Delayed ejaculation is a common side-effect of many psychotropic or antidepressant drugs, in particular of the serotoninergic tricyclic antidepressant clompiramine and the SSRIs fluoxetine, paroxetine, and sertraline [3–5]. These drugs, which are primarily indicated for the treatment of depression, can increase the level of serotonin in the brain, inhibiting the ejaculatory reflex center, and they can prolong IELT for several minutes.
Dosing levels of SSRIs are generally lower for PE than for depression, and various dosing regimens have been tested (including continuous, daily, or situational). Despite this, the adverse-event profile appears to be similar; adverse events include dry mouth, drowsiness, nausea, and reduced libido [6].
There is also the potential for development of a serious drug interaction that can lead to serotoninergic syndrome, which manifests itself as headache, nausea, sweating, and dizziness in mild cases and as hyperthermia, rigidity, and delirium in severe cases [6]. Many physicians may consider the side-effects hard to justify for the treatment of PE, in which the primary outcome is patient satisfaction, although the AUA has suggested that the level of adverse events is acceptable for the benefit derived by the patient with PE, and the type and rate of occurrence of side-effects also appears to be acceptable to most patients [6].
Dapoxetine, a novel SSRI, is the first oral agent specifically developed for the management of PE and it has been shown to be effective, well tolerated, and suitable for on-demand use [7]. Further research with this drug continues despite the US Food and Drug Administration’s non-approval of dapoxetine for the treatment of PE in 2005 [7]. The drug (as Priligy) has been approved in several European countries.
21.2 Rationale for the Use of Local Anesthetics
There are a variety of theories concerning the etiology of PE [2].
Historically, PE was considered a learned behavior and, as a result, behavioral therapy was the standard treatment. However, it is now generally accepted that both biological and psychological factors are important in the etiology of PE. Men with PE appear to have a heightened sensory response to penile stimulation, with a vibration threshold significantly lower than normal individuals [8, 9]. They also generally exhibit other abnormal reflex pathways for the ejaculatory process leading to the conclusion that there is a link between penile hypersensitivity and premature ejaculation [10]. Considering these sensory differences, drugs that selectively produce some degree of penile desensitization or act within the afferent–efferent reflex could provide effective therapy. Thus, reducing the sensitivity of the glans penis with local anesthetics could delay ejaculatory latency without adversely affecting the sensation of ejaculation [10]. In fact the use of topical anesthetic creams was first described by Schapiro back in 1943 [11].
21.3 Current Status of Local Anesthetic Treatments for PE
Apart from the limited approval of dapoxetine (Priligy), there is no approved pharmacological therapy for PE. This has led to the use of over-the-counter remedies and the ‘off-label’ use of local anesthetics. However, there are also novel desensitizing agents in development specifically designed to treat PE.
Compared with oral treatments for PE, topical treatments are appealing in that they can be applied on an as-needed basis and because systemic sideeffects are likely to be minimal. However, the application of a desensitizing agent to the penis does have the potential for some degree of penile hypoesthesia and theoretically, transvaginal contamination and female genital hypoesthesia as side-effects.
An important consideration for physician and patient, in this era of evidence-based medicine, is whether there is adequate supportive clinical data for the use of these off-label and novel topical agents. The efficacy and adverse-events profiles for topical treatments, where available, are discussed in the following sections.
21.4 Over-the-Counter Topical Treatments
21.4.1 Lidocaine Spray
Lidocaine 9.6 % spray, marketed as ‘Studd 100’ or ‘Premjact’, has been available over the counter for over 25 years in some countries and, as their names suggest, these are marketed as products for delaying ejaculation. However, the absence of reliable data from clinical trials means that the validity of the claims by the manufacturers cannot be assessed.
21.4.2 Severance Secret-Cream
Severance secret-cream (SS-cream; Cheil Jedan Corporation, Seoul, Korea), developed at the Yong-Dong Severance Hospital in Korea is made with extracts from nine natural products. Some of these products have local anesthetic as well as vasoactive properties. Several studies using SS-cream on men with PE have been carried out in Korea, however the cream is not approved for use in Europe or the USA and is not legally available outside Korea.
SS-cream is applied to the glans penis 1 h before intercourse and washed off immediately prior to coitus. Both the latency and amplitude of somatosensory evoked potential measured at the glans penis were increased over baseline although lower than that of normal men [9].
This product has been shown to increase the penile vibratory threshold at the glans penis in a dose-dependent fashion [12]. Xin et al. reported significantly prolonged ejaculatory latency in 89.2 % of patients treated with SS-cream [13]. Adverse effects were noted in 5.9 % of patients; these included mild local irritation (local burning or pain) and delayed ejaculation.
The prolongation of IELT has been shown to be dose dependent with an optimal dose of 0.2 g cream. In a multi-center, double-blind study involving 106 patients, the use of 0.2 g of SS-cream was reported to increase the mean stop-watch-measured IELT from a baseline of 1.37 to 10.92 min, compared with 2.45 min with placebo (p < 0.001) and was 27 times more effective than placebo in increasing sexual satisfaction (p < 0.001). However, almost 19 % of episodes of use were associated with mild localized irritation, including pain and burning, and 12 patients reported negative sexual sideeffects such as delayed ejaculation, an-ejaculation, and erectile dysfunction [14].
Despite these promising results, SS-cream has an unpleasant smell and color, which makes it unacceptable to many patients. A reformulation has resulted in ‘renewed SS-cream’ (RSSC) which is a new topical agent composed of the two main components of the original SS-Cream: Korean ginseng and Bufonis venenum in a hydrobase and enhancer without the unpleasant smell or color [15]. So far, only the results of animal studies have been published. The authors claim that RSSC delays the latencies of the spinal somatosensory evoked potentials in rabbits more effectively than the original SS-cream. However, the ingredient Bufonis venenum has been shown to produce contact dermatitis [16] and the likelihood of this cream gaining regulatory approval outside of Korea appears to be remote.
21.5 Off-Label Topical Treatments
21.5.1 Lidocaine–Prilocaine Cream
Separately, lidocaine and prilocaine are crystalline solids. When mixed together in equal quantities by weight, however, they form a liquid eutectic mixture that can be formulated into preparations without the use of a non-aqueous solvent. This allows higher concentrations of anesthetic to be formulated into the preparation and maintained during application. EMLA (eutectic mixture of local anesthetic; AstraZeneca) is a local anesthetic cream containing 2.5 % each of lidocaine and prilocaine for topical application. Developed to anesthetize intact skin, it is available as an over-the-counter product in some countries.
The first pilot study evaluating lidocaine–prilocaine cream for the treatment of PE included 11 subjects [17]. The cream (2.5 g) was applied to the whole glans and shaft of the penis 30 min prior to intercourse and covered with a condom, which could be removed prior to intercourse (and the cream wiped off) if desired. Nine of the 11 patients rated their performance as ‘excellent’ or ‘better’ and all 11 partners were satisfied with the treatment results [17].
In order to determine the optimal time that the anesthetic cream should be on the penis prior to intercourse, Atikeler et al. carried out a placebo-controlled trial with 40 patients (10 in each treatment group), varying the application time from 20 to 45 min, with a condom. In the 20- and 30-min application groups the IELT increased compared to placebo, but all men in the 45-min group suffered from penile numbness and loss of erection. The optimal application time was considered to be 20 min [18].
The largest double-blind, placebo-controlled clinical trial of lidocaine-prilocaine cream to date involved 42 patients, 21 in each group [19]. Patients were asked to apply a thin layer of cream to the glans penis, extending the coverage for up to 2 cm on the penile shaft. They were then asked to cover the cream with a condom for 10–20 min before intercourse and to use this treatment each time they had intercourse over 30–60 days. The treatment resulted in a 5.6-fold increase in IELT from 1.49 to 8.45 min. However, only 29 of the initial 42 participants completed the study. Of the patients completing the study, 11 out of the 16 who responded reported ‘great’ or ‘excellent’ sexual satisfaction.
Loss of penile sensation, retarded ejaculation, and penile irritation were a problem for 5 men, and 1 female partner reported decreased vaginal sensitivity.
It can be concluded that lidocaine–prilocaine cream has some degree of efficacy in the treatment of PE but is inconvenient, messy, and slow-acting, and it is not approved for this indication. It also has problems associated with hypoesthesia.
21.6 Novel Topical Agents in Development
21.6.1 Dyclonine–Alprostadil Cream
A cream containing 0.5 % dyclonine (a local anesthetic commonly used in dentistry) and 0.4 % alprostadil has been in development as a potential agent for use in PE. To date the only available report (abstract only) is a pilot study involving 30 patients which shows a synergistic effect when the cream containing both dyclonine and alprostadil was compared with one containing the individual components only [20]. Mild to moderate local side effects were noted in 17.5 % of subjects. More research is needed to further evaluate this potential of this product in the management of PE.
Related posts:
Endocrine Control of Ejaculation
Patient Reported Outcomes Used in the Assessment of Premature Ejaculation
Complementary, Surgical, and Experimental Modalities for Management of Premature Ejaculation
Risks Factors in Premature Ejaculation: The Neurological Risk Factor and the Local Hypersensitivity
Treatment of Premature Ejaculation with Selective Serotonin Re-Uptake Inhibitors
Anatomy and Physiology of Ejaculation
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
