Phosphodiesterase Type 5 Inhibitor Tadalafil Reduces Resting Anal Opening Pressure in Healthy Women: a Randomized, Double-blind, Placebo-controlled Trial

doi:10.21203/rs.3.rs-4328759/v1

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Phosphodiesterase Type 5 Inhibitor Tadalafil Reduces Resting Anal Opening Pressure in Healthy Women: a Randomized, Double-blind, Placebo-controlled Trial

https://doi.org/10.21203/rs.3.rs-4328759/v1

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Purpose

Existing first-line treatments for chronic anal fissures aim to reduce internal anal sphincter pressure and increase healing rates. However, availability and side effects challenge the use of these treatment strategies. Phosphodiesterase inhibitors, known for their smooth muscle relaxant properties, have been proposed as alternative treatment candidates. This trial assessed the effect of the long-acting phosphodiesterase inhibitor, tadalafil, on anal opening pressure in healthy women.

Methods

Twenty-four healthy female volunteers participated in this randomized, placebo-controlled crossover trial. Participants were randomized to receive a single oral dose of 40 mg tadalafil or placebo at their first visit and the opposite treatment at their second visit. Two hours post-administration, coinciding with the time of peak plasma concentration for tadalafil, anal opening pressure was measured using anal acoustic reflectometry during rest and voluntary squeezes.

Results

Tadalafil reduced resting anal opening pressure with 12.9 (95% CI 5.0 to 20.9, p = 0.003) cmH₂O compared with placebo. A minor, statistically insignificant reduction in pressure was observed during squeeze (5.7 95% CI − 6.0 to 17.3 cmH₂O, p = 0.3). The most common adverse events were headaches, with 15 reports during tadalafil treatment and 3 with placebo.

Conclusion

Single-dose tadalafil moderately decreased resting anal opening pressure in healthy female volunteers, supporting its potential therapeutic role in managing chronic anal fissures. Further studies are needed to determine the dose-response relationship, therapeutic efficacy, and risk-benefit profile of tadalafil for this application.

Phosphodiesterase inhibitors

Tadalafil

Anal pressure

Chronic anal fissure

Anal Acoustic Reflectometry

Chronic anal fissure is a common, painful condition characterized by a longitudinal split in the anoderm of the distal anal canal [1]. The exact pathogenesis of chronic anal fissures is not fully understood. Nevertheless, the association between chronic anal fissures and hypertonicity of the internal anal sphincter (IAS) has long been recognized [2–4]. The prevailing theory suggests that this hypertonicity of IAS leads to an elevated resting sphincter pressure, which, in turn, impairs the perfusion of the anoderm. Subsequent ischemia potentially contributes to both the development of the fissure and its slow healing process [5, 6]. In keeping with this understanding, treatment of chronic anal fissures aims to relieve pain and improve the healing of the fissure by reducing the hypertonicity of the IAS. The primary surgical management, the lateral internal sphincterotomy, decreases anal resting pressure, relieves pain and promotes healing. Although effective, a considerable risk of complications, notably permanent flatus incontinence, compromises this approach. Botulinum toxin injections also lower anal pressure effectively and improve healing of chronic anal fissures by paralyzing the IAS temporarily [7, 8]. However, this intervention also has drawbacks, particularly the necessity of repeated injections, the risk of temporary incontinence, and a relatively high recurrence rate. Therefore, pharmacological approaches to reduce anal sphincter pressures have replaced the invasive interventions as first-line treatment. Glyceryl trinitrate ointment and a topical preparation of diltiazem, a calcium channel blocker, have both been shown to reduce anal resting pressure and improve healing rates and currently constitute the first-line non-invasive treatment [9, 10]. However, a high rate of side effects associated with glycerol trinitrate treatment, particularly headache, coupled with the lack of a commercially available topical diltiazem formulation, challenge the use of these treatment strategies.

Phosphodiesterase type 5 (PDE5) inhibitors have been proposed as an alternative treatment approach for chronic anal fissures due to their smooth muscle relaxant properties. PDE5 plays a central role in the physiological regulation of vascular and visceral smooth muscle contractility. By inhibiting the PDE5 enzymes, PDE5 inhibitors augment the nitric-oxid-initiated smooth muscle relaxation. Accordingly, it has been demonstrated that the PDE5 inhibitor sildenafil relaxes the tone of isolated IAS tissue in vitro [11, 12]. Moreover, findings from small-scale clinical studies suggest that an experimental topical sildenafil formulation lowers the anal resting pressure and promotes the healing of chronic anal fissures [13, 14]. However, the effect of PDE5 inhibition on anal resting pressure has not been investigated in a placebo-controlled setting. Further, it remains unknown whether a reduction in anal resting pressure can be achieved with oral administration of a PDE5 inhibitor.

In the current trial, we evaluated the effect of a single oral dose of the long-acting PDE5 inhibitor tadalafil on anal opening pressure in healthy female volunteers.

Trial oversight

In this trial, we investigated the effect of a single oral 40 mg dose of tadalafil on urethral and anal pressure in healthy women. We have published the results from the urethral outcomes and a detailed description of the trial design and methodology elsewhere [15]. The trial protocol was approved by the Danish Medicines Agency (EudraCT number 2020-005839-76) and the Regional Ethics Committee (H-2100186) and registered at www.ClinicalTrials.gov (ID NCT05095077). We obtained written informed consent from all participants, and the Good Clinical Practice Unit of the Copenhagen University Hospital monitored the trial.

Trial design and participants

The trial was an investigator-initiated, randomized, double-blind, placebo-controlled crossover trial. In brief, we enrolled healthy female participants and randomly assigned them (in a 1:1 ratio) to one of two treatment sequences (either tadalafil followed by placebo or placebo followed by tadalafil). The participants had consecutive randomization numbers, which specified the random treatment sequence. We conducted the trial over two trial visits, separated by a minimum of 6 days’ washout period, corresponding to approximately eight half-lives of tadalafil [16].

At each trial visit, the participants received either a single 40 mg dose of tadalafil or a visually matching placebo. After two hour's rest at the clinic, which aligns with the mean time to peak plasma concentration for tadalafil [16], we measured the urethral and anal pressure using urethral pressure reflectometry (UPR) and anal acoustic reflectometry (AAR).

Outcome measures

The resting anal opening pressure (AOP) measured two hours after study drug administration (tadalafil vs placebo) was the primary outcome for the anal assessments. The corresponding measure during voluntary contractions (squeeze) was a secondary outcome.

The method for measuring the AOP using AAR has been described in detail in previous papers [17, 18]. In short, the AAR technique involves the use of sound waves to continuously measure the pressure and cross-sectional areas of the anal canal using an ultra-thin and flexible polyurethane bag. The participant lies in supine position, and the polyurethane bag is gently inserted into the anal canal. The bag is then gradually inflated with air, increasing the pressure from 0 to 200 cmH₂O over 7 seconds, before being reduced back to 0. This process enables the evaluation of the pressure required for opening and closing the anal canal. During rest, ten measurements of AOP are obtained, while five are obtained during voluntary contractions (squeeze).

Adverse events were recorded during the trial visits and at a follow-up phone call six days after the last visit. Trial data were collected and managed using REDCap (Research Electronic Data Capture), a platform operated by the Capital Region of Denmark [19, 20].

Sample size and statistical analysis

The sample size was calculated based on previous single-dose pharmacodynamic UPR and AAR trials [15, 21]. Assuming the mean within-subject standard deviation (SD) was 16.4 cmH₂O and using a two-tailed alpha of 0.05, a total of 24 participants would provide a power of 85% to detect a difference of 15 cmH₂O in AOP.

We conducted all data management and statistical analyses while blinded to the sequence allocation of the participants. The differences in AOP (tadalafil vs placebo) were analyzed using analysis of covariance (ANCOVA) models with participant number, treatment (tadalafil and placebo), and period fitted as fixed effects. These tests provide mean effect estimates, 95% confidence intervals (CIs), and p-values. We performed the analyses using SAS software, version 7.15 of the SAS system for Windows (SAS Institute Inc., Cary, NA, USA), and created visual illustrations using GraphPad Prism version 10.1.2 for Windows (GraphPad Software, San Diego, CA, USA).

Between August 8, 2021, and January 10, 2022, 24 healthy female volunteers were screened and included in the trial. All 24 participants completed the protocol. Compared with placebo, a single dose of 40 mg tadalafil reduced mean resting AOP by 12.9 (− 12.9 95% CI − 20.7 to − 5.0, p = 0.003) cmH₂O and squeezing AOP by 5.7 (− 5.7 95% CI − 17.3 to 6.0, p = 0.3) cmH₂O; Fig. 1.

In total, 41 adverse events (AEs) were reported during the trial visits and at follow-up (36 during tadalafil treatment and 5 during placebo). All AEs were managed by a blinded investigator. Headache and flushing were the most frequently reported AEs; Table 1.

Table 1

Adverse events
	Tadalafil (n = 24)	Placebo (n = 24)
Headache	15	3
Flushing	8	-
Fatigue	2	1
Dizziness	2	1
Nasal congestion	2	-
Nausea	1	-
Migraine	1	-
Back pain	1	-
Photophobia	1	-
Eye swelling	1	-
Ear congestion	1	-
Genital swelling	1	-
Total	36	5
Footnote:
In total, 18 out of 24 participants reported at least one adverse event following an oral 40-mg dose of tadalafil.

In this randomized, double-blind, placebo-controlled crossover trial, we investigated the effect of a 40 mg oral dose of tadalafil on AOP in 24 healthy female volunteers. This is, to the best of our knowledge, the first study to assess the impact of an orally administered long-acting PDE5 inhibitor on anal sphincter tone. Our findings revealed a 12.9 (95% CI 5.0 to 20.9) cmH₂O reduction in the resting AOP of the anal sphincter after administering tadalafil compared with placebo. While we also observed a minor reduction (5.7 95% CI − 6.0 to 17.6 cmH₂O) in AOP during voluntary sphincter contractions, this reduction was not statistically significant. The observation that tadalafil has a more marked effect during rest indicates that it primarily affects the smooth muscle of the IAS rather than the striated external anal sphincter. This supports prior in vitro findings that PDE inhibitors exert a relaxant effect on IAS smooth muscle [22].

These outcomes also align with a previous manometric study exploring the effect of a topical formulation of the PDE5 inhibitor sildenafil on anal pressure. In this study involving 19 patients with chronic anal fissures, Torrabadella et al. found a 21.5 (± 13 [variability measure not defined]) cmH₂O reduction in maximum resting pressure of the anal canal after applying 75 mg sildenafil topically when compared with baseline pressure [13]. Although a considerable risk of bias compromises this finding due to the open-label, uncontrolled study design, this suggests, along with previous preclinical [9, 10] and our present clinical results, that PDE5 inhibitor administration induces relaxation of IAS tone. A single study has evaluated the clinical efficacy of topical sildenafil in 61 patients with chronic anal fissures. In this study, the self-reported healing rate after nine days of treatment with topical sildenafil formulation (equivalent to 75 mg sildenafil) was reported to be 100% in the topical sildenafil group (n = 31) compared with 0% in the placebo group (n = 30). However, the findings should be interpreted with caution due to the high risk of bias associated with critical methodological issues, including—but not restricted to—the lack of objective evaluation of anal fissure healing and a 100% loss to follow-up in the control group. Thus, the clinical efficacy of PDE5 inhibitor administration in treating chronic anal fissures remains uncertain.

Although rigorous clinical studies assessing the effect of phosphodiesterase inhibitors in the treatment of chronic anal fissures are lacking, the link between a pharmacological-induced reduction in anal resting pressure and improved healing of chronic anal fissures has been established. Lund et al. investigated the effect of 0.2% glycerol trinitrate ointment vs. placebo twice daily on healing rate, pain score, maximum anal resting pressure, and anodermal blood flow in patients (n = 80, 42 women) with chronic anal fissures. They reported healing of the fissure in 68% of the patients in the active group after eight weeks of treatment as opposed to 8% in the placebo group. This improved healing rate in the active group was accompanied by a reduction in maximum anal resting pressure from a mean (SD) pretreatment value of 115.9 (31.6) cmH₂O to 75.9 (30.1) cmH₂O after the first application of the ointment (p < 0.001, Student's paired t-test) in the active group [23]. Several other studies also have reported enhanced healing outcomes in chronic anal fissures associated with variable reductions in anal resting pressure [24–26]. Similarly, both topical and oral diltiazem have been shown to reduce anal resting pressure (compared with baseline) in healthy volunteers [27], and both decrease anal resting pressure and improve healing in patients with chronic anal fissures [28].

Various methodological differences across the studies challenge a direct comparison of the effectiveness of topical glycerol trinitrate and diltiazem with oral tadalafil in reducing anal pressure. First, the measurement techniques vary. Whereas the studies investigating topical glycerol trinitrate and diltiazem use different anorectal manometry systems, we assessed the anal pressure using the AAR technique. The range of different fixed-diameter catheters and various pull-through protocols used in anorectal manometry studies contribute to considerable variation in results. In contrast, AAR, considered a catheter-free technique, has been shown to have increased sensitivity and reproducibility compared with manometry [29]. Further, the study population and study design differ across the studies. In the present trial, oral tadalafil was evaluated against placebo in healthy female volunteers with no anorectal disease. The effect of topical glycerol trinitrate and diltiazem have been assessed in both healthy volunteers [27, 30] and in patients with chronic anal fissures [23–26, 28]. Although topical glycerol trinitrate and diltiazem appear to decrease anal resting pressure compared to baseline measurements in both populations, these analyses have not been adjusted for placebo, compromising the comparability. Taken together, the observed PDE5 inhibitor-induced reduction in anal resting pressure suggests that it may have a similar effect in treating chronic anal fissures as topical glycerol trinitrate and diltiazem. However, the dose-response characteristics and therapeutic efficacy of tadalafil remain to be determined.

A potential advantage of tadalafil over topical trinitrate and diltiazem might be its oral formulation and prolonged half-life, which allows for once-daily oral administration. Compared with topical application of an ointment to the skin of the anal canal suffering from a painful anal fissure, oral administration might be preferred by the patients. However, the potential side effects of tadalafil must also be considered carefully and weighed against the risk-benefit profile of existing therapies. Generally, tadalafil has proven safe and tolerable for long-term treatment [31]. In the present trial, the adverse effect profile of tadalafil resembles that of longer-term clinical trials [31, 32]. However, headaches were more frequently reported in this trial, possibly because we administered a single high dose (40 mg) of tadalafil to treatment-naïve women. Meanwhile, previous longer-term trials up-titrated the dose of tadalafil over a longer timeframe [31, 33]. In these trials, headaches were reported by approximately 15% of individuals receiving 20 mg tadalafil, which is comparable to the rate of headaches during glycerol trinitrate treatment (overall rate of 16%), but higher than the rate of headache during diltiazem treatment (4.5%) [1].

This randomized, double-blind, placebo-controlled crossover trial examined the effects of a single 40 mg oral dose of tadalafil on AOP in 24 healthy female volunteers. We observed a moderate decrease in resting AOP following tadalafil administration, adding to the evidence supporting the therapeutic potential of PDE5 inhibitors in the management of chronic anal fissures. Further research is required to determine the dose-response relationship, the therapeutic efficacy, and the risk-benefit profile of tadalafil in this regard.

Compliance with Ethical Standards

Ethical approval was obtained from the Regional Ethics Committee (H-2100186) on February 25, 2021, and approval from the Danish Medicines Agency on February 15, 2021. The trial was registered on www.ClinicalTrials.gov (ID NCT05095077) on August 26, 2021. We obtained written informed consent from all participants.

Conflicts of Interests

The authors declare no competing interests.

Funding

This trial was supported by Helsefonden (Grant Number 21-B-0489), Aage og Johanne Louis-Hansen Foundation (Grant Number 21-2B-9735), Aase og Ejnar Danielsens Foundation (Grant Number 21-10-0210), and the clinical departments.

Author Contribution

All authors contributed to the conception and design of the study. Funding was acquired by Thea Christoffersen, David P. Sonne, and Niels Klarskov. Investigations were performed by Thea Christoffersen, Troels Riis, and Niels Klarskov. Thea Christoffersen, David P. Sonne, and Niels Klarskov analyzed the data. The first draft of the manuscript was prepared by Thea Christoffersen, and all authors commented on previous versions of the manuscripts. All authors reviewed and approved the final manuscript.

Data Availability

The data that support the findings of this study are not openly available due to reasons of sensitivity and are available from the corresponding author upon reasonable request. Data are located in controlled access data storage at Copenhagen University Hospital.

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No competing interests reported.

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Phosphodiesterase Type 5 Inhibitor Tadalafil Reduces Resting Anal Opening Pressure in Healthy Women: a Randomized, Double-blind, Placebo-controlled Trial

Status:

Version 1

Abstract

Purpose

Methods

Results

Conclusion

INTRODUCTION

MATERIALS AND METHODS

Trial oversight

Trial design and participants

Outcome measures

Sample size and statistical analysis

RESULTS

DISCUSSION

CONCLUSION

STATEMENTS AND DECLARATIONS

Compliance with Ethical Standards

Conflicts of Interests

Funding

Author Contribution

Data Availability

REFERENCES

Additional Declarations

Status:

Version 1