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Tramadol is an effective pharmacological intervention in human premature ejaculation (PE). To investigate whether the inhibitory action of tramadol is primarily caused by its selective serotonin reuptake inhibitory (SSRI) effects we tested the dose–response effects of tramadol on sexual behavior in serotonin transporter wild type (SERT+/+), heterozygous (SERT+/-), and knockout (SERT-/-) rats. To investigate whether other mechanisms contribute to the inhibitory effects, WAY100,635, a 5-HT1A receptor antagonist and naloxone, a μ-opioid receptor antagonist, were tested on sexual behavior together with tramadol. Tramadol dose-dependently decreases sexual activity in all genotypes. In all studies, SERT+/- rats did not respond differently from SERT+/+ rats. WAY100,635 did not affect sexual activity in SERT+/+, but dose-dependently reduced sexual activity in SERT-/- rats. WAY100,635 (0.3 mg/kg) combined with tramadol (20 mg/kg) significantly reduced sexual activity in SERT+/+ and even stronger in SERT-/- rats. Naloxone did not affect sexual behavior consistently in SERT+/+ rats, while in SERT-/- rats all doses reduced ejaculation frequency mildly. Combining naloxone (20 mg/kg) and tramadol (20 mg/kg) decreased ejaculation frequencies in both genotypes. Interestingly, combining tramadol (20 mg/kg), WAY100,635 (0.3 mg/kg) and naloxone (20 mg/kg) led to complete elimination of all sexual activity in both SERT+/+ and SERT-/- rats. These findings suggest that the inhibitory effects of tramadol on male sexual behavior in SERT+/+ rats is mainly, if not exclusively, due to SERT inhibition, with an important role for 5-HT1A receptors, although influence of other systems (e.g., noradrenergic) cannot be excluded. As SSRIs exert their sexual inhibition after chronic administration, tramadol may be therapeutically attractive as “on demand” therapy for PE. [ABSTRACT FROM AUTHOR]

Introduction. The intravaginal ejaculation latency time (IELT) behaves in a skewed manner and needs the appropriate statistics for correct interpretation of treatment results. Aims. To explain the rightful use of geometrical mean IELT values and the fold increase of the geometric mean IELT because of the positively skewed IELT distribution. Methods. Linking theoretical arguments to the outcome of several selective serotonin reuptake inhibitor and modern antidepressant study results. Main Outcome Measures. Geometric mean IELT and fold increase of geometrical mean IELT. Results. Log-transforming each separate IELT measurement of each individual man is the basis for the calculation of the geometric mean IELT. A drug-induced positively skewed IELT distribution necessitates the calculation of the geometric mean IELTs at baseline and during drug treatment. In a positively skewed IELT distribution, the use of the “arithmetic” mean IELT risks an overestimation of the drug-induced ejaculation delay as the mean IELT is always higher than the geometric mean IELT. Strong ejaculation-delaying drugs give rise to a strong positively skewed IELT distribution, whereas weak ejaculation-delaying drugs give rise to (much) less skewed IELT distributions. Ejaculation delay is expressed in fold increase of the geometric mean IELT. Conclusions. Drug-induced ejaculatory performance discloses a positively skewed IELT distribution, requiring the use of the geometric mean IELT and the fold increase of the geometric mean IELT. Waldinger MD, Zwinderman AH, Olivier B, and Schweitzer DH. Geometric mean IELT and premature ejaculation: Appropriate statistics to avoid overestimation of treatment efficacy. J Sex Med 2008;5:492–499. [ABSTRACT FROM AUTHOR]

Abstract: Lifelong premature ejaculation is characterized by early ejaculations occurring at nearly every intercourse, with nearly every female partner, and most often from the first sexual encounters in puberty and adolescence. Premature ejaculation has always been regarded as a psychological disorder that had to be treated by psychotherapy. However, there is no evidence supporting general psychological causes and efficacy of behavioural treatment for this male sexual complaint. In contrast, there is increasing evidence for the efficacy of daily treatment with some selective serotonin reuptake inhibitors (SSRIs) and on-demand treatment with clomipramine and anesthetic ointments. Data of recent epidemiological stopwatch research of the intravaginal ejaculation latency time (IELT) support an ejaculation distribution theory, of a continuum of IELT in the general male population. Using the 0.5 and 2.5 percentile as accepted standards of disease definition, lifelong premature ejaculation has been defined as a neurobiological dysfunction with an unacceptable increase of risk to develop sexual and psychological problems at any time during a lifetime. It is proposed that all men with an IELT of less than 1minute have “definite” premature ejaculation, while men with IELTs between 1 and 1.5minutes have “probable” premature ejaculation. In addition, it is proposed to define the severity of premature ejaculation (none, mild, moderate, severe) in terms of associated psychological problems. [Copyright &y& Elsevier]

Recently, the idea has emerged that on-demand use of serotonin reuptake inhibitors (SSRIs), particularly short half-life, should be equally effective in delaying ejaculation as daily SSRI treatment of premature ejaculation.To provide evidence that SSRI-induced ejaculation delay is mainly dependent on pharmacodynamic properties of the drug and hardly on pharmacokinetic factors, and that combined SSRI administration with specific 5-hydroxytryptamine (5-HT) receptor antagonism leads acutely to stronger ejaculation delay than acute SSRI monoadministration.We performed a detailed analysis of serotonin neurotransmission and reviewed animal studies with 5-HT1A receptor antagonists. In addition, we critically reviewed existing on-demand SSRI treatments publications and the current debate on a definition of premature ejaculation.Intravaginal ejaculation latency time (IELT).Acute SSRI administration leads to only a mild or no increase of 5-HT neurotransmission and concomitant stimulation of postsynaptic 5-HT receptors. Existing on-demand SSRI treatment studies suffer from methodological insufficiencies, and the reported high-fold increases of ejaculation time contradict with neuropharmacological insights from serotonin metabolism. Animal studies show that SSRI coadministration with 5-HT1A receptor antagonists significantly increases the ejaculation time acutely compared to acute SSRI monoadministration.On-demand SSRI treatment has less ejaculation-delaying effects than daily SSRI treatment. SSRIs with a short half-life are likely leading to much less ejaculation delay than current registered SSRIs. Combined use of SSRIs with 5-HT1A receptor antagonists increases the likelihood of clinically relevant ejaculation delay after on-demand treatment. On-demand SSRIs with short half-life that insufficiently delay ejaculation in men with IELTs less than 1 minute should be called ejaculation-delaying drugs rather than drugs against premature ejaculation. [ABSTRACT FROM AUTHOR]

Objective: To investigate the degree of ejaculation delay induced by on-demand treatment with 20 mg paroxetine and 25 mg clomipramine and to assess the type and severity of non-sexual side-effects of treatment at the day of and the day after treatment with these drugs.Method: A randomized, double-blind, fixed-dose, on-demand study in 30 men with lifelong premature ejaculation was performed. During a 1-month baseline period and a 4-week drug treatment period patients assessed the intravaginal ejaculation latency time (IELT) at home with a stopwatch. Only men with an IELT <1 min were randomly assigned to drug treatment. Patients assessed the drug coitus interval time (DCIT) and used the UKU side effect scale questionnaire at baseline, the day of and the day after intercourse.Results: On-demand treatment with 25 mg clomipramine, with a mean DCIT of 5.14 h, led to a 4.05 (95%CI: 3.26–5.02) fold-increase of the IELT. On-demand treatment with 20 mg paroxetine, with a mean DCIT of 5.39 h, led to a 1.41 (95%CI: 1.22–1.63) fold-increase of the IELT. Both drugs had a high incidenc of non-sexual side effects at the coitus day and the next day. At the day of coitus paroxetine led to significant sleepiness and yawning compared to clomipramine. At the day after coitus clomipramine induced significant nausea compared to paroxetine.Conclusion: On-demand treatment with 25 mg clomipramine led to a clinical relevant ejaculation delay. In contrast, 20 mg paroxetine had no clinical relevant ejaculation delay in men with lifelong premature ejaculation with an IELT of less than 1 minute. Both drugs exert mostly mild yet annoying non-sexual side effects both at the coitus day and the next day. [Copyright &y& Elsevier]

Selective serotonin reuptake inhibitors (SSRIs) cause sexual dysfunctions in humans. However, because SSRIs are used to treat depression, it is unclear whether the problems are caused by the drug, by the depression itself, or an interaction between both. The present study investigated the effects of chronic paroxetine treatment on sexual behavior in female rats. Furthermore, we tested whether 5-hydroxytryptamine (5-HT) receptors were desensitized in these females. Ovariectomized female rats, either sub-primed with estradiol or fully primed with estradiol and progesterone, were tested in a paced mating test. Proceptive (darting and hopping), receptive (lordosis), and paced mating-related (percentages of exits and contact-return latencies) behaviors were quantified during the course of 56 days of chronic paroxetine treatment (10 mg/kg and 20 mg/kg per day). The 5-HT/5-HT receptor agonist (±)-8-hydroxy-2-(dipropylamino)tetralin hydrobromide ((±)8-OH-DPAT) alone and in combination with the selective 5-HT receptor antagonist WAY-100635 was administered to study putative 5-HT desensitization in the same females. Proceptive, receptive, and paced mating behaviors were quantified. Acute and chronic paroxetine treatment did not change proceptive and receptive behaviors in both sub-primed and fully primed female rats. In all groups, (±)8-OH-DPAT showed a clear dose-dependent inhibition of sexual behaviors in vehicle-treated females and a right-shifted dose-response effect in the paroxetine-treated rats. WAY-100635 attenuated the inhibiting effect of the 5-HT receptor agonist in all females. These data suggest 5-HT receptor desensitization after chronic paroxetine treatment. Chronic paroxetine treatment does not cause sexual side effects in sub- or fully hormonally primed female rats. Furthermore, chronic treatment causes adaptive changes in the serotonin system such as desensitization of 5-HT receptors, which may counteract the inhibiting effects of increased extracellular serotonin levels in the chronic paroxetine-treated rats. [ABSTRACT FROM AUTHOR]

Abstract: The existence of sexual dysfunctions in men, including premature and retarded ejaculation poses challenges to develop translational models in rats that may help in improving treatment and delineate the neural mechanisms of action. Most of our current understanding of the neurobiology, neuroanatomy and psychopharmacology of sexual behavior and ejaculatory function has been derived from preclinical studies in the rat. When large populations of male rats are tested on sexual activity during four successive tests, over time individual rats display a very stable sexual behavior that is either slow, normal or fast as characterized by the number of ejaculations performed. These sexual endophenotypes are postulated as rat counterparts of premature (fast rats) or retarded ejaculation (slow rats). Psychopharmacology in these endophenotypes may help to delineate the underlying mechanisms and pathology. This is illustrated by the effects of serotonergic antidepressants and serotonergic compounds on sexual and ejaculatory behavior of rats. Further unravelling of sexual endophenotypes may benefit from the use of chromosomal substitution strains in mice that enable the localization of relevant chromosomal areas and genes involved in ejaculation processes. These preclinical studies and models contribute to a better understanding of the neurobiology of ejaculation and boost the development of novel drug targets to treat ejaculatory disorders such as premature and retarded ejaculation. [Copyright &y& Elsevier]

Introduction. Selective serotonin reuptake inhibitors (SSRIs) differ in the severity of induced ejaculation delay. Various studies indicate that oxytocin is involved in sexual behavior. Aim. To review and evaluate the involvement of oxytocin in SSRI-induced ejaculation delay. Main Outcome Measures. Oxytocine release, 5-hydroxytryptamine (5-HT) neurotransmission, and desensitization of 5-HT1A receptors. Methods. A review and critical analysis of animal studies investigating the interaction of serotonergic and oxytocinergic neurotransmission in relation to the ejaculation process. Results. Although acute treatment with the SSRIs fluoxetine and paroxetine immediately causes increased serotonin levels, delayed ejaculation does not occur. The increased serotonin levels induce oxytocin release via activation of 5-HT1A receptors, and this might compensate for the inhibitory actions of serotonin on sexual behavior. Chronic treatment with fluoxetine and paroxetine desensitizes 5-HT1A receptors on oxytocin neurons, and that might in part determine the onset of delayed ejaculation. Desensitization of 5-HT1A receptors is less strong following chronic treatment with the SSRIs fluvoxamine or citalopram, which may attenuate the degree of delayed ejaculation. Conclusions. Preliminary data suggest that the severity of chronic SSRI treatment-induced delayed ejaculation and the differences between the various SSRIs in inducing ejaculation delay is related to gradual desensitization of 5-HT1A receptors on oxytocin neurons. de Jong TR, Veening JG, Olivier B, and Waldinger MD. Oxytocin involvement in SSRI-induced delayed ejaculation: A review of animal studies. J Sex Med 2007;4:14–28. [ABSTRACT FROM AUTHOR]