JOURNAL OF UROLOGY, Volume 183, Issue 4, Supplement, April 2010
Phenotypically Directed Multimodal Therapy For Chronic Prostatitis/Chronic Pelvic Pain Syndrome: A Prospective Study Using UPOINT
Daniel Shoskes*,a, Dolinga Roberta, Curtis Nickelb
INTRODUCTION AND OBJECTIVES
Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is likely multifactorial. Multicenter placebo controlled trials have failed their primary endpoints using “one size fits all” therapies. In order to phenotype CP/CPPS patients we developed the UPOINT system with six yes/no domains (Urinary, Psychosocial, Organ Specific, Infection, Neurologic/Systemic and Tenderness of muscles). We have shown a direct correlation between domain number and symptom duration as well as NIH-Chronic Prostatitis Symptom Index (CPSI) scores. In this study, we treated patients with multimodal therapy based on the UPOINT phenotype (one therapy recommended for each positive domain) and hypothesized that patients would have significant long term symptom improvement.
METHODS
From March 2008 to April 2009, patients with CP/CPPS were classified according to UPOINT and offered multimodal therapy based on the positive domains (eg. Urinary: alpha blocker or antimuscarinic, Organ specific: quercetin; Neurologic: pregabalin, Tenderness: physical therapy). One hundred patients agreed to therapy and were re-examined at least 26 weeks later. Primary endpoint was a minimum 6 point drop in total CPSI (90% power for a 1.2 point drop).
RESULTS
Mean age was 46 years and median symptom duration was 24 months. A median of 3 UPOINT domains were positive (range 1-5), the most common being Organ specific (70%), Tenderness (64%) and urinary (59%). With a minimum follow up of 26 weeks and median of 50 weeks, 84% had a 6 point or greater fall in total CPSI. Number of positive domains and initial CPSI score did not predict treatment response. Average changes for the CPSI subscores were pain 11.5+/-3.2 to 6.1+/-3.9, urine 4.7+/-3.1 to 2.6+/-2.0, QOL 9.1+/-2.3 to 4.5 +/-2.8 and total 25.2 +/-6.1 to 13.2+/-7.2 (all pairs p<0.0001). No individual phenotype predicted symptom improvement, however use of quercetin was the only individual therapy associated with a higher drop in total CPSI (8.47+/-6.4 vs 13.9 +/-6.2, p<0.0001).
CONCLUSIONS
Phentoypically directed multimodal therapy using the UPOINT system leads to significant improvement in symptoms and quality of life in men with CP/CPPS. While a placebo controlled trial for every therapy combination is not feasible, the results using UPOINT compare favorably to all large trials of monotherapy. This algorithmic technique is simple to use (
https://www.ucpps.men/1/upoint.html) and a major improvement over the status quo of empiric therapy.
Chronic Pelvic Pain Is Associated With Mast Cell Activation And Is Amenable To Mast Cell Directed Therapies
Praveen Thumbikat*, Charles Rudick, David Klumpp, Anthony Schaeffer
INTRODUCTION AND OBJECTIVES
Pain is the hallmark of patients with chronic prostatitis (CP) and chronic pelvic pain syndrome (CPPS). The etiology and pathogenesis of this disease syndrome remains unknown. We hypothesized that mast cells and factors released by activated mast cells contribute to the pathogenesis of CPPS. We therefore examined clinical samples from CPPS patients for mast cell activation products. Mechanisms of chronic pelvic pain were further defined in a murine experimental autoimmune prostatitis (EAP) model.
METHODS
Expressed prostatic secretions (EPS) from patients with CPPS were tested for the presence of mast cell degranulation products using substrate-based assays. Prostatitis was induced in wild type and mast cell deficient male mice using rat prostate antigen with adjuvant. Mice were tested prior to antigen injection (baseline) and at various times post-injection. Referred hyperalgesia and tactile allodynia were tested using von Frey filaments applied to the abdomen and the plantar region of the hind paw. Therapy was administered to mice with inhibitors of mast cell degranulation as well as functional inhibitors of mast cell activated factors.
RESULTS
Activated factors released by mast cells were significantly elevated in EPS from CPPS patients compared to controls. In the murine model of pelvic pain, increased recruitment and activation of mast cells was detected along with expression of nerve growth factor and enhanced neuronal density. In contrast, mast cell deficient mice demonstrated significantly attenuated pelvic pain. Finally, treatment of mice with inhibitors of mast cell degranulation as well as functional inhibitors of mast cell activated factors significantly attenuated pelvic pain behavior.
CONCLUSIONS
Our results demonstrate that mast cells and their activation products play an important role in the pathogenesis of chronic pelvic pain and may be involved in pain mechanisms in CP/CPPS. Furthermore, therapies targeting mast cell activation appear to be efficacious in reducing established pelvic pain in animal models.
Descriptive Epidemiology Of Urologic Pain Symptoms In Men And Women
Jessica Brewer*,a, Carol Linka, Paul Eggersb, John Kusekb, John McKinlaya
INTRODUCTION AND OBJECTIVES
It is commonly assumed that most non-malignant urologic conditions worsen as individuals age. However, data from cross-sectional studies indicate that the prevalence of chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) and interstitial cystitis/painful bladder syndrome (IC/PBS) is lower with advancing age. We examined the epidemiology of symptoms suggestive of IC/PBS and CP/CPPS in a longitudinal study.
METHODS
Analyses were performed using baseline and follow-up data from a population-based survey which used a stratified 2-stage cluster design to sample adults aged 30-79 years. This analysis reports on data from 3407 participants (1268 men and 2139 women; 1102 Black, 1083 Hispanic, and 1222 White) with both baseline and follow-up data. The average number of years between baseline and follow-up was 4.7. Symptoms suggestive of IC/PBS were defined as pain increasing as the bladder fills and/or pain relieved by urination (fairly often, usually, almost always) for at least 3 months. Symptoms suggestive of CP/CPPS were defined as perineal and/or ejaculatory pain and a Chronic Prostatitis Symptom Index pain score of 4+. We present prevalence, remission, and incidence of IC/PCS and CP/CPPS over the 4.7 y period.
RESULTS
Baseline Mean age of men and women reporting symptoms of IC/PBS and CP/CPPS was 53.8 and 44.8 years respectively. Overall, 3.9% of men (n=62) reported symptoms of CP/CPPS at baseline. 80.1% of those men did not report these symptoms at follow-up. Baseline prevalence of symptoms of IC/PBS was 1.2% in men (n=23) and 2.5% in women (n=80). At follow-up, 84.3% of those men and 88.2% of those women did not report symptoms. Estimates of incidence of symptoms characteristic of both conditions were: CP/CPPS 1.1%, and IC/PBS 0.9% in men and 1.3% in women.
CONCLUSIONS
Symptoms suggestive of CP/CPPS and IC/PBS are not reported in over three-fourths of the sample after a period of nearly five years. Identification of factors that may promote remission of symptoms need to be examined.
Dutasteride Reduces Prostatitis Symptoms Compared To Placebo In Men Enrolled In The Reduce (Reduction By Dutasteride Of Prostate Cancer Events) Study
J. Curtis Nickel*,a, Teuvo L.J. Tammelab, Claudio Telokenc, Timothy H. Wilsond, Ivy L. Fowlerd, Roger S. Rittmasterd
INTRODUCTION AND OBJECTIVES
REDUCE is a completed 4-year study of prostate cancer risk reduction with dutasteride. This analysis examines the effects of dutasteride vs. placebo on prostatitis-like symptoms as measured by the Chronic Prostatitis Symptom Index (CPSI).
METHODS
CPSI was administered at baseline and every 6 months in men (aged =50 and =75 years, who had a serum PSA =2.5 and =10 ng/ml and negative baseline biopsy) randomized to dutasteride or placebo. Changes in total and sub scores of the CPSI from baseline were compared in patients identified with prostatitis-like pain (CPSI pain sub score =5) and prostatitis-like syndrome (perineal and/or ejaculatory pain + CPSI pain sub score =4), using a general linear model with effects for baseline score. Comparison of responders, defined as those who had at least a 4-point (at least minimal response) or 6-point (at least moderate response) decrease in total CPSI were compared using the Fisher's Exact Test.
RESULTS
CPSI score was available in 2682 and 2696 men in the placebo and dutasteride groups, respectively. There were 337 (mean CPSI 15.36) and 328 (mean CPSI 14.96) men with prostatitis-like pain and 182 (mean CPSI 14.92) and 184 (mean CPSI 14.93) men with prostatitis-like syndrome identified at baseline in the placebo and dutasteride groups, respectively. There was a significant decrease in total and most sub-scores of the CPSI at 48 months in the dutasteride group compared with the placebo group (Table). In the prostatitis-like pain subgroup and prostatitis-like syndrome subgroup, there were significantly more 4-point responders (63.3% and 58.6% respectively) and 6-point responders (49.2% and 46.6% respectively) in the dutasteride groups compared with placebo groups (49.8 % and 45.4% respectively for 4-point responders; 37.5% and 32.8% respectively for 6-point responders).
CONCLUSIONS
Treatment with dutasteride over 4 years improved prostatitis-related symptoms in older men identified with prostatitis-like pain and prostatitis-like syndrome.
The Role Of Mepartricin In Category Iii Chronic Nonbacterial Prostatitis/ Chronic Pelvic Pain Syndrome (CPPS): A Randomized Prospective Placebo-Controlled Trial
Aldo Franco De Rose, Paolo Traverso*, Tommaso Montanaro, Giorgio Carmignani
INTRODUCTION AND OBJECTIVES
Primary outcome is verify the efficacy of mepartricin versus placebo with regard to the improvement of symptoms in patients with CPPS. Secondary outcome is record hormonal assessment of these patients.
METHODS
30 patients with CPPS have been included in our study and randomized in two groups of 15 subjects each. Group A patients were treated with mepartricin (80mg daily). Group B patients with placebo. All patients underwent the treatment for 60 days. At the beginning and at the end of therapy, all patients were evaluated using a standardized history, physical examination, LH, FSH, testosterone, beta estradiol dosages and a NIH-CPSI questionnaire.
RESULTS
We observed a decrease in total NIH score from 24.0 to 6.0 in group A, and from 25.0 to 19.0 in group B, showing about a 70% and 18% improvement in Group A and Group B, respectively. A statistically significant decrease was observed with regard to pain (from 12.0 to 3.0 and from 10.0 to 7.0, respectively) and to quality of life (from 10.0 to 4.0 and from 10.0 to 9.0). No significant difference was observed in urinary dysfunctions. LH, FSH, and testosterone values were similar in both groups before and after treatment, whereas 17 beta estradiol levels were significantly lower in Group A with respect to Group B, at the end of the study.
CONCLUSIONS
Mepartricin, as showed in the past, provides a significant symptomatic improvement in men with CPPS, versus the treatment with placebo. In this study we tested 80 mg a day, with an higher response than a previous trial performed with 40 mg. From this data we can confirm the role of mepartricin to decrease estrogen plasmatic levels and their concentration in the prostate, perhaps related to the recorded clinical improvement.
Pelvic Floor Injection Of Botulinum Toxin A For Pelvic Pain: A Randomized, Controlled Pilot Study
Henry Gottsch*, Richard Berger, Jane Miller, Claire Yang
INTRODUCTION AND OBJECTIVES
Male chronic pelvic pain syndrome (CPPS) and interstitial cystitis/painful bladder syndrome (IC/PBS) patients often have physical examination findings of pelvic floor muscle tension and tenderness. These patients have been shown to benefit from regimens directed at these myofascial manifestations. Botulinum toxin A (Allergan, Irvine CA) (BTX) has been an effective pain treatment for muscle spasticity and over activity. We tested the hypothesis that transperineal BTX injection improves chronic pelvic pain.
METHODS
Forty-nine patients were enrolled in the study. Twenty-nine men with CPPS and 20 women with IC/PBS completed the study. Baseline symptom evaluation of male and female patients was assessed using validated symptom indices, including Visual Analog Scale (VAS), NIH Chronic Prostatitis Symptom Index, AUA Symptom Index, Graded Chronic Pain Scale, and Perceived Stress Scale. Patients were assigned to either BTX or placebo (normal saline) in a randomized, double-blind fashion. Men were injected with 100 units of BTX, diluted in 2 cc normal saline (NS), or placebo injection of 2 cc of NS. An electromyography injection-needle electrode was utilized to localize and inject the bulbospongiosis muscle and superficial perineal musculature. Female patients underwent transperineal periurethral injection targeting the bladder base with 50 units of BTX diluted in 2 cc NS, 1 cc per injection site or placebo. Follow-up consisted of monthly symptom scales and exams for 3 months. We compared response rates between treatment arms, for both CPPS and IC/PBS cohorts.
RESULTS
No men were enrolled in the IC/PBS group. 13 men with CPPS received BTX injection and 16 received placebo, and 9 women with IC/PBS received BTX injection and 11 had placebo. Baseline characteristics were similar between the BTX and placebo groups, in both CPPS and IC/PBS. No symptom improvement was noted in the BTX groups compared to placebo groups, in either CPPS or IC/PBS. At 3 months the change in the VAS for BTX versus placebo was 0.65 out of 10 (p=0.14) and 0.13 out of 6 (p= 0.82) for the CPPS and IC/PBS groups, respectively. Men had decreased perineal muscle tension to palpation on follow-up, and no physical exam changes were noted in the women. No adverse events were reported, including urinary or fecal incontinence, urinary retention, or systemic side effects.
CONCLUSIONS
In this pilot study of transperineal BTX injection for chronic pelvic pain, there was no improvement in patient symptoms
Early Lifetime Trauma Impacts Symptom Severity Of Interstitial Cystitis And Chronic Pelvic Pain
Chad Baxter*,a, Roger Bolusb, Emeran Mayerc, Deborah Ackermanc, Larissa V. Rodriguezc
INTRODUCTION AND OBJECTIVES
Interstitial cystitis (IC) and chronic pelvic pain (CPP) are complex, multifactorial conditions of uncertain etiology. The impact of early lifetime trauma on symptom severity and quality of life has not been fully elucidated. Objective: We examined the UCLA database of patient-reported, validated questionnaires to determine the impact of early (<18 years age) general, physical, sexual, emotional, and total trauma exposure on symptom severity and quality of life in adult patients with Interstitial Cystitis and Chronic Pelvic Pain.
METHODS
223 patients with diagnoses of IC and/or CPP completed the Early Trauma Inventory (ETI), Physical Health (somatization and panic), Short-Form-36, Hospital Anxiety and Depression, Coping Strategies (catastrophizing), and Brief Pain Inventory questionnaires. 97 patients (43%) recorded responses on ETI questionnaire and were further evaluated. Only one responding patient reported no trauma
RESULTS
Each ETI domain is scored from 0-100. Mean and SD for each domain were: general (37.3, 22.0); physical (43.7, 36); sexual (31.2, 36.0); emotional (53.2, 39.5); total (165.5, 102.2). IC and/or CPP patients differed only in more physical trauma in CPP-only patients (p=0.004). ETI Total among all patients correlates significantly with somatization (p<0.000), catastrophizing (p<0.000) of symptoms, increased anxiety (p=0.014) and depression (p=0.009), as well as poorer scores on physical and mental components of SF-36 (p=0.001, p=0.029). Early general, physical or sexual trauma does not correlate with higher pain score among any patients. Early emotional trauma, however, does correlate strongly with higher pain severity scores (p=0.025).
CONCLUSIONS
Early lifetime traumatic events, particularly emotional trauma, significantly impact patient perception of disease and disease severity in IC and/or CPP patients. Identifying and addressing these issues may significantly impact treatment outcome. Evaluation of treatment outcomes will further clarify the impact of early lifetime trauma.
Defining The Etiology Of Erectile Dysfunction In Men With Chronic Pelvic Pain Syndrome
Doron S. Stember*, Keith O'Brien, John P. Mulhall
INTRODUCTION AND OBJECTIVES
CPPS is an enigmatic condition associated with significant personal distress and reduction in quality of life (QOL). Alteration in QOL is often associated with sexual problems. Our clinical experience is that men presenting with CPPS frequently have concomitant ED. This study was undertaken to define the etiology of ED in this population.
METHODS
Men presenting for evaluation of penile or ejaculatory pain who complained of concomitant ED completed the International Index Of Erectile Function (IIEF) and the NIH CPPS questionnaire. Men with Peyronie's disease were excluded. Men with IIEF erectile function domain (EFD) scores <26 and CPPS scores =10 constituted the study population. Demographic data, comorbidity parameters and treatment history were recorded. All patients had early morning testosterone levels measured and underwent duplex Doppler penile ultrasound in a trimix re-dosing fashion. Criteria for normal erectile hemodynamics were PSV>30cm/s and EDV<5cm/s. Correlation was sought between the IIEF EFD and CPPS scores.
RESULTS
46 patients met all criteria. Mean age was 32±9 years. 50% were partnered. Mean number of vascular comorbidities was 1±1 (0-2) and included hypertension 13%, dyslipidemia 15%, and cigarette smoking 26%. Mean (median) duration of CPPS symptoms was 9±12 (13) months while mean (median) duration of ED was 7±16 (12) months. 96% of patients had ED that post-dated the onset of CPPS symptoms. 76% had penile pain, while 50% had ejaculatory pain. CPPS treatment strategies used included alpha blockers 83%, gabapentin 20%, amitriptyline 33%, biofeedback 30%, other 65%. PDE5 inhibitors had been used by 50% of patients. No patient had a serum T <300 ng/dl with mean total T levels of 496±125 ng/dl. Mean EFD score was 15±5 and CPPS score was 16±4.5. ED severity: 15% mild, 61% moderate, 24% severe. Mean PSV was 46±12 cm/s, EDV 1.5+1.5 cm/s, and RI 0.94±0.11. PSV values were abnormal for 4% of patients (both with 2 vascular comorbidities), while none had an abnormal EDV value. Of note, 83% of patients had an elevated EDV after a single intracavernosal injection. Mean number of trimix injections required for normalization of EDV was 2.2±0.6. The correlation between CPPS score and EFD score was moderate (r=-0.32). There was also a correlation between CPPS score and the number of injections required during penile ultrasound (r=-0.22).
CONCLUSIONS
Men meeting the criteria for the diagnosis of CPPS that present with ED almost always have psychogenic ED. Duplex Doppler ultrasound in this population is fraught with error when a single dose of vasoactive agent is utilized.
Tanezumab Reduces Pain And Urgency In Interstitial Cystitis: Results Of A Phase 2 Trial
Robert Evans*,a, Robert Moldwinb, Nandini Cossonsc, Amanda Darekarc, David Scholfieldc, Ian Millsc
INTRODUCTION AND OBJECTIVES
Tanezumab, a humanized antibody specific for nerve growth factor, reduces pain in conditions such as osteoarthritis of the knee and low back pain. A phase 2 trial was performed to evaluate the safety and efficacy of tanezumab 200 ug/kg for the treatment of interstitial cystitis (IC).
METHODS
This was a randomized, double-blind, placebo-controlled study in patients with moderate to severe IC (O'Leary-Sant Interstitial Cystitis Symptom Index [ICSI] score of >=7 and Pelvic Pain and Urgency/Frequency [PUF] symptom score of >=13). After recording daily pain scores over 7 days and completing a daily urinary symptom diary for 3 of those days, patients with a mean pain intensity score of >=4 on an 11-point (0-10) Numeric Rating Scale (NRS) and a mean micturition frequency of >=8 per 24 hours, were randomized to receive a single dose of either tanezumab 200 ug/kg or placebo IV. During the 16 weeks post-treatment, patients attended 5 study visits (weeks 2, 4, 6, 10, 16). Patients were asked to record daily pain scores (using the 11-point NRS) for the 7 days prior to attending each study visit, and also to complete a daily urinary symptom diary for 3 of those days. The primary endpoint was change from baseline in average daily pain score at Week 6 as measured by the 11-point NRS. Secondary endpoints included changes in urgency episode frequency per 24 hours, micturition frequency per 24 hours, and mean voided volume (MVV) per micturition derived from the 3-day urinary symptom diary. Adverse events (AE) were monitored throughout the study.
RESULTS
Of the 65 patients enrolled in the study, 34 (91% female; mean age of 43.5 years) received tanezumab 200 ug/kg, 30 (87% female; mean age of 45.2 years) received placebo, and 1 patient did not receive treatment. At Week 6, tanezumab produced clinically significant improvements in average daily pain score and urgency episode frequency per 24 hours versus placebo, but had no clinically significant effect on micturition frequency per 24 hours or MVV per micturition versus placebo (Table 1). Overall, 47% of tanezumab patients and 40% of placebo patients had a treatment-related AE, the most common of which were paraesthesia (tanezumab: 15%; placebo 3%) and headache (12%; 7%).
- tanezumab.gif (20.2 KiB) Viewed 494 times
CONCLUSIONS
Tanezumab 200 ug/kg can effectively reduce both pain and urgency episode frequency in patients with IC and appears safe and well tolerated.
Source of Funding: Pfizer, Inc.
