Combination of Sertraline and Sildenafil versus Sertraline Monotherapy in the Treatment of Acquired Premature Ejaculation without Concomitant Diseases

Premature Ejaculation (PE) is one of the most common sexual dysfunctions, affecting 20%-40% of sexually active men [1-3]. There were various definitions of PE by different professional organizations [4,5]. However, since the underlying physiopathology of PE was not well understood, there were no universally accepted definition of PE until the International Society for Sexual Medicine (ISSM) established the first evidence-based definition of lifelong PE in 2007 [6]. Subsequently, Waldinger et al. proposed a new classification for PE in 2008, which included four subtypes: lifelong PE (LPE), acquired PE (APE), natural variable PE (NVPE), and Premature-Like Ejaculatory Dysfunction (PLED) [7,8].


Introduction
Premature Ejaculation (PE) is one of the most common sexual dysfunctions, affecting 20%-40% of sexually active men [1][2][3]. There were various definitions of PE by different professional organizations [4,5]. However, since the underlying physiopathology of PE was not well understood, there were no universally accepted definition of PE until the International Society for Sexual Medicine (ISSM) established the first evidence-based definition of lifelong PE in 2007 [6]. Subsequently, Waldinger et al. proposed a new classification for PE in 2008, which included four subtypes: lifelong PE (LPE), acquired PE (APE), natural variable PE (NVPE), and Premature-Like Ejaculatory Dysfunction (PLED) [7,8].
In recent years, although a lot of therapies have been proved to be efficacious in the treatment of PE, most research has focused on the treatment of LPE, or ignored the different types of PE [9,10]. There are few studies concerning the treatment of APE, although Serefoglu et al. revealed that APE was more severe than other subtypes [11]. To our knowledge, this is the first randomised trial to show sertraline monotherapy and a combination of sildenafil and sertraline in the treatment of APE in patients without concomitant diseases. Therefore, we conducted this clinical study to evaluate the efficacy of 50 mg sertraline daily and a combination of 50 mg sildenafil as needed and 50 mg sertraline daily in the treatment of APE in patients without concomitant diseases.

Subjects
Patients from outpatient clinics of the First Affiliated Hospital of Anhui Medical University in Hefei, Anhui, China who complained of APE but without concomitant diseases were recruited from May 2012 until April 2013. One hundred and twenty heterosexual consecutive men were enrolled in the study, as well as their partners. All patients were informed of the possible side-effects and provided informed consent before their participation in this study. Also, the study was approved by the local medical ethics committee. And it was registered in the Chinese Clinical Trial Registry.
APE was defined as IELT of less than 2 minutes, but with normal ejaculation experiences before, with onset either sudden or gradual.
The dysfunction might be a result of urological dysfunction, thyroid dysfunction, psychological or relationship problems, and the patient's lack of the ability to delay ejaculation, as Waldinger et al. proposed [7]. In this study, only subjects with APE but without concomitant diseases were enrolled.
A thorough medical history was taken, and biochemical, haematological, and endocrine testing, and physical examination were performed for each patient. To be included in the study, other criteria needed to be met: (1) male patient aged ≥ 18 years; (2) in a heterosexual, stable, and monogamous sexual relationship with the same female partner for >6 months, and possible sexual attempts of once a week or more; (3) without any concomitant diseases, such as prostatic inflammation, Erectile Dysfunction (ED), psychological diseases, hyperthyroidism, diabetes, etc. (4) with an International Index of Erectile Function-5 (IIEF-5) score ≥ 22, indicating normal erectile function; (5) without known hypersensitivity to Selective Serotonin Reuptake Inhibitors (SSRIs) or concomitant use of SSRIs, tricyclic antidepressants, or other medications during the study. Patients with previous therapies of PE, including psychological or medical, were excluded from the study. During the study, the patients were not allowed to use condoms, topical anaesthetic, or any behaviour therapy, such as the stop-start technique or the squeeze technique.

Study design and procedure
Patients were randomly divided into two groups according to the sequence of visit. The men in group A were treated with 50 mg sertraline daily at 16:00, and the subjects in group B were treated with sertraline 50 mg daily at 16:00 as well as 50 mg sildenafil 30 minutes before the desired sexual intercourse during an 8-week period. The previous self-estimated IELT and PEP at baseline of each group were recorded during a 2-week period before their participation in the study. The same outcomes were assessed for each participant after 4-week and 8-week periods of treatment, as well as the CGIC and adverse effects of the drugs. According to Kaufman et al., all efficacy analyses were conducted based on the Modified Intent-To-Treat (MITT) population. Patients who took one or more doses of study medication and answered the PEP and CGIC questions at baseline and at one or more sample times after baseline were included in calculating the MITT population [12].
Patient or partner reports of IELT, PEP, and CGIC were used to assess the efficacy of the two therapies and TEAEs were used to assess the safety in this study.

Main outcome measures
IELT: IELT was the interval between the start of vaginal intromission and the start of intravaginal ejaculation. And patient or partner reports of ejaculatory latency was used as a measure of IELT in this study, since studies have indicated that patient or partner self-report of ejaculatory latency correlate relatively well with objective stopwatch latency and might be useful as a proxy measure of IELT [13,14]. Furthermore, it was stipulated that only the first would be noted if intercourse occurred more than once in a single session.
PEP: PEP included perceived control over ejaculation, personal distress and interpersonal difficulty related to ejaculation, as well as satisfaction with sexual intercourse. Each measure was assessed on fivepoint scales. For perceived control over ejaculation and satisfaction with sexual intercourse, the scales ranged from 0=Very poor, 1=Poor, 2=Fair, 3=Good, and 4=Very good. For personal distress and interpersonal difficulty, the scales range from 0=Extreme, 1=Quite a bit, 2= Moderate, 3=A little bit, and 4=Not at all. The PEP index score was the mean of all four measures [15]. A composite Patient-Reported Outcome (PRO) definition of clinical benefit was defined as patients who reported at least a two-category increase in perceived control over ejaculation and at least a one-category increase in personal distress related to ejaculation from baseline to study endpoint [16,17].
CGIC: CGIC was a single-item measure assessed by asking patients about improvement or worsening of PE compared with the start of the study. It was evaluated on a seven-point scale: much worse, worse, slightly worse, no change, slightly better, better, or much better [18].
TEAEs: Safety of the two therapies was assessed by recording TEAEs, such as nausea, headache, dizziness, sexual desire difficulties, ED, flushing, etc., including the incidence, severity, type, etc.

Statistical analysis
Statistical analysis was performed using SPSS 13.0 software (SPSS Inc., Chicago, USA). For the quantitative data, results are expressed as mean ± Standard Deviation (SD) and a two-tailed unpaired Student t test was used. The comparison of proportions was performed by the chi-square test or Kruskal-Wallis Test. All statistical analysis was twosided, and a P value of <0.05 was considered statistically significant.

Subject disposition
A total of 168 patients were screened, and 120 patients meeting the criteria were randomised; 108 (90%) subjects receiving at least one dose of study drug were included in the MITT population, including 53 subjects treated with sertraline 50 mg daily and 55 subjects treated with sertraline 50 mg daily and 50 mg sildenafil as needed. One hundred and three patients successfully completed the 8-week treatment period ( Figure 1). Among the 48 subjects who failed the screening, over half were related to ED or prostatitis. Nobody withdrew from this study due to the lack of efficacy and TEAEs. Baseline demographic information and clinical characteristics for the study population in the two groups are shown in Table 1. There were no significant differences in the demographic information and clinical characteristics at baseline between the two groups.
Concerning on the effectiveness of the two therapies, our study showed that both groups had significant improvements in IELT and PEP measures compared with pretreatment (P<0.001). And group B had significantly greater values of IELT (7.20 ± 2.93 vs. 5.04 ± 2.79), PEP measures, and CGIC compared to Group A (P<0.05 for all). With regard to the safe of treatments, adverse effects including headache, flushing, etc. were found in both groups, and the total incidence was higher in group B than group A (31.7% vs. 23.3%, respectively), but the difference was not significant.

IELT
The average self-estimated IELT is shown in Table 2. The mean ± SD self-estimated IELT values were 1.36 ± 0.53 and 1.47 ± 0.52 minutes in the sertraline group and combination treatment groups at baseline, respectively. After the 8-week treatment period, significant improvements in mean self-estimated IELT from 1.36 ± 0.53 to 5.04 ± 2.79 minutes in the sertraline group and from 1.47 ± 0.52 to 7.20 ± 2.93 minutes in the combination group were observed (P<0.001 for both). In addition, the increases were significantly greater in self-estimated IELT in the combination treatment group than in the sertraline group (P<0.01). Table 2 also shows the significantly greater scores observed in all four PEP measures in both of the two groups after 8-week treatment (P<0.001 for all items). Also, the scores were significantly higher concerning personal distress related to ejaculation, satisfaction with intercourse, and interpersonal difficulty related to ejaculation in the combination treatment group than in the sertraline group (P<0.05). For perceived control over ejaculation, the mean score of the combination group (2.55 ± 0.60) was higher compared with the sertraline group (2.34 ± 0.71), but the difference was not significant. In addition, the PEP index score was significantly higher in the combination treatment group (2.49 ± 0.53) compared with the sertraline group (2.83 ± 0.47, P<0.01).

PEP measures
The percentage of subjects achieving one-category or greater improvement in perceived control over ejaculation, personal distress related to ejaculation, satisfaction with intercourse, and interpersonal difficulty related to ejaculation was 73.6%, 56.6%, 66.0%, and 52.8%, respectively, in the sertraline treatment group and 72.4%, 60.0%, 90.9%, and 63.6%, respectively in the combination treatment group ( Table 2). The only significant difference between the two groups was observed in satisfaction with intercourse (P<0.01). All improvements in PEP measures are shown in Figure 2.  Percentages may not sum to 100% due to rounding

Treatment benefit and CGIC
At study end, a significantly greater percentage of subjects achieved the composite PRO-defined level of clinical benefit with the combination of sertraline and sildenafil (34.5%) versus sertraline monotherapy (15.1%, P<0.05). At the same time, the combination treatment group also achieved a significantly greater percentage of CGIC rating of at least 'better' (58.2%) versus the sertraline group (35.8%, P<0.05). The percentages of CGIC rating in the two groups are shown in Figure 3.

Safety
In general, TEAEs were reported by 23.3% in the sertraline group and 31.7% in the combination group. The adverse effects included nausea, headache, dizziness, flushing, ED, sexual desire difficulties, etc. There were no significant differences between the two groups concerning TEAEs (Table 3). On the other hand, all the adverse effects that occurred in this study were mild and tolerated, and gradually disappeared with continued treatment. Nobody in our study dropped out due to side-effects.

Discussion
Due to the absence of causal therapy for PE that target the aetiology, there are no US Food and Drug Administration (FDA) approved treatments for PE, and a lot of treatment options for PE have been used, consisting of behavioural therapies, psychotherapy, topical anaesthetic creams, oral pharmacotherapy, etc.
Among oral pharmacotherapies, SSRIs were considered as the first choice of treatment for PE [19] Figure 3: Clinical Global Impression of Change (CGIC): Percentages of subjects reporting "no change", "slightly better", "better", or "much better".
significant improvement was seen in both groups in terms of the index of premature ejaculation questionnaire results [20]. Arafa et al. report a large prospective placebo-controlled crossover study of sertraline in premature ejaculation. In this study, 127 (81%) of 157 subjects experienced a significant increase in their Arabic Index of Premature Ejaculation (AIPE) total score after sertraline treatment [21]. Our results also showed that sertraline led to a statistically significant improvement in all measured parameters in patients with APE compared with baseline, which suggested that sertraline was efficacious not only for LPE, but also for APE in patients without concomitant diseases. The main mechanism of SSRIs in the treatment of PE might be due to increased serotonergic neurotransmission and activation of the 5-HT2C receptor, and adjustment of the threshold to a higher level, thereby leading to a delayed ejaculation. In addition, SSRIs act as an antidepressant, with effects on depression and anxiety, which might contribute to the treatment of PE [22]. Besides, SSRIs might increase the penile sensory threshold and reduce penile hypersensitivity, according to the study of Yilmaz et al. [23].
A great deal of previous studies indicated that sertraline was efficacious and safe in the management of PE. On the other hand, some research suggested that phosphodiesterase type 5 (PDE-5) inhibitors such as sildenafil also had efficacy in the treatment of PE [9,[24][25][26]. Hosseini et al. chose 91 patients with PE who were given 20 mg fluoxetine daily or plus 50 mg sildenafil as needed [26]. IELT were significantly improved in patients treated with combination therapy of fluoxetine plus sildenafil compared with patients taking fluoxetine only. Wang et al. carried out a prospective clinical study in 180 patients with primary PE [9]. Compared with 20 mg paroxetine daily, the squeeze technique, and pretreatment, after 3 or 6 months, patients taking 50 mg sildenafil as needed had significant increases in IELT and intercourse satisfactory score. The results of our study indicated that compared with sertraline monotherapy, combined use of sertraline and sildenafil resulted in statistically significant increases in IELT and PEP measures of APE patients without concomitant diseases. These results are similar to those of previous studies in LPE. The efficacy of sildenafil, a PDE-5 inhibitor, has been suggested to be due to central and peripheral mechanisms. Possible peripheral mechanisms include: 1) decrease of the contractile response of the vas deferens, seminal vesicles, and urethra; 2) alleviation of penile hypersensitivity by inducing peripheral analgesia via activation of the NO/cGMP signalling pathway; 3) prolongation of the total duration of erection. Possible central mechanisms include: 1) a potential role in the central nervous system NO/cGMP pathway in  ejaculatory function; and 2) decrease of the central sympathetic output to the periphery [27].
Combined therapy of sertraline and sildenafil was demonstrated to be efficacious in the treatment of APE in patients without concomitant diseases in our study. However, it must be admitted that the use of SSRIs or PDE-5 inhibitors has some adverse effects, such as sexual desire difficulties, delayed ejaculation, an ejaculation, absent or delayed orgasm, headache, nausea, dyspepsia, flushing, etc. [28,29]. In our study, some of the patients reported side-effects of nausea, dizziness, etc., and the incidence rate was higher in the combination treatment group than the monotherapy group. However, these side-effects were all mild and tolerated, and gradually disappeared with continued treatment. None of the patients in our study dropped out because of side-effects.
Some limitations and shortcomings of our study should be taken into consideration. Firstly, it was not a placebo-controlled study, so we could not eliminate the effect of placebo. Secondly, this study was a randomised, open-label trial. Although the selection of therapy for patients was randomised, a source of potential bias in the current trial was the lack of double blinding. Thirdly, we used PRO clinical benefit to assess the treatment outcomes which was defined as patients who reported at least a two-category increase in perceived control over ejaculation and at least a one-category increase in personal distress related to ejaculation. However, it was not validated by proper validation studies, Although McMahon et al. used the same approach [16,17]. Fourthly, we used patient or partner reports of IELT to assess mean IELT and not the geometric mean of IELT measured by a stopwatch, which might have had an effect on the results. Fifthly, we chose only subjects with APE but without concomitant diseases, and a further study to evaluate the efficacy and safety of these two therapies should be conducted in patients with comorbidities, since patients with APE are likely to have comorbidities. Besides, only 120 subjects were enrolled into our study and only followed up for 8 weeks, a larger patient sample, long-term follow-up and a placebo-controlled study in men with APE are needed to confirm our results.

Conclusions
Overall, both daily sertraline monotherapy and a combination of on-demand sildenafil and daily sertraline led to significant increases in IELT and PEP measures of APE in patients without concomitant diseases. Although some adverse side-effects were found, they were all tolerated, slight, and gradually disappeared with continued treatment. Both therapies were effective and safe, and the combination therapy had a much higher efficacy than sertraline monotherapy in the treatment of APE. To determine which therapy is the best one in the treatment of APE, a double-blind, placebo-controlled, and multicentre trial with a large number of patients should be performed in future.