Tamsulosin,Solifenacin,and Their Combination for the Treatment of Stent-Related Symptoms: A Randomized Controlled Study

Abstract

Purpose:

To properly use the Ureteric Symptom Score Questionnaire (USSQ) to evaluate, in a randomized control study, the effect of tamsulosin, solifenacin, and their combination in improving symptoms and quality of life in patients with indwelling ureteral stents.

Materials and Methods:

After institutional review board approval, 260 patients with a ureteral stent were randomly assigned to receive tamsulosin 0.4 mg, solifenacin 5 mg, or placebo and further randomized to receive their combination. The validated USSQ was completed 1 and 4 weeks after stent insertion and 4 weeks after stent removal. Kruskal-Wallis test, chi-squared test (or Fisher's exact test), one-way analysis of variance, and T-test (or Wilcoxon rank-sum test if not normal data) were used for statistical analysis. The results were considered significant at p < 0.05.

Results:

Patients receiving tamsulosin or solifenacin expressed significantly lower urinary (p < 0.001), pain (p < 0.001 with stent in situ), and general health index (p = 0.002 in first and p < 0.001 in fourth week with stent in situ) scores. Sexual life and quality of work were also positively influenced. Patients on combination therapy expressed lower urinary (p < 0.001) and pain (p < 0.001) scores in the fourth week with stent in situ and work performance in the first week and with stent in situ (p = 0.001) and after stent removal (p = 0.005). No patients had to discontinue medication due to side effects.

Conclusions:

Stent-related morbidity is a reality in the majority of patients. Simple medication, such as tamsulosin and solifenacin alone or in combination, improves stent-related symptoms and has a positive impact on quality of life.

Introduction

Ureteral stents are routinely used in urology, suggesting a useful and indispensable tool in everyday practice for more than four decades. However, there is considerable controversy over whether a stent is needed, especially in uncomplicated ureteroscopy cases,^1,2 whereas stent placement is associated with significant morbidity and has a negative impact on the patient's quality of life.³ Since ureteral stents are profoundly associated with side effects and considerable patient morbidity, there have been efforts to engineer solutions regarding stents per se (shape, material, or drug coating), as well as pharmacology aiming at reducing stent-related morbidity.⁴ A useful and validated tool to better estimate the negative impact on patients' life has been established about a decade ago, called the Ureteric Symptom Score Questionnaire (USSQ). Apart from its usefulness in everyday practice, it is crucial to be properly assessed, as has originally been set by Joshi and colleagues.⁵

The efficacy of several pharmaceutical agents has been evaluated, in general, in several recent studies, with many of them being randomized controlled trials as well as meta-analyses. Interestingly, almost all aforementioned studies are not uniformly designed; however, we should underline that although they used the only validated stent-related symptom questionnaire (USSQ), unfortunately the vast majority did not report or did not evaluate all aspects of USSQ. Furthermore, in most of them, the USSQ has been assessed at several time points instead of the first and fourth week with the stent in situ and fourth week after stent removal, as has been suggested by Joshi and colleagues.⁵ The aforementioned facts deliberately impede the proper data evaluation as well as underpower their statistical significance, since their results cannot be compared with similar studies.

In the present randomized placebo-controlled study, we set out to overcome aforementioned limitations, to properly use USSQ to evaluate simultaneously the efficacy of tamsulosin with solifenacin compared with placebo, and to further compare for the first time in the literature the aforementioned agents with a combination of tamsulosin plus solifenacin. The proper use of USSQ should be underlined for the sake of accuracy and objectivity.

Materials and Methods

After institutional review board approval and verbal informed consent were obtained, 260 patients, 131 men and 129 women, aged 17 to 84 (median 48 years), with a unilateral Double-J ureteral stent were included in this randomized controlled study. All patients underwent insertion of a Double-J ureteral stent, routinely placed for 4 weeks. The indications for stent placement were extracorporeal shockwave lithotripsy (SWL) (124 patients), ureteroscopic stone treatment (URL) (69 patients), and unilateral hydronephrosis or any reason (67 patients). All patients were prospectively randomized with a box with random numbers into three groups (groups 1, 2, and 3) from April 2012 to March 2015. In group 1, 60 patients (30 men and 30 women, median age 48 years) received 0.4 mg of tamsulosin once daily for 4 weeks. In group 2, 60 patients (27 men and 33 women, median age 49 years) received 5 mg of solifenacin once daily for 4 weeks. In group 3, 60 patients (32 men and 28 women, median age 45 years) received placebo once daily for 4 weeks. At this point of our study, after institutional review board approval, we decided to add group 4, where patients received a combination of tamsulosin 0.4 mg plus solifenacin 5 mg once daily again after verbal informed consent was obtained; whereas groups 1, 2, and 3 continued to receive their medication as originally set. From March 2015 to March 2016, we randomized patients into four groups: group 1 with 20 patients (12 men and 8 women, median age 53.5 years), group 2 with 20 patients (10 men and 10 women, median age 55 years), group 3 with 20 patients (9 men and 11 women, median age 53.5 years), and group 4 with 20 patients (11 men and 9 women, median age 44 years), respectively. At the end of our study, we had randomized 80 patients in group 1, 80 patients in group 2, 80 patients in group 3, and 20 patients in group 4 (Fig. 1).

FIG. 1.

CONsolidated Standards of Reporting Trials (CONSORT) diagram for study cohort.

The inclusion criteria were cases with ureteral stones <10 mm with or without concomitant dilation of renal pelvis, calices, or ureter and cases with dilation of ureter and/or pelvicaliceal system or any other reason. The exclusion criteria included patients with renal stones, pregnancy, patients with bilateral or “forgotten” stents, stent placement during percutaneous, laparoscopic or open transperitoneal procedures, patients with history of pelvic irradiation and/or surgical procedures in the minor pelvis, and patients with history of reconstructive ureteric surgical procedures. During the stenting period, analgesic intake was standardized with 4 weekly prescriptions of paracetamol (500 mg when needed, up to four times per day, total of 28 tablets). The overall analgesic intake was registered at the end of the 4-week period, with the total tablet intake documented and compared. The same Double-J ureteral stent was used (Percuflex plus, Boston Scientific, Natick, MA) in all patients. The stent size varied (6F/24 cm or 6F/26 cm); it was selected according to the patient's somatometric characteristics and was inserted under fluoroscopic control in all cases.

All consenting patients were fully informed regarding the potential side effects of tamsulosin and solifenacin. To assess the stent-related morbidity, patients completed the validated USSQ 1 and 4 weeks after stent insertion and 4 weeks after stent removal, as it was originally set by Joshi and colleagues.³ Given the fact that the USSQ validation process in Greek language is ongoing, all questionnaires were translated at the time of assessment by the same non-medical professional person with professional English language skills. The end of the study was 4 weeks after the stent removal with the final USSQ completed.

The USSQ is a self-administered multidimensional measure designed for use in clinical and research settings. It evaluates stent-related morbidity in six sections, including urinary symptoms, body pain, general health, work performance, sexual matters, and additional problems with each section calculated score providing the urinary index score (UIS), pain index score (PIS), general health index score (GHIS), work performance score (WPS), and sexual matters score (SMS), respectively.

Statistical analysis

We chose a sample size of 60 patients in each group to have an 80% power at 5% significance level to detect a 4% difference in UIS, a 4% difference in PIS, a 9% difference in GHIS, a 9% difference in WPS, and a 23% difference in SMS. Later, we chose a sample size of 20 patients in each group to have an 80% power at 5% significance level to detect a 7%, 7%, 14%, 14%, and 35% difference, respectively. Statistical analysis was performed by using the Kruskal-Wallis test for independent samples for non-normally distributed variables and the chi-squared test (or Fisher's exact test in cases with small numbers in cells) to check for independence between categorical variables. One-way analysis of variance (ANOVA) for independent samples was applied to compare for differences in case of normally distributed continuous variables, and the T-test (or Wilcoxon rank-sum test if not normal data) was used to test the hypothesis that two independent samples are from populations with the same distribution. The results were considered significant at p < 0.05. Descriptive statistics, including mean, median, and range for continuous variables, and number and percentage for categorical variables were obtained for each study variable. All analyses were carried out in STATA/SE 14.1 (Copyright 1985–2015 StataCorp LP).

Results

Patient characteristics are detailed in Table 1. There were no statistical significant differences between patients' characteristics among groups. After adding the group 4 in our randomization, a significant difference regarding intervention was observed (p = 0.002). In total, 124 patients underwent SWL, with 89 (71.8%) of patients being stone free, 69 had URL (all of them stone free), and 67 patients had an indwelling stent inserted because of ureteral and/or pelvicaliceal system dilation or any other reason.

Table 1.

Patient Characteristics

Initial randomization (April 2012 to March 2015)
Characteristic	Placebo, n (%)	Solifenacin, n (%)	Tamsulosin, n (%)	p
Age	45 (19–80)	49 (20–81)	48 (17–78)	0.852^a
Gender				0.656^b
Female	28 (47)	33 (55)	30 (50)
Male	32 (53)	27 (45)	30 (50)
Intervention				0.414^b
SWL	33 (55)	33 (50)	41 (68)
URL	18 (30)	21 (35)	13 (22)
None	9 (15)	6 (10)	6 (10)
Sexually active
First week	42 (70)	45 (75)	38 (63)	0.380^b
Fourth week	44 (73)	45 (75)	41 (68)	0.698^b
Post-stent	50 (83)	45 (75)	40 (67)	0.108^b
Employment status				0.360^c
Full time	23 (38)	23 (38)	25 (42)
Part time	11 (18)	12 (20)	12 (20)
Retired on health ground	5 (8)	0 (0)	3 (5)
Student	4 (7)	2 (3)	4 (7)
Unemployed	4 (7)	12 (20)	7 (12)
Retired for other reason (incl. age)	13 (22)	11 (18)	9 (15)

Further randomization (March 2015 to March 2016)
Characteristic	Placebo, n (%)	Solifenacin, n (%)	Tamsulosin, n (%)	Combined, n (%)	p
Age, median (range)	53.5 (27–79)	55 (19–81)	53.5 (19–84)	44 (17–70)	0.186^a
Gender					0.801^b
Female	11 (55)	10 (50)	8 (40)	9 (45)
Male	9 (45)	10 (50)	12 (60)	11 (55)
Intervention					0.002^c
SWL	4 (20)	2 (10)	2 (10)	9 (45)
URL	7 (35)	2 (10)	2 (10)	6 (30)
None	9 (45)	16 (80)	16 (80)	5 (25)
Sexually active
First week	13 (65)	14 (70)	13 (65)	13 (65)	0.983^b
Fourth week	13 (65)	14 (70)	13 (65)	13 (65)	0.983^b
Post-stent	13 (65)	13 (65)	13 (65)	14 (70)	0.983^b
Employment status					0.424^b
Full time	8 (40)	5 (25)	7 (35)	9 (45)
Part time	6 (30)	4 (20)	4 (20)	4 (20)
Retired on health ground	3 (15)	1 (5)	1 (5)	0 (0)
Student	0 (0)	2 (10)	2 (10)	4 (20)
Unemployed	0 (0)	2 (10)	2 (10)	2 (10)
Retired for other reason (incl. age)	3 (15)	6 (30)	4 (20)	1 (5)

ANOVA.

Chi-squared test.

Fisher's exact test.

SWL = extracorporeal shockwave lithotripsy; URL = ureteroscopic lithotripsy.

Our overall results are listed in Table 2. All of our patients were divided into two cohorts: the first with initial randomization in three groups of patients (tamsulosin, solifenacin, and placebo groups, respectively) and the second with further randomization after the addition of group 4 (patients with tamsulosin plus solifenacin combination).

Table 2.

Overall Results

Initial randomization (April 2012 to March 2015)
Characteristic	Placebo, mean	Solifenacin, mean	Tamsulosin, mean	p	p-Value surgery correlation	p-Value adjusted for surgery
Urinary index score
First week	19.9	17.7	17.2	<0.001^a	0.579^b	<0.001
Fourth week	19.1	14	14	<0.001^a	0.695^c	<0.001
Post-stent	12.6	11.8	11.7	<0.001^d	<0.001^c	<0.001
Pain index score
First week	16.9	14.8	14.1	<0.001^d	0.930^c	<0.001
Fourth week	16.5	12	11.9	<0.001^a	0.267^c	<0.001
Post-stent	8.7	9.1	8.6	0.083^d	<0.001^c	0.463
General health index score
First week	8.6	8	7.8	0.002^a	0.106^c	0.002
Fourth week	8.2	7.1	6.9	<0.001^d	0.939^c	<0.001
Post-stent	6.4	6.3	6.2	0.794^d	0.046^c	0.719
Work performance score
First week	7.2	7.1	7.2	0.937^d	0.063^c	0.724
Fourth week	7.3	6.8	7.1	0.021^a	0.065^b	0.010
Post-stent	6.9	7	7	0.749^d	0.003^c	0.971
Sex matters score
First week	3.1	3	3.4	0.057^d	0.060^c	0.341
Fourth week	2.7	2.3	2.5	0.168	0.003^c	0.105
Post-stent	2.4	2.1	2.1	0.006^d	<0.001^c	0.096

Further randomization (March 2015 to March 2016)
Characteristic	Placebo, mean	Solifenacin, mean	Tamsulosin, mean	Combined, mean	p	p-Value surgery correlation	p-Value adjusted for surgery
Urinary index score
First week	16.3	17.5	16.8	16.5	0.930^d	0.031^c	0.866
Fourth week	18.4	14.6	14.8	14.1	<0.001^a	0.223^c	<0.001
Post-stent	12.8	13.9	13.8	12	0.004^d	<0.001^c	0.189
Pain index score
First week	17.5	16.1	16.1	16.3	0.808^a	0.008	0.585
Fourth week	17.9	14.5	13.4	13.3	<0.001^a	0.198	<0.001
Post-stent	10.4	13.4	11.6	9	0.003^a	0.803	0.003
General health index score
First week	7.6	7.8	8.1	7.8	0.881^d	0.025^c	0.327
Fourth week	8.5	7.3	7.2	7.2	0.012^d	0.002^c	0.004
Post-stent	6.5	7.2	7.1	6.4	0.023^d	0.629^c	0.005
Work performance score
First week	6.1	7.3	7.3	7.3	0.001^a	0.989	0.001
Fourth week	6.3	6.9	7.2	7	0.052^d	0.822	0.039
Post-stent	6.1	6.9	7.2	6.9	0.005^d	0.808^c	0.002
Sex matters score
First week	3	2.4	2.4	3.5	0.005^a	0.001^c	0.258
Fourth week	3	2.3	2.3	2.5	0.185^d	0.282^c	0.073
Post-stent	3	2.3	2.1	2.4	0.067^d	0.744^c	0.047

ANOVA.

T-test.

Wilcoxon rank-sum test.

Kruskal-Wallis test.

In the first cohort, patients on either tamsulosin or solifenacin expressed a significantly lower UIS, PIS, and GHIS (overall p < 0.001, p < 0.001 with stent in situ and p = 0.002 and p < 0.001 with stent in situ, respectively), with the latter reflecting better general health. SMS was also positively influenced in the post-stenting period (p = 0.006), whereas there was a marginally non-significant change in the first week (p = 0.057). As far as WPS is concerned, it was positively influenced significantly only in the fourth week (p = 0.021). Interestingly, when the p-value is adjusted for intervention (cases with SWL and URL and cases with simple stent insertion), our results were similar, apart from SMS. This fact shows that the positive impact of agents is significant, irrespective of any kind of intervention. There was no significant difference among the groups on tamsulosin or solifenacin, favoring the one or the other regimen as better in relation to stent symptom relief.

In the second cohort, patients on combination of drugs expressed a significant improvement in UIS and PIS in the fourth week with stent in situ (p < 0.001 and p < 0.001, respectively) and WPS after stent removal (p = 0.001) compared with patients on tamsulosin, solifenacin, or placebo, with no significant improvements in other USSQ sections. Solifenacin significantly improved GHIS in the fourth week (p = 0.012) and SMS in the first week (p = 0.009). Both tamsulosin and solifenacin significantly improved SMS in the first week (p = 0.009), whereas both aforementioned regimens and their combination significantly improved WPS in the first week (p < 0.003). When the p-value is adjusted for intervention in this cohort, our results showed the same fluctuations, a fact showing that the positive impact of agents and their combination is significant, irrespective of any kind of intervention. There was no significant difference among the groups on tamsulosin, solifenacin, or their combination, favoring the one, the other, or their combination as better in relation to stent symptom relief, although our sample was relatively small. What is of importance in this cohort of patients is that combination therapy showed a marginally significant improvement when administered to male patients (p = 0.048) in UIS in the fourth week.

No patients had to discontinue medication because of side effects or underwent stent removal before the due date.

Discussion

This study is the first in the literature to evaluate the effectiveness of two commonly used pharmaceutical agents, tamsulosin and solifenacin, either sole or in combination compared with placebo in relieving stent-related symptoms. Tamsulosin is an already known agent with proven effectiveness in stent-related morbidity,⁶ whereas solifenacin has been used to overcome symptoms caused by the involuntary contraction of the bladder due to the distal end of the stent in the urinary bladder, with encouraging results.⁷ We planned to use the combination of the two agents in an attempt to combine their activity and to compare the combination effectiveness with tamsulosine, solifenacin, and placebo.

This comparison constitutes the originality of our work, since it is evaluated with the proper use of USSQ in the first and the fourth week with the indwelling stent in situ and 4 weeks after stent removal.⁵ The use of such a validated questionnaire facilitates the uniform evaluation of different stents and the efficacy of medication for stent-related morbidity. In the literature, although there are numerous prospective studies using several agents, they do not assess the USSQ as it is suggested by its inventors in their vast majority. As a result, we cannot properly evaluate or compare their results nor can we earn safe conclusions regarding effectiveness issues.

The initial concept of a α-blocker administration in patients with indwelling stents was that these patients were suffering of symptoms mimicking benign prostatic hyperplasia-related symptoms. In the pioneering study of Deliveliotis et al.,⁸ it was the first time where alfuzosin, a competitive antagonist of α₁-receptors, was used in clinical practice to improve stent-related symptoms. In their prospective randomized placebo-controlled study, the authors concluded that alfuzosin improved symptoms and quality of life, whereas sexual life and general health were better preserved. The pitfall of that study was that they only administered the USSQ 4 weeks after stent insertion. After the aforementioned study, there have been several other trials that are prospective in nature, evaluating orally administered agents and dosages, but with considerable heterogeneity in design and methodology. Even the most recent of them^{6,7,9

–20} (Table 3), although the USSQ is the only validated questionnaire for the assessment of stent-related symptoms per se with established accuracy, failed to uniformly use it in the stent morbidity evaluation. Apart from that, only almost half of them were placebo controlled,^{6,7,10,13,14,16,19,20} four studies had a control group,^11,15,17,18 and two studies were not controlled at all.^9,12

Table 3.

Recent Studies Evaluating Agents for the Treatment of Stent-Related Symptoms

Study	No. of patients	Pharmaceutic agent (Pts)	USSQ	Results
Dellis et al.⁶	150	Tamsulosin 0.4 mg/day (50)	Yes	Lower UIS compared with placebo both during the stenting and the post-stenting period (p < 0.001).^a
				Mean PIS in men is significantly less (p < 0.001) with stent in situ and not significantly (p < 0.128) after stent removal in all groups, in women significantly less in the first and fourth week with the stent in situ (p < 0.001) and during the post-stent period (p < 0.038).^a
		Alfuzosin 10 mg/day (50)		GHIS is significantly less in all groups of patients (p < 0.002, p < 0.001, and p < 0.001, respectively, in the first week, fourth week, and post-stenting).^a
				QoW is not significantly influenced.^a
		Placebo (50)		SL is positively influenced in the first week and the post-stent period (p < 0.045 and p < 0.004, respectively), with no statistically significant change in the fourth week (p < 0.073).^a
				QoL is positively influenced in the fourth week with the stent in situ and in the post-stent period (p < 0.028 and p < 0.037, respectively), with no impact in the first week.^a
Maldonado-Avila et al.⁹	51	Tamsulosin 0.4 mg/day (17)	Yes^b	Mean UIS of 22.3 vs 15.5 in Tamsulosin+Oxybutinin group (p < 0.001) at first and third weeks, respectively.
		Oxybutinin 5 mg/day (17)		Mean QoW score is 6.6 vs 8.1 (p = 0.049), favoring Tamsulosin.
				Mean SL score is 0.5 vs 1.5 (p = 0.03).
		Tamsulosin+Oxybutinin/day (17)		No significant difference between PIS and GHIS.
Aggarwal et al.¹⁰	153	Tadalafil 5 mg/day (52)	Yes ^b	Tadalafil and Tamsulosin significantly decreased UIS, PIS, SL, GHIS, and QoW at third week compared with first week.
		Tamsulosin 0.4 mg/day (51)		Decrease in UIS, QoW, and additional problems are similar in Tadalafil and Tamsulosin groups.
				Improvement in PIS, SL, and GHIS is significantly more in Tadalafil group than in Tamsulosin or placebo.
		Placebo (50)		In multivariate analysis to assess symptom score difference of first and third week among three groups, both Tadalafil and Tamsulosin are comparable in relieving UIS, GHIS, and QoW; Tadalafil is more effective in relieving PIS, SL, and additional problems than Tamsulosin (p < 0.05).
El-Nahas et al.⁷	131	Placebo (44)	Yes^b	Tamsulosin and Solifenacin show significantly better scores than the control group in the total score (p = 0.002 and p < 0.001, respectively).
		Tamsulosin 0.4 mg/day (44)		The comparison between Tamsulosin and Solifenacin shows statistically significant differences in favor of Solifenacin in total USSQ score (p < 0.001) and the scores of all domains except SL.
		Solifenacin 5 mg/day (43)
Park et al.¹¹	81	Control (23)	Yes^b	UIS at week 2 and week 6 are not significantly different between the four groups (p = 0.323 and p = 0.430, respectively).
		Tamsulosin 0.2 mg/day (20)		The other five USSQ domain scores at week 2 are similar among the four groups; QoW at week 6 are different between the four groups (p = 0.022).
		Solifenacin 5 mg/day (20)		UIS at week 2 and week 6 are similar [Tamsulosin (p = 0.595 and p = 0.615, respectively), Solifenacin (p = 0.182 and 0.571, respectively)].
		Tamsulosin+Solifenacin/day (18)		All other scores, except GHIS, at week 2 are not different (all p > 0.05).
				GHIS for Tamsulosin at week 2 are significantly higher than those who did not take Tamsulosin (p = 0.038), indicating a poorer QoL for patients on Tamsulosin.
Singh et al.¹²	60	Lactobacillus 400 M/day (30)	Yes^b	In patients receiving Tamsulosin, there is a significant decrease in the UIS (p < 0.001), PIS (p < 0.001), QoW (p < 0.01), need for antibiotics (p < 0.02), and number of hospital visits (p < 0.01) at the end of the fourth week.^a
		Tamsulosin 0.4 mg/day (30)
Tehranchi et al.¹³	94	Placebo (24)	No	Decrease in the total IPSS scores (p = 0.002), irritative subscore (p = 0.039), QoL (p = 0.001), flank pain (p = 0.013), voiding pain (p = 0.01), and amount of analgesics used (p = 0.02) in the groups.
		Terazosin 2 mg twice/day (23)		Obstructive subscore and suprapubic pain do not improve significantly (p = 0.251 and p = 0.522, respectively).
		Tolterodine 2 mg/day (23)		Terazosin plus Tolterodine significantly reduce total IPSS, irritative symptoms, QoL, flank pain, voiding pain, and analgesic use.^a
		Terazosin+Tolterodine/day (24)
Shalaby et al.¹⁴	327	Placebo (81)	No	Statistically significant differences in all scores in favor of Tamsulosin, Solifenacin, and combination (p < 0.005).^a
		Tamsulosin 0.4 mg/day (82)
		Solifenacin 10 mg/day (80)
		Tamsulosin+Solifenacin/day (84)		Combination shows statistically significant differences in total IPSS, QoL score, and OABq score as compared with Tamsulosin and Solifenacin (p < 0.001).
Lee et al.¹⁵	140	Control (70)	Yes^b	Solifenacin has a significantly lower total symptom score (p < 0.01), urgency score (p < 0.01), and urgent incontinence score (p < 0.01) compared with the control.
		Solifenacin 10 mg/day (70)		As for stent-related pain, solifenacin has a significantly lower item flank pain score (p < 0.01), abdominal pain score (p < 0.01), urethral pain score (p < 0.01), and hematuria score (p < 0.01).
Nazim and Ather¹⁶	130	Alfuzosin 10 mg/day (65)	Yes^b	Alfuzosin has significantly less UIS (p < 0.05), QoL (p < 0.001), and PIS (p < 0.001).^a
		Placebo (65)
Kuyumcuoglu et al.¹⁷	108	Diclofenac 50 mg 3 times/day (23)	No	None of the medical therapies could prevent the increase of IPSSs, IPSS-QoL, and OABq scores.^a
		Flavoxate 200 mg 3 times/day (22)
		Tolterodine 4 mg/day (21)
		Doxazosin 4 mg/day (21)
		Control (21)
Lim et al.¹⁸	168	Control (48)	No	Combination has a significant positive impact compared with the control (p = 0.015) and Tamsulosin (p = 0.031) in the IPSS total score and compared with the control in the obstructive subscore (p = 0.003).
				There are no statistically significant differences in the irritative subscore, QoL, or VAPS (p = 0.075, 0.068, and 0.088, respectively).
		Tamsulosin 0.2 mg/day (43)		On the day of stent removal, all scores are significantly different in each group, except the VAPS (p < 0.001, p < 0.001, p < 0.001, and p < 0.001).
				All scores are significantly lower in combination, except for VAPS.
		Solifenacin 5 mg/day (45)		In Tamsulosin only, the obstructive score is significantly lower.
				The total and irritative subscores are significantly lower in Solifenacin.
		Tamsulosin+Solifenacin/day (32)		Stent-related symptoms improve more in the combination group than in the control.
				Symptoms do not significantly improve in the other groups.
Mokhtari et al.¹⁹	73	Terazosin 2 mg/day (37)	No	Terazosin improves mean VAS score (p < 0.001), flank pain during urination (p < 0.001), and all IPSS criteria (p = 0.0001).^a
		Placebo (36)
Sivalingam et al.²⁰	80	Tamsulosin+Tolterodine/day (44)	Yes^b	There is no significant difference in urinary symptoms, body pain, and activities of daily living from baseline to just before stent removal (p = 0.95, 0.40, and 0.95, respectively).
		Tamsulosin 4 mg/day (36)		Both groups show improvement in urinary symptoms from the time of initial stent insertion to just before stent removal (difference −0.50 for combination therapy and −0.40 for monotherapy). The mean stent indwelling time does not differ between groups (p = 0.67).
				No significant impact on results (p = 0.64).

Compared with placebo.

Improper USSQ assessment.

GHIS = General Health Index Score; IPSS = International Prostate Symptoms Score; OABq = Overactive Bladder Questionnaire; PIS = Pain Index Score; Proper = first and fourth week with stent in situ, fourth week post-stenting; QoL = quality of life; QoW = quality of work; SL = sexual life; UIS = Urinary Index Score; USSQ = Ureteric Symptom Score Questionnaire; VAPS = Visual Analogue Pain Scale; VAS = Visual Analog Scale.

Furthermore, several meta-analyses have been published during the past 5 years^21

–26 (Table 4). The common conclusion of all of them is that α-blockers significantly improve UIS and PIS. In all other meta-analyses' end-points, there is a wide spectrum of conclusions from significant to insignificant improvements of other USSQ sections, whereas there are cases where a meta-analysis could not be performed due to insufficient or unavailable data on relevant USSQ sections.^22,23

Table 4.

Meta-Analyses of Randomized Controlled Trials on Treatment Agents for Stent-Related Symptoms

Study	No. of studies	No. of Pts	Agents (no.)	Comments
Yakoubi et al.²¹	4	341	Alfuzosin 10 mg (3)	α-Blockers associated with a significant improvement in UIS (p < 0.005), PIS (p < 0.0004), and GHIS (p < 0.001).
			Tamsulosin 0.4 mg (1)	α-Blockers not associated with a benefit in QoW and SL (p = 0.24 and p = 0.33, respectively).
Lamb et al.²²	5	416	Alfuzosin 10 mg (3)	α-Blockers associated with improvement in UIS and PIS (p < 0.001, p < 0.001, p = 0.032, significant and p = 0.327, respectively) and (p = 0.04, p = 0.02, p = 0.047, significant and p = 0.107, respectively).
			Tamsulosin 0.4 mg (2)	α-Blockers improved GHIS, where reported, but not significantly.
				No evidence of improvement in QoW and SL, where reported.
Zhou et al.²³	13	1408	Alfuzosin 10 mg (6)	α-Blockers significantly decreased UIS (p = 0.0001) and PIS (p < 0.00001).
			Tamsulosin 0.4 mg (5)	No further meta-analyses on other outcomes of USSQ were performed because of insufficient available data.
			Tamsulosin 0.2 mg+Tolterodine 4 mg (1)	Antimuscarinics decreased the total IPSS (p < 0.00001), QoL (p = 0.001), and VAPS (p < 0.00001).
			Tamsulosin 0.4 mg+Solifenacin 10 mg (1)	Combination therapy improved statistically significantly total IPSS (p < 0.00001), VAPS (p = 0.01), and QoL (p < 0.00001).
			Terazosin 4 mg+Tolterodine 2 mg (1)
Kwon et al.²⁴	7	696	Alfuzosin 10 mg (5)	α-Blockers significantly improved UIS (p < 0.001) and PIS (p < 0.001).
			Tamsulosin 0.4 mg (3)
Zhang et al.²⁵	14	1075	Alfuzosin 10 mg (4)	α1-Blockers significantly improved UIS (p = 0.001) and IPSS voiding symptom sub-score (p = 0.02) but not IPSS storage symptom sub-score (p = 0.18).
			Doxazosin 4 mg (1)	α1-Blockers significantly improved PIS (p < 0.00001) and VAPS (p < 0.0001).
			Tamsulosin 0.2 mg (1)	α1-Blockers significantly improved QoL (p = 0.0009) and IPSS (p = 0.02).
			Tamsulosin 0.4 mg (6)	α1-Blockers significantly improved GHIS (p < 0.00001), but not SL (p = 0.77), QoW (p = 0.40), or OABq (p = 0.19).
			Terazosin 2 mg (2)
He et al.²⁶	16	1489	Alfuzosin 10 mg (4)	α-Blockers significantly improved UIS (p < 0.00001), PIS (p < 0.00001), GHIS (p < 0.00001), SL (p < 0.0001), and QoL (p < 0.00001) but not QoW (p = 0.09) or additional problems score (p = 0.32).
			Doxazosin 4 mg (1)
			Tamsulosin 0.4 mg (9)
			Tamsulosin 0.2 mg (1)
			Terazosin 2 mg (2)

Our study is very important for several reasons. First of all, it is the first and sole study with a direct comparison of an α-blocker, an anticholinergic, and their combination with placebo and it was designed to overcome all aforementioned limitations regarding diversity of data assessment. Although in the literature there were several studies comparing the impact of α-blockers with anticholinergics or combination therapies on stent-related urinary symptoms, work performance, or sexual life, there were no published data comparing an α-blocker with an anticholinergic, with their combination and placebo. In addition, we have to underline that our study is one of the very few in the relevant literature where the validated USSQ is properly assessed for all included patients as it has originally been introduced by Joshi and colleagues.³ The rationale for questionnaire administration to determine baseline symptoms after stent removal is that many patients before stent insertion will have significant pain from a ureteral stone, whereas some of them might have complaints because of the intervention as well. Furthermore, for the first time, it is evaluated whether SWL or the endoscopic intervention influences the effectiveness of administered agents. This could be used to better cover our patients with painkillers or a combination of agents in any case of intervention, especially complicated ones or SWL in cases of larger stone burdens.

Of course, our study has several drawbacks. First, our sample size, although the second biggest in the recent literature, was statistically small to detect small differences, especially between the isolated agents and their combination. We evaluated the impact on patients' life for certain agents only, not for new agents, such as silodosin or mirabegron. Although the USSQ is self-administered, since there is no validated translation of USSQ in Greek, we were forced to translate all questionnaires at the time of assessment. No patients discontinued medication or their combination because of side-effects; however, we did not formally evaluate any side effects caused by their use. The fact that we included and compared different interventions might be reserved as a limitation, but since the intervention per se is proved statistically insignificant we retrospectively consider this variety an advantage. Finally, although we tried to evaluate and compare the combination of tamsulosin and solifenacin with tamsulosine, solifenacin, and placebo, the fact that we further randomized patients in a second cohort perhaps weakens our study's statistical power.

Conclusions

Adopting the proper use of USSQ, apart from confirming tamsulosin and solifenacin's positive impact on several aspects of patients' lives, it seems that their combination is further more efficient compared with each one of them and placebo in certain USSQ aspects, although larger populations are needed to strengthen statistical power. Interestingly, combination therapy seems to have a marginally significant positive impact on men UIS. Since new agents have already shown up and added in our armamentarium in the α-blockers family as well as mirabegron, further research is needed to determine whether these new agents or their combination with already existent formulas could offer more in stent-related symptoms management. Randomized controlled studies with larger patient populations, even multicenter ones, could earn more accurate and safe conclusions regarding benefits or pitfalls in the field of ureteral stent-related symptom relief.

Footnotes

Author Disclosure Statement

No competing financial interests exist.

Abbreviations Used

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