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Efficacy of sertraline hydrochloride in treatment of premature ejaculation: a placebo-controlled study using a validated questionnaire

Abstract

Selective serotonin reuptake inhibitors (SSRIs) are increasingly used to treat premature ejaculation. We report a large prospective placebo-controlled crossover study of sertraline in premature ejaculation (PE) using Arabic Index of Premature Ejaculation (AIPE). One hundred and forty-seven men suffering from PE were enrolled in a randomized single-blinded crossover study of sertraline hydrochloride and placebo. Patients were randomized into group 1 (n=77) and group 2 (n=70). Both groups received sertraline and placebo interchangeably for 4 weeks. Overall, 127 (81%) of 157 subjects experienced a significant increase in their AIPE total score after sertraline treatment. Sixty-six (66%) of 100 patients available for follow-up experienced relapse of PE within 6 months after sertraline withdrawal. The active drug was generally well tolerated. Our relatively large study, using a validated questionnaire (AIPE), confirmed the useful effect of sertraline on PE.

Introduction

Premature ejaculation (PE) is regarded as the most common male sexual disorder, affecting 30–40% of sexually active men,1, 2, 3 and according to a rough estimation of one author perhaps as many as 75% of men at some points in their lives.4 Premature ejaculation, like erectile dysfunction (ED), also could impact a man's life in many aspects, such as self-esteem and relationship with the opposite sex.

There have been many attempts to try to accurately define PE. The Diagnostic and Statistical Manual of Psychiatry (DSM-IV) defines premature ejaculation as ‘ejaculation that occurs before the individual wishes because of recurrent and persistent lack of reasonable voluntary control of ejaculation and orgasm during sexual activity…’.5 Other authors related PE to inability to inhibit ejaculation long enough for the partner with normal sexual function to reach orgasm 50% of the time.6 Others tried to confine PE to strict time limit or number of thrusts limits.6 Recently, an updated proposal for PE definition and diagnosis has been provided after the second consultation on sexual dysfunctions.7

Ejaculatory latency of less than 1–1.5 and perhaps 2 min may qualify a man for the diagnosis.8, 9 According to DSM-IV-TR and the AUA, the diagnosis can only be made when there is marked distress.7 We recently reported a new diagnostic tool for PE using a validated questionnaire, the Arabic Index of Premature Ejaculation (AIPE)10 (Appendix A1).

The etiology of PE is uncertain in most cases, and likely includes a combination of organic and psychogenic factors. Negative conditioning and penile hypersensitivity are the most frequently cited etiological factors in PE, although neither mechanism has received adequate experimental support to date.10

Premature ejaculation may be primary or secondary to several organic causes. Primary PE may be owing to performance anxiety, fear or psychological trauma. Men with PE progress very rapidly from excitement to orgasm, which is often experienced as minimally pleasurable. They appear to have a hypersensitive ejaculatory reflex.10 The fact that anxiety plays a role in this process, however, is attested by the frequent situational nature of the problem and the almost universal experience of good ejaculatory control during solitary masturbation.10

Although the cornerstone of treatment has for a long time been short-term directive sex therapy, PE is increasingly treated pharmacologically with a variety of different medications or with a combined pharmacotherapy and/or behavioral therapy according to patient/partner preference.7

Pharmacological agents used to treat PE either act centrally or locally to retard the psychoneurological control of ejaculation and subsequent orgasm. Although these agents can be used to treat PE, their efficacy is unfortunately counteracted by the high incidence of adverse side effects including drowsiness, tardive dyskinesia and other extrapyramidal adverse effects. In recent years, an increasing number of studies have shown the clinical efficacy of daily and on-demand treatment of PE by the antidepressant clomipramine 25–50 mg and the clinically relevant ejaculation-delaying effects of daily treatment with some selective serotonin reuptake inhibitors (SSRIs), particularly 20 mg paroxetine, 50–100 mg sertraline and 20 mg fluoxetine.11, 12 This paper reports the results of a large prospective single-blinded placebo-controlled crossover study of sertraline in PE using a validated questionnaire.

Methods

A total of 147 normally potent men suffering from PE were enrolled in a randomized single-blinded crossover comparative study of sertraline hydrochloride and placebo. All men were heterosexual, had no other sexual disorders and were either married or in a stable relationship. Premature ejaculation was defined as ejaculation that occurred within 2 min of vaginal intromission. All patients were asked to complete the AIPE before inclusion in the study. Patients scoring 31 or more were diagnosed as not having PE and were excluded, whereas patients scoring 30 or less were considered as having PE and were included in further investigations. Before the study, all men completed the Sexual Health Inventory for men (Arabic version)13 for diagnosis of ED. Patients with ED, reduced sexual desire, inhibited male orgasm, chronic psychiatric or physical illness, alcohol or substance abuse and use of medication, including psychotropic medication, were excluded from the trial. Written informed consent was obtained from all patients before study inclusion.

Patients were randomized into two treatment groups. Group 1 comprised 77 men with a mean age of 40 years and group 2 comprised 70 men with a mean age of 42 years. In phase 1 of the study, group 1 received 50 mg sertraline daily for 4 weeks and group 2 received placebo daily for 4 weeks. Placebo tablets were identical to the active drug. Patients were reviewed weekly. Group crossover was conducted at the end of phase 1, and after a 4-week drug-free washout period phase 2 of the study was commenced. In phase 2 of the study, group 1 received placebo daily for 4 weeks and group 2 received 50 mg sertraline daily for 4 weeks. None of the patients received any formal psychosexual counseling. All patients were blinded regarding the type of treatment received. Partners were asked to measure ejaculatory latency time, during a 4-week baseline period and throughout the study, using a stopwatch and to record time. Patients were asked not to use condoms, or topical penile anesthetic creams or sprays. The study was approved by our relevant institutional review board. Student's t-test was used to compare the frequency of coitus and ejaculatory intervals during the sertraline and placebo treatment phases. At the end of each phase, men were asked to complete the AIPE.

At the completion of the crossover study, monthly follow-up (for 6 months) of all patients who had achieved an increase in ejaculatory latency times over pretreatment levels with active drug in the initial crossover study was performed. Patients were asked to complete AIPE during each office visit.

Student's t-test was used to compare the frequency of coitus and ejaculatory intervals during the sertraline and placebo treatment phases.

Results

The mean age of the 147 men was 41 years (range 19–70) and pretreatment ejaculatory latency time was 0.3 min, with a range of ejaculation occurring from during foreplay or at intromission to 1 min after intromission. Of the men, 16 had primary premature ejaculation and 131 described secondary premature ejaculation with previous acceptable ejaculatory control. None of the men with primary premature ejaculation reported extra-vaginal ejaculation. Mean frequency of coitus in groups 1 and 2 during treatment with sertraline was not statistically different from placebo at all weeks.

The frequency of intercourse for patients treated with 4-week sertraline compared to those treated with 4-week placebo did not change significantly from previous pretreatment levels (sertraline 2.4±0.6 vs 2.8±0.8; placebo 2.7±0.5 vs 2.6±0.4) (P>0.05). Overall, 127 (81%) of 157 subjects experienced a significant increase in their AIPE total score after sertraline treatment. In group 1, the total AIPE scores increased from a pretreatment mean of 18.2±2.3 during the initial sertraline treatment phase to a mean of 31.3±2.3 after 4 weeks of treatment, respectively (Table 1). During the 4-week washout phase, the AIPE scores dropped significantly to 19.7±1.3 by the eighth week. During the final placebo treatment phase, total scores were 19.8±4.1 after 4 weeks. In group 2, the total AIPE scores changed from a pretreatment mean 16.6±3.1 during the initial placebo treatment phase to a mean 18.8±1.6 after 4 weeks of treatment. During the 4-week washout phase, mean ejaculatory latency time remained within a similar range. During the final sertraline treatment phase, total AIPE scores significantly increased to 31.5±2.3 by the twelfth week (Table 1). The AIPE total scores in groups 1 and 2 during treatment with sertraline were statistically superior to that achieved with placebo during treatment period (P<0.001). Table 2 illustrates the mean Intravaginal Ejaculatory Latency Time (IELT) of all responsive patients during different study phases. The mean IELT increased significantly from baseline levels after sertraline treatment but remained less than 1 min during the placebo phase.

Table 1 Mean (s.d.) total scores of AIPE of responsive patients (n=147) during different study phases
Table 2 Mean (s.d.) IELT (min) of responsive patients (n=127) during different study phases

Only 100 (79.3%) of 126 patients with improved ejaculation status were available for follow-up following drug withdrawal. Sixty-six (66%) of 100 patients experienced relapse of PE within 6 months after sertraline withdrawal, evidenced by low AIPE scores. The other 34 patients reported good control of their ejaculation. The active drug was generally well tolerated. Most side effects were minor and none prompted withdrawal from the study. Drowsiness and anorexia occurred in one patient. Two patients experienced minor gastrointestinal upset. Erectile dysfunction, reduced libido or reduced orgasmic intensity was not noted.

Discussion

Early ejaculation is considered a neurobiological phenomenon that may become perceived as premature ejaculation and consequently may secondarily lead to psychological distress.14 The selective serotonin reuptake inhibitors block serotonin (5-HT) reuptake, and this results in an increased 5-HT neurotransmission and activation of postsynaptic 5-HT receptors. Selective serotonin reuptake inhibitor-induced delayed ejaculation and anorgasmia is probably related to an increased central 5-HT neurotransmission and activation of postsynaptic 5-HT receptors.15, 16 In his excellent review on PE, Waldinger14 suggested that activation of 5-HT2C receptors delays ejaculation, whereas activation of 5-HT1A receptors accelerates ejaculation latency. Consequently, the ejaculation-delaying effect of some SSRIs may be used therapeutically to treat premature ejaculation.17, 18, 19, 20

The beneficial effect of sertraline, a well-known SSRI, was demonstrated in many previous studies.12 However, not all these studies used evidence-based medicine methodological approaches to precisely examine the effects of sertraline on ejaculation. In an excellent meta-analysis of PE studies in literature, Waldinger et al.12 concluded that in the current literature only eight (18.5%) studies on antidepressant treatment fulfilled all criteria used in evidence-based medicine, for example, randomized and with prospective real-time (stopwatch) assessment of the IELT at each intercourse. Moreover, only four of these studies involved the effect of sertraline on PE.12

Our study is the first report, to our knowledge, to investigate the effect of sertraline on PE using a validated index that incorporates several parameters including mean intravaginal ejaculation time as its determinants. Arabic index of premature ejaculation's determinants include sexual desire, erectile function, IELT, ejaculation control, patient satisfaction, partner satisfaction and anxiety–depression status. These different factors can accurately differentiate patients with PE and those without PE.10 During AIPE development and validation, each of the seven items was scored on a five-point ordinal scale where lower values represent poorer sexual function. Thus, a response of 1 for a question was considered the least functional, whereas a response of 5 was considered the most functional. Possible scores for the AIPE range from 7–35. The corresponding sensitivity was found to be 0.98 whereas the specificity was 0.88. The estimated κ coefficient of 0.85 indicated substantial agreement, above and beyond chance, between clinical diagnosis and predicted diagnosis.10

In this study, 126 patients with PE treated with 4-week sertraline experienced a significant increase in five out of the seven modules of the AIPE compared to their pretreatment responses and to placebo. These results clearly demonstrate the high efficacy of sertraline in treatment of PE over a short period of time. Unlike other antidepressants that can cause ED and low sexual desire,12 sertraline treatment did not result in any alteration of erectile function or libido.

The rapid prolongation of ejaculatory interval achieved by sertraline suggests a direct blocking effect on central serotoninergic re-uptake. Also, sertraline may have caused reduction in performance anxiety resulting in improvement in ejaculatory control and overall sexual satisfaction. The antidepressant effect of sertraline in ejaculatory control enhancement observed in our patients cannot be entirely eliminated. None of our patients reported suffering major psychiatric disorder; however, absence of adequate evaluation of their psychological status prevented us from drawing any further conclusion.

The sustained effect of SSRI drugs on ejaculation time following drug withdrawal is not widely recognized.21 McMahon21 reported a more prolonged sustained effect of sertraline on ejaculation time leading to 67% (20 out of 29 patients) discontinual rate following staged drug withdrawal. However, no data are present on the long-term follow-up of these patients. In our study, following withdrawal of sertraline, approximately 66% of all patients with PE successfully treated with sertraline experienced a relapse within 6 months of drug stoppage. A key difference between this study and the present report is the lack of staged withdrawal, explaining the contradictory results.

Sertraline appears to be well received by the patients enrolled in this study. None of the three patients who had adverse effects of drowsiness and gastrointestinal upset regarded these side effects as disabling or considered withdrawing from the study. This finding may be related to the low dose of sertraline used in this study compared to the higher doses used for depression.

Conclusions

Our relatively large study, using a validated questionnaire (AIPE) confirmed the useful effect of sertraline on ejaculation time. Further large cohort studies with long-term follow-up are needed to evaluate sertraline sustained effects on ejaculation latency, specifically after drug discontinuation.

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Correspondence to R Shamloul.

Appendix A1

Appendix A1

Arabic Index of Premature Ejaculation

Patient's name:______________ Patient's number:____________

Please respond to each question by circling ONLY ONE statement that best describes your condition.

Q1. How do you rate your sexual desire?

  1. a)

    very low

  2. b)

    low

  3. c)

    average

  4. d)

    high

  5. e)

    very high

Q2. How often do you have hard erections, with sexual stimulation, sufficient to complete sexual intercourse?

  1. a)

    almost never

  2. b)

    rarely

  3. c)

    sometimes

  4. d)

    often

  5. e)

    most of the time

Q3. How much time does it take from intromission to ejaculation (using a stop-watch)?

  1. a)

    <30 s

  2. b)

    around 1 min

  3. c)

    1–2 min

  4. d)

    2–3 min

  5. e)

    >3 min

Q4. How difficult is it for you to prolong your ejaculation time?

  1. a)

    most of the time

  2. b)

    often

  3. c)

    sometimes

  4. d)

    rarely

  5. e)

    almost never

Q5. How often was sexual intercourse satisfactory for you?

  1. a)

    almost never

  2. b)

    rarely

  3. c)

    sometimes

  4. d)

    often

  5. e)

    most of the time

Q6. How often was sexual intercourse satisfactory for your partner?

  1. a)

    almost never

  2. b)

    rarely

  3. c)

    sometimes

  4. d)

    often

  5. e)

    most of the time

Q7. During sexual intercourse, do you feel anxious, depressed or stressed?

  1. a)

    most of the time

  2. b)

    often

  3. c)

    sometimes

  4. d)

    rarely

  5. e)

    almost never

Date of assessment:_________________Doctor's initials:__________

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Arafa, M., Shamloul, R. Efficacy of sertraline hydrochloride in treatment of premature ejaculation: a placebo-controlled study using a validated questionnaire. Int J Impot Res 18, 534–538 (2006). https://doi.org/10.1038/sj.ijir.3901469

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Keywords

  • premature ejaculation
  • sertraline
  • questionnaires

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