Introduction

Premature ejaculation is a male sexual dysfunction that affects ~22.7% of men [1]. There are several therapies for this condition, including pharmacological treatment, behavioral therapy, and psychotherapy [2,3,4,5,6,7]. While dapoxetine on demand is currently recommended as a first line treatment, this drug often produces side effects, such as headaches, dizziness, nausea, diarrhea, insomnia, and tiredness [2, 5].

At physiological and anatomical levels, micturition and ejaculation involve similar structures, such as the sympathetic centers (T12-L1), the somatic and parasympathetic centers (S1-S3), the pudendal nerve, the hypogastric nerve, and Onuf’s nucleus [8]. The physiological process of ejaculation starts with the stimulus of sexual cues and sensory inputs from erogenous areas of the body that are processed by the cerebral cortex and the thalamus and subsequently travel to the hypothalamus, then to the ventral tegmental area and finally to the nucleus paragigantocellularis. The excitatory stimulus travels through the efferent peripheral nervous system, composed of the sympathetic center (emission), the thoracolumbar segments T12-L1 (expulsion) and the parasympathetic center S1-S3 (secretion). When the excitatory stimulus passes to the spinal centers, the ejaculatory process begins [9]. Ejaculation consists of two stages, emission and expulsion, and these stages also depend on the synchrony of the sympathetic and parasympathetic systems that synergistically participate in this process [8,9,10,11]. The emission stage is mediated mainly by the sympathetic system (T12-L1) and is characterized by the closure of the bladder neck sphincter, followed by the ejection of secretions, or seminal fluids, which accumulate in the prostatic urethra, creating a high-pressure chamber. The subsequent expulsion stage is controlled mainly by the sacral parasympathetic and somatic center (S2-S3 and S4) and is activated by the increased pressure in the chamber behind the prostatic urethra. The expulsion stage refers to the ejection of semen through the urethral meatus where the semen is propelled through the rhythmic contractions of the pelvic, bulbospongiosus, and ischiocavernosus muscles [10, 11].

The posterior tibial nerve is a mixed (sensory and motor) nerve containing fibers that have medullary origins in the sacral plexus, as does the innervation of the structures of the pelvic floor [12, 13]. Our hypothesis is that transcutaneous posterior tibial nerve stimulation has an effect on the anatomical structures that depend on the sacral plexus, such as the musculature of the pelvic floor, urethra, prostate, and seminal glands, generating an inhibition of parasympathetic and subsequent sympathetic stimuli and delaying ejaculation. The objective of this study was to evaluate whether this therapeutic modality is sufficiently effective and safe to treat premature ejaculation.

Subjects and methods

A phase II single-arm clinical trial was conducted in a specialized health center to evaluate the safety and efficacy of this therapy to control the ejaculatory reflex for patients with premature ejaculation. This study was registered with ClinicalTrials.gov (NCT03204890) and approved by an independent research ethics committee (Bioethics Institute—Pontificia Universidad Javeriana).

The participants included in this study were adult men diagnosed with premature ejaculation based on the American Psychiatric Association Diagnostic and Statistical Manual, DSM V:[14, 15]

  1. (1)

    In almost all or all (75–100%) sexual activity, a pattern of ejaculation occurring during partnered sexual activity within 1 min after vaginal penetration and before the individual wishes it.

  2. (2)

    The symptoms above have persisted for at least 6 months.

  3. (3)

    The symptoms above cause significant distress to the individual.

  4. (4)

    The dysfunction cannot be better explained by a nonsexual mental disorder, a medical condition, the effects of a drug or medication, severe relationship distress or other significant stressors.

The patients had to be within a stable heterosexual relationship for over 6 months, with a frequency of intercourse not less than once per week, with no PE treatment during the previous 6 months. Patients were excluded if they had any of the following criteria: diagnosis of erectile dysfunction (measured by the simplified International Index of Erectile Function - IIEF-5 questionnaire [16]), a premature ejaculation diagnostic tool (PEDT) [17] score under 8, premature ejaculation before penetration, installed a pacemaker or heart defibrillator, comorbid epilepsy or seizures, evidence of venous insufficiency or cutaneous wounds or lesions on lower limbs, congenital or acquired anatomical anomalies of the penis, use of medications that affect ejaculatory control (psychiatric drugs, analgesic opioids, medications for prostate pathologies, such as alpha blockers), use barrier contraceptives or local anesthetics, psychological or psychiatric disorders that would prevent the patient from carrying out the established treatment and measurement protocols, or unavailability to visit the clinic three times per week to complete the protocol. Informed consent was obtained from all subjects before starting the study.

Three sessions per week were conducted for 12 weeks, during which transcutaneous stimulation of the posterior tibial nerve was applied using a continuous current, with a frequency of 20 Hz and a pulse width of 200 µsec, for 30 min. This technique was chosen because it is less invasive than the percutaneous technique and more accepted by patients, therefore with more expected adherence to the treatment. The therapy was unilateral, and surface electrodes were used. The tibial nerve was located 3 cm above the internal malleolus and 1 cm behind the tibia. A Chattanooga® Intelect® tents standard device (DJO Global, UK) was used.

The intravaginal ejaculation latency time (IELT) was measured by the patient using a chronometer, counting the time between vaginal penetration and ejaculation during each intercourse, and recording that time on a dairy, which was reviewed at each medical follow-up appointment. This measurement was started 2 weeks prior to the therapy to help the patient become accustomed to the study evaluation and to obtain a more exact baseline value.

The main outcome was clinical improvement in premature ejaculation, defined as a threefold increase in IELT over baseline at week 12. Other outcomes evaluated were changes in the IELT and PEDT score after 18 therapy sessions (week 6), upon finishing treatment (week 12), after 3 months (week 24), and 9 months (week 48) of follow-up, and the type, frequency, and severity of adverse events during therapy.

The sample size estimation for this trial was performed using the “single-stage procedure” proposed by Fleming [18]. We hypothesized that 30% of patients would have a threefold increase in IELT upon completing therapy. With P0 = 10%, P1 = 30%, a type-1 error of 5%, and a type-2 error of 20%, 18 patients needed to be included.

Baseline clinical variables were reported using descriptive statistics. The distribution of the outcome variables was checked by graphical methods and the Shapiro–Wilk test. As the data were not normally distributed, the results were expressed as geometric means or medians. To evaluate the hypothesis that 30% of patients showed tripled IELT scores, the one-sample equality of proportions test was used with a theoretical proportion of 0.3. An equality test of matched pairs of observations was used to evaluate the change in PEDT score at weeks 6, 12, 24, and 48. Therapy safety was evaluated by estimating the incidence of adverse events or secondary effects over the course of the study and during the 3 months of follow-up. The data were analyzed with Stata 15.1 (College Station, TX: StataCorp LLC) using one-sided statistical testing at the p < 0.05 significance level. Database is available in Supplementary 1.

Results

Ninety subjects with premature ejaculation were invited to participate in the study. Twenty-six men fulfilled the selection criteria and were enrolled between June 14, 2017 and March 14, 2018. Fourteen participants had an IELT value >1 min during the evaluation with a stopwatch in the 2 weeks prior to the start of therapy and were excluded from the study. One patient abandoned treatment after 20 sessions; the cause of his withdrawal was not enough time to go to the therapy sessions (Fig. 1). Eleven patients provided data on their IELT at the end of the treatment (main outcome).

Fig. 1
figure 1

Patient flowchart

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Table 1 summarizes the baseline characteristics of the subjects participating in the study. The median age was 30 years (range 21–49 years), no comorbidities associated with premature ejaculation were found in any of the patients, and the median IIEF-5 score was 25 (range 22–25). The baseline geometric mean IELT was 32.4 s (CI 95%, 23.5–44.7), and the baseline median PEDT score was 16 (range 11–20).

Table 1 Patients baseline characteristics
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In the main outcome analysis, six out of eleven patients who finished the treatment showed clinical improvement at week 12, define as a threefold increase in IELT over the baseline (54.5%; CI 95%, 25.1–83.9%; p = 0.037). Eight out of nine patients who reported sexual intercourse at 24 weeks and six out of seven patients at 48 weeks showed tripled IELT scores (88.8%; CI 95% 37.4–99.0%; p = 0.0048 and 85.7%; CI 95% 25.6–99.0; p = 0.0006, respectively). When the twelve patients who started the therapy were included in the analysis, the proportion of subjects who showed threefold increase in IELT over baseline decreased to 50% (CI 95%, 21.7–78.2%, p = 0.065) at week 12; 66.6% (CI 95%, 39.9–93.3%, p = 0.0028) at week 24 and 50% (CI 95%, 21.7–78.2%, p = 0.065) at week 48.

The baseline geometric mean IELT was increased to 90.7 s (CI 95% 59.1–139.2) at week 6, 156.7 s (CI 95% 94.3–260.3) at week 12, 223.9 s (CI 95% 152.8–327.9) at week 24 and 176.7 s (CI 95% 102.9–303.6) at week 48. The fold increase of the IELT respect to baseline was 2.79 at week 6, 4.8 at week 12, 6.8 at week 24, and 5.4 at week 48. Figure 2 presents the increase in the IELT for each participant.

Fig. 2
figure 2

Increase in IELT by patient

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The median PEDT score was 12.5 points at week 6 (range 7–19; p = 0.0059), 12 points at week 12 (range 3–15; p = 0.0005), 13.5 points at week 24 (range 3–17; p = 0.001) and 7 points at week 48 (range 3–14; p = 0.0039). Four (36.4%) patients obtained a PEDT questionnaire score ≤8 at the end of the treatment. Figure 3 shows the median PEDT change for each evaluation point.

Fig. 3
figure 3

Change in Premature Ejaculation Diagnostic Tool - PEDT score

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In terms of the safety of the therapy, all treatment sessions were well tolerated by the patients. Two adverse events occurred: during one session, the patient reported feeling heat in the perineal region, which stopped when the treatment session ended, and after 12 sessions, another patient reported constipation, which was treated with changes in diet, including increased fiber, resulting an improvement. No other adverse events occurred. No sequels were presented as a result of the adverse events.

Discussion

Premature ejaculation is a pathology that causes significant deterioration in the quality of life of the persons affected and their partners [17, 19, 20]. Treatment is currently based on the use of different types of medications, such as antidepressants, serotonin reuptake inhibitors, phosphodiesterase-5 (PDE-5) inhibitors, and topical anesthetics, which are associated with secondary effects [2,3,4,5,6,7, 21].

Because the beneficial or harmful effects of transcutaneous posterior tibial nerve stimulation therapy in men with premature ejaculation were unknown, we were conservative and developed a phase-2 clinical trial to determine if at least 30% of the patients showed clinical improvement, defined as a threefold increase in the baseline IELT without pharmacologic treatment. The findings of this clinical trial showed that 54.5% of the participants showed tripled baseline times with this therapy, which was a significantly higher effect than the hypothesis proposed (p = 0.037). In addition, this effect was maintained in all patients after 3 months of completing therapy, in contrast to the effects typically observed after suspending pharmacological treatment [22].

The results of this study revealed that transcutaneous posterior tibial nerve stimulation therapy in men with premature ejaculation increases IELT by 4.82-fold, which is similar to the efficacy of pharmacological therapy. In a meta-analysis published in 2004, Waldinger et al. reported that clomipramine, fluoxetine, paroxetine, and sertraline improved IELT 3 to 8 times over baseline, depending on the drug evaluated, whereas placebo increased the baseline time by only 0.5 [23]. In a more recent meta-analysis published in 2016, Castiglione et al. evaluated the effectiveness of the current treatments for premature ejaculation, including PDE-5 inhibitors [24]; this study showed an increase in the IELT ranging from 2.1- to 11.6-fold, showing the highest increase with 20 mg of daily paroxetine and the lowest increase with 50 mg of tramadol on demand, while dapoxetine, the only on-demand drug approved in many countries to treat premature ejaculation, showed a threefold increase over the IELT baseline [24].

In addition to the IELT increase, an important finding in our study was that patients treated with transcutaneous posterior tibial nerve stimulation therapy did not present adverse events that affected adherence to the therapy. With pharmacologic treatments, patients are continually exposed to adverse events, such as nausea, dizziness, diarrhea, headache, decreased libido, anejaculation, or erectile dysfunction, which affect their adherence to treatment [21, 23, 24].

The results obtained in this clinical trial can be explained by a physiological theory based on the function and anatomical location of sacral roots, which, when stimulated retrogradely through the stimulation of the posterior tibial nerve, decreases the parasympathetic pathway of the overactive response of the ejaculatory reflex arc (Fig. 4).

Fig. 4
figure 4

Mechanism of action of transcutaneous posterior tibial nerve stimulation in men with premature ejaculation. The mechanism of action of the electrostimulation is based on the anatomy and mixed function (sensitive/motor) of the posterior tibial nerve originating at t4-s3 roots. This stimulation acts in three ways to modulate the ejaculatory reflex: (1) it modulates the sacral plexus, affecting the ejection phase of the ejaculation through the spinal reflex center s2-s4; it also affects t4-t2, which is part of the sympathetic spinal cord center that controls the emission phase of ejaculation; (2) parasympathetic ejaculatory stimulation is inhibited, generating a global delay in ejaculation due to the coupling of the autonomic nervous system (sympathetic-parasympathetic) in the normal ejaculatory reflex; and (3) changes are induced at the cortical level that could explain the long-term effect

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This study has several limitations: (1) a small sample size, decreasing the power of the study to 51%; (b) measurement bias risk due to the subjective way in which IELT was measured, which could be inexact because an artificial factor was introduced into the normal development of sexual intercourse; (3) the assessment of the change in PEDT score as a secondary outcome, which, nevertheless, is a diagnostic tool that was not designed to evaluate the efficacy of premature ejaculation treatments; and (4) the use of the PEDT and IIEF-5 questionnaires in Spanish without validation studies conducted prior to the start of our study. Finally, given the design of the study, which was a phase II clinical trial without a control group, the results are limited to evaluating the safety and efficacy of the therapy under controlled conditions.

Despite these limitations, our study suggests that transcutaneous posterior tibial nerve stimulation therapy is a safe, nonpharmacological treatment for premature ejaculation, converting this pelvic floor physiotherapy into a new tool for one of the most common male sexual dysfunctions and thereby widening the range of treatment possibilities for patients with premature ejaculation. Nevertheless, these results need to be verified in controlled clinical trials to determine with certainty the beneficial effect of this therapy and its possible adjuvant effect in men with pharmacological treatment.