STUDIES

Interstitial cystitis or bladder pain syndrome is a frustrating symptom complex for both the patient and the clinician. Classic Hunner’s lesion interstitial cystitis is clearly a bladder disease and treating the bladder improves symptoms. Non-Hunner’s lesion interstitial cystitis or bladder pain syndrome likely has multiple aetiologies and in many cases the bladder is an innocent bystander in a bigger pelvic process. For many years, non-Hunner’s lesion interstitial cystitis has been treated with bladder-directed therapies, with poor overall outcomes.

Many patients are overwhelmed and burdened by the disease, especially after failing therapies directed at their bladders. HLIC is a bladder disease, responds to bladder directed therapy, and should be considered a separate disease from N-HLIC/BPS. A multidisciplinary approach is crucial for success in treating N-HLIC/BPS. It is critical to carefully phenotype these patients, identify pain triggers, and direct therapy towards these triggers. A hypertonic pelvic floor is often overlooked during the evaluation of a patient with symptoms suggestive of IC/BPS. In the authors’ opinion, identifying and treating PFD with physical therapy, trigger point injections, pudendal nerve blocks, integrative medicine treatments, psychological support, and neuromodulation offer the best success in the management of the refractory IC/BPS patient.

The bladder is often an innocent bystander in a bigger pelvic process. It is time to think beyond the bladder!

 

In this study, we examined the influence of psychological stress on artemin levels, bladder hyperalgesia and properties of the primary afferent neurons.


Chronic stress plays a substantial role in the development, maintenance and enhancement of functional bladder disorders including painful bladder syndrome/interstitial cystitis (PBS/IC). Studies have shown that more than half of patients with PBS/IC report daily or constant pain and urinary frequency, which are exacerbated by stressful circumstances. In fact, patients tell their physicians that stress plays a major role in their symptom flares. However, the mechanisms underlying the relationship between stress and hypersensitivity of the urinary bladder are not well understood. Altered levels of neurotrophins have been correlated with bladder hyperexcitability and pain.

These findings indicate for the first time that artemin levels exhibit a pattern that correlates with the duration of the physiological stress. Artemin increases in early phases of stress (e.g. 1-6day WAS) and decreases with ‘chronic’ stress (10day WAS). We find that decreasing artemin levels partially mitigated visceral hyperalgesia which supports the view that an early increase in artemin could sensitize nociceptive afferents, contributing to acute pain. Because recent findings show that many IC patients are high stress responders, these findings may represent an underlying mechanism for exacerbation of IC pain during flares.

Chronic stress triggers a number of changes that ultimately can exacerbate or predispose to disease such as PBS/IC. These novel findings support the concept that stress can alter levels of the neurotrophic factor artemin, which can impact the expression and/or function of nociceptive TRPA1 channels and contribute to visceral sensitivity and pain. Thus, fluctuations in artemin levels with progression of stress-induced cystitis may correlate with neuronal sensitization and aberrant signalling in the periphery and spinal cord. From a clinical perspective, these experiments provide important insights regarding an appropriate window for treatment. For example, intervening with anti-artemin treatment during the initial ‘acute’ state may prevent neuronal changes, but if this treatment is administered at a later stage it may be deleterious. At later chronic stages, increasing artemin levels and/or activating artemin intracellular pathways may be beneficial. Manipulation of artemin expression and/or signalling pathways may therefore offer a new pain treatment strategy for PBS/IC patients.

 

The bladder microbiome, bacterial infection, inflammation, and urothelial permeability contribute to the development of peripheral afferent hyperexcitability that is fundamental to the development of frequency and urgency in OAB, and pain in IC/PBS. In addition, the higher psychological stress levels, increased prevalence of anxiety and depression, as well as clinical co-morbidities with other visceral pain disorders suggests pathological plasticity within the CNS is an important component in the mechanisms underlying both OAB and IC/PBS. Determining the underlying mechanisms of bladder hypersensitivity is paramount to providing novel targets for the development of safer and more efficacious treatments.

 

The AUA guidelines have mapped out a stepwise fashion to treat IC/BPS; at our institution we separate patients with HL IC from those with N-HL IC/BPS prior to them entering a treatment pathway. We identify the rarer patient with HL as having classic ‘IC’; this cystoscopic finding is critical in guiding treatment. We believe HL IC is a distinct disease from N-HL IC/BPS and therapy should focus on the bladder. The vast majority of patients with N-HL IC/BPS need management of their pelvic floor muscles as the primary therapy, complemented by bladder-directed therapies as needed as well as a multidisciplinary team to manage a variety of other regional/systemic symptoms. Ongoing research into IC/BPS will help us better understand the pathophysiology and phenotypes of this complex disease while exciting and novel research studies are developing promising treatments.

 

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