Sections

Treatment

Approach Considerations

The difficulty in treating interstitial cystitis begins in the primary care office, where knowledge of the condition is suboptimal.^[58]An integral part of therapy for interstitial cystitis is extensive patient education regarding the chronic nature of the disease and realistic assessments of the condition, prognosis, and potential responses to therapy. Ongoing reassurance and physical and emotional support are important as the diagnostic evaluation progresses and therapies are applied.

Only rarely will patients with interstitial cystitis have an immediate, complete, and durable response to any particular therapy. They must be counseled at length regarding the lack of universally effective therapies. Often, referral to one of the local interstitial cystitis support groups, especially a local chapter of the Interstitial Cystitis Association, can be helpful in providing a continuing network of support for the patient.

Ideally, in clinical practice, the treatment of interstitial cystitis should be initiated with the least invasive, least expensive, and most reversible therapy. In general, this consists of a program of dietary and fluid management, time and stress management, and behavioral modification. The 2022 American Urological Association guidelines recommend tailoring treatments to the patient's specific symptoms, with the aim of optimizing quality of life.^[3]

The level of initial treatment may also be influenced by clinical judgment, taking into account the severity of presenting symptoms and patient-specific factors. At times, multiple simultaneous treatments may be used in select patients. In patients who have shown no response to multiple treatment modalities, reassessment for any underlying patient condition should be undertaken.^[3]

Interventions may include the following:

Oral pharmacologic agents (eg, pentosan polysulfate sodium [Elmiron], antihistamines, tricyclic antidepressants, analgesics, anti-inflammatory agents)
Intravesical therapy (ie, medications intermittently instilled directly into the bladder via a catheter)
Surgical therapies
Electrical stimulation
Complementary therapies (eg, acupuncture, hypnosis, pelvic floor massage)

In a chronic, often poorly controlled condition such as interstitial cystitis, patients may seek alternative, holistic, or complementary therapies. These patients should be cautioned that such therapies, while potentially successful, often have not been validated scientifically. Desperate patients should be counseled to avoid potentially harmful, unproven therapies. However, one such complementary therapy, pelvic floor massage, has been shown to have some modest efficacy in a select group of patients in a well-done controlled trial.^[59]

Following each intervention, the patient is reassessed for response. Unfortunately, therapies are often applied in a haphazard, "hit-or-miss" fashion, combining numerous different therapies before the patient's response to each therapy is truly assessed. This approach is sometimes partly driven by unrealistic patient demands and expectations regarding the success of various therapeutic interventions.

Again, patients must receive extensive counseling regarding the nature and prognosis of their condition and its response to therapy. This is critically important, and such counseling must be initiated prior to embarking on invasive interventions for which no proven overwhelming benefit may be achieved.

Behavioral Therapy

Biofeedback and pelvic floor rehabilitation, bladder training programs (ie, progressively increasing the voiding interval over the course of weeks to months), and other behavioral measures are excellent initial interventions and have been used by some authors with some success.^{[60, 61]}The urinary frequency and urgency components seem to respond better to these interventions than the pelvic pain component.

Treatment decisions

Ultimately, the decision to abandon or augment behavioral therapy and to pursue other therapeutic options is made by the patient and physician when a general lack of progress occurs or when symptoms progress. Very few, if any, studies have looked at the minimal duration of time necessary to assess response to behavioral therapy in patients with interstitial cystitis. Furthermore, an optimal behavioral program has also not been defined.

Given the chronic nature of the condition and the possibility of spontaneous improvement or remission, progressively more invasive and expensive treatment should be initiated with caution. Generally, if tolerated by the patient, a trial of 3-6 months of behavioral therapy is warranted prior to proceeding to more invasive or expensive therapies.

Dietary Therapy

Various dietary measures have been examined as therapy for interstitial cystitis.^[62]These dietary measures and the previously mentioned behavioral measures can be effective when used alone, but they can also be complementary to virtually all other interventions for interstitial cystitis. Some studies have reported that up to 90% of patients reported symptom exacerbations linked to food, beverage, and dietary supplements.^[63]

Foods that have been implicated in aggravating symptoms of interstitial cystitis and, in the opinion of some authors, can precipitate symptomatic flares, include the following:

Coffee
Alcohol (beer, red wine, white wine, champagne)
Carbonated beverages
Monosodium glutamate (MSG)
Artificial sweeteners
Tomatoes
Vinegar
Citrus
Spicy foods
Chocolate
Cranberry juice
Particular fruits and vegetables

Avoiding these food items or substituting other food items is often advised. In a 2011 study, use of calcium glycerophosphate, sodium bicarbonate, or both before eating foods that triggered symptoms showed a trend toward improvement of symptoms.^[64]

Patients may be instructed to fill out a food diary, recording the relationship between the consumption of various food and drink items and their interstitial cystitis symptoms. In this manner, items that provoke or exacerbate the interstitial cystitis symptom complex can be eliminated from the diet in a methodical fashion.

Common theories for dietary exacerbations include the hypothesis that the disrupted urothelial barrier is sensitive to metabolites of these foods. Alternative theories include the mechanism of "cross-talk," or the idea that stimuli from one organ can lead to changes in another organ by integrated sensory pathways. In other words, stimulation of the bowel by certain dietary substances can modulate pelvic pain in interstitial cystitis/bladder pain syndrome (IC/BPS).^[65]

On the other hand, foods that have been identified as least bothersome to patients with IC/BPS include the following^[65]:

Water
Milk
Bananas
Bluberries
Melon
Carrots
Broccoli
Mushrooms
Peas
Chicken
Eggs
Most meats
Rice
Popcorn

Oral Medication

Oral medications should be considered only after the aforementioned conservative measures have failed. With the exception of pentosan polysulfate sodium, the drugs listed in the Medication section are not specific for the treatment of interstitial cystitis; however, all of them have demonstrated some degree of efficacy in controlled or uncontrolled studies.

The duration of individual pharmacotherapy is variable. The clinical studies on pentosan polysulfate sodium seem to suggest that maximal effects are not observed until the patient has been on drug therapy for 5-6 months. Other medications are dispensed and their effects are reevaluated as per the expected pharmacokinetics. For example, steady-state serum levels of many tricyclic antidepressants are not attained until 6-8 weeks of stable dosing. Only at this time can the drug dose be safely and reasonably adjusted.

A study funded by the National Institutes of Health found that using pentosan polysulfate sodium alone or in combination with hydroxyzine was slightly beneficial, but this was not significant. The study compared placebo with oral pentosan polysulfate sodium, hydroxyzine, and a combination of both.^[66]

In a randomized, double-blind, placebo-controlled study, amitriptyline was shown to provide statistically significant improvement in the O'Leary-Sant interstitial cystitis symptom index and problem index, pain, and urgency intensity. Common adverse effects of amitriptyline include dry mouth, weight gain, constipation, and sedation.^[67]

In a 2010 intention-to-treat study by Foster et al, 271 women were randomized to behavioral therapy alone or therapy with amitriptyline dose escalation. No difference was found between the amitriptyline and placebo groups overall. However, subgroup analysis showed a mild improvement in symptoms in women on 50 mg of amitriptyline as compared with placebo.^[68]

Cimetidine is a second-line therapy according to the AUA guidelines and is thought to demonstrate effectiveness via competitive inhibition of the H2 histamine receptor.^[15]

Anticholinergic agents such as oxybutynin and tolterodine can be used to treat the urinary frequency component of interstitial cystitis; however, these agents can impair bladder emptying and thus may exacerbate pelvic pain. They should be used with caution in patients with interstitial cystitis, and the patient should be informed that these agents are not indicated specifically for the treatment of interstitial cystitis.

In a randomized, prospective, nonblinded study, cyclosporine (a calcineurin inhibitor) significantly reduced micturition frequency and demonstrated superior clinical response rates when compared with pentosan polysulfate sodium; however, treatment-related toxicity was higher in the cyclosporine arm.^[69]Further, response rates in some studies were much lower after treatment with cyclosporine in patients without Hunner ulcers.^[70]Cyclosporine is currently included in the American Urological Association (AUA) guidelines as a treatment option for patients with Hunner lesions refractory to fulguration and/or triamcinolone.^[3]

Studies of immune modulators not evaluated in the AUA guidelines can be found in primary literature. These include mycophenolate mofetil (MMF), tanezumab, and certolizumab pegol.^{[71, 72]} Data on MMF are sparse, and the response was poor in patients with refractory interstitial cystitis/bladder pain syndrome (IC/BPS) in a well-done controlled trial.^[73]

Treatment algorithm

The treatment of interstitial cystitis is complex and various algorithms have been developed. The 2022 AUA guidelines no longer include a treatment algorithm and instead encourage the use of an individualized clinical approach based on the unique characteristics of each patient.^[3]

The authors' algorithm for treatment is largely based on whether the patient has predominantly pelvic pain or urgency/frequency. In the authors' experience, patients with pelvic pain and minimal voiding symptoms represent a pharmacologic challenge, making an early pain-management clinic referral a useful adjunct.

In patients with significant voiding symptoms, the authors suggest an algorithm proposed by Hanno. Conservative treatment may include patient education, dietary manipulation, nonprescription analgesics, and pelvic floor relaxation. If the improvement in symptoms is inadequate, begin oral therapy with antispasmodics/antimuscarinics and nonnarcotic analgesics. In addition, a trial of amitriptyline for 8 weeks may be warranted. If amitriptyline fails, a trial of hydroxyzine for 8 weeks is suggested. If no response is observed, follow hydroxyzine with pentosan polysulfate sodium.

A 6- to 9-month course of pentosan polysulfate sodium (100 mg tid) is followed by a reassessment of interstitial cystitis symptoms. The authors have found that lower doses of this compound are not as effective, but we have not used the higher doses advocated by some authors. Additionally, adverse effects with pentosan polysulfate are dose dependent. One complication, particularly with long-term use, is macular disease, which may impair vision.^{[74, 75]}

We attempt to try single-agent therapy first, moving down the ladder of medications, rather than treating patients with multiple agents from the outset. If conservative measures and medical therapy fail to provide adequate relief, surgical therapy should be considered.

Pain Management

Managing the pain component can be difficult in patients with interstitial cystitis. The etiology of the pain remains unclear, but various authors have postulated the etiology to be mediated centrally, peripherally, or locally via a neurogenic or inflammatory mechanism. Increasing evidence has implicated central mechanisms and sensitization in women with interstitial cystitis/bladder pain syndrome (IC/BPS). A study by Lai et al showed segmental hyperalgesia to mechanical stimulation in patients with IC/BPS.^[76]

Additionally, it has been shown that there is excessive adrenergic stimulation in patients with IC/BPS, and iatrogenic stimulation shows heightened response in IC/BPS patients with pathologic findings of increased mucosal mastocytosis and increased sympathetic nerve density.^[77]

Some patients require long-term pain medications, while others rely on analgesics only during periods of symptomatic flares.

Agents used for pain relief include the following:

Anti-inflammatory drugs
Acetaminophen
Gabapentin (Neurontin)
Tricyclic antidepressants
Selective serotonin reuptake inhibitors (SSRIs)
Various other agents

Most clinicians tend to avoid the extensive use of narcotics in patients with interstitial cystitis. When the pain component becomes unresponsive to nonnarcotic agents, referral to a chronic pain management facility may be helpful.

Transcutaneous electrical nerve stimulation (TENS) units, electrical stimulation (intravaginal), acupuncture, and intrathecal and intraspinal infusions have all been used. Topical anesthetics such as lidocaine have been applied directly to the bladder intravesically and have yielded some success.

Instillation Therapy

Patients in whom medical therapy fails may benefit from another bladder hydrodistention if the initial diagnostic hydrodistention was therapeutic. In the rare patient in whom a Hunner ulcer is seen on cystoscopy, fulguration (electrocautery) and/or injection of triamcinolone should be performed..^[3]

If patients still do not respond, intravesical therapy may be initiated, beginning with weekly dimethyl sulfoxide (DMSO) therapy for 6 courses. Monthly maintenance DMSO instillations have been advocated by some clinicians in order to prevent flares, although data supporting this approach are lacking.

DMSO may be combined with steroids, bicarbonate, and heparin. Intravesical lidocaine may also be added. Some patients with refractory interstitial cystitis symptoms self-catheterize at home and instill a variety of these medications intravesically on an as-needed basis for symptom flares or simply for long-term therapy. In patients who respond poorly to DMSO, intravesical heparin or sodium oxychlorosene (Clorpactin) may be tried.

Long-term application of capsaicin, a component of hot pepper, has been associated with the desensitization of C fibers, the unmyelinated nerve fibers known for transmitting pain. Intravesical instillation of capsaicin has been limited in its use in interstitial cystitis because of the sensation of severe burning.

Resiniferatoxin, a capsaicin analogue, is 100-10,000 times more potent than capsaicin and is not associated with severe burning. However, resiniferatoxin has shown poor effectiveness after single administration, with no significant improvement in symptoms of interstitial cystitis, and adverse effects of dose-dependent pain and urgency symptoms.^[78]A meta-analysis by Guo et al in 2013 showed that no significant improvement was achieved in patients treated with resiniferatoxin in terms of frequency, nocturia, incontinence, or involuntary detrusor contractions.^[79]At this time, the AUA recommends against this treatment.^[80]

Hyaluronic acid glycosaminoglycan replenishment therapy has yielded moderate results in non–placebo-controlled studies. In a study of weekly instillation of a 50-mL solution of phosphate-buffered solution containing 40 mg of sodium hyaluronate, 85% and 84% of patients reported symptomatic and quality-of-life improvement, respectively, with 50% of patients reporting a lasting effect at 5-year follow-up.^[81]Patients in this study had demonstrated abnormal results on a modified potassium sensitivity test. Lower response rates are seen in patients without evidence of a urine-tissue barrier abnormality.^[81]Currently, several studies with level 2b evidence support hyaluronic acid instillation. Patients report decreases in visual analog pain scores. Multicenter randomized trials do not exist, however.^[82]

In combination with hydrodistension, hyaluronic acid has been shown to maintain or prolong the effect of hydrodistension in some patients with IC/BPS.^[83]

Additional smaller studies have shown that both hyaluronic acid and chondroitin sulfate produced sustained improvement in symptomatology (up to 3 y) in patients with refractory IC/BPS.^[84]Unfortunately, other small studies have not been able to support the use of chondroitin sulfate as a monotherapy for IC/BPS, despite small improvements in pain scores.^[85]

Intravesical bacillus Calmette-Guérin (BCG) has been hypothesized to suppress inflammation within the bladder. A randomized, placebo-controlled trial in patients with refractory interstitial cystitis revealed borderline statistical significance for global response assessment questioning, as well as most secondary outcome measures, including capacity, pain scores, urgency/frequency symptoms, and interstitial cystitis inventories.^[86]As with resiniferatoxin, the AUA currently recommends against this treatment.^[80]

Experimental therapies include treatment with intravesical liposomes, which are vesicles composed of concentric phospholipid bilayers.^[87]These adsorb to cell surfaces and act as a delivery mechanisms for various chemicals. Animal models have shown decreased bladder sensitivity to potassium chloride,^[88]and small human studies have shown promising results in reduction of frequency, nocturia, pain, urgency, and O'Leary-Sant scores.^[89]While these results are initially promising, large, randomized trials are still lacking.

In animal models, direct transplantation of stem cells into the bladder has proved beneficial. In addition, animal experiments suggest that stem cells may provide an autologous cell source for bladder tissue regeneration, in patients requiring bladder augmentation.^[90]

Hyperbaric oxygen is also an emerging treatment. As this has been successfully used to treat hemorrhagic cystitis from cyclophosphamide and radiation, it was used in a pilot study in patients with refractory IC/BPS.^[91]Seven of 11 patients showed durable improvement in pain scores and urgency symptoms lasing over 2 years. This may also be a useful adjunct to DMSO instillation.^[92]

Bladder Hydrodistention

Cystoscopy under anesthesia with short-duration, low-pressure hydrodistension may be performed. This is usually performed at 60-80 cm water for less than 10 minutes. Hydrodistention at pressures greater than 100 cm water or for a duration exceeding 10 minutes is associated with adverse outcomes, including bladder rupture. AUA guidelines recommend against high-pressure, long-duration hydrodistention.^[3]

The mechanism of action of bladder hydraulic distention is unknown. Hypotheses include neurapraxias by mechanical trauma and epithelial damage from mechanical trauma.

Surgical Therapies

Currently, no specific surgical therapies are directed towards interstitial cystitis. All surgical therapies currently used for treatment have been adapted from other therapeutic areas, and applied, sometimes successfully and sometimes not, to the population with interstitial cystitis.

Neuromodulation, or InterStim, is indicated for the treatment of some types of refractory voiding dysfunction, including urgency, frequency, and urge incontinence. This involves surgical placement of an electrode into the S-3 foramen to provide direct sacral nerve root stimulation. This technique has demonstrated some promising results in select patients with interstitial cystitis in some but not all studies, especially in the long term.

Studies in patients with interstitial cystitis refractory to conservative measures (ie, behavioral modification, diet, medications, hydrodistention) have found that sacral neuromodulation improved daytime frequency, nocturia, and mean voided volumes and decreased pain and interstitial cystitis symptom and problem index scores. In patients on long-term narcotics for refractory pain associated with interstitial cystitis, sacral neuromodulation has been shown to decrease (but not eliminate) narcotic requirements.

However, some authors have challenged these results. The frequency that arises in patients with IC/BPS is one in which patients void frequently to avoid pain with bladder filling. The studies showing benefit from sacral neuromodulation are all observational, small, single-center studies. Patients should be made aware that the indications for sacral neuromodulation are for voiding symptoms, and any effect on pain is unpredictable.

This should only be used as a fourth-line therapy.^[93]A 2011 meta-analysis of sacral neuromodulation for chronic pelvic pain showed widely variable response rates and equally variable follow-up times, further questioning the use of this as a therapy for patients with IC/BPS.^[94]However, as this has been shown to be a somewhat effective therapy in many patients, and as it is minimally invasive, it may be considered prior to any major invasive surgical interventions.^[95]

In addition, sacral neuromodulation has been shown to normalize the abnormally high levels of antiproliferative factor (APF) and the abnormally low levels of heparin-binding epidermal growth factor in the urine of patients with interstitial cystitis.

Pudendal nerve stimulation has also been evaluated in patients with interstitial cystitis and has been compared with sacral nerve stimulation. In a small series, overall reduction in symptoms was 59% for pudendal nerve stimulation and 44% for sacral nerve stimulation.^{[96, 97, 98]}

Botulinum toxin has been used for the treatment of interstitial cystitis as an isolated treatment, as well as in combination with other treatments. Results are mixed and patients should be counseled regarding the potential adverse effect of urinary retention.

Transurethral intradetrusor injection of onabotulinumtoxinA (OBA) coupled with therapeutic hydrodistention has been shown to be superior to hydrodistention alone in improving symptoms and bladder capacity in patients with interstitial cystitis. However, higher doses appear to increase the risk of postoperative voiding dysfunction and urinary retention. The use of intradetrusor OBA for this indication remains investigational.^{[99, 100, 101]}

Multicenter trials investigating OBA use for refractory IC/BPS have shown significant benefit in a small number of patients, but overall no improvement in O'Leary-Sant scores.^[102]

Other long-term studies have shown improvements in pain scores, with symptom relief lasting from 6-12 months, with an average duration of relief of 9.9 months.^[103]Evidence indicates that location of injection of OBA is important. In a small 2011 study, investigators attempted to block urethral visceral afferent fibers with OBA. No improvement in pain symptoms was noted.^[104]This is in contrast to other studies, in which OBA was injected directly into the detrusor muscle or trigone.^[103]Unfortunately, the heterogeneity of studies with OBA has prevented effective meta-analysis, despite these studies suggesting a trend toward short-term benefit.^[105]

Potential mechanisms for the effectiveness of OBA include down-regulation of vascular endothelial growth factor (VEGF) and an afferent sensory effect.^[106]

Rarely indicated surgical therapies include the following:

Laser photoradiation (poor results)
Electrical stimulation
Transcutaneous electrical nerve stimulatio (TENS; more marked effect on bladder pain than on urinary frequency)
Peripheral denervation (rarely indicated)
Bladder augmentation (controversial because pain usually does not improve)
Urinary diversion (most invasive; usually reserved as last resort)

Indications for urinary tract reconstruction or urinary diversion are very limited in patients with interstitial cystitis. Candidates for these procedures should have exhausted all reasonable and available medical, pharmacologic, and behavioral therapies for their condition. They should also understand that even technically successful urinary tract reconstruction or urinary diversion still may not relieve the underlying symptoms of pain and urinary urgency.

Some studies have investigated a role for diversion in the absence of cystectomy as a therapy. Norus et al showed that no differences in symptoms were reported in patients who underwent ileal conduit after cystectomy compared with those who underwent ileal conduit without cystectomy, suggesting this as an appropriate option in carefully selected patients.^[107]In a study by Peters in 2013, 10 women with previous ulcerative IC/BPS underwent cystectomy and urinary diversion (1 with a neobladder, 9 with ilealconduit). Despite 6 of the patients requiring reoperation, 8 of 9 reported significant improvements in quality of life and would make the same decision again. IC/BPS pain had resolved in 8 of 9 respondents in follow-up surveys.^[21]

Surgeons should be reminded, however, that significant improvements were seen in those with ulcerative IC/BPS, and results in those with nonulcerative disease had poorer outcomes.^[108]

However, as these therapies are highly invasive and evidence in the literature is composed only of very small studies, they should be reserved for patients who have been extensively counseled and in whom prior therapies have failed. As severe, refractory IC/BPS is considered by some to be an "orphan disease," treatments should be tailored to the individual to offer the best chance for a successful outcome.^[108]

These reconstructive procedures are large surgical undertakings and, for the most part, are irreversible. Only limited success has been reported; thus, patients should be extensively counseled prior to undergoing this type of surgical therapy for interstitial cystitis.

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Author

Eric S Rovner, MD Professor, Department of Urology, Medical University of South Carolina College of Medicine

Eric S Rovner, MD is a member of the following medical societies: Alpha Omega Alpha, American Association of Clinical Urologists, American College of Surgeons, American Urological Association, International Continence Society, International Society of Urology, Society of Pelvic Reconstructive Surgeons

Disclosure: Nothing to disclose.

Coauthor(s)

Justin D Ellett, MD, PhD Partner, Lowcountry Urology Clinics

Justin D Ellett, MD, PhD is a member of the following medical societies: American Association of Clinical Urologists, American Urological Association

Disclosure: Nothing to disclose.

Colin Murrah Goudelocke, MD Assistant Professor, Department of Urology, Medical University of South Carolina College of Medicine

Colin Murrah Goudelocke, MD is a member of the following medical societies: American Urological Association

Disclosure: Nothing to disclose.

Chief Editor

Edward David Kim, MD, FACS Professor of Urology, Department of Urology, University of Tennessee Graduate School of Medicine; Consulting Staff, University of Tennessee Medical Center

Edward David Kim, MD, FACS is a member of the following medical societies: American Society for Reproductive Medicine, American Urological Association, Sexual Medicine Society of North America, Society for Male Reproduction and Urology, Society for the Study of Male Reproduction, Tennessee Medical Association

Disclosure: Serve(d) as a speaker or a member of a speakers bureau for: Endo, Antares.

Acknowledgements

Matthew Eskridge, MD Physician, Alliance Urology Specialists, Greensboro, NC

Matthew Eskridge, MD is a member of the following medical societies: American Urological Association and Christian Medical & Dental Society

Disclosure: Nothing to disclose.

Colin Goudelocke, MD, Physician, Academic Urology, Chattanooga, TN

Disclosure: Nothing to disclose.

Ricardo Sanchez-Ortiz, MD Assistant Professor of Urologic Oncology, University of Puerto Rico School of Medicine; Adjunct Assistant Professor, Department of Urology, The University of Texas MD Anderson Cancer Center

Ricarco Sanchez-Ortiz, MD is a member of the following medical societies: Alpha Omega Alpha

Disclosure: Nothing to disclose.