Start Stop Method

Archive for the ‘Start Stop Method’ Category

Sympatholytics
Adrenergic, dopaminergic and serotonergic systems are
all involved in the regulation of male sexual function
[107–109]. Sympatholytic agents such as phenoxybenzamine,
yohimbine and doxazosin have been shown to inhibit the
response of rat seminal vesicle to electrical field stimulation
[110]. Human ejaculation is peripherally activated by

Probable mechanism of these drugs is the enhancement of net serotonergic transmission by blocking the presynaptic 5-hydroxytryptamine (serotonin, 5-HT) uptake site [20,55]. Pre-clinical researches clearly indicate the role of serotonin in ejaculatory processes. Among the different subtypes of 5- HT receptors, the most important ones on ejaculation are HT1A, 5-HT1B, 5-HT1D, and 5-HT2C receptors. Administration SSRIs, results in active blockade of presynaptic membrane 5-HT transporters, and the resultant higher synaptic cleft levels of 5-HT activate post-synaptic 5-HT2C and 5-HT1A receptors and delay ejaculation. 5-HT1A receptor activation
by the selective 5-HT1A receptor agonist 8-OH-DPAT (8-hydroxy-2-(di-n-propylaminotetralin) or flesinoxan inhibits the release of 5-HT in the synaptic cleft, shortens the ejaculation latency time and reduces the number of intermissions preceding ejaculation in animals. 5-HT2C receptor
agonistsD-LSD (D-lysergic acid diethylamide) and quipazine cause ejaculation delay [56]. In summary, SSRIs activate the 5-HT2C receptor and therefore switch the threshold to a higher level, leading to a delay in ejaculation. There are 2 drug treatment strategies to treat PE with SSRIs: 1) daily treatment 2) as-needed treatment. Waldinger et al. reported that, on-demand SSRI treatment has less ejaculation-delaying effects than daily SSRI treatment [57]. Acute administration of various SSRIs, such as,citalopram clomipramine, paroxetine, sertraline, fluoxetine and fluvoxamine did not have any delaying effects on ejaculation in male rats [58]. After acute paroxetine (a SSRI) administration there is an initial increased serotonin release, rapidly followed by a decreased serotonergic neurotransmission associated with minimal post-synaptic 5-HT2C
receptor stimulation. After chronic paroxetine administration, however, ejaculation delay is not only due to an important increased amount of serotonergic (5-HT) neurotransmission but also to desensitization of presynaptic 5-HT1A autoreceptors and post-synaptic 5-HT2C receptors. The net effect of chronic SSRI administration is thus a stronger enhancement
of 5-HT neurotransmission with a consequently  stronger activation of postsynaptic 5-HT receptors compared with acute SSRI administration [20,55]. Also human studies demonstrated that, acute SSRI administration has only weak IELT delaying effect [59]. Some prefer that these agents be
taken “as needed” rather than as chronic drug treatment, because of the reduced risk, side effects and cost [60,61]. Our preference is daily administration of these agents. All SSRIs have potential side effects. These drugs are well absorbed from the gastrointestinal tract and are metabolized by the liver and excreted by the liver and kidneys. Therefore, the dose should be adjusted downward in men with hepatic or renal impairment. The adverse event profiles of the SSRIs reported in the treatment of PE are
similar to those reported in patients being treated for depression. The type and rate of occurrence of side effects appear to be acceptable to most patients and typically include gastrointestinal upset, dry mouth, drowsiness, dizziness, headache and reduced libido. All the SSRIs are absolutely contraindicated in combination with the monoamine oxidase inhibitors (MAOIs). The SSRI should also not be prescribed to men with prior or
active seizure disorders, anxiety disorders, or recent myocardial infarctions [39]. Except for fluoxetine it is advised not to stop the SSRIs acutely, but to do so gradually over 3–4 weeks, to avoid withdrawal symptoms [6].
Since the late 1980s, five SSRIs have been licensed for  the treatment of depression: citalopram, paroxetine, sertraline, fluoxetine, and fluvoxamine.
Citalopram Ranking SSRIs regarding their selectivity reveals citalopram,
sertraline, paroxetine, fluvoxamine, and fluoxetine, in decreasing order [62]. If selectivity for the serotonergic system over other systems would be the determining factor for the inhibitor process on ejaculation, it would be expected that citalopram would cause considerable delay in ejaculation. Work on citalopram has been inconsistent. For example, in a randomized, double-blind study 31 men with PE were randomly assigned to receive paroxetine (20 mg/day) and citalopram (20 mg/day) for 5 weeks. Paroxetine
exerted a strong delay (8.9-fold increase, whereas citalopram mildly delayed ejaculation (1.8-fold) [62]. However, a later study showed clear benefit [63]. Thirty men were randomly assigned to two groups on a double-blind basis. Fifteen
patients received citalopram (group 1) for 8 weeks while the
remainders receive no therapy (group 2). Patients in group 1
initially received 20 mg/day citalopram for 1 week; this was
titrated up to 60 mg/day according to the patient’s tolerability
and clinical response (Final dose of citalopram, 30.7mg).
IELT increased from 38.5 seconds at baseline to 362 seconds
after 8 weeks of treatment. Atmaca et al. reported that
citalopram treatment considerably increases IELT [64].
Williamson et al. [65] and de Jong et al. [66] had found that
acute administration of citalopram in male rats had nosignificant effects on copulatory parameters, including ejaculation
time and number of ejaculations. The recommended
dose of citalopram is 20mg/day.
Paroxetine
Paroxetine has proved to be effective, well tolerated oral
treatment for PE in patients without any organic causes
[59,67,68]. The drug is absorbed well via gastrointestinal
tract and is metabolized by the liver. A steady-state
concentration is reached in the serum within 7–14 days, and
64% is excreted by the kidneys and 36% by the liver [67]. A
meta-analysis of all drug treatment studies, conducted by
Waldinger et al. [9] showed that paroxetine exerts the
greatest ejaculation delay. The rank order of efficacy (fold
increase of IELT) is (1) paroxetine (8.8; 95% CI: 5.9–13.2);
(2) clomipramine (4.6; 3.0–7.4); (3) sertraline (4.1; 2.6–7.0);
and (4) fluoxetine (3.9; 3.0–5.3) [11].
Waldinger et al. reported the first trial of an SSRI for PE
in 1994 [59]. This randomized, double-blind, placebocontrolled
study found that paroxetine significantly improved
PE. Giammusso et al., Ludovico et al. and McMahon have
also reported significant improvement in ejaculatory control
with paroxetine [67,69,70]. Daily administration of
paroxetine however, was more efficacious than as needed
[71]. On-demand 20 mg paroxetine had no clinical relevant
ejaculation delay in men with life long PE with an IELT of
less than 1 minute [71]. In a double-blind stopwatch study in
men with life long PE, it was found that on-demand
treatment with 20 mg paroxetine exerted a fold-increase
IELT of only 1.41 (95% CI: 1.22–1.63) at a drug coitus
interval time of approximately 5 hours [71]. The daily dose
of 20 mg paroxetine is an adequate treatment for PE.
Sertraline
Recently, sertraline turned out to be a potentially very
useful drug. Mendels et al. described the first use of
sertraline in PE in 1995 showing that sertraline increased
IELT in men with PE [72]. In a cross-over, single-blind,
placebo-controlled trial, sertraline 50 mg once daily for 4
weeks significantly increase IELT (mean 0.3 increased to 3.2
min) in 37 men with PE [73]. In another double-blind,
placebo-controlled, cross-over trial, Kim and Seo [74]
compared the efficacy of placebo, fluoxetine 40 mg once
daily, sertraline 100 mg once daily and clomipramine 50 mg
once daily over 4 weeks for the treatment of PE. The mean
pre-treatment IELT was less than 1 min and over 4 weeks
this was significantly increased to 2.27, 2.3, 4.27 and 5.75
min, respectively.
In one study, two thirds of the patients on continuous
sertraline for 7 months maintained their improvement after
drug withdrawal [75]. The majority of evidence shows
effectiveness with 50 mg daily dosing.
Fluoxetine
The fluoxetine hydrochloride is an antidepressant with
strong action as selective serotonin re-uptake inhibitor. In
addition of its SSRI property, it increases IELT seemingly by
its action of elevating the penile sensory threshold value
without changing the variables of cortical somatosensory
evoked potential and sacral evoked response tests [76].
Fluoxetine inhibits ejaculation in male rats presumably by
influencing serotonergic receptors in the nucleus paragigantocellularis.
In an animal study the ejaculation delay
induced by fluoxetine was reversed by the administration of
oxytocin [77]. This finding suggests that fluoxetine induced
delayed ejaculation is also related to inhibited oxytocin
release.
In various double-blind, placebo controlled studies 20 mg
fluoxetine, have been shown to be effective for treatment of
PE [78,79]. Manasia et al. [80] compared the efficacy and
safety of 90 mg fluoxetine weekly with 20 mg fluoxetine
daily. There was no statistical difference between the
different doses. However, the cure rate was greater with 90
mg fluoxetine weekly. They concluded that this new dose of
fluoxetine for the treatment of PE has the advantage of
administration of 1 capsule per week. Their study also
showed that 90 mg fluoxetine weekly increased significantly
IELT. The recommended dose of fluoxetine is 20 mg/day.
Fluvoxamine
Fluvoxamine is a selective serotonin reuptake inhibitor
and is widely used in the treatment of depression and other
psychiatric disorders [81]. Waldinger et al. [82] compared
the efficacy of fluoxetine, fluvoxamine, paroxetine, and
sertraline in 60 men with PE. At baseline, the mean IELT
was approximately 20 seconds. After 6 weeks of treatment,
fluoxetine, paroxetine, and sertraline all increased the mean
IELT above this placebo level significantly while fluvoxamine
did not. In another study, 100 mg. fluvoxamine daily
resulted only mild to moderate delay in IELT [19]. The mild
delay of fluvoxamine was replicated in a placebo controlled
male rat study using a chronic administration treatment
model [83]. Fluvoxamine is therefore not recommended for
the treatment of PE.
Tricyclic Antidepressants
Clomipramine
Clomipramine is a tricyclic antidepressant that inhibits
the reuptake of norepinephrine as well as serotonin and was
the first to be investigated in men who suffered from PE
[84,85]. Clomipramine activate 5-HT2C receptor and,
therefore, change the set point to a higher level, leading to a
delay in ejaculation [15]. Clomipramine has also been shown
to be effective in the treatment of PE by its action to elevate
the penile sensory threshold without changing the variables
of cortical somatosensory evoked potential and sacral evoked
response tests [86]. Besides serotonin reuptake inhibition,
clomipramine also inhibits the reuptake of noradrenaline.
Selective noradrenaline reuptake inhibitors nortriptyline and
protriptyline have been found to be associated with delayed
ejaculation [87]. Eaton published the first open study of
clomipramine in men with PE in 1972 [88]. Later case
reports and double-blind studies, repeatedly demonstrated
the effectiveness of clomipramine at low daily doses for
delaying ejaculation [84,89-91]. Clomipramine, sertraline
and paroxetine appear to be comparable in terms of safety
and efficacy [9]. Clomipramine has improved IELT and
other measures of PE when prescribed at doses of 25 and 50
mg/day or 25 mg 4 to 24 hours prior to intercourse [92].
Three on-demand studies with 25 mg of clomipramine taken4–6 hours prior to intercourse induced a six [85], and four
fold-increase [61,71,93] of the ejaculation time, respectively.
The side-effects of clomipramine may consist of nausea, dry
mouth and fatigue. Sometimes clomipramine and the SSRIs
may give rise to reversible feelings of diminished libido or
moderately decreased rigidity of the penis [6]. Generally for
treatment of PE, clomipramine is administered 25mg/day.
Monoamine Oxidase Inhibitors
Case reports of the delaying effects of nonselective,
irreversible monoamine oxidase inhibitors, for example
isocarboxazid [94] and phenelzine, [95] were published.
However, the use of these various drugs is not recommended
for treatment of PE due to their disturbing and sometimes
quite serious side effects [9]. It must be remembered that, all
the SSRIs are absolutely contraindicated in combination with
the monoamine oxidase Inhibitors.
Topical Anesthesia
Some investigators have evaluated patients with PE by
penile biothesiometry and have demonstrated that patients
with primary PE have penile hypersensitivity and can be
treated by desensitizing preparations [96]. Patients with PE
have changes in the autonomic reflex pathways related to
ejaculation [97], including a lower vibratory threshold for
ejaculation, shorter bulbocavernous reflex latency time, and
higher bulbocavernous evoked potentials [96]. Therefore
local anesthetic creams have been used to reduce sensory
stimulation from the body and glans penis during foreplay
and intercourse and thereby prolong ejaculatory latency. The
use of topical anesthetic ointments is probably the oldest
treatment for delaying ejaculation. The disadvantage of
topical desensitizing creams is the unpleasant effect of penile
numbness. Also, some men report that their partners complain
of vaginal or clitoral anesthesia, especially if the man does
not use a condom. In addition, possible transvaginal
absorption can results in vaginal numbness and resultant
female anorgasmia unless a condom is use. Condoms are
always advised when using these preparations to avoid
transferring the cream to the partner. The condom may be
removed prior to sexual intercourse and the penis washed
clean of any residual active compound. Topical anesthetics
are contraindicated in patients who are either allergic
themselves or have partners who are allergic to any
component of the product.
EMLA Cream
Lidocaine 2.5% and prilocaine 2.5% cream is a eutectic
mixture of local anesthetics (EMLA), which can penetrate
intact skin and provide reliable local analgesia. The local
topical anesthetic combination of prilocaine and lidocaine is
among the most effective formulations. When EMLA Cream
is applied for 15 min, both the sensory and the pain
thresholds increase further and dermal analgesia persist for
1–2 h after removal of the cream [98]. Prolonged application
of topical anesthetic (30 to 45 minutes) has been reported to
result in loss of erection due to numbness of the penis in a
significant percentage of men [99]. EMLA Cream has been
found to be efficient for local anesthesia in PE [100]. This
agent has also been successfully used off-label for treating
PE [99]. Application of EMLA Cream for 20 min has been
determined as the optimum period in the treatment of
premature ejaculation [99].
SS-Cream
Another pharmacologic treatment option is the topical
SS-cream. This made from the extracts of nine natural
products. It has not yet been approved by the FDA and is not
available in USA. The pharmacological constituents and
active chemical have not been described [101]. In the Far
East good results were reported with SS-cream, a regionally
manufactured cream consisting of various herbs [101-103],
used 1–2 h before intercourse. Xin et al. reported a decrease
in the amplitude of somatosensorial potentials with the use of
SS-cream, applied to the glans penis of patients with PE
[102]. Once available in USA, physicians may wish to
suggest it to their patients.
Neuroleptics
In the 1960s case reports described the ejaculation
delaying effects of some neuroleptics. Thioridazine
[104,105] and chlorprothixene [106] delayed ejaculation by
blocking central dopamine receptors. However, the use of
neuroleptics is not recommended, because they have
disturbing and sometimes quite serious side effects.

The three major forms of male sexual dysfunction are ejaculatory dysfunction, erectile dysfunction (ED), and decreased libido. PE is the most prevalent male sexual dysfunction. Erectile dysfunction and decreased libido are less common [1]. The World Health Organization (WHO) includes the right to sexual health among its fundamental rights for the individual. There should be “a freedom from organic disorders, disease and deficiencies that interfere with sexual and reproductive freedom”. PE has been associated
with erosion in sexual self- confidence [2] and low sexual satisfaction in men and their female partners [3]. Before the last decade, the major approach to treating PE was behavioral and psychotherapy, relying on such techniques as
the `pause’ and `squeeze’ methods [4,5]. However, the application of the principles of evidence-based medicine shows that there is little evidence to support the psychological approach and behavioral treatment [6]. This
paper reviews pharmacological agents in treatment of PE. It describes some of the issues for drug development in this indication, reviewing many of the clinical studies that have already been completed.
DEFINITION OF PREMATURE EJACULATION
There are a number of definitions, none of which is wholly satisfactory. Most men with PE readily recognize their problem and there is no lack of self-assessment. Most men who report PE usually ejaculate prior to or within 1–2 min after vaginal intromission. A small proportion of men ejaculate prior to intromission. A universally accepted definition of PE has yet to be established. Masters and Johnson proposed one of the earliest definitions that focused on the inability to delay ejaculation long enough for the
woman to achieve orgasm 50% of the time, assuming that PE is the sole cause of the female anorgasmia [4]. Kaplan first suggested that PE is primarily a problem of voluntary control over timing of ejaculation [5]. It is obvious that their definition is inadequate because it implies that any partners of a woman who has difficulty in reaching orgasm in half the attempts have PE. The American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders (4th Edition Text Revision) (DSM-IV-TR) [7] defines PE as
“persistent or recurrent onset of orgasm and ejaculation with minimal sexual stimulation before, on, or shortly after penetration and before the person wishes it”. Until recently, any scientific basis for the DSM-IV
definition was lacking. For instance, the meaning of ‘persistent’, ‘recurrent’, ‘minimal’ and ‘shortly after’ is vague and certainly needs further qualification. Waldinger et al. [8] attempted to operationalise the DSM-IV criteria for PE. They studied 110 men suffering from life long PE and demonstrated that about 10% of the men ejaculated at 1–2 min but most (90%) ejaculated within 1 min of intromission, and 80% were actually ejaculating within 30 seconds, whereas 60% ejaculated within 15 seconds. They also empirically defined life long PE as an ejaculation of <1 min >90% of episodes of sexual intercourse, independent of  age and duration of relationship. Intravaginal ejaculation latency time (IELT) was measured by methods of verbal estimation, list based, imagined (with clock and without) or by using a stopwatch during intercourse. Most men and partners considered the stopwatch as an accurate measurement of their IELT.
The WHO second International Consultation on Sexual Dysfunction proposed a multivariate definition for PE: “Premature ejaculation is 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.” While the above definitions identify multiple criteria for
a PE diagnosis, IELT has been the most commonly used endpoint in recent PE studies. In general, an IELT of less than 2 minutes—probably most accurately determined using stopwatch methodology [9]—is thought to provide
appropriate definition for PE [10,11]. PE may be classified into various subtypes based on the developmental history and response characteristics. Primary PE is defined as PE that has always been present and secondary PE as the development of PE after a period of perceived normal ejaculatory functioning.

EPIDEMIOLOGY
There is limited information concerning the extent of PE in the general population. In a random survey of 1511 men in the USA, about one third considered that they had ejaculated prematurely over the past year [1]. However, the proportion that perceived their condition as problematic was not stated. Data from the National Health and Social Life Survey have revealed a prevalence of 21% in men ages 18 to 59 in the United States [12]. In general, however, the prevalence of PE is reported as being between 22–38% of adult male population [1,13]. In 1943 Schapiro noted that men with PE seemed to have family members with similar complaints [14]. Waldinger [15] reported that odds of family occurrence is much higher
than the suggested population prevalence rate of 4% to 39% and suggested that premature ejaculation is also genetically determined. In addition the psychiatric literature on the prevalence of such disorders is suggestive of family or genetic origins [16].

PATHOPHYSIOLOGY
The ejaculatory response is triggered by genital and cortical stimulation. The glans penis has tactile receptors that are connected via the dorsal penile and pudendal nerve to the sacral spinal cord. The sympathetic nerves involved in
emission originate from the intermediolateral columns of the spinal cord (T10–L2) and travel via the sympathetic chain and hypogastric nerve to the pelvic plexus and from there via the cavernous nerve to the vas deferentia. Sympathetic impulses produce smooth muscle contractions of the epididymis and vas deferens that move sperm to the posterior urethra.
Seminal vesicles and prostatic glands contract expelling and mixing their fluids with sperm. Eventually this mixture in turn intermixes with fluid from the bulbourethral glands making semen. Semen causes pressure in the wall of the ampullae urethra that culminates to afferent impulses, which reach the spinal cord (S2–4) through the pudendal and pelvic nerves. Expulsion is mediated by motor neurons in the nucleus of Onuf that via the pudendal nerve provide coordinated contractions of the bulbo- cavernosus and
ischio-cavernosus muscles of the pelvic floor. Idiopathic primary premature ejaculators may have lower penile sensory thresholds [17] and/or greater cortical penile representation [18] than their normal counterparts. Animal
and sexual psychopharmacological human studies [19] attributed a serotonergic genesis [20-22] and possible genetic etiology [23] to the neurobiological view of PE. The inhibitory effect of serotonin on libido, ejaculation and orgasms is well documented and has been attributed to a
serotonin-induced decrease in dopamine (a neurotransmitter enhancing sexual function) level in the central nervous system. [24,25] Therefore, tricyclic antidepressants (clomipramine) and selective serotonin reuptake inhibitors (SSRIs); (paroxetine, fluoxetine, sertraline) have merged as safe and effective new treatments for patients with PE. In addition, selective
noradrenaline reuptake inhibitors nortriptyline and protriptyline have been found to be associated with delayed ejaculation [26]. Among the different subtypes of 5-hydroxytryptamine (5-HT) receptors, the most important ones on ejaculation are 5-HT1A, 5-HT1B, 5-HT1D, and 5-HT2C receptors [27]. Because the rapid onset of postponement of ejaculation by some of the SSRIs has a similar time course as their synaptic effect on 5-HT, it is suggested that the effect on ejaculation is mediated by acute enhancement of 5-HT
neurotransmission or by differential activation of different 5- HT receptor populations, notably 5-HT1A and 5-HT2C receptors [28,29]. Activation of the 5-HT1B/1D receptors also inhibit 5-HT release and male rat ejaculatory behavior [30]. The total absence of ejaculation delay in men who took
nefazodone was attributed to its 5-HT2C and 5-HT2A receptor-blocking properties [31]. Organic (e.g. PE secondary to neurological disease, diabetes, pelvic injury, vascular disease, prostatic hypertrophy, chronic prostatitis, hypogonadotrophic hypogonadism, pelvic surgery, radical prostatectomy) psychological, behavioral, and biogenic causes have been implicated [32-34]. Both anxiety and depression have been associated with PE [5]
although this may be a consequence of the condition rather than a cause. Others have failed to find such an association [35]. As with other sexual disorders, PE is probably caused by a combination of biological-psychological, psychophysiological, and sociobiological; except in unusual cases when a pure cause can be demonstrated [32,36,37]. For example, Grenier et al. [38] reported that: “It is more likely that PE is the result of a number of factors that interact than the result of a single factor”. Also in another study, Athanasiadis [39] emphasized that: “The hypothesis about a
possible interaction between factors might propose a more satisfactory explanation for PE than a one-dimensional approach”. A number of genetic theories have also been proposed to explain PE. It is possible that some racial groups are more susceptible than others to PE [40], particularly men from the Indian subcontinent who may present with the Dhat syndrome [41]. Some or all of the following features characterizes this syndrome: concern about spontaneous seminal loss, affective illnesses, psychosomatic complaints and PE.

DIAGNOSIS
American Urological Association (AUA) guideline on the pharmacologic management of PE recommended, “Thediagnosis of PE is based on sexual history alone. A detailed sexual history should be obtained from all patients with ejaculatory complaints” [42]. In most cases an apparent organic cause is not evident at diagnosis [43,44]. Limited attempts to provide a consensus and more objective criteria for the diagnosis of PE have not succeeded. The diagnosis based on DSM-IV relies on subjective self-reported symptoms. Parameters that are necessary and/or sufficient to make a diagnosis of PE according to the DSM-IV are unclear. Organic causes such as those previously mentioned should be ruled out. In general, an IELT of less than 2
minutes—probably most accurately determined using stopwatch methodology —is thought to provide adequate sensitivity for diagnosis.

TREATMENT
General Considerations
Medical treatment in PE needs careful interpretation with respect to design and methodology of studies [45,6]. Subjective estimation and questionnaire assessments of ejaculation latency may lead to higher variability in clinical
outcome measures [45], therefore, for the most accurate determination of ejaculation latency the best method is the use of stopwatch. Treatment of PE should primarily attempt to alleviate concern about the condition as well as to increase sexual satisfaction in the patient and partner. The risks and benefits of all treatment options should be discussed with the patient prior to any intervention. Patient and partner satisfaction is the primary target outcome for the treatment of PE. Men with PE secondary to erectile dysfunction, other sexual dysfunction or organic causes should receive
appropriate etiology specific treatment. Simple measures such as education to discuss sexual norms, and facilitation of sexual negotiation between the couple may be useful. Some medications cause sexual dysfunction as a side
effect (Table 1). Use of  some sympathomimetics [47] such as ephedrine sulfate, pseudoephedrine hydrochloride, and phenylpropanolamine hydrochloride and withdrawal from some other drugs, such as trifluoperazine hydrochloride [48], and opiates [49-51] can cause PE. Simply discontinuing an agent that is thought to cause PE in order to eliminate it from the body may be considered if the general health and
physician permit it.

Psychosexual Behavioral Therapy
Historically the cause of PE has been considered to be psychological. The psychoanalytic idea of unconscious conflicts being the cause of PE has never been investigated in a manner that allowed generalization, as only case reports on psychoanalytic therapy have been published. This is also
true for behavioral therapy. These have included psychoanalytical approaches although it is the behavioral and cognitive approaches that have proven most effective. These include the stop–squeeze method [52] developed in 1956 and later adopted by Masters and Johnson in their sex therapy clinic as well as other approaches that have become the gold
standard for treatment of PE [53]. Stop-start and squeeze techniques or the sensate-focus phase are used in therapeutic programs for the treatment of PE. The techniques are performed as effective treatments that delay PE by reducing or removing stimulation, [4,54] but longitudinal follow-up results of treatment for PE are even rarer than controlled outcome investigations, and long-term success rates are disappointing [36]. In addition, the application of the principles of evidence-based medicine shows that there is
little evidence to support the psychological approach and behavioral treatment [6].

Drug Therapy
The primary therapeutic approach to PE is pharmacotherapy. Pharmacological treatment of men with PE may include a variety of approaches. No pharmacological agents are licensed for use for PE. However many centrally and peripherally acting drugs have been proposed to treat
primary PE. These include

1- Selective serotonin reuptake inhibitors (SSRIs)
2- Tricyclic antidepressants
3- Monoamine oxidase inhibitors
4- Topical anesthesia
5- Neuroleptics
6- Sympatholytics
7- Phosphodiestrase inhibitors
In the next paragraphs an overview will be presented of the various drug treatment studies for premature ejaculation that have been published since 1943. Apart from the phosphodiesterase inhibitor studies, all of these drug
treatment studies have previously been categorized in a systematic review and meta-analysis study, published by Waldinger et al. in 2004 [9].

INTRODUCTION
The three major forms of male sexual dysfunction are ejaculatory dysfunction, erectile dysfunction (ED), and decreased libido. PE is the most prevalent male sexual dysfunction. Erectile dysfunction and decreased libido are less common

[1]. The World Health Organization (WHO) includes the right to sexual health among its fundamental rights for the individual. There should be “a freedom from organic disorders, disease and deficiencies that interfere with sexual and reproductive freedom”. PE has been associated with erosion in sexual self- confidence

[2] and low sexual satisfaction in men and their female partners

[3]. Before the last decade, the major approach to treating PE was behavioral and psychotherapy, relying on such techniques as the `pause’ and `squeeze’ methods

[4,5]. However, the application of the principles of evidence-based medicine shows that there is little evidence to support the psychological approach and behavioral treatment

[6]. This paper reviews pharmacological agents in treatment of PE. It describes some of the issues for drug development in this indication, reviewing many of the clinical studies that have already been completed.

DEFINITION OF PREMATURE EJACULATION

There are a number of definitions, none of which is wholly satisfactory. Most men with PE readily recognize their problem and there is no lack of self-assessment. Most men who report PE usually ejaculate prior to or within1–2 min after vaginal intromission. A small proportion of men ejaculate prior to intromission. A universally accepted definition of PE has yet to be established. Masters andJohnson proposed one of the earliest definitions that focused on the inability to delay ejaculation long enough for the woman to achieve orgasm 50% of the time, assuming that PE is the sole cause of the female anorgasmia [4]. Kaplan first suggested that PE is primarily a problem of voluntary control over timing of ejaculation [5]. It is obvious that their definition is inadequate because it implies that any partners of a woman who has difficulty in reaching orgasm in half the attempts have PE. The American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders (4th Edition Text Revision) (DSM-IV-TR) [7] defines PE as “persistent or recurrent onset of orgasm and ejaculation with minimal sexual stimulation before, on, or shortly after penetration and before the person wishes it”. Until recently, any scientific basis for the DSM-IV definition was lacking. For instance, the meaning of ‘persistent’, ‘recurrent’, ‘minimal’ and ‘shortly after’ is vague and certainly needs further qualification. Waldinger et

al. [8] attempted to operationalise the DSM-IV criteria for PE. They studied 110 men suffering from life long PE and demonstrated that about 10% of the men ejaculated at 1–2 min but most (90%) ejaculated within 1 min of intromission, and 80% were actually ejaculating within 30 seconds, whereas 60% ejaculated within 15 seconds. They also empirically defined life long PE as an ejaculation of <1 min in >90% of episodes of sexual intercourse, independent of age and duration of relationship. Intravaginal ejaculation latency time (IELT) was measured by methods of verbal estimation, list based, imagined (with clock and without) or by using a stopwatch during intercourse. Most men and partners considered the stopwatch as an accurate measurement of their IELT. The WHO second International Consultation on Sexual Dysfunction proposed a multivariate definition for PE: “Premature ejaculation is 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.” While the above definitions identify multiple criteria for a PE diagnosis, IELT has been the most commonly used
endpoint in recent PE studies. In general, an IELT of less than 2 minute—probably most accurately determined using stopwatch methodology [9]—is thought to provide appropriate definition for PE [10,11]. PE may be classified into various subtypes based on the developmental history and response characteristics. Primary PE is defined as PE that has always been present and secondary PE as the development of PE after a period of perceived normal ejaculatory functioning.
EPIDEMIOLOGY
There is limited information concerning the extent of PE
in the general population. In a random survey of 1511 men in
the USA, about one third considered that they had ejaculated
prematurely over the past year [1]. However, the proportion
that perceived their condition as problematic was not stated.
Data from the National Health and Social Life Survey have
revealed a prevalence of 21% in men ages 18 to 59 in the
United States [12]. In general, however, the prevalence of PE
is reported as being between 22–38% of adult male
population [1,13].
In 1943 Schapiro noted that men with PE seemed to have
family members with similar complaints [14]. Waldinger
[15] reported that odds of family occurrence is much higher
than the suggested population prevalence rate of 4% to 39%
and suggested that premature ejaculation is also genetically
determined. In addition the psychiatric literature on the
prevalence of such disorders is suggestive of family or
genetic origins [16].
PATHOPHYSIOLOGY
The ejaculatory response is triggered by genital and
cortical stimulation. The glans penis has tactile receptors that
are connected via the dorsal penile and pudendal nerve to the
sacral spinal cord. The sympathetic nerves involved in
emission originate from the intermediolateral columns of the
spinal cord (T10–L2) and travel via the sympathetic chain and
hypogastric nerve to the pelvic plexus and from there via the
cavernous nerve to the vas deferentia. Sympathetic impulses
produce smooth muscle contractions of the epididymis and
vas deferens that move sperm to the posterior urethra.
Seminal vesicles and prostatic glands contract expelling and
mixing their fluids with sperm. Eventually this mixture in
turn intermixes with fluid from the bulbourethral glands
making semen. Semen causes pressure in the wall of the
ampullae urethra that culminates to afferent impulses, which
reach the spinal cord (S2–4) through the pudendal and pelvic
nerves. Expulsion is mediated by motor neurons in the
nucleus of Onuf that via the pudendal nerve provide
coordinated contractions of the bulbo- cavernosus and
ischio-cavernosus muscles of the pelvic floor.
Idiopathic primary premature ejaculators may have lower
penile sensory thresholds [17] and/or greater cortical penile
representation [18] than their normal counterparts. Animal
and sexual psychopharmacological human studies [19]
attributed a serotonergic genesis [20-22] and possible genetic
etiology [23] to the neurobiological view of PE.
The inhibitory effect of serotonin on libido, ejaculation
and orgasms is well documented and has been attributed to a
serotonin-induced decrease in dopamine (a neurotransmitter
enhancing sexual function) level in the central nervous system.
[24,25] Therefore, tricyclic antidepressants (clomipramine)
and selective serotonin reuptake inhibitors (SSRIs); (paroxetine,
fluoxetine, sertraline) have merged as safe and effective
new treatments for patients with PE. In addition, selective
noradrenaline reuptake inhibitors nortriptyline and protriptyline
have been found to be associated with delayed
ejaculation [26]. Among the different subtypes of 5-hydroxytryptamine
(5-HT) receptors, the most important ones on
ejaculation are 5-HT1A, 5-HT1B, 5-HT1D, and 5-HT2C
receptors [27]. Because the rapid onset of postponement of
ejaculation by some of the SSRIs has a similar time course as
their synaptic effect on 5-HT, it is suggested that the effect
on ejaculation is mediated by acute enhancement of 5-HT
neurotransmission or by differential activation of different 5-
HT receptor populations, notably 5-HT1A and 5-HT2C
receptors [28,29]. Activation of the 5-HT1B/1D receptors also
inhibit 5-HT release and male rat ejaculatory behavior [30].
The total absence of ejaculation delay in men who took
nefazodone was attributed to its 5-HT2C and 5-HT2A
receptor-blocking properties [31].
Organic (e.g. PE secondary to neurological disease,
diabetes, pelvic injury, vascular disease, prostatic hypertrophy,
chronic prostatitis, hypogonadotrophic hypogonadism, pelvic
surgery, radical prostatectomy) psychological, behavioral,
and biogenic causes have been implicated [32-34]. Both
anxiety and depression have been associated with PE [5]
although this may be a consequence of the condition rather
than a cause. Others have failed to find such an association
[35]. As with other sexual disorders, PE is probably caused
by a combination of biological-psychological, psychophysiological,
and sociobiological; except in unusual cases
when a pure cause can be demonstrated [32,36,37]. For
example, Grenier et al. [38] reported that: “It is more likely
that PE is the result of a number of factors that interact than
the result of a single factor”. Also in another study,
Athanasiadis [39] emphasized that: “The hypothesis about a
possible interaction between factors might propose a more
satisfactory explanation for PE than a one-dimensional
approach”.
A number of genetic theories have also been proposed to
explain PE. It is possible that some racial groups are more
susceptible than others to PE [40], particularly men from the
Indian subcontinent who may present with the Dhat
syndrome [41]. Some or all of the following features
characterizes this syndrome: concern about spontaneous
seminal loss, affective illnesses, psychosomatic complaints
and PE.
DIAGNOSIS
American Urological Association (AUA) guideline on
the pharmacologic management of PE recommended, “The

diagnosis of PE is based on sexual history alone. A detailed
sexual history should be obtained from all patients with
ejaculatory complaints” [42]. In most cases an apparent
organic cause is not evident at diagnosis [43,44]. Limited
attempts to provide a consensus and more objective criteria
for the diagnosis of PE have not succeeded. The diagnosis
based on DSM-IV relies on subjective self-reported
symptoms. Parameters that are necessary and/or sufficient to
make a diagnosis of PE according to the DSM-IV are
unclear. Organic causes such as those previously mentioned
should be ruled out. In general, an IELT of less than 2
minutes—probably most accurately determined using
stopwatch methodology —is thought to provide adequate
sensitivity for diagnosis.
TREATMENT
General Considerations
Medical treatment in PE needs careful interpretation with
respect to design and methodology of studies [45,6].
Subjective estimation and questionnaire assessments of
ejaculation latency may lead to higher variability in clinical
outcome measures [45], therefore, for the most accurate
determination of ejaculation latency the best method is the
use of stopwatch. Treatment of PE should primarily attempt
to alleviate concern about the condition as well as to increase
sexual satisfaction in the patient and partner. The risks and
benefits of all treatment options should be discussed with the
patient prior to any intervention. Patient and partner
satisfaction is the primary target outcome for the treatment of
PE. Men with PE secondary to erectile dysfunction, other
sexual dysfunction or organic causes should receive
appropriate etiology specific treatment. Simple measures
such as education to discuss sexual norms, and facilitation of
sexual negotiation between the couple may be useful.
Some medications cause sexual dysfunction as a side
effect (Table 1). Use of some sympathomimetics [47] such
as ephedrine sulfate, pseudoephedrine hydrochloride, and
phenylpropanolamine hydrochloride and withdrawal from
some other drugs, such as trifluoperazine hydrochloride [48],
and opiates [49-51] can cause PE. Simply discontinuing an
agent that is thought to cause PE in order to eliminate it from
the body may be considered if the general health and
physician permit it.
Psychosexual Behavioral Therapy
Historically the cause of PE has been considered to be
psychological. The psychoanalytic idea of unconscious
conflicts being the cause of PE has never been investigated
in a manner that allowed generalization, as only case reports
on psychoanalytic therapy have been published. This is also
true for behavioral therapy. These have included psychoanalytical
approaches although it is the behavioral and
cognitive approaches that have proven most effective. These
include the stop–squeeze method [52] developed in 1956 and
later adopted by Masters and Johnson in their sex therapy
clinic as well as other approaches that have become the gold
standard for treatment of PE [53]. Stop-start and squeeze
techniques or the sensate-focus phase are used in therapeutic
programs for the treatment of PE. The techniques are
performed as effective treatments that delay PE by reducing
or removing stimulation, [4,54] but longitudinal follow-up
results of treatment for PE are even rarer than controlled
outcome investigations, and long-term success rates are
disappointing [36]. In addition, the application of the
principles of evidence-based medicine shows that there is
little evidence to support the psychological approach and
behavioral treatment [6].
Drug Therapy
The primary therapeutic approach to PE is pharmacotherapy.
Pharmacological treatment of men with PE may
include a variety of approaches. No pharmacological agents
are licensed for use for PE. However many centrally and
peripherally acting drugs have been proposed to treat
primary PE. These include
1- Selective serotonin reuptake inhibitors (SSRIs)
2- Tricyclic antidepressants
3- Monoamine oxidase inhibitors
4- Topical anesthesia
5- Neuroleptics
6- Sympatholytics
7- Phosphodiestrase inhibitors
In the next paragraphs an overview will be presented of
the various drug treatment studies for premature ejaculation
that have been published since 1943. Apart from the
phosphodiesterase inhibitor studies, all of these drug
treatment studies have previously been categorized in a
systematic review and meta-analysis study, published by
Waldinger et al. in 2004 [9].
Selective Serotonin Reuptake Inhibitors (SSRIs)
Probable mechanism of these drugs is the enhancement
of net serotonergic transmission by blocking the presynaptic
5-hydroxytryptamine (serotonin, 5-HT) uptake site [20,55].
Pre-clinical researches clearly indicate the role of serotonin
in ejaculatory processes. Among the different subtypes of 5-
HT receptors, the most important ones on ejaculation are
HT1A, 5-HT1B, 5-HT1D, and 5-HT2C receptors. Administration
SSRIs, results in active blockade of presynaptic membrane
5-HT transporters, and the resultant higher synaptic cleft
levels of 5-HT activate post-synaptic 5-HT2C and 5-HT1A
receptors and delay ejaculation. 5-HT1A receptor activation
by the selective 5-HT1A receptor agonist 8-OH-DPAT (8-
hydroxy-2-(di-n-propylaminotetralin) or flesinoxan inhibits
the release of 5-HT in the synaptic cleft, shortens the
ejaculation latency time and reduces the number of intermissions
preceding ejaculation in animals. 5-HT2C receptor
agonistsD-LSD (D-lysergic acid diethylamide) and quipazine
cause ejaculation delay [56]. In summary, SSRIs activate the
5-HT2C receptor and therefore switch the threshold to a
higher level, leading to a delay in ejaculation.
There are 2 drug treatment strategies to treat PE with
SSRIs: 1) daily treatment 2) as-needed treatment. Waldinger
et al. reported that, on-demand SSRI treatment has
less ejaculation-delaying effects than daily SSRI treatment
[57]. Acute administration of various SSRIs, such as,

Table 1. Sexual Side Effects of Common Prescription Medications
Type of drug Generic name Sexual side effects
Antihypertensive medications
Diuretics
Spironolactone
Thiazides,
Furosemide
Decreased libido, breast swelling, impotence
Impotence
None
Centrally acting agents
Methyldopa
Clonidine
Reserpine
Decreased libido, impotence
Impotence
Decreased libido, impotence, depression

The squeeze method is simply a variation of the Masters and Johnson method,
except that your partner presses the end of your penis or at its base (crown of
the penis), just before the point of no return and thus stops the orgasm.
Pressure on the end of your penis forces the blood to retreat from your penis
and reduces your erection.

You can use the “Squeeze” method if the Masters and Johnson does not work for you on its own. You can combine both methods.So, you have learned a little more about how to overcome your premature ejaculation problem.

These two methods are an integral part of the Condensed Method. For some
they are successful after a very long work, however, for a large percentage of
people these two methods are not sufficient.

This means that, to overcome your problem of premature ejaculation, you need
other techniques which will enable you to make more rapid progress, on both
the psychological and the physiological level.

Those who have benefited from the Condensed Method discover and try out
several training techniques which teach them to know their own bodies.
And that is the key to learning, successfully, how to stop the ejaculation reflex,
without disturbing your partner’s increasing pleasure.
Let us not forget that ejaculation is a reflex and it cannot be stopped. Yes,
nobody can stop ejaculation once it has started! Nonetheless, knowing the physiology of your own body will enable you to recognise the start of this reflex, without diminishing your pleasure in making love, on the contrary. You will find several ways in the “Condensed Method”.
To overcome your premature ejaculation problem once and for all.
You will also learn how to make love to your partner in a different way, you
will make love together.
In other words, you will be at one with your partner.

One of the best ways of overcoming premature ejaculation is learning how to
recognize and control your own sensations which precede ejaculation.
The Master and Johnson method is not too bad for this.

The Master and Johnson method requires a lot of patience and practice, that
why you need the Condensed Method to really brings results.
Follow the instructions described below
You can start by masturbating, get yourself close to the point of orgasm, and
stop. This will enable you to relax before starting again.
The more often you start again, the more you will be able to bring yourself
closer to an orgasm; up to the point where you can no longer control yourself.
A lubricant may help (available in the pharmacy).
Repeating the exercise several times on different occasions will help you to
discover your point of no return.
Once you have reached this point, you should be able to ask your partner to
stimulate you, to complete the exercise to its full with her/his help and
cooperation.
The best way of practising this method is to ask your “lover“to participate,
although, at the beginning you can do this exercise alone.
For this exercise, you should not penetrate your partner (she masturbates you
and you stimulate yourself with fellation) and little by little you reach the point
just before ejaculation.
At this moment you must indicate to your partner to stop stimulation (at this
point you can use the so-called „squeeze“method, see below) and try to
diminish the erection a little. Repeat these stages several times so that you
become comfortable with them.

You should do this exercise for several days before proceeding to penetration.
Once you are ready to go on to the penetration stage, lie on your back and
explain to your partner that she should sit on you so that she herself can control
the penetration of your penis.
Your partner starts the “coming and going” gently and very slowly, as soon as
you feel you have reached the critical point (preferably just before), give her a
pre-arranged stop signal; relax so that you can decrease your erection a little.
Give a signal to start again, and then if you feel the need to ejaculate, she
should bring you to ejaculation, either by hand or mouth.

Recommendations for the management of
premature ejaculation: BASHH Special Interest
Group for Sexual Dysfunction
Daniel Richardson BSc MRCP, David Goldmeier MD FRCP,
John Green PhD, Harpal Lamba BSc MRCP and J R W Harris FRCP, FRCPI,
on behalf of the BASHH Special Interest Group for Sexual
Dysfunction
Jane Wadsworth Clinic, Jefferiss Wing, St Mary’s Hospital, London W2 1NY, UK
Summary: We present the British Association for Sexual Health and HIV (BASHH),
Special Interest Group for Sexual Dysfunction updated recommendations for the
management of premature ejaculation. The recommendations outline the physiology,
prevalence, definitions, aetiological factors and patient assessment for this common
sexual problem. Behavioural, local and systemic pharmacological treatments are
discussed along with general recommendations and auditable outcomes.

Introduction
Orgasm and ejaculation constitute the final stage of
the sexual response in men. There are three basic
mechanisms involved in the normal antegrade
ejaculation: emission, ejection and orgasm.1
Ejaculation is a reflex comprising sensory receptors
and areas, afferent pathways, cerebral sensory areas,
spinal motor areas and efferent pathways (Figure 1).
The ejaculation reflex is controlled by a complex
interplay between central serotonergic and dopaminergic
neurons, with a secondary involvement of
cholinergic, adrenergic, nitrergic, oxytocinergic and
GABA (gamma aminobutyric acid)-ergic neurons.2
Seminal emission and ejaculation are integrated into
the complex pattern of copulatory behaviour by
several forebrain and midbrain structures (Figure 1).3
Prevalence of premature ejaculation
Premature ejaculation is one of the most frequently
reported sexual dysfunctions seen in clinical
practice. Varying rates have been estimated from
different populations. A systematic review of 28
studies suggested a prevalence of 15%.4 A large
representative sample of American men, aged
between 18 and 59 years, found that 31% of men
admitted to premature ejaculation occurring for
at least one month over the past 12 months.5
However, a more detailed study in the UK of 5000
16–44-year-old men found that 11.7% said that they
had experienced premature ejaculation for at least
one month in the past year, but only 2.7% hadexperienced the problem for at least six months in
the past year, suggesting that the problem affects
many men some of the time.6 Data from a large
observational study show overlapping distributions
of ejaculation times in men, who subjectively
had premature ejaculation compared with those
who were subjectively normal (Figure 2).7 A
substantial number of men who do not have
premature ejaculation have short ejaculation times
and conversely some men who complain of
premature ejaculation appear to have long ejaculation
times. This suggests that other features of
premature ejaculation have to be considered, as
well as time, i.e. degree of control and distress.
Definition
A universally accepted definition has yet to be
established. Masters and Johnson proposed that
premature ejaculation is the inability of a man to
delay ejaculation long enough for the woman to
reach orgasm 50% of the time.8 Some authors have
defined premature ejaculation as the number of
vaginal thrusts the man makes before ejaculation.
9–11 Clinical studies have used intravaginal
ejaculation times as measured by a stopwatch to
define premature ejaculation. Standardized inventories
may be available in the future, which will
generate individual data on the subjective perception
of lack of control and associated distress. The
DSM IV (American Association of Psychiatrists)
define premature ejaculation as: ‘persistent or
recurrent ejaculation with minimal sexual satisfaction
before, or shortly after penetration and before
the person wishes’.12 The disorder should result in

MSSVD SPECIALIST INTEREST GROUP ON SEXUAL DYSFUNCTION
GUIDELINES ON PREMATURE EJACULATION
Definition of Premature Ejaculation
There are a number of definitions, none of which is wholly satisfactory. The DSM IV categorisation of the American Psychiatric Association defines premature ejaculation (PE) as “ persistent or recurrent ejaculation with minimal sexual stimulation before, on or shortly after penetration, and before the person wishes” (1)  The definition alsostipulates that the PE results in marked distress or interpersonal difficulties, and that drugs (e.g. opiate withdrawal) should not be causative.  Clinicians should also take into account factors such as age (the younger the patient the more likely that quick ejaculation will take place), the novelty of the situation or the partner and the frequency of the sexual activity (1). However, it is important for clinicians to remember that in the community at large men and their partners may learn to adjust to fast ejaculation (e.g. by extended foreplay with brief intravaginal sex) and may not be distressed or dissatisfied in this scenario (2).
Primary PE is defined as PE that has always been present and secondary PE as the development of PE after a period of perceived normal ejaculatory functioning.
Prevalence of  PE
In a  recent, random survey of 1511 men in the USA, about one third considered that they had ejaculated prematurely over the past year (2). However, the proportion that perceived their condition as problematic was not stated.  Studies carried out by the authors, of a GUM population attending a Central London clinic revealed substantial rates of premature ejaculation and erectile dysfunction among routine GUM attenders (3) (4).

Aetiology of PE
The reader is referred to a detailed review of this elsewhere (5). However, the main factors are summarised below.
Idiopathic primary premature ejaculators may have lower penile sensory thresholds (6) and/or greater cortical penile representation (7) than their normal counterparts. Other workers contend that men with PE become sexually aroused more rapidly than normals (8).  Both anxiety and depression have been associated with PE(9) although this may be a consequence of the condition rather than a cause.  Others have failed
to find such an association (10).
A number of psychodynamic theories have been proposed to explain PE, as well as psychosocial and relationship factors (5) (e.g. family problems or a recent new baby). It is possible that some racial groups are more susceptible than others to PE (11), particularly men from the Indian subcontinent who may present with the Dhat syndrome (12) (a clinical picture with some or all of the features of concern about spontaneous seminal loss, affective illnesses, psychosomatic complaints and PE).
There are a number of anecdotal reports of PE being associated with neurological disease, diabetes, pelvic injury, vascular disease, prostatic hypertrophy, chronic prostatitis and hypogonadotrophic hypogonadism (5)
Patient Assessment

(i) History
This should include a brief but thorough assessment of whether the problem is primary or secondary in nature, and any associated personal, social or religious correlates, as well as a brief medical and psychiatric history (including alcohol and illicit drug details).  The presence of sexual desire should be documented Finally it is important to ensure that fast detumescence is in fact not caused by erectile problems rather than PE.  An interpreter may be needed to obtain the correct history.
(ii) Clinical examination
An assessment of the penis and other secondary sexual characteristics is mandatory as well as brief general physical and mental state assessments.
(iii) Investigations
No special investigations are routinely necessary to make the diagnosis of PE.
We consider that all new patients merit at least a 30 minute minimal consultation time for their first appointment.
Treatment of PE
General considerations
Treatment of PE should primarily attempt to alleviate concern about the condition as well as to increase sexual satisfaction in the patient and partner (if he has one). Simple measures such as education to discuss sexual norms, and facilitation of sexual negotiation between the couple (e.g. the man clitorally stimulates his partner to orgasm before vaginal penile entry) may be useful.  Formal cognitive behaviour  therapy (CBT) may be usefully incorporated into the specific techniques described below.
Specific Treatments
These therapeutic options include:-
1.  The squeeze/stop-start techniques
2.  Pharmacotherapies
3.  Other therapies
Squeeze/stop-start techniques
Most men learn to achieve ejaculatory control by various self learned techniques e.g.
thought distraction, transient cessation of penile thrusting.  The techniques described below merely attempt to formally train men in ejaculatory control.
In the “squeeze” technique (13) the glans is firmly squeezed between thumb and forefingers, at the frenular level until some detumesence results.  This is usually accomplished using one hand, with the index finger and forefinger being placed dorsally over the glans and distal shaft and the thumb over the ventral subcoronal frenular area. The “squeeze” is usually accompanied by a diminution of sexual arousal. It should take place before the patient has reached the stage that he feels it is inevitable he is going to ejaculate/orgasm.  This point may not be initially discernible to the patient with PE, but he usually learns to recognise it with time.  A partner usually carries out the squeeze but the patient may train himself to control the
PE by undertaking the squeeze himself.
A similar end point is reached by merely ceasing penile stimulation at the “pre-inevitable point” and then restarting penile stimulation when arousal and the erection have subsided.  This is the so-called “stop-start” technique (14). Both these techniques may be incorporated into a sensate focus regime. This is essentially a series of graded massage exercises, in which an initial ban is put on intercourse and the touching of erotic zones in order to relieve any performance anxiety.  There is a gradual reintroduction of erotic massage, vaginal penetration (using the female –superior position) and, lastly penetrative intercourse. These behavioural techniques may take up to 3-6 months to achieve significant changes (5).
Masters and Johnson reported an initial success rate of greater than 95% in the treatment of PE using the squeeze technique (13).  Less biased surveys indicate initial success rates of about 60%.  Most of the initial treatment gains appear to be lost over follow up with time (15)(16)(17)(18).

Pharmacotherapies

Systemic therapies
A number of placebo-controlled studies show that both clomipramine and the SSRI antidepressants (e.g. fluoxetine, paroxetine, sertraline) significantly retard ejaculation (19)(20)(21)(22)(23). However, they may all produce quite marked side effects, particularly in higher dosages e.g. low sexual desire, erectile dysfunction and fatigue. They can be taken on a continuous basis, which is the usual practice, or as required some hours before sex is anticipated (24)  The intermittent therapy can be commenced de novo (20) or after about a month of daily therapy (24) .
The daily dosages used tend to be lower than those used to treat depression e.g. 10mg to 50 mg of clomipramine, 10mg to 20mg per day of fluoxetine, 10mg to 20mg of paroxetine or 50mg of sertraline.  Once begun, medication needs to be continued to retain its beneficial effect.  However it is possible there can be a learning effect while on medication, as in one study two thirds of the patients on continuous sertraline for 7 months maintained their improvement after drug withdrawal (25).

Local therapies
EMLA cream (prilocaine-lidocaine) or lidocaine ointment used on the frenular area of the penis 15-30 minutes before intercourse (but wiped off before sexual contact) can produce useful results in retarding ejaculation (26).  Titrating the area of application against its effects can minimise penile numbness.
Other treatments
Both pelvic floor rehabilitation (27) and dorsal nerve neurotomy (28) have been shown to give good results in the short term but are experimental techniques at present and are not recommended for routine use. References
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