Vulvodynia is defined as vulvar discomfort in the absence of clinically identifiable or laboratory findings. Its incidence is 17 % and prevalence is 7 %. Latina women have the highest risk [10]. Women describe it as vulvar irritation, soreness, tearing sensation, burning, redness or stinging, infrequently accompanied by an itching sensation and almost always accompanied by painful intercourse. Vulvodynia is classified as either localized or generalized; provoked (elicited by touch, friction, pressure, etc.), unprovoked (spontaneous discomfort/pain) or mixed; and based on the site of the pain [11] (see Table 8.1). There is no one single cause for vulvodynia although genetic, immunologic or embryologic factors, inflammation, infection, neuropathic changes or increased urinary oxalates have been suggested.

After a thorough history and physical examination and absence of laboratory findings reveal vulvodynia, management should be multidisciplinary. This includes treatment of vulvar and vaginal atrophy and hygiene counseling regarding irritants, chemicals, and potential allergens. Management of any associated pelvic floor dysfunction, neuropathies, and psychological factors must be addressed. Patient education, counseling, and support are crucial as vulvodynia is frequently not completely curable.

Endometriosis affects up to 10 % of women of reproductive age. Women will present with CPP, painful intercourse and infertility [12]. Endometriosis is defined as the presence of endometrial tissue external to the uterine cavity. This tissue could be located in the muscle of the uterus (adenomyosis), in the pelvis (peritoneum or ovaries), or distal sites (i.e., bowel, abdominal skin). The mechanisms and theories behind this disease are beyond the scope of this chapter; however, in women of reproductive age who present with cyclical CPP where pain is localized to the bladder or urethra or who have a surgical history that includes a diagnostic laparoscopy for pain, endometriosis should be in the differential diagnosis.

IC/BPS is a chronic and debilitating condition that is comprised of pelvic pain and urinary symptoms, occurs disproportionately in women, and has a poorly understood etiology [13]. A consistent definition of IC/BPS remains elusive and is a major factor in the paucity of research on the subject to date. In fact, although IC/BPS was first recognized in the nineteenth century, acceptance of the first formal definition devised by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) occurred 100 years later [14]. This and other definitions formulated for use in research, however, often do not prove useful in clinical practice, as many who are diagnosed with IC/BPS clinically [15]. An evolution of the definition of IC/BPS is shown in [16, 17].

As previously mentioned, the lack of a consistent definition of IC/BPS necessarily affects the quality of research on the subject. Use of varying definitions renders making comparisons difficult, if not impossible, and prevalence of the condition is challenging to estimate accurately when using either these multiple, inconsistent definitions or one overly restrictive one.

Estimates of prevalence have mostly been carried out using medical records and mailed questionnaires in various specific settings, geographic locations, or with specific subsets of the population. The resulting prevalence range from these studies is 0.45–12.6 % [26–30]. The first population-based symptom prevalence estimate among United States adult females was reported by Berry et al. in 2011, using the 2006 United States Census and a random sampling of households telephoned to question about bladder symptoms or a diagnosis of IC/BPS [1]. Those identified with symptoms were screened a second time with an in-depth 60-min interview. In a previous study, recognizing the shortcomings of established definitions of BPS/IC in epidemiologic research, the authors developed and validated two definitions with expert input, and found that, as was the case in other studies, neither demonstrated both high sensitivity and high specificity, though they were comparable or superior to established definitions (RICE definitions in Table 8.2) [23]. Both of these previously developed and validated definitions were used in the current study. Use of the high sensitivity or most inclusive definition yielded a prevalence estimate of 6.53 %; use of the high specificity definition yielded a prevalence estimate of 2.70 %. Further, while most women in the study saw at least one physician for their symptoms (87.1 %), less than half had a diagnosis for their symptoms (45.8 %) and only one-tenth (9.7 %) were diagnosed with IC/BPS, suggesting that the condition is underdiagnosed and undertreated [1]. Suskind et al. used a modified version of the definitions for use in studying the prevalence in men [31]. The result was a prevalence estimate of 2.9–4.2 % for IC/BPS, suggesting that the prevalence rate in men is closer to that in women, contrary to what has historically been reported and lending support to the under diagnosis of the condition in men, just as has been suggested for women.

Pain or pressure/discomfort, especially suprapubic pain, related to bladder filling is the key symptom in IC/BPS. This sensation can be described by patients as being experienced throughout the pelvis, in the urethra, vulva, vagina, rectum, lower abdomen, and even the back. Other specific aspects of the pain experienced in IC/BPS include pain that worsens with certain foods or drinks, worsens with bladder filling, and/or improves with urination [32].

Typically, IC/BPS patients may also present with marked urinary urgency and frequency. Qualitatively different from the urgency in overactive bladder (OAB), IC/BPS patients tend to void to prevent or relieve pain, rather than to avoid incontinence [16, 24]. About 18–36 % of women with IC/BPS present with a history of a recent culture-positive urinary tract infection (UTI), with subsequent cultures, however, being negative [32]. Many may initially complain of one symptom, such as dysuria, frequency, or pain, with progression to multiple symptoms [33, 34]. It is not uncommon for IC/BPS patients to experience symptom flares, during which their symptoms suddenly intensify for several hours, days, or weeks.

Frequently, these patients have a history of prior pelvic surgery, especially hysterectomy, and levator ani pain, suggesting that trauma or other local factors may contribute to symptoms [35]. In considering this association, it is important to bear in mind that it is possible that these pelvic procedures were performed as a result of a misdiagnosis and were not a contributing factor to patients’ symptoms, themselves.

Finally, IC/BPS patients commonly present with other unexplained medical conditions. These conditions may include fibromyalgia (FM), irritable bowel syndrome (IBS), chronic fatigue syndrome (CFS), allergies, asthma, sicca syndrome, chronic pelvic pain (CPP), endometriosis, back disorders, Sjogren’s syndrome, chronic headaches/migraines, temporomandibular disorder, vulvodynia, depression, and anxiety [36–43].

In light of the complicated history and symptomatology of patients presenting with IC/BPS, diagnosis of the condition is very challenging. Its wide array of symptoms, physical examination findings, and medical test results frequently lead to misdiagnosis, underdiagnosis, and delayed diagnosis [44]. According to the Bladder Pain Syndrome Committee of the International Consultation on Incontinence from 2009, the diagnosis should be made based on exclusion of confounding diseases and confirmation of the specific combination of symptoms of BPS [45].

The group further describes the effort that has been put forth to attempt to identify objective diagnostic criteria including cystoscopy, bladder distention with notation of bladder capacity and/or the presence of glomerulations and Hunner’s lesions, bladder wall biopsies evaluated for inflammation, ulcers, fibrosis, mast cells, etc., and urodynamics with registration of bladder capacity, compliance, and bladder stability. Ultimately, however, the results of those efforts have been frustrating and the group concluded that it is more effective to establish a broad clinical diagnosis, mainly on the basis of symptoms, physical examination, and exclusion of other diseases and then stratifying patients by urodynamic, cystoscopic, histological, and other tests on the basis of the significance of the findings for the treatment and prognosis of disease [46]. With respect to specific testing, the committee further suggests that urodynamics be considered an optional procedure, primarily for patients with a complicated history that suggests the possibility of other diagnoses that may account for the symptoms. The committee designates this guideline as a Level of Evidence 4, Grade of Recommendation C.

The AUA Guideline Amendment from 2015 concludes that insufficient evidence exists for guiding diagnosis of IC/BPS in clinical practice and designates its recommendations as Clinical Principle or Expert Opinion [25]. These recommendations include basic assessment consisting of history, frequency charting, postvoid residual, physical exam, urinalysis/culture, cytology (if smoking history), symptom questionnaire, and pain evaluation. After ruling out other conditions, further testing such as urine cytology, imaging, cystoscopy, urodynamics, laparoscopy, and specialist referral may also be considered.

The etiology of IC/BPS remains unknown, though it is thought to be multifactorial. In fact, especially in the absence of a specific marker that confirms its presence, it is not known if IC/BPS symptoms constitute a single disorder or if they are perhaps symptoms of a more generalized systemic chronic pain disorder affecting the bladder, but also other visceral organs. As described earlier, associations have been shown to exist between IC and many other medical conditions. Warren et al. in 2011 reviewed the cross-sectional studies making associations between IC/BPS and nonbladder syndromes (NBS) and concluded that while additional cross-sectional studies would be helpful to generating more hypotheses about the pathogenesis of IC/BPS, prospective studies will most likely be necessary to test the hypotheses formulated and to discover the temporal relationship of these conditions to the pathophysiology of IC/BPS [47]. Existing theories include: environmental factors, a defective bladder urothelial layer, alteration in afferent sensation, and inflammation.

A group of researchers in Sweden used a large twin database to evaluate genetic and environmental influences on IC/BPS, among other conditions [48, 49]. Genetic influences were found only to be modest in IC/BPS, whereas environmental factors had a pronounced influence. Another proposed model of pathogenesis of IC/BPS is a defective bladder urothelial barrier, due to a deficiency in the glycosaminoglycan (GAG) mucin layer coating that leads to increased epithelial permeability [50]. This increased permeability leads to bladder injury resulting in symptoms of urgency and pain. Specifically, it is hypothesized that the increased permeability allows irritants to pass through the bladder urothelium, activating mast cells, essential for the development of allergic hypersensitivity reactions. A harmful cycle is initiated when bladder injury results in urothelial dysfunction, solute leak, activation of C fibers, and mast cell degranulation, causing further damage [51] (see Fig. 8.3). While data mostly support potassium as the urinary metabolite initiating the cascade of events leading to bladder symptoms when the epithelium is disrupted, it has been proposed that there must be a balance of all urinary cations and anions to prevent damage to the bladder mucus layer. Too little of the protective factors or too many of the toxic cations could increase the risk for bladder disease [52]. Increasing our understanding of this required balance may help to develop treatments to target either end of the uneven distribution of substances in order to reduce this risk.

Inflammation is recognized to play a key role in the development of the symptoms of frequency, urgency, and pelvic pain experienced in IC/BPS. Study findings supporting the role of inflammation have noted significantly higher C-reactive protein (CRP) levels in patients with IC/BPS [53]. Other findings suggest a possible exaggerated C-fiber excitation, associated with inflammation in the bladder [54, 55]. It is postulated that this hyperactivity of the C-fiber afferents may lead to pain with normal distention of the bladder [56]. Further, studies have supported chronic inflammation as an underlying cause by observing increased nerve growth factor (NGF) production and, on histological analysis of the bladders of patients with IC/BPS, marked edema, vasodilation, proliferation of nerve fibers and infiltration of mast cells, as well as significantly greater numbers of nerve fibers expressing substance P, a major neurotransmitter of C-fiber afferents [50, 57, 58].

An association between urinary calculi (UC) and IC/BPS has been supported in a study using a population-based dataset in Taiwan [59]. The authors found that IC/BPS was significantly associated with UC, regardless of stone location, after adjusting for CPP, IBS, FM, CFS, depression, panic disorder, migraine, sicca syndrome, allergy, endometriosis, and asthma. It was theorized that the stone could cause irritation initiating an inflammatory cascade leading to chronic inflammation and recurrent bladder epithelium injury [60].

Although much effort has been exerted in the investigation of the pathogenesis of IC/BPS, ultimately, as Yoshimura et al. 2014 point out, no one pathological process has been identified in every IC/BPS patient. The authors conclude, then, that it is likely that IC/BPS could have multiple etiologies resulting in similar clinical manifestations and that afferent hyperexcitability could therefore be a key pathophysiological basis of IC/BPS that could be targeted with the development of multiple treatment modalities [55].

First-line treatment should be offered to all patients. If the patient has mild symptoms, first-line therapy can be effective, though additional therapy may be required for adequate symptom control. First-line treatment includes education of normal bladder function, information about chronic nature of IC/BPS, a typical course involving symptoms and exacerbations and remission. Also, self-care and behavioral modifications should be discussed with the patient. These include application of local heat or cold over the bladder and perineum; avoidance of certain foods known to be common irritants for IC/BPS patients (e.g., coffee, tea, soda, chocolate, alcohol, artificial sweeteners, tomato-based products, spicy foods, MSG, citrus products); use of over the counter products (e.g., nutraceuticals such as L-arginine, calcium glycerophosphate (Prelief), phenazopyridine (Pyridium)); pelvic floor relaxation; trigger point and hypersensitive area treatments; and bladder training with urge suppression [24, 62–64]. Also, patients should be encouraged to implement stress management techniques to help alleviate or prevent flare-ups, especially in the case of comorbidities such as irritable bowel syndrome, endometriosis, recurrent vaginitis/vestibulitis, depression, or anxiety [65].

Second-line therapy includes: appropriate physical therapy; pain management, including medications, stress management, and manual therapy; and oral medications and bladder instillations. During the initial evaluation of the patient, some patients may experience pelvic floor muscle tenderness, along with other soft-tissue abnormalities. This presentation of pelvic floor muscle tenderness can be interpreted as a primary pain or as a secondary event elicited by the bladder pain of IC/BPS. In these cases, it is suggested that manual physical therapy, targeted on pelvic floor muscle relaxation, can be beneficial for symptom relief [35, 66, 67].

Similar principles should guide pharmacotherapy of pain in IC/BPS as in any other chronic pain management. The goal of pharmacotherapy is to find medication or a combination of medications to provide significant pain relief with minimal side effects. Medications for pain management include urinary analgesics, NSAIDs, opioids, and a variety of nonopioid medications used for chronic pain management, which are also used for the treatment of depression, epilepsy, allergies, arrhythmias, etc. Patients may require opioid medications, which present risks of tolerance and dependence. Thus, there are several principles of pain management of IC/BPS that need to be followed. Whenever using opioid medication, it is important to re-evaluate at least every 3 months to determine whether the benefit outweighs the risk of continuing this therapy. Prescribers should utilize prescription-monitoring programs at least quarterly, as all opioid prescriptions should be coming from a single source. The patient must be appropriately counseled regarding side effects of medications, as well as rights and responsibilities of the patient and treating physician. The lowest effective dose of medication should always be used while maximizing nonopioid medications and alternative therapies. Patients who require long-term opioid therapy may benefit from long-acting opioids, using small doses of short acting opioids for breakthrough pain. In order to minimize dependence, combinations of physical therapy, stress management and counseling should be used. Also, patients need express understanding of reasonable goals, e.g., that 100 % pain relief often cannot be achieved and is unreasonable. The goal of pain management is to minimize discomfort and maximize patient’s ability to function in daily life [61].

Amitriptyline is the most widely used medication for initial pharmacologic treatment of IC/BPS. The dosing regimen is typically started at 10 mg at bedtime, and the dose is titrated up weekly (25 mg, 50 mg, 75 mg or to the maximum tolerated dose). Adverse effects include anticholinergic effects (dry mouth, constipation, urinary retention), sedation, weight gain, orthostatic hypotension, and cardiac arrhythmias [67]. The medication is most likely effective in higher doses; however, many patients cannot tolerate these doses. Conflicting data exist about the efficacy of amitriptyline in the treatment of IC/BPS. One multicenter randomized trial showed that low dose amitriptyline in combination with education and behavioral modification program did not significantly improve symptoms in the treatment of patients with IC/BPS [24], though it can be beneficial in patients who can achieve a daily dose of 50 mg or greater [68].

Pentosan polysulfate sodium can provide symptom reduction in IC/BPS patients. Symptomatic relief usually appears 3–6 months after initiation of therapy. The accepted regimen of pentosan polysulfate sodium is 100 mg three times daily. Side effects can include abdominal bloating and discomfort, which could be relieved by opening up the capsule and sprinkling its contents on food. Adverse events include hair loss and mild elevation of liver enzymes, although they are typically mild and reversible [1].

Use of antihistamines for IC/BPS is based on the hypothesis of hypersensitivity as a pathophysiologic mechanism, although there are no quality data to support the treatment. It is used in patients with IC/BPS and allergic disorders. Hydroxyzine is the most commonly used antihistamine in treatment of IC/BPS. The typical dose of hydroxyzine is 25 or 50 mg. It can be used at bedtime in patients with insomnia, coursed by nocturia.

A pilot trial that compared safety and efficacy rates for oral pentosan polysulfate sodium versus its use combined with hydroxyzine suggested that neither provided benefit to the majority of patients with IC [69]. Medication management of IC/BPS can include bladder instillations. A “cocktail” preparation, including heparin or pentosan polysulfate, sodium bicarbonate, local steroid, and/or lidocaine preparation, which can be administered in office settings, as a weekly preparation, can be used as a treatment providing relief ranging from 6 weeks to 12 months.