Medication and food issues for overactive bladder/lower urinary tract symptoms: When do we eat?

Overactive bladder (OAB) and lower urinary tract symptoms (LUTS) are common conditions that often require chronic medications. Treatment for OAB includes older antimuscarinic agents (oxybutynin) and newer agents (tolterodine, trospium chloride, darifenacin, and solifenacin). Treatment for LUTS includes the 5-α reductase inhibitors, (finasteride and dutasteride) and α1-adrenergic antagonists (prazosin, doxazosin, terazosin, alfuzosin, and tamsulosin). Many medications have the potential to interact with food. This article addresses the effects of food on the current treatments for OAB and LUTS and the clinical considerations for their optimal dosing with regard to food.     

Summary of Anticholinergic Pharmacotherapy Available for Overactive Bladder

The International Continence Society definition of overactive bladder syndrome (OAB) is “urgency, with or without urge incontinence, usually with frequency and nocturia.” OAB syndrome is a very common condition, estimated to affect 12% to 22% of women and men in Europe and 16% to 17% in the United States. The muscarinic receptor antagonists are first-line pharmacotherapy in treatment of OAB. In North America, six antimuscarinic drugs are marketed for treating OAB: oxybutynin, tolterodine, fesoterodine, trospium, darifenacin, and solifenacin. In our review, we summarize the pharmacology, efficacy, and adverse events of commonly used anticholinergic agents.     

Treatment of overactive bladder: selective use of anticholinergic agents with low drug-drug interaction potential

Overactive bladder (OAB) is highly prevalent in the older population and decreases quality of life. Current therapy consists primarily of anticholinergic drugs. Because older individuals typically take multiple medications, clinicians must pay special attention to potential drug-drug interactions that may cause adverse events or alter drug efficacy. The most clinically important drug-drug interactions occur during cytochrome P450 (CYP450) isoenzyme metabolism, resulting in altered metabolism of one or more of the coadministered agents. Of the drugs indicated for OAB, tolterodine, darifenacin, solifenacin, and oxybutynin are extensively metabolized by CYP450, but trospium is not. Trospium is eliminated as unchanged drug, suggesting that it has lower potential for drug-drug interactions and may, therefore, represent a safer treatment option for OAB, particularly in the context of polypharmacy, a significant concern in older adults.     

The Q-T interval and antimuscarinic drugs

Antimuscarinic drugs form the mainstay of pharmacotherapy for the treatment of overactive bladder. The primary sites of activity of the agents for the desired therapeutic effect are the M3 and M2 receptors of the bladder. Drug interaction with other non-vesical muscarinic receptors produces a range of undesired adverse events. In general, certain adverse effects associated with antimuscarinic agents such as dry mouth (salivary) and constipation (colon) may be considered only bothersome, and somnolence and confusion (central nervous system) may be considered more serious in nature. However, effects on the myocardium are considered to be more significant safety issues and increased awareness and understanding of the effect of drugs on the myocardium, including the additional effects of drug-drug interaction, has increased a need for the evaluation of new drugs for cardiac safety. The role of genetics (and the identification of populations at risk) in the causation of congenital dysrhythmias has received specific attention in this area. New drugs now must undergo more intense scrutiny and cardiac testing to evaluate their effects on cardiac rate and rhythm, especially the QT interval. The recently approved agents (trospium, solifenacin, darifenacin) used for the treatment of overactive bladder have been rigorously evaluated for these effects.     

Randomized,Single‐Blind,Parallel Study of the Effectiveness and Safety of Solifenacin versus Propiverine in the Treatment of Overactive Bladder

Objectives: To compare the effectiveness and safety of solifenacin versus propiverine in the treatment of overactive bladder (OAB), in a single‐blind, randomized parallel study. Methods: Sixty‐six patients with OAB (14 men and 52 women) were randomly assigned to groups: solifenacin (5 mg/day) or propiverine (20 mg/day) and treated for 8 weeks. The primary outcome variable was mean change from baseline to end of treatment in urgency of the OAB symptom score (OABSS). Secondary outcomes were bladder diary variables: change over 24 h in the mean number of voids (daytime and nighttime), episodes of micturition urgency and incontinence, and mean volume voided. Patients also completed total OABSS and the King's Health questionnaires. Results: Group backgrounds were comparable except for the male to female proportion; 11:22 for solifenacin (n = 33) versus 3:30 for propiverine (n = 33). Adverse events were 6 of 29 (21%) for solifenacin versus 14 of 26 (54%) for propiverine (P = 0.017). Three patients were withdrawn for voiding difficulty (one in solifenacin and two in propiverine) and one patient for dry mouth (propiverine group). Change in OABSS urgency score was ?2.3 ± 1.4 for solifenacin (n = 28) versus ?1.3 ± 1.7 for propiverine (n = 23), (P = 0.0169). Total OABSS and other individual scores, and voiding diary parameters for both drugs showed improvements; however, between‐group difference was not established. Conclusion: Although both solifenacin 5 mg and propiverine 20 mg were effective in the treatment of OAB, solifenacin appeared to be more effective and tolerable.     

Does the Number of Previous Vaginal Deliveries Affect Overactive Bladder Symptoms and their Response to Treatment?

Objectives: To explore associations between the number of vaginal deliveries (primary aim) or gender (secon‐ dary aim) and overactive bladder (OAB) symptoms as well as their response to treatment with a muscarinic antagonist. Methods: Preplanned secondary analysis of an observational study of solifenacin in OAB patients. Episode frequencies of OAB symptoms, pad use and scores on OAB rating scales were documented in 4450 patients before and after a 12–14 week treatment period with solifenacin 5 or 10 mg. Results: Women without, and with one, two or more than two vaginal deliveries and men were similar in their baseline characteristics. All groups also exhibited rather similar reductions in symptoms and improvements in rating scales upon treatment. Conclusion: These data indicate that solifenacin, and perhaps other muscarinic receptor antagonists, are similarly suitable for the treatment of OAB symptoms in both genders, irrespective of previous vaginal deliveries.     

Pharmakotherapie der Harninkontinenz im Alter

The prevalence and the incidence of Urinary Incontinence is growing. Women suffer predominantly from stress and mixed urinary incontinence and men from urge incontinence. In elderly people, the pathophysiological and the physiological change in the lower urinary tract system must be considered as well as an underlying multimorbidity. Stress urinary incontinence is among others caused by an insufficient urethral closure mechanism and urge incontinence is followed by unhibited detrusor contractions. Medical treatment is beside other important conservative options only one part of the treatment strategy in incontinence. Duloxetine, a serotonine-norepinephrine reuptake inhibitore can increase activity of the external urethral sphincter and is able to reduce incontinence episodes in up to 64?%. Antagonists of muscarinic receptors can reduce urgency, frequency and urge incontinence as well as increase bladder capacity significantly. In Germany, darifenacin, fesoterodin, oxybutynin, propiverine, solifenacin, tolterodine and trospium chloride are available to treat urge incontinence. The efficacy of these agents are almost comparable in the elderly with the exception of oxybutynin IR. However, tolerability is different and not well studied in the elderly population with the exception of fesoterodin. Side effects, especially dry mouth, dizziness and constipation often limit their use. None of the agents show ideal efficacy or tolerability in all patients. Last summer therefore a β₃-agonist mirabegron was also introduced in Germany but was withdrawn.     

Efficacy and Safety of Propiverine and Solifenacin for the Treatment of Female Patients with Overactive Bladder: A Crossover Study

Objectives: To evaluate the clinical efficacy and tolerability of propiverine and solifenacin in female patients with overactive bladder (OAB). Methods: A prospective nonrandomized crossover study of propiverine 20 mg and solifenacin 5 mg was conducted. Female OAB patients were assigned alternately to treatment with propiverine for 8 weeks then solifenacin for 8 weeks (Group P‐S) or solifenacin for 8 weeks then propiverine for 8 weeks (Group S‐P). At baseline, 8th week and 16th week, symptoms were assessed using overactive bladder symptom score (OABSS). Results: A total of 121 patients were enrolled. Overall, 38 patients (31.4%) discontinued or dropped out and 83 patients were available for analysis (39 in Group P‐S and 44 in Group S‐P). In both groups, the total score and each score of OABSS were significantly improved after 8 weeks compared with baseline. In only Group P‐S (changing over from propiverine to solifenacin), urgency score in the 16th week was further improved significantly compared with the 8th week. The most bothersome symptom at baseline was urgency incontinence (50.6%), followed by urgency (37.3%). Even after symptom improvement, more than half of the patients were bothered by urgency or urgency incontinence. The incidence of adverse events of moderate and severe grade was higher during propiverine treatment than solifenacin (11.1% vs 2.9%, P = 0.039). Conclusion: Propiverine 20 mg and solifenacin 5 mg were effective for treating female OAB patients. Urgency was further improved after switching from propiverine to solifenacin, but not after switching from solifenacin to propiverine. Solifenacin was better tolerated than propiverine.     

Adverse events and treatment discontinuations of antimuscarinics for the treatment of overactive bladder in older adults: A systematic review and meta-analysis

IntroductionAntimuscarinics should be used with caution in older adults with overactive bladder (OAB) due to anticholinergic adverse events (AEs). Systematic reviews and meta-analyses (SRMAs) have analyzed safety-related outcomes but have not specified risk in the elderly, the population at highest risk for AEs. The aim of this review is to explore and evaluate AEs and treatment discontinuations in adults 65 or older taking antimuscarinics for OAB.MethodsKeywords were searched in MEDLINE, EMBASE, SCOPUS, and Cochrane Central Register for Controlled Trials. Randomized controlled trials (RCTs) along with sub-analyses and pooled analyses that compared antimuscarinics to placebo or another antimuscarinic were performed in February 2015. Studies assessing AEs or treatment discontinuations in a population of adults 65 or older were included. The Jadad Criteria and McHarm Tool were used to assess the quality of the trials.ResultsA total of 16 studies met the inclusion criteria. Eighty AEs and 27 reasons for treatment discontinuation were described in the included studies and further explored. Anticholinergic AEs were more common in antimuscarinics compared to placebo. Incidence of dizziness, dyspepsia, and urinary retention with fesoterodine, headache with darifenacin, and urinary tract infections with solifenacin were significantly higher compared to placebo. Treatment discontinuation due to AEs and dry mouth were higher in the antimuscarinics when compared to placebo in older adults.ConclusionsTreatment for overactive bladder using antimuscarinics in adults aged 65 or older resulted in significant increases in risk for several AEs compared to placebo including anticholinergic and non-anticholinergic AEs.     

Clinical Differences Between Solifenacin and Tolterodine

Overactive bladder (OAB) is characterized by involuntary detrusor contractions that result in bothersome urinary symptoms. The estimated US prevalence of OAB is 16% among men and 16.9% among women, comprising some 37.4 million Americans. The mainstay of treatment is medication. Although all drugs have variable degrees of efficacy and tolerability, several have emerged that yield good clinical results with tolerable side effects. This review focuses on two frequently prescribed drugs, solifenacin and tolterodine, and compares their clinical efficacy. A PubMed review was conducted with “solifenacin” and “tolterodine” as search words. Articles that compared the two medications were reviewed for content and number of study participants. Those with the most relevant findings and the highest number of participants were included. Both solifenacin and tolterodine show clinical efficacy for the treatment of OAB. Solifenacin seems to have better results in some series, with similar side effects. Antimuscarinic therapy is effective as OAB treatment. Both solifenacin and tolterodine have good clinical efficacy. However, in head—to-head trials, solifenacin seems to have somewhat better outcomes. Solifenacin, 5 mg, has less reported dry mouth than tolterodine, but at 10 mg, the incidence of dry mouth is similar.     

Systematic Review and Meta‐Analysis: Do Clinical Trials Testing Antimuscarinic Agents for Overactive Bladder Adequately Measure Central Nervous System Adverse Events?

Experimental studies in healthy volunteers suggest that some antimuscarinic agents confer a risk of cognitive impairment, yet clinical trials of people with overactive bladder report only rare central nervous system (CNS) side effects. A lack of systematic measurement and reporting of CNS outcomes in clinical trials may partially explain this discrepancy. The purpose of this review and meta-analysis was to ascertain the reporting bias associated with adverse CNS events in clinical drug trials of younger and older adults with overactive bladder. Articles were identified from MEDLINE and EMBASE databases until 2010 using the search terms "clinical trial" AND (one of) "oxybutynin, tolterodine, fesoterodine, propiverine, solifenacin, darifenacin, and trospium." Eligibility criteria included original randomized trials involving adults with overactive bladder; standard doses of medication; reports of confusion, somnolence, sedation, dizziness, drowsiness, asthenia, insomnia, and vertigo; no evidence of dementia at baseline; and trials in English. Seventy-seven percent (242/314) of eligible trials identified in the search neither measured nor reported CNS outcomes. Of the remaining 23%, it was difficult to distinguish whether CNS adverse events were systematically measured or spontaneously reported. Only one of 72 trials that were retained objectively measured changes in cognitive performance (Mini-Mental State Examination). Dizziness was the most frequently reported side effect, in 3% of oxybutynin, 3.2% of propiverine, and 1.8% of tolterodine users, compared with 1.6% with placebo. Confusion was reported in fewer than 1% of cases. Age-stratified analyses of CNS outcomes from trials in adults aged 65 and older with overactive bladder were found in only eight publications. Meta-analyses were conducted with 33 randomized, double-blind, placebo-controlled trials to determine the effect of each drug and dose on different CNS outcomes. Study heterogeneity, dosing inconsistency, and reporting bias limited interpretation of the findings from the meta-analyses. More-detailed standardized measurement of age-stratified CNS outcomes in clinical trials is required to better inform patients and clinicians about CNS risks associated with antimuscarinic agents.     

Who Would Benefit from Solifenacin Add‐On Therapy to Tamsulosin for Overactive Bladder Symptoms Associated with Benign Prostatic Hyperplasia?

Objectives: We evaluated the types of patient factors that influence the efficacy and safety of solifenacin add‐on therapy to tamsulosin in men with overactive bladder (OAB) associated with benign prostatic hyperplasia (BPH). Methods: A total of 130 BPH patients with persistent OAB symptoms despite undergoing alpha1‐adrenagic antagonist monotherapy were enrolled in this study. Their OAB symptoms persisted after monotherapy consisting of tamsulosin 0.2 mg once daily for more than 8 weeks, followed by subsequent solifenacin 5 mg once daily. The patient backgrounds were assessed, as were the changes in their International Prostate Symptom score (IPSS), Quality of Life (QOL) index, and Overactive Bladder Symptom Score (OABSS) before and 8 weeks after the administration of solifenacin. Results: Total IPSS, QOL index, and OABSS improved significantly following solifenacin administration. Multivariate analyses revealed prostate volume was the only predictor that contributed to the improvement of total IPSS. In patients with prostate volume <30 mL, the improvement in total IPSS (?3.5) was superior to that for prostate volume >30 mL (?0.5; P = 0.002). The data also demonstrated that diabetes mellitus was an independent factor preventing OABSS improvement. In patients with diabetes mellitus, OABSS was not sufficiently improved (?0.6) compared to patients without diabetes (?2.1; P < 0.001). Conclusion: Solifenacin add‐on therapy to tamsulosin showed efficacy and good tolerability in BPH patients with OAB symptoms. The findings also indicated that patients with a relatively small prostate and without diabetes mellitus would receive more benefit from this therapy.     

Clinical Impact of Solifenacin on Generic and Symptom‐Specific Quality of Life for Females with Overactive Bladder: Using the Overactive Bladder Symptom Score and Rand Medical Outcomes Study 36‐Item Health Survey

Objectives: We evaluated the effectiveness of antimuscarinic treatment on disease‐specific and generic quality of life (QoL) in females with clinically diagnosed overactive bladder (OAB) by prospectively analyzing improvements in the overactive bladder symptom score (OABSS) and the Rand Medical Outcomes Study 36‐Item Short Form Health Survey (SF‐36). Methods: We prospectively recruited newly diagnosed female patients with OAB. Pretreatment disease‐specific symptoms were documented, and generic QoL questionnaires were administered. All subjects received solifenacin 5 mg/day for >8 weeks. Symptoms and general health‐related QoL (HRQoL) were assessed using the OABSS and SF‐36, respectively. Other objective variables, such as maximum urinary flow rate and postvoid residual urine volume, were also evaluated. Results: Seventy‐eight subjects met all inclusion criteria and no exclusion criteria. After 8 weeks, the mean OABSS decreased by approximately 50% compared with baseline (from 9.1 ± 2.8 to 4.5 ± 3.6). All individual scores in OABSS improved after administration of solifenacin. Before treatment, the scores of the study subjects in all SF‐36 domains were significantly worse than the age‐ and gender‐adjusted Japanese national norms (P < 0.01), except the vitality (VT) scale. Intra‐group comparisons between age groups showed worse mental health (MH) scores in all age groups. In the OAB group, three mean SF‐36 scales (physical function [PF], VT, and MH) significantly improved after treatment. Conclusion: Treatment of OAB with solifenacin is associated with significant improvement in generic HRQoL and disease‐specific symptoms at 8 weeks after drug administration. Particularly for generic HRQoL as measured by the SF‐36, solifenacin treatment effectively improves three SF‐36 scores: PF, VT, and MH.     

Medikamentöse Therapie der Harninkontinenz

Urinary incontinence has a high prevalence in both men and women. Women suffer predominantly from stress urinary incontinence and men from urge incontinence. Other types of incontinence are less frequent. Stress urinary incontinence is caused by an insufficient urethral closure mechanism and urge incontinence by uninhibited detrusor contractions. Medical treatment is beside other conservative options and operations only one part of the treatment strategy in incontinence. Duloxetine, a serotonine-norepinephrine reuptake inhibitor, is used to treat stress urinary incontinence, can increase activity of the external urethral sphincter and is able to reduce incontinence episodes in up to 64%. Antagonists of muscarinic receptors can reduce urgency, frequency and urge incontinence as well as increase bladder capacity significantly. In Germany, trospium chloride, tolterodine, solifenacin, oxybutynin and propiverine are available to treat urge incontinence. Efficacy of these agents are comparable. However, tolerability is different and side effects, especially dry mouth, often limit their use. None of the agents show ideal efficacy or tolerability in all patients and, therefore, new agents and formulations are currently under clinical investigation.     

Antimuscarinic use and discontinuation in an older adult population

IntroductionAlthough antimuscarinics are typically the first-line pharmacological treatment option for overactive bladder, patients often discontinue therapy. The aim of this research project is to identify the rate of antimuscarinic discontinuation, switching, and continuation and differences in discontinuation among different antimuscarinics.MethodsUsing the 5% random sample of Medicare Claims Data, we identified a cohort of patients aged ≥ 66 years old who newly initiated antimuscarinics between January 1, 2007 and December 31, 2012. Treatment discontinuation was defined as no subsequent fills of the initial antimuscarinic in the days’ supply plus a 30 day grace period. We ascertained percentages of patients who discontinued antimuscarinics, switched antimuscarinics, or died within 12 months of antimuscarinic initiation. Cox proportional hazards models were used to determine time to discontinuation of individual antimuscarinics relative to oxybutynin immediate-release (IR).ResultsAmong the 42,886 new-users of antimuscarinics, 71.8% discontinued, 10.8% switched, and 3.2% died prior to antimuscarinic discontinuation or switching while only 14.2% continually filled an antimuscarinic for one year. In the multivariable analysis, patients who were initiated on oxybutynin extended-released (ER), tolterodine, trospium, darifenacin, solifenacin, and fesoterodine were significantly less likely to be discontinued therapy compared to oxybutynin IR (p < 0.001).ConclusionAfter one year of antimuscarinic initiation, only 14% of older adult patients continuously utilized their initial antimuscarinic therapy suggesting a need for clinical interventions to improve continual use of antimuscarinics.     

Trospium chloride for overactive bladder may induce central nervous system adverse events

BackgroundAnticholinergic drugs constitute the first-line pharmacologic treatment for overactive bladder (OAB). Of the various anticholinergic agents available, trospium chloride appears to have potentially favorable chemical and pharmacologic properties leading to reduce the incidence of central nervous system (CNS) adverse reactions, since their ability to cross the blood-brain barrier is reduced (relative to other drugs in this therapeutic class).ObjectiveThe objective of the present survey was to establish whether or not CNS adverse reactions may be associated with trospium exposure by evaluating spontaneous reports made to the French pharmacovigilance database (FPVD).MethodsAll serious adverse drug reactions, specifically confusion, hallucinations, agitation and cognitive impairment, associated with trospium (the immediate-release form only) recorded in the FPVD between September 2005 to September 2011 were identified and analyzed.ResultsWe identified 15 cases of CNS adverse events, according to at least one of the following terms: confusion (n = 9), hallucinations (n = 6), cognitive impairment (n = 4) and agitation (n = 2) and in which trospium chloride was suspected to have a causal link according to their imputability evaluation. The reports concerned 10 women and 5 men, with a mean age of 81 years (range: 62 to 96 years). The symptoms varied from relatively acute states of confusion and/or hallucinations to more progressive cognitive changes. In all these cases, CNS symptoms resolved rapidly after treatment discontinuation.ConclusionDespite the drug's favorable physiochemical properties, we have found pharmacovigilance data indicating that trospium chloride prescribed for OAB can induce CNS adverse reactions, such as confusion, hallucinations, agitation and/or cognitive impairment. Physicians should consider withdrawing trospium chloride if CNS symptoms suggestive of anticholinergic adverse effects occur in patients treated with this drug.     

The placebo effect in overactive bladder syndrome

Overactive bladder syndrome (OAB) is a condition that involves urinary urgency and affected individuals are usually treated with behavioral therapy and antimuscarinic agents as first-line therapies. Existing evidence from clinical trial data suggests that a positive placebo effect occurs in patients receiving treatment for OAB. In our systematic Review of placebo-controlled, randomized trials in OAB, we show statistically significant improvements in three patient-reported outcomes-incontinence episodes per day, micturition episodes per day and mean micturition volume from baseline-after placebo in randomized studies for OAB. The findings could highlight the brain's role in the pathophysiology of OAB or the role of additional bladder training conducted as part of OAB clinical trials. More research is needed to determine the underlying mechanisms of the placebo effect in OAB.     

Evaluation of brain anticholinergic activities of urinary spasmolytic drugs using a high-throughput radio receptor bioassay

OBJECTIVES: To compare the brain anticholinergic activities of five urinary spasmolytic drugs (USDs). DESIGN: In vitro study. SETTING: Laboratory. PARTICIPANTS: None. MEASUREMENTS: A validated 96‐well anticholinergic radio receptor bioassay using small incubation volumes (240 μL per well) was applied in the current study. The different USDs (tolterodine, oxybutynin, solifenacin, darifenacin, and 5‐hydroxy‐methyl‐tolterodine (5‐HMT; the active metabolite of fesoterodine) were dissolved in plasma in their respective therapeutic concentration ranges. The plasma samples were added directly to the wells of 96 filter plates, wherein the incubation, filtration, and counting of undisplaced radioactivity was performed. Standard curves with atropine were used as reference for estimations of anticholinergic activity (AA). RESULTS: 5‐HMT and tolterodine displayed the highest AA of the tested USDs. In the middle of the therapeutic concentration range, the central anticholinergic potency of 5‐HMT and tolterodine was more than 10 times as high as that of oxybutynin, solifenacin, and darifenacin. Darifenacin exhibited the lowest AA at therapeutic serum concentrations (相似文献   

Mirabegron causes vesical and urethral relaxation in rats with spinal cord injury

The effects of solifenacin and mirabegron on vesical and urethral function were compared in rats with or without spinal cord injury (SCI). Isovolumetric cystometry and urethral pressure recording were initially performed in intact rats. Then, the bladder neck was ligated under urethane anesthesia, after which a catheter was inserted through the bladder dome for isovolumetric cystometry and another catheter was inserted into the urethra to measure urethral pressure. Solifenacin (0.03–3 mg/kg) or mirabegron (0.03–3 mg/kg) was injected intravenously, and bladder and urethral activity were recorded. To create rats with SCI, the spinal cord was transected at the lower thoracic level under isoflurane anesthesia. After 2 weeks, a catheter was inserted through the bladder dome for single cystometry and bladder activity was recorded without anesthesia following intravenous injection of solifenacin or mirabegron. Isovolumetric cystometry revealed a larger decrease in maximum bladder contraction pressure after injection of solifenacin, whereas prolongation of the interval between bladder contractions was greater with mirabegron. In SCI rats, single cystometry showed that solifenacin and mirabegron both increased bladder volume at the first non‐voiding bladder contraction and decreased the maximum bladder contraction pressure. Mirabegron also increased the voided volume and decreased the percentage residual volume without altering bladder capacity. Solifenacin and mirabegron both inhibited bladder contractility, and mirabegron possibly also induced urethral relaxation. Mirabegron may be suitable for patients with overactive bladder and residual urine.