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Home , Darifenacin, Dysuria, Flavoxate, Oxybutynin, Phenazopyridine, Renal colic

Eur opean Rev iew for Med ical and Pharmacol ogical Sci ences 2016; 20: 3703-3712 in the symptomatic treatment of : a meta-analysis

P. SWEENEY 1, S. MUTAMBIRWA 2, N. VAN AN 3, J.B. SHARMA 4, P. VANAMAIL 5

1Urology Department, Mercy University Hospital, Grenville Place, Cork, Ireland 2Department of , Dr George Mukhari Academic Hospital/University of Limpopo, Limpopo, South Africa 3Urology Department, Binh Dan Hospital, Ho Chi Minh City, Vietnam 4Department of Obstetrics and Gynaecology AIIMS, New Delhi, India 5Bio Statistics, Department of Obstetrics and Gynaecology AIIMS, New Delhi, India

Abstract. – OBJECTIVE : Overactive bladder Key Words: is a syndrome of urinary frequency and ur - Clinical trial, Meta-analysis, Flavoxate, Placebo, gency, with or without urge incontinence, in the Over active bladder, Detrusor overactivity, Efficacy, absence of local pathological factors. Since Side effects, , Mixed Inconti - multiple causes are responsible for OAB, it re - nence, , Unpleasant , Stranguria. quires proper diagnosis and comprehensive management. For decades, flavoxate is a glob - ally used and accepted molecule by the urolo - gists and the general physicians for the symp - tomatic treatment of OAB. In spite of its exten - sive use in OAB, a meta-analysis of the avail - Introduction able publications for efficacy, safety and tolera - bility of flavoxate has not been conducted. This The International Continence Society defines paper evaluates the strength of evidence of overactive bladder (OAB) as a syndrome of uri - clinical effectiveness of safety and tolerability nary frequency and urgency, with or without urge of flavoxate in the symptomatic treatment of incontinence, which appears in the absence of lo - OAB. cal pathological factors 1. Incontinence, a bother - METHODS: Review articles, original studies some symptom of OAB, increases with age 2. and case reports on MEDLINE, the Cochrane Library, Google Scholar, Scirus, internal repos - Neurologic impairment, immobility, female gen - itory, etc. were searched using the keyword der, and history of hysterectomy are the risk fac - “flavoxate”. For the primary outcome, the com - tors for the development of OAB . Commonly parative data of flavoxate versus comparator urge incontinence coexists with stress inconti - was extracted for following parameters – over - nence , especially in women. all efficacy and its side effect profile. Similarly Detrusor overactivity is a predominant cause as for secondary outcome, data were extracted for the OAB . It may be either idiopathic or neu - for flavoxate per se for overall efficacy, fre - rogenic in origin. The common symptoms com - quency, urinary incontinence, mixed inconti - nence, nocturia, unpleasant urination, stran - plained by OAB patients are urinary urge incon - guria and its side effect profile and were ana - tinence, involuntary leakage accompanied by or lyzed using Comprehensive Meta-Analysis immediately preceded by urgency 3,4 . (CMA) software version 2.0. Prompt diagnosis is crucial for the comprehen - RESULTS: In the current meta-analysis, 43 rel - sive management of OAB . Treatment is instituted evant published studies were considered which according to the type of incontinence and in - clearly demonstrated that flavoxate had im - cludes behavioural training (prompted voiding, proved clinical efficacy than placebo, emeproni - um, propantheline, and . bladder training, pelvic muscle rehabilitation, CONCLUSIONS: Amongst all the interventions pelvic floor exercises), transcutaneous electrical studied, flavoxate was effective and well-tolerat - nerve stimulation, catheterization, use of ab - ed, with almost negligible side effects, making it sorbent pads or pharmacologic or surgical treat - worthy of consideration for the treatment of OAB. ment 5.

Corresponding Author: P. Vanamail, MD; e-mail: [email protected] 3703 P. Sweeney, S. Mutambirwa, N. Van An, J.B. Sharma, P. Vanamail

On the other hand, the pharmacological inter - The secondary outcome was to assess the ef - ventions for the treatment of OAB should focus on fect of flavoxate per se on overall efficacy, fre - patient benefit and therefore patient perceived out - quency, urinary incontinence, mixed inconti - comes, rather than simple symptom resolution nence, nocturia, unpleasant urination, stranguria , alone, should be taken into account 5. Moreover, the as well as its side effect profile in the sympto - efficacy of OAB therapy needs to be balanced matic treatment of OAB. against tolerability, since a low incidence of ad - verse events (AEs) improves compliance with treatment. This balance between efficacy and toler - Data Analysis ability should provide palpable benefits from pa - Meta-analysis was performed using Compre - tient’s perspective, and promote therapy persis - hensive Meta-Analysis (CMA) software version tence. Unfortunately, many older agents have mod - 2.0 procured from Biostat, Inc. USA. Mantel est clinical efficacy and are associated with unfa - Haenszel risk ratio (MH risk ratio) was accessed vorable side effects, leading to poor persistence . for ‘flavoxate versus comparator’ (i.e., placebo, Among various pharmacological interventions , phenazopyridine, emepronium, for the treatment of OAB, flavoxate has been propantheline) and event rate for flavoxate per se widely used and accepted among the urologists in the symptomatic treatment of OAB. Hetero - and the general physicians for decades globally 6. geneity between studies was accessed using Q We performed a meta-analysis on flavoxate to in - value and I square statistics using both fixed and vestigate, based on available evidence, its effica - random effect model. cy, side effects profile , and effects on frequency, urinary incontinence, mixed incontinence, noc - turia, unpleasant urination and stranguria (de - Results fined as slow and painful urination or burning) . The databases searches yielded 86 publica - tions pooled from PubMed, Google Scholar, Methods Medline , Cochrane Database and internal repos - itory 7-49 . According to our inclusion and exclu - Database Search and Data Extraction sion criteria , 43 relevant studies were identified The search was performed between June and (Figure 1) . August 2015 by using the keyword “ flavoxate ” on various search engines like Google Scholar, Medline, Cochrane Database, and personal col - Primary Efficacy Analysis lection of literature No restrictions in terms of publication date were applied. Flavoxate vs. Placebo In total, eight studies included 262 patients on Inclusion and Exclusion Criteria flavoxate and 233 patients on placebo. Of these Publications on either flavoxate versus com - studies, three showed a significant (p < 0.05) re - parator (placebo, oxybutynin, emepronium, duction in the risk with flavoxate as compared propantheline, phenazopyridine) or flavoxate per with placebo (Figure 2) . The overall effect size se in the treatment of OAB were included. Some favouring flavoxate was estimated to be 0.48 publications that were in non-English language (95% CI: 0.38-0.62 ) and it was statistically sig - and could not be translated to English were ex - nificant (Z = -5.721 ; p < 0.001). The Q test for cluded. heterogeneity indicates that the studies were ho - mogeneous [ p = 0.905; Q Value (I 2) = 2.774 Outcomes (0.00); df(Q) = 7]. The primary outcome was represented by the comparative assessment of flavoxate versus com - Flavoxate vs. Oxybutynin parator (placebo, phenazopyridine, oxybutynin, All the three studies that included oxybutynin propantheline, emepronium) for the overall effi - (101 patients in both the flavoxate and oxybu - cacy (defined as the global efficacy of treatment tynin group) show a similar efficacy of flavoxate with intervention in the management of OAB) and oxybutynin (Figure 2). The overall effect size and side effects profile in the symptomatic treat - favouring flavoxate was estimated to be 0.67 ment of OAB . (95% C.I: 0.38-1.17) , but it did not reach statisti -

3704 Flavoxate in the symptomatic treatment of overactive bladder: a meta-analysis

Figure 1. Flow Diagram of Meta-analysis.

cal significance (Z = -1.406; p = 0.160 ). The Q Flavoxate vs. Emepronium test for heterogeneity indicates that the studies Out of the three reports – involving 75 patients were homogeneous [ p = 0.477 ; Q Value (I 2) = on flavoxate and 104 patients on emepronium – 1.481 (0.00); df(Q) = 2 ]. one study showed that flavoxate is associated with significantly (p < 0.05) fewer side effects as Flavoxate vs. Others compared with emepronium (Figure 3). The Comparisons of flavoxate with emepronium or overall effect size favouring flavoxate was esti - phenazopyridine or propantheline was not ana - mated to be 0.32 (95% CI: 0.15-0.66 ) and was lyzed as the number of studies available were statistically significant (p = 0.002) . The Q test for less than three. However, flavoxate showed high - heterogeneity indicates that the studies were ho - er efficacy than emepronium in two studies 7,21 . In mogeneous [ p = 0.989; Q Value (I 2) = 0.023 other two studies 7,20 , flavoxate was overall more (0.00); df(Q) = 2]. effective than propantheline (in study 7, statistical significance was reached, p < 0.05). In another work 16 flavoxate was significantly more effective Flavoxate vs. Propantheline than phenazopyridine (p < 0.05). All the three papers comparing flavoxate with propantheline in terms of adverse effects showed a lower incidence of adverse effects Primary Safety Analysis with flavoxate (Figure 3). The overall effect size favouring flavoxate was estimated to be Flavoxate vs. Placebo 0.194 (95% CI: 0. 09-0.41 ) and it was statisti - In all the five studies that compared the safety cally significant ( p < 0.001 ). The Q test for het - of flavoxate (n = 181) with that of placebo (n = erogeneity indicates that the studies were ho - 191), the incidence of adverse events was compa - mogeneous [ p = 0.809; Q Value (I 2) = 0.425 rable in the two groups (Figure 3). (0.00); df(Q) = 2].

3705 P. Sweeney, S. Mutambirwa, N. Van An, J.B. Sharma, P. Vanamail

Figure 2. Comparison of overall efficacy of Flavoxate vs . Placebo/ Oxybutynin.

Flavoxate vs. Others Secondary Analysis Comparison of flavoxate versus oxybutynin or Supplementary Figures 1-8 summarize the re - phenazopyridine was not analyzed as the number sults of the secondary analysis on flavoxate per se . of studies available were less than three. One Of the 35 studies included in the efficacy study showed showed that side effect was signifi - analysis of flavoxate per se (n=2005), 19 showed cantly lower ( p < 0.05) in flavoxate (26.8%) significant results ( p < 0.05) . The overall effect compared to oxybutynin (90.2%) 15 . Further, com - size for efficacy favouring flavoxate was estimat - pared to phenazopyridine, side effects due to ed to be 0.71 (95% CI: 0. 70-0.74 ) and it was sta - flavoxate were markedly less but not statistically tistically significant (Z = -17.914; p < 0.001) significant 44 . (Supplementary Figure 1) .

3706 Flavoxate in the symptomatic treatment of overactive bladder: a meta-analysis

Figure 3. Comparison of overall safety of Flavoxate vs . Placebo/Emepromium/Propantheline.

3707 P. Sweeney, S. Mutambirwa, N. Van An, J.B. Sharma, P. Vanamail

The analysis of flavoxate on frequency (2 4 Nine reports (n = 92) have assessed the effect studies involving 989 patients ) showed that in all of flavoxate on unpleasant urination, and all individual studies frequency was decreased, showed some effect of this molecule – reaching reaching statistical significance in 11 individual statistical significance in two ( p < 0.05). The studies ( p < 0.05). The overall effect size for de - overall effect size was 0.74 (95% CI: 0.64-0.88), creasing frequency in favouring flavoxate was es - and it was statistically significant ( p < 0.001) timated to be 0.69 (95% CI: 0.66-0.72 ) and it (Supplementary Figure 6) . was statistically significant ( p < 0.001) (Supple - The effect of flavoxate on stranguria - from 13 mentary Figure 2) . studies involving 1300 patients - showed that in With respect to urinary incontinence, the effect all individual papers stranguria was decreased of flavoxate as derived from 21 reports involving and it was significantly decreased in 8 studies (p 2104 patients, was evident in all cases, reaching < 0.05). The overall effect size for decreasing statistical significance in 10 studies ( p < 0.05). stranguria with flavoxate was estimated to be The overall effect size for decreasing urinary in - 0.56 (95% CI: 0.53-0.59) , reaching statistical sig - continence with flavoxate was estimated to be nificance (p < 0.001) (Supplementary Figure 7) . 0.67 (95% CI: 0.65-0.69 ) and it was statistically Lastly , 19 work (n = 3039) were included in significant ( p < 0.000) (Supplementary Figure 3) . side effects profile analysis of flavoxate per se Similar findings were observed for mixed in - (Supplementary Figure 8) . Actual occurrence of continence (4 studies on 490 patients). This side effects due to flavoxate given in the forest symptom was decreased in all studies, reaching plot ranged from 0.8 to 26.8% with an overall in - statistical significance in one (p < 0.05). The cidence of 5.3% (95% CI: 0.04-0.06). However, overall effect size for decreasing mixed inconti - incidence due to each comparator per se may not nence with flavoxate was estimated to be 0.7 1 be discussed as all the reports were not included (95% CI: 0.67-0.75 ) and it was statistically sig - in the analysis. nificant ( p < 0.001) (Supplementary Figure 4) . The effect of flavoxate on nocturia was inves - tigated in 9 researches involving 1186 patients. Discussion In all studies, nocturia was decreased, and it was significantly decreased in three ( p < 0.05). The Overall, the results of the current meta-analy - overall effect size for decreasing nocturia with sis demonstrate clinically-relevant improvements flavoxate was estimated to be 0.63 (95% CI: in all evaluated parameters with flavoxate as 0.60-0.66), reaching statistical significance ( p < compared with all the comparators tested (Figure 0.001) (Supplementary Figure 5) . 4) . Of note, the prevalence of adverse events with

Figure 4. Meta-analysis Outcomes Matrix.

3708 Flavoxate in the symptomatic treatment of overactive bladder: a meta-analysis flavoxate was similar to what observed with flavoxate cured or greatly improved the syn - placebo. The effect of flavoxate was also evident drome in 81.6% of cases, while oxybutynin pro - when this drug was evaluated per se with respect duced the same effects in 78.9%. to a number of bothersome symptoms of OAB In the study 22 , with respect to uninhibited detru - including frequency, urinary incontinence, mixed sor contractions, 1200 mg/day was significantly incontinence, nocturia, unpleasant urination and superior to 600 mg/day. Assessment of urodynam - stranguria. ic variables showed volume at first urge increased However, some limitations should be taken in - significantly ( p < 0.01 ) compared with baseline by to account when evaluating the above-mentioned both the 600 and 1200 mg daily dosages. findings. First, the urodynamic parameters evalu - In the study 25 , improvement of first desire vol - ated (e.g., residual volume and bladder volume at ume, bladder capacity and pressure at capacity first urge) are continuous quantitative data and were clinically and statistically superior with require raw data to generate standard deviations; 1200 mg/day compared with 600 mg/day flavox - moreover, p-values were not available in most of ate hydrochloride. the publications. Therefore, the authors of all re - In the study 10 , the results of cystometrography searches should have been contacted to collect in 7 patients on flavoxate and 7 on placebo raw data , which was not feasible. Moreover, showed that the increase in bladder capacity and there were no head to head clinical trials of the reduction in pressure after flavoxate treat - flavoxate with antimuscarinics like , ment were statistically significant (p < 0.01) but solifenacin, tolterodine , etc . used in practice . not so in the case of placebo. Since pharmacodynamics was not considered for In the study 14 , 66.67% (12 out of 18 patients) meta-analysis, some individual studies and their of patients had decreased residual . results are discussed for the interest of clinicians. In the study 48 , 618 patients without urinary tract In the study 7, the average bladder capacity in - infections or benign prostatic hyperplasia were crease was 83 ml in patients on flavoxate, 39 ml treated with flavoxate only. Bladder volume at first on emepronium and 28 ml on propantheline. urge sensation increased by 55.1 ± 58.8 ml (36%), In the study 12 , nineteen cases of nervous pol - which was comparable to data from the entire lakiuria or female vesicopathy were treated with group (1800 patients). In 89.2% of all patients , the flavoxate 600 mg per day or placebo for one residual urine volume was stable or decreased. week. Cystometry was performed before and af - This work confirms that bladder volume at first ter the administration. Administration of flavox - urge tends to increase, in this instance by an aver - ate gave rise to increase of both at minimum and age of 60 ml (30%), an effect that tended to favour maximum desire to void, particularly that at the patients suffering from sensory urge incontinence. minimum desire. Resting intravesical pressure Average residual urine volumes decreased from both at the minimum and maximum desire to 16.7 ± 25.7 ml to 13.0 ± 20.7 ml in those patients void did not change significantly. Namely, the treated for no longer than 15 days, and the de - pressure curve showed a decline. It was speculat - crease for those treated longer than 15 days was ed that flavoxate might have some action on the similar: from 17.0 ± 29.4 ml to 12.0 ± 23.9 ml. center controlling desire to void besides its relax - For the entire group, a reduction from 21.8 ± 31.7 ing action on the vesical detrusor. Highly signifi - ml to 15.9 ± 25.4 ml was observed. In all patients, cant correlation was proved between the bladder 57.2% were reported to show no change in resid - volume at the minimum desire to void and the ual urine volumes, 32.0% showed a decrease and vesical capacity. The desire to void seemed to be 10.8% showed an increase. There are practically activated by intravesical pressure rather than by no differences between the various forms of urge vesical distention. incontinence, whether reported as sensory, motor In the study 15 , 41 patients (20 affected by sen - urge, or in combination with a stress component. sory urgency and 21 by motor urgency) complet - In the study 38 , the urodynamic data showed a ed both courses of treatment (Flavoxate vs. Oxy - diminishing of the mean pressure during uninhib - butynin) and were evaluated for urodynamic pa - ited detrusor contraction by almost 50% and the rameters. A statistically significant improvement delay of the onset by 80% of bladder capacity. in all urodynamic parameters was present at the However, average bladder capacity increase was end of both treatment courses. The effect on the only 19%. urodynamic parameters of the two treatments In study 23 , treatment with flavoxate did not in - was comparable. According to the patients, crease the end residual urine volume.

3709 P. Sweeney, S. Mutambirwa, N. Van An, J.B. Sharma, P. Vanamail

In the study 24 , an increased bladder capacity in Flavoxate, a flavone derivative, was the first the standing position and a decreased frequency drug to be approved in 1970 by the Food and of detrusor contractions was found in the urody - Drug Administration for the symptomatic treat - namic investigations. The residual urine re - ment of OAB and it has been widely used for mained constant. more than four decades 6. Flavoxate is available in In the study 26 , 12 out of 15 diagnosed motor tablets and it readily absorbed from the gastroin - urge incontinence patients, there was a decreased testinal tract and metabolized (peak blood levels detrusor contraction at average bladder capacity within 20 minutes from administration; plasma 213 ml. In a sensory urge incontinence patients, half-life: 3.5 hours). It is widely distributed in there was a statistically significantly reduction in tissues, liver, and bladder. The identified vesical pressure. principle metabolite is 3-methylflavone-8- In the study 18 , improvement occurred with carboxylic acid (MFCA) with urinary and faecal flavoxate in 75% of the patients with detrusor in - practically completing within 24 h 52 . stability and 50% of those with sphincter dys - Flavoxate exerts direct smooth function as compared to 25% detrusor and 36% activity, specific to by the inhibi - sphincter improvement with emepronium. Nei - tion of phosphodiesterase (PDE) activity and in - ther drug produced any significant increase in hibition of L-type Ca 2+ channels in human detru - residual urine. However, both drugs reduced in - sor 53-55 . It also has some local and anes - travesical pressure in the sphincter dysfunction thetic activity, without exerting any anticholiner - and detrusor instability groups. Flavoxate was gic activity 56 . more effective than emepronium. In patients with According to the Japanese Urological Associ - mixed pathology, flavoxate produced a decrease ation the level of recommendation for flavoxate (p = 0.05) in pressure while emepronium pro - is grade C (supported by level II clinical stud - duced an increase. Both drugs caused a delayed ies). Moreover, the Japanese Urological Associ - first sensation and strong desire in the patients ation underlined the optimal safety profile of and increased overall bladder capacity (Flavoxate flavoxate, as this drug is almost associated with more than emepronium , p < 0.02). Flavoxate was no adverse events: this finding may have great significantly more effective in the sphincter dys - importance in the chronic treatment of OAB, as function group ( p < 0.05) and in the mixed it is potentially associated with improved com - groups. pliance 56 . In the study 19 , both flavoxate and propanthe - line increased bladder capacity significantly, but flavoxate did not increase residual urine in con - Conclusions trast to propantheline. In the study 50 , in one group both flavoxate We believe that the results of the present and propantheline produced increase in bladder meta-analysis, which suggest the efficacy and capacity. Male patients appeared to be more re - safety of flavoxate in the treatment of OAB al - sponsive to flavoxate than propantheline while so when compared with some other molecules female patients showed a comparable increase used in the same setting lend further support to in capacity after both drugs. All changes were the position of the Japanese Urological Associ - statistically significant ( p < 0.05) when com - ation. In particular, the excellent tolerability pared to controlled values. Resting bladder makes flavoxate worthy of consideration as a pressure decreased significantly in female pa - choice in the symptomatic treatment of , tients after administration of either drug. In an - urgency, frequency and incontinence in OAB other group, flavoxate produced a significant in - patients. crease in bladder capacity in 13 of 21 patients while propantheline caused a similar change in ––––––––––––––––– –– 8 of 21 patients. Flavoxate also produced a Acknowledgements slightly greater increase in average bladder ca - Editorial assistance for the preparation of this manuscript pacity when compared to controlled bladder was provided by Luca Giacomelli, PhD, on behalf of Con - tent Ed Net; this assistance was funded by Recordati . measurements. In the study 51 , of the 40 patients with uninhib - –––––––––––––––– –-– –– ited contractions (UC), 18 patients reported posi - Conflict of Interest tive responses to flavoxate. The Authors declare that there are no conflicts of interest.

3710 Flavoxate in the symptomatic treatment of overactive bladder: a meta-analysis

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