Treating erectile dysfunction when PDE5 inhibitors fail

Referral

A busy primary care doctor may decide to refer patients with erectile dysfunction that does not respond to PDE5 inhibitors to a urologist, sexual health specialist, or other specialist.

Patient education

Educating patients on the correct use of the drug can be effective. One study found that 81% of patients initially took sildenafil incorrectly, and education solved the problem in 40% of men who did not respond previously.2 Another study reported a similar response rate of 55% after education in men who had previously not responded.3 Initial education, focusing on the following points, will optimise treatment outcomes.

• Adequate sexual stimulation, ideally with a partner, is required.

• Sildenafil and vardenafil should be taken 30-60 minutes before intercourse, and food and excessive amounts of alcohol should be avoided, as both may reduce the speed and extent of drug absorption.4 5 The absorption of tadalafil is unaffected by food and alcohol, but the drug does not reach maximum plasma concentrations until two hours after dosing.6 Although about half of men respond by 30 minutes, patients are advised to take tadalafil several hours before sexual activity and take advantage of the long duration of its effects (up to 36 hours).

• Sildenafil and vardenafil are active for four to six hours and are rapidly cleared from the body. Tadalafil, with a half life of 17.5 hours, is active for up to 36 hours.6

• Although most men will respond after one or two doses, some men may need six to eight doses before an optimal response occurs.3

Dose optimisation

PDE5 inhibitors may fail because of inadequate dosage. Sildenafil should be started at 50 mg (25 mg for elderly patients and patients with hepatic cirrhosis or renal impairment) and titrated to a maximum dose of 100 mg to achieve maximum response. Doses higher than 100 mg may be effective, but they have a significantly higher risk of side effects and 31% of men discontinue treatment.7 Vardenafil and tadalafil should be started at 10 mg with dose titration to achieve either an optimal response or a maximum dose of 20 mg.4 5

Another consideration is the possibility of tachyphylaxis (decreased responsiveness after repeated doses). One study reported a 17% rate of discontinuation for sildenafil owing to loss of efficacy after two years.8 Another study reported that high concentrations of sildenafil increase PDE5 expression in cultures of cavernosal smooth muscle cells; these findings provide a molecular basis for tachyphylaxis.9 However, this study used higher concentrations than those approved for patients. Tachyphylaxis has not been confirmed clinically, and further long term studies are required. A more plausible explanation of decreased efficacy is progressive worsening of the underlying cause of erectile dysfunction—for example, worsening atherosclerosis or diabetes.

Switching oral agents

Although no study directly compares the efficacy of the three PDE5 inhibitors, efficacy and tolerability are probably similar for the three drugs. Most patients will try another PDE5 inhibitor before they consider more invasive options.

Daily dosing with PDE5 inhibitors

In patients who were unresponsive to on-demand tadalafil, treatment with daily tadalafil significantly improved all treatment outcomes.10 Successful intercourse increased from a mean of 21% with on-demand 20 mg tadalafil to 58% with daily 10 mg tadalafil. This improvement is probably related to improved endothelial function.

Improvement in comorbid conditions

Many men have underlying comorbidities that are risk factors for erectile dysfunction: diabetes, hypertension, cardiovascular disease, depression, prostatic hypertrophy, smoking, drug treatment, a sedentary lifestyle, drug and alcohol misuse, etc. Control of these risk factors is an essential part of first line treatment for erectile dysfunction, to improve erectile function and the patient's response to treatment. One study showed that modifying associated risk factors before sildenafil was started improved the overall success rate to 82%, and 77% of patients had success at every attempt at intercourse.3 The success rate varied with different comorbidities and was lower in patients with more than one risk factor. Another study obtained similar results.11 These findings indicate that modification of risk factors has an important role in the success of oral PDE5 inhibitors.

Psychosexual therapy

To be effective, the treatment of erectile dysfunction must go beyond just restoring erectile function,12 and some cases require integrated treatment using psychosexual therapy and pharmacotherapy. Many psychological factors adversely influence the efficacy of sildenafil and result in non-compliance with treatment.13

Treatment may be perceived as temporary, unnatural, or unacceptable. Expectations may be unrealistic or the patient may worry about side effects and complications. Regaining potency does not necessarily translate into resuming sexual intercourse, and the resistance of partners may result in the failure of pharmacotherapy. Contributing factors include the duration of sexual abstinence before seeking treatment; the man's approach to resuming sexual contact; the partner's physical and emotional readiness to resume sexual contact; and the quality of the non-sexual relationship.12

Sex therapists are trained to deal with these issues and can also remotivate patients in whom treatment with oral PDE5 inhibitors failed, making these patients more likely to try again or seek further options.13 Although data from controlled trials on the efficacy of this integrated approach are lacking, clinical experience indicates that it may be effective in patients with psychosocial issues.

Testosterone for hypogonadal men

Endocrine abnormalities are an uncommon cause of erectile dysfunction. Androgen deficiencies are often associated with reduced libido and frequency of intercourse and less often with decreased frequency and quality of erections.14

However, testosterone is being investigated as a treatment for erectile dysfunction. Animal studies have shown that testosterone reverses apoptosis of cavernosal smooth muscle cells and reduced expression of the genes encoding nitric oxide synthase and PDE5 which occur after castration.15 16 Consistent with these findings, testosterone improves sexual function in hypogonadal men with erectile dysfunction.17

Recent studies show that men with symptoms of hypogonadism have a reduced response to PDE5 inhibitors. Treatment with testosterone significantly improved the response to sildenafil in men with erectile dysfunction who initially had low initial serum concentrations of testosterone.14 Treatment with a 1% testosterone gel improved erectile function in hypogonadal men who did not initially respond to sildenafil.18 In another study, men who did not initially respond to sildenafil but whose response to the drug improved after testosterone replacement had lower serum concentrations of testosterone at baseline than age matched controls who had responded to sildenafil.19 Larger randomised controlled trials will help clarify the evolving role of treatment combining PDE5 inhibitors with testosterone.

Combination treatments

Men who do not respond to oral PDE5 inhibitors alone may respond to treatments that combine agents that act synergistically. This approach may also allow lower drug doses and reduce the incidence of adverse effects.

Alternative treatments