11/3/2017 Prematureejaculation

IndianJUrol.2007AprJun23(2):97108. PMCID:PMC2721550
doi:10.4103/09701591.32056

Prematureejaculation
ChrisG.McMahon
AustralianCentreForSexualHealthSuite24,BerryRoadMedicalCentre1aBerryRdSt.Leonards,Australia
Forcorrespondence:ChrisMcMahon,AustralianCentreForSexualHealthSuite24,BerryRoadMedicalCentre1aBerryRdStLeonards,
Australia.Email:cmcmahon@acsh.com.au

CopyrightIndianJournalofUrology

ThisisanopenaccessarticledistributedunderthetermsoftheCreativeCommonsAttributionLicense,whichpermitsunrestricteduse,
distribution,andreproductioninanymedium,providedtheoriginalworkisproperlycited.

Abstract
Prematureejaculation(PE)isacommonmalesexualdisorder.Recentnormativedatasuggeststhatmenwith
anintravaginalejaculatorylatencytime(IELT)oflessthan1minutehavedefinitePE,whilemenwith
IELTsbetween1and1.5minuteshaveprobablePE.Althoughthereisinsufficientempiricalevidenceto
identifytheetiologyofPE,thereislimitedcorrelationalevidencetosuggestthatmenwithPEhavehigh
levelsofsexualanxietyandinheritedalteredsensitivityofcentral5HT(5hydroxytryptamine,serotonin)
receptors.Pharmacologicalmodulationoftheejaculatorythresholdusingofflabeldailyorondemand
selectiveserotoninreuptakeinhibitorsiswelltoleratedandofferspatientsahighlikelihoodofachieving
improvedejaculatorycontrolwithinafewdaysofinitiatingtreatment,consequentialimprovementsinsexual
desireandothersexualdomains.Investigationaldrugssuchastheejaculoselectiveserotonintransport
inhibitor,dapoxetinerepresentamajordevelopmentinsexualmedicine.Thesedrugsofferpatientsthe
convenienceofondemanddosing,significantimprovementsinIELT,ejaculatorycontrolandsexual
satisfactionwithminimaladverseeffects.

Keywords:Prematureejaculationselectiveserotoninreuptakeinhibitors,dapoxetine,intravaginal
ejaculatorylatencytime,PDE5inhibitors

Prematureejaculation(PE)isoneofthemostcommonmalesexualdisordersandhasbeenestimatedtooccur
in439%ofmeninthegeneralcommunity.[17]TheWorldHealthOrganization(WHO)2ndInternational
ConsultationonSexualHealthdefineditaspersistentorrecurrentejaculationwithminimalstimulation
before,onorshortlyafterpenetrationandbeforethepersonwishesit,overwhichthesuffererhaslittleorno
voluntarycontrolwhichcausesthesuffererand/orhispartnerbotherordistress[8]Thismultivariate
definitionencompassesthemaindimensionsofPEejaculatorylatency,controlandsexualsatisfaction.

Mostcommunitybasedepidemiologicalstudiesarelimitedbytheirrelianceoneitherpatients'selfreportsof
PEorinconsistentandpoorlyvalidateddefinitionsofPE.Arecentmultinationalcommunitybasedage
rangingstudyofanunselectednormalpopulationof500heterosexualcouplesinvolvingstopwatchtiming
oftheintravaginalejaculatorylatencytime(IELT)duringsexualintercourse,hasprovidedpreviouslylacking
normativedata.[9]ThisstudydemonstratedthatthedistributionoftheIELTwaspositivelyskewed,witha
medianIELTof5.4minutes(range,0.5544.1minutes)[Figure1].ThemedianIELTdecreasedwithage
andvariedbetweencountries.Theauthorsregardedthe0.5and2.5percentilesasacceptablestandardsof
diseasedefinitioninthistypeofskeweddistribution.TheyproposedthatmenwithanIELToflessthan1
minute(belongingtothe0.5percentile)havedefiniteprematureejaculation,whilemenwithIELTs
between1and1.5minutes(between0.5and2.5percentiles)haveprobablePE.[10]

Thereislittlepublisheddataontheimpactofbirthcountry,religionorcultureontheprevalenceofPE.An
increasedsusceptibilitytoprematureejaculationinmenfromtheIndiansubcontinenthasbeenreported.
[11,12]Kinsey'sobservationthatAsianmenhaveshortertimestoejaculationthanCaucasians,whointurn
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haveshortertimestoejaculationthanAfroCaribbeans,hasbeeninterpretedtosuggestthatsomeracesare
moresexuallyrestrainedthanothers.[13,14]ArecentstudyreportedapreponderanceofmenfromMiddle
EasternandAsianbackgroundspresentingfortreatmentofPEwhichexceededtherepresentationofthese
ethnicgroupsinthelocalpopulation.[15,16]

Thepremisethatprematureejaculationisapsychosomaticdisturbanceduetoapsychologicallyoveranxious
personalitywasfirstsuggestedbySchapiroin1943.HeclassifiedPEasprimary(lifelong)orsecondary
(acquired).[17]ThebehavioristicviewthatchronicPEwastheresultofperformanceanxietyrelatedtoa
disturbinginitialepisodeofprematureejaculationwasfirstproposedbyMastersandJohnson.[18]Mostof
thebehaviouraltreatmentscurrentlyusedarebasedonthispremise.

Inastudyof1326consecutivemenwithPE,lifelongPEwaspresentin736men(74.4%)andacquiredPE
waspresentin253men(25.6%).[19]MenwithPEappearyoungerthanthosewithoutandafteradjustingfor
concomitanterectiledysfunction(ED),theriskofPEwasfoundtosignificantlydecreasewithaging.[20]
Higherlevelsofeducation,divorceandthepresenceofsocialphobiaappeartoincreasetheriskofPE.
[20,21]AdecreasedriskofPEhasbeenreportedinmenwithtreateddiabetes,whilenoassociationwas
foundwithhypertension,cardiacdisease,hypercholesterolemiaandperipheralorcentralneuropathy.Men
withselfreportedPEhavealowerfrequencyofsexualintercourse,higherlevelsofintercourserelated
anxietyandnotegreaterimpairmentinintercoursesatisfactionandsexualrelationshipsatisfactioncompared
tomenwithoutPE.[22]However,theydonotreportareducedqualityoflife,reducedsexualdesireora
reducedabilitytobecomesexuallyaroused.[8,22]

Overthepast15years,anincreasingnumberofpublicationshavereportedpharmacologicaltreatmentofPE
withavarietyofdifferentmedications,whichactcentrallyorlocallytoretardthepsychoneurologicalcontrol
ofejaculationandsubsequentorgasm.[23]Itiswellestablishedthatmajortranquillisersandselective
serotoninreuptakeinhibitordrugs(SSRIs)retardejaculationsignificantlyandwill,inasmallpercentageof
men,resultinanejaculation.[2426]TheefficacyofSSRIsindelayingejaculationcombinedwiththeirlow
sideeffectprofilemakethemfirstlinetherapeuticagentsforprematureejaculationadministeredeitherona
dailyoranondemandbasis.[27,28]

PHYSIOLOGYOFEJACULATION
Ejaculationisareflexcomprisedofsensoryreceptorsandareas,afferentpathways,cerebralsensoryareas,
cerebralmotorcentres,spinalmotorcentresandefferentpathways.Therearethreebasicmechanisms
involvedinnormalantegradeejaculationemission,ejectionandorgasm.[29]Emissionistheresultofa
sympatheticspinalcordreflexinitiatedbygenitaland/orcerebraleroticstimuliandinvolvesthesequential
contractionofaccessorysexualorgans.Considerableinitialvoluntarycontrolofemissionprogressively
decreasesuntilthepointofejaculatoryinevitability.[30]Ejectionalsoinvolvesasympatheticspinalcord
reflexuponwhichthereislittleornovoluntarycontrol.Ejectioninvolvesbladderneckclosure,rhythmic
contractionsofbulbocavernous,bulbospongiosusandotherpelvicfloormusclesandrelaxationofthe
externalurinarysphincter.[30]Orgasmistheresultofcerebralprocessingofpudendalnervesensorystimuli
resultingfromincreasedpressureintheposteriorurethra,sensorystimuliarisingfromtheveramontanumand
contractionoftheurethralbulbandaccessorysexualorgans.

Theejaculatoryreflexispredominantlycontrolledbyacomplexinterplaybetweencentralserotonergicand
dopaminergicneuronswithsecondaryinvolvementofcholinergic,adrenergic,nitrergic,oxytocinergic,
galanergicandGABAergicneurons.Thecerebraleventswhichoccurduringejaculationandthe
abnormalitiespresentinmenwithPEhavenotbeenclearlydefinedwithpositronemissiontomography
(PET)andfunctionalmagneticresonanceimaging(fMRI)techniques.Seminalemissionandejectionare
integratedintothecomplexpatternofcopulatorybehaviorbyseveralforebrainstructuresincludingthe
medialpreopticarea(MPOA)andthenucleusparagigantocellularis(nPGi)[Figure2].[31,32]Descending
serotonergicpathwaysfromthenPGItothelumbosacralmotornucleitonicallyinhibitejaculation.[32]
DisinhibitionofthenPGIbytheMPOAfacilitatesejaculation.Apopulationoflumbarspinothalamic
neuronshasbeenidentifiedinmalerats(LStcells)thatconstituteanintegralpartofthegenerationof
ejaculation.LStcellssendprojectionstotheautonomicnucleiandmotoneuronsinvolvedintheemissionand
expulsionphaseandreceivesensoryprojectionsfromthepelvis.[33]Severalbrainareasareactivatedafter

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ejaculationbyascendingfibresfromthespinalcordandmayhaveapossibleroleinsatietyandthe
postejaculatoryrefractorytime.

Animalandhumansexualpsychopharmacologicalstudieshaveattributedaserotonergicbasisandpossible
geneticetiologytoprematureejaculation.[3437]Maleratstudiesdemonstratethatserotoninand5HT
receptorsareinvolvedintheejaculatoryprocess.Thespeedofejaculationappearstobedeterminedby5
HT2Cand5HT1Areceptors.Stimulationof5HT2Creceptorswithnonselective5HT2Cagonistsdelays
ejaculationinmaleratswhereasstimulationofpostsynaptic5HT1Areceptorsresultedinshorterejaculation
latency.[38]AdministrationofSSRIsresultsinactiveblockadeofpresynapticmembrane5HTtransporters
andtheresultanthighersynapticcleftlevelsof5HTactivatepostsynaptic5HT2Cand5HT1Areceptors
todelayejaculation.[35,39]

DEFININGPREMATUREEJACULATION
MedicalliteraturecontainsseveralunivariateandmultivariateoperationaldefinitionsofPE.Thelackof
agreementastowhatconstitutesPEhashamperedbasicandclinicalresearchintotheetiologyand
managementofthiscondition.QuantitativemeasuresofintercoursesuchastheIELTandsubjectivepatient
reportedoutcome(PROs)measuresofvoluntarycontroloverejaculationorselfefficacysuchastheextentof
sexualsatisfactionandthelevelofbotherordistresshavebeendescribedandemployedaspatientrelated
outcomesinprematureejaculationclinicaltrials.Eachofthethreecriteriaabovehasbeenoperationalized
althoughnotalwayswithconsistency.[40]

INTRAVAGINALEJACULATORYLATENCYTIME(IELT)
OperationalizationofPEusingthelengthoftimebetweenpenetrationandejaculationtheIELT,formsthe
basisofmostcurrentclinicalstudiesonPE.Thereisconsiderablevarianceofthelatenciesusedtoidentify
menwithPEwithIELTsrangingfrom17minandnoneofthedefinitionsisbasedonnormativedataor
offersanysupportiverationalefortheirproposedcutofftimeforIELT.[4144]Anaveragedurationof
intercourseof47minwasreportedbyGebhard,suggestingthatejaculationbefore4minafterintromission
shouldbeconsideredpremature.[45]

WaldingeretalreportedIELTsoflessthan30secandlessthan60secondsin77and90%of110menwith
PErespectively.[46]McMahonetalreportedsimilarresultsin1346consecutivemenwithPEandamean
IELTof43.4seconds.[19]Predominantanteportalejaculation(duringforeplay)occurredin5.6%ofmen.
Althoughnormativedataislacking,itisreasonableforclinicianstoregardmenwhoejaculatewithin2
minutesofpenetrationassufferingfromPE.Anteportalejaculationorejaculationwithin1minuteshouldbe
regardedasseverePE.

Sexualsatisfaction
MenwithPEreportlowerlevelsofsexualsatisfactioncomparedtomenwithnormalejaculatorylatency.
Patricketalreportedratingsofverypoororpoorforsexualsatisfactionin31%ofmenwithPE
comparedto1%inagroupofnormalcontrols.[47]Theinabilitytocontrolanddeferejaculationuntilthe
femalepartnerwassexuallysatisfiedinatleast50%ofintercourseattemptswasproposedasadefinitionof
PEbyMastersandJohnson.[48]Aninherentproblemexistsindefiningamanasdysfunctionalbasedonthe
sexualresponsivenessofhispartner.Thisdefinitionimpliesthatanymalewhosefemalepartnerhasdifficulty
inreachingorgasmshouldbelabeledasaprematureejaculator.Thisdefinitionisatoddswiththereportthat
only30%ofwomenachieveorgasmduringsexualintercourseregardlessoftheextentoftheirpartner's
ejaculatorycontrolandlatency.Rowlandreportedthatover89.4%ofmenwithselfreportedPEregarded
fulfillingtheirpartner'ssexualneedsasveryorextremelyimportant.[49]

Voluntarycontrol
KaplanandotherauthorshavesuggestedthataninabilitytovoluntarilydeferejaculationdefinesPE.[5053]
Thisdefinitionhasyettobeadequatelyoperationalizedtoallowcomparisonacrosssubjectsoracross
studies.GrenierandByersfailedtodemonstrateastrongcorrelationbetweenejaculatorylatencyand
subjectiveejaculatorycontrol.[4]Theyreportedthatsomemenwithabriefejaculatorylatencytimereported
adequateejaculatorycontrolandviceversaandconcludedthatthedimensionsofejaculatorycontroland

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latencyaredistinctconcepts.Contrarytothis,otherauthorshavereportedamoderatecorrelationbetween
IELTandthefeelingofejaculatorycontrol.[46,47]Patricketalreportedratingsofverypoororpoorfor
controloverejaculationin72%ofmenwithPEascomparedto5%inagroupofnormalcontrols.[47]

DISTRESS
ExistingdefinitionsofPEincludedistressasanimportantdimensionofPE.[8,23,54]However,theword
distresshasnegativesocialimplicationsanditsexistenceisdeniedbymostmenwithPE.Thisdimensionof
PEisbettercapturedbythewordbother.TheextentofbotherdefinestheseverityofPE.Onestudy
reportedthat64%ofmenwithPEratedtheirextentofpersonaldistressasquiteabitorextremely
comparedto4%inagroupofnormalcontrols.[47]

Althoughpartnerdistressisasignificantcontributortotreatmentseekingbehavior,thereislimited
informationregardingtheeffectofPEonthepartner.SeveralstudieshavereportedthattheeffectsofPEon
thefemalepartnerareintegraltounderstandingtheimpactofPEonthemaleandonthesexualrelationship
asawhole.[5557]Patricketal.reportedthat44%ofpartnersofmenwithPEratedtheirextentofpersonal
distressasquiteabitorextremelycomparedto3%inagroupofpartnersofnormalcontrols.[47]Patrick
etalalsoreportedthatpartnerPROmeasuresdifferentiatedmenwithPEfrommenwithoutPEand
correlatedmoderatelywithmeasuresofIELTandsubjectPROmeasures.However,partnerperceptionsof
PEgenerallyindicatedlessdysfunctionthanthoseofsubjects.[47]AlthoughPEadverselyaffectspartner
sexualsatisfaction,itappearstohaveminimalimpactuponrelationshipsatisfaction.[56]Furthermore,
partnersofmenwithPEreportrelativelyhighlevelsoffemalesexualdysfunction.[58,59]Theobservation
thatPEoftenpredatesthetimeofonsetofthewomen'ssexualsymptomssuggeststhatPEmaybearisk
factorforfemalesexualdysfunction.[58]

ThedesignofallfuturestudiesonanyaspectofPEshouldincludeauniformoperationalizedmultivariate
definitionofPEwherethedimensionsoflatency,control,satisfactionanddistress/botheraredefined,
measuredandanalysedascontinuousvariableswithoutarbitrarycutoffvalues.

THEETIOLOGYOFPREMATUREEJACULATION
Historically,attemptstoexplaintheetiologyofPEhasincludedadiverserangeofbiologicaland
psychologicaltheories.Mostoftheseproposedetiologiesarenotevidencebasedandarespeculativeatbest.
Psychologicaltheoriesincludetheeffectofearlyexperienceandsexualconditioning,anxiety,sexual
technique,thefrequencyofsexualactivityandpsychodynamicexplanations.Biologicalexplanationsinclude
evolutionarytheories,penilehypersensitivity,centralneurotransmitterlevelsandreceptorsensitivity,degree
ofarousability,thespeedoftheejaculatoryreflexandthelevelofsexhormones.

ThereislittleempiricalevidencetosuggestacausallinkbetweenPEandanyofthefactorsthoughttocause
PE.Thereis,however,limitedcorrelationalevidencetosuggestthatlifelongPEisageneticallydetermined
biologicalvariablerelatedtotheinheritedsensitivityofcentral5HTreceptorswhereasacquiredPEisdueto
highlevelsofsexualanxiety,EDorlowerurinarytractinfection.

Ejaculatorylatencytimeisprobablyabiologicalvariable,whichisgeneticallydeterminedandmaydiffer
betweenpopulationsandcultures,rangingfromextremelyrapidthroughaveragetoslowejaculation.
Hyposensitivityofthe5HT2Cand/orhypersensitivityofthe5HT1Areceptorshavebeensuggestedasa
possibleexplanationoflifelongPE.[39,60]Menwithlow5HTneurotransmissionandprobable5HT2C
receptorhyposensitivitymayhavetheirejaculatorythresholdgeneticallysetatalowerpointandejaculate
quicklyandwithminimalstimulation.Ontheotherhand,menwithahighersetpointcansustainmore
prolongedandhigherlevelsofsexualstimulationandcanexertmorecontroloverejaculation.Menwitha
veryhighsetpointmayexperiencedelayedorabsentejaculationdespiteachievingafullerectionand
prolongedsexualstimulation.TreatmentwithanSSRIclassdrugactivatesthe5HT2Creceptor,elevatesthe
ejaculatorythresholdsetpointanddelaysejaculation.Theextentofejaculatorydelaymayvarywidelyin
differentmenaccordingtothedosageandfrequencyofadministrationofSSRIandthegenetically
determinedejaculatorythresholdsetpoint.Cessationoftreatmentresultsinreestablishmentoftheprevious
setpointwithin57daysinmenwithlifelongPE.

AnxietyhasbeenreportedasacauseofPEbymultipleauthorsandisentrenchedinthefolkloreofsexual
medicineasitsmostlikelycausedespitescantempiricalresearchevidencetosupportanycausalrole.
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[17,50,61]Severalauthorshavesuggestedthatanxietyactivatesthesympatheticnervoussystemandreduces
theejaculatorythresholdasaresultofanearlieremissionphaseofejaculation.Severalauthorshave
suggestedthepossibilitythathighlevelsofanxietyandexcessiveandcontrollingconcernsaboutsexual
performanceandpotentialsexualfailuremightdistractamanfrommonitoringhislevelofarousaland
recognisingtheprodromalsensationsthatprecedeejaculatoryinevitability.[52,53,6265]Thecausallink
betweenanxietyandPEisspeculative,unsupportedbyanyempiricalevidenceandisinfact,contraryto
empiricalevidencefromsomeresearchers.[66]

RecentdatademonstratesthatalmosthalfofthemenwithEDalsoexperiencePE.[67]MenwithearlyED
mayintentionallyrushsexualintercoursetopreventprematurelossoftheirerectionandejaculatewitha
brieflatency.Thismaybecompoundedbythepresenceofhighlevelsofperformanceanxietyrelatedtotheir
EDwhichservestoonlyworsentheirprematurity.Intheabsenceofathoroughsexualhistory,thesemen
maybeincorrectlydiagnosedassufferingfromPEandnottheunderlyingED.

PEDRUGTRIALDESIGN
TheresultsofPEdrugclinicaltrialsareonlyreliable,interpretableandcapableofbeinggeneralisedto
patientswiththedisorderstudiedwhenconductedinwelldefinedandconsistentpopulations,differentiation
oflifelongandacquiredPEasseparatePEsubgroups,exclusionortreatmentasaseparatesubgroupsubjects
witherectiledysfunction(ED)orothercomorbidsexualdisorders,usingadoubleblindplacebocontrolled
studydesign,andconsistentobjectivephysiologicalmeasuresorsensitive,validatedoutcomeassessment
instrumentsasstudyendpoints.[68]InPEstudies,thestudypopulationshouldbewellcharacterised,
representativeoftheoverallpatientpopulationanddefinedusingamultivariatedefinitionofPE.Asthe
populationofmenwithPEisnothomogenous,lifelongandacquiredPEshouldbetreatedas
demographicallyandetiologicallydistinctdisordersandanalysedasseparatePEsubgroups.[19]Subjects
shouldbeinvolvedinastable,monogamousheterosexualrelationship,preparedtoattemptintercourseona
regularbasisandprovidewritteninformedconsent.ThepresenceofcomorbidEDshouldbeevaluatedusing
avalidatedinstrumentsuchastheInternationalIndexofErectileFunction(IIEF)andpatientswithany
degreeofEDshouldbeeitherexcludedfromthestudyortreatedasaseparatesubgroup.Patientswith
hypoactivesexualdesireorothersexualdisorders,urogenitalinfection,majorpsychiatricdisorders,ahistory
ofdrugandalcoholabuseorcontraindicationstothestudydrugshouldbeexcludedfromthe
study.Measurementoftheintravaginalejaculatorylatencytime(IELT)bystopwatchisthebestmethodto
diagnosePEandtheresponsetotreatmentandshouldbeusedasaprimaryefficacyendpoint.Laboratory
studiesofejaculatorydysfunctionmaybesimplifiedbytheuseoftheSexualAssessmentMonitor(SAM),
anelectronicdatacollectorwhichcomprisesavibratortoinduceejaculationandasensortomeasuretimeto
erectionandIELTbythedetectionofejaculatorypulses,buttheroleofsuchdevicesinlargeathomePhase
IIIclinicaltrialsislimited.[69]RecentnormativeIELTdatasupportsearliersuggestionsbyseveralauthors
thatintravaginalejaculatorylatencytimes(IELTs)oflessthan1minuteorlessthan2minutesberegardedas
cutpointsforinclusioninaclinicaltrial.[9,27,40]Subjectivepatientreportedoutcomes(PROs)of
ejaculatorycontrol,sexualsatisfactionandbother/distressareimportantadditionalefficacyendpointsandcan
beevaluatedusingvalidatedpatientreportedoutcomeinstruments.[7073]Researchintothedevelopmentof
validated,reliableandconsistentpatientreportedoutcomemeasuresisongoing.

TREATMENT

Psychosexualcounselling
Inmanyrelationships,PEcausesfewifanyproblems.Inothers,thecouplemayreachanaccommodationof
theproblemthroughvariousstrategiesyoungmenwithashortrefractoryperiodmayoftenexperiencea
secondandmorecontrolledejaculationduringasubsequentepisodeoflovemaking.Frequentlyhowever,PE
eventuallyleadstosignificantrelationshipproblemswithpartnersregardingthemanasselfishand
developingapatternofsexualavoidance.Thisonlyworsenstheseverityoftheprematurityontheoccasions
whenintercoursedoesoccur.

ThecornerstonesofbehaviouraltreatmentaretheSeman'sstopstartmanoeuvreanditsmodification
proposedbyMastersandJohnson,thesqueezetechnique.BotharebasedonthetheorythatPEoccurs
becausethemanfailstopaysufficientattentiontopreorgasmiclevelsofsexualtension.[48,74]Asmostmen

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withPEareawareoftheiranxiety,thesourcesofsuchanxietybeingrelativelysuperficial,treatmentsuccess
withthesebehaviouralapproachesisrelativelygoodintheshorttermthoughconvincinglongtermtreatment
outcomedataisabsent.[51,7577]

Pharmacologicaltreatment
Pharmacologicalmodulationofejaculatorythresholdrepresentsanovelandrefreshingapproachtothe
treatmentofPEandaradicaldeparturefromthepsychosexualmodeloftreatment,previouslyregardedasthe
cornerstoneoftreatment.TheintroductionofSSRIshasrevolutionizedtheapproachtoandtreatmentofPE.
SSRIsconsistoffivecompoundscitalopram,fluoxetine,fluvoxamine,paroxetineandsertralinewitha
similarpharmacologicalmechanismofaction.Althoughthemethodologyoftheinitialdrugtreatmentstudies
wasratherpoor,laterdoubleblindandplacebocontrolledstudiesreplicatedthegenuineeffectof
clomipramineandSSRIstodelayejaculation.Inspiteofanincreasinginclinationtowardsresearchintomore
evidencebaseddrugtreatment,themajorityofstudiesstilllackadequatedesignandmethodology.[78]A
recentmetaanalysisofalldrugtreatmentstudiesdemonstratedthatonly14.4%hadbeenperformed
accordingtotheestablishedcriteriaofevidencebasedmedicine.Opendesignstudiesandstudiesusing
subjectivereportingorquestionnairesshowedahighervariabilityinejaculationdelaythandoubleblind
studiesinwhichtheejaculationdelaywasprospectivelyassessedwithastopwatch.[78]

Dailytreatmentwithselectiveserotoninreuptakeinhibitors
Paroxetine2040mg,clomipramine1050mg,sertraline50100mgandfluoxetine2040mgcanbeused
fordailytreatment[Figure3].Paroxetineappearstoexertthestrongestejaculationdelay,increasingIELT
approximately8.8foldoverbaseline.[78]Ejaculationdelayusuallyoccurswithin510daysbutmayoccur
earlier.Adverseeffectsareusuallyminor,startinthefirstweekoftreatment,graduallydisappearwithin23
weeksandincludefatigue,yawning,mildnausea,loosestoolsorperspiration.DiminishedlibidoormildED
isnotreportedfrequently.Significantagitationisreportedbyasmallnumberofpatientsandtreatmentwith
SSRIsshouldbeavoidedinmenwithahistoryofbipolardepression.

Ondemandtreatmentwithselectiveserotoninreuptakeinhibitors
Administrationofclomipramine,paroxetine,sertraline,fluoxetine46hoursbeforeintercourseisefficacious
andwelltoleratedbutisassociatedwithlessejaculatorydelaythanwithdailytreatment.Dailyadministration
ofanSSRIisassociatedwithsuperiorfoldincreasesinIELTcomparedtoondemandadministration.Thisis
duetogreatlyenhanced5HTneurotransmissionresultingfromseveraladaptiveprocesseswhichmay
includepresynaptic5HT1aand5HT1b/1dreceptordesensitisation[Figure4].[39]Ondemandtreatment
maybecombinedwitheitheraninitialtrialofdailytreatmentorconcomitantlowdosedailytreatment.
[28,79,80]

Ondemandtreatmentwithdapoxetine

Anumberofrapidacting,shorthalflifeSSRIsareunderinvestigationasondemandtreatmentsforPE.
DapoxetineisthefirstcompoundspecificallydevelopedforthetreatmentofPE.Dapoxetineisapotent
SSRI(pKi=8nM),whichisstructurallysimilartofluoxetine[Figure4].[81]Equilibriumradioligand
bindingstudiesusinghumancellsdemonstratethatdapoxetinebindsto5HT,norepinephrine(NE)and
dopamine(DA)reuptaketransportersandinhibitsuptakeinthefollowingrankorderofpotency:NE<5HT
>>DA.[82]BrainPETstudieshavedemonstratedsignificantdisplaceablebindingofradiolabeled
dapoxetineinthecerebralcortexandsubcorticalgreymatter.[83]

Dapoxetineundergoesrapidabsorptionandeliminationresultinginminimalaccumulationandhasdose
proportionalpharmacokinetics,whichareunaffectedbymultipledosing[Figure5].Thepharmacokinetic
profileofdapoxetinesuggeststhatitisacandidateforondemandtreatmentofPE[Figure6].The
pharmacokineticsofbothsingledosesandmultipledosesover69days(30,60,100,140or160mg)of
dapoxetinehavebeenevaluated.DapoxetinehasaTmaxof1.42.0hoursandrapidlyachievespeakplasma
concentration(Cmax)followingoraladministration.[84]Bothplasmaconcentrationandareaunderthecurve
(AUC)aredosedependentupto100mg.Themeanhalflifeofdapoxetineafterasingledoseis0.50.8
hoursandplasmaconcentrationsrapidlydeclinetoabout5%ofCmaxat24hours.Thepharmacokineticsof
dapoxetineanditsmetaboliteswerenotaffectedbyrepeateddailydosingandsteadystateplasma
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concentrationswerereachedwithin4days,withonlymodestaccumulationofdapoxetine(approximately
1.5fold).[85]Fooddoesnothaveaclinicallysignificanteffectondapoxetinepharmacokinetics.[86]

Nodrugdruginteractionsassociatedwithdapoxetinehavebeenreported.Coadministrationofdapoxetine
withethanoldidnotproducesignificantchangesinthepharmacokineticsofDapoxetineanditsmetabolites.
[87]Druginteractionstudiesdemonstratethattadalafil,aphosphodiesterase5inhibitorusedinthetreatment
ofED,didnotaffectthepharmacokineticsofdapoxetine,whereassildenafilincreasedthedapoxetineAUC
by22%.[88]However,thiswasnotregardedasclinicallyimportant.Dapoxetinedidnotappeartoaffectthe
pharmacokineticsoftadalafilorsildenafil.

Preliminarydatasuggestthatdapoxetine(JohnsonandJohnson)administered12hourspriortoplanned
intercourse,iseffectiveandwelltolerated,superiortoplaceboandincreasesIELT23foldoverbaselineina
dosedependentfashion[Figure7].[89]Inrandomized,doubleblind,placebocontrolled,multicenter,phase
III,12weekclinicaltrialsinvolving2614menwithameanbaselineIELT2minutes,dapoxetine30mgor
60mgwasmoreeffectivethanplaceboforallstudyendpoints.[90]IELTincreasedfrom0.9minutesat
baselineto2.78and3.32minutesattheendofthestudywithdapoxetine30and60mgrespectively.Mean
patientratingofcontroloverejaculationasfair,goodorverygoodincreasedfrom3.5%atbaselineto51.8
and58.4%attheendofthestudywithdapoxetine30and60mgrespectively.Treatmentrelatedsideeffects
wereuncommon,dosedependent,includednausea,diarrhoea,headache,dizzinessandwereresponsiblefor
studydiscontinuationin4%(30mg)and10%(60mg)ofsubjects.

Ondemandtreatmentwithtramadol
TheefficacyofondemandtramadolinthetreatmentofPEwasrecentlyreported.[91]Tramadolisa
centrallyactingsyntheticopioidanalgesicwithanunclearmodeofactionwhichisthoughttoinclude
bindingoftheparentcompoundandM1metabolitetoopioidreceptorsandweakinhibitionofreuptakeof
norepinephrineandserotonin.[92]Serotoninsyndromehasbeenreportedasanadverseeffectoftramadol
aloneorincombinationwithSSRIclassdrugs.[93,94]Inthisdoubleblind,placebocontrolledstudy,theon
demanduseof50mgtramadol,taken2hourspriortointercourse,exertedaclinicallyrelevantejaculation
delayinmenwithPEwitha12.7foldincreaseinIELT.[91]Additionalflexibledosestudiesandlongterm
followupstudiestoevaluatetheriskofopioidaddictionarerequired.

Anaesthetictopicalointments
Theuseoftopicallocalanaestheticssuchaslignocaineand/orprilocaineasacream,gelorsprayiswell
establishedandismoderatelyeffectiveinretardingejaculation.Arecentstudyreportedthatametereddose
aerosolspraycontainingaeutecticmixtureoflidocaineandprilocaineproduceda2.4foldincreasein
baselineIELTandsignificantimprovementsinejaculatorycontrolandthesexualqualityoflifeofboth
patientsandtheirpartners.[95]Theymaybeassociatedwithsignificantpenilehypoanaesthesiaandpossible
transvaginalabsorption,resultinginvaginalnumbnessandresultantfemaleanorgasmiaunlessacondomis
use.[9698]

Phosphodiesteraseinhibitors
Medicationsthatinhibitthephosphodiesterasetype5isoenzyme(PDE5)suchassildenafil,tadalafiland
vardenafil,areeffectivetreatmentsforED.SeveralauthorshavereportedtheirexperiencewithPDE5
inhibitorsaloneorincombinationwithSSRIsasatreatmentforPE.[99112]TheputativeroleofPDE5
inhibitorsasatreatmentforPEisbasedupontheroleoftheNO/cGMPtransductionsystemasacentraland
peripheralmediatorofinhibitorynonadrenergic,noncholinergic,nitrergicneurotransmissionintheurogenital
system.[113]Severalstudiessuggestthatelevationofextracellularnitricoxide(NO)intheMPOA
acceleratesdopaminereleaseandfacilitatesmalecopulatorybehaviourofrats,whereasadecreaseofNO
reducestheircopulatorybehaviour.[114116]HulletaldemonstratedthatmicroinjectionoftheNOsynthase
inhibitor,NnitroLargininemethylester(NAME)notonlydecreasedthenumberoferectionsbutalso
increasedthenumberofseminalemissionsanddecreasedthelatencytothefirstseminalemission.[117]The
resultsindicatethatnotonlydoesnitricoxidepromoteerectioninintactmaleratsbutitmayalsoinhibit
seminalemission.

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Nitricoxidesynthaseisoenzymesarepresentinhumanseminalvesiclesmoothmuscle.[118]Severalauthors
havereportedtheeffectsofNOdonordrugsonelectricallyinducedcontractionsandontissuelevelsof
cyclicguanosinemonophosphate(cGMP)andcyclicadenosinemonophosphate(cAMP)ofisolatedhuman
seminalvesiclesmoothmusclepreparations.TheseauthorshaveconcludedthatNOmightbeinvolvedinthe
controlofsecretoryactivityandsmoothmusclefunctionofhumanseminalvesicles.[119121]Consistent
withthisnotion,KriegsfeldreportedthatmicehomozygousforeNOSgenedeletionhavestrikingejaculatory
anomalies.[122]AsignificantlyhigherpercentageofmicewitheNOSgenedeletionascomparedtonormal
controls,ejaculatedduringthetestingperiod,requiringlessstimulationandfewermountsandintromissions.

Arecentsystematicreviewof14studiespublishedinpeerreviewedjournalsortheproceedingsofmajor
internationalandregionalscientificmeetingsonthePDE5itreatmentofprematureejaculation,examinedthe
roleofNOasaneurotransmitter.Thisrolewasexaminedincentralandperipheralcontrolofejaculation,the
methodologyofphosphodiesterasetype5inhibitor(PDE5i)treatmentstudiesforPE,theadherenceof
methodologytothecontemporaryconsensusofidealPEdrugtrialdesign,theimpactofmethodologyon
treatmentoutcomesandtheroleofPDE5idrugsinthetreatmentofPE.[123]Thesestudiescompriseatotal
of1102subjectssufferingfromPEandtreatedwithsildenafil,[99,103106,112]tadalafil[108]or
vardenafil[107]eitherasmonotherapyorincombinationwithSSRIdrugs,
[99,100,109,99101,106109,111,124]clomipramine[99]ortopicalanaesthetics.[109,112]

MostofthesestudiessupportaroleforPDE5iinthetreatmentofPEandspeculatemultiplemechanismsfor
theirefficacy.Theseinclude1)acentraleffectinvolvingincreasedNOandreducedsympathetictone,2)
smoothmuscledilatationofthevasdeferensandseminalvesiclesand3)reducedperformanceanxiety.The
smoothmuscledilatationofthevasdeferensandseminalvesiclesmayopposethesympathetic
vasoconstrictionanddelayejaculation.Bettererectionsanddownregulationoftheerectilethresholdtoa
lowerlevelofarousalresultingintherequirementofincreasedlevelsofarousaltoachievetheejaculation
thresholdultimatelyresultinreducedperformanceanxiety.

Thesmallnumberofpublicationsandthelackofsufficientdataprecludeanymetaanalysisofresults.
However,examinationofthemethodologyofthesestudies,theadherenceofmethodologytothe
contemporaryconsensusofidealclinicaltrialdesign[68]andtheimpactofstudymethodologyontreatment
outcomes,failstoprovideanyrobustempiricalevidencetosupportaroleofPDE5inhibitorsinthe
treatmentofPEwiththeexceptionofmenwithPEandcomorbidED.Ofthe14studiesreviewed,onlyone
fulfilledthesecriteriaandthisstudyfailedtoconfirmanysignificanttreatmenteffectonIELT.[104]

CautionshouldbeexercisedininterpretingPDE5iandondemandSSRItreatmentdataininadequately
designedstudiesandtheirresultsmustberegardedasunreliable.TheextremelybroadrangeofIELTfold
increasesreportedwithsildenafil(2.715.0,mean6.6),combinedsildenafilandondemandsertraline(3.3
10.0,mean6.9)andcombinedsildenafilandondemandparoxetine(6.614.9,mean10.7)inthissystematic
review,isproofoftheunreliabilityofinadequatestudydesign.Incontrasttothesefindings,therangeof
placeboIELTfoldincreaseswasrelativelynarrow(IELTrange1.21.6,mean1.4)andwasidenticalwith
themean1.4IELTfoldincreasereportedinametaanalysisofotherPEdrugstudies.[125]

PEANDCOMORBIDED
ThereisevidencetosuggestthatPDE5isaloneorincombinationwithaSSRImayhavearoleinthe
managementofacquiredPEinmenwithcomorbidED.Thissystematicreviewincludes3
studies[105,107,111]ofpatientswithPEwithcomorbidEDtreatedwithaPDE5ialoneorincombination
ofsertraline.In45menwithPEandcomorbidEDtreatedwithflexibledosesofsildenafil(50100mg)for
periodsof13months,LietalreportedimprovedEFin40men(89%)andreducedseverityofPEin27men
(60%).[105]ImprovedEFwasreportedbyallofthe27menwithreducedseverityofPE,ofwhom81.5%
describedthemselvesassatisfiedorverysatisfied.Contrarytothesefindings,onlyoneofthe18men(5.6%)
whodidnotobtainimprovementofPEreportedtreatmentsatisfaction.

Inagroupof37menwithprimaryoracquiredPEandabaselineIIEFEFdomainscoreof20.9consistent
withmildED,Sommeretalreportedanda9.7foldIELTincreaseandnormalisationofEF(IIEFEF26.9)
withvardenafiltreatmentasopposedtoonly4.4foldIELTincreasewithondemandsertraline.[107]

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ThehighlevelofcorrelationbetweenimprovedEFwithsildenafilandreducedseverityofPEreportedby
Li[105]andthesuperiorIELTfoldincreaseobservedwithvardenafilreportedbySommeretalindicatesthat
decreaseinPEseverityduetoPDE5iisduetoimprovedEF.[107]The4.4IELTfoldincreaseobservedby
SommeretalwithondemandsertralineislessthanthatreportedinreviewedstudiesonmenwithnormalEF
(mean5.57,range3.08.5).[99,101,106,111]ThissuggeststhatmenwithPEandcomorbidEDareless
responsivetoondemandSSRIsandarebestmanagedwithaPDE5ialoneorincombinationwithanSSRI.
Furthermore,Chia'sreportshowedthatadditionofsertralinetothesildenafiltreatmentofmenwithEDand
comorbidPEwasassociatedwithalowerIELTfoldincrease(3.3).Thisinturnresultedinlowerlevelsof
treatmentsatisfactionascomparedtomenwithlifelongPEandnormalEFtreatedwithondemandsertraline,
whichsuggeststhatthisgroupofmenarelessresponsivetopharmacotherapy.[111]

Thus,thereareheadvantagesofPDE5isasmonotherapyorincombinationwithanSSRIinthetreatment
ofacquiredPEinmenwithcomorbidED.Theseadvantagesinclude1)theabilitytomaintainanerection
followingejaculation,2)reductionoftheerectilerefractoryperiod[104,126,127]andrelianceuponasecond
andmorecontrolledejaculationduringasubsequentepisodeofintercourse,3)areductioninperformance
anxietyduetobettererectionsordownregulationoftheerectilethreshold.Thedownregulationoftheerectile
thresholdtoalowerlevelofarousalleadstotherequirementforincreasedlevelsofarousaltoachievethe
ejaculationthreshold.

Surgery
Severalauthorshavereportedtheuseofsurgicallyinducedpenilehypoanaesthesiaviaselectivedorsalnerve
neurotomyorhyaluronicacidgelglanspenisaugmentationinthetreatmentoflifelongPErefractoryto
behaviouraland/orpharmacologicaltreatment.[128]TheroleofsurgeryinthemanagementofPEremains
unclear.

THEOFFICEMANAGEMENTOFPREMATUREEJACULATION
MenwithPEshouldbeevaluatedwithadetailedmedicalandsexualhistory,aphysicalexaminationand
appropriateinvestigationstoestablishthetruepresentingcomplaintandidentifyobviousbiologicalcauses
suchasgenitalorlowerurinarytractinfection[Figure8].

MenwithPEsecondarytoED,othersexualdysfunctionorgenitourinaryinfectionshouldreceive
appropriateetiologyspecifictreatment.MenwithlifelongPEshouldbeinitiallymanagedwith
pharmacotherapy.Menwithsignificantcontributingpsychogenicorrelationshipfactorsmaybenefitfrom
concomitantbehaviouraltherapy.MenwithPEsecondarytoEDcanbetreatedwitheitherEDspecific
pharmacotherapy,e.g.,PDE5inhibitorsasmonotherapyorincombinationwithPEspecific
pharmacotherapy,e.g.,dailyorondemandSSRIs.RecurrenceofPEishighlylikelyfollowingwithdrawal
oftreatment.MenwithacquiredPEcanbetreatedwithpharmacotherapyand/orbehaviouraltherapy
accordingtopatient/partnerpreference.RestorationofejaculatorycontrolinmenwithacquiredPEislikely
tooccurfollowingcompletionoftreatmentbutistheexceptioninmenwithlifelongPE.Behaviouraltherapy
mayaugmentpharmacotherapytoenhancerelapseprevention.

CONCLUSION
PEisacommonmalesexualdisorder.RecentnormativedatasuggeststhatmenwithanIELToflessthan1
minutehavedefinitePE,whilemenwithIELTsbetween11.5minuteshaveprobablePE.Although
thereisinsufficientempiricalevidencetoidentifytheetiologyofPE,thereislimitedcorrelationalevidenceto
suggestthatmenwithPEhavehighlevelsofsexualanxietyandalteredsensitivityofcentral5HTreceptors.
PharmacologicalmodulationoftheejaculatorythresholdusingdailyorondemandselectiveSSRIsiswell
toleratedandofferspatientsahighlikelihoodofachievingimprovedejaculatorycontrolwithinafewdaysof
initiatingtreatment,consequentialimprovementsinsexualdesireandothersexualdomains.Daily
administrationofanSSRIisassociatedwithsuperiorfoldincreasesinIELTcomparedtoondemand
administrationofSSRIsincludingdapoxetine.Thisisduetogreatlyenhanced5HTneurotransmission
resultingfromseveraladaptiveprocesseswhichmayincludepresynaptic5HT1aand5HT1b/1dreceptor
desensitisation.Ithowever,failstodirectlyaddresscausalpsychologicalorrelationshipfactorsanddataare
eitherlackingorscarceontheefficacyofcombinedpsychosexualcounsellingandpharmacological
treatmentandthemaintenanceofimprovedejaculatorycontrolafterdrugwithdrawal.
Footnotes
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11/3/2017 Prematureejaculation

Footnotes
SourceofSupport:Nil

ConflictofInterest:Authorisaconsultant,memberofanadvisoryboardandinvestigatorforJohnson&Johnson,
PfizerandBayerScheringPharma.

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FiguresandTables

Figure1

Distributionofintravaginalejaculatorylatencytimesvaluesinarandomcohortof491men[60]

Figure2

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Centralnervoussystemareasinvolvedbefore,duringandafterejaculation.Somatosensorytactileinputformthepenis/
genitalsascendstothecerebralcortex.Efferentpathwaysprojectfromthehypothalamustothesacralspinalcordand
genitals.Afterejaculation,informationisreturnedfromthegenitalstoseveralbrainareas.MEApd:Posterodorsalmedial
amygdala,BNSTpm:Posteromedialbednucleusofstriaterminalis,MPOA:medialpreopticarea,nPGi:nucleus
paragigantocellularis,SPFps:medialparvicellularsubparafascicularnucleusofthalamus[60]

Figure3

Selectiveserotoninreuptakeinhibitorsproduceejaculatorydelaywithin510days[27]

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Figure4

A.Synapticcleft5HTand5HTneurotransmissionareregulatedbysomatodendritic5HT1Aautoreceptors,presynaptic5
HT1B/1Dautoreceptorsanda5HTtransporterreuptakesystem.As5HTisreleasedintothesynapticcleftfrom
presynapticaxonalvesicles,5HTtransportersagaintakeupandremove5HTfromthesynapticcleft,preventing
overstimulationofthepostsynapticreceptors.B.Afterblockageof5HTtransportersbyacuteadministrationofselective
serotoninreuptakeinhibitorclassdrugs:SSRIs,synapticcleft5HTincreasesbutiscounteractedbyactivationof5HT1A
autoreceptorswhichinhibitfurther5HTrelease.C.ChronicadministrationofSSRIsresultsingreatlyenhanced5HT
neurotransmissionduetoseveraladaptiveprocesseswhichmayincludepresynaptic5HT1Aand5HT1B/1Dreceptor
desensitisation[35]

Figure5

Molecularstructureofdapoxetine:(+)(S)N,Ndimethyl()[2(1naphthalenyloxy)ethyl]benzenemethanamine
hydrochloride

Figure6

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Plasmaconcentrationprofilesofdapoxetineafteradministrationofasingleormultipledosesofdapoxetine30mg(A)and
dapoxetine60mg(B)[85]

Figure7

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A.Increaseinintravaginalejaculatorylatencytime(IELT)from0.9minutesatbaselineto2.78and3.32minutesattheend
ofthestudywithdapoxetine30and60mgrespectively.B.%ofsubjectsratingcontroloverejaculationasfair,goodorvery
goodincreasedfrom3.5%atbaselineto51.8%and58.4%attheendofthestudywithdapoxetine30and60mg
respectively.C.%ofsubjectsratingSexualSatisfactionasfair,goodorverygoodincreasedfrom51.8%atbaselineto
70.9%and79.2%withdapoxetine30mgand60mgrespectively.(ratingscale05scale,0=verypoorand5=verygood)
[129]

Figure8

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Algorithmfortheofficemanagementofprematureejaculation[8]

ArticlesfromIndianJournalofUrology:IJU:JournaloftheUrologicalSocietyofIndiaareprovidedhere
courtesyofMedknowPublications

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