Document 6430199

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Document 6430199

EURURO-2155; No of Pages 9
european urology xxx (2007) xxx–xxx
available at www.sciencedirect.com
journal homepage: www.europeanurology.com
Review – Sexual Medicine
The Role of Phosphodiesterase Type 5 Inhibitors
in the Management of Premature Ejaculation:
A Critical Analysis of Basic Science and Clinical Data
Juza Chen *, Gal Keren-Paz, Yuval Bar-Yosef, Haim Matzkin
Department of Urology, Tel-Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
Article info
Abstract
Article history:
Accepted August 3, 2007
Published online ahead of
print on August 17, 2007
Objectives: To assess the usefulness of the phosphodiesterase type 5 inhibitors
(PDE5-Is) in the treatment of premature ejaculation (PE) and to describe possible
mechanisms to explain their effect.
Methods: A MedLine search was performed for peer-reviewed articles on the role
of PDE5-Is in managing PE. No meta-analysis method was used.
Results: Five manuscripts that examined the efficacy of PDE5-Is in the treatment
of PE were retrieved. Three studies used sildenafil as monotherapy and two used
it in combination with a serotonin selective reuptake inhibitor (SSRI). Three
studies demonstrated a beneficial effect of sildenafil in the treatment of PE, as
measured by intravaginal ejaculatory latency time (IELT) and by different questionnaires assessing the patients’ subjective feelings of ejaculatory control,
sexual satisfaction, and anxiety. One study showed the superiority of sildenafil
compared to other modalities. Two studies showed that combination therapy of
paroxetine and sildenafil was better than paroxetine alone. One study did not
demonstrate a beneficial effect of sildenafil in prolonging IELT, but showed that
sildenafil improved patients’ perception of ejaculatory control. Another study
showed that topical anesthetics were better than sildenafil in the treatment of
PE but did not use IELT or a validated questionnaire to measure the efficacy
of treatment. Several possible mechanisms could explain effectiveness of the
PDE5-Is for treatment of PE: centrally, through the effect on the nitric oxide/cyclic
guanosine monophosphate pathway; peripherally by causing relaxation of
smooth muscle in the vas deferens, seminal vesicles, prostate, and urethra
and inhibition of adrenergic transmission; or locally by inducing peripheral
analgesia. Another possibility might be prolongation of the duration of erection.
Conclusions: Encouraging evidence supports the role of PDE5-Is for treating PE.
Possible therapeutic mechanisms of action of PDE5-Is are multiple and complex
and include central and peripheral effects. A large population, multicenter,
randomized, double-blind, placebo-controlled study is needed to elucidate the
efficacy of PDE5-Is in the treatment of PE.
Keywords:
Cyclic guanosine
monophosphate
Nitric oxide
Phosphodiesterase 5
inhibitors
Premature ejaculation
Rapid ejaculation
Sildenafil
Tadalafil
Vardenafil
# 2007 European Association of Urology. Published by Elsevier B.V. All rights reserved.
* Corresponding author. Department of Urology, Tel-Aviv Sourasky Medical Center,
6 Weitzmann str., Tel-Aviv 64239, Israel. Tel. +972 36973475; Fax: +972 36974822.
E-mail address: [email protected] (J. Chen).
0302-2838/$ – see back matter # 2007 European Association of Urology. Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.eururo.2007.08.005
Please cite this article in press as: Chen J, et al., The Role of Phosphodiesterase Type 5 Inhibitors in the Management of Premature
Ejaculation: A Critical Analysis of Basic Science and Clinical Data, Eur Urol (2007), doi:10.1016/j.eururo.2007.08.005
2
1.
Introduction
1.1.
Prevalence of premature ejaculation
Ejaculatory dysfunction, erectile dysfunction (ED),
and decreased libido are the major components of
male sexual dysfunction. The introduction of oral
pharmacologic therapy for ED has focused much
attention on this pathology compared to others.
Premature ejaculation (PE), however, is actually
more prevalent, involving up to 31% of men aged
18–59 [1], and is considered to be the most common
among male sexual disorders. PE is more prevalent
in young men and in men who lack sexual
experience and frequency. The risk of PE does not
vary significantly with age, and men with PE are at
risk for suffering from psychological disturbances,
such as depression and anxiety [2].
1.2.
PE definitions
There is no universally accepted definition of PE.
The 4th edition of the Diagnostic and Statistical
Manual of Mental Disorders (DSM-IV) defines PE as
‘‘persistent or recurrent onset of orgasm and
ejaculation with minimal stimulation before, on,
or shortly after penetration and before the person
wishes it,’’ which causes ‘‘marked distress or
interpersonal difficulty’’ [3]. This definition consists of the four elements of PE: ejaculatory
latency, control, distress, and sexual satisfaction.
DSM-IV divides PE into lifelong PE, which had been
present from the onset of sexual life, and acquired
PE, in which the dysfunction developed after a
period of normal sexual function. PE can be further
divided into global (regardless of partner or
situation) and situational (only with certain partners or circumstances). Some authors suggested
defining PE as a syndrome, rather than a complaint, comprising quantification of the ejaculation
time, inability of ejaculatory control, and a
description of severity of PE in terms of psychological distress [4,5]. Still, the absence of an agreedon definition causes wide variations in patient
selection for studies on PE.
1.3.
Physiology of ejaculation and PE pathophysiology
The physiology of ejaculation is still not clearly
understood. Ejaculation involves three stages: emission, ejection, and orgasm. Emission consists of
contractions of seminal vesicles (SVs) and prostate
with expulsion of sperm and seminal fluid into the
posterior urethra and is mediated by sympathetic
nerves (T10–L2). Ejection is mediated by somatic
nerves (S2–4) and involves pulsatile contractions of
the bulbocavernosus and pelvic floor muscles
together with relaxation of the external urinary
sphincter.
Ejaculation is a complex integration of actions
that occur in the central and peripheral nervous
systems. Structures in the central nervous system
(CNS) that are involved in ejaculation include the
medial preoptic area (MPOA), nucleus paragigantocellularis (nPGi), stria terminalis, amygdala, and
thalamus. Whereas the MPOA is involved in stimulation of emission and ejection, the nPGi has an
inhibitory influence. Descending serotonergic pathways from the nPGi to the lumbosacral motor nuclei
inhibit ejaculation. The MPOA can inhibit the nPGi,
which results in ejaculation [6].
Many neurotransmitters are involved in the
control of ejaculation, including norepinephrine,
serotonin, acetylcholine, oxytocin, g-aminobutyric
acid (GABA), and nitric oxide (NO) [7]. Serotonin
(5-hydroxytryptamine [5-HT]) has an inhibitory
effect on ejaculation [8]. The serotonin receptors
5-HT1a and 5-HT2c were associated with ejaculation
[9]. 5-HT1a is a presynaptic autoreceptor that inhibits
serotonin secretion and thus may stimulate ejaculation, whereas the 5-HT2c receptor is postsynaptic
and its activation is related to inhibition of ejaculation [9,10]. NO has a central effect, mostly in the
MPOA, in promoting penile erection, and it may
inhibit seminal emission [11].
Given the obscurity of ejaculation physiology, it
is not surprising that PE pathophysiology is equally
poorly understood. Historically, PE was considered
as being a problem with psychological causes, such
as anxiety, early sexual experiences, sexual conditioning, and sexual technique [12]. It was speculated that anxiety activates sympathetic output
and thus leads to earlier emission and rapid
ejaculation [13]. Currently, a speculated neurogenic cause is either a hyposensitivity of 5-HT2c
receptors or a hypersensitivity of the 5-HT1a
receptors [6]. Other causes might be a hyperexcitable ejaculatory reflex, resulting in faster emission and ejection, prostatic pathologies such as
inflammation or infection [14], high fasting serum
leptin levels [15], hyperthyroidism [16], and genetic
predisposition [17].
1.4.
Current treatments for PE
PE can be treated with behavioral techniques, topical
anesthetics, a-adrenergic receptor antagonists, tricyclic antidepressants, and selective serotonin
reuptake inhibitors (SSRIs). Phosphodiesterase
type 5 inhibitors (PDE5-Is), for example, sildenafil,
3
Self-reported improvement
Both
8
Double-blind
84
Sildenafil alone, sildenafil + EMLA cream,
EMLA cream alone, placebo
PDE5-Is = phosphodiesterase type 5 inhibitors; PE = premature ejaculation; IELT = intravaginal ejaculatory latency time; IIEF = International Index of Erectile Function; IPE = Index of Premature
Ejaculation; DSM-IV = Diagnostic and Statistical Manual of Mental Disorders, 4th edition.
McMahon et al. [19]
Atan et al. [20]
157
Double-blind
8
Lifelong
IELT 3 min
> 50% of time
DSM-IV,
IELT 2 min
DSM-IV
Lifelong
36
Open-label
138
Behavioral treatment, lidocaine,
paroxetine, paroxetine + sildenafil
Sildenafil vs. placebo
Salonia et al. [22]
Chen et al. [23]
80
Open-label
26
Both
Lack of control,
IELT 2 min
IELT 1 min
Lifelong
28
Double-blind
Lifelong vs.
acquired PE
Duration,
wk
Design
Patients,
n
31
Clomipramine, sertraline, paroxetine,
sildenafil, pause-squeeze technique
Sildenafil + paroxetine vs. paroxetine alone
Five manuscripts were found concerning the use of
PDE5-I in PE (Table 1). Two were placebo-controlled
studies [19,20]. None fulfilled the criteria of a level 1
study (double-blind, placebo-controlled, randomized study). Four articles were comparative, using
one or two treatment modalities [20–23]. Three
reports assessed therapy with sildenafil as monotherapy [19–21] and two as combination therapy
with an SSRI [22,23].
In a prospective, randomized, double-blind crossover study, Abdel-Hamid et al assessed the efficacy
of as-needed clomipramine, sertraline, paroxetine,
or sildenafil and the pause-squeeze technique in 31
men with lifelong PE without ED [21]. PE was defined
as patient self-reported intravaginal ejaculation
latency time (IELT) < 2 min and lack or little control
over ejaculation. Sildenafil (50 mg) was given 3–5 h
before intercourse. IELT was measured by the
patient using a stopwatch, and the patient answered
a questionnaire and received a sexual satisfaction
score and an anxiety score. Although all regimens
Treatment
Results
Table 1 – Studies assessing the efficacy of PDE5-Is in the treatment of PE
3.
PE definition
We searched MedLine for peer-reviewed studies published
from January 1, 1990 to February 28, 2007 on treatment with
PDE5-Is for patients suffering from PE and on the pathophysiologic explanation of the action of PDE5-Is on ejaculatory
function. We used the key words ‘‘premature ejaculation,’’
‘‘rapid ejaculation,’’ ‘‘sildenafil,’’ ‘‘tadalafil,’’ ‘‘vardenafil,’’
‘‘PDE5-I,’’ and ‘‘medical treatment of PE.’’ The search was
restricted to publications in the English literature, and letters
to editor were excluded. The results of the individual studies
are presented and discussed; no meta-analysis or integration
of the results was carried out.
Of 111 articles retrieved from the systematic search, we
focused our analysis on the five that appeared in English,
which examined the role of PDE5-Is in the management of
patients with PE. These articles were selected for the quality of
their methodology and the importance of the results presented. We assessed each study protocol in terms of patient
characteristics, definitions of PE used, the study’s primary and
secondary end points, and its outcomes. We obtained
additional information from data of European and International Society for Sexual Medicine guidelines.
Abdel-Hamid et al. [21]
Methods
Authors
2.
Study end points
tadalafil, and vardenafil, inhibit PDE5 both centrally
and peripherally and lead to the accumulation of
intracellular cyclic guanosine monophosphate
(cGMP) [18]. Although used successfully in the management of ED, novel applications include alleviating
PE. In this review, we discuss the role of PDE5-Is in the
treatment of PE and the possible mechanisms of
action of its therapeutic effects.
Stopwatch IELT, sexual satisfaction
score, anxiety score
Stopwatch IELT, IIEF domain,
intercourse frequency
IELT measured by scale,
satisfaction
Stopwatch IELT, IPE
4
showed prolongation of IELT, the effect of sildenafil
was significantly greater (from 1 to 15 min, effective
in 90% of patients) and was correlated to improvement in the sexual satisfaction score and the anxiety
score. The relation between IELT and the questionnaires was not evaluated. The effect of sildenafil
remained during the washout period in 29% of
patients. The incidence of side effects was similar
among groups and included headache, flushing, and
nasal congestion in 18% of the patients who received
sildenafil.
Salonia et al [22] compared the efficacy of
sildenafil and paroxetine to paroxetine alone in
the treatment of 80 potent men with nonorganic PE
as defined by an IELT of <1 min. Eighteen of them
had secondary PE. Forty men received 10 mg
paroxetine daily for 21 d and then 20 mg as needed
for 6 mo, whereas the other 40 men received the
same, only with the addition of as-needed 50 mg
sildenafil 1 h before intercourse. IELT, which was
measured using a stopwatch, was significantly
longer after 6 mo for the patients who received
sildenafil (from a mean of 0.33 min to 5.3 min vs.
4.2 min in patients who received paroxetine alone,
p < 0.05). There were also improvements in intercourse frequency and in sexual satisfaction, as
was measured by the International Index
of Erectile Function (IIEF) questionnaire. Side
effects were more frequent in the group that
received the combination therapy, with 20%
complaining of headache and 15% of flushing.
Nevertheless, 90% of the patients were willing to
continue therapy.
Chen et al [23] examined the efficacy of sildenafil
as adjuvant therapy with paroxetine in potent
patients with primary PE. Patients who reported
that PE occurred in >50% of intercourse attempts
and had a self-reported IELT < 3 min (measured
qualitatively using a questionnaire) were enrolled.
All 138 patients received psychological and behavioral counseling in addition to topical lidocaine
treatment. Patients who remained dissatisfied after
3 mo were then treated with paroxetine daily for 30 d
and then on an as-needed basis. After an additional
3 mo, 25–100 mg sildenafil was added 1 h before
intercourse to dissatisfied patients. Of the 58
patients who received adjuvant sildenafil, 56 were
satisfied (97%) compared to 42% who were satisfied
with paroxetine alone and 28% who were satisfied
with topical lidocaine.
In a randomized, 8-wk, double-blind, placebocontrolled multicenter study, McMahon et al [19]
assessed the efficacy of 50–100 mg as-needed
sildenafil in 157 potent men with lifelong PE, defined
according to DSM-IV criteria and with IELT < 2 min
in 75% of intercourse attempts. IELT, which was
measured using a stopwatch, was prolonged in
patients who were taking sildenafil, but the difference was not statistically significant. The patients
were asked to answer the Index of Premature
Ejaculation (IPE) questionnaire. There was no significant difference in the overall IPE score, but
patients who were taking sildenafil had significantly
higher scores on questions assessing ejaculatory
control and confidence as well as overall sexual
satisfaction. Sildenafil also significantly shortened
the refractory time after orgasm. The correlation
between IELT and the IPE questionnaire was not
evaluated.
Atan et al [20] compared the efficacy of sildenafil
alone, sildenafil with topical EMLA cream, topical
EMLA cream alone, and placebo in 84 potent patients
with lifelong and acquired PE. PE was defined
according to the DSM-IV definition, and improvement was determined solely on the basis of patients’
statement after eight attempts at intercourse. IELT
was not measured. Twenty patients received placebo for 2 mo, 20 patients received 50 mg sildenafil
45 min before intercourse, 22 patients received
sildenafil and topical EMLA cream before intercourse, and 22 patients received EMLA cream alone.
There was no significant improvement in PE
between sildenafil alone and placebo. Only the
groups that received EMLA cream with or without
sildenafil showed significant improvement in PE.
Only the patients who received sildenafil experienced side effects, which included headaches (26%)
and flushing (26%).
We found no peer-reviewed publications on the
role of tadalafil or vardenafil in the treatment of PE,
other than abstracts presented at international
conferences [24,25].
4.
Discussion
4.1.
Possible mechanisms of actions of PDE5-Is in PE
The physiology of ejaculation and the pathophysiology of PE are still not fully understood. Likewise, the mechanisms of action of PDE5-Is in the
treatment of PE still need to be elucidated. Nevertheless, several possible mechanisms could
explain their effects in PE, as has been demonstrated in animal and human studies. PDE5-Is may
exert their influence both centrally and peripherally. We will describe the presence and affects of
the NO/cGMP pathway, the presence of PDE, and
the possible actions of PDE5-Is in each nervous
system.
4.1.1.
Central mechanisms
The NO/cGMP pathway seems to play a role in sexual
behavior via a central effect, as nitric oxide synthase
(NOS) and guanylate cyclase are present and active
in areas of the CNS that are responsible for sex
drive and sexual behavior [26]. Some authors have
demonstrated that NO donors increase cGMP in the
hypothalamus, and infusion of NO donors to the
extracellular environment in the MPOA of rat’s brain
induces erection and copulatory behavior [11]. NO
decreases central sympathetic output to the periphery [27] via a cGMP-dependent mechanism or
through interactions with other neurotransmitters
[28]. Specifically, a decrease of sympathetic tone by
NO activity in the MPOA is related to inhibition of
ejaculation [29]. PDE5 has been demonstrated in the
CNS [30], and PDE5-Is can cross the blood–brain
barrier into the brain [31]. Administration of sildenafil intrathecally in rats increases NO and cGMP in
the MPOA [32]. Moreover, incubation of rat hippocampal slices with vardenafil results in an increase
of cGMP [33].
4.1.2. Peripheral mechanisms
4.1.2.1. Relaxation of smooth muscle in the VD, SVs, prostate,
and urethra. Because the NO/cGMP and NO/cyclic
adenosine monophosphate (cAMP) signaling pathways are involved in relaxation of corporal smooth
muscles, they could also affect smooth muscle in
the VD, SVs, prostate, and urethra. Many lines of
evidence support the presence and activity of the
NO/cGMP and NO/cAMP signaling pathways in the
VD, smooth muscles, prostate, and urethra. Nitrergic innervation and NO synthase activity have
been detected in human VD, SVs, prostate, urethra,
and skeletal muscles [34–37]. NO and NO-donating
agents have been shown to inhibit seminal emissions
in rats [38], whereas NO inhibitors decrease the
latency to emission in rats [39] and reduce the
contractile response of guinea pig VD and human
SVs [40,41]. Moreover, one study on knockout mice
demonstrated that mice homozygous for a deletion in
the gene for endothelial NOS (eNOS) have shorter
latency times with much less stimulation than wildtype mice [42]. Elevation of intracellular cGMP and
cAMP leads to relaxation of smooth muscle in rat and
guinea pig VD [40,43] and in human SVs [44]. PDE5
activity has been demonstrated in the VD, SVs,
prostate, and skeletal muscles [45–48], and sildenafil
has been shown to cause selective potentiation of
nitrergic transmission in urogenital smooth muscle
in mice [49].
Another way in which PDE5-Is can prolong latency
is by inhibiting adrenergic transmission. PDE5-I was
able to reverse adrenergic tension in human prostatic
5
strip preparations [50], and adrenergic transmission
in human VD was inhibited by sildenafil [51].
Medina et al described a mechanism that is independent of the NO/cGMP pathway. They demonstrated that sildenafil also has a direct inhibitory
effect on smooth muscle of human VD by activation
of pre-junctional large conductance Ca2+-activated
K+ channel [51].
4.1.2.2. Induction of peripheral analgesia. One presumed
cause of PE is penile hypersensitivity, leading to the
suggested treatment modality of topical anesthetics.
Sildenafil may mimic this effect given that activation of the NO/cGMP signaling pathway by sildenafil
was shown to induce a state of peripheral antinociception [52]. Another explanation for peripheral
analgesia could be mechanical. PDE5-Is cause
cavernosal congestion by maximal dilatation of
blood vessels supplying the corpus cavernosum,
leading to an increase in intracavernosal volume
and, therefore, to increased pressure on nerve
receptors, thus causing hypoesthesia of the glans
penis and prolongation of ejaculatory latency time.
This theory, however, is highly controversial [53].
4.1.2.3. Prolongation of the duration of erection. To date,
many studies have demonstrated the effect of
different PDE5-Is in prolonging the duration of
erection, as part of the rationale of this treatment
modality in ED. Some works have correlated the
duration of erection with the ejaculation latency time
in such a manner that the longer the duration
of erection, the more prolonged the ejaculatory
latency time [54]. Therefore, PDE5-Is might have a
beneficial effect on PE by improving the duration of
erection.
4.2.
Clinical aspects
4.2.1.
Overall effectiveness of using PDE5-Is for treating PE
Of the five studies we reviewed, three found PDE5-Is
to be helpful in the treatment of PE, whereas two did
not. Three reports assessed the efficacy of sildenafil
as monotherapy [19–21]. One found that sildenafil
was superior to other treatment modalities, such
as clomipramine, sertraline, paroxetine, and the
pause-squeeze technique in terms of IELT and
sexual satisfaction [21]. The other two studies,
which were placebo-controlled, found no significant
advantage to treatment with sildenafil in PE. One
study did not demonstrate any difference between
sildenafil and placebo in terms of improvement in
stopwatch-measured IELT but did show significant
changes in ejaculatory control, confidence, and
overall sexual satisfaction in favor of sildenafil as
6
assessed by the IPE questionnaire [19]. The other
study did not show any advantage of sildenafil over
placebo but rather that topical anesthetics were
better in treating patients with PE; IELT, however,
was not measured and the noted improvement
was based only on the patients’ responses toward
treatment and not according to any validated
questionnaire [20].
Two studies assessed PDE5-Is as part of a
combination therapy with SSRI [22,23]. Both of them
showed that sildenafil with paroxetine is superior to
paroxetine alone in the treatment of PE. Salonia et al
demonstrated improvements in stopwatch-measured IELT, sexual satisfaction, and frequency of
intercourse with sildenafil and paroxetine [22]. Chen
et al showed that the combination of sildenafil and
paroxetine was efficient in 97% of patients so treated
compared to 42% of patients treated with paroxetine
alone [23].
4.2.2.
Differences in PE definitions
The European and International Society for Sexual
Medicine guidelines state that the inclusion criteria
for studies on management of PE must ensure that
participants have PE and no other sexual dysfunction, such as ED, and that the IELT measurement as a
specific entry criterion is not a necessity [55]. The
definition of PE, as reflected by the inclusion criteria,
was varied among the studies we reviewed. All but
one defined PE using IELT, either measured by
stopwatch or self-reported. Two studies defined PE
as IELT < 2 min [19,21], one study defined PE as IELT
< 3 min [23], whereas another defined it as IELT
< 1 min [22]. Two studies used the DSM-IV criteria
for defining PE, one in addition to a measured IELT
[19], whereas the other one based its definition
solely on the DSM-IV [20]. Two more investigations,
which used IELT as a criterion, used also a question
on the subjective feeling of control [21,23]. The
variation in criteria is not surprising in light of the
lack of a widely accepted definition of PE, but
it seems reasonable to include patients with IELT
< 2 min together with a subjective feeling of lack of
ejaculatory control.
4.2.3.
Issues and controversies regarding IELT
The European and International Society for Sexual
Medicine guidelines state that outcome measures
should include IELT, ejaculatory control, and
sexual satisfaction [55]. Only one study did not
use IELT as an end point, but rather patients’ selfreported statements on improvement or no
improvement [20]. All the other studies used IELT
and different questionnaires to assess the patients’
subjective feeling of improvement. IELT in three
studies was measured using a stopwatch [19,21,22]
and in one study based on the patients’ estimations [23].
Although the measurement of IELT by a stopwatch
is the most accepted tool because it is considered to
be ‘‘objective,’’ many authors find this modality to be
controversial, first, due to the inconvenience of the
use of a stopwatch during intercourse, second,
because it may decrease the quality of the sexual
intercourse, and third, because it may not be
acceptable to all patients or their sexual partners.
We believe that the IELT as estimated by the patient
and his partner is comparable to stopwatch-measured IELT and far more convenient.
4.2.4. Overall effectiveness instruments and general
questionnaires
Different types of questionnaires have been used
to assess the patients’ sense of improvement. Two
studies used questionnaires developed originally
for ED patients. Abdel-Hamid et al [21] used an
Arabic questionnaire to assess anxiety and the
first nine items of the sexual satisfaction questionnaire designed originally for ED patients [56]
to assess sexual satisfaction. Salonia et al [22] used
the IIEF questionnaire and a general efficacy question. The other two studies used novel instruments:
Chen et al [23] used a modification of a question from
the Center for Marital and Sexual Health (CMASH)
Ejaculatory Function questionnaire on PE, and
McMahon et al [19] used the IPE and a general efficacy
question. In another PE study [57], we used the Index
of Ejaculatory Control (IEC) 10-item questionnaire,
which was validated and designed to assess the
patient’s feeling of control, sexual satisfaction, and
distress specifically in PE patients [58].
Given that PE may be psychogenic, at least in part,
and possibly related to anxiety while part of its
definition are feelings of lack of ejaculatory control,
bother, and distress, there is considerable room for a
placebo effect in all studies on the management of
PE. For this reason, any well-constructed study
aimed at assessing the effect of PDE5-Is on PE must
be placebo-controlled. In our recent randomized,
double-blind, placebo-controlled, crossover study,
we compared sildenafil with placebo in 61 potent
men with PE [57]. We showed that patients receiving
sildenafil had prolonged IELT compared with those
who received placebo, as measured by a specially
designed visual scale Ejaculatory Latency Time
Questionnaire (ELTQ). Significant improvements
were also observed in the IEC score for patients
who received sildenafil. The number of patients
responding positively to the global assessment
question (‘‘Did you have better control over your
ejaculation?’’) while on sildenafil was significantly
higher than those on placebo ( p < 0.01).
Although ED with PE is considered as an indication for treatment with PDE5-Is [59], we found no
studies that specifically evaluated this condition,
and the studies we did review excluded patients
with ED.
5.
Conclusions
There are limited but encouraging results to support
the use of PDE5-Is in the treatment of patients with
PE with or without additional SSRIs. The physiologic
effects of PDE5-Is in the treatment of PE are multiple
and complex, including central and peripheral
effects, mainly via augmentation of the NO/cGMP
signaling pathway.
Although IELT is an accepted tool for assessing
PE, currently available IELT measurement methods
are not ideal because inherent subjective difficulties in measurement can cause bias in the evaluation of the results. New convenient and efficient
technology to measure IELT, which will be less
dependent on the attention of the sexual partners,
would be very useful. In addition, there is a need to
perform studies to evaluate the correlation between
stopwatch-measured IELT and existing questionnaires.
Finally, the inability to reach decisive clinical
conclusions is derived from the lack of agreed-on
definitions for PE and well-accepted outcome
measures to monitor treatment efficacy. The lack
of conclusive evidence emphasizes the need for a
large population, randomized, double-blind, placebo-controlled study to assess the efficacy of
PDE5-Is in the management of PE.
Conflicts of interest
No authors have direct or indirect financial incentive associated with publication of the article. No
commercial funding was used for preparation of this
manuscript.
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