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
