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NIDDK International Symposium: Frontiers in Painful Bladder Syndrome and Interstitial Cystitis. 26-27 October, 2006. Bethesda, USA

 

Health professionals and patient representatives from the USA and around the world converged on Bethesda on the outskirts of Washington DC to hear about the latest international scientific developments in the field of painful bladder syndrome and interstitial cystitis in this symposium organized by the NIDDK (National Institute of Diabetes and Digestive and Kidney Diseases/National Institutes of Health). It covered two intensive days and was a clear illustration of how much research is being done into this still enigmatic disease. Much emphasis was paid in this symposium to research into pain mechanisms and a new classification system based on types was presented by the European group ESSIC. Although a number of potential new treatments are currently being investigated, there is as yet no revolutionary new treatment available.

 

Session 1
Bladder and Painful Bladder Syndrome/Interstitial Cystitis, moderated by Lori Birder, with speakers Lori Birder, Jerry Apodaca, Jenny Southgate, Susan Keay, Kirsten Bouchelouche and Pedro Vera

 
This session focused on the bladder, urothelium and bladder wall. While in years gone by the bladder wall was considered to be relatively inert and the urothelium primarily a “barrier”, we now know that it is in fact a hive of microscopic activity on which any kind of trauma can have a kind of domino or chain reaction effect.

We learnt for example that:

  • The barrier function of the urothelium can be disrupted in a large number of pathologies.
  • While the urothelium is primarily an autonomous tissue, it interacts with other systems. It is important to understand this cross-talk. This requires collaboration by different disciplines.
  • Urothelial cells exhibit plasticity. Inflammation can alter the properties of these cells.
  • Following changes to the bladder, sensitization of bladder afferents may lead to alterations in neural transmission. In other words, a disruption of the nervous function. This could result in urgency and frequency.
  • A change in permeability of the urothelium, could allow irritant substances from the urine to pass into the bladder wall or cause release of neuroactive chemicals from the urothelium. This in turn could lead to changes in the excitability of afferent receptors in the mucosa.
  • Bladder nerves and urothelial cells share a number of common properties (neuronal-like).
  • Both “sensor” and “transducer” properties can be altered in pathology.
  • It is likely that the symptoms in a number of bladder pathologies are dependent on multiple types of interactions.
  • The uroepithelium, lining the renal pelvis, ureters and inner surface of the bladder, on the one hand forms an impermeable barrier while it also functions as an integral part of a “sensory web”.
  • The detrusor muscle could be a new target for drug therapy.
  • Urothelial ion channels, receptors and/or release mechanisms could be new targets for drugs to treat these conditions.

Many of the themes from this first session were echoed and further elaborated in later sessions on neurological and pain aspects of IC.

 

Session 2 
Epidemiology moderated by Philip Hanno with 5 speakers on Epidemiology studies underway: John Warren, Quentin Clemens, John McKinlay, Magnus Fall and Sandy Berry

 

Philip Hanno reviewed all the epidemiology studies worldwide to date, all with widely differing results, and emphasized that it would only be possible to achieve significant prevalence results from epidemiological studies if the patients were diagnosed on the same basis and the same international definition of IC. Epidemiology is beset with problems. There is a lack of a uniform definition of IC and lack of readily available diagnostic markers.
He ran through all the definitions and criteria to date, emphasizing that the NIDDK criteria were intended to form a basis for research studies and were never intended to be used by clinicians for diagnosis in clinical work because as was later shown in the IC Database study these criteria excluded a substantial percentage of patients with IC. However this is precisely what happened for many years simply because there was nothing else available to use as a basis for diagnosis.
According to Philip Hanno, we now need a validated diagnostic marker, we need evidence-based symptom-specific definitions, studies on true prevalence, incidence and risk factors and need to be able to differentiate IC from the myriad of other voiding dysfunctions with bladder pain.

Photo: Philip Hanno, MD

He explained that redefining IC would be complex and would have an:

  • Impact on how the diagnosis is made
  • Impact on economics of the disease
  • Impact on pharmaceutical companies
  • Impact on spending of research dollars
  • Impact on which kind of physicians or healthcare providers take care of these patients

There are currently several different groups around the world working on IC definitions, criteria and nomenclature: ESSIC (European Society for the Study of IC/PBS) in Europe led by Jorgen Nordling, SICJ (Society of Interstitial Cystitis of Japan) led by Tomohiro Ueda who organizes the ICICJ meetings, the Pan-Asian IC Association based in Taiwan led by Alex Lin and the International Association for the Study of Pain (IASP) with its special interest group Pain of UroGenital Origin (PUGO.).

There are many efforts currently underway in the field of epidemiologic studies, including the following.

 

John Warren discussed Sensitive, evidence-based case definitions of IC/PBS and the EPIC study (Events Preceding Interstitial Cystitis). His team speculated that a careful description of IC/PBS pain could contribute to an evidence-based case definition. A questionnaire mailed to each of 158 participants included three views of the female body: anterior, posterior and perineal. The participant was asked to shade and number the locations of her worst and any other pain. For each pain, the participant noted whether each of 16 events worsened, improved or had no effect upon each pain. They found that most patients had multiple locations of pain, the most common being suprapubic. 87% reported worsened pain with bladder filling, 85% with certain food or drink, and 39% during urination; 65% reported > 1 pain improved during/after urination. Use of the four pain characteristics generates criteria sets that capture > 90% of EPIC participants. Additionally, the most sensitive set (which captured 98%) also captured 95% of the 280 ICDB females who definitely had IC/PBS. So some of these criteria sets may contribute to sensitive case definitions for IC/PBS (i.e. that capture most of those with the disease). Specificity, the ability to exclude other diseases of similar symptoms, awaits comparison with different diseases. The speaker felt that the ICS definition was not sufficiently sensitive for epidemiologic studies.

 

Speaking on Epidemiologic studies of interstitial cystitis, Quentin Clemens stated that since there is as yet no objective marker to establish the presence of interstitial cystitis, studies to define the prevalence of incidence of the condition are difficult to carry out. These studies generally utilize one of three methods:
1. patient self-reported history
2. physician diagnosis
3. identification of symptoms that are suggestive of IC/PBS.
These different methods have resulted in the widely disparate prevalence estimates already referred to by Philip Hanno.

 

While inaccurate patient recall and confusion between IC and other forms of cystitis could lead to a degree of misclassification, many patients on the other hand never seek treatment and patient surveys show that patients may have symptoms for many years before a diagnosis is made. Prevalence could therefore be underestimated when a study depends on diagnosis by a doctor.

The BACH (Boston Area Community Health) survey results were the subject of John McKinlay’s talk on Epidemiology of Painful Bladder Syndrome/Interstitial Cystitis (Prevalence, Correlates and Quality of Life). The survey covered a random sample of 5506 adults. They have a database of over 100 symptoms. They found that the symptoms of PBS were more common in younger women and older men. He emphasized that there is a great deal of overlap of IC symptoms with the symptoms of other urologic conditions for both genders. He also underlined the importance of looking at the impact of IC on the quality of life in IC patients and the everyday burden on the patients’ lives. Impact on quality of life in IC is considerably higher than in heart disease or diabetes.

This session was followed by an energetic discussion on urgency in IC patients which made it very clear that more research is needed into the specific pain sensation in IC patients which makes them feel a recurrent or continuous urgent need to void. It was suggested by one questioner that no further refinement of definitions should take place until research produces more information.
The ICS, however, wishes to reserve the term urgency for urgency incontinence. This would mean that another term equivalent to “urgency” would need to be found for IC patients. After all, IC patients joining a patients’ organization receive a “Can’t Wait Card” to help them gain urgent access to public toilets.

 

Session 3
Different perspectives on PBS/IC was moderated by Philip Hanno with speakers: Thomas Chelimsky, Karl-Erik Andersson and J. Curtis Nickel

 

An Autonomic Neurologist’s Viewpoint was the title of Thomas Chelimsky’s interesting presentation in which he explained that it is increasingly being recognized that abnormalities of autonomic function are increasingly recognized as contributing to certain unexplained disorders such as irritable bowel syndrome, fibromyalgia and complex regional pain syndrome*. It is interesting that IC appears to have an association with some of these disorders which tend to be found in some of the same patients. IC may in fact be only one of an entire family of dysautonomias** which share a common predisposition to aberrant autonomic and sensory processing, usually in the setting of an environmental trigger. These disorders may also include migraine headaches, orthostatic intolerance and syncope (fainting).

* Complex regional pain syndrome (CRPS) is a chronic pain condition that is believed to be the result of  dysfunction in the central or peripheral nervous systems.
** Dysautonomias are conditions where the altered function of one or more components of the autonomic nervous system adversely affects health.

 

A Pharmacologist’s View of IC/PBS: Karl-Erik Andersson explained that our knowledge of the pathophysiology of PBS/IC is incomplete, and different mechanisms may be involved at different stages of the disease. The urothelium, mast cells, autoimmune mechanisms or infection have all been suggested as the source of the disease. However, we do not know which of the different factors involved are major players”, “minor players” or “innocent bystanders”. In particular the pain of IC is poorly understood, but is thought to be a complex entity including nociceptive, visceral and neuropathic components. Since the disease is multifactorial and the main mechanisms behind it are unknown, there is no single effective treatment and available options seem to be based more on trial and error than on scientific rationale. In order to improve pharmacological treatment of IC, it is essential to be able to define the “major players” in any individual at each stage of the disease. In order to be optimally effective, treatment will most probably be a combination of different drugs.

 

Sexual functioning in interstitial cystitis/painful bladder syndrome: a dynamic presentation by J Curtis Nickel who asked: Are we not essentially sexual beings? This is a fact that most urologists and other doctors managing patients with IC seem to have forgotten or ignored. “We carefully assess the pain, urinary frequency and urgency with religious zeal. Yet almost no major IC clinical trial or study in the last 2 decades has addressed the sexual issues of patients suffering from this major genitor-urinary pelvic disorder”. The quality of life of IC patients may be severely impacted by sexual problems related to their disorder about which patients are deeply concerned. There is also a lack of data on sexual functioning in chronic pain syndromes, despite strong signals that sexual functioning is important to patients and that pain has a negative impact. He believes that improving symptoms will improve sexual functioning.

Comment: IC patients will welcome studies and attention focused on this aspect. Sexual dysfunction through pain and urgency/frequency has a major impact on the quality of life of patients, both male and female.
 

Session 4
European opinion on PBS/IC characterizations, moderated by Jorgen Nordling, with speakers: Arndt van Ophoven, Magnus Fall, Kirsten Bouchelouche, Joop van de Merwe, Jorgen Nordling and Andrew Baranowski

 
Photo: ESSIC panel from left to right: Arndt van Ophoven, Magnus Fall, Kirsten Bouchelouche, Joop van de Merwe, Jorgen Nordling and Andrew Baranowski
 
Diagnosis and Standard Investigations for PBS/IC: Arndt van Ophoven explained that ESSIC (European Society for the Study of IC/PBS) published recommendations in 2004 for the diagnosis of IC and standard investigations. These included: medical history, physical examination, laboratory tests, symptom evaluation, urodynamics, revised potassium sensitivity test (optional), cystoscopy and morphological findings.
 
Cystoscopic and Morphological Findings in PBS/BPS/IC: Magnus Fall told us that, in the days of the IC pioneers Skene and Hunner, IC was considered to be a true inflammatory disease. It was later realized that patients may present with the same symptoms but without the typical signs of inflammation. Recently there has been a trend to base diagnosis on symptoms. This led to a need for a broader term than interstitial cystitis. Magnus Fall believes that it is essential to identify relevant PBS/BPS sub-categories in order to achieve progress in the search for etiology and pathogenesis and comparability between scientific studies. He is also of the opinion that good markers combined with endoscopy and histopathy could be used in the future to categorise sub-groups with greater precision.
 
Mast Cells in PBS/IC: Kirsten Bouchelouche outlined the ESSIC recommendations on morphology covering biopsies, including the number of biopsies, biopsy handling, mast cell counting and the pathology report.
 

ESSIC approach to the Design of Diagnostic Criteria in Confusable Diseases: Joop van de Merwe began by defining classification criteria: classification criteria separate patients with the disease from the general population and, more importantly, from patients with confusable diseases. For a diagnosis of PBS/IC, we need to both eliminate confusable diseases and also confirm the presence of PBS/IC as the main cause of the urinary symptoms, he explained. In other words, PBS/IC can in part be diagnosed by systematically excluding other conditions and in part diagnosed on the basis of findings from cystoscopy and if indicated biopsy. However, this does not exclude the possibility that a person with IC may also have a confusable disease as well. According to ESSIC: “The diagnosis of a confusable disease does not necessarily exclude a diagnosis of bladder pain syndrome”. For example: it is perfectly possible to have both IC and endometriosis.
This list of confusables can be found on the second page of the ESSIC consensus document, see: http://www.essic.eu/pdf/ESSICconsensus2006.pdf

The presence of a confusable disease can be eliminated by: medical history, physical examination, dipstick urinalysis, routine and special cultures, serum PSA in males >40 years, flowmetry and post-void residual urine volume measured by ultrasound scanning, cystoscopy with biopsy if necessary.
The problem with confirmation or positive identification is that no feature is unique to PBS/IC, but this problem is shared by many other diseases such as the systemic autoimmune diseases. He compared it to faces of people: none of the individual parts of the face is unique but the combination of these parts is unique. On the basis of the ESSIC definition, the “face” of PBS/IC comprises:

  1. the symptom of (chronic) pain related to the urinary bladder, accompanied by >1 other urinary symptom (“cystitis-like symptoms”;
  2. negative cultures for infectious causes and exclusion of other confusable diseases;
  3. cystoscopy with hydrodistension: glomerulation and/or Hunner’s lesions;
  4. histology: mononuclear inflammatory cells, detrusor mastocytosis, granulation tissue and/or intrafascicular fibrosis.

None are unique to IC but the combination is unique and can be recognised.

Conclusions were that:

  1. diagnostic criteria are necessary to distinguish PBS/IC from confusable diseases;
  2. diagnostic criteria do not require individual features to be unique but the combination of features to be unique;
  3. the diagnosis of PBS/IC should be based on the elimination of confusable diseases as the main cause of the urinary symptoms and confirmation of PBS/IC;
  4. elimination of confusable diseases is based upon medical history, physical examination, urinalysis, cultures, PSA, flowmetry, ultrasound scanning and cystoscopy (and biopsy if indicated);
  5. confirmation of PBS/IC is based on the findings of cystoscopy with hydrodistension and biopsies if indicated.

Further information on definitions, confusable diseases and diagnostic procedures as recommended by ESSIC can be found in:
Nordling J et al. Primary evaluation of patients suspected of having interstitial cystitis (IC). Eur Urol 2004;45:662-9.
Van de Merwe JP, Nordling J. Interstitial cystitis: definitions and confusable diseases. ESSIC Meeting 2005 Baden. Eur Urol Today; March 2006: pp 6,7,16,17

Comment: Bearing in mind that many of the standard investigations and exclusion tests are not being carried out in many countries due to the high cost, it is clear that someone somewhere has to design a package of affordable but comprehensive investigation and exclusion tests that can be used worldwide, including in the developing world and countries where patients have to pay for all their medical investigations and treatment themselves. Without thorough screening, some patients may be receiving the diagnosis of IC when they in fact have another treatable and curable condition.

 
New ESSIC classification system based on types
Jorgen Nordling (Founder and President of ESSIC) then presented the new ESSIC definition and classification system. He said that ESSIC had decided to take a new approach to classifying and defining the disease. First they reached consensus in 2004 on standardized investigational procedures. The next step was to examine all possible confusable diseases which would need to be excluded and agree on a standard list. They then focused on positive findings.

Name change
He explained that ESSIC had decided no longer to use the name interstitial cystitis, but instead the name bladder pain syndrome (BPS) in accordance with IASP taxonomy for pain syndromes, followed by a type indication.

According to the ESSIC consensus: The diagnosis of BPS will be made on the basis of the symptom of pain [now proposed to change this to “chronic pain”] related to the urinary bladder, accompanied by at least one other urinary symptom such as daytime and night-time frequency, exclusion of confusable diseases as the cause of the symptoms and cystoscopy with hydrodistension and biopsy if indicated.

Because it is widely felt that cystoscopy and bladder morphology provide important information, it was decided to make a classification including findings such as glomerulations and Hunner’s lesion* during cystoscopy and hydrodistension and inflammatory or other changes at morphological investigation of bladder biopsies.

*ESSIC decided to change the name Hunner’s ulcer to Hunner’s lesion since this is not a true ulcer but a vulnus.

Comment: as you can see, the symptom of urgency has been omitted by ESSIC. It is felt, however, by patients that further discussions should be held concerning this aspect of IC which is of great importance to the IC patient.

 

ESSIC Classification

The following classification system was developed by ESSIC based on typing symbols.
The BPS type indications will consists of two symbols: the first symbol corresponds to cystoscopy with hydrodistension and the second to biopsy:

  1. first symbols 1, 2 or 3 indicate increasing grade of severity at cystoscopy with hydrodistension
  2. second symbols A,B or C indicate increasing grade of severity of biopsy findings
  3. X indicates not done for both (see table below)
 

ESSIC Classification of bladder pain syndrome (BPS) types

 

 

cystoscopy with hydrodistension

 

 

 

not done

normal

glomerulations(1)

Hunner's
lesion(2)

biopsy

not done

XX

1X

2X

3X

normal

XA

1A

2A

3A

inconclusive

XB

1B

2B

3B

positive(3)

XC

1C

2C

3C

© ESSIC 2006 www.essic.eu 
  1. cystoscopy: glomerulations grade 2-3
  2. with or without glomerulations                                     
  3. histology showing inflammatory infiltrates and/or detrusor mastocytosis and/or granulation tissue and/or intrafascicular fibrosis.

This table is reproduced courtesy of ESSIC. (ESSIC Consensus, www.essic.eu)

Why change the name?
It fell to Andrew Baranowski (pain consultant from the United Kingdom) to provide an explanation as to why it had been decided to change the name yet again [the name “painful bladder syndrome” (PBS) was presented as the new umbrella term at the ICI consultations only 2 years ago in Monaco in June 2004 by the ICI Committee on Painful Bladder Syndrome].

In his presentation entitled “PBS/IC in context of pain syndromes – Fitting it in”, Andrew Baranowski explained that the name “bladder pain syndrome” (BPS) comes from the IASP Taxonomy Group which he chairs. IASP is the International Association for the Study of Pain (www.iasp-pain.org) which has a special interest group on Pain of UroGenital Origin (PUGO). The name BPS is in line with the terminology for other conditions such as urethral pain, vulvar pain etc. In other words in the sequence: organ + pain + syndrome. ESSIC has agreed with this.

Why was it felt to be necessary by ESSIC to do away with the historic name interstitial cystitis? The reasons given by the ESSIC presenters included the following:

  1. Many doctors have been unhappy for some time with the name interstitial cystitis.
  2. The term means inflammation of the interstitium of the bladder wall; however, not all patients with IC actually have signs of inflammation in the bladder wall.
  3. In some countries, however, many patients are excluded from a diagnosis if they do not show signs of inflammation.
  4. Since pain is considered to be a compulsory element of this disease, the name bladder pain syndrome was considered by ESSIC to be more appropriate than interstitial cystitis.

This ESSIC session was followed by a lively and sometimes emotional debate, with the patient organizations quite naturally feeling that they had been presented with a fait accompli and had been unable to participate in decision-making concerning an issue with a very major impact on both the patient support groups and the patients themselves. They felt that attention should also be paid to the practical consequences in the coming years resulting from the ESSIC decision to change the name.

While the original intention of ESSIC was to change immediately to using BPS only and drop the name interstitial cystitis completely, following the deep concerns expressed by the patient organizations with regard to the potential major impact on the patient organizations and patients over a period of years, ESSIC is now considering using BPS/IC in a transitional period. It has not, however, been stated exactly how long this transitional period will be. See the latest version of the consensus document on the ESSIC website: http://www.essic.eu/pdf/ESSICconsensus2006.pdf. This will be updated as changes are made.

Although this outline consensus document has in fact been available to everyone on the ESSIC website for some months, it was nevertheless clear that many symposium delegates had not yet seen it. The ESSIC website can be found at www.essic.eu and it may be advisable to keep a close eye on it from now on to follow developments! It is to be hoped that in the future all parties concerned with PBS/IC (BPS) will be involved in discussions and developments.
 
See ESSIC presentation abstracts: www.essic.eu/pdf/ESSIC_Presentations.pdf
 

Session 5
Advances in research on sensory processing moderated by William de Groat. Speakers: Alan Randich and Jyoti Sengupta

 
Inflammation and visceral afferent activity: Speaker William de Groat made it clear that while much research is ongoing into neurological mechanisms behind IC, very many questions still remain unanswered. Bladder pain requires more than just the bladder and is a complicated process involving the brain, spinal cord and peripheral nerves. Dysfunction can cause urgency, frequency, pain and incontinence. There are clearly different pain components, maybe even with the additional of a pain component from other organs. This multifactorial pain mechanism may be the reason why neuromodulation doesn’t always work.
 
Bladder pain and overactivity occurring in different disorders have been attributed in part to sensitization of bladder afferent nerves. Recent studies have revealed that the urothelium has specialized sensory and signaling properties that allow urothelial cells to respond to their chemical and physical environment and to engage in chemical communications with neighbouring afferent nerves. It is believed that there is a possibility that enhanced signalling between the urothelium and afferent nerves is involved in the triggering of painful bladder sensations. On the other hand, activation of P2Y purinergic receptors on capsaicin-sensitive afferent neurons suppresses excitability. Consequently, purinergic transmitter mechanisms might have both nociceptive and antinociceptive functions.
 
Early-in-life bladder inflammation and interstitial cystitis: this presentation by Alan Randich concerned studies into whether neonatal and/or adolescent exposure to bladder inflammation predisposed female rats to increased bladder hyperalgesia when exposed to bladder inflammation as adults. The results from the studies were consistent with the view that bladder hyperalgesia resulting from bladder inflammation reflects the net effect of two opposing processes: enhanced nociceptive input from the bladder and opioid inhibition, both triggered by bladder inflammation.  He suggested that experience with neonatal bladder inflammation may predispose an organism to adult bladder pain by impairing the development and/or expression of an opioid inhibitory system. He and his team believe that neonatal exposure to painful bladder events may be an important factor to the development of various types of adult bladder pain, including PBS/IC. In other words: early exposure to bladder inflammation may predispose people to develop IC when later exposed to any kind of insult.
 
Neurophysiology of bladder pain sensation: Speaking on bladder sensations, Jyoti Sengupta explained that the main sensations arising from the bladder are a sense of fullness, an urge to void, discomfort and pain. These sensations are conveyed to the central nervous system via two sets of autonomic nerves: hypogastric and pelvic nerves. The integrated activities of these two nerves regulate bladder function. The results of a recent study indicated that acute bladder irritation can induce desensitization of response via TRPV1 channel activation. He concluded that the pelvic nerve afferent fibers play a major role in pain arising from the bladder and that these fibers undergo changes in response
 
Session 6
CNS involvement in PBS/IC: moderated by Tony Buffington. Speakers: Emeran Mayer, Jon Levine, Ken Peters
 
Central changes in interstitial cystitis and related disorders. There is steadily increasing interest in the neurologic relationship and cross-talk between different pelvic organs. Emeran Mayer proposed that both irritable bowel syndrome (IBS) and IC (as well as other functional pain disorders) share abnormalities in the corticolimbic modulation of the homeostatic afferent processing network, resulting in central pain amplification.
 
Role of the autonomic system. Jon Levine, rheumatologist, spoke about the overlap between pain syndromes including the subset of generalized pain syndromes, some of which may be primary and some secondary. These include: fibromyalgia syndrome (FMS), chronic fatigue syndrome (CFS), irritable bowel syndrome (IBS), functional dyspepsia, temporomandibular disorders (TMD), post-infection, acute infection (mono), post-operative, sick building syndrome, repetitive stress syndrome, Gulf war syndrome, radiation therapy syndrome, post-surgery syndrome, clinical toxicity of interferon (and others), overtraining syndrome and many others. It is important to closely examine this overlap if we are to understand the pathophysiology and pathogenesis of these mechanisms. Three conditions that are commonly found together are fibromyalgia, IBS and IC. Patients with very intense symptoms in one of these disorders are more likely to report symptoms of one or more of the other disorders. He emphasized that these conditions may have a very great impact on the quality of life of these patients. Studies undertaken with animals examined for example the effects of stress.
 
Neuromodulation for the treatment of PBS/IC: Kenneth Peters, who together with his team has extensive experience in the field of neuromodulation, reviewed the literature on the use of sacral neuromodulation for the treatment of IC and discussed other approaches to neuromodulation, including pudendal nerve stimulation and tibial nerve stimulation, as well as new neuromodulation devices. The new Interstim generator is about half the size of the original generator and all procedures are greatly improving. Use of neuromodulation has been shown to lead to a reduction in narcotic use with some patients stopping altogether. But it should be emphasized that neuromodulation doesn’t help everyone. He described a study using two leads, one for sacral nerve stimulation and one for pudendal nerve stimulation with good results for pudendal nerve stimulation. He also reviewed the Bion device. This is a rechargeable battery-powered microstimulator for pudendal nerve neuromodulation and is still investigational in the USA.
 

Session 7
Pain and PBS/IC: moderated by Tim Ness, Speakers Roger Fillingim, Tim Ness, Ursula Wesselmann, Karen Berkley

 

Genetics of pain susceptibility. In this presentation by Roger Fillingim, we learnt that there is huge variability in pain reponses in individuals and that there is considerable evidence to suggest that genetic factors contribute to these differences. Some patients will respond very strongly to a specific dose of an opioid, while others will have a very low response to the same dose. The speaker emphasized the importance of incorporating genetic findings into the biopsychosocial model of pain. Environmental factors may also make a significant contribution to pain response. Biological, psychological and sociocultural factors may all influence the way a person responds to pain.

Afferent hypersensitivity in IC patients. Tim Ness posed the question: IC patients have a hypersensitive bladder, but is it possible that they are hypersensitive in other parts of their body?  Many patients have been shown to have multiple pain disorders such as fibromyalgia and irritable bowel affecting different parts of the body. Sensation is a balance between afferent excitation and central inhibitory mechanism Recent studies suggest that a contributing mechanism leading to hypersensitivity may be inadequate endogenous inhibitory systems.
Conclusions gained from his studies of IC subjects were:

  • Hypersensitivity of the bladder in IC subjects
  • Hypersensitivity of deep tissue structures in relation to controls
  • One source of the hypersensitivity may be a failure of endogeonous inhibitory systems
  • Menstrual cycle effects are apparent
  • Humans with IC form two groups: total body increased sensitivity and bladder selective sensitivity; the latter recalled early-in-life UTIs.

Treatment of non-malignant pain. Ursula Wesselmann reminded everyone that pain has always been a very prominent feature of interstitial cystitis. It has also become a more prominent feature of scientific programmes at NIDDK symposiums.

Pain is classified into three categories:

Superficial Pain:
Stimulation of cutaneous structures

Deep pain:
Stimulation of muscle, fascia, joints, bone, vasculature, viscera

Neuropathic pain:
Disturbance of function or pathological change in a nerve

 

She explained that IC falls under the heading of deep pain. Many patients with IC have multiple kinds of uro-gynaecological pain (e.g. IC and vulvodynia; IC and prostatodynia).

She also emphasized that a chronic pain seldom comes alone. IC shares many characteristics with other chronic visceral pain syndromes, and it has been hypothesized that IC should be considered as a chronic non-malignant visceral pain syndrome. Chronic pain leads to a greatly impaired quality of life. Optimal treatment is therefore of major importance.

The goal of pharmacotherapy is to find a medication that produces significant pain relief with minimal side effects for an individual patient. She explained that it is difficult to know which medication to use since few studies have been done on treatment of pain in IC patients. Studies so far have mainly concerned neuropathic pain or post-herpetic pain. There are no analgesics specifically for the treatment of interstitial cystitis.

It is therefore usually a question of trial and error, an adequate trial of the given medication, only titrating one drug at a time, monitoring the effects of a drug on different aspects of pain, starting with the smallest dose available and titrating at frequent intervals. The different underlying pathogenetic mechanisms may require different treatments strategies in different patients. It is not likely that we will have one drug that will be beneficial in all patients with IC. One patient may require several different pain treatments to treat different types of pain. She added that it is important to start pain treatment at the earliest possible stage so as to try to prevent the patients from developing multiple pain syndromes.

 

A very useful pain treatment chart can be found in the following book:
Evaluation and Treatment of Chronic Pain, G.M. Aronoff, Ed. Pages 269-279 Management of Chronic Pelvic Pain by U. Wesselmann. 3rd Edition, Williams and Wilkins, Baltimore, MD, 1998.
An interesting and thought-provoking question she raised was: why do some patients never develop more than one pain syndrome (i.e. IC) while other patients develop multiple pain syndromes? And do these groups of patients need to be treated differently?

Cross-system viscero-visceral interactions: what is the source of PBS/IC symptoms.
Karen Berkley spoke on this very interesting topic in relation to 2 rat model studies carried out by her team. Her first question was: what is pain exactly? She quoted the IASP definition: “An unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage.” This definition avoids tying pain to the stimulus and includes emotional experience. However pain may also be described as an alarm, or call to action. Referring back to an earlier speaker, she suggested that perhaps we should look at IC as a pain syndrome affecting the whole body.
A wonderful table for all kinds of treatments for pain: drugs, somatic and situational, was shown which she has very kindly given us permission to reproduce below.

This table has been adapted from the two following publications:
1. Berkley KJ. On the dorsal columns: translating basic research hypotheses to the clinic. Pain 1997;70:103-107.
2. Berkley, K.J. and Holdcroft, A. Sex and Gender Differences in Pain. In: Wall, P.D. and Melzack, R. (eds) Textbook of Pain, 4th ed, Edinburgh: Churchill Livingstone, 1999, Ch 41, 951-965.

With thanks to Karen Berkley PhD, Florida State University, for her kind permission to reproduce this table.
 
 

She emphasized that treatment should comprise individualized combinations from the above table and that we should not think in terms of either/or, but rather in terms of combinations tailored to the individual patient.

Mechanisms underlying both the chronic pelvic pain and urinary urgency/frequency symptoms of PBS/IC, as well as its co-occurrence with other distressing conditions such as endometriosis, are poorly understood. And this of course once again underlined that when doing diagnostic procedures for IC and excluding confusable diseases, it should be remembered that it is possible for a patient to have both IC and a “confusable” such as endometriosis.

She suggested we should draw a distinction between the source of the bladder pain and the source of the bladder inflammation when looking for the cause of the symptoms.

Karen Berkley’s study findings suggest that the central nervous system provides a dynamic, hormonally modulated substrate by which pathology of other nearby and remote organs. Some of the symptoms and signs of PBS/IC may represent a manifestation of this central process.

 
Session 8
New considerations in PBS/IC treatments. Moderated by Michael Chancellor. Speakers: Mary FitzGerald, Jurjen Bade, Naoki Yoshimura, Tomohiro Ueda, Michael Chancellor
 

Recognizing and treating pelvic floor dysfunction in PBS/IC patients. Speaking on the topic of Urologic Pelvic Pain Syndromes (UPPS), Mary FitzGerald said that these patients almost always display some tenderness of the pelvic floor and/or abdominal wall musculature. An NIH-NIDDK funded pilot randomized study of physical therapies for treatment of UPPS is due to start this year and should produce valuable information.

Current status of intravesical treatments for PBS/IC. Jurjen Bade, who recently emigrated from the Netherlands to sunnier climes in Curaçao, explained the advantages of intravesical treatment as follows:

  • It works directly on the bladder
  • It is in line with theories of urothelial dysfunction as a cause of PBS/IC
  • Many PBS/IC patients fail to respond to oral treatment
  • Many PBS/IC patients are multi-allergic, including to many types of oral medication. Intravesical treatment is often better tolerated with fewer side effects.

It should be considered as a second line treatment after oral medication has been tried, but before any surgical treatment is undertaken.
It is very difficult to measure efficacy since studies may have too few patients to be statistically significant. When treating patients, a specific intravesical treatment may work miraculously in one patient, but not work at all in another. This is a big problem for the clinician. However, the attitude of the urologist to the patient also plays a not insignificant role: a nice understanding doctor may well have much better results. Studies have shown that there may be a substantial placebo effect in treatment of OAB patients and the same applies to IC. Studies are particularly necessary to show whether drugs are truly effective when used generally, or whether they are only effective in the hands of a specific doctor.

There is often a difference between the results of scientific studies and clinical practice. Two examples of treatments in this category are Hyaluronic acid and Resiniferatoxin which produced no significant level of efficacy in scientific studies, but in clinical practice are known to be very effective in treating some patients.

He gave a list of instillations used in his own practice with potential beneficial effect and little risk of side effects.

  • DMSO to try in newly diagnosed PBS/IC patients.
  • Pentosan polysulfate (300 mg), Heparin (20,000 U) or Hyaluronic acid (40 mg) instillations if pain is the most dominant symptom.
  • Oxybutynin (10 mg/50 cc) if frequency is the most dominant symptom.
  • A cocktail of pentosan polysulfate (300 mg) + lidocaine (10% - 2 cc) + bicarbonate (4.8% - 10 cc) as a single instillation in case of exacerbation.
  • New: Resiniferatoxin (0.1 μM) as a single instillation, if others do not help.

He concluded by saying that there is no breaking news yet and that it is a question of trial and error to find a treatment that suits a specific patient. He stressed that it is important for the urologist to be honest with the patient about what he can do and what he can’t do.

Gene therapies for PBS/IC. Naoki Yoshimura discussed studies to examine the feasibility of gene therapy, which can transfer genes of endogenous opioid peptides using replication-deficient herpes simplex virus (HSV) vectors or gene-gun methods, for the treatment of bladder pain. Results of the studies indicate that: (1) using the gene-gun methods, POMC (pro-opiomelanocortin) or PPE (preproenkephalin) genes can be transferred in the bladder and that subsequent increases in expression or endorphin or enkephalin, respectively, in the bladder can suppress nociceptive responses such as urinary frequency induced by bladder irritation; and (2) enkephalin gene therapy using HSV-PPE was effective in suppressing bladder pain responses in both behavioural and functional studies. This supports the potential clinical application of the POMC or PPE gene therapy for the treatment of bladder pain and urinary frequency associated with PBS/IC.

Update on IPD-115IT. Tomohiro Ueda gave delegates an update on IPD-1151T (suplatast tosilate) clinical trials. IPD-1151T is an oral anti-allergic drug, approved in 1995 in Japan for the treatment of bronchial asthma, atopic dermatitis and allergic rhinitis. Since then more than 2 million patients have received this drug. It is classified as a Th2 cytokine inhibitor and specifically suppresses the production of IgE antibodies by inhibiting the production of interleukin 4 (IL-4), a cytokine produced by Th2 cells. Moreover, IPD-1151T has been found to suppress the production of IL-5, which is also produced by Th2 cells and is known as a potent differentiation/migration factor for eosinophils and involved in allergic inflammation. Currently planned are two studies in Japan and the EU/US for the investigation of the efficacy of this drug on PBS/IC as well as changes in a variety of urine markers, and the study results are expected to provide useful information on the pathology of PBS/IC. This drug was also described by Michael Chancellor as the most promising new oral treatment today.

Novel therapies for PBS/IC. Michael Chancellor presented new data on research into three new, promising therapies for PBS/IC:
  1. Use of cannabinoids
    Identifying compounds that are safe and effective in treating pain is a major challenge.
  2. Bladder botulinum toxin injection
    Studies have examined whether botulinum toxin has any effect on conditions of chronic inflammation and pain.  In studies with IC patients, 69% obtained significant improvement in frequency and bladder pain.
  3. Bladder coating with liposomes.
    Liposomes are artificial spherical vesicles consisting of an aqueous core enclosed in one or more phospholipids layers (i.e. fat bubbles filled with water), used as drug carriers and loaded with a great variety of molecules. It has been reported earlier that liposomes can form a film on cell surface and have been tested as possible therapeutic agents to promote wound healing. It was suggested that liposomes might enhance the barrier properties of a dysfunctional uroepithelium and increase resistance to irritant penetration by adhering to the surface of the bladder.

For more information about the above, take a look at the Pittsburgh University Cure-IC website: http://mediasite.cidde.pitt.edu. An excellent website for both patients and professionals with five speakers including Michael Chancellor who explains new research directions for IC.

The scientific programme was rounded off with a panel discussion on future research ideas and perspectives

The symposium ended with addresses by three of the symposium sponsors: Dr Vicky Ratner speaking on behalf of the ICA and Loredana Nasta on behalf of the Italian AICI and MICA both emphasized their deep concern regarding the potentially major impact of the name change on the patients and patient organizations, while Jane Meijlink speaking on behalf of the International Painful Bladder Foundation made a plea for international cooperation and consultation between all parties involved in PBS/IC.

 
Abstracts and Poster Session
 

79 abstracts were selected for posters at this NIDDK symposium. Four of these abstracts were chosen by a panel of judges as top abstracts and presented with travel awards.

Our own abstract on the Patient Survey on Nomenclature and Definition of Painful Bladder Syndrome/Interstitial Cystitis and the Nature of Urgency in PBS/IC Patients was also selected for this NIDDK poster session and proved to be very topical, bearing in mind some of the scientific presentations concerning urgency and nomenclature! A link to the abstract and poster can be found on the home page of www.painful-bladder.org. A more detailed report will follow shortly.
We would like to take this opportunity to thank all the patients who participated in the survey and made this possible.

We would like to express our sincere thanks to the NIDDK and the organizing committee for this excellent stimulating and thought-provoking symposium.

Photo: Jane Meijlink (Chairman IPBF) and Florentina Ferreyra (President of the Mexican patient support group and IPBF board member) in front of the Patient Survey poster.
 
Jane Meijlink

 

 

The IPBF endeavours to ensure that all information it provides is correct and accurate, but does not accept any liability for errors or inaccuracies.

The International Painful Bladder Foundation (IPBF) does not engage in the practice of medicine. It is not a medical authority nor does it claim to have medical knowledge. The IPBF advises patients to consult their own physician before undergoing any course of treatment or medication.

updated 20.04.2007 10:50 © 2006-2014 - International Painful Bladder Foundation (IPBF). All rights reserved.