Relevance of methodological design for the interpretation of efficacy of drug treatment of premature ejaculation: a systematic review and meta-analysis.

Early ejaculation represents a major market, and indeed in 18-65 year olds it represents the predominant sexual dysfunction, affecting at least 20% of men. The global annual market for the treatment of early ejaculation has been estimated at $4 billion (for an analysis of male health care markets click here). However due to the absence of readily available therapeutics fewer than 10% of patients seek treatment for early ejaculation. Successful pharmaceutical development in this field may therefore reap immense rewards. The daily use of some selective serotonin reuptake inhibitors (SSRIs) offers a clinical relevant treatment strategy.

Early ejaculation may be life-long or acquired. In the latter form men have usually had normal ejaculatory functioning. The acquired form may be caused by erectile disorders or urinary infections.

Waldinger et al have suggested that life-long early ejaculation is a neurobiological phenomenon related to decreased central serotonergic neurotransmission, 5-HT2C receptor hyposensitivity and/or 5-HT1A hypersensitivity. Furthermore they postulated that lifelong early ejaculation is not an acquired disorder due to learned behavior, but, instead, belongs to the normal biological variability of the intravaginal ejaculation latency time (IELT) in men, with a possible familial genetic vulnerability.

One particular problem associated with the development of new treatments of early ejaculation is the choice of methodology used to evaluate clinical candidates. This issue must be resolved to optimize future R&D efforts and in an attempt to address this situation, Waldinger et al have recently conducted a meta analysis of previous studies.

The results of this study have been published in the International Journal of Impotence Research. All drug-treatment studies published between 1943 and 2003 were identified and the meta-analysis was conducted on studies using the tricyclic clomipramine and selective serotonin reuptake inhibitor antidepressants for the daily treatment of premature ejaculation.

The meta analysis revealed a rank order of efficacy of paroxetine > sertraline = clomipramine = fluoxetine > placebo. Single-blind and open studies produced greater variability than did double-blind studies. This suggests that the recent trend from double-blind, placebo-controlled clinical trials towards single-blind and open label studies could impede drug development. In addition, the meta-analysis also showed that retrospective assessment by subjective report or the use of a questionnaire during prospective drug treatment studies have led to a significantly higher variability of the percentage increase of the ejaculation time, compared with the prospective use of a stopwatch during each intercourse.

The authors conclude that objective assessment of efficacy, especially through the use of the recently adopted intravaginal ejaculation latency time (IELT), should be the preferred outcome measure. The authors noted however that when used as a measure of efficacy, absolute values of IELT were frequently not reported (either at baseline or after treatment).

In addition IELT cut off values required for inclusion were variable with a majority of studies defining early ejaculators as having a IELT of <1min and other studies setting this value at <3min or even <5 min. Hence to optimize drug development the use of available measures of efficacy should be more stringent.

When only randomized, prospective, double-blind clinical trials employing an objective measure of efficacy were analyzed percentage IELT increases were considerably lower than less rigorously conducted studies. Remarkably, the rank order of efficacy of the SSRIs and clomipramine was generally unaffected by the use of sub-optimal methodologies. This was concluded to reflect the robust pharmacological efficacy of paroxetine. However, in order to improve the development of treatments for early ejaculation the authors argue in favor of adopting randomized, prospective, double-blind clinical trials using IELT as a measure of efficacy. When adopted absolute IELT values should be provided (both at baseline and following treatment); likewise the IELT value required for inclusion should also be stated.

Perhaps with these guidelines implemented, the identification of optimal dose ranges and the development of novel pharmacological strategies will proceed more rapidly allowing the drug development sector to meet the needs of the patient more effectively.

Entry date Wednesday, September 01, 2004

Adapted from Waldinger et al, Int J Impot Res. 2004 Aug;16(4):369-381.