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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
Introduction. 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.

Key Words. 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 [1]. However, mance anxiety occur more frequently in younger this also means that almost 30% of men who are age groups [4]. 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 performance
Figure 1 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 [5]. The rela- routine use in cases of ED [7]. 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 [6]. 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 [8].
sildenafil failures [1]. 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) [8] 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 [10]. 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 [11]. In search of improvement in theclinical results of sildenafil, various combinationshave been reported. Testosterone supplements in Discussion
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 [9]. There with sildenafil [12]. Another study has shown that EDIS score
Figure 2 Erectile Dysfunction Inten-
sity Scale (EDIS) score before andafter treatment.
Individual patients
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 Figure 3 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 [13].
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 Conclusions
by breaking the vicious cycle as follows: Combining trazodone with sildenafil has been Poor performance→Guilt→Depression→Pre- 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 Corresponding Author: 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: None declared.
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