Tramadol for premature ejaculation: a systematic review and meta-analysis

Premature ejaculation (PE) is commonly defined by a short ejaculatory latency, a perceived lack of ejaculatory control; both related to self-efficacy; and distress and interpersonal difficulty [ 1]. PE can be either lifelong (primary), present since first sexual experiences, or acquired (secondary), beginning later [ 2]. The recently updated International Society of Sexual Medicine’s Guidelines for the Diagnosis and Treatment of Premature Ejaculation (PE) propose that PE is a male sexual dysfunction characterised by ejaculation within about one minute of vaginal penetration (lifelong PE) or a reduction in latency time to ≤3 minutes (secondary PE), the inability to delay ejaculation, and negative personal consequences [ 3].

The treatment of PE should attempt to alleviate concern about the condition as well as increase sexual satisfaction for the patient and the partner [ 4]. Available treatment pathways for the condition are varied and treatments may include both behavioural and/or pharmacological interventions. Tramadol is a centrally acting analgesic agent that combines opioid receptor activation and re-uptake inhibition of serotonin and noradrenaline, prescribed off-label for the treatment of PE. Dapoxetine (a selective serotonin re-uptake inhibitor) is currently the only approved oral drug to treat PE. In May 2009, the US Food and Drug Administration released a warning letter about tramadol's potential to cause addiction and difficulty in breathing [ 5]. Tramadol has previously been evaluated by three systematic reviews [ 6– 8], two of which have pooled data in a meta-analysis [ 7, 8]. The search methodology and inclusion criteria vary across these reviews. Of the two reviews including a meta-analysis, one [ 7] pooled data across different study types (observational studies and RCTs) using a mean difference [ 7]. One review pooled IELT effect estimates across studies using a standardised mean difference [ 8]. The European Association of Urology guidelines for the management of PE summarise that tramadol has shown a moderate beneficial effect with a similar efficacy as dapoxetine. However, that the beneficial effect of tramadol in PE is yet not supported by a high level of evidence [ 9].

The aim of this study was to systematically review the evidence base for tramadol in the management of PE, by summarising evidence from randomised controlled trials (RCTs) and reporting a mean difference meta-analysis of RCT IELT data. The review addressed the question “in men with premature ejaculation, what is the clinical effectiveness of tramadol as compared with a non-active comparators or other treatments, evaluated in randomised controlled trials”. The review is registered on PROSPERO 2013:CRD42013005289. Available from http://​www.​crd.​york.​ac.​uk/​PROSPERO/​display_​record.​asp?​ID=​CRD42013005289.

The review was undertaken in accordance with the general principles recommended in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement [ 10].

Pooled evidence across four RCT study groups (721 participants), suggests that tramadol is significantly more effective than placebo at increasing IELT over eight to 12 weeks. However, a high level of between-trial statistical heterogeneity is evident. The largest between-group effect size (3.52 min) was notable for one RCT [ 19]. Three clinical studies by the same investigator have been retracted in the past three years. However, excluding this RCT from the analysis did not significantly alter the overall effect size (1.02 min) or reduce the between-trial heterogeneity (I-squared = 71%).

The placebo-controlled RCTs prescribed tramadol doses from 25 mg to 89 mg. Reporting of the methodological quality across these RCTs was limited. Blinded outcome assessment was not reported by any of the RCTs, which may have contributed to detection bias. Allocation concealment was not reported by five of RCTs, which may have contributed to selection bias [ 16– 18, 20– 22]. One of the RCTs randomised participants according to their presentation sequence at clinic, which may have also contributed to selection bias [ 17]. As such, these results should be interpreted with caution.

The evidence from one RCT (70 participants) suggests that there is no difference in IELT between tramadol taken two to three hours prior to sexual intercourse and paroxetine daily [ 15]. Conversely, evidence from another RCT (59 participants) indicates that tramadol is significantly more effective than paroxetine taken on-demand at increasing IELT [ 16]. However, concealment of allocation and blinded outcome assessment were not reported by either RCT, and treatment duration was relatively short (six and four weeks respectively). As such, these results should be interpreted with caution. One of these RCTs also did not include a placebo group comparison [ 15]. Commonly used SSRIs in the management of PE including paroxetine (20 to 40 mg/d), are prescribed daily [ 9]. SSRIs such as paroxetine are absorbed slowly [ 24]. The half-lives of fluoxetine, paroxetine and sertraline range from 16 to 96 hours [ 25]. The pharmacokinetic properties of paroxetine may also account for the diverse results for the effects of tramadol compared with paroxetine on IELT.

Single RCT evidence also suggests that tramadol is significantly more effective than sildenafil, lidocaine gel, or behavioural therapy on IELT in men with PE. However, reporting of the methodological quality is limited in terms of concealment of group allocation and blinding of the outcome assessment across all RCTs included by this review.

Various assessment methods in terms of ejaculation control, patient/partners sexual satisfaction, anxiety and other patient-reported outcomes have been used across RCTs to measure the effectiveness of tramadol. Across placebo-controlled RCTs, tramadol was reported as significantly more effective than placebo for various patient-reported outcomes. Pooled evidence across trials (817 participants) suggests that tramadol is associated with significantly more adverse events including: erectile dysfunction, constipation, nausea, headache, somnolence, dry mouth, dizziness, pruritus (itching), and vomiting, than placebo or behavioural therapy over eight to 12 weeks of treatment. Addiction to tramadol by patients treated with tramadol for PE was not assessed in the current evidence base. Likewise, patient acceptability of treatment was not reported. However, one RCT reported 100% follow-up of all patients prescribed 25 mg, 50 mg or 100 mg of tramadol over 24 weeks [ 20]. All participants at all doses (100%) reported somnolence. The trial was considered of unclear methodological quality.

With the exception of one RCT [ 18], all of the included RCTs were conduction in non-EU countries, five being conducted in Middle East and Arab State countries [ 15– 17, 19, 20]. In a population-based stopwatch study, Waldinger et al.[ 26] observed the largest difference in IELT observed between Turkey and participants from the United Kingdom and the United States. Because characteristics of PE may differ culturally, the observations from this review might not be generalizable across men from EU countries.

The risk of bias assessment indicates the majority of RCTs of tramadol in the treatment of PE are of unclear risk of detection bias, mainly due to limited reporting regarding blinding of the outcome assessment. Key aspects of best practice in RCT design to minimise bias include a robust randomisation method, concealment of treatment group allocation, and, where possible, blinding of participants and trial personnel, and blinded outcome assessment; all of which should be clearly stated in the RCT report [ 27].

Although our database search strategy was comprehensive, the possibility of a publication bias cannot be discounted. Insufficient numbers of RCT comparisons were available for any meaningful assessment of funnel plot symmetry to be undertaken. Nonetheless, although the RCTs identified for inclusion were of unclear methodological quality, it could be considered unlikely that any additional unpublished data for the effects of tramadol compared with placebo would contribute significantly to the overall findings of this review.

The RCTs evaluating tramadol identified for inclusion evaluated treatments over four to 12 weeks and none reported a long-term follow-up on efficacy and safety outcomes, including addiction potential. However, more important is a requirement for clearer evaluations of the relationship between treatment-related increases in IELT, ejaculatory control and sexual satisfaction associated with tramadol. Adverse event data suggest that tramadol is associated with a number of adverse events, but that these appear tolerable. However, the long-term use of tramadol for the treatment of PE in terms of a safety profile including addiction potential is unclear from the current evidence base.

The results observed by this review for the effectiveness of tramadol in treatment of PE are comparable with other reviews [ 6– 8]. However, where meta-analyses have previously been undertaken, methodological errors are evident [ 7, 8]. This review has pooled data across RCTs, where appropriate, in a meta-analysis using a mean difference to summarise IELT outcomes and has avoided double-counting of participants in the analysis.

The European Association of Urology 2014 Guidelines on male sexual dysfunction recommend that pharmacological treatment options include ‘on demand’ dapoxetine, daily use of a longer acting selective serotonin reuptake inhibitor (SSRI) [off-label use], daily use of clomipramine (off-label use), ‘on demand’ topical local anaesthetic agents (off-label use) and ‘on demand’ tramadol (off-label use) [ 9]. Given that tramadol has been extensively evaluated against placebo for the treatment of PE in the current evidence base, with limited head-to-head comparisons between tramadol and other treatments (paroxetine, sildenafil and lidocaine gel), further direct comparisons between tramadol and other SSRIs including dapoxetine, other PDE5 inhibitors, and other topical anaesthetics should now be investigated. Whilst the observed increases in IELT were statistically significant in favour of tramadol, it is difficult to quantify how acceptable and meaningful these changes are for men with PE, without being able to evaluate the relationship between IELT, ejaculation control, and sexual satisfaction from the current RCT evidence base for tramadol. The trade-off between IELT and other effectiveness outcomes versus adverse effects and addiction potential should also be further evaluated.

Tramadol appears more effective than placebo or behavioural therapy in the treatment of PE. However, these findings should be interpreted with caution given the observed levels of between-study heterogeneity and the methodological quality of the available evidence.