PDE-5 Inhibitors
McMahon et al. subsequently published a systematic review of the efficacy of PDE-5 inhibitors in the treatment of PE in 2006. They found that 13 of the 14 published studies did not fulfill evidence-based medicine criteria for ideal PE drug trial design (double-blind, placebo-controlled study, differentiation of lifelong and acquired PE subgroups, exclusion or categorization as a separate subgroup men with concurrent ED or other sexual disorders, and consistent and objective physiological measurements or use of sensitive, validated outcome assessment instruments as study endpoints).
The one study that did fulfill these ideal design criteria reported that the treatment with sildenafil failed to increase baseline IELT in men with PE. The authors concluded that there is no convincing evidence to support any role for the use of PDE-5 inhibitors in men with lifelong PE and normal erectile function. They did, however, acknowledge that there is limited evidence for the role of PDE-5 inhibitors either alone or in combination with on-demand or daily SSRI agents for men with PE and concurrent ED.
They proposed that the mechanisms of action in these men include: the ability to maintain an erection after ejaculation, reduction of the erectile refractory period with reliance on a second, subsequent erection which may be better controlled, reduction in performance anxiety with resultant better erections, and/or a decrease in erectile threshold to a diminished level of arousal, facilitating a relatively greater level of arousal to achieve ejaculation threshold.
Selective Serotonin Reuptake Inhibitor (SSRI) Agents
The SSRI class of medications has been used widely to treat PE. Serotonin is active in the nerve synapse, and low levels are known to cause depression. The tricyclic antidepressant (TCA) and SSRI agents were developed for the treatment of depression. While the TCA agents prevent the reuptake of both serotonin and norepinephrine, the SSRI agents are more specific and work by inhibiting the reuptake of serotonin into the presynaptic nerve terminal. These agents thus prolong or promote serotonin’s effects. Therefore, it is not surprising that many patients who were administered SSRI agents, which were developed for the treatment of depression, complained of increased time to reach ejaculation on this therapy.
The ICSD reported that daily paroxetine pro-vides the most robust delay in ejaculation, and delay with daily use of any of these agents is noted by the second week of therapy. Regarding efficacy of on-demand therapy with antidepressants, the ICSD was unable to provide conclusions due to the limited number of studies, insufficient number of patients, and inadequate study designs.
At the time of the publication of the AUA Guideline on the Pharmacological Management of PE document, as well as at this time, there is no pharmacological agent approved by the US Food and Drug Administration (FDA) for the treatment of PE. As is stated in the AUA Guideline, PE can be treated successfully with several different SSRI agents. The off-label use of the SSRI agents, fluoxetine, paroxetine, sertraline, and the TCA agent clomipramine, were noted in the Guideline to have demonstrated enhanced benefit over placebo in the treatment of PE. Other agents, such as nefazodone, citalopram, and fluvoxamine, were reported to be ineffective in treating PE.
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