Painful Conditions of the Lower Urinary Tract and Bladder

Painful Conditions of the Lower Urinary Tract and Bladder

Kristina Cvach

Anna Rosamilia


Painful conditions of the bladder and urethra fall under chronic pelvic pain syndrome (CPPS) as outlined in the International Association for the Study of Pain taxonomy document.1 In general, these conditions present with persistent or recurrent pain that the patient attributes to the bladder or urethra with no identifiable local pathology as the causative agent. Although peripheral mechanisms exist, central nervous system neuromodulation may be more important and systemic disorders such as fibromyalgia, irritable bowel syndrome, or chronic fatigue syndrome may also be present.2 As in most chronic pain states, there is an association with emotional, behavioral, and sexual dysfunction.

Although diagnosis and management of CPPS is challenging, much can be achieved by employing the primary principles of pain management: education; psychological support; and physical, medical, and complementary and alternative medical (CAM) therapies. Using multiple strategies and working across craft groups, to provide multimodal and multidisciplinary management, provides optimal care of the patient with chronic pain.


Bladder pain syndrome (BPS) is a condition characterized by pain attributable to the bladder. Although at least one other bladder-related symptom (urinary frequency/nocturia and/or urgency) is required to define the syndrome, pain perception is always the primary complaint. The use of the word syndrome connotes that pain is the disease process where the role of the nervous system in generating the sensations is pivotal. Patients may have difficulty describing their symptoms and not always report the presence of pain. The use of the word pain has many cultural overtones; for instance, in Japan women would rarely volunteer the symptom of pain.3 Other descriptors used may be pressure, discomfort, burning, or a constant awareness of the bladder. The urinary frequency is driven by fear of pain or discomfort, not of incontinence; this is a key difference with overactive bladder syndrome. Patients often describe increasing pain/pressure with bladder filling and relief, albeit temporary, with voiding; however, many patients will also describe dysuria or increasing pain after voiding.

It is important to exclude other conditions with overlapping symptomatology such as urinary tract infection, overactive bladder syndrome, urethral diverticulum, or underlying bladder pathology such as malignancy. The duration of symptoms needed to be classified as BPS varies according to different guidelines. The American Urological Association (AUA) only requires 6 weeks of symptoms in an effort to institute treatment in a timely fashion.4 The European Association of Urology (EAU) and the European Society for the Study of Bladder Pain Syndrome/Interstitial Cystitis (ESSIC) define the condition if there has been persistent or recurrent pain over 6 months, in an effort to capture those patients with fluctuating symptoms.5,6 However, there is an absence of evidence to support either definition of BPS based on duration of symptoms. This has prompted the most recent publication from the International Consultation on Incontinence (ICI) Committee to suggest that the duration of symptoms required to diagnose the chronic condition be up to the discretion of the clinician and patient.7

Interstitial cystitis (IC) was first described by Skene8 as an inflammatory condition destroying the mucous membrane of the bladder, but over the last two decades, the nomenclature has changed to reflect a broader symptom complex defined as BPS which is not necessarily associated with histologic changes. A full description of the historical changes in terminology is beyond the scope of this chapter but can be found in the ICI BPS document.7 In 1915, Hunner described a bladder ulcer, now termed Hunner lesion (HL), identified at time of cystoscopy in patients with frequency and bladder pain. HL, although initially thought to have a prevalence rate of 5% to 10% of BPS patients, has also been reported with prevalence rates of up to 57%.9,10 The appearance is of patches of red mucosa and small vessels radiating to a central pale scar, which
ruptures following bladder distension. Ronstrom and Lai11 have recently published an atlas of HL which is useful in identifying the variations in appearance of HL. Fall et al.12 described BPS as a heterogenous syndrome comprising two main categories: ulcerative and nonulcerative. The term interstitial cystitis is now reserved for those patients who have mucosal (HLs) and histologic (evidence of inflammatory infiltrate on biopsy) changes at cystoscopy and hydrodistension and are thought to represent a distinct phenotype of BPS (Fig. 38.1).13


Clear and accurate estimates of the prevalence of BPS are difficult to ascertain due to changing definitions of the condition, different populations studied, and the methodology used to collect the data. Acknowledging these difficulties in producing prevalence data, a United States-based study found prevalence rates of 2.7% to 6.5%.14 BPS is 2 to 5 times more common in females than males.15,16,17


Although there is no unifying model or definitive evidence for the pathogenesis of BPS, a number of theories have been proposed to be involved in the initiation and maintenance of the disease process that then results in the clinical condition of BPS.

Urothelial dysfunction/increased bladder permeability

The urothelium is a highly specialized transitional epithelium lining the upper and lower urinary tracts (Fig. 38.2). It consists of three layers of cells. The basal layer is responsible for all cell division; the partially differentiated intermediate layer is responsible for rapid differentiation to replace lost apical/umbrella cells; and the apical layer provides the main protective barrier through tight intercellular junctions, plaques of uroplakins (cell membrane proteins), and the glycosaminoglycan (GAG) layer.18 The urothelium provides
the interface between the bladder lumen and the interstitium which collectively contains the connective and muscular tissue, the vasculature and neural networks. It prevents urinary solutes, toxins, and bacteria from penetrating into the interstitium. It is postulated that dysfunction of the tight intercellular junctions allows these noxious agents to permeate into the interstitium, setting up the inflammatory and neural pathways that are proposed to drive the disease process.19,20

A defect in the protective GAG layer of the urothelium may also play a role in the increased permeability of the urothelium seen in patients with BPS. The GAG layer is composed of hyaluronic acid, chondroitin sulphate, heparin sulphate, dermatan sulphate, and keratin sulphate.21 This GAG layer also provides protection against absorption of urine constituents into the interstitium. Parsons et al.22 noted the increased uptake of urea in patients with BPS compared with normal controls (25% vs. 4.5%, P < .005) and that patients with HLs had higher absorption than those BPS patients without HLs (34.5% vs. 22.8%, P = .002). Hauser et al.23 also showed GAG layer abnormalities with a change in the distribution of the proteoglycans in controls versus BPS. Control bladder biopsies showed a greater expression of the proteoglycans in the luminal layer of the urothelium with decreased expression down through to the basal layers, whereas biopsies from patients with BPS showed uniform expression throughout the urothelium with absent strong luminal staining.23

Impairment of cell proliferation

Defects in the GAG layer may result in an alteration in the actions of cytokines which then result in increased urothelial permeability due to failure of the urothelium to differentiate properly in patients with BPS. This has been postulated to occur through a number of mechanisms. Hauser et al.23 suggested that GAGs are able to bind a number of cytokines such as tissue growth factor-beta, platelet-derived growth factor and vascular endothelial growth factor thereby regulating the availability of each ligand. A deficiency in GAGs could then potentially alter the growth and differentiation of urothelial cells from the basal and intermediate layers and result in deficient replacement of the apical cells.23


The role of the immune system in the inflammatory response seen in patients with BPS, and particularly in those with HLs, has been widely studied. Mast cells, which are highly specialized immune cells involved in autoimmune and neurogenic immune responses, can be activated by the damaged or dysfunctional urothelium seen in BPS. They secrete several biologically active molecules, including histamine, serotonins, leukotrienes, and cytokines. These proinflammatory mediators are capable of inducing the inflammation, vasodilation and angiogenesis, fibrosis, and smooth muscle contraction associated with BPS.24

In support of the role of mast cell activation in BPS, several studies have identified increased concentrations of histamine and its metabolites in the urine of patients with BPS, higher eosinophil density and prostaglandin E2 (also known as dinoprostone) excretion, and high mast cell density particularly in the detrusor muscle.25 Although detrusor mastocytosis has been proposed as a biomarker for BPS with density cutoffs of greater than 20 microcoulomb/mm2 to greater than 32 microcoulomb/mm2, the sensitivity and positive predictive values are variable.26,27,28

Neural upregulation

The neural control of bladder function is a complex interplay between the peripheral and central nervous system, with ultimate conscious control of voiding by the prefrontal cortex. Sensory signals originating from the bladder arise from afferents embedded within the detrusor muscle and urothelium. They are sensitive to mechanical distension as well as transmitting sensory stimuli resulting from bladder infection, urothelial inflammation, and barrier breakdown29 and are therefore responsible for inducing sensations ranging from fullness to pain.30

Proinflammatory mediators are known to directly sensitize the bladder afferent nerve terminals,31 leading to the peripheral sensitization that is an essential mechanism for the induction of normal wound healing.32 During prolonged or severe inflammation, chronic sensitization of the afferents can occur, reducing the pain threshold and amplifying the responsiveness of nociceptors. This process drives the allodynia and hyperalgesia to bladder distension that is observed in patients with BPS. Both animal and human studies have shown a role for upregulation of receptors and channels associated with nociception (predominantly driven by C fibers, which respond to chemical, mechanical and thermal stimuli) in BPS as well as increased levels of serum and urinary nerve growth factor with resultant increase in afferent nerve density.33,34,35

Central sensitization with changes within the spinal cord and brain can occur following persistent activation of dorsal horn neurons. These changes can then result in the mediation of pain even after resolution of inflammation or other pelvic insult. Central sensitization is a common feature of chronic pain conditions, and functional brain imaging has enhanced knowledge of central nervous system control of the bladder and other pelvic organs. For instance, increased functional brain activation in regions known to be involved in sensory perception and pain has been shown in BPS patients with a full bladder. White matter changes have also been noted in
women with BPS compared to controls and correlated with bladder pain and urinary symptoms.36

The peripheral and central sensitization occurring in BPS may also explain the high prevalence of vulvodynia of 50% to 85% observed in women with BPS.37,38 Patients with vulvodynia have been found to have increased nociceptors (specialized sensory neurons that respond to noxious or injurious stimuli), with enhanced pain signaling, compared to normal controls.39

Pelvic organ cross talk

Shared sensory pathways involving the dorsal root ganglia, the spinal cord, and the brain exist between the colon, bladder, and reproductive organs. These pathways are necessary for the mediation of normal pelvic organ function; however, this also provides a pathway for dysfunction of one pelvic organ leading to functional changes in another.40

Animal and clinical studies have shown that diseases of the colon (irritable bowel syndrome, inflammatory bowel disease) can induce pathology in the bladder. In a mouse model of colitis, changes in bladder voiding parameters that replicate urgency/frequency, increased bladder permeability, as well as increased bladder afferent sensitivity to bladder distension have been observed.41,42,43 Conversely, induced bladder inflammation has resulted in colonic changes with lower thresholds for sensation of distension and increased colonic permeability in the absence of inflammatory changes.

Pelvic organ cross talk may also be responsible for the observation that women with endometriosis develop or have coexisting BPS. Prevalence studies have identified that, of women presenting with CPPS with a diagnosis of endometriosis, up to 60% will have BPS.44,45 A recent population-based study assessing the incidence of BPS in women with endometriosis has shown a hazard ratio for BPS among these women of 3.74 compared to that of controls.46

Urinary microbiome

Although once considered sterile, it is now known that urine contains extensive numbers of bacteria in the healthy individual, much like the vagina and gastrointestinal tract. This population of bacteria is referred to as the urinary microbiome and has been shown to be altered in a number of pathologic states. The role of the urinary microbiome in BPS is unclear with conflicting study results. Abernethy et al.47 studied the urinary microbiome in 40 women with and without BPS and found women with BPS had a less diverse microbiome, with fewer Lactobacillus species and higher levels of proinflammatory cytokines. Meriwether et al.,48 in a study of 41 women with and without BPS, did not find a significant difference in either urinary or vaginal microbiomes.

Cortical regulation: stress, anxiety, depression

There is mounting evidence that chronic stress can result in changes in the balance of autonomic function with a shift to sympathetic nervous system predominance. This then can lead to an exacerbation of sympathetic-mediated pain sensation. This may be one mechanism by which psychological stress increases the severity and duration of pain symptoms in BPS.49,50

Diagnosis and Assessment

The diagnosis of BPS is largely based on the clinical criteria of bladder “pain,” urinary frequency/nocturia, and/or urgency. As previously discussed, it is a diagnosis of exclusion and duration of symptoms required to make the diagnosis is also variable. The National Institute of Diabetes and Digestive and Kidney Diseases proposed a definition of IC with very strict inclusion and exclusion criteria.51 This definition was devised in order to homogenize patients participating in IC research studies and not to serve as a diagnostic tool. It has subsequently been shown to be too restrictive, but the list of conditions under exclusion criteria still holds and is mirrored by the ESSIC list of confusable diseases (Table 38.1) and must be assessed for in the workup of any patients presenting with irritative voiding symptoms. These are broadly urogenital malignancy and infection, cystitis (radiation, chemotherapy, immunotherapy, anti-inflammatory), urethral diverticulum, bladder outlet obstruction (BOO)/urinary retention, and urinary tract stone disease. It is important, however, to understand that patients may have a confusable disease and BPS.


Patients may have difficulty in describing the pain component of BPS and often have trouble localizing or describing their sensations. The pain may be referred to other areas of the pelvis. Besides the typical pain over the suprapubic area, which may be relieved by voiding, BPS patients may complain of referred urethral pain, such as dysuria, strangury, or constant burning. They may also complain of low back pain, vulval pain, rectal pain, and dyspareunia. Quantitation of the severity of pain is quite difficult because of the waxing-waning presentation of symptoms, and there are no formal quantitative objective measures of bladder or pelvic pain.

Urinary urgency is another symptomatic component of BPS that can be difficult to separate from pain in some patients. BPS patients may describe a constant strong urge to void, despite low bladder volumes, that
when severe is described as pain. Urinary frequency is a manifestation of the actual act of voiding, but BPS patients have been known not to void because they realize that frequent voiding does not necessarily lead to relief of pain and urge sensations. From the standpoint of quantification of BPS symptoms, measurement of voiding frequency may be the best objective parameter.

Other points on history:

  • History of previous urinary tract infections

  • Urologic/pelvic surgery

  • Triggers

    • Diet: Although no research links BPS symptoms to certain foods or drinks, some patients may notice worsening symptoms with ingestion of caffeinated beverages, carbonated drinks, alcohol, tomatoes, hot and spicy foods, chocolate, citrus juices and drinks, monosodium glutamate, and high-acid foods.

    • Hormonal: Some women note perimenstrual flares in BPS symptoms.52

  • Evidence of pelvic organ cross talk or systemic disease clusters: endometriosis, bowel symptoms (irritable bowel syndrome, inflammatory bowel disease), fibromyalgia, chronic fatigue syndrome, migraine, autoimmune diseases (Sjögren disease)

  • Psychological conditions: anxiety, depression


General physical examination is important but focused on the abdomen and pelvis. Pain mapping should be performed.

  • Suprapubic tenderness

  • Vulva—exclude vulval/vestibular disease, cotton swab test to assess and score sites of tenderness

  • Vagina—evidence of vaginismus, tenderness on palpation of the urethra or anterior vaginal wall/bladder base, evidence of levator ani spasm/trigger points suggestive of pelvic floor hypertonicity; exclude urethral diverticulum (suburethral mass)

Symptom questionnaires

Although not diagnostic, symptom questionnaires can help in tracking response to treatment, with lower scores generally indicating less severe symptoms. Questionnaires also provide objective assessment of treatment effect in research studies with a number of validated questionnaires available.

One questionnaire instrument was developed by O’Leary et al.53 in 1997 specifically to assess BPS patients. The questionnaire has two subscales to quantify symptoms and their impact on quality of life: the Interstitial Cystitis Symptom Index (ICSI) and Interstitial Cystitis Problem Index (ICPI). A second symptom measurement instrument, the University of Wisconsin IC Scale (UW-ICS), has also been developed and validated.54 The UW-ICS is a 7-point, 0-to-6 rating scale with each item anchored between the extremes of 0 (not at all) and 6 (a lot). Parsons et al.55 developed the Pelvic Pain and Urgency/Frequency (PUF) questionnaire to capture symptoms of pelvic pain and dyspareunia in patients with BPS, assessing both symptom severity and impact on quality of life. Any of these validated instruments should be administered to the patient with BPS to quantitate symptoms during the course of evaluation and treatment. It is important to use these standardized instruments so that changes in a patient’s symptoms and quality of life can be followed as objectively as possible.

Specific assessment of pain can be achieved on a visual analog scale, a validated subjective measure for acute and chronic pain. Scores are recorded by making a handwritten mark on a 10-cm line that represents a continuum between “no pain” and “worst pain” (Table 38.2).

Bladder diary

A bladder diary provides a very useful insight into the patient’s bladder function over 1 to 3 days. This typically shows increased urinary frequency during the day and overnight, with small voided volumes and low maximal functional bladder capacity. It also allows assessment of fluid intake which may require adjustment as patients often limit their fluid intake to minimize voiding frequency, not understanding that severe fluid restriction leading to concentrated urine may exacerbate their symptoms. Changes in voiding parameters can be objectively monitored as treatment progresses, hopefully providing independent positive feedback to the patient or highlighting that current management is not working and prompting change in treatment strategies. In mild BPS without significant pain, bladder retraining using repeat bladder diaries can be a useful therapeutic strategy.


Urine microscopy and culture must be performed to exclude intercurrent urinary tract infection. It also allows assessment of microscopic hematuria or sterile pyuria to direct further investigations, that is, urine cytology/cystoscopy/renal imaging to exclude renal tract malignancy or stone disease and urine culture for tuberculosis. There is more emphasis on the possibility of low-grade intracellular infection with elevated urinary leucocyte count causing lower urinary tract symptoms (LUTS) which in some units are being treated with prolonged low-dose antibiotics with some success and controversy.56

Screening for voiding dysfunction to exclude it as a cause of urinary frequency/urgency/bladder pressure should be performed. This can be done by catheter or preferably by bedside bladder scan or formal renal tract imaging. If screening is positive, then urodynamic testing should be carried out. Otherwise, the use of urodynamics in the assessment of patients with BPS is not recommended and is usually extremely uncomfortable. If performed, the findings would include voiding dysfunction, a low-capacity bladder, or poor compliance. The Interstitial Cystitis Database Study Group analyzed urodynamic data and compared them to data collected from voiding diaries.57 It showed that urodynamic data closely correlated with the findings of the voiding diaries, and therefore, it has been suggested that urodynamics are unnecessary in the evaluation of BPS because the voiding diary, which is noninvasive, captures the necessary information.

Cystoscopy without anesthesia can be used to exclude confusable bladder pathology such as malignancy or bladder stone disease and on inspection can reveal HLs on filling but does not allow for sufficient hydrodistension of the bladder and assessment for the presence of glomerulations (pinpoint petechial hemorrhages), cascade bleeding, maximum bladder capacity, or therapeutic interventions. Although there are technical variations in how hydrodistention is performed, Nordling et al.58 outlined a detailed description. It is performed with the patient under general or regional anesthesia with a full cystoscopic examination of the bladder performed first. Cystoscopic irrigant (water, saline, or glycine) is then
infused at a pressure of 80 to 100 cm H2O (this distance above the bladder, i.e., gravity fill) into the bladder until filling into the drip chamber stops; this may require urethral occlusion as water may bypass the cystoscope around the urethra. During filling, the anesthetist may note patient tachycardia or increased respiratory rate indicative of pain. The bladder is distended for 2 to 5 minutes before all the irrigant is released from the bladder under direct vision. The volume of instilled fluid is measured and noted as the patient’s anesthetic bladder capacity. Glomerulations may be noted as petechial hemorrhages during bladder emptying and should be quantified as to the number of bladder quadrants in which they are observed (Fig. 38.3). The bladder is then refilled to 20% to 50% of bladder capacity to allow visualization of HLs (Fig. 38.4), appearing as fissures or cracks in the epithelium (these findings are often seen on first fill), and biopsies (both superficial and deep including detrusor muscle) taken if required. Although HLs are considered pathognomic of IC, the presence of glomerulations is not, occurring in up to 45% of normal subjects without symptoms of BPS at volumes higher than their usual functional bladder capacity. For example, 9 out of 20 asymptomatic women had glomerulations when having tubal ligation and cystoscopy with bladder fill volume of 950 mL.59 Conversely, glomerulations are often not found in subjects with symptomatic BPS, and therefore, absence of identifiable epithelial changes at cystoscopy does not exclude BPS.