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- Review -
Premature ejaculation: current and future treatments
Levent Gurkan, Matthew Oommen, Wayne J. G. Hellstrom
Section of Andrology, Department of Urology, Tulane University Health Sciences Center, New Orleans, LA 70112, USA
Premature ejaculation (PE) is recognized to be the most common male sexual disorder. PE provides difficulties
for professionals who treat this condition because there is neither a universally accepted definition nor a medication
approved by the Food and Drug Administration (FDA). Despite these shortcomings, physicians continue to diagnose
their patients with PE according to major guidelines and treat them with either behavioral therapies or off-label
medications. This review focuses on current and emerging treatment options and medications for PE. Advantages
and limitations of each treatment option are discussed in the light of current published peer-reviewed
literature. (Asian J Androl 2008 Jan; 10: 102_109)
Keywords: premature ejaculation; male sexual disorder; ejaculation
Correspondence to: Wayne J. G. Hellstrom, MD, FACS, Section of Andrology, Department of Urology, Tulane University Health Sciences Center,
1430 Tulane Ave., SL-42, New Orleans, LA 70112, USA.
Tel: +1-504-988-7308 Fax: +1-504-988-5059
Although premature ejaculation (PE) is recognized to be the most common male sexual disorder, it provides
difficulties for the professionals who treat men with PE because there is neither a universally accepted definition nor
a medication approved by the Food and Drug Administration (FDA) with which to treat it. The lack of a globally
accepted definition causes difficulties in determining the prevalence, which has been cited as being anywhere from
4% to 66%. Most authorities accept that around 25%_40% of all men suffer from this condition at some point of their
life . The following review will focus on non-medical and medical treatment options of this common male sexual
disorder including the off-label use of medications.
Clinicians tend to use definitions of PE as described in one of the major guidelines, such as The Diagnostic and
Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV-TR), The International Consultation on Urological
Disease or The American Urological Association Guideline. The DSM-IV-TR  has defined PE as "persistent or
recurrent ejaculation with minimal sexual stimulation before, on, or shortly after penetration and before the person
wishes it". This definition of PE requires that the condition "must also cause marked distress or interpersonal
difficulty", and states that it "is not due exclusively to the direct effects of a substance". Very similar definitions are
given in The International Consultation on Urological Disease and The American Urological Association (AUA) Guideline.
The former defines it as "persistent or recurrent ejaculation with minimal stimulation before, on or shortly after
penetration and before the person wishes it, over which the sufferer has little or no voluntary control which causes the
sufferer and/or his partner bother or distress". The latter defines PE as ejaculation that "occurs sooner than desired,
either before or shortly after penetration, causing distress to either one or both partners" . All of these definitions
share three main qualifications: short time interval between penetration and ejaculation, lack of control over ejaculation
and distress by one or both partners. Only the International Classification of Diseases, Tenth
Edition  issued by the World Health Organization (WHO), gives us a quantified cut-off point as it describes PE as "the inability to delay
ejaculation sufficiently to enjoy lovemaking, which is manifested by either an occurrence of ejaculation before or very
soon after the beginning of intercourse (if a time limit is required: before or within 15 s of the beginning of intercourse)
or ejaculation occurs in the absence of sufficient erection to make intercourse possible". For the most part,
researchers are dissatisfied with these definitions, as the former three are based on subjective complaints and fail to define an
objective cut-off point that can be easily used in a study while the latter fails to provide peer-reviewed literature to
support any defined cut-off value.
In 1994, Waldinger and colleagues  introduced
and defined the term "intravaginal ejaculatory latency time"
(IELT)-the time from vaginal penetration to the start of
intravaginal ejaculation-as an objective outcome measure.
The IELT is positively skewed with a median of 5.4 min.
The 0.5 percentile equates to an IELT of 0.9 min and the
2.5 percentile an IELT of 1.3 min . It is generally
accepted but not included in most guidelines that men
with an IELT of less than 1 min have "definitive" PE.
Although IELT covers only one parameter of PE, namely
"short time interval between penetration and ejaculation",
and ignores other patient-reported outcomes (PROs) such
as "lack of control over ejaculation" and "distress
experienced by one or both partners", it was welcomed by
the research community as it provided a tool to
objectively assess the efficacy of pharmacological or surgical
interventions. For this review, we will employ IELT as
the main measure for comparing different treatment
options as it is the most universally accepted tool and newly
developed PE questionnaires are in need of further
validation in larger scale studies. It should be noted that PE
questionnaires such as the Premature Ejaculation
Questionnaire (36 items), The Index of Premature Ejaculation
(10 items) or The Chinese Index of Premature
Ejaculation (10 items) take evaluation one step further, as they
include questions about perception of control over
ejaculation, interpersonal distress, and overall sexual
satisfaction. We do not believe the use of IELT is
reliable as the only parameter for defining treatment success
in a clinical setting. PE has a significant impact on men
and their partners' sexual life and the goal for treatment of
PE should be improvement in patient and partner
satisfaction in relation to sexual intercourse and quality of life .
2 Non-medical treatment of PE
Historically, and through the early 1990's, PE was
considered to be a psychological (rather than a physiological) problem and behavioral psychosexual
therapies were considered the treatment of choice. In
1956, urologist Semans  described one of the earliest
behavioral interventions, namely the "stop-start
technique". This method involves the partner
stimulating the man's penis until he has the sensation of almost
climaxing, at which time stimulation is ceased until this
feeling abates. This cycle is repeated until the
ejaculation can be controlled voluntarily. A similar technique
was proposed by sex therapists Masters and Johnson in
1970 . Their technique differed from the previous in
that the partner squeezes the frenulum of the penis after
cessation of the stimulus, resulting in a partial loss of
erection. The female partner resumes sexual stimulation
after at least 30 seconds have passed. Although the
teaching of these specific techniques to delay ejaculation seems
to be the mainstay of psychosexual therapy, the primary
goals of traditional psychosexual treatment for PE are to
aid the male in regaining confidence in his sexual
performance, reduce performance anxiety, resolve any
interpersonal difficulties and increase couple
communication. Typically, these psychological approaches have high
initial success rates (45%_65%); however, the effects
are not long-lasting. Hawton and colleagues  reported
that 75% of men with PE who initially responded to
behavioral therapy showed no long lasting improvement
after 3 years of follow-up. Ejaculation is actually a
spinal reflex under strong control from higher spinal and
cortical centers, much like urination and defecation.
Control can be learned and is greatly influenced by past
experiences and the present context under which the
response is occurring. However, as demonstrated by
Waldinger and colleagues, the patients with real PE
occupy the far left edge of a normal distribution curve which
may suggest a genetically inherited physiological response
that may be caused by inherited serotonin receptor
sensitivities. This proposal is based on animal studies
and is not universally accepted. However it gives us a
reason for the failure of psychosexual treatment
strategies as the capacity of the higher centers to control
ejaculation is not without limits, e.g. when sexual stimulation
becomes so intense the ejaculation can no longer be
inhibited . From an evolutionary perspective, some
authors suggest that PE might provide a survival
advantage in regards to natural selection as rapid copulation
allows for passage of genes to one's progeny. Other
possible organic factors that can be treated include
alterations in sex hormone levels and diseases of the genital
organs (primarily prostatitis) .
Combination therapy is currently the suggested
solution for patients with severe PE. These patients need
more than pharmacotherapy to overcome obstacles to
effective sexual activity and require targeted
psychoeducational interventions termed "coaching"
. Recently, Althof  and Perelman  independently
described combination therapy as a "concurrent or
stepwise integration of psychological and medical
interventions". Clinicians and non-MD healthcare
professionals (i.e. sex therapists) act as a multidisciplinary
team to treat patients suffering with recalcitrant PE
3 Medical treatment of PE
Although sex therapy is effective, it is
labor-intensive and requires involvement of a cooperative partner.
For this reason pharmacological options have become
popular for treating PE. However, it should be noted
that all of the medications currently used for treatment
of PE were originally developed to treat other medical
disorders such as depression or erectile dysfunction (ED).
Their use is considered "off-label" as they have not been
approved by the regulatory bodies in America or Europe
for the treatment of PE.
Current accepted pharmacological treatment options
include topical desensitizing agents, antidepressives,
phosphodiesterase type 5 (PDE-5) inhibitors and
alpha-blockers. Combined uses of these medications are not
included in this review as they usually exhibit
non-synergistic effects and generally have a higher incidence of
3.1 Topical desensitizing drugs
The oldest form of therapy for PE is the use of local
anesthetic agents as described by Schapiro  in 1943.
The rationale for use has traditionally been based on
penile hypersensitivity in patients with PE . However,
a recent study failed to show any significant correlation
between IELT and penile sensitivity . Topical
desensitizing drugs likely act by diminishing pleasurable
sensations for men in order to prolong time of sexual
intercourse, a questionable trade-off. In comparison with
systemic treatments, topical agents exhibit a low
systemic side effect profile. They are recognized to cause
penile hypoaesthesia, ED, female genital anaesthesia, and
skin reactions. Disruption of spontaneity is another
drawback for some couples. Topical drugs for PE include
lidocaine-prilocaine cream, SS cream, lidocaine-prilocaine
spray and dyclonine-alprostadil cream.
3.1.1 Lidocaine-prilocaine cream
Although lidocaine and prilocaine are both crystalline
solids at room temperature, when mixed together in equal
amounts they form a liquid eutectic mixture with a 16ºC
melting point and thus can be formulated into
preparations without the use of a non-aqueous solvent. This
allows for higher concentrations of active ingredients
within the preparation, in this case 2.5% each for
EMLA® (AstraZeneca, London, UK). Although this product is
widely available and frequently used to treat PE, the
literature on its effects is scant. Two relevant publications
include a 2002 study designed in a single blind,
placebo-controlled, randomized fashion to determine the optimum
time that anesthetic cream should be on the penis before
vaginal intercourse, in this case 20 min . Prolonged
administration resulted in penile numbness and eventual
loss of erection in all patients after 45 min. A second
randomized, double-blind, placebo-controlled study aimed
to determine the efficacy of EMLA cream in treating PE
. Although 42 patients were initially recruited, only
29 completed the study; however, none of the drop-outs
were due to adverse effects. The treatment resulted in a
5.6-fold increase in IELT. Of the patients completing
the study in the treatment arm, 11 of 16 reported very
good or excellent sexual satisfaction. Results showed
16% of patients experiencing adverse effects with two
patients having penile numbness and associated retarded
ejaculation, two men reporting penile irritation and one
female complaining of decreased vaginal sensitivity.
3.1.2 SS cream
SS cream® (Cheil Jedan Corporation, Seoul,
Korea)is applied to the glans penis 1 h before intercourse and is
washed off before sexual intercourse. The major
disadvantage of the product is the unpleasant color and smell.
This cream is comprised of nine different compounds,
some with local anesthetic and vasodilatatory properties.
SS cream is available for use only in Korea, and to date
all eight studies conducted on its efficacy were published
by the same group and took place there. These studies
demonstrated success rates of 89.2% with an 8-fold
increase in IELT. However, at the optimum dose of 0.2 g
cream, almost 19% of episodes were associated with
localized irritation . Because of the unpleasant smell
and color, a reformulation was designed by the
producers that contains only two of the main components
present in the original cream. Unfortunately, only animal
data is available for this new formulation which claims
higher efficacy than the original formulation .
3.1.3 Lidocaine-prilocaine spray
The topical eutectic mixture for PE
(TEMPE®, Plethora Solutions Holdings PLC, London, UK) is a
metered-dose spray of lidocaine and prilocaine under
development. It delivers 7.5 mg lidocaine and 2.5 mg
prilocaine per dose. It is designed to optimize tissue
penetration such that the onset of effect is more rapid than
with the cream formulations and a condom is not required.
The product is incapable of penetrating keratinized skin,
hence only anesthetizing the glans and reducing the
incidence of penile numbness related anejaculation. There
are only two studies on this product and among them
only the phase-II study has a prospective, double-blind,
placebo-controlled design. Besides focusing on
objective outcome measures, this study uses questionnaires
to evaluate control over ejaculation and quality of sex
life. A treatment regime of three self-administered
applications onto the glans penis 15 min before sexual
intercourse was chosen for this study. Results indicate a
2.4 times higher IELT for TEMPE compared to placebo and
a significant improvement in control over ejaculation.
TEMPE was generally well tolerated with 12% of patients experiencing numbness of the penis and one man
experiencing erectile dysfunction. Although TEMPE
provides a significant improvement in IELT with a rise from
1.0 min at the baseline to 4.9 min, its effectiveness is
somewhat lower than EMLA cream, but with a better adverse effect profile .
A preparation which combines the local anesthetic,
dyclonine, with the vasodilator, alprostadil, is under
development. This product is applied 5_20 min before
intercourse to the tip of the penis in the region of meatus.
The one pilot study claims the combined preparation
produces a synergistic effect but fails to provide baseline
IELT and details about adverse effects observed.
Further studies are needed before any conclusions about this
product can be made.
3.2 Oral medication
Oral treatments for PE consist mainly of selective
serotonin reuptake inhibitors (SSRIs) and the tricyclic
antidepressant, clomipramine. The PDE-5 inhibitors and
tramadol are also included as these medications are
subject to scientific research.
Clomipramine (Anafranil®, Mallinckrodt
Pharmaceutical Products, Hazelwood, MS, USA) is a tricyclic
antidepressant with the greatest effect on the serotonergic
system. In the midst of the era when behavioral
psychotherapy was the main treatment option for PE, Eaton
 published his novel report on the efficacy of
clomipramine in 1973 and numerous subsequent publications have confirmed its effectiveness. The
meta-analysis by Waldinger  showed that, if used on a
daily basis, clomipramine increases IELT 4.6 fold which
is not statistically different from sertraline or fluoxetine.
On-demand use of clomipramine is effective if used
3_6 h prior to intercourse. The only head to head study
evaluating on-demand use of paroxetine 20 mg and clomipramine 25 mg revealed a 4.05- and 1.41-fold
increase in IELT for clomipramine and paroxetine,
respectively . The most common adverse side effect is
nausea which is experienced on the day of sexual
intercourse and the day after. Patients with initial ejaculatory
latencies over 60 s, self-reported sexual satisfaction of 5
or higher (on a seven-point scale) and ejaculation frequency
of twice or more weekly were more likely to benefit from
on-demand 25 mg clomipramine therapy .
Although none of the SSRIs are approved by
regulatory bodies for the treatment of PE, their common
"adverse effect" of delaying ejaculation in 30%_50% of
otherwise healthy depressed patients has made them the
preferred "off-label" treatment option for PE . The
effect of this class is not restricted to PE patients as use
by otherwise healthy subjects can also significantly
delay ejaculation . Currently four different SSRIs are
used commonly in the treatment of PE, namely fluoxetine
(Prozac®, Eli Lilly and Company, Indianapolis, IN, USA),
sertraline (Zoloft®, Pfizer, New York, NY, USA),
paroxetine (Paxil®, GlaxoSmithKline PLC, Philadelphia,
PA, USA) and citalopram (Celexa®, Forest Laboratories,
New York, NY, USA). Among the SSRIs, fluvoxamine  and venlafaxine  have been shown to be
ineffective. Developers of dapoxetine (Johnson & Johnson,
New Brunswick, NJ, USA), another molecule of this class
with a unique pharmacokinetic profile, are seeking to
obtain formal approval for the treatment of PE.
The first publication about the delaying effect of
paroxetine was in 1994 and numerous studies have since
confirmed the effectiveness of each of the
aforementioned SSRIs in treating PE. However, none of these
agents have gained regulatory approval for this indication,
most likely because of concerns about the negative
impact of emphasizing a side effect in the marketing for its
major indication, depression. This class of drugs is
generally well tolerated by PE patients, who exhibit a slightly
different side effect profile than depressed patients using
the same medications. SSRIs have different short term
and long term adverse effects. The most commonly observed short term adverse effects are yawning, mild
nausea, excessive perspiration, fatigue and loose stools.
These adverse effects are generally mild and gradually
disappear within 2_3 weeks of use in most patients. Less
well known adverse effects that have been reported in
depressive patients include bleeding , priapism ,
weight gain related type II diabetes mellitus  and bone
mineral density loss with prolonged treatment , and
these certainly need to be taken into account when
treating PE patients. Decreased sexual desire and erectile
dysfunction are frequently reported in patients being
treated for depression , while these are not as
common in PE patients without depression. The reason for
this difference is not entirely clear . Patients must
be advised not to abruptly discontinue long term SSRI
use in order to prevent possible SSRI discontinuation
syndrome . The use of SSRIs, especially in young
depressed patients, is reported to increase the suicide
rate . While this issue is currently controversial,
great caution should be taken when treating this
subgroup of PE patients, and psychiatric consultation is
Although the efficacy of this class of drugs is well
established, there are a number of unanswered questions
such as "Is daily or on-demand treatment better?",
"Which is the most effective medication?", or "What is
the preferred dosing regimen?".
A meta-analysis regarding the use of SSRIs between
1943 and 2003 was published in 2004. An obvious
draw-back of this meta-analysis is its reliance on IELT and
absence of patient reported outcomes (PROs) in its
evaluation of efficacy . On a daily treatment basis
paroxetine revealed the highest efficacy with a geometric
mean fold increase of 8.8, followed by sertraline
(4.1) and fluoxetine (3.9). This increase was significant compared
to the 1.4-fold increase achieved with placebo . A
new molecule, citalopram, and its S-enantiomer, escitalopram
(Lexapro®, Forest Laboratories, New York,
NY, USA), have recently been subject to studies in the
treatment of PE and have provided inconsistent results
[39, 40]. Of the currently available SSRIs, escitalopram
has the highest selectivity for the human serotonin
transporter relative to noradrenalin and dopamine transporters.
In a recent randomized, placebo-controlled, double-blind
study, treatment with escitalopram demonstrated a 4.9
fold increase in geometric mean IELT . Both of these
molecules increased sexual intercourse satisfaction and
sexual intercourse frequency. On a daily treatment
scheme, the onset of effect usually takes 2_3 weeks.
The onset of efficacy is gradual and some patients
experience a change in as early as 5_7 days. Generally this
class is effective but some patients will not respond to
the treatment and even when they do respond some men
lose efficacy over time . Neither this phenomenon,
called tachyphylaxis, nor the lack of efficacy has a
satisfying scientific explanation to date.
There are only a limited number of publications
focusing on on-demand use of SSRIs for PE and the data
available is difficult to compare as it is heterogeneous in
terms of medications used, study design and outcome
reporting. This makes it difficult to draw any absolute
conclusions about the efficacy of a particular medication.
However it can be stated that the overall efficacy achieved
by daily treatment is generally higher than by on-demand
treatment. Paroxetine appears to be the most effective
medication again; however, well designed head to head
trials are needed for confirmation.
Dapoxetine, a new SSRI with a unique pharmacokinetic profile, is promising for on-demand treatment of
PE. In contrast to conventional SSRIs, maximum plasma
concentrations are achieved 1.01 h after a 30-mg oral
dose, initial half-life is 1.42 h and 24 h after administration,
plasma concentrations decrease to less than 5% of peak
Two phase III, randomized, placebo controlled studies
that enrolled 2 614 PE patients showed that dapoxetine
increased IELT, perception of control over ejaculation
and satisfaction with sexual intercourse of both the man
and his partner. The IELT increase was 2.8 and 3.3 fold
for the 30 mg and 60 mg group, respectively, whereas it
was 1.8 fold for placebo. While the efficacy was lower
than with daily SSRIs this agent is convenient and fast
acting for on-demand use . Approval by the FDA
has not been granted in its initial application.
A related study examined patient preferences for PE
treatment. In this study, PE patients were offered an
anesthetic ointment, on-demand use of an SSRI or daily
continuous treatment with an SSRI. Eighty-one percent
of patients preferred daily treatment whereas 16% and
3% preferred on-demand SSRIs and anesthetic ointment,
respectively. Those patients who initially preferred daily
treatment did not change their view after receiving
standard information about efficacy and side effects, while
nine of 17 men who initially preferred on-demand
treatment switched their preferences to daily treatment. The
conclusion that all patients prefer daily treatment over
on-demand needs to be interpreted with caution  based
on this single study as patients were offered only
conventional SSRIs which need to be taken 4_6 h before
intercourse which interferes with the spontaneity of sex.
Preference profiles will likely be different with a PE
medication with a fast onset of action.
Tramadol (Ultram®, Johnson & Johnson, New
Brunswick, NJ, USA) is an effective analgesic that has
been on the market for a number of years. Tramadol is
a centrally acting analgesic with two distinct mechanisms
of action: one enantiomer exerts a predominantly weak
µ-opioid effect, whereas the other inhibits
norepinephrine and serotonin reuptake, activating descending
monoaminergic inhibitory pathways. Peak plasma
concentrations are attained within 1.6_1.9 h after oral
administration. Initial distribution half life is 6 min
followed by a second phase of 1.7 h. It is mainly excreted
by the kidneys with a mean elimination half-life of 5_6
hours. Currently, only two publications are available on
the use of tramadol in the treatment of PE. The
double-blind, placebo-controlled, fixed-dose, randomized study
by Safarinejad et al.  demonstrated a 13-fold increase
in IELT for the on-demand use of 50 mg tramadol.
28.1% of the participants in the tramadol arm reported
adverse effects including nausea, vomiting and dizziness
while 15.6% of the patients in the placebo arm reported
similar adverse effects . Another study by Salem
et al.  was a single blind, placebo-controlled,
cross-over, two-period prospective study to evaluate the
efficacy of on-demand 25 mg tramadol. The treatment group
experienced a 6.3 fold increase in IELT compared to a 1.7
fold increase in the placebo group. 13.3% of the patients
reported adverse effects with tramadol including
dyspepsia and mild somnolence . Although initial studies
are encouraging, further studies are needed.
3.2.4 PDE-5 inhibitors
At least 30% of PE men have concomitant ED .
Successful use of PDE-5 inhibitors in this subgroup of
patients has raised the question of whether PDE-5
inhibitors can be efficacious in the treatment of primary PE.
A study comparing the effectiveness of sildenafil
with the squeeze technique and on-demand use of two
different SSRIs (paroxetine and sertraline) and clomipramine
in primary PE patients was preformed in a double-blind,
prospective, cross-over design. A placebo arm was not
included in the study. All medications were used 3_5 hours
prior to sexual intercourse. The study demonstrated a
15- fold increase in IELT for the sildenafil group whereas
SSRIs, clomipramine and the squeeze technique caused a
2_4-fold increase. Sexual satisfaction increased
dramatically with sildenafil treatment. Adverse effects were more
common in the clomipramine group (25%) whereas
17.9% of the patients with sildenafil treatment reported
adverse effects, mainly headaches and flushing .
Another study compared the effectiveness of a
PDE-5 inhibitor (sildenafil) with a daily SSRI (paroxetine) and
the squeeze technique in primary PE patients without
concomitant ED. This head to head, non-placebo
controlled study also evaluated intercourse satisfaction
using a questionnaire. At 6 months follow-up there was a
5.7-, 4.4- and 2.5-fold increase in IELT for sildenafil,
paroxetine and the squeeze technique, respectively.
Improvements in sexual satisfaction for both patient and
partner were highest in the sildenafil group. Adverse
effects were more frequent in the sildenafil and paroxetine
groups compared to the squeeze technique group. The
most frequent adverse effects were headache (11.7%)
and nasal congestion (8.3%) for sildenafil .
The only placebo-controlled, randomized,
double-blind, prospective multicenter study evaluating the
effectiveness of sildenafil in the treatment of PE in potent
men failed to demonstrate a significant increase in IELT.
The 2.6-fold increase in IELT was not statistically
different from placebo. However using the Index of
Premature Ejaculation questionnaire, there was a significant
increase in ejaculatory control, ejaculatory confidence
and improved overall sexual satisfaction scores . A
related study comparing placebo, sildenafil, EMLA cream
and a combination of EMLA cream and sildenafil
treatment arms failed to demonstrate a significant difference
between placebo and the sildenafil treated groups .
In summary, these studies failed to demonstrate any
significant benefit in PE patients who did not have ED.
PDE-5 inhibitors are not of benefit in the first line therapy
of primary PE patients, however they may be in men
with ED and secondary PE [53, 54].
In this context, intracavernosal injections have been
proposed as a treatment for PE. The benefit is achieved
by providing rigidity after ejaculation. Limited study has
been done on this topic .
3.2.5 α1-adrenoceptor antagonist
As ejaculation is controlled by the sympathetic
nervous system peripherally, it has been hypothesized that
α-blockers, which are commonly employed to improve
obstructive urinary symptoms, might also be effective in
treating PE. This hypothesis has been supported by
animal studies demonstrating a decreased vasal and seminal
vesicle pressure in response to hypogastric nerve
stimulation . One clinical study demonstrated significant
improvement in 50% of PE patients resistant to
psychotherapy . Although the number of patients in this study
was too small to draw any conclusions about the efficacy
of α-blockers, its use in the PE patient with concomitant
lower urinary track symptoms may be of benefit .
4 Experimental treatment options
Besides behavioral and pharmacological treatment
options, researchers are searching other avenues on the
treatment of PE. Virtual reality can speed up the
therapeutic psychodynamic process, wherein the patient wears
a helmet with miniature television screen and earphones
to discuss and summarize his thoughts . Another
experimental device is a "desensitizing band" which,
when worn during masturbation, does not constrict blood
flow and helps the PE sufferer gain control over
ejaculation . A surgical approach consisting of a dorsal
neurectomy with glandular augmentation using hyaluronic
acid gel has been reported . While these preliminary
reports are interesting, they are not considered standard
5 Emerging treatment options for PE
The ideal drug for PE should be an on-demand-dosed
treatment with a high rate of efficacy and a short onset
of action, should not interfere with sexual spontaneity,
and should not have sexual side effects . Two areas
of interest are being investigated.
The first is a purely pharmacological approach. The
concept is to mimic the desensitization of the
5-HT1A receptor agonist during chronic administration of SSRIs.
For this purpose, two 5-HT1A receptor blockers, namely
WAY-100635  and Robalzotan , were used in animal models of ejaculation and both drugs delayed
ejaculation acutely when administered together with an SSRI.
However, when used alone they had no effect on
ejaculation. This confirms the hypothesis that the
5-HT1A receptors are activated in response to elevated
extracellular serotonin levels after acute SSRI administration.
Although this pharmacological combination is very promising, further clinical research is needed to evaluate
potential adverse effects of this combination.
A second approach is to increase the success of
treatment by using combined behavioral and physiological
therapies. PE is a multidimensional condition and most
likely reflects a predetermined physiological response in
conjunction with intrapsychic and interpersonal issues.
Perelman suggests that physicians and sex therapists
working together could significantly improve initial and
long term treatment response rates for PE by combining
the two treatment modalities. There is growing evidence
that combination therapy using new pharmaceuticals and
psychotherapy will become the treatment of choice .
PE is a self reported disorder and one in which the
diagnosis is mainly based on history. Currently none of
the guidelines recommend any formal diagnostic testing.
A history should include all three aspects of PE, namely
short IELT, lack of control and distress for both partners.
Although our methods of diagnosis are in evolution,
currently available questionnaires that document PROs and
determination of IELT are sufficient to make a correct
diagnosis. Therapy should be tailored for each patient as
one treatment does not fit all. Each treatment option
should be discussed with the PE patient including the
success rate and possible adverse effects such that the
patient participates in the decision making. This will
improve compliance and success of therapy. In
recalcitrant PE, collaboration between physicians and sex
therapists will improve success rates.
1 Carson C, Gunn K. Premature ejaculation: definition and
prevalence. Int J Impot Res 2006; 18 (Suppl 1): S5_13.
2 American Psychiatric Association. Diagnostic and statistical manual
of mental disorders, 4th edition. Text Revision. Washington, DC:
American Psychiatric Association 2000.
3 Montague DK, Jarow J, Broderick GA, Dmochowski RR, Heaton
JP, Lue TF, et al. AUA Erectile Dysfunction Guideline Update
Panel. AUA guideline on the pharmacological management of
premature ejaculation. J Urol 2004; 172: 290_4.
4 World Health Organization. The ICD-10 classification of
mental and behavioral disorders: diagnostic criteria for research.
Geneva: World Health Organization, 1993.
5 Waldinger MD, Zwinderman AH, Olivier B, Schweitzer DH.
Proposal for a definition of lifelong premature ejaculation based on
epidemiological stopwatch data. J Sex Med 2005; 2: 498_507.
6 Semans JH. Premature ejaculation: a new approach. South Med
J 1956; 49: 353_8.
7 Masters WM, Johnson VE. Human Sexual Inadequacy. Boston:
Little, Brown; 1970.
8 Hawton K, Catalan J, Martin P, Fagg J. Long-term outcome of
sex therapy. Behav Res Ther 1986; 24: 665_75.
9 Rowland DL, Motofei IG. The aetiology of premature
ejaculation and the mind-body problem: implications for practice. Int
J Clin Pract 2007; 61: 77_82.
10 Perelman MA. A new combination treatment for premature ejaculation:
a sex therapist's perspective. J Sex Med 2006; 3: 1004_12.
11 Althof S. The psychology of premature ejaculation: therapies
and consequences. J Sex Med 2006; 3 (Suppl 4): 324_31.
12 Schapiro B. Premature ejaculation: a review of 1 130 cases. J
Urol 1943; 3: 374_9.
13 Xin ZC, Chung WS, Choi YD, Seong DH, Choi YJ, Choi HK.
Penile sensitivity in patients with primary premature ejaculation.
J Urol 1996; 156: 979_81.
14 Vanden Broucke H, Everaert K, Peersman W, Claes H,
Vanderschueren D, Van Kampen M. Ejaculation latency times
and their relationship to penile sensitivity in men with normal
sexual function. J Urol 2007; 177: 237_40.
15 Atikeler MK, Gecit I, Senol FA. Optimum usage of
prilocaine-lidocaine cream in premature ejaculation. Andrologia 2002; 34:
16 Busato W, Galindo CC. Topical anesthetic use for treating
premature ejaculation: a double-blind, randomized, placebo-controlled
study. BJU Int 2004; 93: 1018_21.
17 Choi HK, Jung GW, Moon KH, Xin ZC, Choi YD, Lee WH,
et al. Clinical study of SS-cream in patients with lifelong premature
ejaculation. Urology 2000; 55: 257_61.
18 Tian L, Xin ZC, Xin H, Fu J, Yuan YM, Liu WJ,
et al. Effect of renewed SS-cream on spinal somatosensory evoked potential in
rabbits. Asian J Androl 2004; 6: 15_8.
19 Dinsmore WW, Hackett G, Goldmeier D, Waldinger M, Dean J,
Wright P, 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:
20 Eaton H. Clomipramine in the treatment of premature
ejaculation. J Int Med Res 1973; 1: 432_4.
21 Waldinger MD, Zwinderman AH, Schweitzer DH, Olivier B.
Relevance of methodological design for the interpretation of
efficacy of drug treatment of premature ejaculation: a systematic
review and meta-analysis. Int J Impot Res 2004; 16: 369_81.
22 Waldinger MD, Zwinderman AH, Olivier B. On-demand
treatment of premature ejaculation with clomipramine and paroxetine:
a randomized, double-blind fixed-dose study with stopwatch
assessment. Eur Urol 2004; 46: 510_5.
23 Rowland DL, Tai WL, Brummett K, Slob AK. Predicting
responsiveness to the treatment of rapid ejaculation with 25 mg
clomipramine as needed. Int J Impot Res 2004; 16: 354_7.
24 Balon R. SSRI-associated sexual dysfunction. Am J Psychiatry
2006; 163: 1504_9.
25 Wang WF, Chang L, Minhas S, Ralph DJ. Selective serotonin
reuptake inhibitors in the treatment of premature ejaculation.
Chin Med J (Engl) 2007; 120: 1000_6.
26 Waldinger MD, van De Plas A, Pattij T, van Oorschot R, Coolen LM,
Veening JG, et al. The selective serotonin re-uptake inhibitors
fluvoxamine and paroxetine differ in sexual inhibitory effects after
chronic treatment. Psychopharmacology (Berl) 2002; 160: 283_9.
27 Kilic S, Ergin H, Baydinc YC. Venlafaxine extended release for
the treatment of patients with premature ejaculation: a pilot,
single-blind, placebo-controlled, fixed-dose crossover study on
short-term administration of an antidepressant drug. Int J Androl
2005; 28: 47_52.
28 Halperin D, Reber G. Influence of antidepressants on hemostasis.
Dialogues Clin Neurosci 2007; 9: 47_59.
29 Dent LA, Brown WC, Murney JD. Citalopram-induced priapism.
Pharmacotherapy 2002; 22: 538_41.
30 Raeder MB, Bjelland I, Emil Vollset S, Steen VM. Obesity,
dyslipidemia, and diabetes with selective serotonin reuptake
inhibitors: the Hordaland Health Study. J Clin Psychiatry 2006;
31 Haney EM, Chan BK, Diem SJ, Ensrud KE, Cauley JA,
Barrett-Connor E, et al. For the Osteoporotic Fractures in Men Study
Group. Association of low bone mineral density with selective
serotonin reuptake inhibitor use by older men. Arch Intern Med
2007; 167: 1246_51.
32 Montejo AL, Llorca G, Izquierdo JA, Rico-Villademoros F.
Incidence of sexual dysfunction associated with antidepressant agents:
a prospective multicenter study of 1 022 outpatients. Spanish
Working Group for the Study of Psychotropic-Related Sexual
Dysfunction. J Clin Psychiatry 2001; 62 (Suppl 3): 10_21.
33 Waldinger MD. Premature ejaculation: definition and drug
treatment. Drugs 2007; 67: 547_68.
34 van Geffen EC, Hugtenburg JG, Heerdink ER, van Hulten RP,
Egberts AC. Discontinuation symptoms in users of selective
serotonin reuptake inhibitors in clinical practice: tapering versus
abrupt discontinuation. Eur J Clin Pharmacol 2005; 61: 303_7.
Epub 2005 May 20.
35 Cohen D. Should the use of selective serotonin reuptake
inhibitors in child and adolescent depression be banned? Psychother
Psychosom 2007; 76: 5_14.
36 Gibbons RD, Brown CH, Hur K, Marcus SM, Bhaumik DK, Mann
JJ. Relationship between antidepressants and suicide attempts:
an analysis of the Veterans Health Administration data sets. Am
J Psychiatry 2007; 164: 1044_9.
37 Waldinger MD, Zwinderman AH, Schweitzer DH, Olivier B.
Relevance of methodological design for the interpretation of
efficacy of drug treatment of premature ejaculation: a systematic
review and meta-analysis. Int J Impot Res 2004; 16: 369_81.
38 Waldinger MD. Premature ejaculation: definition and drug
treatment. Drugs 2007; 67: 547_68.
39 Waldinger MD, Zwinderman AH, Olivier B. SSRIs and ejaculation:
a double-blind, randomized, fixed-dose study with paroxetine and
citalopram. J Clin Psychopharmacol 2001; 21: 556_60.
40 Safarinejad MR, Hosseini SY. Safety and efficacy of citalopram
in the treatment of premature ejaculation: a double-blind
placebo-controlled, fixed dose, randomized study. Int J Impot Res
2006; 18: 164_9.
41 Safarinejad MR. Safety and efficacy of escitalopram in the treatment
of premature ejaculation: a double-blind, placebo-controlled,
fixed-dose, randomized study. J Clin Psychopharmacol 2007; 27: 444_50.
42 Posternak MA, Zimmerman M. Dual reuptake inhibitors incur lower
rates of tachyphylaxis than selective serotonin reuptake inhibitors: a
retrospective study. J Clin Psychiatry 2005; 66: 705_7.
43 Dresser MJ, Kang D, Staehr P, Gidwani S, Guo C, Mulhall JP,
et al. Pharmacokinetics of dapoxetine, a new treatment for
premature ejaculation: Impact of age and effects of a high-fat meal.
J Clin Pharmacol 2006; 46: 1023_9.
44 Hellstrom WJ, Heintz JW. Treatment of premature ejaculation:
new drugs and treatment strategies. Curr Urol Rep 2006; 7: 473_8.
45 Waldinger MD, Zwinderman AH, Olivier B, Schweitzer DH. The
majority of men with lifelong premature ejaculation prefer daily
drug treatment: an observation study in a consecutive group of
Dutch men. J Sex Med 2007; 4 (4 Pt 1): 1028_37.
46 Safarinejad MR, Hosseini SY. Safety and efficacy of tramadol in
the treatment of premature ejaculation: a double-blind,
placebo-controlled, fixed-dose, randomized study. J Clin Psychopharmacol
2006; 26: 27_31.
47 Salem EA, Wilson SK, Bissada NK, Delk JR, Hellstrom WJ, Cleves
MA. Tramadol HCL has promise in on-demand use to treat
premature ejaculation. J Sex Med 2007; 14; Epub ahead of print.
48 Laumann EO, Paik A, Rosen RC. The epidemiology of erectile
dysfunction: results from the National Health and Social Life
Survey. Int J Impot Res 1999; 11 (Suppl 1): S60_4.
49 Abdel-Hamid IA, El Naggar EA, El Gilany AH. Assessment of as
needed use of pharmacotherapy and the pause-squeeze technique
in premature ejaculation. Int J Impot Res 2001; 13: 41_5.
50 Wang WF, Wang Y, Minhas S, Ralph DJ. Can sildenafil treat
primary premature ejaculation? A prospective clinical study. Int
J Urol 2007; 14: 331_5.
51 McMahon CG, Stuckey BG, Andersen M, Purvis K, Koppiker N,
Haughie S, et al. Efficacy of sildenafil citrate (Viagra) in men
with premature ejaculation. J Sex Med 2005; 2: 368_75.
52 Atan A, Basar MM, Tuncel A, Ferhat M, Agras K, Tekdogan U.
Comparison of efficacy of sildenafil-only, sildenafil plus topical
EMLA cream, and topical EMLA-cream-only in treatment of
premature ejaculation. Urology 2006; 67: 388_91.
53 Chen J, Mabjeesh NJ, Matzkin H, Greenstein A. Efficacy of
sildenafil as adjuvant therapy to selective serotonin reuptake
inhibitor in alleviating premature ejaculation. Urology 2003;
54 Li X, Zhang SX, Cheng HM, Zhang WD. Clinical study of
sildenafil in the treatment of premature ejaculation complicated
by erectile dysfunction. Zhonghua Nan Ke Xue 2003; 9: 266_9.
55 Fein RL. Intracavernous medication for treatment of premature
ejaculation. Urology 1990; 35: 301_3.
56 Kim SW, Lee SH, Paick JS. In
vivo rat model to measure hypogastric nerve stimulation-induced seminal vesicle and vasal pressure
responses simultaneously. Int J Impot Res 2004; 16: 427_32.
57 Cavallini G. Alpha-1 blockade pharmacotherapy in primitive
psychogenic premature ejaculation resistant to psychotherapy.
Eur Urol 1995; 28: 126_30.
58 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.
59 Optale G, Pastore M, Marin S, Bordin D, Nasta A, Pianon C.
Male sexual dysfunctions: immersive virtual reality and
multimedia therapy. Stud Health Technol Inform 2004; 99: 165_78.
60 Jan Wise ME, Watson JP. A new treatment for premature
ejaculation: case series for a desensitizing band. Sex and Relation
Ther 2000; 15: 345_50.
61 Kim JJ, Kwak TI, Jeon BG, Cheon J, Moon DG. Effects of glans
penis augmentation using hyaluronic acid gel for premature
ejaculation. Int J Impot Res 2004; 16: 547_51.
62 Mulhall JP. Current and future pharmacotherapeutic strategies
in treatment of premature ejaculation. Urology 2006; 67: 9_16.
63 Looney C, Thor KB, Ricca D, Marson L. Differential effects of
simultaneous or sequential administration of paroxetine and
WAY-100,635 on ejaculatory behavior. Pharmacol Biochem Behav
2005; 82: 427_33.
64 Williamson IJ, Turner L, Woods K, Wayman CP, Van Der Graaf
PH. The 5-HT1A receptor antagonist robalzotan enhances
SSRI-induced ejaculation delay in the rat. Br J Pharmacol 2003;
138(Suppl 1): PO32.