International Journal of Urology (2016)
13202
Review Article
Current and emerging therapies in premature ejaculation: Where we
are coming from, where we are going
Christopher Martin, Hunter Nolen, Jason Podolnick and Run Wang
Department of Urology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, Texas,
USA
Abbreviations & Acronyms
5-HT = 5-hydroxytryptamine
DPN = dorsal penile nerve
ED = erectile dysfunction
FDA = US Food and Drug
Administration
IELT = intravaginal
ejaculatory latency time
PDE5 = phosphodiesterase
type 5
PE = premature ejactulation
RCT = randomized control
trial
SNRI = serotonin-
norepinephrine reuptake
inhibitor
SSRI = selective serotonin
reuptake inhibitor
TCA = tricyclic
antidepressant
Correspondence: Run Wang
M.D., F.A.C.S., Department of
Urology, McGovern Medical
School, The University of Texas
Health Science Center at
Houston, 6341 Fannin Street,
Suite 6.018, Houston, TX
77030, USA. Email:
run.wang@uth.tmc.edu
Received 8 April 2016; accepted
9 August 2016.
© 2016 The Japanese Urological Association
doi: 10.1111/iju.
Abstract: Premature ejaculation is the most common form of sexual dysfunction
among men. The pathophysiology of premature ejaculation appears to be multifactorial,
implicating the need for multimodal therapeutic regimens to successfully treat premature
ejaculation. Multiple treatment regimens have been shown to be effective in extending
the time between penetration and ejaculation. These treatment modalities include
everything from behavioral modifications and medications to diet alterations and major
surgery. The goal of the present article was to review the commonly used treatment
regimens used in the treatment of premature ejaculation, as well as to introduce and
discuss the newest treatment routines under study for the treatment of premature
ejaculation.
Key words: ejaculation, premature, therapy, treatment.
Introduction
The studies on the prevalence of PE place this pathology as the most common sexual dys-
function among men.1 Various studies have found that between 20% and 30% of men experi-
ence PE; however, this condition is commonly underreported because of embarrassment of
both the patient and the physician, as well as lack of awareness.1 At first glance, the diagnosis
of PE would seem straightforward; however, the diagnostic criteria have been hotly
debated.2,3
There are several competing ideas about the correct way to diagnose PE. A psychological
approach, which was initially used in DSM-IV, diagnoses the pathology based on subjective
feelings rather than utilizing specific cut-off points for ejaculation time.2,3 Using this defini-
tion, PE was defined as ejaculation with both minimal stimulation and before the patient
desires. This use of vague language had the potential to overdiagnose men who do not suffer
from PE, and to underdiagnose men who do.2,3 Recently, this was changed in the DSM-V to
include a cut-off time of ejaculation within 1 min of vaginal penetration that causes signifi-
cant distress.3 In contrast to the psychological theory, a definition created by Waldinger et al.
proposed that PE should be defined solely based on the time between beginning intercourse
and ejaculation, known as the IELT.2 The World Health Organization’s ICD-10 definition of
PE includes both an inability to control ejaculation, as well as a cut-off of ejaculation within
15 s of beginning intercourse.3
This debate over the definition of PE makes the assessment and diagnosis difficult for pro-
viders, further obscuring the prevalence of the pathology and delaying treatment.1–3 For this
reason, it is difficult to determine a true estimate of the prevalence of PE in the population.
Many patients suffering from PE experience increased distress, anxiety and depression, as
well as overall dissatisfaction with sexual intercourse.1,3 Clarifying the diagnostic criteria for
PE might allow undiagnosed patients to receive treatment that could improve their quality of
life.1–3
For the purposes of the present review, we focused on an IELT of <1 min that causes dis-
tress in the individual. We did not delineate between primary and acquired causes, as primary
is much more prevalent and many studies do not readily distinguish between the two. With
this definition in mind, our treatment goal was to extend the time between penetration and
ejaculation. Subjective sexual satisfaction scores were taken into consideration, but were not
the primary outcome focus. Many therapies have been found to be superior to placebo in
RCTs, and are commonly used in practice today. Many treatments can boast an improvement
1
C MARTIN ET AL.
of 75–90%.4 However, even with the best therapies, this mea-
surement does not reflect a cure rate; rather, it shows an
improvement in IELT that could be as low as a single sec-
ond. This fact leaves the all-important question: is there a
true solution to PE? If so, what is it?
Current therapies
Behavioral techniques
Two of the most common behavioral therapies used in the
treatment of PE are the “start–stop” technique and the
“squeeze” technique. Developed by Semans in 1956, the
“start–stop” technique involves stimulating the penis until
one feels the urge to ejaculate, then removing the stimulation
until the urge to ejaculate subsides.5 By repeating this maneu-
ver multiple times before allowing oneself to ejaculate, the
“start–stop” technique allows the patient to improve control
over the ejaculatory response by learning to identify the
physical and emotional parameters involved in arousal.6
Although once considered the gold standard for the treatment
of PE, the “start–stop” technique has been under scrutiny, as
recent studies disagree on the effectiveness of this behavioral-
based treatment.7–9 The “squeeze” technique, established by
Masters and Johnson in 1970, involves squeezing the glans
of the penis until the urge to ejaculate subsides.10 Similar to
the “start–stop” technique, the “squeeze” technique was origi-
nally reported to have a 97.8% success rate; however, this
has not been replicated in more recent studies.11
SSRIs
Although the pathophysiology of PE is relatively unknown,
one hypothesis behind the etiology of PE is the dysfunction
of 5-HT receptors.12 Elevated concentrations of 5-HT are pre-
sent at many receptors that have been found to be involved
with ejaculatory control, and activation of the central 5-HT-
mediated system has an overall inhibitory effect on ejacula-
tion.13 Specifically, activation of 5-HT1B and 5-HT2C recep-
tors has been shown to have inhibitory effects on the
ejaculation pathway, delaying ejaculation, whereas activation
of 5-HT1A receptors has been found to precipitate ejacula-
tion.13 The role of the 5-HT1A in mediating ejaculation is
shown by the fact that fluvoxamine, an SSRI that has a high
specificity for the 5-HT1A receptor, does not show a signifi-
cant increase in IELT.13,14
Furthermore, Waldinger et al. proposed that the pathophys-
iology of PE could possibly be a result of hypofunction of
the 5-HT2C receptor and/or hyperfunction of the 5-HT1A
receptor.14,15 This hypofunction of the 5-HT2C receptor, as
well as low levels of 5-HT transmission in general, is thought
to be associated with a low threshold for sexual arousal and
ejaculation. SSRIs can activate 5-HT2C receptors and raise
this threshold, subsequently increasing the IELT.15
It is believed that SSRIs induce delayed ejaculation by
inhibiting presynaptic and somatodendritic serotonin trans-
porters, thereby increasing total central 5-HT neurotransmis-
sion and activation of postsynaptic 5-HT receptors.16 An
alternate theory is that by increasing the amount of serotonin
in the synaptic cleft, SSRIs desensitize 5-HT1A and 5-HT1B
2 © 2016 The Japanese Urological Association
receptors, causing an overall inhibitory effect on the ejacula-
tion pathway.16 The effect of SSRIs on PE has been seen as
early as a few days after starting the medication; however,
most patients notice a significant increase in ejaculatory time
1–2 weeks after beginning the medication, strengthening the
thought that SSRIs treat PE through receptor desensitiza-
tion.17 Furthermore, because 5-HT receptor desensitization
can cause the body to upregulate the production of 5-HT
receptors, the efficacy of SSRIs might decrease after 6–
12 months of consistent use.17
SSRIs used in the off-label treatment of PE include fluox-
etine, paroxetine, citolapram, fluvoxamine and sertraline.12
Currently, no SSRIs are approved by the FDA for the treat-
ment of PE. One SSRI, dapoxetine hydrochloride, has been
approved for the treatment of PE in some European and
Asian countries.18 Adverse effects, such as reduced libido,
mild headache, nausea, sweating and dizziness, have been
associated with the use of SSRIs.19
SNRIs
SNRIs are a class of drugs commonly used in the treatment
of psychiatric disorders and chronic pain syndromes.20,21
SNRIs, by increasing serotonin and norepinephrine in the
synaptic cleft, might have a role in the management of PE
given the hypothesis that the pathophysiology of PE could
stem from the abnormal neuromodulation of central and
peripheral serotonin receptors.13 Athanasios et al. showed
that duloxetine, when compared with a placebo, increases
IELT in patients suffering from PE.22 Furthermore, dulox-
etine was shown to increase sexual desire and partner satis-
faction when used in patients with PE.22 Because personal
distress and perceived control over ejaculation are thought to
play a vital role in the pathophysiology of PE, duloxetine
might also help patients with PE through regulation of mood
and emotions.23–25 One study carried out by Ozcan et al.
showed that duloxetine improved IELT, as well as personal
distress related to control over ejaculation, in men with PE.26
TCAs
Because primary PE is thought to be a result of dysfunc-
tional 5-HT receptors, TCAs are another class of drugs that
have been studied in the treatment of this condition. The
first published study showing the effectiveness of TCAs in
the treatment of PE was carried out by Eaton in 1973. In
that study, Eaton reported that there was “an almost 100%
positive reaction” when using clomipramine in the treatment
of PE.27 Like SSRIs and SNRIs, TCAs exert their effects
by acting as serotonin and norepinephrine transport inhibi-
tors, increasing the amount of serotonin and norepinephrine
in the synaptic cleft, and delaying ejaculation through activ-
ity at 5-HT receptors.15,28 There have been multiple studies
showing that TCAs, particularly clomipramine daily, have a
positive effect on sexual satisfaction when used to treat
PE.29–31 In fact, one study showed that daily clomipramine
had a greater effect on IELT than fluoxetine or sertraline.32
Compared with other TCAs, clomipramine has been shown
to have a particularly strong affinity for serotonin

transporters, possibly explaining why it has a stronger effect
on PE than other TCAs.28 The effect of clomipramine might
also be enhanced by its ability to inhibit contraction of the
vas deferens, which plays a role in ejaculation.13 One draw-
back of using TCAs is the side-effect profile, which
includes, fatigue, nausea, dry mouth, hypotension, flushing
and dizziness.32
Local anesthetics
One of the physiological factors believed to play a role in
the pathophysiology of PE is a hypersensitive response to
penile stimulation.33 The ejaculatory response consists of an
afferent neuronal input, which is carried through the puden-
dal nerves and is triggered by penile stimulation, and an
efferent neuronal output carried by the sympathetic nerves
of the T10–T12 paraspinal sympathetic ganglia to the male
reproductive organs to trigger ejaculation.34 Multiple studies
have shown that men with PE have a lower penile vibratory
threshold, higher bulbocavernosus-evoked potentials and lar-
ger dorsal nerve somatosensory evoked potential ampli-
tudes.33,35–37 These findings suggest that by masking the
sensory input from the glans through local anesthetics
applied directly to the penis, men who suffer with PE could
increase their IELT.38 Local anesthetics are membrane-stabi-
lizing drugs that inhibit voltage-gated sodium channels,
thereby decreasing synaptic transmission and neuronal
hypersensitivity, thus increasing the threshold for ejacula-
tion.39 Topical anesthetics used in the treatment of PE
include topical lidocaine, benzocaine, prilocaine and SS
Cream. One of the most studied local anesthetic mixtures
used in the treatment of PE is the mixture of lidocaine and
prilocaine. Lidocaine and prilocaine are two solids that
when mixed together form a liquid mixture without the use
of a solvent.40 This cream, which contains 2.5% of both
lidocaine and prilocaine and has been named EMLA or
eutectic mixture of local anesthetic, has been shown in mul-
tiple studies to increase patients’ IELT and satisfaction of
sexual performance if applied to the penis before inter-
course.41–43 Tempe, another anesthetic mixture of lidocaine
and prilocaine, is one of the newest products being devel-
oped for the treatment of PE. Unlike most mixtures of lido-
caine and prilocaine, which are creams, Tempe is an aerosol
formulation that is dissolved in a non-chlorofluorocarbon
propellant, which is unique in the fact that it does not pene-
trate fully keratinized skin.44 This allows Tempe to concen-
trate its desensitizing effect on the glans penis, decreasing
the potential for unwanted side-effects.45 The newest local
anesthetic used in the treatment of PE is Promescent.
Promescent is a lidocaine-only topical spray that can be
applied to the penis before intercourse to desensitize the
glans and therefore theoretically increase IELT.46 Currently,
no clinical trials have reported a statistically significant
increase in IELT with the use of Promescent. Promescent is
unique in the fact that it does not contain prilocaine, which
when applied topically can cause the unusual side-effect of
methemoglobinemia.47 Promescent, unlike Tempe, was
allowed by the FDA for treatment of PE, and is available
prescription-free in North America.48
© 2016 The Japanese Urological Association
Current and emerging therapies in PE
Tramadol
Tramadol is a potent centrally acting opioid-based analgesic
used in the treatment of acute and chronic pain.49 Tramadol
exerts its analgesic effects by binding to centrally located mu
opioid pain receptors, and by inhibiting the reuptake of both
serotonin and norepinephrine.50 Interestingly, tramadol has
also been shown to act as a 5-HT2C receptor antagonist.51 It
is thought that tramadol’s effectiveness in the treatment of PE
is due to the neuromodulation of serotonin and nore-
pinephrine receptors.51,52 Tramadol has shown promising
results in multiple studies examining its use in the medical
management of patients with PE.53–58 Khan et al. showed a
significant increase in IELT in patients that were treated with
tramadol.53 A comprehensive meta-analysis carried out by
Wu et al. showed an increase in IELT of 3 min when com-
paring tramadol with a placebo.54 Unlike other treatments for
PE, tramadol does have a potential for both abuse and depen-
dence; however, these episodes are rare, especially in patients
that use tramadol intermittently.55
Alpha-blockers
The prostate and the seminal vesicles play a vital role in the
physiology of ejaculation, and the smooth muscle of both of
these organs contains alpha-1 receptors.59,60 Considered the
gold standard for the treatment of lower urinary tract symp-
toms in men with benign prostatic hyperplasia, alpha-1 block-
ers have been reported to cause ejaculatory dysfunction.61
Although this ejaculatory dysfunction was originally thought
to be caused by retrograde ejaculation, recent studies have
shown that it is caused by contraction failure of the seminal
vesicles, resulting in emission reduction.61,62 Given these
data, researchers began studying the effects of alpha-1 block-
ers on the treatment of PE. Multiple studies have shown the
effectiveness of alpha-1 blockers in minimizing PE.63,64 The
most common alpha-1 blockers used in the treatment of PE
include tamsulosin, silodosin, terazosin and alfuzosin, with
all showing a statistically significant increase in IELT.65 At
therapeutic doses, side-effects of alpha-blockers are rare, but
include anorgasmia, dry mouth, nasal congestion, drowsiness
and orthostatic hypotension.66
Phosphodiesterase inhibitors
PDE5 inhibitors are drugs that have been approved by the
FDA for the treatment of ED.67 Recently, multiple studies
have shown that PDE5 inhibitors might also play a role in
the treatment of PE.68–71 The exact mechanism behind the
effectiveness of PDE5 inhibitors in the medical management
of patients with PE is currently unknown. In a systematic
review on the efficacy of PDE5 inhibitors in the treatment of
PE, McMahon et al. hypothesized that PDE5 inhibitors might
exert their effects through multiple mechanisms including
reduced performance anxiety, increased nitric oxide release,
reduced sympathetic tone, and dilatation of the smooth mus-
cle of the vas deferens and seminal vesicles, which could
possibly delay ejaculation.70,72 Frequently prescribed off-label
as a treatment for PE, sildenafil, a commonly used PDE5, has
3
C MARTIN ET AL.
been shown to be helpful in the treatment of PE.73 However,
studies are conflicting on the effectiveness of sildenafil
monotherapy on IELT, with some studies failing to show any
significant increase in IELT, whereas others show an increase
in IELT.74,75 Furthermore, sildenafil has been shown to be
more effective in increasing IELT and sexual satisfaction
when supplemented with paroxetine.76 One drawback in the
use of sildenafil and paroxetine as a duo therapy for PE is in
increase in adverse side-effects.76 In patients that suffer from
both ED and PE, PDE5 inhibitors should be considered as a
first-line treatment in the medical management of PE.75
Experimental treatments
Dorsal nerve modulation
Modulation of the DPN currently shows promising potential
as a treatment for PE.77–81 Patients with PE have been found
to have an increased number of branches of their DPN.82,83
This increased frequency could be a potential cause of the
increased sensitivity found in patients with PE. With knowl-
edge of this underlying pathophysiology, the two resulting
treatment options are modulation of the nerves or permanent
ablation. Two trials involving DPN resection increased the
IELT compared with placebo.80,81 Interestingly, the authors
were able to include a placebo arm to the trial by using cir-
cumcision as the control procedure.80 Of the previous trials
involving dorsal nerve ablation, the longest follow up was
<2 years.80,81
Although there has been no trial comparing modulation
with ablation, radiofrequency modulation seems the more
viable option moving forward. Dorsal nerve modulation has a
theoretical decreased permanency and risk of ED.79 Neuro-
modulation has already been proven safe and effective in
dealing with urinary and fecal incontinence.84 So far, the evi-
dence for treatment based on neuromodulation is weak, as
only case series have been carried out.79 Prospective cohorts
or RCTs are necessary to verify the validity of the previous
reports. Also, increasing the length of time for follow up after
the treatment is important to identify ongoing rates of ED
after the procedure. Additionally, biothesiometry testing of
the penis in patients with PE before and after dorsal nerve
neuromodulation are also future directions of research.
Acupuncture
The efficacy of acupuncture in treating PE has been tested in
several RCTs.85–87 A systematic review found that just three
RCTs have shown acupuncture to be more effective than a
placebo (sham acupuncture) in treating PE or ED.85
Acupuncture has not been shown to be as effective when
compared with paroxetine; however, acupuncture with electri-
cal stimulation in conjunction with paroxetine was more
effective than paroxetine alone.86,88 Standard acupuncture or
its electrical counterpart is likely not a truly effective individ-
ual treatment for PE. However, with polypharmacy becoming
more of a problem in finding treatments for patients with
multiple comorbidities, having non-pharmacological options
that have shown efficacy can be extremely beneficial. In
future studies, the particular steps of acupuncture and the
4 © 2016 The Japanese Urological Association
location of needle placement need to be more clearly demon-
strated.85 It could be that these treatments involved different
patterns of neural stimulation due to lack of standardization,
leaving the acupuncture treatments in each of these trials dis-
similar. Additionally, further testing of acupuncture as an
adjunctive therapy is likely to be of benefit.
Yoga
Yoga has been proposed as a potential treatment for PE. It
has shown efficacy in significantly prolonging the IELT in
prospective studies.89 However, some trials have shown no
improvement of PE with yoga in comparison with a pla-
cebo.90 The difference in outcomes could be attributed to
longer length of treatment in the statistically significant tri-
als.89,90 Also, the type of yoga was not readily distinguished
between the trials. The underlying mechanism of yoga treat-
ment is unknown. The potential mechanism could lie in
strengthening or decreasing the tension of the pelvic muscu-
lature, but none of the studies included any physical parame-
ters in their data.89,90 Any improvement in IELT could
instead be as a result of the emphasis in yoga for bodily
awareness that could potentially increase the patient’s aware-
ness of impending ejaculation, allowing more effective with-
drawal and pause methods. Future trials need to more readily
include the specific variables of the type of yoga being car-
ried out.
Future developments
Medical or sexual device
The utilization of medical devices to allow an increase in
IELT is a future possibility for the treatment of PE. Surpris-
ingly, although many devices are in the marketplace, none
have been put to scientifically rigorous studies. Unfortunately,
the only study involving a vibration device utilized it in addi-
tion to psychological or behavioral therapy.9 Furthermore, the
devices used in these studies were not designed for men with
PE. Future devices could potentially increase the threshold to
which men with PE respond to sexual stimuli.
Botulinum toxin
Botulinum toxin has been thoroughly utilized in different
aspects of medicine. It is used in dermatology for smoothing
skin; it is used in gastrointestinal for decreasing the hyperto-
nia of dysfunctional sphincters. In urology, it is approved for
treatment of hyperactive bladder or detrusor over activity.91
Botulinum toxin has been proposed as a potential treatment
for PE.92 The mechanism would likely rely on the toxin’s
ability to paralyze the neural end-plate, decreasing the ability
of the muscles associated with ejaculation to contract.92 In
an RCT using rat models, injections of botulinum toxin into
each bulbospongiosus muscle increased the IELT relative to
the group with saline injections.93 Interestingly, there was no
effect on the rats’ ability to achieve and maintain an erec-
tion.93 In transitioning to human studies, it will be increas-
ingly important to measure the effect that the treatment has
on ED and libido.

Circumcision
Circumcision has been proposed as a permanent treatment for
PE caused by hypersensitivity of the glans. In a recent
prospective cohort, patients post-circumcision at 1-year fol-
low up had significantly higher IELT, sexual satisfaction and
subjective control over ejaculation when compared with
uncircumcised controls.94 However, multiple systematic
reviews published 2 years prior found that the rate of PE or
other sexual dysfunctions were not significantly different
between circumcised and uncircumcised men in the general
population.95,96 Another systematic review correlating the his-
tological and anatomical differences caused by circumcision
found that the prepuce does not serve a sexual function, and
circumcision likely has no effect on sexual functioning.97 The
differences between the first study’s findings could be due to
a number of factors. First, circumcision is a surgical proce-
dure, and there was no sham procedure included to account
for its placebo effect.94 Second, there could be a fundamen-
tally different neural or physiological response to circumci-
sion carried out as an adult in comparison with childhood.98
The relationship between PE and circumcision is further mud-
dled, because circumcision after the age of 7 years has been
found to be a risk factor for PE.99 A large prospective cohort
would help to address these issues by following children to
adulthood and determining long-term risks of childhood cir-
cumcision for PE. Also, future trials utilizing circumcision as
a treatment arm need to include a sham procedure to better
act as the placebo arm of the trial.
Caffeine
Caffeine is a recently proposed pharmacological treatment for
PE. A recent double-blind RCT found that using 100 mg of
caffeine 2 h before the onset of intercourse significantly
increased the IELT of patients with PE.100 The paper only
included 40 patients, and the placebo portion of the trial was
not well described.100 However, with the use of caffeine so
ubiquitous in modern society, the ease of treating PE with
over-the-counter caffeine tablets is clearly appealing. There is
a strong social stigma associated with PE. Practitioners might
find that utilizing a treatment that has very little underlying
stigma might help the psychological impact of the patient’s
disease process. Future studies are clearly necessary to eluci-
date the relationship between caffeine and PE. Such studies
will require much larger treatment groups and a more aptly
described placebo arm of the trial. Additionally, it would be
helpful to know the optimal time variable between caffeine
consumption and intercourse. Finally, it could be helpful to
attempt to use consumption of coffee instead of just caffeine
pills.
Penile frenulum lengthening
Lengthening of the penile frenulum has been tested as a
potential treatment for PE. Only one study was found in our
search. A case series involving 34 men with PE and a short-
ened penile frenulum found that surgically increasing the
penile frenulum length led to a significant increase in IELT
© 2016 The Japanese Urological Association
Current and emerging therapies in PE
and subjective sexual satisfaction.101 That study had a signifi-
cant proportion of patients with underlying ED that showed
improvement of these symptoms after treatment.101 Because
of the high comorbidity of ED in this population, the results
of that study are likely due to the improvement of ED leading
to a concomitant improvement in PE.102 Future cross-sec-
tional research would be helpful in understanding the rate of
PE in patients with a shortened penile frenulum; however,
research in the general population is unlikely to be beneficial,
as there are no data suggesting an improvement in erectile
function in patients with an already normal penile frenulum
length.
Varicocelectomy
Varicoceles are another anatomical abnormality that has been
associated with PE.103 Case series have shown that treatment
of a patient’s varicocele increased IELT in patients with and
without PE.103,104 Interestingly, there might be an increase in
erectile function and testicular testosterone production after
treatment.103 The mechanism of varicocelectomy for improve-
ment PE has not been elucidated. It could be as a result of
the increase in postoperative testosterone, improvement in
ED, or a difference in blood flow or testicular pressure. Cor-
relational studies to the incidence of PE in patients with
underlying varicoceles would be helpful to understand this
relationship. However, this treatment will continue to only be
a possible treatment for patients with concomitant PE and
varicocele.
DA-8031
Although SSRIs are already a common treatment for PE, and
dapoxetine has emerged as an on-demand treatment of PE, a
new compound, DA-8031, has shown excellent efficacy in
animal models and could be a viable PE treatment in the
future.105–107 Like the other SSRIs, it works specifically on
the serotonin receptor, increasing the amount of extracellular
serotonin in the dorsal raphe nucleus.106 The molecule works
by inhibiting the muscular contractions of the bulbospongio-
sus muscle, and decreasing seminal vesicle pressure during
both electrical and chemical stimulation of ejaculation in rat
models.107 DA-8031 also increased the IELT in rats without
affecting the mating attempts or the refractory period between
ejaculations.108 Although its pharmacological parameters have
not yet been tested in humans, based on animal models this
medication would likely be used as an on-demand treatment
for PE. Much like dapoxetine in humans, the compound has
a short half-life when consumed orally by rat models.108 DA-
8031 has a half-life of approximately 1.8 h in rats, compared
with dapoxetine’s average of 18 h in humans.18 This could
allow for increased dosages with potentially fewer side-
effects as a result of the rapid removal of the drug from the
body. Future research in human studies needs to readily
appreciate the efficacy of DA-8031 in comparison with cur-
rent SSRIs. Additionally, it will be important to identify DA-
8031’s pharmacological parameters, and determine if it can
be dosed with an improved side-effect profile as a result of
its shortened half-life.
5
C MARTIN ET AL.
Pelvic floor rehabilitation
Pelvic floor rehabilitation in treatment of PE involves steps to
understand and control the contraction of the pelvic muscles
in regard to sexual arousal, sexual stimulus, and ejacula-
tion.109,110 These treatments involve initial sessions in which
patients are taught about the role that pelvic muscles play in
ejaculation, followed by later sessions in which patients learn
how to control those muscles throughout sexual inter-
course.109 It has shown benefit in increasing the IELT in case
series.111 However, this process was only tested on a short-
term basis after treatment, and at 6 months, the effects had
already begun to decrease.111 Pelvic floor rehabilitation was
also not as effective as SSRIs when compared in a random-
ized study. However, the authors failed to include a placebo
arm to the trial, so the total effect of pelvic floor rehabilita-
tion is undetermined.112 Pelvic floor rehabilitation also
improves the quality of erections and increases the intracaver-
nosal pressure.6 Some or all of the improvement in PE could
be due to a concomitant improvement in ED.6 A previous
systematic review noted that behavioral therapies are signifi-
cantly effective both individually and as a combination with
drug therapy.113 It will be important for future studies to
readily identify the specific form of behavioral therapy being
undertaken. Additionally, it would be helpful to compare pel-
vic floor rehabilitation with the traditional “stop–start” or
“squeeze” techniques. Pelvic floor rehabilitation represents a
fairly cheap therapy without the risk of pharmacological side-
effects. Its addition to any existing treatment for PE should
be considered.
Resiniferatoxin
Resiniferatoxin is a naturally occurring plant-based resin,
which is an incredibly potent version of capsaicin.114 The
compound has the ability to activate primary afferent sensory
neurons by increasing calcium permeability. This influx is
initially met with a significant burning sensation followed by
analgesia as a result of neuronal death caused by calcium
overload.115,116 Resiniferatoxin has been shown to improve
IELT in patients with PE.117 Strangely, resiniferatoxin was
significantly more effective in patients with redundant pre-
puce, further complicating the relationship between circumci-
sion and PE.94,95,117 Unfortunately, in patients without
redundant prepuce, the treatment was not more effective than
a placebo, but the study population was particularly small.117
Further study is necessary in nearly every aspect of resinifer-
atoxin’s mechanism and potential utility. It will be important
to compare the efficacy of resiniferatoxin with previously
used anesthetics, and to thoroughly determine the long-term
risk of PE as a result of potentially permanent damage to
nerve endings.
Hyaluronic acid injections
Hyaluronic acid injection is an interesting subcategory of
potential PE treatments. The injections are placed in the der-
mis, increasing the distance between nerve endings and the
skin.118 It serves the dual purpose of decreasing sensation
6 © 2016 The Japanese Urological Association
while increasing the volume and girth of the penile head,
theoretically increasing the sexual satisfaction of the
patient’s partner.118,119 After treatment, patients had an
increased IELT as well as increased satisfaction from both
partners.119,120 However, the constancy of the changes in
the volume of the penis has not been fully deter-
mined.118,119 At 5-year follow up, the injection had
decreased by an average of 15%.121 Additionally, the
authors claim that the injections do not affect erection qual-
ity; however, that determination is not based on standard-
ized criteria.119–121 Future studies of hyaluronic acid will
need to utilize a saline or phosphodiesterase injection to
allow a comparison and placebo arm with continued moni-
toring for exacerbation of erectile function.
Folic acid
Folic acid is water soluble and readily available over the
counter. The vitamin’s cheap cost and absence of negative
side-effects makes it an ideal pharmacological treatment for
PE.122 Folic acid levels have been found to be negatively
correlated with PE, with folic acid deficiency being consid-
ered a risk factor for decreased ejaculatory latency.123
Because of the benefit of SSRIs in the treatment of PE, the
mechanism proposed has been folic acid’s effect on the sero-
tonin pathway.124 However, previous studies have shown a
correlation between folic acid deficiency and ED.125 Addi-
tionally, folic acid supplementation has been shown to
improve erectile function when given concomitantly with a
phosphodiesterase inhibitor.126 Therefore, the association of
folic acid and PE could be due to folic acid’s beneficial effect
on patients’ erectile function.126 Although folic acid appears
to play more of a role in ED, the vitamin’s cheap and benign
nature necessitates thorough study in association with PE.
Ongoing studies need to assess folic acid’s ability to improve
PE when used as monotherapy, as well as its potential aug-
mentation of SSRI treatment.
Experimental animal models
Satureja montana
The plant, Satureja montana has been tested on rat models as
a potential treatment for PE.127 It is unclear how the hypothe-
sis originated, as there are no previous studies or professional
suggestion that the plant had sexual properties. In rat models,
S. montana was able to increase the ejaculatory latency while
also decreasing the refractory time.127 The proposed mecha-
nism included the plant’s ability to increase levels of testos-
terone in male rats.127 Although that study seems promising,
future studies need to further illustrate the underlying mecha-
nism of S. montana. Unfortunately, testosterone levels have
not been found to be a negative predictor for PE in
humans.128,129 In fact, studies have shown that patients with
PE have been found to have higher testosterone levels than
normal controls.128,130 Further study of S. montana in animal
models is necessary to identify its ability to increase the ejac-
ulatory latency. If its mechanism lies outside of its ability to
increase testosterone, then it could still be a potential treat-
ment for PE in the future.
 Current and emerging therapies in PE

Table 1 Premature ejaculation treatment guidelines

Level of evidence
Drug Description (LE) and grade (Gr)
SSRI (dapoxetine on demand; other Activation of 5-HT1B and 5-HT2C receptors have inhibitory effects on the ejaculation LE 1a
SSRIs including citalopram, pathway Gr A
fluoxetine, fluvoxamine, paroxetine
and sertraline daily)
SNRI Increase serotonin and norepinephrine in the synaptic cleft increasing the activation of 5- LE 2b
HT1B and 5-HT2C receptors. May also help alleviate PE through its regulation of mood Gr B
and emotions
Tramadol (on demand) Neuromodulation of serotonin and norepinephrine increasing activation of 5-HT1B and 5- LE 2a
HT2C receptors. Potential for abuse and dependence Gr B
Local anesthetic (lidocaine-prilocaine Decreases the hypersensitive response to penile stimulation LE 1b
cream on demand) Gr A
Alpha-blockers Reduced contraction of seminal vesicles resulting in emission reduction LE 1b
Gr B
PDE5 inhibitors (on demand) Reduced performance anxiety, increased nitric oxide release, reduced urogenital LE 3a
sympathetic tone, and dilatation of the smooth muscle located in the vas deferens and Gr C
the seminal vesicles
TCA (clomipramine daily) Similar to SSRIs, TCAs activate 5-HT1B and 5-HT2C receptors, inhibiting the ejaculatory LE 1a
pathway. One drawback to the use of TCAs is their myriad of adverse side-effects Gr A
Behavioral therapy (“start–stop” and Improved control over the ejaculatory response by learning to identify the physical and LE 3b
“squeeze” technique) emotional parameters involved in arousal Gr C
Dorsal nerve modulation Decreases the sensitivity of the of the penis to physical stimulation LE 2b
Gr C
Acupuncture Mechanism of action is poorly understood LE 2a
Gr B
Yoga Mechanism of action unknown LE 2b
Gr C
Medical or sexual device Experimental LE 5
Gr D
Botulinum toxin Toxin paralyzes the neural end-plate decreasing the ability of the muscles involved in Experimental
ejaculation
Circumcision (use limited to Decreases the hypersensitivity of the glans penis LE 2b
uncircumcised patients) Gr B
Caffeine (on demand) Mechanism of action unknown LE 2b
Gr B
Penile frenulum lengthening Mechanism of action unknown LE 4
Gr C
Varicocelectomy (use limited to Possibly due to an increase in postoperative testosterone, improvement in erectile LE 4
patients with a varicocele) dysfunction, or increase in testicular blood flow Gr C
DA8031 Neuromodulation of serotonin receptors, inhibition of bulbospongiosus contraction, and Experimental
decreased seminal vesicle pressure
Pelvic floor rehabilitation (monotherapy Improvement of erectile dysfunction, improved control over the ejaculatory response by LE 2a
and in combination with drug learning to identify and control the contraction of the pelvic muscles in regard to sexual Gr B
therapy) arousal, sexual stimulus and ejaculation, and increase in intracavernosal pressure
Resiniferatoxin (use limited to patients Increases the neuronal permeability to calcium causing neuronal death via calcium LE 2b
with redundant prepuce) overload thereby decreasing penile sensation Gr B
Hyaluronic acid injections Increase the distance between nerve endings and the skin decreasing penile sensation LE 4
Gr C
Folic acid Affects the synthesis of serotonin LE 5
Gr D
Satureja Montana Increases testosterone levels Experimental in
animal studies
Epelsiban Inhibition of the oxytocin receptor LE 1b (that its use
is NOT effective)

pressure.132 Epelsiban works as an oxytocin receptor antago-

Epelsiban
There is evidence that oxytocin receptors play an important role
in the modulation of ejaculation.131 In rat models, blockade of
the oxytocin receptor has been shown to inhibit ejaculation with-
out affecting the penile musculature or seminal vesicle
nist.133 However, in its only study when randomized and dou-
ble-blinded, it did not perform significantly better than
placebo.134 Although epelsiban might not be effective in treat-
ment of PE, this does not necessarily discredit this class of medi-
cation from being a potential treatment option in the future.

© 2016 The Japanese Urological Association 7

C MARTIN ET AL.

Patient presents with or complains of ejaculating too quickly

Hypertension or History and physical

Alpha Ensure no underlying Erectile PDE-5
blocker enlarged prostate medical condition dysfunction Blocker

Refr t
acto
ry to tmen
trea trea
tme ry to
nt • Have patient measure acto
Refr
IELT
• Drink a cup of caffeinated
coffee two hours prior to
intercourse
Appropriate response to Appropriate response to
treatment or patient • Begin stop and squeeze treatment or patient
satisfied with results technique satisfied with results
and no desire to seek and no desire to seek
additional treatments Refractory to additional treatments
therapy, IELT <1
minute or patient
not satisfied

SSRI/SNRI/DA-
8031
+Pelvic floor rehab
/l

Re sa
sa

n
ou

fra tis
io
ct
ar

ct fie
un

or d
w

sf
Lo

yo
dy

rn
e
til

ot
ec
Er

Add or increase PDE-5 Refractory Add local anesthetic

+/–Condoms

Large component negative

Large component stress
rumination

Sexual Refractory
Yoga or
counseling acupuncture

Consider surgical options

Circumcision, hyaluronic acid
injections, or dorsal nerve modulation

Fig. 1 Flowchart outlining a potential treatment algorithm for the practicing urologist with advanced knowledge of premature ejaculation treatments.

8 © 2016 The Japanese Urological Association


Conclusions
Moving forward, urologists, psychiatrists and primary care
doctors alike have to tailor their treatment of PE to the patient
as an individual to improve outcomes. Each presentation of PE
is unique in and of itself. As we increase our understanding of
PE, a single cause has not been found; instead, we continue to
discover underlying differences in patients with PE. A patient’s
pathology has the potential to have different amounts of
anatomical, physiological and psychological components, and
the understanding of how each of these processes works
together is difficult to elucidate pathophysiologically. As medi-
cal professionals strive to discover new treatment options for
PE, it will be imperative to continue developing multimodal
therapeutic regimens using both current and emerging therapies
in order to expand treatment strategies for resistant cases
(Table 1). One potential strategy is the development of a stan-
dardized treatment algorithm (Fig. 1). With such an algorithm,
clinicians can initially utilize the most successful and cost
effective treatment options, adding or exchanging additional
treatments based on patient response and the suspected under-
lying disease process.
Acknowledgment
This study did not require approval by the institutional
review board at McGovern Medical School at the University
of Texas Health Science Center at Houston, Texas, USA.
Conflict of interest
None declared.
References
1 Patrick DL, Althof SE, Pryor JL et al. Premature ejaculation: an observa-
tional study of men and their partners. J. Sex. Med. 2005; 2: 358–67.
2 Waldinger MD. Relevance of an evidence-based ejaculation time cutoff
point for neurobiological research of premature ejaculation. J. Comp. Neu-
rol. 2005; 493: 46–50.
3 Serefoglu EC, McMahon CG, Waldinger MD et al. An evidence-based uni-
fied definition of lifelong and acquired premature ejaculation: report of the
second international society for sexual medicine ad hoc committee for the
definition of premature ejaculation. Sex. Med. 2014; 2: 41–59.
4 Gameel TA, Tawfik AM, Abou-Farha MO, Bastawisy MG, El-Bendary
MA, El-Gamasy AEN. On-demand use of tramadol, sildenafil, paroxetine
and local anaesthetics for the management of premature ejaculation: a ran-
domised placebo-controlled clinical trial. Arab. J. Urol. 2013; 11: 392–7.
5 Semans JH. Premature ejaculation: a new approach. South. Med. J. 1956;
49: 353–7.
6 Cooper K, Martyn-St James M, Kaltenthaler E et al. Behavioral therapies
for management of premature ejaculation: a systematic review. Sex. Med.
2015; 3: 174–88.
7 Seftel AD, Althof SE. Premature ejaculation. In: Mulcahy JJ (ed). Diagnosis
and Management of Male Sexual Dysfunction. Igaku-Shoin, New York,
1997; 196–203.
8 de Carufel F, Trudel G. Effects of a new functional-sexological treatment
for premature ejaculation. J. Sex Marital Ther. 2006; 32: 97–114.
9 Jern P. Evaluation of a behavioral treatment intervention for premature ejac-
ulation using a handheld stimulating device. J. Sex Marital Ther. 2014; 40:
358–66.
10 Masters W, Johnson V. Human Sexual Inadequacy. Little Brown & Co,
Boston, 1970.
© 2016 The Japanese Urological Association
Current and emerging therapies in PE
11 Melnik T, Althof S, Atallah AN, Puga ME, Glina S, Riera R. Psychosocial
interventions for premature ejaculation. Cochrane Database Syst. Rev. 2011;
CD008195.
12 Wespes EC, Eardley I, Giuliano F et al. Guidelines on Male Sexual Dys-
function: Erectile Dysfunction and Premature Ejaculation. European Associ-
ation of Urology, Arnhem, 2013.
13 Giuliano F. 5-Hydroxytryptamine in premature ejaculation: opportunities for
therapeutic intervention. Trends Neurosci. 2007; 30: 79–84.
14 Waldinger MD, Olivier B. Selective serotonin reuptake inhibitors (SSRIs)
and sexual side effects: differences in delaying ejaculation. In: Sacchetti E,
Spano EP (eds). Advances in Preclinical and Clinical Psychiatry, Vol. I.
Fluvoxamine: Established and Emerging Roles in Psychiatric Disorders.
Excerpta Medica, Milan, 2000; 117–30.
15 Waldinger MD. The neurobiological approach to premature ejaculation. J.
Urol. 2002; 168: 2359–67.
16 Olivier B, van Oorschot R, Waldinger MD. Serotonin, serotonergic recep-
tors, selective serotonin reuptake inhibitors and sexual behaviour. Int. Clin.
Psychopharmacol. 1998; 13(Suppl 6): S9–14.
17 Waldinger MD. Premature ejaculation: definition and drug treatment. Drugs
2007; 67: 547–68.
18 McMahon CG. Dapoxetine: a new option in the medical management of
premature ejaculation. Ther. Adv. Urol. 2012; 4: 233–51.
19 Montague DK, Jarow J, Broderick GA et al. AUA guideline on the pharma-
cologic management of premature ejaculation. J. Urol. 2004; 172: 290–4.
20 Cipriani A, Koesters M, Furukawa TA et al. Duloxetine versus other anti-
depressive agents for depression. Cochrane Database Syst. Rev. 2012;
CD006533.
21 Bril V, England J, Franklin GM et al. Evidence-based guideline: treatment
of painful diabetic neuropathy. Neurology 2011; 20: 1758–65.
22 Athanasios Z, Polyanthi P, George K. The efficacy of duloxetine in the
treatment of premature ejaculation. Int. Urol. Nephrol. 2007; 39: 115–8.
23 Basu M, Duckett JR. Update on duloxetine for the management of stress
urinary incontinence. Clin. Interv. Aging 2009; 4: 25–30.
24 Giuliano F, Patrick DL, Porst H et al. Premature ejaculation: results
from a five-country European observational study. Eur. Urol. 2008; 53:
1048–57.
25 Patrick DL, Rowland D, Rothman M. Interrelationships among measures of
premature ejaculation: the central role of perceived control. J. Sex. Med.
2007; 4: 780–8.
26 Ozcan L, Polat EC, Otunctemur A, Ozbek E. Duloxetine, dual serotonin
and norepinephrine reuptake inhibitor, versus paroxetine, selective serotonin
reuptake inhibitor, in the treatment for premature ejaculation. Int. Urol.
Nephrol. 2015; 47: 283–7.
27 Eaton H. Clomipramine in the treatment of premature ejaculation. J. Int.
Med. Res. 1973; 1: 432.
28 Gillman PK. Tricyclic antidepressant pharmacology and therapeutic drug
interactions updated. Br. J. Pharmacol. 2007; 151: 737–48.
29 Strassberg D, Brazao CDG, Rowland D, Tan P, Slob A. Clomipramine in
the treatment of rapid (premature) ejaculation. J. Sex Marital Ther. 1999;
25: 89–101.
30 Segraves R, Saran A, Segraves K, Maguire E. Clomipramine versus placebo
in the treatment of premature ejaculation: a pilot study. J. Sex Marital Ther.
1993; 19: 198–200.
31 Althof S, Levine S, Corty E, Risen C, Stern E, Kurit D. A double-blind
crossover trial of clomipramine for rapid ejaculation in 15 couples. J. Clin.
Psychiatry 1995; 56: 402–7.
32 Kim SC, Seo KK. Efficacy and safety of fluoxetine, sertraline and clomipra-
mine in patients with premature ejaculation: a double-blind, placebo con-
trolled study. J. Urol. 1998; 159: 425–7.
33 Xin ZC, Chung WS, Choi YD, Seong DH, Choi YJ, Choi HK. Penile sensi-
tivity in patients with primary premature ejaculation. J. Urol. 1996; 156:
979–81.
34 Guyton AC. Textbook of Medical Physiology. W.B. Saunders, Philadelphia,
1991.
35 Xin ZC, Choi YD, Rha KH, Choi HK. Somatosensory evoked potentials in
patients with primary premature ejaculation. J. Urol. 1997; 158: 451–5.
36 Vignoli G. Premature ejaculation: new electrophysiologic approach. Urology
1978; 11: 81–2.
37 Colpi GM, Fanciullacci F, Beretta G, Negri L, Zanollo A. Evoked sacral
potentials in subjects with true premature ejaculation. Andrologia 1986; 18:
583–8.
9
C MARTIN ET AL.
38 Dinsmore WW, Hackett G, Goldmeier D et al. Topical eutectic mixture for
premature ejaculation (TEMPE): a novel aerosol-delivery form of lidocaine-
prilocaine for treating premature ejaculation. BJU Int. 2007; 99: 369–75.
39 Yagiela JA. Vasoconstrictor agents for local anesthesia. Anesth. Prog. 1995;
42: 116–20.
40 Wyllie MG, Powell JA. The role of local anaesthetics in premature ejacula-
tion. BJU Int. 2012; 110: E943–8.
41 Berkovitch M, Keresteci AG, Koren G. Efficacy of prilocaine-lidocaine cream
in the treatment of premature ejaculation. J. Urol. 1995; 154: 1360–1.
42 Atikeler MK, Gecit I, Senol FA. Optimum usage of prilocaine-lidocaine
cream in premature ejaculation. Andrologia 2002; 34: 356–9.
43 Busato W, Galindo CC. Topical anaesthetic use for treating premature ejac-
ulation: a double-blind, randomized, placebo-controlled study. BJU Int.
2004; 93: 1018–21.
44 Henry R, Morales A, Wyllie MG. TEMPE: topical eutectic-like mixture for
premature ejaculation. Expert Opin. Drug Deliv. 2008; 5: 251–61.
45 Dinsmore WW, Wyllie MG. PSD502 improves ejaculatory latency, control
and sexual satisfaction when applied topically 5 min before intercourse in
men with premature ejaculation: results of a phase III, multicentre, double-
blind, placebo-controlled study. BJU Int. 2009; 103: 940–9.
46 Gilbert R. Promescent. Absorption Pharmaceuticals, LLC (Online), 2015.
(Cited 3 Mar 2016.) Available from URL: https://www.promescent.com/
about-promescent/promescent-and-psd-502.
47 Astra Pharmaceutical Products Inc. Brief Summary of Prescribing Informa-
tion: Citanest Plain and Citanest Forte {Package insert}. Astra Pharmaceu-
tical Products Inc, Westborough, MA, 1992.
48 Garcia F, Capomacchia A, Kongkeo S, Brock G. Non-medical components
are an important factor in drug delivery in topical therapies: a study of
topical lidocaine therapy for premature ejaculation. Proceedings of the 20th
Annual Fall Scientific Meeting of the Sexual Medicine Society of North
America. Miami Beach, Florida, 2014.
49 Pubchem Open Chemistry Database. Tramadol hydrochloride. [Cited 1 Oct
2016.] Available from URL: https://pubchem.ncbi.nlm.nih.gov/compound/
63013.
50 Leppert W. Tramadol as an analgesic for mild to moderate cancer pain.
Pharmacol. Rep. 2009; 61: 978–92.
51 Ogata J, Minami K, Uezono Y et al. The inhibitory effects of tramadol on
5-hydroxytryptamine type 2C receptors expressed in Xenopus oocytes.
Anesth. Analg. 2004; 98: 1401–6.
52 Bar-Or D, Salottolo KM, Orlando A, Winkler JV; Tramadol ODT Study
Group. A randomized double-blind, placebo-controlled multicenter study to
evaluate the efficacy and safety of two doses of the tramadol orally disinte-
grating tablet for the treatment of premature ejaculation within less than
2 minutes. Eur. Urol. 2012; 61: 736–43.
53 Khan AH, Rasaily D. Tramadol use in premature ejaculation: daily versus
sporadic treatment. Indian J. Psychol. Med. 2013; 35: 256–9.
54 Wu T, Yue X, Duan X et al. Efficacy and safety of tramadol for premature
ejaculation: a systematic review and meta-analysis. Urology 2012; 80: 618–
24.
55 Kirby EW, Carson CC, Coward RM. Tramadol for the management of pre-
mature ejaculation: a timely systematic review. Int. J. Impot. Res. 2015; 27:
121–7.
56 Eid MA, Ahmed HH, Ismail NN, Shehada SY. Comparative study between
tramadol (50 mg) on demand and paroxitine HCl (20 mg) on demand in the
treatment of premature ejaculation. Hum. Androl. 2011; 1: 69–73.
57 Alghobary M, El-Bayoumy Y, Mostafa Y, Mahmoud e-H, Amr M. Evalua-
tion of tramadol on demand vs. daily paroxetine as a long-term treatment of
lifelong premature ejaculation. J. Sex. Med. 2010; 7: 2860–7.
58 Kaynar M, Kilic O, Yurdakul T. On-demand tramadol hydrochloride use in
premature ejaculation treatment. Urology 2012; 79: 145–9.
59 Nasu K, Moriyama N, Kawabe K et al. Quantification and distribution of
alpha 1-adrenoceptor subtype mRNAs in human prostate: comparison of
benign hypertrophied tissue and non-hypertrophied tissue. Br. J. Pharmacol.
1996; 119: 797–803.
60 Solomon HM, Wier PJ, Ippolito DL, Toscano TV. Effect of prazosin on
sperm transport in male rats. Reprod. Toxicol. 1997; 11: 627–31.
61 Debruyne FM. Alpha blockers: are all created equal? Urology 2000; 56(5
Suppl 1): 20–2.
62 Hisasue SI, Furuya R, Itoh N, Kobayashi K, Furuya S, Tsukamoto T. Ejacu-
latory disorder caused by alpha-1 adrenoceptor antagonists is not retrograde
ejaculation but a loss of seminal emission. Int. J. Urol. 2006; 13: 1311–6.
10
63 Basar MM, Yilmaz E, Ferhat M, Basar H, Batislam E. Terazosin in the
treatment of premature ejaculation: a short-term follow-up. Int. Urol.
Nephrol. 2005; 37: 773–7.
64 Cavallini G. Alpha-1 blockade pharmacotherapy in primitive psychogenic pre-
mature ejaculation resistant to psychotherapy. Eur. Urol. 1995; 28: 126–30.
65 Akin Y, Gulmez H, Ates M, Bozkurt A, Nuhoglu B. Comparison of alpha
blockers in treatment of premature ejaculation: a pilot clinical trial. Iran.
Red Crescent Med. J. 2013; 15: e13805.
66 Debruyne FM, Van der Poel HG. Clinical experience in Europe with urose-
lective alpha 1-antagonists. Eur. Urol. 1999; 36(Suppl 1): 54–8.
67 Kandeel FR. Treatment of Erectile Dysfunction in Men with Heart Disease.
Male Sexual Dysfunction: Pathophysiology and Treatment. CRC Press,
Cleveland, Ohio, 2013.
68 Aversa A, Pili M, Francomano D et al. Effects of vardenafil administration
on intravaginal ejaculatory latency time in men with lifelong premature ejac-
ulation. Int. J. Impot. Res. 2009; 21: 221–7.
69 Mattos RM, Marmo Lucon A, Srougi M. Tadalafil and fluoxetine in prema-
ture ejaculation: prospective, randomized, double-blind, placebo-controlled
study. Urol. Int. 2008; 80: 162–5.
70 G€okcße A, Demirtas A, Halis F, Ekmekcioglu O. In vitro measurement of
ejaculation latency time (ELT) and the effects of vardenafil on ELT on life-
long premature ejaculators: placebo controlled, double-blind, cross-over lab-
oratory setting. Int. Urol. Nephrol. 2010; 42: 881–7.
71 Mathers MJ, Klotz T, Roth S, Lummen G, Sommer F. Safety and efficacy
of vardenafil versus sertraline in the treatment of premature ejaculation: a
randomised, prospective and crossover study. Andrologia 2009; 41: 169–75.
72 McMahon CG, McMahon CN, Leow LJ, Winestock CG. Efficacy of type-5
phosphodiesterase inhibitors in the drug treatment of premature ejaculation:
a systematic review. Br. J. Urol. 2006; 98: 259–72.
73 Chen J, Keren-Paz G, Bar-Yosef Y, Matzkin H. The role of phosphodi-
esterase type 5 inhibitors in the management of premature ejaculation: a crit-
ical analysis of basic science and clinical data. Eur. Urol. 2007; 52: 1331–
9.
74 McMahon CG, Stuckey BG, Andersen M et al. Efficacy of sildenafil citrate
(Viagra) in men with premature ejaculation. J. Sex. Med. 2005; 2: 368–75.
75 Abdel-Hamid IA, El Naggar EA, El Gilany AH. Assessment of as needed
use of pharmacotherapy and the pause-squeeze technique in premature ejac-
ulation. Int. J. Impot. Res. 2001; 13: 41–5.
76 Salonia A, Maga T, Colombo R et al. A prospective study comparing
paroxetine alone versus paroxetine plus sildenafil in patients with premature
ejaculation. J. Urol. 2002; 168: 2486–9.
77 Zhou XJ, Zhang ZG, Hao L, Zhang WD, Dong BZ, Han CH. Elective
microscopic resection of dorsal penile nerves for primary premature ejacula-
tion: a clinical observation. Zhonghua Nan Ke Xue. 2013; 19: 1003–6.
78 Basal S, Goktas S, Ergin A et al. A novel treatment modality in patients
with premature ejaculation resistant to conventional methods: the neuromod-
ulation of dorsal penile nerves by pulsed radiofrequency. J. Androl. 2010;
31: 126–30.
79 Seftel AD. Re: percutaneous CT-guided cryoablation of the dorsal penile
nerve for treatment of symptomatic premature ejaculation. J. Urol. 2013;
189: 1836–7.
80 Zhang GX, Yu LP, Bai WJ, Wang XF. Selective resection of dorsal nerves
of penis for premature ejaculation. Int. J. Androl. 2012; 35: 873–9.
81 David Prologo J, Snyder LL, Cherullo E, Passalacqua M, Pirasteh A, Corn
D. Percutaneous CT-guided cryoablation of the dorsal penile nerve for treat-
ment of symptomatic premature ejaculation. J. Vasc. Interv. Radiol. 2013;
24: 214–9.
82 Zhang CY, Li XH, Yuan T, Zhang HF, Liu JH, Ye ZQ. Regional anatomy
of the dorsal penile nerve and its clinical significance. Zhonghua Nan Ke
Xue. 2009; 15: 130–3.
83 Zhang HF, Zhang CY, Li XH, Fu ZZ, Chen ZY. Dorsal penile nerves and
primary premature ejaculation. Chin. Med. J. (Engl). 2009; 122: 3017–9.
84 Haddad M, Besson R, Aubert D et al. Sacral neuromodulation in children
with urinary and fecal incontinence: a multicenter, open label, randomized,
crossover study. J. Urol. 2010; 184: 696–701.
85 Tsai MY, Liu CT, Chang CC, Chen SY, Huang ST. Overview of the rele-
vant literature on the possible role of acupuncture in treating male sexual
dysfunction. Acupunct. Med. 2014; 32: 406–10.
86 Sunay D, Sunay M, Aydogmusß Y et al. Acupuncture versus paroxetine for
the treatment of premature ejaculation: a randomized, placebo-controlled
clinical trial. Eur. Urol. 2011; 59: 765–71.
© 2016 The Japanese Urological Association

87 Chen ZX. Control study on acupuncture and medication for treatment of pri-
mary simple premature ejaculation. Zhongguo Zhen Jiu. 2009; 29: 13–5.
88 Li T, Tan Y, Xie ZP et al. Clinical efficacy of Paroxetine combined with
mid-frequency electrical pulse acupoint stimulation for premature ejacula-
tion. Zhonghua Nan Ke Xue. 2015; 21: 921–4.
89 Dhikav V, Karmarkar G, Gupta M, Anand KS. Yoga in premature ejacula-
tion: a comparative trial with fluoxetine. J. Sex. Med. 2007; 4: 1726–32.
90 Mamidi P, Gupta K. Efficacy of certain yogic and naturopathic procedures
in premature ejaculation: a pilot study. Int. J. Yoga 2013; 6: 118–22.
91 Chung E. Botulinum toxin in urology: a review of clinical potential in the
treatment of urologic and sexual conditions. Expert Opin. Biol. Ther. 2015;
15: 95–102.
92 Serefoglu EC, Silay MS. Botulinum toxin-A injection may be beneficial in the
treatment of life-long premature ejaculation. Med. Hypotheses 2010; 74: 83–4.
93 Serefoglu EC, Hawley WR, Lasker GF et al. Effect of botulinum-A toxin
injection into bulbospongiosus muscle on ejaculation latency in male rats. J.
Sex. Med. 2014; 11: 1657–63.
94 Gao J, Xu C, Zhang J et al. Effects of adult male circumcision on prema-
ture ejaculation: results from a prospective study in China. Biomed Res. Int.
2015; 2015: 417846.
95 Morris BJ, Krieger JN. Does male circumcision affect sexual function, sensi-
tivity, or satisfaction? A systematic review. J. Sex. Med. 2013; 10: 2644–57.
96 Tian Y, Liu W, Wang JZ, Wazir R, Yue X, Wang KJ. Effects of circumci-
sion on male sexual functions: a systematic review and meta-analysis. Asian
J. Androl. 2013; 15: 662–6.
97 Cox G, Krieger JN, Morris BJ. Histological correlates of penile sexual sen-
sation: does circumcision make a difference? Sex. Med. 2015; 3: 76–85.
98 Alp BF, Uguz S, Malkoc E et al. Does circumcision have a relationship
with ejaculation time? Premature ejaculation evaluated using new diagnostic
tools. Int. J. Impot. Res. 2014; 26: 121–3.
99 C€ucelo glu EA, Hosßrik ME, Ak M, Bozkurt A. The effects of age at circum-
cision on premature ejaculation. Turk Psikiyatri Derg. 2012; 23: 99–107.
100 Saadat SH, Ahmadi K, Panahi Y. The effect of on-demand caffeine con-
sumption on treating patients with premature ejaculation: a double-blind ran-
domized clinical trial. Curr. Pharm. Biotechnol. 2015; 16: 281–7.
101 Song B, Hou ZH, Liu QL, Qian WP. Penile frenulum lengthening for pre-
mature ejaculation. Zhonghua Nan Ke Xue. 2015; 21: 149–52.
102 Jannini EA, Isidori AM, Aversa A, Lenzi A, Althof SE. Which is first? The
controversial issue of precedence in the treatment of male sexual dysfunc-
tions. J. Sex. Med. 2013; 10: 2359–69.
103 Ahmed AF, Abdel-Aziz AS, Maarouf AM, Ali M, Emara AA, Gomaa A.
Impact of varicocelectomy on premature ejaculation in varicocele patients.
Andrologia 2015; 47: 276–81.
104 Li HC, Zhang LD, Gao M et al. Spermatic vein ligation and intra-vaginal
ejaculation latency. Zhonghua Nan Ke Xue. 2014; 20: 531–5.
105 Sim~ oes Pacßo J, Jorge Pereira B. New therapeutic perspectives in premature
ejaculation. Urology 2016; 88: 87–92.
106 Park HS, Jung IS, Lim NH et al. Proof of mechanism study of a novel sero-
tonin transporter blocker, DA-8031, using [11C]DASB positron emission
tomography and in vivo microdialysis. Urology 2014; 84: 245.e1–7.
107 Kang KK, Ahn GJ, Sung JH, Kim SH, Kim H, Lee S. Ejaculatory responses
are inhibited by a new chemical entity, DA-8031, in preclinical rodent mod-
els of ejaculation. Urology 2013; 81: 920.e13–8.
108 Kang KK, Sung JH, Kim SH, Lee S. Effect of DA-8031, a novel oral com-
pound for premature ejaculation, on male rat sexual behavior. Int. J. Urol.
2014; 21: 325–9.
109 La Pera G. Awareness and timing of pelvic floor muscle contraction, pelvic
exercises and rehabilitation of pelvic floor in lifelong premature ejaculation:
5 years experience. Arch. Ital. Urol. Androl. 2014; 86: 123–5.
110 La Pera G, Nicastro A. A new treatment for premature ejaculation: the reha-
bilitation of the pelvic floor. J. Sex Marital Ther. 1996; 22: 22–6.
111 Pastore AL, Palleschi G, Fuschi A et al. Pelvic floor muscle rehabilitation
for patients with lifelong premature ejaculation: a novel therapeutic
approach. Ther. Adv. Urol. 2014; 6: 83–8.
112 Pastore AL, Palleschi G, Leto A et al. A prospective randomized study to
compare pelvic floor rehabilitation and dapoxetine for treatment of lifelong
premature ejaculation. Int. J. Androl. 2012; 35: 528–33.
© 2016 The Japanese Urological Association
Current and emerging therapies in PE
113 Lavoisier P, Roy P, Dantony E, Watrelot A, Ruggeri J, Dumoulin S. Pelvic-
floor muscle rehabilitation in erectile dysfunction and premature ejaculation.
Phys. Ther. 2014; 94: 1731–43.
114 Szallasi A, Blumberg PM. Resiniferatoxin, a phorbol-related diterpene, acts
as an ultrapotent analog of capsaicin, the irritant constituent in red pepper.
Neuroscience 1989; 30: 515–20.
115 Lebovitz EE, Keller JM, Kominsky H, Kaszas K, Maric D, Iadarola MJ.
Positive allosteric modulation of TRPV1 as a novel analgesic mechanism.
Mol. Pain. 2012; 21: 70.
116 B€olcskei K, Tekus V, Dezsi L, Szolcsanyi J, Petho G. Antinociceptive
desensitizing actions of TRPV1 receptor agonists capsaicin, resiniferatoxin
and N-oleoyldopamine as measured by determination of the noxious heat
and cold thresholds in the rat. Eur. J. Pain 2010; 14: 480–6.
117 Shi B, Li X, Chen J et al. Resiniferatoxin for treatment of lifelong prema-
ture ejaculation: a preliminary study. Int. J. Urol. 2014; 21: 923–6.
118 Littara A, Palmieri B, Rottigni V, Iannitti T. A clinical study to assess the
effectiveness of a hyaluronic acid-based procedure for treatment of prema-
ture ejaculation. Int. J. Impot. Res. 2013; 25: 117–20.
119 Kim JJ, Kwak TI, Jeon BG, Cheon J, Moon DG. Effects of glans penis aug-
mentation using hyaluronic acid gel for premature ejaculation. Int. J. Impot.
Res. 2004; 16: 547–51.
120 Abdallah H, Abdelnasser T, Hosny H, Selim O, Al-Ahwany A, Shamloul R.
Treatment of premature ejaculation by glans penis augmentation using hya-
luronic acid gel: a pilot study. Andrologia 2012; 44(Suppl 1): 650–3.
121 du Moon G, Kwak TI, Kim JJ. Glans penis augmentation using hyaluronic
acid gel as an injectable filler. World J. Mens Health. 2015; 33: 50–61.
122 Bailey LB, Gregory JF 3rd. Folate metabolism and requirements. J. Nutr.
1999; 129: 779–82.
123 Yan WJ, Yu N, Yin TL, Zou YJ, Yang J. A new potential risk factor in
patients with erectile dysfunction and premature ejaculation: folate defi-
ciency. Asian J. Androl. 2014; 16: 902–6.
124 Yin TL, Yang J, Zhang B et al. Folic acid supplementation as adjunctive
treatment premature ejaculation. Med. Hypotheses 2011; 76: 414–6.
125 Karabakan M, Erkmen AE, Guzel O, Aktas BK, Bozkurt A, Akdemir S.
Association between serum folic acid level and erectile dysfunction.
Andrologia 2016; 48: 532–5.
126 Hamidi Madani A, Asadolahzade A, Mokhtari G, Shahrokhi Damavand R,
Farzan A, Esmaeili S. Assessment of the efficacy of combination therapy
with folic acid and tadalafil for the management of erectile dysfunction in
men with type 2 diabetes mellitus. J. Sex. Med. 2013; 10: 1146–50.
127 Zavatti M, Zanoli P, Benelli A, Rivasi M, Baraldi C, Baraldi M. Experimen-
tal study on Satureja Montana as a treatment for premature ejaculation. J.
Ethnopharmacol. 2011; 133: 629–33.
128 Corona G, Jannini EA, Lotti F et al. Premature and delayed ejaculation: two
ends of a single continuum influenced by hormonal milieu. Int. J. Androl.
2011; 34: 41–8.
129 Jern P, Westberg L, Ankarberg-Lindgren C et al. Associations between
salivary testosterone levels, androgen-related genetic polymorphisms, and
self-estimated ejaculation latency time. Sex. Med. 2014; 2: 107–14.
130 Mohseni MG, Hosseini SR, Alizadeh F, Rangzan N. Serum testosterone and
gonadotropins levels in patients with premature ejaculation: a comparison
with normal men. Adv. Biomed. Res. 2014; 3: 6.
131 Veening JG, de Jong TR, Waldinger MD, Korte SM, Olivier B. The role of
oxytocin in male and female reproductive behavior. Eur. J. Pharmacol.
2015; 753: 209–28.
132 Clement P, Bernabe J, Compagnie S, Alexandre L, McCallum S, Giuliano
F. Inhibition of ejaculation by the non-peptide oxytocin receptor antagonist
GSK557296: a multi-level site of action. Br. J. Pharmacol. 2013; 169:
1477–85.
133 Borthwick AD, Liddle J, Davies DE et al. Pyridyl-2,5-diketopiperazines
as potent, selective, and orally bioavailable oxytocin antagonists: synthe-
sis, pharmacokinetics, and in vivo potency. J. Med. Chem. 2012; 55:
783–96.
134 Shinghal R, Barnes A, Mahar KM et al. Safety and efficacy of epelsiban in
the treatment of men with premature ejaculation: a randomized,
double-blind, placebo-controlled, fixed-dose study. J. Sex. Med. 2013; 10:
2506–17.
11