REV ARGENT COLOPROCT | 2021 | VOL.

32, N° 1: 11-15 ORIGINAL ARTICLE

DOI: 10.46768/racp.v32i01.16

Efficacy of the Use of Topical Tadalafil in The Treatment

of Anal Fissure. Results of a Cooperative Study
Hugo A. Amarillo,1 Eduardo J. Vaccarezza,2 Paula Casares,1 Luis Montilla1
1
Sanatorio Modelo Tucumán. San Miguel de Tucumán, Argentina.
2
Centro Médico Alberti. Buenos Aires, Argentina.

ABSTRACT
Introduction: The medical treatment of chronic anal fissure has multiple options. Tadalafil was hardly analyzed in the literature
as a therapeutic option.
Objective: To evaluate the safety and effectiveness of the use of topical Tadalafil for the medical treatment of anal fissure.
Design: Observational non-randomized prospective study.
Patients and methods: Patients with chronic anal fissure lasting more than 8 weeks treated with Tadalafil during the 2011-
2018 period were analyzed. Those who did not complete treatment were excluded. Cure rate, adverse effects, treatment time
and its relationship with response were recorded.
Setting: Two private medical institutions.
Results: Eighty-six patients, 53 men (61%), 77 of them older than 55 years, were analized. Cure was achieved by 82.5%
of patients, 11.6% underwent surgery, and the remaining patients continue chronic medical treatment with a good clinical
response. Seventy-two percent of patients had 2 months of treatment (p = 0.002); 7 patients, 3 months; 12, between 3 and
6 months; and 5, more than 6 months. Sixty-four percent of patients did not present previous anal pathology and the rest
did not modify their results despite the association. No adverse was presented in 95% of patients and those reported (rush,
thrombosis, light bleeding) were mild.
Conclusion: Treatment with Tadalafil has a high cure rate and symptomatic resolution with almost no side effects. In failure
cases surgery resolved the condition. The performance of other comparative studies with other pharmacological methods
and/ or surgical treatment could affirm these results.

Keywords: Anal fissure; Tadalafil; Sphincterotomy; Nitrites

INTRODUCTION the smooth muscle cell, and its inhibition by Tadala-

fil translates into the persistence of high levels of cyclic
Anal fissure is one of the most frequent condition in the GMP with the consequent relaxation of the anal sphinc-
proctological consultation and despite the fact that the- ter. Additionally, in an optimal state of functioning, the
re is sufficient evidence and numerous therapeutic pos- smooth muscle cell is capable of synthesizing type III co-
sibilities, treatment is still challenging, in some cases llagen, proteoglycans and elastin that promote healing.6
controversial and refractory in a considerable number of The objective of this study was to assess the safety
patients.1,2 and effectiveness of the use of topical Tadalafil for the
Anal fissure is a painful lesion that presents as an ulcera- treatment of anal fissure.
tion, usually located in the posterior anal canal. It is acute
when does not extend beyond 6 to 8 weeks. After this pe- MATERIAL AND METHODS
riod, it is considered chronic, associated with the persis-
tence of symptoms and physical findings of hypertrophic All patients who spontaneously attended the outpatient
papilla, sentinel hemorrhoids, and visualization of the in- clinic of two private medical institutions (one university)
ternal anal sphincter (fissure syndrome).3,4 between July 2011 and July 2019 and had anal fissure evi-
Given the possible disability associated with surgery, the dent on physical examination, and symptoms duration ≥ 8
immediate future with the consequent risk of continen- weeks were prospectively registered.
ce disturbances, new medical treatment alternatives are Patients with previous medical or surgical treatment or
being considered.2-5 The use of Tadalafil, a potent selecti- associated anal pathologies were not considered as exclu-
ve phosphodiesterase inhibitor, is recent and has not been sion criteria. Patients who could not or did not comple-
sufficiently studied as a therapeutic option to heal anal te treatment for reasons not related to treatment were ex-
fissures. There is no national history with this treatment. cluded.
It has been shown in vitro that phosphodiesterase 5 is Patients who met the selection criteria were consecuti-
responsible for the degradation of cyclic GMP within vely included in a spreadsheet database (Microsoft Ex-
cel®) registering age, gender, previous surgery, length of
Hugo Amarillo
[email protected]
treatment, treatment results, adverse effects of the drug
Received: May 2020. Approved: September 2020 and associated complications.
The authors declare the absence of conflicts of interest The definition of variables was as follows:

Hugo A. Amarillo - https://orcid.org/0000-0001-9824-2531; Eduardo J. Vaccarezza - https://orcid.org/0000-0001-5314-505X; Paula Casares - https://orcid.org/0000-0002-3542- 11

0844; Luis Montilla - https://orcid.org/0000-0001-7637-8876
 REV ARGENT COLOPROCT | 2021 | VOL. 32, N° 1: 11-15 ORIGINAL ARTICLE
DOI: 10.46768/racp.v32i01.16

• Treatment outcome with Tadalafil was defined as:

◦ Healing: definitive cure with medical treatment.
◦ Chronification: need to continue medical
treatment due to persistence of disease.
- Need for surgery due to lack of response.
• Time of treatment was defined as the length of time
from the beginning to the end of treatment with
Tadalafil:
◦ 1 month.
◦ 2 months.
◦ 3 months.
◦ > 3 months.
• Previous anal pathology was defined as:
◦ None: no medical history.
◦ Hemorrhoids, fistula, etc.
◦ Previous surgery for anal fissure
All patients were clinically evaluated before treatment
and during follow-up monthly for 6 months and then
annually.

Setting
Figure 1: Gender distribution.
Coloproctology Service of Sanatorio Modelo de Tucu-
mán, , and the Centro Médico Alberti, Buenos Aires,
Argentina.

Formula
Tadalafil topical cream, applied 3 times a day, was pre-
pared masterfully at both medical centers based on the
formula proposed by Alfonzo Nuñez et al., 6 and con-
sisted of:
• Polyester mucopolysaccharide of sulfuric acid (he-
parinoid organ) 4 mg.
Figure 2: Age distribution.
• Prednisolone 1 mg.
• Oxypolyethoxydodecane 50 mg.
• Hexachloraphene 5 mg.
• 2% lidocaine hydrochloride.
• Tadalafil 40 mg.

RESULTS

A total of 86 patients, 53 (61%) men, diagnosed with anal

fissure were studied (Fig. 1).
According to age,77 were over 55 years. No significant
difference could be shown between the three age groups Figure 3: Treatment results.

evaluated (Fig. 2). spare surgical treatment. If all cases with a favorable res-
Results of treatment withTadalafil, detailed in Fig 3, ponse to symptoms withTadalafil were included, a cure
show that 71 (82.5%) patients achieved cure, while 10 rate of 88% should be considered (Fig. 3).
(11.6%) had to undergo surgery due to failure. The re- Regarding the length of Tadalafil treatment, it was ob-
maining 5 (5.8%) patients continue chronic medical served that 62 (72%) patients applied the cream at least
treatment, although with a final good response and disap- for 2 months 7(8%) for 3 months, 12 (14%) between 3 and
pearance of symptoms. These patients were assessed se- 6 months and 5 (6%) for more than 6 months (p = 0.002)
parately from the ones cured, although they were able to (Fig. 4).

EFFICACY OF THE USE OF TOPICAL TADALAFIL IN THE TREATMENT OF ANAL FISSURE. RESULTS OF A COOPERATIVE STUDY 12
Hugo A. Amarillo, Eduardo J. Vaccarezza, Paula Casares, Luis Montilla
REV ARGENT COLOPROCT | 2021 | VOL. 32, N° 1: 11-15 ORIGINAL ARTICLE
DOI: 10.46768/racp.v32i01.16

chronic medical treatment (Fig. 5).

With regard to the variable prior anal pathology, 64%
of patients had none, while hemorrhoidal disease was the
most prevalent (17%), without statistical significance.
Regarding the adverse effects variable, it was observed
that 82 (95%) patients did not present any, while 2 had a
skin rush that subsided with the progressive suspension of
treatment, 1 had an external thrombosis and 1 had mild
bleeding that resolved spontaneously. No case of heada-
che, pressure sensation or heaviness similar to that produ-
Figure 4: Length of treatment with Tadalafil.
ced by the use of oral vasodilators was recorded. Likewise,
there were no central or peripheral cardiovascular effects,
or continence alterations of any kind (Fig. 6).Follow-up
was monthly for the first 6 months and then annually up
to 2 years. This follow-up (2 years) could be achieved in
91% of cases, and no early recurrence was recorded after
healing was achieved. Two patients recurred after 2 years
and required surgery.

DISCUSSION

The treatment of anal fissure is based on hygienic-diete-

Figure 5: Relationship between treatment time and Medical treatment - surgery
tary measures and pharmacological methods that relax
the smooth muscle such as ointments based on nitric oxi-
de (neurotransmitter that prevents muscle contraction),
calcium channel blockers (nifedipine and diltiazem ), or
the application of botulinum toxin.1,2,7-10
Some of these drugs (nitroglycerin and calcium bloc-
kers) are associated with various adverse effects such as
headache, lipothymia, dizziness and hypotension, leading
to discontinuation of treatment.3-5
With regard to botulinum toxin, a clear association
among dose, preparation, injection site, and cure ra-
tes was found, apart from to the high cost of treatment
and the possibility of recurrence ≥60% after stopping
treatment.11
Sphincterotomy is more effective than botulinum toxin
at 3 years, despite an incontinence rate of 9%.11 For lateral
sphincterotomy 92-100% of healing and 3.3-16% of in-
continence have been informed.7,10
In a Cochrane review, medical treatment with nitrites,
calcium blockers ,or botulinum toxin have better results
than placebo, although is less effective than surgery. Ni-
Figure 6: Adverse effects of treatment with Tadalafil . trites heal up to 49% of patients with a 50-60% recurren-
ce. The efficiency of botulinum toxin is 67.5%.2
When analyzing the relationship between treatment Nifedipine is superior to nitrites with fewer side effects
time and its outcome, it was observed that 83% of patients and drug interactions.7,8
that achieve cure required 2 months of treatment (n=59) Medical treatment has fewer consequences than surgery
and 3 of that group required surgery. On the other hand, (recommendation 1B); for this reason and its safety repre-
2/7 patients treated for 3 months and 5/12 patients trea- sents the first-line treatment (recommendation 1B).5 Cal-
ted during 3 to 6 months were operated on, overall 11% cium channel blockers have fewer side effects and cons-
underwent surgical treatment (p = 0.54) and 6% needed titute the first line (recommendation 1A).5 Botulinum

EFFICACY OF THE USE OF TOPICAL TADALAFIL IN THE TREATMENT OF ANAL FISSURE. RESULTS OF A COOPERATIVE STUDY 13
Hugo A. Amarillo, Eduardo J. Vaccarezza, Paula Casares, Luis Montilla
REV ARGENT COLOPROCT | 2021 | VOL. 32, N° 1: 11-15 ORIGINAL ARTICLE
DOI: 10.46768/racp.v32i01.16

toxin is similar to medical treatment with better healing In the analysis of the duration of treatment and its rela-
and constitutes the second line treatment (recommenda- tionship with results, no significant evidence was found,
tion 1 C).5,8-10 so a new line of research indicates the need of a larger
The side effects of nitrites (headache), the transient in- sample of patients to be treated with Tadalafil, since our
continence secondary to botulinum toxin informed in experience reflected that its use was favorable for the cure
some reports and the definitive incontinence associated of the disease as first line therapy. It would also be neces-
with surgery, despite its high effectiveness make it neces- sary to compare its efficacy with other drugs.
sary considering other treatments. The limitation of this study, although includes experien-
There is almost no bibliography regarding the use of to- ces from two distant institutions with similar populations
pical Tadalafil in the treatment of anal fissure. Currently and results, is the small sample size and the lack of com-
it is not commercially available for topical application, so parison with other medical and surgical methods. Howe-
we made a magisterial formula according to that propo- ver, similarly to Alfonzo Nuñez et al.,6 we consider the
sed by Alfonzo Nuñez, et al.,6 whose results we were able treatment is effective in a high percentage of cases, has
to reproduce. Although in the international pharmaceu- high adherence and almost no adverse effects, despite the
tical market Tadalafil exists as an oral product or topical difficult access due to its high cost of production. The ab-
jelly, we could not found evidence of its use for the topi- sence of effects such as headache, hypotension, and other
cal treatment of anal fissure, except for the aforementio- symptoms related to the use of nitrites or oral vasodila-
ned study. tors is a highlight and contributed to high adherence to
Our series showed that 83% of patients who used Tadala- treatment. For these reasons, in patients with previous
fil during an average time of 2 months achieved cure. If we surgery for a fissure or other anal pathology, or with as-
consider those that improved their clinical picture but for sociated morbidity that contraindicates surgery, Tadala-
multiple reasons continued their treatment chronically, the fil could be an excellent option despite requiring prolon-
rate reached almost 88%, constituting in these cases an op- ged treatment.
tion for patients with a contraindication to surgery.
In correlation to Alfonzo Nuñez, et al. study,6 publis- CONCLUSION
hed in 2012, we demonstrated a high rate of satisfactory
response with the use of Tadalafil. It was demonstrated in Treatment of chronic anal fissure with topical Tadalafil is
this study that 10% of patients required surgery for reso- feasible and has a high healing rate. It is a safe method gi-
lution, an index slightly higher than the series reported by ven that did not present any associated cardiovascular or
each of the participating centers in this study separately. other serious side effects.
Unfortunately, there are no comparative studies of Ta- It is a valid option for patients with contraindication to
dalafil with lateral sphincterotomy or with other medical surgery or continence disorders.
treatments. In this series, the non-comparative design is
based on the high rate of side effects observed with other ACKNOWLEDGMENT
drugs (nitrites) and the low response rate associated with
these and common creams. In the same way, surgery is The authors thank Pharmaceutical María Muñoz for her
only indicated after the failure of medical therapy. collaboration in the elaboration of the product.

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3. Latif J, Rodriguez Martin J, Sanchez I. Fisura anal, opciones R. The management of patients with primary chronic anal fissure: A
terapéuticas actuales. Rev Argent Coloproct 2008;19:1-12. position paper. Tech Coloproctol 2011;15: 135-41.
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org.ar. 2009;III-377:1-13. et al. Operative and medical treatment of chronic anal fissures–A
5. Stewart DB, Gaertner W, Glasgow S, Migaly J, Feingold D, Steele review and network meta-analysis of randomized controlled trials. J
SR. Clinical Practice Guideline for the management of anal fissures. Gastroenterol 2017;52:663-76.
Dis Colon Rectum 2017;60:7-14. 11. Barbeiro S, Atalaia-Martins C, Marcos P, Goncalves C, Canhoto
6. Alfonzo Nuñez R, Cardozo Madrid O, Garcia D, Bacarini D. M, Arroja B, et al. Long-term outcomes of botulinum toxin in
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EFFICACY OF THE USE OF TOPICAL TADALAFIL IN THE TREATMENT OF ANAL FISSURE. RESULTS OF A COOPERATIVE STUDY 14
Hugo A. Amarillo, Eduardo J. Vaccarezza, Paula Casares, Luis Montilla
REV ARGENT COLOPROCT | 2021 | VOL. 32, N° 1: 11-15 ORIGINAL ARTICLE
DOI: 10.46768/racp.v32i01.16

COMENTARIO
Gran parte de los paciente con fisura anal resolverán el cuadro clínico sin intervención quirúrgica, solo modificando há-
bitos o con la implementación de tratamiento médico, sin embargo existen diferentes tipos de tratamientos y opciones
quirúrgicas para aquellos que no responden.
La mayoría de los tratamientos tienen como principal objetivo actuar sobre la hipertonía esfinteriana, principal fac-
tor implicado en la fisiopatogenia de la fisura anal. Para conseguir tal efecto se han implementado formulaciones con 2
o más drogas como principios activos, combinados con dosis fijas. Está demostrado que la combinación es beneficiosa
cuando los ingredientes son incorporados de manera segura y efectiva en un número significativo de pacientes, y ofrece
algunas ventajas sobre la administración simultánea de diferentes preparados de un solo componente activo, ya que me-
jora la compliance, eficacia y reduce los efectos adversos locales y costos.
Las preparaciones tópicas que contienen corticoides y anestésicos locales, son extensamente utilizadas para aliviar sín-
tomas en diferentes patologías, especialmente la patología anal.
Los corticoides actúan mediante la unión a receptores esteroides reduciendo la síntesis de mediadores inflamatorios, la
dilatación de capilares y el edema, por lo cual la mejora de los síntomas no es inmediata. En cambio, los anestésicos lo-
cales proveen alivio inmediato del dolor luego de su aplicación por lo que se logra un efecto sinérgico con la combina-
ción de ambos componentes.
Si a esta combinación se le suma un principio activo como el tadalafilo (utilizado ampliamente para patología uroló-
gica), podría generar un mayor beneficio al actuar sobre la relajación de la musculatura esfinteriana, pero no puede atri-
buírsele directamente el éxito de la cura de la fisura
Si bien es una limitante del trabajo descripta por los autores, se aguardan trabajos que demuestren el efecto de la droga
como único principio activo, esto podría lograrse con un grupo control.
Romina Bianchi
Hospital José María Penna y Hospital Universitario Fundación Favaloro, Ciudad Autónoma de Buenos Aires, Argentina

EFFICACY OF THE USE OF TOPICAL TADALAFIL IN THE TREATMENT OF ANAL FISSURE. RESULTS OF A COOPERATIVE STUDY 15
Hugo A. Amarillo, Eduardo J. Vaccarezza, Paula Casares, Luis Montilla