Probably one of the main reasons why patients affected by erectile dysfunction complain no efficacy of oral drugs is an inadequate counseling from their physician. In fact, most common mistakes that can jeopardize PDE5-inhibitors effectiveness are:

Erectile dysfunction and cardiovascular and metabolic disease are closely related. Therefore the presence of metabolic syndrome components can impair clinical response to PDE5-inhibitors. So diabetic patients, obese men, patients affected by cardiovascular disease or hyperlipidemia could not properly respond to oral PDE5-inhibitors treatment [11].

Some patients can be initially considered as non-responders to PDE5 inhibitors, due to misdiagnosis. The most frequent eventuality is represented by patients affected by hypogonadism or hyperprolactinemia, who need specific hormonal treatment to improve erectile function. Although there is no complete agreement, testosterone deficiency seems to determine a poor response to PDE5-inhibitors and testosterone replacement therapy could be helpful to improve PDE5-inhibitors effectiveness. Another possible reason for PDE5-inhibitors failure could be a undiagnosed Peyronie’s disease, who needs specific treatment for pain and penile curvature.

Response to PDE5-inhibitors can be altered by patient’s unrealistic expectations, such as considering drug a sexual enhancer, fear of side effects and anxiety about the recovery of their sexual life. In addition, all psychological issues that have been not recognized during the diagnostic process could compromise oral drugs’ effectiveness.

In the same way, sexual dysfunction in female partners (anorgasmia, lack of lubrication, pain during intercourses, lack of sexual desire) can determine therapeutic failure.

Before proposing to a patient a second line therapy, whose results are not always satisfactory, some possible strategies should be taken under consideration in order to try to convert “non-responders” in “responders” (Fig. 17.1). Pre-treatment counseling is as important as the treatment itself.

First of all, it has been demonstrated that an adequate trial with PDE5-inhibitors should take into account at least six attempts before classifying a patients as non-responders [12]. This consideration is crucial as, in clinical practice, it is quite common that patients refer ineffectiveness of oral drugs after only one or two administrations and almost always after not more than four attempts. It is also mandatory to advise patients that the use of oral drugs for erectile dysfunction treatment requires an adequate sexual stimulation.

Patients should receive correct information about time of onset of therapeutic effect and interference of food and alcohol intake on clinical effectiveness for each prescribed drug. Sildenafil, Vardenafil and Avanafil have a similar rapid onset of action (30–60 min), with avanafil claimed to be the faster drug (15–30 min). Nevertheless the time between drug intake and onset of therapeutic effect is widely variable from one patient to another. So, in clinical practice, it is appropriate to advise patients that if a drug does not work after a short time, maybe the effects can be seen later with a longer latency time. Sildenafil works better when swallowed under fasting condition, while tadalafil absorption is independent by the food intake. Vardenafil and Avanafil effectiveness could be affected by a high fat meal. Just giving this information, more than 45 % of non-responders to PDE5-inhibitors become responders [7].

Another possible strategy to improve effectiveness of PDE5-inhibitors is to titrate oral drug dosage to the maximum tolerated. Patients who do not respond to low doses of PDE5-inhibitors often have a therapeutic effect with the maximum dosage [6].

In clinical practice, the acronym FAST (Follow-up, Adjustment of dosing, Sexual stimulation and Titration to the maximum tolerated dose), created by Hatzichristou in 2002, can be useful to remind the basic principles of patient information (Table 17.2) [6].

Another important issue is to ask patient where he bought the drugs in order to ensure that he has taken a licensed medication. In fact, more than 70 % of drugs purchased online result to be counterfeit, containing only a small amount of active drug (less than 50 %) and sometimes some harmful substances (lead paint, rat poison, printer ink, floor wax, drywall, chalk, boric acid, etc.) [13].

Regarding patients affected by testosterone deficiency, although evidences are contrasting about the role of testosterone replacement therapy in improving PDE5-inhibitors effectiveness, hypogonadal patients who are non-responders to PDE5 inhibitors might benefit from restoring testosterone levels, especially in men with low baseline testosterone levels (<3 ng/ml) [14].

Modification of other risk factors like hyperlipidemia, diabetes or hypertension improves the response to PDE5 inhibitors in non-responders, but predictive factors of this response are not known. A physichosexual counseling could be helpful when psychological or relationship issues were recognized.

Some data suggest that switching from one PDE5-inhibitors to another could improve the response to oral drug and it could be explained by the differences in term of pharmacokinetics between drugs [15]. Use of chronic administration (daily or two/three times per week) of a PDE5-inhibitors and the possible combination of a chronic regimen of tadalafil and a short-acting PDE5-inhibitor can be possible alternative strategies to manage non-responders before offering them a second line therapy [16].

When patients do not respond to oral first line therapy despite all above described maneuvers or present contraindication to PDE5-inhibitors, they should be offered a second line treatment. Historically, intracavernosal injections (ICI) represented the most widely used treatment before development of PDE5-inhibitors and to date are the preferred second choice treatment. Nevertheless, some other options are available to manage non-responders men and it is not possible to define a gold standard and all the possibilities should be discussed and proposed to patients. Main indications and most frequent side effects for each second line treatment are summarized in Tables 17.3 and 17.4.