Treatment of OAB – QOL Perspectives

LUTS and OAB: underscoring the impact

Lower urinary tract symptoms (LUTS) represent a non-sex-specific, non-organ-specific group of urinary symptoms, which are sometimes age related and progressive.¹Chapple CR, Wein AJ, Abrams P, et al. Eur Urol. 2008 Sep;54(3):563-9.   A combination of these symptoms may be seen in different disorders, though dependent on the nature of their presentation and temporal relationship to the micturition cycle, they are divided into three broad categories – storage, voiding, and postmicturition symptoms (Table 1).²Andersson KE. Neurourol Urodyn. 2007 Oct;26(6 Suppl):934-47.  ^,3Abrams P, Cardozo L, Fall M, et al. Urology. 2003 Jan;61(1):37-49.   Herein, overactive bladder (OAB) is the one symptom complex that is considered synonymous with the storage subcategory of LUTS. This affiliation has also been affirmed by the International Continence Society (ICS), which defines OAB as a condition with “urgency, with or without urge

incontinence, usually with frequency and nocturia“.⁴Jayarajan J, Radomski SB. Res Rep Urol. 2013 Dec 6;6:1-16.   The condition is quite common in practice, and can be seen in individuals of both sexes and all age groups. Yet, despite this epidemiological and clinical significance, and effective management strategies being available, OAB frequently remains underdiagnosed and undertreated, accounting for significant quality-of-life (QOL) concerns to the affected.^5-95) Colli E, Digesu GA, Olivieri L. Expert Opin Investig Drugs. 2007;16(7):999-1007.
6) Wolff GF, Kuchel GA, Smith PP. Res Rep Urol. 2014 Oct 3;6:131-8.
7) Hashim H, Abrams P. Curr Opin Urol. 2007 Jul;17(4):231-6.
8) Vrijens D, Drossaerts J, van Koeveringe G, et al. J Psychosom Res. 2015 Feb;78(2):95-108.
9) Wagner TH, Hu TW, Bentkover J, et al. Am J Manag Care. 2002 Dec;8(19 Suppl):S598-607.   A number of barriers, including embarrassment, poor communication, and low patient adherence, contribute to this undertreatment of patients with burdensome urinary symptoms, indicating an ongoing need for screening to reduce the time gap between symptom onset and diagnosis and treatment of OAB.¹⁰Filipetto FA, Fulda KG, Holthusen AE, et al. BMC Family Practice 2014;15:96.  

Epidemiology of OAB and future trends

OAB affects approximately 17% of the general population, including both men and women, and its prevalence increases with the aging population. The EPIC study – a large population-based survey – assessed the prevalence rates of OAB, urinary incontinence, and other LUTS in 19,165 individuals > 18 years; and found that OAB was more prevalent than all other types of urinary incontinence combined (11.8% vs. 9.4%).¹¹Irwin DE, Milsom I, Hunskaar S, et al. Eur Urol. 2006 Dec;50(6):1306-14; discussion 1314-5.   The differential pattern of symptomatic presentation also revealed that nocturia was the most prevalent LUTS in both men (48.6%) and women (54.5%). Relating to categories of LUTS, the prevalence of storage symptoms was higher than that of voiding and post-micturition symptoms combined (Figure 1).¹¹Irwin DE, Milsom I, Hunskaar S, et al. Eur Urol. 2006 Dec;50(6):1306-14; discussion 1314-5.   Later, a secondary analysis of data from EPIC study demonstrated substantial overlap of storage, voiding, and post-micturition symptoms among all men, and in men with OAB symptoms; hence, men with OAB symptoms were more likely to experience multiple LUTS subtypes.¹²Irwin DE, Milsom I, Kopp Z, et al. European Urology 2009;56:14-20.  

Trends in prevalence: a cause of concern in near future, particularly in Asia

Trends related to worldwide estimates are in line with the high prevalence of LUTS, OAB, urinary incontinence and LUTS suggestive of bladder outlet obstruction; and suggest that the numbers of affected individuals will increase with time. In a study designed to estimate and predict worldwide and regional prevalence of LUTS, OAB, urinary incontinence and LUTS suggestive of bladder outlet obstruction from 2008 to 2018, consistent with the ICS symptom definitions in adults aged >20 years; Irwin DE et al¹³Irwin DE, Kopp ZS, Agatep B, et al. BJU Int. 2011 Oct;108(7):1132-8.   used an estimation model, with gender- and age-stratified prevalence data from the EPIC study and gender- and age-stratified worldwide and regional population estimates from the US Census Bureau International Database. The authors demonstrated an estimated 45.2%, 10.7%, 8.2% and 21.5% of the 2008 worldwide population (4.3 billion) to be affected by at least one LUTS, OAB, urinary incontinence and LUTS/ bladder outlet obstruction, respectively; and projected that by 2018, an estimated 2.3 billion individuals will be affected by at least one LUTS (18.4% increase; 63.6% in total), 546 million by OAB (20.1%), 423 million by urinary incontinence (21.6%) and 1.1 billion by LUTS/ bladder outlet obstruction (18.5%) (Figure 2).¹³Irwin DE, Kopp ZS, Agatep B, et al. BJU Int. 2011 Oct;108(7):1132-8.   Of note, the regional burden of these conditions is estimated to be greatest in Asia owing to significant increase in the numbers of affected individuals.

Evaluation in OAB patients

Clinically; in absence of a well-defined etiology, and seeing the definition provided by the ICS – “urgency, with or without urge incontinence, usually with increased frequency and nocturia” – OAB is better considered a symptom complex, and not a diagnosis with specific pathophysiological implications. As such, while diagnosis remains mostly empiric, the extent of evaluation would be highly specific to the individual patient as they present varied combination of storage, voiding and post-micturition symptoms.⁶Wolff GF, Kuchel GA, Smith PP. Res Rep Urol. 2014 Oct 3;6:131-8.   Even so, seeing that the severity of OAB symptoms progresses dynamically, and is also sustained over time, the importance of symptom assessment, impact on QOL, physical examination and urinalysis is emphasized for such patients presenting with LUTS.¹⁴Abrams P, Chapple C, Khoury S, et al. J Urol. 2009 Apr;181(4):1779-87.   The history, which per se seems the key constituent in the workup, should be directed at eliciting the presence, quality and quantity of urine by including information on the voiding frequency and fluid intake.⁴Jayarajan J, Radomski SB. Res Rep Urol. 2013 Dec 6;6:1-16.   Urgency is a principal symptom of OAB and thus assessing this symptom and its impact on the health-related QOL (HRQOL) is important.¹⁵Ku JH, Kim SW. Handbook of Disease Burdens and QOL Measures 2010;pp 2195-2210.   Besides, history related to prior surgery, medications, medical conditions and symptoms suggestive of bladder dysfunction/urinary problems will help to identify and/or exclude possible causes of voiding dysfunction or comorbidities, which may complicate treatment. In men, the presence of locally advanced prostate cancer should be excluded as

it can also produce LUTS, and neurologic examination should assess lower extremity neuromuscular function and anal sphincter tone besides patient’s general mental status and ambulatory status. Urinalysis is required to screen for hematuria and urinary tract infection (UTI), whereas recording of urinary flow rate and measuring postvoid residual urine are other optional tests which may follow initial evaluation.

QOL considerat ions

The term QOL is widely used but often without a clear definition and commonly linked to the World Health Organization’s definition of health. However, it is now known that QOL in not just about health status. As follows, the term has gradually superseded the concept of ”well-being,” and serious attempts have been made to understand and define its meaning using both subjective and objective measures. A consensus in this context supports that it should be viewed as a multidimensional concept, with dimensions grouped under broad headings of physical, functional, psychological, and social health (Figure 3).¹⁶Chartier-Kastler E, Davidson K. European Urology Supplements 2007; 6:576-584.   These broader headings should include important concepts, such as energy/vitality, pain, depression, and other cognitive functions, which can be explored through indepth interviews or questionnaires. The latter approach is though definitely better since self-reported levels of QOL have wide fluctuations that are typically quite high; this finding is however often influenced by the interviewing methods, depending on how and in what order the questions are asked and answered.

QOL in OAB: from personal to social impact

Even if not life-threatening, the impact of OAB is enormous owing to its considerable detrimental effect on multiple aspects of patient’s QOL. The impact is especially significant when the OAB is “wet” and associated with incontinence, resulting in notable physical, psychological, occupational, domestic, and social stigmas.⁶Wolff GF, Kuchel GA, Smith PP. Res Rep Urol. 2014 Oct 3;6:131-8.  ^,7Hashim H, Abrams P. Curr Opin Urol. 2007 Jul;17(4):231-6.  ^,17-1917) Stewart WF, Van Rooyen JB, Cundiff GW, et al. World J Urol. 2003;20(6):327-36.
18) Sacco E, Tienforti D, D’Addessi A, et al. Open Access Journal of Urology 2010;2:11-24.
19) Heidler S, Mert C, Wehrberger C, et al. Urol Int. 2010;85(4):443-6.     As such, OAB patients have clinically and significantly lower QOL scores, higher depression scores, and poorer quality of sleep, when compared to matched controls. These patients have been observed to exhibit strong association with depression and anxiety, with characteristic implications on patients’ behaviour. This may in fact be evident by the finding that OAB patients often feel anxious in unfamiliar surroundings, and may be preoccupied with concerns such as avoiding activities far from home, locating the closest bathroom, looking for passageway seating, and estimating the time until their next work break.¹⁸Sacco E, Tienforti D, D’Addessi A, et al. Open Access Journal of Urology 2010;2:11-24.   These personal implications frequently traduce socially, and anxiety, embarrassment, frustration, annoyance, depression, and fear of odor can negatively impact daily activities, such as travel, interpersonal relationships and sexual function, resulting in social isolation. In isolation, the effect on sexual function – leading to an impaired sex life — can result in greater emotional problems, worse marital relationships, and lower sexual satisfaction.

Besides urgency; often a considerable proportion of the bother associated with OAB may be attributable to nocturia, which is another highly prevalent bothersome storage symptom in patients with LUTS and OAB.¹¹Irwin DE, Milsom I, Hunskaar S, et al. Eur Urol. 2006 Dec;50(6):1306-14; discussion 1314-5.  ^,12Irwin DE, Milsom I, Kopp Z, et al. European Urology 2009;56:14-20.   In part, this could be directly related to the effect of nocturia on the quality of sleep, which in turn may have a significant negative impact on how the patient feels the next day; by reducing patient’s vitality and concentration, negatively affecting the mood, and ultimately impairing their overall QOL. Both men and women with OAB (both wet and dry) are likely to have high rates of daily work interference, report absenteeism, and have significantly reduced work productivity.¹⁸Sacco E, Tienforti D, D’Addessi A, et al. Open Access Journal of Urology 2010;2:11-24.   It thus reflects that beyond clinical impacts, LUTS also have significant economic implications attributable to indirect costs of absenteeism (missing work) or decreased productivity at work.²⁰Hu TW, Wagner TH, Bentkover JD, et al. Urology. 2003 Jun;61(6):1123-8.   Some of the clinical and economical impact may also be related to patients’ compliance to treatment, which may prove challenging due to the long-term nature of therapy. It has been seen that treatment persistence rates are generally low in OAB, especially in patients less than 60 years of age.⁴Jayarajan J, Radomski SB. Res Rep Urol. 2013 Dec 6;6:1-16.  ^,21Wagg A, Compion G, Fahey A, et al. BJU Int. 2012 Dec;110(11):1767-74.   Furthermore, not only OAB affects life of the patients, but that of family members and care-givers as well. Family members often report that the patient’s urinary frequency limits several activities they could do together due to patient’s persistent, and often urgent, need to find a toilet. As well, the partner’s OAB may have dominant emotional impact including anxiety, embarrassment, anger, irritation, stress, frustration, annoyance and strain on the relationship.¹⁸Sacco E, Tienforti D, D’Addessi A, et al. Open Access Journal of Urology 2010;2:11-24.  

Measures for assessment of QOL in OAB

In practice, while OAB is often diagnosed empirically, however, physician’s only assessment of the disease burden is often inaccurate and non-reproducible, suggesting the need for improved methods for assessment of the disease impact on QOL. The rationale is that since OAB is defined by symptoms, the patient is the best source of information for assessing the impact on HRQOL.²²Margolis MK, Vats V, Coyne KS, Kelleher C. Patient. 2011;4(3):177-87.   As follows, psychometrically robust self-completion patient-reported questionnaires have been developed that are supposed to provide a valid, reproducible and rapid assessment of patient-reported disease impact by objectively eliciting the impact of symptoms. These questionnaires encompass different variables related to the bother associated with symptoms, interference with daily activities, urinary continence, sexual functioning and HRQOL, and thus help in not only identifying the burden of the disease but are also useful in evaluating efficacy of an intervention.

Generally, varieties of patient-derived outcome (PRO) questionnaires are available to measure the HRQOL; and can be broadly classified into two major categories: generic questionnaires and diseasespecific questionnaires. Generic instruments measure broad aspects of health, thus being suitable for a wider range of patient groups and even for screening in the general population. In fact, they can be applied to patients with any medical condition to provide a measure of morbidity. Incidentally, the Medical Outcomes Survey 36-item short form (SF-36) is the commonly used generic HRQOL questionnaire in LUTS research; consisting of a single item assessing health transition, and an 8-scale profile of physical and mental health. Use of SF-36 in different studies has repeatedly shown that OAB patients have impaired HRQOL when compared to the general population. Short-form versions of SF-36 (SF-20 and SF-12) have also been developed.¹⁸Sacco E, Tienforti D, D’Addessi A, et al. Open Access Journal of Urology 2010;2:11-24.  

While generic questionnaires measure the multidimensional nature of health status, disease specific questionnaires are designed to measure specific impact of a particular disease. Therefore, while the former (generic questionnaires) are suitable for a broad range of illnesses and populations but may be less sensitive to clinically relevant change in conditions like OAB, disease-specific questionnaires are better suited to measure the specific impact of a particular disease on the QOL. In fact, it is seen that these condition-specific questionnaires offer greater sensitivity and responsiveness to change in QOL assessment of specific patient groups. These diseasespecific questionnaires can be either specific to certain types of problem, i.e., lower urinary tract dysfunction (e.g., KHQ, BFLUTS, I-QOL) or a specific aspect of that problem, i.e., OAB specific (e.g., OAB-q). Per se, the OAB-questionnaire (OAB-q) is validated as the most widely used condition-specific instrument designed specifically for the OAB patients. It is a multi-item symptom-based questionnaire, consisting of an 8-item symptom bother scale and 25-item HRQOL scale with four domains: coping, concern/worry, sleep and social interaction (Table 2; page 8).^23-2623) Coyne K, Margolis MK. Available at: http://www.ics.org/Abstracts/Publish/180/000198.pdf [Accessed on 9/2/2015].
24) Lin Y, Chou EC. Incont Pelvic Floor Dysfunct 2009; 3(Suppl 1):9-14.
25) Coyne K, Revicki D, Hunt T, et al. Qual Life Res. 2002 Sep;11(6):563-74.
26) Donovan J, Bosch R, Gotoh M, et al. Available at: http://www.ics.org/Publications/ICI_3/v1.pdf/chap10.pdf n 10/2/2015].      OAB-q reliably discriminates between normal and clinically diagnosed continent and incontinent OAB participants, and demonstrates that both continent and incontinent OAB symptoms cause a significant negative impact on HRQOL. The questionnaire has been shown to be psychometrically valid with strong internal consistency, reliability and construct validity, and is widely accepted for measuring OAB-related symptoms and HRQOL, and evaluating treatment outcomes.¹⁸Sacco E, Tienforti D, D’Addessi A, et al. Open Access Journal of Urology 2010;2:11-24.   The Kings Health Questionnaire (KHQ) is another multi-dimensional disease-specific validated questionnaire with large number of items (33). Originally designed for women with urinary incontinence (UI), KHQ has been validated in both women and men to assess the impact of OAB on HRQOL,²²Margolis MK, Vats V, Coyne KS, Kelleher C. Patient. 2011;4(3):177-87.   but only in those whose symptoms include UI.¹⁸Sacco E, Tienforti D, D’Addessi A, et al. Open Access Journal of Urology 2010;2:11-24.   It has more than 30 linguistic validations, which make it ideal for assessment in multinational studies. The Bristol Female LUTS (BFLUTS) questionnaire²⁷Jackson S, Donovan J, Brookes S, et al. Br J Urol. 1996 Jun;77(6):805-12.   – developed to assess female LUTS with emphasis on quantifying the frequency and extent of UI – is also a 33-item questionnaire that may be used to screen patients for LUTS and obtain a brief yet comprehensive summary of the level and impact of urinary symptoms.¹⁸Sacco E, Tienforti D, D’Addessi A, et al. Open Access Journal of Urology 2010;2:11-24.   Numerous other questionnaires have been validated for use in patients with LUTS, including the Incontinence QOL Questionnaire (I-QOL), the Urogenital Distress Inventory (UDI), short-version of UDI (UDI-6), and the Incontinence Impact Questionnaire (IIQ) and its short-form (IIQ-7). The I-QOL consists of 22 items [further grouped into 3 subscales: avoidance and limiting behaviour (8 items), psychosocial impacts (9 items), and social embarrassment (5 items)],²⁸Chen G, Tan JT, Ng K, Iezzi A, Richardson J. Health and QOL Outcomes 2014;12:133.   that was designed as a QOL measure for people with UI, with particular reference to emotions and feelings.¹⁸Sacco E, Tienforti D, D’Addessi A, et al. Open Access Journal of Urology 2010;2:11-24.  

In addition to these multi-item questionnaires, some single-item summary questionnaires and severity scales have also been developed to assess the symptom complex and severity of symptoms. The OAB symptoms score (OABSS) by Homma et al, which integrates four symptoms (daytime frequency, nighttime frequency, urgency, and urgency incontinence) into a single score, is a valid symptom questionnaire to assess the symptom complex of OAB patients, and is useful for clinical practice (Table 3; page 9).²⁴Lin Y, Chou EC. Incont Pelvic Floor Dysfunct 2009; 3(Suppl 1):9-14.  ^,29Homma Y, Yoshida M, Obara K, et al. Available at: http://www.ics.org/Abstracts/Publish/43/000441.pdf [A/2/2015].   As urgency is the main symptom of OAB, OABSS by Homma et al aimed at showing a clear distinction between those with and without OAB. The score has been shown to roughly but sufficiently infer patient perceptions of bladder condition and symptom bother by estimating symptom severity with the OABSS.³⁰Homma Y, Gotoh M. BJU International 2009;104(7):968-972.   Blaivas and colleagues also developed a similar scale with 7-item symptom score, and found it valid for assessment of all aspects of OAB.²⁴Coyne K, Revicki D, Hunt T, et al. Qual Life Res. 2002 Sep;11(6):563-74.  ^,31Blaivas JG, Panagopoulos G, Weiss JP, et al. J Urol. 2007 Aug;178(2):543-7; discussion 547.   However, in contrast to the score by Homma et al, OABSS given by Blaivas et al quantifies all aspects of OAB, and provides graded response for urgency, but omits an evaluation of HRQOL; and thus appears more inclined towards OAB symptoms rather than QOL. The questions include one each for frequency, nocturia, urge incontinence, 3 for urgency, and one general question on bladder control (Table 4; page 10); the total score range is 0 to 28; the higher the score, the worse are the symptoms. Coyne et al further developed a single global question [Patient Perception of Bladder Condition (PPBC)] to assess overall bladder condition as perceived by the patient, and provide patients’ subjective measure of current urinary problems (Table 5; page 10).²⁴Lin Y, Chou EC. Incont Pelvic Floor Dysfunct 2009; 3(Suppl 1):9-14.  ^,32Coyne KS, Matza LS, Kopp Z, et al. Eur Urol. 2006 Jun;49(6):1079-86.  

Though not specific for the condition, Self-Assessment Goal Achievement (SAGA) questionnaire can also be used for initiating treatment and observing the response in OAB.³³Marschall-Kehrel D, Spinks J. European Urology Supplements 2011;10:23-27.   The score serves as a patient reported outcome measure designed to identify individual treatment goals and assessing treatment goal achievement in patients with LUTS; however, it can be used for patients with OAB as well as it allows physicians and patients to discuss and prioritize OAB symptoms and to establish realistic treatment expectations and goals, regardless of the treatment.

It is worth mentioning here that both multi-item and single-item questions have their advantages and limitations. While multi-item questionnaires are a rich source of information on numerous domains of patients’ QOL, the time taken to complete large number of items may make the patient uncomfortable, posing a limitation in clinical practice as scoring and quick interpretation is difficult. Single-item questions may seem practical here because of its concision and ease of use. However, single-item scores do not provide depth of information, as that provided by multi-item measures. As such, to identify individual’s

concerns and needs in conditions like OAB with multiple and assorted symptoms, where treatment may have differential effects on different domains of patient’s QOL, multi-item questionnaire seems more appropriate. This might be the reason why OAB-q is per se the most widely used validated condition-specific instrument specifically designed to assess symptom bother and QOL in the OAB patients.

Treatment in OAB patients

Similar to the tailored evaluation approach required in OAB patients, therapeutic interventions also need to be specific to the individual – it should start with education and behavioral therapy, and most importantly set feasible goals for the specific patient. Non-surgical approach is thus the mainstay of therapy for OAB, and it encompasses both pharmacological and non-pharmacological options. Individual choices amongst these options may frequently be used in combination for more effective clinical outcomes.⁴Jayarajan J, Radomski SB. Res Rep Urol. 2013 Dec 6;6:1-16.   Herein, non-pharmacological options include lifestyle and dietary modifications (Box 1), biofeedback, bladder training, and electrical stimulation.⁵Colli E, Digesu GA, Olivieri L. Expert Opin Investig Drugs. 2007;16(7):999-1007.  ^,34-3634) Suzuki S, Platz EA, Kawachi I, et al. Am J Clin Nutr. 2002 Apr;75(4):689- 97.
35) Rohrmann S, Giovannucci E, Willett WC, et al. Am J Clin Nutr. 2007 Feb;85(2):523-9.
36) Burgio KL, Locher JL, Goode PS. J Am Geriatr Soc. 2000 Apr;48(4):370-4.  

The significance of drug therapy

Even if there are numerous therapeutic options for OAB symptoms, pharmacotherapy holds specific significance as a treatment of choice in favor of its express association with improvements in symptoms and QOL.³⁷Basra RK, Wagg A, Chapple C, et al. BJU Int. 2008 Sep;102(7):774-9.   Additionally, pharmacological treatment of LUTS has also been shown to be economically cost effective regardless of the underlying cause.³⁸Rosenberg MT, Staskin DR, Kaplan SA, et al. Int J Clin Pract. 2007;61(9):1535-46.   In the past, medical therapy in males presenting with LUTS was disproportionately dominated by an emphasis only on obstructive pathology, reliant on the postulate that urinary urgency and frequency result because of incomplete emptying due to partial bladder outlet obstruction, whereas storage symptoms of OAB were infrequently treated. However, such an approach targeting only the obstruction is definitely not consistent with the ICS definition of OAB, which relies on interplay between the bladder and the outlet. The obstruction centered approach fails to consider the bladder’s role, and hence often fails to alleviate the storage symptoms of OAB; consequently, a considerable proportion of patients may be left undertreated. Overall, it thus seems prudent that in OAB, pharmacotherapy should be both ‘obstructioncentered’ and ‘symptom-centered’.

Anticholinergics in OAB

Pharmacological treatment of OAB patients commonly utilizes anticholinergic agents like oxybutynin, tolterodine and solifenacin.³⁹Madhuvrata P, Cody JD, Ellis G, Herbison GP, Hay-Smith EJ. Cochrane Database Syst Rev. 2012 Jan 8;1:CD005429. doi: 10.1002/14651858.CD005429.pub2.   However, issues related to tolerability and long-term compliance might be a limitation to use of anticholinergics, mainly in long-term; term; both peripheral and central adverse reactions have been reported with use of anticholinergic drugs.⁴Jayarajan J, Radomski SB. Res Rep Urol. 2013 Dec 6;6:1-16.  

Many studies though suggest that antimuscarinic therapy alone, or in combination with α1-adrenoceptor antagonists, can improve OAB symptoms in patients with and without bladder outlet obstruction.³⁸Rosenberg MT, Staskin DR, Kaplan SA, et al. Int J Clin Pract. 2007;61(9):1535-46.  ,⁴⁰Yamaguchi O, Aikawa K, Shishido K, et al. World J Urol. 2009;27(6):723-8.  ,⁴¹Chapple CR, Roehrborn CG. Eur Urol. 2006;49(4):651-8.   Antimuscarinics have in fact remained a mainstay of drug therapy for OAB,42 and hence frequently used as first-line with or without an alpha-blocker. This practice pattern is essentially supported by numerous trials which express the efficacy and safety of antimuscarinics in treating LUTS, alone, or in combination with alphablocker therapy.^42-4542) Chung DE, Sandhu JS. Curr Urol Rep. 2011;12(1):77-85.
43) Radomski SB. Can Urol Assoc J. 2014 Jul;8(7-8 Suppl 5):S148-50.
44) Abrams P, Andersson KE. BJU Int. 2007 Nov;100(5):987-1006.
45) Lee SH, Lee JY. Prostate Int 2014;2(2):43-49.   Additionally, the combination of 5-α-reductase inhibitors with antimuscarinic agents is another effective treatment.

Flavoxate: the first approved antispasmodic for OAB

As mentioned earlier, treatment of OAB with anticholinergic drugs has been considered hazardous because of concerns of adverse events, including acute urinary retention (AUR).⁴⁶Novara G, Galfano A, Secco S, et al. Eur Urol. 2008 Oct;54(4):740-63.  ,⁴⁷Armitage J, Emberton M. Curr Opin Urol. 2008 Jan;18(1):11-5.   Herein, flavoxate appears an appropriate alternative agent as it is largely devoid of anticholinergic side effects seen with other drugs; hence exhibiting an excellent tolerability profile (Table 6). It in fact enjoys the status of being the first antispasmodic agent approved by the Food and Drug Administration (FDA) for treatment of OAB symptoms.⁴⁸Hesch K. Proc (Bayl Univ Med Cent). 2007 Jul;20(3):307-14.  

Since its emergence in 1967, the drug has been used to treat several urogenital tract disorders regardless of the etiology, though its main indications have been OAB and urge symptomatology.⁴⁹Zor M, Aydur E, Dmochowski RR. Int Urogynecol J. DOI 10.1007/s00192-014-2585-5.   This rationale could be supported by the finding that flavoxate was found to increase bladder capacity significantly, without increasing the end-residual urine volume, and required no adjustment for renal or hepatic dysfunction.⁵⁰Pedersen E. Urol Int. 1977;32(2-3):202-8.  ,⁵¹Gu FL, Reng ZY, Shang GZ, et al. J Int Med Res. 1987 Sep- Oct;15(5):312-8.   Additionally, the presence of phosphodiesterase enzymes in the prostate and the detrusor muscle of the bladder also seem to validate application of flavoxate owing to its phosphodiesterase inhibitory effects; moreover, flavoxate has local anaesthetic and analgesic action as well. Such proposed favorable use of flavoxate has indeed been shown in clinical studies also. For instance in a drug utilization observation study of 1800 patients, subgroup of 618 patients without UTI or BPH, who were treated with flavoxate only, showed a reduction of dysuria (37%), nocturia (53%), and both daytime (61%) and nighttime urge (69%).⁵²Fehrmann-Zumpe P, Karbe K, Blessman G. Int Urogynecol J Pelvic Floor Dysfunct. 1999;10(2):91-5.  

In another study, flavoxate was found to completely cure the symptoms of urgency/incontinence in 67% patients with urgency/incontinence of various types; patients received 200 mg drug three times daily, orally, for 2 weeks. Flavoxate was also effective in 77.4% of patients refractory to previous anticholinergic treatment.⁵¹Gu FL, Reng ZY, Shang GZ, et al. J Int Med Res. 1987 Sep- Oct;15(5):312-8.   Likewise, similar clinical evidence exists to support the safety of flavoxate. While Gu et al,⁵¹Gu FL, Reng ZY, Shang GZ, et al. J Int Med Res. 1987 Sep- Oct;15(5):312-8.   in their study, documented that adverse events occurred only in 1.3% patients with urgency and urge incontinence treated with flavoxate; the drug trended to be superior even in comparative studies. For instance in a doubleblind multi-clinic crossover study comparing the efficacy and tolerance of a 4-week treatment course with flavoxate, with that of oxybutynin in women with idiopathic sensory or motor urgency (20 affected by sensory urgency and 21 by motor urgency);⁵³Milani R, Scalambrino S, Milia R, et al. International Urogynecology 1993;4(1):3-8.   flavoxate was found to have comparable efficacy to oxybutynin

in relieving the urge syndrome, but was associated with fewer and milder side effects. These evidences clearly suggest flavoxate an effective and well-tolerated drug for patients with OAB, which would help to alleviate the symptoms, and thus improve their QOL. The fact that OAB manifests with alterations in urodynamics further supports the use of flavoxate. Clinical studies have demonstrated that flavoxate improves the urodynamic parameters like volume at first urge, mean pressure during uninhibited detrusor contraction, end-residual volume, reduction in pressure, bladder capacity and pressure at capacity.⁵¹Gu FL, Reng ZY, Shang GZ, et al. J Int Med Res. 1987 Sep- Oct;15(5):312-8.  ,^53-5753) Milani R, Scalambrino S, Milia R, et al. International Urogynecology 1993;4(1):3-8.
54) Milani R, Scalambrino S, Carrera S, et al. J Int Med Res. 1988 May-Jun;16(3):244-8.
55) Gaudenz R, Weil A. Urol Int. 1980; 35(1):1-12.
56) Jonas U, Petri E, Kissel J. Eur Urol. 1979;5(2):106-9.
57) Milani R, Scalambrino S, Carrera S, et al. J Int Med Res. 1988 Jan-Feb;16(1):71-4.       Flavoxate may hence be used in patients with urgency/incontinence of various causes, who do not achieve symptom relief and QOL improvement with conservative methods. A recently published reevaluation of flavoxate in urogynecology also mentions that the minimal side effects and high tolerability of flavoxate make it worthy of consideration for treatment of several clinical urogynecological conditions, primarily OAB.⁴⁹Zor M, Aydur E, Dmochowski RR. Int Urogynecol J. DOI 10.1007/s00192-014-2585-5.  

Conclusion

OAB is an important lower urinary tract syndrome, which negatively impacts the QOL of millions of people worldwide, impairing several areas with physical, social, emotional and sexual limitations. The disease affects both men and women, though evaluation and treatment seems more intricate in males because of overlapping mechanisms for LUTS, BPH and OAB. While the diagnosis of OAB is often empiric and based on symptoms, use of a structured tool (questionnaire) is indeed superior to an unstructured interview in quantifying the symptom severity and frequency, and also evaluating treatment outcomes. A variety of such questionnaires are available for use in OAB patients, frequently showing that patients with OAB have health utility scores that are amongst the lowest than many other chronic conditions. OAB-q is the most widely used validated condition-specific instrument specifically designed to assess symptom bother and QOL in the OAB patients.

Despite availability of such validated scores and effective treatment options, many symptomatic patients remain untreated, in part due to underreporting. In addition, in many cases, physicians more likely use agents directed at the obstructive pathology to improve emptying, while underestimating the bladder component. For OAB, anticholinergics have been the mainstay of treatment, but their use may be limited by the side-effects. In this scenario, recent evidence suggests considering flavoxate as it has minimal side effects and high tolerability. Clinical studies have demonstrated that flavoxate improves the urodynamic parameters like volume at first urge, mean pressure during uninhibited detrusor contraction, end-residual volume, reduction in pressure, bladder capacity and pressure at capacity. Flavoxate may therefore be added to the regimen for more effective control of OAB in patients with persistent storage symptoms. The data also supports the combination of flavoxate and alpha-blockers in patients with concomitant OAB and bladder outlet obstruction, identifying it as a more appropriate choice for urgency/incontinence of various causes. The treatment is effective and welltolerated and would improve QOL, which per se is the cause of significant concern as it affects daily activities and living. Finally, it is important that physicians in care of such patients follow an individualized approach for overall improvement across different measures of patients’ QOL.

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