Long-term Tolerance With Viagra

Wayne J. G. Hellstrom, MD, FACS

Disclosures

August 22, 2003

Question

Is there any evidence that there is tolerance or dependence when Viagra is used over long periods of time?

Response from Wayne J. G. Hellstrom, MD, FACS

Erectile dysfunction (ED) is defined as the inability to attain or maintain an adequate penile erection for satisfactory sexual intercourse.[1] Since the introduction into clinical practice of sildenafil (Viagra; Pfizer Pharmaceutical Corp.; New York, NY), there has been a dramatic change in the treatment algorithm for men with ED. No longer do all men suffering from ED have to resort to the surgical implantation of a penile prosthesis, intracavernosal injections or transurethral insertions of vasoactive agents, or vacuum tumescence devices in order to resume sexual relations. Numerous placebo-controlled clinical ED studies lasting less than 1 year have documented the safety and efficacy of sildenafil in patients with ED of various etiologies.[2]

An unanswered question in regard to long-term sildenafil use is that of tachyphylaxis, a pharmacokinetic process in which tissue responsiveness to a drug diminishes. A corresponding manuscript by El-Galley and colleagues[3] published in 2001 reported that sildenafil produced tachyphylaxis, since 20% of the patients who were followed for 2 years needed increased dosages and 17% discontinued treatment because of the eventual lack of efficacy.

The results of the El-Galley study were largely discounted upon poor follow-up; 50% of the men on sildenafil did not respond to a telephone interview at 2 years' follow-up. In contrast, a 3-year follow-up study in nerve-sparing radical prostatectomy patients (n = 41) revealed that 71% (29/41) were still responding to the same dose of sildenafil.[4] Of the 29% of dropouts, half (6/12) stopped because of return of spontaneous erections, with only 5 of 12 gradually losing efficacy. Hence, most authorities have attributed loss of sildenafil efficacy not to tachyphylaxis, but to progression in organic disease from associated comorbidities and aging.

However, a recent study using cultured rat cavernosal smooth muscle cells demonstrated molecular upregulation of the phosphodiesterase type 5 (PDE-5) enzyme when the cells treated with high doses of sildenafil for at least 7 days.[5] These findings suggest that sildenafil is safe and effective when used at normal clinical doses and recommended dosing frequencies. However, additional clinical research will be needed to evaluate the tachyphylaxis effect in chronic PDE-5 inhibitor use, especially when these agents possess long half-lives.

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