Phenotypic Approach to the Management of the Chronic Prostatitis/ Chronic Pelvic Pain Syndrome

REVIEW ARTICLE Phenotypic approach to the management of the chronic prostatitis/ chronic pelvic pain syndrome

BJUIBJU INTERNATIONAL J. Curtis Nickel and Daniel A. Shoskes* Queen’s University, Kingston, Ontario, Canada, and *Glickman Urological and Kidney Institute, Cleveland, OH, USA

Accepted for publication 22 April 2010

• Our traditional approach to managing the chronic prostatitis (CP) syndromes has not been very successful for many of our patients. • Our developing understanding of CP/chronic pelvic pain syndrome (CP/CPPS) as a heterogeneous syndrome rather than a homogenous disease has allowed us to develop treatment strategies based on individual patient characteristics. • By considering each patient as a unique individual and tailoring treatments to a speciﬁc patient’s clinical ‘phenotype’ we improve our therapeutic outcomes.

KEYWORDS chronic prostatitis, chronic pelvic pain syndrome, phenotype, classiﬁcation, therapy

INTRODUCTION In an attempt to understand our failure to improve therapies for patients with CP/CPPS, we reviewed our traditional approach to chronic prostatitis and re-examined the mostly negative evidence based treatment data from the last decade of randomized placebo controlled CP/CPPS trials. Based on this critical review of the evidence and extensive clinical experience and review of the literature, we have formulated and validated a novel phenotypic classification system that should improve management of our patients with this syndrome. Our evaluation has led us to the awareness that patients with CP/CPPS are individuals with different and varying etiologies, progression pathways and response to therapy. We describe our new classification system, termed UPOINT for Urinary, Psychosocial, Organ-specific, Infection, Neurologic- systemic, Tenderness (of pelvic floor skeletal muscles). It is proposed that patients be classified into one or more of these phenotypic domains as a way to characterize them and direct specific therapy. We further describe our validation of the system in CP/CPPS patients and show the positive results of our initial attempt at employing the strategy for treatment.

OUR HISTORICAL APPROACH TO CHRONIC seemed reasonable as many physicians PROSTATITIS (CP) anecdotally thought that their patients’ symptoms, including the pain and voiding For most of the past century, urologists have symptoms of CP, appeared to improve with approached CP as an infectious and/or this approach. Studies showed that at least 5– inflammatory disease [1]. In the 1960s 10% of patients presenting this way, actually researchers were beginning to think that did have a bacterial infection and should many patients presenting with prostatitis respond to antibiotics [2]. It is certainly might not have an actual infection and others understandable why for decades we used probably did not even have inflammation. antibiotics to treat real or perceived infection Despite this developing understanding of and anti-inflammatories to try to relieve the condition, prostatitis thought to be of inflammation and pain [3]. Furthermore, in nonbacterial aetiology, called, nonbacterial the last decade or so, urologists have been or abacterial prostatitis (inflammatory using prostate-centric medications such as prostatitis) or prostatodynia (non- α-blockers [3] and 5α-reductase inhibitors inflammatory prostatitis), continued to be (5ARIs) [4]. This also seems reasonable as treated with antibiotics (even without positive prostatitis, by its very name, suggests the cultures) and anti-inflammatories (without disease is centred in the prostate gland. For documented inflammation). This certainly years, patients were treated, then with

PHENOTYPIC APPROACH TO MANAGING CP/CPPS

to therapy in a disease with no objective TABLE 1 NIH Classification system for the prostatitis syndromes parameters. CP/CPPS, the most common prostatitis syndrome and most difficult to Classification Description understand and assess is, indeed, a pain Category I – acute bacterial prostatitis Acute infection of the prostate gland. syndrome which can be described by a Category II – chronic bacterial Chronic infection of the prostate characterized by recurrent constellation of symptoms. Until objective prostatitis UTIs parameters such as biopsy, microbial Category III – CP/CPPS Symptoms of discomfort or pain in the pelvic region for ≥3 identification (although the cultures have to months in the absence of uropathogenic bacteria be negative for the diagnosis), or any specific cultured by standard techniques. blood test (e.g. like PSA in prostate cancer) Category IIIA – inflammatory CPPS Significant number of leukocytes in EPS, VB3 or semen becomes available, the CPSI remains the best (ejaculate) outcome to both evaluate and follow the Category IIIB – non-inflammatory CPPS No evidence of significant leukocytes are found in EPS, VB3 symptoms in our patients [11]. or semen Category IV – asymptomatic Leukocytes in EPS, VB3, semen or prostate tissue during These new developments in the field led to inflammatory prostatitis evaluation for other disorders in men without symptoms a flurry of research activity that allowed the of prostatitis. research community to finally compare the various traditional therapies against placebo EPS, expressed prostatic secretion; VB3, voided bladder 3. in well-designed randomized controlled trials (RCTs). However, the results showed that our traditional therapies might not antibiotics, anti-inflammatories and prostate who are now categorized as CP/chronic pelvic have been as good as we had thought. centric drugs such as α-blockers and 5ARIs pain syndrome (CP/CPPS). CP/CPPS category Large, well-designed clinical trials were not without very much real evidence. Up to the represents >90% of men who are managed able to absolutely confirm the effectiveness mid-1990s almost all the evidence available for a CP syndrome. The next important of our traditional therapies including to urologists was related to the efficacy of the advance was the various antibiotics being considered for development of an regulatory approval for the <10% of patients accepted universal with bacterial CP [5]. method to measure ‘the CPSI remains the best outcome to both symptoms for evaluate and follow the symptoms in our patients’ comparison of EVIDENCE-BASED APPROACH TO patients and follow- CP THERAPY up of patients in epidemiological and clinical antibiotics, anti-inflammatories, and the treatment trials. The NIH CP symptom index prostate-specific drugs finasteride and The era of evidence-based medicine for CP (CPSI) met this need [9]. It was validated to various α-blockers [12,13]. Based on began towards the end of the 1990s when the differentiate patients from asymptomatic assessment of the primary study outcome, USA National Institutes of Health (NIH) men without prostatitis and was found to be most (but not all, particularly in the developed a now universally accepted robust and responsive in clinical trials α-blocker class) of these studies evaluating research (and clinical) definition [6] and evaluating therapies [10]. This index allows our traditional medical therapies were classification system [7] for the prostatitis the researcher and physician to determine the reported as a failure of the particular syndromes (Table 1). Researchers and location, frequency and severity of the pain, therapy in effectively treating CP/CPPS. practising urologists are now all speaking the describe the irritative and obstructive voiding Table 2 [14–18] outlines the most important same language when it comes to defining and symptoms, and determine the impact on of these particular studies. classifying this difficult population of men. activities and health-related quality of life This is particularly important for the men who (HRQL; Fig. 1). This index has allowed us to It is interesting to note that several clinical used to be diagnosed with nonbacterial (or compare patients and various patient trials evaluating untraditional therapies, such abacterial) prostatitis and prostatodynia [8] populations as well as determine the response as phytotherapies (herbal-based compounds),

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FIG. 1. The NIH CPSI is a validated symptom-scoring instrument that has proven useful in prostatitis research and clinical practice. It allows clinicians to document and quantify the important parameters of pain (location, frequency and severity), voiding symptoms and impact/HRQL in men presenting with CP/CPPS and can be used to follow progress with treatment. Reproduced with permission from [9].

NIH -Chronic Prostatitis Symptom Index (NIH-CPSI)

Pain or Discomfort

1. In the last week, have you experienced any pain or discomfort in the following areas? 6. How often have you had to urinate again less than two Yes No hours after you finished urinating, over the last week? a. Area between rectum and 1 0 testicles (perineum) 0 Not at all b. Testicles 1 0 1 Less than 1 time in 5 c. Tip of the penis (not related to 1 0 2 Less than half the time urination) 3 About half the time d . Below your waist, in your 1 0 4 More than half the time pubic or bladder area 5 Almost always

2. In the last week, have you experienced: Impact of Symptoms Yes No a . Pain or burning during 1 0 7. How much have your symptoms kept you from doing urination? the kinds of things you would usually do, over the b . Pain or discomfort during or 1 0 last week? after sexual climax (ejaculation)? 0 None 3. How often have you had pain or discomfort in any of 1 Only a little these areas over the last week? 2 Some 3 A lot 0 Never 1 Rarely 8. How much did you think about your symptoms, over the 2 Sometimes last week? 3 Often 4 Usually 0 None 5 Always 1 Only a little 2 Some 4. Which number best describes your AVERAGE pain or 3 A lot discomfort on the days that you had it, over the last week? Quality of Life 0 1 2 3 4 5 6 7 8 9 10 NO PAIN AS 9. If you were to spend the rest of your life with your PAIN BAD AS symptoms just the way they have been during the last YOU CAN week, how would you feel about that? IMAGINE 0 Delighted Urination 1 Pleased 2 Mostly satisfied 5. How often have you had a sensation of not emptying 3 Mixed (about equally satisfied and dissatisfied) your bladder completely after you finished urinating, over the last week? 4 Mostly dissatisfied 5 Unhappy 0 Not at all 6 Terrible 1 Less than 1 time in 5 ______2 Less than half the time Scoring the NIH-Chronic Prostatitis Symptom Index 3 About half the time Domains 4 More than half the time 5 Almost always Pain: Total of items 1a, 1b, 1c, 1d, 2a, 2b, 3, and 4 = ____

Urinary Symptoms: Total of items 5 and 6 = ____

Quality of Life Impact: Total of items 7, 8, and 9 = ____

PHENOTYPIC APPROACH TO MANAGING CP/CPPS

TABLE 2 The ‘best’ clinical trials evaluating traditional treatments for CP/CPPS (antibiotics, α-blockers and prostate-centric therapies)

Duration, Patients, n Responders, % Change in NIH-CPSI Treatment Active agent weeks Active Placebo Active Placebo Active Placebo effect Antibiotic Levofloxacin [14] 6 35 45 42 37 −5.4 −2.9 2.5 Ciprofloxacin [15] 6 49 49 22 22 −6.2 −3.4 2.8 α-blocker Tamsulosin [15] 6 49 49 24 22 −4.4 −3.4 1.0 Alfuzosin [16] 12 138 134 49.3 49.3 −7.1 −6.5 0.6 Anti-inflammatory Rofecoxib, 25 mg [17] 6 53 59 46 40 −4.9 −4.2 0.7 Rofecoxib, 50 mg [17] 6 49 59 63* 40 −6.2 −4.2 2.0 5ARI Finasteride [18] 24 33 31 33 16 −3.0 −0.8 2.2

None of these trials reported a statistically signiﬁcant treatment effect (CPSI score) of the active therapy compared with placebo. *P < 0.05.

TABLE 3 Clinical trials evaluating some untraditional treatments for CP/CPPS

Duration, Patients, n Responders, % Change in NIH-CPSI Treatment Active agent weeks Active Placebo Active Placebo Active Placebo effect PPS [23] 16 51 49 37* 18 −5.9 −3.2 2.7 Mepartricin [25] 8 13 13 NK NK −15.0* −5.0 10.0 Quercetin [20] 4 15 13 67* 20 −7.9* −1.4 6.5 Pollen extract [21] 51 60 62* 43 −7.7* −5.2 2.5 Pregabalin [24] 6 103 106 47.2† (31*)‡ 35.8† (19)‡ −6.6* −4.2 2.4

PPS, pentosan polysulphate sodium; NK, not known. *P < 0.05 active vs placebo; †Primary endpoint (CPSI responders); ‡Global Response Assessment responders.

did show efficacy in randomized placebo- RCT evaluating the gabapentinoid, pregabalin, A DEVELOPING UNDERSTANDING OF controlled trials [19]. Quercetin was shown to in a large multicentre North American study, CP/CPPS AETIOLOGY be superior to placebo in one small RCT [20]. failed to show efficacy compared with There are several trials suggesting that pollen placebo [24]. These clinical trials examining It was not the mandate of this review to extract has beneficial effects in CP [19], but it untraditional approaches to CP/CPPS are examine the aetiological mechanisms of CP/ was only the recently published German outlined in Table 3 [20,21,23–25]. CPPS, but it is important to examine them, as multicentre RCT that confirmed that the effective treatment will need to be based, in specific pollen extract, Cernilton, was superior How can we reconcile these randomized part, on the aetiology of the condition. to placebo [21]. Based on the premise held by placebo-controlled trial results and the fact Various mechanisms have been suggested for many investigators that interstitial cystitis/ that we continue to painful bladder syndrome (IC/PBS) and CP/ use these agents in CPPS are very similar entities [22], several treating our patients clinical trials have investigated pentosan with what we ‘We really do need a new look at how we clinically polysulphate sodium, an oral therapy for IC/ believe in clinical characterize and treat CP/CPPS’ PBS. In this study, a secondary endpoint was practice is variable positive in favour of pentosan polysulphate but poor clinical success? If we try and follow the aetiology and pathogenesis of CP/CPPS. compared with placebo [23]. As prostate- a ‘pure’ evidence-based approach to treating This includes infection (occult or specific therapies did not appear to be patients with CP/CPPS, both clinicians and nonculturable infection included), genetic, generally effective, presumably because CP/ patients would become frustrated and would anatomical, physiological, neurological, and CPPS is now understood to be a more probably just give up. What other treatments immunological factors [26–28]. There is a generalised pain syndrome, the NIH further should we use and how should we use them? sound theoretical reason for each of these undertook a study to examine the effect of We really do need a new look at how we mechanisms, animal model study oral neuromodulation. A recently completed clinically characterize and treat CP/CPPS. confirmation for most and clinical data that

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FIG. 2. Proposed aetiological pathways that lead to a man being diagnosed with CP/CPPS.

Initiation Trauma Infection Ductal reflux Voiding Phase Dysfunction

Acute Event Inflammation and Tissue Damage Induction Phase Recurrent Infection

Chronic Events Immunologic factors Inflammation, Neurologic factors Neurologic Endocrine factors Alterations Muscle factors

Maintenance Chronic Psychological factors Phase Pelvic Pain Syndrome

Neuropathic Voiding Muscular Psychosocial Progression Pain Dysfunction Dysfunction Dysfunction Phase

Systemic Pain Syndromes

could be used to validate a claim that one or aimed at a particular mechanism, failed to more of these aetiological mechanisms may show clinical efficacy in a large population of be involved in the pathogenesis of CP/CPPS, in patients that were not specifically selected at least a proportion of patients. But, in fact, based on any particular mechanism. we now think that there is not one all encompassing aetiological mechanism for CP/ CPPS. It is more likely that different patients A RE-EXAMIMATION OF CP/CPPS diagnosed with CP/CPPS have different CLINICAL TRIALS aetiological mechanisms and certainly different progression pathways. In fact, some As alluded to in an earlier section and patients may have more than one mechanism described in Table 2, RCTs designed to as either an aetiology or promoter of their determine the efficacy of a single therapy, syndrome. Figure 2 outlines possible seemed to indicate that the traditional aetiological pathways by which various therapies we use in clinical practice are patients may reach the same clinical outcome, ineffective. This is undoubtedly the case if we that of CP associated with variable voiding follow a pure evidence-based approach and problems. Just based on mechanisms alone, it believed that the RCTs mirror clinical practice. appears that patients diagnosed with CP/ To start with, the patients in clinical trials CPPS are not exactly were eligible to enroll in the study based on alike and probably very strict inclusion and exclusion criteria. In represent numerous the large NIH RCTs in CP/CPPS [15,16,24], ‘it appears that patients diagnosed with CP/CPPS variations, making >90% of screened patients were not enrolled are not exactly alike and probably represent each patient a for various reasons. It is very likely that numerous variations, making each patient a unique individual patients enrolled in these RCTs, whom we rely unique individual’ (the snowflake on for our evidence-based approach to hypothesis) [29]. In therapy, may not entirely represent the retrospect, we can patients we manage in day-to-day clinical now understand the reason why the various practice. Similarly, the realisation that our therapies evaluated in clinical trials that were patients may have different aetiologies,

PHENOTYPIC APPROACH TO MANAGING CP/CPPS

to be no better than placebo in amelioration TABLE 4 An alternative interpretation of available RCT data suggests there may be subgroups of patients of CP/CPPS symptoms. Further review of the who benefit from the tested intervention patients enrolled in those studies would show that they were very chronic (many years of Intervention Interpretation symptoms or since diagnosis), had many Ciprofloxacin 2 × 2 factorial design has limitations. other treatments including previous antibiotic [15] Cohort was heavily pretreated and long duration. therapy in most, and had seen numerous Other studies show benefit in more antibiotic naïve patients with recent diagnosis physicians for their condition. In two other, [30,31] less controlled studies (no placebo arm), Levofloxacin Less heavily pretreated cohort investigators showed that patients who were [14] Significant benefit at 3 weeks diagnosed earlier in the course of their Marginally significant benefit at 6 weeks (P = 0.06) symptoms and were more naïve to previous Other studies show benefit in more antibiotic naïve patients with recent diagnosis antibiotic therapy faired much better [30,31] (50–75% response rate to ofloxacin, Rofecoxib [17] Significant benefit at 50 mg dose for secondary outcome (Subjective Global ciprofloxacin and levofloxacin) [30,31]. Assessment) • Anti-inflammatories: There is only one Tamsulosin 2 × 2 factorial design has limitations contemporary RCT evaluating anti- [15] Cohort was heavily pretreated and long duration inflammatories vs placebo and that particular Other trials show benefit (see four positive α-blocker trials describe below [32–34]) trial was reported as negative according to a Alfuzosin [16] α-blocker-naïve, recently diagnosed primary outcome that was the change in the Other trials show benefit (see four positive α-blocker trials describe below [32–34]) CPSI score [17]. However, with the higher dose Terazosin [32] This was a positive trial that showed that 14 weeks of terazosin was superior to of the cyclooxygenase-2 inhibitor, placeboin α-blocker naïve patients significantly more patients responded to 6 Alfuzosin [33] This was a positive trial that showed that 6 months of alfuzosin was superior to weeks of therapy compared with placebo placebo indicating that there was a clinical benefit in Tamsulosin This was a positive trial that showed that 6 weeks of tamsulosin was superior to at least some of the patients. A further study [34] placebo in relatively α-blocker naïve, recently diagnosed patients examining high doses of pentosan Finasteride Underpowered study polysulphate (one mechanism of action [18] Marginally significant benefit (P = 0.06) for primary and secondary outcome includes an anti-inflammatory effect) showed PPS [23] Significant benefit for secondary outcome (% of Subjective Global Assessment similar results; negative by primary outcome responders) but a positive result when the secondary Pregabalin Significant benefit seen for all important secondary outcomes (Global Response outcome, subjective responder analysis, was [24] Assessment, total and subscore NIH-CPSI, pain questionnaire examined [23]. Quercetin [20] A small but positive study according to both primary and secondary endpoints • α-blockers: Two major NIH studies showing that 4 weeks of quercetin was superior to placebo examining α-blockers concluded that Cernilton [21] A well designed multicentre study reasonably well powered showing that 12 tamsulosin [15] and alfuzosin [16] were no weeks of pollen extract was superior to placebo (primary and secondary better than placebo. The first trial evaluating endpoints) tamsulosin enrolled chronic, heavily pretreated patients while the second trial PPS, pentosan polysulphate sodium. evaluating alfuzosin enrolled early-diagnosed patients who were naïve to α-blocker therapy. In both of these patient populations (chronic, heavily pretreated and early, relatively different progression pathways and different possible or alternative explanations of the treatment naïve) the results were reported as clinical presentations (clinical phenotypes available data from RCTs. These important negative. One could assume that the case associated with CP/CPPS to be discussed later RCTs, while providing valuable data and should be closed and that α-blockers should in this review) may mean that different insight, cannot be used to completely drive not be used in any patient with CP/CPPS. Yet, patients may respond differently to the our clinical management strategy. there are three other (actually many more in various therapies we use in practice. the non-Western literature), albeit smaller • Antibiotics: It is worthwhile to re-examine those Antibiotics have supposedly negative RCTs and try to always been our ‘Most of all we need to understand why we understand the ramifications of the findings traditional standard continue to use these various medical therapies rather than base our clinical practice on only treatment for CP the primary outcome report. Most of all we including CP/CPPS. when the evidence tells us otherwise’ need to understand why we continue to use Two very large well- these various medical therapies when the designed evidence tells us otherwise. Table 4 multicentre RCTs have reported that and less controlled randomized placebo- [14–18,20,21,23,24,30–34] outlines the levofloxacin [14] and ciprofloxacin [15] appear controlled studies, that were in fact positive.

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These studies which evaluated terazosin [32], individuals with different and varying alfuzosin [33] and tamsulosin [34], would aetiologies, progression pathways and suggest that α-blockers may benefit some response to therapy. The NIH has recently patients in our practice. Certainly, the large initiated an extremely well-funded 5-year negative NIH RCTs did not select patients multicentre Multidisciplinary Approach to with voiding symptoms, a clinical Pelvic Pain (MAPP) research effort to evaluate presentation that may be predicted to do the importance and impact of the various better with α-blockers than patients without clinical phenotypes in patients being such symptoms. diagnosed with CP/CPPS (as well as IC/PBS) • 5ARIs: Similarly, finasteride has only been [www.mappnetwork.org]. This ambitious evaluated in one contemporary trial [18] that, research programme will evaluate unfortunately, was underpowered. In that neurological, endocrine, neuromuscular, underpowered study, the primary endpoint immunological, infectious and psychosocial (change in CPSI score) was negative; however, correlates associated with CP/CPPS as well as twice as many patients responded to examine the relationship between CP/CPPS finasteride compared with placebo. In a recent and other poorly defined pain syndromes report, dutasteride significantly (both such as irritable bowel syndrome, statistically and clinically) reduced CP/CPPS fibromyalgia, and chronic fatigue syndrome. A symptoms in men with prostatitis-like major objective of MAPP is to discover and symptoms that were enrolled in a prostate validate specific biomarkers for the various cancer prevention trial [35]. clinical phenotypes. While improving our • Herbal therapies: While herbal therapies therapeutic algorithm for CP/CPPS is not an are usually thought to be ineffective, as objective, there is no doubt that a better described in a previous section, two understanding of the pathophysiology and contemporary RCTs using the CPSI as an the discovery of novel biomarkers will lead to outcome parameter have shown that the better treatment discoveries and better specific herbal therapies quercetin management strategies. (specifically Prosta-Q) [20] and pollen extract (specifically Cernilton) [21] were superior to The promise of exciting discoveries that may placebo suggesting again that some patients eventually change our management approach certainly respond to these specific to CP/CPPS is many years in the future. interventions. Clinicians require a better approach to • Neuromodulatory therapies: The last major management now, one that can be modified NIH clinical study in CP/CPPS examined the and revised as our understanding of oral neuromodulatory gabapentinoid, mechanisms develop and new biomarkers are pregabalin, in chronic, treatment-refractory discovered. Based on extensive clinical patients with CP/CPPS [24]. Again, while the experience and review of the literature, primary outcome (CPSI responders) was several prostatitis investigators formulated a negative, all the other important secondary novel phenotypic classification system that outcomes (mean CPSI score, pain score, has not only been shown to work in clinical subjective responder rate, etc.) were positive. practice, but also useful in formulating Many patients did have a clinically favourable improved individualized treatment plans. This response despite the negative conclusion of classification system has been termed that RCT. ‘UPOINT’ [36] for Urinary, Psychosocial, Organ-specific, Infection, Neurological/ This re-evaluation of available data from systemic, Tenderness (of pelvic floor skeletal recent RCTs indicates that there is a strong muscles). It was proposed by these signal that many patients do in fact respond researchers that patients be classified into to these specific medical interventions. This one or more of these phenotypic domains as a realisation and awareness are changing the way to characterize them and direct specific paradigm by which we evaluate and manage therapy. our patients with CP/CPPS. The UPOINT classification system can be used, not only in research [37], but also effectively PHENOTYPIC CLASSIFICATION OF in clinical practice [38,39]. We have also CP/CPPS: ‘UPOINT’ shown that this approach is effective in understanding the heterogeneity of patients Researchers and clinicians have become presenting with IC/PBS [40,41]. In this system, aware that patients with CP/CPPS are patients are evaluated in the clinic, similar to

PHENOTYPIC APPROACH TO MANAGING CP/CPPS

urine analysis and culture, determination of TABLE 5 Evaluation of a man with CPPS pelvic myofascial pain and muscle spasm, and some added questions regarding a few Evaluative steps Description psychosocial problems that some patients Mandatory History face. Patients are characterized into the Physical examination with DRE (includes pelvic floor assessment) urinary domain by documentation of irritative Urine analysis and urine culture and obstructive voiding symptoms and Recommended Pre- and post-massage two glass test for culture dysuria. The psycho-social domain includes Symptom inventory or index (NIH-CPSI) patients with clinical depression, poor coping Flow rate and residual urine determination skills, social interaction problems, and a Assessment for depression, maladaptive social and/or coping behaviour psychological condition termed Questions regarding associated conditions (e.g. irritable bowel syndrome, etc.) ‘catastrophizing’ (magnification, followed by Optional (for specific Urine cytology rumination of symptoms and then, finally, indications) Semen analysis and culture helplessness). The organ-specific domain in Urethral swab for culture patients with CP/CPPS include those patients Pressure flow studies with tenderness on light palpation of the Videourodynamics (including flow-electromyography) prostate and further by patients who have Cystoscopy confirmed inflammation of the prostate gland TRUS by microscopic examination of either Pelvic imaging (ultrasound, CT, MRI) expressed prostatic secretion or the post- PSA prostatic massage urine sediment. The infection domain patients have confirmed This suggested approach allows for clinical phenotyping of patients that will be helpful in directing infection in the lower urinary tract, either specific therapy (see text). recurrent UTIs or uropathogenic bacteria cultured in prostate-specific specimens (expressed prostatic secretion or post- prostatic massage urine sediment). Patients TABLE 6 Clinical descriptions of the six UPOINT domains with neurological/systemic as the main categorization have other ‘unexplained’ Domain Clinical description conditions that appear to be related to a > Urinary CPSI urinary score 4 central neuropathy. These would include Patient complaint of bothersome urgency, frequency, or nocturia irritable bowel syndrome, fibromyalgia, and < Flow rate 15 mL/s and/or obstructed pattern even chronic fatigue syndrome and migraine > Postvoid residual urine volume 100 mL headaches. Patients identified with a Psychosocial Clinical depression tenderness domain have demonstrable Poor coping or maladaptive behaviour, e.g. evidence of tenderness, pain, spasm in the perineum, catastrophizing (magnification or rumination in regard to pelvic floor or have actual myofascial painful symptoms, hopelessness) or poor social interaction trigger points during the perineal and pelvic Organ specific Specific prostate tenderness examination done at the time of the DRE. Leukocytosis in prostatic fluid Table 6 summarizes the clinical findings that Haematospermia allow characterization of the six UPOINT Extensive prostatic calcification domains. Infection Exclude patients with clinical evidence of acute (acute infection) or chronic bacterial prostatitis recurrent infection that is localized to Patients are therefore classified in one or prostate specimen between infections) more domains. Our initial study [37] has Gram-negative bacilli or enterococcus localized to prostatic fluid shown that about half of the patients were Documented successful response to antimicrobial therapy classified in the urinary domain, one third in Neurological/systemic Pain beyond abdomen and pelvis the psychosocial domain, two thirds in the conditions Irritable bowel syndrome organ-specific domain, one in six in the Fibromyalgia infection domain, one third in the Chronic fatigue syndrome neurological/systemic domain and, finally, Tenderness of skeletal muscles Palpable tenderness and/or painful muscle spasm or trigger points in half of the patients in the tenderness domain. perineum or pelvic floor or sidewalls during DRE examination Only one in five patients were identified with a single domain while one third of patients were classified in two domains. The rest were current clinical practice. Table 5 outlines the process involves a focused history that classified in three, four, or more domains. Four evaluative steps required to adequately assess includes a symptom and bother assessment, a separate studies have now examined the a patient with CP/CPPS and characterize them focused physical examination that includes a UPOINT system in CP/CPPS [37,42–44], in into one or more UPOINT domains. The pre- and post-massage urine collection for 1469 patients. The prevalence and distribution

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TABLE 7 Prevalence of UPOINT domain diagnoses in recent reports; >20% of patients will be typically categorized with multiple domains

Prevalence, % Study 1 [37] Study 2 [42] Study 3 [43] Study 4 [44] UPOINT domain N = 100 N = 50 N = 1219 N = 100 Urinary 52 52 65 59 Psychosocial 34 36 35 37 Organ speciﬁc 61 38 84 70 Infection 16 38 10 16 Neurological/systemic conditions 37 36 41 39 Tenderness of skeletal muscles 53 32 62 64

of the each of the six UPOINT domains from directed towards that particular domain (or these separate studies are remarkably similar domains). This means that most patients will and are shown in Table 7 [37,42–44]. These be treated with a multimodal therapeutic studies have been approach, rather than a single medication as able to show we have usually done in the past [38,39]. conclusively that Table 8 describes some of the treatments that ‘there is a strong correlation between the number there is a strong the authors use for each of the six UPOINT of phenotypic domains identified in a patient and correlation between domains. It is obvious that these treatments severity of symptoms’ the number of encompass not only our traditional therapies phenotypic domains (antibiotics, anti-inflammatories, prostate- identified in a specific therapies such as α-blockers and patient and severity of symptoms (as the 5ARIs), but also include phytotherapies (the number of domains increase, so does the CPSI herbal therapies quercetin and pollen score) [37,42,43]. Interestingly, duration of extracts), neuromodulators (the symptoms but not age is correlated with the gabapentinoids and amitriptyline), analgesics, number of UPOINT domains a patient is skeletal muscle relaxants, as well as identified with [37]. Furthermore, the UPOINT physiotherapy (conservative and aggressive domains that have the highest impact on including prostate massage and local heat HRQL and activities are the psychosocial, therapy) and even counselling and neurological/systemic, and to a lesser extent psychotherapy. tenderness domains [37,42], all clinical domains that are not prostate-centric. We examined 100 consecutive men with CP/CPPS clinically categorized according to UPOINT [44]. They were treated according to TREATMENT STRATEGIES BASED ON the UPOINT strategy outlined above and UPOINT CHARACTERIZATION followed for ≥6 months. At 6 months, 85% of patients had at least a 6-point decrease in Once we can accept that our traditional CPSI, a decrease that was clinically significant treatment approach to CP/CPPS was not that for patients. In fact, the main total CPSI successful [45], we can modify our decreased from a high of 25 before UPOINT therapeutic strategy. All patients diagnosed strategy was employed to 13 after 6 months with CP/CPPS should be managed with a of individual patient-directed therapy. As standardized conservative approach together would be expected, those patients with only a with more aggressive medical or other single domain had almost 100% response rate therapy as required. Conservative therapy while those with more domains ranged from includes education, counselling, exercise 40 to 60% (responders defined as those that (excluding high-impact exercise), stress and had at least a 50% improvement). anxiety reduction and avoidance of activities, Interestingly, when we looked at each one of foods and drinks that exacerbate their specific the CPSI categories, we noted that this symptoms [46]. Once the patient has been strategy not only improved the pain classified according to his specific UPOINT symptoms of CP/CPPS, but also improved the domains, more aggressive therapy is then urinary symptoms and HRQL. The UPOINT

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