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

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

Blackwell Publishing IncMalden, USAJSMJournal of Sexual Medicine1743-6095© 2007 International Society for Sexual Medicine200851188193Original ArticlesTreatment of Premature Ejaculation with Tramadol HCLSalem et al.
188
ORIGINAL RESEARCH—EJACULATORY 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
ABSTRACT
Introduction. Premature ejaculation (PE) is a worldwide problem without an approved treatment. Selective serotonin reuptake inhibitors (SSRIs) are widely used “off label” as pharmacotherapeutic agents in the treatment of PE.
Aim. This study investigates Tramadol efficacy for on-demand treatment of PE.
Main Outcomes Measures. Intravaginal ejaculation latency time (IELT) was used as an objective tool to assess the
efficacy 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 defined 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 1–2 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 significantly 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-inflammatory 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;5:188–193.
Key Words. Design; Methodology of Clinical Trials; Causes and Treatment of Ejaculatory/Orgasmic Disorders;
Premature Ejaculation
Introduction
P
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
J Sex Med 2008;5:188–193
(ED), affects men of all ages equally. However,
both PE and ED coexist, and often PE can masquerade 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 men’s quality of life, it is only
© 2006 International Society for Sexual Medicine
Treatment of Premature Ejaculation with Tramadol HCL
recently that attention has been focused on investigating the causes of PE and developing new therapeutic strategies.
A universally accepted definition of PE has yet
to be established. Various definitions of PE have
been used by different researchers, and include
partner satisfaction, male voluntary control, duration of ejaculatory latency, and number of intravaginal thrusts [4]. Kaplan first suggested that PE
was primarily a problem of voluntary control over
timing of ejaculation, a concept on which most of
the current definitions are based [5]. According to
The Diagnostic and Statistical Manual of Mental
Disorders , Fourth Edition (DSM-IV-TR®), PE is
defined as “persistent or recurrent ejaculation with
minimal sexual stimulation, and before the subject
wishes it” and is associated with “marked distress
or interpersonal difficulty” [6]. The American
Urological Association Guideline on Premature
Ejaculation defines 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 classified as
either primary (lifelong) that begins when a
male first 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]. Primary PE is hypothesized to have a strong biological component with a variable psychological
contribution [9]. Although psychological or situational stressors may contribute to secondary
PE, certain medical conditions and medications
may also be associated. Another classification
invokes the terms “global” or “universal” (e.g.,
occurs regardless of situation or partner) or “situational” (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 ejaculation 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 first
introduced by Eaton in 1973 [12].
Tramadol [cis-2-[(dimethylamino) methyl]-1(3-methoxyphenyl) cyclohexanol] is a centrally
acting synthetic opioid analgesic with a Cmax of
300 µg/L after 100 mg single oral dose [13]. The
brand name in the United States is Ultram. It has
189
been prescribed for many years and its safety profile is acceptable. Tramadol’s mode of action is not
completely understood. From animal tests, at least
two complementary mechanisms appear applicable: binding of parent and M1 metabolite to
µ-opioid receptors (antinociceptive effect) and
inhibition of reuptake of norepinephrine and serotonin which may stand for its effect on delaying
ejaculation. Tramadol’s action on 5-HT1A and
5HT2C needs further investigations.
Safarinejad and Hosseini [14] recently published a double-blind, placebo-controlled, fixeddose study indicating that on-demand use of
50 mg Tramadol exerted a significant 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 advertisement and consented for participation. PE was
defined according to the DSM-IV-TR definition
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 International Index of Erectile Function [15]. All patients
had primary PE (lifelong PE since their first 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 conducted 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 8week trial, patients were instructed to stop treatment 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 1–2 hours before sexual activity and frequency of sexual intercourse episodes
was required to be at least once per week. IELT at
J Sex Med 2008;5:188–193
190
Salem et al.
each intercourse was reported by patients or partners. 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 specific 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 satisfied with your
control over ejaculation with the treatment?”, “Are
you satisfied with your sexual act with the treatment?” Patients were also asked about their tolerance to the drug and if there were any side effects.
Intravaginal ejaculation latency time improvement, defined 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 significant
treatment by period interaction in an analysis of
variance (ANOVA) framework. Because there was
no evidence of a significant carryover effect, the
Table 1
difference between IELT improvement under
Tramadol hydrochloride treatment and placebo
treatment (irrespective of the order of administration) 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 first 30 patients started with placebo, while the next 30 patients started with Tramadol (Table 1).
The baseline (mean ± SD) IELT for patients
before treatment was 1.17 ± 0.39 minutes (range
0.09–1.96), 1.22 ± 0.36 minutes (range 0.68–1.96)
for group 1 and 1.11 ± 0.42 minutes (range 0.09–
1.92) for group 2. At the end of treatment,
The baseline IELT before treatment, and with either treatment
Placebo then Tramadol (group 1)
Tramadol then placebo (group 2)
No.
Age (years)
Baseline
Placebo
Tramadol
Age (years)
Baseline
Tramadol
Placebo
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
32
54
26
35
39
22
45
42
38
37
46
23
26
51
29
30
31
40
57
28
32
36
29
30
62
41
31
25
27
38
0.82
0.77
0.98
1.23
1.65
0.99
1.12
0.78
1.66
1.42
1.85
1.69
1.01
1.03
0.97
0.68
0.99
1.01
1.03
1.25
1.96
1.78
1.38
1.09
1.63
1.08
1.07
1.65
1.32
0.79
1.45
1.99
2.06
2.88
2.05
2.44
2.05
1.88
3.08
1.98
2.03
2.05
1.86
1.56
2.05
2.33
1.86
1.99
1.56
2.07
4.02
2.06
2.33
2.13
1.89
1.53
1.09
1.96
2.05
2.06
7.35
12.32
6.32
8.56
9.02
7.06
11.02
5.01
4.65
9.05
8.23
3.87
9.88
12.06
11.01
5.63
7.63
6.98
6.52
3.85
5.32
8.02
6.08
7.98
6.98
5.12
7.65
10.88
4.09
8.25
31
24
51
43
37
38
29
26
35
36
51
42
32
42
29
38
32
26
38
27
40
41
32
39
29
48
46
37
28
31
0.88
1.87
0.96
0.98
1.92
1.03
1.05
1.06
1.25
1.18
1.19
1.17
1.35
1.65
1.09
1.54
0.86
0.89
1.09
1.08
1.55
0.66
1.03
1.02
0.22
0.09
0.53
1.65
1.08
1.44
12.35
2.68
6.03
6.87
7.09
3.86
5.63
7.33
4.03
5.68
13.08
8.26
6.32
8.91
6.18
6.77
10.96
11.36
6.33
7.66
6.88
9.86
4.98
5.08
3.02
4.8
6.01
11.85
7.32
8.53
1.09
2.05
1.08
1.15
1.56
2.98
1.35
1.86
2.06
1.98
3.18
2.66
1.86
2.42
1.18
2.86
0.91
1.08
1.86
4.35
1.68
2.98
1.89
1.65
0.19
1.98
0.88
1.99
2.86
2.53
IELT = intravaginal ejaculation latency time.
J Sex Med 2008;5:188–193
191
Treatment of Premature Ejaculation with Tramadol HCL
the mean IELT was increased significantly in
patients on Tramadol treatment to reach
7.37 ± 2.53 minutes (range 2.68–13.08) (Wilcoxon
matched-pairs signed-ranks test, P < 0.0001).
Patients on placebo showed mean IELT of
2.01 ± 0.71 minutes (range 0.19–4.35) (Table 1).
There was a 6.3-fold increase in IELT for Tramadol and 1.7-fold increase for placebo.
In total, 59 of 60 Patients (98%) who received
Tramadol reported significant (satisfactory) increases in their control over ejaculation from baseline and significant benefits 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 ejaculation was not satisfying for him with either treatment. 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 satisfied with their tolerance
to the treatment drugs (Tramadol and placebo).
However, eight patients (13.3%) reported the
experience of mild dyspepsia (5) and mild somnolence (3) with Tramadol. No serious side effects
were reported by any patient.
Intravaginal ejaculation latency time improvement was defined as the difference between IELT
at the end of each treatment period and baseline.
There was no evidence of a significant carryover
effect for IELT improvement (P = 0.6919). Therefore, whether patients received Tramadol hydrochloride treatment in the first 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 Tramadol hydrochloride was 5.14 minutes longer than
while they when taking the placebo. This difference was highly significant (Wilcoxon matchedpairs signed-ranks test, P < 0.0001) (Table 2).
Discussion
Over the past 20–30 years, clinical investigators
have participated in a growing number of controlled studies that are developing our basic
understanding about PE. The emergence of wellconducted clinical trials has given us knowledge of
the prevalence of PE, its etiology and pathophysiology, and additionally, its impact on patient and
partner quality of life.
There are currently no regulatory or Food and
Drug Administration (FDA)-approved pharmacological therapies for treating PE. Although SSRIs
are intended for chronic use in the treatment of
depression and are designed to have pharmacokinetic profiles that would allow them to provide
constant systemic concentration with long-term
administration, it takes about 2–3 weeks to reach
a maximum steady-state concentration in order to
exhibit efficacy [16]. Therefore, SSRIs are commonly 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 suggested that on-demand treatment with SSRIs possessing 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 Tmax and short T / on 5-HT neurotransmission [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
efficacy for the on-demand use. A double-blind,
1
2
Table 2 Median and mean improvement from baseline intravaginal ejaculation latency time (IELT) by treatment and
sequence
Treatment
Placebo
Tramadol
Treatment sequence
Median
Mean (SD)
Median
Mean(SD)
P value
Placebo then Tramadol (N = 30)
Tramadol then placebo (N = 30)
Overall* (N = 60)
0.86
0.70
0.79
0.86 (0.49)
0.83 (0.84)
0.84 (0.68)
6.31
5.28
5.93
6.32 (2.47)
6.08 (2.69)
6.20 (2.57)
<0.0001†
<0.0001†
<0.0001‡
*Overall effect ignoring treatment sequence.
†
Two-sample Wilcoxon-Mann–Whitney rank-sum test.
‡
Wilcoxon matched-pairs signed-ranks test.
J Sex Med 2008;5:188–193
192
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 dapoxetine, 3.20 minutes with 100 mg dapoxetine, vs.
2.05 minutes with placebo. In this study, patients
reported a small, statistically significant increase in
their control over ejaculation and expressed benefits in their sexual satisfaction. Although this study
and other research demonstrated potentially encouraging 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 ejaculation or anejaculation inspired the use of Tramadol
empirically since 2000 in patients with PE. The
second factor was the available data about serotonin syndrome with over dosage of Tramadol, or
combination treatment with Tramadol and SSRIs
[19]. Recently, in February 2006, Safarinejad and
Hosseini [14] published the first study on the ondemand use of 50 mg Tramadol to treat PE showing a significant 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 Tramadol compared with 1.7-fold increase with placebo, 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 satisfaction 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 specific validated questionnaire for PE, we used IELT as an objective method
for follow-up. In addition, patients were specifically asked about their control over ejaculation and
their satisfaction with the sexual act. A valid criticism 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 shortcoming was there was no questionnaire that
addressed PE specifically as a cause of sexual
dysfunction.
J Sex Med 2008;5:188–193
Salem et al.
Despite recent and current clinical investigations studying on-demand use of newer SSRI
drugs such as dapoxetine, Waldinger et al. [20] has
consistently reported that on-demand SSRI treatment (1–2 hours prior to coitus) is seriously limited because of counter-regulatory processes of
normal serotonergic neurotransmission. In a similar, more recent study, Waldinger concluded that
on-demand SSRI treatment has only a slight ejaculation-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 Tramadol’s
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 Tramadol’s ondemand efficacy favors the “off label” use of this
drug in the treatment of PE instead of SSRI antidepressants. These preliminary data should stimulate more investigative activity to elucidate its
exact mechanism of action. Furthermore, efficacy
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 Sciences—Urology, 4301 W
Markham, Little Rock, AR 72205, USA. Tel:
(+1) 501 686 5241; Fax: (+1) 501 686 5277; E-mail:
[email protected]
Conflict of Interest: Dr. Salem holds U.S. Patent application number 60-759916. Steven K. Wilson is a consultant, investigator, investor for AMS. John Delk is a
consultant, investigator for AMS. Wayne Hellstrom is
a lecturer and consultant for Auxilium; consultant, advisor, lecturer, investigator, scientific study trial for AMS;
consultant, advisor, lecturer, scientific study trial for
Johnson & Johnson/OrthoUrology; consultant, advisor,
lecturer, investigator, scientific study for Lilly ICOS;
consultant, advisor, investigator for Mentor; lecturer,
scientific study trial for Pfizer; consultant, advisor, lecturer, investigator for Sanofi-Aventis; consultant, advisor, investigator for Vivus.
Treatment of Premature Ejaculation with Tramadol HCL
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