J Sex Med 2008;5:188193 2006 International Society for Sexual Medicine

188

Blackwell Publishing IncMalden, USAJSMJournal of Sexual Medicine1743-6095 2007 International Society for Sexual Medicine200851188193Original Articles

Treatment of Premature Ejaculation with Tramadol HCLSalem et al.

ORIGINAL RESEARCHEJACULATORY DISORDERS

Tramadol HCL has Promise in On-Demand Use to Treat
Premature Ejaculation

Emad A. Salem, MD,* Steven K. Wilson, MD,* Nabil K. Bissada, MD,* John R. Delk II, MD,*
Wayne J. Hellstrom, MD,

and Mario A. Cleves, PhD*

*Department of Urology, University of Arkansas for Medical Sciences, Little Rock, AR, USA;

Tulane University Health
Sciences Center, New Orleans, LA, USA
DOI: 10.1111/j.1743-6109.2006.00424.x

A B S T R A C T

Introduction.

Premature ejaculation (PE) is a worldwide problem without an approved treatment. Selective sero-
tonin reuptake inhibitors (SSRIs) are widely used off label as pharmacotherapeutic agents in the treatment of PE.

Aim.

This study investigates Tramadol efcacy for on-demand treatment of PE.

Main Outcomes Measures.

Intravaginal ejaculation latency time (IELT) was used as an objective tool to assess the
efcacy of the investigated treatments.

Materials and Methods.

Single-blind, placebo-controlled, crossover, stopwatch monitored two-period study was
conducted, on 60 patients with lifelong PE. PE was dened as IELT of

<

2 minutes in 80% of intercourse episodes.
A total of 25 mg of Tramadol hydrochloride was given to one group (30) prior to intercourse and placebo was
supplied for the other group (30) for 8 weeks. Drugs were taken 12 hours before sexual activity and sexual
intercourse was required at least once per week. After the initial treatment period, the two groups took the alternate
medication for another 2 months. The two 8-week treatment periods were separated by 1 week washout period.
IELT was timed by a stopwatch at each intercourse and was reported by patients or partners.

Results.

The baseline (mean

SD) IELT for patients before treatment was 1.17

0.39 minutes. At the end of the
treatment period utilizing the active drug, the mean IELT was increased signicantly in patients on Tramadol
treatment to 7.37

2.53 minutes. The same patients on placebo medication had mean IELT of only
2.01

0.71 minutes. Patients uniformly reported satisfaction with their resulting control over ejaculation.

Conclusions.

Tramadol, a drug with a proven safety record as an anti-inammatory agent, shows promise as a drug
for treating rapid ejaculation.

Salem EA, Wilson SK, Bissada NK, Delk JR II, Hellstrom WJ, and Cleves MA.
Tramadol HCL has promise in on-demand use to treat premature ejaculation. J Sex Med 2008;5:188193.

Key Words.

Design; Methodology of Clinical Trials; Causes and Treatment of Ejaculatory/Orgasmic Disorders;

Premature Ejaculation

Introduction

remature ejaculation (PE) is the most common
male sexual disorder, and is estimated to affect
up to 30% of men worldwide [1]. Although the
etiology is unclear, there is emerging evidence that
men from different ethnic backgrounds may be
more at risk [2]. PE, unlike erectile dysfunction
P

(ED), affects men of all ages equally. However,
both PE and ED coexist, and often PE can mas-
querade or be misdiagnosed as ED in many men.
This is, in part, due to the lack of knowledge about
PE, the absence of performing a careful history,
and the nonexistence of diagnostic tools for PE
[3]. Despite its high prevalence and recognized
adverse effects on mens quality of life, it is only
Treatment of Premature Ejaculation with Tramadol HCL

189

J Sex Med 2008;5:188193

recently that attention has been focused on inves-
tigating the causes of PE and developing new ther-
apeutic strategies.
A universally accepted denition of PE has yet
to be established. Various denitions of PE have
been used by different researchers, and include
partner satisfaction, male voluntary control, dura-
tion of ejaculatory latency, and number of intrav-
aginal thrusts [4]. Kaplan rst suggested that PE
was primarily a problem of voluntary control over
timing of ejaculation, a concept on which most of
the current denitions are based [5]. According to

The Diagnostic and Statistical Manual of Mental
Disorders

, Fourth Edition (DSM-IV-TR

), PE is
dened as persistent or recurrent ejaculation with
minimal sexual stimulation, and before the subject
wishes it and is associated with marked distress
or interpersonal difculty [6]. The American
Urological Association Guideline on Premature
Ejaculation denes PE as Ejaculation that occurs
sooner than desired, either before or shortly after
penetration, causing distress to either one or both
partners [3].
Premature ejaculation has been classied as
either primary (lifelong) that begins when a
male rst becomes sexually active or secondary
(acquired), meaning that a male previously had
an acceptable level of ejaculatory control and
developed the condition later in life [7,8]. Pri-
mary PE is hypothesized to have a strong bio-
logical component with a variable psychological
contribution [9]. Although psychological or situ-
ational stressors may contribute to secondary
PE, certain medical conditions and medications
may also be associated. Another classication
invokes the terms global or universal (e.g.,
occurs regardless of situation or partner) or sit-
uational (e.g., limited to certain situations or
partner) [10]. Waldinger and Schweitzer also
suggested another PE type Natural Variable
PE which is not a typical syndrome but rather a
cluster of inconsistent symptoms of rapid ejacu-
lation and belongs to the normal variability of
sexual performance [11].
Selective serotonin reuptake inhibitors (SSRIs)
are widely used off label as pharmacotherapeutic
agents in the treatment of rapid ejaculation. The
potential of antidepressants to treat PE was rst
introduced by Eaton in 1973 [12].
Tramadol [cis-2-[(dimethylamino) methyl]-1-
(3-methoxyphenyl) cyclohexanol] is a centrally
acting synthetic opioid analgesic with a C

max

of
300

g/L after 100 mg single oral dose [13]. The
brand name in the United States is Ultram. It has
been prescribed for many years and its safety pro-
le is acceptable. Tramadols mode of action is not
completely understood. From animal tests, at least
two complementary mechanisms appear applica-
ble: binding of parent and M1 metabolite to

-opioid receptors (antinociceptive effect) and
inhibition of reuptake of norepinephrine and sero-
tonin which may stand for its effect on delaying
ejaculation. Tramadols action on 5-HT

1A

and
5HT

2C

needs further investigations.
Safarinejad and Hosseini [14] recently pub-
lished a double-blind, placebo-controlled, xed-
dose study indicating that on-demand use of
50 mg Tramadol exerted a signicant ejaculation
delaying effect in men with PE. In the current
single-blind, placebo-controlled study in men with
PE, we independently investigated the on-demand
use of 25 mg Tramadol.

Methods

This study included 60 patients with PE, age
ranged from 22 to 62 years with mean (36

8.87)
treated from September, 2003 to May, 2004. The
study was approved by the local medical ethics
committee. Patients were recruited by advertise-
ment and consented for participation. PE was
dened according to the DSM-IV-TR denition
of PE as persistent or recurrent ejaculation with
minimal sexual stimulation before, at, or shortly
after penetration and before the subject wishes it.
All patients had an active sexual life with score

22
on the erectile function domain of the Interna-
tional Index of Erectile Function [15]. All patients
had primary PE (lifelong PE since their rst sexual
experience).
The intravaginal ejaculation latency time
(IELT), with at least one intercourse episode per
week, for all patients was

<

2 minutes in 80% of
intercourse attempts in a 4-week test period prior
to the start of treatment. This was an inclusion
criterion for all the patients in our study.
A single-blind, placebo-controlled, crossover,
stopwatch monitored two-period study was con-
ducted with a dose (25 mg, PRN) of Tramadol
hydrochloride (T) for one group (30) and placebo
for the other group (30) for 8 weeks. After the 8-
week trial, patients were instructed to stop treat-
ment for 1 week as a washout period. After the
washout period, the two groups took the alternate
medication for another 2 months. The drug was
required to be taken 12 hours before sexual activ-
ity and frequency of sexual intercourse episodes
was required to be at least once per week. IELT at
190

Salem et al.

J Sex Med 2008;5:188193

each intercourse was reported by patients or part-
ners. Patients were instructed to measure the IELT
by stopwatch from the start of penetration to the
start of ejaculation by either the patient or the
partner. All patients completed the study period.
All patients were asked about their satisfaction
with their control over ejaculation with either
treatment. No specic validated questionnaire was
used in this study. The subjects were asked about
satisfaction with their sexual act on either drug
with two questions Are you satised with your
control over ejaculation with the treatment?, Are
you satised with your sexual act with the treat-
ment? Patients were also asked about their toler-
ance to the drug and if there were any side effects.
Intravaginal ejaculation latency time improve-
ment, dened as the difference between IELT at
the end of each treatment period and baseline,
was selected as the main outcome of interest in
the crossover analysis. Presence of a carryover
effect was assessed by testing for a signicant
treatment by period interaction in an analysis of
variance (

ANOVA

) framework. Because there was
no evidence of a signicant carryover effect, the
difference between IELT improvement under
Tramadol hydrochloride treatment and placebo
treatment (irrespective of the order of adminis-
tration) was tested by a nonparametric Wilcoxon
matched-pairs signed-ranks test. The crossover
analysis was performed using the PKCROSS
procedure implemented in the Stata statistical
package (Stata Corporation, College Station,
TX, USA).

Results

This study was conducted on 60 patients. All of
them had lifelong PE. Four week (pretreatment)
data of the IELT by patients showed IELT

<

2 minutes in more than 80 % intercourse
attempts. The rst 30 patients started with pla-
cebo, while the next 30 patients started with Tra-
madol (Table 1).
The baseline (mean

SD) IELT for patients
before treatment was 1.17

0.39 minutes (range
0.091.96), 1.22

0.36 minutes (range 0.681.96)
for group 1 and 1.11

0.42 minutes (range 0.09
1.92) for group 2. At the end of treatment,

Table 1

The baseline IELT before treatment, and with either treatment

No.
Placebo then Tramadol (group 1) Tramadol then placebo (group 2)
Age (years) Baseline Placebo Tramadol Age (years) Baseline Tramadol Placebo
1 32 0.82 1.45 7.35 31 0.88 12.35 1.09
2 54 0.77 1.99 12.32 24 1.87 2.68 2.05
3 26 0.98 2.06 6.32 51 0.96 6.03 1.08
4 35 1.23 2.88 8.56 43 0.98 6.87 1.15
5 39 1.65 2.05 9.02 37 1.92 7.09 1.56
6 22 0.99 2.44 7.06 38 1.03 3.86 2.98
7 45 1.12 2.05 11.02 29 1.05 5.63 1.35
8 42 0.78 1.88 5.01 26 1.06 7.33 1.86
9 38 1.66 3.08 4.65 35 1.25 4.03 2.06
10 37 1.42 1.98 9.05 36 1.18 5.68 1.98
11 46 1.85 2.03 8.23 51 1.19 13.08 3.18
12 23 1.69 2.05 3.87 42 1.17 8.26 2.66
13 26 1.01 1.86 9.88 32 1.35 6.32 1.86
14 51 1.03 1.56 12.06 42 1.65 8.91 2.42
15 29 0.97 2.05 11.01 29 1.09 6.18 1.18
16 30 0.68 2.33 5.63 38 1.54 6.77 2.86
17 31 0.99 1.86 7.63 32 0.86 10.96 0.91
18 40 1.01 1.99 6.98 26 0.89 11.36 1.08
19 57 1.03 1.56 6.52 38 1.09 6.33 1.86
20 28 1.25 2.07 3.85 27 1.08 7.66 4.35
21 32 1.96 4.02 5.32 40 1.55 6.88 1.68
22 36 1.78 2.06 8.02 41 0.66 9.86 2.98
23 29 1.38 2.33 6.08 32 1.03 4.98 1.89
24 30 1.09 2.13 7.98 39 1.02 5.08 1.65
25 62 1.63 1.89 6.98 29 0.22 3.02 0.19
26 41 1.08 1.53 5.12 48 0.09 4.8 1.98
27 31 1.07 1.09 7.65 46 0.53 6.01 0.88
28 25 1.65 1.96 10.88 37 1.65 11.85 1.99
29 27 1.32 2.05 4.09 28 1.08 7.32 2.86
30 38 0.79 2.06 8.25 31 1.44 8.53 2.53

IELT

=

intravaginal ejaculation latency time.
Treatment of Premature Ejaculation with Tramadol HCL

191

J Sex Med 2008;5:188193

the mean IELT was increased signicantly in
patients on Tramadol treatment to reach
7.37

2.53 minutes (range 2.6813.08) (Wilcoxon
matched-pairs signed-ranks test,

P



<

0.0001).
Patients on placebo showed mean IELT of
2.01

0.71 minutes (range 0.194.35) (Table 1).
There was a 6.3-fold increase in IELT for Tram-
adol and 1.7-fold increase for placebo.
In total, 59 of 60 Patients (98%) who received
Tramadol reported signicant (satisfactory) in-
creases in their control over ejaculation from base-
line and signicant benets in their sexual
satisfaction (with their sexual intercourse episodes)
when taking Tramadol. Only one patient (no. 2)
in (group 2) reported that his control over ejacu-
lation was not satisfying for him with either treat-
ment. This patient has had IELT of 1.87 minutes
before treatment, 2.05 minutes with placebo, and
2.86 minutes with Tramadol.
All patients were satised with their tolerance
to the treatment drugs (Tramadol and placebo).
However, eight patients (13.3%) reported the
experience of mild dyspepsia (5) and mild somno-
lence (3) with Tramadol. No serious side effects
were reported by any patient.
Intravaginal ejaculation latency time improve-
ment was dened as the difference between IELT
at the end of each treatment period and baseline.
There was no evidence of a signicant carryover
effect for IELT improvement (

P



=

0.6919). There-
fore, whether patients received Tramadol hydro-
chloride treatment in the rst or second period of
the crossover trial was ignored, and the effect of
Tramadol hydrochloride was compared with that
of placebo for all patients. The median IELT
improvement for patients while received Trama-
dol hydrochloride was 5.14 minutes longer than
while they when taking the placebo. This differ-
ence was highly signicant (Wilcoxon matched-
pairs signed-ranks test,

P



<

0.0001) (Table 2).

Discussion

Over the past 2030 years, clinical investigators
have participated in a growing number of con-
trolled studies that are developing our basic
understanding about PE. The emergence of well-
conducted clinical trials has given us knowledge of
the prevalence of PE, its etiology and pathophys-
iology, and additionally, its impact on patient and
partner quality of life.
There are currently no regulatory or Food and
Drug Administration (FDA)-approved pharmaco-
logical therapies for treating PE. Although SSRIs
are intended for chronic use in the treatment of
depression and are designed to have pharmacoki-
netic proles that would allow them to provide
constant systemic concentration with long-term
administration, it takes about 23 weeks to reach
a maximum steady-state concentration in order to
exhibit efcacy [16]. Therefore, SSRIs are com-
monly used in a daily dosing schedule for the
treatment of PE [3]. In addition to the potentially
desirable effect of delaying ejaculation, this dosing
regimen for long-acting SSRIs is associated with
a number of undesirable side effects, such as
decreased libido and ED. With the success of daily
SSRI use in delaying ejaculation, it has been sug-
gested that on-demand treatment with SSRIs pos-
sessing a short half-life and short Tmax would be
equally effective, more convenient, and exhibit
fewer serotonergic side effects than that observed
with daily treatment. Despite that, there is not
much known about the effect of SSRIs with a very
short T

max

and short T

1

/

2

on 5-HT neurotransmis-
sion [17].
Dapoxetine was the newly developed serotonin
transporter inhibitor for the on-demand treatment
of PE. The drug was subjected to research studies
for pharmacokinetics, pharmacodynamics, and
efcacy for the on-demand use. A double-blind,

Table 2

Median and mean improvement from baseline intravaginal ejaculation latency time (IELT) by treatment and
sequence

Treatment sequence
Treatment

P

value
Placebo Tramadol
Median Mean (SD) Median Mean(SD)
Placebo then Tramadol (N

=

30) 0.86 0.86 (0.49) 6.31 6.32 (2.47)

<

0.0001

Tramadol then placebo (N

=

30) 0.70 0.83 (0.84) 5.28 6.08 (2.69)

<

0.0001

Overall* (N

=

60) 0.79 0.84 (0.68) 5.93 6.20 (2.57)

<

0.0001

*Overall effect ignoring treatment sequence.

Two-sample Wilcoxon-MannWhitney rank-sum test.

Wilcoxon matched-pairs signed-ranks test.
192

Salem et al.

J Sex Med 2008;5:188193

placebo-controlled crossover phase II study of
dapoxetine for on-demand treatment of PE [18]
showed a mean baseline IELT increase form
1.01 minutes to 2.94 minutes with 60 mg dapoxet-
ine, 3.20 minutes with 100 mg dapoxetine, vs.
2.05 minutes with placebo. In this study, patients
reported a small, statistically signicant increase in
their control over ejaculation and expressed bene-
ts in their sexual satisfaction. Although this study
and other research demonstrated potentially en-
couraging results, dapoxetine was considered by
the FDA for approval in the United States and
initially rejected. Its sponsors are conducting
additional trials.
The initial impetus behind this study was our
observations of the effect on sexual function of
patients taking Tramadol for analgesia. The fact
that many of these patients had delayed ejacula-
tion or anejaculation inspired the use of Tramadol
empirically since 2000 in patients with PE. The
second factor was the available data about seroto-
nin syndrome with over dosage of Tramadol, or
combination treatment with Tramadol and SSRIs
[19]. Recently, in February 2006, Safarinejad and
Hosseini [14] published the rst study on the on-
demand use of 50 mg Tramadol to treat PE show-
ing a signicant effect of 50 mg dosage. In the
current single-blind study, we investigated the
on-demand use of 25 mg Tramadol. Compared
with the study of Safarinejad, we found 6.3-fold
increase in IELT on treatment with 25 mg Tram-
adol compared with 1.7-fold increase with pla-
cebo, while in Safarinejad study, they reported
13-fold increase in IELT with 50 mg Tramadol
which may indicate a dose-dependent effect of
the drug in delaying ejaculation. In this study,
Tramadol seemed to be a very effective drug for
treatment of PE, with increased IELT, improved
control over ejaculation, and increased satisfac-
tion with sexual intercourse. We empirically
selected the use of 25 mg Tramadol for dosage as
this was the lowest dose commonly prescribed as
an analgesic.
Because there is no specic validated question-
naire for PE, we used IELT as an objective method
for follow-up. In addition, patients were speci-
cally asked about their control over ejaculation and
their satisfaction with the sexual act. A valid criti-
cism of our study is that we did not ask the patients
to complete another validated questionnaire as we
did pre treatment. Our reasoning for this short-
coming was there was no questionnaire that
addressed PE specically as a cause of sexual
dysfunction.
Despite recent and current clinical investiga-
tions studying on-demand use of newer SSRI
drugs such as dapoxetine, Waldinger et al. [20] has
consistently reported that on-demand SSRI treat-
ment (12 hours prior to coitus) is seriously lim-
ited because of counter-regulatory processes of
normal serotonergic neurotransmission. In a sim-
ilar, more recent study, Waldinger concluded that
on-demand SSRI treatment has only a slight ejac-
ulation-delaying effect and is less effective than
prolonged daily treatments [17].
The exact mechanism of action of Tramadol to
delay ejaculation is not known. Its known weak
serotonin and norepinephrine reuptake inhibitory
action is unlikely to be the only explanation for its
effectiveness in patients with PE. Whether it has
other central actions on serotonin receptors needs
further investigations.

Conclusions

This is the second study showing the Tramadols
impressive results in delaying ejaculation. While
our initial results are encouraging, more studies
are needed on larger scale with different drug
doses. Our demonstration of Tramadols on-
demand efcacy favors the off label use of this
drug in the treatment of PE instead of SSRI anti-
depressants. These preliminary data should stim-
ulate more investigative activity to elucidate its
exact mechanism of action. Furthermore, efcacy
and tolerability studies combining Tramadol with
lower doses of SSRIs and/or phosphodiesterase 5
inhibitors for treatment of PE might also be
enlightening.

Corresponding Author:

Emad Salem, MD, University
of Arkansas for Medical SciencesUrology, 4301 W
Markham, Little Rock, AR 72205, USA. Tel:
(

+

1) 501 686 5241; Fax: (

+

1) 501 686 5277; E-mail:
dr_emadsalem@yahoo.com

Conict of Interest:

Dr. Salem holds U.S. Patent applica-
tion number 60-759916. Steven K. Wilson is a consult-
ant, investigator, investor for AMS. John Delk is a
consultant, investigator for AMS. Wayne Hellstrom is
a lecturer and consultant for Auxilium; consultant, advi-
sor, lecturer, investigator, scientic study trial for AMS;
consultant, advisor, lecturer, scientic study trial for
Johnson & Johnson/OrthoUrology; consultant, advisor,
lecturer, investigator, scientic study for Lilly ICOS;
consultant, advisor, investigator for Mentor; lecturer,
scientic study trial for Pzer; consultant, advisor, lec-
turer, investigator for Sano-Aventis; consultant, advi-
sor, investigator for Vivus.
Treatment of Premature Ejaculation with Tramadol HCL

193

J Sex Med 2008;5:188193

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