Opposing Views: CPPS Syndrome or Disease

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Dimdem
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Opposing Views: CPPS Syndrome or Disease

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A pair of short articles in the July 2009 Journal of Urology.

"Chronic Prostatitis/Chronic Pelvic Pain: The Syndrome"
J. Curtis Nickel
"In conclusion, I believe that CP/CPPS is a syndrome diagnosed by recognizable signs and symptoms that are not due to any single known disease process. The CP/CPP syndrome is further characterized by clearly identifiable and distinct clinical phenotypes that can occur singly or more often together to define a heterogeneous population of truly unique individuals. This new awareness of the benefits of a phenotypic approach to pelvic pain will enhance our understanding of the syndrome, encourage incorporation of new basic science and biomarker discoveries, and lead to a better individualized management strategy for CP/CPPS."

"Chronic Prostatitis/Chronic Pelvic Pain: The Disease"
Michel Pontari
"While I agree that on some level every patient is a unique individual, this can be said of any patient with a given disease. Not all diabetics are alike. However, overlap in biological presentations allows us to group them in recognizable patterns to enable treatment. The inconsistent response to treatment so far indicates that we are not yet able to accurately group patients into the correct subcategory associated with the correct treatment. This is what Nickel and Shoskes are proposing we do with the UPOINT proposal. How fitting that 2 men from Canada are putting snowflakes into recognizable groups that will allow us to better treat this disease."
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Re: Opposing Views: CPPS Syndrome or Disease

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I agree with neither, actually. Nickel says CPPS is"not due to any single known disease process." This is a terribly premature statement that pre-empts possible and even probably findings in the future. Neither man talks about trigger points, although Pontari gets close. I think Anderson and Wise are much nearer to the truth, in many respects.

Let me relate a personal anecdote: I have developed trigger points in my RHS upper chest and upper back muscles, simply from the tiny "holding" nervous tension that I am sending to my hand and arm to control my computer mouse. Over time, this seemingly insignificant electrical activity has caused pain so severe in my shoulder and chest that I was unable to sleep on my right hand side and unable to straighten my arm. Working on the clearly palpable trigger points in these muscles with a Theracane has *dramatically* eased the pain. This stuff is real, not fringe hocus-pocus!

It seems incredible, but simply sitting with your pelvis slightly tensed for long periods can cause tremendous pain. Until urologists accept that, we shall not make progress. UPOINT does have validity still, because there are many roads to this mildly elevated, abnormal and chronic neuromuscular tension, from anxiety/stress to "guarding" caused by infection or trauma. But at some point I believe there *is* a dovetailing into a common pathway, and the denial of this probability by Nickel is unwise at this stage.
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Dimdem
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Re: Opposing Views: CPPS Syndrome or Disease

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webslave wrote:I agree with neither, actually. Nickel says CPPS is"not due to any single known disease process." This is a terribly premature statement that pre-empts possible and even probably findings in the future.
I don't follow this, given that he says any single known disease process. That leaves open the possibility of a future discovery. Besides, the Stanford people freely admit that their approach doesn't work with everyone, if I recall correctly.
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Re: Opposing Views: CPPS Syndrome or Disease

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If you want to split hairs, the science behind trigger pt formation is a well-hypothesised disease process, although conventional medicine has only recently started to accept it. Nickel never heard about it when he was trained, of that you can be sure.

While Wise-Anderson admit their approach does not work with everyone, they also say that some (significant proportion of) people cannot apply the treatment properly. We have seen that here on many occasions, most typically in men who completely ignore the paradoxical relaxation side of treatment (which many say is more important than resolving trigger points). For myself, I also maintain food allergens have a role and may act as catalysts to trigger point formation or TrP-->mast cell effects in the GU tract.
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Re: Opposing Views: CPPS Syndrome or Disease

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For the other readers of this thread, here is the full exchange between Nickel and Pontari:
Dr Nickel writes:

FOR decades we have used a disease orientated approach to manage prostatitis based on the traditional concept that the condition was an infectious and/or inflammatory disease of the prostate gland. However, the recent literature is littered with well intentioned, well designed but essentially negative clinical trials evaluating antibiotics, anti-inflammatories and prostate centric therapies (a-blockers and 5-alpha-reductase inhibitors).1 We have recently proposed a different approach to chronic prostatitis/ chronic pelvic pain syndrome (CP/CPPS) based on the concept that these conditions represent a syndrome with variable but identifiable clinical phenotypes.

To be truly classified as a disease, we must determine a unified mechanism that causes the specific signs and symptoms associated with CP/CPPS. The various hypotheses include infection (cryptic or otherwise), genetic, anatomical, physiological, neuropathic, neuromuscular, endocrine, immune (including autoimmune) and psychological mechanisms. Each of these "theories" has not proven to cause all or even the majority of cases of CP/CPPS, but each has a solid theoretical basis, usually confirmation from animal model studies and at least some scientific or clinical validation in selected patients. I believe that although patients appear to have a similar end stage "syndrome" (or "disease" as suggested by Pontari in his view), we must accept that there is no 1 unifying mechanism that will explain all signs and symptoms. Rather patients in whom this condition develops likely have a genetic or anatomical abnormality that potentiates an initial triggering event (for example infection or trauma), and further mechanisms (including neurological mechanisms as proposed by Pontari) allow maintenance and/or promote progression of the condition into its chronic syndrome.

It is worth looking at those important "negative" randomized, placebo controlled, clinical trials (RCTs) again to determine if reinterpretation of the results can explain why some "disease specific" treatments that are not effective in clinical trials appear to benefit many patients suffering from the "syndrome" in clinical practice.2 For example, while antibiotics proved to be no better than placebo in multicenter RCTs, examination of the less chronic and/or heavily pretreated patients has shown that 50% to 75% have significant short and long-term symptomatic improvement.

The National Institutes of Health (NIH) sponsored RCTs evaluating a-blockers in heavily pretreated patients with CP/CPPS of long duration and in recently diagnosed patients with a-blocker naïve CP/CPPS showed no benefit with the active drug compared to placebo. Yet 4 RCTs with less stringent inclusion criteria clearly demonstrated improvement in men with CP/CPPS treated with various a-blockers compared to placebo. While trials assessing anti-inflammatories, pentosanpolysulfate, finasteride and pregablin were considered negative according to the primary end point, each of these therapies showed significant (or approaching significance) improvement according to validated secondary end points. These reevaluations of our presumed "negative" trials would suggest that some patients with a chronic prostatitis "syndrome" do respond favorably to these specific "disease" targeted therapies. Furthermore, it would be interesting to reflect on the results of these therapies in the many patients who were screened but not entered into these studies (more than 90% of screened patients with CP/CPPS patients were not enrolled in the 3 major NIH trials).

So what do these alternate interpretations of etiological mechanisms and treatment trial results mean to our CP/CPPS patients? I believe that not only do we have to accept that there is no 1 etiological mechanism that defines a specific disease process, but that our patients are a heterogeneous population of unique individuals with different triggers, maintenance mechanisms, symptom complexes and progression trajectories. In other words, each patient with this syndrome has a unique clinical phenotype, a hypothesis we call the "Snow Flake Hypothesis" (first coined by Pontari at the June 2008 meeting of the NIH sponsored Urologic Chronic Pelvic Pain Workshop). We recently described the 6-point (much like the 6 points of a snowflake) UPOINT (U for Urinary, P for Psychosocial, O for Organ specific, I for Infection, N for Neurologic/systemic and T for Tenderness of muscles) Clinical Phenotype classification system.3

The UPOINT system refers to 6 distinct, clinically relevant and identifiable domains, each of which is associated with potentially effective therapies. A description of these 6 domains and suggested associated therapies has been published previously, including an article in this issue of The Journal of Urology®.2–5 Subsequently we have validated the concept in patients being evaluated at chronic prostatitis4 and interstitial cystitis5 clinics. The percentage of CP/CPPS patients identified for each domain was 52%, 34%, 61%, 16%, 37% and 53%, respectively. Of the patients 22% were positive for only 1 domain while the others were positive for 2 to 6 domains. Duration of symptoms but not age was associated with the number of domains, while the number of domains was associated with symptom severity (phenotypic progression over time?). The domains outside the prostate (T) and particularly those outside the pelvis (P and N) were associated with the most impact on quality of life.

Our international multicenter research group is presently completing deep phenotyping studies in the psychosocial, infection and neurologic/systemic domains and case control studies to evaluate associated medical conditions, as well as developing a urologist friendly UPOINT phenotyping patient questionnaire. We are anticipating that the enormous resources that NIH has funded the MAPP (Multidisciplinary Approach to the study of chronic Pelvic Pain) program ($37.5 million) will result in a new understanding of mechanisms and development of specific biomarkers that will further allow subcategorization of the UPOINT domains. We have just initiated 2 UPOINT phenotypically directed real-life clinical practice treatment trials.

In conclusion, I believe that CP/CPPS is a syndrome diagnosed by recognizable signs and symptoms that are not due to any single known disease process. The CP/CPP syndrome is further characterized by clearly identifiable and distinct clinical phenotypes that can occur singly or more often together to define a heterogeneous population of truly unique individuals. This new awareness of the benefits of a phenotypic approach to pelvic pain will enhance our understanding of the syndrome, encourage incorporation of new basic science and biomarker discoveries, and lead to a better individualized management strategy for CP/CPPS.

J. Curtis Nickel
Department of Urology
Queen’s University
Kingston, Ontario, Canada

REFERENCES
1. Schaeffer AJ: Chronic prostatitis and chronic
pelvic pain syndrome. N Engl J Med 2006; 355:
1690.
2. Nickel JC and Shoskes DA: Phenotypic approach
to the management of chronic prostatitis/
chronic pelvic pain syndrome. Curr Urol Rep
2009; in press.
3. Shoskes DA, Nickel JC, Rackley RR and Pontari
MA: Clinical phenotyping in chronic prostatitis/
chronic pelvic pain syndrome and interstitial cystitis:
a management strategy for urologic chronic
pelvic pain syndromes. Prostate Cancer Prostatic
Dis 2009; in press.
4. Shoskes DA, Nickel JC, Dolinga R and Prots D:
Clinical phenotyping of chronic prostatitis/chronic
pelvic pain patients and correlation with symptom
severity. Urology 2009; 73: 538.
5. Nickel JC, Shoskes D and Irvine-Bird K: Clinical
phenotyping of women with interstitial cystitis/
painful bladder syndrome (IC/PBS): a key to classification
and potentially improved management.
J Urol 2009; 182: 000.

---------------------------------------------------------------
OPPOSING VIEW from Dr Pontari:

CHRONIC prostatitis was a disease 40 years ago. Bacterial infection in the prostate produced symptoms of urinary frequency, urgency and pelvic pain. Many men responded to antibiotics and those who did not were considered to have a persistent bacterial source in the prostate causing problems, and so were given more antibiotics. Since then we have gone through 2 classifications of prostatitis and have separated chronic bacterial prostatitis (category II) from chronic prostatitis/chronic pelvic pain syndrome (category III). We found that the bacterial localization studies for men with CP/CPPS were no different than those for age matched asymptomatic controls, and that most of the patients do not have inflammation on prostate biopsy. So the constellation of symptoms of pain in the perineum, testes, penis, suprapubic area, dysuria and with ejaculation went from being a disease to being a syndrome because we did not know the etiology.

CP/CPPS is now on its way back to being a disease. Given that the cardinal symptom of this condition is pain, it was logical to think that there are alterations in the central and/or peripheral nervous system causing the problem. Evidence from the last decade has begun to confirm what was once suspected. Animal studies have indicated that peripheral inflammation and injury from 1 site in the pelvis or perineum could result in central nervous system inflammation in the spinal cord, and an expanded field of pain and inflammation beyond the location of the original injury. A common scenario is an injury, infection or inflammatory process starting in 1 area in the pelvis that then becomes a more global pelvic process. We know now that the sacral cord appears to develop neurogenic inflammation from 1 peripheral source and then produces inflammation and pain in other pelvic areas.1

Two studies of patients from the University of Washington have since demonstrated neurological abnormalities. Men with CP/CPPS had hypersensitivity to thermal stimuli applied to the perineum compared to asymptomatic controls.2 In a followup study the same authors measured changes in heart rate variability after postural change and demonstrated different responses in the CP/CPPS patients compared to those of the controls.3 These 2 studies indicate abnormalities in the afferent and efferent nervous system of patients with CP/CPPS as well as indications of central sensitization.

Our current working model of CP/CPPS is that in men who are susceptible because of genetic predisposition or prior injury, an inciting factor such as infection, local trauma or even psychological stress results in alterations in the central nervous system and hyperexcitability of neurons in the dorsal horn. Normally nonpainful stimuli become painful (allodynia), normally painful stimuli become more painful (hyperalgesia) and the area of pain distribution expands beyond the area of the normal distribution of the affected nerves—in short, central sensitization.

Two other levels of complexity must be considered in the pathophysiology of CP/CPPS. The nervous system can be influenced by immune/inflammatory factors, endocrine abnormalities and even psychological factors.4 Alterations in all of these areas have been demonstrated in men with CP/CPPS. Given the extensive interplay between these domains it may be artificial to separate them into distinct organ or physiological systems. Neurons in the sacral cord co-localize with receptors for sex steroid hormones. Psychological stress can induce inflammation. CP/ CPPS could be called psycho-immuno-neuroendocrine dysfunction disease. Another level of consideration in the experience of pain is the social context. What is different from other purely neurological diseases such as stroke is that the pain experience must be put in a biopsychosocial context.5 Not all patients with identical biological alterations will have similar levels of pain. Not all patients with the same degree of pain will have the same deterioration in quality of life.

Nickel states that abnormalities have not been found in most patients. For the nervous system abnormalities indicating central sensitization, few patients have been tested. The current NIH sponsored MAPP initiative should provide further data to support the premise that this is a disease with more extensive testing of neuroimaging, biomarkers and genetics than has ever before been performed in a systematic manner. He also concludes that a single unified mechanistic cause must be present to be classified as a disease. Describing CP/CPPS as an abnormal neurological response to trauma perpetuated by alterations in psycho-immuno-neuroendocrine mechanisms with variable penetrance and presentation based on genetic and psychosocial factors does not mean that this is not a cause or mechanism. It is just not as simple as bacteria producing an episode of acute prostatitis. As with any disease, both cause significant morbidity.

While I agree that on some level every patient is a unique individual, this can be said of any patient with a given disease. Not all diabetics are alike. However, overlap in biological presentations allows us to group them in recognizable patterns to enable treatment. The inconsistent response to treatment so far indicates that we are not yet able to accurately group patients into the correct subcategory associated with the correct treatment. This is what Nickel and Shoskes are proposing we do with the UPOINT proposal. How fitting that 2 men from Canada are putting snowflakes into recognizable groups that will allow us to better treat this disease.

Michel Pontari
Department of Urology
Temple University School of Medicine
Philadelphia, Pennsylvania

REFERENCES
1. Ishigooka M, Zermann DH, Doggweiler R and
Schmidt RA: Similarity of distributions of spinal
c-Fos and plasma extravasation after acute chemical
irritation of the bladder and the prostate.
J Urol 2000; 164: 1751.
2. Yang CC, Lee JC, Kromm BG, Ciol MA and
Berger RE: Pain sensitization in male chronic
pelvic pain syndrome: why are symptoms so
difficult to treat? J Urol 2003; 170: 823.
3. Yilmaz U, Liu YW, Berger RE and Yang CC:
Autonomic nervous system changes in men with
chronic pelvic pain syndrome. J Urol 2007; 177:
2170.
4. Pontari MA and Ruggieri MR: Mechanisms in prostatitis/
chronic pelvic pain syndrome. J Urol 2004; 172: 839.
5. Nickel JC, Tripp DA, Chuai S, Litwin MS, McNaughton-
Collins M, Landis JR et al: Psychosocial variables
affect the quality of life of men diagnosed with
chronic prostatitis/chronic pelvic pain syndrome. BJU
Int 2008; 101: 59.
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