Current best practice management of interstitial cystitis/bladder pain syndrome

Abstract

Introduction:

Over the last 100 years, the terminology and diagnosis criteria for interstitial cystitis have evolved. Many therapeutic options have changed, but others have endured. This article will review the idea of separating ‘classic’ Hunner lesion interstitial cystitis (HL IC) from non-Hunner lesion interstitial cystitis and bladder pain syndrome (N-HL IC/BPS) and their respective treatment algorithms.

Methods/Results:

A literature search was performed to identify articles and research on HL IC and N-HL IC/BPS including definitions, etiological theories, and treatments. This article is an overview of the existing literature. We also offer insight into how HL IC and N-HL IC/BPS are approached at our tertiary referral center. Additionally, American Urological Association guidelines have been integrated and newer treatment modalities and research will be introduced at the conclusion.

Conclusion:

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.

Background: what’s in a name?

As it turns out for interstitial cystitis (IC), everything. Throughout the last century, IC has been discovered, defined and redefined innumerable times; originally Skene defined it as ‘an inflammation that has destroyed the mucous membrane partly or wholly and extended to the muscular parietes’.¹ In 1915, Hunner defined it as ‘a peculiar form of bladder ulceration whose diagnosis depends ultimately on its resistance to all ordinary forms of treatment in patients with frequency and bladder symptoms’.² The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) criteria of 1990 and 1997 included exclusion criteria not meant to define the disease but to ensure the patients included in these basic and clinical research studies would have been relatively comparable. Of note, glomerulations and Hunner ulcers were removed as necessary criteria in 1997. This has not only made prevalence and incidence estimations difficult to calculate but it has also led to confusion in research, and more importantly, in practice.

Part of the confusion has also resided in the coevolution of its nomenclature. In 2002, the International Continence Society (ICS) agreed on the term ‘painful bladder syndrome’ (PBS) because IC was a ‘specific diagnosis that required confirmation by typical cystoscopic and histologic features’.³ But these cystoscopic and histologic features were not clearly defined. In 2004, the International Consultation on Incontinence (ICI) argued against ‘painful bladder syndrome’ and for ‘bladder pain syndrome (BPS)’ because ‘the former did not focus on the actual symptom complex but instead on the misconception of its pathology’.⁴ This suggested the manifestation of bladder pain as part of a generalized systemic disorder.

At present, the most accepted terms and definitions for what has historically been known as IC are listed below. The ICS defines PBS as ‘suprapubic pain related to bladder filling, accompanied by other symptoms such as increased daytime and night-time frequency, in the absence of proven urinary infection or other obvious pathology’.³ The ICI and European Society for the Study of Interstitial Cystitis defines BPS as, ‘chronic pelvic pain, pressure, or discomfort perceived to be related to the urinary bladder accompanied by at least one other urinary symptom such as persistent urge to void or urinary frequency. Confusable diseases as the cause of symptoms must be excluded’.⁵ The American Urological Association (AUA) has adopted the definition provided by the Society for Urodynamics, Female Pelvic Medicine & Urogenital Reconstruction (SUFU): ‘An unpleasant sensation (pain, pressure, discomfort) perceived to be related to the urinary bladder, associated with lower urinary tract symptoms of more than six weeks duration, in the absence of infection or other identifiable causes’.^6,7

Adding to these definitions and terms, in 2013 ‘hypersensitive bladder’ (HB) was suggested as an umbrella term since a substantial proportion of patients do not complain of pain as would be suggested by BPS and PBS. HB was defined as ‘increased bladder sensation, usually associated with urinary frequency and nocturia, with or without bladder pain’. IC was subsequently defined by three requirements: HB symptoms, bladder pathology [clearly stated either as Hunner lesions (HLs) or glomerulations after hydrodistention (HD)], and no other contributing diseases.^8,9

Unfortunately, no consensus for the definition and terminology of IC/BPS has been reached. Our institution continues to use the definition and guidelines provided by the AUA and SUFU for IC/BPS. Critical to our thought process and clinical decision making, we subcategorize IC/BPS into HL IC and non-HL IC/BPS (N-HL IC/BPS). Although HL IC is relatively rare, we, and others, have found this classic form is clearly of bladder origin^10–12 while N-HL IC/BPS typically represents myofascial pain (MFP) and pelvic floor dysfunction (PFD). PFD and MFP have been found in as many as 85% of patients with the diagnosis of IC/BPS.^13,14 In this review, we provide a framework of treatments for IC/BPS divided into those for HL IC and N-HL IC/BPS subtypes.

Treatment options

Hunner lesion interstitial cystitis

The key difference between HL IC and N-HL IC/BPS is the presence of HLs on cystoscopy. HLs are typically circumscribed, reddened mucosal areas with small vessels radiating towards a central scar.^15,16 (The nomenclature has changed from Hunner ‘ulcer’ to ‘lesion’ since it is not a true ulcer.¹⁷) Therefore, we find cystoscopy is critical to diagnose HL IC. Doiron and colleagues found that HL IC did not have a distinct bladder centric phenotype and concluded the diagnostic benefits of cystoscopy outweighed its risks and cost and facilitates targeted therapy of the lesions.¹⁸

HL IC is relatively rare, with prevalence ranging from 5% to 20%.^13,19,20 Patients with HL IC tend to be older, have a more severe form of the disease with lower bladder capacity and greater urinary frequency, and have histologic changes that implicate an inflammatory process.^11,18,21,22 In our practice we are most likely to do office cystoscopy in patients who have a rapid onset of IC/BPS symptoms that occur after the age of 40 to assess for HL. In the 2015 guidelines amendment,⁷ it was recognized that HLs are more commonly found in male patients with IC/BPS,²³ and that male IC/PBS incidence could be higher than previously published.²⁴ Importantly, we have found the HL IC subtype has fewer comorbid diagnoses, less of a systemic disease, than the N-HL IC/BPS group that have associated diseases including fibromyalgia, depression, temporomandibular joint disorder, and migraine.¹² There is no evidence to support progression or remission between the two forms of the disease, further suggesting two separate disease processes.²⁵

Hunner lesion interstitial cystitis first-line treatments

Bladder-directed therapy is critical and the patient should understand that acceptable symptom control may require trials of multiple therapeutic options.²⁶ It should be discussed that there are many unanswered questions in the field of IC/BPS, including HL IC, and a working relationship between provider and patient is critical.

Elimination diets have been suggested. In our experience, these diets are cumbersome for many patients but effective for some. It is, however, a noninvasive option and a list of foods can be found on the IC Association website (www.ichelp.org).⁷ Oh-oka and colleagues²⁷ found symptoms in women with HL IC placed on intensive systematic dietary modification (ISDM) were significantly better than placebo (normal diet). All patients had glomerulations after HD or HLs. In general, the ISDM group was advised to avoid tomatoes, tomato-containing products, soybean, soybean-containing products, spices (pepper, curry powder, hot pepper, green horseradish paste, and others), high-potassium foods, citrus, and foods with a strong acid taste (caffeine, carbonic acid, and citric acid). At 3 months and 1 year the ISDM group improved on all variables of the O’Leary-Sant Symptom Index (OSSI) and O’Leary-Sant Problem Index (OSPI), and also in urinary urgency, bladder and pelvic pain, and subjective measure of quality of life (QoL).²⁷ Lastly, although pelvic floor physical therapy (PFPT) can concurrently be prescribed for patients with HL IC, we discuss this in detail later in the N-HL IC/BPS section.

Hydrodistention

In the past, HD was used to identify and treat glomerulations, however, the literature has been conflicting regarding the significance of glomerulations as well as the efficacy of HD.^28–32 Therefore, per AUA guidelines, it is a third-line option when other treatments have failed. The guidelines also inform us that the presence or absence of glomerulations is nonspecific and their presence does not diagnose the disease if the clinical symptoms do not fit. Thus, HD has no role in the diagnosis of IC/BPS, and its only purpose is to improve symptoms.²⁶ Symptom relief has been found to be short lived (<6 months) with less than 20% achieving excellent improvement and 50–60% achieving partial relief.^31–33 If performed, it should be done under anesthesia with pressures ranging from 60 to 80 cm H₂O for less than 10 min.

We often see referred patients who have been given the IC/BPS diagnosis years ago. Because we have found 85% of patients referred with this diagnosis in fact have N-HL IC/BPS,¹³ we perform cystoscopy early on to identify HLs (and thus HL IC) and guide them into the correct treatment pathway. We perform HD at the time of fulguration because the lesion tends to split and crack defining the borders of HLs that aids in electrocautery (EC) of the HL. Finally, 69% (36/52) of our patients rank HD in the top three forms of treatments they have had.¹⁰

Cystoscopic treatments

When HLs are identified, fulguration with laser³⁴ or EC should be performed. The guidelines suggest the technique of fulguration begins by outlining the lesion and working towards the center, which helps to delineate the true lesion edge from a reactive erythema when working in the opposite direction.²⁶ At our institution, we perform EC by using a resectoscope with a roller ball at 25 W of current. We rapidly roll the ball over the area of inflammation in order to avoid a deep burn.

Many studies have shown improvement in symptoms for patients after EC of HLs but with varying durability.^15,35–37 Historically, there have been studies reporting a loss in bladder capacity after transurethral resection of HLs.^38,39 A long-term study published by our institution has shown no reduction in bladder capacity after single/multiple episodes of cautery of HLs (p = 0.437).¹⁰ EC procedures were performed in 76 patients (undergoing 214 EC procedures in total) with a significant decrease in frequency, urgency, and pain (p < 0.001) for all. The mean number of EC procedures was 2.98 ± 0.25 (range 1–11) and the mean time between sessions was 14.5 ± 1.34 months (range 1–121 months). Ninety percent of patients noted some improvement, 56% noted marked improvement, 84% reported EC was the most beneficial treatment they had received, and 98% would undergo EC again.

The AUA guidelines also recommend triamcinolone injection as a form of treatment.^26,40 Although we have limited experience with this, Cox and colleagues performed submucosal triamcinolone injections on 30 patients with HL IC and found significant improvement in pre- and postoperative pelvic pain, urgency/frequency symptom scale and patient global impression of change.⁴⁰

Independent of approach, it is recommended that HLs be treated with the understanding that repeat treatment may likely be required. In the event of repeat cauterization, however, no loss in bladder capacity has been observed.

Cyclosporine A

Cyclosporine A (CyA) is a fifth-line treatment option per AUA guidelines. CyA inhibits calcineurin thereby suppressing T-cell activation;⁴¹ it has been used in a variety of autoimmune diseases as well as in patients who have undergone a transplant. Suppression of the immune system (and subsequently bladder inflammation) is the rationale behind its use in IC/BPS. Several studies have shown patients with HL IC are more responsive to CyA therapy,^17,42–44 again suggesting a distinctly different etiology for HL IC from N-HL IC/BPS.

Most urologists are unfamiliar with the drug as well as the drug-monitoring process and its use has not been widespread. However, many studies reported excellent outcomes for CyA in IC/BPS, including superior outcomes compared with pentosan polysulfate sodium (PPS).^42,45–49 A recent study by Crescenze and colleagues concluded that, although close monitoring is needed, the dosage used in IC/BPS is low which decreases the risk of toxicity.⁴³ By monitoring a combination of C2 levels⁵⁰ (CyA blood concentration at 2 h after oral intake), creatinine, and blood pressure, providers could minimize toxicity and improve drug safety. Patients were dosed at 3 mg/kg divided twice daily for 3 months. Dosages were decreased based on the above variables measured every 3 months. They did observe reversible renal function decline with discontinuation of therapy in the short term. The AUA guidelines recommend a dose of 2 mg/kg since outcomes from three tertiary center studies were similar when using 2 mg/kg versus 3 mg/kg.⁷

At our institution, we prescribe CyA 100 mg twice a day for 1 month followed by 100 mg daily thereafter. Blood pressure and renal function are routinely monitored.

Reconstructive surgery

Substitution cystoplasty or urinary diversion with or without cystectomy is an option offered by the AUA guidelines when all other therapies have failed.²⁶ It is emphasized that these patients should be evaluated by an IC/BPS expert prior to major surgery to assure proper patient selection. Interestingly, Rossberger and colleagues⁵¹ found reconstructive surgery (noncontinent ureteroenterocutaneostomy, supratrigonal cystectomy and ileocystoplasty, continent urinary diversion, continent orthotopic diversion and cecocystoplasty) resulted in resolution of symptoms in 82% (28/34) of patients with refractory HL IC while only 23% (3/13) of patients with N-HL IC/BPS benefited from reconstructive surgery. The patients with HL IC had significantly smaller functional bladder capacity as well as total bladder capacity under anesthesia. They noted one patient with a large bladder capacity in the HL IC group did not improve post reconstructive surgery.

Similarly, Kim and colleagues⁵² compared pre- and postsurgery OSSI and OSPI scores along with changes in pain, urgency, frequency, functional bladder capacity, and maximal cystometric capacity under anesthesia in patients with refractory HL IC undergoing augmentation ileocystoplasty combined with supratrigonal cystectomy. They found augmentation with supratrigonal cystectomy significantly decreased pain and frequency, and significantly increased bladder capacity. Surgery relieved symptoms in 80% (32/40) of their patients. They noted a higher treatment failure compared with other studies due to a more strict criterion of greater than 30% reduction in scores from baseline at the last follow up.

Although reconstructive surgery is an option with potential benefits, it should be reserved as a last-line therapy for carefully selected patients with refractory HL IC; based on the literature, these patients should have a small bladder capacity. We do not recommend this treatment for patients with N-HL IC/BPS.

Non-Hunner lesion interstitial cystitis/bladder pain syndrome

Patients with N-HL IC/BPS often have the frequency, urgency, and bladder pain found in those with HL IC. Importantly, these patients commonly have coexisting systemic comorbidities/symptom complexes, include fibromyalgia, depression, temporomandibular joint disorder, inflammatory bowel disease, chronic fatigue syndrome, Sjögren’s syndrome, endometriosis, and migraines.^12,53–58 Importantly, these patients commonly report sexual dysfunction including dyspareunia, vulvodynia, and bowel symptoms including constipation and straining. In this section, we will address symptom-specific treatments for N-HL IC/BPS, including bladder-directed therapies and pelvic floor muscle treatments often requiring multimodal therapies directed at the underlying pelvic floor dysfunction (PFD).

Diet and stress management

As for patients with HL, it is a reasonable first step for patients with N-HL to try elimination diets as this is noninvasive. A list of foods can be found on the IC Association website (www.ichelp.org).⁷ Along with education and diet, it is a clinical principle that patients should implement stress management techniques to improve coping strategies and manage stress-induced symptom exacerbations.²⁶ We often explain to our patients different people carry stress in different areas of the body. Some individuals experience stress in the form of tension headaches, temporomandibular joint disease, low back pain, or even irritable bowel disease; it is logical to deduce other individuals (patients with IC/BPS) carry their stress in their pelvis. We highly encourage patients to look for stress management practices that will work for them. Additional alternative therapies will be covered later in this review.

Oral and intravesical therapies for non-Hunner lesion interstitial cystitis/bladder pain syndrome

Second-line treatments per AUA guidelines include oral (amitriptyline, cimetidine, hydroxyzine, and PPS) and intravesical [dimethyl sulfoxide (DMSO), heparin, lidocaine, or a combination] agents. DMSO and PPS are both US Food and Drug Administration (FDA) approved for IC/BPS. We find these treatments may be helpful for patients who have bladder centric symptoms but do not have HL IC. The use of DMSO for N-HL IC/BPS has stemmed from its anti-inflammatory, analgesic, and muscle-relaxant properties.⁵⁹ The updated AUA guidelines mentioned recent cohort studies of intravesical DMSO cocktails;^60,61 all previous controlled trials had used DMSO alone. In the two studies mentioned, response rates were reported at 61%⁶¹ and 66%.⁶⁰ There was, however, a difference in the definition of response (30% versus 50% reduction in symptoms), making response rates difficult to compare. To date, there have been no trials comparing DMSO alone versus a DMSO cocktail with other ingredients. A recent review of the literature⁵⁹ revealed the shortcomings of DMSO studies which include a lack of uniform diagnostic criteria, short-term follow up, lack of uniform criteria for clinical efficacy, and lack of uniform protocol of administration. The study notes a need for standardization as well as the potential for biomarkers to better subtype the right patient for its use. Other various combination studies (using heparin, lidocaine, sodium bicarbonate, intravesical PPS, chondroitin sulfate, and hyaluronic acid) have been conducted.^62–67 Per guidelines, however, there is no single correct answer; instillations should be individualized for each patient. It is also recommended that the potential benefit be weighed against the increased expense with the addition of ingredients.²⁶

The leaky epithelium theory of IC suggests diffusion of irritating components from normal urine into the bladder wall sets up a chronic inflammatory cycle leading to pain, urgency, and frequency.⁶⁸ PPS is a semisynthetic, sulfated polysaccharide, which is chemically and structurally similar to heparin and glycosaminoglycans (GAGs).⁶⁹ GAGs line the surface of the bladder mucosa, are hydrorepellent in nature, and breaks in the GAG layer lead to a leaky epithelium.⁷⁰ Parsons and colleagues⁷¹ first described significant success with PPS in a randomized, multicenter, double-blinded, placebo-controlled study in 1987. Recently, however, Nickel and colleagues⁷² performed a dose-ranging study for PPS which was placebo controlled. Their results revealed no significant difference between groups receiving the standard dose of 100 mg three times a day when compared with groups receiving 100 mg daily or matching placebo for 24 weeks. Several limitations were mentioned, including high dropout rates, early termination, as well as study design (including non-PPS naïve patients); they did not recommend abandonment of the use of PPS despite these results.

The other oral agents including amitriptyline, cimetidine, and hydroxyzine are proposed to affect mast cell degranulation within the bladder wall, possibly related to histamine release. Cimetidine was found to be more effective than placebo in patients who had inflammation on bladder biopsy.⁷³ In a multicenter randomized controlled trial comparing hydroxyzine with oral PPS, 121 patients were randomized over 18 months with 79% completing follow up. Neither drug was found to provide significant benefit to the majority of patients with IC/BPS (hydroxizine: p = 0.26; PPS: p = 0.064).⁷⁴

The mechanism of amitriptyline is unknown; however, it has been found to have three pharmacological actions: central and peripheral anticholinergic properties; norepinephrine and serotonin reuptake inhibition; and sedation with a presumed centrally based action and antihistamine properties.^75–79 In a recent multicenter, randomized, double-blind placebo controlled clinical trial of amitriptyline in patients with IC/BPS, in those who were naïve to therapy, amitriptyline plus education and behavioral modification did not significantly improve symptoms over placebo.⁸⁰ In this dose-escalation study, a significantly higher response rate was seen in the subgroup of subjects who were able to achieve a dose of 50 mg or greater. Only 46% of the patients in the amitriptyline group, however, were able to tolerate 50 mg per day throughout the 12-week follow up. The most common side effects were fatigue, constipation or dry mouth, and dizziness or somnolence.

We have found intravesical and oral therapies to be efficacious in a subgroup of patients. Successful phenotyping of these patients has not yet been achieved. We do offer trials of cimetidine and amitriptyline as they are more affordable than PPS. In our practice, either drug is started at 25 mg nightly and titrated to 75 mg as needed.

Pelvic floor physical therapy

Patients with N-HL IC/BPS often have tight, tender muscles and connective tissue in the pelvis, lower abdomen, thighs, groin, and buttocks. Women often have deep dyspareunia and the diagnosis can be confirmed on physical examination with palpation of the pelvic floor. We previously reported that 87% of patients presenting with a prior diagnosis of IC/BPS had PFD.⁸¹ Bassaly and colleagues reviewed 186 patients with the diagnosis of IC/BPS and found 78.3% had at least one palpable myofascial trigger point on physical exam, and 67.9% had multiple trigger points.¹⁴ The number of trigger points correlated to worse scores on the Pelvic Pain, Urgency and Frequency (PUF) questionnaire, Pelvic Floor Distress Inventory (PFDI-20), and Pelvic Floor Impact Questionnaire (PFIQ-7).

PFPT may be used to treat the tenderness and tightness in these muscles, and indirectly improve the associated urinary, sexual, and bowel symptoms. It is another second-line recommendation by the AUA guidelines in treating IC/BPS.²⁶ During PFPT, specially trained physical therapists perform manipulation of the external trunk and lower extremity connective tissue as well as intravaginal myofascial release techniques. This treats the muscles and tissues of the vagina, rectum, abdomen, hips, thighs, and lower back.

Several studies have demonstrated the benefit of PFPT for tight and tender pelvic muscles associated with IC/BPS. A retrospective review of PFPT in urologic patients included 10 with IC/BPS, and demonstrated moderate to marked improvement in 70%.⁸² A larger study reported 63% of patients had significant pain improvement, and this was proportional to the number of physical therapy visits.⁸³ A National Institutes of Health sponsored trial showed a positive treatment outcome in patients with IC/BPS treated with internal pelvic muscle physical therapy compared with general therapeutic massage (GTM), both in the multicenter feasibility trial and in the second clinical trial.^84,85 The clinical trial enrolled 81 women with IC, who were then randomized to 8 weeks of PFPT versus GTM. Symptom improvement was observed in 59% in the PFPT group and 26% in the GTM group.⁸⁵ Given the high efficacy of PFPT with minimal risk or adverse side effects, we recommend this treatment in patients with N-HL IC/BPS, particularly for those with tight or tender pelvic floors or trigger points on physical exam.

OnabotulinumtoxinA

Originally the AUA guidelines cited the use of onabotulinumtoxinA (Botox, BTX) for symptomatic relief of urgency and frequency and that patients should be made aware their symptoms of pain could persist after BTX injection.²⁶ Many studies, however, have proposed a dual mechanism of action of BTX affecting not only efferent but afferent mechanisms; BTX has been shown to inhibit the release of acetylcholine, norepinephrine, adenosine triphosphate (ATP), and substance P from the urothelium and nerve fibers.^86–88 Therefore, BTX may cause peripheral afferent desensitization and induce the inhibition of purinergic receptor expression.^89–91 This afferent mechanism, theoretically, is what provides added relief for patients with N-HL IC/BPS.

In the updated AUA guidelines, BTX was moved to a fourth-line treatment from a fifth-line treatment after an updated literature review found 100 units (U) of BTX with or without HD to consistently reduce morbidity [including pain visual analog scale (VAS), frequency, QoL, nocturia and bladder capacity].⁷ These studies looked at BTX injections alone as well as combined with HD and had long-term follow up (years rather than months).^92–94

Most retreatment studies reinjected 100 U with or without HD at around 6 months. Most of the patients were followed for 2 years with significant improvement (in pain VAS scores, IC Symptom and Problem Index scores, frequency, nocturia, and/or bladder capacity) maintained over time with repeat injections as well as with low adverse events (AEs) despite increased number of treatments.^93–97 AEs included urinary tract infections ranging from 4.9% to 19% after each treatment. Dysuria was reported in 30% of patients after each treatment, and one patient (n = 81) went into acute retention requiring 3 months of intermittent catheterization.⁹⁵ Two of these studies^96,98 noted HL did not improve with the BTX regimens; the lesions were subsequently successfully treated with EC.

Pinto and colleagues^93,97 followed patients for up to 3 years after they received a 100 U injection into the trigonal wall with retreatment upon symptom return. They found improvements in pain VAS, frequency, voided volume, and QoL that lasted 9–10 months after each treatment.

Kuo and colleagues⁸⁸ randomized patients into three groups: HD only, BTX 100 U and HD, BTX 200 U and HD. Only the BTX groups demonstrated significant improvements in pain VAS scores and maximum bladder capacity; the 200 U dose was not more effective than the 100 U dose yet had greater AEs, including increased post void residual and dysuria. The AUA therefore recommends the use of 100 U of BTX as a fourth-line treatment due to its substantially reduced morbidity.⁷

We continue to offer intravesical BTX injections for urgency and frequency relief. As recommended, we only administer BTX in patients who are willing to perform self catheterization or have an indwelling catheter; this is particularly important in the IC/BPS population as catheterization can add to their discomfort.

Trigger point injections and pudendal nerve blocks

Patients with IC/BPS may have such significant tightness or pain/tenderness of the pelvic floor that the muscles are resistant to manual therapy with the therapist. In these patients, we recommend injection of the muscle trigger points specifically, and the pelvic floor in general, in a systematic fashion with a combination of a long-acting local anesthetic and steroid. This is done in a series of three sets of injections spaced 6–8 weeks apart. We recommend the use of ropivacaine rather than bupivacaine given the decreased risk of myonecrosis demonstrated both acutely and chronically in animal models.^99,100 A transvaginal approach is usually well tolerated in the office with no sedation or general anesthetic needed; sedation is an option if the patient prefers.¹⁰¹ Several studies have demonstrated the efficacy of trigger point injections in improving pelvic pain.^101–104 Langford and colleagues reported that in women with pelvic pain, both with and without a diagnosis of IC/BPS, trigger point injections with a combination of bupivacaine, lidocaine, and triamcinolone caused immediate pain relief after injection.¹⁰¹ Mean VAS score decreased from 88.8% (100% scale) to 36% at 3-month follow up, with 33% of patients completely pain free. Zoorob and colleagues randomized patients to PFPT or trigger point injections with the same solution (bupivacaine, lidocaine, and triamcinolone) and demonstrated improvement in pelvic floor myalgia, sexual function and global symptoms, although no statistically significant differences were observed between the two treatment groups.¹⁰³ Tadros and colleagues studied 37 men with pelvic pain refractory to PFPT (n = 34) or who had refused PFPT (n = 3); resolution or improvement of pain was seen in 64.7% after trigger point injections with local anesthetic.¹⁰² Of note, none of the three patients who had previously refused PFPT improved, thus reinforcing the use of trigger point injections as an adjunct to PFPT rather than as an isolated therapy.

Trigger point injections with BTX have also been extensively studied in patients with pelvic pain and N-HL IC/BPS. Multiple trials have demonstrated improvement in many symptoms, including pelvic pain, dyspareunia, sexual function, and QoL.^105–110 There are minimal self-limiting adverse side effects,¹¹⁰ with benefits sustained after multiple repeat injections.¹⁰⁹ Abbott and colleagues reported decreased subjective pelvic pain and decreased pressures on vaginal manometry in a double-blinded placebo-controlled randomized trial of 60 women with chronic pelvic pain for more than 2 years; 30 women received 80 units of BTX and 30 with saline.¹⁰⁵ A more recent open-label prospective pilot trial enrolled 21 patients with high-tone PFD, nine of whom had been diagnosed with IC/BPS.¹⁰⁷ Patients were treated with up to 300 U of BTX injected with electromyography guidance. Overall 61.9% of subjects reported improvement from baseline at 4 weeks and 80.9% at 8, 12, and 24 weeks post injection. Tenderness was decreased on digital exam at all visits, and vaginal manometry demonstrated significant decreases in vaginal resting pressures. Halder and colleagues studied the combination of BTX injections with PFPT in 50 women with myofascial pelvic pain and noted significant improvements in the number of trigger points on exam and pelvic pain scores; a majority of women (58%) reported overall improvement.¹⁰⁶

Pudendal nerve blocks can be performed independently or in conjunction with trigger point injections in patients with N-HL IC/BPS and PFD. Pudendal blocks can be performed transvaginally or transgluteally using local anesthetic with or without steroids. The technique has been described for over half a century in the obstetric literature as a means of anesthetic during childbirth.¹¹¹ These nerve blocks can not only improve the tolerability of the trigger point injections, but pain improvement following a pudendal nerve block is required to diagnose pudendal neuralgia per Nantes criteria.¹¹² This is a particularly useful tool as pudendal neuralgia is common in patients with PFD, either as a cause of pelvic floor myalgia or as a result of nerve irritation due to pelvic floor muscle spasm.

Neuromodulation

Sacral neuromodulation has been shown to be a safe and efficacious option if other treatments fail^113–116 and has been shown to decrease narcotic medication requirements in these refractory patients.¹¹⁴ Results have been shown to be durable with a reported success rate of 72% at a median follow up of 61.5 months.¹¹⁶ A recent meta-analysis of 17 studies and 583 patients who underwent sacral neuromodulation for refractory IC noted a pooled overall success rate of 84% with minimal AEs.¹¹⁷ In addition to decreased pelvic pain, the authors also noted that Interstitial Cystitis Problem and Symptom Index scores improved, as did nocturia, daytime frequency, voids per 24 h, urgency, and average voided volumes.

There are, however, obstacles with this therapy as the surgical procedure and device (Interstim, Medtronic, Minneapolis, MN) are expensive.Interstim is also not approved by the FDA for treatment of pain caused by IC/BPS. It is, however, approved for treatment of urge incontinence and frequency–urgency syndrome, which these patients commonly have.

Pudendal neuromodulation has been studied in patients with N-HL IC/BPS and pudendal neuralgia, with excellent results.^118–120 We reported a series of 84 patients who underwent implantation of a pudendal neurostimulator with the indication of pelvic pain in 42 patients.¹¹⁸ After 12 months, Interstitial Cystitis Symptom and Problem Index scores were significantly improved in this subset. In our series of 19 patients with pain secondary to pudendal neuralgia who underwent placement of a pudendal neurostimulator, all patients had improvement in pain, including six who had previously failed to respond to sacral neuromodulation.¹¹⁹

Complimentary therapies

Due to the complex, often multisystem, nature of N-HL IC/BPS, we offer a variety of complimentary medicines including acupuncture, massage, guided imagery, and Reiki therapy. Psychological therapies including cognitive and behavioral therapy (CBT), interpersonal therapy, and emotionally expressive therapy (EET) are also offered. CBT helps patients develop effective coping strategies for managing stress and worry that may accompany pain as well as urological problems. This is particularly important in light of recent studies which highlight the importance of psychological intervention in addition to medical therapy for comorbidities associated with N-HL IC/BPS, such as endometriosis.¹²¹ Interpersonal therapy helps patients manage intimacy aspects that often develop with N-HL IC/BPS, and EET helps patients work through painful experiences that often precede the onset of N-HL IC/BPS.

Although N-HL is the most common subtype of IC/BPS, the bladder may be an innocent bystander in a larger pelvic process. We are convinced that in these patients, management of the pelvic floor is the primary goal, complemented by a multidisciplinary team to manage a variety of other systemic symptoms. There are a minority of patients who have bladder centric symptoms with no PFD or those who have undergone successful treatment of their PFD but with persistent bladder symptoms. For the majority of patients with N-HL IC/BPS, however, the pelvic floor plays an important role and successful treatment requires a holistic, multidisciplinary approach.

Upcoming treatments and new developments

There are many exciting studies ongoing in IC/BPS treatment. Nickel and colleagues conducted an open-label trial of 16 patients who kept a continuous lidocaine releasing intravesical system (LiRIS) device for 2 weeks.¹²² They reported a global response assessment showing sustained rates of symptom improvement of 64% at 1 and 2 weeks as well as an 83% (five out of six) resolution of HLs with an intravesical lidocaine system. The phase II placebo-controlled LiNKA trial for LiRIS in patients with HL IC/BPS is completing soon.

There have also been pilot placebo-controlled studies published on the use of intravesical liposome for delivery of topical BTX, thereby avoiding cystoscopic needle injection. The intravesical instillation of the liposomal formulation of BTX significantly reduced frequency and urgency without adverse side effects, increasing residual urine volume, or increasing the need for clean intermittent catheterization.^123,124 Liposomal delivery of BTX is currently being studied in a multicenter, prospective, placebo-controlled, double-blind trial.¹²⁵ At our institution, we are currently enrolling for a prospective randomized trial to evaluate bladder-directed instillations compared with PFPT for N-HL IC/BPS, funded by the Department of Defense.

Although InterStim is not approved for pain, a new wireless electrode with a programmable receiver (StimWave, Inc., Pompano Beach, FL) recently received approval for peripheral nerve stimulation for pain. This electrode can be placed percutaneously at the pudendal nerve, and is powered by a small wearable rechargeable battery and antenna placed near the receiver. Further studies of this device in patients with N-HL IC/BPS, PFD, and pudendal neuralgia are forthcoming.

Novel agents that modify the SHIP1 pathway are also being studied for pelvic pain symptoms. AQX-1125 is a SHIP1 activator which inhibits the phosphoinositide 3 kinase (PI3K) pathway. When the PI3K pathway is overactive, proinflammatory signaling molecules are produced that can concentrate in tissues resulting in chronic inflammation. Although still in the early stages, preliminary data on the effect of blocking this pathway have been promising.¹²⁶

Other recent developments include identifying biochemical markers for IC/BPS. Corcoran and colleagues¹²⁷ found significant reduction in post-HD urine levels of monocyte chemotactic protein 3 (MCP-3) and tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) when compared with pre HD in patients with IC/BPS up to 1 month post distention. Parker and colleagues¹²⁸ have found etiocholan3α-ol-17-one sulfate (Etio-S) which is a sulfoconjugated 5-β reduced isomer of testosterone, distinguished female IC/BPS from control subjects with over 90% sensitivity and specificity. Etio-S was found to be higher in patients with IC/BPS which also correlated with elevated symptom scores and could resolve high- from low-symptom-score subgroups.

In an effort to distinguish IC/BPS from comorbid pain (including somatic syndromes such as fibromyalgia, irritable bowel syndrome, and chronic fatigue syndrome), Schrepf and colleagues¹²⁹ found toll-like receptor 4 inflammatory responses in peripheral blood mononuclear cells were significantly higher in patients endorsing extra-pelvic pain.

Other studies have looked into identifying chemokines and cytokines to differentiate HL IC from N-HL IC/BPS. CXCL 10 is a potent angiogenesis inhibitor that has been suggested to predominate in mediating the pain symptoms in HL IC while MCP-1 has been indicated for N-HL IC/BPS pain symptoms.¹³⁰ Tyagi and colleagues¹³¹ found a significant 5- to 20-fold increase in CXC chemokine ligand 10 and 1, interleukin 6, and nerve growth factor in HL IC compared with N-HL IC/BPS. More recently, Jhang and colleagues¹³² found endothelial nitric oxide synthase to be significantly higher in the HL IC group than in the N-HL IC/BPS group.

Conclusion

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; exciting and novel research studies are developing promising treatments.