© Springer International Publishing AG 2017
Waguih William IsHak (ed.)The Textbook of Clinical Sexual Medicine10.1007/978-3-319-52539-6_1919. Treatment of Premature Ejaculation
(1)
Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, PA, USA
(2)
Private Practice in Psychiatry and Neurosexology, De Schulp 4, 1181, NA, Amstelveen, The Netherlands
Keywords
Premature ejaculationEarly ejaculationIntravaginal ejaculation latency time (IELT)Selective serotonin reuptake inhibitors (SSRIs)DapoxetineIntroduction
In the 1920s, Bernard Schapiro developed Präjaculin, which was the first oral drug for the treatment of lifelong PE [1]. Präjaculin was produced by the German company Promonta in Hamburg from 1932 until the mid-1960s [1]. Therefore it is important to know that oral drug treatment for PE has been available since the first publications of PE in medical literature, even more than a decade before the first review article on PE was published by Schapiro in 1943 [2] and long before behavioral treatments were advocated as the first choice of treatment [3]. However, case reports of potential new drugs to delay ejaculation, such as monoamine oxidase inhibitors (MAOIs) , mellaril , and clomipramine , started only to appear in the 1970s and 1980s. It was only after the introduction of the selective serotonin reuptake inhibitors (SSRIs) in the early 1990s that drug treatment of PE became revolutionized [4]. In those days, a lack of an operationalized definition of PE and the absence of an objective measure of the ejaculation time hampered a truly scientific approach to investigate the efficacy of drugs in delaying ejaculation.
Evidence-Based Approach to Treatment
Therefore, and in order to develop an evidence-based methodology and design of drug treatment research, Waldinger et al. [5] introduced in 1994 the intravaginal ejaculation latency time (IELT) as a standardized measure of the ejaculation time. The IELT was defined as the time between the start of intravaginal penetration and intravaginal ejaculation [5]. By definition the IELT of an ejaculation outside the vagina (ejaculatio ante portam) is zero. The most objective way to measure the IELT is the use of a stopwatch, handled by the female partner [6]. In order to compare the extent of ejaculation delay, it is required to measure the IELT with a stopwatch at each coitus in a baseline period for a few weeks when no medication is used and to measure it as well at each coitus in an active drug treatment period of a few weeks. By comparing the IELT values of both periods the extent of ejaculation delay is calculated. As the IELT values of one person may have outliers, the statistically best way to calculate this difference is to calculate the geometrical mean IELT of both the baseline period and the active treatment period [7]. After having calculated the geometric mean IELT of both periods, it is easy to finally calculate the fold-increase of the geometric mean IELT. The fold-increase (FI) of the geometric mean IELT = geometric mean IELT value at end of drug treatment/geometric mean IELT value at baseline [5].
A fold increase of 1 means that there is no ejaculation delay induced by a drug. Placebo-controlled studies have shown that a fold-increase of 1 to 2 is a placebo response [8]. Clinically relevant ejaculation delay usually occurs between a fold-increase of 4 to 5. But a fold-increase higher than 7 means a really relevant ejaculation delay [8].
Apart from this prospective stopwatch-mediated methodology to measure the IELT, the design of such drug treatment studies is only evidence-based when one performs a randomized, double-blinded, placebo-controlled research protocol [4]. And of course it is required that the participants of such a study are quite similar. For example, they should not drink alcohol before intercourse, they should not use other drugs that may affect ejaculation, and they should fulfill to a lot of other inclusion and other exclusion criteria.
Drug Treatment of PE
There are six major treatments of premature ejaculation; (1) daily use of SSRIs, (2) on-demand use of dapoxetine, (3) on-demand use of clomipramine, (4) on-demand use of topical local anesthetics, (5) on-demand use of tramadol, and (6) on-demand use of phophodiesterase type-5 inhibitors [8].
With the exception of dapoxetine , all these treatments are off-label [8]. Although daily SSRI treatment very effectively delays ejaculation, none of the companies producing the SSRIs (paroxetine, fluoxetine, sertraline, citalopram, and escitalopram) has been interested to get a Food and Drug Administration (FDA) or European Medicine Agency (EMA) registration for the treatment of PE, as it was argued that it would acknowledge an unwanted sexual side effect of their antidepressant drug [9]. In 2005 the EMA has registered dapoxetine 30 mg and 60 mg, a fast acting SSRI, for the on-demand treatment of PE [10].
Daily Treatment with SSRIs
In scientific studies—but not in daily practice—the IELT has to be measured with a stopwatch. A substantial number of randomized, double-blind, placebo-controlled studies have shown the efficacy of daily SSRIs treatment in mentally healthy men with complaints of PE [8]. With exception of fluvoxamine the SSRIs exert a clinically relevant ejaculation delay [8].
A meta-analysis of daily SSRI treatment studies [8] revealed a rather low placebo-effect, e.g., a geometric mean 1.4-fold IELT increase (95% CI: 1.2–1.7). The meta-analysis also demonstrated a rank order of efficacy: (a) paroxetine 8.8 FI (95% CI: 5.9–13.2); (b) clomipramine 4.6 FI (3.0–7.4); (c) sertraline 4.1 FI (2.6–7.0), and (d) fluoxetine 3.9 FI (3.0–5.4). Thus, in general, daily SSRI treatment studies generate a 2.6–13.2 geometric mean IELT fold increase, dependent on the type of SSRI [8]. Moreover, of all SSRIs, daily use of 20 mg paroxetine exerts the strongest ejaculation delay in the investigated males. The meta-analysis also demonstrated that compared to stopwatch studies measuring the IELT, open and single-blind studies lead to exaggerated IELT values and that retrospective assessment of the IELT by a questionnaire or subjective report lead to far more variability of the IELTs [8].
The outcome data of the SSRI treatment studies published between 2003 and 2014 hardly distort the findings of the meta-analysis of 2004 and therefore its conclusions are still valid today [9, 11, 12].
Dosages of Daily SSRI Treatment
Daily treatment can be performed with paroxetine 20 mg, clomipramine 10–40 mg, sertraline 50–100 mg, fluoxetine 20 mg, citalopram 20 mg, and escitalopram 20 mg [13]. Ejaculation delay usually starts a few days after intake. However, a clinically relevant effect only gradually occurs within 1–3 weeks. Most often the delay continues to exist for years, as long as the SSRI is used, but sometimes it may disappear after 6–12 months. The cause of this tachyphylaxis has not yet been clarified [9, 12].
Daily SSRI treatment is effective in delaying ejaculation, but it does not delay ejaculation in every patient and in the same extent. Ejaculation delay occurs in 70–80% of men. In about 20% of men with lifelong PE, SSRIs do not have relevant ejaculation delaying effect. In such cases one may switch to another SSRI, but other SSRIs may not have an ejaculation-delaying effect either [12].
Advantages and Disadvantages of Daily SSRI Treatment
A clear advantage of daily SSRI treatment is that there is a delayed ejaculation at every spontaneous sexual event. Daily intake does not interfere with the spontaneity of sexual activity. However, a disadvantage is the risk of specific side effects on the short and long term, the risk of a discontinuation syndrome [14, 15], very rare side effects such as bleeding [16] and priapism [17, 18], effects on spermatozoa [19, 20] and very rare side effects such as restless genital syndrome (ReGS) in the male [21], and the extremely rare post SSRI sexual dysfunction (PSSD) [22, 23].
SSRI-Induced Side Effects
Side Effects on the Short Term
On the short-term fatigue, yawning, mild nausea, loose stools, or perspiration may occur. These side effects are usually mild, start in the first 1–2 weeks of treatment, and most often gradually disappear within 2–3 weeks [9, 12]. Although a head-to-head comparative study has not yet been performed, drug treatment studies seem to indicate that in contrast to the side-effects in depressed patients, diminished libido and erectile dysfunction occur less frequently and also to a lesser extent in healthy non-depressed men with lifelong PE [9, 12].
Side Effects on the Long Term
On the long term weight gain may occur, and sexual side effects. These sexual side effects are reversible, but in extremely rare cases they are irreversible [9].
SSRI Discontinuation Syndrome
Patients should be advised not to stop taking the SSRI acutely in order to prevent the occurrence of an SSRI discontinuation syndrome, which is characterized by symptoms like tremor, shock-like sensations when turning the head, nausea and dizziness [15]. One should inform the patient at the beginning that discontinuation of the treatment should be carried out very gradually within about 2 and sometimes even 3 months.
Interaction with Other Drugs of Substances
It is recommended that patients should diminish their use of alcohol particularly in the first weeks of SSRI treatment, as SSRIs may facilitate a “typsi” state [9]. Young men should be informed not to use XTC while taking an SSRI [9]. Its interaction may cause the potentially life-threatening serotonergic syndrome . Older men should be informed not to take tramadol as its interaction with an SSRI may also lead to a serotonergic syndrome . One should not prescribe SSRIs to men <18 years, and to men known with depressive disorder particularly when associated with suicidal thoughts. In those cases, referral to a psychiatrist is indicated.
Negative Effects of SSRIs on Spermatozoa
Particularly in young patients, one should inform the patients that hardly anything is known about the effect of SSRIs on spermatozoa, as research on this topic has hardly been performed [9]. However, a few small studies have shown potential harmful effects of SSRIs on spermatozoa [19, 20]. It is recommended that in case of a wish for pregnancy the male should not start SSRI treatment or when he is already using an SSRI for PE to gradually diminish the dosage of the SSRI and stop taking the drug for 3–4 months [9, 12]. As it takes quite some time for spermatozoa to be renewed, it is advised to make love with a condom for 3 to 4 months after discontinuation of the drug, after which pregnancy is allowed. Notably, this advice is not based on any hard evidence, but only to prevent possible problems in the future when it may perhaps appear that SSRIs used by the male, affect fertility or even may lead to congenital disorders.
Restless Genital Syndrome (ReGS) in the Male
In rare cases, decreasing the dosage of an SSRI or discontinuation of an SSRI may give rise to the Restless Genital Syndrome (ReGS) [21]. In males, ReGS is presumably caused by a sensoric neuropathy of the dorsal nerve of the penis, which is an end branch of the pudendal nerve [21]. ReGS in the male is characterized by persistent, unwanted, disturbing penile sensations of ejaculatory urgency, usually at the basis and top of the penis, in the absence of erection, sexual desire, and/or sexual arousal. However, often these men also report some sort of penile sexual arousal.
Post SSRI Sexual Dysfunction (PSSD)
Usually SSRI-induced sexual side effects are reversible, e.g., their intensity diminishes with dose reduction and they disappear within a few days after SSRI discontinuation. However, in extremely rare cases the sexual side effects are irreversible, e.g., after SSRI discontinuation they do not disappear [22, 23]. Recently, Waldinger distinguished two types of PSSD [23]. Characteristic of both types is the occurrence of penile anesthesia or numbness of the penis, which may be the first symptom of PSSD. Therefore, patients using SSRIs should be informed to stop taking the SSRI as soon as the patient experiences genital anesthesia [23]. PSSD may start within a few days to a few weeks after the start of SSRI treatment with complaints of sudden complete loss of libido, arousal, erection, and ejaculation with genital anesthesia, or it may become manifest after SSRI discontinuation as an aggravation of already existing moderate sexual side effects [23]. So far the pathophysiology and treatment of PSSD remains unclear.
On-Demand Treatment with Oral Drugs and Topical Anesthetics
On-demand treatment with oral drugs may also give rise to side effects or interactions with other drugs. Patients should be informed about the risk of a serotonergic syndrome in case serotonergic drugs (dapoxetine/tramadol) are taken together with other serotonergic drugs [9, 12].
Advantages and Disadvantages of On-Demand Drug Treatment
A clear advantage of on-demand oral drug treatment is that there is no risk of getting the side effects of long term drug treatment. Another advantage is that one can use the drug only when it is required for a better sexual performance. However a disadvantage is that on-demand oral drug treatment may negatively interfere with the spontaneity of sexual activity, particularly when one is inclined to have sex at the spur of the moment [9].
On-Demand Treatment with Dapoxetine
Dapoxetine hydrochloride is a short-acting SSRI. It inhibits serotonin reuptake in the synapse similar to all other SSRIs. However, this mechanism of action occurs faster after intake. Dapoxetine is the first drug that is registered by the EMA for on-demand treatment of PE [10, 24–28]. Dapoxetine (either 30 mg or 60 mg), should be taken 1–3 h prior to intercourse. Its efficacy and side effects have been investigated in more than 6000 patients. Although the extent of ejaculation delay is usually rather small, studies have shown a 3.6–4.5-fold increase, reporting also that dapoxetine may lead to satisfaction and more feelings of control in men with lifelong and acquired PE. In the studies performed dapoxetine showed a good safety profile and a reasonable prevalence of dose-dependent side effects. The most common side effects include nausea, dizziness and headache. Importantly, no SSRI discontinuation syndrome following abrupt withdrawal has been reported [28].
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