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European UrologyVolume 61, issue 4, pages e23-e40, April 2012
Tramadol for the Treatment of Premature Ejaculation
Published online 27 September 2011, pages 744 - 745
Refers to article:
A Randomized Double-Blind, Placebo-Controlled Multicenter Study to Evaluate the Efficacy and Safety of Two Doses of the Tramadol Orally Disintegrating Tablet for the Treatment of Premature Ejaculation Within Less Than 2 Minutes
Accepted 18 August 2011
April 2012 (Vol. 61, Issue 4, pages 736 - 743)
In 1887, Gross presumably first described rapid ejaculation in the medical literature . Premature ejaculation (PE) recently received significant attention with the development of dapoxetine, a short-acting selective serotonin-uptake inhibitor, for on-demand treatment of PE .
Epidemiologic, experimental, and clinical studies have been undertaken to better understand the PE condition. The International Society of Sexual Medicine has proposed a new definition for primary lifelong PE, and the European Association of Urology guidelines for the management of PE have been released  and .
PE is highly prevalent; however, the low level of distress associated with PE may partly explain the limited use of dapoxetine in several European countries despite its demonstrated risk-benefit ratio. Moderate efficacy, lack of awareness, and nonreimbursement for dapoxetine may have also contributed to such unexpected low use.
It should be remembered that there is no physiologic deficiency in PE. Each physiologic event involved in ejaculation, including emission and expulsion, is normal in PE . PE clearly differs from a condition like erectile dysfunction, for which a pathophysiologic mechanism—vascular, neural, tissular, or mixed—can often be identified. Apart from the particularly rare case of ante portas ejaculation with possible impaired fertility, the only potential consequence of PE is the dissatisfaction of the couple during sexual intercourse, affecting their quality of sexual life. The condition can sometimes be very bothersome; therefore, there is still a need for new treatments in PE.
Tramadol hydrochloride (HCl) is an opioid analgesic indicated for the treatment of moderate to severe pain, like codeine. It was developed in the late 1970s. Tramadol has been also reported as effective in restless legs syndrome and fibromyalgia. Tramadol is a centrally acting analgesic with a unique mechanism of action that involves both μ-opioid receptor binding and norepinephrine and serotonin reuptake inhibition. This mechanism of action distinguishes tramadol from other opioids, including morphine. However, the US Food and Drug Administration released in May 2009 a warning letter regarding an addictive potential of tramadol and the possibility of difficulty breathing. The most commonly available dose of tramadol is the 50-mg generic tablet made by several manufacturers. Tramadol is also available in a combined formulation of 37.5-mg tramadol and 325-mg paracetamol.
In this issue of European Urology, Bar-Or et al. present a randomized, double-blind, placebo-controlled, multicenter, 12-wk study evaluating the efficacy and safety of two doses of tramadol (62 and 89 mg) orally disintegrating tablet (ODT) for the treatment of PE in patients with an intravaginal ejaculation latency time (IELT) of <2 min . A bioequivalence study was previously performed that demonstrated equivalence between tramadol ODT and tramadol HCl, as communicated by the authors. Because tramadol has an unpleasant mildly bitter taste, the tramadol ODT preparation has been formulated to taste like a mint and to dissolve in the mouth without the use of water.
In patients with an history of lifelong PE and an IELT ≤120 s, increases of the median IELT of 0.6 min (1.6-fold), 1.2 min (2.4-fold), and 1.5 min (2.5-fold) were reported for placebo, 62-mg tramadol ODT, and 89-mg tramadol ODT, respectively. It should be noted that there was no dose-response effect with tramadol. The tolerability during the 12-wk study period was acceptable for the concerned condition.
Overall, tramadol has shown a moderate beneficial effect similar to that of dapoxetine . The tramadol data, however, are from an insufficiently powered combined analysis of two terminated clinical trials. Efficacy and tolerability of tramadol would have to be further confirmed in more patients and over a longer term.
Three comments should be made on this interesting clinical trial:
- • The mechanism of action by which tramadol delays ejaculation needs to be elucidated. This would be an exciting opportunity to increase our knowledge about the physiology and the pharmacology of ejaculation in humans.
- • Because tramadol HCl is widely available as a generic drug for the treatment of pain, it would be advisable to also assess its efficacy as an on-demand treatment for PE. Tramadol HCl is expected to be an effective treatment option for males complaining of PE, especially in the countries where dapoxetine is not available.
- • Because of the delaying effect of tramadol on ejaculation, patients treated with tramadol and complaining of delayed ejaculation should be informed that interruption of tramadol may improve their sexual function. I do have at least one patient per week in my practice for whom this recommendation works.
Conflicts of interest
The author has nothing to disclose.
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-  C.G. McMahon, S.E. Althof, M.D. Waldinger, et al. An evidence-based definition of lifelong premature ejaculation: report of the International Society for Sexual Medicine (ISSM) ad hoc committee for the definition of premature ejaculation. J Sex Med. 2008;5:1590-1606 Crossref.
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-  D. Bar-Or, K.M. Salottolo, A. Orlando, J.V. Winkler, for the Tramadol ODT Study Group. A randomized double-blind, placebo-controlled multicenter study to evaluate the efficacy and safety of two doses of the tramadol orally disintegrating tablet for the treatment of premature ejaculation within less than 2 minutes. Eur Urol. 2012;61:736-743 Abstract, Full-text, PDF, Crossref.
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Raymond Poincaré Hospital, Université de Versailles St-Quentin-en-Yveline, Garches, France
© 2011 European Association of Urology, Published by Elsevier B.V.
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