Phosphodiesterase type 5 (PDE5) inhibitors induce, via nitric oxide mediated intracellular increases of cyclic GMP, smooth muscle relaxation in tissues containing PDE5. The vascular smooth muscle in the male corpus cavernosum have shown the highest abundance of PDE5 [1], however, PDE5 expression has also been reported in other tissues, including vascular smooth muscle in other tissues and the internal anal sphincter (IAS). Hypertonicity of IAS is a key pathophysiological trait in patients with anal fissure and treatment with topical application of the PDE5 inhibitor sildenafil has, therefore, been evaluated in patients suffering from chronic anal fissure. These studies have shown reduction in anal resting pressure and symptom relief [2,3]. However, the effect of PDE5 inhibition on IAS pressure has not been evaluated in a placebo-controlled setting. This study aimed at investigating the effect of the long-acting PDE5 inhibitor tadalafil on anal pressure in healthy women using anal acoustic reflectometry.

For this double-blind, randomized, placebo-controlled crossover study, we recruited healthy female volunteers by advertisement. Participants were randomly assigned to either a single dose of tadalafil (40 mg) or matching placebo at the first visit, and then switched to the opposite treatment at the second visit (50% tadalafil at 1st clinic session). To avoid carry-over effect, the clinic sessions were separated by a washout phase of at least six days. At specified time of peak plasma drug concentration, we assessed anal opening pressure (AOP) under resting and squeezing conditions using anal acoustic reflectometry. Adverse events were collected at the end of each clinic session, and by a phone call six days after the last visit. With a sample size of 24 women we had a power of 99% to detect a 15 cmH2O difference in anal pressure (tadalafil vs. placebo) at a 5% significance level. Endpoints were analysed in multiple regression models with subjects, period, and treatment as covariates (SAS statistical software v. 9.4.6).

From August to December 2021, we screened and included 24 healthy women. The procedures were well tolerated by the participants, and there were no dropouts. Single-dose tadalafil induced a decrease in resting AOP of 12.9 cmH2O (95% confidence interval [CI] 5.0–20.7, p=0.003) compared to placebo. The effect during squeezing condition was not statistically significant (−5.7 cmH2O [95% CI −17.3–6.0, p=0.3]). The participants reported a total of 41 adverse events (36 during tadalafil and 5 during placebo treatment). The most common adverse events were headache (15 related to tadalafil and 3 related to placebo) and flushing (8 related to tadalafil and 0 related to placebo). There were no serious adverse events.

In this double-blind, randomized, placebo-controlled, crossover study in healthy women, single oral dose of tadalafil (40 mg) reduced resting AOP statistically significantly compared to placebo. This finding supports previous studies demonstrating beneficial effect of topical sildenafil in patients with IAS hypertonicity associated with anal fissure. The relatively high incidence of adverse events observed during tadalafil treatment, especially complaints about headache, may reflect the relatively high dose (40 mg) administered to treatment-naive, healthy women. A lower starting dose (e.g. 5 mg) with up-titration over time could likely reduce such side effects.

Single-dose tadalafil reduces anal resting pressure significantly compared to placebo suggesting that oral doses of tadalafil might be beneficial as a pharmacological treatment alternative for patient with chronic anal fissure.

Morelli A, Filippi S, Mancina R, Luconi M, Vignozzi L, Marini M, et al. Androgens Regulate Phosphodiesterase Type 5 Expression and Functional Activity in Corpora Cavernosa. Endocrinology. 2004 May;145(5):2253–63.
Torrabadella L, Berman IR. Manometric Study of Topical Sildenafil (Viagra®) in Patients With Chronic Anal Fissure: Sildenafil Reduces Anal Resting Tone. Dis Colon Rectum. 2004;47(5):6.
Moghimi M, . IG. Topical Sildenafil (Viagra®) in the Treatment of Chronic Anal Fissure: A Randomized Double Blind Controlled Trial. International J of Pharmacology. 2006 Oct;2(6):608–12.

Continence 2S2 (2022) 100370
DOI: 10.1016/j.cont.2022.100370