Current management of refractory overactive bladder

Overactive bladder (OAB) is a common condition affecting one‐sixth to one‐fifth of the global population. The treatment of refractory OAB remains a challenge for urologists. Current treatment options include the use of combination therapy with antimuscarinic agents and beta‐3 adrenoceptor agonists, and treating underlying curable disorders. Intravesical botulinum toxin type A (BoNT‐A) injection, percutaneous tibial nerve stimulation, and sacral nerve stimulation are third‐line management therapies suggested by the American Urological Association/Society of Urodynamics, Female Pelvic Medicine & Urogenital Reconstruction (AUA/SUFU) guidelines. In rare cases, more invasive surgical interventions can be considered after explaining the benefits and risks to the patients. Augmentation cystoplasty has a high success rate; however, it has also been associated with a high complication rate. In contrast, detrusor myomectomy is an easy procedure, but the treatment outcome remains controversial. Liposome‐encapsulated BoNT‐A is administered via bladder instillation, and promising results have been obtained in preliminary studies. More therapies are currently being investigated, and transient receptor potential vanilloid 1 antagonists may be new type of medication. Radiofrequency ablation and other targets for neuromodulation have also been studied; however, more evidence is needed to confirm their efficacy.     

Treatment of overactive bladder in the aging population: focus on darifenacin

Anticholinergics are commonly used in primary and secondary care settings for the treatment of overactive bladder syndrome. The number of anticholinergic drugs available on the market is increasing and various studies, both observational and randomized controlled trials, have evaluated effectiveness of the different preparations available. When anticholinergic therapy is prescribed, there is still uncertainty about which anticholinergic drugs are most effective, at which dose, and by which route of administration. There is also uncertainty about the role of anticholinergic drugs in different patient groups, particularly in the elderly. The rationale for using anticholinergic drugs in the treatment of overactive bladder syndrome is to block the parasympathetic acetylcholine pathway and thus abolish or reduce the intensity of detrusor muscle contraction. There are currently five recognized subtypes of muscarinic receptor; the M₁, M₂, and M₃ subtypes are of interest in bladder activity. Muscarinic receptors are found in other parts of the body, eg, in the gut, salivary glands, tear ducts. Side effects associated with non-selective antimuscarinics can be particularly distressing in the elderly. The development of bladder selective M₃ specific antagonists has the advantage of providing increased efficacy with minimal side effects. Darifenacin is one such preparation. The aim of this review is to assess the pharmacology, interactions and the safety and tolerability of darifenacin in the treatment of overactive bladder in the elderly population with particular reference to clinical trial data available.     

Efficacy,safety, and tolerability of extended-release once-daily tolterodine treatment for overactive bladder in older versus younger patients

OBJECTIVES: To evaluate the efficacy, safety, and tolerability of a new, once-daily extended-release (ER) formulation of tolterodine in treating overactive bladder in older (> or =65) and younger (<65) patients. DESIGN: A 12-week double-blind, placebo-controlled clinical trial. SETTING: An international study conducted at 167 medical centers. PARTICIPANTS: One thousand fifteen patients (43.1% aged > or =65) with urge incontinence and urinary frequency. INTERVENTION: Patients were randomized to treatment with tolterodine ER 4 mg once daily (qd) (n = 507) or placebo (n = 508) for 12 weeks. MEASUREMENTS: Efficacy, measured with micturition charts (incontinence episodes, micturitions, volume voided per micturition) and subjective patient assessments, safety, and tolerability endpoints were evaluated, relative to placebo, according to two age cohorts: younger than 65 and 65 and older. RESULTS: Mean age in the older and younger patient cohorts was 74 (range 65-93) and 51 (range 20-64), respectively. Compared with placebo, significant improvements in micturition chart variables with tolterodine ER showed no age-related differences. Irrespective of age, significantly more tolterodine ER recipients than placebo recipients reported an improvement in urgency symptoms. After 12 weeks of treatment with tolterodine ER, a fivefold increase in the percentage of patients able to finish tasks before voiding in response to urgency was noted in both age groups (<65: from 6.5-32.8%, > or =65: from 5.1-26.2%). Tolterodine ER recipients, irrespective of age, also had significant improvements in their bladder condition than did placebo recipients. Overall, a greater percentage of patients, irrespective of age, perceived any benefit with tolterodine ER than with placebo (P <.001). Dry mouth (of any severity) was the most common adverse event in both the tolterodine ER and placebo treatment arms, irrespective of age (<65: ER 22.7%, placebo 8.1%; > or =65: ER 24.3%, placebo 7.2%). Few patients (<2%) experienced severe dry mouth. No central nervous system, visual, cardiac (per electrocardiogram), or laboratory safety concerns were noted. Withdrawal rates due to adverse events on tolterodine ER 4 mg qd were comparable in the two age cohorts (<65: 5.5%; > or =65: 5.1%; P =.87). CONCLUSIONS: The new, once-daily ER formulation of tolterodine is efficacious, safe, and well tolerated in the treatment of patients with symptoms of overactive bladder, irrespective of age.     

Pathophysiology of refractory overactive bladder

Overactive bladder (OAB) is a common condition. The International Continence Society defines OAB as a symptom complex characterized by urgency with or without urge incontinence, usually with frequency and nocturia. The first‐line treatment for OAB includes behavioral therapy, such as caffeine reduction, fluid intake modification, weight reduction, bladder training, and pelvic floor muscle training, as well as treatment with antimuscarinic or β₃‐adrenoceptor agonist medications. However, less than half of all cases achieve satisfactory outcomes following first‐line treatment. Second‐line therapy considered if satisfactory responses are not achieved after 8 to 12 weeks treatment with first‐line therapy include intradetrusor botulinum toxin injection, neuromodulation, and surgical treatment. Patients with refractory OAB may have more severe symptoms or underlying pathophysiologies that were not resolved by the initial medication. The pathophysiologies of refractory OAB include occult neurogenic bladder, undetected bladder outlet obstruction, urethral‐related OAB, urothelial dysfunction with aging, chronic bladder ischemia, chronic bladder inflammation, central sensitization, and autonomic dysfunction. This article discusses the possible pathophysiologies of refractory OAB.     

Transdermal oxybutynin in the treatment of overactive bladder

Overactive bladder is a dreadful syndrome that affects a considerable number of patients. Antimuscarinics are the mainstay of pharmacotherapy for this condition. Transdermal (TD) oxybutynin (OXY) bypasses the first-pass metabolism and reduces the formation of N-desethyloxybutynin, a compound believed to be associated with anticholinergic side effects. The 3.9 mg matrix TD system is applied twice weekly and transports OXY directly into the systemic circulation. The patch can be applied to abdomen, buttock, and hip, and provides continuous OXY delivery that minimizes peak and trough fluctuations in plasma levels. In clinical trials, TD and oral OXY produced a significant reduction in incontinence episodes, with no difference between oral and TD treatments. In addition, TDOXY was similar to tolterodine, and it produced a significant improvement in the number of urinary incontinence episodes, complete continence, and urodynamic and quality of life parameters compared with placebo. The incidence of anticholinergic adverse events with TDOXY was similar to placebo. Most common adverse events were mild–moderate skin reactions. Treatment satisfaction survey suggested patients’ preference to use the TD system in the future. Counseling on healthy skin care and appropriate product use can enhance patients’ knowledge about TDOXY for overactive bladder treatment.     

Antimuscarinic drugs for overactive bladder and their potential effects on cognitive function in older patients

Antimuscarinic agents are the predominant pharmacological treatment for patients with overactive bladder (OAB). These drugs are thought to act primarily through antagonism at muscarinic M3 receptors located at neuromuscular junctions in the human bladder detrusor muscle. Several of these drugs have been shown to be efficacious in ameliorating the symptoms of OAB in older patients, but most currently available agents lack selectivity for the M3 receptor subtype, and interaction with other muscarinic receptor subtypes throughout the body may adversely affect a variety of physiological functions and result in unwanted side effects, including cognitive dysfunction. With the recent availability of antimuscarinic agents that show increased selectivity for M3 receptors relative to other muscarinic subtypes, an invitational expert panel meeting was convened to review not only the mechanisms by which antimuscarinic agents could affect cognitive function, but also the published literature on cognitive adverse events. A review of the literature shows that the cholinergic system in the central nervous system (CNS) exerts a major influence on cognitive processes, in particular memory via M1 cholinergic receptors. In addition, recent evidence suggests a role for M2 receptors in mediating cognitive function. Thus, cognitive dysfunction (including memory loss) during treatment with nonselective antimuscarinic agents for OAB is of growing concern, particularly in older patients and those with mild cognitive impairment or dementia. Increased blood-brain barrier permeability, which can occur with advanced age and certain comorbidities, may also facilitate CNS access of antimuscarinic agents (regardless of their physiochemical properties) and add to antimuscarinic burden. On the basis of available evidence, antimuscarinic agents with selectivity for M3 over M1 and M2 receptors, limited CNS penetration, or both may therefore offer a favorable balance of efficacy in treating OAB together with a reduced risk of adverse cognitive events in the older population.     

新型抗胆碱能药物舍尼亭治疗膀胱过度活动症的疗效观察

目的探讨舍尼亭治疗膀胱过度活动症的疗效。方法对60例诊断为膀胱过度活动症的患者行舍尼亭治疗。以自由尿流率的主要参数如最大尿流率(Qmax)、平均尿流率(Qave)、排尿量(VV)和尿道征症状评分(FUSS)、生活质量评分(QOL)为主要疗效指标,来观察治疗效果。结果治疗前尿流率参数值(Qmax、Qave、VV)、FUSS、QOL相比较,≥60岁患者较<60岁患者差异显著(P<0.05);治疗后尿流率参数值(Qmax、Qave、VV)、FUSS、QOL相比较,治疗≥60岁患者疗效较<60岁患者无统计学意义。所有患者治疗前后均有统计学意义(P<0.05),总有效率为85.00%。结论舍尼亭可作为膀胱过度活动症的一种有效治疗手段。     

Prevalence of xerostomia with or without overactive bladder symptoms

Overactive bladder (OAB) occurs idiopathic or secondary to a neurological cause. In addition, OAB may also occur due to xerostomia, because it causes excessive drinking of water. If xerostomia is one of the causes of OAB, treating xerostomia may be effective. This study aimed to investigate the prevalence of xerostomia with or without overactive bladder symptoms. A web-based questionnaire was administered to investigate the prevalence of xerostomia with or without overactive bladder symptoms. The survey included questions concerning age, gender, medical history, medications, OAB symptoms by the Overactive Bladder Symptom Score (OABSS), and xerostomia by the Dry Mouth Scale (DMS). From the analysis, a total of 21 (13.0%) participants were identified as having OAB. The prevalence of xerostomia was six (28.6%) in the OAB group and 14 (10.0%) in the non-OAB group. OABSS and DMS were significantly higher in the OAB group than in the non-OAB group. Urgency score and urgency incontinence score of OABSS were substantially higher in xerostomia participants than non-xerostomia participants. The adjusted odds ratio of OAB showed DMS total score, xerostomia symptoms, accompanying symptoms, and other symptoms that were all significantly associated with OAB. These results suggested that OAB subjects, even untreated subjects, had xerostomia. It may be beneficial for clinicians to perform dry mouth management in parallel with careful choice pharmacotherapy for the wellness of OAB patients.     

Effects of overactive bladder syndrome on female sexual function

This study was to evaluate the impact of the symptoms of overactive bladder (OAB) syndrome on female sexual function. Seventy nine patients with OAB (OAB group) and 79 healthy women (control group) underwent physical examination at our center, and had their sexual function evaluated using the female sexual function index (FSFI). In accordance with the presence or absence of urge incontinence, the OAB group was further divided into the wet and dry groups. The sexual function was evaluated again after 3 months of pharmacotherapy. We investigate the difference of sexual function between OAB and control group. The effect of OAB severity and OAB pharmacotherapy on sexual function was also explored. There were no significant differences between OAB group and control group, including age, body mass index (BMI), education, occupation, fertility, parity, childbirth, and menopause. Compared with the control group, the OAB group had significantly lower FSFI scores. The respective mean ± standard error FSFI scores in the control group and the OAB group were 2.98 ± 1.07 and 2.27 ± 0.96 for desire, 3.48 ± 1.16 and 2.32 ± 1.44 for arousal, 4.60 ± 1.13 and 3.10 ± 1.95 for lubrication, 3.37 ± 0.87 and 2.63 ± 1.04 for orgasm, 3.58 ± 1.02 and 2.41 ± 1.35 for sexual satisfaction, 3.58 ± 1.02 and 2.41 ± 1.35 for sexual pain, and 22.24 ± 5.29 and 15.59 ± 7.47 for the total score (P < .05 for all comparisons). The scores for desire, lubrication, orgasm, sexual satisfaction, pain, and total FSFI between the OAB-dry and OAB-wet subgroup were similar while score of arousal in OAB-wet subgroup was significantly increased compared with that of OAB-dry. OABSS score was commonly used in the assessment of OAB severity. The difference of the FSFI scores among mild OAB group, moderate OAB group, and severe OAB group was statistically significant (P < .05). Female FSFI sexual function scores were significantly improved after OAB pharmacotherapy (P < .05). Women with OAB syndrome have poorer sexual function than healthy women. Patients with more serious OAB experience more disturbing sexual dysfunction. Female sexual function scores were significantly improved after OAB pharmacotherapy.     

Risk Factors for De Novo Mixed Urinary Incontinence and Stress Urinary Incontinence Following Surgical Removal of a Urethral Diverticulum

Objectives: The aim of the present study was to investigate the risk factors for the development of de novo stress urinary incontinence (SUI) and mixed urinary incontinence (MUI) after surgical removal of a urethral diverticulum (UD). Methods: We identified 35 consecutive women that underwent surgical removal of a UD between November 2002 and December 2009, and we retrospectively reviewed their medical records, including patient demographics, pelvic magnetic resonance imaging (MRI), presenting symptoms related to voiding, and outcomes. Results: Among the 35 patients we identified, 28 were included in the study. After UD removal, five of the 28 patients (17.8%) developed de novo MUI, and four of the 28 patients (14.2%) developed de novo SUI. The incidences of SUI and MUI were significantly higher in patients who had a UD that measured over 3 cm in diameter and in patients in whom the UD was located in the proximal urethra. Of the seven patients with a diverticulum over 3 cm, SUI occurred in three (42.8%) (P = 0.038) and MUI occurred in five (45.4%) (P < 0.001). Of the 11 patients with a diverticulum located in the proximal urethra, SUI occurred in five (45.4%) (P = 0.011) and MUI occurred in four (36.4%) (P = 0.011). Conclusion: Significant risk factors for the development of SUI and MUI after transvaginal simple diverticulectomy include a UD measuring over 3 cm and a UD located in the proximal urethra.     

Monotherapy with mirabegron had a better tolerance than the anticholinergic agents on overactive bladder: A systematic review and meta-analysis

Background:We conducted this meta-analysis to explore the tolerance of monotherapy with mirabegron (50 mg) on an overactive bladder, compared with a common dosage of anticholinergic agents.Materials and methods:A comprehensive search for all randomized controlled trials that evaluated the safety of mirabegron and anticholinergic agents on overactive bladder was performed, and we searched the Cochrane Central Register of Controlled trials databases, Pubmed, Embase, and relevant trials from 2013.02 to 2019.10.Results:Eight studies included 5500 patients with treatment of monotherapy on overactive bladder were identified. The total number of treatment-emergent adverse events had no significantly difference between two monotherapies (RR = 0.88 95%CI: 0.76–1.01; P = .08); however, patients would have a better tolerance with mirabegron (50 mg) in adverse events of dry mouth (RR = 0.42; 95%CI: 0.33–0.53; P < .01) and tachycardia (RR = 0.52; 95%CI: 0.29–0.94; P = .03); and there were no significant differences between two groups in hypertension (RR = 1.02; 95%CI: 0.80–1.30; P = .90), constipation (RR = 0.91; 95%CI: 0.65–1.26; P = 0.57), blurred vision (RR = 1.03; 95%CI: 0.60–1.77; P = 0.92), and urinary tract infection (RR = 0.90; 95%CI: 0.70–1.16; P = .41).Conclusions:Treatment-emergent adverse events in patients with overactive bladder who underwent monotherapy of mirabegron (50 mg) or the anticholinergic agents had no significant differences, but mirabegron has a better tolerance in the aspect of dry mouth and tachycardia.