G.A. Fink, R. Macdonald, I.R. Rootx, and T.J. Wilt

Geriatric Research Education and Clinical Center, Department of General Internal Medicine, Center for Chronic Disease Research and Cochran’s Prostate and Urologic Cancer Review Team Coordinating Center, VA Medical Center, Minneapolis, USA.

Experimental medicine allows the reader to draw certain conclusions about the capabilities of a particular drug under given conditions and to identify errors made in the study of its effectiveness. Unfortunately, meta-analyzes and systematic reviews of specialist literature often read about the failed concepts of many studies. The Minneapolis-based authors conducted their own study of the clinical potential of trazodone in the treatment of rectal dysfunction in men. Drawing the attention of readers to the not very high quality of many studies, they put forward their own vision of the reasons for this. In their opinion, trazodone may well be useful for patients with ED (possibly in an increased dosage), as well as for patients with erectile dysfunction of a psychogenic nature.

Research task

Determining the efficacy and safety of trazodone in the treatment of erectile dysfunction (ED) in a meta-analysis.

Methodology

Data Sources: Medline and Cochran Libraries (Jan 1966 – May 2002), bibliographies of retrieved articles and review articles, and conference minutes and abstracts / abstracts. The review included data only for men with ED who took trazodone or a control drug who were randomly assigned to study groups for at least 7 days of the study and who had clinically significant results. In the course of two reviews, research quality was independently assessed and standardized.

These studies were conducted by searching the Medline computer database (from January 1, 1966 to May 31, 2002) using the Cochrane Collaboration Optimally Sensitive Search Strategy [14]. The search strategy included the terms trazodone, antiserotonergic substances, and α-blockers combined with the words impotence and erectile dysfunction, including all subheadings. In addition, we reviewed the recovered study data bibliography and review articles, as well as the AUA national collection abstracts for January 1995 – May 2002 (by manual search). We reviewed the specialized registry of the Cochran Library and the Prostate and Urologic Cancer Group for additional research data. There were no language restrictions.

Selection criteria

We were interested in studies that: (i) included men with ED; (ii) randomized studies; (iii) studies – trazodone / placebo or trazodone / active control drug; (iv) studies lasting at least 7 days; (v) studies evaluating the clinical outcomes of treatment for ED (eg success of sexual attempts and an overall assessment of patient outcomes). For each of the studies, two independent experts assessed the eligibility of including a particular study in our research, and issues related to discrepancies in the assessment of such eligibility were resolved through general discussion.

Evaluation of results

For each study, its characteristics were studied: demographic data of patients, criteria for inclusion and exclusion, patient withdrawal from the study, treatment efficacy and adverse reactions that occur during treatment. This data was extracted from a common database by two independent reviewers in a standard manner. Differences of opinion were resolved through discussion. Previously, we believed that the most clinically reliable criterion for the effectiveness of ED treatment is a successful sex life [15]. This means that “the success of attempts at sexual relations” became the main component in the derivation of the general result of any research devoted to this problem. Secondary research tools: a specific questionnaire on sexual function, overall scores, overall assessments of improved erection, and other patients’ reported “positive response to treatment.” In terms of adverse reactions, we looked at the percentage of men reporting and dropping out of the study. For missing or additional data, we contacted the authors of the works.

Determination of methodological quality

We determined the quality of concealment of arbitrary designation of research sites on the scale developed by Schultz and colleagues [16], defining a score of 1 as the worst and 3 as the best. We also determined whether the subjects themselves and the researchers knew in advance about the planned course of treatment, whether the studies conducted an analysis of the prescribed treatment, as well as the percentage of subjects who dropped out of the studies and did not undergo control (after the study) examination. education.

Statistical analysis

To categorize treatment outcomes, we set the percentage of men who achieved each of the expected outcomes as measured by treatment. To determine efficacy (none of the studies we studied followed the same outcome criteria as the others), we first presented results from individual studies only, without pooling them. Then we brought them into a single pool by comparing the increase in the number of patients with a “positive response to treatment” in trazodone and control groups, calculating the weighted relative benefit increase (RBI) and its 95% CI in a special computer program [17]. Based on adverse reactions and withdrawals from studies, we compared the increase in the number of patients taking trazodone with negative reactions to it with similar indicators in the control groups, thus calculating the “relative risk increase” (RRI) and its 95% CI. We assessed the weighted RBI and RRI using meta-analytic models of voluntary negative reactions, which allow us to discount the heterogeneity of studies.

Clinical decision made: Include in the meta-analysis only those studies in which treatment efficacy was assessed with trazodone monotherapy versus placebo. For all of these studies (except one) [18], results were presented that allowed the meta-analysis to be combined into a single pool. The data obtained were checked for heterogeneity in terms of the level of evidence P <0.10.

Results

Six studies conducted (with 396 male subjects) met the inclusion criteria; they were carried out on different groups of subjects. In terms of volume, these studies were small and short, and in some cases, methodologically weak. Three out of six studies showed an obvious, clinically significant effect of trazodone in the treatment of ED compared with placebo; the differences in results were statistically significant in the two studies. The pooled results showed that trazodone monotherapy was significantly faster than placebo in leading to “positive responses to treatment,” although the difference was not statistically significant here (37% versus 20%; relative increase in benefit: 1.6; 95 % confidence interval (Cl: 0.8-3.3). Subgroup analysis suggested that men with psychogenic ED were more likely to benefit from trazodone than those with mixed or physiological ED. The efficacy of trazodone in the treatment of ED was dose dependent and the best results were achieved with 150-200 mg per day versus 50 mg. Men randomly assigned to the trazodone group were not significantly more likely than the placebo group to drop out of the study for one reason or another (adverse drug reaction or certain side effects), but a wide confidence interval (CI) did not exclude an increase in the risk for patients from these effects that could occur when taking it. Adverse reactions to trazodone included dry mouth (19%), sedation (16%), dizziness (16%) and fatigue (15%).

Output

Trazodone may help men with ED (especially at higher dosages) and men with psychogenic ED. In the future, studies are needed to compare trazodone with placebo and with other antidepressants in terms of their effect on psychogenic ED.

BJU International, 2003.