Hypothesis / aims of study
Fecal incontinence, defined as the involuntary discharge of liquid or solid stool, is a prevalent and debilitating condition with limited treatment options. Anal sphincter dysfunction, accompanied by decreased anal pressure, is an important cause of fecal incontinence in women. Therefore, drugs that increase the tone of the anal sphincters constitute potential pharmacological treatments of fecal incontinence. On the other hand, drugs that decrease the anal pressure may contribute to fecal incontinence. While an observational study suggests that selective serotonin reuptake inhibitors (SSRI) are associated with urinary incontinence [1], clinical studies indicate that reboxetine, a noradrenaline reuptake inhibitor (NaRI), increases the urethral pressure and alleviates urinary incontinence symptoms [2,3]. Because the physiology of fecal continence resembles the corresponding urinary continence process, we hypothesized that reboxetine increases and citalopram decreases the anal pressure. This study aimed to evaluate the effect of reboxetine and citalopram on anal opening pressure (AOP) in healthy women.
Study design, materials and methods
We recruited healthy women (age 18–55 years, body mass index 18.5–30 kg/m2) for this single-site, randomized, double-blind, placebo- and active-controlled crossover study. At three clinic visits, the participants received single oral doses of 40 mg citalopram (and reboxetine-matched placebo), 8 mg reboxetine (and citalopram-matched placebo), and two placebos, respectively. We measured AOP at rest and under voluntary contraction (squeeze) using anal acoustic reflectometry at the reported time of peak plasma drug concentrations (tmax). The administration of study drugs was split into two timepoints due to a one-hour difference in reported tmax. The washout period between clinic visits was a minimum of eight days. Randomization of participants to one of six possible treatment sequences was balanced for period, and sequence allocation was concealed to participants, investigators, and outcome assessors. Adverse events were collected at the end of each visit, by phone one day after each visit, and eight days after last visit.
Results
We screened and randomized 24 women and had no dropouts. Compared to placebo, reboxetine increased AOP with 23.4 cmH2O (95% confidence interval [CI] 16.5-30.2, p<0.001) in resting condition and 22.5 cmH2O (95% CI 15.2-29.8, p<0.001) in squeezing condition. Citalopram did not change AOP statistically significantly compared to placebo (resting: 4.2 cmH2O [95% CI -2.7-11.1, p=0.2]; squeezing: 3.0 cmH2O [95% CI -4.3-10.3, p=0.4]) (Figure 1). Adverse drug reactions (ADRs) were more common with reboxetine and citalopram vs. placebo, (nausea: 11% vs. 17% vs. 0%; insomnia: 11% vs. 6% vs. 2%; dizziness: 9% vs. 6% vs. 0%; and headache: 2% vs. 8% vs. 2% of total ADRs). No serious adverse events were reported.
Interpretation of results
This is the first randomized, placebo-controlled study evaluating the effect of reboxetine and citalopram on anal pressure in humans using anal acoustic reflectometry. We found that reboxetine induced a substantial increase in both resting and squeezing AOP, suggesting that reboxetine enhances the tone of both the internal and external anal sphincter. An effect of this magnitude is likely to be clinically relevant for the prevention of fecal incontinence, however, clinical studies in women with fecal incontinence are needed to elucidate the potential role of reboxetine in the management of fecal incontinence. Citalopram did not cause any statistically significant change in AOP, suggesting that SSRI treatment will not influence fecal incontinence pathophysiology.