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\begin{document}

\title{Effects of Mirabegron on JJ Stent-Related Symptoms: A Multicentric Study}



\author[1]{Onder Cinar}%
\author[2]{Yiloren Tanidir}%
\author[3]{Selcuk Ozer}%
\author[2]{Sezer  Cizmeci}%
\author[4]{Oguzcan  Erbatu}%
\author[2]{Turan Ozdemir}%
\author[2]{Reha Girgin}%
\author[5]{Sakir Ongun}%
\author[2]{Oktay Ucer}%
\author[2]{Fuat Kizilay}%
\author[6]{Volkan Sen}%
\author[7]{Bora Irer}%
\author[8]{Ozan Bozkurt}%
\affil[1]{Zonguldak Bulent Ecevit University }%
\affil[2]{Affiliation not available}%
\affil[3]{Dokuz Eylul Universitesi Hastanesi}%
\affil[4]{Manisa Celal Bayar Universitesi}%
\affil[5]{Balikesir University}%
\affil[6]{Manisa State Hospital}%
\affil[7]{Izmir Metropolitan Municipality Esrefpasa Hospital}%
\affil[8]{Dokuz Eylül University}%


\vspace{-1em}



  
  \date{May 25, 2024}


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\selectlanguage{english}
\begin{abstract}
Purpose: To investigate the effect of mirabegron 50 mg/daily for JJ
stent-related symptoms after ureteroscopic stone surgery. Methods:
Medical records of 145 patients who were given a single daily oral dose
of 50 mg of mirabegron for relieving stent-related symptoms were
retrospectively analyzed. Demographic and clinical data and stone
parameters were recorded. All participants completed the Turkish version
of the Ureter Symptom Score Questionnaire (USSQ-T) on the postoperative
seventh day, and again after at least three weeks, before JJ stent
removal. The severity of stent-related symptoms was statistically
compared before and after the mirabegron treatment. Results: The mean
urinary symptoms score decreased significantly from 30.87 \selectlanguage{ngerman}± 9.43 to
22.61 ± 6.78 (p \textless{} 0.0001), mean body pain score decreased
significantly from 21.82 ± 11.22 to 14.03 ± 7.52 (p \textless{} 0.0001),
mean work performance score decreased from 10.50 ± 8.61 to 7.02 ± 6.51
(p \textless{} 0.0001), and mean general health score decreased
significantly from 15.43 ± 6.50 to 11.12 ± 3.70 (p \textless{} 0.0001).
The mean sexual matters score significantly decreased from 3.88 ± 3.40
to 2.48 ± 2.03 (p \textless{} 0.0001), the additional problem score
decreased from 9.31 ± 4.61 to 6.51 ± 2.83 (p \textless{} 0.0001), and
the overall quality of life (QoL) score decreased from 5.18 ± 1.94 to
4.23 ± 1.71 after mirabegron use (p \textless{} 0.0001). Conclusion:
Daily use of 50g of mirabegron significantly improved stent-related
symptoms, sexual matters, and quality of life.%
\end{abstract}\selectlanguage{ngerman}%



\sloppy


\textbf{Introduction}

Ureteral JJ stenting is an integral part of endoscopic ureteral stone
surgery which provides urine passage against either internal or external
obstructive causes {[}1{]}. The incidence of stent-related symptoms
(SRS), including frequency, urgency, dysuria, hematuria, pain, and
sexual problems, varies from 19--76\% {[}2--5{]}. The International
Prostate Symptom Score, Visual Analog Pain Scale, and Overactive Bladder
Symptom Score were used to evaluate SRS in clinical studies until Joshi
et al. developed the Ureteral Stent Symptom Questionnaire (USSQ), which
included six main domains {[}6{]}. The USSQ has been translated into
different languages, including Turkish (USSQ-T), and has been widely
used in clinical trials to investigate patients' discomfort {[}7{]}.

The storage and voiding function of the bladder is regulated by the
brain, spinal cord, and otonomous nervous system. The urine storage and
relaxation of the bladder occurs via activation of
noradrenaline-mediated beta-3-adrenoreceptors, and bladder
contraction/urination occurs via activation of acetylcholine-mediated
receptors {[}8, 9{]}. M1, M2, and M3 subtypes of muscarinic receptors
have been shown in the human bladder. Activation of the M3 receptors by
acetylcholine causes detrusor contraction, and subsequently micturition
starts. Antimuscarinic agents, alpha-blockers, and combination therapies
have been reported to improve SRS {[}10, 11{]}. Mirabegron is the first
selective beta-3-adrenoreceptor agonist that has been reported to be an
effective treatment for overactive bladder syndrome, reducing bladder
contractions, urgency, and frequency of urination {[}12, 13{]}.

In the present study, we aimed to investigate the impact of mirabegron
use in the treatment of JJ stent-related symptoms after
ureterorenoscopic stone surgery using the USSQ-T.

\textbf{Patients and Method}

This multicentric, retrospective study was carried out after approval
was given by the Ethics Committee of Zonguldak Bulent Ecevit University
(approval no: 2019/14). The number of patients was determined by power
analysis. Demographic and clinical data of patients who underwent
unilateral JJ stent placement after ureteroscopic stone surgery (USS)
were evaluated. Because patients with JJ stents show a marked increase
in SRS score from the seventh postoperative day {[}14, 15{]}, all
participants were assessed for the presence of SRS at least one week
after the surgery, called the ``first control visit.'' Patients were
given the validated Turkish version of the USSQ, which consists of six
main domains: urinary symptoms, body pain, general health, work
performance, sexual matters, and additional problems. The scores of each
domain were summed, and the higher the total score, the higher the
severity of SRS-related discomfort. Patients were given 50 mg of
mirabegron once a day to relieve SRS from the first control visit and
continued for at least three weeks until stent removal. Each patient was
examined by a urologist to rule out urinary tract infection (UTI) and
SRS before the JJ stent removal. The JJ stent was removed endoscopically
after kidney-ureter-bladder (KUB) X-ray films were performed. The
patient completed the USSQ-T form before stent removal. The design of
the study is summarized in Figure 1.

\textbf{Inclusion Criteria}

\begin{itemize}
\tightlist
\item
  Patients above the age of 18 years.
\item
  Patients who had undergone unilateral ureteroscopy stone surgery.
\item
  Patients with stone-free status.
\item
  Patients who had been catheterized with six French (Fr) JJ stents.
\item
  Patients with SRS and without UTI at the first control visit.
\end{itemize}

\textbf{Exclusion Criteria}

\begin{itemize}
\tightlist
\item
  Concomitant use of alpha-adrenergic receptor antagonists or
  antimuscarinics.
\item
  Pre-existing neurogenic bladder, interstitial cystitis, overactive
  bladder syndrome, chronic prostatitis, or chronic pelvic pain
  syndrome.
\item
  Concomitant UTI.
\item
  JJ stent displacement.
\item
  Presence of significant residual stone fragment in the ureter.
\item
  History of urinary tract surgery or any drug allergy.
\item
  History of neurologic or psychiatric disease, or dementia.
\item
  Pregnancy.
\item
  Uncontrolled hypertension.
\end{itemize}

\textbf{Statistical Analysis}

All statistical results were analyzed using the Statistical Package for
the Social Sciences version 21.0 (SPSS Inc, Chicago, IL, USA) for
Microsoft Windows. The data of the patients were given as mean \selectlanguage{ngerman}±
standard deviation (SD) and numbers (\%). Results were analyzed using
the paired samples \emph{t} -test. A \emph{p} value \textless{} 0.05 was
considered statistically significant.

\textbf{Results}

After the patients with incomplete data were excluded, 145 patients (100
men and 45 women) were evaluated. The mean age of the patients was 47.0
± 15.0 years, and the mean body mass index (BMI) was 26.93 ± 6.18
kg/m\textsuperscript{2}. The stone localization was grouped as proximal
(\emph{n} = 71), middle (\emph{n} = 31), and distal ureter (\emph{n} =
43) and the mean stone width and length was 9.2 ± 4.0 mm and 11.6 ± 5.9
mm, respectively. Demographic data and other characteristics of the
patients are summarized in Table 1.

The mean urinary symptoms scores were 30.87 ± 9.43 and 22.61 ± 6.78 at
first visit and before stent removal (after mirabegron therapy),
respectively (\emph{p} \textless{} 0.0001). The mean body pain scores
were 21.82 ± 11.22 and 14.03 ± 7.52 (\emph{p} \textless{} 0.0001); the
mean work performance scores were 10.50 ± 8.61 days and 7.02 ± 6.51 days
(\emph{p} \textless{} 0.0001); the mean general health scores were 15.43
± 6.50 and 11.12 ± 3.70 (\emph{p} \textless{} 0.0001); the mean sexual
matters scores were 3.88 ± 3.40 and 2.48 ± 2.03 (\emph{p} \textless{}
0.0001); the mean additional problems scores were 9.31 ± 4.61 and 6.51 ±
2.83 (\emph{p} \textless{} 0.0001); and the global quality of life (QoL)
scores were 5.18 ± 1.94 and 4.23 ± 1.71 at the first control visit and
after mirabegron monotherapy (\emph{p} \textless{} 0.0001), respectively
(Table 2).

\textbf{Discussion}

In the present study, we showed that mirabegron significantly improved
JJ stent-related symptoms. For a long time, ureteral JJ stents have been
used in urology practice used to prevent ureteral obstruction. However,
stent-related pain and urinary symptoms negatively affect the quality of
life in patients with JJ stents after ureteroscopic surgery {[}6, 16{]}.
Several treatment options have been attributed to overcome these
problems, including antimuscarinic agents, alpha-adrenergic receptor
antagonists, or combination therapies {[}10, 11{]}. Alpha-adrenergic
receptor antagonists alleviate the symptoms related to the JJ stent and
reduce the use of analgesics {[}11, 17{]}. Similarly, mirabegron, a
beta-3 receptor agonist, is being used in the treatment of overactive
bladder disease, and has also been shown to improve urinary symptoms due
to JJ stent insertion {[}18, 19{]}.

Until recently, non-specific questionnaires such as the International
Prostate Symptom Score or Overactive Bladder Symptom Score {[}18, 20{]}
were used to evaluate the effect of mirabegron use for JJ stent-related
symptoms. However, the non-specific nature of these questionnaires
undermined the value of these studies. Therefore, in the present study,
we used the Turkish-validated USSQ-T questionnaire {[}7{]}. In addition,
the USSQ was used in only two studies to evaluate the effect of
mirabegron for JJ stent-related symptoms. Tae et al. showed that
mirabegron slightly lowered the mean urinary symptoms score from 32.58 ±
6.67 to 27.92 ± 7.72 (\emph{p} = 0.582) {[}19{]}. Considering that
mirabegron shows its maximum antimuscarinic effect after three weeks, a
clinically insignificant decrease in mean urinary symptoms score can be
explained by the fact that mirabegron was only used for two weeks in
that study {[}19{]}. Yavuz et al. reported the results of 180 patients
regarding the changes on the ureteral stent symptom questionnaire four
weeks after ureterolithotripsy plus ureteral stenting. They randomized
the patients into three groups receiving placebo, tamsulosin, and
mirabegron (50\selectlanguage{english} mg) once a day and found similar rates of urinary
symptoms scores between the mirabegron and control patients (27.8 vs
24.5, \emph{p} = 0.423) {[}21{]}. In contrast to that study, we compared
the impact of mirabegron on changes of urinary symptoms scores in
patients between postoperative first visit and at least four weeks after
surgery. For the first time in the literature, we showed that mirabegron
monotherapy significantly decreased the SRS compared to pretreatment
levels.

In addition to an increased rate of SRS, patients with a JJ stent may
also suffer from stent-related pain {[}22{]}. Although the mechanism of
urinary symptoms and pain has not been exactly defined yet, ureteric
spasm, trigonal irritation, and urinary reflux to the renal pelvis may
play a role {[}23{]}. Trigonal irritation provokes detrusor contractions
mediated by muscarinic receptors. Antimuscarinics alone or in
combination with an alpha-receptor antagonist have been reported to be
effective for SRS reduction {[}10, 11{]}. Recent meta-analyses have
demonstrated that antimuscarinic monotherapy reduces the SRS and body
pain scores {[}11, 24, 25{]}. Several reports showed that all subtypes
of beta-adrenergic receptors were expressed in the human ureteral smooth
muscle {[}26, 27{]}, and use of beta-1 and beta-3 agonists might help to
reduce symptoms secondary to ureteral smooth muscle spasm {[}18{]}. In a
recent study, mirabegron monotherapy was shown to reduce the USSQ body
pain score and the overall pain score compared to the control group
{[}19{]}. In accordance with the literature, this present study showed
that JJ stent placement increased patients' pain score, and mirabegron
monotherapy significantly reduced the stent-related pain score.

Ureteral stenting causes stent-related sexual dysfunction in both
genders {[}3, 28{]}. Joshi et al. also reported that sexual dysfunction
was observed in 38\% and work performance was negatively affected in
58\% of ureteral stent patients {[}22{]}. Deliveliotis et al. showed
that alfuzosin, an alpha-adrenergic receptor blocker, improved SRS and
sexual function {[}29{]}. Another study showed that a tamsulosin and
oxybutynin combination restored the work performance, additional
problems, and general health scores {[}30{]}. In accordance with these
studies, our results showed that mirabegron use significantly reversed
JJ stent-related decreased work performance and sexual dysfunction, and
increased quality of life.

This present study has some limitations:

1. Retrospective design of the study.

2. Lack of a control group.

\textbf{Conclusion}

In conclusion, mirabegron monotherapy improved the JJ stent-related
urinary symptoms, body pain, work performance, sexual matters,
additional problems, and general health scores. Further studies are
needed to clarify the role and mechanisms of mirabegron in the
management of SRS.

\textbf{Competing interests:} The authors declare that they have no
competing interests.

\textbf{Endnotes:} None

\textbf{Acknowledgment:} None

\textbf{Funding source:} Authors declare they did not receive any
funding or support for the present study.

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\textbf{Figure Legends:Figure 1.} The study design.\textbf{Table 1.}
Demographic features.\textbf{Table 2.} USSQ scores.

\selectlanguage{english}
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