Premature ejaculation (PE) is considered to be the most common male sexual dysfunction. The realization that PE may co-exist with ED prompted the use of PDE5-i's alone or in combination with selective serotonin reuptake inhibitors (SSRIs) for treating ejaculatory disorders. Until recently, there was little evidence that PDE5-i's alone may have a role in the treatment of PE in the absence of ED, and current available treatments include only on-demand dapoxetine. However, available data indicate that there is clinical, anatomical, physiological, pharmacological and genetic evidence to explain the efficacy of PDE5-i's. Nine manuscripts that examined the efficacy of PDE5-i's in the treatment of PE, alone or in combination with SSRIs, were retrieved. All studies reported some significant changes in the intravaginal ejaculatory latency time and sexual satisfaction scores, although not all were clinically meaningful. Well-designed multicenter studies are urgently required to further elucidate the efficacy and safety, as well as the mechanisms of action of PDE5-i's in the treatment of PE. The aim of this review is to discuss basic rationale and to show clinical evidence sustaining the possibility to use off-label PDE5-i's to treat PE.
Premature ejaculation (PE) is a common male sexual dysfunction, with prevalence rates of 20–30% in the general community.1 PE may be classified as either primary (lifelong; LL) or secondary (acquired). The latter differs in that sufferers develop early ejaculation at some point in their life having previously had normal ejaculation experiences; it may be due to psychological or relationship problems, ED, prostatitis or thyroid dysfunction.2 However, it remains poorly defined and inadequately characterized. As a result, there is disparity between the reported incidence of PE in many epidemiological studies3 (which rely heavily on self-reported PE) and the incidence suggested by community-based normative stop-watch intravaginal ejaculatory latency time (IELT) studies.4 The core symptoms of PE include early ejaculation and the inability to delay ejaculation, resulting in personal and interpersonal distress, bother, frustration and/or avoidance of sexual intimacy. The etiology of PE is unknown, with little data to support suggested biological and psychological hypotheses, including anxiety, penile hypersensitivity and serotonin receptor dysfunction.5 In contrast to ED, the prevalence of PE is not affected by age.2
Men with LL-PE suffer from early ejaculations from their first sexual contacts. At almost each coitus and with every woman or sexual partner, they experience an early ejaculation. Limited data suggest that the prevalence of LL-PE is as low as 2–5%.6 It is defined as a male sexual dysfunction characterized by a cluster of core symptoms including ejaculation, which always or nearly always occurs before or within ≈1 min of vaginal penetration, the inability to delay ejaculation on all or nearly all vaginal penetrations, as well as negative personal consequences, such as distress, bother, frustration and/or avoidance of sexual intimacy.7 The 1-min IELT threshold should not be applied in the most absolute sense and must be interpreted as giving the clinician sufficient flexibility to diagnose PE also in men who report an IELT as long as 90 s.7 A diminished ability to delay ejaculation is only valid as a criterion of LL-PE if the same individual always or nearly always ejaculates within ∼1 min.7 Evidence-based definitions seek to limit errors of classification and thereby increase the likelihood that existing and newly developed therapeutic strategies are truly effective in carefully selected dysfunctional populations.8
The aim of this review will be to raise awareness on the use of PDE5-i's in the treatment of PE especially when secondary to ED, even if there are few evidence-based medicines supporting the off-label use of this class of drugs.
Basic rationale for the use of PDE5-i's in PE
Approaching a mechanism of action of PDE5-i's is really twisted because of the uncompleted knowledge of the physiology and the pathophysiology of ejaculation. It is our opinion, derived from both animal and human studies, that PDE5-i's may exert their influence both centrally and peripherally. Possible mechanisms that are involved include relaxing the smooth muscles of vas deferens (VD), seminal vesicle (SV), prostate and urethra,9 decreasing the central sympathetic output, inducing peripheral analgesia, prolonging the duration of erection, increasing confidence, the perception of ejaculatory control, overall sexual satisfaction and decreasing the post-orgasmic refractory time to achieve a second erection after ejaculation.
The nitric oxide (NO)–cyclic guanosine monophosphate (cGMP) pathway seems to have a role in sexual behavior through a central effect as PDE5 has been demonstrated to be expressed in the central nervous system,10 and PDE5-i's can cross the blood–brain barrier.11 Supporting these theories, some authors demonstrated that NO donors increase cGMP in the hypothalamus, and infusion of NO donors to the extracellular environment in the medial preoptic area of the rat's brain induces erection and copulatory behavior.12 NO decreases central sympathetic output to the periphery13 through a cGMP-dependent mechanism or through interactions with other neurotransmitters.14 In particular, a decrease in sympathetic tone by NO activity in the medial preoptic area is related to inhibition of ejaculation.15 Hull et al.16 demonstrated that microinjection of the NO synthase (NOS) inhibitor, NAME (N-nitro-L-arginine methyl ester), decreased the number of erections, but also increased the number of seminal emissions and decreased the latency to the first seminal emission. These results indicate that not only does NO promote erection in intact male rats but it may also inhibit seminal emission. Furthermore, at the central level, it is known that in rats, treatment with vardenafil increases cell proliferation in the dentate gyrus and enhances 5-hydroxytryptamine synthesis and tryptophan hydroxylase expression in the dorsal raphe in a dose- and duration-dependent manner.17 These findings suggest that the increasing effect of vardenafil on neurogenesis is closely associated with the enhancing effect of vardenafil on serotonin expression under normal conditions and could account for by a potential effect on ejaculatory control.
The significance of the L-arginine–NO–cGMP pathway in the regulation of smooth muscle tone in the human genitourinary tract has been recently investigated; however, information on the relevance of NO-mediated signal transduction in the functional control of mammalian SVs is still sparse.18 NOS isoenzymes are present in human SV smooth muscle, and it is known that NO–cGMP and NO–cyclic adenosine monophosphate signaling pathways are not only involved in the relaxation of human penile smooth muscles but they could also affect smooth muscle relaxation in the VD, SV, prostate, urethra and skeletal muscles.19 Thus, cyclic nucleotide-mediated signaling is of importance in the control of the contractile response of human SV and might explain how drugs known to enhance the intracellular production of cyclic adenosine monophosphate and cGMP, such as PDE inhibitors and NO donors, could affect the hyperexcitatory disturbances of ejaculatory function.20 The autonomic control of the human VD and SV is provided by several immunohistochemically distinct nerve populations,21 and NOS is present in a proportion of both the noradrenergic and the non-noradrenergic nerves.22 Thus, evidence for the hypothesis that the contractility of human SV is regulated by the peripheral balance between the generation and degradation of NO and cGMP is present. These findings give a rationale for the use of NO donors in the pharmacotherapy of hyperexcitatory disturbances of ejaculatory function. Both NO donors and PDE5-i's are known to reduce the contractile response of human SVs,23 to reverse postsynaptic contraction of isolated human SV with different potency24 and to inhibit seminal emissions in rats,25 whereas NOS inhibitors, such as L-NAME, decrease the latency to emission.26 It is noteworthy that not only the bladder neck, urethra and prostate but also the SV and VD show a typical mRNA distribution for α-adrenoceptors,27 which accounts for by their capacity to delay or abolish ejaculation reported in clinical studies in men with prostatic hyperplasia (up to 7% of cases reported with tamsulosin). It is supposed that ejaculatory disorders caused by selective α1A-adrenoceptor antagonists are not a result of retrograde ejaculation but a loss of seminal emission (dry ejaculation).28
Epididymal contractile activity is mediated not only by neurotransmitters but also by an array of non-neuronal locally derived factors and hormones, such as oxytocin (OT) and endothelin-1 (ET-1), which create an autocrine–paracrine contractile loop in the epididymis.29 Hence, epididymal epithelial cells retain the capacity to synthesize both OT and ET-1, which mediate epididymal contractility through the activation of their cognate receptors, OT receptor and ET type A receptor. No evidence has been reported on the possible, agonist-mediated, regulation of OT receptor and ET type A receptor expression. Epididymal epithelial cells have been demonstrated to express neurophysin 1, an OT synthesis-associated protein, and a specific ET-1-converting enzyme. In addition, it is known that estrogens could positively regulate both ET-1- and OT-mediated contractility by activating their common downstream effectors. We have recently demonstrated that exposure to tadalafil and sildenafil increases aromatase expression in human adipocytes,30 and that this effect is not reproduced by vardenafil (data not published). Thus, it can be speculated that the lack of prompt increase in local estrogen levels at the epididymis level induced by vardenafil administration may be one of the mechanism/s involved in the control of ejaculatory function (Figure 1). Sildenafil also has a direct inhibitory effect on the smooth muscle of human VD by activation of pre-junctional large-conductance Ca2+-activated K+ channel.31 Consistent with this, Kriegsfeld et al.32 reported that mice homozygous for endothelial NOS gene deletion have striking ejaculatory anomalies. A significantly higher percentage of endothelial NOS gene deletion mice than normal controls ejaculated during the testing period, requiring less stimulation and fewer mounts and intromission.
On the other hand, another presumed cause of PE is penile hypersensitivity, leading to the suggested treatment modality of topical anesthetics. Jain et al.33 have demonstrated that sildenafil exhibited a dose-dependent anti-nociception in both male and female mice, suggesting that sildenafil-induced analgesia is mediated by the inhibition of PDE5 and that its effect can be potentiated by sodium nitroprusside and L-arginine, probably through the activation of the NO–cGMP pathway. However, the evidence that such an effect is also present in humans is weak at present.
Clinical studies assessing the efficacy of PDE5-i's in PE
The pathophysiology of both LL- and secondary-PE seems to be either neuro-biogenic or psychogenic. Although psychogenic factors seem to be contributory to PE, pharmacological intervention of PE can modify both IELT and post-ejaculatory refractory time, which suggest that these measures represent a biological variable, and are likely dependent on different neurotransmitters, such as serotonin, noradrenaline and dopamine. For these reasons, PDE5-i's have been successfully used in combination with either serotonin-selective reuptake inhibitors (SSRIs) or noradrenergic drugs to improve IELT. Nowadays, many studies have demonstrated the effect of different PDE5-i's in prolonging the duration of erection, as part of the rationale of this treatment modality.34, 35 Some studies have correlated the duration of erection with IELT in such a manner that the longer the duration of erection, the more prolonged the post-ejaculatory refractory time. Therefore, PDE5-i's might have a beneficial effect on PE by improving the duration of erection. At present, the mechanisms of action of PDE5-i's in the treatment of PE still need to be elucidated.36 The small number of publications and the lack of sufficient data preclude any meta-analysis of results.
An extensive Medline search was performed including the following words: ‘premature ejaculation’, ‘phosphodiestrase-type 5 inhibitor’ and ‘males’. The search up to 1 May 2010 was restricted to English-language articles and studies of human participants. The identification of relevant abstracts and the subsequent data extraction were performed independently by two of the authors (DF and RB), and conflicts resolved by the third investigator (AA). This systematic review identified 9 studies published in peer-reviewed journals covering a total of 407 subjects suffering from PE and treated with sildenafil, tadalafil and vardenafil either as a monotherapy or in combination with SSRIs or noradrenergic drugs (Table 1); however, only three were randomized placebo-controlled trials using a PDE5-i as a monotherapy (level of evidence=1; grade of recommendation=A). The quality of randomized clinical trials was assessed using some selected parameters among those proposed by Jadad et al.37 The first study compares sildenafil with placebo.38 Although IELT was not significantly improved, sildenafil increased confidence, the perception of ejaculatory control and overall sexual satisfaction, as well as reduced anxiety and decreased the refractory time required to achieve a second erection after ejaculation. The second study compares vardenafil with placebo.39 In this study, patients who took vardenafil (vs placebo) reported significantly increased ejaculatory control, improved overall sexual satisfaction and distress scores, respectively. Interestingly, multiple regression analysis for IELT by the number of attempts at sexual intercourse showed significant differences between the slopes of lines for placebo and vardenafil. Accordingly, the secondary end point of the study demonstrated that vardenafil was effective upon recovery of hard erections for successive sexual intercourse in a shorter time than placebo. This fact might have contributed to the amelioration of parameters of sexual confidence and well-being, as reported by questionnaires. Indeed, this effect on post-ejaculatory refractory time had been previously demonstrated in other pilot studies. In a controlled study in normal healthy volunteers, Aversa et al.40 first demonstrated that 100 mg sildenafil reduced post-ejaculatory refractory time by four to fivefold; these data were further confirmed in normal volunteers by Mondaini et al.41 in a subsequent study using lower doses of sildenafil (25 mg on demand). The third study was aimed to evaluate the effects of vardenafil on IELT in men with LL-PE in a laboratory setting.42 The authors demonstrated that vardenafil exerted a three-fold increase in ejaculation delay outside the vagina compared with placebo in patients with LL-PE. These findings might imply that vardenafil might be a real useful agent in patients with PE.
Comparative studies that aimed to investigate the efficacy of SSRIs and PDE5-i's in the treatment of PE clearly indicate that the latter seem to be superior to other modalities, including topical creams. Mathers et al.43 reported that PE grade improved by 2.7 points in the vardenafil group vs 1.9 points in the sertraline group, and IELT increased by 5 min in the vardenafil group and by 3 min in the sertraline group. Wang et al.44 demonstrated the superiority of sildenafil vs paroxetine and squeeze technique, as well as Abdel-Ahmid et al.,45 who challenged patients with clomipramine and sertraline also. Another study was designed to investigate the efficacy of tadalafil 20 mg on IELT in men with LL-PE, taken before intercourse in association with SSRI taken once a week (fluoxetine 90 mg) or alone.46 The authors found that the increase in IELT was greater in patients who used fluoxetine 90 mg taken once a week and tadalafil 20 mg before sexual relations, when compared with placebo, fluoxetine or tadalafil alone. However, this study had no cross-over of the groups that would probably allow better understanding of whether such results remained consistent. In addition, there was no quality-of-life questionnaire to interpret how satisfied patients were, and no data after discontinuation of treatment were provided. In the remaining studies, the combination of an SSRI plus PDE5-i resulted in a further improvement in both IELT and sexual satisfaction compared with SSRI alone.47, 48, 49 Overall, these were open-label trials without a placebo arm, and included most individuals suffering from secondary PE, presumably as a result of untreated ED. We can conclude that extreme caution should be exercised in interpreting data obtained from inadequately designed studies of PDE5-i's and on-demand SSRI treatment, so that their result should be considered as unreliable due to the extremely broad range of IELT fold increases.
Current indication for the use of PDE5-i's in PE
The current pharmacological management of PE allows the physician to prescribe only newly released on-demand dapoxetine. Dapoxetine, a potent SSRI with a short half-life, is the first officially approved medication for PE. Clinicians need to be familiar with its pharmacology, as there are significant limitations including side effects, onset of activity, duration of pharmacologic activity and dosing strategies that are consistent with sexual behavior that even in optimal circumstances is not a daily event. An integrated analysis of phase III studies clearly showed that in men (n=2228) with PE, dapoxetine 60 mg determined a mean two-fold IELT increase compared with placebo.50 Even if comparative data regarding dapoxetine vs PDE5-i's are not available at present and evidence-based medicine with PDE5-i's is scarce, current data suggest that the latter are superior in terms of IELT fold increase without determining severe adverse events (see Table 1). At present, daily use of SSRIs other than dapoxetine is also commonly used in clinical practice. This chronic, off-label use of SSRIs, the side-effect profiles of which include delaying ejaculation (fluoxetine, sertraline, paroxetine and clomipramine), is still popular but it is associated with an increased adverse event profile encompassing dry mouth, nausea, drowsiness, withdrawal ‘syndrome’ and reduced libido.51 Another promising off-label drug used to treat PE is tramadol HCl, a centrally acting synthetic opioid analgesic that is available in generic form in most countries. A preliminary study by Safarinejad and Hosseini52 suggests that it has a significant effect on IELT at the 50 mg dosage when used on demand. In a subsequent single-blind study,53 on-demand tramadol 25 mg determined a 6.3-fold increase in IELT compared with a 1.7-fold increase with placebo, whereas in the study by Safarinejad and Hosseini, they reported a 13-fold increase in IELT with tramadol 50 mg, which may indicate a dose-dependent effect of the drug in delaying ejaculation. Although its potential mode of action in PE is not clear, tramadol and its primary metabolite might inhibit noradrenaline and serotonin reuptake in addition to their anti-nociceptive actions on μ-opioid receptors. Similar to dapoxetine, tramadol is rapidly absorbed and eliminated and has few side effects,54 which are desirable properties for an as-needed dosing regimen. Notably, PDE5-i's also have modest and transient side effects, with the result to prolong erections so that they can be recommended for men with PE secondary to ED. However, latest clinical controlled trials suggest that there may be some difference between different PDE5-i efficacies in treating PE. In fact, although the efficacy of sildenafil and tadalafil seems to be limited, the more selective vardenafil seems to be a very promising agent.
It is our opinion that PE has a neurobiological origin. Psychological and situational stressors may contribute significantly, as well as associated conditions such as ED, prostatitis, urethritis, prescription and recreational drugs. Ejaculating rapidly is the hallmark of PE; loss of erection before ejaculation is just one sign of ED. Some men with ED have conditioned themselves to ejaculate before loss of erection. In men with concomitant PE and ED, the latter should be treated first. In these men, the use of first-line PDE5-i's combined with behavioral techniques seems to be very promising. Unfortunately, PDE5-i's are not government-approved medicines for PE and have to be administered off-label. Thus, we recommend re-consideration of the use of on-demand PDE5-i's, especially in those men with PE in which dapoxetine is contraindicated or ineffective.
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The authors declare no conflict of interest.
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Cite this article
Aversa, A., Francomano, D., Bruzziches, R. et al. Is there a role for phosphodiesterase type-5 inhibitors in the treatment of premature ejaculation?. Int J Impot Res 23, 17–23 (2011). https://doi.org/10.1038/ijir.2010.34
- intravaginal ejaculatory latency time
- nitric oxide
- sexual distress
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