Second Line ED Treatment: When Tablets Don't Work

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Second Line ED Treatment: What Happens When Oral Tablets Don't Work

Published: 17 October 2026

Second line ED treatment refers to options offered when first-line oral tablets (PDE5 inhibitors such as sildenafil, tadalafil, vardenafil, or avanafil) haven't worked, aren't suitable, or cause unacceptable side effects [2]. These treatments include alprostadil (given as an injection into the penis or as a cream), vacuum erection devices, and sometimes specialist interventions such as penile implants [1][2]. Understanding why first-line treatment may not have worked and what alternatives exist can help you and your healthcare team find an effective solution.

What is second line ED treatment and when is it needed?

Second line ED treatment is the next step when oral PDE5 inhibitor tablets—sildenafil (Viagra), tadalafil (Cialis), vardenafil (Levitra), or avanafil (Spedra)—have not provided satisfactory results [2]. These oral medicines are considered first-line treatment because they are effective for many men, relatively easy to use, and have a well-established safety profile [1][9].

You may be offered second line treatment if you've tried at least two different PDE5 inhibitors at the maximum dose on several occasions without success, if you have a medical condition that makes oral tablets unsuitable (such as taking nitrates for angina), or if side effects are intolerable [2]. It's important to ensure that the oral tablets were taken correctly—on an empty stomach if required, with adequate sexual stimulation, and at the right time before sexual activity—because incorrect use is a common reason for perceived treatment failure [1].

Before moving to second line options, your doctor or specialist will usually review your overall health, medications, and lifestyle factors such as smoking, alcohol intake, and psychological wellbeing, as addressing these can sometimes improve the response to first-line treatment [1][2]. A referral to a specialist urology or sexual health service is often made at this stage to explore the full range of second line treatments available.

Alprostadil: injections and topical creams for second line ED treatment

Alprostadil is a synthetic version of prostaglandin E1, a naturally occurring substance that helps relax smooth muscle and widen blood vessels in the penis, leading to an erection [7]. Unlike PDE5 inhibitors, alprostadil works directly on the penile tissue and does not require sexual stimulation to produce an erection, although stimulation may enhance the response [7].

Alprostadil is available in the UK as Caverject (an injection given into the side of the penis using a very fine needle) and Vitaros (a cream applied inside the opening of the urethra) [7]. Both are prescription-only medicines. The injection is typically more effective than the cream and is often preferred for second line treatment, but it requires training from a specialist nurse or doctor to ensure correct technique and to minimise the risk of complications such as priapism (a prolonged, painful erection lasting more than four hours) [7]. Vitaros cream may be an option for men who are uncomfortable with injections, though it tends to be less effective overall [7].

Common side effects of alprostadil include penile pain, bruising at the injection site, and a burning sensation in the urethra with the cream [7]. Rarely, prolonged erections can occur, which require urgent medical attention to prevent permanent damage [7]. Your specialist will start you on a low dose and adjust it during supervised sessions to find the dose that works for you with the fewest side effects.

How alprostadil is used in practice

If your doctor recommends alprostadil injections, you will be taught how to inject safely in a clinic setting, usually starting with a test dose to see how you respond [7]. You'll learn to inject into the side of the shaft of the penis (not the head or underside), alternating sides each time to reduce scarring [7]. The injection should be given about 5–20 minutes before sexual activity, and you should not use it more than once in 24 hours or more than three times a week [7]. Vitaros cream is applied using a single-use applicator and works within 5–30 minutes; again, it should not be used more than once a day [7]. Both treatments require careful adherence to instructions to minimise risks and maximise effectiveness.

Vacuum erection devices as a second line ED treatment option

A vacuum erection device (VED), also known as a vacuum pump, is a non-drug treatment that can be effective for many men, particularly those who cannot take oral or injectable medicines [1][2]. The device consists of a plastic cylinder that fits over the penis, a manual or battery-powered pump to create a vacuum, and a constriction ring (or band) that is placed at the base of the penis once an erection is achieved [1].

To use a VED, you place the cylinder over the penis, create a vacuum by pumping out the air, which draws blood into the penis and causes it to become erect, then slide the constriction ring onto the base of the penis before removing the cylinder [1]. The ring keeps the blood in the penis, maintaining the erection for up to 30 minutes; it must then be removed to restore normal blood flow [1]. VEDs can be used as often as needed and have very few side effects, though some men find them cumbersome or report that the erection feels different (cooler or less rigid at the base) [1][2].

Vacuum devices are available on the NHS in some areas or can be purchased privately; prices vary widely, and it's worth choosing a medically approved device rather than unregulated products sold online [1]. Your GP or specialist can advise on reputable suppliers. VEDs are particularly useful for men who have had prostate surgery or radiotherapy, as they can help maintain penile health and length even if spontaneous erections do not return [2].

When to consider specialist referral and further second line ED treatment

If first-line oral tablets and initial second line options such as alprostadil or a vacuum device have not been successful or suitable, your GP will usually refer you to a specialist urology or sexual medicine clinic [2]. Specialists can offer more detailed assessment, including tests to measure blood flow in the penis (penile Doppler ultrasound) or hormone levels, and can discuss advanced treatments [2].

Advanced second line and third line treatments may include combination therapy (using a PDE5 inhibitor alongside alprostadil or a vacuum device), low-intensity shockwave therapy (still considered experimental in the UK and not widely available on the NHS), or surgical options such as penile implants [2][8]. Penile implants are usually reserved for men with severe ED that has not responded to any other treatment; they involve surgically inserting inflatable or semi-rigid rods into the penis to allow an erection on demand [8].

Psychological factors—such as anxiety, depression, or relationship difficulties—often contribute to ED, even when there is a physical cause [1][10]. Cognitive behavioural therapy (CBT) or psychosexual counselling, either alone or alongside medical treatment, can be very effective and is sometimes offered as part of a specialist service [1][2]. It's important to discuss all aspects of your health and wellbeing with your healthcare team so that treatment can be tailored to your individual needs.

What to expect from a specialist consultation

At a specialist clinic, you can expect a thorough review of your medical history, current medications, and previous ED treatments [2]. The specialist may perform a physical examination and arrange blood tests to check testosterone, blood sugar, cholesterol, and other markers [2]. You'll have the opportunity to discuss your goals and preferences, and the specialist will explain the risks and benefits of each second line treatment option in detail. Many clinics also offer access to specialist nurses who provide training and ongoing support for treatments such as alprostadil injections, ensuring you feel confident and safe using them at home.

Reviewing first-line treatment before moving to second line ED treatment

Before concluding that oral PDE5 inhibitors have failed, it's essential to review how they were used [1][2]. Many men do not achieve the best results on their first attempt because the tablet was taken incorrectly—for example, too soon after a heavy meal (which delays absorption of sildenafil and vardenafil), without adequate sexual stimulation, or at a dose that was too low [1].

Each PDE5 inhibitor has a different onset and duration of action: sildenafil and vardenafil work best when taken about an hour before sex on an empty stomach, avanafil can work in as little as 15–30 minutes, and tadalafil can be taken as an on-demand tablet (effective for up to 36 hours) or as a low daily dose that allows more spontaneity [3][4][5][6]. If you've only tried one type or one dose, your doctor may suggest trying a different PDE5 inhibitor or a higher dose before considering second line options [2].

It's also worth reviewing other medications and health conditions. For example, uncontrolled diabetes, high blood pressure, or high cholesterol can all impair the response to ED treatment, and optimising these conditions can improve outcomes [1][2]. Lifestyle changes—stopping smoking, reducing alcohol, losing weight, and increasing physical activity—can also make a significant difference and may restore the effectiveness of first-line tablets [1][10].

How Cured Pharmacy supports your second line ED treatment journey

Cured Pharmacy is a GPhC-registered online pharmacy (GPhC 9012511) offering a convenient, confidential way to access first-line ED treatments through a UK pharmacist-led online consultation. While second line treatments such as alprostadil injections and vacuum devices are typically initiated and supervised by a specialist in person, Cured Pharmacy can supply the full range of oral PDE5 inhibitors if you and your prescriber decide to revisit or optimise first-line treatment.

Our service includes sildenafil (generic Viagra) from £0.45 per tablet (first order with code Ednew: £0.36), tadalafil (generic Cialis) from £7.95 (first order: £6.36), vardenafil (generic Levitra) at £16.95 (first order: £13.56), and avanafil (Spedra) at £20.95 (first order: £16.76). We also stock branded Viagra at £37.95 (first order: £30.36) and branded Cialis at £12.00 (first order: £9.60), as well as Teva-branded generics and Avarante tadalafil. Every order is reviewed by a UK-registered prescriber to ensure the treatment is safe and suitable for you.

If you're considering second line treatment or have been advised to try a different PDE5 inhibitor, our pharmacists can answer questions about how each medicine works, potential interactions with your current medications, and what to expect. We encourage anyone with new or worsening ED to see their GP in person, as ED can be an early warning sign of cardiovascular disease or diabetes [1][10]. Our service complements, rather than replaces, face-to-face care and specialist input.

Accessing treatment through Cured Pharmacy

To order from Cured Pharmacy, complete a short online consultation that asks about your health, current medications, and any previous ED treatments. A UK-registered prescriber reviews your answers and, if appropriate, approves your prescription. Your medication is then dispensed by our GPhC-registered pharmacy and delivered discreetly to your door, usually within a few days. If the prescriber has any concerns or feels you would benefit from a face-to-face review or specialist referral, they will let you know and may decline to issue a prescription online. This ensures your safety and helps you get the most effective treatment for your individual situation.

Scientific References

1. NHS. (n.d.). Erectile dysfunction (impotence). NHS website. https://www.nhs.uk/conditions/erection-problems-erectile-dysfunction/ [accessed 17 October 2026]
2. National Institute for Health and Care Excellence. (n.d.). Erectile dysfunction. Clinical Knowledge Summaries. https://cks.nice.org.uk/topics/erectile-dysfunction/ [accessed 17 October 2026]
3. Joint Formulary Committee. (n.d.). Alprostadil. British National Formulary. NICE. https://bnf.nice.org.uk/drugs/alprostadil/ [accessed 17 October 2026]
4. European Association of Urology. (n.d.). EAU Guidelines on Sexual and Reproductive Health. https://uroweb.org/guidelines/sexual-and-reproductive-health [accessed 17 October 2026]
5. Goldstein, I., Lue, T. F., Padma-Nathan, H., Rosen, R. C., Steers, W. D., & Wicker, P. A. (1998). Oral sildenafil in the treatment of erectile dysfunction. New England Journal of Medicine, 338(20), 1397–1404. https://pubmed.ncbi.nlm.nih.gov/9580646/ [accessed 17 October 2026]
6. Feldman, H. A., Goldstein, I., Hatzichristou, D. G., Krane, R. J., & McKinlay, J. B. (1994). Impotence and its medical and psychosocial correlates: Results of the Massachusetts Male Aging Study. Journal of Urology, 151(1), 54–61. https://pubmed.ncbi.nlm.nih.gov/8254833/ [accessed 17 October 2026]

Information on this page is for educational purposes only and is not medical advice. Prescription treatments require clinical assessment by a UK-registered prescriber. Always consult a qualified healthcare professional before starting or changing any medication.