Clinical phenotyping in chronic prostatitis/chronic pelvic pain syndrome and interstitial cystitis: a management strategy for urologic chronic pelvic pain syndromes

DA Shoskes¹, JC Nickel², RR Rackley¹ and MA Pontari³

¹Glickman Urological and Kidney Institute, The Cleveland Clinic, Cleveland, OH, USA; ²Department of Urology, Queens University, Kingston, Ontario, Canada and ³Department of Urology, Temple University, Philadelphia, PA, USA

The urologic chronic pain conditions such as chronic prostatitis/chronic pelvic pain syndrome and interstitial cystitis are syndromes whose evaluation and management are controversial. Part of the difficulty in diagnosis and therapy is the heterogeneity of etiologies and symptoms. We propose a six-domain phenotype, which can classify these patients clinically and can direct the selection of therapy in the most evidence based multimodal manner. The domains are urinary, psychosocial, organ specific, infection, neurologic and tenderness of skeletal muscles. This system is flexible and responsive to new biomarkers and therapies as their utility and efficacy are proven.

Prostate Cancer and Prostatic Diseases advance online publication, 22 July 2008; doi:10.1038/pcan.2008.42

Keywords: chronic prostatitis; interstitial cystitis; chronic pain

Introduction

          Chronic prostatitis (CP) and interstitial cystitis (IC) are perplexing disorders for both patients and physicians. Definitions and classifications for these conditions remain clinical syndrome based. The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) classification of prostatitis has replaced the older terms ‘nonbacterial prostatitis’ and ‘prostatodynia’ with category III chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS or now commonly call CPPS).¹ These patients have pelvic and genital pain, often associated with urinary and sexual symptoms, but no history of documented urinary tract infection (UTI). Despite conclusive evidence that empiric antibiotic therapy is not effective for CPPS, most physicians do not culture anything but urine and use antibiotics as primary therapy regardless of the culture results.² Several therapies have been shown to help the symptoms of CPPS in small clinical trials, and while multimodal therapy may be the most effective approach,³ it is the most difficult to test in a systematic, stratified and controlled way. One of the largest barriers to successful therapy is the lack of biomarkers that can stratify patients into etiologic or therapeutic categories. Clinical trials on CPPS are, by the nature of the syndrome, treating patients with multiple etiologies and therefore may fail on the basis of a heterogeneous population.
           IC similarly has several proposed etiologies and therapeutic options. Given the nature of symptoms, the
condition is being referred to as painful bladder syndrome (PBS) and more recently, bladder pain syndrome.⁴ Beyond symptoms, the value of biomarkers (for example, antiproliferative factor) and definitive objective diagnostic tests (hydrodistension, potassium sensitivity) is controversial, and do not appear to predict therapy outcome.⁵ Again, multimodal therapy has been proposed as the best approach to manage this condition,⁶ but has not been studied in a systematic way. Given the overlap of symptoms, the NIDDK has proposed an umbrella term for CPPS and IC as Urologic chronic pelvic pain syndromes (UCPPS). This ‘lumping’ rather than ‘dividing’ as a strategy to lead to a better understanding and management of these conditions remains untested. We propose that instead of including all patients under a homogenous envelope, it is best to classify the various subtypes of UCPPS patients and manage individual patients according to the subtype classification. As the etiology and pathogenesis of these syndromes remain unknown, few objective parameters are available to differentiate patients and the various potential biomarkers have not yet been feasible to use or validated as useful, we propose a purely clinical phenotyping of patients with UCPPS and then therapy directed at the individual phenotype(s) based on best available evidence.

Etiological framework for classification of the UCPPS patient

There are multiple interrelated mechanisms that can contribute to the symptoms of UCPPS (Figure 1). By history, most patients describe an initial event such as a UTI, sexually transmitted disease or local trauma that instigated an acute symptomatic episode that set in motion the events that eventually led to UCPPS. These initiating events often respond to therapy (for example, antibiotics) but then may recur. All forms of organ injury leads to an injury—response, which includes inflammation, upregulation of chemokine expression and cytokine release. If the tissue injury is not controlled, the injury– response may cause additional organ damage in a vicious cycle. Loss of bladder epithelial integrity may allow irritation of subepithelial nerves by substances in the urine. Inflammation can also cause pain that may produce contraction of smooth muscle at the bladder outlet and skeletal muscle of the pelvic floor. This muscular contraction may lead to lower urinary tract symptoms, genital and intercourse-related pain (postejaculatory pain and dyspareunia) and pain in other muscle groups (for example, abdominal or thigh). Prolonged pain can lead to central and peripheral neuropathies, which may be evident by hyperalgesia (increased perception to pain) and allodynia (perception of pain without a painful stimulus).⁷ Pain, inflammation, muscle spasm and neuropathy all can have damaging psychological effects, which in turn can perpetuate the pain cycle through catecholamine release and neurogenic inflammation. Patients with chronic pain may have increased stress, depression and exhibit catastrophizing, a response of hopelessness, pessimism and agitation, which can lead to a heightened emotional response to pain.⁸
This etiologic framework highlights the difficulty of selecting and assessing therapy for these syndromes. Any two patients may have identical symptoms, yet one may have voiding dysfunction with an increased bladder neck tonicity and the other may have persistent inflammation, pelvic floor spasm and suffer from depression and catastrophizing. Clearly ideal therapy in both cases would be different and likely multimodal. Similarly, if both patients entered a clinical trial for one type of therapy such as an a-blocker, the first patient may do well and the second patient poorly.
      In summary, men and women with UCPPS have syndromes defined by their symptoms and no current
way to be further classified based on biomarkers, etiology or likelihood of response to therapy. Nevertheless, much has been learned in the past 10 years about potential mechanisms and promising therapies. What is required is a classification framework that can both guide evidenced-based therapy and can also accommodate new data as valid biomarkers and treatment approaches become available.

A phenotypic classification of UCPPS

      It is apparent that a classification system is required for UCPPS to help guide clinical research and therapy, analogous to the tumor nodes metastasis (TNM) system for cancer. Like the TNM system, this classification should be easy to reproduce, be based on clinical evidence, have potential therapies associated with a given category and be flexible enough to incorporate new data as it becomes available (for example, a new prognostic marker). Individual features should not be so rare that fewer than 5% patient will be so classified. To be clinically relevant, the domains of the classification system should each be associated with therapy that has at least some documented efficacy. Although objective biomarkers would be ideal to assist stratification, currently none exist that fulfill these criteria, although some such as antiproliferative factor for IC and seminal and/or prostatic secretion chemokines and oxidative stress markers in prostatitis have strong preliminary evidence. We propose therefore a phenotypic classification of UCPPS based on six common clinical features, each of which can be linked to specific therapy.
      The six domains of the classification system are Urinary symptoms, Psychosocial dysfunction, Organspecific findings, Infection, Neurologic dysfunction and Tenderness of muscles. This produces the mnemonic UPOINT. The following sections describe each domain, including clinical features and therapy. By including the findings of a particular investigation (for example, cystoscopy with hydrodistension) we are not necessarily advocating doing such a test on all UCPPS patients, but giving these tests as examples of ways to define the domains employing current and available assessments used routinely by clinicians in practice. We have suggested other measures that may prove useful, but may be less feasible in normal clinical practice.

Clinical assessment

Physical examination. The physical examination and evaluation of men and women with UCPPS will include both a thorough examination of the pelvic region but also other nonpelvic areas that may be involved in the chronic pain syndrome including neural assessment. This is to include a full gynecological examination in women and a thorough genital and rectal/prostate examination in men. These are to include a standardized assessment of pain/tenderness (severity, sites) during abdominal, external genitalia, perineal, pelvic floor and rectal examination in men and bimanual examination in women.

Standard investigations. Patients should have a urine analysis and culture (midstream urine for women, 4- or 2-glass test for men¹⁴). A male patient, particularly one with a history of recurrent UTI with same organism should undergo a lower urinary tract culture localization test. In general practice, the pre- and post-massage 2- glass test is easy to administer (culture results of midstream urine is compared to initial stream urine culture of specimen collected after prostatic massage) and provides a reasonably consistent result when compared to the more difficult Meares–Stamey 4-glass test. Male patients with a history of recurrent UTI with the same organism that is localized to prostate-specific specimen (VB3 and/or expressed prostatic secretions (EPS)) will be classified as category II chronic bacterial prostatitis and not further phenotyped. A female patient with a history of recurrent UTI whose symptoms and documented bacteriuria including atypical organisms such as Ureaplasma and Mycoplasma cultures respond to antimicrobial therapy (either acute, suppressive or prophylactic dosing) will not be further phenotyped.¹⁵

Optional investigations. A number of evaluations may influence the clinical phenotype and should be included in the evaluation when performed. These include cystoscopy, post void residual, flow rate, bladder hydrodistension, bladder anesthetic challenge test, pelvic magnetic resonance imaging (for urethral diverticulum) and pelvic and transrectal ultrasound. When pelvic pathology is suspected, laparoscopy may be indicated.

Clinical phenotyping

The previously described history, physical examination and investigations listed above will allow clinically phenotyping into one or more of the UPOINT domains.

Urinary symptoms. Although pain is the defining and most prevalent symptom in UCPPS, urinary storage and voiding symptoms are common and may be debilitating (particularly in IC). Nevertheless some patients, especially men with CPPS may have no urinary symptoms. A patient included in the urinary phenotype would be one with bothersome frequency, urgency and/or nocturia. Suggested objective measures would include a residual urine greater than 100 ml, a CPSI urine score greater than 4, nocturia greater than two times and/or bothersome frequency, urgency or nocturia. Therapies for patients with a urinary phenotype could include a-blockers, anticholinergics, specific intravesical treatments (IC specific—see under ‘Organ specific’), dietary changes (for example, avoid caffeine, reduce fluids) and possibly neuromodulation therapies.

Psychosocial. Patients with chronic pain often have maladaptive coping mechanisms (for example, catastrophizing) and may suffer from depression, anxiety, stress and/or have a history of sexual or other physical abuse. For patients who demonstrate these features based on specific history or questionnaire, therapy would include counseling, cognitive behavioral therapy and antidepressant medication (to be prescribed and monitored by a suitably trained practitioner).

Organ specific (bladder and/or prostate). Although injury (trauma, infection, inflammation) of the bladder and prostate are common triggers of UCPPS, it is not uncommon to find patients with long-standing symptoms whose ongoing pain is perpetuated by nerves and muscles beyond these organs. Certainly there have been patients whose pain has not abated following radical prostatectomy or cystectomy. Therefore, organ-specific therapies should be reserved for those with evidence for ongoing organ-specific injury. The patient with an organspecific phenotype would be identified with pain localized to the prostate on physical examination and those whose pain is affected by bladder recycling (filling and emptying). Further evidence of the organ-specific phenotype would include documentation of ongoing inflammation (for example, leukocytosis of prostatic fluid or extensive prostatic calcification on transrectal ultrasound (TRUS)), Hunner’s ulcers in the bladder, typical glomerulations with hydrodistension, biopsy documentation of inflammation, or relief of pain following the anesthetic bladder challenge test.¹⁶
      There are several therapies that can be effective for prostate and bladder injury and inflammation. Quercetin¹⁷ and bee pollen (Urolo-Q^TM, Sunn Biolabs, California USA) can improve symptoms and inflammation in CPPS as well lowering oxidative stress.¹⁸ Therapies used with varying success for bladder specific injury in IC/PBS include quercetin,¹⁹  (Cysturol^TM, Sunn Biolabs, California USA) misprostol,²⁰ pentosan polysulfate, intravesical therapy (for example, dimethyl sulfoxide, alkalinization, alkalized lidocaine, heparin, steroids), dietary modifications, restriction of offending agents (for example, nonsteroidal anti-inflammatory drugs²¹) and surgery for definitive indications (for example, electrocoagulation of Hunner’s ulcers).⁴

Infection. In both CPPS and IC/PBS, empiric antibiotic therapy is both overused and ineffective. Nevertheless there are patients whose symptoms and culture results place them within the syndrome of UCPPS, but who nevertheless have an infection which may respond to antimicrobial therapy. These include uropathogens(Gram-negative bacilli and Gram-positive Enterococcus)found in the mid-stream urine at low counts or localizedto EPS or post-massage urine in men with no history of recurrent or documented UTI. It may include other Gram-positive bacteria found in completely antibiotic naive patients. It can also include other atypical organisms in the urethra or urine of men and women (for example, Ureaplasma, Chlamydia, Mycoplasma). Certainly a number of prospective clinical trials have indicated that some patients with chronic prostatitis who do not have typical uropathogen localization²² and women with IClike symptoms do respond to antimicrobial regimes.²³ Male patients would be identified by documenting any organism localized to the prostate-specific specimens, whereas women may be identified with organisms (atypical or low ‘insignificant count of uropathogens) cultured in midstream urine. It may be inferred that patients may be included in this group if they have never had a documented UTI but have a history of favorable response to antibiotics in past.
      Therapy for these culture positive patients would ideally be antibiotics selected on the basis of bacterial culture sensitivity or known sensitivity patterns (in the case of atypical organisms). However, practically, the antibiotics are usually prescribed empirically. A caveat however is that if patients do not respond to adequate antibiotic therapy, no further antimicrobial treatment should be initiated.

Neurological/systemic conditions. Patients with UCPPS have a high incidence of concomitant, but associated medical conditions that are often pain related or have features of autonomic dysfunction, as well as peripheral and central nervous system sensitization (neuropathic).²⁴ These include irritable bowel syndrome, fibromyalgia, vulvodynia, chronic fatigue syndrome, migraine headaches and low back/leg pain. These patients are phenotyped into the neurological/systemic phenotype by good history taking supplemented by physical examination.
      In addition to specific therapy for these other conditions, such patients may benefit from neuroleptic medications, such as gabapentin, pregabalin, nortryptiline and amitriptyline, and complementary neuromodulation therapies such as acupuncture.²⁵

Tenderness of muscles. A significant proportion of UCPPS patients has abnormal findings when skeletal muscle of the pelvic floor, pelvic and abdomen is properly examined. These include muscle spasm and muscle or fascial ‘trigger points’.²⁶ Specific therapy for this phenotype includes pelvic muscle physical therapy,²⁷ stress reduction, behavior modification (cushion when sitting for long periods, modified bicycle seat) and possibly oral antispasm drugs, such as cyclobenzaprine or tizanidine. Neuromodulation may also has a role, either by neurotoxin²⁸ or surgical means.²⁹
      The UPOINT classification system and therapies related to each domain are summarized in Figure 2.

Classification and therapy

Based on these simple clinical investigations, UCPPS patients can be classified into one or more of the UPOINT phenotypes. This should be combined with a validated score (NIH CPSI, O’Leary-Sant) that will allow determination of symptom severity and more objective follow-up during treatment. Multimodal therapy can then be selected as indicated by the phenotype domains experienced by individual patients. For example, a CPPS patient with bothersome urinary symptoms, prostate tenderness and pelvic side wall spasm might be prescribed a combination of alfusozin, quercetin/bee pollen (Urolo-Q^TM, Sunn Biolabs, California USA) and pelvic physical therapy. A patient with severe urinary symptoms related to bladder filling, clinical depression, catastrophizing and fibromyalgia could be prescribed pentosan polysulfate, nortryptiline, bladder anesthetic instillations and psychological counseling. Success of therapy should be monitored both by reduction in symptom severity, improvement in quality of life and decrease in disability. Certainly a change in phenotype (or number of phenotypes) may point to successful therapy, but success in UCPPS is not measured by cure, but rather amelioration of symptoms.

Future directions and goals
The literature is littered with well-intentioned prospective randomized placebo-controlled trials evaluating a
single promising therapy in patients with CPPS and IC. Unfortunately these have invariably been negative trials, leaving clinicians to ponder what to do for their patients. In our opinion, the main reason these therapies have failed is that the population of men and women with UCPPS are not homogenous, but rather are made up of heterogenous groupings of phenotypes. It is not unreasonable to expect single therapy treatment trials directed at all patients with UCPPS would be doomed to failure. Our clinical phenotyping management strategy addresses these concerns. The next step to assess the utility of clinical phenotyping with the UPOINT system is to prospectively classify patients with UCPPS and determine the prevalence of individual as well as combination phenotypes. Next, the phenotypes will need to be correlated with symptom severity and duration to look for clues of etiology as well as chronicity. Finally and perhaps most importantly, the success of multimodal therapy driven by the UPOINT system will need to be compared with current conventional therapy. Flexibility and responsiveness is an important feature, and new criteria and therapy can be added as medical evidence is published.

Conclusion

Clinicians and patients who are discouraged by the recent reporting of multiple negative clinical trials in CPPS and IC should consider this proposed management strategy of clinically phenotyping UCPPS patients employing standard clinical evaluations and then directing multimodal therapy according to a patient’s individual phenotype(s). The system is adaptable to our evolving understanding of etiology, development of appropriate biomarkers and evaluation of novel therapies. We believe that clinical phenotyping is the future of UCPPS management.

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