Men with low 5­HT neurotransmission and prob­

Pharmacological Treatment

able 5­HT2C receptor hyposensitivity may have

their ejaculatory threshold genetically “set” at a

The introduction of the serotonergic tricyclic

lower point and ejaculate quickly and with mini­

clomipramine and the SSRIs paroxetine, sertra­

mal stimulation whereas men with a higher set­

line, fluoxetine, citalopram, and fluvoxamine,

point men can sustain more prolonged and

has revolutionized the approach to and treat­

higher levels of sexual stimulation and can exert

ment of PE. These drugs block axonal re­uptake

more control over ejaculation. This is supported

of serotonin from the synaptic cleft of central

by the recent report that genetic polymorphism

and peripheral serotonergic neurons by 5­HT

of the 5­HTT gene determine the regulation of

transporters, resulting in enhanced 5­HT neu­

the IELT and that men with LL genotypes have

rotransmission and stimulation of post­synap­

statistically shorter IELTs than men with SS and

tic membrane 5­HT2C autoreceptors. Although

SL genotypes.71

the methodology of the initial drug treatment

studies was poor,later double blind and placebo­

Treatment of Premature

controlled studies confirmed the ejaculation­

delaying effect of clomipramine and SSRIs.

Ejaculation

Daily Treatment with Selective

Premature ejaculation treatment strategies inc­

Serotonin Reuptake Inhibitors (SSRIs)

lude psychosexual counseling, daily or on­

demand pharmacotherapy, either alone or in

Daily treatment with paroxetine 10–40 mg, clo­

combination as part of an integrated treatment

mipramine 12.5–50 mg, sertraline 50–200 mg,

program.

fluoxetine 20–40 mg, and citalopram 20–40 mg

is usually effective in delaying ejaculation (Table

Psychosexual Counseling

29.2).77­82 A meta­analysis of published data sug­

The cornerstones of behavioral treatment are the

gests that paroxetine exerts the strongest ejacu­

lation delay, increasing IELT approximately

Seman’s “stop­start” maneuver and its modifica­

8.8­fold over baseline.77 However, the use of

tion proposed by Masters and Johnson, the

these drugs is limited by the lack of Food and

squeeze technique. Both are based on the theory

Drug Administration (FDA), European Medi­

that PE occurs because the man fails to pay suffi­

cines Agency (EMEA), or other regulatory

cient attention to pre­orgasmic levels of sexual

agency approval and the need to prescribe “off­

tension.1,2 As most men with PE are aware of their

label.” This largely reflects the failure of the

anxiety and the sources of that anxiety tend to be

pharmaceutical industry to appreciate the prev­

relatively superficial, treatment success with these

alence of PE, the unmet treatment need, and the

behavioral approaches is relatively good in the

commercial opportunity of an approved drug

short term but convincing long­term treatment

treatment for PE.83

outcome data are lacking.52,72­74 Cognitive behav­

Ejaculation delay usually occurs within

ioral therapy (CBT), especially when combined

5–10 days of starting treatment, but the full

with pharmacotherapy, is an effective interven­

therapeutic effect may require 2–3 weeks of

tion for acquired PE related to sexual performance

treatment and is usually sustained during long­

anxiety and a substantial proportion of men

term use.29 Although tachyphylaxis is uncom­

report sustained improvements on ejaculatory

mon, some patients report a reduced response

latency and control following cessation of phar­

after 6–12 months of treatment. Adverse effects

macotherapy.29,36,75 However,men with lifelong PE

are usually minor, start in the first week of treat­

rarely achieve symptomatic improvement with

ment, gradually disappear within 2–3 weeks,

CBT alone and are best managed with either phar­

and include fatigue, yawning, mild nausea, diar­

macotherapy alone or in combination with CBT if

rhea, or perspiration. Hypoactive desire and ED

there is a significant secondary psychogenic con­

is infrequently reported and appear to have a

tribution, where cessation of pharmacotherapy

lower incidence in non­depressed PE men com­

invariably results in a return to pre­treatment

pared to depressed men treated with SSRIs.22

latency and control within 1–2 weeks.

Waldinger et al. have suggested that this may be

related to the protective effects of increased

their experience with selective a1­adrenergic

oxytocin release in men with lifelong PE.70

blockers, alfuzosin and terazosin, in the treat­

Neurocognitive adverse effects include signif­

ment of PE. Both drugs are approved only for

icant agitation and hypomania in a small num­

the treatment of lower urinary tract symptoms

ber of patients, and treatment with SSRIs should

(LUTS) in men with obstructive benign pros­

be avoided in men with a history of bipolar

tatic hyperplasia (BPH). In a double blind pla­

depression.84 Systematic analysis of randomized

cebo­controlled study, Cavallini reported that

controlled studies indicates no statistical evi­

both alfuzosin (6 mg/day) and terazosin (5 mg/

dence of an increased risk of suicide with SSRIs

day) were effective in delaying ejaculation in

in adults.85,86 However, an FDA meta­analyses of

approximately 50% of the cases.96 Similarly,

all pediatric randomized clinical trials (RCTs) of

Basar reported that terazosin was effective in

antidepressants suggested a small increase in the

67% of men.97 However, both studies were lim­

risk of suicidal ideation or suicide attempts in

ited by the use of subjective study endpoints of

youth.86 This effect is quite variable across SSRIs

patient impression of change and sexual satis­

and it is not clear if that variance is a mea­

faction and did not evaluate objective endpoints

surement error or represents a real difference

such as IELT. Additional controlled studies are

between medications. Furthermore, systematic

required to determine the role of a1­blockers in

questionnaire data, epidemiological and autopsy

the treatment of PE.

studies, recent cohort surveys, and the negligible

number of youth suicides taking antidepressants

On-Demand Treatment with Selective

at the time of death do not support the hypoth­

esis that SSRIs induce suicidal acts and suicide,

Serotonin Reuptake Inhibitors

raising concerns over ascertainment artifacts in

the AE report method.85 However, it would seem

Administration of clomipramine, paroxetine,

prudent to not prescribe SSRIs to young men

sertraline, and fluoxetine 4–6 h before inter­

aged 18 years or less, and to men with a depres­

course is modestly efficacious and well tolerated

sive disorder particularly when associated with

but is associated with substantially less ejacula­

suicidal thoughts. Patients should be advised to

tory delay than daily treatment (Table 29.2).98­101

avoid sudden cessation or rapid dose reduction

Following acute on­demand administration of

of SSRIs which may be associated with a SSRI

an SSRI, increased synaptic 5­HT levels are

withdrawal syndrome, characterized by dizzi­

downregulated by presynaptic 5­HT1A and

ness, headache, nausea, vomiting, and diarrhea,

5­HT1B/1D autoreceptors to prevent overstimu­

and occasionally agitation, impaired concentra­

lation of postsynaptic 5­HT2C receptors. How­

tion, vivid dreams, depersonalization, irritabil­

ever, during chronic daily SSRI administration, a

ity, and suicidal ideation.87,88

series of synaptic adaptive processes that may

Platelet serotonin release has an important

include presynaptic 5­HT1A and 5­HT1B/1D

role in hemostasis,89 and SSRIs especially with

receptor desensitization greatly enhances syn­

concurrent use of aspirin and non­steroidal

aptic 5­HT levels resulting in superior­fold

anti­inflammatory drugs are associated with an

increases in IELT compared to on­demand

increased risk of upper gastrointestinal bleed­

administration (Fig. 29.2).69 On­demand treat­

ing.90,91 Priapism is a rare adverse effect of SSRIs

ment may be combined with either an initial

and requires urgent medical treatment.92­94

trial of daily treatment or concomitant low­dose

Long­term SSRIs may be associated with weight

daily treatment.98­100

gain and an increased risk of type­2 diabetes

The assertion that on­demand drug treatment

mellitus.95

of PE is preferable to daily dosing parallels the

rationale for the treatment of ED but is contrary

Daily Treatment with

to the results of the only PE drug preference

study.47 The methodology of this trial was not

a1-Adrenoceptor Antagonists

ideal as it involved comparison of preference for

daily paroxetine, on­demand clomipramine, or

Ejaculation is a sympathetic spinal cord reflex

topical anesthetic based only on subject infor­

that could theoretically be delayed by a1­adren­

mation/questionnaires and not on actual use of

ergic blockers. Several authors have reported

the drug. Well­designed preference trials will