Impotence Support - Recent Medical Article on PE

Author

Recent Medical Article on PE

Timothy Hutchinson, Sr Partner

2006-01-23, 1:47 am

New Findings in the Treatment of Premature Ejaculation CME

Wayne J. G. Hellstrom, MD, FACS

Background

The introduction of effective oral agents for the treatment of erectile
dysfunction (ED) has heightened the awareness and interest of both the lay
public and healthcare professionals on the topic of sexual dysfunction.
Along the same lines, the observation of delayed ejaculation as a
consequence of some serotonergic antidepressant medications has stimulated
increased interest in the use of this class of agents for the treatment of
premature ejaculation (PE).

PE was long thought to be a learned behavior or conditioned response
resulting from early sexual experiences that were rushed and associated with
anxiety. Anxiety activates the sympathetic nervous system, lowers the
ejaculatory threshold, and increases the release of adrenalin, which further
contracts the smooth muscle of the penis and causes secondary ED. Early
behavioral strategies instituted by psychologists and sex therapists
included psychoanalysis, the Semans "stop-start" method, and Masters &
Johnson's "squeeze" technique. Efficacy rates were originally reported as
60% to 95%; however, clinical research over time revealed success rates
declining to less than 25% at 3 years after treatment cessation.
Disadvantages of behavioral therapy include cost, time-consuming sessions,
commitment by the partner, and stability of the relationship.

PE and the consequences of ejaculating too soon have been referenced in the
literature for many years. In a study to evaluate the impact of PE on men's
self-confidence, self-esteem, and relationship satisfaction, the 14-item
validated Self-Esteem & Relationship (SEAR) questionnaire was administered
to 207 men diagnosed with PE and 1,380 men without PE at different time
points.[1] SEAR subscales included sexual relationship (8 items);
self-esteem (3 items); confidence (6 items); and overall relationship (2
items). Overall results revealed that men with PE exhibit significantly
lower self-esteem and confidence, and more sexual and overall relationship
difficulties than men without PE.

Over the past 3 decades, clinical investigators have attempted to establish
a standardized definition of PE to use in studies on the prevalence,
etiology, and impact of PE on quality-of-life for both patient and partner.
The American Urological Association (AUA) guideline committee provides the
following succinct working definition: "Premature ejaculation is ejaculation
that occurs sooner than desired, either before or shortly after penetration,
causing distress to either one or both partners."[2]
Diagnosis

There are no specific medical laboratory tests for PE. The only objective
criterion for PE that has been globally accepted is a nonexistent or
severely shortened intravaginal ejaculatory latency time (IELT). This
translates simply into ejaculation that occurs after intromission and "too
soon." Subjective criteria have focused on 3 parameters: (1) reduced control
over ejaculation; (2) decreased patient and/or partner satisfaction with
intercourse, and (3) patient and/or partner distress or bother about the
condition. Few men and/or their partners can define a "normal" time to
ejaculation. In one 4-week, multicenter, US observational study in males at
least 18 years of age with and without PE, data was collected from both men
and their partners, including IELT, using a stopwatch and subjective
patient-reported outcome measures.[3] This study included 207 men with PE
diagnosed using the DSM-IV TR criteria and 1380 men without PE. Stepwise
logistic regression analysis was used to determine the significant factors
associated with the diagnosis of PE and were identified as: control over
ejaculation, personal distress, and IELT less than 2 minutes. While IELT
does discriminate between men with and without PE, substantial overlap
between these groups exists when IELT is used alone. Discrimination between
men with and without PE is enhanced substantially when the 2
subject-reported measures (control of ejaculation and personal distress) are
used in combination with IELT in a clinical evaluation.

While stopwatch IELT is mandated for use in clinical trials, estimated IELT
is more commonly used in clinical practice. A study was performed to
determine the how closely objective measurement of IELT matches estimated
IELT.[4] From observations of 207 men with PE and 1380 men without PE, each
subject was asked to estimate his IELT at the first study visit. Following
this visit, subjects and partners were provided with a stopwatch and event
log. The IELT of each episode of sexual intercourse during the ensuing
2-week study interval was measured and recorded by the female partner. The
results showed both PE and non-PE subjects slightly overestimated their IELT
compared with the stopwatch-recorded IELT. For subjects with PE, the mean
measured value of IELT was 1.8 minutes and the mean estimated value was 2.0
minutes. For subjects without PE mean measured value was 7.3 minutes and
estimated value was 9.0 minutes. Hence, patient-estimated IELT is generally
reliable (although slightly high) and for clinical purposes a
stopwatch-assessment is not mandatory.
Epidemiology

According to a number of academic and pharmaceutical-company-sponsored
epidemiologic studies, PE affects an estimated 25% to 35% of men aged 18 to
59 years. In a corresponding community practice-based study, 614 men were
asked to complete 13 demographic questions and the 32-question Male Sexual
Health Questionnaire (MSHQ).[5] PE was the most common sexual dysfunction
(32.7% of men), with ED (10.6%) and decreased libido (10.3%) ranked second
and third. Men with PE were found to be significantly less likely to be
satisfied with their overall sexual relationship, quality of sex life, and
their overall partner relationship.
Topical Treatment

Besides the behavioral approaches mentioned previously, clinicians have
focused on topical and medical treatments of PE. Topical treatments
(anesthetics and SS-cream) appear to increase IELT, but are associated with
mild local adverse effects (AEs), may be messy, can be indiscreet, and
require partner cooperation. Frequent use can lead to anorgasmia,
anejaculation, and genital numbness in the female. PDE5 inhibitors are
effective in the treatment of secondary PE when caused by mild ED.[2] By
improving a man's failing erections, it is hypothesized that his anxiety is
reduced, thereby alleviating his secondary PE.
Pharmacologic Treatment

Selective serotonin reuptake inhibitors (SSRIs), which were found to delay
ejaculation, have been used off-label for the treatment of PE for the last 1
to 2 decades. The optimal dose and regimens for these agents for the
treatment of PE have not been established; however, data show greater
success with chronic vs on-demand (PRN) dosing. However, chronic use of
SSRIs is associated with a variety of AEs, including dry mouth, nervousness,
gastrointestinal upset, diarrhea, headache, drowsiness, and restlessness.
These AEs make current SSRIs less than ideal for the treatment of PE.

The ideal drug for PE should have a number of characteristics: (1) its use
should be discreet, preferably oral; (2) it would have a rapid onset of
action (< 1 hour), rapid elimination, and minimal accumulation; (3) it
should have good tolerability with few AEs; (4) it should be effective on
demand, without requiring chronic use or a loading dose; and (5) it should
have demonstrated efficacy on IELT and patient-related outcomes in
large-scale, long-term, placebo-controlled trials. None of the current
off-label medications fulfill all these criteria.

In a community-based practice study 32.7% (201/614) of men reported PE.[6]
None of the men with self-declared PE in this study were currently seeking a
treatment, but most (80%) reported that if they sought treatment for PE,
their primary goal would be sexual satisfaction for both themselves and
their partner. Eighty-one percent reported that a pill to prolong IELT would
be their treatment of choice.
Dapoxetine

Dapoxetine hydrochloride is the first oral compound developed specifically
for the treatment of PE. In preclinical studies, dapoxetine was found to be
a potent inhibitor of serotonin reuptake and is considered by authorities in
the field to be a serotonin transporter inhibitor.

In experimental animal studies, researchers from Paris, France, evaluated
the emission and expulsion phases of ejaculation using
p-chloroamphetamine-induced ejaculation in anesthetized rats.[7] Different
doses of intravenous dapoxetine reduced both the emission and expulsion
phases in a dose-dependent manner. Similar experiments in the same
anesthetized-rat model were conducted to elucidate the drug's mechanism of
action. These studies revealed that dapoxetine worked by increasing the
pudendal motor neuron reflex latency period.[8]

Dapoxetine has previously demonstrated its efficacy in the treatment of PE
in 2 identically designed, double-blind, randomized, placebo-controlled,
12-week phase III trials.[9] An open-label, long-term (1 year) on-demand
study of dapoxetine efficacy was presented.[10] Of the 1774 men enrolled in
the 3-month studies (placebo, dapoxetine 30 mg and 60 mg) all were provided
with dapoxetine 60 mg to be taken as needed 1 to 3 hours before sexual
intercourse. Patients were evaluated at 1, 2, 3, 6, and 9 months in this
extension study. The final results showed that the improvements in
satisfaction with sexual intercourse, control of ejaculation, symptom
severity, and benefit from the medication were maintained through the
duration of the study.

Further analysis of the data sets from different groups of researchers
revealed that dapoxetine equally improved IELT in men with both acquired and
lifelong PE.[11] Additionally, men with PE who had the lowest IELTs appeared
to benefit most. Men with a baseline IELT < 30 seconds had a 6.8-fold
increase; those with a baseline IELT > 30 seconds and < 1 minute had a
4.4-fold increase; and those with baseline IELT > 1 minute and ¾ 2 minutes
had a 3.2-fold increase.[12]

Additional studies involving dapoxetine showed minimal food effects.[13]
Mean maximal plasma concentrations of dapoxetine decreased slightly after a
high-fat meal, from 443 ng/mL (fasted) to 398 ng/mL (fed), and were delayed
by approximately 0.5 hours following a high-fat meal (1.3 hours fasted, 1.63
hours fed). There was no effect of food on elimination of this agent, with <
5% of peak plasma concentration being present 24 hours after oral
administration. Interestingly, the most frequent AE with dapoxetine is
nausea, which was decreased after a high-fat meal (24% of fasted and 14% of
fed subjects). Perhaps a complete steak dinner will be required with this
medication for the patients who complain of nausea.

The question of daily dosing and accumulation was reported in a study of 42
healthy males.[14] Dapoxetine was rapidly absorbed with mean maximal plasma
concentrations achieved at 1.01 and 1.27 hours after single doses of
dapoxetine 30 and 60 mg. With repeated daily dosing, steady-state plasma
concentrations were reached within 4 days, with modest accumulation
(1.5-fold). Elimination of dapoxetine was rapid and biphasic, with initial
and terminal half-lives of 1.4 and 20 hours. The authors concluded that the
pharmacokinetic profile of dapoxetine is ideally suited to an on-demand oral
therapy for PE.
Educational Need

Even though PE is the most common male sexual dysfunction, it seems to be
under-reported by patients and underestimated by physicians. There have been
2 large surveys conducted -- one that looked at the prevalence and attitudes
regarding PE among 11,543 men from the United States, Germany, and Italy,
and another querying 271 physicians (primary care physicians, urologists,
and psychiatrists) from the United States, Germany, Italy, and Mexico..[15]
Seventy-two percent of men with self-reported PE claimed significant worry
about their ability to last during intercourse, with 59% reporting
frustration at climaxing too soon. In contrast, > 90% of physicians thought
that PE caused only minor or no distress to their patients. Approximately
12% of men stated that they had consulted a physician for this condition,
with 80% claiming to have initiated the conversation and 85% reporting
little or no improvement from this medical interaction. Obviously medical
enlightenment is needed.

Clearly, PE is a common and distressing condition for a sizeable segment of
the male population. Patients and couples often seek expensive and
ineffective off-label therapies. education about PE, its prevalence, and
beneficial therapies for both consumers and physicians is urgently needed.

LMac

2006-01-23, 1:47 am

Timothy Hutchinson, Sr Partner wrote:

> New Findings in the Treatment of Premature Ejaculation CME
>
>
>
> Wayne J. G. Hellstrom, MD, FACS
>
> -====== snip ======-
>
An interesting note among the papers was that many patients had reported
PE to their MD without receiving feedback on possible treatment. That
has been my experience dating from 2001. (One GP and two Uros.)

Many thanks to Timothy for the post -- have burned it to a CD and will
give it to my Uro during spring visit.

Many thanks again .... LMac