Lifestyle Changes

Besides tons of piece of information dealing on the link between ED and the atherosclerotic coronary and peripheral vascular diseases, as well as the metabolic syndrome – characterized by obesity, abnormal lipids profile, insulin resistance, and hypertension – numerous scientific evidences have stated the strict correlation between ED and incorrect lifestyles. Indeed, ED has been linked to unhealthy diet, smoking, and excessive alcohol consumption/intake [17–19].

The beneficial effect of lifestyle changes was firstly demonstrated in a randomized, single-blind trial of 110 obese men (body mass index >30) age 35–55 years, without metabolic syndrome but with ED (International Index of Erectile Function – Erectile Function (IIEF-EF) domain score ≤21). The mean IIEF score improved in the intervention group (from 13.9 ± 4.0 to 17 ± 5; P < 0.001), but remained stable in the control group [20]. Thereafter, further studies have confirmed similar findings [21].

According to the EAU guidelines, a complete evaluation of the patient seeking medical help for ED must identify reversible risk factors for ED as a first line approach; thereof, lifestyle changes and risk factors modification must precede or accompany any physical or/and any pharmacological treatment [16].

Psychosexual Therapy

This approach is particularly indicated in patients presenting with evidence of psychological problems. Psychosexual therapy alone or in combination with pharmacological treatment, in a specific group of patients, may result in a cure of the problem. In this context, ED in young individuals has been mainly regarded as a psychogenic disorder [16]. In a study conducted on 948 men with an IIEF score below 21, findings showed that 85.2% of those younger than 40 years had psychogenic ED as their primary ED aetiology as compared with 14.8% exhibiting a specific cause for an organic form of ED (i.e., vasculogenic, neurogenic, hormonal, drug-induced, or mixed [22]).

Recent approaches to sex therapy have included cognitive-behavioural interventions focused on challenging or correcting maladaptive cognitions, behavioural techniques, exploration of past developmental experiences on present behaviour, and couples’ therapy [3].

However, psychosexual therapy requires ongoing follow-up and has had variable results [16].

Pharmacologic Therapy

Phosphodiesterase type 5 inhibitors—To date , seven molecules (sildenafil, tadalafil, vardenafil, avanafil, lodenafil, mirodenafil, and udenafil) with different dosages and formulations are available with a geographically-inhomogeneous availability [23]; of those, only sildenafil, tadalafil, vardenafil and avanafil are actually available in all continents. Overall, all these drugs have largerly demonstrated to be safe, easy-to-use and highly effective in enhancing erectile function across a wide range of outcome measures, causes of ED and patients subgroups [23]. Efficacy comparisons among PDE-5Is are not feasible because of the differences in the trial designs which had tested the effectiveness of each molecule in the clinical setting; as a whole, they appear to be equivalent in terms of efficacy with minimal side effects and similar warnings [16, 24].

Mechanism of action—As described in the previous paragraphs, sexual stimulation determines the release of NO from the nerve endings of cholinergic preganglionic neurons, which then diffuses into vascular and cavernous smooth muscle cells of the corpus cavernosum [25]. As a result, the levels of cGMP elevate in the smooth muscle cells, lowering the cytoplasmic calcium and resulting in smooth muscle relaxation and subsequent penile erection. PDE-5 physiologically inhibits the cGMP pathway; for this reason, PDE-5Is intake eventually enhances erectile function [25]. Of major relevance, without sexual stimulation and the resultant NO release, however, these inhibitors are ineffective; therefore, the efficacy of these drugs is strictly related to the presence of sexual stimulation [3, 25].

Clinical efficacy—The clinical efficacy and safety of sildenafil, vardenafil, tadalafil and avanafil have been evaluated in many placebo-controlled, double-blind trials, as well as in numerous open label studies [24, 26–28]. Currently, there is no strong evidence supporting the superiority of one molecule toward the other [23]. In a meta-analysis including 118 trials and more than 31,000 patients, Yuan et al. [29] compared the efficacy of different classes of oral PDE5is; they reported that all investigated compounds were associated with a significant higher improvement in the IIEF-EF domain score as compared with placebo, with a mean difference ranging from 5.6 to 7.4 points among the different molecules. Similar results were achieved in terms of response to the Global Assessment Questionnaire question 1 (GAQ1) and the Sexual Encounter Profile question 2 and 3 (SEP2-3) [29].

Sildenafil was the first PDE-5Is launched on the market in 1998; its efficacy was tested in a study conducted by Goldstein et al. which comprised a first phase of dose response and a second phase of dose escalation test [28] In the dose response phase, 532 men were prescribed with oral sildenafil (25, 50, or 100 mg) or placebo; as a result, increasing doses of sildenafil were associated with significantly improved erectile function. In the dose escalation phase 69% of all attempts at sexual intercourse were successful for those men actually receiving sildenafil, as compared with 22% for those conversely receiving placebo (P < 0.001) [28].

A subsequent meta-analysis conducted in 2016 confirmed these results in a wider cohort of 11,364 ED men, using pooled data from 48 randomized, double-blinded, placebo-controlled, parallel-group, flexible-dose trials. The percentage of men reporting improved erections on the global assessment question was statistically significantly higher with sildenafil than after placebo for all age subgroups, although the efficacy of sildenafil tended to decrease for increasing ages (<65 years, 80%; 65–74 years, 69%; ≥75 years, 59%) [30].

Tadalafil was licenced as a ED treatment in February 2003. Its molecule is unique since it has a long elimination half-life of approximately 18 h [31], with the potential advantage that sexual spontaneity may be more easily restored using this compound [27]. The specific pharmacokinetics profile of tadalafil allows the administration of the drug both in on-demand doses of either 10 or 20 mg, and as an once a day dose of 5 mg [23]. The efficacy of tadalafil has been established in almost every subgroup of patients with ED, thus including difficult-to-treat subgroups (e.g. diabetes mellitus) [16]. In a meta-analysis comparing the efficacy of PDE-5Is, tadalafil showed a small advantage in terms of efficacy compared to the other drugs [absolute effect for IIEF-EF: 9.21 (CI: 8.17–10.21)] [29]. Because of its longer half-life and the convenient 5-mg daily dose, tadalafil has been the most widely assessed PDE-5Is also in patients with lower urinary tract symptoms (LUTS) and ED, thus resulting the only drug currently licensed as an on-label treatment for male LUTS. Roehrborn et al. [32] performed a dose-finding trial that enrolled 1058 men with LUTS randomized to either placebo or tadalafil at 2.5, 5, 10 or 20 mg once daily for 12 weeks. All tadalafil doses resulted in a significant improvement of urinary symptoms as compared with placebo, with a clear dose–response effect. The efficacy of tadalafil therapy in patients with LUTS was then confirmed in other well-conducted RCTs and meta-analyses [33, 34].

Vardenafil became commercially available in March 2003. Vardenafil is a potent and selective PDE-5I with a chemical structure which differs from that of both sildenafil and tadalafil, therefore reflecting differing pharmacological properties. In vitro studies have shown that the potency of vardenafil in inhibiting PDE5 purified from human corpus cavernosum tissue was approximately 25-fold greater than that of sildenafil and 48 times greater than that of tadalafil (IC50 values 0.14, 3.5, and 6.74 nmol/L, respectively) [35]. Three different dosages for film-coated oral tablets (5, 10, 20 mg) have been approved and marketed as on demand ED treatments. In a dose-response study, improved erections were reported by 66%, 76% and 80% of a general ED population taking 5, 10 and 20 mg vardenafil, respectively, compared with 30% of men taking placebo [36, 37]. Vardenafil significantly improved patient scores for IIEF, Sexual Encounter Profile (SEP2, SEP3) and GAQs and treatment satisfaction. Moreover, the orodispersible tablet (ODT) formulation of vardenafil 10 mg launched in 2012 was the first available ODT among PDE-5Is. Debruyne et al. [38] published the results of a post-hoc integrated analysis performed on data from two 12-week, double-blind, RCT of vardenafil ODT. They reported that the mean per-patient SEP3 success rate was 62.5% for study medication compared to 29.4% for placebo within 15 min post-dosing, with corresponding overall SEP3 success rates of 59.8% and 38.2%, respectively.

The latest PDE5-Is that was released on the market and widely approved for the treatment of ED was avanafil. Avanafil is a highly selective and potent second-generation oral inhibitor of the cGMP-specific PDE5 [39]. It was launched in 2013 and the main characteristic is related to its selectivity compared to other PDE-5Is, thus allowing this drug to be effective while lowering to the minimum the rates of treatment-emergent adverse events (TEAEs). Goldstein et al. assessed clinical efficacy and safety of three different dosages of avanafil (50, 100, 200 mg) vs. placebo randomly assigned to 646 subjects [40]. The analysis showed a significant improvement in both SEP2 and 3 and IIEF-EF scores compared to placebo, with a more significant improvement for 100 and 200 mg doses over 50 mg dose. Similar results were reported by other four RCTs [40]. Avanafil was found to have a consistent time course of action across all doses, with the peak response occurring within 15–40 min after avanafil administration. In a recent study evaluating the efficacy of avanafil treatment in the general population with ED, the treatment was associated with higher rates of successful sexual intercourses as compared with placebo, with higher rates of success for higher doses of avanafil (i.e., avanafil 200 mg) [40, 41].

Recently, Chen et al. [42] performed a meta-analysis with a complete assessment of efficacy and side effects across different drugs and direct benchmarking of treatments. The results of this trade-off analysis, including 47,626 patients for the efficacy analysis and 20,325 patients for the TEAEs analysis, confirmed the overall established higher efficacy of all PDE-5Is compared to placebo, and suggested a possible advantage of sildenafil 50 mg in terms of efficacy and tadalafil 10 mg in terms of tolerability; still, the choice of a specific drug should still rely on patient’s preferences in relation to the different pharmacokinetics profiles of the molecules themselves [42].

Pharmacokinetic profiles—The rapid onset of action of a PDE-5Is has been observed to have a significant impact in terms of patient’s compliance toward a specific drug, either per se or as a perception of lack of efficacy of the compound itself in case of delayed onset of action [43]. However, success rates after 20 min are much less than after 1 h. High-fat meal intake has been shown to delay absorption of vardenafil and sildenafil; conversely, this effect is not seen with tadalafil and avanafil [24]. However, clinically speaking, it has been recommended to take a pill with sufficiently in advance to the attempts of sexual activity, and preferably far from meals to increase the better the chances of therapeutic success.

Tadalafil therapy has the broader therapeutic window, with an half-life of approximately 18 h. Avanafil has a half-life variable between 6 and 17 h, while vardenafil and sildenafil has the lower half-life with approximately 3.7–3.9 h [16].

Adverse events—Overall, the meta-analysis comparing efficacy and safety of PDE-5Is demonstrated their excellent safety profiles [29, 42]. Drugs-related adverse events are generally mild in nature; more specifically, class-specific TEAEs usually include flushing, headache, nasal congestion or rhinitis, musculoskeletal symptoms (myalgia and back pain) and dyspepsia [44]. Chen et al. [42] analysed data from 72 trials, reporting an overall rates of TEAEs for each starting dose of 10.23% for tadalafil 10 mg, 11.42% for udenafil 100 mg, 16.12% for mirodenafil 50 mg, 18.14% for avanafil 100 mg, 18.15% for vardenafil 10 mg, and 18.42% for sildenafil 50 mg, respectively thus suggesting an overall better tolerability for tadalafil 10 mg.

Despite the higher specificity of PDE-5Is for the PDE5 enzyme isoform, each molecule shows a different level of inhibition also for other PDE isozymes, thus possibly resulting in small differences in terms of AEs [44]. Visual disturbances, due to a weak inhibition of PDE6, have been more often associated with sildenafil, followed by vardenafil [22, 23]; similarly, the low selectivity for PDE1 resulted in slightly higher rates of vascular AEs (hypotension, flushing and tachycardia) associated with sildenafil [23]; likewise, higher rates of back pain have been reported with tadalafil possibly because of its effect toward PDE11 [24].

An important aspect to consider while prescribing these drugs is related to cardiac safety. Many post marketing studies for all the approved PDE-5Is have demonstrated no increased risk of myocardial infarction or cardiovascular events in the treated population compared to an age-matched general population, stating the cardiovascular safety of these drugs [16]. However, patients with resting hypotension or hypertension, with an history of myocardial infarction or life-threatening arrhythmias in the last 6 months, unstable angina or congestive heart failure should not be treated with PDE-5Is [16]. Furthermore, an absolute contraindication to PDE-5Is intake is represented by patients who are using any form of organic nitrate (e.g. nitroglycerine, isosorbide mononitrate, and isosorbide dinitrate) or NO donors. The reason for this absolute contraindication is related to the fact that both these drugs act enhancing the levels of cellular cGMP, thus resulting in unpredictable falls in the blood pressure levels [16].

PDE-5Is starting doses—The recommended starting doses are 50 mg for sildenafil, 10 mg for vardenafil and tadalafil and 100 mg for avanafil. For this latter molecule, the usual starting dose in clinical terms has been rapidly moved to 200 mg. The dose should be then adjusted based on the efficacy and the TEAEs profile developed by each single patient.

Intracavernous Injections (ICI)—ICI of vasoactive drugs is considered the second line therapy for ED, once oral agents have eventually failed [16]. However, ICI could be also used as a first line treatment in specific groups of patients, such those previously submitted to pelvic surgery with an extrafascial approach (therefore, without formal neurovascular bundles preservation).

Men who have failed first-line oral pharmacotherapy constitute the largest group of ICI-treated patients, with a significant erectile response rate of >85% demonstrated among PDE-5Is non-responders, indicating that progression to second-line injection therapy is appropriate [3, 23].

Overall, ICI treatment offers several potential advantages, including a rapid onset of action, reduced incidence of systemic complications and drug interactions compared to oral treatments [16].

Papaverine—Papaverine, an alkaloid isolated from the opium poppy, induces relaxation of cavernous smooth muscle and penile vessels via nonspecific inhibition of PDE, elevates cAMP, and impairs calcium influx through blockage of voltage-dependent calcium channels. Advantages of this drug are low cost and stability at room temperature; however, papaverine injection is also associated with higher incidences of priapism (up to 6%), corporal fibrosis (6–30%), and elevation of liver enzymes [45].

Alprostadil (prostaglandin E1)—Alprostadil was the first and only drug approved for intracavernous treatment of ED [46, 47]. Alprostadil causes smooth muscle relaxation, vasodilation, and inhibition of platelet aggregation through elevation of intracellular cAMP. It is metabolized by the enzyme prostaglandin 15-hydroxydehydrogenase.

This drug showed success rates as high as 70–75% in the general ED population, as well as in patient subgroups (e.g. diabetes or CVD), with reported sexual activity of 94% after ICI and satisfaction rates of 87–93.5% in patients and 86–90.3% in patients’ partners [46, 47]. Common TEAEs include pain at the injection site or during erection (11–15%), small hematoma or bruising, penile fibrosis (1–3%), and burning sensation at time of injection. Rates of priapism are quite low (1–3%) and systemic side effects are actually rare [45].

Beside prostaglandin E1 (PGE1)-based monotherapy, several combinations of different drugs have been introduced and popularized, counting on the synergistic effects of different compounds on penile vasodilation. Among them, the Tri-Mix preparation with papaverine, phentolamine and PGE1, is currently indicated in poor responders to alprostadil monotherapy, showing higher efficacy rates compared to PGE1 alone in a randomized trial (50 vs. 22%), with overall less reported pain (12.5 vs. 41%) [29]. Finally a Quadri-Mix preparation, adding atropine to the previous triple combination of drugs has been introduced [23]; the addiction of atropine to this combination should ensure also the block of the anti-erectile arm of the cholinergic pathway in the CC [48]. However, a RCT failed to demonstrate a superiority of Quadri-Mix toward Tri-Mix in terms of penile rigidity (35.1 vs. 39.1%) [49]. It is relevant to outline that, although effective, those reported combinations are still off-label in most countries, deserving galenic preparations.

Patient acceptance—Despite the high rates of success in determining a satisfactory erectile function, patients’ acceptance toward ICI is variable and the drop-out rate is quite high. The percentage of men who accept a therapy with ICI ranges from 49 to 84%, and patient’s discontinuation rate is between 20 and 60% [46, 47, 50]. Most drop-outs occur within the first 2–3 months of therapy. Reasons for discontinuation have historically included lack of partner (26%), poor response (23%), fear of needles (23%), fear of complications (22%), and lack of spontaneity (21%). Careful counselling of patients during the office-training phase is of major importance in addressing patient withdrawal from an ICI programme [16].

Adverse effects—Priapism and fibrosis are the two more serious side effects associated with ICI therapy. Priapism occurred in 1.3% of 8090 patients in 48 studies with alprostadil, which is about five times lower than with papaverine [51].

Contraindications—Therapy with ICI is contraindicated in patients with sickle cell anemia, schizophrenia or severe psychiatric disorders. In patients with poor manual dexterity, the sexual partner can be instructed to perform the injection.

Other Treatments

Topical/Intraurethral Alprostadil

Alprostadil can be administered in three different ways: as an intracavernous, as a topical or as a per urethra compound. These last two modalities have been actually described as less invasive, but clinical data are, to date, still limited.

The recently launched topical alprostadil cream (Vitaros^®) combines PGE1 (300 μg) with a chemical enhancer to increase skin permeation; this tool showed promising results in two multicentre placebo-controlled trials including 1.732 patients, with a satisfactory erectile response ranging between 74 and 83% of patients [53, 54]. More recently, an update form of administration has been suggested in order to increase drug effectiveness while reducing patients’ discomfort [55]. Overall, side effects include penile erythema, penile burning and pain. Systemic side effects are very rare [54, 56].

Lastly, the intraurethral insertion of alprostadil uses a dedicated medicated pellet (MUSE™) [57]. This compound showed higher rate of successful intercourse compared to placebo (64.9 vs. 18.6% in 1511 patients) [53], although in a direct comparison with ICI the erectile efficacy was rated as 43 vs. 70%, respectively [57]. The most common TEAES are local pain (29–41%) and dizziness with possible hypotension (1.9–14%). MUSE™ is not broadly available any longer.

Psychological/Behavioural Strategies (BT) for PE

In the context of PE patients , psychotherapy has two overlapping goals: (1) to help men developing sexual skills that enable them to delay ejaculation while broadening their sexual scripts, increasing sexual self-confidence and diminishing performance anxiety; (2) to focus on resolving psychological and interpersonal issues that may have precipitated, maintained or being the consequence of PE symptom for the man, partner or couple.

There is a lack of strong data dealing with BT because, the majority of the psychotherapy treatment outcome studies are uncontrolled, un-blinded trials and few meet the requirements for evidence-based studies [65].

The behavioural strategies applied for the treatment of PE are mainly the ‘stop-start’ technique and the ‘squeeze’ technique. Both those latter approaches are usually applied with the goal to re-training the man to recognise the feeling of ejaculatory inevitability.

As said, the ‘stop-start’ technique, developed by Semans, involves the man or his partner stimulating the penis until he feels the urge to ejaculate, then stopping until the sensation passes; this is repeated a few times before allowing ejaculation to occur [66]. The aim is to learn to recognize the feelings of arousal in order to improve control over ejaculation.

In the “squeeze” technique, proposed by Masters and Johnson, the man’s partner stimulates the penis until he feels the urge to ejaculate, then squeezes the glans of the penis until the sensation passes; this is repeated before allowing ejaculation to occur [66].

Regarding the sensate focus or sensate focusing [67], the man and his partner begin by focusing on touch, which excludes breasts, genitals, and intercourse, to encourage body awareness while reducing performance anxiety; this is followed by gradual reintroduction of genital touching and then full intercourse [68].

Pelvic floor muscle rehabilitation exercises may also assist with ejaculatory control [69].

Psychological factors may be associated with PE and should be addressed in treatment. These factors mainly relate to anxiety, but could also include relationship factors [70]. The limited studies available suggest that behavioural therapy, as well as functional sexological treatments, lead to improvement in the duration of intercourse and sexual satisfaction [71, 72].

The results regarding the efficacy of these techniques are limited; however, short term success rates have been reported to be around 50–60% [71, 72]. Even if improvements achieved with these techniques are generally not maintained in the long-term [73], behavioural strategies may represent an added value to the pharmacological therapy, which nowdays represents the best treatment option for this condition.

A recent systematic review analysed randomized controlled trials for behavioral therapies in the management of PE [74]. Four trials compared BT against waitlist control, of which two (involving squeeze, stop-start, and sensate focus) reported IELT differences of 7–9 min, whereas two (web-based sensate focus, stimulation device) reported no difference in terms of ejaculatory latency after treatment. Some study reported that BT was superior to waitlist in improving sexual satisfaction, desire, and self-confidence, whereas others were not significant. Combined behavioural and drug treatment was superior than drug treatment alone, with small but significant differences in IELT (0.5–1 min) and significantly better results in terms of other sexual outcomes (e.g., sexual satisfaction, ejaculatory control, and anxiety). Direct comparisons of behavioural therapy vs. drug treatments gave mixed results, mostly either favouring drug treatment or showing no significant differences. In comparison with a pharmacological treatment, most BTs require a willingness of the man and his partner to engage with the therapy and practice the relevant techniques. The suitability of a BT is likely to depend on individual patient (and partner) preference. Combinations of medical and psychological approaches may be useful where there is a clear psychosocial or relationship issue.

Pharmacotherapy

Currently only two drugs have been officially approved as on-label treatments for lifelong PE, e.g. the oral drug dapoxetine and the topical anesthetic Fortacin™ (lidocaine + prilocaine (spray).

Dapoxetine—Dapoxetine hydrochloride is a derivative drug belonging to the class of SSRI, with a short acting pharmacokinetics profile and without any anti-depressant profile. It has a rapid onset of action and a short half-life [75]. It is approved for on-demand treatment of PE in European countries but not in the USA. The recommended starting dose for all cases is 30 mg, taken approximately 1–3 h prior to sexual activity, with no more than one dose taken every 24 h [76]. A pooled analysis of several randomized control studies showed that oral dapoxetine 30 or 60 mg induced significantly greater improvements from baseline in the geometric mean IELT at all time points measured, as compared with placebo [77].

At 12-week follow up, the geometric mean IELT increased from a baseline of approximately 0.8 min to 2.0 and 2.3 min with dapoxetine 30 and 60 mg, respectively, as compared with 1.3 min for placebo, corresponding to a 2.5-fold and 3.0-fold increase in the geometric mean IELT respectively (vs. a 1.6-fold increase for placebo) [77].

Dapoxetine showed a good safety profile and reasonable TEAEs prevalence, with a dose-dependent profile. Nausea, headache, and vertigo were the most common side effects. Dapoxetine side effects were reported in 47.0% and 60.3% of patients receiving 30 and 60 mg, respectively, with dapoxetine-related discontinuation occurring in 3.5% and 8.8% of these patients [77].

Off-label use of antidepressants: SSRIs and clomipramine—Serotonin pathway is key in regulating ejaculation , specifically 5-hydroxytryptamine exhibit an ejaculation-retarding effects due to the activation of 5-HT1B and 5-HT2C receptors, both spinally and supraspinally [78].

SSRIs are used to treat mood disorders, but can delay ejaculation and are therefore widely used as ‘off-label’ compounds for PE. As for depression, SSRIs must be given for 1–2 weeks to be effective in PE [78]. Administration of chronic SSRIs causes prolonged increases in synaptic cleft serotonin, which desensitises the 5-HT1A and 5-HT1B receptors [79].

Five different SSRIs have been studied for daily PE treatment: paroxetine 20 mg, sertraline 50 mg, fluoxetine 20 mg, citalopram 20 mg, and fluvoxamine 100 mg.

All these drugs were effective in delaying ejaculation in men with PE [80]. Among them, daily paroxetine 20 mg led to the longest ejaculatory delay. Interestingly, the efficacy of paroxetine seems to be independent of baseline IELT.

These drugs have been reported in several meta-analysis to increase the geometric mean IELT by 2.6–13.2-fold [81].

In clinical practice, two different dose regimens for long-acting SSRIs have been proposed: daily and OD treatments. Ejaculation delay usually starts a few days after intake. However, a clinically relevant effect only gradually occurs within 1–3 weeks.

Common side-effects of SSRIs include fatigue, drowsiness, yawning, nausea, vomiting, dry mouth, diarrhea and perspiration [82, 83]. Decreased libido, anorgasmia, anejaculation and ED have also been reported.

Patients should be advised not to stop taking the SSRI acutely in order to prevent the occurrence of an SSRI discontinuation syndrome, which is characterized by symptoms like tremor, shock-like sensations when turning the head, nausea, and dizziness.

Few studies explored the efficacy of OD use of SSRIs, administered 3–6 h before expected sexual intercourse [84–86]. OD treatment with citalopram and paroxetine before sexual intercourse were found to be more efficacious than placebo [84–86]. These data were confirmed by Gameel et al. who reported that daily treatment with paroxetine led to significantly longer mean IELT compared to placebo [85].

A clear advantage of on-demand oral drug treatment is that there is no risk of getting TEAEs of long-term drug intake. Another advantage is that one can use the drug only when it is required for a better sexual performance. However a disadvantage is that on-demand oral drug treatment may negatively interfere with the spontaneity of sexual activity.

Phosphodiesterase Type 5 Inhibitors (PDE-5Is)

PDE-5Is represent the gold standard first-line treatment for ED. PDE-5Is were also proposed as potential treatment for PE; of them, the compounds that have been studied in PE include sildenafil, vardenafil, and tadalafil. A systematic review reported that PDE-5Is treatment was significantly more effective than placebo in increasing IELT [80]. However, the method and designs of studies are insufficient, thus hampering a generalized conclusion of their efficacy in terms of ejaculation delay. However, in the case of acquired PE due to erectile difficulties, ED should be treated first with a PDE-5I [16].

Topical anaesthetic agents—The oldest strategy to treat PE was based on the use of topical anaesthetic agents. To date, several trials have demonstrated the efficacy of topical anaesthetics in reducing the sensitivity of the glans penis thereby delaying ejaculatory latency. By diminishing the glans penis sensitivity it is argued that the spinal and cerebral input of sexually arousable impulses is also reduced.

Two recent meta-analyses confirmed the efficacy and low side effect profile of topical anesthetics [87, 88]. Too much application may cause penile hypesthesia, numbness or erectile difficulties. Transfer of the cream to the female partner may lead to vaginal numbness. Topical anaesthetics are contraindicated in patients or partners with an allergy to any ingredient in the product.

Currently, there are three off-label local anesthetics for the treatment of PE: eutectic mixture of local anesthetics (EMLA) cream, Stud-100 spray, and Promescent spray.

Lidocaine-prilocaine spray—Fortacin™ is a metered-dose aerosol spray that delivers topical anesthesia to the glans penis. It contains purely base (uncharged) forms of the local anesthetics lidocaine 150 mg/ mL and prilocaine 50 mg/mL, with no excipients except the spray propellant (norflurane). The active substances block transmission of nerve impulses in the glans penis, reducing its sensitivity, which is then translated into a IELT delaying without adversely affecting the sensation of ejaculation and orgasm. The clinical efficacy of on-demand Fortacin™ in the treatment of lifelong PE has been evaluated in five studies [89].

The first phase III study showed that Fortacin™ produced significant, clinically meaningful improvements in IELT, control, and satisfaction [90]. Fortacin™ lead to a 6.3-fold and 1.7-fold increase in adjusted geometric mean IELT, demonstrating a significant difference between treatments in favour of the active treatment, which was also efficacious in restoring control with significantly greater increases from baseline to month 3 for the IPE domain scores of ejaculatory control, sexual satisfaction, and distress [90].

The incidence of TEAEs was low in both patients (9.6%) and their female partners (6.0%). The most frequent side effects reported in male patients were local effects of genital hypoesthesia (4.5%) and ED (4.4%). The most frequent side effects reported in female partners were vulvo-vaginal burning sensation (3.9%), and genital hypoesthesia (1.0%).

Tramadol—Tramadol exhibits an effect both on the opioid receptor (activation) acting as an analgesic, and on the re-uptake inhibition of serotonin and noradrenaline; for these reasons in effective in the treatment of PE [16].

Tramadol is readily absorbed after oral administration and has an elimination half-life of 5–7 h.

A randomised, double-blind, placebo-controlled, multicentre 12-week study was carried out to evaluate the efficacy and safety of two doses of tramadol (62 and 89 mg) by ODT in the treatment of PE [91]. In patients with a history of lifelong PE and an IELT <2 min, increases in the median IELT of 0.6 min (1.6-fold), 1.2 min (2.4-fold) and 1.5 min (2.5-fold) were reported for placebo, 62 mg of tramadol ODT, and 89 mg of tramadol ODT, respectively [16, 91]. Other trials showing the efficacy of tramadol vs. placebo have been conducted, but the quality of their design was frequently quite poor to draw definitive conclusions [80].

Overall, pruritus and somnolence were the most common side effects; moreover, tramadol was associated with a negative influence on vigilance. Nausea, vomiting, and dizziness were less frequently complaints.

Tramadol may be an effective option for the treatment of PE. However, it may be considered when other therapies have failed because of the risk of addiction and side effects. It should not be combined with an SSRI because of the risk of serotonin syndrome, a potentially fatal outcome. Further well-controlled studies are required to assess the efficacy and safety of tramadol in the treatment of PE patients (LOE2).