Conjoint Urological Society of Australia and New Zealand (USANZ) and Urogynaecological Society of Australasia (UGSA) Guidelines on the management of adult non-neurogenic overactive bladder.

Due to the myriad of treatment options available and the potential increase in the number of patients afflicted with overactive bladder (OAB) who will require treatment, the Female Urology Special Advisory Group (FUSAG) of the Urological Society of Australia and New Zealand (USANZ), in conjunction with the Urogynaecological Society of Australasia (UGSA), see the need to move forward and set up management guidelines for physicians who may encounter or have a special interest in the treatment of this condition. These guidelines, by utilising and recommending evidence-based data, will hopefully assist in the diagnosis, clinical assessment, and optimisation of treatment efficacy. They are divided into three sections: Diagnosis and Clinical Assessment, Conservative Management, and Surgical Management. These guidelines will also bring Australia and New Zealand in line with other regions of the world where guidelines have been established, such as the American Urological Association, European Association of Urology, International Consultation on Incontinence, and the National Institute for Health and Care Excellence guidelines of the UK.

Viscerosympathetic reflexes in human spinal cord injury: relationships between detrusor pressure, blood pressure and skin blood flow during bladder distension.

Autonomic dysreflexia, a dangerous and sustained increase in blood pressure brought about by widespread, reflexly generated vasoconstriction, can be induced by visceral or somatic sensory inputs originating below the lesion following spinal cord injury (SCI). We assessed whether cutaneous vasoconstriction below the lesion could serve as a proxy marker of incipient autonomic dysreflexia during bladder distension. Skin blood flow (pulse plethysmography), sweat release, blood pressure, heart rate, bladder and rectal pressures were recorded during routine cystometry (urodynamics) in 16 patients with SCI. Eight urological patients without SCI served as control subjects. In all SCI patients, who had sustained injuries 2 months to 44 years previously at levels C3-T3, bladder filling (mean ± SD, 339 ± 132 ml) induced increases in detrusor (bladder-rectal) pressure (52 ± 25 cmH(2)O) and cutaneous vasoconstriction in the fingers, but no consistent increases in sweat release. This occurred irrespective of whether the spinal lesions were complete [American Spinal Injury Association (ASIA) grade A, n = 6] or incomplete (ASIA B-D; n = 10). Group mean blood pressure for the SCI patients increased by 17 ± 15 mmHg, but in four patients the pressure decreased or did not change. Despite similar bladder volumes (423 ± 126 ml) in the control patients, the increases in detrusor pressure (14 ± 8 cmH(2)O) and blood pressure (9 ± 12 mmHg) were significantly smaller than in the SCI patients; moreover, there were no consistent changes in skin blood flow in the control subjects. In all SCI patients, changes in finger pulse amplitudes were inversely correlated to changes in detrusor pressure (mean r = -0.62 ± 0.17). Changes in finger pulse amplitudes correlated inversely to changes in blood pressure in nine of 15 patients. It is concluded that cystometry in SCI patients is associated with detrusor and cardiovascular reflex effects that are exaggerated compared with those in intact subjects and that measurement of skin blood flow from the fingers in patients with a high spinal lesion provides a supplementary, clinically useful, non-invasive and continuous marker of spinally mediated viscerosympathetic reflex activity below the lesion in such patients.

Correlation between cystometric volumes, ATP release, and pH in women with overactive bladder versus controls.

AIMS: In the bladder, ATP is an important signaling molecule, which is released by bladder stretch and acid. We hypothesized that ATP might play a unique role in patients with OAB, characterized by low bladder volumes at first desire to void (FDV) and maximal cystometric capacity (MCC) and symptoms of frequency/urgency [mild bladder pain syndrome (BPS)]. Our aim was to investigate the correlation between ATP release and urodynamic parameters, as well as urine pH, in OAB patients. METHODS: Routine cystometry was performed in a consecutive series of 249 women. The voided urodynamic fluid (VUF) was stored at -20°C and ATP measured using bioluminescence. Catheter urine was collected for pH measurement. Correlations between two factors were tested by linear regression analysis. RESULTS: Subjects with urinary tract infection, voiding dysfunction, and detrusor overactivity (DO) were excluded. For OAB patients (n = 25), there was an inverse correlation between ATP concentration in VUF and FDV (r(2) = 0.25; P = 0.01) but not MCC. This was not seen in controls (n = 69). In OAB, but not controls, there was a significant reverse correlation (r(2) = 0.16; P = 0.047) between ATP in VUF and urine pH. Urine pH was not significantly correlated with MCC in either group. CONCLUSIONS: In OAB patients, ATP is an important factor for initial perception of need to urinate (as indicated by FDV). This is similar to our previous findings in patients with DO, suggesting that ATP may mediate initial afferent sensation in patients with bladder dysfunctions characterized by urgency. ATP release was also strongly affected by urine pH, in patients with OAB (at FDV).

Comparison of receptor binding characteristics of commonly used muscarinic antagonists in human bladder detrusor and mucosa.

Recent studies have described muscarinic receptors on the mucosa and the detrusor of the human urinary bladder. Muscarinic receptor antagonists are effective in the treatment of overactive bladder (OAB), but their site(s) of action and actual therapeutic target are unclear. Our aim was to compare, in human bladder mucosa and detrusor, the radioligand binding characteristics of newer, clinically effective agents: darifenacin, its hydroxylated metabolite UK-148,993, fesoterodine, solifenacin, tolterodine, and trospium. Specimens were collected from asymptomatic patients (50-72 years old) undergoing open bladder surgery. Radioligand binding studies with the muscarinic antagonist [3H]quinuclidinyl benzilate (QNB) were performed separately on detrusor and mucosal membranes. All antagonists displayed high affinity when competing for [3H]QNB binding in both detrusor and mucosa. Inhibition constants were also obtained for all antagonists against individual muscarinic receptor subtypes expressed in Chinese hamster ovary cells. Here, fesoterodine showed anomalous binding results, suggesting that some conversion to its metabolite had occurred. Global nonlinear regression analysis of bladder binding data with five antagonists demonstrated 82% low-affinity sites in mucosa and 78% low-affinity sites in detrusor, probably representing M(2)/M(4) receptors. There was an excellent correlation (r(2) = 0.99) of low-affinity global estimates between detrusor and mucosa, whereas the corresponding high-affinity estimates ( approximately 20% of sites) were dissimilar. In conclusion, commonly used and clinically effective muscarinic receptor antagonists bind to receptors located on the bladder mucosa and the detrusor, providing support for the hypothesis that muscarinic receptors in the mucosa may represent an important site of action for these agents in OAB.

Long-term darifenacin treatment for overactive bladder in patients aged 65 years and older: analysis of results from a 2-year, open-label extension study.

OBJECTIVES: This analysis evaluated the long-term safety, tolerability and efficacy of darifenacin, a muscarinic M3 selective receptor antagonist, in the treatment of overactive bladder (OAB) in patients > or = 65 years of age. METHODS: Patients who completed one of two 12-week, placebo-controlled, double-blind, feeder studies received once-daily (o.d.) treatment with darifenacin 7.5 mg for the first 2 weeks of the 2-year, open-label extension study. The dose could be subsequently adjusted (7.5 or 15 mg o.d.) according to need. Safety and tolerability were assessed, and efficacy variables/endpoints were evaluated from patient diary data. RESULTS: 214 patients (65-89 years) entered and 137 (64.0%) completed the 2-year extension study, amounting to 308 patient-years' drug exposure. Darifenacin was well tolerated with no new safety concerns. The most common adverse events (AEs) were dry mouth and constipation, which infrequently resulted in discontinuation (2.3% and 4.2%, respectively). Darifenacin produced significant improvements in OAB symptoms that were maintained over the 2-year period (median reduction from feeder-study baseline to 2 years: -11.0 [-83.7%] for incontinence episodes/week and -1.2 [-12.4%] for micturitions/day, both p < 0.05), with 44.4% patients achieving > or = 90% reduction in incontinence episodes at 2 years. CONCLUSIONS: Darifenacin demonstrated good tolerability and safety in older patients with OAB. The improvement in OAB symptoms was sustained throughout the 2-year extension, resulting in high treatment persistence rates. Results were comparable with those in the overall OAB population from this study, indicating that darifenacin treatment is effective and well tolerated irrespective of age.

Age-related changes of P2X(1) receptor mRNA in the bladder detrusor from men with and without bladder outlet obstruction.

The urinary bladder purinergic system is reported to change with age and with bladder dysfunction. Here, we examined the expression of purinergic P2X(1) receptors in detrusor and mucosa (urothelium+lamina propria) from male control bladder and investigated age-related P2X(1) receptor mRNA expression in control and obstructed detrusor. Biopsy specimens were obtained at cystoscopy from control patients (n=46, age range 30-86years) and patients diagnosed with outlet obstruction (n=29, 46-88years). Calponin expression (measured by RT-PCR) was similar in control and obstructed detrusor and did not change with age. Quantitative competitive RT-PCR was used to measure P2X(1) receptor and GAPDH mRNA in control and obstructed detrusor. P2X(1) receptor mRNA expression was 9-fold (p<0.0001) higher in the detrusor than in the mucosa. Expression of mRNA for the internal control GAPDH remained stable with age and across control and obstructed detrusor. No difference in P2X(1) receptor expression was observed between control and obstructed detrusor (p=0.35). However, an age-related decrease in P2X(1) mRNA expression was observed in control (n=27; p=0.0054; Spearman coefficient r=-0.520) but not obstructed detrusor (n=19; p=0.093; r=-0.396). Downregulation of P2X(1) mRNA expression might occur as a result of an increased component of neural ATP release in the aging bladder.

Molecular characterization of M2 and M3 muscarinic receptor expression in bladder from women with refractory idiopathic detrusor overactivity.

OBJECTIVE: To examine the expression of muscarinic M2 and M3 receptors in human bladder detrusor and mucosa, from controls and patients with idiopathic detrusor overactivity (IDO), as antimuscarinic agents are the primary pharmacological treatment for IDO. PATIENTS AND METHODS: Biopsies from the bladder body were collected at cystoscopy from 20 women with urodynamically confirmed refractory IDO (age range 25-86 years); biopsies were also collected from 30 asymptomatic female controls (age range 32-87 years). Samples were collected into RNA extraction medium and dissected into mucosa (urothelium plus lamina propria) and detrusor. RNA was extracted and the expression of M2 and M3 receptor mRNA determined by quantitative competitive reverse transcription-polymerase chain reaction. Results were normalized to beta-actin expression in the same sample. RESULTS: Expression of M3 receptor mRNA, in mucosa of IDO patients (median 0.057 pg M3/100 ng total RNA; interquartile range 0.03-0.13, 12 samples), was four times (P = 0.039, Mann-Whitney) lower than from the control (median 0.22 pg M3/100 ng total RNA; 0.13-0.51, 11 samples). The expression of muscarinic M3 receptor mRNA was higher (14-35 times) in detrusor (control median 3.17; 26 samples) than in mucosa and did not change in IDO (median 2.03; 14 samples). M2 expression was not significantly different with region or with IDO. CONCLUSIONS: These data show that M3 muscarinic receptor mRNA expression was significantly less in mucosa from IDO patients than from age-matched controls. The role of mucosal M3 receptors is unknown at present and elucidation of this role might provide a greater understanding of the aetiology of IDO.

The molecular basis of urgency: regional difference of vanilloid receptor expression in the human urinary bladder.

AIM: Treatments targeting vanilloid receptor TRPV1 are effective in some bladder disorders. Our aim was to determine the expression profiles of TRPV1 in regions of human bladder and test the hypothesis that there would be an upregulation of TRPV1 in mucosa of patients with bladder hypersensitivity but not idiopathic detrusor overactivity (IDO). MATERIALS AND METHODS: Women with sensory urgency (SU), interstitial cystitis (IC), and IDO were investigated by videourodynamics and cystoscopy. Control biopsies were used for comparison. Biopsies were dissected into mucosa and muscle, and evaluated for TRPV1 mRNA expression using quantitative competitive RT-PCR (QC-RT-PCR). RESULTS: TRPV1 mRNA from SU trigonal mucosa was significantly higher than control trigonal mucosa or SU bladder body mucosa. In contrast, in IDO patients, there was no difference between trigonal mucosa and body mucosa. In IC biopsies, RNA quality was substandard and unable to be used for analysis. The most striking finding was that TRPV1 mRNA expressed in SU trigonal mucosa was significantly inversely correlated with the bladder volume at first sensation of filling during cystometry. No such relationship was seen for IDO trigonal mucosa. No difference was seen in bladder body mucosa from any disease groups compared with age-matched control. CONCLUSIONS: The symptoms of SU were associated with the increased expression of TRPV1 mRNA in the trigonal mucosa. No upregulation or regional differences of TRPV1 mRNA were seen in IDO patients. TRPV1 may play a role in SU and premature first bladder sensation on filling.

Safety and tolerability of tolterodine for the treatment of overactive bladder in men with bladder outlet obstruction.

PURPOSE: Antimuscarinic therapy for men with OAB and BOO is perceived as a potential risk for urinary retention. Using pressure flow urodynamics, we evaluated the safety of tolterodine vs placebo in men with OAB and BOO. MATERIALS AND METHODS: Men (older than 40 years) with BOO and confirmed detrusor overactivity were randomized to tolterodine (2 mg twice daily in 149) or placebo (in 72) for 12 weeks. Primary end points were Qmax and pdetQmax. RESULTS: Median treatment differences in Qmax (-0.7 ml per second, 95% CI -1.6 to 0.4) and pdetQmax (-7 cm H2O, 95% CI -3 to 11) were comparable. Tolterodine significantly reduced the BOOI vs placebo (-9 vs 0, p < 0.02). There were significant treatment differences in volume to first detrusor contraction (+59 ml, 95% CI 19-100) and maximum cystometric capacity (+67 ml, 95% CI 35-103), favoring tolterodine over placebo (p < 0.003). Change in PVR was significantly greater among patients treated with tolterodine (+25 ml) than placebo (0 ml, p < 0.004). There were no significant between-group differences in the incidence of adverse events. Urinary retention was reported by 1 patient treated with placebo. CONCLUSIONS: Tolterodine did not adversely affect urinary function in men with OAB and BOO. Urinary flow rate was unaltered, and there was no evidence of clinically meaningful changes in voiding pressure and PVR or urinary retention. Tolterodine was well tolerated. These results suggest that antimuscarinics can be safely administered in men with BOO.

A pooled analysis of three phase III studies to investigate the efficacy, tolerability and safety of darifenacin, a muscarinic M3 selective receptor antagonist, in the treatment of overactive bladder.

OBJECTIVE: To evaluate the efficacy, tolerability and safety of darifenacin, a muscarinic M3 selective receptor antagonist (M3 SRA), from an analysis of pooled data from three phase III, multicentre, double-blind clinical trials in patients with overactive bladder (OAB). PATIENTS AND METHODS: After a 4-week washout/run-in period, 1059 adults (85% women) with symptoms of OAB (frequency and urgency with urge incontinence) for > or = 6 months were randomized to once-daily oral treatment with darifenacin (7.5 mg, 337; or 15 mg, 334) or matching placebo (388) for 12 weeks. Efficacy was evaluated using electronic patient diaries that recorded incontinence episodes (including those resulting in a change of clothing or pads), frequency and severity of urgency, voiding frequency, and bladder capacity (volume voided). Safety was evaluated by analysis of adverse events (AEs), withdrawal rates and laboratory tests. RESULTS: Relative to baseline, 12 weeks of treatment with darifenacin resulted in a significant reduction in the median (% change, interquartile range) number of incontinence episodes per week; 7.5 mg (-8.8, -68.4%, -15.1 to -4.4); 15 mg; (-10.6, -76.8%, -17.3 to -5.8: both P < 0.01 vs placebo). There was a significant dose-response trend in each study for which darifenacin 7.5 and 15 mg were evaluated (P < 0.01). There were also significant decreases in the frequency and severity of urgency, voiding frequency, and number of significant leaks (incontinence episodes resulting in a change of clothing or pads; both P < or = 0.001 vs placebo), together with an increase in bladder capacity (both P < 0.01 vs placebo). Darifenacin was well tolerated; the most common AEs were dry mouth and constipation, although together these resulted in few discontinuations (darifenacin 7.5 mg 0.6% of patients; 15 mg 2.1%; placebo 0.3%). The incidence of peripheral/central nervous system and cardiovascular AEs were comparable with those on placebo. CONCLUSIONS: Darifenacin (7.5 and 15 mg once daily) is effective in the treatment of patients with OAB. As predicted by its M3 selectivity and associated M1/M2-sparing profile, darifenacin was well tolerated with no central nervous system or cardiovascular safety concerns.

Muscarinic receptor subtypes in human bladder detrusor and mucosa, studied by radioligand binding and quantitative competitive RT-PCR: changes in ageing.

1. We investigated muscarinic receptors in the detrusor and mucosa of the human bladder body. Radioligand-binding studies with [(3)H]QNB were conducted using specimens collected from patients (36-77 years) with normal bladder function, undergoing surgery. For RT-PCR, biopsies of normal bladder were obtained from patients (30-88 years) undergoing check cystoscopy. 2. Binding of [(3)H]QNB in detrusor (n=20) was of high affinity (K(D) 77.1 (55.2-99.0) pM) and capacity (B(max) 181+/-7 fmol mg protein(-1)). Similar values were obtained in mucosa (n=6) (K(D) 100.5 (41.2-159.9) pM; B(max) 145+/-9 fmol mg protein(-1)). 3. Competition-binding experiments in detrusor membranes with muscarinic receptor antagonists including trospium, darifenacin, 4-DAMP, methoctramine, AQ-RA 741, AF-DX 116 and pirenzepine indicated a receptor population of 71% M(2), 22% M(3) and 7% M(1). In the mucosa, 75% of sites were M(2) receptors, with 25% M(3)/M(5). 4. Using RT-PCR, expression of M(1), M(2), M(3) and M(5) mRNA was demonstrated in both detrusor and mucosa. 5. The presence of a high density of mainly M(2) muscarinic receptors in the mucosa appears to be a novel finding and raises the question of their physiological significance and the source of their endogenous ligand. 6. There was a negative correlation of receptor number (B(max)) with age in detrusor muscle from male patients (P=0.02). Quantitative competitive RT-PCR demonstrated a selective age-related decrease in mRNA for muscarinic M(3) but not M(2) receptors, in both male (P<0.0001) and female (P=0.019) detrusor. These findings correspond with reports of decreased detrusor contractility with ageing.

Reduced perception of urgency in treatment of overactive bladder with extended-release tolterodine.

OBJECTIVE: To evaluate the effect of once-daily, extended-release tolterodine on urinary urgency in patients with overactive bladder. METHODS: Patients with urinary frequency (eight or more micturitions per 24 hours) and urge incontinence (five or more episodes per week) were randomized to oral treatment with tolterodine extended release 4 mg once daily (n=398) or placebo (n=374) for 12 weeks. Efficacy was assessed by use of patient perception evaluations. RESULTS: The results presented are a secondary analysis of this double-blind, placebo-controlled study. Of patients treated with tolterodine extended release, 44% reported improved urgency symptoms (compared with 32% for placebo), and 62% reported improved bladder symptoms (placebo, 48%) (both P<.001 compared with placebo). The odds of reducing urgency and improving bladder symptoms were 1.68 and 1.78 times greater, respectively, for patients in the tolterodine extended release group than for patients receiving placebo. In response to urgency, there was a more than six-fold increase in the proportion of patients able to finish a task before voiding in the tolterodine extended release group. The proportion of patients unable to hold urine upon experiencing urgency was also decreased by 58% with tolterodine, compared with 32% with placebo (P<.001). The proportion of patients reporting "much benefit" from treatment was greater for tolterodine extended release than for placebo (43% versus 24%; P<.001). The only adverse events with an incidence of greater than 5% were dry mouth, headache, and constipation, with only dry mouth markedly more frequent with tolterodine than with placebo. CONCLUSION: Tolterodine extended release has demonstrable efficacy in reducing the severity of urinary urgency and is associated with improvements in overactive bladder symptoms that are meaningful to patients.

Enhancement of neurokinin A-induced smooth muscle contraction in human urinary bladder by mucosal removal and phosphoramidon: relationship to peptidase inhibition.

Neurokinin A (NKA) is potent in contracting the human detrusor muscle. Here, we have investigated whether these contractile responses are influenced by the presence of the mucosa, by the peptidase inhibitor phosphoramidon or by possible modulators, prostaglandins and nitric oxide. Contractile responses to neurokinin A were unaffected by indomethacin or N-omega-nitro-L-arginine, but were significantly reduced in strips containing mucosa. Phosphoramidon, an inhibitor of neutral endopeptidase 24.11 (neprilysin, CD10), was ineffective at 10 microM, but at 100 microM, significant increase in the maximum response was achieved by neurokinin A in detrusor strips with and without mucosa. In immunohistochemical studies, neutral endopeptidase immunoreactivity occurred in peripheral nerve trunks in the detrusor and in a fibrous meshwork in the subepithelial lamina propria. Our data indicate that neutral endopeptidase is present in bladder mucosa and detrusor, and support the concept that this metalloprotease and/or related enzymes are important in regulating the actions of tachykinins.

Evaluation of constricted affect in chronic pain: an attempt using the Toronto Alexythymia Scale.

The Toronto Alexythymia Scale (TAS) was applied as a potential measure of constricted affect among a sample of patients with chronic, non-malignant pain (n = 195). As previously demonstrated with non-clinical samples, the scale was found to possess moderate reliability with two principal internal factors. These factors seemed to reflect social introversion and a lack of proneness to fantasy. There was a moderate, negative association between them. The domain sampled by the TAS was apparently heterogeneous, with total scores showing no relationship to reported disability or pain intensity and a low relationship to reported distress. These results suggest potential limitations of the TAS and the alexythymia construct as means for evaluating constricted affect that accompanies chronic pain.