Although previous studies have investigated the safety and efficacy characteristics of oral drugs in patients with premature ejaculation (PE), the available results remained inconsistent. Hence, this article was conducted to comprehensively compare the effectiveness of oral drugs and several relevant complications in patients with PE. Relevant researches were comprehensively searching from the databases PubMed, EMBASE, and Web of Science, up to May 1st, 2018. The pooled standard mean difference (SMD) or odds ratios (ORs) with 95% Credible interval (CrI) was respectively utilized to evaluate the safety and efficacy of oral drugs in PE. A total of 25 relevant research were ultimately included in this network meta-analysis. PE oral drugs mainly included serotonin reuptake inhibitors (SSRIs) and phosphodiesterase type 5 inhibitors (PDE5i). Our results successfully shed light on the efficacy differences of oral drugs for the treatment of PE. The cumulative rank probability of IELT at 4–6 weeks from best to worst was SSRIs + PDE5i, PDE5i, and other SSRIs alone. In addition, this meta-analysis also showed fluoxetine 20 mg, dapoxetine 60 mg, PDE5i, and SSRIs + PDE5i had a higher, whereas other SSRIs alone had a relatively lower incidence rate of clinically relevant complications. In summary, our results showed that the usage of PDE5i only or in combination with SSRIs might be stronger than SSRIs alone in the efficacy of PE oral drugs. Nevertheless, it also has a problem about the side effects of PDE5i including gastrointestinal or central nervous systems complications, which prevents it as the first-line treatment drug. Despite the development of some promising new therapeutic options, SSRIs remained as the first line of therapeutic PE oral drug through a synthetical consideration at present.
Premature ejaculation (PE) is one of the most common sexual disorders in male, with the prevalence rates of 20–30% in the general male population [1, 2]. Although PE remains poorly defined and inadequately characterized, it represents a frustrating problem that can reduce the enjoyment of sex, harm marital relationships, and impair the quality of life . To date, PE has no universally agreed diagnostic criteria or ideal definition. Although the cause of PE has been thought to be psychological in the majority of patients, little is known about its organic basis [3,4,5]. Thus, available treatment pathways for the condition are varied and treatments may include both behavioral and/or pharmacological interventions.
According to the criteria for PE stated in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, text revision (DSM-IV-TR), PE has been defined as uncontrolled ejaculation whose essential feature is the recurrent or persistent orgasm with minimal sexual stimulation before, on, or shortly after penetration and before the person desires it; marked distress or interpersonal difficulty; not exclusively due to direct effects . Various approaches have been utilized for the treatment of PE including psychological, behavioral, and pharmacologic interventions like local anesthetic sprays, vascular surgery, propranolol, serotonin reuptake inhibitors (SSRIs), and phosphodiesterase type 5 inhibitors (PDE5i) . Nevertheless, certain sexual side effects related to the use of antidepressant drugs have been reported such as decreased libido, orgasm inhibition, erectile dysfunction, and priapism [6, 8]. Indeed, pharmacotherapy is still based on an incomplete knowledge of the organic basis of PE pathogenesis, which limits the opportunity to make treatments that are really targeted on the patient’s characteristics [7, 8]. The multifactorial nature of PE suggested strongly that outcome measurements in PE should be more than the intravaginal ejaculatory latency time (IELT) alone and fully validated that multidimensional measures to assess different aspects were required . In most studies, IELT is believed to be the most sensitive parameter for evaluating the efficacy of treatment of PE .
The optimal medical treatment for PE has not been established in previous studies, but single dosing prior to sexual relations can work for some men, while in others, achieving a blood level through daily use of the medication may be necessary, as in the treatment of clinical depression [11, 12]. Obviously, if single dosing is successful, therapy is simpler and is associated with fewer adverse effects . Therefore, this may be the preferred initial therapy. In addition, several oral drugs have been reported to significantly improve symptoms of patients with PE [7, 8, 13]. However, due to the limited sample sizes, these studies provided no conclusive results. Hence in this study, we performed a systemic review and a network meta-analysis including all randomized controlled trials (RCTs) to investigate the safety and efficacy characteristics of oral drugs in patients with PE.
Materials and methods
Relevant studies were comprehensive retrieved based on PubMed, EMBASE, and Web of Science, which were published until May 1st, 2018. The search strategy consisted of two parts (ejaculatory latency and relevant complications), using the following keywords in combination with Medical Subject Headings terms and text words: fluoxetine, paroxetine, sertraline, dapoxetine, citalopram, duloxetine, tramadol, PDE5i, PE, and RCTs. Other potentially eligible literatures were collected manually by referring to relevant reviews and the references of original studies included for the meta-analysis. Besides, based on inclusion criteria, all reserved articles were re-evaluated to prevent overlapping datasets. Furthermore, because of the data from previously published studies, no ethical approval and informed consent were required.
Inclusion and exclusion criteria
Studies enrolled in this article had to meet the following criteria: (1) The language of the article was limited to English; (2) The study was designed as RCTs; (3) The necessary data could be extracted from original studies including first author’s name, year of publication, IELT of 4–6 or 12 weeks, relevant complications (dizziness, headache, and nausea), and endpoints; (4) The studies should mention and compare at least two of them; (5) Clinical outcomes of the involved studies should include IELT at 4–6 weeks or 12 weeks, related side effects.
In addition, studies would be excluded if they meet the following criteria: (1) The language of the article was non-English; (2) The study was not designed as RCTs; (3) Nonsufficient and unavailable data could be extracted from the article; (4) Duplication of previous publications.
All available studies were independently determined from the eligible studies identified by two blind investigators (Qin ZQ and Wang Y), according to the above inclusion and exclusion criterion. Discrepancies were addressed a by discussing with a third reviewer (Zhu JD) until arriving at a consensus. All the important information were extracted from the original articles in a standardized form, including first author’s name, year of publication, country, ethnicity, IELT of 4–6 or 12 weeks, relevant complications (dizziness, headache, and nausea), and endpoints. All of the aforementioned data were comprehensively presented in Table 1. According to the Cochrane Handbook , qualities of eligible studies were evaluated by the potential source of bias as follows: (1) Random sequence generation; (2) Allocation concealment; (3) Blinding of participants and personnel; (4) Blinding of outcome assessment; (5) Incomplete outcome data; (6) Selective reporting; (7) Other bias. The judgments were graded as a low, high, or unclear risk of bias (http://www.cochrane-handbook.org; Figs. 1 and 2).
A pair-wise meta-analysis was performed to make direct comparison between two PE oral drugs, and the results were evaluated by the pooled odds ratio (OR) and standardized mean difference (SMD) with 95% confidence interval. I-square test was adopted to assess the heterogeneity and I2 > 50% was considered as existence of significant heterogeneity. According to I2 of study heterogeneities, the pooled ORs were calculated either with the fixed effects model (a Mantel–Haenszel method) or with the random effects model (a DerSimonian–Laird method). If there was no indication of substantial heterogeneity, the fixed effects model would be performed. Otherwise, the random effects model was selected to conduct this meta-analysis. Besides, publication bias was examined by Begg and Egger’s test . P values were adopted by a two-sided test and P < 0.05 was regarded as statistically significant. In addition, all above statistical analyses in traditional meta-analysis were conducted by Stata software (version 12.0; StataCorp LP, College Station, TX).
In addition to traditional meta-analysis, a network meta-analysis with regards to multiple treatments was performed by a random effect model within a Bayesian framework, using package “gemtc” version 0.8.2 of R-3.4.0 software [16, 17]. OR with 95% credible interval (CrI) was calculated by Markov chain Monte Carlo methods. The function mtc.run would be used to generate samples by means of the Markov chain Monte Carlo sampler. We set 10,000 simulations for each chain as the “burn-in” period, yielding 50,000 iterations to obtain the OR of model parameters, when three Markov chains run simultaneously. The model convergence was accessed by Brooks–Gelman–Rubin plots method, trace plot, and density plot . Meanwhile, rank probabilities would be calculated, which indicated the hierarchy of each treatment. Based on the results of rank probabilities, clinical surgeons could make the choice which treatment would be best, second and so on . The matrix of rank probabilities and the plot of rank probabilities were provided by the “gemtc” package simultaneously.
Besides, the pooled ORs from network meta-analysis and traditional meta-analysis were respectively obtained to estimate the consistency between direct and indirect comparisons. To access the inconsistency, the node-splitting method was applied by reporting its Bayesian P value, by means of separating the evidence concerning certain comparison into direct and indirect evidence, when a loop connecting three arms existed . Last but not least, the mtc.anohe command of the “gemtc” package would be utilized to evaluate the global heterogeneity on the bias of the magnitude of heterogeneity variance parameter I2.
In general, a total of 568 related articles through a primary search of databases and reference lists were initially identified according to the searching criteria. Ultimately, 25 eligible studies met the inclusion criteria and were involved in the present network meta-analysis for further evaluation [7, 13, 21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43]. The included studies covered eight different PE oral drugs: fluoxetine, paroxetine, sertraline, dapoxetine, citalopram, duloxetine, PDE5i, and SSRIs plus PDE5i. The flowchart of literature searching and screening process is shown in Fig. 3.
Quantitative synthesis results
In this study, all detailed characteristics of these enrolled 25 studies were summarized in Table 1. All of these enrolled studies were RCTs and the quality of evidence was evaluated by the Cochrane Handbook (Figs. 1 and 2). Clinical outcomes of involved articles included IELT and several related complications, including dizziness, headache, and nausea, respectively.
Network meta-analysis results
A total of 19 studies including nine different PE oral drugs (fluoxetine 20 mg, paroxetine 20 mg, sertraline 50 mg, dapoxetine 30 mg, dapoxetine 60 mg, citalopram 20 mg, duloxetine 40 mg, PDE5i, and SSRIs plus PDE5i) contributed to the analysis of IELT at 4–6 weeks. The network structure diagram of different PE oral drugs is shown in Fig. 4a, in which the thicknesses of the lines were proportional to the number of comparisons and the diameters of the circles were proportional to the number of treatments included in the network meta-analysis. The efficacy of different PE oral drugs using SMD and corresponding 95% CrIs is displayed in Fig. 5a. The cumulative rank probability of IELT at 4–6 weeks from best to worst was SSRIs plus PDE5i, PDE5i, paroxetine 20 mg, and other SSRIs alone (Fig. 6a). Bayesian P values of node-splitting method were allå 0.05 except paroxetine versus placebo, which indicated that the direct and indirect evidences were basically consistent (Fig. 7a).
In addition, there are a total of six studies including five different PE oral drugs (fluoxetine 90 mg, dapoxetine 30 mg, dapoxetine 60 mg, PDE5i, and SSRIs plus PDE5i) contributed to the analysis of IELT at 12 weeks. The network structure diagram of different PE oral drugs is shown in Fig. 4b. The efficacy of different PE oral drugs using SMD and corresponding 95% CrIs is displayed in Fig. 5b. As indicated in the result, compared to dapoxetine 30 mg and dapoxetine 60 mg, SSRIs plus PDE5i have significantly more IELT (SMD = 0.53, 95% CrI 0.22–0.79; SMD = 3.00, 95% CrI 1.40–4.70, separately); Meanwhile, the effect of SSRI + PDE5i and fluoxetine 90 mg on IELT is obviously better than dapoxetine 60 mg (SMD = 2.50, 95% CrI 0.84–4.20; SMD = 1.10, 95% CrI 0.029–2.10, separately). The cumulative rank probability of IELT at 12 weeks from best to worst was SSRIs plus PDE5i, fluoxetine 90 mg, PDE5i, dapoxetine 60 mg, dapoxetine 30 mg, placebo (Fig. 6b). In the above-mentioned study, we found that all Bayesian P values of node-splitting method were >0.05, which indicated that the direct and indirect evidences were consistent (Fig. 7b).
Relevant complications (dizziness, headache, and nausea)
A total of 11 studies including seven different PE oral drugs (fluoxetine 20 mg, paroxetine 20 mg, sertraline 50 mg, dapoxetine 30 mg, dapoxetine 60 mg, PDE5i, and SSRIs plus PDE5i) contributed to the analysis of the relevant complications, including dizziness, headache, and nausea. In terms of relevant complications (dizziness, headache, and nausea), the network structure diagrams are displayed in Fig. 4. The risk of relevant complications (dizziness, headache, and nausea) of these oral drugs in patients with PE using ORs and corresponding 95% CrIs is shown in Fig. 5. Amongst them, we found that the toxic and side effects of dapoxetine 30 mg were lower than that of dapoxetine 60 mg, in terms of dizziness (OR = 0.50, 95% CrI 0.39–0.65, Fig. 5c). Besides, in terms of nausea, dapoxetine 30 mg and paroxetine have significantly lower toxic and side effects, compared with dapoxetine 60 mg (OR = 0.41, 95% CrI 0.32–0.58; OR = 0.39, 95% CrI 0.16–0.87, separately, Fig. 5e). As indicated in Fig. 6, we found that fluoxetine 20 mg, dapoxetine 60 mg could induce more incidence of dizziness (Fig. 6c). Besides, in case of headache, the most incidence of it was PDE5i, SSRIs plus PDE5i, dapoxetine 60 mg (Fig. 6d). Moreover, dapoxetine 60 mg, SSRIs plus PDE5i had a higher incidence of nausea (Fig. 6e).
The management recommendation for both acquired PE and lifelong PE are similar, which includes a behavioral/psychotherapy, a pharmacotherapy, and a combination of these treatments . To date, the drug treatment for PE remain immaturity and some new promising therapeutic options have been proposed. However, gold standard remains as selective SSRIs like dapoxetine or paroxetine for the oral drugs of treating PE . In the subsequent years, topical anesthetics, tramadol, alpha-1 blockers, and PDE5i will be the next strategies .
As is known to us, selective SSRIs are gold standard for the pharmacotherapy in PE. However, topical therapy with local anesthetics including lidocaine/prilocaine is also reported effective for some patients . In addition, PDE5is, as effective treatments for ED, are also suggested using alone or in combination with SSRIs as an alternative treatment for PE [45,46,47]. Systematic reviews of multiple studies have showed the supportive role of PDE5i in men with PE, especially those combined with erectile dysfunction [48, 49]. The treatment of LPE with PDE5i in men with “normal” erectile function is not recommended and further evidence-based research is necessary to synthesize conflicting data . Recently, Sun et al. reported a meta-analysis of using PDE5i for PE with concomitant erectile dysfunction and showed a significant improvement of symptoms and quality of sexual life with PDE5i alone compared with both placebo and other SSRIs alone . What is more, it also suggested that the combination of PDE5i with SSRI showed an obvious improvement compared with SSRI alone in patients with PE. However, more adverse event was exhibited not only in the use of PDE5i when compared with placebo but also in the use of PDE5i combined with SSRI when compared with SSRI alone  Hence, this network meta-analysis was conducted to find out the most optimal oral drug for the therapy of PE.
The most common adverse effects were related to the gastrointestinal and central nervous systems—mild nausea, diarrhea, headache, fatigue, yawning, or perspiration—and seemed to be dose related, but led to treatment discontinuation in only a few patients . In addition, systematic analysis of RCTs of SSRIs in patients with depression suggested that youth but not adults have a small risk of suicidal ideation or suicide attempts [52, 53]. Previous study found that PDE5i probably caused a small increase in the risk of nonarteritic ischemic optic neuropathy, and evidence on increased rates of melanoma and PCa recurrence was weak and controversial . In current meta-analysis, the results confirmed that the cumulative rank probability in different PE oral drugs from best to worst was fluoxetine 20 mg, dapoxetine 60 mg, PDE5i, and SSRIs plus PDE5i, in terms of relevant complications, including dizziness, headache, and nausea. What is more, our analysis demonstrated that the incidence rate of complications in drug combination was increased while all the adverse effects were tolerable and manageable. In recent years, the abuse of SSRIs and PDE5i and the use of counterfeit medications have presented a series of serious global health concerns. Sometimes they might be also life-threatening although the major complications appeared to be rare. Thus, we should pay more attention to the safety of oral drugs for the treatment of PE.
Recently, increasing relevant studies researched the clinical efficacy characteristics and related complications of oral drugs in patients with PE [13, 33, 34, 36, 48, 51, 55]. To the best of our knowledge, this study was for the first time a network meta-analysis that comprehensively and systematically investigated the efficacy and adverse events in PE drug treatments, in order to elucidate such differences. However, the outcomes remained inconsistent or unclear. The conflict among them might partially own to the relatively small sample size of individual studies, the different ethnicities and the possible limited effect of individual patient's data. All these contributed to the limited statistical power in the published studies. Therefore, we needed a comprehensive method to assess the efficacy and complications of oral drugs in the treatment of PE. In addition, quite a few meta-analyses explored the differences of efficacy of various oral drugs in the treatment of PE [48, 51, 55], but the results in previous articles involved differed a lot. What is more, lack of further researches by different types of drug treatments in the present meta-analyses limited comprehensive understanding of the disparity and difference between different drugs. Furthermore, additional studies about such distinction had been published since the previous meta-analysis, which might generate great influences on the results. All the factors contributed to the necessity of the current network meta-analysis.
This network meta-analysis of individual patient data confirmed that SSRIs plus PDE5i exerted the best efficacy for the treatment of PE. Meta-analysis as a powerful tool could provide more reliable results than a single study especially in explaining controversial conclusions . Meanwhile, network meta-analysis could also provide the most comprehensive information by comparing different treatment methods. However, in view of relevant complications, the cumulative rank probability in different PE oral drugs from best to worst was fluoxetine 20 mg, dapoxetine 60 mg, PDE5i, and SSRIs plus PDE5i. Thus, results of our network meta-analysis illustrated that SSRIs plus PDE5i could increase the efficacy of PE oral drug, while the incidence of relevant complications might escalate at the same time. Furthermore, more rigorous high-quality researches were needed to confirm these findings.
To a certain extent, several limitations in this meta-analysis should be taken into account. Firstly, the results were based on unadjusted estimates with limiting numbers of published studies and insufficient number of patients. Meanwhile, inclusion criteria about data of each patient in previous articles were with difference a lot. Hence, more researches should focus on the influence of different factors in the future to guaranty reliability of our meta-analysis. Secondly, many factors could affect the efficacy characteristics of oral drugs in patients with PE, such as the half-life of drugs, individual differences in patients and toxic side effects of these drugs, while they were not considered in our systems analysis. More convincing evaluation system was required by more researches in the future. Thirdly, as we mentioned in the results, the consistency between direct and indirect evidence was not perfect that some inconsistent results were observed, which might lessen the validity of our results. In addition, although various protocols were applied in different studies, significant heterogeneity was existed among studies. Moreover, it was also controversial whether we could summarize results from studies with different protocols and calculated the pooled ORs. Finally, sample size of some studies was relatively small in the network meta-analyses, which have no enough statistical power to explore the efficacy of oral drugs in patients with PE. Notably, although RCTs had shown higher efficacy for PDE5is in combination with SSRIs included patients reporting both ED and PE, those results may not be applicable to all patients with PE. Accordingly, it was required that more high-quality studies should be performed to elucidate the differences in the effectiveness of oral drugs in patients with PE.
In summary, the results of the current network meta-analysis indicated that PDE5i alone or in combination with SSRIs might be stronger than SSRIs. Nevertheless, it also has a problem about the safety issue of PDE5i including gastrointestinal or central nervous systems complications, which preventing this as the first-line treatment drug. Although the drug treatment for PE was still developing and some promising new therapeutic options have been proposed, it was important that SSRIs remained to be the first line of therapeutic oral drug through a synthetical consideration. Additional high-quality and multicentre large-scale RCTs are needed to further to confirm these new options in subsequent articles.
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WZ, NHS, and ZJW: protocol/project development; JDX, CQ, and WW: data collection or management; KZ, RL, LZ, and XHM: data analysis; ZQQ, YW, and JDZ: manuscript writing/editing.
Conflict of interest
The authors declare that they have no conflict of interest.
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