Efficacy of Tamsulosin, Oxybutynin, and their combination in the control of double-j stent-related lower urinary tract symptoms

Abstract

Introduction and objective:
Indwelling double J ureteral stents are used routinely in the resolution of ureteral obstruction caused by different etiologies. Evaluation of urinary symptoms related to double-J stent, indicate that these affect 73-90% of patients. We conducted a prospective, randomized study, to evaluate the efficacy of tamsulosin, oxybutinin and combination therapy in improving the urinary symptoms.

Methods:
Patients who underwent ureteral stent placement after ureterolithotripsy (total 51), were randomized into three groups: Group I: Tamsulosin 0.4 mg. Once per day(17 patients), Group II: Oxybutinin 5 mg. once per day (17 patients), Group III: Tamsulosin+ oxybutynin once per day (17 patients). All the groups received the drugs for three weeks and completed a Spanish validated Ureteral Stent Symptom Questionnaire (USSQ) at day 7 and 21.

Results:
Repeated measures ANOVA showed mean urinary symptom index score was 22.3 vs. 15.5 in group three (p<0.001) at day 7 and 21 respectively. The mean work performance index was 6.6 vs 8.1 (p=0.049) favoring tamsulosin group, the mean sexual score was 0.5 vs 1.5 (p=0.03). Among additional problems the mean was 7.2 vs 6.2 (p=0.03). No significant difference was noted among pain and general health index. No side effects were reported.

Conclusions:
Combination therapy with tamsulosin and oxybutynin improved irritative symptoms and work performance as well as sexual matters. Combination therapy should be considered for patients who complained of stent related symptoms.

Full text

ORIGINAL ARTICLE
487
Efficacy of Tamsulosin, Oxybutynin, and their combination
in the control of double-j stent-related lower urinary tract
symptoms
_______________________________________________
Miguel Maldonado-Avila 1, Leopoldo Garduño-Arteaga 1, Rene Jungfermann-Guzman 1, Hugo A.
Manzanilla-Garcia 1, Emmanuel Rosas-Nava 1, Nestor Procuna-Hernandez 1, Alejandro Vela-Mollinedo 1,
Luis Almazan-Treviño 1, Jose Guzman-Esquivel 2
1 Departamento de Urologia, Hospital Geral de Mexico, Ciudad de Mexico, 2 Instituto Mexicano del Seguro
Social Colima, no México
ABSTRACT ARTICLE INFO
______________________________________________________________ ______________________
Introduction and objective: Indwelling double J ureteral stents are used routinely
in the resolution of ureteral obstruction caused by different etiologies. Evaluation
of urinary symptoms related to double-J stent, indicate that these affect 73-90%
of patients.
We conducted a prospective, randomized study, to evaluate the efficacy of tamsulo-
sin, oxybutinin and combination therapy in improving the urinary symptoms.
Methods: Patients who underwent ureteral stent placement after ureterolithotripsy
(total 51), were randomized into three groups: Group I: Tamsulosin 0.4 mg. once
per day(17 patients), Group II: Oxybutinin 5 mg. once per day (17 patients), Group
III: Tamsulosin+ oxybutynin once per day (17 patients). All the groups received the
drugs for three weeks and completed a Spanish validated Ureteral Stent Symptom
Questionnaire (USSQ) at day 7 and 21.
Results: Repeated measures ANOVA showed mean urinary symptom index score was
22.3 vs. 15.5 in group three (p<0.001) at day 7 and 21 respectively. The mean work
performance index was 6.6 vs 8.1 (p=0.049) favoring tamsulosin group, the mean
sexual score was 0.5 vs 1.5 (p=0.03). Among additional problems the mean was 7.2
vs 6.2 (p=0.03). No significant difference was noted among pain and general health
index. No side effects were reported.
Conclusions: Combination therapy with tamsulosin and oxybutynin improved irri-
tative symptoms and work performance as well as sexual matters. Combination the-
rapy should be considered for patients who complained of stent related symptoms.
Keywords:
tamsulosin [Supplementary
Concept]; oxybutynin
[Supplementary Concept]; Lower
Urinary Tract Symptoms
Int Braz J Urol. 2016; 42: 487-93
_____________________
Submitted for publication:
March 31, 2015
_____________________
Accepted after revision:
August 11, 2015
INTRODUCTION
The placement of ureteral double-J stents
has become routine clinical practice for resolving
ureteral obstruction caused by different etiolo-
gies (1-4). The estimated incidence of stent-rela-
ted symptoms varies from 19-76% and includes
frequency, urgency, dysuria, incomplete voiding,
flank pain, suprapubic pain, urinary incontinence,
and hematuria (5-10).
The objective evaluation of stent-related
symptoms through the visual analog scale (VAS)
Vol. 42 (3): 487-493, May - June, 2016
doi: 10.1590/S1677-5538.IBJU.2015.0186

IBJU | COMBINATION THERAPY AND URETERAL STENT SYMPTOMS
488
and the International Prostate Symptom Score
(IPSS) is complex and nonspecific (11-13). Joshi
et al. developed the ureteral stent symptoms ques-
tionnaire (USSQ), which is a validated and safe
psychometric instrument for evaluating the im-
pact of ureteral stents on symptoms and quality
of life. This questionnaire explores 6 areas that
include urinary symptoms, body pain, general he-
alth status, work performance, sexual matters, and
other additional problems (14). It has been utilized
in numerous clinical trials and translated into di-
fferent languages, including Spanish (15).
The efficacy of pharmacologic manage-
ment of these symptoms related to the double-J
stent, with alpha-1 adrenergic blockers, tamsu-
losin and alfuzosin (16, 12, 17-19) and the an-
timuscarinic agents, oxybutynin and tolterodine,
has been demonstrated (20). In fact, there is a me-
ta-analysis that evaluates the efficacy of alpha-
-blockers and concludes that they are associated
with improvement in ureteral stent symptoms and
supports their use in routine clinical practice (21).
Nevertheless, at present there is no study directly
comparing tamsulosin and oxybutynin. Therefore,
the aim of this study was to evaluate the efficacy
and safety of these two drugs for the control of
lower urinary tract symptoms and their impact on
quality of life.
MATERIALS AND METHODS
Patient selection
From November 2012 to October 2013, pa-
tients of both sexes were included in the study;
they were above 18 years of age and had unila-
teral double-J stent placement after ureteroscopy
that was performed at the Hospital General de Mé-
xico.
Inclusion criteria were patients of either
sex above the age of 18 years that had undergone
ureteroscopy for lithiasis in the lower third of the
ureteral tract, with stones under 15mm, and that
required unilateral double-J stent placement.
The exclusion criteria were patients with
a previous diagnosis of benign prostatic hyper-
plasia (IPSS≥7), a previous diagnosis of overac-
tive bladder, a history of interstitial cystitis or
chronic cystitis, a history of chronic prostatitis or
chronic pelvic pain, chronic medication with al-
pha blockers, anticholinergic agents and analge-
sics, ureteral obstruction caused by malignancy,
pregnant patients, patients unable to understand
or sign an informed consent, patients with a his-
tory of postural hypotension (decrease in blood
pressure>20mmHg of the systolic or diastolic me-
asurements) or syncope, patients with severe or
unstable heart failure, severe renal failure, severe
liver failure, or patients with a history of urinary
retention, gastric retention, or uncontrolled wide-
-angle glaucoma.
A single-blind, randomized, prospective,
comparative, and experimental clinical trial was
conducted that included 51 patients (26 women,
25 men).
They were assigned to one of the following
three groups by means of a randomization Table:
Group 1 - Tamsulosin 0.4mg PO before
food every 24h for 21 days
Group 2 - Extended release Oxybutynin
5mg PO every 24h for 21 days
Group 3 - Tamsulosin 0.4mg PO before
food every 24h for 21 days+oxybutynin 5mg PO
every 24h for 21 days.
The sample size was calculated with the
formula for comparing independent means, based
on previous studies on the efficacy of alpha blo-
ckers versus placebo (20). A power of 90% and a
significance level of 0.05% were used in accor-
dance with a finite population of 60 cases (the
number of ureteroscopies per year at our hospital).
Methods
Once the diagnosis of ureteral lithiasis
was established and it was confirmed that the
patients met the protocol selection criteria, the
characteristics of the study were explained to
them. Upon accepting to participate in the study,
the patients signed statements of informed con-
sent, following the principles of the Declaration
of Helsinki.
This study was approved by the institutio-
nal ethics and research committees in accordan-
ce with good clinical practices, with registration
number DI/12/105/04/081.
Data were collected in a case report file
that contained each patient’s personal information,

IBJU | COMBINATION THERAPY AND URETERAL STENT SYMPTOMS
489
demographic data, clinical history, and complete
physical examination results.
Each patient underwent ureterolithotrip-
sy and a polyurethane 24 or 22cm X 6Fr double-
-J stent (Cook, USA) was placed after endoscopic
extraction of the stone. Adequate ureteral double-J
stent placement was verified through a plain abdo-
minal film in the immediate postoperative period.
The ureteral stent symptoms questionnai-
re (USSQ) was applied to all patients on posto-
perative days 7 and 21, registering the scores of
each of the 6 topics evaluated with the assessment
tool. Each section has a total score; the higher the
number, the worse the general health status of the
patient.
Antibiotic was administered for 7 days (Ci-
profloxacin 500mg PO bid), followed by urinary
antiseptic (Nitrofurantoin 100mg PO every 24h)
until removal of the stent, three weeks later. Keto-
rolac PO 10mg was administered as needed by the
patient, with a maximum of 4 tablets in 24 hours.
Each patient kept a personalized register of the
daily analgesic intake.
Statistical analysis
Values were expressed as means±standard
deviation (SD) and the statistical analysis was car-
ried out using the repeated measures ANOVA test
for comparing the independent means of the 3 tre-
atment groups.
Results were considered statistically signi-
ficant with a value set at p<0.05. The IBM SPSS
Statistics 20.0 for Windows (SPSS, Chicago, IL,
USA) statistical package was used.
RESULTS
A total of 56 patients were enrolled in the
study. Five were eliminated; four due to spon-
taneous stone expulsion and one for having an
IPSS score above 21 points.
The remaining 51 patients (26 women and
25 men) were randomly distributed as follows:
Group 1 - Tamsulosin (17 patients)
Group 2 - Extended release oxybutynin
(17 patients)
Group 3 - Combination therapy (17 patients)
Table-1 shows the demographic charac-
teristics of the study population. There were no
statistically significant differences per group
with respect to age, sex, weight, height, BMI, or
stone size (p>0.05).
Repeated measures ANOVA showed a
mean urinary symptom score of 22.3 versus
15.5 in Group 3 (p<0.001) at days 7 and 21, res-
pectively (Figure-1). The mean work performan-
ce score was 6.6 versus 8.1 (p=0.049), favoring
the tamsulosin group, and the mean sexual per-
formance score was 0.5 versus 1.5 (p=0.03). For
the additional problems, the mean was 7.2 ver-
sus 6.2 (p=0.03). No significant difference was
noted between pain and general health scores
(Table-2). No side effects were reported and the-
re were no differences in analgesic consumption
between groups.
Table 1 - Demographic characteristics of the study patients.
Variable Tamsulosin Oxybutynin Both p*
Patients (n) 17 17 17
Gender (M:F) 9:8 7:10 9:8 0.73
Age (years) 42.5±7.3 40.4±11.2 45.7±10.3 0.293
Weight (kg) 73.7±13.4 75±8.9 71.2±12.1 0.623
Height (cm) 166.9±5.7 161.4±5.0 161.2±5.7 0.342
BMI (Kg/m) 27.5±6.5 28.6±3.2 27.6±4.1 0.729
Stone size (mm) 8.8±3.2 11.2±4.0 10±3.02 0.135
*significance<0.05

IBJU | COMBINATION THERAPY AND URETERAL STENT SYMPTOMS
490
Figure 1 - Mean urinary symptoms score.
Table 2 - USSQ score comparison among the 3 groups on postoperative days 7 and 21.
Variable Tamsulosin
(Mean±SD)
Oxybutynin
(Mean±SD)
Tamsulosin + Oxybutynin
(Mean±SD)
p*
Urinary symptom
score
Day 7 21.4±4.78 22.4±4.9 22.3±7.2
<0.001*
Day 21 21.5±6.27 17.8±5.5 15.5±5.0
Pain score Day 7 13.4±2.2 11.2±2.7 13.8±5.0
0.207
Day 21 14.2±4.3 10.9±3.1 11.2±5.8
General health score Day 7 11.7±1.4 11.0±1.4 11.5±1.5
0.699
Day 21 11.6±1.2 11.7±1.3 11.2±2.5
Work performance
score
Day 7 6.6±4.0 6.3±2.5 7.0±2.3
0.049*
Day 21 8.1±1.8 7.2±1.9 7.7±1.5
Sexual performance
score
Day 7 0.6±1.1 0.5±0.8 2.6±3.8
0.036*
Day 21 1.2±1.2 1.5±1.2 2.6±2.5
Additional problem
score
Day 7 8.05±2.6 6.8±1.9 7.2±1.7
0.03*
Day 21 7.4±3.0 6.4±1.1 6.2±2.8
*Repeated measures ANOVA.

IBJU | COMBINATION THERAPY AND URETERAL STENT SYMPTOMS
491
DISCUSSION
Ureteral stent placement for upper urinary
tract diversion has been employed for more than
four decades (22) and has become routine pro-
cedure in various urologic surgeries performed
for different indications. Ureteral stents prevent
urinary flow obstruction caused by edema of the
mucosa; they aid in the mucosal healing process
after a complicated procedure and they passively
dilate the ureter, and facilitate the passage of re-
sidual stones (1).
Nevertheless, up to 76% of the patients
will have symptoms associated with the presence
of the stent, on occasion requiring its early re-
moval (8). New stent designs, coatings, and bio-
materials have been developed for the purpose of
reducing these problems, but the ideal stent has
yet to be produced (23).
Even though the exact pathophysiology
of the symptoms related to the double-J stent is
not known, it has been suggested that the me-
chanism involved could be an increase in the
pressure transmitted toward the renal pelvis du-
ring micturition and bladder irritation due to the
intravesical portion of the stent (24).
Both anticholinergic drugs and alpha-
-adrenergic blocking agents have been used to
improve symptoms related to the double-J stent
with good results in the majority of cases (20 21).
Our study showed that tamsulosin and
oxybutynin combination therapy improved irri-
tative urinary symptoms, as well as work perfor-
mance and sexual aspects.
The combination of tamsulosin and oxy-
butynin was clearly superior in improving uri-
nary symptoms. This is a very relevant clinical
situation, given that symptomatology is present
in 73 to 90% of patients with double-J stent. The
same was true for the area of additional problems.
In our study, the group with tamsulosin,
alone, had a higher work performance score,
compared with the other two groups.
Even though there were statistically sig-
nificant differences in relation to the sexual
sphere, we felt that the USSQ was not very use-
ful, especially during the first postoperative days,
because the patients were more concerned about
the result of the surgery and their general health
than their sexual performance. In fact, the ma-
jority of patients stated that they had made no
attempt at having sexual activity.
There are few controlled clinical trials
that evaluate the pharmacologic agents used in
the treatment of double-J stent-related symp-
toms, and to the best of our knowledge this is the
first head-to-head study comparing long-acting
tamsulosin and oxybutynin. It is well known that
stent-related symptoms are similar to those of
benign prostatic hyperplasia caused by urethral
resistance and bladder instability. Damiano et al.
reported that tamsulosin administration impro-
ved urinary symptoms and pain when evaluated
through the visual analog scale, as well as qua-
lity of life (13).
Wang et al. stated that the selective al-
pha-1 blocker, tamsulosin, improved urinary
symptoms, flank pain, and pain during micturi-
tion (19). Beddingfield et al. reported that patients
treated with 10mg daily of alfuzosin showed im-
provement with respect to micturition frequency,
lumbar pain, and sleep disorders (25). Deliveliotis
et al. had similar study results of improved stent-
-related symptoms in patients treated with alfu-
zosin, especially in reference to pain, as well as
sexual function, and general health (26).
Symptoms associated with double-J ure-
teral stent are similar to those of overactive
bladder caused by involuntary bladder contrac-
tions, and antimuscarinic agents have been used
with good results (27). Norris et al. reported that
there were no statistically significant differen-
ces between patients treated with oxybutynin
compared with placebo or phenazopyridine (28).
Agarwal et al. demonstrated that patients that
had received oxybutynin or tolterodine prior to
surgery showed greater relief in regard to bla-
dder discomfort compared with patients in the
placebo group (29).
A limitation of our study resulted from
the fact that even though the sample size was
adequately calculated, the number of patients in
each group was small and this could possibly re-
duce the capacity to detect other potential effects
of these drugs in patients with double-J stent,
when evaluated through the USSQ.

IBJU | COMBINATION THERAPY AND URETERAL STENT SYMPTOMS
492
CONCLUSIONS
The administration of tamsulosin and oxy-
butynin markedly reduced the irritative symptoms
commonly associated with a double-J stent. The-
se drugs were also effective in the improvement
of sexual performance and work performance, as
well as other related problems. There was no di-
fference with respect to pain and general health.
CONFLICT OF INTEREST
None declared.
REFERENCES
1. Chew BH, Knudsen BE, Denstedt JD. The use of stents in
contemporary urology. Curr Opin Urol. 2004;14:111-5.
2. Saltzman B. Ureteral stents. Indications, variations, and
complications. Urol Clin North Am. 1988;15:481-91.
3. Denstedt JD, Wollin TA, Reid G. Biomaterials used in
urology: current issues of biocompatibility, infection, and
encrustation. J Endourol. 1998;12:493-500.
4. Cormio L, Talja M, Koivusalo A, Mäkisalo H, Wolff H, Ruutu
M. Biocompatibility of various indwelling double-J stents. J
Urol. 1995;153:494-6.
5. Vega Vega A, García Alonso D, García Alonso CJ.
[Characterization of urinary tract symptoms and quality of
life in patients with double-pig-tailed ureteral stents]. Actas
Urol Esp. 2007;31:738-42.
6. Miyaoka R, Monga M. Ureteral stent discomfort: Etiology
and management. Indian J Urol. 2009;25:455-60.
7. Dellis A, Joshi HB, Timoney AG, Keeley FX Jr. Relief
of stent related symptoms: review of engineering and
pharmacological solutions. J Urol. 2010;184:1267-72.
8. Joshi HB, Okeke A, Newns N, Keeley FX Jr, Timoney AG.
Characterization of urinary symptoms in patients with
ureteral stents. Urology. 2002;59:511-6.
9. Borboroglu PG, Amling CL, Schenkman NS, Monga M,
Ward JF, Piper NY, et al. Ureteral stenting after ureteroscopy
for distal ureteral calculi: a multi-institutional prospective
randomized controlled study assessing pain, outcomes and
complications. J Urol. 2001;166:1651-7.
10. Richter S, Ringel A, Shalev M, Nissenkorn I. The indwelling
ureteric stent: a ‘friendly’ procedure with unfriendly high
morbidity. BJU Int. 2000;85:408-11.
11. Erturk E, Sessions A, Joseph JV. Impact of ureteral stent
diameter on symptoms and tolerability. J Endourol.
2003;17:59-62.
12. Lee SJ, Yoo C, Oh CY, Lee YS, Cho ST, Lee SH, et al. Stent
Position Is More Important than α-Blockers or Anticholinergics
for Stent-Related Lower Urinary Tract Symptoms after
Ureteroscopic Ureterolithotomy: A Prospective Randomized
Study. Korean J Urol. 2010;51:636-41.
13. Damiano R, Autorino R, De Sio M, Giacobbe A, Palumbo IM,
D’Armiento M. Effect of tamsulosin in preventing ureteral
stent-related morbidity: a prospective study. J Endourol.
2008;22:651-6.
14. Joshi HB, Stainthorpe A, MacDonagh RP, Keeley FX
Jr, Timoney AG, Barry MJ. Indwelling ureteral stents:
evaluation of symptoms, quality of life and utility. J Urol.
2003;169:1065-9.
15. Olvera-Posada D, Suárez-Santos M, Castillejos-Molina R,
Gabilondo-Navarro F, Méndez-Probst CE. Validation of the
Spanish version of Ureteral Stent Symptom Questionnaire:
prevalence of symptoms in a tertiary care center in Mexico.
J Endourol. 2014;28:377-82.
16. Buzelin JM, Fonteyne E, Kontturi M, Witjes WP, Khan A.
Comparison of tamsulosin with alfuzosin in the treatment
of patients with lower urinary tract symptoms suggestive
of bladder outlet obstruction (symptomatic benign prostatic
hyperplasia). The European Tamsulosin Study Group. Br J
Urol. 1997;80:597-605. Erratum in: Br J Urol 1998;81:510.
17. Wang CJ, Huang SW, Chang CH. Effects of specific alpha-
1A/1D blocker on lower urinary tract symptoms due to
double-J stent: a prospectively randomized study. Urol Res.
2009;37:147-52.
18. Navanimitkul N, Lojanapiwat B. Efficacy of tamsulosin 0.4 mg/
day in relieving double-J stent-related symptoms: a randomized
controlled study. J Int Med Res. 2010;38:1436-41.
19. Wang CJ, Huang SW, Chang CH. Effects of tamsulosin
on lower urinary tract symptoms due to double-J stent: a
prospective study. Urol Int. 2009;83:66-9.
20. Lim KT, Kim YT, Lee TY, Park SY. Effects of tamsulosin,
solifenacin, and combination therapy for the treatment
of ureteral stent related discomforts. Korean J Urol.
2011;52:485-8.
21. Yakoubi R, Lemdani M, Monga M, Villers A, Koenig P. Is there
a role for α-blockers in ureteral stent related symptoms? A
systematic review and meta-analysis. J Urol. 2011;186:928-34.
22. Zimskind PD, Fetter TR, Wilkerson JL. Clinical use of long-
term indwelling silicone rubber ureteral splints inserted
cystoscopically. J Urol. 1967;97:840-4.
23. Lange D, Chew BH. Update on ureteral stent technology.
Ther Adv Urol. 2009;1:143-8.
24. Thomas R. Indwelling ureteral stents: impact of material and
shape on patient comfort. J Endourol. 1993;7:137-40.
25. Beddingfield R, Pedro RN, Hinck B, Kreidberg C, Feia K,
Monga M. Alfuzosin to relieve ureteral stent discomfort: a
prospective, randomized, placebo controlled study. J Urol.
2009;181:170-6.

IBJU | COMBINATION THERAPY AND URETERAL STENT SYMPTOMS
493
26. Deliveliotis C, Chrisofos M, Gougousis E, Papatsoris A,
Dellis A, Varkarakis IM. Is there a role for alpha1-blockers
in treating double-J stent-related symptoms? Urology.
2006;67:35-9.
27. Park SC, Jung SW, Lee JW, Rim JS. The effects of tolterodine
extended release and alfuzosin for the treatment of double-j
stent-related symptoms. J Endourol. 2009;23:1913-7.
28. Norris RD, Sur RL, Springhart WP, Marguet CG, Mathias
BJ, Pietrow PK, et al. A prospective, randomized, double-
blinded placebo-controlled comparison of extended release
oxybutynin versus phenazopyridine for the management
of postoperative ureteral stent discomfort. Urology.
2008;71:792-5.
29. Agarwal A, Dhiraaj S, Singhal V, Kapoor R, Tandon M.
Comparison of efficacy of oxybutynin and tolterodine
for prevention of catheter related bladder discomfort: a
prospective, randomized, placebo-controlled, double-blind
study. Br J Anaesth. 2006;96:377-80.
_______________________
Correspondence address:
Miguel Maldonado-Avila, MD
Departamento de Urología
Hospital General de México,
Dr. Balmis 148 Col. Doctores
Distrito Federal, 06800, Mexico
E-mail: mimalavi@yahoo.com