nothing. They get more anxious, which makes it worse. The medication becomes part of the problem - a reminder of failure every time they take it.

In those cases, the solution often isn't more medication. It's addressing the underlying psychology. Sometimes that's therapy. Sometimes it's just time and reduced pressure. Sometimes it's recognising that the problem isn't physical at all.

There's a subset of people who respond beautifully to a low dose of a PDE5 inhibitor not because they have vascular disease, but because knowing the medication is on board reduces performance anxiety enough that arousal can happen naturally. The medication isn't really doing much mechanistically. It's a psychological safety net. And that's fine. If it works, it works.

Medication Interactions: When Other Drugs Interfere

Some medications interfere with erectile function directly. Antidepressants - particularly SSRIs - are notorious for this. They dampen sexual desire and delay orgasm, which makes arousal harder to achieve. Beta-blockers, used for high blood pressure and heart disease, can reduce erectile function by affecting blood flow and possibly by dampening sympathetic nervous system activity.

Antipsychotics, some antihistamines, finasteride (used for hair loss and prostate enlargement) - they all have sexual side effects in some people. If you're on one of those medications and a PDE5 inhibitor isn't working, it might be because the other drug is actively suppressing the processes the PDE5 inhibitor is trying to enhance.

This is where the conversation gets tricky. You can't always stop the other medication. If someone needs an SSRI for severe depression, stopping it to improve erectile function might not be a good trade-off. Sometimes you can switch to a different antidepressant with fewer sexual side effects - bupropion, mirtazapine - but sometimes you can't.

In those cases, you're managing expectations. The PDE5 inhibitor might help, but not fully. And that's okay. You work with what you have.

Dosing and Timing: When the Problem Is Technical

Sometimes the medication doesn't work because it wasn't taken correctly. Sildenafil should be taken on an empty stomach - or at least not after a heavy, high-fat meal, which delays absorption. If someone takes it right after eating a large dinner, it might not peak in time, or the peak might be blunted.

Tadalafil is more forgiving with food, but timing still matters. If someone takes it expecting immediate results, they'll be disappointed. Both drugs need time to work - 30 to 60 minutes for sildenafil, sometimes a bit longer for tadalafil.

And then there's dosing. Sildenafil comes in 25 mg, 50 mg, and 100 mg. Tadalafil in 2.5 mg, 5 mg, 10 mg, and 20 mg. Most people start at a mid-range dose - 50 mg for sildenafil, 10 mg for tadalafil. If that doesn't work, sometimes increasing the dose helps. But not always. If the underlying problem isn't dose-responsive, doubling the medication won't fix it.

There's also the question of what "doesn't work" means. Some people expect an erection that lasts hours. That's not realistic. Others expect an erection without any arousal at all. Also not realistic. Sometimes recalibrating expectations is part of the solution.

When to Investigate Further

If someone tries a PDE5 inhibitor at an appropriate dose, taken correctly, and it doesn't work after several attempts, that's a signal to dig deeper. Check testosterone. Check cardiovascular risk factors - cholesterol, blood pressure, glucose. Consider vascular imaging if there's concern about arterial insufficiency. Review medications for interactions. Screen for depression and anxiety.

Sometimes the answer is simple - adjust the dose, change the timing, switch from sildenafil to tadalafil or vice versa. Sometimes it's more complex - treat the underlying diabetes, start testosterone replacement, adjust antidepressants, refer for therapy.

And sometimes, honestly, the answer is that PDE5 inhibitors aren't the right tool for that person. There are alternatives - intracavernosal injections, vacuum devices, penile implants - but they're more invasive, more complicated, and not everyone wants to go there. That's a conversation that takes time.

What About Trying Both?

Some people ask if they can combine sildenafil and tadalafil, or switch between them rapidly. The answer is no - at least not without medical guidance. Both drugs work through the same mechanism, so combining them increases the risk of side effects (headaches, flushing, hypotension, priapism) without significantly improving efficacy.

Switching between them is fine if one doesn't work well and you want to try the other. But give each one a fair trial - several attempts at the correct dose, taken correctly - before deciding it's not effective.

There's also the question of daily tadalafil. Some men who don't respond well to on-demand dosing do better with a low daily dose (2.5 mg or 5 mg), which maintains a steady level of the drug in the system. This doesn't work for everyone, but for some, especially those with more consistent sexual activity or those who prefer spontaneity, it's a better approach.

The Reality of Non-Response

Not everyone responds to PDE5 inhibitors. The overall success rate is around 60-70%, which is good but not perfect. For men with severe vascular disease, advanced diabetes, complete nerve damage, or very low testosterone, the response rate is lower.

That doesn't mean they're out of options. It means the treatment plan has to be more comprehensive. It's not just about the pill. It's about optimising cardiovascular health, managing diabetes, addressing hormonal deficiencies, treating psychological factors, and sometimes accepting that full restoration of function isn't possible - but improvement is.

I think that's the part people struggle with most. The expectation that there's always a perfect solution. Sometimes there is. Sometimes there isn't. Sometimes you get 70% of what you used to have, and that has to be enough.

Moving Forward

If a PDE5 inhibitor doesn't work, the first step is figuring out why. That requires a conversation - about timing, dosing, arousal, stress, medications, medical history. It requires investigation - bloodwork, maybe imaging, sometimes referral to a specialist.

But it doesn't mean failure. It means you're dealing with something more complex than a simple mechanical issue. And that's okay. Most medical problems are more complex than they first appear. You just have to be willing to dig a little deeper to find the real answer.