Received: 8 April 2020 Accepted: 22 April 2020

DOI: 10.1111/luts.12320

ORIGINAL ARTICLE

Does tamsulosin or mirabegron improve ureteral stent-related

symptoms? A prospective placebo-controlled study

Abdulmecit Yavuz1 | Muhammet F. Kilinc2 | Mustafa Aydin3 |

Yilmaz Ofluoglu4 | Göksel Bayar5

1
Urology Department, Gelisim Private
Hospital, Hatay, Turkey Abstract
2
Urology Department, Ankara Training and Objective: The main objective of this study was to evaluate the efficacy of tam-
Research Hospital, Ankara, Turkey
sulosin or mirabegron on ureteral stent-related symptoms.
3
Urology Department, Samsun Training and
Research Hospital, Samsun, Turkey Patients and methods: This was a prospective, randomized, controlled, and single-
4
Urology Department, Medical Park Private blinded study. In total, 180 patients who had undergone ureterolithotripsy and ure-
Hospital, Trabzon, Turkey
teral stent insertion were included. Patients were randomly divided into three groups
5
Urology Department, Sancaktepe Martyr Prof
Dr Ilhan Varank Training and Research
as follows: Group 1 was the control group taking placebo; group 2 was administered
Hospital, Istanbul, Turkey tamsulosin (0.4 mg) once a day; and group 3 received mirabegron (50 mg) once a day.

Correspondence
Göksel Bayar, Urology Department,
Sancaktepe Martyr Prof Dr Ilhan Varank
Training and Research Hospital, Istanbul,
Turkey.
Email: goxelle@yahoo.com
The Turkish version of the ureteral stent symptom questionnaire was filled out after
4 weeks.
Results: After excluding patients who were lost to follow-up, 161 patients were
included in the final analysis. Analgesic usage doses were lower in the tamsulosin
(5.1 ± 1.8) and mirabegron (4.5 ± 1.4) groups than in the control group (5.9 ± 2.1;
P < .001). The urinary symptoms score was lower in tamsulosin group than it was in
the control group (22.1 vs 27.8; P = .001); however, the other scores (body pain, gen-
eral health, work performance, sexual matters, and other problems) were similar
between the groups.
Conclusions: Tamsulosin improves only urinary symptoms due to the ureteral stent
and decreases the need for analgesics. Mirabegron has no effect on ureteral stent-
related symptoms, but it decreases analgesic need.

KEYWORDS

lower urinary tract symptoms, mirabegron, tamsulosin, ureteral stent

1 | I N T RO DU CT I O N
Ureteral stents (USs) are widely used in urology practice to resolve
obstruction, to help recovery of ureteric injury, or are routinely
1
inserted after surgery. However, about 80% of patients experience
stent-related pain, and more than half of them have lower urinary
tract symptoms (LUTSs; frequency, urgency, dysuria, and incomplete
2-4
emptying). For these patients, their working capacity decreases and
sexual health deteriorates; thus, their quality of life is adversely
affected due to pain and urinary symptoms.5 Two main mechanisms
are blamed for causing all these disorders: The first is high pressure
transmitted to the renal pelvis during urination from the bladder by
reflux; the second is a distal ureter (even whole ureter) and bladder
spasms due to irritation from the US.6,7
Tamsulosin is a selective inhibitor of alpha-1a (minimal 1d) adren-
ergic contraction; alpha-1a is present in the smooth muscles of the
distal ureter, trigone, and bladder neck.8 Tamsulosin has also long
been used for pain and US-related symptoms.9-12 Mirabegron is a
beta-3 adrenergic receptor agonist that is currently available for treat-
ment of overactive bladder symptoms.13 Beta-3 adrenergic receptors

Lower Urinary Tract Symptoms. 2020;1–5. wileyonlinelibrary.com/journal/luts © 2020 John Wiley & Sons Australia, Ltd 1
2 YAVUZ ET AL.
are present in the smooth muscle of the bladder and ureter.14 Previ-
ously, mirabegron was only investigated in one study focusing on US-
15
related symptoms. Our hypothesis is that by reducing intravesical
and intraluminal ureter pressure via medical treatment, resulting in
less ureter and renal pelvic pressure, the symptoms associated with
USs would improve.
The use of a validated tool is essential for objectively assessing
the symptom complex. The Turkish version of the Ureteral Stent
Symptoms Questionnaire (T-USSQ) is a reliable and robust tool that
can be self-administered in Turkish patients with US in clinical stud-
16
ies. The aim of the study was to compare the efficacy and safety of
tamsulosin (0.4 mg) and mirabegron (50 mg) with a control group in
patients with US inserted following ureterolithotripsy.
2 | P A T I E NT S A N D M E TH O D S
This was a prospective, controlled, randomized, and single-blinded
study conducted at four hospitals. The study protocol was approved
by the local ethics committee. Written informed consent was
obtained from all patients before screening. Eligible were adult
patients older than 18 years who underwent unilateral retrograde
ureteroscopy with US insertion for ureteral stones. The exclusion
criteria were as follows: bilateral stent insertion, concomitant urinary
tract infection, pregnancy, childhood, neurogenic bladder, overactive
bladder syndrome, history of or current treatment for stress/urge/
mixed urinary incontinence, LUTSs related to benign prostatic hyper-
plasia, and chronic pelvic pain syndrome. We also excluded patients
with major complications after ureteroscopy (avulsion or major
perforation).
Under general anesthesia, ureteroscopic ureterolithotripsy was
performed with a semirigid ureteroscope. Stones were dusted with
laser, and large pieces were removed by basket catheter. After stone
removal, the same type of 4.8 Fr polyurethane double-J US (Plasti-
med, Istanbul, Turkey) with three different lengths (24, 26, and 28 cm)
was used in all patients; the length of the stent used was based on the
patient’s estimated ureteral length,17 which was calculated via com-
puted tomography. A kidney ureter bladder graphic was taken from all
patients before discharge. All stents were removed 4 weeks later to
provide homogenization.
The minimum sample size was calculated based on previous study
results2 to find differences between groups. With the 20% difference
for the mean index scores of “urinary symptoms,” at least 48 patients
are needed with an 80% power and 20% probability error. Assuming a
25% loss (due to withdrawal, lack of follow-up, or use of prohibited
drugs) and a block size of three, we aimed to recruit 180 patients. We
used type-1 generation on a website (www.randomization.com) for
randomization. Eligible patients were randomly divided into three
groups. Group 1 was the control group that did not take medication
but a placebo, group 2 received tamsulosin (0.4 mg; Flomax, Astellas
Pharma Inc, Tokyo, Japan) once a day, and group 3 received
mirabegron (50 mg; Betmiga, Astellas Pharma Inc, Tokyo, Japan) once
a day. The medication started after the operation day and was taken
until the day the stent was removed. Ibuprofen 100 mg was pre-
scribed to all patients to use as analgesic on demand, and one tablet
was accepted as one dose. Patients were asked to maintain a diary
recording analgesic usage amounts. The T-USSQ was filled out after
4 weeks for all the patients by a physician who was blinded to the
patient groups; this was done via face-to-face interviews before stent
removal to prove accuracy of scoring. Complications (visible hematu-
ria, symptomatic urinary tract infection) from the stent were recorded.
The primary endpoints were the USSQ body pain score and USSQ uri-
nary symptom score. The secondary efficacy outcomes included
scores in the other four domains of the USSQ (body pain, general
health, work performance, sexual matters, and other problems). A
one-way analysis of variance test was used to compare the groups
and the Tukey test for post hoc analysis. A P value <.05 was accepted
as significant. The SPSS 17 software package for Windows (Chicago,
Illinois) was used for statistical analysis.
3 | RE SU LT S
Between February 2017 and May 2018, a total of 180 patients from
four medical institutions were randomly assigned to the treatment
and control groups. After excluding 19 patients, 161 patients were
included in the final analysis (Figure 1).
The demographic and clinical data are listed in Table 1. The mean
ages (P = .794) and body mass indexes (P = .166) were similar
between the three groups (P = .794). There were no differences in
gender, side distribution, selection of US length and diameter, or
crossing the midline between groups (Table 1).
Table 2 shows the US-related symptom scores for the three
groups. The USSQ body pain scores were similar at 14.7 ± 5.2 in the
control group, 16 ± 6.6 in the mirabegron group, and 15.5 ± 6.9 in
the tamsulosin group (P = .561); however, analgesic use was lower in
the tamsulosin (5.1 ± 1.8 doses) and mirabegron groups (4.5 ± 1.4
doses) compared with the control group (5.9 ± 2.1 doses; P < .001).
As determined by post hoc analysis (Figure 2), the urinary symptoms
score was lower in the tamsulosin (22.1 ± 8.8) group than it was in the
control group (27.8 ± 7.3; P = .001); the other scores (general health,
work performance, sexual matters, and other problems) were similar
between the groups (Table 2).
Visible hematuria was seen in 20 patients (35.7%) in the control
group, 21 (38.2%) in the tamsulosin group, and 15 (30%) in the
mirabegron group. The visible hematuria ratio was similar between
the groups, and none of the patients needed hospitalization. Symp-
tomatic urinary tract infection was seen in four patients (7%) in the
control group, five (9.1%) in the tamsulosin group, and three (6%) in
the mirabegron group. The symptomatic urinary tract infection
ratios were similar, and all infections were controlled with oral
antibiotics.
Adverse events were seen in 10 patients in the tamsulosin group,
but only two of them stopped medication due to hypotension (the
YAVUZ ET AL. 3

F I G U R E 1 Study design and

Enrollment
participant inclusion
Assessed for eligibility (n= 245)

Excluded (n=65 )
♦ Has excluding criteria (n= 43)
♦ Declined to participate (n= 22)

Randomized (n= 180)

Allocation

Allocated to control group Allocated to tamsulosin Allocated to mirabegron

Received allocated group group
intervention (n= 60) Received allocated Received allocated
intervention (n= 60) intervention (n= 60)

Follow-Up

Lost to follow-up (n=4) Lost to follow-up (n=3) Lost to follow-up (n= 8)

Stopped medication due to Stopped medication due to

adverse events (n= 2) adverse events (n= 2)

Analysis

Analyzed (n= 55) Analyzed (n= 50)

Analyzed (n= 56)

TABLE 1 Comparison of patient

Control Tamsulosin Mirabegron P value
details
Number of patients 56 55 50
Gender (m/f) 40/16 43/12 30/20 .122
Mean age (y) 45.5 ± 11 46.6 ± 13.7 44.8 ± 15.5 .794
Side (right/left) 21/35 20/35 26/24 .307
Mean body mass index (kg/m2) 28.1 ± 3.7 27.3 ± 3.7 26.7 ± 4.4 .166
Diameter (4.8/6 F) 16/40 19/36 18/32 .684
Stent length (24/26/28 cm) 3/42/11 8/32/15 9/34/7 .128
Crossing midline (%) 26.8 16.4 20 .394
a
Result is lower than that of the control group on post hoc analysis.
*P values are significant below .05.

TABLE 2 Comparison of patients’

Control Tamsulosin Mirabegron P value
outcomes
a a
Analgesic using (n dose) 5.9 ± 2.1 5.1 ± 1.8 4.5 ± 1.4 <.001*
Urinary symptoms 27.8 ± 7.3 22.1 ± 8.8a 24.5 ± 6.9 .001*
Body pain 14.7 ± 5.2 15.5 ± 6.9 16 ± 6.6 .561
General health 13.4 ± 4.2 14.4 ± 6.3 12.1 ± 5.1 .082
Work performance 7 ± 2.5 8.7 ± 4.1 8.2 ± 5.3 .085
Sexual matters 4.8 ± 1.9 4.5 ± 2 4.3 ± 2.9 .456
Other problems 7.8 ± 2.4 8.4 ± 3.9 8.8 ± 2.2 .227
a
Result is lower than that of the control group on post hoc analysis.
*P values are significant under .05.
4 YAVUZ ET AL.
P=.01 Placebo Tamsulosin Mirabegron
27.8
24.5
22.1
15.5 16
14.7 14.4
13.4
12.1
8.7 8.2
7
4.8 4.5 4.3
URINARY BODY PAIN GENERAL WORK SEXUAL
SYMPTOMS HEALTH PERFORMANCEMATTERS
others exhibited ejaculation disorders). In the mirabegron group,
adverse events (hypertension, flushing) were seen in two patients and
medication was stopped. The four patients who stopped medication
due to adverse events were excluded from the final analysis.
4 | DISCUSSION
USs are an important complement to the endourological procedure,
and it seems likely that it will be continued in future. LUTSs and pain
related to USs are reported in about 80%, sexual dysfunction in 32%,
and reduced work performance in about 58% of all the patients.2 As
the use of USs continues, the fight against symptoms related to them
will continue.
The mechanism of alpha-blockers in reducing US-related symp-
toms is probably the associated reduction of bladder outlet resistance
to soothe flank pain in male patients, along with bladder outlet
obstruction; this prevents reflux due to decreased voiding pressure
and decreased trigon spasm by irritation of the US.8,18 In addition,
alpha-1 adrenergic receptors are expressed in all portions of the ure-
ter, especially in the distal part; thus, alpha-blocker drugs decrease
ureter spasms and pain.19 Tamsulosin has been reported to be a
promising agent for the treatment of stent-related symptoms.9-12
Damiano et al9 reported that tamsulosin improves the urinary symp-
toms score compared with the control group (14.1 vs 26.4, P = .008);
in this study, the urinary symptoms scores were 22.1 in the tamsulosin
group and 27.8 in the control group (P = .001). Abdelaal et al12
reported that tamsulosin improves all domain scores of USSQ; how-
ever, we could not find any difference in the domain scores except
the urinary symptoms score between groups. Park et al20 reported no
difference between the tamsulosin and control groups in terms of any
USSQ domain score, and they stated that tamsulosin does not
improve any stent-related symptoms; however, distinct from our
study, they used a tamsulosin dose of 0.2 mg. The pain score or anal-
gesic need was lower in the tamsulosin group in all studies.9-12 In our
F I G U R E 2 Mean urinary stent
symptom scores for the domain
scores in the groups
8.8
7.8 8.4
OTHER
PROBLEMS
study, we found that the analgesic need was lower in the tamsulosin
group than it was in the control group.
Beta-adrenergic receptors are present in the smooth muscle and
urothelium of the ureter, and they are responsible for relaxation.21
Shen et al14 reported that the use of beta-adrenergic agonists acting
on ureteric smooth muscle may help reduce ureteric smooth muscle
spasms. In addition, beta-3 agonists inhibit bladder contraction and
decrease bladder pressure; so, they can prevent reflux and decrease
pressure in the ureter and renal pelvis.22 When mirabegron was given
before ureteroscopy, it was observed that it increased the success
thanks to the dilatation in the ureter.23 Mirabegron was used for
stent-related symptoms as a beta-3 agonist in only one study: Tae
et al15 reported that mirabegron decreased body and overall pain
scores but did not improve USSQ urinary symptom scores (32.58 vs
27.92, P = .582) or USSQ general health scores. In the study, we
found that the analgesic need was lower in the mirabegron than it
was in the control group, but the urinary symptoms scores (27.8 vs
24.5, P = .423) and other domain scores of the USSQ were not differ-
ent between the mirabegron and control groups.
The main limitation of this study is its multicentric nature. How-
ever, randomization, data collection from papers, and processing were
done in one center; we think that this procedure ensured homogeni-
zation of the results. This is the first study comparing an alpha-blocker
and beta-3 agonist in terms of efficacy on US-related symptoms. We
could not find any influence of mirabegron on symptoms other than
pain; this should be confirmed in future studies.
5 | CONC LU SIONS
Tamsulosin and mirabegron decrease the analgesic need due to US-
related pain. Tamsulosin slightly improves urinary symptoms related
to USs, but it does not affect any other symptoms or bothersome situ-
ation (body pain, general health, work performance, or sexual matters).
Mirabegron does not improve any US-related symptoms.
YAVUZ ET AL.
DIS CLOSURE
Authors declare no conflict of interest.
ORCID
Abdulmecit Yavuz https://orcid.org/0000-0001-6141-3931
Muhammet F. Kilinc https://orcid.org/0000-0002-2515-7106
Göksel Bayar https://orcid.org/0000-0003-1506-9732
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How to cite this article: Yavuz A, Kilinc MF, Aydin M,
Ofluoglu Y, Bayar G. Does tamsulosin or mirabegron improve
ureteral stent-related symptoms? A prospective placebo-
controlled study. Lower Urinary Tract Symptoms. 2020;1–5.
https://doi.org/10.1111/luts.12320