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.
