Safety and Efficacy of Sildenafil Citrate for the Treatment of Female Sexual Arousal Disorder: A Double-Blind, Placebo Controlled Study

Among women who received treatment according to protocol, 3 women in the placebo group and 1 in the sildenafil group developed intermittent Hamilton depression scores of between 10 and 15. These were self-limited, transient, symptomatic changes distinguished from major depressive disorder relapse and not considered clinically meaningful to warrant intervention.

• Doctors may prescribe sildenafil off-label for women based on individual assessment.
• Patient education about realistic expectations is essential when using sildenafil.
• Sildenafil’s mechanism involves enhancing nitric oxide signaling in blood vessels.
• Women with liver or kidney problems need careful evaluation before sildenafil use.
• Viagra was initially tested for women before focusing on men’s erectile issues.
• Alternative options like vaginal lubricants are also common for female sexual problems.

No recurrence or relapse of major depressive disorder occurred in any of the women continuing a stable dose of antidepressants during the trial (Table 2).

• Some studies suggest sildenafil might help women with sexual arousal disorder.
• The drug's vasodilating effects can have cardiovascular implications in women.
• Women should be cautious of counterfeit or unapproved sildenafil products.
• Combining sildenafil with other ED drugs in women is not recommended without medical advice.
• Psychological support remains an important aspect of treating female sexual dysfunction.
• Ongoing clinical trials aim to establish the safety and efficacy of sildenafil for women.

Mean (SD) baseline values for all endocrine values were within the normal range without significant differences between groups (Table 3).

Independent of treatment assignment, a comparison of women whose sexual function improved with those whose sexual function did not improve showed higher mean baseline levels of free testosterone (P ≤ .01) and thyroxine (P ≤ .01) among SRI-associated sexual dysfunction treatment responders. At study end, 76.9% (30 of 39) of women took a mean (SD) dose of 91.7 (19.8) mg of sildenafil and 86.5% (32 of 37) took 93.1 (17.5) mg of placebo. The maximum dose for the study was 100 mg.

The mean (SD) number of doses per 2-week interval was 5.0 (2.5) mg for sildenafil and 5.2 (2.5) for placebo, which supports the notion that the lack of efficacy in placebo patients was not due to a lack of attempts (P = .67).

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The F test of the overall hypothesis test was first conducted before multiple comparisons analyses. Sample-size calculations were based on detecting a difference in full response rates at 8 weeks, assuming a response rate of 70% for sildenafil and 35% for placebo. Thus, a sample size of 82 evaluable patients (41 per group) was expected to detect a significant difference with 90% power for a type I error rate of α = .05 between sildenafil and placebo (2-sided). Assuming 20% attrition, 100 patients were planned to be randomized and 98 patients were entered. The sample size determination assumed no interactions of treatment with site or antidepressant.

Vyleesi (Bremalontide)

The primary analysis was according to assignment at randomization. In addition to determination of this narrow measure of efficacy based on all randomized patients and imputing the worst rank scores for early exclusions due to protocol violations before and without taking the trial drug, there was a general efficacy analysis for all protocol-treated patients and all trial completers. Adjusted means (SDs) were determined and reported. Where applicable, 95% confidence intervals (CIs) are provided. Analyses were performed with SAS version 9.1.3 (SAS Institute Inc, Cary, North Carolina). The most common adverse event was headache, reported by 43% of women taking sildenafil and 27% taking placebo (P = .09).

Less frequent were flushing, 24% vs 0% (P<.001); dyspepsia, 12% vs 0% (P = .01); nasal congestion, 37% vs 6% (P<.001); and transient visual disturbances, 14% vs 2% (P = .03), respectively.

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One hundred women (Figure) of the 145 screened met eligibility requirements. Among the most frequent causes for exclusion were ineligible protocol criteria (ie, lack of acceptable and verifiable form of contraception, perimenopausal with irregular cycles or amenorrhea, non-SRI sexual dysfunction augmentation, switching antidepressant agent, other treatments for sexual dysfunction), and other miscellaneous reasons (partner issues, abnormal Papanicolaou test results, medical comorbidity, excessive alcohol use, or relationship or partner problems). Two eligible participants were withdrawn after they sildenafil citrate 120 mg were screened but before they were randomized. One patient had a change in antidepressant dose made by her primary care physician. The other patient withdrew due to her partner's serious injuries.

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The 2 nonrandomized and untreated women did not differ on any demographic characteristics from those who entered the trial and were not included in the analyses. A total of 98 women were randomly assigned to receive active sildenafil (n = 49) or placebo (n = 49). The mean (SD) age of the women was 36.7 (7.1) years. They had been taking antidepressant medication for 27.7 (34.6) months. Distribution of prescribed antidepressants was comparable between groups. Adverse events more common in the placebo group than in the sildenafil group were nausea 16% vs 2% (P = .01) and anxiousness 6% vs 2% (P = .31).

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Independent samples t tests compared baseline patient characteristics and Clinical Global Impression sexual function scores between the study groups at end point. The χ2 analyses were used to evaluate group differences in categorical measures. Analyses were based on intent-to-treat with the last-observation-carried-forward analyses performed on all variables and included data from all protocol-treated patients. All randomized patients received and took at least 1 dose of study trial medication, had at least 1 efficacy assessment, and were included regardless of protocol deviations or whether they completed the study. The final analysis included women who completed the trial, but for the women who did not complete the trial, their baseline value was carried forward in separate analyses.

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The change in sexual functioning by Clinical Global Impression sexual function score and all other questionnaires from baseline to each patient's own end point were the dependent measures of efficacy. A repeated measures analysis of variance was used to determine differences between placebo and sildenafil in the change from baseline to end point for the measures of efficacy and depression severity (time × group interaction). In addition, exact nonparametric methods were applied to the efficacy measures to substantiate results that rely on distributional assumptions. Findings were also confirmed with analysis of covariance and Wilcoxon rank sum tests for primary analyses. All statistical tests were 2-sided, and all hypotheses were evaluated at the 5% significance level. No serious adverse events related to trial medication were reported (Table 4).

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There were no statistically significant differences between treatment groups in number or type of sexual problems or in number or percentage success of sexual attempts at baseline (Table 1). The difference from baseline to end point in the mean (SD) change in the Clinical Global Impression scale sexual function improvement by intent-to-treat last-observation-carried-forward analyses (ie, lower ordinal score) was 4.8 (0.7) to 2.8 (1.0) with a difference of 1.91 (95% CI, 1.57-2.26) for the sildenafil group vs 4.7 (0.9) to 3.6 (0.9) with a difference of 1.10 (95% CI, 0.75-1.46) for the placebo group, which sildenafil citrates showed a significant difference of 0.8 (95% CI, 0.6-1.0, P = .001) between groups (Table 2). To adjust for potential bias introduced by patients who prematurely discontinued, a more conservative intent-to-treat analysis assigning return-to-baseline values carried forward of those who did not complete the study showed a baseline-to-end point mean difference in the Clinical Global Impression scores of 1.5 (95% CI, 1.1-1.9) among women taking sildenafil vs 0.9 (95% CI, 0.6-1.3) for women taking placebo and a significant 0.6 (95% CI, 0.3-0.8) mean change difference between groups (P = .03). Clinically, 73% of women taking placebo compared with 28% of women taking sildenafil reported no improvement with treatment (Clinical Global Impression score >3 was rated as no improvement). Sexual Function Questionnaires.Table 2 shows the mean (SD) scores on the secondary outcome measures from baseline to study end for both treatment groups.

Exclusion Criteria

In comparing the baseline sexual function questionnaire domain scores with those at the end of the study, women in the sildenafil group had a higher mean (SD) improvement (orgasm, P=.01) than women taking placebo for all domains except for pain. In the Arizona and the University of New Mexico questionnaires, the ability to reach orgasm and experience orgasm satisfaction was significantly better for those in the sildenafil group than for those in the placebo group for a mean difference from baseline of 0.5 (95% CI, 0.1-1.0; P = .01) for reaching orgasm for the Arizona questionnaire and 0.7 (95% CI, 0.1-1.3; P = .01) for the New Mexico questionnaire. In measuring depression, at baseline, women in both groups had nearly identical Hamilton scores. At the end of the study, their scores remained similar (P=.90) indicating persisting remission in depression. The difference in change scores between treatment groups did not achieve statistical significance (P = .86). To our knowledge, this is the first randomized trial to demonstrate a significant reduction in adverse sexual effects, measured by the Clinical Global Impression sexual function, that compared sildenafil with placebo among women with SRI-associated sexual dysfunction, specifically including delayed orgasm responses and inadequate lubrication, while continuing stable-dose antidepressant treatment.

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There were no statistically significant differences between baseline demographics in the assigned treatment groups (Table 1). Systematic review for any protocol deviations in patient enrollment was undertaken before unbinding. The 98 randomized women constituted the last-observation-carried-forward analysis. Seventy-six women (77.6%) completed the study: with 75.5% (37 of 49) in the placebo group and 79.6% (39 of 49) in the sildenafil citrate drug sildenafil group and constituted the completer population. Nine women in the placebo group and 4 in the sildenafil group discontinued prematurely for lack of efficacy.

A note about sex and gender

The other 6 in sildenafil and 3 in the placebo groups were lost to follow-up. No discontinuations for intolerable or serious adverse events were reported (Figure). As determined by the inclusion criteria, the prevalence of sexual problems was high and the mean (SD) number of problems reported was 3.0 (0.7) for the sildenafil group and 2.8 (0.7) the placebo group (P = .21), with 95.8% of women reporting more than 1 complaint. They reported disturbances in desire (87.8%), subjective arousal (80.6%), lubrication (79.6%), orgasm delay (98.7%), and other difficulties (23.6%), which included anorgasmia, lack of pleasure, and pain. Prior to study entry, the women self-reported a mean (SD) of 6.0 (5.2) sexual attempts per month, of which 1.4 (2.0), or 29.6% (34.9%), were considered successful.