Karl J. Kreder

Tolterodine once-daily: superior efficacy and tolerability in the treatment of the overactive bladder.

OBJECTIVES To evaluate the efficacy and tolerability of a new extended-release (ER), once-daily, capsule formulation of tolterodine, relative to placebo and the existing immediate-release (IR), twice-daily, tablet formulation, for treatment of the overactive bladder. METHODS This was a double-blind, multicenter, randomized, placebo-controlled trial. One thousand five hundred twenty-nine patients (81% women) with urinary frequency (eight or more micturitions every 24 hours) and urge incontinence (five or more episodes per week) were randomized to oral therapy with tolterodine ER 4 mg once daily (n = 507), tolterodine IR 2 mg twice daily (n = 514), or placebo (n = 508) for 12 weeks. Efficacy was assessed at the end of the treatment period on the basis of the micturition diary variables. Tolerability and safety were assessed by evaluating the adverse events, electrocardiogram parameters, laboratory values, and treatment withdrawals. RESULTS Tolterodine ER 4 mg once daily (P = 0.0001) and tolterodine IR 2 mg twice daily (P = 0.0005) both significantly reduced the mean number of urge incontinence episodes per week compared with placebo. The median reduction in these episodes as a percentage of the baseline values was 71% for tolterodine ER, 60% for tolterodine IR, and 33% for placebo. The ER formulation was 18% more effective than the IR formulation (P <0.05). Treatment with both formulations of tolterodine was also associated with statistically significant improvements in all other micturition diary variables compared with placebo. For both formulations, the mean decreases in micturition frequency (P <0.0079) and pad usage (P <0.0145) were significant, and the mean volume voided per micturition increased (P = 0.0001). The rate of dry mouth (of any severity) was 23% for tolterodine ER, 30% for tolterodine IR, and 8% for placebo. The overall dry mouth rate for patients taking tolterodine ER was 23% lower than for tolterodine IR (P <0.02), and the rate of severe dry mouth in the ER group was only 1.8%. The rates of withdrawal were comparable for the two active groups and the placebo group. No safety concerns were noted. CONCLUSIONS Tolterodine ER 4 mg once daily is effective and well tolerated in the treatment of overactive bladder with no safety concerns. Tolterodine ER demonstrated an improved efficacy for reducing urge incontinence episodes and a lower frequency of dry mouth compared with the existing IR twice-daily formulation.

Efficacy of pelvic floor muscle exercises in women with stress, urge, and mixed urinary incontinence

OBJECTIVES Our purpose was (1) to evaluate the efficacy on an intent-to-treat basis of a 3-month course of pelvic floor muscle exercises as first-line therapy for urinary incontinence in consecutive women seen in a tertiary care center with stress, urge, and mixed urinary incontinence and (2) to evaluate whether a specially designed audiotape improves compliance and efficacy of the exercises. STUDY DESIGN A prospective randomized trial wa conducted with 71 women seen for treatment of urinary incontinence in two tertiary care center referral clinics (in the departments of gynecology and urology). The primary outcome measure was the number of incontinent episodes, as documented with a 3-day voiding diary. Statistical analysis included t tests and Wilcoxon signed-ranks test, as appropriate. A value of p < or = 0.05 was considered significant. RESULTS Forty-four percent of all enrollees had a > or = 50% improvement in the number of incontinent episodes per day. This increased to 56% of enrolles who completed the treatment course. For all enrollees the mean number of incontinent episodes per day decreased from 2.6 to 1.7 for genuine stress incontinence, from 3.5 to 2.3 for detrusor instability, and from 3.9 to 3.2 for mixed incontinence. For enrollees who completed the 3-month course the mean number of incontinent episodes per day decreased from 2.5 to 1.4 for genuine stress incontinence, from 2.8 to 0.5 for detrusor instability, and from 3.0 to 1.7 for mixed incontinence. Six months after completing the course of exercises approximately one third of all enrollees reported that they continued to note good or excellent improvement and desired no further treatment. There was no difference in outcome measures and no difference in compliance between the women who exercised with the aid of the audiotape and those who exercised according to our usual office routine (p > 0.05). CONCLUSIONS One third of all participants remained improved to the patients satisfaction 6 months after completion of a risk-free, inexpensive, simply provided therapy. Our audiotape did not improve our success rate or decrease the dropout rate. In this study the exercises were equally effective for all three urodynamic diagnoses. Inexpensive methods that could be used by primary care providers to improve the success rate of this therapy merits further attention.

Laparoscopic Partial Nephrectomy: Initial Experience and Comparison to the Open Surgical Approach

During an 18-month period, 6 laparoscopic partial nephrectomies were attempted, 4 of which were successful. The surgical technique was modified and improved between cases aided by new laparoscopic instrumentation, such as the argon beam coagulator and the 7.5 MHz. ultrasonic sector scanning system. In a retrospective comparison between laparoscopic and open partial nephrectomy, estimated blood loss was 525 ml. for the former versus 708 ml. for the latter procedure. However, operating time was more than 2 hours longer with the laparoscopic approach. The major advantages of the laparoscopic procedure appear to be a more rapid return to full diet, less postoperative pain and less requirement for parenteral narcotics. Despite the small size of this series and limited followup data, convalescence may be shortened by 4 weeks after laparoscopic partial nephrectomy. Patients with benign diseases of the kidney, especially with a duplicated collecting system, who require partial nephrectomy may be considered candidates for the laparoscopic approach. The advantages to the patient, however, may be offset by the technical demands on the surgeon.

Stress and symptoms in patients with interstitial cystitis: a life stress model.

Objectives. Stress-related exacerbation of interstitial cystitis (IC) symptoms has frequently been reported. Previous research has found stress-related IC symptom exacerbation in an experimental model. However, this relationship has not been objectively examined with daily life stressors. We used a prospective daily symptom diary method to investigate the relationships among stress and bladder symptoms in patients with IC and age-matched healthy controls.Methods. Forty-five previously diagnosed female patients with IC completed a bladder symptom and stress diary nightly for 1 month; 31 female age-matched healthy controls completed a similar diary for 7 days. The symptom questions were modified from the Interstitial Cystitis Data Base study.Results. Patients reported greater mean daily stress, bladder pain, urgency, and daytime and nocturnal frequency than controls (all P values less than 0.001). Among all patients, a significant relationship between stress and urgency was observed. In addition, a significant relationship between stress and pain was observed among patients with moderate and severe disease. As the disease severity increased, more pronounced relationships between stress and the symptoms of urgency and pain were evidenced. Greater stress was associated with greater nocturnal frequency among patients with more severe disease. These stress-symptom relationships were not observed among the controls.Conclusions. Higher levels of stress were related to greater pain and urgency in patients with IC but not in the controls. In addition, the relationship of stress and these IC symptoms was stronger among patients with more severe disease. The results indicate that life stress is associated with greater IC symptoms, particularly among patients whose disease is not well controlled.

Effect of amitriptyline on symptoms in treatment naive patients with interstitial cystitis/painful bladder syndrome.

PURPOSE Amitriptyline is frequently used to treat patients with interstitial cystitis/painful bladder syndrome. The evidence to support this practice is derived mainly from a small, single site clinical trial and case reports. MATERIALS AND METHODS We conducted a multicenter, randomized, double-blind, placebo controlled clinical trial of amitriptyline in subjects with interstitial cystitis/painful bladder syndrome who were naïve to therapy. Study participants in both treatment arms received a standardized education and behavioral modification program. The drug dose was increased during a 6-week period from 10 up to 75 mg once daily. The primary outcome was a patient reported global response assessment of symptom improvement evaluated after 12 weeks of treatment. RESULTS A total of 271 subjects were randomized and 231 (85%) provided a global response assessment at 12 weeks of followup. Study participants were primarily women (83%) and white (74%), with a median age of 38 years. In an intent to treat analysis (271) the rate of response of subjects reporting moderate or marked improvement from baseline in the amitriptyline and placebo groups was 55% and 45%, respectively (p = 0.12). Of the subgroup of subjects (207) who achieved a drug dose of at least 50 mg, a significantly higher response rate was observed in the amitriptyline group (66%) compared to placebo (47%) (p = 0.01). CONCLUSIONS When all randomized subjects were considered, amitriptyline plus an education and behavioral modification program did not significantly improve symptoms in treatment naïve patients with interstitial cystitis/painful bladder syndrome. However, amitriptyline may be beneficial in persons who can achieve a daily dose of 50 mg or greater, although this subgroup comparison was not specified in advance.

COMPARISON OF CYSTOSCOPIC AND HISTOLOGICAL FINDINGS IN PATIENTS WITH SUSPECTED INTERSTITIAL CYSTITIS

PURPOSE Although the exact etiology of interstitial cystitis remains elusive, bladder inflammation appears to be common in many patients. The National Institutes of Health (NIH) have established diagnostic criteria for interstitial cystitis based on the presence of irritative voiding symptoms in the absence of other identifiable pathology. Cystoscopic examination with hydrodistention performed in patients under anesthesia is part of the NIH diagnostic criteria. We determine if the severity of cystoscopic findings correlated with histological evidence of inflammation in patients with suspected interstitial cystitis. MATERIALS AND METHODS A total of 69 patients who met NIH symptom criteria for interstitial cystitis and underwent cystoscopy, hydrodistention and bladder biopsy under anesthesia were reviewed. There were 2 investigators blinded to the histological data who independently reviewed operative reports. A urological pathologist blinded to the clinical data reviewed biopsies for inflammation severity. Cystoscopic and histological findings were then converted to a numeric scale. Numeric data were analyzed using the Pearson correlation coefficient. RESULTS Cystoscopic examination revealed no evidence of interstitial cystitis in 6 patients (9%), mild changes in 27 (39%), moderate changes in 23 (33%) and severe changes in 13 (19%). Histological examination revealed no inflammation in 21 patients (30%), mild inflammation in 28 (41%), moderate inflammation in 11 (16%) and severe inflammation in 9 (13%). Histological scores correlated poorly with total and scaled cystoscopic severity scores (r = 0.295 and 0.349, respectively). CONCLUSIONS Severity of cystoscopic findings observed during hydrodistention with anesthesia does not appear to correlate with the degree of inflammation identified histologically in patients with suspected interstitial cystitis.

Duloxetine compared with placebo for treating women with symptoms of overactive bladder

To evaluate duloxetine (a serotonin‐noradrenaline reuptake inhibitor) in women with symptoms of overactive bladder (OAB), as it has been shown to increase the bladder capacity in an animal model.

COPING STRATEGIES IN PATIENTS WITH INTERSTITIAL CYSTITIS: RELATIONSHIPS WITH QUALITY OF LIFE AND DEPRESSION

PURPOSE Previous research has demonstrated that interstitial cystitis patients experience depressive symptoms and decrements to quality of life. However, to our knowledge the extent to which patients may be able to influence quality of life and depressive symptoms through coping strategies has not been investigated in this population. In a number of other chronic conditions specific coping strategies have been associated with the degree of impairment beyond disease severity. Therefore, the association of coping strategies with depressive symptoms, quality of life and self-reports of pain was assessed in patients with interstitial cystitis. MATERIALS AND METHODS A total of 64 females with interstitial cystitis were recruited from a urology clinic at a tertiary medical center. Questionnaires assessing depression, quality of life, coping and symptom severity were completed and returned at a clinic appointment. Depression was also measured through a standardized semi-structured interview (Hamilton Rating Scale for Depression). All analyses controlled for age. RESULTS Patients coping by greater catastrophizing reported greater impairments in various domains, including depressive symptoms, general mental health, social functioning, vitality and pain. Greater venting was associated with greater depressive symptoms and poorer mental health. Seeking instrumental social support was associated with fewer depressive symptoms. CONCLUSIONS These findings suggest that maladaptive coping strategies are associated with higher levels of depressive symptoms and quality of life decrements in patients with this condition. Psychosocial interventions aimed at increasing adaptive coping may positively impact the female experience with interstitial cystitis.

The MAPP research network: a novel study of urologic chronic pelvic pain syndromes

Urologic chronic pelvic pain syndrome (UCPPS) may be defined to include interstitial cystitis/bladder pain syndrome (IC/BPS) and chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS). The hallmark symptom of UCPPS is chronic pain in the pelvis, urogenital floor, or external genitalia often accompanied by lower urinary tract symptoms. Despite numerous past basic and clinical research studies there is no broadly identifiable organ-specific pathology or understanding of etiology or risk factors for UCPPS, and diagnosis relies primarily on patient reported symptoms. In addition, there are no generally effective therapies. Recent findings have, however, revealed associations between UCPPS and “centralized” chronic pain disorders, suggesting UCPPS may represent a local manifestation of more widespread pathology in some patients. Here, we describe a new and novel effort initiated by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the U.S. National Institutes of Health (NIH) to address the many long standing questions regarding UCPPS, the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network. The MAPP Network approaches UCPPS in a systemic manner, in which the interplay between the genitourinary system and other physiological systems is emphasized. The network’s study design expands beyond previous research, which has primarily focused on urologic organs and tissues, to utilize integrated approaches to define patient phenotypes, identify clinically-relevant subgroups, and better understand treated natural history and pathophysiology. Thus, the MAPP Network provides an unprecedented, multi-layered characterization of UCPPS. Knowledge gained is expected to provide important insights into underlying pathophysiology, a foundation for better segmenting patients for future clinical trials, and ultimately translation into improved clinical management. In addition, the MAPP Network’s integrated multi-disciplinary research approach may serve as a model for studies of urologic and non-urologic disorders that have proven refractory to past basic and clinical study.Trial registrationClinicalTrials.gov identifier: NCT01098279 “Chronic Pelvic Pain Study of Individuals with Diagnoses or Symptoms of Interstitial Cystitis and/or Chronic Prostatitis (MAPP-EP)”.

DEPRESSIVE SYMPTOMS AND QUALITY OF LIFE IN PATIENTS WITH INTERSTITIAL CYSTITIS

PURPOSE Previous research suggests that patients with interstitial cystitis have poorer quality of life and higher levels of depressive symptoms. However, most studies to date have been limited by the lack of standard measures to describe the experience of living with interstitial cystitis. In addition, to our knowledge no study has used a structured interview to assess depressive symptomatology. We investigated the extent of depressive symptoms and impaired quality of life in a sample of female patients with interstitial cystitis compared with healthy controls. Relationships among physician rated symptom severity, quality of life and depressive symptoms were also examined. MATERIALS AND METHODS At a clinic visit 65 female patients previously diagnosed with interstitial cystitis and 40 age matched, healthy controls completed questionnaires on depressive symptoms (Beck Depression Inventory) and quality of life (Medical Outcomes Study 36-Item Short Form), and a structured interview on depressive symptoms (Hamilton Rating Scale for Depression) with trained interviewers. RESULTS Patients reported compromised quality of life compared with healthy controls across various domains, including physical functioning, ability to function in ones normal role and vitality. They also had more severe depressive symptoms on the 2 depression measures. In patients, greater interstitial cystitis severity was associated with greater compromise in physical and social functioning, and mental health but not in other quality of life domains or depressive symptoms. CONCLUSIONS A diagnosis of interstitial cystitis is related to poorer functioning in various life domains. Decrements increase with disease severity.