Asian Journal of Andrology (2013) 15, 138–142

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ORIGINAL ARTICLE

Safety and efficacy of tramadol hydrochloride on

treatment of premature ejaculation
Bayoumy I Eassa1 and Mohamed A El-Shazly2

Premature ejaculation (PE) is the most common sexual disorder. It affects 20%–30% of adult men; the aetiology of this condition has
not yet been elucidated. The aim of this study is to evaluate the efficacy, safety, tolerability, undesirable effects and improved
satisfaction with sexual intercourse with tramadol hydrochloride at different dosages for the treatment of PE. A total of 300 patients
who presented with lifelong (primary) PE were included in this study. The study was performed for 28 weeks, in which placebo (starch
tablet) was given for 4 weeks, and active ingredient (tramadol hydrochloride) was administered at different therapeutic dosages for 24
weeks. Patients were divided into three equal groups, each consisting of 100 patients. The first group (A) was given tramadol
hydrochloride capsule 25 mg. The second group (B) was given tramadol hydrochloride capsule 50 mg. The third group (C) was given
tramadol hydrochloride capsule 100 mg. All of the 300 participants included completed the study voluntarily. The age of the patients
varied from 25 to 50 years. After the treatment period, the recorded data were collected for each group and analysed. The results
showed a highly significant increase in the mean intravaginal ejaculatory latency time (IELT) in all groups compared to baseline data
(P,0.0001). We concluded that using tramadol hydrochloride at different doses on demand for the treatment of PE is effective, safe
and tolerable, with minimal undesirable effects, and approval for this indication should be sought.
Asian Journal of Andrology (2013) 15, 138–142; doi:10.1038/aja.2012.96; published online 29 October 2012

Keywords: early ejaculation; erectile dysfunction; intravaginal ejaculation latency time; premature climax; premature ejaculation; PE;
rapid ejaculation; tramadol

INTRODUCTION sexual dysfunction characterized by ejaculation that always or nearly

Ejaculatory dysfunction is a common and distressing cause of male always occurs prior to or within approximately 1 min of vaginal pe-
sexual difficulties. It also represents a significant cause of male factor netration, the inability to delay ejaculation on all or nearly all vaginal
subfertility, posing distinct reproductive challenges for couples penetrations, and negative personal consequences, such as distress,
attempting to conceive. Ejaculatory dysfunction can be classified along bother, frustration and/or the avoidance of sexual intimacy.5
a spectrum ranging from premature ejaculation (PE), retarded or In 1994, the concept of IELT was introduced.6 IELT has been
delayed ejaculation (DE), to complete anejaculation (AE), along with defined as the length of time between vaginal entry (IELT), anal (anal
retrograde ejaculation (RE).1 ejaculatory latency time) or oral penetration (oral ejaculatory latency
PE is the most common male sexual dysfunction, affecting approxi- time), or the initiation of masturbation (masturbatory ejaculatory
mately 20%–30% of the male population at any given time.2 latency time) and ejaculation.7 IELT forms the basis of most current
Masters and Johnson3 first suggested the concept that first inter- clinical studies on PE.8
course experiences that were rushed and associated with nervousness Based on Dutch data,9 the baseline IELT defining ejaculation that
at the time of inexperienced sex led to PE. occurred prematurely was estimated at less than 1 min. Some publica-
The medical literature contains several definitions of PE. The lack of tions stated that any ejaculation occurring within 1, 2, 3, or even 7 min
agreement on what constitutes PE has hampered basic and clinical of penetration is considered premature; others specify the number of
research into the aetiology and management of this condition. penile thrusts, considering 8–15 thrusts as a criterion for PE. Still
Quantitative measures of intercourse, such as the intravaginal ejacu- others consider partner satisfaction, suggesting that a man experiences
latory latency time (IELT), the number of thrusts between penetration PE if he is unable to delay his ejaculation until his partner is sexually
and ejaculation, the extent of partner sexual satisfaction, and the satisfied in at least 50% of their coital connections.10
patient’s assessment of his voluntary control over ejaculation, have Anteportal ejaculation is the term for men who ejaculate prior to
been described. Each of the four criteria above has been operationa- vaginal penetration and is considered the most severe form of PE. Such
lized, although not always with consistency.4 men/couples typically present when they are having difficulty concei-
The International Society of Sexual Medicine (ISSM) recently pub- ving children. It is estimated that 5% of lifelong PE men suffer from
lished an evidence-based definition of lifelong (primary) PE as a male anteportal PE.11
1
Department of Dermatology, Venereology and Andrology, Al-Azhar University, Cairo 11884, Egypt and 2Department of Urology, Menoufiya University, Cairo 32511, Egypt
Correspondence: Dr BI Eassa (bayeassa@yahoo.com)
Received: 15 April 2012; Revised: 17 May 2012; Accepted: 25 July 2012; Published online: 29 October 2012
 Tramadol and premature ejaculation
BI Eassa and MA El-Shazly
139

PE has been classified as either primary (lifelong), which begins Investigations

when a male first becomes sexually active, or secondary (acquired), Routine laboratory investigations were performed for all patients and
meaning that a male previously had an acceptable level of ejaculatory included complete blood count, urine analysis, liver function test,
control and developed the condition later in life,12 and it has been renal profile, lipid profile, blood sugar, hormonal profile (follicle-
associated with chronic prostatitis and specific endocrinopathies, stimulating hormone, luteinizing hormone, testosterone, and prolac-
including diabetes mellitus and hyperthyroidism.13 In these instances, tin and thyroid profile (thyroid-stimulating hormone, T3 and T4).
PE is usually reversed when the underlying disorder is treated.14
The second international consultation on erectile and sexual dys- Assessment method (IELT)
functions recommends the use of the term early ejaculation rather The duration of IELT is the time from penetration (vaginal penetra-
than PE; however, PE will continue to be used for the near future.15 tion) until ejaculation (release of semen) and was timed on a stop-
Tramadol hydrochloride was developed in the late 1970s.16 It pos- watch by ‘start’ (penetration) to ‘stop’ (ejaculation). Either of the
sesses weak agonist action at the m-opioid receptor, releases serotonin partners was allowed to handle the stopwatch; however, it was
and inhibits the reuptake of norepinephrine.17 Its mode of action is requested that the same person remain responsible for every IELT
not completely understood. From animal tests, at least two comple- measurement for the duration of the study, and they were asked to
mentary mechanisms appear applicable: the binding of parent and M1 be honest in recording the time. They were instructed to calculate and
metabolites to m-opioid receptors (antinociceptive effect), and the record the exact time after ejaculation.
inhibition of the reuptake of norepinephrine and serotonin (5-HT), After explanation of the purpose of the study, all of the patients
which may account for its effect on delaying ejaculation.18 agreed to participate in the study, and written informed consent was
Tramadol undergoes hepatic metabolism via the cytochrome P450 requested from all patients and signed before starting treatment. They
isozyme CYP2D6 and is O- and N-demethylated to five different were provided with a stopwatch and a sexual events diary, were care-
metabolites. Of these, M1 (O-desmethyltramadol) is the most signifi- fully instructed on how to measure the IELT and were reminded and
cant metabolite, because it has 200 times the m-affinity of tramadol and confirmed during the follow-up visits (every 2 weeks).
has an elimination half-life of 9 h compared with 6 h for tramadol. In
the 6% of the population who have slow CYP2D6 activity, there is a Exclusion criteria
slightly reduced analgesic effect. Phase II hepatic metabolism renders Exclusion criteria included patients with secondary (organic) PE;
the metabolites water soluble, and they are excreted by the kidneys; sexual dysfunction (decreased sexual interest, erectile dysfunction
thus, reduced doses may be used in renal and hepatic impairment.19 according to the International Index of Erectile Function, painful
The objective of this study was to evaluate the efficacy, safety, toler- intercourse, urinary tract infection, or female sexual dysfunction that
ability, undesirable effects, improved satisfaction with sexual inter- affected the sexual relationship); current physical illness (e.g., diabetes
course and control over ejaculation with tramadol hydrochloride at mellitus, liver diseases, dyslipidaemia, hypertension, heart diseases,
different dosages for the treatment of PE. renal diseases, thyroid diseases and hormonal disorders); history of
a psychiatric or neurological disorder; substance abuse (alcohol or
PATIENTS AND METHODS drug); previous pelvic trauma or surgery; spinal cord injury; or cur-
Subjects rently taking a drug known to affect sexual function, including either
A total of 300 heterosexual men complaining of lifelong (primary) PE topical penile applications or systemic drugs. All male patients had
were recruited from the outpatient clinic of Al-Hussein University been circumcized at birth and were asked to avoid condom use.
Hospital, Al-Azhar University, Cairo, Egypt, from January 2009 to
December 2011. The study was approved by the local medical ethics Statistical analysis
committee. The enrolled men aged 25–50 years had been in a stable, The computer software Stat View 5 (SAS Institute Inc., Cary, NC,
monogamous, heterosexual relationship with regular sexual inter- USA) was used for data analysis. Paired t-test was used for comparison
course at least twice per week with a cooperative female partner and between the mean values. A P,0.05 was considered significance.
had been married for at least 2 years. The study was performed for 28
weeks, during which the placebo was given for 4 weeks, and the active RESULTS
ingredient (tramadol hydrochloride) (Grünenthal GmbH, Aachen, All 300 participants included in this study completed the period vol-
Germany) was administered at different therapeutic dosages for 24 untarily. The age of the patients varied from 25 to 50 years (mean
weeks. 34.4768.16, 33.8668.31 and 33.1567.24 years in groups A, B and C,
respectively). No changes in hormonal profile were recorded before
Study design and after treatment.
Patients were randomly divided through a simple (complete) rando- At the end of the first 4 weeks (placebo period), recorded data were
misation process into three groups, each consisting of 100 patients, collected from all patients and analysed by paired t-test. The results
and administered placebo tablets (starch) for 4 weeks before being showed that the mean IELT was f4 min. The mean baseline of IELT
administered active ingredient (tramadol hydrochloride). The first before treatment was 2.8260.89 in group A, 2.7960.95 in group B,
group (A) was given tramadol hydrochloride capsule 25 mg. The and 2.9960.86 in group C (Table 1).
second group (B) was given tramadol hydrochloride capsule 50 mg. At the end of the study, i.e., after 24 weeks of treatment with tra-
The third group (C) was given tramadol hydrochloride 100 mg. All of madol hydrochloride, the recorded data were collected from each
the patients were instructed to take the drug with a cup of water 2–3 h group and analysed. As shown in Table 1, the mean IELT in all groups
before intercourse. All of the patients were asked about their satisfac- was significantly different compared to baseline data (P,0.0001). The
tion and control of ejaculation before and after treatment, in addition IELT was 13.1761.83 min (range 8.00–15.00 min) in group A,
to their tolerance to the drug and whether there were any side effects. 23.4361.78 min (range 18.00–25.00 min) in group B and 36.4963.25
No specific validated questionnaire was used in this study. (range 29.00–40.00 min) in group C (Table 1). All of the patients

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 Tramadol and premature ejaculation
BI Eassa and MA El-Shazly
140

Table 1 Statistical comparison between all groups Table 2 Undesirable side effects in all groups
IELT pre-treatment IELT post- P value Symptoms Group A Group B Group C
(placebo) (min) treatment (min)
Somnolence 100% (100/100) 100% (100/100) 100% (100/100)
Group A 2.8260.89 13.1761.83 ,0.0001 Pruritus 100% (100/100) 100% (100/100) 100% (100/100)
Group B 2.7960.95 23.4361.78 ,0.0001 Dizziness — 18% (18/100) 38% (38/100)
Group C 2.9960.86 36.4963.25 ,0.0001 Headache — 16% (16/100) 30% (30/100)
Mouth dryness — 13% (13/100) 28% (28/1000
Nausea — — 20% (20/100)
treated with tramadol hydrochloride at different dosages gained sa- Vomiting — — 17% (17/100)
tisfactory control over ejaculation compared to baseline data in each
group, and the drug was well tolerated (Figure 1).
Regarding undesirable effects, patients in all groups complained of This is, in part, due to the lack of knowledge about PE, the absence of
somnolence (light sleeping or insomnia) and pruritus (itching with- performing a careful history, and the nonexistence of diagnostic tools
out skin lesions), and the severity and intensity were dose-dependent. for PE.23
However, the patients in groups B and C complained of additional The diagnostic criterion for many authors is the time between pen-
undesirable effects, including dizziness (18% and 38%, respectively), etration and ejaculation, and this time is agreed to be 1 min.24
light headache (heaviness) (16% and 30%, respectively), and dryness Rowland et al.4 suggested that an IELT of 2 min or less may serve as
of mouth (13% and 28%, respectively). Nausea (20%) and vomiting an adequately sensitive criterion for defining PE. Other authors con-
(17%) were only reported in group C (Table 2). All of these undesir- cluded that any ejaculation occurring within 1, 2, 3, or even 7 min of
able effects usually resolved approximately 10 h after ingestion of the penetration should be considered premature,10 but none of the defini-
drug. tions offer any supportive rationale for their proposed cut-off time.8
Most of the patients (90% (270/300)) treated with tramadol hydro- Waldinger et al.25 published multinational reports of IELT (The
chloride reported an increase in penile rigidity during intercourse Netherlands, United Kingdom, United States, Spain and Turkey),
throughout the treatment period, and this claim was confirmed by and they found that the median IELT was 5.4 min (range 0.55–
their partners. 44.1 min) and that the distribution of IELT in all five countries was
positively skewed.
The exact aetiology of PE is unknown, but it is believed to include
DISCUSSION
neurobiological and/or psychological components and/or penile
Human sexual function includes sexual libido, penile erection, ejacu-
hypersensitivity.26
lation and orgasm. Patients with PE can be divided into primary and
There are multiple reports in the literature on the use of a variety of
secondary PE. Primary (lifelong) PE patients are patients who have
drugs in the treatment of PE. These drugs facilitate ejaculation
suffered chronically from the beginning of their sexual lives, and se-
through either a central dopaminergic or anti-serotoninergic mech-
condary PE patients have suffered from PE after years of normal sexual
anism of action.27,28
functioning.20
PE has been treated with various modalities, including behavioural
PE is the most common form of male sexual dysfunction, affecting therapy3, topical anaesthetic creams or sprays,29 and off-label use of
30% of men, and it is defined as an inability to exert voluntary control oral pharmacotherapy, such as phosphodiesterase-5 inhibitors,30
over the ejaculatory reflex, resulting in rapid orgasm.21 Currently, selective serotonin reuptake inhibitors (SSRIs) (fluoxetine, citalopram
available data suggest that only 1%–12% of males self-reporting PE and duloxetine),31 and a tricyclic antidepressant (clomipramine) that
receive treatment for their dysfunction.2 In a recent study conducted blocks serotonin, dopamine and norepinephrine transporters.32 These
in Korea, the self-reported prevalence rate was 27.5%.22 modalities are associated with variable rates of success when taken
PE, unlike ED, affects men of all ages equally. However, both PE and daily,33,34 and intracavernosal vasoactive drug injection has also been
ED coexist, and PE can often be misdiagnosed as ED in many men. reported.35 In contrast, some reports suggest that these drugs may be
effective when received as needed.36,37
Other agents, including a-adrenoreceptor antagonists (terazosin
and alfuzosin)38 and an analgesic opioid receptor agonist and nora-
drenalin reuptake inhibitor (tramadol), have also been investigated for
treating PE.39 Psychotherapy and behavioural therapy also have a role,
although well-designed, controlled trials that use such approaches are
lacking.40
PE management is dependent upon aetiology. When secondary to
ED, aetiology-specific treatment is employed. When PE is lifelong,
initial pharmacotherapy (SSRI, topical anaesthesia, or phosphodies-
terase-5 inhibitors) is appropriate. When PE is associated with psy-
chogenic/relationship factors, behavioural therapy is indicated. When
PE is acquired, pharmacotherapy and/or behavioural therapies are
preferred2. Melnik et al.41 concluded that there is weak and inconsist-
ent evidence regarding the effectiveness of psychological interventions
for the treatment of PE.
Currently, there is no US Food and Drug Administration (FDA)-
Figure 1 Mean IELT in all groups before and after treatment. IELT, intravaginal approved pharmacological therapies for treating PE.42 To date, the lar-
ejaculatory latency time. gest trials of a treatment for PE have been conducted with dapoxetine, a

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141

short-acting SSRI that is the only oral agent approved for the treatment receptor antagonist.53 5-hydroxytryptamine type 2C receptor an-
of PE in several European, Asia-Pacific and South American countries.43 tagonist,54 5-nicotinic acetylcholine receptor antagonist,55 M1 and
Tramadol is almost completely absorbed when given orally, and it M3 muscarinic acetylcholine receptor antagonist,56 and a serotonin
has an apparent elimination half-life of 6 h in humans. Its bioavail- and norepinephrine modulator.23 It is possible that one or a combina-
ability of 70% after a single administration can be entirely attributed to tion of these effects leads to a delay in ejaculation.
first-pass metabolism. After multiple dosing, the bioavailability Safarinejad and Hosseini45 hypothesized that tramadol affects PE
increases to almost 100%. Twenty percent of the drug is bound to through a multimodal mechanism, including inhibiting the neuronal
plasma proteins. Approximately 90% of the administered dose is reuptake of serotonin, inhibiting the neuronal reuptake of noradrenaline,
recovered in urine either unchanged (30%) or as metabolites (60%), enhancing serotonin efflux, antinociceptive effects and inhibiting
and the remainder is eliminated in the faeces.44 spinal somatosensory evoked potentials; thus, it has anaesthetic-type
Safarinejad and Hosseini45 published a double-blind, placebo-controlled, effects on peripheral sensory nerves.
fixed-dose study indicating that the on-demand use of 50 mg trama- Most of the patients included in this study reported that the drug
dol exerted a significant ejaculation-delaying effect in men with PE. reduced penile sensitivity, especially the gland penis, and this result is
Additionally, Salem et al,42 in a single-blind, placebo-controlled study in agreement with Safarinejad and Hosseini, who mentioned the
in men with PE, concluded that the on-demand use of 25 mg tramadol anaesthetic-type effect on peripheral sensory nerves,45 and in disagree-
showed impressive results in delaying ejaculation.42 ment with Paick et al.,57 who failed to identify any penile hypersensi-
In an open-label crossover comparative study of daily paroxetine tivity factors in patients with PE.
(20 mg) and on-demand tramadol (50 mg) in 35 subjects with lifelong Tramadol has been used off-label and empirically since 2000 for the
PE, superior IELT fold increases and responses were demonstrated with treatment of PE, because of its acceptable safety profile and because
paroxetine (22 fold vs. fivefold for tramadol) after 12 weeks of treatment.39 patients taking tramadol for analgesia reported delayed ejaculation.48
Hellstrom46 stated that tramadol for the treatment of PE showed As a result of its short half-life, tramadol can be used in an on-demand
promise, but the data available from small trials need to be corrobo- dosing protocol.58
rated. In addition, long-term studies are warranted to investigate the The inability to control and defer ejaculation until the female part-
risk of opioid addiction. Bar-Or et al.47 concluded that using the ner is sexually satisfied in at least 50% of intercourse attempts was
tramadol orally disintegrating tablet on demand is an effective treat- proposed as a definition of PE by Masters and Johnson.3 An inherent
ment for PE at a small (62 mg) and safe therapeutic dose, and it problem exists in defining a man as dysfunctional based on the sexual
provides a new option for managing mild to severe PE. response of his partner, as only 30% of women achieve orgasm during
Xiong et al.48 found that the treatment of PE with tramadol hydro- sexual intercourse, regardless of the extent of their partner’s ejacula-
chloride with behavioural modification showed positive effects in tory control and latency.2
prolonging IELT and improving partners’ intercourse satisfaction. The undesirable effects reported from the patients in this study were
More multicentre and double-blind studies are required to evaluate its minimal, temporary and not serious compared to other medications
efficacy and safety as a routine therapy for PE. Kaynar et al.49 also stated used for the treatment of PE, especially SSRIs, in which delayed ejacu-
that the use of low-dose tramadol on demand is effective for lifelong PE. lation occurs at the expense of a decrease in libido and a moderate
In our study, we concluded that the use of tramadol hydrochloride decrease in penile rigidity.59 In our study, most of the patients
at 25, 50 or 100 mg, 2–3 h on demand before sexual activity showed a reported an increase in penile rigidity during intercourse throughout
highly significant delay in ejaculation and a 10- to 20-fold increase in the treatment period.
IELT compared to mean baseline data. At the same time, the drug was Zin et al.60 stated that the most important priorities that need to be
well accepted and tolerated regarding its side effects, especially at low addressed in the research of PE are the lack of a standard animal model
dosage (25 and 50 mg). This result is in agreement with previous and adequately powered aetiological studies enrolling both PE
studies.39,42,45–49 patients and unafflicted control males. There remains a long way to
Tramadol has long been considered to have a low abuse potential. go in terms of future research.
Although it is an opioid agonist, it has not been classified as a sche- The ideal treatment for PE should meet the following criteria: on-
duled substance. According to the US FDA, the rate of addiction was 1 demand treatment with quick onset of action so as not to interfere
in 100 000 during the last 18-month period of surveillance.50 Because with sexual spontaneity, high rates of efficacy after early doses and
the M1 metabolite is the principal agonist for m-opioid receptors, the minimal sexual and other adverse effects.61 We met the above criteria
in our study, with minimal adverse effects and no reduction in sexual
delayed agonist activity reduces dependence liability. The noradrena-
activities.
lin reuptake effects may also play a role in reducing dependence.51
A trial in a chronic pain population of 11 352 enrolled subjects, 8139
of whom completed the trial and 68.2% of whom were female, iden- CONCLUSIONS
tified that the rate of abuse with tramadol (2.7%) was not significantly We concluded that using tramadol hydrochloride on demand at small
greater than nonsteroidal anti-inflammatory drugs (2.5%) and less dosages (25 and 50 mg) for the treatment of PE is acceptable for
than oxycodone (4.9%).52 managing PE because it is effective, safe, and tolerable, with non-
Regarding addiction to tramadol hydrochloride, we believe that the serious side effects, and approval for this indication should be sought.
use of this drug on demand is safe and tolerable, especially within the
therapeutic dose range from 50–400 mg daily (mentioned in the pack- AUTHOR CONTRIBUTIONS
age insert). According to the US FDA, the rate of addiction was low and BIE contributed to conception, design, acquisition, analysis and inter-
mostly reported in patients with a prior history of substance abuse.49,50 pretation of data, drafting the manuscript, revising it critically for
Although the mechanism by which tramadol delays ejaculation has important intellectual content, and giving final approval of the version
not been elucidated, numerous laboratory studies have shown that to be published. MAE contributed to conception, interpretation of
tramadol acts as a mild m-opioid agonist,23 N-methyl-D-aspartate data, and final approval of the version to be published.

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BI Eassa and MA El-Shazly
142

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