Chronic Prostatitis and Sensory Urgency: Whose Pain Is It? Ricardo R. Gonzalez, MD and Alexis E. Te, MD

Address Department of Urology, Weill Medical College of Cornell University, 525 East 68th Street, F918, New York, NY 10021, USA. E-mail: [email protected] and [email protected] Current Prostate Reports 2004, 2:196–200 Current Science Inc. ISSN 1544-1865 Copyright © 2004 by Current Science Inc.

Difficulties encountered in diagnosing and effectively treating chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is frustrating for clinicians and patients. Scientific evidence cannot establish an exact relationship between the prostate and the symptoms of CP/CPPS, and the prostate continues to be the diagnosis of convenience in this complex syndrome in men. However, if the pain is not the prostate’s, whose pain is it? A heterogeneous group of insults can result in a common neurogenic pain response, resulting in recurring pain and voiding or sexual dysfunction. To add to this dilemma, certain life-threatening diagnoses, such as carcinoma-in-situ, is in the differential diagnosis and must be excluded. Urodynamics may be useful in evaluating and treating patients whose voiding symptoms predominate. However, many patients with CP/ CPPS will not have measurable abnormalities by conventional methods and likely suffer from a functional somatic syndrome that is best treated with a multimodality approach.

Definition, Prevalence, and Cost The National Institutes of Health (NIH)/National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) consensus classified prostatitis as types I through IV. Chronic nonbacterial prostatitis and prostatodynia are now classified as Category III CPPS [1•]. Patients with CPPS present with more than 3 months of pain or pelvic discomfort with no uropathogenic bacteria localized to prostatespecific specimens on culture. A diagnosis of CP is common, costly to society, and severely impacts patients’ quality-of-life. Community-based surveys estimate that 11% of men have been diagnosed with prostatitis by a physician at some point in their lives [2,3]. A prostatitis diagnosis represents 8% of patients’ visits to urologists; it is the most common diagnosis made in men under the age of 50 years and the third most common in men older than 50 years [4]. For each affected man, CP/ CPPS has a severe impact on quality of life comparable with that for patients suffering with Crohn’s disease or angina pectoris [5]. The socioeconomic cost of diagnostic tests, repeated physician visits, and ineffective treatments, in addition to costs associated with time off from work, disability, and personal productivity, likely result in billions of dollars each year in the United States [6].

Introduction

Prostate Inflammation and Bacteria Do Not Correlate with Symptoms

Difficulties diagnosing and effectively treating chronic prostatitis (CP)/chronic pelvic pain syndrome (CPPS) create a frustrating situation for patients and clinicians. The term “prostatitis” is a diagnosis of exclusion for multiple overlapping syndromes that are challenging to diagnose and care for. The pain, voiding symptoms (eg, frequency, urgency, nocturia), and sexual disorders that are labeled “CP/CPPS” are not solely attributable to the prostate. However, if the pain is not the prostate’s, whose pain is it? The purpose of this paper is to review the less “prostatocentric” etiologies of the multiple disorders labeled as CP/ CPPS, its crossover to other symptom-driven disease states such as interstitial cystitis and even overactive bladder (OAB), and emphasize the importance of establishing an accurate diagnosis for patients with voiding symptoms and pelvic pain.

Although the NIH/NIDDK classification system has been useful in establishing antibiotic treatment guidelines for prostatic disease, it does not explain the symptoms or mechanisms for neurogenic pain in men with CP/CPPS. Leukocyte counts in expressed prostatic secretions—the basis for prostatitis classification—do not correlate with symptom severity, nor do they have proven value in selecting treatment or predicting treatment response [7••]. Likewise, there is no concrete evidence that bacteria cause CP/CPPS [7••]. Despite this, surveyed urologists always (40%) or frequently (42%) prescribe antibiotics to patients they diagnose with CP/CPPS, although rarely (47%) or never (33%) do they perform the four-glass test for localization cultures [8•]. In the only published randomized, placebo-controlled trial of an antibiotic in men with CP/ CPPS, 6 weeks of levofloxacin 500 mg daily administered orally resulted in symptom improvement that was not signifi-

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Table 1. Overlap of symptom domains in select validated scales used to evaluate voiding symptoms and pelvic pain* Pain domain Pain NIH-CP IPSS PUF IC-CSPI ICIQ-OAB SF

• • •

Bother • • •

Voiding symptom domain Irritative Obstructive • • • • •

• •

Nocturia • • • •

Sexual domain Bother • • • • •

Sex

•

Bother

•

*These clinical scales intended for use in evaluating symptoms have not been validated as purely diagnostic tools. ICIQ-OAB SF—International Continence Society Questionnaire Overactive Bladder, short form; IC-CSPI—O'Leary-Sant Interstitial Cystitis Symptom and Problem Indices; IPSS—International Prostate Symptom Score; NIH-CP—National Institutes of Health Chronic Prostatitis Symptom Index; PUF—Parson's Pelvic Pain and Urgency/Frequency Questionnaire.

cantly different from that with placebo at the end of treatment or at follow-up [9••]. For now, antimicrobial therapy remains an unproven therapy for CP/CPPS, likely because prostatic leukocytosis and bacteria are not solely responsible for symptoms of CP/CPPS.

Diagnosis of Exclusion Lower urinary tract symptoms (LUTS) can be caused by many, often overlapping pathophysiologic mechanisms, which may contribute to individual variation in response to treatment [10•]. Similar LUTS are caused by ureteral or bladder stones, benign prostatic hyperplasia (BPH), OAB, interstitial cystitis (IC)/painful bladder syndrome, carcinoma-insitu (CIS), urinary tract infections (UTI), primary vesical neck obstruction, and CP/CPPS. Certain diagnoses are concrete and easier to establish, such as in the case of a distal ureteral stone or culture-proven UTI. However, when the cause is not as obvious, the diagnosis is based on symptoms and response to empiric treatment and may reflect physician bias. For example, a physician with a focus on BPH may administer an International Prostate Symptom Score (IPSS) questionnaire, whereas a physician with a focus on pelvic pain disorders may administer an NIH-CP symptom index. To further emphasize the lack of disease specificity for these sets of symptoms, there is overlap of symptoms between CIS and BPH. If a patient with occult CIS is diagnosed with BPH and has a high IPSS score, he likely will be treated with αblockers for presumed BPH. In this scenario, symptoms resulting from CIS are not likely to improve and a delay in diagnosing his CIS is likely. In this case, urine cytology and cystoscopy with biopsy are the appropriate assessment tools to evaluate this symptom complex. As a specialist evaluating patients with irritative voiding symptoms, one should always consider the exclusion of dangerous conditions such as CIS. In 1974, a report of 486 patients treated for IC found that 1.3% of 224 women and 23% of 53 men were found to have CIS [11]. In a current review of 600 patients at an IC center at a tertiary care facility,

six patients (1%) previously diagnosed with IC were found to have transitional cell carcinoma CIS as the cause of their symptoms, and four (67%) of these had no hematuria [12]. Similarly, in a study of 150 patients evaluated for nonbacterial prostatitis, three (2%) were found to have CIS and only one had hematuria [13•]. We cannot overstate the importance of careful and accurate diagnosis and the need to address life-threatening conditions such as CIS.

First-Come, First-Served Within the cluster of disorders that share pain or voiding symptoms, most have validated indices for assessing current symptoms. Examples of these symptom assessment tools include the NIH-CP symptom index, the O’Leary-Sant Interstitial Cystitis Symptom and Problem Indices, the Pelvic Pain and Urgency/Frequency Scale (PUF), and the widely used IPSS. Physicians frequently misuse these as diagnostic tools, despite the lack of proof supporting such use. In fact, published evidence has demonstrated a low agreement between CP symptom index-like pain measures and physician-diagnosed prostatitis [14•]; this tool is best used to evaluate the severity of current symptoms rather than to diagnose the presence or absence of prostatitis. There is a considerable overlap in shared symptoms between these indices, especially in the domains focused on voiding symptoms, and a wide range of pain symptoms focused in the pelvic region, many of which may easily represent pain referred from another pelvic area. It is not surprising that “whose pain,” whether it be CP/CPPS, IC, OAB, CIS, or BPH, sometimes depends on the type of questionnaire first handed to the patient. The voiding domains are common to the validated tools mentioned previously (Table 1). However, one area that deserves highlighting is urgency or sensory urgency. It is a symptom complex that can be reinterpreted as pain by a patient. For example, severe urgency or sensory urgency can be described as pain in the bladder or even pain at the tip of the penis. Much work is focused on distinguishing and characterizing these areas of pelvic pain and has led to controversies in

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distinguishing CP from IC and the related CPPS disorders. These self-reporting surveys often reveal commonalities among these various pelvic pain disorders and do not necessarily help distinguish among them. Therefore, the domains of pain, sensory/urgency and irritative symptoms, potentially can overlap on a questionnaire in any given patient.

Extraprostatic Etiologies Interstitial cystitis There is considerable overlap in the presentation Category IIIa CPPS and IC because both disorders can present with pelvic pain, urgency, and frequency. For example, pain with bladder filling is a classic feature of IC, but up to 45% of patients with CP/CPPS have similar complaints [15]. A subset of patients initially diagnosed with CP/CPPS eventually is found to have IC; there is a 2-year median delay in diagnosing IC in men who present with symptoms of prostatitis [16]. Distinguishing IC from CP/CPPS can be confusing. The response of men with loosely defined prostatitis to potassium sensitivity testing, as described by Parsons and Albo [17], has been shown to be nearly identical to that of IC patients. In contrast, the same potassium sensitivity testing was not diagnostic in differentiating men with CP/CPPS as defined with the NIH-CPPS symptom index, a validated instrument in assessing severity of CPPS symptoms, from control subjects [18]. On the other hand, the discovery of antiproliferative factor (APF), a promising marker for IC, may prove to be useful in separating men with IC from those with CP/CPPS. Although voided epithelial APF activity levels in men with CP/CPPS did not differ significantly from asymptomatic control subjects, men with IC had significantly higher levels of APF activity than control subjects and men with CP/ CPPS [19•]. In men with pelvic pain and irritative voiding symptoms, APF levels may help identify men with IC and potentially reduce the observed delay in diagnosing and treating IC. Voiding dysfunction A subset of patients misdiagnosed with CP/CPPS actually has an underlying voiding disorder that can be demonstrated with videourodynamics and treated appropriately. In a series of 137 men younger than 50 years of age who we evaluated for a prior diagnosis of refractory nonbacterial prostatitis, most of their symptoms could be explained by abnormal findings on videourodynamics. Seventy-four men (54%) had primary vesical neck obstruction, 33 (24%) had pseudodyssynergia (ie, obstruction localized to the membranous urethra), 23 (17%) had impaired bladder contractility, and the remaining seven (5%) had acontractile bladders [20••]. When an urodynamic abnormality is identified, focused treatment is paramount in improving the patients’ symptom profiles. In a series of 34 men who carried a misdiagnosis of prostatitis for a minimum of 2 years and were later found to

have vesical neck obstruction on videourodynamics, transurethral incision of the bladder neck was safe and effective in relieving symptoms and improving flow rates [21]. In 43 patients with pseudodyssynergia misdiagnosed as nonbacterial prostatitis, biofeedback and behavior modification were successful in decreasing symptoms in 35 (83%) men at 6 months [22]. Although many of these men misdiagnosed with CP also reported perineal pain or discomfort, chronic irritative and obstructive voiding symptoms remained the hallmark complaint before treatment. Videourodynamic evaluation of all men with LUTS or pelvic pain is not practical or cost effective. However, the need to appropriately identify and treat voiding dysfunction in these men is crucial. To determine which group of men with LUTS to evaluate using videourodynamics, Nitti et al. [23•] evaluated 85 consecutive men 18 to 45 years of age prospectively with multiple noninvasive measures and videourodynamics. Men with an abnormal noninvasive uroflow study and significant voiding symptoms on the IPSS had the highest probability of having voiding dysfunction on videourodynamics evaluation [23•]. The most common disorder in this cohort was primary vesical neck obstruction in 40 (47%) patients, similar to the aforementioned studies.

Myofascial pain syndrome The 12% to 24% of men with pseudodyssynergia on urodynamics have symptoms that likely are perpetuated by pelvic floor tension and autonomic dysregulation, similar to other myofascial pain syndromes [24]. In a study of 62 men with CPPS III and 89 healthy control subjects without pelvic pain, pelvic floor musculature was examined by a licensed physical therapist. Compared with control subjects, patients with CPPS were found to have significantly more muscle spasm, increased muscle tone, and pain with transrectal palpation of the levator ani and coccygeus muscles [25]. No differences were observed in strength of lower abdominal and oblique muscles. Abnormalities of the pelvic floor musculature are responsible for the symptoms of CPPS in some men [24, 25]. Identifying pelvic floor tension myalgia with a thorough examination or urodynamics (eg, pseudodyssynergia) will allow prompt treatment. Biofeedback-assisted techniques of neuromuscular reeducation and bladder training have been shown to be effective in the treatment of CP/ CPPS symptoms [22,26,27]. Functional somatic syndrome The lack of objective findings, from the prostate or elsewhere, in many patients with CP/CPPS suggests that these patients suffer a functional somatic syndrome (FSS) [24]. An FSS is a syndrome that, after appropriate medical assessment, cannot be explained in terms of a conventional medical disease. Wessely et al. [28••] reports that somatic symptoms may account for up to 20% of primary care consultations. These patients do not simply represent the “worried well;” many are severely disabled with FSS.

Chronic Prostatits and Sensory Urgency • Gonzalez and Te

When identified by clinicians, these FSSs typically are named according to the subspecialist who identify them. For example, consider chronic fatigue syndrome diagnosed by infectious disease specialists, irritable bowel syndrome (IBS) by gastroenterologists, atypical chest pain by cardiologists, and fibromyalgia by rheumatologists. Wessely et al. [28••] suggest that a unifying syndrome may exist, based on three key observations. First, patients with FSS share multiple unifying symptoms, meeting criteria for other somatic disorders, resulting in overlapping syndromes. Second, many of these patients share common factors, including emotional disorders, history of childhood abuse, disappointment with the medical community, and eagerness to try alternative therapies. Finally, FSSs respond to similar treatments, such as presence of a supportive caregiver, prescription of antidepressants, and relaxation therapy. Thinking of CP/CPPS as an FSS can help reduce frustrations experienced by urologists treating the disorder. Understanding and explaining to patients that a multimodal approach to therapy, rather than using a monotherapy strategy such as antibiotic therapy, is more likely to ameliorate symptoms [24,29]. On the other hand, when thinking of CP/CPPS as an FSS or psychiatric disorder, clinicians must be cognizant that these patients still can develop infections, cancer, and objective voiding dysfunction. They still should be screened routinely according to “best practice” guidelines and any significant change in symptoms should be re-evaluated thoroughly.

Common Neurogenic Pain Response and Pelvic Cross-sensitization Chronic prostatitis/CPPS may share similarities to syndromes such as IBS, IC, and fibromyalgia because of a common neurogenic pathophysiology. Basic science studies have shown that various insults to the bladder (eg, mechanical, chemical, and immune) lead to increased nerve growth factor (NGF) production and morphologic changes (ie, neuroplasticity) in sensory and motor neurons [30•]. Different insults, including a prostate or bladder infection, theoretically could result in a common neuroinflammatory response that potentially could lead to persistent symptoms, even when the initial inflammatory stimulus subsides [30•,31]. The original insult does not necessarily have to occur in the same organ. Inflammation elsewhere in the pelvis can result in neurotrophic changes in a neighboring pelvic organ. For example, chemically induced colitis has been shown to cause neurogenic inflammation in the bladder, pain posturing, and increased voiding frequency in rats [32]. It is likely that afferent sensitization of one pelvic organ may adversely influence and sensitize the other through direct neuronal connections or reflexes. In humans, increased NGF has been found to correlate with pelvic pain in CP/CPPS in urothelial cells from patients with IC and painful bladder syndromes [33•,34,35]. This further supports a common neurogenic pathophysiology in

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distinct syndromes with similar symptoms. The allodynia and relative hyperalgesia that characterize syndromes such as CP/CPPS, IC, and IBS may develop from neurogenic inflammation and nociceptive sensitization, which theoretically could have resulted from any insult to any pelvic organ.

Conclusions Unfortunately, many men suffer from CP/CPPS. The difficulties encountered in diagnosing and effectively treating CP is frustrating to clinicians and patients. Scientific evidence cannot establish an exact relationship between the prostate and the symptoms of CP/CPPS and the prostate continues to be the convenient diagnosis of exclusion in this complex syndrome. However, if the pain is not the prostate’s, whose pain is it? It is our opinion that a heterogeneous group of insults can result in a common neurogenic pain response, resulting in recurring pain, voiding, or sexual dysfunction. Until the underlying problem is better understood and accurately diagnosed, we will be unable to effectively treat these patients. Life-threatening diagnoses, such as CIS, must be excluded. If the underlying disorder is accurately diagnosed as a voiding dysfunction on videourodynamics, suitable treatment can rapidly ensue and should be effective in ameliorating symptoms. However, many patients with CP/CPPS will not have measurable abnormalities by conventional methods and likely suffer from an FSS that is best treated with a multimodality approach.

References and Recommended Reading Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance 1.• Krieger JN, Nyberg L Jr, Nickel JC: NIH consensus definition and classification of prostatitis. JAMA 1999, 282:236–237. Explains the current definition, rationale, and classification system of prostatitis. 2. Nickel JC, Downey J, Hundter D, Clark J: Prevalence of prostatitis-like symptoms in a population-based study using the National Institutes of Health Chronic Prostatitis Symptom Index. J Urol 2001, 165:842–845. 3. Roberts RO, Jacobson DJ, Girman CJ, et al.: Prevalence of prostatitis-like symptoms in a community-based cohort of older men. J Urol 2002, 168:2467–2471. 4. McNaughton-Collins M, Stafford RS, O’Leary MP, et al.: How common is prostatitis? A national survey of physician visits. J Urol 1998, 159:1224–1228. 5. Wenninger K, Hieman JR, Rothman I, et al.: Sickness impact of chronic non-bacterial prostatitis and its correlates. J Urol 1996, 155:965–968. 6. Calhoun EA, McNaughton Collins M, Pontari MA, et al.: The economic impact of chronic prostatitis. Arch Intern Med 2004, 164:1231–1236. 7.•• Schaeffer AJ, Knauss JS, Landis JR, et al.: Leukocyte and bacterial counts do not correlate with severity of symptoms in men with chronic prostatitis: the National Institutes of Health Chronic Prostatitis Cohort Study. J Urol 2002, 168:1048–1053. Interesting study, given the importance of leukocyte counts in prostatic secretions in the NIH classification system of prostatitis.

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8.• McNaughton Collins M, Fowler FJ, Elliott DB, et al.: Diagnosing and treating chronic prostatitis: Do urologists use the four-glass test? Urology 2000, 55:403–407. Despite the fact that urologists rarely perform localization cultures, they frequently prescribe antibiotics for the treatment of prostatitis. This study draws attention to the popular misuse of antibiotics in the treatment of prostatitis. 9.•• Nickel JC, Downey J, Clark J, Casey RW, et al.: Levofloxacin for chronic prostatitis/chronic pelvic pain syndrome in men: a randomized, placebo-controlled, multicenter trial. Urology 2003, 62:614–617. The first randomized, placebo-controlled trial comparing antibiotic with placebo in treating prostatitis. It is not surprising that although both treatments improved symptoms, antibiotics did not alleviate symptoms more so than placebo. 10.• Andersson KE: Storage and voiding symptoms: pathophysiologic aspects. Urology 2003, 62(suppl 2):3–10. Thorough review of the overlap of symptoms in various pathophysiologic causes of lower urinary tract symptoms. Discusses the variables that contribute to individual variations in response to treatment. 11. Utz DC, Zincke H: The masquerade of bladder cancer in situ as interstitial cystitis. J Urol 1974, 111:160–161. 12. Tissot WD, Diokno AC, Peters KM: A referral center's experience with transitional cell carcinoma misdiagnosed as interstitial cystitis. J Urol 2004, 172:478–480. 13.• Nickel JC, Ardern D, Downey J: Cytologic evaluation of urine is important in the evaluation of chronic prostatitis. Urology 2002, 60:225–227. Retrospective review of 150 patients with nonbacterial prostatitis in which three (2%) were found to have CIS as the cause of their symptoms. Surprisingly, only one had hematuria. Emphasizes the importance of urine cytology in working up irritative voiding symptoms. 14.• Roberts RO, Jacobson DJ, Girman CJ, et al.: Low agreement between previous physician-diagnosed prostatitis and the National Institutes of Health Chronic Prostatitis Symptom Index pain measures. J Urol 2004, 171:279–283. Demonstrates that CP symptom index scores do not necessarily correlate with clinician diagnosis of prostatitis. This symptom index is for assessing the severity of current symptoms rather than to diagnose the presence or absence of prostatitis. 15. Moldwin R: Similarities between interstitial cystitis and male chronic pelvic pain syndrome. Curr Urol Rep 2002, 3:313–318. 16. Driscoll A, Teichman JM: How do patients with interstitial cystitis present? J Urol 2001, 166:2118–2120. 17. Parsons CL, Albo M: Intravesical potassium sensitivity in patients with prostatitis. J Urol 2002, 168:1054–1057. 18. Yilmaz U, Liu YW, Rothman I, et al.: Intravesical potassium chloride sensitivity test in men with chronic pelvic pain syndrome. J Urol 2004, 172:548–550. 19.• Keay S, Zhang CO, Chai T, et al.: Antiproliferative factor, heparinbinding epidermal growth factor-like growth factor, and epidermal growth factor in men with interstitial cystitis versus chronic pelvic pain syndrome. Urology 2004, 63:22–26. Describes the use of a promising marker to help accurately diagnose and distinguish IC from CP/CPPS. The validity of APF needs to be replicated and proven at independent centers worldwide. 20.•• Kaplan SA, Ikeguchi EF, Santarosa RP, et al.: Etiology of voiding dysfunction in men less than 50 years of age. Urology 1996, 47:836–839. Illustrates the importance of urodynamics in the evaluation of LUTS in men. Identification of an abnormality can help tailor treatment to most effectively ameliorate LUTS.

21.

Kaplan SA, Te AE, Jacobs BZ: Urodynamic evidence of vesical neck obstruction in men with misdiagnosed chronic nonbacterial prostatitis and the therapeutic role of endoscopic incision of the bladder neck. J Urol 1994, 152:2063–2065. 22. Kaplan SA, Santarosa RP, D'Alisera PM, et al.: Pseudodyssynergia (contraction of the external sphincter during voiding) misdiagnosed as chronic nonbacterial prostatitis and the role of biofeedback as a therapeutic option. J Urol 1997, 157:2234–2237. 23.• Nitti VW, Lefkowitz G, Ficazzola M, et al.: Lower urinary tract symptoms in young men: videourodynamic findings and correlation with noninvasive measures. J Urol 2002, 168:135–138. Report that found that men with abnormal noninvasive uroflow results and significant voiding symptoms on IPSS had the highest probability of having voiding dysfunction on videourodynamics. This is important considering that the urodynamic evaluation of all men with LUTS or pelvic pain is not practical or cost effective. 24. Potts JM: Diagnosing the prostatitis patient: the dilemma continues. Curr Urol Rep 2002, 3:319–323. 25. Hetrick DC, Ciol MA, Rothman I, et al.: Musculoskeletal dysfunction in men with chronic pelvic pain syndrome typeIII: a case-control study. J Urol 2003, 170:828–831. 26. Nadler RB: Bladder training biofeedback and pelvic floor myalgia. Urology 2002, 60(suppl 6):42–43. 27. Clemens JQ, Nadler RB, Schaeffer AJ, et al.: Biofeedback, pelvic floor re-education, and bladder training for male chronic pelvic pain syndrome. Urology 2000, 56:951–955. 28.•• Wessely S, Nimnuan C, Sharpe M: Functional somatic syndromes: one or many? Lancet 1999, 354:936–939. Logical, well-organized essay proposing that syndromes such as CP/ CPPS could be part of a unified functional somatic syndrome because of shared characteristics. 29. Nickel JC, Downey J, Ardern D, et al.: Failure of a monotherapy strategy for difficult chronic prostatitis/chronic pelvic pain syndrome. J Urol 2004, 172:551–554. 30.• Dupont MC, Spitsbergen JM, Kim KB, et al.: Histological and neurotrophic changes triggered by varying models of bladder inflammation. J Urol 2001, 166:1111–1118. Basic science experiments demonstrating how various insults to the bladder result in common neurotrophic changes. This explains how symptoms may persist, even after an inflammatory stimulus subsides. 31. Saban MR, Nguyen NB, Hammond TG, et al.: Gene expression profiling of mouse bladder inflammatory responses to LPS, substance P, and antigen-stimulation. Am J Pathol 2002, 160:2095–2110. 32. Pezzone MA, King WE, Fraser AM, et al.: Bi-directional, crosssensitization of the urinary bladder and distal colon of the rat: AUA Abstract. J Urol 2003, 169(suppl):260. 33.• Miller LJ, Fischer KA, Goralnick SJ, et al.: Nerve growth factor and chronic prostatitis/chronic pelvic pain syndrome. Urology 2002, 59:603–608. Describes how NGF levels correlate with pelvic pain symptoms in CP/ CPPS. In doing so, supports the idea of neurogenic inflammation in the prostate or associated urothelium in this group of patients. 34. Lowe EM, Anand P, Terenghi G, et al.: Increased nerve growth factor levels in the urinary bladder of women with idiopathic sensory urgency and interstitial cystitis. Br J Urol 1997, 79:572–577. 35. Pontari MA, Ruggieri MR: Mechanisms in prostatitis/chronic pelvic pain syndrome. J Urol 2004, 172:839–845.