Long-term results of amitriptyline treatment for interstitial cystitis

Purpose:

We performed a prospective, open label study to examine the safety and efficacy of the long-term administration of the tricyclic antidepressant amitriptyline in patients with interstitial cystitis (IC).

Materials and Methods:

A total of 94 patients were stratified into 2 groups, namely a National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) group of those who fulfilled NIDDK criteria for IC and a nonNIDDK group of those who presented with characteristic IC symptoms but met at least 1 NIDDK exclusion criterion. Amitriptyline was received strictly at bedtime following an established self-titration protocol without a limitation of the maximum daily dose. Patients reporting improvement in a global response assessment questionnaire were considered treatment responders. Further efficacy measures were changes in pain and urgency, functional bladder capacity and frequency. Changes in the O′Leary-Sant IC index and rating of overall satisfaction with the therapeutic outcome were also reported.

Results:

Mean study followup ± SD was 19.0 ± 12.5 months. The response rate was 64% (60 patients). The overall mean dose was 55 mg (range 12.5 to 150). Side effects occurred in 79 patients (84%), including dry mouth in 79% and weight gain in 59%. Patient overall satisfaction with the therapeutic result was excellent or good in 43 (46%). The dropout rate was 31% (29 patients) after a mean treatment period of 6 weeks at a mean dose of 70 mg. Nonresponse to treatment was the primary reason for dropout in all cases, while side effects contributed to dropout in 25 (86%). Improvement in the various IC symptoms was statistically significant compared with baseline.

Conclusions:

Long-term administration of amitriptyline is a feasible, safe and effective treatment for IC, provided that the drug is used judiciously to minimize adverse effects. The therapeutic response to amitriptyline was uniformly observed in patients fulfilling NIDDK criteria and in those with the pure clinical diagnosis of IC.     

Intravesical resiniferatoxin for the treatment of interstitial cystitis: a randomized, double-blind, placebo controlled trial

PURPOSE: Interstitial cystitis is a painful bladder condition of unknown etiology and poorly understood pathophysiology. Current therapies have met with limited success. Vanilloid receptor agonists such as resiniferatoxin (RTX) desensitize C-fibers that transmit pain; it is hypothesized that such drugs will be effective in the treatment of interstitial cystitis and painful bladder syndrome by decreasing the pain that leads to urinary frequency and urgency. MATERIALS AND METHODS: A randomized, double-blind, placebo controlled study was conducted in 163 patients with interstitial cystitis. Participants were randomly assigned to receive a single intravesical dose of 50 ml of either RTX 0.01 microM, 0.05 microM, 0.10 microM, or placebo. Safety and efficacy was evaluated over 12 weeks. The primary efficacy endpoint was the Global Response Assessment, a 7-point scale rating overall change in symptoms of interstitial cystitis after 4 weeks. Secondary efficacy endpoints included reduction in pain, urgency, frequency, nocturia, average void volume, and the O'Leary-Sant Symptom and Problem Indexes. RESULTS: RTX did not improve overall symptoms, pain, urgency, frequency, nocturia, or average void volume during 12 weeks followup. RTX resulted in a dose-dependent increase in the incidence of instillation pain, but was otherwise generally well tolerated. CONCLUSIONS: In the largest prospective, randomized clinical trial reported to date with intravesical vanilloid therapy, single administration of RTX at doses of 0.01 microM to 0.10 microM was not effective in patients with interstitial cystitis.     

The dual serotonin and noradrenaline reuptake inhibitor duloxetine for the treatment of interstitial cystitis: results of an observational study

PURPOSE: We report an observational study to evaluate the efficacy and tolerability of duloxetine for interstitial cystitis. MATERIALS AND METHODS: A total of 48 women were prospectively treated for 2 months following an uptitration protocol to the target dose of 2 x 40 mg duloxetine per day. Patients received the target dose for 5 weeks. The efficacy of duloxetine treatment was assessed at week 8. The primary end point was a change in the overall well-being evaluated by a patient reported global response assessment. Secondary end points were changes in pain and urgency (visual analog scales), frequency and functional bladder capacity (48-hour voiding log), and changes in overall symptom severity (O'Leary-Sant index). RESULTS: There were 5 patients (10.4%) who were identified as responders and 17 patients (35.4%) who dropped out of the study exclusively due to side effects, with nausea present in all dropouts. No severe adverse events were reported. All 5 responders reported onset of symptom improvement but not until they had reached the target dose. Regarding secondary outcome parameters, duloxetine treatment did not result in statistically significant improvement of symptoms. Maximum urinary flow rate and residual volume were influenced more prominently in patients at the target dose, however, the changes did not appear to be clinically meaningful. CONCLUSIONS: Treatment of interstitial cystitis with duloxetine did not result in significant improvement of symptoms. The drug administration was safe but the tolerability of the drug was poor mainly due to nausea occurring with the starting dose of 20 mg per day. Based on the preliminary data of this observational trial we currently cannot recommend duloxetine as a therapeutic approach for interstitial cystitis.     

A prospective, double-blind, randomized cross-over study evaluating changes in urinary pH for relieving the symptoms of interstitial cystitis

OBJECTIVE: To provide evidence for the clinical efficacy of changes in urinary pH on the pain associated with interstitial cystitis (IC). PATIENTS AND METHODS: A prospective, randomized, double-blind cross-over study was conducted with 26 women with IC between 2000 and 2002, consisting of cross-over instillations of urine at physiological pH (5.0), and neutral buffered pH (NaH(2)PO(4) buffered to pH 7.5). The outcome measured was the subjective symptom of pain assessed using a visual analogue scale at baseline, after the initial instillation of solution, at washout, and after the crossover instillation. Data were analysed using repeated-measures analysis of variance. RESULTS: There was no statistically significant difference between the mean (sd) change from baseline pain scores after instilling neutral buffered solution, at 0.50 (2.78), and acidic solution, at 0.33 (3.43) (P = 0.85). Secondary outcomes were analysed, including baseline variability and treatment-order effects; neither were significantly different between the groups. CONCLUSIONS: There was no statistically significant difference in subjective pain scores on instilling urine at physiological pH or sodium-phosphate buffered saline in these patients with IC. Further work is required to define the role, if any, of urinary pH in the pathophysiology and treatment of IC.     

Intravesical bacillus Calmette-Guerin and dimethyl sulfoxide for treatment of classic and nonulcer interstitial cystitis: a prospective, randomized double-blind study

PURPOSE: We conducted a prospective, double-blind study with a crossover design of intravesical bacillus Calmette-Guerin (BCG) and dimethyl sulfoxide to determine whether patients with classic and nonulcer interstitial cystitis, respectively, might benefit from either regimen. MATERIALS AND METHODS: A total of 21 patients, including 11 with classic and 10 with nonulcer interstitial cystitis, randomly underwent treatments with intravesical BCG or dimethyl sulfoxide and, if not improved, were treated with the other substance after a washout period. All 21 patients were evaluated with symptom questionnaires, including a visual analog pain scale and voiding diaries. RESULTS: Regardless of regimen, there was no improvement in maximal functional capacity. There was a reduction in urinary frequency following dimethyl sulfoxide treatment but only in the classic subtype (p <0.05), whereas no reduction was seen following BCG in either subtype. A substantial pain decrease was noted in classic (p <0.05) as well as nonulcer (p <0.05) interstitial cystitis following dimethyl sulfoxide. CONCLUSIONS: Intravesical BCG has been presented as a promising new option for treatment of interstitial cystitis. We failed to demonstrate benefit from this treatment. Dimethyl sulfoxide had no positive effect on maximal functional capacity but resulted in a significant reduction in pain and urinary frequency, although only in patients with classic interstitial cystitis.     

A randomized controlled trial of intravesical bacillus calmette-guerin for treatment refractory interstitial cystitis

PURPOSE: We compared intravesical bacillus Calmette-Guerin (BCG) to placebo instillations in patients with treatment refractory interstitial cystitis (IC). MATERIALS AND METHODS: Subjects who met the National Institutes of Health-National Institute for Diabetes and Digestive and Kidney Diseases criteria for IC, and reported at least moderate pain and frequency for a minimum of 6 months before study entry, were randomized to 6 weekly double-blinded intravesical instillations of either BCG or placebo, and then followed for a total of 34 weeks. The primary outcome was a patient reported global response assessment at week 34, supplemented with medications for IC during weeks 31 to 34. Secondary outcomes included a 24-hour voiding diary, pain, urgency, validated IC symptom indexes and adverse events. The target sample size was 260 participants, designed to detect a difference in response rates between placebo and BCG of 30% and 50%, respectively. RESULTS: A total of 265 participants were randomized and 17 (6%) patients withdrew from study. The response rates for the primary outcome were 12% for placebo and 21% for BCG (p = 0.062). Small improvements were observed for all secondary outcomes, some more so with BCG, but these differences were of borderline statistical significance. Although a large number of adverse events were reported in the BCG arm, there was no statistically significant difference between the treatment arms in overall adverse event rates. CONCLUSIONS: Although the BCG safety profile was acceptable, the response rate for the primary outcome was low. Effective medical treatment for patients with moderate to severe interstitial cystitis remains elusive.     

阿米替林联合透明质酸钠、肝素治疗间质性膀胱炎的临床疗效评价

目的探讨口服阿米替林联合膀胱灌注透明质酸钠、肝素治疗间质性膀胱炎/膀胱疼痛综合征（interstitial cystitis/painfulbladder syndrome,IC/PBS）的临床疗效和安全性。方法 24例IC/PBS患者行口服阿米替林联合膀胱灌注透明质酸钠、肝素治疗。麻醉下膀胱镜检查及水扩张后,诊断明确所有患者即开始口服阿米替林25mg/d,最大剂量75mg/d;同采用透明质酸40mg、肝素25 000U混合液膀胱灌注、每周1次,4次后改每月1次。观察治疗前及治疗后3、6个月的排尿次数、排尿量和Oleary saint问卷表评分（OLeary-Sant patient symptom/problem index scores,ICSI/ICPI）;盆腔疼痛及尿频评分（pelvic painand urgency frequency questionnaire,PUF）;第6月复查膀胱镜。结果 22例患者完成本研究,随访3、6月时,每日排尿次数明显减少,尤其是夜尿次数,平均每次尿量明显增加,ICSI、ICPI、PUF评分明显降低,差异有统计学意义（P〈0.001）;治疗6月与治疗3月相比差异除夜尿次数及PUF评分外,其他各项指标均无统计学意义（P〉0.05）。6月复查膀胱镜检查,19例黏膜下出血点消失或减轻,3例膀胱三角区炎性改变。结论阿米替林联合透明质酸钠、肝素治疗IC/PBS安全有效。     

阿米替林与二甲基亚砜治疗间质性膀胱炎的临床研究

目的探讨口服阿米替林及膀胱灌注二甲基亚砜（DMSO）治疗间质性膀胱炎的临床有效性及安全性。方法2004年7月~2008年5月,采用美国国立肾病、消化病和糖尿病研究所（NIDDK）制定的标准诊断间质性膀胱炎19例,口服阿米替林25mg／d。治疗1周效果不佳的患者加服阿米替林至50mg／d,最大不超过75mg／d。对无效或不能耐受阿米替林副作用的患者加用50％DMSO50mL膀胱灌注连续10次（其中2例用50％DMSO50mL＋1万单位低分子肝素钠灌注）,总疗程3个月。观察指标：O’Leary间质性膀胱炎症状指数、间质性膀胱炎问题指数、视觉疼痛模拟量表及排尿日记。结果19例患者均完成治疗,17例患者取得良好的效果,2例患者效果较差。结论口服阿米替林及膀胱灌注DMSO是治疗间质性膀胱炎简单有效的方法,可以缓解患者的临床症状,提高生活质量,其副作用可以被大多数患者耐受。     

Cyclosporine A and pentosan polysulfate sodium for the treatment of interstitial cystitis: a randomized comparative study

PURPOSE: In a previous retrospective analysis, cyclosporine A (CyA) was highly efficient in treating patients with interstitial cystitis. A prospective randomized study with this immunosuppressive agent was warranted. We compared CyA to pentosan polysulfate sodium (PPS) in patients with interstitial cystitis. MATERIALS AND METHODS: A total of 64 patients with interstitial cystitis meeting the National Institute of Diabetes and Digestive and Kidney Diseases criteria were enrolled in a randomized prospective study. Patients were randomized in a 1:1 ratio to 1.5 mg/kg CyA twice daily (27 women, 5 men) or 100 mg PPS 3 times daily (26 women, 6 men) for a period of 6 months. The primary end point was daily micturition frequency, and secondary end points were mean and maximal voided volume, number of nocturia episodes, O'Leary-Sant symptom and problem indexes, visual analogue scale for pain, and subjective global response assessment. RESULTS: CyA was superior to PPS in all clinical outcome parameters measured at 6 months. Micturition frequency in 24 hours was significantly reduced in the CyA arm compared to the PPS arm (-6.7 +/- 4.7 vs -2.0 +/- 5.1 times). The clinical response rate (according to global response assessment) was 75% for CyA compared to 19% for PPS (p <0.001). Although there were more adverse events in the CyA arm than in the PPS arm, 29 patients completed the 6-month followup in both groups. CONCLUSIONS: CyA is more effective than PPS in interstitial cystitis.     

阿米替林治疗间质性膀胱炎的临床研究

目的 探讨阿米替林治疗间质性膀胱炎的有效性和安全性. 方法 采用前瞻性研究.间质性膀胱炎患者54例,病程19～72个月,平均(40.7±11.6)个月.口服阿米替林治疗,起始剂量25 mg/次,每晚1次.1周后,若症状不缓解,可加量至50 mg/次;再观察1周,若症状仍不缓解,则可加量至75 mg/次;维持能够缓解症状的最小剂量,总疗程3个月.观察用药前及用药3个月后患者的临床症状(每日排尿次数、最大排尿容量、尿痛程度评分)和O'Leary-Sant间质性膀胱炎问卷表评分及生活质量评分情况.并记录不良反应发生情况. 结果 ①用药3个月后每日排尿次数明显减少,治疗前后分别为(28.5±8.4)和(15.6±3.3)次;最大排尿容量明显增加,治疗前后分别为(108.7±62.2)和(171.0±53.9)ml;尿痛程度评分明显下降,治疗前后分别为6.4±1.5和2.2±1.5,上述指标用药前后相比,差异均有统计学意义(P<0.01).②患者用药3个月后问卷评分和生活质量评分均明显减少,治疗前后分别为26.9±4.0和13.7±5.7及5.5±0.5和2.5±0.6;用药前后比较,差异有统计学意义(P<0.01).③45例在服药第1个月内有不同程度的困倦,43例1个月后自行缓解,2例由于困倦严重且不能缓解而停药.10例服药3个月后体质量增加(5.8±1.8)kg.11例有轻度便秘症状,可以耐受.9例有口干症状,可以耐受.3例出现重度排尿困难,停药后改为其他方法治疗. 结论 阿米替林口服治疗能有效缓解间质性膀胱炎患者的临床症状,改善生活质量,且耐受性及安全性好.     

躯体功能及总体健康感在女性间质性膀胱炎治疗过程中的变化

目的探讨间质性膀胱炎（IC）治疗前后躯体功能（PF）及总体健康感（GH）的变化。方法2005年5月-2009年5年,依据症状及膀胱镜检查诊断间质性膀胱炎31例,其中23例符合美国国立糖尿病、消化病和。肾病研究所（NIDDK）的诊断标准。所有患者开始均口服阿米替林25mg,1次／d。治疗一周效果不佳者加服阿米替林至50mg／d,最大不超过100mg／d。对效果不佳或不能耐受阿米替林副作用的患者加用500g／L二甲基亚砜50mL膀胱灌注连续10次（其中4例用500g／L二甲基亚砜50mL＋10000u低分子肝素钠灌注）,总疗程3个月。观察指标：O’Leary间质性膀胱炎症状指数及问题指数、PF及GH。结果31例患者均完成治疗,25例患者取得良好的效果,6例患者效果较差。结论随着女性IC患者病情好转其躯体功能得到改善,患者的总体健康满意度提高。     

The cysteinyl leukotriene D4 receptor antagonist montelukast for the treatment of interstitial cystitis

PURPOSE: The presence of leukotriene D4 receptors in human detrusor myocytes and increased urinary leukotriene E4 in patients with interstitial cystitis and detrusor mastocytosis imply a role for cysteinyl containing leukotrienes as proinflammatory mediators in this disease. We examined the efficacy of the cysteinyl leukotriene 1 receptor antagonist montelukast for treating patients with interstitial cystitis and detrusor mastocytosis. MATERIALS AND METHODS: Ten women in whom interstitial cystitis was diagnosed according to National Institute of Diabetes and Digestive and Kidney Diseases criteria and who also had detrusor mastocytosis with a minimum of 28 mast cells per mm.2 muscle tissue were included in this study. Patients received a single dose of montelukast daily for 3 months. The efficacy of treatment was determined by 24-hour urinary frequency, nocturia and pain using visual analog scales. RESULTS: After 1 month of montelukast treatment there was a statistically significant decrease in 24-hour urinary frequency, nocturia and pain which persisted during the 3 months of treatment. After 3 months 24-hour urinary frequency had decreased from 17.4 to 12 voidings (p = 0.009), nocturia had decreased from 4.5 to 2.8 (p = 0.019) and pain had decreased from 46.8 to 19.6 mm. on a visual analog scale (p = 0.006). No side effects were observed during treatment. CONCLUSIONS: Montelukast treatment resulted in significant improvement in urinary frequency and pain. Its efficacy for decreasing urinary frequency and pain imply a role of leukotriene receptor antagonists for managing interstitial cystitis but further placebo controlled clinical studies are needed.     

Percutaneous sacral nerve root neuromodulation for intractable interstitial cystitis

PURPOSE: We evaluated the efficacy of percutaneous sacral nerve root neuromodulation in women with refractory interstitial cystitis. MATERIAL AND METHODS: We prospectively evaluated 15 consecutive women with a mean age of 62 years who had refractory interstitial cystitis to determine the efficacy of percutaneous stimulation of the S3 sacral roots. The mean duration of symptoms before evaluation was 5.2 years. All women fulfilled the National Institute of Arthritis, Diabetes and Digestive and Kidney Diseases criteria for the diagnosis of interstitial cystitis and were unresponsive to standard oral or intravesical therapy. The response to treatment was assessed using pain scores, urinary diary variables and quality of life surveys. RESULTS: Mean voided volume during treatment increased from 90 to 143 ml. (p <0.001). Mean daytime frequency and nocturia decreased from 20 to 11 and 6 to 2 times (p = 0.012 and 0.007, respectively). Mean bladder pain decreased from 8.9 to 2.4 points on a scale of 0 to 10 (p <0.001). As indicated by the Short Urinary Distress Inventory and SF-36 Health Survey, the quality of life parameters of social functioning, bodily pain and general health significantly improved during the stimulation period. Of the women 73% requested to proceed to complete sacral nerve root implantation. CONCLUSION: Women with intractable interstitial cystitis respond favorably to percutaneous sacral stimulation with significant improvement in pelvic pain, daytime frequency, nocturia, urgency and average voided volume. Permanent sacral implantation may be an effective treatment modality in refractory interstitial cystitis but further long-term evaluation is required.     

A referral center's experience with transitional cell carcinoma misdiagnosed as interstitial cystitis

PURPOSE: There has been a recent trend to diagnose interstitial cystitis (IC) in a noninvasive way using a potassium sensitivity test, and a pelvic pain, urgency and frequency questionnaire. The concern is that significant pathology causing the bladder symptoms may be missed, such as transitional cell carcinoma. We present our experience with patients "labeled" as having IC who truly had cancer as the cause of irritative symptoms. MATERIALS AND METHODS: A retrospective review of patient records at our IC center was performed from 1998 to 2002. A total of 600 patients were seen at that time with the diagnosis of interstitial cystitis. RESULTS: Six patients (1%) previously diagnosed as having IC were found to have transitional cell carcinoma as the cause of symptoms, 4 of whom (67%) had no hematuria. Mean time from the diagnosis of IC to diagnosis of transitional cell carcinoma was 29.8 months. Irritative bladder symptoms resolved after identifying and treating the malignancy. CONCLUSIONS: Patients with irritative voiding symptoms require a thorough evaluation which may include cystoscopy, cytology and upper tract imaging. Hematuria was not a good predictor of cancer in our series. In the era before widespread use of minimally invasive means to diagnose IC (ie potassium sensitivity test, pelvic pain, urgency and frequency questionnaire) 1% of patients who were considered to have IC actually had transitional cell cancer as the cause of symptoms. One would expect that this number would increase if the criteria to diagnose IC and initiate treatment were oversimplified. Interstitial cystitis remains a diagnosis of exclusion.     

Pilot study of sequential oral antibiotics for the treatment of interstitial cystitis

PURPOSE: Interstitial cystitis is a chronic disease of unknown etiology characterized by bladder pain, urgency and frequency. Although a single microbe has not been implicated as a cause of interstitial cystitis, several groups noted various organisms in the urine of some women with interstitial cystitis and some patients reported that antibiotics decrease symptoms. Consequently we performed a prospective, randomized, double-blinded, placebo controlled pilot study of sequential oral antibiotics. MATERIALS AND METHODS: We randomized 50 patients with interstitial cystitis to receive 18 weeks of placebo or antibiotics, including rifampin plus a sequence of doxycycline, erythromycin, metronidazole, clindamycin, amoxicillin and ciprofloxacin for 3 weeks each. RESULTS: Intent to treat analysis demonstrated that 12 of 25 patients (48%) in the antibiotic and 6 of 25 (24%) in the placebo group reported overall improvement (p = 0.14), while 10 and 5, respectively, noticed improvement in pain and urgency (p = 0.22). In the antibiotic group 20 participants (80%) had adverse effects compared with 10 (40%) in the placebo group (p = 0.009). CONCLUSIONS: Our findings suggest that these antibiotics alone or in combination may sometimes be associated with decreased symptoms in some patients but they do not represent a major advance in therapy for interstitial cystitis.     

A comparison of multiple urine markers for interstitial cystitis

PURPOSE: We measured several urine markers in 24-hour specimens from patients with interstitial cystitis and healthy controls. For each marker we determined whether the urine level was significantly different in interstitial cystitis and control cases, and whether the marker level correlated with the symptom score. MATERIALS AND METHODS: Study participants included 36 female patients with interstitial cystitis and 36 age matched female volunteers. Multiple urine aliquots were obtained to measure the various markers. RESULTS: Certain markers were significantly increased in interstitial cystitis, including anti-proliferative factor, epidermal growth factor, insulin-like growth factor (IGF) binding protein-3 and interleukin (IL)-6. Markers significantly decreased in interstitial cystitis were heparin-binding epidermal growth factor-like growth factor, cyclic guanosine monophosphate and methylhistamine. Other markers were not significantly different in the interstitial cystitis and control groups, including total glycosaminoglycans, epitectin, hyaluronic acid, IL-8, IL-1 and nitrates plus nitrites. IGF-1 was undetectable in 24-hour urine samples but spot voided samples from the same interstitial cystitis population had IGF-1 levels similar to previously reported levels. The only significant association of marker with symptom score was a positive correlation of IL-6 with nocturia. For all markers the conclusions were the same whether the marker was normalized to creatinine or to 24 hours. CONCLUSIONS: This study confirmed several previously reported urine alterations in interstitial cystitis, including increased anti-proliferative factor, epidermal growth factor, IGF binding protein-3 and IL-6, and decreased heparin-binding epidermal growth factor-like growth factor and cyclic guanosine monophosphate. Of all markers studied anti-proliferative factor had the least overlap in the interstitial cystitis and control groups, and so it is the most likely candidate to become a diagnostic test.