Overactive bladder (OAB) is a group of symptoms defined by the International Continence Society as urinary urgency, with or without urge incontinence, usually along with frequent urination and waking at night to urinate, when there are no local or metabolic causes to explain these symptoms [1]. The term "overactive bladder" is used when there is no proven infection or other clear cause [2]. Worldwide, about 11% of people aged 20 or older have OAB symptoms, and this number was expected to rise by 20% to 546 million by 2018, mainly because of an aging population [3]. OAB becomes more common as people get older. The EPIC study found that OAB affected 8% of men and 9% of women under 30, rising to 15% and 16% in those aged 65–69, and to 21% and 22% in people 70 and older [4]. In Pakistan, a cross-sectional study reported that 23.28% of women had OAB symptoms [5]. OAB symptoms often occur together with detrusor overactivity seen in urodynamic tests, but they can also result from other types of bladders or urethral dysfunction [6]. According to the current ICS definition, urgency is the main symptom, as it leads to other issues like frequent urination, waking at night, and urge incontinence [7]. Studies have shown that urinary incontinence leads to significant healthcare costs. For example, in the United States, the economic burden of OAB was estimated at 12 billion USD in 2000 [8], and in Sweden, urinary incontinence accounts for about 2% of national healthcare costs [9]. OAB also lowers quality of life and overall health, especially as it becomes more common with age. Aging is a major risk factor for OAB because of changes in body tissues, other health conditions, lifestyle, and personal health factors [10]. Many medications have been tested in randomized controlled trials for OAB, including antimuscarinics, tricyclic antidepressants, desmopressin, hormone replacement therapy, β₃-adrenergic agonists, and botulinum toxin injections into the bladder [11]. Of these, antimuscarinic drugs such as oxybutynin, tolterodine, propiverine, trospium, darifenacin, solifenacin, flavoxate, and fesoterodine are still the main treatment [12]. These drugs have shown consistent effectiveness in many randomised controlled trials, with strong recommendations based on Level 1, Grade A evidence [13]. In a study by Kristen Hesch, taking tolterodine 2 mg twice a day for 12 weeks led to a 27% increase in the amount of urine passed each time, compared to a 7% increase with placebo [14]. Similarly, Drutz and colleagues found a 21% increase in urine volume with tolterodine, compared to only a 5% increase with placebo, and this difference was statistically significant [15]. So far, no studies have looked at how well tolterodine works for increasing urine volume per urination in Pakistani women. Given the high burden of OAB, this two-centre study will assess the effectiveness of tolterodine (2 mg twice daily) in women aged 20 and above. The results will help measure the clinical benefit in terms of increased urine volume and will be shared with local urologists and healthcare professionals to support better understanding and evidence-based treatment decisions.

This study took place from 11-03-2023 to 07-07-2023 at the Urology Outpatient Departments of Teaching Hospital Timergara and Regional Headquarter Hospital Skardu. It included 146 female patients aged 20 to 50 who met strict inclusion criteria. These included having at least one episode of urinary urgency per week, with or without incontinence, urinating at least eight times per day, and experiencing at least one episode of nocturia per night for more than three months. Patients were enrolled using consecutive non-probability sampling. Those with known causes of lower urinary tract symptoms, such as urinary tract infections, bladder stones, pelvic cancers, or stress incontinence, as well as those with significant post-void residual volume (150 ml or more), or any other condition or treatment history that could affect the results, were excluded to keep the study valid. Informed written consent was obtained from all participants. After baseline assessments, which included taking patient history, physical exams, and relevant tests like ultrasound and urine analysis, participants were randomly assigned to two equal groups using block randomisation. Group A received a placebo (Tab. Iberet Folic OD), and Group B received Tolterodine 2 mg twice daily along with the same placebo supplement. Both groups followed this treatment for four weeks. Urine volumes per micturition were measured before and after treatment. Data were collected using a structured form and analysed with SPSS version 20. For continuous variables such as age, OAB score, and urinary volumes, the mean and standard deviation were calculated. For categorical variables like efficacy, frequencies and percentages were used. Changes in urine volume per micturition were analysed by age to see if age affected the results. An independent-samples t-test compared mean differences, with p-values of 0.05 or less considered statistically significant

The patients were stratified into 2 groups at a 1:1 ratio. In Group A (Placebo Group), 73 patients received Tab. Ibret Folic once daily as a placebo, while in Group B (Treatment Group), 73 patients received Tolterodine 2mg twice daily and Tab. Ibret Folic once daily. All the patients were female. The Mean ± SD age of the study population was 34.09 ± 6.84 years. The youngest patient was 23 years old, and the eldest was 49. The Mean ± SD age of Group A (Placebo Group) was 33.90 ± 6.7 years, ranging from 24 years to 48 years. The Mean ± SD age of Group B (Treatment Group) was 34.28 ± 6.98 years, ranging from 23 years to 49 years. There was no statistically significant difference in age between the two groups (P-value = 0.76). The Mean ± SD OAB Score of the study population was 10.23 ± 2.78. The lowest score was 4, while the highest OAB Score was 14. The Mean ± SD OAB Score of Group A (Placebo Group) was 10.35 ± 2.78, while the OAB score for Group B (Treatment Group) was 10.10 ± 2.79. There was no statistically significant difference between the two groups with respect to OAB Score (P-value = 0.57). The Mean ± SD pre-treatment urine volume voided per micturition in the total study population was 190.71 ± 9.21 ml. The Mean ± SD pre-treatment urine volume voided per micturition in Group A was 191.13 ± 10.03 ml. The Mean ± SD pre-treatment urine volume voided per micturition in Group B was 190.30 ± 8.30 ml. There was no statistically significant difference between the two groups in pre-treatment volume (P-value = 0.57). The Mean ± SD post-treatment urine volume voided per micturition in the total study population was 226.50 ± 21.11 ml. The Mean ± SD post-treatment urine volume voided per micturition for Group A was 214.91 ± 21.35 ml, while that for Group B was 238.09 ± 13.0 ml. There was a statistically significant difference between the two groups (P-value < 0.0003). The Mean ± SD change in urine volume voided per micturition in the total study population was 35.78 ± 22.44 ml. The change in volume was significantly greater in Group B than in Group A (P-value < 0.0001). In our study, Tolterodine was found to be significantly more effective than placebo (P-value < 0.0001). In group A, 36.98% were efficacious, while in group B, Tolterodine was effective in 75.34% of patients. The change in urine volume voided per micturition was stratified by age. Patients were stratified into two subgroups: those below 35 years of age and those 35 years of age and above. Both intra-group and inter-group comparisons were done. There was no statistically significant difference between groups (i.e., group A and group B) regarding the change in urine volume voided per micturition in those below or above 35 years of age. However, the change in urine volume voided per micturition was significantly greater in Group B (Treatment group) than in Group A (Placebo group) in both subgroups. Tolterodine was significantly effective at increasing the volume of urine voided per micturition, irrespective of age group (P-value < 0.0001 for both age groups)

Table 01: Age of Study Population

P-value: 0.76

Table 02: Overactive Bladder Score (OABS)

P-value: 0.57

Table 03: Pre-treatment Volume of Urine Void per Micturition (ml)

P-value: 0.57

Table 04: Post-treatment Volume of Urine Void per Micturition (ml)

P-value < 0.0003

Table 05: Change in Volume of Urine Voided per Micturition (ml)

P-value < 0.0001

Table 06: Frequency Distribution of Efficacy

Chi square = 21.81
P-value < 0.0001

Table 07: Comparison of Change in Volume of Urine Voided per Micturition in Different Age Groups within Group A (Placebo Group)

P-value: 0.87

Table 08: Comparison of Change in Volume of Urine Voided per Micturition in Different Age Groups within Group B (Treatment Group)

P-value: 0.06

Table 09: Comparison of Change in Volume of Urine Voided per Micturition in Patients Below 35 Years of Age

P-value < 0.0001

 Table 10: Comparison of Change in Volume of Urine Voided per Micturition in Patients 35 Years and Above

P-value < 0.0001

Tolterodine was shown to be effective in managing overactive bladder symptoms compared to placebo in our two-centre study (p < 0.05) [16]. The safety and effectiveness of immediate-release tolterodine (Tolt-IR) in older adults were also studied in a multicenter, phase 3, randomized, double-blind, placebo-controlled trial over four weeks. This trial included 177 patients aged 65 and older (115 women and 62 men; mean age: 75 years, range: 62–92), all with urinary urgency, increased frequency (at least 8 times per 24 hours), and/or urgency incontinence (at least 1 episode per 24 hours), as recorded in micturition diaries [17]. Patients were randomly assigned in a 3:3:2 ratio to receive Tolt-IR 1 mg twice daily, Tolt-IR 2 mg

twice daily, or placebo. There were no significant changes in ECGs or lab results between groups. Both doses of tolterodine were generally well tolerated, with 87% of patients completing the study in each active group and 91% in the placebo group. Dry mouth was the only side effect reported more often in the Tolt-IR groups (30% with 1 mg and 48% with 2 mg) than in the placebo group (9%). Most cases were mild to moderate, and only 3% of patients on Tolt-IR stopped treatment due to dry mouth, compared to 2% in the placebo group. No patients developed acute urinary retention or central nervous system side effects. Tolt-IR 2 mg twice daily was significantly more effective than placebo in improving micturition measures. There was a significant reduction in daily micturition frequency (mean reduction: –0.7; 95% CI: –1.1 to –1.3; p = 0.0001), urgency incontinence episodes (mean reduction: –0.7; 95% CI: –1.3 to –0.2; p = 0.0074), and an increase in voided volume per micturition (mean increase: +16 mL; 95% CI: 5–30 mL; p = 0.0099) [18]. The 1 mg dose did not show significant changes in these measures. Another multicenter, single-blind study also supported the effectiveness and tolerability of tolterodine for OAB. In this study, 505 patients aged 18 and older with urinary frequency (at least 8 times per 24 hours) and urgency, with or without urge incontinence, were randomly assigned to receive either tolterodine 2 mg twice daily alone or with simplified bladder training (BT) [19]. A total of 501 patients (75% women) were included in the analysis (244 in the tolterodine + BT group, 257 in the tolterodine-only group). Voiding diary data were collected at 2, 12, and 24 weeks, along with patient-reported symptoms and side effects. Tolterodine alone significantly reduced voiding frequency and increased voided volume at all time points, and these improvements were even greater when combined with bladder training. By the end of the study, the median reduction in voiding frequency was higher in the tolterodine + BT group than in the tolterodine-only group (33% vs. 25%, p < 0.001), and the median increase in voided volume per void was 31% versus 20% (p < 0.001) [20]. Both groups had similar reductions in urgency episodes, and the median incontinence reduction from baseline was 87% in the combination group and 81% with tolterodine alone, though this difference was not statistically significant. Patient-reported improvement was slightly higher in the combination group (76% vs. 71%) [21]. Our results from this two-centre study are in line with international research. The mean increase in voided volume of 47.79 ml (about a 25% increase from baseline) in the tolterodine group compares well with the 27% increase reported by Hesch [14] and the 21% increase found by Drutz et al. [15]. The placebo response rate of 36.98% in our study is similar to the 30-40% usually seen in OAB trials, which shows the psychological aspect of the condition and the need for well-designed randomized controlled trials. These results confirm that tolterodine, especially at 2 mg twice daily, is an effective and generally well-tolerated treatment for OAB, including for patients from different backgrounds and treatment centers. The findings support its use as a first-line medication according to clinical guidelines [22–26]. Our two-centre study design improves the generalizability of these results, as patients came from different regions of Pakistan (Khyber Pakhtunkhwa and Gilgit-Baltistan) and represented a range of ethnic and socioeconomic backgrounds. This strengthens the external validity of our conclusions and supports recommending tolterodine as a first-line treatment for OAB in the Pakistani population.

Tolterodine is effective in patients with overactive bladder irrespective of the age and OAB Score at the time of initial presentation. The significant increase in voided volume per micturition (47.79 ml vs. 23.78 ml with placebo, p < 0.0001) demonstrates its clinical efficacy. The two-center study design confirms that these benefits are consistent across different patient populations and healthcare settings in Pakistan.

 Acknowledgement
The authors thank the staff at both study centers and all participating patients.

Conflict of Interest
None declared.

Funding
None.

Author Contribution
IK (Irshad Khan): conception, design, data acquisition (Timergara), drafting, critical revision. IA: data acquisition (Skardu), analysis, manuscript writing. GU: patient recruitment, data collection, literature review. AW: data acquisition, follow-up, center coordination. SH & IK (Irfan Khan): supervision, conception, design, analysis, writing, final approval. IU: interpretation of data. All authors approved the final manuscript.

Research Gap
No prior study in Pakistan has evaluated tolterodine's efficacy specifically using increase in voided volume per micturition as the primary outcome measure in female OAB patients, nor compared its effectiveness across different geographic regions (Khyber Pakhtunkhwa vs. Gilgit-Baltistan) within the country.

1. Yamaguchi, O., Honda, K., Nomiya, M., Shishido, K., Kakizaki, H., Tanaka, H., et al. (2007). Defining overactive bladder as hypersensitivity. Neurourology and Urodynamics, 26(6 Suppl), 904–907.
2. Morris, V., & Wagg, A. (2014). Does fesoterodine have a role in the treatment of poorly managed patients with overactive bladder? Drug Design, Development and Therapy, 8, 113–119.
3. Tahir, S., & Abdullah, A. (2014). Frequency of overactive urinary bladder in females and assessment of gynaecological and obstetrical risk factors for its worsening. Journal of Surgery International Pakistan, 19(1), 35–39.
4. Guralnik, M. L., Gimsby, G., Liss, M., Szabo, A., & O'Connor, R. C. (2010). Objective difference between overactive bladder patients with and without urodynamically proven detrusor overactivity. International Urogynecology Journal, 21(3), 325–329.
5. Saleem, A. (2011). In women with urinary incontinence how necessary is cystometry? Journal of the Pakistan Medical Association, 60(5), 356–359.
6. Natalin, R., Lorenzetti, F., & Dambros, M. (2013). Management of OAB in those over age 65. Current Urology Reports, 14(5), 379–385.
7. Qaseem, A., Dallas, P., Forciea, M. A., Starkey, M., Denberg, T. D., Shekelle, P., et al. (2014). Nonsurgical management of urinary incontinence in women: A clinical practice guideline from the American College of Physicians. Annals of Internal Medicine, 161, 429–440.
8. Ellsworth, P., & Kirshenbaum, E. (2010). Update on the pharmacologic management of overactive bladder: the present and the future. Urologic Nursing, 30(1), 29–38.
9. Ginsberg, D., Schneider, T., Kelleher, C., & Swift, S. (2013). Efficacy of fesoterodine compared with extended-release tolterodine in men and women with overactive bladder. BJU International, 112, 373–385.
10. Jayarajan, J., & Radomski, S. B. (2014). Pharmacotherapy of overactive bladder in adults: A review of efficacy, tolerability, and quality of life. Research and Reports in Urology, 6, 1–16.
11. Reynolds, W. S., McPheeters, M., Blume, J., & Surawicz, T. (2015). Comparative effectiveness of anticholinergic therapy for overactive bladder in women. Obstetrics & Gynecology, 125, 1423–1432.
12. Hesch, K. (2007). Agents for treatment of overactive bladder: A therapeutic class review. Proceedings (Baylor University Medical Center), 20(3), 307–314.
13. Drutz, H., Appell, R., Gleason, D., et al. (1999). Clinical efficacy and safety of tolterodine compared to oxybutynin and placebo in patients with overactive bladder. International Urogynecology Journal, 10, 283–289.
14. Yamaguchi, O., Honda, K., Nomiya, M., Shishido, K., Kakizaki, H., Tanaka, H., et al. (2007). Defining overactive bladder as hypersensitivity. Neurourology and Urodynamics, 26(6 Suppl), 904–907.
15. Guralnik, M. L., Gimsby, G., Liss, M., Szabo, A., & O'Connor, R. C. (2010). Objective difference between overactive bladder patients with and without urodynamically proven detrusor overactivity. International Urogynecology Journal, 21(3), 325–329.

Saleem, A. (2011). In women with urinary incontinence how necessary is