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Oral agents for the treatment of premature ejaculation: review of efficacy and safety in the context of the recent international society for sexual medicine criteria for lifelong premature ejaculation

Oral Agents for the Treatment of Premature Ejaculation:
Review of Efficacy and Safety in the Context of the Recent
International Society for Sexual Medicine Criteria for Lifelong
Premature Ejaculationjsm_23862707.2725

Chris G. McMahon, MBBS, FAChSHM* and Hartmut Porst, MD† *Australian Centre for Sexual Health, St. Leonards, NSW, Australia; †Private Urology and Andrology Practice andHospital, Hamburg, Germany A B S T R A C T
Introduction. New diagnostic criteria for lifelong premature ejaculation (PE) have been proposed by the Interna-
tional Society of Sexual Medicine (ISSM), including an intravaginal ejaculatory latency time (IELT) of less than
about 1 minute, lack of control over ejaculation, and PE-related distress or bother.
Aim. The aim of this study was to review evidence supporting the efficacy and safety of oral agents for the treatment
of PE in the context of the new ISSM criteria.
Methods. The PubMed database was searched for randomized, double-blind, placebo-controlled studies of oral
agents in PE that included stopwatch measurements of IELT.
Main Outcome Measures. The main outcome measure used for this study was a review of the efficacy and safety data
of oral agents for PE aligned with ISSM criteria.
Results. Since the latest meta-analyses using similar criteria (conducted in 2004 and 2005 for selective serotonin
reuptake inhibitors [SSRIs] and phosphodiesterase type 5 [PDE-5] inhibitors, respectively), eight studies evaluated
SSRIs vs. placebo, one compared SSRIs, two evaluated PDE-5 inhibitors, and one evaluated an SSRI/PDE-5
inhibitor combination. New agents included dapoxetine (five studies) and tramadol (one study). Six studies enrolled
men who met an approximation of the ISSM criteria. Although evidence suggests that most SSRIs, tramadol, and
dapoxetine increase IELT to varying degrees, few studies included control over ejaculation and PE-related distress
or bother as enrollment criteria or used validated patient-reported outcome instruments to evaluate these param-
eters. Among studies that provided comprehensive adverse event data, safety and tolerability observations in men
with PE were generally similar to those observed in other populations; however, with the exception of dapoxetine,
known SSRI-class effects (e.g., withdrawal syndrome) were not evaluated in men with PE.
Conclusions. This systematic review of well-controlled clinical trials in PE has demonstrated that while many oral
agents, particularly SSRIs, tramadol, and dapoxetine, have proven effective and safe for the treatment of men with
PE, few have been evaluated for their effects on the specific elements of the ISSM criteria. McMahon CG and Porst
H. Oral agents for the treatment of premature ejaculation: Review of efficacy and safety in the context of the
recent international society for sexual medicine criteria for lifelong premature ejaculation. J Sex Med
2011;8:2707–2725.

Key Words. Premature Ejaculation; IELT; ISSM Criteria; Control over Ejaculation; Bother; Distress
Introduction
inhibitor (SSRI) antidepressants [1–3], the tricyclicantidepressant clomipramine that blocks seroto- C ommon treatment interventions for prema- nin, dopamine, and norepinephrine transporters ture ejaculation (PE) include off-label use of [4], phosphodiesterase (PDE)-5 inhibitors [1], or oral agents, such as selective serotonin reuptake topical anesthetic creams or sprays [1–3,5]. Other 2011 International Society for Sexual Medicine agents, including a1-adrenoreceptor antagonists were identified by searching for the keyword [6,7] and the analgesic opioid receptor agonist and “premature ejaculation” in the PubMed database.
noradrenaline reuptake inhibitor tramadol [8,9] This search was then manually cross-referenced have also been investigated for treating PE [2,10].
for all papers, and well-designed studies of oral Psychotherapy and behavioral therapy also have a agents were manually extracted. Well-designed role, although well-designed, controlled trials that studies were defined as randomized, double-blind, use such approaches are lacking [3,5,10]. To date, placebo-controlled trials that included stopwatch- the largest trials of a treatment for PE have been measured IELT as an outcome measure [17,18].
conducted with dapoxetine [11–14], a short-acting Studies of SSRIs and clomipramine published SSRI that is the only oral agent approved for the prior to 2004 were identified from a meta-analysis treatment of PE in several European, Asia-Pacific, and systematic review by Waldinger [19], and studies evaluating PDE-5 inhibitors and SSRI/ Evidence-based criteria for the diagnosis of life- PDE-5 inhibitor combination therapies published long PE have recently been proposed by the Inter- prior to 2005 were identified from a systematic national Society for Sexual Medicine (ISSM) [15], review by McMahon [20] and another recent study including an intravaginal ejaculatory latency time [21] (summarized in Table 2). Studies were (IELT) of approximately 1 minute or less, lack of selected for inclusion in this review after evalua- control over ejaculation, and negative psycholo- gical consequences such as distress, bother, fru-stration, and/or sexual avoidance. Consequently,recent proposals recommend that studies of PE Evidence Synthesis
should include stopwatch assessments of IELT and validated patient-reported outcome (PRO) mea- The basis of ideal PE clinical trial design sures for control over ejaculation and PE-related involves adequately defining the trial population, a cohort or case-study observational trial design, a This systematic review qualitatively examines double-blind placebo-controlled interventional the efficacy and safety of oral agents evaluated randomized clinical trial design, or a double-blind, for the treatment of PE, including not only those crossover randomized clinical intervention prefer- agents for which data have accumulated over many ence trial, and the use of sensitive, validated, and years, but also on novel treatments for which data have recently become available. The majority of PROs can be assessed using validated single- these data has been collected prior to the formal item questions, validated multi-item multi-domain inclusion of IELT in the definition of PE; there- PE inventories, or validated omnibus sexual fore, the purpose of this review was to reexamine inventories. PROs for use in clinical trials of how this evidence supports the use of these treat- investigational drugs be have robust reliability, ments in the context of the new ISSM criteria reproducibility, and internal validity and should conform to the guidelines of the relevant regula-tory agency [30]. Although each of the three PROs Evidence Acquisition
of PE (IELT, control, and distress) has been opera- All studies of oral treatments for PE published tionalized, they may not be equally weighted, may in peer-reviewed medical journals since 2004 vary in importance between subjects, and may have Definition of approximations of the ISSM criteria for lifelong PE Applied consensus criteria for elements of ISSM = International Society for Sexual Medicine; PE = premature ejaculation; IELT = intravaginal ejaculatory latency time; PRO = patient-reported outcome.
Efficacy and Safety of Oral Agents for PE Efficacy and Safety of Oral Agents for PE differing meanings in different cultures where the Impression-Improvement (CGI-I) scale. None attitude of the partner and culturally determined of these studies enrolled men who met an appro- extent of emancipation may have an impact upon ximation of the ISSM criteria. A meta-analysis the subject’s subjective diagnosis of PE. Inven- of published data suggests that daily dosing of tories must be psychometrically validated to paroxetine exerts the strongest ejaculation delay, demonstrate reliability, convergent and divergent increasing IELT approximately 8.8-fold over validity, and sensitivity between individual items and items within domains in order to provide areliable tool to detect changes in subjects with PE.
Many of the inventories used in contemporary PE A 2005 systematic review [20] identified a single observational and interventional trials have been study of PDE-5 inhibitors that fulfilled the criteria for a well-designed PE trial. This study [27] showed that men (N = 144) who met an approxi- measure in PE studies is IELT, reported as an mation of the ISSM criteria for PE had a nonsig- average (arithmetic mean) [11,12,14,31], geomet- nificant (P = 0.3) increase in IELT (minutes) after ric mean [12,14,31], or fold-increase (proportional 8 weeks of treatment with sildenafil (baseline, 1.04; increase from baseline) [31]. Some studies do not endpoint, 2.60) compared with placebo (baseline, describe how IELT data were collected and/or 0.96; endpoint, 1.63). Subjects randomized to analyzed [4,23–27], and those studies were not sildenafil demonstrated significantly higher scores for the IPE items of ejaculatory control (1.8 vs.
Control over ejaculation and PE-related dis- 1.5, respectively), ejaculatory confidence (2.2 vs.
tress or bother have not been as commonly evalu- 1.9, respectively), and overall sexual satisfaction ated, and their assessment has been hampered by (3.1 vs. 2.8, respectively) at the end of treatment the array of instruments available. These PROs are (P < 0.05 vs. placebo for all); PE-related distress or assessed using single-item questions or as part of bother were not evaluated. One additional well- validated instruments, such as the Index of Prema- designed study [21] was identified, in which 42 ture Ejaculation (IPE) [32], the Premature Ejacu- potent men with lifelong PE (based on the ISSM definition) were randomized to receive on-demand Chinese Index of Premature Ejaculation (CIPE) vardenafil or placebo. In this study, vardenafil was [34], the Arabic Index of Premature Ejaculation associated with a 7.5-fold increase in geometric (AIPE) [35], and the Premature Ejaculation Profile mean IELT (0.6 Ϯ 0.3 vs. 4.5 Ϯ 1.1 minute with (PEP) [11,13,36,37]; other instruments, such placebo; P < 0.01), and significant improvements as the International Index of Erectile Function in the IPE domains of ejaculatory control, confi- (IIEF) [38,39] and Yonsei Sexual Function Inven- dence, overall sexual satisfaction, and distress.
tory (YSFI) [40], have also been utilized. Studies This study suggests that the role of PDE-5 inhibi- that did not include PROs were not excluded from tors should be further evaluated in additional well-designed studies. A 2007 review of PDE-5inhibitors for PE considered preclinical and Efficacy of Oral Agents in the Treatment of PE clinical data to understand potential central and Table 3 summarizes the efficacy results from peripheral mechanisms of action of these agents well-designed studies (randomized, double-blind, and their overall effectiveness in PE [42]. The placebo-controlled trials that included stopwatch- authors concluded that data were limited but measured IELT) of oral agents in the treatment of encouraging, and emphasized the need for large, studies of these agents in men with PE.
This review identified five well-designed studies Sexual Dysfunction (ICSD) and International of SSRIs and clomipramine for the treatment Society for Sexual Medicine’s Guidelines for the of PE. Compared with placebo, daily fluoxetine Diagnosis and Treatment of Premature Ejacula- [22,24], citalopram [26], duloxetine [25], and clo- tion have assigned level 4d evidence to support the mipramine [4] significantly increased IELT. Few efficacy and safety of off-label on-demand or daily validated PROs were reported, although duloxet- dosing of PDE-5 inhibitors in the treatment of ine [25] and citalopram [26] were associated with lifelong PE in men with normal erectile function.
improvements in PE based on the Clinical Global Treatment of lifelong PE with PDE-5 inhibitors in Efficacy and Safety of Oral Agents for PE Efficacy and Safety of Oral Agents for PE men with normal erectile function is not recom- mended and further evidence-based research is Sexual Dysfunction (ICSD) and International encouraged to understand conflicting data [43,44].
Society for Sexual Medicine’s Guidelines for theDiagnosis and Treatment of Premature Ejacula- tion have assigned level 2d evidence to support No well-designed studies of a1-receptor antago- the efficacy and safety of daily dosing of nists in treating PE were identified, although two a1-adrenoceptor antagonists and tramadol in the studies were found that evaluated measures of sat- treatment of PE and their use as a treatment for isfaction and subjective feelings of improvement [6,7]. In the first study [6], subjects received tera- zosin, alfuzosin, and placebo for 2 months each, One well-designed study [23] compared the effi- and approximately 50% of the subjects reported cacy of fluoxetine and tadalafil alone and in com- that their ejaculation time had been sufficiently bination in men who met an approximation of prolonged to satisfy both partners following active the ISSM criteria for lifelong PE. Mean IELT treatment (vs. 24% with placebo, P < 0.05 for increased from 51.3 seconds across groups at base- both). In the second study [7], 35% of men with line to 233.6 seconds with fluoxetine, 186.5 PE and lower urinary tract symptoms (without seconds with tadalafil, and 336.1 seconds with flu- chronic prostatitis or benign prostatic hyperplasia oxetine plus tadalafil (vs. 67.8 seconds with [BPH]) treated with terazosin for 1 month were placebo; P Յ 0.001 for all). Assessments of control able to delay their ejaculation until their partner over ejaculation or ejaculation-related distress or reached orgasm, and 33.3% were able to increase their time to ejaculation; however, it is unclearhow time to ejaculation was measured. Both studies were limited by the use of nonvalidated Dapoxetine was evaluated in five large random- endpoints of patient impression of change and ized, double-blind, placebo-controlled phase III sexual satisfaction, and they did not evaluate actual trials including >6,000 men in >25 countries; four of these trials met the criteria for a well-designedstudy [11,12,14], while one study was conducted primarily to evaluate safety [13]. Dapoxetine is the While no studies met the criteria for a well- only SSRI for which well-designed studies in PE designed study, tramadol has been evaluated in a populations have included on-demand dosing.
single-blind, placebo-controlled study, and in an Results summarized in Table 3 report each manu- open-label study. On-demand tramadol (25 mg) script individually; data below are from an inte- significantly increased IELT vs. placebo in 60 men grated analysis [31] and is the only study where with lifelong PE (P < 0.0001) [8,9]. In the open- results are reported separately for men with IELTs label crossover comparator study of daily paroxet- of Յ1 minute and Յ0.5 minute, as well as for the ine (20 mg) and on-demand tramadol (50 mg) in overall study population. In the four studies that 35 subjects with lifelong PE, superior IELT fold- evaluated IELT, increases in IELT were signifi- increases and PRO responses were demonstrated cantly (P < 0.001) greater with dapoxetine vs.
with paroxetine (22-fold vs. fivefold for tramadol) placebo beginning with the first dose, which was after 12 weeks of treatment [9]. Although this maintained at all subsequent time points [31].
study was limited by the use of the Diagnostic and Dapoxetine 30 and 60 mg on-demand significantly Statistical Manual of Mental Disorders Fourth increased arithmetic and geometric mean IELT Edition Text Revision (DSM-IV-TR) definition compared with placebo (1.9 and 1.2 minutes for to diagnose PE, 66% of men had an IELT of placebo, 3.1 and 2.0 minutes for dapoxetine 30 mg, Յ1 minute at baseline, suggesting that the overall and 3.6 and 2.3 minutes for dapoxetine 60 mg, population is reasonably representative of the respectively). This represents a 1.6-, 2.5-, and 3.0- ISSM definition. A large, international, prospec- fold increase over baseline geometric mean IELT tive, randomized, placebo-controlled, double- for placebo, dapoxetine 30 mg, and dapoxetine blind trial of tramadol for the treatment of PE 60 mg, respectively. IELT increases with dapoxet- (NCT00983151) was recently stopped prema- ine were significantly (P < 0.001) greater than turely, although no reason has been provided; placebo beginning with the first dose, which was maintained at all subsequent time points. Similar stopped because of recruitment difficulties.
results were observed in men with IELTs Յ1 minute and Յ0.5 minute at baseline. Progressively lation at Week 12 (vs. 41.9% with placebo, greater fold-increases were observed with decreas- P < 0.001) and to 34.9% and 28.8% with dapoxet- ing baseline average IELTs. Subjects with baseline ine 30 and 60 mg, respectively, among men with average IELTs of 1.5–2 minutes, 1–1.5 minutes, IELT values of <1 minute at baseline (vs. 50.7% 0.5–1 minute, and less than 0.5 minute showed with placebo, P < 0.001). Approximately, one- geometric mean fold-increases of 1.5, 1.6, 1.6, and third of the subjects reported “quite a bit” or 1.7, respectively, with placebo treatment; 2.2, 2.3, “extremely” for their level of ejaculation-related 2.4, and 3.4, respectively, with dapoxetine 30 mg; interpersonal difficulty at baseline; by Week 12, and 2.6, 2.5, 3.0, and 4.3 with dapoxetine 60 mg.
this decreased among the overall population to The PEP [45] or individual PEP items were 16.0% and 12.3% with dapoxetine 30 and 60 mg, used to evaluate control over ejaculation (five respectively (vs. 23.8% with placebo, P < 0.001) trials), satisfaction with sexual intercourse (five and to 17.7% and 13.9% with dapoxetine 30 and trials), and ejaculation-related personal distress 60 mg, respectively, among men with IELT values and interpersonal difficulty (three trials). Clinical of <1 minute at baseline (vs. 28.2% with placebo, global impression of change (CGI) in PE was P < 0.001). Significantly more men receiving also measured on a 7-point scale (five trials). Two dapoxetine 30 or 60 mg reported that their PE was studies [12,14] included stopwatch-measured at least “better” at Week 12 (30.7% and 38.3%, IELT and all four PEP items and enrolled men respectively, among the overall population and based on an IELT of Յ2 minutes on 75% of 25.2% and 34.9% for men with IELT values of <1 occasions, low control over ejaculation, and minute at baseline, respectively) compared with placebo (13.9% and 9.4% among the overall popu- varied populations in each study, and the use of the lation and for men with IELT values of <1 minute DSM-IV-TR definition to diagnose PE, the at baseline, respectively; P Յ 0.05 for all).
overall population was reasonably representative The dapoxetine phase III study populations of of the ISSM definition of lifelong PE (64.9% had >6,000 men represented a heterogeneous popula- lifelong PE; 58% had an IELT <1 minute).
tion with both lifelong and acquired PE and Overall, subjects reported significant improve- included some men with mild erectile dysfunction ments in all PEP items with dapoxetine (P Յ 0.001 (ED). In a post-hoc analysis of data from three vs. placebo for all), and results were similar for phase 3 clinical trials [46], study-end dapoxetine men with IELT values of <1 minute at baseline mean IELT and PRO responses were superior [31]. “Good” or “very good” control over ejacula- to placebo and dose-dependent, with a similar tion was reported by <1% across groups at baseline pattern for men with lifelong and acquired PE.
However, the presence of mild ED diminished tion (26.2% with dapoxetine 30 mg and 30.2% PRO responsiveness in both subtypes, particularly with dapoxetine 60 mg vs. 11.2% with placebo; P < 0.001 for both) and among men with IELT Female partners also reported improvements in values of <1 minute at baseline (19.7% with dapox- sexual functioning [31], including their perception etine 30 mg and 26.0% with dapoxetine 60 mg vs.
of the male subject’s control over ejaculation 7.2% with placebo; P < 0.001 for both) at 12 and CGIC and their own satisfaction with sexual weeks. Similarly, “good” or “very good” satisfac- intercourse in three studies [11,12], and their tion with sexual intercourse was reported by own ejaculation-related interpersonal difficulty approximately 15.0% of men across groups at and personal distress in one study [12]. Significant baseline and increased among the overall popula- improvements in partner perception of the man’s tion (37.9% with dapoxetine 30 mg and 42.8% control over ejaculation and CGIC were observed with dapoxetine 60 mg vs. 24.4% with placebo; at Week 12; 26.7% and 34.3% reported the man’s P < 0.001 for both) and among men with IELT control over ejaculation as “good” or “very good” values of <1 minute at baseline (32.9% with dapox- with dapoxetine 30 and 60 mg, respectively, vs.
etine 30 mg and 40.0% with dapoxetine 60 mg vs.
11.9% with placebo (P < 0.0001 for both) [31].
32.9% with placebo; P < 0.001 for both) at 12 Female partners of men treated with dapoxetine weeks. At baseline, ~70% of subjects across groups also reported significant improvements in their reported their level of ejaculation-related personal own satisfaction with sexual intercourse, with distress as “quite a bit” or “extremely,” which 37.5% and 44.7% reporting “good” or “very decreased to 28.2% and 22.2% with dapoxetine 30 good” satisfaction with sexual intercourse with and 60 mg, respectively, among the overall popu- dapoxetine 30 and 60 mg, respectively, vs. 24.0% Efficacy and Safety of Oral Agents for PE with placebo at Week 12 (P < 0.001 for both). Sig- that withdrawal-like symptoms following abrupt nificant improvements in female partner-rated discontinuation of citalopram are mild and tran- ejaculation-related personal distress and interper- sient, and are likely associated with the re- sonal difficulty related to ejaculation were also emergence of depression [51]. None of the observed with dapoxetine vs. placebo.
well-designed studies of SSRIs in men withPE specifically evaluated class-related effects, although improvements in psychometric assess- The safety and tolerability findings from well- ments, including Symptom Checklist 90-R scores, designed studies of oral agents for PE are summa- Dyadic Adjustment Scale scores, and measures of anxiety were reported with clomipramine [4].
In well-designed studies of SSRI antidepressants In the two well-designed studies of PDE-5 inhibi- in PE subjects, adverse events (AEs) were reported tors (sildenafil and vardenafil) identified in this by 3 of 13 men receiving citalopram [25,26] and 3 review, the overall incidence of AEs was not of 10 men receiving duloxetine, but AE incidence reported; however, the most common AEs included was not reported in every study (Table 4). The headache (10–15%), flushing (12–15%), dyspepsia most common AEs included nausea, dry mouth, (5–10%), abnormal vision (5%), and rhinitis (5%), headache, and insomnia. Two of nine men receiv- which tended to attenuate and disappear with con- ing fluoxetine discontinued because of AEs (nausea tinued use [21,27]. These data are similar to those and insomnia) [24]. None of these studies reported reported in a recent systematic review [52] of the the incidence of serious AEs. It is important to use of PDE-5 inhibitors in men with ED. In that note that these studies used chronic daily dosing, analysis, overall AE rates were 50% with sildenafil based on the dosing schedule used in the approved and 47% with tadalafil; the overall AE rate for indications. However, these agents may be taken as needed or continuously [47], which may alter the included headache (13–17%), dyspepsia (3.8– incidence of AEs and may influence patient pref- 10%), flushing (4.8–13%), and rhinitis (3.1–7.9%).
erence for a particular dosing schedule [48].
The rate of serious AEs was low (1.2–2.5%).
The majority of safety and AE information for SSRIs is derived from studies in subjects with In the study [6] by Cavallini comparing alfuzosin depression and other psychiatric/behavioral disor- and terazosin with placebo, hypotension was the ders. In a meta-analysis [49] of studies in patients most common AE leading to discontinuation (four with major depressive disorder, the incidence of patients [4.4%]; two each with terazosin and alfu- AEs with SSRIs ranged from 8.5% to 16.3% and zosin). Other AEs included headache (one patient included dry mouth, nausea, dizziness, head- with alfuzosin) and headache with epigastralgia ache, fatigue, constipation, diarrhea, somnolence, (one patient with terazosin), neither of which insomnia, nervousness, sweating, and anorexia.
resulted in discontinuation. In the study by Bas¸ar SSRIs have several class-related effects, includ- and coworkers of terazosin vs. placebo daily for 1 ing agitation, irritability, unusual changes in month [6], published safety data were limited to behavior, anxiety, impulsivity, akathisia, hypoma- the finding that none of the patients discontinued nia, mania, and the potential for suicidality in chil- treatment because of AEs. These data in men with dren, adolescents, and young adults. Abrupt PE are comparable to what has been observed discontinuation of SSRIs may result in SSRI with- in men with hypertension or BPH. The most drawal syndrome (typically characterized by head- common AEs with terazosin include postural ache, diarrhea, nausea, vomiting, chills, dizziness, hypotension (3.9%), dizziness (9.1%), somnolence or fatigue). One retrospective study [50] of (3.6%), nasal congestion/rhinitis (1.9%), and patients (N = 352) who were treated with SSRIs impotence (1.6%) [53]. With alfuzosin, common reported that 30.8%, 20.0%, and 2.2% of subjects AEs in men with BPH include dizziness (5.7%), who discontinued treatment with clomipramine, upper respiratory infections (3.0%), headache paroxetine, and sertraline, respectively, experi- enced withdrawal symptoms; no subjects reportedsymptoms following discontinuation of fluoxetine.
Data on SSRI withdrawal symptoms with citalo- In the single-blind, placebo-controlled study, eight pram are limited; however, it has been reported (13.3%) men experienced mild dyspepsia (n = 5) Efficacy and Safety of Oral Agents for PE Efficacy and Safety of Oral Agents for PE and mild somnolence (n = 3) with tramadol [8].
and 60 mg, respectively, most commonly because Tramadol was generally tolerated in the open-label of nausea, dizziness, and diarrhea. Syncope study, with gastric upset being the most common (including loss of consciousness), which appeared AE [9]. No serious AEs or AE-related discontinu- to be vasovagal in nature and generally occurred ations were reported in either study. These AEs within 3 hours of the first dose, was reported in are similar to what has been reported with trama- 0.05%, 0.06% and 0.23% of subjects with placebo, dol in other populations. A recent meta-analysis dapoxetine 30 mg, and dapoxetine 60 mg, respec- [54] of 11 controlled studies of tramadol in more tively [31]. Syncope occurred more frequently than 1,000 patients with osteoarthritis reported when dapoxetine was administered at one of the that the most common AEs were nausea, vomiting, study sites (onsite [0.31%] vs. offsite [0.08%]), dizziness, somnolence, tiredness, and headache, appeared to be related to syncope-associated and approximately 20% of patients receiving tra- onsite study procedures (e.g., blood draws or madol or tramadol/acetaminophen experienced orthostatic maneuvers) and occurred almost exclu- nonserious AEs. Although tramadol is reported to sively with dapoxetine 60 mg, with only one have a lower risk of dependence than traditional reported episode with the 30-mg dose. Similar opioids, its use as an on-demand treatment for PE observations have been reported with other SSRIs, is limited by the potential risk of addiction [55]. In and these events resolved without sequelae.
community practice, dependence does occur, but Dapoxetine is the only agent for which studies appears to be minimal [56]. Adams and colleagues have been adequately powered and designed to [57] reported abuse rates of 0.7% for tramadol assess SSRI class-related effects in a PE popu- compared with 0.5% for nonsteroidal anti- lation. Dapoxetine was not associated with inflammatory drugs and 1.2% for hydrocodone, treatment-emergent anxiety (measured by the based on application of a dependency algorithm as Hamilton Anxiety Scale), depression (measured by a measure of persistence of drug use.
the Montgomery-Åsberg Depression Rating Scaleand the Beck Depression Inventory II), or suicid- ality [31]. Abrupt discontinuation of dapoxetine There are limited data regarding the safety and was not associated with an increased incidence tolerability of combination treatments for PE. In of withdrawal syndrome compared with placebo the study that evaluated fluoxetine, tadalafil, and fluoxetine plus tadalafil, the overall incidence of Discontinuation-emergent Signs and Symptoms AEs was higher with the combination (40%) com- pared with either drug alone (fluoxetine, 33%; tad-alafil, 26%) or placebo (12%); common AEs withfluoxetine plus tadalafil included somnolence, Discussion
nausea, palpitation, and muscle soreness [23].
This review is limited by the author’s attempt to retrospectively apply the contemporary ISSM Similar AE profiles have been reported across the definition of lifelong PE to previously conducted phase III trials of dapoxetine [20]. In the integrated intervention studies that employed differing analysis of these studies [31], AEs occurred in 651/ inclusion/exclusion criteria and study endpoints.
1,857 (35.1%), 760/1,616 (47.0%), 1,270/2,106 The attempt to approximate data from studies (60.3%), and 341/502 (67.9%) subjects with enrolling a heterogenous population of both life- placebo, dapoxetine 30 mg prn, dapoxetine 60 mg long and acquired PE to the ISSM definition of prn, and dapoxetine 60 mg qd, respectively. The lifelong PE is somewhat balanced by the recently published post-hoc analysis of dapoxetine phase 3 nausea, diarrhea, headache, dizziness, insomnia, baseline and treatment outcome data suggesting somnolence, fatigue, and nasopharyngitis. Nausea that there are substantial similarities in baseline was the most common AE associated with discon- IELT, PROs and response to dapoxetine between tinuation. Sexual function AEs occurred in a low percentage of subjects across groups.
While many of the well-designed studies of oral Severe or serious AEs occurred infrequently agents in PE included in this review may be con- (~3% and Յ1%, respectively), and most AEs were sidered to have at least partially met the ISSM of mild to moderate severity [31]. Across trials, criteria for lifelong PE for their study populations, AE-related discontinuation occurred in 1.7–4.0% few used validated PRO measures for control over and 5.1–10.0% of subjects receiving dapoxetine 30 ejaculation and PE-related distress or bother, or included detailed prospective reporting of SSRI Administration schedules also varied among class-related AEs. All of these studies were con- studies. As mentioned above, in the studies of ducted prior to the existence of the ISSM defini- SSRI antidepressants included in this review, tion of lifelong PE and the development of PE chronic daily dosing was used. SSRIs were devel- inventories; however, these elements have been oped for daily use in chronic diseases, and their included in most earlier criteria, such as those pro- pharmacokinetic profiles are characteristic of posed by the DSM-IV-TR [58], the American agents intended to remain at therapeutic concen- Urological Association [59], and the International trations for extended periods of time. Daily Consultation on Urological Diseases [60].
administration of these agents results in the There is a wide disparity in AE reporting chronic blockade of serotonin transport, leading to amongst studies of oral agents. By convention, the desensitization of presynaptic 5-HT1A autore- AEs are reported retrospectively by the subject at the next trial visit, and are recorded and rated by receptors and resultant greater increases in 5-HT the investigator using Medical Dictionary for neurotransmission [62–65], a principal factor Regulatory Activities [61] coding by their relation thought to contribute to both the therapeutic and to the trial drug. However, trial visits may be up to adverse effects of these agents. Daily dosing also 4 weeks apart, prompting concerns regarding the results in significant accumulation (approximately reliability of subject recall of the AE frequency, eightfold with paroxetine [66] and twofold with severity, duration and/or temporal relation to sertraline [67]. PDE-5 inhibitors, tramadol, and administration. Prospective reporting of AEs dapoxetine are all intended for and evaluated with within 24 hours in a subject diary using a validated on-demand administration. In contrast to long- questionnaire, such as the Udvalg for Kliniske acting SSRIs, dapoxetine has a rapid pharmacoki- Undersogelser (UKU) side effect rating scale netic profile; maximum plasma concentrations are for psychotropic/neuroleptic drugs, has been reached approximately 1 hour after oral adminis- tration and fall to less than 5% of this peak within A wide range of diagnostic criteria were used for PE in these clinical trials. Few trials enrolled men Current understanding of the safety and toler- who approximately met the ISSM criteria. While ability of SSRIs, PDE-5 inhibitors, a1-antagonists, all of the studies included here implemented an and tramadol in the treatment of PE relies heavily IELT threshold in their enrollment criteria, differ- on results from studies in other patient popula- ent thresholds were applied (i.e., <1 minute, Յ2 tions (e.g., depression, ED, BPH, and chronic, minutes); differences in baseline IELT may have a severe musculoskeletal pain). In addition, men profound impact on the apparent magnitude of with many of the approved indications for these IELT increases with treatment. Further, no more treatments are excluded from PE trials, despite the than a handful of studies incorporated both an fact that men with PE frequently have comorbid IELT threshold and PRO measures for control conditions such as depression or ED. Further over ejaculation and PE-related distress or bother study is necessary to determine the safety and tol- [11,12,14,21,27], leaving only IELT as the main erability of these agents in a PE population and in outcome measure for contrasting efficacy results men with PE and comorbid conditions.
The ISSM criteria for lifelong PE provide an The wide variability among PE study designs evidence-based definition of PE that can be used as also complicates their comparison and interpreta- a standard in future trial design; in contrast, no tion. Studies have ranged in length from 4 to 24 evidence-based definition of acquired PE has been weeks, and the impact of treatment duration put forth. The ISSM was unable to define acquired on outcomes is unclear. Various methods were PE because of a lack of sufficient normative data used for reporting IELT outcomes, including [15]. As noted recently by Jannini [69], clinical trials arithmetic mean, geometric mean, or fold-increase of dapoxetine contained men with acquired PE as from baseline. Further, a wide range of validated well as men with lifelong PE, and dapoxetine was and unvalidated PRO instruments have been used, shown to be effective in both groups. These trials complicating the comparison of PRO results typically included stopwatch-measured IELT and between studies. There is a need for consensus on validated PRO measures of control over ejaculation the appropriate use and application of PRO mea- and distress or bother related to PE; therefore, sures to ensure interpretability of results across information from these trials may provide some insight into the clinical picture of acquired PE.
Efficacy and Safety of Oral Agents for PE Conclusions
Statement of Authorship
Improvements in PE with treatment should be evaluated based on the characteristics that define (a) Conception and Design
the condition. According to the new ISSM cri- teria, the parameters of importance are IELT, (b) Acquisition of Data
control over ejaculation, and negative psychologi- cal consequences such as distress, bother, fru- (c) Analysis and Interpretation of Data
stration, and sexual avoidance. This systematic review of well-designed trials in PE demonstratedthat many agents, particularly SSRI antidepres- sants and dapoxetine, are effective and well tol- (a) Drafting the Article
erated for the treatment of men with PE.
(b) Revising It for Intellectual Content
Evidence for the effectiveness of PDE-5 inhibi- tors, a1-receptor antagonists, and tramadol iscurrently weak and none are currently recom- mended as treatment for PE with the exception (a) Final Approval of the Completed Article
acquired PE. While most studies now reportstopwatch-measured IELT, the ISSM lifelong PEcriteria of control-over-ejaculation and PE- References
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