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Dapoxetine for Premature Ejaculation: a Harmful Placebo?
Abstract and Figures
Background: Recently, dapoxetine was approved by the European Medicines Agency (EMA) as an effective and safe pharmacological agent for the treatment of premature ejaculation (PE). The objective of this study was to systematically review the efficacy and harm of dapoxetine.
Methods: We included randomized controlled trials that investigated the efficacy of dapoxetine for PE by comparing to placebo. We searched for both published and unpublished relevant trials using PUBMED, EMBASE, the Cochrane Central Register of Controlled Trials, a clinical trials register (clinicaltrials.gov), the EMA and the Food and Drug Administration clinical reviews through december 2013. We evaluated the blinding status of trials with the Cochrane Risk of Bias (ROB) Tool, using the domains of allocation sequence concealment, blinding of participants, healthcare providers and outcome assessors. For the latter 3 ROB domains, we applied additional criteria. Across these domains, studies that scored low risk of bias were judged to be adequately blinded and the remaining studies were judged to be inadequately blinded. Reporting followed PRISMA guidelines.
Results: We included 8 studies that involved 6,954 randomized participants; Seven studies had a short duration (6 to 12 weeks). Information on study blinding was mostly absent, many participants dropped out of studies (short (21%) vs long (47%) term studies) and many conflicts of interests were found. One adequately blinded study reported ejaculation delayed on dapoxetine with 42 [-8, 76] seconds. Inadequately blinded studies reported ejaculation time was 2.29 [1.37, 3.21] and 1.70 [0.50, 2.90] minutes on dapoxetine and placebo respectively. Risk ratios for the most common adverse events (AEs) were: nausea RR 5.93 [4.31, 8.18], headache RR 1.21 [0.94, 1.55], dizziness RR 3.17 [2.25, 4.47], diarrhoea RR 3.18 [2.06, 4.92]. One study reported substantially more headache RR 5.16, more dizziness RR 7.22 and more diarrhoea RR 11.35.
Conclusions: We found no evidence that dapoxetine is effective. Any small ejaculation-time delaying effects seem to result from a placebo effect. The data suggest that dapoxetine may add around 30 seconds to postpone an man's ejaculation, but this could not be statistically confirmed. Unfortunately, dapoxetine comes with its risks. It has several adverse effects and a significant proportion of patients quit dapoxetine early. Dapoxetine's overall risk/benefit profile is unfavourable.
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Supplementary resources (6)
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows: To assess the role of selective serotonin re-uptake inhibitors in the treatment of premature ejaculation.
Introduction: In 2009, the International Society for Sexual Medicine (ISSM) convened a select panel of experts to develop an evidence-based set of guidelines for patients suffering from lifelong premature ejaculation (PE). That document reviewed definitions, etiology, impact on the patient and partner, assessment, and pharmacological, psychological, and combined treatments. It concluded by recognizing the continually evolving nature of clinical research and recommended a subsequent guideline review and revision every fourth year. Consistent with that recommendation, the ISSM organized a second multidisciplinary panel of experts in April 2013, which met for 2 days in Bangalore, India. This manuscript updates the previous guidelines and reports on the recommendations of the panel of experts.
Aim: The aim of this study was to develop clearly worded, practical, evidenced-based recommendations for the diagnosis and treatment of PE for family practice clinicians as well as sexual medicine experts.
Method: A comprehensive literature review was performed.
Results: This article contains the report of the second ISSM PE Guidelines Committee. It offers a new unified definition of PE and updates the previous treatment recommendations. Brief assessment procedures are delineated, and validated diagnostic and treatment questionnaires are reviewed. Finally, the best practices treatment recommendations are presented to guide clinicians, both familiar and unfamiliar with PE, in facilitating treatment of their patients.
Conclusion: Development of guidelines is an evolutionary process that continually reviews data and incorporates the best new research. We expect that ongoing research will lead to a more complete understanding of the pathophysiology as well as new efficacious and safe treatments for this sexual dysfunction. We again recommend that these guidelines be reevaluated and updated by the ISSM in 4 years. Althof SE, McMahon CG, Waldinger MD, Serefoglu EC, Shindel AW, Adaikan PG, Becher E, Dean J, Giuliano F, Hellstrom WJG, Giraldi A, Glina S, Incrocci L, Jannini E, McCabe M, Parish S, Rowland D, Segraves RT, Sharlip I, and Torres LO. An update of the International Society of Sexual Medicine's guidelines for the diagnosis and treatment of premature ejaculation (PE). Sex Med 2014;2:60–90.
Introduction:
In 2009, the International Society for Sexual Medicine (ISSM) convened a select panel of experts to develop an evidence-based set of guidelines for patients suffering from lifelong premature ejaculation (PE). That document reviewed definitions, etiology, impact on the patient and partner, assessment, and pharmacological, psychological, and combined treatments. It concluded by recognizing the continually evolving nature of clinical research and recommended a subsequent guideline review and revision every fourth year. Consistent with that recommendation, the ISSM organized a second multidisciplinary panel of experts in April 2013, which met for 2 days in Bangalore, India. This manuscript updates the previous guidelines and reports on the recommendations of the panel of experts.
Aim:
The aim of this study was to develop clearly worded, practical, evidenced-based recommendations for the diagnosis and treatment of PE for family practice clinicians as well as sexual medicine experts.
Method:
A comprehensive literature review was performed.
Results:
This article contains the report of the second ISSM PE Guidelines Committee. It offers a new unified definition of PE and updates the previous treatment recommendations. Brief assessment procedures are delineated, and validated diagnostic and treatment questionnaires are reviewed. Finally, the best practices treatment recommendations are presented to guide clinicians, both familiar and unfamiliar with PE, in facilitating treatment of their patients.
Conclusion:
Development of guidelines is an evolutionary process that continually reviews data and incorporates the best new research. We expect that ongoing research will lead to a more complete understanding of the pathophysiology as well as new efficacious and safe treatments for this sexual dysfunction. We again recommend that these guidelines be reevaluated and updated by the ISSM in 4 years.
The purpose of this study is to investigate the prevalence rate and risk factors of depression in outpatients who were diagnosed with PE. Therefore, between September 2009 and September 2011, 1801 outpatients at andrology clinics were enrolled and consented to participate in our survey by completed a verbal questionnaire. It included the following: (1) demographic data (e.g., age, body mass index), (2) PE duration, medical history, and sexual history, (3) self-estimated intravaginal ejaculatory latency times, (4) the Zung Self-rating Depression Scale (SDS), and (5) the National Institute of Health Chronic Prostatitis Symptom Index (NIH-CPSI) and (6) the International Index of Erectile Function (IIEF-5). The results showed that a total of 1,206 patients were diagnosed with PE. The prevalence rate of depression in these PE patients was 26.78%. Depression was associated with PE duration, NIH-CPSI score, and IIEF-5 score. Risk factors for depression specifically included PE durations for 13-24, 25-60, or ≥61 months, CPSI scores of 15-30 or ≥31, and IIEF-5 scores <22. These findings suggested that several associated factors (PE duration, CPSI scores, and IIEF-5 scores) were the risk factors of depression in men with PE.
Background:
Clinical trials are commonly done without blinded outcome assessors despite the risk of bias. We wanted to evaluate the effect of nonblinded outcome assessment on estimated effects in randomized clinical trials with outcomes that involved subjective measurement scales.
Methods:
We conducted a systematic review of randomized clinical trials with both blinded and nonblinded assessment of the same measurement scale outcome. We searched PubMed, EMBASE, PsycINFO, CINAHL, Cochrane Central Register of Controlled Trials, HighWire Press and Google Scholar for relevant studies. Two investigators agreed on the inclusion of trials and the outcome scale. For each trial, we calculated the difference in effect size (i.e., standardized mean difference between nonblinded and blinded assessments). A difference in effect size of less than 0 suggested that nonblinded assessors generated more optimistic estimates of effect. We pooled the differences in effect size using inverse variance random-effects meta-analysis and used metaregression to identify potential reasons for variation.
Results:
We included 24 trials in our review. The main meta-analysis included 16 trials (involving 2854 patients) with subjective outcomes. The estimated treatment effect was more beneficial when based on nonblinded assessors (pooled difference in effect size -0.23 [95% confidence interval (CI) -0.40 to -0.06]). In relative terms, nonblinded assessors exaggerated the pooled effect size by 68% (95% CI 14% to 230%). Heterogeneity was moderate (I(2) = 46%, p = 0.02) and unexplained by metaregression.
Interpretation:
We provide empirical evidence for observer bias in randomized clinical trials with subjective measurement scale outcomes. A failure to blind assessors of outcomes in such trials results in a high risk of substantial bias.
To assess both the acceptance and the discontinuation rates from dapoxetine, the first oral pharmacological agent indicated for the treatment of premature ejaculation (PE).
One hundred twenty consecutive potent patients (mean age 40.3 years; range 18-63 years) seeking medical treatment for lifelong PE were enrolled in a prospective phase II study. Moreover, they were assessed regarding detailed medical and sexual history, intravaginal ejaculatory latency time (IELT), International Index of Erectile Function (IIEF), and complete physical examination. The patients received a dapoxetine prescription (30 mg on demand) and unresponded cases received increased dose (60 mg after 3 months). The patients were evaluated at 1, 3, 6, and 12 months, and requested to complete a multiple-choice global assessment questionnaire regarding specific reasons for eventual therapy discontinuation.
Twenty-four of the patients (20%) decided not to start dapoxetine. Fear of using a "drug" was the most frequently reported reason for treatment nonacceptance (50%) and the cost of treatment was the reason for 25% of the patients. Ninety-six patients (80%) started the therapy. Twenty-six percent dropped out after 1 month, 42.7% dropped out after 3 months, 18.7% dropped out at 6 months, 2% dropped out at 12 months, and 10.4% are continuing the therapy after 1 year. The main reasons were effect below expectations 24.4%, costs 22.1%, side effects 19.8%, loss of interest in sex 19.8%, and no efficacy 13.9%.
Twenty percent of lifelong PE patients seeking medical treatment for early ejaculation freely decided not to start treatment with dapoxetine, and roughly 90% of the patients who started therapy discontinued after 1 year.
Background
Sexual dysfunction (SD) is an important underestimated adverse effect of antidepressant drugs. Patients, in fact, if not directly questioned, tend to scarcely report them. The aim of the present meta-analysis was to quantify SD caused by antidepressants on the basis of studies where sexual functioning was purposely investigated through direct inquiry and specific questionnaires.
Methods
A literature search was conducted using MEDLINE, ISI Web of Knowledge, and references of selected articles. Selected studies performed on patients without previous SD were entered in the Cochrane Collaboration Review Manager (RevMan version 4.2). Our primary outcome measure was the rate of total treatment-emergent SD. Our secondary outcome measures were the rates of treatment-emergent desire, arousal, and orgasm dysfunction.
Results
Our analyses indicated a significantly higher rate of total and phase-specific treatment-emergent SD compared with placebo for the following drugs in decreasing order of impact: sertraline, venlafaxine, citalopram, paroxetine, fluoxetine, imipramine, phenelzine, duloxetine, escitalopram, and fluvoxamine, with SD ranging from 25.8% to 80.3% of patients. No significant difference with placebo was found for the following antidepressants: agomelatine, amineptine, bupropion, moclobemide, mirtazapine, and nefazodone.
Discussion
Treatment-emergent SD caused by antidepressants is a considerable issue with a large variation across compounds. Some assumptions, such as the inclusion of open-label studies or differences in scales used to assess SD, could reduce the significance of our findings. However, treatment-emergent SD is a frequent adverse effect that should be considered in clinical activity for the choice of the prescribed drug.
The Cochrane Handbook for Systematic Reviews of Interventions (the Handbook) has undergone a substantial update, and Version 5 of the Handbook is now available online at www.cochrane-handbook.org and in RevMan 5. In addition, for the first time, the Handbook will soon be available as a printed volume, published by Wiley-Blackwell. We are anticipating release of this at the Colloquium in Freiburg. Version 5 of the Handbook describes the new methods available in RevMan 5, as well as containing extensive guidance on all aspects of Cochrane review methodology. It has a new structure, with 22 chapters divided into three parts. Part 1, relevant to all reviews, introduces Cochrane reviews, covering their planning and preparation, and their maintenance and updating, and ends with a guide to the contents of a Cochrane protocol and review. Part 2, relevant to all reviews, provides general methodological guidance on preparing reviews, covering question development, eligibility criteria, searching, collecting data, within-study bias (including completion of the Risk of Bias table), analysing data, reporting bias, presenting and interpreting results (including Summary of Findings tables). Part 3 addresses special topics that will be relevant to some, but not all, reviews, including particular considerations in addressing adverse effects, meta-analysis with non-standard study designs and using individual participant data. This part has new chapters on incorporating economic evaluations, non-randomized studies, qualitative research, patient-reported outcomes in reviews, prospective meta-analysis, reviews in health promotion and public health, and the new review type of overviews of reviews.