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A Rational Combination Pharmacotherapy in Men with Erectile
Dysfunction who Initially Failed to Oral Sildenafil Citrate Alone:
A Pilot Study
Pushpawati Singhania Research Institute—Surgical Division, New Delhi, India
A B S T R A C T
Erectile dysfunction (ED) is a complex condition wherein men with minimal organic ED may develop
a variable degree of psychogenic component sufﬁcient to reduce the efﬁcacy of medical management. A combination
of trazodone with sildenaﬁl has been used to overcome both organic as well as psychogenic components, thus
improving the results of medical management.Aim.
To evaluate the efﬁcacy of combination of trazodone with sildenaﬁl citrate in treatment of ED in men with
initial failure to sildenaﬁl citrate alone.Main Outcome Measures.
The symptoms of ED were evaluated using the Erectile Dysfunction Intensity Scale
(EDIS) before and after the treatment.Methods.
Eighteen men with ED who initially failed to respond to sildenaﬁl citrate alone were enrolled in the study
between February 2004 and December 2004. All these men were given a priming dose of trazodone for a 2-week
period before giving them sildenaﬁl citrate.Results.
Of the 18 men, 12 responded favorably to the above treatment and continued to enjoy good sexual activity
while on trazodone and sildenaﬁl. The score on EDIS improved considerably in 12 (66.7%) men, marginally in two
(11.1%) men, and did not improve at all in four (22.2%) men.Conclusions.
Priming the patients with trazodone appears to be a reasonably good alternative in patients who have
initial failure to oral sildenaﬁl citrate and have been found to have no organic cause of ED. However, large
double-blind studies are required to potentiate this hypothesis. Taneja R. A rational combination pharmaco-
therapy in men with erectile dysfunction who initially failed to oral sildenafil citrate alone: A pilot study.
J Sex Med 2007;4:1136–1141.
Erectile Dysfunction; Sildenaﬁl Failure; Combination Pharmacotherapy
various researchers have been inadequate patientinformation, suboptimal dose, and insufﬁcient
E ver since sildenaﬁl citrate has been approved number of attempts [2,3]. In addition to these
by the U.S. Food and Drug Administration to
factors, performance anxiety, depression, and
be used in patients with erectile dysfunction (ED),
partner-related factors might have adverse effects
men have come forward openly seeking help
on the ﬁnal outcome of sildenaﬁl therapy. It has
regarding this hitherto “private” problem. The
been shown that although vascular and endocrine
high response rate approaching 70% of sildenaﬁl
causes of ED are more common in elderly age
when used alone in ED has inﬂuenced the algo-
groups, depression, marital discord, and perfor-
rithm of treatment of this condition . However,
mance anxiety occur more frequently in younger
this also means that almost 30% of men who are
age groups . The documented improvement in
administered this drug do not beneﬁt from it
nocturnal penile tumescence with oral sildenaﬁl in
adequately. The causes of failure, as studied by
men who have initial clinical failure of the same
2007 International Society for Sexual Medicine
Erectile Dysfunction and Sildenafil Failure
Psychological impact of poor
drug emphasizes the role of performance anxiety
drowsiness as a major side effect that limits its
as a deterrent to the clinical success . The rela-
routine use in cases of ED . The dose of traz-
tionship of psychological factors with ED is a
odone used in this study is signiﬁcantly lower than
complex one. While failure to have successful
the standard recommendation for use as a single
intercourse leads to depression, the same may in
agent in cases of ED in order to reduce the side
turn be responsible for poor sexual performance
effects while utilizing its antidepressant property.
(Figure 1). Hence, it is worthwhile to break this
The combination of trazodone and sildenaﬁl has
cycle by intervening at multiple levels.
not been licensed for use in general practice as of
Keeping this in view, we designed this protocol
for treatment of men with ED who had failures withinitial treatment by sildenaﬁl. Apart from educating
the couples, men were administered a priming doseof trazodone. All antidepressants except for traz-
The present study is an endeavor to combine the
odone have an inherent depressive effect on erectile
advantages of the two oral agents to overcome the
function via sympathetic nervous stimulation. Tra-
failure of treatment with sildenaﬁl alone.
zodone is a sedating anxiolytic antidepressant witha speciﬁc side effect of altering the penile blood
ﬂow in a peculiar, incompletely understood mannerwhich is likely to be related to its antagonistic effect
All men who had initial therapeutic failure with
on alpha adrenergic receptors . This has been
sildenaﬁl and were referred to our tertiary care
held responsible for priapism encountered in some
center for treatment of ED between February 2004
of the men taking trazodone over long periods of
and December 2004 were investigated to exclude
time. Trazodone has been studied as a single oral
other treatable causes of ED. The overall exclusion
agent for treatment of ED with variable results. In
criteria have been listed in Table 1. Eighteen men
addition to the peripheral action on penile blood
were found suitable for inclusion into the study. All
ﬂow, trazodone is also known to enhance the libido
these men had followed appropriate instructions
through its effect on brain. However, the dose at
regarding medication, tolerated sildenaﬁl citrate
which trazodone alone has been shown to be useful
well in the dose of 100 mg, and had at least four
is rather high, more than 200 mg per day, with
unsuccessful attempts before being labeled as
1. Active coronary heart disease2. Continuing nitrate therapy3. Cavernous artery insufficiency as documented by color Doppler study following intracavernosal injection of vasoactive substance4. Neurogenic factors such as history of radical prostatectomy or any other known factor affecting neural integrity. Neurological deficits
were excluded by detailed clinical examination
5. Obvious severe mental instability so as to require immediate psychiatric help6. Presence of factors which may adversely affect pharmacodynamics of sildenafil e.g., chronic renal insufficiency, concomitant use of
7. Penile fibrosis8. Retinitis pigmentosa9. Hypogonadism
sexual stimulation, how often wereyour erections hard enough forpenetration (entering your partner)?
how often were you able topenetrate (enter your partner)?
often were you able to maintainyour erection after you hadpenetrated (entered) your partner?
difficult was it to maintain yourerection to completion of intercourse?
Adapted from erectile dysfunction (ED) intensity and impact scales, recommendation of the first international consultation on ED, Paris, 1999, as in Campbell’sUrology, Eighth Edition .
sildenaﬁl failures . After informed consent was
trazodone. All the men were then asked to continue
obtained, the participants were administered a
trazodone as 100 mg once a day and in addition
questionnaire to record their symptoms, duration,
were given four doses of 100-mg sildenaﬁl and
and existing comorbidities if any. The symptoms
advised to report after an additional period of
were evaluated using the Erectile Dysfunction
2 weeks. They were also allowed to take an addi-
Intensity Scale (EDIS)  before and after the
tional dose of sildenaﬁl after telephonic discussion,
should such a need arise. At the end of this 2-week
The Erectile Dysfunction Intensity Scale has not
period, their symptoms were evaluated again using
been reported widely in the literature even though
it was recommended by the ﬁrst international con-sultation on ED in 1999. If examined closely, this
consists of the ﬁrst ﬁve questions of the IIEF15,which pertain directly to erectile function.
All the 18 men were available for compilation of
All these men were interviewed on the day of
data. The mean age of the patients enrolled was
induction and on day 14. During the initial consul-
39.83 years (range 22–72 years). The duration of
tation, they were explained the importance of
symptoms ranged from 2 months to 48 months
appropriate timing of sildenaﬁl in reference to food
(mean 14.61 months). The coexisting medical dis-
and sexual activity. They were also encouraged to
orders included diabetes mellitus in three patients,
come forward with their own queries if any regard-
hypertension in three and bronchial asthma in one
ing the reasons for initial failure of sildenaﬁl. An
attempt was made to reassure and explain to the
The only side effects reported were sedation in
participants in simple language the basis of combi-
eight (44.4%), dizziness in three (16.6%), and
nation pharmacoatherapy. The supportive role of
fatigue in one (5.5%) cases. These were never so
the female partner was also emphasized wherever
severe as to warrant discontinuation of treatment.
possible. All men were advised to take trazodone
The analysis of EDIS feedback prior to the treat-
tablets at bed time, 50 mg for ﬁrst three nights
ment revealed the total score to be a minimal 5/25
followed by 100 mg for rest of the 11 nights; they
in 11 (61.1%) patients, 6/25 in ﬁve (27.7%) cases,
were warned about the possibility of drowsiness
and 7/25 in two (11.1%) cases. At the end of
following medication and were asked to contact the
4 weeks, the score improved considerably in 12
investigator in case of any complaints. The patients
(66.6%) patients, ranging between 14 and 21.
were asked to report after 2 weeks. During the
Couples in this group had successful intercourse
second consultation, patients were asked about the
more than once during the 2-week period following
side effects, if any, as experienced following oral
the second counseling session. Four of these men
Erectile Dysfunction and Sildenafil Failure
asked by telephone for more doses of sildenaﬁl for
are a substantial number of such patients, almost
30% of the total number, who have an initially
However, the total EDIS score improved mar-
poor response to sildenaﬁl alone leading to dis-
ginally in two (11.1%) cases and became 9/25.
couragement and an adverse impact on their
These two men reported deﬁnite improvement in
psyche . Patient education regarding sildenaﬁl
the quality of erections, which were ill-sustained.
usage alone has been shown to salvage around
Though their erections were sufﬁcient enough
40–58% of initial sildenaﬁl failures [1,9].
for penetration, they could not achieve orgasm
because of early detumescence. In four (22.2%)
research in the pharmacotherapeutic development
cases, it did not change at all and remained at the
of various oral agents for safe and effective treat-
ment of ED . In search of improvement in theclinical results of sildenaﬁl, various combinationshave been reported. Testosterone supplements in
late onset hypogonadal men have been used to
Sildenaﬁl has become the ﬁrst-line treatment for
improve the clinical outcome of treatment of ED
ED as used by primary care physicians . There
with sildenaﬁl . Another study has shown that
Erectile Dysfunction Inten-
sity Scale (EDIS) score before andafter treatment.
the female partners. None of the patients neededto discontinue the treatment because of theminimal side effects which were encounteredduring the study.
An inverse relationship has been found between
the duration of symptoms and response to treat-
ment as illustrated by cases 4, 6, 10, 15. All these
patients were much older than the mean age ofthe study group, i.e., 55, 48, 60, and 58 yearsagainst mean 39.83 years. The longer durationof symptoms i.e., 48, 12, 24, and 42 months also
Overall improvement in erectile function.
points toward some form of organic/endothelialdefect. If one is inclined to consider psychogenic
the addition of atorvastatin improves the efﬁcacy
factors in this group, then it might be assumed that
of sildenaﬁl in treatment of ED .
the repeated inability to perform over a long
The present study has indicated encouraging
period of time might have had a deep impact on
results of a combination pharmacotherapy proto-
their psyche, resulting in lack of conﬁdence in
col to improve the overall results of treatment of
addition to underlying organic condition, if any.
patients with ED in cases of initial failures
Lance et al. have reported similar observations in
(Figure 3). Patient education regarding proper
another study. They have found that the duration
dosing schedule, adequate number of attempts, the
of ED was inversely related to the response to
need for sexual stimulation, and realistic expecta-
tions go a long way in improving the efﬁcacy of
Encouraged by the results of this study, one
may be inclined to use the above combination in
The mean age of the present cohort is very
selected de novo cases of ED as primary therapy
young as compared with the standard ED popula-
especially in men with signiﬁcant anxiety at the
tion as documented in other series. This is perhaps
because in India young men have a lot of perfor-
In rural Indian society, where much misguiding
mance anxiety, as they are amenable to suggestion
cheap literature is the prime source of sex educa-
by cheap and misguiding literature, which is freely
tion, many unscientiﬁc myths prevail that are de-
available while authentic sex education is scanty.
trimental to the sexual health of young men. Many
Sociodemographic conditions have been docu-
such young men develop performance anxiety and
mented to be risk factors in a study of epidemiol-
seek medical help. Simply prescribing sildenaﬁl to
such individuals is expected to result in higher
The exact role and the extent of contribution of
failure rates. Appropriate use of combination phar-
trazodone is difﬁcult to assess. It may, however, be
macotherapy in such situations may be rewarding.
presumed that the antidepressant action of traz-odone along with its complex effect on penilehemodynamics has a bearing on the overall result
by breaking the vicious cycle as follows:
Combining trazodone with sildenaﬁl has been
shown to have encouraging initial results in cases
performance anxiety→Poor performance.
of primary sildenaﬁl failures with no organic
It may be appreciated that in order to conclu-
cause of ED. However, larger, preferably placebo-
sively prove this hypothesis, a large-scale, random-
controlled studies are required to conclusively
ized, double-blind, placebo-controlled study is
prove the efﬁcacy and advantage of this combina-
required. The delicate and highly vulnerable psy-
chological state of these individuals may make thiskind of study difﬁcult to be carried out by further
Rajesh Taneja, MS (General
Surgery), MCh (Urology), Surgical Division, Pushpa-
In the present series, use of trazodone and
wati Singhania Research Institute, Press Enclave Road,
sildenaﬁl has been shown to convert initial non-
Sheikh Sarai, Phase II, New Delhi-110017, India. Tel:
responders to successful responders in almost
(+91) 11 29252516; Fax: (+91) 11 29250548; E-mail:
67% of cases. However, no separate attempt was
made to quantify the amount of satisfaction of
Conﬂict of Interest:
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