Approach
There is no consensus on the approach to treating patients. This is because the etiology is relatively unknown and multiple disease phenotypes exist. Many large-scale studies have been performed on patients with IC/BPS, but most predate the belief that this is not a bladder-centered disease. One Chochrane review found that evidence for all included treatments was low to very low certainty.[44] The failure of bladder-centered therapy is likely applicable to those with pelvic floor dysfunction and central sensitization, but may be indicated in those with ulcerative IC.
We recommend dividing patients into those with and without ulcers, as well as phenotyping patients based on pelvic floor dysfunction. Treatments should be directed toward a patient's primary symptoms (pain, urge, frequency).
Treatment choice should be guided by shared decision-making, individual patient factors, and clinical judgment.[1] Thus concurrent, multimodal therapies may be offered, but initial therapy should be nonsurgical for patients without ulcers.[1] Treatment is escalated until the patient obtains relief from symptoms. Success or failure of a specific therapy is assessed with Pelvic Pain and Urgency/Frequency (PUF) Questionnaire scores or Global Response Assessment (GRA).
Successful therapies are indicated by a 30% to 50% reduction in serial PUF scores or by "mostly or very much improved" on GRA. Ineffective treatments should be discontinued.[1] The American Urological Association recommends reconsidering the diagnosis if multiple treatment appraoches fail to improve symptoms.[1]
Supportive therapies
Patients should be educated as to the chronic nature of their condition and must have a clear understanding of their prognosis. Physical and emotional support are important because patients must often try various treatment options over time, as immediate, complete response to individual therapies is rare. Referral to a support group or to the Interstitial Cystitis Association website can be helpful. Interstitial Cystitis Association Opens in new window Referral to a specialist pain clinic is recommended. Comorbid conditions should be treated appropriately.
Chronic pain is a significant life stressor and must be recognized in the context of long-term lifestyle changes. Multimodal support, integrative medicine, and psychological support is required to address the multidimensional nature of patient symptoms. The known associations of IC/BPS with physical and psychological abuse, sexual dysfunction, and depression necessitate a close working relationship with psychiatry or psychological counseling.
Noninvasive therapies
Noninvasive therapies include dietary changes, stress management, and behavioral modification (e.g., bladder training techniques and avoiding activities that exacerbate the condition).[1][15] Some patients may choose to try noninvasive therapies alone initially, while others may benefit from concurrent pharmacologic or intravesical therapy.[1]
Often the establishment of a diagnosis is beneficial for patients who do not understand their symptom pattern. Applying a disease label allows the patient to accept the diagnosis and focus on treatments and improvement. Counseling regarding symptom improvement rather than cure allows for setting expectations and tracking response to interventions.
A variety of foods, including alcohol, coffee, vinegar, tomatoes, chocolate, spicy foods, and certain fruits and vegetables, have been noted to exacerbate symptoms. Various lists of foods that should be avoided have been proposed, but there is no evidence to support that these dietary changes decrease exacerbations. Patient should be asked to fill in a food diary so a direct link between specific foods/beverages and symptom occurrence may be ascertained.[15] It is then recommended that items that are found to provoke or exacerbate symptoms be eliminated from the patient's diet.[1]
[Figure caption and citation for the preceding image starts]: Foods and beverages patients with IC may try or should avoidFrom the personal collection of Serge P. Marinkovic, MD [Citation ends].
Pelvic-floor rehabilitation by a trained pelvic rehabilitation specialist is critical for treatment of patients with myofascial trigger points and pelvic floor dysfunction.[3] Biofeedback and/or bladder retraining programs are considered excellent initial interventions aimed at dyspareunia and urgency/frequency symptoms, but consistency is the key to achieving long-term improvement. Bladder retraining is a method where patients are instructed to retain their urine a little longer each time (e.g., goal to urinate every hour at first, then every 2 hours, etc.). Patience is necessary because this method may take a few months to reduce frequency. Patients are instructed to learn self-guided exercises and massage between rehabilitation specialist visits. Internal manipulators or vaginal dilators are helpful for patients with severe pelvic floor dysfunction and spasm.
Hypnosis is an option, but has not been well studied for this condition; no data are available on its use. Acupuncture is another alternative therapy that has been used, but symptoms have not improved in studies.[45]
Patients may have a higher incidence of concomitant psychiatric illness (e.g., anxiety, depression), which can also exacerbate symptoms. For patients who have an established psychiatric history, working with the psychiatrist can benefit the physician and the patient.
Initial pharmacologic therapy
Medications may be offered concurrently with less invasive therapies. Initial therapies include antihistamines (e.g., hydroxyzine), pentosan polysulfate sodium, and mild analgesics such as ibuprofen or acetaminophen. Combinations of these medications may be required.
Pentosan polysulfate sodium is the only FDA-approved medication for IC, though efficacy data are limited and in some countries its use in IC/BPS is not recommended.[20] The proposed mechanism of action is binding to the urothelial layer and replacement of the glycosaminoglycan layer. Bioavailability is poor and the cost of the medication can be prohibitive.[46] Symptom improvement may take up to 6 months. Modest efficacy has been demonstrated in several studies.[46][47] However, a randomized trial was halted early, showing no benefit of pentosan polysulfate sodium over placebo.[48] Studies have shown an association between prolonged pentosan polysulfate sodium use and the development of a unique retinal pigmentary maculopathy causing difficulty reading, slow adjustment to low or reduced light environments, and blurred vision. Patients need to be counseled regarding this risk and a retinal examination prior to initiating therapy in those with pre-existing ophthalmologic conditions and within 6 months of initiation for all patients is recommended.[1]
Antihistamines target histamine release involved in mast cell degranulation. They block mast cell secretion, and may also have a neurogenic action resulting from the inhibition of serotonin secretion from the thalamic mast cells and neurons.[49] An open-label study of hydroxyzine demonstrated a 40% improvement in symptom scores from baseline, while symptom scores improved an additional 55% in study patients with concomitant seasonal allergies.[50] However, a pilot study found hydroxyzine to be no more effective than placebo in improving quality of life or number of voids.[51]
Tricyclic antidepressants (e.g., amitriptyline) have also been proposed for patients with central sensitization and pelvic pain. Studies have shown durable response as long as treatment is continued.[52] Amitriptyline is useful because of its anticholinergic, sedative, mast cell stabilization effects and serotonergic effects.[53] One study found significant improvements in symptom scores compared with placebo.[54]
The anticonvulsant gabapentin has proved useful in treating neuropathic pain conditions, such as reflex sympathetic dystrophy, diabetic neuropathy, and postherpetic neuralgia.[55] While the mechanism of action in ameliorating pain in these patients is unclear, the drug's analgesic effect may arise from calcium-channel modulation.[55] A pilot study of women with chronic pelvic pain showed better improvement in pain in patients randomized to gabapentin at 6 months compared with placebo.[56]
Anticholinergic medications may be beneficial for those symptoms of urgency and frequency, but not for pain. There are no data to support one particular anticholinergic over another. Factors to consider are cost, side effects of dry mouth and constipation, and dosing frequency. Newer beta-3 agonists (e.g., mirabegron) have shown similar efficacy in urgency/frequency treatment without the anticholinergic side effects. This has not been adequately tested in the IC/BPS population.
Patients with ulcerative forms of IC have a clear inflammatory pathway that causes direct damage to the bladder lining. Systemic immune modulators have been shown to be beneficial in symptom and ulcer relief.[57] Nonsteroidal treatments such as cyclosporine have been shown to be effective with response rates of 85% in those with ulcers versus 30% in those without ulcers.[58]
Many physicians reserve opioid analgesics for patients who do not respond to treatment, though upregulation of opioid receptors in patients with chronic pain, as well as side effects and addiction, should limit their use in common practice. Excellent guidelines for maintaining patients on chronic opioids exist.[59]
Intravesical therapy
Intravesical therapy is recommended in patients who show no response to oral pharmacologic therapy, have predominant bladder-centered pain, and have no pelvic floor dysfunction. It may also be used as a bridging therapy, given adjunctively when oral drugs are initiated, as some medications may take 1 to 3 weeks before a response is seen. Drugs are instilled in the bladder through a catheter, where the solution is held for a specific time (usually 10-15 minutes) before being emptied.
Dimethyl sulfoxide (DMSO), an industrial solvent, is the most commonly used drug, and the only FDA-approved intravesical therapy for IC. It is thought to decrease inflammation in the bladder and prevent muscle contractions. Limited evidence exists from small, mostly unblinded and nonplacebo controlled studies.[15] Adverse effects include garlic-odor breath, hepatic dysfunction, and ocular opacification. One 2016 meta-analysis showed good treatment efficacy and cost-effectiveness with use of sodium hyaluronate (hyaluronic acid).[60] Various other cocktails of heparinoids, sodium bicarbonate, and lidocaine have been described in the literature.[61][62] Heparin has also been used on its own, but data are limited.[3] Lidocaine is usually used in combination with sodium bicarbonate, as alkalinization improves urothelial penetration.[1] Consult an expert for guidance on intravesical combinations; these formulations need to be made by a pharmacist and should only be used under specialist supervision.
The limitation of all drugs instilled is their relatively short duration of action; frequent redosing may be required for lasting relief. Selected patients may self-administer treatment at home.
Intravesical injection of onabotulinumtoxinA has also been evaluated for patients with IC/BPS. This treatment is thought to work on blocking the afferent pathway, reducing pain and urgency. It also blocks acetylcholine release, which leads to bladder muscle relaxation. A single injection can give a short-term (3-9 month) improvement in 67% to 85% of patients, but a recent randomized study showed that repeat injections are necessary to maintain long-term outcomes.[63][64][65]
Pelvic-floor trigger point injections
For patients with myofascial trigger points and levator spasms, periodic transvaginal trigger point injections can provide substantial symptom relief. The use of a long-acting anesthetic such as 0.5% ropivacaine mixed with a steroidal anti-inflammatory works to break the pain-spasm-pain cycle. Multiple injections separated by several weeks may be necessary. The patients should also be actively enrolled in physical therapy to continue to focus on relaxing these muscle groups.
An emerging use of onabotulinumtoxinA has been for patients who respond to trigger-point injections but do not achieve long-term relief. The pelvic floor may be injected in a similar manner, though onabotulinumtoxinA is injected directly into the levator complex. This serves to break the spasm-pain-spasm cycle. The patient should be counseled about the risks of lower extremity weakness or urinary incontinence following injections.[66]
Cystoscopy and hydrodistention
Some patients with bladder-centered pain and no myofascial trigger points will respond to bladder distention under anesthesia. Up to 50% may see improvement, though this may be short-lived.[32] The American Urological Association recommends short-duration, low-pressure hydrodistention as a treatment option, but the European Association of Urology states that its role in treatment is limited due to lack of evidence.[1][3] The bladder is distended to 80 cm with water for 2 minutes and repeated. Prolonged distention should be avoided in order to avoid bladder necrosis and perforation. Treatments may be repeated as pain and urgency recur, though usually not more than every 3 to 6 months.
Neuromodulation
For patients with urgency and frequency, sacral neuromodulation (InterStim) is a viable and efficacious treatment. This involves the placement of a permanent tined electrode at the S3 nerve root foramen and an implanted pulse generator in the subcutaneous pocket. Greater than 50% improvement in voiding symptoms and progression to permanent implantation of the generator is seen in 70% to 80% of patients. A 2-week trial of lead placement or shorter office-based percutaneous placement allow for patient trial and screening. Reports show decrease in urgency and frequency, as well as decreased narcotic requirements.[67] New novel placement of the lead at the pudendal nerve allows for greater afferent signal recruitment at the sacral nerve roots and has been shown to be effective for patients with IC/BPS.[68] This approach is not yet FDA approved. Although efficacy of sacral neuromodulation for urgency and frequency has been established, smaller studies support its use for selected patients with pelvic pain.[69]
A less invasive form of neuromodulation, posterior tibial nerve stimulation (PTNS), has also been used for patients with IC/BPS. This is performed with a thin needle placed percutaneously at the posterior tibial nerve and stimulated weekly in the ambulatory setting. Again, a more distal nerve location theoretically recruits more afferent signals through the sacral cord, though unlike sacral neuromodulation this treatment is intermittent. Initially described for urinary frequency, PTNS has been shown to improve patient quality of life and pain scores for those with chronic pelvic pain.[70] It is virtually without side effects and does not require invasive procedures and costly implants.
Chemical neuromodulation with botulinum toxin has become a standard treatment for patients with medication-resistant urinary urgency and frequency. Currently, onabotulinumtoxinA is FDA approved for neurogenic and non-neurogenic urinary frequency. This therapy is not indicated for the pain or pelvic floor component of IC/BPS, but is effective for urgency and frequency symptoms.[71] Small studies have shown efficacy for this treatment combined with hydrodistention, though the results have generally been poor for patients with ulcerative IC.
Surgery
Surgery should only be considered in selected patients. The presence of ulcers should alert the clinician to the possibility of fulguration and/or resection under anesthesia. Durable and substantial responses have been shown after fulguration and/or triamcinolone injection of the ulcers.[30]
Patients with an "end stage" bladder have a fibrotic and poorly compliant bladder that has a very low volume, often <250 mL. Pain may be severe and is localized to the bladder. Storage symptoms are extreme and these patients have usually endured years of therapies. This select population may be considered candidates for either bladder augmentation or cystectomy with urinary diversion. Several case series support these treatments with reasonable outcomes. In one study of patients undergoing cystectomy with diversion, 8 of 9 would undergo the surgery again and all had improved quality of life and reduction in pain. One patient with symptoms for longer than 10 years did not feel any improvement in pain symptoms.[72] In one systematic review, 77.2% of patients experienced symptom improvement after surgery for treatment-refractory IC/BPS, but the rate of complications was 26.5%.[73] Urethrectomy (with its added morbidity) is not necessary to achieve the improvement in pain.[74] Because this treatment carries considerable morbidity, it should not be offered to patients unwilling to accept the complications. Certainly patients with pain, but normal bladder capacity under anesthesia and pelvic floor dysfunction, should never be considered for diversion or cystectomy.
Immunosuppressants
Cyclosporine has found utility at low doses in patients with severe IC/BPS. It is used following cystoscopy and ulcer fulguration for ulcer recurrences. Patients need to be free of active infections and undergo routine complete blood counts after starting therapy. Blood pressure should be checked routinely, as this medication can cause hypertension. Substantial improvement in bladder capacity and decreased frequency after treatment was reported in patients taking the drug for 1 year or more.[57]
Oral prednisone is sometimes used for the short-term to manage symptom flares in patients with ulcerative IC, but there is a lack of evidence for its use.[1][3] Nonsteroidal treatments are preferred and corticosteroids should not be used for long-term treatment.
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