ORIG INAL ARTICLE
Safety and efficacy of venlafaxine in the treatment of premature ejaculation:a double-blind,
placebo-controlled,fixed-do,randomid study M.R.Safarinejad
Urology and Nephrology Rearch Center,Shahid Beheshti University(MS),Tehran,Iran
Introduction
From an epidemiological perspective,premature ejacula-tion(PE)has been reported as the most common male xual dysfunction with overall prevalence rates estimated at around30%(Laumann et al.,1999).PE is defined by the Diagnostic and Statistical Manual of Mental Disorders (revision IV)(DSM-IV-TR)as‘the persistent or recurrent ejaculation with minimal stimulation before,on,or shortly after penetration and before the person wishes it’(American Psychiatric Association,1994).It can be a source of distress for many men,and its effect can extend to the xual partner,becau PE hampers them in expe-riencing pleasing feelings of intimacy and vaginal-induced orgasm.The causal pathophysiology of PE is largely unknown,although both physiological and psychological components have been propod.
Behavioural therapy and psychological counlling are the historically initial approaches in the treatment of PE. There is no evidence that nondrug therapy is able to guarantee long-term cure or improvement of PE(Ron, 2004).The techniques require active involvement of the patients and their partners and the benefits are gen-erally short-lived,and patients usually relap.In addi-tion,the therapies may not be applicable for some cultural and socioeconomic groups.Therefore,some pharmacological agents have been propod for the treatment of PE.The rotoninergic system has an inhibitory effect on the ejaculatory reflex.Selective ro-tonin reuptake inhibitors(SSRIs)(paroxetine,fluoxetine, rtraline,citalopram)are reported to be effective for treating PE(Ron,2004;Safarinejad&Hosini, 2006a).In addition,lective noradrenaline reuptake inhibitors nortriptyline and protriptyline have been
Keywords
Escitalopram—premature ejaculation—rotonin—xual dysfunction—treatment
Correspondence
M.R.Safarinejad,MD,Urology and Nephrology Rearch Center,Shahid Beheshti University(MS),PO Box19395-1849,Tehran, Iran.
Tel.:+982122454499;
Fax:+982122456845;
E-mail:safarinejad@urologist.md
admireAccepted:October12,2007Summary
Venlafaxine is a rotonin–noradrenaline reuptake inhibitor antidepressant. Two hundred and twenty-two married men(mean age,34years)with prema-ture ejaculation(PE)were randomly assigned to receive75mg of venlafaxine extended relea(n=112)(group1)or placebo(n=110)(group2)for 12weeks.Pre-treatment evaluation included history and physical examination, geometric mean intravaginal ejaculatory latency time(IELT)and International Index of Erectile Function(IIEF).The efficacy of two treatments was assd every2weeks during treatment,and at the end of study,using respons to IIEF,IELT evaluation,mean intercour satisfaction domain,mean weekly coitus episodes and adver drug effects.At the end of treatment period,the geometric mean IELT in venlafaxine and placebo group demonstrated1.7-fold (95%CI:0.76–1.96)and 1.6-fold(95%CI:0.87–1.84)increa respectively (P=0.1).The mean weekly intercour episodes incread from pre-treatment values of1.2and1.18to2.1and1.9for venlafaxine and placebo respectively (P=0.08).Balin
e mean intercour satisfaction domain values of IIEF12 and12reached to13and12at12-week treatment in groups1and2respec-tively(P=0.07).Mean number of adver events was32for venlafaxine and8 for placebo(P=0.02).Venlafaxine is not better than placebo in treatment of PE.
found to be associated with delayed ejaculation(Pollack et al.,1992).Psychopharmacological studies suggest that PE might be due to decread rotonergic neurotrans-mission through pathways that control ejaculation (Waldinger et al.,1998).
Ejaculation delay induced by SSRIs is due to alterations in specific rotonin receptors in the central nervous sys-tem.The ejaculation-retarding effect of5-hydroxytrypta-mine(5-HT,rotonin)has been attributed to the activation of5-HT1B and5-HT2C receptors.By contrast, stimulation of5-HT1A receptors has facilitator effect on ejaculation(Giuliano,2007).The net effect of acute SSRI administration is only a mild or no increa of5-HT neu-rotransmission and mild or no stimulation of the various post-synaptic rotonin receptors(Waldinger et al.,2005). In contrast,chronic SSRI administration is associated with more5-HT(rotonin)relea into the synap,stronger increa of5-HT neurotransmission,and as a result dura-ble activation of post-synaptic5-HT receptors(Blier et al.,1988).
Venlafaxine(1-[2-(dimethylamino)-1-(4-methoxy-phenyl) ethyl]cyclohexanol hydrochloride)is thefirst member of a newer class of antidepressants now referred to as rotonin–noradrenaline reuptake inhibitors(SNRIs) (Holliday&Benfield,1995).Venlafaxine inhibits the neuronal reuptake of both rotonin and noradrenaline. Noradrenaline facilitates libido and erections(Pfaus& Everitt,1995)and the benefit effects of rotonin on x-ual function become manifest only when central nor-adrenaline activity is intact(Fernandez-Guasti et al., 1986).It has been shown that dopamine agonists enhance psychogenic erections and xual motivation(Ferrari et al.,2002).Venlafaxine is also a weak inhibitor of dopa-mine reuptake(Muth et al.,1986).Therefore,venlafaxine may be a more effective treatment for PE than other SSRIs.
Notably,an extended-relea formulation of venlafaxine (i.e.venlafaxine XR)is now available.Once-daily dosing exhibits a better benefit/risk ratio than does the immedi-ate relea formulation(Entsuah&Hitra,1997).In a pilot,single-blind,placebo-controlled,fixed-do cross-over study,short-term u of venlafaxine XR75mg day)1 has only a placebo effect on ejaculation latency and xual satisfaction scores(Kilic et al.,2005). Pharmacological management of PE with various agents has been yielded variable success rates.In some reports,after the end of therapy,the PE recurs in as much as90%of patients(Ludovico et al.,1996).There is still a need for the development o
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f a clinically effec-tive treatment for this xual dysfunction.To our knowledge,this is thefirst controlled long-term study to asss the efficacy of venlafaxine in the treat-ment of PE.Materials and methods
Study design
Between January2005and July2006,222married men with PE entered the study(mean age,34years;range 22–48years).PE was defined as an intravaginal ejacula-tory latency time(IELT)of<2min that occurred in more than90%of intercours.The IELT was the time between the start of vaginal inrtion and the start of intravaginal ejaculation(Waldinger et al.,1994).After procedures and possible side effects were explained to patients,all subjects gave their written informed connt before entering the study,which was conducted in accordance with the Declaration of Helsinki.The local Medical Ethical Committee approved the study.At the first visit,patients and their wives were interviewed individually by the author.All men were married,had no other xual disorders,were in a stable relationship with their wives for at least the previous6months and had possible xual intercour‡1per week.They received a diary in which to record coitus frequency and adver drug-related effects and were asked to mea-sure IELT using a stopwatch.Couples were also instructed not to u condoms or topical anaesthetic cream,not to pau during intercour or t
o have inter-rupted intromission.Furthermore,they requested if intercour took place more than once in a single s-sion,only thefirst intercour be measured.A stop-watch and instructions on how to measure the IELT were also provided.The study was not advertid,and no remuneration was offered.
Evaluations
The initial evaluation of each patient included a medi-cal and xual history,physical examination and struc-tured interview diagnostic of mental and physical disorders,IELT and lf-administration of International Index of Erectile Function(IIEF)(Ron et al.,1997). Pre-treatment IELT was measured by wives during a4-week baline period,during which patients were requested to experience coitus at least four times.Pre-treatment frequency of xual intercour was the mean number of attempts per week during the previous 4weeks.To be able to exclude organic xual dysfunc-tion,fasting blood gluco level,urine analysis,com-plete blood count,x hormones and prolactin levels were measured.Meares–Stamey test was also performed to exclude genital tract infection when necessary.All patients were asked to indicate their xual satisfaction on a scale of0–5as propod by Kim&Paick(1999), with0being extremely dissatisfied and5extremely satisfied.
Venlafaxine for treatment of premature ejaculation M.R.Safarinejad
Inclusion/exclusion criteria
Only patients without any obvious organic cau of PE, possible xual intercour‡1per week and initiation to ek medical help for what they considered PE were included.All patients were free of all medications for at least the previous4weeks.Patients with erectile dysfunc-tion according to IIEF,reduced xual desire,inhibited male orgasm,chronic psychiatric or physical illness,alco-hol or substance abu and u of medication,including psychotropic medication,an organic cau of PE includ-ing anatomical abnormalities,genital infection and neuro-logical disorder,organic illness causing limitation in SSRI u and rious relationship problems were excluded from the trial.There were no statistical differences in IELT, IIEF and mean coitus attempts per week between two groups.
Medical treatment
Each eligible patient was given a randomisation number using an interactive voice respon system,which fol-lowed a randomisation table generated by the method of random permuted blocks.At baline(week0),the patients were randomly assigned to take75mg of venla-faxine XR orally daily(group1,n=112),or a similar regimen of placebo(group2,n=110)during the 12-week treatment period.The placebo was a starch com-pound with the same colour and size of venlafaxine.
All of the men were asked not to consume alcoholic drinks within6hours of xual activity.None of the patients underwent formal psychoxual counlling.Treatment was administered in a randomid quence that remained unknown to the patient and to the physicians. Persons who geographically and operationally were inde-pendent from the study investigator did the randomisa-tion of the study.
Outcome measures
Patients were screened on week)4.Baline measure-ments were taken on day)1,and efficacy asssments were made every2weeks after the initial do of venla-faxine on day1,and at the end of12-week treatment per-iod.For the analysis of efficacy and safety,all patients were evaluated in each visit by the author,asssing changes in IELT,mean intercour satisfaction domain, mean weekly intercour episodes and adver drug effects.Patients and their wives were interviewed pa-rately.Safety and tolerability were evaluated on the basis of spontaneously reported adver effects,clinical labora-tory tests,ECGs and physical examinations(including vital signs and weight).All ECGs were resting12-lead,and ECG parameters[PR,RR,and QTcB(Bazzet’s cor-rection)].Supine pul rate and supine and standing blood pressure were measured.
Statistical analysis
boulevard of broken dreamsThe study sample size of222patients was powered for a difference of approximately1SD between the active drugs and placebo group with a statistical power of85% (b=0.15)and assuming an overall10%dropout rate.As the IELT in individual patients usually follows a skewed distribution,we measured geometric mean IELT instead of mean IELT.Thus,the IELT values were logarithmically transformed before statistical analysis,and the results are reported as fold increas from baline with associated 95%confidence intervals(CI).The independent sample tow-tailed t-test was ud to compare the IELTs and frequency of coitus by venlafaxine and placebo.Qualita-tive variables were compared with the u of chi-squared test with Yates correction or Fisher’s exact,when neces-sary.A P value of<0.05was considered statistically signif-icant.Statistical analysis was performed using the computer statistical package spss/10.0(SPSS,Chicago,IL, USA)and sas/6.4(SAS Institute,Cary,NC,USA). Results
Patient disposition/demographics
All patients were en with their wives and interviewed parately about their xual activity and patient’s ejacula-tion function.At baline,the study and placebo groups were similar in demographic and clinical characteristics (Table1).Two hundred and twenty-two patients were recruited,but only192(86.5%)completed the whole randomid trial study(94of112in the venlafaxine group and98o
f110in the placebo group).Thirty patients(13.5%)did not complete the study:eight becau of a lack of effects(four in each group),12 becau of adver effects(10in the venlafaxine group, two in the placebo group)and10were lost to follow-up (four in the venlafaxine group,six in the placebo group). The dropout rates were significantly higher in group1 (P=0.04).Mean patient age was31.5years(range22–46years)in group1and31.3years(range22–46years) in group2(P=0.07).
Treatment efficacy
After12weeks of treatment,IELT did not differ signifi-cantly between the two treatment groups.At the end of 12-week treatment,the venlafaxine group had a1.7-fold (95%CI:0.76–1.96)increa of the geometric mean IELT,
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M.R.Safarinejad Venlafaxine for treatment of premature ejaculation
while after placebo the geometric mean IELT incread 1.6fold (95%CI:0.87–1.84)(P =0.1).During the study,from week 1onward and at the study endpoint (week 12),there were no significant differences between the treatment groups (P =0.1)(Table 2).Neither treatment had significant effect in mean intercour satisfaction rate and mean weekly intercour episodes.The mean pre-treatment weekly intercour episodes were 1.2per week for venlafaxine compared with 1.18for plac
美国大学入学要求ebo.Venlafax-ine did not demonstrate superiority in increasing mean pre-treatment coitus frequency.The mean intercour fre-quency at 12-week treatment was 2.1and 1.9for venla-faxine and placebo respectively (P =0.08)(Table 3).Baline and 12-week mean intercour satisfaction domain values of the IIEF were 12,12and 13,12in groups 1and 2respectively.The patients in venlafaxine group did not report significantly greater intercour sat-isfaction than tho in placebo group (P =0.07)(Table 4).Before treatment,24of the 192patients reported never having experienced intravaginal ejacula-tion.Intravaginal ejaculation was achieved by one of the 13patients (mean age,26.8years)who had never
achieved it at the end of treatment with venlafaxine.Intravaginal ejaculation was not achieved in 11patients with placebo (P =0.1).Data analysis did not show any statistically significant difference in men with lifelong and acquired PE in terms of average baline or 12-week geo-metric mean IELT.Similarly,data did not show signifi-cant differences in men with lifelong and acquired PE regarding geometric mean IELT,IIEF domain,mean weekly coitus episodes and adver effects profiles.Safety
More adver effects were associated with venlafaxine treatment (P =0.02)(Table 5).Thirty-two (28.6%)venla-faxine and eight (7.3%)placebo patients reported treat-ment-related adver events:th
e most common in the
Table 1Patient characteristics
Variables
Venlafaxine (n =106)
Placebo (n =106)
P -value
Mean age,years (range)Patients 31.5(22–46)31.3(22–46)NS Partners
28.5(20–48)27.2(21–48)NS Duration of marriage,years (range)4(1–21)5(1–22)NS Education level Patients Lower 2322NS Middle 3331NS Higher 5657NS Partners Lower 2320NS Middle 2830NS Higher
6160NS Premature ejaculation Lifelong 4043NS Acquired
6257NS Never ejaculated intravaginally 13
11
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NS
NS,not significant.
Table 2Mean IELT (cond)in men with PE in various asssment points Group Baline 2weeks P -value 4weeks P -value 6weeks P -value 8weeks P -value 10weeks P -value 12weeks P -value Venlafaxine 2632NS 38NS 40NS 42NS 44NS 44NS Placebo
29
32
NS
39
NS
technique40
NS
42
NS
48
NS
49
NS
IELT,intravaginal ejaculatory latency time;NS,not significant;PE,Premature ejaculation.
Table 3Mean IELT,frequency of coitus and mean intercour satis-faction domain values of the IIEF
Baline
12weeks
P -value
Group 1
Mean IELT (s)
22440.itus per week 1.2 2.10.08Mean intercour satisfaction domain values of the IIEF 12130.07
Group 2
Mean IELT (s)
29540.itus per week 1.18 1.90.08Mean intercour satisfaction domain values of the IIEF
12120.1
the blind sideIELT,intravaginal ejaculatory latency time,IIEF,International Index of Erectile Function.
Table 4Sexual satisfaction rates of the patients and wives
Satisfied (%)Moderately satisfied (%)Dissatisfied (%)Patients小学生国庆节演讲稿
Wives
Patients
Wives
Patients
Wives
Group 1Baline –––61009412weeks 0*0*4*14*96*86*Group 2Baline –––71009312weeks
1
1
4
12
95
87
*P =0.1versus group 2.
Venlafaxine for treatment of premature ejaculation M.R.Safarinejad
venlafaxine group were naua(30,26.8%),dry mouth (22,19.6%),agitation(12,10.7%),constipation(11, 9.8%)and headache(10,8.9%)(Table5).Ten(8.9%) patients were dropped out of the study becau of side effect in venlafaxine group.The adver events that most commonly resulted in discontinuation were naua,agita-tion and headache.Overall,few clinically important changes in vital signs,body weight or electrocardiographic results were obrved.
Discussion
Premature ejaculation can lower a man’s xual lf-confidence and lf-esteem and negatively affect the overall quality of life of men and their partners.There-fore,PE reprents a major unmet medical challenge. This study was designed to evaluate the effectiveness of venlafaxine XR for the tr
eatment of PE.The study indicates that off-label u of venlafaxine XR,at75mg day)1,is not better than placebo in all outcome mea-sures.Adver effects were noted in the treatment group when compared with the placebo group.The adver effects were significantly more frequent in the venlafaxine group.All of the SSRI studies in PE are not randomid clinical trials(RCTs),and there were some differences in sample size,treatment duration and study design among SSRI efficacy studies.Therefore, major differences in results may be due in part to the differences in design,patient lection and pharmaco-logical properties of drug.Overall,the results of this trial illustrate the challenges now facing clinical phar-macotherapy studies.For example,there is clearly con-siderable difficulty demonstrating that effective SSRIs actually are superior to placebo in contemporary RCTs in long-term follow-up.Despite the potential beneficial effect of SSRIs in the treatment of PE,the mechanism of action has not been fully elucidated.SSRIs have varying affinities for different receptors,including the noradrenaline and dopamine transporters,which might help to explain their differing efficacy in the treatment of PE.For pharmacotherapy rearch of PE,it is recom-mended to u a randomid,double-blind,placebo-controlled,prospective design,the u of the geometric mean IELT,the u of a stopwatch and a scientific defi-nition of PE.There is considerable plurality in5-HT receptors.Therefore,efforts should be focud on the identification of specific receptor(s)for ejaculation. SSRIs,which are ud for the treatment of psychiatric disorders,ca
n delay ejaculation in humans,and are widely ud‘off-label’for the treatment of PE.There are no US Food and Drug Administration-approved medica-tions for the treatment of PE.For delaying ejaculation, stimulation of5-HT2C,5-HT1B and,perhaps,5-HT7 receptors may be effective.8-hydroxy-2-(di-n-propylami-notetralin)(8-OH-DPAT),a lective agonist of5-HT1A receptors,has facilitator effect on ejaculation.A review of the literature indicates a change in focus in the manage-ment of PE from a behavioural model to the other treat-ment modalities,especially drug treatments.Other nonbehavioural methods for the treatment of PE include densitising rings,topical anaesthetic creams or sprays and constriction bands.In dealing with PE,factors affect-ing duration of the excitement pha,such as age,nov-elty of the xual partner or situation and frequency of xual activity,should also be considered.SSRIs require 1–2weeks’chronic dosing to be effective,similar to their u for the treatment of depression.In clinical practice, chronic dosing with an SSRI produces significant ejacula-tion delays;paroxetine has the strongest effect(Walding-er et al.,2004).On-demand SSRI treatment will not lead to within1–2h)relevant stimulation of5-HT post-synaptic receptors(Blier et al.,1988).Clinical expe-rience also indicates that repetitive discontinuation of an-tidepressants could reduce their efficacy(Tiihonen et al., 2006).
Therapeutic window of SSRIs is frequently localid to the period of drug assumption.Thus,the ag
ents are a symptomatic therapy.Human ejaculation is peripherally activated by a1-noradrenergic nerve stimulation (Waldinger et al.,1998).It has been shown that a1-block-ers alphuzosin and terazosin are effective in the treatment of PE(Cavallini,1995).Venlafaxine has an a-agonistic effect.This agonistic effect might also be explanatory for the failure of venlafaxine in treatment of PE.The experi-mental study of Maj&Rogoz(1999)gives us invaluable information about the pharmacology of venlafaxine. They showed that repeated venlafaxine administration decreas the responsiveness of5-HT2receptors to their agonists2,5-dimethoxy-4-iodophenyl-2-aminopropane and L-5-hydroxytryptophan,thus attenuating5-HT neuro-transmission.
To develop effective medical treatments,numerous animal and clinical studies have focud on the roles of
Table5Drug-related side effects
Group1,n(%)Group2,n(%)P-value
Naua30(26.8)1(0.9)0.02
Dry mouth22(19.6)00.02
Agitation12(10.7)1(0.9)0.02
Constipation11(9.8)00.02
minus怎么读Headache10(8.2)2(1.8)0.02
Dizziness3(2.7)2(1.8)0.07
Erectile dysfunction2(1.7)2(1.8)0.09
Loss of libido3(2.7)2(1.8)0.07
M.R.Safarinejad Venlafaxine for treatment of premature ejaculation
