Introduction

Premature ejaculation (PE) is considered to be the commonest male sexual disorder, affecting 20% to 66% of sexually active men [1,2,3,4]. Several definitions had described PE in the last few decades [1]. The international society for sexual medicine (ISSM) in 2014 had unanimously agreed that the items necessary to define PE are time from penetration to ejaculation, inability to delay ejaculation and negative personal consequences from PE [5]. The ISSM committee also agreed that ≤ 1 min IELT cutoff point should be considered for lifelong premature ejaculation (LPE), while reduced IELT to 3 min or less after a period of normal experience should be considered for acquired (secondary) premature ejaculation (APE) [5]. PE is mainly classified as lifelong (primary) (LPE) or acquired (secondary) (APE) [6]. Such classification was originally suggested by Waldinger & Schweitzer (2006) who proposed a new evidence based definition for PE through utilizing DSM-V and ICD 11 [7]. The exact aetiology of PE is unknown, with little data to support suggested biological and psychological hypotheses, including affective, cognitive, inter-personal or developmental psychological factors, penile hypersensitivity, prostatic congestion, chronic prostatitis and 5 hydroxytryptamine (5-HT) and dopamine receptor dysfunction [8]. However, Waldinger et al (1998) confirmed a genetic component for LPE [9]. Hormones might also play a role in the atieopathogensis of PE [6]. Additionally, some urological conditions might contribute to PE including prostatitis that causes APE [10, 11]. Interestingly, varicocele had been postulated to cause PE [12]. Duloxetine hydrochloride is an antidepressant included in the pharmacological class of serotonin (5-HT)-norepinephrine (NE) reuptake inhibitors (SNRIs) [13].

Pharmacokinetic and pharmacodynamic data of duloxetine had been reported for several studies, whose evidence suggested that duloxetine was generally well-tolerated [14]. However, duloxetine increases both levels of serotonin and norepinephrine which are directly correlated with adverse events including tachycardia and hypertension [15]. Hitherto, duloxetine is used as an off label therapy for PE. However, few studies showed that daily dose of duloxetine was an effective treatment option with very few adverse events in PE patients [16, 17]. Besides, a very recent study in China had demonstrated that dapoxetine was associated with a very high rate of discontinuation as results of over expectation of efficacy and high cost [18]. Henceforth, we aimed in the current study to assert the efficacy and safety profile of daily intake of 30 mg duloxetine in treating LPE patients and APE patients.

Patients and methods

The current randomized clinical trial assessed (150) patients for eligibility criteria with 50 patients excluded and 32 dropped out patients during the follow up period (Fig. 1). Finally, 68 patients having LPE and APE continued the study. The study was conducted in andrology outpatient clinic at Kasr Al-Ainy hospital from May 2022 to December 2022. The institutional review board had approved the work (MS-48–2022) that conforms to Helsiniki declaration (2013) [19]. All participants signed an informed consent prior to enrollment and were randomized by numbering method. The current study complied with the guidelines for reporting randomized parallel clinical trials (Fig. 1) [20].

Fig. 1
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Shows a CONSORT flow chart diagram that represents the methodology of the study

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Inclusion criteria of the patients

Male patients aged 25 to 45 years old, suffered from PE (primary or secondary) with stable and committed relationship having IELT < 3 min or less were included.

Exclusion criteria of the patients

Patients with erectile dysfunction (ED), reduced sexual desire or inhibited male orgasm or active genitourinary tract infection (confirmed by two glasses of urine and expressed prostatic secretions) or known mental disorders (depression, anxiety, schizophrenia) or uncontrolled physical illnesses (hepatic, renal, cardiac, neurological, endocrinal) were excluded from the study. Finally, any alcohol or drug abuser or patient with known hypersensitivity to duloxetine was excluded from the study.

Personal and past histories were taken from the participants. General and local examinations were done for all participants. Then patients were divided into two groups. Group (A) patients with LPE and APE received duloxetine 30 mg daily over a period of one month followed by every other day for another month as tapering then stop medication for 2 months as washout period followed by placebo intake (starch granules) daily for 1 month then tapered for another month in the same way as duloxetine. Duloxetine was prescribed after breakfast for all cases. However, cases who suffered from dizziness were advised to intake it after dinner. Group (B) patients with LPE and APE received placebo (starch granules) daily over a period of one month then every other day for another month as tapering then stop placebo for 2 months as wash out period followed by duloxetine 30 mg daily for 1 month then tapered for another month in the same way as previously mentioned.

Also, the validated Arabic version of the International index of erectile function (IIEF-5) was used initially to exclude ED [21]. Females were provided with a stopwatch that they received from andrology department and instructions on how to record the IELT. IELT that occurred before penile penetration into vagina was recorded as 0 min. The couples were required to experience a minimum of four coital attempts, with intervals of 3–7 days and to calculate a geometric mean IELT. They were instructed that if coitus took place more than once in a single session, only the first one would be recorded [22]. It was calculated using the following formula: IIELT = stopwatch IELT divided by half the male’s expected IELT + half the female’s expected IELT [22]. Also, the Arabic index of premature ejaculation (AIPE) was used initially to diagnose PE [23]. Furthermore, it was repeated after duloxetine and placebo to assess any change in the ejaculatory function [23]. Subjects were asked to rate their sexual desire, sexual potency, IELT time, their ability to delay IELT, sexual satisfaction to his partner [24]. Further, the level of stress or anxiety associated with sexual intercourse was also evaluated [24]. Additionally, the sexual quality of life men’s version (SQoL-M) was utilized in the current study initially and after duloxetine and placebo intake. The questionnaire has very good internal consistency as well as good test–retest reliability and convergent validity [25].

Statistical analysis

Statistical analysis was conducted using SPSS 22nd edition (IBM Corp. Released 2013. IBM SPSS Statistics for Windows, Version 22.0. Armonk, NY: IBM Corp.), quantitative variables were presented in mean, SD for parametric data, and median, range for non-parametric data after normality testing using Shapiro–Wilk test.

Comparison of quantitative variables between groups was conducted using student T test for age, and Mann Whitney U test all scores assessed in the current study, paired comparison of assessed scores was conducted using Wilcoxon sign rank test. Categorical variables were presented in frequency and percentages and compared using Chi square test. Any p value < 0.05 was considered significant.

Sample size determination

Clinical sample size calculator was used; with 0.05 alpha error and power of the study 0.80 with 1:1 enrollment ratio to calculate minimal sample size needed to detect effect of duloxetine (30 mg) in treating PE. The total sample size calculated was 62 PE patients (31 in each arm of the study). A random sample of PE patients with inclusion and exclusion criteria would be assigned to the study. Each individual would be randomized and allocated to either intervention arm: duloxetine 30 mg treatment daily in the first month and followed by 30 mg every other day in the next month then washout for 2 months and then cross over to placebo or control arm: placebo for 2 months then washout 2 months and cross over to duloxetine 30 mg. Thus, a concealed random allocation method was adopted till reaching the required total sample size.

Results

The mean age of patients was 38.4 ± 6.1 years. APE accounted for 91.2%. Sociodemographic characteristics are shown in Table 1. Comparison after 2 months from randomization, treatment group showed statistically significant median AIPE score 26 versus 19.5, longer duration of median IELT 180 s versus 60 s and higher median male SQOL score 45 vs 21 (p value < 0.001 for all) (Table 2).

Table 1 Shows sociodemographic characteristics of participants
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Table 2 Compares between baseline characteristics and effect of treatment after 2 months among participants
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Comparison between study groups in terms of baseline AIPE, baseline IELT, baseline male SQOL showed no statistically significant difference between study groups (Table 2). However, group (A) patients revealed a statistically significant male SQOL compared to group (B) patients (p value = 0.029) (Table 3). Paired comparison of AIPE, IELT (Sec), IQR and male SQOL in group (A) patients at baseline and after duloxetine intake showed statistically significant improvement among treated patients (p values < 0.001 all) (Table 4). Paired comparison of AIPE, IELT (Sec), IQR and male SQOL in group (A) patients at baseline and after placebo intake showed no significant improvement of male SQOL (Table 4). Furthermore, AIPE and IELT returned to baseline scores after discontinuation of duloxetine (p values 0.729; 0.892, respectively) (Table 4). Paired comparison of AIPE, IELT (Sec), IQR and male SQOL in group (B) patients at baseline and after placebo intake showed almost same scores of patients in group (A) who received placebo for 2 months after a 2 month washout period (p values 1.000 for all) (Table 5). Paired comparison of AIPE, IELT (Sec), IQR and male SQOL in group (B) patients at baseline and after duloxetine intake showed statistically significant improvement among all treated patients (p values < 0.001 all) (Table 5). It is worth mentioning that none of our patients stopped the drug due to side effects as we used only 30 mg. However, it should be noted that mild dizziness forced some patients to intake the drug after dinner instead of breakfast.

Table 3 Compares between study groups after cross over
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Table 4 Shows a paired comparison of baseline scores and post duloxetine and post placebo in group A
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Table 5 Shows a paired comparison of baseline scores and post duloxetine and post placebo in group B
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Discussion

A total of 68 patients continued the study where the majority of them did not improve on dapoxetine prior to joining the current study. Before inclusion, all patients were asked to measure their IELT for a month using a stop-watch. The median IELT of the patients in our study was 60 s.

The median AIPE in the current study was 19 that considered as moderate severity. Moreover, the median male SQOL was 20 indicating a low quality of life. The low baseline data showed significant improvement after daily intake of 30 mg duloxetine over one month then followed by every other day tapering for another month in the two groups. Notably, 32 patients from the two groups were lost to follow up. Consistently, when the two groups compared together after 2 months of duloxetine intake, they revealed statistically significant AIPE, longer duration of IELT and higher male SQOL score. Dizziness was the main side effect that reported by all patients treated with duloxetine in the current study. In light of the current knowledge, few studies assessed the role of duloxetine in PE. Athanasios et al. (2007) demonstrated that duloxetine was more competent than placebo in treating PE when administered on chronic basis as well as a major improvement in psychological parameters determined by clinical global impression-improvement Scale (CGI-I) [16]. In the same line, Ozcan et al. (2015) had shown that duloxetine was safe and effective for treating for PE [17]. PE was associated with increased anxiety and depression, frustration, anger and loss of sexual confidence [26]. Consistently, a recent Egyptian study by Hanafy et al. (2019) revealed a significant affection of the QoL in PE patients [27]. Henceforth, it is important to evaluate the sexual quality of life in PE patients as in the current study, the male SQOL significantly improved after duloxetine intake for 2 months in the two groups. Interestingly, group (A) patients who started duloxetine first showed significant improvement in their sexual quality of life compared to group (B) patients who started placebo first. Thus, patients who started duloxetine first felt such improvement compared to group (B) who continued to suffer for 4 months before receiving duloxetine. In the same context, Athanasios et al. (2007) and Ozcan et al. (2015) revealed similar findings [16, 17].

In contrast, Lui et al. (2020) conducted a systemic meta-analysis that showed that drug combination of selective serotonin reuptake inhibitor plus phosphodiestrase type 5 inhibitor was the most effective PE therapy on chronic basis [28]. However, the favourable effects of duloxetine on PE demonstrated in the current study can be explained by several facts. Firstly, in vitro experimental studies had shown that duloxetine preferentially inhibits 5-HT reuptake more than NE reuptake [29, 30]. Furthermore, chronic duloxetine administration has a long-term modulatory effect on 5-HT and NE pathways without an effect on basal 5-HT, NE, or dopamine levels in the cerebral cortex, a moderate effect on 5-HT and NE release in the hippocampus and a substantial desensitization of terminal α2-heteroreceptors but not 5-HT1B receptors [31]. Thus, it can be suggested that chronic duloxetine administration results in adaptive changes of autoreceptor functions equivalent to chronic administration of selective serotonin reuptake inhibitors and noradrenaline reuptake inhibitors [32]. However, such adaptive changes fail to reset 5-HT and NE levels, respectively [32].

Limits of the study

Admittedly, small sample size and inability to follow up the cases for longer duration can be seen as the major limitation of the study. Also, the utility of AIPE for diagnosing cases of PE can be added as another limitation as it is of little clinical use. Besides, sexual quality of life in all participants was evaluated by a questionnaire that was not validated in Arabic. Moreover, inclusion of LPE and APE in the same group can be considered as another limitation of the study. Furthermore, all cases of APE suffered from IELT < 2 min and not < 3 min can be added for the limitations of the study. Finally, there was a significant loss of follow up that was attributed mainly to difficult transportation as most patients were coming from far areas.

Thus, it could be repharsed that an intuition-to-treat analysis was performed and maybe the lost patients were the ones that were unhappy with treatment.

Conclusion

A daily intake of duloxetine 30 mg had an effective role in decreasing PE severity and improving sexual quality of life in LPE and APE patients. Larger studies are needed to assert it’s superiority compared to other known therapeutic modalities for PE.