Treatment of Premature Ejaculation:
There are many treatment options available for PE. This includes counseling, behavioral therapy, topical therapies and systemic pharmacological agents. In this section each therapy is discussed.
There are two commonly used behavioral therapies that include the 'stop-start' and 'squeeze technique'. The "squeeze technique" was first described by Masters and Johnson in 1970 and the “stop-start method” described by Semans in 1956.
For this kind of techniques the couple must undergone counseling and training from well trained sex therapists.These therapies demands commitment from the man and his partner.
In the stop-start technique; the man stimulating himself to the point just before ejaculation and then stops. After the sensations have fall downed, he starts again. This should be repeated three times. The length of time before each stop gets gradually longer. The squeeze technique involves the partner (or man) using their fingers to squeeze the glans of the penis to cause the erection (and ejaculation) to subside.
Pharmacological Treatment for Premature Ejaculation:
A) Topical Agents:
The hypothesis that men with PE may have 'penile hypersensitivity' gives rise to the development of topical desensitizing agents. In 1943 Schapiro described the use of local anesthetic treatment to delay ejaculation for the first time.
Topical agents can be used as needed basis and there is a less possibility of systemic side effects hence topical agents are very attractive options.
Reported evidence suggests that topical agents are efficacious. However these studies were small and in many times local side effects were reported.
B) Systemic Therapies:
- SS Cream:
Severance-secret cream (Cheil Jedan Corporation, Seoul, Korea) is a mixture of nine traditional medicines, including Korean ginseng, bufonoid venom and cinnamon. Some of these have local anesthetic as well as vasoactive properties. In one randomized, double blind, placebo-controlled trial of SS-cream versus placebo, there was an increase in mean Intravaginal Ejaculatory Latency Time (IELT) drug, the mean from 1.37 minutes before treatment to 10.92 minutes in the SS-cream group. The SS cream is available for use only in Korea. It has been recommended to be used an hour before intercourse and washed off immediately before intercourse. Some patients complained about the unpleasant smell and color of the cream. SS cream is not approved for use in Europe or the USA.
- Lignocaine Spray
The active ingredient is lignocaine (9.6%). This spray works in the same way as other topical anesthetic agents. However there is a limited data to support its use in PE.
- Lidocaine/prilocaine Cream:
This is a local anesthetic cream that contains 2.5% of both lidocaine and prilocaine for topical application. In the small study it was reported that the IELT was increased from 1.49 minutes to 8.45 minutes following 2 months use of this local anesthetic cream. Genital hypoesthesia was reported in both sexes in this study.
Dyclonine is a local anesthetic used in the field of dentistry. It has been combined with the vasodilator alprostadil for the treatment of PE. The product has to be applied to the tip of the penis in the region of the meatus. However the data for this product is limited.
Tramadol, has been used for the treatment of PE. It is a centrally acting oral opioid analgesic with dual mechanisms of action. Tramadol and its metabolite, O-desmethyl (M1), bind to opioid receptors. The metabolite, M1, has a 200-fold higher affinity to the opioid receptors. Tramadol has also been shown to inhibit the uptake of norepinephrine and serotonin, suggesting that its anti-nociception activity is mediated by both opioid and nonopioid mechanisms.
Its mechanism of action in PE is not well known, however it is thought to be related to its action on the opioid receptor, which may reduce sensitivity, as well as the inhibition of serotonin reuptake, which may delay ejaculation.
Efficacy Tramadol for on-demand treatment of PE was assessed in single-blind, placebo-controlled, crossover, and stopwatch monitored two-period (8 weeks each with 1 week washout) study in 60 patients with lifelong PE. The baseline (mean±SD) intravaginal ejaculation latency time (IELT) for patients before treatment was 1.17 ± 0.39 minutes. At the end of the treatment period utilizing the active drug, the mean IELT was increased significantly in patients on Tramadol treatment to 7.37 ± 2.53 minutes. The same patients on placebo medication had mean IELT of only 2.01 ± 0.71 minutes. Patients uniformly reported satisfaction with their resulting control over ejaculation. Study concluded that Tramadol is a promising agent for treating rapid ejaculation. Similar results were also reported by Safarinejad MR et al in a double-blind, placebo-controlled, fixed-dose, randomized study in 64 patients of PE. However these studies are of small sample size and further studies are required.
Clomipramine is a tricyclic antidepressant that inhibits the reuptake of noradrenaline and serotonin. It is commonly used in the treatment of obsessive-compulsive disorders. Daily dosing with clomipramine was successful in treating premature ejaculation in men who were unresponsive to clomipramine 25 mg on an "as needed" basis. Four men who, in an earlier study, were nonresponders to clomipramine 25 mg "as needed" participated in a 12 week study in which they took clomipramine 0, 10, 20, and 30 mg daily, each dose for 3 weeks. Latencies were significantly longer with the 30-mg per day dose than with the previous 25-mg regimen. Ejaculatory control, sexual arousal, and penile rigidity were not significantly affected by treatment. All subjects reported satisfaction with the treatment. Side-effects were mild and generally transient. Of the 3 men who opted to continue clomipramine treatment, 1 chose 30 mg as needed, and 2 chose 20 mg daily.
Clomipramine 25 mg, as needed, effectively increased ejaculatory latency in men with primary premature ejaculation. In a prospective, double-blind, placebo controlled, crossover study, patients with primary premature ejaculation (n=8), premature ejaculation and erectile dysfunction (n=6), and controls (n=8) were randomly given clomipramine for a 3 week period and placebo for 3 a week period. Each was to be used 12 to 24 hours before sexual activity. Patients with ejaculatory latency increased their time to ejaculation from approximately 2 to 8 minutes (p=0.035). No significant effects occurred in controls and men with premature ejaculation and erectile dysfunction.
Clomipramine was useful in the treatment of premature ejaculation. Twenty patients with premature ejaculation were randomly allocated to treatment with clomipramine or placebo in a double-blind study. Mean estimated time to ejaculation after vaginal penetration increased to 6.1 minutes on Clomipramine 25 mg and to 8.4 minutes on Clomipramine 50 mg. These estimated times were significantly different from estimated time to ejaculation while on placebo. The results suggest that low-dose Clomipramine may be useful in the treatment of premature ejaculation.
- Serotonergic antidepressants:
Selective serotonin reuptake inhibitors (SSRIs) have been used to prolong the ejaculation. They can prolong intra-vaginal ejaculatory latency time for several minutes. SSRI are used for the treatment of depression, and it was noted that delayed ejaculation was one of their common side-effects. For PE they are used at lower doses than when used to treat depression. The commonly encountered side effects are: dry mouth, drowsiness, nausea and reduced libido as well as erectile dysfunction.
Currently four SSRIs are commonly used in the treatment of PE are: Sertraline, paroxetine, fluoxetine, citalopram.
Three serotonin receptor subtypes viz. 5-HT1A, 5-HT1B and 5-HT2C are having a role in ejaculation. 5-HT1A receptor activation has a pro-ejaculatory effect while the 5-HT1B and 5-HT2C activation delays ejaculation. Serotonin which is released from the pre-synaptic neurons into the synapse activates the 5-HT1B receptors. This resulted in reduced release of serotonin in the synapse. The SSRI's block 5-HT transporter mechanisms and so increase 5-HT within the synapses. This in turn activates 5-HT1A and 5-HT1B receptors
resulting in inhibition of serotonin release into the synaptic cleft. The result is minimal increase in synaptic 5-HT Levels that cause sustained mild stimulation of all post - synaptic 5-HT2C receptors. After several days to weeks of SSRI treatment, the receptors become desensitized and so there is a reduction of that inhibitory action they have on serotonin release. The overall effect is more serotonin released into the synapse. Activation of 5-HT2c receptors adjusts the ejaculatory set
point and delays ejaculation, however the extent of this delay depends on several factors including the type, dose and frequency of the SSRI administration as well as the genetically determined ejaculatory threshold set point.
Reported evidence suggests that paroxetine 20-40 mg, clomipramine 10-50 mg, sertraline 50-100 mg and fluoxetine 20-40 mg can be used for daily treatment. The strongest ejaculation delay was reported with paroxetine, which increased the IELT approximately 8.8 fold over baseline. Ejaculation delay usually reported within 5-10 days but may occur earlier. Adverse effects reported are minor, and start in the first week of treatment, gradually diminish within 2-3 weeks. Adverse effects include fatigue, yawning, mild nausea, loose stools or perspiration. Small number of patients reported agitation. Treatment with SSRIs is generally avoided in patients with a history of bipolar depression.
Compared to the daily treatment of clomipramine, paroxetine, sertraline, fluoxetine; administration of 4-6 hours before intercourse is efficacious and well tolerated but is associated with less ejaculatory delay. Compared to on-demand administration, daily administration of an SSRI is reported with superior fold increases in IELT. This is due to greatly enhanced 5-HT neurotransmission resulting from several adaptive processes which may include presynaptic 5-HT1A and 5-HT1B / 1D receptor desensitization. On-demand treatment may be combined with either an initial trial of daily treatment or concomitant low dose daily treatment.
Synaptic cleft 5 HT and 5-HT neurotransmission are regulated by somatodendritic 5 HT1A autoreceptors, presynaptic 5 HT1B / 1D autoreceptors and a 5 HT transporter re uptake system. As 5-HT is released into the synaptic cleft from presynaptic axonal vesicles, 5 HT transporters again take up and remove 5 HT from the synaptic cleft, preventing overstimulation of the postsynaptic receptors.
After blockage of 5 HT transporters by acute administration of selective serotonin re-uptake inhibitor class drugs: SSRIs;, synaptic cleft 5 HT increases but is counteracted by activation of 5 HT1A autoreceptors which inhibit further 5 HT release.
Chronic administration of SSRIs results in greatly enhanced 5-HT neurotransmission due to several adaptive processes which may include presynaptic 5-HT1A and 5-HT1B / 1D receptor desensitization.
Figure is adopted from Indian J Urol 2007; 23:97-108