Abstract
Premature ejaculation (PE) is the most common sexual dysfunction disorder in men. It affects men of all ages and can have a serious impact on the quality of life of men and their partners. There are currently no authorised pharmaceutical preparations for use in the UK, so medicines on this subject are used off-label. Behavioural therapies have been used to treat PE, but the results of this treatment have not been long lasting. A number of topical treatments have been used, including severance-secret (SS) cream, lignocaine spray, lidocaine-proparacaine cream, and lidocaine-proparacaine spray (TEMPE).
Recently there has been a rise in the use of selective 5-HT reuptake inhibitors (SSRIs) to treat PE because local anesthetics have a common side effect – delayed ejaculation. The SSRIs now being used have some non-sex-related side effects and long half-lives, so there has been interest in developing a short-acting, elixir SSRI to treat premature ejaculation. Several groups have been evaluating the efficacy of dapoxetine in PE for some time now, and so far the results seem quite promising.
Introduction
Premature ejaculation (PE), premature or rapid ejaculation, is the most common sexual dysfunction affecting men. A national survey on sexual attitudes and lifestyles found that the prevalence of premature ejaculation lasting 1 month reached 11.7% in the last 1 year, while the prevalence of PE lasting 6 months reached 2.9%. Unlike erectile dysfunction (ED), PE affects men of all ages equally; and, like ED, it can have a serious impact on the quality of life of the patient and his partner.
It may be lifelong, it may be temporary, triggered by the onset of sexual maturation, or it may be normal before premature ejaculation, for example secondary to urological or psychological disorders. It has also been suggested that there may be other forms of PE, including premature ejaculation-like ejaculatory dysfunction – where a man has a normal ejaculatory latency but he feels he is ejaculating too early – and including natural variant PE – which may occur in a specific context.
The diagnosis of PE is in a state of evolution, but a recommended definition of PE is the persistent or frequent ejaculation during or shortly after penile penetration, after minimal sexual stimulation, before the patient wishes it to occur, and during which the patient has no voluntary control, resulting in severe distress or interpersonal difficulties. It cannot be attributed to the direct action of a single substance (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision, DSM-IV-TR).
The International Society of Sexual Medicine (ISSM) defines PE as a sexual dysfunction in men. Ejaculation always or almost always occurs within 1 minute of penile vaginal penetration; inability to delay ejaculation after full or almost full vaginal entry; and negative effects on the individual, such as pain, annoyance, frustration, and/or avoidance of sexual intimacy.
In fact, intravaginal ejaculation latency (IELT) is often used to quantify treatment efficacy and as a standardized method for comparing treatments in clinical trials.IELT is defined as the time from penile insertion into the vagina to the onset of intravaginal ejaculation.
Until recently, treatment of PE was primarily through behavioral therapy. For example, the “squeeze technique”, first described by Masters and Johnson in 1970, and the “stop-and-start method”, described by Semans in 1956. The “stopCstart method” was described by Semans in 1956. Although this disorder is very common, little research has been done on its causes, which seem to have both physical and psychological factors.
Oversensitivity of the penis, an overexcited ejaculatory reflex, enhanced sexual arousal, underlying endocrinopathies, genetic predisposition to disease, and 5-hydroxytryptamine (5-HT) receptor dysfunction have all been suggested as physiological triggers. Some psychologically relevant risk factors include anxiety, social phobia, relationship problems, less sexual intercourse and lack of sexual experience.
There are currently no pharmacological agents licensed for the treatment of PE in the UK, so all are used outside of the approved indications. There are several viable treatment options for patients with premature ejaculation, including behavioral therapy, topical therapy, and systemic pharmacotherapy.
1. Behavioral therapy
Behavioral therapies include the “motion-stop technique” and the “squeeze technique”. These require the cooperation of the patient and partner, and the guidance of a trained sex therapist. The “move-stop technique” requires the patient to stimulate himself to the threshold before ejaculation, then stop and start stimulating himself again when the arousal subsides. This should be repeated three times. The time before each “stop” is gradually lengthened.
The “squeezing technique” requires the patient’s partner (or the patient himself) to squeeze the head of the penis with his fingers to control erection and ejaculation. Unfortunately, most patients do not get lasting improvement after using these methods.
2. Drug therapy
Topical medication
The theory that “fast men” may have an overly sensitive penis provides a logical basis for the use of topical agents (such as local desensitizers). The use of local anesthetic therapy to delay ejaculation was first described by Schapiro in 1943. Topical agents are appealing because they can be administered in the amount needed and the systemic side effects seem to be kept to a minimum. They have been reported to be very effective, however, studies in this area are usually scarce and local side effects are often seen.
SS cream (Severance-secret cream)
SS cream is a mixture of nine traditional medicines, including ginseng, toadstool and cinnamon. Some of these drugs have local anesthetic and vascular affecting properties. In a randomized, double-blind, placebo-controlled trial of SS cream, the mean IELT in the group treated with SS cream increased from 1.37 minutes before treatment to 10.92 minutes after treatment. SS cream is for use in Korea only, and all studies evaluating its efficacy were conducted in that country and have been studied by the same group.
SS cream had to be applied 1 hour before the start of intercourse and was rinsed off immediately before intercourse; some patients complained of hating its smell and color. A modified SS cream was later formulated, which contained the two main ingredients of the original SS cream, namely hydrolyzed galbanum and toadstool, and an enhancer, but without the odor and color of the original SS cream. SS cream is not approved for use in Europe or the U.S.
Lignocaine spray (Lignocaine spray)
Made commercially available as Stud 100 or Premjact, this spray has been available for many years and you can buy it directly over the counter without a prescription. The active ingredient in this spray is the local anesthetic lignocaine (9.6%). In theory, this spray should work similarly to other local anesthetic agents, but there is a lack of data from clinical trials to support its efficacy.
Lidocaine-proparacaine cream (LidocaineCprilocaine cream)
Local anesthetic low eutectic mixture Enna (EMLA), is a topical anesthetic cream containing 2.5% lidocaine and 2.5% proparacaine for topical application. There have been few trials of topical use in patients with premature ejaculation. In a trial of 42 male patients, only 29 completed the study, and intravaginal ejaculation latency increased from 1.49 minutes to 8.45 minutes after 2 months of using this topical cream. However, blunted genital sensation was reported to occur in both men and women in this study.
Lidocaine-propylocaine spray (LidocaineCprilocaine spray)
Tempe, a topical low eutectic mixture for the treatment of PE (TEMPE), is a formulation of lidocaine and proparacaine in a dosing aerosol transmission system. Each spray delivers 7.5 mg of lidocaine and 2.5 mg of proparacaine. This spray has a fast-acting effect and seems to work well in small studies. It does not penetrate the keratinized epithelial tissue, so only the glans is anesthetized; but there also seems to be some sensory dullness associated with its use. In a Phase II trial of 56 patients, IELT was prolonged 2.4 times more with Tempe than with placebo. In another larger multicenter Phase III trial of 300 patients, Tempe increased IELT from 0.6 minutes to 3.8 minutes and was well tolerated by the patient and his partner, with 66% of patients treated with this spray rating it as “good” or “very good. Very good”. Although female partners did not report any dulling of sensation with this product, a small percentage of female partners reported a burning sensation during intercourse.
Dyclonine/Alprostadil
Dyclonine is a local anesthetic that is commonly used in the dental field. It is used in combination with the vasodilator Prostil to treat PE, which is used at the end of the penis near the urethra. A preparatory trial claimed good efficacy for its use, but data are limited. Further studies are necessary if conclusions about this combination are to be drawn.
Systemic therapy
Tramadol (Tramadol)
Tramadol, an oral opioid analgesic, has been used to treat PE. it is a central analgesic with two mechanisms of action. It acts at mu-opioid receptors but also inhibits norepinephrine and 5-HT reuptake. Its mechanism of action on premature ejaculation is poorly understood, but it is thought to be related to its action at the μ-opioid receptor, which may reduce sensitivity and inhibit 5-HT reuptake, which may delay ejaculation.
Two small clinical trials both showed that tramadol significantly prolonged IELT compared to placebo. a single-blind crossover study of 60 men comparing 25 mg of tramadol with placebo showed that tramadol prolonged IELT from 1.17 minutes to 7.37 minutes. Tramadol increased the patients’ control of ejaculation and also increased their satisfaction with their sexual experience.
A further study of 64 men comparing 50mg of tramadol to placebo showed that tramadol extended the IELT from 19 seconds to over 4 minutes. While the results from these studies are encouraging, we need further studies to be sure.
Chlorpromazine (Clomipramine)
Chlorpromazine is a tricyclic antidepressant that inhibits norepinephrine and 5-HT reuptake. It is commonly used to treat obsessive-compulsive psychosis. Studies using continuous and on-demand dosing have shown a significant prolongation of IELT. A retrospective analysis evaluating the systemic treatment of PE found that chlorpromazine can be effective in treating PE, especially after the use of continuous dosing. The results also showed that its efficacy could compete with selective 5-HT reuptake inhibitors (SSRIs). Some results show that on-demand chlorpromazine can prolong IELT by 4-fold, however, it also has a high incidence of side effects.
Serotonergic antidepressants
SSRIs have been used to delay ejaculation and do prolong the IELT by a few minutes. They are often used to treat depression, but delayed ejaculation has been noted as one of their common side effects. Side effects include dry mouth, sleepiness, nausea, decreased libido, and ED. four common SSRIs currently used to treat PE are: fluoxetine (Prozac), paroxetine (Percocet), sertraline (Zoloft), and citalopram (Cipro).
At least three 5-HT receptor subtypes have been identified as having an effect on ejaculation, including 5-HT1a, 5-HT1b and 5-HT2c. Activation of 5-HT1a receptors has a pro-ejaculatory effect, but activation of 5-HT1b and 5-HT2c has a delayed ejaculation effect. To prevent overstimulation of postsynaptic 5-HT receptors, 5-HT is moved from postsynaptic to presynaptic neurons at any time during 5-HT transport.
5-HT is released from the presynaptic neuron to the synapse and activates 5-HT1b receptors. This results in a decrease in 5-HT release from the synapse. 5-HT transport mechanisms such as SSRIs increase 5-HT at the synapse. this in turn activates 5-HT1a and 5-HT1b receptors to inhibit the release of 5-HT in the synaptic gap. The result is a sustained mild stimulation of all postsynaptic 5-HT receptors.
After a few days of treatment with SSRIs, the receptors become insensitive and therefore their inhibition of 5-HT release is reduced. Eventually more 5-HT is released to the synapse. activation of 5-HT2c receptors regulates ejaculation threshold and delays ejaculation, but the extent of this delay depends on a variety of factors, including the type of SSRI, dose, frequency of use, and genetically determined ejaculation threshold.
Paroxetine, sertraline, and fluoxetine have all been evaluated for the treatment of PE, with paroxetine having the best efficacy, followed by sertraline and fluoxetine. However, the drawback that has been identified is that these drugs have other sex-related side effects such as hypoactive sexual desire, orgasmic disorder, and ED. observing all such drugs, other side effects unrelated to sex include insomnia, fatigue, nausea, constipation, and loss of appetite.
Discontinuation syndrome can occur with the abrupt cessation or reduction of SSRI therapy and symptoms include dizziness, nausea, vomiting, fatigue, headache, ataxia, drowsiness, anxiety, agitation, and insomnia. Symptoms begin 24-72 hours from discontinuation and may persist for more than 1 week. It is generally recommended that SSRIs should not be discontinued abruptly, but rather the dose should be tapered over several weeks, which is a more common occurrence due to the short half-life of SSRIs.
Waldinger and colleagues evaluated that the use of 25 mg of clomipramine or 20 mg of paroxetine, while having significant efficacy, did not, on the other hand, show that this approach significantly prolonged IELT. modality significantly prolonged IELT.
Abdel-Hamid ) and his colleagues, evaluating the effects of SSRIs, found that paroxetine was superior to the pause-and-squeeze approach, yet only slightly increased the median IELT, which was 3 and 4 minutes before, after pause-and-squeeze, and after paroxetine treatment, respectively, which was slightly prolonged from 1 minute before treatment.
It has been observed that on-demand treatment and traditional SSRIs-like drugs for PE are successful when combined with 5-HT1a receptor antagonists or some other treatments that stimulate rapid 5-HT release. 5-HT1a receptor antagonists in combination with sensitive SSRIs have been clinically shown to delay ejaculation, but not effectively on their own. This is very promising, but further research must be done on this combination before conclusions can be drawn.
Although SSRIs are also useful in the treatment of PE, they must be used with caution. Patients must be informed of the risk of suicidal ideation associated with the use of this class of drugs. Patients must be followed up and documented so that they are aware that they are being treated “out of indication” and that there is a low probability of occurrence but risk associated with suicide.
The demand for effective drugs for PE treatment has led to advances in research on dapoxetine for this specific use.
Dapoxetine
Dapoxetine (Priligy) is a new class of SSRIs, similar to other SSRIs, that exerts its effects by inhibiting 5-HT reuptake transport. Pharmacological studies have demonstrated that this drug is a potent transporter inhibitor. Dapoxetine is a short-acting SSRI and therefore may be more suitable as an “on-demand” treatment for PE. Several randomized placebo-controlled trials have evaluated dapoxetine.
Using doses of 30 and 60 mg, peak plasma concentrations of 1.01 and 1.27 hours were observed after dosing; the drug was also eliminated rapidly, with a half-life of 1.3 to 1.4 hours, and appeared to accumulate in very small amounts. The other SSRIs have half-lives of 1 to 4 days, with significant accumulation after prolonged use.
Dapoxetine significantly improves IELT compared to pre-treatment and placebo. several studies have shown IELTs of 1.66, 3.03 and 3.15 minutes for 30 mg and 60 mg dapoxetine in the pre-treatment and placebo groups, 30-60 minutes before intercourse, respectively. The IELTs for placebo, 30 mg and 60 mg dapoxetine 3 to 4 hours prior to intercourse were 1.79, 3.06 and 3.97 minutes, respectively.
Not only did dapoxetine significantly increase IELT compared to placebo, it was also effective when the initial dose was taken 1 to 3 hours prior to intercourse. Further analysis of the data from this trial suggests that men taking the drug were better able to prolong IELT, control their ejaculation, and more likely, weaponize the dapoxetine trial. phase III placebo-controlled trials using dapoxetine 60 mg over a period of more than 9 weeks have shown significant improvements in patient-reported outcomes.
A recent phase III clinical trial from 22 countries evaluating dapoxetine 30 mg and 60 mg versus placebo showed that dapoxetine resulted in a significant prolongation of IELT. At the end of the trial after 24 weeks, IELT increased from 0.9 minutes before treatment to 1.9 minutes, 3.1 minutes, and 3.5 minutes in the placebo, 30 mg, and 60 mg dapoxetine treatment groups, respectively.
All patients reported significantly improved outcomes compared to placebo. Dapoxetine is currently not approved for use in the treatment of PE in men in the UK, but has been approved in several other European countries. However, there appears to be evidence that it is effective and well-tolerated.
PDE-5 inhibitors
Many men with PE, also have ED. It is not known whether ED is related to anxiety during the progression of the patient’s PE; or whether the patient ejaculates before intercourse and his erections fail. However, the hypothesis that this class of drugs is effective in treating PE has been raised given that patients can prolong erections with PDE-5 inhibitors. A study comparing chlorpromazine, sertraline, paroxetine, sildenafil, and the pause – squeeze method found a 15-fold increase in IELT in the men taking sildenafil group, a 3-4 fold increase over other treatments, and sildenafil was the most satisfactory for patients.
Further studies, comparing sildenafil, paroxetine and squeeze technique for PE but not ED, again showed that sildenafil was more effective than the other two groups. Unfortunately, further studies found that IELT failed to increase significantly in the sildenafil group.
However, a recent small randomized, prospective, crossover study using vardenafil compared to placebo or sertraline in men with long-term PE showed a significant increase in IELT with vardenafil as well as improvements in other patient-reported outcomes. Two small studies showed a significant improvement in IELT with paroxetine combined with sildenafil than with paroxetine alone, but unfortunately a higher incidence of side effects with combination therapy. Clearly, further expansion of studies using PDE-5 inhibitors is warranted.
3. Experimental treatment protocols
Wise and Watson invented a new device based on the penile allergy hypothesis, which made a significant prolongation of IELT by desensitization. The device is cycled for 6 weeks for 30 minutes per day. Once it is worn out, the patient will need to masturbate alone or with a sexual partner at least 3 times a week for 5 minutes each time until he can barely control ejaculation, repeating 2-3 times and eventually ejaculating by masturbation. The device is no longer only available to patients who can afford it, and it may once again be one of the means by which more and more male patients go to the clinic for treatment.
Dorsal plexus neurectomy or hyaluronic acid gel glans injection procedure. Despite the positive results reported of a significant increase in IELT after surgery, both groups receiving dorsal plexus neurectomy or dorsal neurectomy + hyaluronic acid gel glans injection had significant side effects, including penile numbness, abnormal sensation and pain. One group receiving hyaluronic acid glans injection only reported no side effects. Dorsal nerve dissection is not widely practiced. However, there are now 5 years of study data showing that hyaluronic acid glans injections hold up well, showing long-term efficacy for the treatment of PE.
Pulsed radiofrequency neuromodulation has been used to desensitize the dorsal plexus nerve of the penis for the treatment of PE. This was a small study including 15 cases of primary PE. preliminary results from this pilot study indicate that after treatment with this method, patients had a significant increase in IELT compared to pre-treatment; no problems such as pain, hyposensitivity of the penis or ED have been reported.
4. Conclusion
PE is a common condition, occurring in men of all ages. It has a significant impact on the quality of life of men and their sexual partners, making it an important sexual issue. There are no licensed drugs for the treatment of PE in the U.K. A number of drugs have been used to treat PE, including the use of local anesthetics, the opioid analgesic tramadol, the SRIs class of drugs, and PDE-5 inhibitors. Dapoxetine, a short-acting SSRI drug, has been used specifically for the treatment of PE, and the results so far appear to be very promising.