PE is common male sexual dysfunction associated with negative consequences such as distress, bother, frustration, and/or the avoidance of sexual intimacy. Men with PE and their female partners are more likely to report low satisfaction with their sexual relationship. [4]
The exact aetiology of PE is unknown. Anxiety, penile hypersensitivity and 5-hydroxytryptamine (HT) receptor dysfunction have been considered as possible causes. [5-7]
Despite of its serious negative psychological and quality of life consequences, few men seek treatment. This is owing to the embarrassment of patients to discuss their sexual life and the belief that there is no treatment for PE.
Treatment options for PE include various behavioral and sexual therapy techniques, pharmacotherapy, and combination treatment (Pharmacotherapy with behavioral therapy). Some of them have variable outcomes and are unsatisfactory for many patients.
Pharmacotherapy of PE includes either dapoxetine on-demand or using topical desensitising agents such as lidocaine/prilocaine spray. Off-label SSRI antidepressants and off-label tramadol are other alternatives. [8]
Dapoxetine is a short-acting SSRI and is currently the only EMA-approved (European Medicine Approval) oral drug for treatment of PE. DPX is associated with a 3- to 4.3-fold increase in IELT over baseline. Carson et al concluded in a meta-analysis of three large placebo-controlled trials. [9]
Several studies support the therapeutic effect of daily SSRIs on PE. It was reported that SSRIs increase the geometric mean IELT by 2.6-13.2-fold. [10]
The use of local anesthetics to delay ejaculation is the oldest form of pharmacological therapy for PE. However, they are often criticized for not being optimized for PE. [11]
A recent meta-analysis by Liu et al concluded that local anesthetics were best among the other treatment options for PE including SSRIs, dapoxetine, PDE5Is and tramadol. [12]
Behavioral therapy such as stop start and squeeze techniques. allows the patient to delay ejaculation, increase sexual confidence, and reduce anxiety. In a systematic review done by Cooper et al, they found that behavioral therapy appears to improve IELT when compared with placebo in two out of four studies. [13]
In other studies, behavioral therapy had no significant differences when compared with SSRI’s.[14, 15]
The lack of a definitive treatment for PPE causes patient disappointment because a tablet or spray/cream is needed for every sexual intercourse. In a study by Park et al; 79.1% of patients stopped treatment within 6 months and 90.1% at 2 years, the authors concluded that novel effective therapies are required. [16]
The emission and expulsion phases refer to the two stages of male sexual response that occur during ejaculation. During the emission phase, the vas deferens, seminal vesicles, and prostate gland contract to move semen into the urethra, where it is held until the expulsion phase. During the expulsion phase, the muscles at the base of the penis, known as the bulbospongiosus and pubococcygeus muscles, contract rhythmically to propel semen out of the body. The emission and expulsion phases of ejaculation are controlled by different parts of the nervous system and involve a complex interplay of neurotransmitters, hormones, and muscle contractions. The emission phase is under the control of the sympathetic nervous system, while the expulsion phase is under the control of the somatic nervous system. [17-19]
Ejaculation is a spinal cord reflex, which is constituted by emission and expulsion phases. During expulsion, rhythmic contractions of the bulbospongiosus and ischiocavernosus muscles propel semen antegrade through the bulbar and penile urethra.
Botulinum A toxin is a neurotoxin which has revolutionized the management of numbers of lower urinary tract dysfunction.
It binds to the nerve endings that control muscle contractions and prevents the release of acetylcholine. This results in temporary paralysis of the targeted muscles. The effects of BTX-A typically last for several months before the nerve endings regenerate and muscle function returns. [20]
In 2010, use of botulinum A toxin for treatment of lifelong PE was contemplated. It was thought that injection of botulinum A toxin injection in bulbospongiosus muscle will inhibit rhythmic contractions and may prolong ejaculatory latency. [21]
In 2014, Serefoglu et al. injected botulinum-A toxin percutaneously into the bulbospongiosus muscles of male rats. They reported an increase in ejaculatory latency times. But the difference in post-treatment ejaculatory latency between botulinum A toxin injection and saline was not statistically significant. [22]
The only clinical trial used injection of botulinum A toxin in bulbospongiosus muscle as a treatment of primary PE was done by Li et al in 2018. They randomly assigned 70 patients with PE to a treated (100 U botulinum A was injected) and a control group (saline was injected). The trial group showed a significantly longer IELT (intravaginal ejaculatory latency time) at 4 weeks after treatment compared to the control group, and also had significant improvement in PEP-ejaculation scores, PEP-sexual satisfaction, PEP-PE-related distress, and PEP-PE-induced difficult relationship with the partners. The female partners of the treated group also showed significant improvement in sexual satisfaction scores. [23]
In our current study, we used botulinum A toxin for treatment of 30 patients with PPE and compared them to other 30 received placebo. The results in this current study showed no significant changes regarding the IELT, PEP or partner satisfaction between both groups. However, there was a significant improvement in the PEP score in the treatment group compared to baseline. The improvement in the PEP score was not associated in improvement in the IELT because albeit the statistical significance, these changes were not clinically significant as clinical improvement should be at least 4-point increase in the PEP score.
At 1 month, 5 patients (17%) showed improvement in the treated group compared to none in the placebo group (P= 0.02). After 3 and 6- months: only 2 (7%) showed maintained improvement in the Botox group (P=0.1), the median (IQR) PEP score was 1.6 and 0.9 at 1 month and 3 months respectively. Whereas insignificant changes were noted at 6 months, with a mean difference of 0.13, P=0.6). The 5 patients who had statistically significant improvement in the PEP score did not report any clinically significant changes as per their IELT score and refused any suggestion of reinjection.
It is important to note that the injection of Botox into the bulbospongiosus muscle only affects the expulsion phase of ejaculation. This means that while it can prevent the ejaculate from being expelled to the outside, it does not stop the emission of semen into the posterior urethra.
Based on the findings of our conducted study, we did not observe significant clinical improvement with this treatment approach and it can be concluded that inhibiting pelvic floor muscle contraction through Botox injection into the bulbospongiosus muscle does not provide substantial clinical improvement in terms of ejaculation.
The adverse effects were observed in 6 cases (17.65%) in Li et al trial. While adverse effects in our study were reported in 3 cases (5%) of the study population. 2 patients in the treated group suffered from loss of rigidity during erection and post voiding dribbling. And one patient in control group had mild bleeding per urethra which stopped spontaneously. All patients reported normal ejaculation, no drippling of ejaculation was detected in any patient.
To the best of our knowledge, this is the second study in the literature investigating the effect of Botulinum A toxin injection into the bulbospongiosus muscle for treatment of PPE and the first to deny its clinical efficacy. Limitations of our study include short follow up period and small sample size.