Premature Ejaculation Review


Rapid ejaculation, also referred to as early, uncontrolled, or premature ejaculation, was first described by Gross in 1887 and is the most common form of male sexual dysfunction.(1)

A review of literature reveals that there is little agreement on the exact definition of the problem. DSM-IV-TR incorporates some of the earlier definitions of premature ejaculation and lists three criteria (A-C) in the diagnostic features of this disorder:(2)

A. Persistent or recurrent onset of orgasm and ejaculation with minimal sexual stimulation before, on, or shortly after penetration and before the person wishes it.

B. Marked distress or interpersonal difficulty as a cause of the disturbance.

C. The condition is not exclusively due to the direct effects of a substance (such as alcohol).

DSM-IV-TR also recommends that physicians take into consideration factors such as age, the novelty of the sexual experience and the recent frequency of sexual activity that may influence the duration of the excitement phase.

Althof has further elaborated on the definition of premature ejaculation by combining the criterion sets of ICD-10 (3) and DSM-IV to diagnose the disorder along four dimensions:(4)

1. ejaculatory latency

2. voluntary control

3. presence of marked distress or interpersonal disturbance

4. the exclusionary criterion that the symptoms are not due to another mental, behavioral or physical disorder.

couple with premature ejaculationThe ability of the patient to control ejaculatory latency under different circumstances in order to satisfy himself and/or his partner is the underlying foundation of most definitions of premature ejaculation.

A recurring problem in the vast majority of premature ejaculation-related investigations has been lack of standardization of the definition of PE. The parameter of intravaginal latency time was introduced by Waldinger and coworkers in 1994 and was defined as the time between intravaginal entry and the beginning of intravaginal ejaculation. (5)

More reliable objective assessment of premature ejaculation was introduced in 1998 when Waldinger and coworkers added the stopwatch, initially proposed by Tanner in 1973, to allow the female partner to measure ejaculatory latency time during each intercourse in a 4-week period. (1,7)

Intuitively intrusive and unnatural, stopwatch measurement of ejaculatory time was feared to bias patient behavior and adversely influence outcomes. Interestingly, however, in a study on the pharmacotherapy of rapid ejaculation with clomipramine, Althof reported that patients did not object to the use of a stopwatch. (4,8)

Epidemiology

Premature ejaculation is a highly prevalent sexual disorder with the prevalence rate in the primary care setting reported to be between 2 and 31%.(9,10)

In a re-analysis of the findings of 22 general population sex surveys to assess the prevalence and distribution of psychosexual dysfunctions as defined by DSM-III, Nathan estimated the prevalence of premature ejaculation to be 35%.(11)

couple with premature ejaculationOther general population prevalence estimates have reported rates from 4 to 39%, although most estimates fall between 22 and 38%. (12-14) The wide variability in the reported rates may well be due to lack of a standardized definition for premature ejaculation.

Despite the highest reported prevalence rates among sexual dysfunctions, it is noteworthy and ironic that premature ejaculation is the disorder for which patients are least likely to seek professional assistance and the problem may therefore be more common than is currently estimated. (13,14)

On the other extreme of the spectrum is delayed or deficient ejaculation, a rarer condition affecting 1-4% of men that has been associated with a variety of psychological etiologies (strict religious background, lack of attraction to the female partner, over-controlled personality) as well as drug therapies including selective serotonin reuptake inhibitors (SSR1s), haloperidol, trazodone and some benzodiazepines. (15)

Physiology of ejaculation

The prostate contributes approximately 10%, the vasa 10%, and the seminal vesicles 75-80% to the normal ejaculate. The ejaculated semen is typically 1.5-5.0 ml. in volume and also contains small amounts of mucus secreted by the bulbourethral glands.

A low volume (<1 ml) ejaculate with an acidic PH (<7.0) that is composed mainly of prostatic fluid may be found secondary to bilateral obstruction of the ejaculatory ducts or absence/atrophy of the seminal vesicles. The seminal vesicles contribute most of the final portion of the ejaculate.

couple with premature ejaculationEmission, bladder neck closure and antegrade  propulsion constitute the three distinct phases of ejaculation and are reflex events dependent on autonomic-somatic coordination. Emission, the first phase, is associated with an impending sensation of orgasmic inevitability and is governed by the sympathetic nervous system.

Efferent sympathetic fibers emanating from the thoracolumbar spine at T10-12 mediate vaso-epididymal smooth muscle contractions and the initial deposition of the seminal fluid components from the vasa, vasal ampullae, prostate and seminal vesicles into the posterior urethra.

In the second phase of the ejaculatory process (bladder neck closure), seminal fluid reflux into the bladder is prevented by coaptation of the circular smooth muscle fibers of the bladder neck under sympathetic influence.

Finally, the forceful expulsion of seminal components through the urethra (antegrade propulsion), is mediated by somatic efferent fibers arising from S2-S4.

It is unclear how emission and antegrade propulsion are coordinated, but it is hypothesized that at least one of the triggers for antegrade propulsion may be posterior urethral distension (i.e. secondary to emission). (16)

Antegrade propulsion of the ejaculate results from rhythmic contractions of the bulbocavernosus, ischiocavernosus, and pelvic floor muscles under the influence of the pudendal nerve and nucleus of Onuf motor neurons. (17)

There is simultaneous relaxation of the external urethral sphincter. Sensory information arising from genital skin triggers the ejaculatory process and is transmitted via the dorsal nerve, the sensory branch of the pudendal nerve. The pelvic splanchnic nerves transmit sensory stimuli from the prostate, vas deferens and the seminal vesicles to the spinal cord.

The various components of the ejaculatory reflex (higher cerebral neural inputs, sensory fiber afferents from the genitalia, and the sympathetic and somatic efferent motor outflow) are integrated at the ejaculatory reflex center between T12 and L2. Ejaculatory dysfunction may result from various disorders of the different components of this intricate neural network.

Pathophysiology of premature ejaculation

Both physiological/medical and psychological etiologies have been suggested as causes of premature ejaculation. Many investigators have intuitively sought life stressors, medications and psychosocial etiologies for acquired premature ejaculation in contrast to lifelong or primary premature ejaculation that may have a more obvious non-psychogenic etiology.

Hong has importantly observed the brevity of intercourse in animals under conditions where the animal may be forced to fight or flee to protect itself from other elements and predators. (17)

Based on this finding, it is not far-fetched to postulate that prolongation of intercourse may be a learnt response that evolves as humans age. The role of other qualitative descriptions such as male voluntary control, female partner satisfaction, and anxiety on premature ejaculation have been further elucidated by Kaplan as well as Masters and Johnson.(18,19)

These authors have focused on such concepts as anxiety due to poor sexual education and blockage of pre-ejaculatory sensations secondary to anxiety. (15, 18-20)

The definition of premature ejaculation according to Masters and Johnson is closely tied to female partner satisfaction and  entails failure of ejaculatory inhibition such that the partner is unable to achieve orgasm in 50% of intercourse attempts. (19)

This definition has been criticized for assuming that the female partner should be able to achieve orgasm 50% of the time and for misdiagnosing the male partner as a rapid ejaculator under circumstances when the problem may be solely due to the female partner's inability to achieve orgasm. (6)

The role of anxiety and subjective distress in general has been questioned by other investigators.

 For example, in a self-stimulation study (where there is presumably minimal or absent sources of distress), it was shown that premature ejaculators reached orgasm in about half the time as non-premature ejaculators and there was no significant difference between the two groups in the level of self-reported anxiety. (21,22)

Although there may indeed be a difference in the etiology and pathophysiology of acquired and lifelong premature ejaculation, a purely psychogenic etiology may be challenged in both groups.

As an example, Kuhr et at have reported six men without any prior history of premature ejaculation who developed sudden, severe premature ejaculation after thoracolumbar spinal cord injury. (16)

Sexual therapy was not successful in treating these men. The authors postulated that disinhibition of the ejaculatory reflex resulted from injury in the conus area of the spinal cord causing an inhibition of supraspinal influences on the spinal ejaculatory center or alternatively, that spinal cord injury may result in a decreased threshold for emission in the spinal cord. (16)

No obvious endocrine abnormalities have been identified in patients with premature ejaculation. In a study of the pituitary testicular system in premature ejaculators (those with and without evidence of anxiety and avoidance behavior toward coital activity), no significant differences were found in the levels of luteinizing hormone, total testosterone, and free testosterone between patients and controls. (23)

From a neurological perspective, the medial preoptic area of the hypothalamus is actively involved in the ejaculatory process through electrical stimulation and an inhibitory effect on the serotonergic pathways of the nucleus paragigantocellularis. (6,24)

Penile hypersensitivity and a more rapid bulbocavernosal reflex as the cause of premature ejaculation was suggested by Fanciullaci et al. (79)

Their hypothesis was further supported by other investigators who showed that uncontrolled ejaculation may be due to excessive neural stimuli secondary to hypersensitivity and hyperexcitability of the glans penis. (25)

Xin et al used somatosensory evoked potentials to compare premature ejaculators with normal controls and found that the mean latency was significantly decreased in both the dorsal nerve and the glans penis in the group with premature ejaculation. (26)

In contrast, Paick et at prospectively evaluated the penile sensitivity of 18 patients with a lifelong history of premature ejaculation and 15 controls and found no statistically significant difference in vibratory threshold between the two groups.

They also did not find statistically significant differences in sensitivity of the glans penis, dorsum of the penile shaft, or frenulum of the penis between the two groups and concluded that penile hypersensitivity, as measured by a vibrometer, does not appear to be a major factor contributing to premature ejaculation. (27)

More recent research has shed light on other possible organic causes for premature ejaculation. Neurobiology and genetics have assumed increasingly more important roles relative to the concept of 'learned behavior' that was in the forefront of rapid ejaculation research in the second half of the twentieth century. (6)

It has been suggested that premature ejaculation in rats results from inhibition of dopamine neurotransmission and the hypothesis is further supported by the finding that 6 hours after haloperidol administration, rats achieve more rapid ejaculation. (28)

Yet another interesting investigation in support of biological causes and pointing toward possible genetic etiologies is a study in which 9 1 % of men with premature ejaculation had a first-degree relative who was similarly affected. (29)

Additional animal studies in male rats defined an important role for 5-HT (serotonergic) receptors in ejaculatory function.

More specifically, it was discovered that non-selective agonists of the 5-HT2C receptors delay ejaculation, but selective 5-HT2A agonists do not have a similar effect and selective 5-HT1A agonists cause a shorter ejaculatory latency compared to 5-HT2C agonists. (30,31)

These findings led to the hypothesis by Waldinger et al that premature ejaculation in humans may be secondary to relative hyposensitivity of the 5-HT2C receptors and/or 5-HT1A hypersensitivity. (32) Waldinger later supported the effect of postsynaptic 5-HT receptor activation on delayed ejaculation by using different SSRIs. (7,33-35)

Therapies for premature ejaculation

Behavioral and non-pharmacological therapies

Depth therapies with attempts at unconscious conflict resolution or reorganization of deep-rooted personality traits have not been found to be effective in the treatment of cases of premature ejaculation.

A number of investigators have reported superiority of symptom-focused behavior modification techniques to depth psychotherapy. (36,37)

With a male and female therapist team treating both the premature ejaculator and the female partner, Masters and Johnson reported successful treatment of 186 cases of premature ejaculation with only four failures in Human Sexual Inadequacy in 1970. (19)

Based on a view of premature ejaculation as 'learned behavior' and emphasizing the need to simultaneously treat the female partner, Masters and Johnson's well-known and intensive model applies the 'squeeze technique' modification of Seman's start-stop method introduced in 1956.

Seman's technique involves penile stimulation until the sensation immediately 'premonitory to ejaculation' is experienced at which point all stimulation is stopped and is subsequently restarted. By reapplication of this technique, longer periods of stimulation are tolerated by the affected patient. (38)

Though effective in the masturbation setting, it was found that self- application of the squeeze technique frequently failed during intercourse.

As a result, it has been suggested that the success of the Masters and Johnson technique is rooted not so much in 'deconditioning of a heightened physiological reflex', but rather in reducing anxiety during intercourse. Another example of behavioral/ feedback therapy and sensate focus exercise for couples is the 'quiet vagina'.

This is an exercise where the premature ejaculator is slowly 'desensitized' to the stimulating effects of vaginal penetration. The initial approach is to start penetration without repeated thrusts until the brain gets used to the vaginal sensation for prolonged periods. In a modification of the stop-start technique, movement is gradually introduced and stopped just prior to ejaculation.

Although a variety of individual and group psychotherapy approaches have appeared over the years, most have been criticized by the lack of long, term sustainable efficacy.

Masters and Johnson provided 5-year follow-up data with relatively consistent results, but have been faulted for lack of the use of a standardized/structured questionnaire during the follow-up period. DeAmicis et al evaluated the status of 38 couples who had been treated at a clinic for sexual dysfunction 3 years previously and found that in men with premature ejaculation, with the exception of length of foreplay, other post-therapy gains were not sustained at the 3-year follow-up. (41)

Other barriers prohibiting the success of these behavioral and non-pharmacological approaches include embarrassment and resistance to the idea of visiting, or introducing one's partner to, a mental health professional, lack of time, or lack of a steady partner for such conjoint therapies.

Others have suggested that in male dominated societies such as those in eastern Asia, it is anticipated that behavioral therapies will have a lower success rate due to men's reluctance to ask partners for co-operation. (41) Tables 1 and 2 list some of the more common modes of premature ejaculation treatment with their associated potential adverse effects and disadvantages.

Pharmacotherapy

Centrally acting drugs with efficacy in delaying ejaculation and local pharmacotherapies in the form of topical anesthetics or cavernosal medications were used to treat premature ejaculation during the twentieth century.

Schapiro and Aycock independently reported on the medical approach to premature ejaculation in 1943 and 1949, respectively, while other investigators sought to address the problem by using alpha-aminobenzoate as well as non-selective (phenoxybenzamine) or selective (alfuzosin, terazosin) alpha-blockers starting in the 1960s. (6, 42-46)

Other important historical points in the use of medications for treatment of premature ejaculation include reports on the ejaculatory delaying properties of dopamine antagonist neuroleptics such as thioridazine (Mellaril) as well as non-selective monoamine oxidase (MAO) inhibitors such as isocarboxazid and phenelzine. (6,47-49) Most of these drugs, however, were phased out of mainstream therapeutic regimens due to adverse effects.

The efficacy of clomipramine in delaying ejaculation was first shown by Eaton in 1973 and later confirmed by Girgis et al in a placebo controlled, double-blind trial using 10 mg doses. (50,51) Other investigators showed efficacy of a chronic or on demand administration regimen. (52, 53)

Althof et al conducted a double-blind, randomized placebo controlled study of the effects of clomipramine in delaying ejaculatory latency and noted significant increases in latency (249% with 25 mg, 517% with 50 mg). (54) Kim and Seo compared the efficacy and safety of fluoxetine, sertraline, clomipramine and placebo for the oral pharmacotherapy of premature ejaculation by evaluating 36 men who had intravaginal ejaculation latency of less than 2 minutes.

Patients took each of three drugs and the placebo consecutively during a 4-week period. Efficacy and adverse event data were obtained by a self-reported patient questionnaire that rated intravaginal ejaculation latency, sexual satisfaction of patient and partner, and possible side effects.

After 4 weeks of treatment, the authors found that patient sexual satisfaction after treatment with clomipramine was significantly higher than with sertraline, fluoxetine or placebo. However, the incidence of side effects with clomipramine was also significantly higher compared to those of the other study medications or placebo.

The authors concluded that while clomipramine was the most efficacious drug in treating premature ejaculation, treatment with sertraline was nearly as effective and had a lower incidence of side effects. (55) Clearly, the advantages in lower cost as well as reduced side effects make 'on-demand' regimens more appealing to patients.

Table 1 Common modes of therapy and associated classifications for premature ejaculation

Mechanism/Classification

Stop-start / Seman's original description (biofeedback)

Pause-squeeze / Masters and Johnson; modification of stop-start (biofeedback)

Sensate focus / Anxiety reduction; heightened awareness of arousal (biofeedback)

Quiet vagina / Desensitization exercise (biofeedback)

Multiple condoms / Decreased sensory perception (self-help)

Repeated masturbation / Increased ejaculatory threshold (self-help)

Clomipramine / Antidepressant; (pharmacologic)

Paroxetine, sertraline / Antidepressant (SSRIs); (pharmacologic)

SS cream / Herbal cream with anesthetic properties (topical)

Prilocaine-lidocaine / Cream with anesthetic properties (topical)

Prostaglandins / Intracavernosal agent; erectogenic (cavernosal)

Sildenafil / Phosphodiesterase inhibitor, erectogenic (pharmacologic)

(SSRIs = selective serotonin reuptake inhibitors)

Table 2 Common modes of therapy for premature ejaculation with associated potential adverse effects/disadvantages

 

Therapy Possible disadvantages and adverse events
Stop-start Requires partner participation; poor long-term efficacy
Pause-squeeze Requires partner participation; poor long-term efficacy
Sensate focus Requires partner participation; poor long-term efficacy
Quiet vagina Requires partner participation; poor long-term efficacy
Multiple condoms Decreased sensory perception and possible decreased pleasure
Repeated masturbation Possibly decreased coital pleasure
Clomipramine Anticholinergic effects, genital anesthesia, loss of libido
Paroxetine, sertraline, fluoxetine Generally mild. Dry mouth, constipation, erectile dysfunction (sertraline), fatigue and yawning (paroxetine), anxiety (fluoxetine)
SS cream Mild local burning sensation and pain
Prilocaine-lidocaine Possible excessive anesthesia
Prostaglandins Priapism, possible corporal fibrosis
Sildenafil Headaches, flushing, visual disturbances, variable absorption with food ingestion, contraindicated with concomitant nitrate use

Delayed ejaculation by an average of 6 minutes with 25 mg of clomipramine has been reported when the medication is taken 12-24 hours before intercourse and by an average of 3 minutes when taken 4-8 hours before intercourse. (56,57) Rowland et al. have recommended an initial 'on-demand' regimen of 25 mg or less 4-24 hours before intercourse, to be changed to a daily dose of clomipramine (10-30 mg) if the on-demand strategy is unsuccessful. (58)

The adverse events experienced by patients on clomipramine usually decrease with time and are dose related. (51,54) However, the improvements in latency disappeared with discontinuation of the medication in Althof et al's study. (57)

Furthermore, long-term treatment with higher doses of clomipramine (75 mg, 3 months or more), has been reported to have a potential adverse effect on seminal parameters. (59) Mousavizadeh et al have recently demonstrated calcium channel blocking activity by clomipramine, thioridazine and SSRIs.

Through inhibition of vasal/epididymal contractility or interference with individual sperm motility, this pharmacological property may have an adverse effect on seminal parameters and reproductive potential, although the latter has not been conclusively demonstrated. (60) Other adverse effects that have been reported include dry mouth, fatigue or low energy, and dizziness. (57)

As with clomipramine, case reports indicating adverse events during SSRI therapy for depression led to further investigations on the effective use of these agents in treating premature ejaculation. In 1993, Patterson reported delayed or absent ejaculation in 45 of 60 men who were treated with daily doses of the SSRI fluoxetine (20 mg) for depression. (61)

 One year later, Forster and King suggested the use of fluoxetine while Waldinger et al. published the first placebo controlled study of paroxetine 40 mg daily for successful treatment of premature ejaculation. (5,62) Other studies demonstrated efficacy of paroxetine in on-demand as well as daily-dose regimens. (63-65)

SSRIs have differential effects in delaying ejaculation and orgasm in men. The incidence of 'abnormal ejaculation' in separate 6-week double-blind placebo controlled studies of major depression has been reported to be only 4.5% on a 50 mg/day regimen of sertraline and 6.5% on a 20 mg/day regimen of paroxetine. (66)

However, data on patients with psychiatric disorders, in whom there may be other confounding factors related to depression, may not be directly applicable to the non-depressed patients with premature ejaculation. In men with rapid ejaculation, it has been shown that SSRIs have a larger effect on ejaculation and male orgasm as compared with libido or erections. (7)

Among the SSRIs, paroxetine exerts the strongest delay in ejaculation followed by fluoxetine and sertraline. The paroxetine-induced change in intravaginal ejaculation latency (IELT) is independent of the baseline IELT and the beneficial ejaculatory delaying properties of some SSRIs may therefore be applied to men with lifelong premature ejaculation as well as those with milder, less rapid ejaculatory dysfunction.

The effects of fluvoxamine on delaying ejaculation are not significantly different from placebo and it is unclear why differential effects on inhibition of ejaculation are noted with different SSRIs. However, given the absence of significant ejaculatory delaying properties, fluvoxamine has been suggested as an ideal treatment for depressive illness when sexual side effects, such as a delayed ejaculation, are not desired. (7)

Yilmaz et al demonstrated the effects of fluoxetine on IELT, penile sensory threshold, and variables of sacral evoked response and cortical somatosensory evoked potential in patients with premature ejaculation and concluded that the efficacy of fluoxetine is most likely due to its effect of increasing the penile sensory threshold. (67)

The amplitudes and latencies of sacral evoked response and cortical somatosensory evoked potential were not significantly affected in their study.

The relatively long half-life of some SSRIs prompted investigators to further pursue possibilities for 'on-demand' administration. McMahon and Tourna showed that paroxetine (24-hour half-life) appears to be a well-tolerated medication for on-demand administration and that the best results are likely to be achieved after initial chronic dosing that is later switched (after 4 weeks) to an on-demand mode. (64) Fifty-nine percent of patients in the McMahon study achieved satisfactory results.

It is also noteworthy that eight of the 10 who responded favorably to paroxetine therapy had been considered to have had severe premature ejaculation refractory to therapy with psychosexual counseling.

Improved ejaculatory control on paroxetine is typically achieved after 2 weeks when drug steady-state levels are achieved systemically. Paroxetine is a selective inhibitor of 5-HT uptake in the brain with little affinity for dopamine or central beta-adrenergic receptors and has a side effect profile that is mainly sexual and gastrointestinal.

The tremors and agitation experienced on fluoxetine are rarely seen, but drug interactions with warfarin, dilantin and tryptophan have been reported. (64)

Similarly, Kim and Paick evaluated as needed use of sertraline for the treatment of premature ejaculation and demonstrated that with a regimen consisting of 2 weeks of chronic therapy (50 mg or, if unsuccessful, 100 mg) followed by on-demand administration on the day of anticipated intercourse, significant increases in ejaculation latency and sexual satisfaction scores may be achieved. (41)

The side effects of sertraline were also mild (excessive ejaculatory delay, numbness of the extremities, and fatigue) and there were no dropouts in the study because of adverse events.

Self-help techniques such as repeated pre-coital masturbation, use of multiple layers of condoms, and mind-distraction exercises have been used by men over the years to overcome premature ejaculation.

Since the basis of many of these strategies is to achieve decreased sensory perception in the penis, it is not surprising that many investigations have focused on the use of topical agents. Furthermore, patients have been shown to have consistently decreased vibratory threshold (i.e. increased sensitivity) that is not age dependent in penile biothesiometry studies. (25)

Unfortunately, there is a paucity of reliable, controlled reports in this field. In nine of 11 men with premature ejaculation, prilocaine, lidocaine cream (EMLA, Astra Pharmaceuticals, Wayne, Pennsylvania) was shown to markedly improve IELT without any reported adverse events. (68)

Comparison of application 20, 30 and 45 minutes before intercourse showed 20 minutes before anticipated intercourse to be the optimum period for topical application of EMLA. (69)

The SS cream (CJ Corporation, Seoul, Korea) consists of extracts of nine herbal medicines that is applied to the penis 1 hour before intercourse and subsequently removed with a wet towel prior to intravaginal penetration.

The active components are bufosteroid and eugenol, which have been reported to possess topical desensitization effects as shown in corneal sensitivity tests. (70) Choi et al investigated ejaculatory latency with use of SS cream and considered the therapy effective if ejaculatory latency was prolonged by more than 2 minutes and satisfaction increased by more than 20%.

A dose-dependent increase in both ejaculatory latency and rates of satisfaction was reported. The mean ejaculatory latencies were significantly prolonged after using various test drugs (placebo, 2.270.32; SS cream: 0.05 g, 4.470.81, 0.10 g, 5.340.79, 0.15 g, 6.220.87, 0.20 g, 11.061.17 minutes). The rate of satisfaction was also significantly increased in a dose-dependent manner (placebo, 26%; SS cream: 0.05 g, 60%, 0.10 g, 70%, 0.15 g, 78%, 0.20 g, 90%). (71)

However, the authors did not report use of a validated questionnaire for evaluation of satisfaction rates. The side effects (mild local burning sensation and pain) were reported as mild and affected 39 of 250 patients in the study.

Hsieh et al evaluated the therapeutic potential of sympatholytic agents (phenoxybenzarnine, prazosin, WB-4101, chloroethylclomidine, yohimbine and RX 821002) at various concentrations on premature ejaculation in rats by investigating seminal vesicle pressure change in response to electrical stimulation of the lesser splanchnic nerve.

All test drugs suppressed the seminal vesicle contractile response to electrical nerve stimulation in a dose-dependent manner and the authors suggested that these drugs may have clinical therapeutic potential. (72)

Fein has reported on the use of intracavernous erectogenic agents in eight patients (i.e. phentolamine mesylate 1.0 mg/ml and papaverine hydrochloride 30 mg/ml) for the treatment of premature ejaculation. (73) 

With drug induced erections lasting from 2 to 4 hours despite ejaculation, three patients stated they were cured and stopped the treatment, while five patients continued using the medication after 14 months.

The rationale for this type of therapy is that while the patients may be undergoing psychological or behavioral/biofeedback therapy, they are able to enjoy intercourse and this, in turn, will lead to heightened confidence and less anxiety.

Abdel Hamid et al compared the safety and efficacy of the as-needed use of clomipramine, sertraline, paroxetine, sildenafil and the pause-squeeze technique in treatment of primary premature ejaculation in a prospective double-blind randomized cross-over study. The IELT was statistically significantly increased with use of all modalities.

The authors attributed the newly discovered success with sildenafil to a possible reduction in patient anxiety, increased ejaculatory latency secondary to increased erection time or a central effect. (74)

The investigators further noted an excellent correlation between ejaculatory latency and sexual satisfaction score as measured by the erectile dysfunction inventory of treatment satisfaction (EDITS) and reported that the lowest success rate was achieved with Masters and Johnson's pause-squeeze technique (54.8%).

The EDITS satisfaction score (6 versus 30) and the ejaculatory latency time (3 versus 15 minutes) were lower than sildenafil, but comparable to sertraline and clomipramine. (74)

Despite the relatively short half-lives of sildenafil (3-5 hours compared to half-life greater than 20 hours for the SSRIs), maintenance of increased ejaculatory latency during the sildenafil washout period was observed in 29% of patients and attributed to possible reduction in anxiety levels.

The authors reported the overall safety and efficacy of clomipramine, sertraline, and paroxetine to be equivalent when used on an as-needed basis (although there were higher side effects noted with clomipramine that were not statistically significant). Sildenafil was reported as being 'decidedly the most effective' and was recommended as a valid alternative to the SSRIs in the treatment of PE. (74)

The study has been criticized for using a questionnaire (EDITS) that was designed to assess treatment satisfaction pertaining to erectile dysfunction rather than premature ejaculation and for failing to put forward the possibility that improved IELT may have simply resulted from the ability of the patients to achieve a second or third erection and respond to sexual desire after an initial coital episode. (75)

Salonia and coworkers compared paroxetine alone versus paroxetine in combination with sildenafil in the treatment of patients with premature ejaculation. (76)

The authors reported that at the time of 6 month follow-up, paroxetine taken on a chronic basis and later switched to an on-demand mode was safe and effective in increasing the ejaculatory latency time compared to controls (0.330.04 versus 4.20.03 minutes) and that 75% reported improved quality of sexual activity.

Furthermore, the combination of paroxetine with sildenafil resulted in a statistically significant increase in ejaculatory latency (compared to paroxetine alone) with a mild increase in the incidence of adverse events. (76)

As in the Abdel-Hamid study (74), these investigators noted that improved control of ejaculation and increased ejaculatory latency was associated with improved overall sexual satisfaction (follow-up at 3 and 6 months with the international index of erectile function (IIEF) and general assessment questions).

Other investigators have demonstrated the efficacy of sildenafil as adjuvant therapy in combination with SSRIs and psychosexual counseling in patients with premature ejaculation refractory to other modes of management. (77) Based on a report by Balon that ejaculatory latency may be dependent on erection time, it is possible that improved ejaculatory control may be an indirect effect of prolonged erections. (78)

Although other hypotheses related to the potential central effect of sildenafil on nitric oxide pathways have also been put forward, objective data are lacking and the exact mechanism of action of sildenafil in increasing ejaculatory latency has not been satisfactorily demonstrated.

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