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Mini Reviews
TOPICAL TREATMENTS FOR PREMATURE EJACULATION
MORALES
et al.
The three mini-reviews this month
cover several areas of interest,
including premature ejaculation,
urological malignancies after renal
transplantation and the muchvexed issue of the relevance of
prostate size to prostate disease.
Each of these should help to keep
the readers up-to-date with each
of these important topics.
A review of the current status of
topical treatments for premature
ejaculation
Alvaro Morales, James Barada* and Michael G. Wyllie†
Centre for Applied Urological Research, General Hospital & Queens University,
Kingston, Ontario, Canada, *Centre for Male Sexual Health, Albany, New York,
USA, and †Plethora Solutions Plc, London, UK
Accepted for publication 9 March 2007
We examine the progress that has been
made towards the development of topical
treatments for premature ejaculation (PE).
Although generally regarded as one of
the most common male sexual problems,
the lack of approved pharmacological agents
for PE means that treatment options are
limited to behavioural therapy, where
available, and the use of drugs ‘off-label’.
There are various theories on the aetiology
of PE, but it seems likely that both biological
and psychological factors are important.
One theory, that men with PE might have
a heightened sensory response to penile
stimulation, provides the rationale for using
topical therapy; reducing the sensitivity of
the glans penis with topical desensitizing
agents (e.g. local anaesthetics) might
improve ejaculatory latency without adversely
affecting the sensation of ejaculation. Offlabel topical treatments are now relatively
widely used, despite limited supportive
efficacy data. There are also new topical
treatments in various stages of development,
designed specifically for use in PE. Treatments
reviewed include TEMPE spray, containing a
eutectic mixture of the topical anaesthetics
lidocaine and prilocaine, and several creams,
including one containing natural products
(SS-cream), and preliminary results from
another containing the local anaesthetic
dylonine, with alprostadil (prostaglandin E1).
Despite wide variations in the methods of
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clinical trials, it is possible to conclude that all
placebo-controlled studies of topical
treatments have reported a significant
increase in intravaginal ejaculatory latency
time compared to baseline and placebo.
Topical treatments for PE are appealing in
that they can be applied as needed and
only minimal systemic effects are likely.
However, without well-controlled drug
delivery there is the theoretical possibility
of penile hypoaesthesia and/or transvaginal
contamination. Unlike the cream
formulations, the TEMPE spray has a
well-controlled delivery system, making it
easy to administer locally, and it appears
to be well tolerated in early clinical trials.
It appears that topical treatments might
be able to satisfy many of the requirements
of an ideal treatment for PE, and certainly
have the potential for use as a first-line
treatment.
KEYWORDS
premature ejaculation, rapid ejaculation,
topical treatments, sexual dysfunction,
therapy, treatment
INTRODUCTION
Premature ejaculation (PE; rapid or early
ejaculation) is generally regarded as one of
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the most common male sexual problems
experienced by men in all countries surveyed.
In most studies an incidence of 20–30% of
men is reported [1–4], although the actual
incidence of PE depends on the definition
used. Some physicians have even suggested
that the prevalence might be as high as 75%
[5]. It therefore appears to be a problem
affecting many men some of the time and
rather fewer all of the time. In practice, most
cases of PE are not medically diagnosed, as
few men with PE consult a physician. The
reasons for this are varied, but are likely to
include embarrassment and particularly the
belief that there is no effective treatment [6],
a view shared by many physicians.
There are numerous definitions of PE but one
of the most commonly accepted is from the
Diagnostic and Statistical Manual of Mental
Disorders, Fourth Edition [7]. This definition
includes an element of self-diagnosis and
does not include a set period of delay.
However, in practice the intravaginal
ejaculatory latency time (IELT) is commonly
used as a way of quantifying treatment
success and as a standardized way of
comparing treatments in clinical research,
mostly measured with a stopwatch. There is
considerable variation as to where the
threshold IELT should be set to define PE in a
clinical setting, although the consensus of
opinion seems to be that men with PE tend to
have an IELT of ≤1–2 min [8–10]. The impact
that PE has on quality of life is significant [3],
with a similar qualitative impact on the
individual as erectile dysfunction (ED) [6]. As a
result, there is now general agreement that
although IELT comparisons are valuable, in a
well-designed clinical trial, treatments should
be evaluated in terms of sexual satisfaction
(by the man and his partner), and perception
of control over ejaculation, in addition to IELT
[9,11].
There are currently no pharmacological
agents approved for use in PE and all drugs
have to be administered ‘off-label’. There
are several treatment options for men
directed at different components of the
complex mechanism of the ejaculatory
process. These include behavioural therapy
(such as the ‘stop-start’ and ‘squeeze’
techniques), systemic treatments and locally
acting topical therapy.
Behavioural therapies for PE require a high
level of commitment and the involvement
of the man’s sexual partner. Although such
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therapies can be useful for some couples, they
are rarely successful in the long term, as most
benefits are lost within 3 years of treatment
without regular follow-up therapies [12,13].
In addition, the high cost and limited
availability of well-trained sex therapists
means that this approach is not always a
practical first-line treatment, and indeed is
unsuitable for men with no steady and
supportive sexual partner. Drug therapy
(albeit off-label) is therefore often the
preferred first-line therapy.
SYSTEMIC THERAPIES
The AUA currently recommends three drug
treatment strategies to treat PE [14]: (i) Daily
treatment with serotonergic antidepressants;
(ii) as needed treatment with serotonergic
antidepressants; (iii) anaesthetic topical
treatment.
Delayed ejaculation is a common side-effect
of many psychotropic or antidepressant
drugs. In particular, the selective serotonin reuptake inhibitors (SSRIs) primarily indicated
for the treatment of depression can increase
the level of serotonin in the brain, inhibiting
the ejaculatory reflex centre, and can prolong
IELT for several minutes [15,16].
Dosing levels of SSRIs are generally lower for
PE than for depression, and various dosing
regimens have been tested (including
continuous, daily or situational). Despite this
the adverse-event (AE) profile appears to be
similar, including dry mouth, drowsiness,
nausea and reduced libido [17]. There is
also the potential for the development of a
serious drug interaction that can lead to
‘serotoninergic syndrome’ which manifests as
headache, nausea, sweating and dizziness in
mild cases, and in hyperthermia, rigidity and
delirium in severe cases [17]. Many physicians
might consider the side-effects hard to
‘justify’ for the treatment of PE, where the
primary outcome is patient satisfaction,
although the AUA has suggested that the
level of AEs is acceptable for the benefit
derived in the patient with PE, and the type
and rate of occurrence of side-effects also
appears to be acceptable to most patients
[14].
Dapoxetine, a novel SSRI, is the first oral
agent specifically developed for managing PE,
and it was shown to be effective, well
tolerated and suitable for on-demand use
[18]. Further research with this drug
continues despite the US Food and Drug
Administration’s apparent refusal to approve
dapoxetine for treating PE [19].
RATIONALE FOR THE USE OF
TOPICAL TREATMENT
There are various theories on the aetiology of
PE [9]. Historically, PE was considered to be a
learned behaviour and as a result, behavioural
therapy was the standard treatment.
However, it is now generally accepted that
both biological and psychological factors are
important in the aetiology of PE. Men with PE
appear to have a heightened sensory response
to penile stimulation, with a vibration
threshold significantly lower than that of
normal men [20,21]. They also generally have
other abnormal autonomic reflex pathways
for the ejaculatory process, including shorter
bulbocavernosal latency time, and higher
bulbocavernosal evoked potentials [21–23].
Should this be the case, drugs which
selectively produce some degree of penile
desensitization or act within the afferentefferent reflex arc should be effective therapy
for PE.
The use of local anaesthetic treatment to
delay ejaculation is indeed the oldest form of
pharmacological therapy for PE, and was first
described by Schapiro in 1943 [24]. The
hypothesis is that reducing the sensitivity of
the glans penis with topical desensitizing
agents (e.g. local anaesthetics) would delay
ejaculatory latency without adversely
affecting the sensation of ejaculation. This
has led to the ‘off-label’ use of one product
marketed for another indication, as well as
the development of novel topical agents
specifically designed to treat PE. Within
this context such off-label use of topical
treatments for PE is now relatively
widespread, and available in cream, ointment
and spray formulations. The issue for
physician and patient is whether, in the
present climate of evidence-based medicine,
there is adequate supportive clinical data.
Comparative efficacy data for topical
treatments, where available, are presented in
Table 1 [25–30].
Compared to systemic treatments for PE,
topical treatments are appealing in that they
can be applied on an ‘as needed’ basis and
systemic side-effects are likely to be minimal.
However, in applying a local anaesthetic to
the penis there is of course the theoretical
possibility of penile hypoaesthesia, and
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TABLE 1 Comparative efficacy and adverse event data for clinical trials of topical treatments for PE
N completing study Baseline IELT,
(mean age, years)
mean (SD) min
Follow-up IELT
(mean), min
Applied to glans
penis and penile
shaft 30 min
before intercourse;
covered with
condom
111 (36)
ND
ND
5/11 excellent
4/11 better
2 no change2
1/11, numbness
of penis
[37] 2.5 g (placebocontrolled,
dose-finding
4 groups ×10 men;
3 applying 2.5 g,
covered with
condoms and
waiting 20, 30 or
45 min, + placebo
group
403 (29.4)
<1 min
Placebo 1.0
20 min 6.71 (2.54)
30 min 8.7 (1.7)
45 min loss of
erection in all
ND
16/40 erection
loss (numbness)
6/10 in 30-min
10/10 in 45-min
[38] Double-blind,
placebocontrolled
Thin layer applied to
294 (completed
glans penis and up
study) placebo
to 2 cm penile shaft;
(32.3)
covered with
EMLA (33.4)
condom for
10–12 min
Placebo 1.67 (0.7) Placebo 1.95 (0.12)
EMLA 1.49 (0.9)
EMLA 8.45 (0.9)
P < 0.001 (placebo
vs EMLA)
Great/excellent5
EMLA
11/16
Placebo
3/13
Men, all, 17%
(5/29)6
Instructed to apply 3–5 113 (42)
sprays (30–50 mg)
direct onto glans
penis – in situ
for 15 min; wipe off
before contact with
partner
1.4 (1.1)
11.35 (10.72)
P = 0.008 vs
baseline
8/11 better/much
better2
7/11 partners
better/much
better2
Men7
3/11
Women
2/11
Instructed to apply 3–5 543
sprays (30–50 mg)
TEMPE (38.5)
direct to glans penis, Placebo (39.3)
in situ for 15 min;
wipe off before
contact with partner
TEMPE 1.0 (1.2)
Placebo 0.9 (0.7)
TEMPE 4.9 (4.9)
Mean change in
Placebo 1.6 (1.6)
SQoL points
P < 0.01 vs baseline
baseline to end
of treatment8
Men: TEMPE 7.0
Placebo 5.5
(P = 0.48)
Women TEMPE 3.3
Placebo 1.8
(P = 0.56)
TEMPE
3/26 hypoasthesia
1/26 ED
Women
1/26 mild burning
sensation
Not stated
Plac 2.34 (0.34)
Dyclo 3.21 (0.31)
Alpro 3.75 (0.34)
Dyclo/alpro
4.08 (0.31)
P < 0.05 vs
placebo
Placebo 5%
Dyclo 17.5%
Alpro 20%
Dyclo/alpro
17.5%
Ref Treatment
EMLA cream
[36] 2.5 g (pilot study)
Methods
TEMPE spray
[29] 30–50 mg (proof
of concept)
[30] 30–50 mg
(doubleblind, placebocontrolled)
Dyclonine/alprostadil cream
[28] Comparison
‘to the tip of the penis’ 309 (28–62)
(i) dyclonine 1%,
at the meatus’
(ii) alprostadil
5–10 min before
0.4%
coitus
(iii) dyclonine
0.5%/ alprostadil
0.4% (placebocontrolled)
All AEs local and
mild to
moderate
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Satisfaction (man)
% ‘yes’ to PSQ in
diary
Placebo 66.7
Dyclo 73.3
Alpro 83.3
Dyclo/alpro 86.7
AE details,
incidence
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TABLE 1 Continued
N completing study Baseline IELT,
(mean age, years)
mean (SD) min
Follow-up IELT
(mean), min
Applied 1 h before
sexual contact;
washed off before
intercourse
18610 (42.3)
1.50 (0.58)
10.89 (5.60)
P < 0.001 vs
baseline
Satisfaction
with treatment11
Not satisfied
10.8%
Satisfied 89.2%
Overall
5.9% (11/186)
7/186 mild local
irritation
4/186 delayed
ejaculation
[26] 0.05 g
0.10 g
0.15 g
0.20 g (placebocontrolled)
Applied 1 h before
sexual contact;
washed off before
intercourse
503 (37)
1.35 (0.07)
Plac 2.27 (0.32)
0.05 g 4.47 (0.81)
0.10 g 5.34 (0.79)
0.15 g 6.22 (0.87)
0.20 g 11.06 (1.17)
SSR12
Plac 26%
0.05 g 60%
0.10 g 70%
0.15 g 78%
0.20 g 90%
All test trials
14.8% (37/250),
mild local
burning
sensation;
0.04% (1/250),
mild penile
pain; reports of
mild local
burning
sensations
increased in a
dose-dependent
fashion
[27] 0.2 g (doubleblind, placebocontrolled)
Applied 1 h before
sexual contact;
washed off before
intercourse
106 (38.7)
1.37 (0.12)
Plac 2.45 (0.29)
SS 10.92 (0.95)
P < 0.001 (between
treatments)
SSR13
Plac 19.81
SS 82.2%
All test trials
14.7% (78/530)14,
mild burning
3.8% (20/530),
mild pain 18.5%
(98/530)
Ref
Treatment
SS-cream
[25] 0.1 g
Methods
Satisfaction (man)
AE details,
incidence
ND = not done; 1Patients with self-diagnosed PE; history of primary or secondary PE not stated. 2Satisfaction assessed on a scale of −1 for worse, 0 for no change,
1 for better than usual, 2 for excellent; 3Self-diagnosed primary PE; 4Patients with self-diagnosed primary and secondary PE; 5Level of satisfaction defined using
a linear scale pf 1–10, as bad (1–4), regular (5,6), good (7), great (8,9) or excellent (10); 6Men, 2/29 retarded ejaculation, 2/29 loss of sensitivity, 2/29 penile irritation;
Women 1/29 decreased vaginal sensitivity; 72/11 numbness of penis, 1/11 burning sensation on first use, 3/11 difficulty maintaining erection in 15 min wait;
women 2/11 numbness of vagina; 8Study-specific male and female sexual quality-of-life questionnaires, each containing 10 statements; 9Entry criteria not
stated; 10132 with primary PE and 54 with secondary PE, and including 64 patients with PE combined with mild ED; 11Patients were asked to estimate the degree
of satisfaction for both their partners and themselves; 12SST, sexual satisfaction ratio; method of determining sexual satisfaction not stated; 13SSRs determined
by adding the percentage of patients who reported being satisfied (effective) and very satisfied (excellent); 14total patients 3/106 ED, 4/106 delayed ejaculation,
5/106 no ejaculation.
transvaginal contamination and female
genital anaesthesia, unless drug delivery is
well-controlled; comparative data on such
AE, where available, are also presented in
Table 1.
‘SEVERANCE SECRET-CREAM’
(SS-CREAM)
Severance Hospital in Korea, is made with
extracts from nine natural products. Some of
these products have local anaesthetic as well
as vasoactive properties. Several studies using
SS-cream on men with PE were conducted in
Korea, but the cream is not approved for use
in Europe or the USA, and is not legally
available outside Korea.
SS-cream (Cheil Jedan Corporation, Seoul,
Korea), developed at the Yong-Dong
SS-cream is applied to the glans penis
1 h before intercourse and washed off
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immediately before coitus. Both the latency
and amplitude of somatosensory evoked
potentials measured at the glans penis were
increased over baseline after applying SScream [31], which has also been shown to
increase the penile vibratory thresholds at the
glans penis in a dose-dependent fashion [32].
Xin et al. [25] reported significantly prolonged
ejaculatory latency in 89.2% of patients
treated with SS-cream. AEs were noted in
5.9% of patients, which included mild local
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irritation (local burning or pain) and delayed
ejaculation. The prolongation of IELT was
shown to be dose-dependent [26], with an
optimal dose of 0.2 g cream.
In a multicentre double-blind study involving
106 patients, the use of 0.2 g of SS-cream was
reported to increase the mean stopwatchmeasured IELT from a baseline of 1.37 min
to 10.92 min, compared to 2.45 min with
placebo (P < 0.001), and was 27 times
more effective than placebo in increasing
sexual satisfaction (P < 0.001). However,
almost 19% of episodes of use were
associated with mild localized irritation,
including pain and burning, and 12 patients
reported negative sexual side-effects such as
delayed ejaculation, anejaculation and ED
[27].
Despite these promising results, SS-cream
has an unpleasant smell and colour, which
makes it unacceptable to many patients.
A reformulation has resulted in ‘renewed
SS-cream’ which is a new topical agent
composed of the two main components of the
original SS-cream, i.e. Korean ginseng and
bufonis venenum in a hydrobase and
enhancer with no smell or colour [33]. So far,
only the results of animal studies have been
published. The authors claim that renewed
SS-cream delays the latencies of the spinal
somatosensory evoked potentials in rabbits
more effectively than the original SS-cream.
However, the ingredient Bufonis venenum has
been shown to produce contact dermatitis
[34] and the likelihood of this cream gaining
regulatory approval outside Korea appears to
be remote.
DYCLONINE/ALPROSTADIL CREAM
Dyclonine, a local anaesthetic used most
commonly in dentistry, has been combined
in a cream formulation with alprostadil
(prostaglandin E1; a vasodilator used in
treating ED), and is under development
(NexMed Inc, USA) as a topical treatment for
PE. So far only one pilot study has been
published (in abstract form) in which creams
containing dyclonine alone, alprostadil alone
or dyclonine/alprostadil combined, with two
different drug concentrations, were compared
in a double-blind cross-over trial [28]. This
pilot study involved 30 patients who applied
the cream 5–20 min before intercourse. There
was a significant synergistic effect with the
cream containing 0.5% dyclonine/0.4%
alprostadil compared with creams containing
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1% dyclonine alone or 0.4% alprostadil alone
(P < 0.05; Table 1). Baseline IELTs were
unfortunately not reported, but the mean
IELTs after dosing were 2.34 and 4.08 min in
the placebo and dyclonine/alprostadil
combination groups, respectively (P < 0.05).
AEs were reported by 17.5% of men and were
described as local, mild to moderate and with
a mean duration of 18.2 min. Details of the
AEs and whether or not any of the patients’
partners had AEs were also not provided. The
most frequently reported AE in patients using
alprostadil cream to treat ED are application
site-related, e.g. penile burning, genital pain
and genital erythema, mostly resolving within
2 h [35].
LIDOCAINE-PRILOCAINE CREAM
Separately, lidocaine and prilocaine are
crystalline solids, but when mixed together in
equal quantities by weight they form a liquid
eutectic mixture which can be formulated
into preparations without the use of a
non-aqueous solvent. This allows higher
concentrations of anaesthetic to be
formulated into the preparation and
maintained during application. The eutectic
mixture of local anaesthetic (EMLA,
AstraZeneca, UK) is a local anaesthetic
cream containing 2.5% each of lidocaine/
prilocaine for topical application. Developed
to anaesthetize intact skin, it is available
as an ‘over-the-counter’ product in some
countries.
The first pilot study evaluating lidocaineprilocaine cream for treating PE included 11
men [36]; the cream (2.5 g) was applied to the
whole glans and shaft of the penis 30 min
before intercourse and covered with a
condom, which could be removed before
intercourse (and the cream wiped off) if
desired. Nine of the 11 patients rated their
performance as ‘excellent’ or ‘better’ and all 11
partners were satisfied with the treatment
results [36].
To determine the optimum time that the
anaesthetic cream should be on the penis
before intercourse, Atikeler et al. [37] carried
out a placebo-controlled trial with 10 patients
in each treatment group, varying the
application time from 20 to 45 min, with a
condom. In the 20- and 30- min groups
the IELT increased compared with placebo,
but all men in the 45-min group had
penile numbness and loss of erection. The
optimum application time was considered to
be 20 min.
The largest double-blind clinical trial of
lidocaine-prilocaine cream to date involved
42 patients, 21 in each group [38]. Patients
were asked to apply a thin layer of cream
to the glans penis, extending the coverage for
up to 2 cm on the penile shaft. They were then
asked to cover the cream with a condom for
10–20 min before intercourse and to use this
treatment each time they had intercourse
over 30–60 days. The treatment resulted in a
5.6-fold increase in IELT. However, only 29 of
the initial 42 participants completed the
study. Of the patients completing the study, 11
of 16 reported ‘great’ or ‘excellent’ sexual
satisfaction. Loss of penile sensation, retarded
ejaculation and penile irritation were a
problem for five men, and one female
partner reported decreased vaginal
sensitivity.
It can be concluded that lidocaine-prilocaine
cream has some efficacy in the treatment of
PE but is cumbersome and slow-acting.
Genital hypoaesthesia in both partners has
been reported.
LIDOCAINE SPRAY
Lidocaine 9.6% spray, marketed as ‘Studd
100’ or ‘Premjact’, has been available over
the counter for over 25 years in some
countries, and as their names suggest, are
marketed as products for delaying
ejaculation. However, the absence of reliable
data from clinical trials means that the
validity of the claims by the manufacturers
cannot be assessed.
PRILOCAINE-LIDOCAINE SPRAY
TEMPE (Topical Eutectic Mixture for
Premature Ejaculation, Plethora Solutions Plc,
London, UK) is a proprietary formulation of
lidocaine and prilocaine in a metered-dose
aerosol-delivery system specifically designed
for use in PE, delivering 7.5 mg lidocaine base
plus 2.5 mg prilocaine base per actuation. The
mixture is alcohol-free so there is little risk of
stinging on application, and although oil-free,
the mixture forms a clear, slightly oily,
odourless solution that remains adherent to
the application site. It can easily be wiped off
if necessary with a damp cloth, so no condom
is required [29].
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The metered-dose spray-delivery system
allows the desensitizing agents to be
deposited in a dose-controlled, concentrated
film on the glans penis, which can then
penetrate the glans within 5–10 min [29]
(Fig. 1). The eutectic mixture is less capable of
penetrating intact keratinized skin and as
such is less likely to anaesthetise the shaft of
the penis or the hands [30].
FIG. 1. The mode of action of TEMPE. TEMPE aerosol spray contains purely base (uncharged) forms of local
anaesthetics whilst creams contain a mixture of base and ionised forms. Only the uncharged base forms are
able to penetrate skin or mucous membranes. Local anaesthetics produce localized reversible inhibition of
nerve conduction by reducing the permeability of the neuronal membranes to sodium ions, the movement of
which is necessary for the transmission of nerve impulses.
Effective delivery = layer of pure LA base at a pH close to the pKa of the drug
Aerosol spray
Cream/ointment
In the first open-label pilot study, 11 patients
recorded stopwatch-timed IELTs at baseline
and on five subsequent encounters when
using the spray 15 min before intercourse.
The average IELT increased from 1.4 min to
11.35 min (P = 0.008), representing a mean
eight-fold increase over baseline. In addition,
eight of the 11 patients and seven of 11
partners rated their sexual satisfaction as
‘better’ or ‘much better’.
LA un-ionised
LA ionised
Proton
axon
10
8
6
4
2
7]
[2
g
[2
0.2
g
SS
–c
re
am
0.2
SS
–c
re
am
0.1
SS
–c
re
am
re
am
–c
SS
6]
6]
g
5
g
0.1
5
0.0
re
am
–c
sp
ra
SS
[2
[2
6]
6]
g
in
m
15
g
m
50
0–
y3
[2
[3
[3
in
m
12
0–
r1
lay
e
in
EM
TE
M
PE
th
498
0]
8]
0
LA
Whilst phosphodiesterase-5 inhibitors such as
sildenafil are highly effective in treating ED,
their use for treating PE is limited to patients
with ED and coexisting PE, and none of the
current guidelines for managing PE include
these inhibitors as first-line agents. A study
comparing the use of lidocaine-prilocaine
cream in PE to lidocaine-prilocaine combined
Improvement over placebo
Placebo
Baseline
12
A summary of the potential of topical
agents as monotherapy is shown in Fig. 2
[26,27,30,38]. All placebo-controlled studies
reviewed here reported a significant increase
in IELT for topical treatments compared to
baseline or placebo. Figure 2 shows the mean
increase in IELT over baseline and placebo for
placebo-controlled trials, but differences
between studies should be interpreted
cautiously due to differences in methods, as
detailed in Table 1.
TOPICAL TREATMENTS AS AN ADJUNCT TO
ORAL THERAPY
Na+ channel
FIG. 2. Improvements in IELT over baseline/placebo in placebo-controlled trials of topical agents to
treat PE.
IELT min
In a recently published phase II, placebocontrolled trial [30], 54 patients using TEMPE
were able to prolong their IELT from a baseline
of 1.0 min to 4.9 min. The treatment was also
well tolerated, with only three patients (12%)
experiencing hypoaesthesia (numbness of the
penis) and a fourth having ED, none resulting
in treatment discontinuation. TEMPE was also
well tolerated by the female partners, with
only one partner experiencing a mild burning
sensation during intercourse each time her
partner used the spray, which did not result in
discontinuation.
Mucous
Membrane
with oral sildenafil, in which patients selfassessed their improvement, showed that
there was no statistical advantage in adding
sildenafil to topical prilocaine-lidocaine
treatment [39]. Similarly, lidocaine ointment
has been used in combination with the SSRI
fluoxetine taken daily [40] or ‘as needed’ [41].
Although the authors claim that the
combined treatment is more effective than
the SSRI alone, neither study included either
lidocaine-only or placebo groups, meaning
that the results are of limited value. It appears
that it is generally unnecessary to think of
topical treatments as an adjunct to oral
therapy for PE, as they tend to be effective
when used alone.
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FIG. 3. Management algorithm for PE, modified
from McMahon et al. [9]
Patient complaining of
premature ejaculation (PE)
Patient/Partner History
•
•
•
•
•
•
•
•
Establish presenting complaint
Intravaginal Ejaculatory Latency Time
Perceived degree of ejaculatory control
Degree of patient/partner distress
Onset and duration of PE
Psychosocial history
Medical history
Physical examination
requires a 20-min application of the cream,
covered with a condom [37]. In comparison,
TEMPE spray is easy to administer locally,
remains adherent to the glans penis after
application, and by exploiting the properties
of a eutectic mixture, the local anaesthetic is
less likely to penetrate intact keratinized skin
and will not anaesthetize the shaft of the
penis [30]. Importantly, with TEMPE spray no
condom is required, as long as it is wiped off
before the penis comes into contact with the
partner.
TREATMENT ALGORITHM
Manage
primary
cause
PE secondary to ED or
other sexual dysfunction
Yes
No
Acquired
Lifelong PE
Treatment
First Line
Pharmacotherapy
• SSRI agents
• Topical agents
Second Line
Behavioural Therapy
• Stop/start
• Squeeze technique
• Sensate Focus
Relationship counselling
OR
Combination Treatment
Attempt graduated withdrawal of
pharmacotherapy after 6 to 8 weeks
ADVANTAGES AND DRAWBACKS OF
TOPICAL TREATMENT
Compared to systemic treatments for PE,
topical treatment can be applied when needed
and systemic side-effects are unlikely,
although they have several potential
drawbacks; they can be messy, interfere with
spontaneity and can possibly cause
hypoaesthesia in the man and/or his partner.
Depending on the formulation, they also
require a period of time between application
and maximum effect, and need to either be
used with a condom or for the product to be
washed or wiped off before intercourse, which
might decrease arousal and reduce
spontaneity.
However, there are differences among the
products. The lidocaine-prilocaine cream
©
Current recommendations from the AUA [14]
and the Second International Consultation on
Sexual Dysfunctions (ICSD) [9] recognize that
PE is a self-reported diagnosis and emphasize
the important role of obtaining a
comprehensive sexual history when making a
diagnosis, i.e. no laboratory or physiological
tests are usually required. It is recommended
that clinicians also determine if there is
concomitant ED and, if present, it should
be treated first [9,14]. The management
algorithm for PE produced by the ICSD
recommends pharmacotherapy with SSRI or
topical anaesthetics as the first-line
treatment in patients with lifelong PE, and
second-line, after behavioural therapy, in
patients with acquired PE [9]. In reality,
pharmacotherapy is likely to be used as the
first line in both cases, due to the limited
availability of skilled behavioural therapists
and relationship councillors. The choice
between oral therapy with SSRI (daily or ‘asneeded’), or the use of a topical agent is a
decision to be made jointly by the patient/
couple and physician, after ascertaining their
desires and expectations. If acceptable to the
patient/couple, a trial of a topical agent could
be a prudent first step due to the favourable
risk/benefit ratio of these products. This is
reflected in the proposed treatment algorithm
shown in Fig. 3.
DISCUSSION
Historically, the first-line treatment for PE has
been behavioural, as was originally the case
with ED, but the last decade has seen an
increase in the pharmacological treatment of
PE, coupled with an increase in the number of
published studies on PE. As would be expected
for a condition where there has traditionally
been considerable debate over the definition,
there is also considerable variation in the
methods used in these studies. A critical
review of the methods of studies in PE [42]
showed the scale of the differences and the
resultant difficulties in comparing results
from these studies. It is therefore important
to exercise some caution when comparing
‘headline’ results. Recommendations for
standards for clinical trials in PE [9,11,42]
include: the use of a precise definition of PE
(e.g. ‘ejaculation that occurs within 1 min
after vaginal penetration in >90% of
attempts’); a randomized double-blind
prospective design; the use of validated
outcome measures (such as IELT and patient
reported outcomes); and the use of a
stopwatch at each coitus, both during
baseline and during drug treatment. Use
of such standardized variables in all
future trials would enable a meaningful
meta-analysis.
CHARACTERISTICS OF AN
IDEAL TREATMENT
As the frequency of sexual intercourse is
highly variable, and spontaneity in sexual
intercourse is usually an important factor,
the ideal treatment for PE would be a discrete
and ‘on-demand’ therapy with rapid action,
effective from the first dose and with high
efficacy on IELT and patient-reported
outcomes, a low incidence of side-effects, and
have no unwanted effects on the partner [15].
It was also suggested that medication could
be used to restore confidence together with
behavioural treatment, where available, to
help men learn to overcome PE on their own
[43,44]. PE is of course not a life-threatening
condition; therefore safety should be a
primary consideration when deciding on a
course of treatment [14].
PE is a self-diagnosed condition and
most men with the condition do not seek
treatment from a physician, for reasons of
embarrassment, shame or the belief that no
effective treatment exists, but they might try
self-help techniques or self-medication. In a
large multinational survey of >11 500 men in
the USA, Italy and Germany, <12% of men
who self-reported PE had sought professional
treatment [45]. In a small survey involving indepth interviews with 28 men with selfdiagnosed PE, 89% had tried some form of
treatment (including behavioural,
pharmaceutical, over-the-counter remedies,
herbal remedies, creams and condoms),
regardless of whether or not they had
consulted a healthcare professional [6]. Such
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M O R A L E S ET AL.
a high figure clearly indicates that men with
PE are highly motivated to seek
a solution or treatment, and that most
men/couples at present self-diagnose and
therefore self-treat their PE. Unfortunately,
the interest and understanding of the
condition by physicians in general and
specialists in particular is erratic at best
and superficial to non-existent at worst.
This in part is due to the lack of large, welldesigned studies showing reliable values for
safety and efficacy of many of the treatments
available.
The demand for treatment for PE is growing,
perhaps due to changes in expectation of
sexual fulfilment by both sexual partners.
Until effective products are licensed for
treating PE, patients (or indeed any man
wanting to extend his IELT) will continue to
turn to over-the-counter products of
questionable efficacy and safety, and solely
based on the manufacturers’ claims but with
limited supporting evidence.
7
8
9
10
11
CONFLICT OF INTEREST
12
James Barada and Alvaro Morales are
Consultants to, and Study Investigators, for
Plethora Solutions. Michael Wyllie is a Board
Member of Plethora Solutions.
13
REFERENCES
1
2
3
4
5
6
Reading A, Weist W. An analysis of selfreported sexual behaviour in a sample of
normal males. Arch Sex Behav 1984; 13:
69–74
Frank E, Anderson C, Rubinstein D.
Frequency of sexual dysfunction in
‘normal’ couples. N Eng J Med 1978; 299:
1111–5
Rowland D, Perelman M, Althof S et al.
Self-reported premature ejaculation and
aspects of sexual functioning and
satisfaction J Sex Med 2004; 1: 225–32
Dunn KM, Croft PR, Hackett GI. Sexual
problems: a study of the prevalence and
need for health care in the general
population. Family Pract 1998; 15: 519–24
McMahon CG. Treatment of premature
ejaculation with sertraline hydrochloride:
a single-blind placebo-controlled
crossover study. J Urol 1998; 159: 1935–8
Symonds T, Roblin D, Hart K. How does
premature ejaculation impact a man’s
life? J Sex Marital Ther 2003; 29: 361–70
500
14
15
16
17
18
American Psychiatric Association.
Diagnostic and Statistical Manual of
Mental Disorders, 4th edn. Text Revision.
Washington DC: American Psychiatric
Association, 2000
Waldinger MD, Quin P, Dileen M,
Mundayat R, Schweitzer DH, Boolell M.
A multinational population survey of
intravaginal ejaculatory latency time.
J Sex Med 2004; 2: 492–7
McMahon CG, Abdo C, Incrocci L et al.
Disorders of orgasm and ejaculation in
men. In Lue TF, Basson R, Rosen R,
Guiliano R, Khoury S, Montorsi F eds.
Sexual Medicine: Sexual Dysfunctions in
Men and Women. Edition 21. Paris: 2005:
411–68
Patrick D, Althof S, Pryour J et al.
Premature ejaculation. an observational
study of men and their partners. J Sex Med
2005; 2: 358–68
Hirsch M, Donatucci C, Glina S,
Montague D, Motorsi F, Wyllie M.
Standards for clinical trials in male sexual
dysfunction. Erectile dysfunction and
rapid ejaculation. J Sex Med 2004; 1: 87–
91
De Amicus LA, Goldberg DC, Lo Piccolo
J, Friedman J, Davies L. Clinical followup of couples treated for sexual
dysfunction. Arch Sex Behav 1985; 14:
467–89
Metz M, McCarthy B. Coping with
Premature Ejaculation: How to
Overcome PE, Please Your Partner &
Have Great Sex. Oakland, CA: New
Harbinger, 2003
Montague D, Jarrow J, Broderick GA
et al. The AUA Erectile Dysfunction
Guideline Update Panel. AUA guideline on
the pharmacologic management of
premature ejaculation. J Urol 2004; 172:
290–4
Hellstrom W. Current and future
pharmacotherapies of premature
ejaculation. J Sex Med 2006; 3 (Suppl. 4):
332–41
Girgis S, El-Haggar S, El-Hermouzy S. A
double-blind trial of clomipramine in
premature ejaculation. Andrologia 1982;
14: 364–9
Sharlip ID. Guidelines for the diagnosis
and management of premature
ejaculation. J Sex Med 2006; 3 (Suppl. 4):
309–17
Pryor J, Althof S, Steidle C, Miloslavsky
M. Efficacy and tolerability of dapoxetine
in the treatment of premature ejaculation.
J Urol 2005; 173: 201
19 AZLA Corporation: press release.
Available at http://www.jnj.com/news/
jnj_news/20051026_164127.htm.
Accessed April 2007
20 Rowland DL, Haensel SM, Blom JH, Slob
AK. Penile sensitivity in men with
premature ejaculation and erectile
dysfunction. J Sex Marital Ther 1993; 19:
189–97
21 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
22 Vignoli GC. Premature ejaculation: New
electrophysiologic approach. Urology
1978; 11: 81–2
23 Xin ZC, Choi YD, Rha KH, Choi HK.
Somatosensory evoked potentials in
patients with primary premature
ejaculation. J Urol 1997; 158: 451–5
24 Schapiro B. Premature ejaculation, a
review of 1130 cases. J Urol 1943; 50:
374
25 Xin ZC, Choi YD, Lee SH, Choi HK.
Efficacy of a topical agent SS-cream in
the treatment of premature ejaculation:
preliminary clinical studies. Yonsei Med J
1997; 38: 91–5
26 Choi HK, Xin ZC, Choi YD et al.
Safety and efficacy study with
various doses of SS-cream in patients
with premature ejaculation in a doubleblind, randomized, placebo controlled
clinical study. Int J Impot Res 1999; 11:
261–4
27 Choi HK, Jung GW, Moon KH
et al. Clinical study of SS-cream in
patients with lifelong premature
ejaculation. Urology 2000; 55: 257–61
28 Gittleman MC, Mo J, Lu M. Synergistic
effect of meatal application of dyclonine/
alprostadil cream for the treatment of
early ejaculation (EE) in a double-blind
and crossover study. Presented at the 8th
Congress of the European Society for
Sexual Medicine, Copenhagen, Denmark
December 4–7, 2005. J Sex Med 2006; 3
(Suppl 3): 176
29 Henry R, Morales A. Topical lidocaineprilocaine spray for the treatment
of premature ejaculation: a proof of
concept study. Int J Imp Res 2003; 15:
277–81
30 Dinsmore WW, Hackett G, Goldmeier
D et al. Topical eutectic mixture for
premature ejaculation (TEMPE): a novel
aerosol-delivery form of lidocaineprilocaine for treating premature
ejaculation. BJU Int 2007; 99: 369–75
©
JOURNAL COMPILATION
©
2 0 07 T H E A U T H O R S
2 0 07 B J U I N T E R N AT I O N A L
TOPICAL TREATMENTS FOR PREMATURE EJACULATION
31 Xin ZC, Choi YD, Seong DH, Choi HK.
Sensory evoked potential and the effect of
SS-cream in premature ejaculation.
Yonsei Med J 1995; 36: 397–401
32 Xin ZC, Choi YD, Lee WH et al. Changes
in ejaculatory latency and penile vibratory
threshold with SS-cream in patients with
primary premature ejaculation. Sex
Dyfunction 1998; 1: 89–93
33 Tian L, Xin ZC, Xin H et al. Effect of
renewed SS-cream on spinal
somatosensory evoked potentials in
rabbits. Asian J Androl 2004; 6: 15–8
34 Lee TY, Lam TH. Irritant contact
dermatitis due to a Chinese herbal
medicine lu-shen-wan. Contact
Dermatitis 1988; 18: 213–8
35 Padma-Nathan H, Yeager JL. An
integrated analysis of alprostadil topical
cream for the treatment of erectile
dysfunction in 1732 patients. Urology
2006; 68: 386–91
36 Berkovitch M, Kerestechi AG, Koren G.
Efficacy of prilocaine-lidocaine cream in
the treatment of premature ejaculation.
J Urol 1995; 154: 1360–1
37 Atikeler MK, Gecit I, Senol FA.
Optimum usage of prilocaine-lidocaine
cream in premature ejaculation. Androlog
2002; 34: 356–9
©
38 Busato W, Galindo CC. Topical
anaesthetic use for treating premature
ejaculation: a double-blind, randomized,
placebo-controlled study. BJU Int 2004;
93: 1018–21
39 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
40 Atan A, Basar MM, Aydoganli L.
Comparison of the efficacy of fluoxetine
alone vs fluoxetine plus lidocaine
ointment in the treatment of premature
ejaculation. Arch Esp Urol 2000; 53: 856–
8
41 Metin A, Kayigil Ö, Ahmed SI. Does
lidocaine ointment increase fluoxetine
efficacy in the same group of patients
with premature ejaculation? Urolog Int
2005; 75: 231–4
42 Waldinger MD. Towards evidence-based
drug treatment research on premature
ejaculation: a critical evaluation of
methodology. Int J Imp Res 2003; 15:
309–13
43 Altof SE. Prevalence, characteristics and
implications of premature ejaculation/
rapid ejaculation. J Urol 2006; 175:
842–8
44 Perelman MA. A new combination
treatment for premature ejaculation: a
sex therapist’s perspective. J Sex Med
2006; 3: 1004–12
45 Porst H. Factors related to seeking
treatment for premature ejaculation.
results from the Premature Ejaculation
Prevalence and Attitudes (PEPA)
Survey. Presented at the 7th
Congress of the European Society
for Sexual Medicine, London, UK,
December 5–8, 2004. J Sex Med
2005; 2 (Suppl. 1): 1–87
Correspondence: Mike Wyllie, Plethora
Solutions Plc, London, UK.
e-mail: [email protected]
Abbreviations: PE, premature ejaculation;
IELT, intravaginal ejaculatory latency
time; ED, erectile dysfunction; SSRI,
selective serotonin re-uptake inhibitor;
AE, adverse event; SS-cream, ‘Severance
Secret-Cream’; EMLA, eutectic mixture
of local anaesthetic; TEMPE, topical
eutectic mixture for PE; ICSD,
International Consultation on Sexual
Dysfunctions.
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