Selective serotonin reuptake inhibitors (SSRIs) are reported to be effective for treating premature ejaculation (PE). Psychopharmacological studies suggest that PE might be due to decreased serotonergic neurotransmission through pathways that control ejaculation 1,2.
Ejaculation delay induced by SSRIs is due to alterations in specific serotonin receptors in the central nervous system. The ejaculation-retarding effect of 5-hydroxytryptamine (5-HT, serotonin) has been attributed to the activation of 5-HT1B and 5-HT2C receptors. By contrast, stimulation of 5-HT1A receptors has a facilitator effect on ejaculation 3.
The net effect of on-demand SSRI administration is only a mild increase in 5-HT neurotransmission and mild stimulation of the various postsynaptic serotonin receptors. In contrast, chronic SSRI administration is associated with greater 5-HT (serotonin) release into the synapse, stronger increase in 5-HT neurotransmission, and, as a result, durable activation of postsynaptic 5-HT receptors 4.
Escitalopram, one of the SSRIs, has been claimed to have the highest selectivity for the human serotonin transporter relative to the noradrenaline or dopamine transporters 5. This might be associated with greater clinical efficacy. Most adverse events reported by escitalopram-treated patients are mild and transient.
Tramadol hydrochloride is a centrally acting synthetic opioid analgesic. Tramadol is used to treat moderate to moderately severe chronic pain. It is a synthetic analgesic that acts centrally through binding of the opiod mu-receptors and through a tricyclic-like mechanism, inhibiting the neuronal reuptake of serotonin and norepinephrine within the central nervous system. The aim of this study was to compare on-demand use of 50 mg tramadol hydrochloride capsules with continuous use of 10 mg escitalopram tablets in the treatment of PE with respect to efficacy and side effects.
Patients and methods
The present study included 60 married men seeking medical help for PE in the outpatient clinic of the Andrology department, Kasr El-Einy (Cairo University Hospital), Cairo, Egypt. We included those with intravaginal ejaculation latency time (IVELT) less than 1 min and having regular sexual intercourse at least twice weekly. Patients with IIEF-5 (International Index of Erectile Function) less than 20 were excluded. We excluded those with chronic psychiatric or physical illness, alcohol, or substance abuse. Those with organic illness causing limitation of SSRI use – for example, chronic liver cirrhosis and renal failure – were also excluded.
All patients were enrolled and randomly assigned to two groups (group A or group B). The study was carried out in two phases: In phase 1, group A1 patients (n=30) received a daily dose of 10 mg escitalopram tablets in the evening for 4 weeks and group B1 patients (n=30) received 50 mg tramadol hydrochloride capsules twice weekly 2 h before intercourse, for 4 weeks. After the initial treatment period (phase 1), the two groups switched medication for another 4 weeks (phase 2). The patients did not take any medication for 4 weeks (washing-out period of the drugs) after finishing phase 1 and before starting phase 2.
In phase 2, group A2 (n=30) received 50 mg tramadol hydrochloride capsules twice weekly 2 h before intercourse for 4 weeks and group B2 patients (n=30) received 10 mg escitalopram tablets daily in the evening for 4 weeks.
The patients in the two groups were assessed by self-administration of IIEF-5 (International Index of Erectile function) (Arabic version) and pretreatment (baseline) IVELT was measured at least three times.
Every patient received a stopwatch to record IVELT, which was used by the wife. Patients were encouraged to perform sexual intercourse at least twice weekly. Each patient had to record his average baseline IVELT 1 week before starting the drug. All patients recorded IVELT at every sexual intercourse in order to calculate the weekly average 5. We supplied both drugs to all patients on a weekly basis. All patients was interviewed every 2 weeks to report their recorded IVELT in the previous 2 weeks and to report any side effect caused by the drug. The two drugs were taken only for 4 weeks, whereas follow-up (observation and recording of the patients’ weekly results) continued for 4 weeks after cessation of the drugs in both phases of the study. All patients were prevented from taking any other drugs that might delay ejaculation.
Outcome measures were change in IVELT in terms of fold increase between the studied groups.
Data were statistically described in terms of mean±SD, frequencies (number of cases), and percentages when appropriate. Quantitative variables between the study groups were compared using the Student t-test for independent samples when the data were normally distributed and the Mann–Whitney U-test when not normally distributed. Within-group comparison of quantitative variables was made using the paired t-test when data were normally distributed and the Wilcoxon signed rank test for paired (matched) samples when not normally distributed. A probability value (P value) less than 0.05 was considered statistically significant.
Background characteristics of our participants are illustrated in Table 1.
The IVELT was found to be significantly increased with tramadol than with escitalopram after 4 weeks. The tramadol groups showed an 11.8-fold increase, whereas the escitalopram groups showed a three-fold increase in IVELT readings after 4 weeks of treatment. However, on withdrawal, after cessation of the drugs, recurrence was more rapid with tramadol than with escitalopram (Tables 2–4).
As regards safety, the two drugs were well tolerated. Four escitalopram (13.4%) and six tramadol patients (20%) reported treatment adverse events after 2 weeks. The most commonly reported in the escitalopram group were nausea (two patients) and headache (one patient), which disappeared at the end of treatment, and in the tramadol group the most common side effects were drowsiness (reported by three patients after 2 weeks, but only by one patient after 4 weeks) and nausea (reported by three patients after 2 weeks, but by only one patient after 4 weeks). However, all patients who completed the study reported that these side effects were mild and tolerated.
Pharmacological treatment of men with PE may include a variety of approaches. However, none of the pharmacological agents are licensed for use in PE treatment. These include SSRIs, tricyclic antidepressants, monoamine oxidase inhibitors, topical anesthesia, neuroleptics, sympatholytics, phosphodiestrase inhibitors, and tramadol hydrochloride 6.
Both drugs used in the present study (tramadol HCL 50 mg capsules and escitalopram 10 mg tablets) improved IVELT readings of PE patients in the studied groups. Tramadol is more effective than escitalopram in delaying ejaculation in PE patients. This was observed in IVELT readings in the tramadol groups, which showed a 11.8-fold increase, whereas the escitalopram groups showed a three-fold increase in IVELT readings after 4 weeks of treatment. However, on withdrawal, after cessation of the drugs, recurrence was seen, more rapidly with tramadol than with escitalopram.
As regards side effects in our study, the two drugs were well tolerated. Four escitalopram (13.4%) and six tramadol (20%) patients reported treatment adverse events after 2 weeks. The most commonly reported adverse effects in the escitalopram group were nausea (two patients) and headache (one patient), which disappeared at the end of treatment, and in the tramadol group the most common side effects were drowsiness (reported by three patients after 2 weeks, but by only one patient after 4 weeks) and nausea (reported by three patients after 2 weeks but by only one patient after 4 weeks). However, all patients who completed the study reported that these side effects were mild and tolerated.
Similar to other opioids, tramadol may cause dependence, tolerance, and addiction, which happens more likely with prolonged therapy. As seen in community practice, dependence on this agent may occur after as little as 3 months of use at the maximum dose (generally 400 mg/day). Abrupt discontinuance may result in symptoms of withdrawal (e.g. anxiety, sweating, insomnia, rigors, pain, nausea, tremors, diarrhea, upper respiratory symptoms, and, occasionally, hallucinations). Symptoms may be avoided by tapering the dosage when the drug is discontinued. Also it can be abused by the patients because of its ability to produce euphoria, similar to other opioid analgesics 7.
Evidence of tramadol abuse in the US comes primarily from federally operated programs collecting adverse drug event (ADE) data. The MedWatch program of the Food and Drug Administration provides a central depository for receiving and compiling postmarketing voluntary case reports. Although passive reporting systems can significantly underestimate serious ADE numbers, these reports are often the first evidence of an ADE after a new drug’s release into the market. MedWatch has received 766 case reports of abuse associated with tramadol, as well as 482 cases of withdrawal associated with tramadol from the drug’s initial US marketing in 1995 through September 2004 8.
Currently, two publications are available on the use of tramadol in the treatment of PE. These are similar to those obtained from our study. In the double-blind, placebo-controlled, fixed-dose, randomized study by Safarinejad and Hosseini 9 64 potent men with PE were randomly assigned to receive 50 mg tramadol (group 1, n=32) or placebo (group 2, n=32) ∼2 h before planned sexual activity, for 8 weeks. Pretreatment evaluation included history and physical examination – IVELT. Tramadol demonstrated a 13-fold increase in IVELT, whereas placebo demonstrated a 1.4-fold increase; 28.1% of the participants in the tramadol arm reported adverse effects including nausea, vomiting and dizziness, and 15.6% of the patients in the placebo arm reported similar adverse effects.
Another study was a single blind, placebo-controlled, crossover, two-period prospective study to evaluate the efficacy of on-demand 25 mg tramadol. Sixty potent men with PE were randomly assigned to receive 25 mg tramadol (group 1, n=30) or placebo (group 2, n=30) for 8 weeks ∼2 h before planned sexual activity. The treatment group experienced a 6.3-fold increase in IVELT compared with a 1.7-fold increase in the placebo group. In all, 13.3% of patients reported adverse effects with tramadol, including dyspepsia and mild somnolence 10.
In our study, the onset of delay in ejaculation latency exerted by escitalopram was observed by an increase in IVELT after the second week and was attributed to escitalopram, which is a member of SSRIs and enhances 5-HT neurotransmission and activates 5-HT receptors by blocking presynaptic and somatodendritic 5-HT reuptake transporter receptors. After blockage of 5-HT transporters, synaptic cleft 5-HT increases but is counteracted by activation of 5-HT1A autoreceptors, which inhibits further release of 5-HT.
After chronic administration of an SSRI, Waldinger and colleagues suggested that adaptive processes, possibly including presynaptic 5-HT1A and 5-HT1b/1d receptor desensitization, may play a role in achieving the observed greatly enhanced 5-HT neurotransmission. In our study that was observed as a marked and progressive improvement of IVELT during the second, third, and fourth weeks 11.
The progressive decline of IVELT after treatment was attributed to the pharmacokinetics of escitalopram and tramadol. In-vitro studies show that escitalopram is at least seven and 27 times more potent than S-DCT and S-DDCT, respectively, in the inhibition of serotonin reuptake, suggesting that the metabolites of escitalopram do not contribute significantly to the antidepressant actions of escitalopram. S-DCT and S-DDCT also have no or very low affinity for serotonergic (5-HT1–7) receptors 12.
Therefore, upon escitalopram withdrawal, its weak metabolites (S-DCT and S-DDCT) have a very low therapeutic effect on IVELT. This is in contrast to the other SSRI, fluoxetine, which is also metabolized in the liver by demethylation, similar to escitalopram, but to an active metabolite, norfluoxetine, which has equivalent potency and selectivity as an SSRI to its parent molecule. Both fluoxetine and norfluoxetine are slowly eliminated, ensuring significant accumulation of both species with chronic dosing, and persistence of active drug for several weeks after drug withdrawal 13.
PE is not a life-threatening condition, and therefore safety should be a primary consideration in pharmacotherapy. In addition, the US Food and Drug Administration has approved none of the medical therapies currently administered in the treatment of PE for this specific indication. Generally, though, SSRIs have been introduced for continuous administration, and their benefits in the treatment of depression are better documented after a period of consistent drug administration. Conversely, continuous administration may cause patient noncompliance. This study showed that tramadol at the dosage used in the management of PE was more effective in delaying ejaculation in PE patients and recurrence is seen more rapidly after withdrawal with tramadol than with escitalopram. However, it is not recommended as treatment for PE because of the hazards of dependence and abuse of the drug; at the same time, continuous use of escitalopram also improved the condition of PE patients, but after a period of time.
In this study we demonstrated that, although on-demand use of 50 mg tramadol is more effective than continuous use of escitalopram at a fixed dose of 10 mg/day in delaying ejaculation and prolonging IVELT in PE patients, we do not recommend its use because of the possibility of addiction, dependence, and abuse by patients. Further, after cessation of the drugs, recurrence was more rapid with tramadol than with escitalopram. Larger randomized studies with longer duration are recommended.
Conflicts of interest
There are no conflicts of interests.
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