Erectile Dysfunction Treatments: Medication Options Explained

Erectile dysfunction (ED) The inability to attain or sustain an erection adequate to perform satisfactory sexual activity is one of the most widespread medical conditions that affect men in all parts of the world. The Massachusetts Male Aging Study determined that about 52 percent of men between 40 and 70 years of age have some level of ED with the figure rising as they grow older. When the individual reaches 70 years, complete ED occurs in an estimated 15 percent of men.

Even with this prevalence, ED has been one of the least attended as a result of embarrassment, stigma, and the misconception that ED is the normal result of aging as opposed to a disease that can be caused and treated. This myth is not purely theoretical: in addition to the direct effect on sexual performance and quality of life, as well as relations, ED is now considered a predictor of cardiovascular risk in its own right – it is a symptom of systemic vascular disease, precursors of which major cardiac events by 3-5 years.

Fortunately, ED treatment has grown exponentially in the last 25 years, with a monolithic drug group, to an arsenal of tools to include oral therapy, intravenous therapy, mechanical therapy, hormonal therapy, and surgery. This reference offers an in-depth, evidence-based action plan of all of the major medication categories that can be used in the ED – enabling patients to have effective, knowledgeable conversations with their doctors.

Discussion of Physiology of Erectile Dysfunction

The first step towards effective treatment is the comprehending of the cause of ED. To achieve an erection, a combination of:

• Neurological stimulation – brain (desire, arousal) and peripheral nerves (parasympathetic sacral outflow).
• Vascularity – normal arterial inflow and good venous occlusion.
• Hormonal environment – sufficient testosterone to sustain libido and vascularity.
• Structural integrity – normal cavernous tissue that can relax and expand.

Failure at any of these levels may result in ED and in many cases, the condition is caused by a combination of many factors. Knowledge of etiology can be used to select treatment.

Common Causes of ED

Vasculogenic (preponderance, about 70% of organic ED): Atherosclerosis, hypertension, diabetes, smoking, hyperlipidemia -all weaken the blood supply of the penis in the arteries.

• Neurogenic: Spinal cord injury, multiple sclerosis, Parkinson’s disease, pelvic surgery (radical prostatectomy), diabetic peripheral neuropathy
• Hormonal: Low testosterone levels (hypogonadism), hyper prolactinism, thyroid disorders.
• Psychogenic: Performance anxiety, depression, relationship conflict, trauma history – may be primary or superimposing organic ED.
• Drug-induced: antidepressants (especially SSRIs), B-blockers, thiazide diuretics, antipsychotics, finasteride, anti-androgens.
• Structural: Peyronie disease (penile fibrosis and curvature), post-traumatic priapism.

PDE5 Inhibitors First-Line Treatment

The pharmacological treatment of ED is first-line pharmacological treatment that involves the use of phosphodiesterase type 5 (PDE5) inhibitors across all major guidelines (AUA, EAU, ISSM). They are the safest, most effective and widely studied orally used ED drugs, and have decades of evidence base with hundreds of clinical trials.

Mechanism of Action of PDE5 Inhibitors.

When stimulated sexually, nitric oxide (NO) is released into the corpus cavernosum, the location where guanylate cyclase is activated to generate cGMP. cGMP relaxes smooth muscle of cavernous arteries permitting inflow of blood and erection. PDE5 typically hydrolyzes cGMP, and the erection is terminated. PDE5 inhibitors inhibit this degradation, and extend the erectile response.

Critical principle: PDE 5 inhibitors are not automatic erections, they require sexual stimulation.

Available PDE5 Inhibitors

Sildenafil (Viagra, generic)

• Approved: 1998 (FDA)
• Starting dose: 50 mg; range 25–100 mg
• Onset: 30 to 60 minutes (quicker when starving)
• Duration: 4–6 hours
• Important considerations: When used on an empty stomach, it must be taken and allowed to take effect quickly, and has side effects on the visual (PDE6 inhibition).
• Generic cost: Extremely low – $0.50 to $3 per dose.
• Best: Men who like to time their sex; men who want the least expensive, the quickest-acting.

Tadalafil (Cialis, generic)

• Approved: 2003 (FDA)
• On-demand dose: 10–20 mg; Daily dose: 2.5–5 mg
• Onset: 30 minutes to 2 hours.
• Time frame: 36 hours maximum.
• Considerations: Food: No effect on absorption; distinguishing side effects: Back pain/myalgia; PDE5 inhibitor is the only approved medication in BPH; PDE5 inhibitor provides the ability to take it on a daily basis.
• Best in: Men who want spontaneity; comorbid BPH; men with dietary flexibility requirements.

Vardenafil (Levitra, Staxyn)

• Approved: 2003 (FDA)
• Normal dose of tablet: 10-20mg (initial dosage 10 mg)
• Orally dissolved tablet (Staxyn): 10mg.
• Onset: 25–60 minutes
• Duration: 4–6 hours
• The main considerations Structurally equivalent to sildenafil; some data of better performance in diabetic ED compared to sildenafil; absorption slower with high-fat meal; not generic in the US.
• Notable exception: Contraindicated with the class IA antiarrhythmics (quinidine, procainamide) and class III antiarrhythmics (amiodarone, sotalol) – important difference with other PDE 5 inhibitors.

Avanafil (Stendra)

• Approved: 2012 (FDA)
• Doses: 50 mg, 100 mg, 200 mg
• Onset: Within 15 minutes – the quickest acting oral ED drug.
• Time frame: 6 hours maximum.
• Important factors: highest PDE5-selective of four; least cardiovascular side effects; can be administered with food; can be administered as little as 15-30 minutes before sexual activity.
• Best in: Men with the fastest onset; men with more side effects to PDE5 inhibitor.

PDE5 Inhibitors Comparative Efficacy

General response rates (erections adequate to have intercourse) are widely similar:

• Sildenafil: 70–85% of attempts
• Tadalafil: 75–85% of attempts
• Vardenafil: 75–85% of attempts
• Avanafil: 65–80% of attempts

The decision between the two is not based on the difference in effectiveness but rather on the pharmacokinetic preference and side effects profile.

Cross-Contraindications of All PDE5 Inhibitors

• Organic nitrates (nitroglycerin, isosorbide mononitrate, isosorbide dinitrate): Absolute contraindication – possibly fatal hypotension.
• Soluble guanylate cyclase stimulators (riociguat): Contraindication.
• High cardiovascular risk (unstable angina, recent MI, decompensated heart failure): Sexual activity and PDE5 inhibitors are both contraindicated until cardiovascular stabilization.

PED5 Inhibitor failure: Second-Line interventions

Around 30-35 percent of men lack appropriate response to PDE5 inhibitors, or are unable to take them because of the use of nitrates or other contraindications. The second-line alternatives are very effective in the case of these men.

Intracavernosal Injections (ICI)

• Alprostadil (Caverject, Edex) – intracavernosal injection – is one of the best therapies in the treatment of ED, with about 80-90 percent of men who are properly using it attaining erections, even after failure on PDE5 inhibitors.
• Mechanism: Alprostadil is a prostaglandin E1 (PGE1) that is synthesized artificially. When injected directly into the corpus cavernosum, it stimulates adenylate cyclase and raises intracellular cAMP, leading to relaxation of smooth muscle and dilation of the arteries independent of the NO/cGMP pathway – and hence its activity even when PDE5 inhibitors fail (e.g. in severe neurogenic ED or following radical prostatectomy).

Available formulations:

• Alprostadil, alone (Caverject, Edex): The most common.
• Bi-Mix (alprostadil + papaverine)
• Tri-Mix (alprostadil + papaverine + phentolamine): This is the most effective compounded mix; it tends to give better results when alprostadil alone is not enough.
• Quad-Mix (Tri-Mix + atropine): In the most refractory cases.

Dosing:

• Alprostatil: 1.25-2.5 mg initial dose, increasing to effective dose (usually 5-40 mg).
• Goal: 3060 minutes erection.

Side effects:

• Pain where injection is done (approximately 30 percent – most frequent cause of discontinuation)
• Priapism – prolonged erection of more than 4 hours that is an emergency; the risk is reduced through appropriate dose titration.
• Penile fibrosis – of long standing use; reduced by changing points of injection.
• Ecchymosis (bruising)

Intraurethral Alprostadil (MUSE)

MUSE (Medicated Urethral System to Erection) is a delivery of alprostadil as a small pellet, which is inserted into the urethra using a specially designed applicator. Less effective than ICI (response rates of about 60 to 65), it is less invasive, and removes the fear of injections.

Doses: 125, 250, 500, 1000 mcg

The ring of penis constriction (included in the MUSE system) at the penis base increases effectiveness by decreasing the outflow of venous blood.

Side effects:

• Urethral burning/pain (~30%)
• Hypotension and syncope (~3%)
• Penile/testicular pain

Topical Alprostadil (Vitaros)

Topical alprostadil creams to the urethral meatus (Vitaros) are approved and not FDA approved in the US, but provide an alternative, non-injected, non-urethral treatment with about 5060% efficacy. It enjoys the benefit of being the least invasive alprostadil preparation.

Hormonal Therapy: Testosterone Replacement Therapy

Testosterone replacement therapy (TRT) is not an adjunct to treatment, but a primary treatment, when ED is attributable to hypogonadism (clinically and biochemically confirmed low testosterone).

Testosterone promotes erectile activity in several ways: preserving penile nitric oxide synthase activity, cavernosal smooth muscle integrity, libido and central sexual motivation.

Diagnosis requires:

Hypogonadism (symptomatic, loss of libido, fatigue, depression, loss of muscle mass, ED)

Verified biochemically: two morning fasting concentrations of total testosterone that are below the lower limit of normal in the laboratory (usually <300 ng/dL)

TRT Formulations

Intramuscular injections: Testosterone cypionate or enanthate, 100-200 mg once every 1-2 weeks; or once every 10 weeks long-acting undecanoate (Aveed).

Topical gels: AndroGel (Testim), Testim, testosterone gel (AndroGel, Testim), daily to shoulder/abdomen; convenience offset by risk of transfer to partners/children.

Transdermal patches Androderm: apply every day; skin irritation is frequent.

Subcutaneous pellets (Testopel): Implanted at 3-6months; extremely stable but produced slight surgical intervention.

Notable: TRT by itself is frequently not adequate in ED where there is an extensive co-occurring vascular or neurogenic pathology. It may require combination with a PDE5 inhibitor. TRT should not be used in men with prostate cancer or breast cancer, and PSA monitoring is necessary in suitable-aged men.

Vacuum Erection Devices (VEDs)

Vacuum erection devices Vacuum erection devices (also called penis pumps or vacuum constriction devices) are devices that form a vacuum around the penis, which pulls blood into the cavernous tissue and causes an erection. The blood is trapped by the constriction ring found at the base of the penis.

• Mechanism: No drugs, pure mechanical.
• Efficacy: With proper technique, about 6090% of men are able to produce erections that are adequate to allow intercourse.

Advantages:

• None of the systemic side effects.
• Easily tolerant with practically all drugs, including nitrates.
• One time expense (no recurrent drug cost).
• Especially applicable in penile rehabilitation following prostate surgery.

Limitations:

• Demands manual dexterity (difficult with some men due to arthritis, neurological disorders, or obesity)
• The constriction ring should be taken off in 30 minutes to prevent vascular complications.
• Erections can be different (cold, less hard at the base)
• Poor partner acceptance of certain relationships.

Surgery: Penile Prosthesis Implant

In men with inorganic severe ED that has not responded to any pharmacological and mechanical therapy, the implantation of penile prostheses (PPI) is the most conclusive intervention, and the highest satisfaction rates of any ED intervention – 80-95% patient and partner satisfaction.

Penile Prosthesis types

Three-piece inflatable (most popular, e.g., AMS 700, Coloplast Titan):

• Corpora cavernosa Two inflatable cylinders implanted in corpora cavernosa.
• A scrotal pump.
• A fluid-filled pelvis reservoir.
• The man is inflating (erecting) and deflating through a release valve by using the scrotal pump.
• Gives the most natural erection and flaccid look.

Two-piece inflatable:

• Reservoir incorporated in the pump; less complex surgery.
• Less natural when deflated.

Semi-rigid (malleable) rods:

• Less complex; does not have any moving components (more robust)
• Cylinder is permanently semifirm; it is bent down to be hidden, bent up to copulate.
• Less satisfactory than inflatable; suitable in men with poor manual dexterity.

Emerging and Investigational Therapies

Low-Intensity Shockwave Therapy (LiSWT)

LiSWT involves the use of acoustic waves that are targeted to the penile tissue to induce angiogenesis (new blood vessel formation) and neuroregeneration. Several studies and meta-analyses confirm its effectiveness, especially in vasculogenic ED – and unlike any existing pharmacological intervention, it seems to treat a root cause, not just enable the erection. It has been approved and is generally available in Europe; most devices await FDA approval in the US.

Platelet-Rich Plasma (PRP) / “P-Shot”

PRP treatment is a procedure that entails injection of concentrated autologous platelet derived growth factors into penile tissue. Evidence is now sparse and inconclusive; not to be used in general guidelines, but studies are being conducted.

Topical Minoxidil

Topical minoxidil to the penis is undergoing studies as a non-prescription ED treatment; early evidence is promising. Next, awaiting approval of this indication.

Note on Psychogenic ED

Sex therapy, cognitive behavioral therapy and couples counseling can prove to be most effective in men with mainly psychogenic ED (especially younger men) with no vascular risk factor – without pharmacological treatment. The psychological elements of ED (performance anxiety, fear of failure, relationship conflict) often superimpose organic factors even in older men, and their management increases the efficacy of all other interventions.

Frequently Asked Questions (FAQ)

Q1: What is the most effective medication for ED?

PDE5 inhibitors are the most effective and best-tolerated first-line option. Intracavernosal injections (Tri-Mix) have the highest success rate (~85–90%) of any pharmacological treatment but require injection. Penile prosthesis has the highest overall satisfaction rate.

Q2: Can ED be cured, or only managed?

In some cases — particularly when ED is caused by a correctable cause (e.g., hypogonadism, medication-induced ED, psychogenic ED, severe obesity) — it can be effectively treated at the source. In vasculogenic ED, treatments manage the symptom; aggressive cardiovascular risk reduction (exercise, diet, smoking cessation) may produce genuine improvement over time.

Q3: Is ED a sign of heart disease?

ED involving penile arterial insufficiency is increasingly recognized as a marker of systemic vascular disease, often preceding cardiac events. The penile arteries (1–2 mm diameter) develop atherosclerotic plaques before larger coronary arteries (3–4 mm). Men with unexplained vasculogenic ED should receive a cardiovascular risk evaluation.

Q4: Do ED medications affect fertility?

PDE5 inhibitors do not impair fertility and may actually improve sperm function in some research. Testosterone replacement therapy, however, strongly suppresses spermatogenesis and can cause azoospermia — men wishing to father children should avoid TRT or use alternative fertility-preserving strategies.

Q5: Are there natural or over-the-counter treatments that work?

Some evidence supports L-arginine (a nitric oxide precursor), combined with pycnogenol, for mild ED. Regular exercise, particularly aerobic and resistance training, significantly improves erectile function through vascular and hormonal mechanisms. Yohimbine has some evidence but significant cardiovascular side effects. Most OTC supplements marketed for ED have no credible clinical evidence.

Q6: Does the dose of sildenafil (or tadalafil) matter?

Yes, significantly. Many men who report PDE5 inhibitors “don’t work” have either never tried the maximum dose or have not used them correctly (sildenafil taken with food, insufficient sexual stimulation). Optimizing the dose and conditions of use often resolves apparent non-response.

References

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