I. Definition of premature ejaculation
There is still no consensus on the definition of PE.
The Diagnostic and Statistical Manual of Mental Disorders IV-Text Revision (DSM- IV -TR) [1] defines PE as “unwanted ejaculation, always or often before, during, or just after vaginal penetration, with minimal sexual stimulation. The clinician must take into account various factors that can affect the duration of the arousal period, such as age, novelty to the sexual partner, changes in the environment of intercourse, and the frequency of recent intercourse”.
The Guidelines on Disorders of Ejaculation [2] state that PE is defined as “the inability to control ejaculation for a sufficient period of time before penile insertion into the vagina”.
The Guideline on the Pharmacologic Management of Premature Ejaculation defines PE as “ejaculation that occurs before the individual expects it, whether before or after penetration, and causes distress to the other person or to both parties” [3].
The above definitions are not evidence-based and are no longer recommended in clinical practice, but all of them include 3 elements: 1) short latency to ejaculation, 2) poor ejaculatory control, and 3) low sexual satisfaction.
The International Society for Sexual Medicine (ISSM) states that the definition of premature ejaculation should include the following three elements from an evidence-based medical perspective: 1) ejaculation always or almost always occurs within 1 minute of penile insertion into the vagina; 2) inability to delay ejaculation after full or almost full entry into the vagina; and 3) negative personal psychological factors such as distress, apprehension, frustration and/or avoidance of sexual activity. This definition is limited to men with primary PE who have transvaginal intercourse, and published objective data are not sufficient to provide an evidence-based medical definition of secondary PE [4]. Because of its evidence-based medical basis, this definition is currently recommended for clinical use.
II. Classification of premature ejaculation
Premature ejaculation as a syndrome, scholars have divided premature ejaculation into two categories: primary and secondary premature ejaculation. Recently, some scholars have proposed two premature ejaculation syndromes that are very different from primary premature ejaculation and secondary premature ejaculation. Both premature ejaculation syndromes have normal ejaculatory latency and often show normal ejaculatory performance, so they are often regarded as non-pathological syndromes [5]. The four manifestations of premature ejaculation are now classified as primary premature ejaculation, secondary premature ejaculation, situational premature ejaculation, and premature ejaculation-like ejaculatory dysfunction [6, 7, 8].
(A) Primary premature ejaculation (1ifelong PE)
Primary premature ejaculation is rare and difficult to diagnose, characterized by (1) occurrence at first intercourse, (2) lack of selectivity for sexual partners, and (3) occurrence of premature ejaculation at every intercourse.
(B) Secondary premature ejaculation (acquired PE)
Secondary premature ejaculation is acquired premature ejaculation with a clear physical or psychological etiology. It is characterized by (1) premature ejaculation occurring at a definite time; (2) normal ejaculation time before premature ejaculation occurs; (3) may occur gradually or suddenly; and (4) may be secondary to urological, thyroid, or psychological disorders.
(3) Situational premature ejaculation (natural variable PE)
Some domestic scholars also call this type of premature ejaculation “natural variable premature ejaculation”. The ejaculation time of such patients may be long or short, and premature ejaculation may occur from time to time. This kind of premature ejaculation is not necessarily a pathological process. The specific characteristics are: (1) premature ejaculation does not occur continuously, and the time of occurrence is not regular: (2) when ejaculation is about to occur, the ability to control ejaculation decreases, but sometimes it is normal, which is not a necessary condition for diagnosis.
(d) Premature-like ejaculatory dysfunction (premuture-like ejaculatory dysfunction)
The latency time of ejaculation in such patients is often within the normal range, and the patient subjectively believes that he or she is prematurely ejaculating. This type of premature ejaculation cannot be considered a true pathological process, but usually hides a psychological disorder or a relationship problem with the sexual partner. The characteristics of this type of premature ejaculation are: (1) subjective perception of persistent or non-persistent rapid ejaculation; (2) patient’s own imagined premature ejaculation or inability to control ejaculation anxiety; (3) actual vaginal insertion with normal or even long ejaculation latency time; (4) reduced ability to control ejaculation when ejaculation is about to occur; and (5) patient’s anxiety not explained by other psychiatric disorders.
Diagnosis of premature ejaculation
1. Medical history (recommended)
(1) History of sexual life
(2) General medical history
For primary premature ejaculation:
Family or genetic history; growth and life history; history of trauma; psychosexuality and sexual orientation.
2. Intravaginal ejaculation latency (recommended)
Intravaginal ejaculation latency is an important index that can be measured to evaluate premature ejaculation and is widely used in the diagnosis of premature ejaculation and clinical research. However, its application alone is insufficient for the diagnosis of premature ejaculation because the temporal overlap of intravaginal ejaculatory latency is too great in men with and without premature ejaculation [1], and on the other hand, the artificial determination of intravaginal ejaculatory latency produces a significant direct effect on the sense of self-control of ejaculation, but not on the ejaculation-related psychological behavior [2]. In clinical practice, intravaginal ejaculatory latency alone has 80% specificity and 80% sensitivity for diagnosing premature ejaculation [3], and its specificity can reach 96% if one of control of ejaculation, satisfaction with sexual behavior and resulting psychological distress and interpersonal disorders is also added [4].
3. premature ejaculation assessment questionnaire (optional)
Questionnaires based on patient-reported outcomes should be applied to evaluate premature ejaculation and to identify and diagnose patients with premature ejaculation accordingly. These questionnaires mainly include the Premature Ejaculation Diagnostic Tool [5], the Arab Premature Ejaculation Index [6] and the Chinese Premature Ejaculation Questionnaire [7].
1, Premature ejaculation diagnostic tool (Table 1) evaluates ejaculatory control, frequency of premature ejaculation, psychological distress and interpersonal difficulties.
2, Arab Premature Ejaculation Index (Table 2) evaluates sexual desire, firm erection to complete full intercourse, time to ejaculation, ejaculatory control, patient and partner satisfaction, and anxiety or depression.
3.Chinese premature ejaculation questionnaire (Table 3)
Other scales expressing the characteristics of premature ejaculation and determining its efficacy include the premature ejaculation spectrum [8] and the premature ejaculation index [9]. (Tables 4,5)
4, Premature ejaculation examination
(1) Physical examination (a) Genital examination (optional): penis, testes, epididymis, prostate, male secondary sexual characteristics
(b) Neurological examination (not recommended): testicular reflex, bulbocavernosus reflex, anal sphincter tension
(2) Laboratory tests (not recommended): prostatic fluid routine, semen routine, endocrine hormone test
(3) Special auxiliary examinations (not recommended)
(a) Neurophysiological examination: dorsal nerve sensory evoked potentials, neuromyography
(b) Autonomic nerve function examination
(c) penile vascular examination
(d) Cystoscopy
(e) Transrectal ultrasonography
(f) Urine flow rate examination
(g)Erectile function test
(h) Penile vibration stimulation test
(4)Psychosexual and related psychological disease assessment of patient and spouse (optional)
Treatment of premature ejaculation
According to the survey, about 21%-33% of adult men are troubled by premature ejaculation, and many of these cases are caused by psychological factors, so their treatment should be limited to sexual life guidance and psychological interventions, such as reducing operational anxiety and improving self-confidence. Before starting treatment for PE, the patient’s intravaginal ejaculation latency (IELT), duration of PE and its type should be fully evaluated, which is particularly important for individualized treatment of premature ejaculation, as well as clarifying whether it is accompanied by ED or other sexual dysfunctions, and the associated diseases such as combined ED, chronic prostatitis, reproductive tract infection, circumcision and hyperthyroidism need to be treated first or simultaneously.
Behavioral therapy is effective in the treatment of PE, but it is time-consuming, requires the cooperation and assistance of sexual partners, is difficult to implement, and its long-term efficacy is unclear. Therefore, behavioral therapy is not recommended as first-line treatment in primary PE and may be considered when the patient refuses pharmacological treatment or has difficulty tolerating drug-induced adverse effects. Pharmacotherapy is the first choice for the treatment of premature ejaculation, and selective 5-hydroxytryptamine reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs), and local anesthetic drugs are currently available with varying efficacy for the treatment of primary or secondary PE. In patients with refractory or particularly severe PE (IELT <30-60s< span=""> or ejaculation before vaginal insertion), oral SSRIs combined with behavioral therapy or local anesthetic drugs can achieve better efficacy and are significantly better than monotherapy.
1.Pharmacological treatment
1.1 Selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs)
Neuropharmacological studies have found that inhibition of 5-hydroxytryptamine (5-HT) reuptake can delay the male ejaculatory impulse. SSRIs function to delay ejaculation by inhibiting presynaptic membrane 5-HT reuptake, increasing the concentration of 5HT in the synaptic gap, and activating postsynaptic membrane-associated 5-HT receptors to raise the ejaculatory threshold.
SSRIs and TCAs were originally used to treat depression, but clinical studies found that prolonged use of SSRIs and TCAs delayed ejaculation and thus began to be used in the treatment of premature ejaculation. SSRIs take 1-2 weeks to take effect in the treatment of premature ejaculation. The SSRIs paroxetine was first reported to be effective in the treatment of premature ejaculation in 1970, and the TCAs clomipramine was reported to be used for the treatment of PE in 1973. At present, SSRIs have become the drugs of choice for the treatment of premature ejaculation. The SSRIs commonly used in clinical practice include dapoxetine, sertraline, paroxetine, fluoxetine, citalopram, fluvoxamine maleate, etc. The TCAs include clomipramine, etc.
1.1.1 Dapoxetine (Dapoxetine)
Dapoxetine is currently the first and only drug approved by the FDA for the treatment of premature ejaculation and will soon be available in China. Dapoxetine has been studied in more than 6,000 clinical trials in multiple centers around the world, and its efficacy has been confirmed and is now approved as a prescription drug for the clinical treatment of premature ejaculation in several countries. As an on-demand SSRI for premature ejaculation, it has a fast onset of action and short half-life, with a rapid absorption of 1.5h to peak. In a double-blind randomized controlled clinical study, patients were given placebo, dapoxetine 30 mg and 60 mg 1-3 h before intercourse, and the results showed that both doses of dapoxetine were significantly more effective than placebo in the treatment of premature ejaculation, with improvement in IELT from 0.9 min to 1.75 min (placebo group), 2.78 min (30 mg group), 3.32 min (60 mg group), and patients felt increased ejaculatory control, increased sexual pleasure and self-confidence, and significantly increased sexual satisfaction. For patients with IELT baseline <= 0.5 min< span="">, IELT increased 3.4 and 4.3-fold from baseline after taking the above doses of drugs, respectively.
Dapoxetine has similar efficacy in primary and secondary PE. Adverse effects of dapoxetine were less common and mainly included nausea (8.7%-20.1%), drowsiness (3.1%-4.7%), diarrhea (3.9%-6.8%), headache (5.9%-6.8%), dizziness (3.0%-6.2%), and rhinitis (3.2%-2.9%) in a dose-dependent manner. In contrast to other SSRIs, no significant withdrawal syndrome or treatment-emergent suicidal tendencies were observed during treatment with dapoxetine.
There is 1a evidence to support the efficacy and safety of on-demand dapoxetine for primary and secondary PE.
1.1.2 Other non-drug approved labeled SSRIs and TCAs for the treatment of premature ejaculation.
With oral SSRIs and TCAs, delayed ejaculation usually occurs 5-10 days after initiation of treatment, but full onset of effect often requires 2-3 weeks of treatment. Because of the time required for receptor desensitization, long-term continuous use is recommended to ensure efficacy. The effect may be maintained for several years, with rapid tolerance generally occurring after 6-12 months. On-demand SSRIs and TCAs taken 3-6 h before intercourse are not as effective as daily dosing, although they are well tolerated by patients. On-demand dosing can be combined with other treatments or used as a supplement to low-dose daily oral therapy to reduce adverse drug reactions.
There is level 1a evidence to support the efficacy and safety of daily SSRIs and TCAs for both primary and secondary premature ejaculation.
1.1.1.2.1 SSRIs
Daily doses of paroxetine 10-40 mg, sertraline 25-200 mg, fluoxetine 10-60 mg, clomipramine 12.5-50 mg, and citalopram 20C40 mg were often effective in delaying ejaculation. A Meta-analysis showed that the improvement in IELT from baseline with different types of SSRIs for PE was: paroxetine (20 mg/d): 8-fold, sertraline (50 mg): 5-fold, fluoxetine (20-40 mg): 5-fold, and citalopram (20-40 mg): 2-fold. Limited evidence suggests that citalopram is less effective than other SSRIs for the treatment of premature ejaculation, and fluvoxamine maleate may be ineffective.
Adverse effects of SSRIs for PE are rare, generally mild, and tolerable, often occurring in the first week of treatment and resolving after 2-3 weeks of continuous treatment. Adverse effects include malaise, fatigue, yawning, nausea, dry mouth, diarrhea, or sweating, etc. Other effects such as decreased libido, loss of sexual pleasure, ED, and non-ejaculation have also been reported sporadically. Therefore, if a patient and his or her sexual partner have a need for sexual activity and require treatment for PE, the medication should be taken for a long time. When taking SSRIs for a long period of time or at higher doses, attention should be paid to the occurrence of SSRI withdrawal syndrome, which is the onset of psychosomatic and vegetative symptoms, sometimes leading to suicidal ideation, on the 3rd-4th day after abrupt discontinuation or high-dose tapering of SSRIs. Therefore, patients who have been taking SSRIs for PE for a long time or at higher doses should be tapered before discontinuation.
1.1.1.2.2 TCAs (clomipramine)
A clinical study reported that the TCAs clomipramine 12.5-50 mg taken as needed 4-6 hours before sexual intercourse resulted in varying degrees of improvement in IELT compared to the same daily dose of clomipramine, with the former showing a 4-fold increase from baseline and the latter a 6-fold increase. The major adverse effects of clomipramine included fatigue (3C30%), vomiting (30%), dizziness (14%), dry mouth (10C23%) and ED (20%). Based on the inhibition of monoamine oxidase reuptake by clomipramine, clomipramine enhances the effects of endogenous and exogenous catecholamines, manifesting as quinidine-like effects and anti-adrenergic-like effects such as abnormal ECG and the appearance of palpitations.
1.2 Local anesthetic drugs
The use of local anesthetic drugs for the treatment of PE started in 1943 and was the first method used for the pharmacological treatment of PE. They were used in the treatment of premature ejaculation because of their ability to reduce penile sensitivity and prolong ejaculatory latency, and because they do not affect the sensation of ejaculation. Commercially available topical anesthetic medications commonly used to date include lidocaine and/or proparacaine mixes in gel, cream, or spray form, with several small-sample clinical studies showing lidocaine/proparacaine mixes to be approximately 80% effective (based on improvement in patient self-symptoms or IELT). Large randomized controlled studies evaluating the efficacy of local anesthetics for premature ejaculation based on the IELT or questionnaire format are still lacking.
The lidocaine/proparacaine mixture should be used 10-20 min before intercourse. Adverse effects are dose-related and include numbness of the glans due to overdose, occasional reports of ED, and lack of sexual pleasure due to vaginal numbness caused by vaginal absorption of the drug during intercourse if the applied drug is not wiped off prior to sexual intercourse.
There is 1b evidence to support the effectiveness and safety of using local anesthetics for the treatment of primary PE.
1.2.1 Lidocaine-proparacaine cream
The results of a small randomized double-blind controlled trial showed that lidocaine-proparacaine cream prolonged IELT from 1 min to 6.7 min at baseline in patients with PE, but some patients may have penile weakness due to significant penile numbness and a higher incidence of vaginal numbness and loss of sexual pleasure in sexual partners. To avoid causing vaginal numbness in sexual partners, condoms can be used after application or washed before intercourse.
1.2.2 SS cream
SS cream is a compound preparation made from extracts of various herbs and is applied to the penile head 1h before intercourse and washed before intercourse. In a double-blind randomized placebo-controlled study, SS cream prolonged IELT from 1.37 min to 10.92 min at baseline with 82% sexual satisfaction. 18.5% of patients complained of local burning sensation and pain in the head of the penis without adverse effects such as occurrence of ED and vaginal numbness.
1.2.3 Lidocaine and/or proparacaine spray
A new lidocaine/proparacaine spray, PSD502, is currently in a phase III clinical trial, and preliminary results indicate a 6.3-fold increase in IELT in the PSD502 treatment group compared to baseline, accompanied by increased ejaculatory control and improved sexual satisfaction. Due to the unique formulation of this formulation, vaginal numbness and lack of sexual pleasure in sexual partners were significantly reduced compared to other formulations.
1. 3 Phosphodiesterase type V (PDE5) inhibitors.
Many studies support the effectiveness of PDE5 inhibitors in the treatment of ED, the exact mechanism of which is unclear. Some literature reports may be due to PDE5 inhibitors inhibiting PDE5 activity on the smooth muscle of the ejaculatory duct, vas deferens, seminal vesicles, and posterior urethra, resulting in smooth machine diastole and prolonged ejaculatory latency. There is also literature analyzing that patients taking PDE5 inhibitors may reduce anxiety and downregulate the sexual arousal threshold of erection due to increased erectile hardness of the patient, thus allowing an increase in the ejaculatory threshold.Abdel-Hamid et al [] reported that the PDE5 inhibitor cedirafil alone was significantly higher than chlorpromazine, sertraline, paroxetine, and behavioral therapy in increasing ejaculatory latency in patients with premature ejaculation. However, most scholars advocate the use of combinations, and more literature supports the efficacy of PDE5 inhibitors combined with SSRIs or local anesthetic drugs, which are significantly better than those used alone. There are fewer reports on the use of other PDE5 inhibitors for the treatment of premature ejaculation. For patients with premature ejaculation in combination with ED, PDE5 inhibitors or combination therapy may be used. For patients with premature ejaculation without ED, this guideline does not recommend PDE5 inhibitors as the treatment of choice.
1.4 Other drugs
1.4.1 α1-adrenergic receptor antagonists
Two clinical studies with small samples reported the efficacy of alpha1-adrenergic receptor antagonists – terazosin and alfuzosin – for the treatment of PE. Although reported to be 50% effective in delayed ejaculation and partner satisfaction, their widespread use has yet to be studied in large multicenter clinical studies due to the lack of data from randomized controlled studies based on pre- and post-treatment IELT improvement and questionnaire scores. α1-adrenergic receptor antagonists for the treatment of PE have the possible mechanism of decreasing the ejaculatory ducts such as the vas deferens, prostate and posterior Urethral smooth muscle sympathetic excitability, delaying ejaculation. It may also act on alpha receptors in the central nervous system to control the ejaculatory reflex and relieve the symptoms of premature ejaculation by inhibiting the excitability of the central nervous system.
1.4.2 Tramadol
Tramadol is a central opioid receptor agonist that is approved as an analgesic and widely used in clinical practice. Current clinical studies reporting tramadol for PE in the literature include a placebo-controlled study and two open studies. In a small sample of placebo-controlled studies, tramadol was administered to 60 patients with primary PE with a pretreatment IELT <= 2 min< span=""> and tramadol 25 mg as needed 1-2 h before sexual intercourse occurred, and the IELT was prolonged from 1.17 min to Dyspepsia and drowsiness were the main adverse effects, with an incidence of 8% and 5%, respectively. Another study reported an increase in IELT from 19 to 243 seconds from baseline with an associated adverse effect of nausea, vomiting and dizziness with an incidence of 28% when 50 mg of tramadol was taken as needed. Tramadol is only recommended for consideration in selected patients based on the addictive nature of the drug and the high number of adverse effects associated with long-term use. This guideline does not recommend it.
There is 2d evidence of the effectiveness and safety of alpha blockers and tramadol for the treatment of premature ejaculation.
II. Psychological/behavioral therapy
The goals of psychotherapy for premature ejaculation should focus on the gender relationship between the patient and his or her sexual partner and include (i) improving not only the patient’s self-confidence in sexual ability but also his or her overall self-confidence; (ii) reducing operant anxiety; (iii) enhancing communication and communication with the sexual partner and improving couple bonding; and (iv) addressing interpersonal issues that may contribute to premature ejaculation. Because most psychological treatments reported in the literature are small samples or small non-randomized controlled studies, and because of the lack of long-term follow-up, their immediate efficacy has been reported inconsistently and their long-term efficacy is unknown. This guideline recommends psychotherapy for situational PE or premature ejaculation-like ejaculatory dysfunction.
Behavioral therapies began in the 1970s and include Semans’ “stop-and-go” technique and Masters/Johnson’s “squeeze and pinch” technique. Patients undergo a series of progressive exercises to master and build ejaculatory control. The method begins with self-stimulation, changes to partner stimulation, followed by non-pumping intercourse, and finally the “stop-motion-stop” technique. This repeated training can weaken the patient’s response to sexual stimulation so that the patient can receive more stimulation, maintain the appropriate intensity of stimulation at the ejaculatory threshold and prolong the duration of stimulation. A few studies have reported that behavioral therapy results in prolonged IELT, increased sexual self-confidence and self-esteem in patients. Masturbation before intercourse is a frequent method used by many young PE patients. Masturbation decreases penile sensitivity after ejaculation and prolongs ejaculatory latency during the inactivity period. Behavioral therapy for PE, although in the short term to achieve a certain degree of effectiveness, but because of the need for long-term close cooperation with the female partner, many patients because of the difficulty of persistence and affect the long-term results. Behavioral therapy is generally effective in about 2 weeks and can be continued for 3-6 months to consolidate the effect.
The purpose of the “stop-and-go” technique is to increase the ejaculatory stimulation threshold. The partner stimulates the patient’s penis until the patient feels that ejaculation is imminent, then immediately stops stimulation and gives stimulation again after the ejaculation premonition disappears completely, and so on for more than 3 times. The specific method of the “squeeze and pinch” technique is for the woman to place her thumb at the tether of the penis, her index finger and middle finger below the edge of the coronal sulcus, squeeze and press the head of the penis for 3 to 4 seconds.
When the ejaculation threshold is reached, the spouse holds the penis body until the feeling of ejaculation disappears. Recently, a few medical centers have adopted sexual function therapy devices to desensitize patients with premature ejaculation and train them to control ejaculation through physical stimulation.
The principle is similar to that of behavioral therapy and is effective in about half of the patients. The guidelines recommend considering a combination of these treatments for patients who have failed to respond to pharmacologic treatment or who have had poor results.
The use of
The evidence for the effectiveness of psychological/behavioral interventions for PE is at the 2b level
Surgical treatment
For patients with primary PE who are unsuccessful with behavioral and/or pharmacologic treatment, surgical treatment has been reported, including selective dorsal penile neurectomy and glans penis enlargement with hyaluronic acid gel. However, its overall and long-term efficacy needs to be further explored and studied in a multicenter, large sample with long-term follow-up.
Based on the fact that the reported clinical studies on the surgical treatment of premature ejaculation are all single-center, non-randomized controlled studies with small samples, there is a lack of evidence-based and long-term follow-up data in large samples, and the risks of surgical procedures may lead to hyposensitivity, ED or even permanent loss of penile erectile function, which far outweigh the benefits. Therefore, this guideline recommends caution in its adoption and does not routinely recommend it.