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Blackwell Science, LtdOxford, UKJSMJournal of Sexual Medicine1743-6095Journal of Sexual Medicine 2005 20052S2103109Original ArticlePremature Ejaculation: The Physician’s PerspectiveSharlip
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Diagnosis and Treatment of Premature Ejaculation:
The Physician’s Perspective
Ira Sharlip, MD
University of California San Francisco, San Francisco, CA, USA
Corresponding Author: Ira Sharlip, MD, 2100 Webster Street, Suite 222, San Francisco, CA 94115, USA. Tel: 415202-0250; E-mail: [email protected]
ABSTRACT
Premature ejaculation (PE) is a common condition associated with signiﬁcant adverse effects on
the sexual and overall quality of life of men with this condition. Behavioral therapies, such as the
“squeeze” and “stop–start” techniques, and psychotherapy, have been the mainstay of PE management for many years. However, evidence of their short-term efﬁcacy is limited while support for
their long-term beneﬁt is lacking. There are currently no medications licensed speciﬁcally for the
treatment of PE. This paucity of pharmacological treatment may, in turn, contribute to the absence
of systematic procedures for the identiﬁcation, evaluation, and treatment of PE patients. Current
“off-label” pharmacotherapeutic approaches include topical anesthetics, phosphodiesterase-5 inhibitors, and serotonin reuptake inhibitors. Of these, the serotonin reuptake inhibitors show the
greatest efﬁcacy and an increasing body of evidence is illuminating their mode of action. Nevertheless, all current “off-label” pharmacotherapeutic approaches fall short of the ideal therapy for
PE. In the absence of a cure, such a treatment should be tolerable, inconspicuously used, effective
from ﬁrst dose, rapid in onset of action, and available as a prn-dosing regimen. It is anticipated that
agents in development for the speciﬁc indication of PE will come closer to this ideal than existing
pharmacotherapeutic approaches.
Key Words. Premature Ejaculation; Intravaginal Ejaculatory Latency Time; Seretonin;
Phosphodiesterase-5 (PDE-5) Inhibitors
Introduction
Evaluation of Premature Ejaculation
C
The lack of a universally accepted clinical deﬁnition of PE has impeded the development of
systematic strategies for the identiﬁcation and
treatment of the condition. Indeed, there is even
confusion over which healthcare practitioners are
most appropriate to conduct patient evaluation
and treatment. For instance, many specialties,
including primary care physicians, urologists,
psychiatrists, and psychologists, come into contact with potential PE patients, and all of these
practitioners are therefore well placed to help
manage the condition. This, in turn, raises the
question of whether practitioners should proactively seek identiﬁcation of the condition. For
example, should primary care physicians ask
urrently, strategies for the diagnosis and
treatment of premature ejaculation (PE) are
not widely understood or used. The American
Urological Association (AUA) has recently published its guideline on the pharmacologic management of PE [1]. Most patients remain unaware that
PE is a medical condition, while many physicians
remain unaware of the available treatment
approaches. This article provides a perspective on
how the diagnosis and treatment of PE can be
improved. It discusses the ways in which the condition can be identiﬁed, provide an overview of the
currently available treatment approaches and discusses some of the characteristics sought in the
ideal pharmacotherapy.
J Sex Med 2005; Supplement 2
104
about PE, or should they wait until the patient
presents with the problem? While there is no
deﬁnitive answer to this question at the moment,
it is very probable that, as more effective therapies become available, the number of patients
seeking help will increase.
There are several considerations in ensuring
that an accurate evaluation and diagnosis is performed. Of primary importance is the differentiation of PE from other sexual dysfunctions. For
instance, it is common for patients with ED to
present with the chief complaint of PE when the
actual problem is the patient’s haste to achieve
orgasm before the failure of an erection. In these
cases, successful treatment for ED may often
resolve the secondary PE [2]. It is also important
to understand that there are links between sexual
function, overall health, and quality of life [3–5].
This is particularly true for PE because it can have
a major impact on the sexual and overall quality of
life of both the patient and his partner.
Establishing an accurate sexual and psychosocial history is critical in identifying the etiology of
PE and establishing an effective treatment regimen. There are several key areas that should be
addressed when taking the history of a patient with
possible PE. For instance, it is extremely important to establish the level of distress experienced
by both the patient and his partner. Indeed, this is
a central component of current diagnostic criteria
[2,6]. A second important area of discussion is the
patient’s perception of ejaculatory control. Specifically, it is important to determine the extent to
which the patient can exert voluntary control over
the ejaculation. It may also be helpful to ask
patients for an estimate of their intravaginal ejaculatory latency time (IELT). While this may not
be accurate, and may differ signiﬁcantly from
the partner’s estimate, it can provide important
insights into the patient’s perception of the severity of the problem. Questions about the onset and
duration of PE can help to establish whether the
condition is primary or secondary. In this regard,
psychosocial aspects of the patient history are very
important, particularly if there is a history of
childhood physical or sexual abuse. Such a history
may indicate the need for psychotherapy as part of
the treatment regimen.
A comprehensive medical history is equally
important in the evaluation of PE because of the
established relationship between some medical
conditions, such as diabetes and other neuropathies, with ejaculatory dysfunction [7,8]. Furthermore, PE is an acknowledged consequence of
J Sex Med 2005; Supplement 2
Sharlip
substance abuse, particularly during withdrawal
from opiates [9,10].
Current Treatment Approaches for
Premature Ejaculation
Current treatment approaches for PE can be
divided into two broad categories: psychotherapeutic/behavioral and pharmacotherapeutic (Table 1). Two types of behavioral therapy
have been widely advocated: the “stop–start” and
“squeeze” techniques. There are currently no
pharmacotherapies speciﬁcally licensed for the
treatment of PE, but a number of agents have been
used “off label” to treat the condition. These pharmacotherapeutic approaches can be divided into
three groups: topical agents; phosphodiesterase5 (PDE-5) inhibitors; and serotonin reuptake
inhibitors (SRIs).
Behavioral Therapy and Psychotherapy
Behavioral therapy has long been a mainstay of
treatment for PE and remains, in the absence of
anything better, a common approach today. Part
of the popularity of this approach is due to the
paucity of other effective therapies. Semans was
the ﬁrst to advocate the squeeze technique in a
report published in 1956 [11], but it was more
extensively popularized in the 1970s by Masters
and Johnson’s report [12]. This technique involves
withdrawal of the penis during intercourse and
prior to the moment of ejaculatory inevitability.
The sexual partner is instructed to give a very
sharp and hard squeeze to the glans penis to abort
the ejaculation. However, many practitioners and
patients report that this technique is unpractical.
The stop–start technique has been used, with
variations, for some three decades and was particularly popularized by Kaplan in 1983 [13]. This
method requires the man to pause during sexual
stimulation, just prior to impending ejaculation.
The pause allows the patient to acclimatize to the
sensation and eventually to condition himself to
increased ejaculatory control. This technique may
Table 1 Current treatment options for premature
ejaculation
Behavioral techniques
Pharmacotherapies
Squeeze technique [11,12]
Stop–start technique [13]
Topical local anesthetics
Phosphodiesterase-5 (PDE-5)
inhibitors
Selective serotonin reuptake
inhibitors (SSRIs)
Psychotherapy
Premature Ejaculation: The Physician’s Perspective
be effective for two reasons: it heightens a man’s
awareness of his sexual sensations and decreases
the emphasis on coitus as the all-important activity
during sexual interaction.
Psychotherapy can be effective in some men,
with or without the use of behavioral therapy.
Some patients can learn to modulate their psychosexual responses to sexual stimulation and gain
some conscious control of their ejaculatory
reﬂexes. While behavioral and/or psychotherapeutic approaches are commonly used, they are
associated with signiﬁcant drawbacks. For obvious
reasons, they work best in a stable relationship, as
they require the committed assistance and understanding of the partner. Time must also be given
to learning and using these approaches, and the
cost of the psychotherapy, with the accompanying
instruction, is often substantial. Furthermore,
behavioral techniques are slow to be effective and,
even so, there are mixed reports of efﬁcacy: Clarke
and Parry reported that 60% of men using the
squeeze technique received beneﬁt in the short
term [14], while De Amicis et al. found that any
success achieved by behavioral therapy was not
maintained at 3-year follow-up [15].
Current Pharmacotherapeutic Options
Local anesthetics have been a commonly used
pharmacotherapeutic option for PE. Anesthetics
such as the lidocaine–prilocaine combination and
herbal preparations such as the Korean product
known as SS cream are applied to the glans penis
and can diminish sensitivity and delay the point
of ejaculation. SS cream has been reported to
improve ejaculatory control in a high percentage
of patients [16]. However, there are several drawbacks that make local anesthetics a less than ideal
therapeutic option. Local irritation can occur with
herbal preparations [17] and signiﬁcant penile
hypoesthesia may occur. This latter effect can be
severe enough to prevent the patient from achieving an orgasm [18]. Additionally, there are reports
that the use of local anesthetics can induce mild
erectile dysfunction and lowering of sexual arousal
[19]. There is also a potential for transvaginal
absorption of the drugs, which could induce vaginal numbness and even female anorgasmia,
although these problems can be prevented with
condom use [18].
Phosphodiesterase-5 inhibitors are widely used
for the treatment of erectile dysfunction [20] and
have also been tested in clinical studies for the
treatment of PE. However, to date, there is little
105
convincing evidence to show that PDE-5 inhibition signiﬁcantly increases IELT [21–23]. Furthermore, the studies of PDE-5 inhibitors in PE have
used uncontrolled, open-label protocols using
self-diagnosed patients and IELT estimates gathered through patient recall. A mechanism of action
for a delay of ejaculation by PDE-5 inhibition has
not been identiﬁed.
The third class of widely used pharmacotherapeutic agents is the SRIs. The potential of antidepressants to treat PE was ﬁrst suggested by
Ahlenius et al. in 1979 [24]. This study showed
that the tricyclic antidepressant, clomipramine (a
nonselective SRI), prolonged ejaculatory latency
in rats by blocking central serotonin reuptake [24]
and were shortly followed by the appearance of
clinical studies on the efﬁcacy of clomipramine in
PE [25,26]. However, the use of clomipramine was
associated with a high incidence of adverse events,
including anticholinergic effects, reduced sexual
desire, and genital anesthesia [26,27].
There is now considerable neurophysiological
and neuropharmacological evidence to suggest
how inhibition of 5-HT uptake may delay ejaculation. The medial preoptic area (MPOA) and
paraventricular nucleus (PVN) of the hypothalamus play essential roles in the integration of sexual
responses in men [28,29]. Both MPOA and PVN
send efferent projections to the serotonergic
nucleus paragigantocellularis (nPGi) in the brainstem (Figure 1). Serotonergic projections from the
nPGi exert a tonic inhibition of ejaculation via the
lumbosacral motor nuclei in the spinal cord [30]
making the nPGi a pivotal nucleus in the central
control of ejaculation. Nevertheless, the way in
which 5-HT inﬂuences the ejaculatory pathway is
complex and incompletely understood. Some 14
different 5-HT receptor subtypes have been
identiﬁed [31].
Of the serotonergic processes studied to date,
the activity of the 5-HT1A, 5-HT2C receptors, and
the serotonin transporter (5-HTT) appear to be
most important for the modulation of ejaculatory
function and may be appropriate pharmacotherapeutic targets for PE. The 5-HT1A receptor
is principally a presynaptic (somatodendritic)
autoreceptor that, when stimulated, reduces the
rate of the ﬁring of 5-HT neurones [32]. Acute
administration of selective serotonin reuptake
inhibitors (SSRIs) blocks the 5-HTT, leading to
elevated extracellular 5-HT levels, and consequently increased activation of the 5-HT1A autoreceptor. Thus, the rate of ﬁring of 5-HT neurones
decreases, as does the release of 5-HT into the
J Sex Med 2005; Supplement 2
106
Sharlip
Figure 1 Central 5-HT function and
premature ejaculation. Ejaculation is
determined by the complex interplay
of local and distal influences. Although
ejaculation is a spinal sympathetic
reflex generated in the lumbosacral
spinal cord, it is influenced by genital
sensory input and by tonic descending
inhibitory serotonergic control from
the nucleus paragigantocellularis
(nPGi). The nPGi receives modulatory
influences from the medial preoptic
area and paraventricular nucleus of
the hypothalamus.
synaptic cleft, although this effect is counterbalanced by the ongoing blockade of 5-HTT, which
allows released 5-HT to remain longer in the
extracellular. The net effect is either neutral or a
mild increase of 5-HT neurotransmission and a
small upregulation of stimulation of postsynaptic
5-HT receptors [33].
The effects of chronic SSRI treatment are
markedly different (Figure 2). The chronic
blockade of 5-HTT and the resultant persistence
of elevated levels of extracellular 5-HT lead to a
desensitization of the 5-HT1A autoreceptor. The
combined effect of this desensitization and the
continued blockade of 5-HTT is to markedly
Figure 2 Proposed chronic action of SSRIs on 5-HT transmission. Schematic description of the chronological
sequence of neurochemical events involved in the enhancement of serotonergic neurotransmission by chronic SSRI
administration. (Adapted from McMahon and Samali, 1999)
[18].
J Sex Med 2005; Supplement 2
disinhibit the ﬁring of 5-HT neurones. Thus,
5-HT neurotransmission is strongly enhanced
[30,33].
The mechanism described above explains not
only why chronic SSRI administration is more
effective for anti-PE and antidepressant activity
but also why SSRIs show limited acute activity to
delay ejaculation. Interestingly, Waldinger’s group
have compared the pharmacology of the SSRIs
and selective 5-HT receptor agonists on ejaculatory function, concluding that the characteristics
of SSRIs most closely resemble those of 5-HT2C
agonists [30,33]. Evidence that this receptor subtype plays a key role in ejaculation comes from two
key animal studies. Ahlenius et al. showed that
nonselective 5-HT2C agonists delay ejaculation in
rats, while a selective 5-HT2A agonist did not [34].
Subsequently, Foreman et al. showed that 1(2,5-dimethoxy-4 -iodophenyl)-2-aminopropane,
a nonselective 5-HT2 agonist that stimulates both
5-HT2A and 5-HT2C, also delays ejaculation in rats
[35].
There is evidence too of a functional interaction between 5-HT2C and 5-HT1A receptors as the
behavioral response to activation of 5-HT1A agonists in rats is attenuated or completely abolished
by the coactivation of 5-HT2C receptors [36].
Based on this evidence, Waldinger et al. have
hypothesized that PE may be a result of a hypersensitive 5-HT1A receptor system and/or a
hyposensitive 5-HT2C system and that the action
of SSRIs may restore a balance between these two
systems [30,33].
Following the introduction of the nonselective
serotonin reuptake inhibitor clomipramine as an
Premature Ejaculation: The Physician’s Perspective
IELT (minutes)
antidepressant, more tolerable SSRIs were developed and since the late 1980s, ﬁve SSRIs have
been licensed for the treatment of depression:
citalopram, paroxetine, sertraline, ﬂuoxetine, and
ﬂuvoxamine.
Waldinger et al. reported the ﬁrst trial of
an SSRI for PE in 1994 [37]. This randomized,
double-blind, placebo-controlled study found that
paroxetine signiﬁcantly improved PE. Shortly
thereafter, Mendels et al. described the ﬁrst use of
sertraline in PE in 1995 showing that sertraline
increased IELT in men with PE [38].
Figure 3 shows the results of another study of
sertraline in men with PE [39]. Like most of the
studies of SSRIs in PE, the protocol was based
on chronic, rather than prn dosing. The study
enrolled 37 men with PE and randomized them in
a crossover fashion to receive either placebo or
sertraline (50 mg/day). At baseline the mean IELT
of the men was less than half a minute. Over a
period of 1–3 weeks after initiation of therapy,
IELT increased to the range of 3 minutes. There
was a decrease in IELT on termination of treatment and after approximately 4 weeks mean IELT
was similar to pretreatment baseline. Despite a
minor placebo response rate, the effect of sertraline was clearly signiﬁcant (P < 0.001 at 4 weeks
vs. placebo). In the crossover phase of the trial,
after the 4-week washout period, the effects of
sertraline mirrored the ﬁrst round of therapy [39].
Evidence from a comparative randomized,
double-blind, placebo-controlled trial shows that
there is considerable variation in the efﬁcacy of
SSRIs in the treatment of PE [40]. The trial
Time (weeks)
Figure 3 Time-dependent effect of sertraline on ejaculatory
latency in men with premature ejaculation. Effects of daily
sertraline (50 mg/day) or placebo on intravaginal ejaculatory
latency time (IELT) in minutes during 4 week dosing periods.
The arrow shows the peak response, at 4 weeks, in the
group given sertraline first. (Data from McMahon et al.,
1998) [39].
107
compared the efﬁcacy of ﬂuoxetine, ﬂuvoxamine,
paroxetine, and sertraline in 60 men with PE.
At baseline, the mean IELT was approximately
20 seconds.
As with the sertraline trial mentioned above, a
small placebo response rate was observed. However, after 6 weeks of treatment ﬂuoxetine, paroxetine, and sertraline all increased the mean
IELT above this placebo level signiﬁcantly while
ﬂuvoxamine did not. In this study, paroxetine
was by far the most effective SSRI, for which
the mean IELT increased from a baseline of
approximately 30 seconds to over 450 seconds
after 6 weeks.
Apart from the variability in efﬁcacy, there are
other drawbacks with the existing SSRIs, not least
that these agents are associated with adverse
events such as nausea, drowsiness, cognitive
impairments, and sexual side-effects including
abnormal ejaculation, decreased libido, male and
female sexual dysfunction, and menstrual disorders [18]. Furthermore, to work optimally, they
must be administered over periods of weeks (see
Figure 3). Waldinger et al. emphasized the importance of chronic administration in a comparative
trial of clomipramine and paroxetine [41]. The
study enrolled 30 men with PE and showed that,
while on-demand treatment with clomipramine
(25 mg) led to a clinically signiﬁcant 4.05-fold
increase [95% conﬁdence intervals (CI): 3.26–
5.02] in IELT, a similar regimen for paroxetine
(20 mg) led to a clinically meaningless 1.41-fold
increase (95% CI: 1.22–1.63) in IELT. Furthermore, both therapies were associated with “mostly
mild, but annoying non-sexual side-effects” [41].
A further drawback of the slow onset of action of
SSRIs and relatively long half-life of these agents
is the risk of accumulation and an exacerbation of
SSRI-related adverse events [18].
These shortcomings emphasize the need for the
development of therapies more speciﬁcally tailored for the treatment of PE. Such a therapy
would be an oral formulation that is effective from
the ﬁrst dose. It would have a rapid onset of action
and pharmacological half-life commensurate with
the purpose recognized by the patient; that is the
time from the beginning of sexual interest through
to the conclusion of mutually satisfying sexual
intercourse. Equally important, the therapy
should have a low incidence of adverse events.
Although a drug matching this proﬁle is not currently available, there are candidates in the pipeline that have the potential to meet these
therapeutic requirements more closely.
J Sex Med 2005; Supplement 2
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Sharlip
Conclusions
Behavioral techniques and psychotherapy have
dominated the therapeutic approach to PE for
many years, however these methods can be cumbersome and expensive, with limited long-term
efﬁcacy. The dawning of the pharmacological age
of PE treatment offers hope for the many men
who suffer from PE. However, maximum patient
beneﬁt will only come from improvements in the
pharmacotherapy of PE if they are coupled with
the development of systematic approaches to the
identiﬁcation and evaluation of patients with the
condition. Current diagnostic criteria for PE are
inconsistent. Similarly, optimum methods of evaluation and treatment have only recently been
recommended [1].
Current pharmacotherapies offer some degree
of efﬁcacy for men with PE, but are far from ideal.
Their clinical utility is limited by several factors,
including a signiﬁcant incidence of adverse events.
The ideal agent for the treatment of PE would be
oral, well tolerated, effective from ﬁrst dose and
available as a prn-dosing regimen. Agents currently in development may come closer to the
ideal therapy for PE. Such tailored therapies will
be a welcome addition to the armamentarium
available to healthcare professionals and, most of
all, to men suffering from PE and their partners.
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