Eur opean Rev iew for Med ical and Pharmacol ogical Sci ences 2015; 19: 719-731 Flavoxate: present and future D. ARCANIOLO, S. CONQUY 1, T. TARCAN 2 Department of Urology, University “Federico II”, Naples, Italy 1Department of Urology, Cochin Hospital, Paris Descartes University, Paris, France 2Department of Urology, Marmara University School of Medicine, Istanbul, Turkey Abstract. – OBJECTIVE: This non-systemat - condition 1,2 . This condition has a high preva - ic review discusses the available evidence on lence, which has been estimated to be 17%-32% the use of flavoxate in the treatment of overac - in the general population 3-7 . The prevalence of tive bladder (OAB). OAB increases with age, and reaches 40% in METHODS: Medline was searched for inclu - 4,8 sion of relevant studies. No limitations in time subjects aged > 75 years , and is higher in men 9 were considered. of Afro-American or Hispanic ethnicity . RESULTS: Flavoxate hydrochloride is an anti - A marked proportion of patients with OAB (up spasmodic agent which exerts an inhibition of to 68% according to the recent EpiLUTS survey) the phosphodiesterases, a moderate calcium experience a marked deterioration in health-relat - antagonistic activity, and a local anesthetic ef - ed quality of life (QoL) 10-13 . In particular, impor - fect. Results from preclinical and clinical stud - ies show that flavoxate significantly increases tant reductions in mental health, with a possible bladder volume capacity (BVC), with greater re - association with anxiety and depression, health sults if compared to other drugs such as eme - perceptions and sexual health have been pronium bromide and propantheline. Moreover reported 10,14-15 . Patients affected from OAB show in clinical trials, both versus placebo or versus increased pain when compared with unaffected active comparators, flavoxate treatment was as - controls 13 . Moreover, about 30% of patients with sociated with a significant improvement in dif - OAB suffer from incontinence 16 , and OAB is fre - ferent low urinary tract symptoms, such as di - urnal and night frequency, urgency and urinary quently associated with infections of the low uri - 17 incontinence, suprapubic pain, dysuria, hesi - nary tract . Lastly, OAB results in lower levels tancy and burning. In addition flavoxate was as - of work productivity 18 . sociated with an overall more favourable safety The above-mentioned consequences of OAB profile than competitors. are particularly evident in the elderly 19 . In addi - CONCLUSIONS: Several researches and a tion, there are a number of other consequences: number of years of clinical practice have proven the efficacy and tolerability of flavoxate for instance, urinary urgency, nocturia and incon - administration in the treatment of OAB and as - tinence may be associated with an increased oc - sociated symptoms. However, new studies are currence of falls and fractures. Therefore, health - necessary to collect more evidence on the role care costs related to OAB will increase with the of this molecule in the treatment of OAB and to increasing life expectancy of the population 20 . further explore its use in other indications such Treatment of OAB may consist of behavioral as symptomatic treatment of lower urinary tract training (prompted voiding, bladder training, infections. pelvic muscle rehabilitation), non-pharmacologi - cal measures such as transcutaneous electrical Key words: nerve stimulation, catheterization, and use of ab - Flavoxate, OAB, Urodynamics, Lower urinary tract in - sorbent pads, and pharmacological therapy 17,21 . In fections. particular, pharmacological treatment for OAB is based on a number of medications like darife - nacin, flavoxate hydrochloride, hyoscyamine, Introduction oxybutynin chloride, tolterodine tartrate, trospi - um chloride, scopolamine transdermal, and so - Overactive bladder (OAB) syndrome is de - lifenacin succinate and the novel fesoterodine fu - fined by the International Continence Society marate 21,22 . (ICS) as ‘urgency, with or without urge inconti - Despite the availability of multiple pharmaco - nence, usually with frequency and nocturia in ab - logical options, uncertainty remains on the opti - sence of an underlying metabolic or pathological mal drug of choice 21,23,24 . Anticholinergic agents Corresponding Author: Davide Arcaniolo, MD; e-mail: [email protected] 719 D. Arcaniolo, S. Conquy, T. Tarcan are widely used, but when using these agents, it Criteria for Selection of Evidence is necessary to adequately consider adverse reac - tions due to systemic blockade of muscarine re - With the aim to identify the key publications ceptors, according to the Guidelines issued by on flavoxate for potential inclusion in this pa - Neurogenic Bladder Society 25 . per, a literature search was conducted in the on - Among different drugs, flavoxate hydrochlo - line database Medline using different combina - ride was the first antispasmodic agent to be ap - tions of pertinent keywords: “flavoxate ” AND proved by the FDA for the treatment of OAB 26 . (“overactive bladder ” OR “urinary inconti - This molecule is widely used in clinical practice, nence ”) Only articles written in English lan - and its efficacy and safety have been tested in guage were selected. The search was last updat - several clinical trials. The mechanism of action ed on the 17 th May 2013, without any limitation (MoA) of flavoxate also suggests the potential on the publication date. use of this molecule in indications other than Articles were selected for inclusion according OAB, such as low urinary infections , in combina - to their relevance, as judged by the Authors; tion with antibiotics. other references could also be retrieved by man - This review will discuss available evidence on ually browsing the reference list of the identi - the use of flavoxate in the treatment of OAB, and fied articles, and other papers from Authors’ will comment on the potential applications of personal collections of literature could be con - this drug. sidered as well. Figure 1 . A, Inhibition of phosphodiesterase activity in bladder tissue induced by aminophylline, flavoxate and MFCA. B, Calcium antagonist activity of flavoxate on Guinea Pigs. 720 Flavoxate: present and future Mechanism of Action tivity 30,27 . In Guinea Pigs, flavoxate reduced peri - staltic motility, endoluminal pressure and longi - Flavoxate, administered as a prodrug (flavox - tudinal muscle contractility, thus, showing a my - ate hydrochloride) , acts as a direct spasmolytic orelaxant effect. In the same test, anticholinergic on smooth muscle and maintains anticholinergic compounds such as atropine, hyoscine and eme - as well as local analgesic properties 21 . This drug pronium failed to relax this tissue. In another se - exerts an inhibition of the phosphodiesterases, a ries of experiments the effects of flavoxate and moderate calcium antagonistic activity, and a lo - anticholinergic drugs on the contraction elicited cal anesthetic effect 27 . by vagal electrical stimulation of the guinea-pig In particular, the phosphodiesterase enzymes isolated stomach in toto were assayed: the results play a key role in the activity of the detrusor mus - obtained suggest that the action of flavoxate is cle of the bladder; therefore, the inhibition of these due to direct smooth muscle relaxation and does enzymes exerted by flavoxate contributes to a re - not involve anticholinergic activity 30 . duction of the contraction of this muscle. Of note, the inhibitory effect of flavoxate on the phosphodi - esterase activity in the bladder tissue is greater than Urodynamic Effects that associated with aminophylline, a non-selective inhibitor of phosphodiesterase (Figure 1A) 28-30 . The urodynamic effects of flavoxate were in - Flavoxate also presents a calcium antagonist vestigated in a number of preclinical studies. activity, as shown by studies on Guinea Pigs (Fig - More than 30 years ago, a preliminary experi - ure 1B) 29 . More in detail, flavoxate suppresses mental study 33 showed that both flavoxate and carbachol- and calcium ion (Ca 2+ )-induced con - propantheline significantly increased bladder ca - tractions of isolated detrusor strips in a noncom - pacity (from 383 ml at baseline to 425 ml with petitive and a competitive manner, respectively 31 . flavoxate and to 550 ml with propantheline). In addition, animal studies show that intra - However , the two drugs differed in their effect on venous flavoxate suppresses both initial phasic, residual urine: flavoxate induced a decrease in and later tonic, bladder contractions induced by volume from 60 ml at baseline to 45 ml, while electrical stimulation of the distal end of the pelvic propantheline administration resulted in an in - nerve 31 . This action abolishes isovolumetric rhyth - crease in residual urine volume, up to 105 ml. mic bladder contractions and the associated effer - The effects of flavoxate on urodynamics, ent pelvic nerve activity, without any effect on compared with those associated with other baseline vescical pressure and afferent pelvic drugs used for the stabilization of the detrusor nerve activity. When administered in cerebral ven - muscle, were further investigated in a rat model tricles or intrathecally, flavoxate abolishes isovolu - (Figure 2A and B) 34 . More in detail, emeproni - metric rhythmic bladder contractions. In cats, um bromide, oxybutynin and nifedipine affect - flavoxate microinjected into the nucleus reticularis ed, in a dose-dependent fashion, the micturition pontis