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

J. Curtis Nickel, MD, and Daniel Shoskes, MD

         

          There is no one unifying etiological mechanism or specific curative therapy for chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS). However, there is sufficient evidence to suggest that each of the proposed mechanisms may be important in some patients, and that many of our evaluated treatments do in fact work in subgroups of patients. We hypothesize that CP/CPPS patients are not a homogenous group suffering from a single disease entity. Rather, CP/CPPS patients are actually unique individuals with differing clinical phenotypes based on various etiological mechanisms with distinctive symptom complexes and progression trajectories. We call this the “Snow Flake Hypothesis.” We propose the UPOINT (urinary, psychosocial, organ-specific, infection, neurologic/systemic, and tenderness domains) clinical phenotyping classification; we have validated the concept in a CP/CPPS cohort and have suggested that phenotypically directed therapy will improve our clinical treatment outcomes.
 

Corresponding author
J. Curtis Nickel, MD
Department of Urology, Queen’s University, Kingston General
Hospital, 76 Stuart Street, Kingston, Ontario K7L 2V7, Canada.
E-mail: jcn@queensu.ca
Current Urology Reports 2009, 10:307–312
Current Medicine Group LLC ISSN 1527-2737
Copyright © 2009 by Current Medicine Group LLC
 

 

Introduction

Urologists in general urological practice have begun to notice that multiple recent publications in the field
of chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) describing basic science studies investigating etiological mechanisms and clinical trials evaluating treatment strategies have failed to discover a uniform etiological mechanism or a specific effective treatment in this condition. Epidemiological studies continue to confirm that CP/CPPS is a very prevalent chronic pain condition [1] that results in significant economic costs [2]; it is also associated with a severe impact on the quality of life of diagnosed patients [3]. We have proposed
that men diagnosed with CP/CPPS are not a homogenous population of similar patients, but rather, a heterogeneous group of unique individuals. Each individual CP/CPPS patient likely has different etiological mechanism(s), disease characteristics, symptom complexes, and progression trajectories. These differences can be described in terms of a patient’s clinical phenotype. We have reported a 6-point clinical phenotyping classification system, UPOINT (urinary, psychosocial, organ-specific, infection, neurologic/systemic, and tenderness domains), that can be used to describe individual patient phenotypes that may be of significant benefit in directing specific phenotype-directed therapies [4••]. We have further examined and validated this concept in patients attending a prostatitis clinic [5••]. This article reviews the rationale and importance of phenotyping CP/CPPS patients and its utility in clinical practice in diagnosing, classifying, and treating CP/CPPS patients.

Etiological Considerations

Despite decades of basic science research attempting to unravel the mechanisms and pathogenesis of CP/CPPS, we have to accept that we do not have an answer to what causes this condition. Various theories associated with very solid supportive data include infection (history of urinary tract infection and/or nonculturable organisms) and abnormalities of anatomy (refluxing prostatic ducts, obstruction), voiding (dysfunctional high pressure and/or turbulent flow), endocrine (hypothalamic-pituitary axis abnormalities, adrenal dysfunction), immune system (autoimmune mechanism), neurological system (peripheral and/or central sensitization), and muscles (pelvic floor dysfunction), and psychological associations (stress) [6]. It is obvious now that none of these single mechanisms is responsible for all patients with CP/CPPS. It is very likely that we will never discover a single, all-encompassing, etiological mechanism responsible for all cases of CP/CPPS. We hypothesize that patients have different, even multiple, etiological pathways that eventually result in their symptom complex.

Treatment Considerations

           Over the past decade, a number of randomized placebocontrolled trials using accepted definitions of CP/CPPS [7], accepted inclusion criteria [8], and validated outcomes [9] have evaluated the most common treatments for CP/CPPS that we regularly use in clinical practice. Trials evaluating antibiotics [10,11], anti-inflammatories [12], α-blockers [11,13], finasteride [14], pentosan polysulfate [15], and gabapentinoids [16•] have all been considered negative studies. In fact, the three most recent National Institutes of Health (NIH)-sponsored, randomized placebo-controlled trials—studies considered to be the bestdesigned and the best implemented treatment trials in CP/CPPS [11,13,16•]—evaluating ciprofloxacin/tamsulosin, alfuzosin, and pregabalin were negative in regard to the apriori primary outcome. In other words, in well-designed trials, none of our standard therapies appears to be more effective than placebo. However, it is worth reconsidering these trials from a different perspective (Table 1).
           Two major randomized controlled trials (RCTs) comparing antibiotics with placebo showed that ciprofloxacin [11] and levofloxacin [10] were no better than placebo. In the NIH ciprofloxacin trial, although there is no question that the results were unarguable, the conclusions were only valid in a cohort of CP/CPPS men who had a very long duration of symptoms/diagnosis and had been heavily pretreated, including those treated previously with antibiotics [11]. The effectiveness of levofloxacin compared with placebo in a less chronic and pretreated cohort showed statistically significant improvement at 3 weeks and approached statistical significance (P = 0.06) at 6 weeks [10]. In a recent prospective study evaluating ciprofloxacin and levofloxacin in chronic prostatitis, 4 weeks of antibiotics in a cohort of men who did not have uropathogenic organisms localized to prostate specimens (therefore considered to be CP/CPPS) resulted in significant clinical improvement in 75% of men [17•]. These men had only a 4-week median duration of symptoms (8-week average) for that specific episode of prostatitis. Antibiotics, therefore, may be effective in a distinct population of men with CP/CPPS, that is, men with recent symptoms and/or those with nonpathogenic bacteria localized to the prostate (in effect, CP/CPPS diagnosis).
           Although it would seem intuitive that a pain syndrome believed to be associated with inflammation would respond to anti-inflammatories, the only large study evaluating anti-inflammatory therapy using accepted definitions and validated outcomes (rofecoxib vs placebo) was essentially a negative trial (based on primary outcome analysis) [12]. However, patients randomly assigned to the higher 50-mg dose of rofecoxib had statistically and clinically superior improvement compared with placebo when evaluated with a valid secondary end point (subjective global assessment).
           The two well-designed NIH studies evaluating α-blockers—tamsulosin in very chronic heavily pretreated CP/CPPS [11] and alfuzosin in recently diagnosed α-blocker–naïve CP/CPPS [13]—were negative. These trials had very rigid inclusion/exclusion criteria, and approximately 90% of men seen and screened in a clinical setting were not enrolled in the studies. Four smaller and less restrictive RCTs were, in fact, positive in terms of showing the effectiveness of terazosin [18], alfuzosin [19], doxazosin [20], and tamsulosin [21] over placebo. Although the evidence clearly shows that, overall, α-blockers cannot be considered an effective cure, there is likely a subgroup of CP/CPPS men who may respond to this approach [22,23].
           5-α-Reductase inhibitors have been commonly used by urologists who consider prostatitis a prostate-centric disease. An RCT comparing 6 months of fi nasteride with placebo noted no superiority of fi nasteride compared with placebo in terms of the trial’s primary end point (NIHCPSI [National Institutes of Health Chronic Prostatitis Symptom Index] score). However, there was a strong signal of marginal improvement in the finasteride arm when examining the percentage of men reporting marked or moderate improvement on global response assessment (P = 0.06) [14]. This suggests that some men, perhaps those with co-occurring benign prostatic hyperplasia, could benefit from 5-α-reductase inhibitor therapy.
           Many urologists consider that men with CP/CPPS are very similar to men diagnosed with interstitial cystitis (with respect to etiology and clinical presentation) and treat CP/CPPS with pentosan polysulfate. An RCT comparing 16 weeks of high-dose pentosan polysulfate to placebo, although negative in terms of primary end point (average subjective global assessment numeric score—an end point that has never been validated), showed significant improvement in the pentosan polysulfate arm compared with placebo when evaluating the percentage of men who reported a marked or moderate improvement in symptoms (P < 0.05 for this valid secondary outcome) [15]. Pentosan polysulfate may indeed show marginal effectiveness, perhaps working better in men with voiding symptoms similar to interstitial cystitis.
           There is general consensus that many patients suffering from CP/CPPS for long duration have developed a neuropathic type of pain. Based on the success of gabapentinoids in other neuropathic pain syndromes, the NIH undertook an evaluation of pregabalin in patients with treatment refractory CP/CPPS of long duration [16•]. This recently reported trial was again negative in regard to the primary end point (in which a responder was defined as a patient experiencing a 6-point drop in NIH-CPSI). However, the trial showed significant benefit in terms of important and validated secondary outcomes (global response assessment, mean total and subscore NIH-CPSI score, and McGill Pain Questionnaire). Again, this was another negative trial in which there was a statistically significant number of men who had benefit compared with placebo when measured by different, but valid, outcomes.
           So what do all these seemingly negative trials mean to physicians treating CP/CPPS and to patients diagnosed with CP/CPPS? It is very likely that we will never discover a cure for all patients diagnosed with this condition. This reevaluation of trial results, however, strongly suggests that some patients do, in fact, respond to these various therapies. Our aim must be to identify patients who may respond to specific therapies.

A Clinically Relevant Phenotypic Classifi cation System for Chronic Pelvic Pain Syndromes
We recently described a clinical classification system for urologic chronic pelvic pain syndromes [4••], and validated the approach in CP/CPPS [5••] and interstitial cystitis [24]. In developing this classification system, we knew that the specific phenotypic domains must be discrete, clinically relevant and identifiable, associated with potentially effective therapy, and should be flexible enough to incorporate new advances in our understanding of mechanisms or development of new biomarkers. The 6-point UPOINT (urinary, psychosocial, organ-specific, infection, neurologic/systemic, and tenderness domains) phenotypic classification system fulfills these criteria (Fig. 1). This system has been previously described in detail for urological chronic pelvic pain syndromes [4••] and specifically for CP/CPPS [5••].
           Each domain is clinically identifiable by employing our standard clinical evaluation for CP/CPPS (Table 2). The urinary domain is identified in CP/CPPS patients with bothersome voiding complaints, including urinary frequency, urgency, and nocturia. The psychosocial domain includes patients who have been identified with psychosocial conditions that have been associated with CP/CPPS severity (eg, depression, anxiety, stress, and maladaptive coping mechanisms [eg, catastrophizing, poor social support]). Patients included in the organ-specific domain include those with significant and discrete prostate tenderness and those with significant inflammation identified in microscopy of their prostate-specific specimens. The infection domain is identified in patients who have significant bacteria localized to prostate-specifi c cultures, using some form of lower urinary tract localization method (eg, the pre- and postmassage test), and those who have an unequivocally successful response to antimicrobial therapy. These patients do not have category II chronic bacterial prostatitis because they do experience recurrent urinary tract infection, even if they respond favorably to antibiotics. The neurologic/systemic domain includes patients with evidence of neuropathy and/ or associated regional and/or systemic pain conditions (eg, irritable bowel disease and fibromyalgia). The tenderness domain includes those identified with abdominal and/or pelvic myofascial tenderness.

UPOINT in Chronic Prostatitis/Chronic Pelvic Pain Syndrome

          A recent evaluation of UPOINT was conducted in a cohort of CP/CPPS patients assessed in a specialized prostatitis clinic [5••]. The percentage of patients positive for each domain was 52%, 34%, 61%, 16%, 37%, and 53% for the urinary, psychosocial, organ-specifi c, infection, neurologic/systemic, and tenderness domains, respectively. Twenty-two percent of patients were positive for only one domain, and a signifi cant stepwise increase was found in the total NIH-CPSI score as the number of positive domains increased (Fig. 2).
The duration of time since diagnosis correlated with the number of domains, but not with age. Interestingly, the domains with the most impact on symptoms and quality of life were the two outside of the pelvis, the psychosocial and neurologic/systemic domains, and to a lesser extent, the tenderness domain (which is non organ-specific).
          Treatment for CP/CPPS is directed against the specific UPOINT domains identified in each individual patient. Presently, recommendations for specific UPOINT domains are intuitive, theoretical, and based on best known mechanisms and evidence (Table 2). α-Blockers, anticholinergics, and phenazopyridine are suggested for the urinary domain. For the psychosocial domain, antidepressants, antianxiolytics, cognitive behavioral therapy,and various psychological supportive therapies could be of benefi t. Organ-specifi c domain therapies include anti-infl ammatories, prostate massage, and α-blockers. Neuromodulatory medications, such as amitriptyline and the gabapentinoids, are indicated for the neurologic/systemic domain, whereas specific therapies directed against associated conditions (eg, therapies for irritable bowel syndrome and fibromyalgia) will add to the therapeutic benefits. The tenderness domain is managed with muscle relaxants, general physiotherapy, and focused pelvic physiotherapy. Multimodal therapy has been shown to be superior to monotherapy in CP/CPPS [25,26], and it is anticipated that more focused multimodal therapy directed toward individual UPOINT domains will increase the overall effectiveness of therapy.

Phenotypic Approach to Chronic Prostatitis/Chronic Pelvic Pain Syndrome: The Future

          Most physicians managing patients with CP/CPPS will accept the premise that this condition comprises a heterogeneous group of patients with very different etiologies, symptom complexes, and progression trajectories. This explains why we have not been able to discover either a single etiological mechanism or a simple cure for this condition. It is therefore rational to evaluate CP/CPPS patients as individuals with differing clinical phenotypes. UPOINT is a clinical system that identifies CP/CPPS patients into one or more domains and then allows individualization of therapy by specifically directing it toward the identified phenotype(s). We have already confirmed that we can identify UPOINT domains using standard clinical assessment. As epidemiologists and basic scientists help us unravel mechanisms and discover biomarkers for specific phenotypes, we will adapt the UPOINT system by creating evidence-based subcategories within domains. Deep phenotyping studies presently underway will further illuminate these UPOINT domains and provide the data required to develop a UPOINT questionnaire that will be of great assistance to physicians managing these patients. We are currently undertaking real-life clinical practice studies to attempt to confirm that this approach will further improve our overall treatment results in CP/CPPS. Finally, we anticipate that based on our poor experiences with randomized placebo-controlled trials and our new awareness of phenotypic differences in CP/CPPS patients, future clinical trials will evaluate therapy in cohorts selected for clinical phenotypes best predicted to respond to that specific therapy.

Conclusions

A phenotypic approach to pelvic pain allows us to better understand our failure to discover a single unifying etiological mechanism or a universal cure for CP/CPPS. By treating each patient as a phenotypically unique individual and tailoring individual therapies to the patient’s identified phenotype domains, we should be able to improve our therapeutic outcomes.

Disclosure

Dr. J. Curtis Nickel has received consulting fees from Merck, GlaxoSmithKline, Ortho Women’s Health, Farr
Labs, Watson, Medtronic, NeurAxon, and Genyous Biomed. He has received research support from Merck, GlaxoSmithKline, Allergan, Watson, and American Medical Systems.
Dr. Daniel Shoskes has investment interest in Tri Urol, and has received consulting fees from Farr Labs.

References and Recommended Reading

Papers of particular interest, published recently, have been highlighted as:
• Of importance
•• Of major importance