Analgesics

The long-term, appropriate use of pain medications forms an integral part of the treatment of a chronic pain condition such as IC. Most patients can be helped markedly with medical pain management using pain medications commonly used for chronic neuropathic pain syndromes, including antidepressants, anticonvulsants, and opioids (Wesselmann et al, 1997). Many nonopioid analgesics including acetaminophen and the nonsteroidal anti-inflammatory drugs (NSAIDs) and even antispasmodic agents (Rummans, 1994) have a place in therapy along with agents designed to specifically treat the disorder itself.

Studies on the use of analgesics for BPS are sparse, and the majority of data is inferred from non-BPS types of pain and expert opinion. Health care professionals should ask about pain, and the patient’s self-report should be the primary source of assessment. Clinicians should assess pain with easily administered rating scales and should document the efficacy of pain relief at regular intervals after starting or changing treatment.

Unlike opioids, with increasing doses acetaminophen, aspirin, and the other NSAIDs all reach a ceiling for their maximum analgesic effect (Drugs for pain, 1998). Gabapentin, introduced in 1994 as an anticonvulsant, has found efficacy in neuropathic pain disorders including diabetic neuropathy (Backonja et al, 1998) and postherpetic neuralgia (Rowbotham et al, 1998). It demonstrates synergism with morphine in neuropathic pain (Gilron et al, 2005). It may give some benefit in chronic pelvic pain syndromes and BPS/IC (Sasaki et al, 2001). Pregabalin is also reported to be effective for neuropathic pain and the pain of fibromyalgia (Freynhagen et al, 2005; Arnold et al, 2008).

With the results of major surgery anything but certain, the use of long-term opioid therapy in the patient who has failed more conservative therapies also may be considered (Table 12–13). Opiates are seldom the first choice of analgesics in chronic pain states, but they should not be withheld if less powerful analgesics have failed (Portenoy et al, 1997; Bennett, 1999). This is a difficult decision that requires much thought and discussion between patient and urologist, and involvement of a pain specialist is indicated. A single practitioner has to take responsibility for pain treatment and write all prescriptions for pain medications (Brookoff, 1997). Opioids are effective for most forms of moderate and severe pain and have no ceiling effect other than that imposed by adverse effects. The common side effects include sedation, nausea, mild confusion, and pruritus. These are generally transient and easily managed. Respiratory depression is extremely rare if they are used as prescribed. Constipation is common, and a mild laxative is generally necessary. The major impediment to the proper use of these drugs when they are prescribed for long-term nonmalignant pain is the fear of addiction. Studies suggest the risk is low (Gourlay, 1994). The long-acting narcotic formulations that result in steady levels of drug over many hours are preferable.

Table 12–13 General Guidelines for the Use of Opioids in Chronic/Nonacute Urogenital Pain

1. All other reasonable treatments must have been tried and failed.

2. The decision to instigate long-term opioid therapy should be made by an appropriately trained specialist in consultation with another physician (preferably the patient’s family doctor).

3. When there is a history or suspicion of drug abuse a psychiatrist or psychologist with an interest in pain management and drug addiction should be involved.

4. The dose required needs to be calculated by careful titration.

5. The patient should be made aware (and possibly give written consent):

a That opioids are strong drugs and associated with addiction and dependency

b The opioids will normally only be prescribed from one source

c The drugs will be prescribed for fixed periods of time and a new prescription will not be available until the end of that period

d The patient will be subjected to spot urine and possibly blood checks to ensure that the drug is being taken as prescribed and that non-prescribed drugs are not being taken

e Inappropriate aggressive behavior associated with demanding the drug will not be accepted

f Hospital specialist review will normally occur at least once a year

g The patient may be requested to attend a psychiatric/psychology review

h Failure to comply with the above may result in the patient being referred to a drug dependency agency and the use of therapeutic analgesic opioids being stopped.

6. Morphine is the first-line drug, unless there are contraindications to morphine or special indications for another drug. The drug should be prescribed in a slow release/modified release form. Short-acting preparations are undesirable and should be avoided when possible. Parenteral dosing is undesirable and should be avoided when possible.

Modified from Fall M, Baranowski A, Elneil S et al. Guidelines on chronic pelvic pain. In: European Association of Urology; 2008. p. 1–99. www.uroweb.org/professional-resources/guidelines/.

Chronic pain patients often receive inadequate doses of short-acting pain medications, which put them on cycles of short-term relief, anxiety, and pain. It leads to doctor shopping and to drug-seeking behavior confused by physicians with drug addiction. Although physical dependence to opioids will be unavoidable, physical addiction, a chronic disorder characterized by the compulsive use of a substance resulting in physical, psychological, or social harm to the user and the continued use despite that harm, is rare. Chronic opioid therapy can be considered in carefully selected patients. It is best administered in a pain clinic setting, requiring frequent reassessment by both patient and physician (Portenoy and Foley, 1986).

Key Points

Oral Therapies

• Few of the oral therapies commonly used for the treatment of BPS have unequivocal evidence of efficacy in large, multicenter, randomized controlled clinical trials.

• There is little evidence that any change the natural history of the disease, although many seem effective in individual patients.

Intravesical and Intradetrusor Therapies

Assessments according to the Oxford System for intravesical therapy for BPS are shown in Table 12–14.

Table 12–14 Intravesical Therapy for BPS: Assessments According to Oxford System

INTRAVESICAL AGENT	LEVEL OF EVIDENCE	GRADE OF RECOMMENDATION
DMSO	2	B
Heparin	3	C
Hyaluronic acid	1	D
Chondroitin sulfate	4	D
Pentosan polysulfate	4	D
Capsaicin/resiniferatoxin	1	−A (ineffective)
Bacillus Calmette-Guérin (BCG)	1	−A (ineffective
Oxybutynin	4	D
Lidocaine	2	C
Botulinum toxin	4	D

From Hanno P, Lin AT, Nordling J, et al. Bladder pain syndrome. In: Abrams P, Cardozo L, Khoury S, Wein A, editors. Incontinence. Paris: Health Publication Ltd.; 2009. p. 1459–518.

Silver Nitrate

Although the evidence base for treating BPS/IC using intravesical preparations is limited and the potential for meta-analysis reduced by variation in the outcome measures used (Dawson and Jamison, 2007), intravesical lavage with one of a variety of preparations has remained a mainstay of treatment in the therapeutic armamentarium of BPS. Perhaps the oldest of the intravesical therapies is silver nitrate. The use of silver nitrate has been attributed to Mercier (cited in Pool and Rives, 1944), who reported in 1855 that excellent results with bladder instillations had been obtained in patients suffering from symptoms compatible with IC. Dodson (1926) advocated the use of solutions of silver nitrate in increasing strengths as the treatment of choice for this condition. Pool and Rives (1944) reported on 74 patients with IC treated with intravesical silver nitrate. The treatment was carried out as follows:

A urethral catheter is inserted and the contents of the bladder are evacuated. The bladder is then irrigated with a saturated solution of boric acid. Then 30 to 60 mL of a 1 : 5000 solution of silver nitrate is instilled into the bladder and permitted to remain there for 3 or 4 minutes if it does not cause intolerable irritation. At the end of this period the solution is permitted to run out through the catheter, which is then withdrawn. The patient usually experiences some dysuria and vesical irritability for 2 or 3 hours. Treatments are repeated every other day. At subsequent treatments the concentration of silver nitrate in the solution is increased to 1 : 2500, 1 : 1000, 1 : 750, 1 : 500, 1 : 400, 1 : 200, and finally 1 : 100. If at any time the reaction is too severe, the concentration is increased more slowly (Pool and Rives, 1944).

Although the initial treatments are performed with the patient under general anesthesia, later treatments are given on an outpatient basis. Ureteral reflux would be a contraindication, and it goes without saying that bladder biopsy would be contraindicated just before instillation for fear of extravasation. Twenty-three years later, Pool (1967) wrote that he still considered this treatment regimen the most efficacious form of treatment. He reported excellent results in 70% of patients with a mean response of 7.6 months. Burford and Burford (1958) reported a 14% cure rate and 79% improved figure. DeJuana and Everett (1977) had a 50% response rate in 102 patients.

Although silver nitrate is rarely used in the current treatment of BPS, an animal study showing that intravesical administration of nanocrystalline silver (1%) decreased urine histamine, bladder TNF-α, and mast cell activation in an experimental inflammation model without any toxic effect may restimulate interest in silver compounds (Boucher et al, 2008).

Clorpactin

O’Connor (1955) reported the use of intravesical Clorpactin WCS 90. Clorpactin is a generic term for closely related, highly reactive chemical compositions having a modified derivative of hypochlorous acid in a buffered base. Its activity depends on the liberation of hypochlorous acid and its resulting oxidizing effects, wetting and penetrating properties, and detergency. Wishard treated 20 patients with 0.2% Clorpactin gently lavaged in the bladder for 3 to 5 minutes without anesthesia, of whom 14 reported subjective improvement (Wishard et al, 1957). Murnaghan and coworkers (1970) noted improvement in 14 of 17 patients, although 10 required further treatment during the average 2-year follow-up. Most commonly the treatments are given as described by Messing and Stamey (1978), using 0.4% solution administered at 10 cm H₂O under anesthesia. Multiple instillations can be given, with a 1-month pause after the first 2 instillations to await a therapeutic response. The success rate of these researchers was 72%, with average 6-month duration of response. La Rock and Sant (1995) noted a 50% to 55% meaningful improvement rate occurring within 4 to 6 weeks of treatment. A case of ureteral fibrosis complicating the treatment prompted the recommendation that vesicoureteral reflux be considered a contraindication to the procedure (Messing and Freiha, 1979). Our method of Clorpactin delivery is as follows:

Reflux is excluded with a cystogram. Under anesthesia the bladder is distended for 2 minutes at 60 to 80 cm H₂O and emptied. The perineum is shielded with a moistened towel. A solution of 0.4% freshly prepared Clorpactin (4 g in 1000 mL of sterile water) is instilled by gravity drainage (the Foley catheter held 10 cm above the level of the bladder) in 150- to 200-mL aliquots for a dwell time of 2 to 3 minutes and drained by gravity. This continues until the entire 1000-mL solution has been used. The bladder and introitus are then irrigated with normal saline, and the catheter is removed.

Dimethyl Sulfoxide

A mainstay of the treatment of BPS is the intravesical instillation of 50% DMSO (Sant, 1987). DMSO is a product of the wood pulp industry and a derivative of lignin. It has exceptional solvent properties and is freely miscible with water, lipids, and organic agents. Pharmacologic properties include membrane penetration, enhanced drug absorption, anti-inflammatory, analgesic, collagen dissolution, muscle relaxant, and mast cell histamine release. In-vitro effects on bladder function belie its positive effects in vivo (Freedman et al, 1989), where histamine release has not been demonstrated after treatment (Stout et al, 1995). It has been suggested that DMSO actually desensitizes nociceptive pathways in the lower urinary tract (Birder et al, 1997). Tests for DMSO for treatment of human illness began in the 1960s in the areas of musculoskeletal inflammation and the cutaneous manifestations of scleroderma.

Stewart and colleagues (1968) are credited for popularizing intravesical DMSO for BPS/IC. In the mid 1960s they applied it to the skin over the suprapubic area in a group of patients whose condition was refractory to conventional forms of therapy. Results were poor, but intravesical delivery of 50 mL of a 50% solution instilled for 15 minutes by catheter and repeated at intervals of 2 to 4 weeks showed positive effects in 6 of 8 patients lasting 2 to 12 months. The lack of side effects, other than a garlic-like odor on the breath, and of the need for inpatient administration were significant breakthroughs over previous treatments. Further reports by this group confirmed safety and efficacy (Stewart et al, 1971, 1972; Stewart and Shirley, 1976; Shirley et al, 1978) with symptom-free intervals of 1 to 3 months in 73% of patients. Ek and associates (1978) reported a 70% success rate but found most patients ultimately required re-treatment or further therapy with other modalities. Prospective series of Fowler (1981) and Barker and associates (1987) revealed symptomatic success rates of greater than 80%, although relapse was not uncommon. Fowler noted only minimal improvements in functional bladder capacity and attributed the beneficial effects of DMSO to a direct effect on the sensory nerves of the bladder. Perez-Marrero and associates (1988) compared DMSO with saline and showed a 93% objective improvement and 53% subjective improvement compared with 35% and 18%, respectively, for saline. Patients with bladder instability do not respond (Emerson and Feltis, 1986).

With its ease of administration (Biggers, 1986), low morbidity, and reasonable symptomatic results, DMSO certainly merits its place as a useful treatment for BPS/IC. In-vivo studies on rat bladder strips exposed to various concentrations of DMSO for 7 minutes showed absence of electrical field stimulation contraction at a 40% concentration and diminished compliance at 30% concentration (Melchior et al, 2003). Concentrations of 25% or less had negligible effects in this model. How it relates to use of DMSO in humans is unknown. A rare case of eosinophilic cystitis has been reported after DMSO instillation (Abramov et al, 2004).

Glycosaminoglycans

Exogenous GAGs have been shown to be effective in providing an epithelial permeability barrier in bladders in which the epithelium has been injured with protamine (Nickel et al, 1998). Heparin, which can mimic the activity of the bladder’s own mucopolysaccharide lining (Hanno et al, 1978), has anti-inflammatory effects as well as actions that inhibit fibroblast proliferation, angiogenesis, and smooth muscle cell proliferation. Because of its numerous effects the possibility that heparin could be used for therapeutic reasons other than the control of coagulation has been the subject of much inquiry and speculation (Lane and Adams, 1993). Weaver and associates (1963) first reported intravesical heparin for IC treatment. Given intravesically there is virtually no systemic absorption, even in an inflamed bladder (Caulfield et al, 1995). Although uncontrolled studies suggested some beneficial effect for subcutaneous administration (Lose et al, 1983, 1985), the obvious risks of anticoagulation and osteoporosis have prevented this form of administration from undergoing further trials and general usage. Ten thousand units can be administered intravesically in sterile water either alone or with DMSO at varying intervals, with good results being reported (Perez-Marrero et al, 1993; Parsons et al, 1994a). Kuo (2001) reported 50% or more improvement in the International Prostate Symptom Score in 29 of 40 women with IC treated with 25,000 units intravesically twice weekly for 3 months.

Parsons (2000) has used daily intravesical doses of 40,000 units of heparin in 20-mL sterile water administered by the patient daily and held for 30 to 60 minutes. “Reasonable improvement of symptoms” can be expected between 6 months and 2 years after starting therapy. Adding alkalinized lidocaine to the heparin instillation provides better pain relief (Parsons, 2005). These encouraging outcomes must be kept in perspective, given that they are unproven by any placebo-controlled trial. The addition of 8 mL of 2% lidocaine and 4 mL of 8.4% sodium bicarbonate may improve results (Welk and Teichman, 2008). In fact, a combination of 200 mg of lidocaine with 8.4% sodium bicarbonate (10 mL total solution) without heparin showed a 30% response rate 3 days after completion of daily intravesical administration for 5 days and was statistically superior to a placebo cocktail (Nickel et al, 2009b).

Another GAG analogue, pentosan polysulfate (PPS), administered intravesically at 300 mg twice weekly in 50 mL of normal saline, showed some modest benefit in a small trial (Bade et al, 1997a). A 41-patient trial comparing oral PPS with oral and intravesical administration showed that the 24% reduction in O’Leary-Sant scores with oral therapy alone rose to a 46% reduction in the group that also received intravesical PPS (Davis et al, 2008).

The nonsulfated GAG, hyaluronic acid, has also been used intravesically. Trials using 40 mg dissolved in 40 mL of normal saline weekly for 4 to 6 weeks and then monthly treatments thereafter have had response rates varying from 71% (Morales et al, 1996) to 30% (Porru et al, 1997). In the summer of 2003, Bioniche Life Science (Interstitial Cystitis Association, 2003), and in the spring of 2004 Seikagaku Corporation, reported double-blind, placebo-controlled, multicenter clinical studies of their hyaluronic acid preparations (40 mg or 200 mg/mL, respectively), and neither showed significant efficacy of sodium hyaluronate compared with placebo. These negative studies have not been published in peer-reviewed literature. Neither preparation has been approved for use for BPS/IC in the United States. An Austrian open-label study showed 13 of 27 patients with BPS and a positive potassium test responded to intravesical hyaluronic acid, 40 mg, given weekly for 10 weeks, although initial nonresponders at 5 weeks also were treated with intravesical PPS 200 mg thrice weekly for the remaining 5 weeks (Daha et al, 2008). The best results for hyaluronic acid come from Riedl and colleagues (2008), who studied 126 patients with a positive modified potassium test who could hold the solution for 2 hours, using 40 mg weekly for a minimum 10 weeks. Eight-four percent had significant improvement. Treatment-resistant cases have been managed with a combination of sequential bladder distention under anesthesia accompanied by a hyaluronic acid instillation every 1 to 3 months depending on response, with a 74% success rate in 23 patients (Ahmad et al, 2008). Although used in Europe and Canada, the efficacy of hyaluronic acid for BPS/IC remains unproven in controlled and blinded trials (Iavazzo et al, 2007).

Hurst (2003) has shown by immunohistochemistry a deficit of chondroitin sulfate from the luminal bladder surface in IC patients. Small uncontrolled studies using intravesical chondroitin sulfate have shown success rates of 33% (Steinhoff et al, 2002) to 50% (Sorensen, 2003). A multicenter, open-label study using 2% solution of sodium chondroitin sulfate weekly for 6 weeks and then monthly for 4 months had a 60% response rate with no safety issues (Nickel et al, 2009a). A large open-label experience using the device for all forms of “chronic cystitis” concluded that it was effective in improving urgency, voided volumes, and nocturia and well-tolerated when administered weekly for a maximum of eight instillations (Nordling and van Ophoven, 2008). The GAGs can be combined for instillation (Cervigni et al, 2008).

Other Intravesical Therapies

Doxorubicin (Khanna and Loose, 1990) and the mast cell stabilizer cromolyn sodium (Edwards et al, 1986; Kennelly and Konnak, 1995) have been tried in pilot trials with the promising results we come to expect in such studies. Follow-up studies are lacking, and these drugs have not become a part of the intravesical pharmacopeia.

The use of intravesical bacillus Calmette-Guérin (BCG) for IC was first reported by Zeidman and colleagues (1994). A subsequent randomized, prospective, double-blind, placebo controlled trial of 30 patients treated weekly for 6 weeks and followed for a mean of 8 months noted a 60% response rate compared with a 27% placebo response (Peters et al, 1997). Surprisingly, BCG was tolerated as well as placebo. Even more surprisingly, 8 of 9 BCG responders continued to have an excellent response in all parameters measured at 27 months of follow-up (Peters et al, 1998). It is unclear how BCG achieved this result, but immunologic and/or anti-inflammatory mechanisms have been postulated (Peters et al, 1999). A double-blind crossover Swedish study comparing DMSO to BCG failed to substantiate the efficacy of BCG (Peeker et al, 2000c).

A large multicenter randomized controlled trial by NIDDK comparing BCG with placebo found a 12% response rate for placebo compared with a 21% response for BCG. Placebo responders in the trial had the same durability of response (up to 68 weeks) as the BCG responders (Propert et al, 2008). In a follow-up open-label phase of the trial the response rate was 18% in both the group originally randomized to BCG and the group initially randomized to placebo, indicating a second course of therapy does not improve response rate (Propert et al, 2007). The small response rate in the randomized controlled trial failed to reach statistical significance at the P = .05 level, and this large study of 265 patients suggests that BCG has no place in the treatment of moderate to severe BPS/IC (Mayer et al, 2005). Although the BCG safety profile was considered acceptable in the NIDDK trial, adverse events were not uncommon and rare hypersensitivity reactions to intravesical BCG can occur (Parker et al, 2004). Although small, uncontrolled trials showing efficacy of BCG have been reported (Aghamir et al, 2007; El-Bahnasy et al, 2009), the NIDDK trial dampened enthusiasm for this treatment modality.

Efforts to bring new therapies directly to the bladder continue to be the focus of investigators. Oxybutynin has shown efficacy in preliminary studies when administered intravesically at doses of 10 mg dissolved in saline (Bade et al, 2000; Barbalias et al, 2000). Electromotive drug administration, the active transport of ionized drugs by the application of an electric current, using lidocaine and dexamethasone, has shown a 25% success rate up to 6 months after instillation (Rosamilia et al, 1997). A similar trial using repeated instillations noted success rates of 60% with a mean duration of 6.6 months (Riedl et al, 1997). Capsaicin, the main pungent ingredient in hot peppers of the genus Capsicum, is a specific neurotoxin that desensitizes C fiber afferent neurons. Resiniferatoxin (RTX), an ultrapotent analogue of capsaicin appears to have similar effects with less of the acute pain and irritation associated with capsaicin application. Both compounds have been tested intravesically for the relief of bladder instability and hyperreflexia (Chancellor and de Groat, 1999). Clinical trials for the use of these compounds in bladder pain and urgency/frequency could show this to be a new and viable treatment modality in the future, but current data on efficacy in BPS are lacking (Cruz et al, 1997; Lazzeri et al, 1996, 2000). A phase 2 safety and proof of concept multicenter, placebo-controlled trial conducted by ICOS Corporation (Bothell, WA, USA) found no significant efficacy of a single intravesical administration RTX compared with placebo, although no safety issues were identified (Payne et al, 2005). Studies using other concentrations and multiple administrations may be worthwhile (Peng and Kuo, 2007).

Key Points

Intravesical Therapies

• The potential for high efficacy combined with safety and low side effect profile that is gained by applying a treatment directly to the bladder lining has made research into new methods of intravesical therapy a high priority of researchers and pharmaceutical companies.

• Patients in whom pain and other symptoms are not related directly to a pathologic process of the bladder would not be expected to respond well to this type of organ-directed therapy.

Intradetrusor Therapies

The therapeutic value of botulinum toxin type A (Botox) stems partially from its ability to temporarily inhibit acetylcholine release and cause flaccid paralysis in a dose-related manner. It can correct focal dystonia when injected into a muscle. In recent years there has been increasing evidence that Botox might also have analgesic properties (Rajkumar and Conn, 2004). Initially this was thought to be due to relief of muscle spasm. However, botulinum has been shown to reduce peripheral sensitization by inhibiting the release of several neuronal signaling markers, including glutamate and substance P, and reducing c-FOS gene expression. It may affect the sensory feedback loop to the central nervous system by decreased input from the muscle tissue, possibly by inhibiting acetylcholine release from gamma motor neurons innervating intrafusal fibers of the muscle spindle (Rosales et al, 1996). It inhibits the release of sensory neurotransmitters from isolated bladder preparations in rat bladder models of both acute injury and chronic inflammation (Lucioni et al, 2008). Botox has been used effectively for years in different conditions with muscular hypercontractions. Intravesical Botox administration blocks the acetic acid–induced calcitonin gene–related peptide release from afferent nerve terminals in the bladder mucosal layer in rats (Chuang et al, 2004). In an animal model of bladder permeability barrier disruption, intravesical Botox minimized bladder irritability and restored afferent neural responses to baseline levels (Vemulakonda et al, 2005). These results support clinical trials of Botox for the treatment of BPS/IC and other types of visceral pain (Chancellor and Yoshimura, 2004).

A multi-institutional case series using Botox or Dysport intravesical injections in 13 patients with refractory BPS/IC reported improvement in 9 patients. Improvements in symptoms lasted a mean of 3.72 months (mean, 1 to 8 months). No systemic complications were observed, although 2 patients had a diminished flow with some need to strain to void (Smith et al, 2004). Rackley and colleagues (2005) at the Cleveland Clinic reported no change in objective or subjective outcome measures in a series of 10 BPS/IC patients in whom the trigone was spared in the injection technique. A 1-year follow-up in 15 patients treated with 200 units Botox in 20 mL of normal saline showed that the success rate fell from 86.6% at 3 months to 26.6% at 5 months and was 0 at 12 months (Giannantoni et al, 2008). Bladder biopsy specimens 2 weeks after Botox intradetrusor injection show nerve growth factor production levels fall to those of controls in patients who respond (Liu et al, 2009). It is hypothesized that treatment-refractory patients may have developed antibodies after initial botulinum injection (Schulte-Baukloh, 2008). At this time Botox can be recommended for BPS/IC use only in the context of carefully controlled clinical trials (Cruz and Dinis, 2007; Del Popolo, 2008; Apostolidis et al, 2009).

Submucosal injection of 10 mL of 40 mg/mL triamcinolone acetonide injected in 0.5-mL aliquots was used for the treatment of Hunner lesions in 30 patients (Cox et al, 2009). Seventy percent of patients were very much improved, and duration of improvement was estimated to be 7 to 12 months.

Neuromodulation

Because it is a chronic pain syndrome it is reasonable to consider therapeutic options that directly interface with the nervous system in the treatment of PBS/IC. This approach is further supported by the association of pelvic floor dysfunction with pelvic pain syndromes (Zermann et al, 1999).

Pain diversion by transcutaneous electrical nerve stimulation (TENS) is routine in a variety of painful conditions (Fall, 1987). Fall and colleagues (1980) were the first to use electrical stimulation in IC, reporting on 14 women treated successfully with long-term intravaginal or TENS. Subsequently McGuire and coworkers (1983) noted improvement in 5 of 6 patients treated with electrical stimulation.

The primary intention in applying peripheral electrical nerve stimulation in IC is to relieve pain by stimulating myelinated afferents in order to activate segmental inhibitory circuits. As a secondary effect, urinary frequency may also be reduced. In the most complete review of the subject to date (Fall and Lindstrom, 1994) 33 patients with ulcerative IC and 27 patients with nonulcerative IC were treated by means of suprapubic TENS. Electrodes were positioned 10 to 15 cm apart immediately above the pubic symphysis. High- or low-frequency (2-50 Hz) TENS was employed. If there was no effect with high frequency after 1 month, low frequency was used. Thirty to 120 minutes of TENS was prescribed daily. Pain improved more than frequency. Good results or remission were described in 26% of nonulcer patients and in a surprising 54% of patients with ulcerative disease. The authors caution that the experience is based on open studies, relatively few patients, and the knowledge of a significant placebo effect with peripheral pain stimulation.

Acupuncture has been used to treat frequency, urgency, and dysuria (Chang, 1988). Twenty-two of 26 patients treated at the Sp. 6 point had clinically symptomatic improvement. A study looking at both acupuncture and TENS in IC showed limited effects of both modalities (Geirsson et al, 1993). Lumbar epidural blockade is the subject of a positive recent case report (Pelaez et al, 2004) but in an earlier series resulted in only short-term (mean 15 days) pain relief in IC (Irwin et al, 1993). Posterior tibial nerve stimulation was successful in 60% of 37 patients with symptoms of bladder overactivity in an uncontrolled Dutch study (van Balken et al, 2001). An Australian double-blind placebo controlled study of transdermal posterior tibial nerve laser therapy showed no benefit in 56 patients when comparing active to placebo arms, but the placebo effect was remarkably strong, indicating the importance of such trials when evaluating invasive therapies (O’Reilly et al, 2004). A Chinese study of posterior tibial nerve stimulation twice weekly for 5 weeks in BPS/IC patients failed to show improvement in pain scores, and none of 18 patients thought the treatment had a significant effect (Zhao et al, 2008).

Direct sacral nerve stimulation has been explored in the treatment of IC and urgency/frequency and is referred to as neuromodulation, a technique whose urologic potential was developed through the basic and clinical research of Tanagho and Schmidt (Schmidt, 1993; Fandel and Tanagho, 2005). They and others have observed that patients who do best with this treatment modality are those who have identifiable pain and dysfunction in the pelvic muscles (Everaert et al, 2001; Siegel et al, 2001; Aboseif et al, 2002). Those patients reporting pelvic pain in the absence of demonstrable pelvic floor dysfunction and levator tenderness did poorly (Schmidt, 2001). As initially practiced, trial stimulation was performed with a percutaneous temporary electrode for a 3- to 4-day temporary stimulation period to access efficacy. The S₃ nerve is most frequently used. A wire electrode is inserted into the foramen and connected to an external pulse generator (Medtronic Inc., Minneapolis, MN, USA). If the trial is successful, the patient would be considered for implantation of a permanent neural prosthesis. More recently, a staged procedure has supplanted the traditional percutaneous approach, because the response to stimulation can be better assessed with more accurate lead placement and stability than through the more hit-or-miss percutaneous lead placement (Peters et al, 2003). Peters’ test to implant rate increased from 52% to 94%. Other reports have noted a test to implant rate in the percutaneous technique from 76% in 33 PBS/IC patients (Whitmore et al, 2003) to 40% in 211 patients with refractory urge incontinence, urgency-frequency syndrome, and urinary retention (Scheepens et al, 2002b).

Neuromodulation has been shown to be effective in treating refractory urinary urge incontinence (Schmidt et al, 1999; Spinelli et al, 2001). Studies on therapeutic potential in BPS/IC followed (van Kerrebroeck, 1999). The University of Maryland group described decrease in antiproliferative activity and normalization of HB-EGF levels in patients with successful test stimulation (Chai et al, 2000a). Peters and coworkers (2003) reported success in two thirds of BPS/IC patients with sacral nerve stimulation; Global Response Assessment as determined by the patient correlated with objective findings (Peters et al, 2008). In another study (Comiter, 2003) success was noted in 17 of 25 patients with test stimulation and they went on to permanent implantation of the Interstim device (Medtronics, St. Paul, MN). Thirteen of 15 who underwent staged implantation were permanently implanted versus 4 of 10 undergoing percutaneous test stimulation. With a mean follow-up of 14 months, in 16 of 17 patients the treatment was judged successful, giving an intent-to-treat success rate of 64%. Although sacral neuromodulation can decrease narcotic requirements significantly in refractory BPS/IC, the majority of patients taking chronic narcotics for pain will likely continue to use them for pain relief even after implantation (Peters and Konstandt, 2004). One center reported a long-term improvement rate of 45% for the urgency/frequency indication (Elhilali et al, 2005).

Unilateral stimulation should be performed before bilateral sacral stimulation is considered (Oerlemans and van Kerrebroeck, 2008). A bilateral test stimulation could be indicated when a unilateral test fails (Steinberg et al, 2007). The only prospective randomized crossover trial to compare the unilateral with bilateral sacral nerve stimulation found no significant differences comparing the results (Scheepens et al, 2002a). The presence of pain is a predictor of adverse events (White et al, 2009); and although sacral neuromodulation is effective in 56% of patients with urgency/frequency, when pain is the major complaint then caution is indicated. Surgical revision rates are 7% to 18% (van Kerrebroeck et al, 2007). When used for BPS symptoms, frequent reprogramming is often required (Maxwell et al, 2008).

Key Points

Neuromodulation

• The association of pelvic floor dysfunction with pelvic pain syndromes makes neuromodulation a rational therapeutic alternative.

• Patients with pelvic pain in the absence of demonstrable pelvic floor dysfunction and levator tenderness may not respond as well as those with urgency/frequency associated with pelvic floor dysfunction. Controlled trials of sacral nerve stimulation for bladder pain syndrome are needed.

Surgical Therapy

Hydrodistention

Hydrodistention of the bladder under anesthesia, while technically a surgical treatment, is often the first therapeutic modality employed, often as a part of the diagnostic evaluation. Because there have been no standard methods of distention (Turner and Stewart, 2005), results vary markedly. Frontz (1922) first suggested hydraulic overdistention of the bladder for IC, and Bumpus (1930) reported the first series 8 years later. Simple bladder filling at cystoscopy will give relief to some patients (Hald et al, 1986); others have reported an office-based procedure with intravesical lidocaine anesthesia using electromotive drug administration (Rose et al, 2005), whereas Dunn and associates (1977) reported on 25 patients whose bladders were distended under anesthesia to the level of the systolic blood pressure for up to 3 hours. Sixteen of the patients were symptom free with a mean follow-up of 14 months; 2 patients suffered bladder rupture. The bladder in IC patients can be very thin, and the possibility of perforation or rupture must always be kept in mind and discussed with the patient (Badenoch, 1971; Hamer et al, 1992). Prolonged distention probably has little or no benefit over a short-term distention measured in minutes (Taub and Stein, 1994; McCahy and Styles, 1995). Using epidural anesthesia and a balloon distention technique to the mean arterial pressure for 3 hours continuously, Glemain and colleagues (2002) reported good but transient efficacy in patients with a bladder capacity of greater than 150 mL on predistention cystometry. In their prospective series of 30 patients, 18 had maintained a therapeutic response at 6 months and 13 at 1 year of follow-up. Moderate hematuria was almost universal, worsening of symptoms occurred in 5% of patients, and low back and hypogastric pain were common sequelae. There was one bladder rupture, one episode of sepsis, and one episode of prolonged retention.

Our method is to perform an initial cystoscopic examination (which is generally unremarkable), obtain urine for cytology, and distend the bladder for 1 to 2 minutes at a pressure of 80 cm H₂O. The bladder is emptied and then refilled to look for glomerulations or ulceration. A therapeutic hydraulic distention follows for another 8 minutes. Biopsy, if indicated, is performed after the second distention. Therapeutic responses in patients with a bladder capacity under anesthesia of less than 600 mL showed 26% with an excellent and 29% with a fair result compared with 12% excellent and 43% with a fair result in patients with larger bladder capacities (Hanno and Wein, 1991). Most favorable responses were extremely brief, however, with the exceptional patient noting improvement for 6 months and thus being a candidate for repeat therapeutic distention.

Acute hydrodistention does not seem to result in any long-term bladder dysfunction (Kang et al, 1992; Lasanen et al, 1992). Any efficacy is probably related to damage to mucosal afferent nerve endings (Dunn et al, 1977). It has no benefits in patients with detrusor hyperreflexia or instability (Taub and Stein, 1994; McCahy and Styles, 1995). Over half of men with prostate pain and without bacteriuria may have glomerulations. Symptoms in this group have been reported to improve with hydrodistention (Berger et al, 1998). While many patients with IC have sensory urgency at awake capacities of less than 100 mL, hydrodistention under anesthesia seems to allow for “staging” of the disease, giving the clinician some idea of the capacity he or she has to work with conservative therapies. A capacity under anesthesia of under 200 mL would not bode well for the likelihood of success of medical therapy. Fortunately these cases are relatively rare.

Surgical Considerations

Please see the Expert Consult website for more discussion on this topic.

Major extirpative and/or reconstructive surgical therapy for BPS is an option after all trials of conservative treatment have failed; a point that cannot be overemphasized. BPS/IC, although a cause of significant morbidity, is a nonmalignant process with a temporary spontaneous remission rate of up to 50% (Held et al, 1990) that does not directly result in mortality. Deaths are either self-inflicted or the complications of therapy. Nowhere does the caveat “primum non nocere” bear more relevance; the treatment must be no worse than the disease process (Siegel et al, 1990). Surgery should be reserved for the motivated and well-informed patient who falls into the category of extremely severe, unresponsive disease, a group that comprises less than 10% of patients (Irwin and Galloway, 1994; Parsons, 2000).

Historical Procedures

Many surgical approaches have been employed for IC, and it is worth mentioning a few for historical perspective alone. Sympathectomy and intraspinal alcohol injections have been used to treat pelvic pain (Greenhill, 1947). Differential sacral neurotomy was reported in 3 patients with good results (Meirowsky, 1969) but like most de-innervation procedures never gained popularity because of subsequent poor results. Transvesical infiltration of the pelvic plexuses with phenol failed in 5 of 5 patients with IC (Blackford et al, 1984). With a significant complication rate of 17% (McInerney et al, 1991) it is rarely if ever currently used for sensory urgency disorders or detrusor hyperreflexia. There are several reports on cystolysis going back to Richer in 1929 (Bourque, 1951). Worth (1980) and Worth and Turner-Warwick (1973) reported some short-term benefit, but unpredictable long-term results. Freiha and Stamey (1979) used it in 6 IC patients with good results in 4. Albers and Geyer (1988) reported long-term follow-up in 11 IC patients and had success in only 1. Denervation procedures have a notoriously high late-failure rate, and the procedure is not justified for BPS/IC (Walsh, 1985; Stone 1991). In fact, Rogers (2003) has concluded that there exist no convincing clinical studies to recommend surgical procedures to interrupt visceral nerve pathways in women suffering with any type of chronic pelvic pain.

Surgery of Hunner Lesion

Transurethral resection of a Hunner lesion, as initially reported by Kerr (1971), can provide symptomatic relief. Fall (1985) resected ulcerated lesions in 30 patients, resulting in initial disappearance of pain in all and a decrease in urinary frequency in 21. Similar results have been attained with the neodymium-yttrium-aluminum-garnet (YAG) laser (Shanberg et al, 1985; Shanberg, 1989; Rofeim et al, 2001). Extreme caution is critical if using a laser in a BPS/IC bladder, because forward scatter through these thin bladders with resulting bowel injury is an ever-present danger. There would seem to be no justification in the literature for using the laser to treat areas of glomerulation or in the nonulcerative form of the disease (Shanberg and Malloy, 1997).

Major Surgical Procedures

Supratrigonal cystectomy and the formation of an enterovesical anastomosis with bowel segments (substitution cystoplasty) has been a popular surgical procedure for intractable IC. The diseased bladder is resected in its entirety, sparing only a 1-cm cuff around the trigone to which the bowel segment is anastomosed (Worth and Turner-Warwick 1972; Irwin and Galloway, 1994). Although it is not always clear in the literature how much bladder has been resected, the results reported using these procedures for IC have been mixed at best. Badenoch (1971) operated on 9 patients, with 4 becoming much worse and 3 ultimately undergoing urinary diversion. Flood and colleagues (1995) reviewed 122 augmentation procedures, 21 of which were done for IC. Patients with IC had the poorest results of any group, with only 10 having an “excellent” outcome. Wallack and colleagues (1975) reported two successes; Seddon and associates (1977) had success in 7 of 9 patients; and Freiha and coworkers (1980) ended up performing formal urinary diversion in 2 of 6 patients treated with augmentation cecocystoplasty. Weiss and associates (1984) had success in 3 of 7 patients treated with sigmoidocystoplasty, and Lunghi and colleagues (1984) had no excellent results in 2 patients with IC. Webster and Maggio (1989) reviewed their data in 19 patients and concluded that only patients with bladder capacities under anesthesia less than 350 mL should undergo substitution cystoplasty. Hughes and coworkers (1995) lowered the threshold to less than 250 mL.

More recent series on subtotal cystectomy plus augmentation have been somewhat more positive (Costello et al, 2000; Chesa et al, 2001). Peeker and associates (1998) had good results in all 10 patients with ulcerative IC but poor results in the 3 patients operated on with nonulcerative disease. They no longer perform the procedure in the latter group. Linn and coworkers (1998) had success in 20 of 23 patients (only 2 with ulcerative IC) treated with subtotal cystectomy and orthotopic bladder substitution with an ileocecal pouch. They recommend a supratrigonal cystectomy. In a Spanish series success was reported in 13 of 17 procedures with a mean follow-up of 94 months (Rodriguez Villamil et al, 1999). The University of Alabama group reported long-term success in 1 of 4 patients with orthotopic neobladders and 1 of 3 with augmentation cystoplasty (Lloyd, 1999). A German report on substitution cystoplasty sparing the trigone was quite enthusiastic, detailing a 78% pain-free rate in 18 patients treated with ileocecal augmentation (10 patients) or ileal substitution (8 patients) at a mean follow-up of 57 months (van Ophoven et al, 2002). Two patients failed to get any pain relief, and 4 required either long-term intermittent catheterization or suprapubic drainage to empty the neobladder.

Not all patients empty the bladder spontaneously after substitution cystoplasty. Although the need for clean intermittent catheterization would not obviate a successful outcome in the patient treated for bladder contraction from tuberculous cystitis, it can be a painful disaster in the IC patient. Nurse and colleagues (1991) have gone one step farther, recommending trigone biopsy before substitution cystoplasty. Diversion and/or total cystourethrectomy is recommended if the trigone is “affected” by IC. It is not clear how this is determined histologically, because IC has no pathognomonic findings by histology and generally is not a localized process. Nielsen and coworkers (1990) described 8 women treated with substitution cystoplasty. The treatment failed in 6 patients, and the results of postoperative biopsies from the trigone showed no difference in the amount of fibrosis, degree of degenerative changes in the muscle, and mast cell density between the 2 cured patients and the others.

There has been a controversy over whether the IC process can occur in a transposed bowel patch (McGuire et al, 1973; Kisman et al, 1991; Singh and Thomas, 1996) or even in the ureter (Smith and Christmas, 1996). If so, not only would this be a relative contraindication to the procedure but it would also provide support for the view that a substance in the urine might be involved in pathogenesis. There is, however, evidence that inflammation and fibrosis are the usual reactions of bowel to exposure to urine and, therefore, pathologic findings alone would not be conclusive of spread of IC in those patients (MacDermott et al, 1990).

Augmentation cystoplasty has many potential complications from the rare incidence of bladder neoplasm (Golomb et al, 1989) to the more common complication of upper tract obstruction (Cheng and Whitfield, 1990). In the best of hands complications can involve almost 50% of patients, requiring surgical intervention in 25% (Khoury et al, 1992; Bunyaratavej et al, 1993). Although problems are more common in patients operated on for disorders other than IC, the risk-benefit ratio of substitution cystoplasty seems to have discouraged its use in the past several years.

Urinary diversion with or without cystourethrectomy is the ultimate surgical answer to the dilemma of IC, akin to cutting the “gordian knot.” If diversion alone is chosen, one must keep in mind potential problems that can befall the remaining bladder, including pyocystitis, hemorrhage, severe pain, and unremitting feelings of incomplete emptying and spasm (Eigner and Freiha, 1990; Adeyoju et al, 1996). Bladder carcinoma has also been reported after urinary diversion but is not specifically associated with BPS (Hanno and Tomaszewski, 1982). Consideration of cystourethrectomy is indicated only in patients who are miserable and have not only failed all other therapies but have demonstrated chronicity such that remission is considered extremely unlikely. Fortunately few patients fall into this category. Theoretically, conduit diversion seems to be reasonable if one is concerned about disease occurring in any continent storage type of reconstruction. The extended simple cystectomy performed for intractable IC may lend itself to anterior enterocele formation from weakening of the anterior vaginal wall, and prevention of this entity is warranted at the time of cystectomy (Anderson et al, 1998).

Bejany and Politano (1995) reported excellent results in 5 patients treated with total bladder replacement and recommend neobladder reconstruction. Keselman and coworkers (1995) had two failures in 11 patients treated with continent diversion and attributed this to surgical complications. A Finnish group noted failure in 2 of 4 patients treated with cystectomy and conduit diversion because of persistent pain (Lilius et al, 1973). Baskin and Tanagho (1992) also cautioned about persistence of pelvic pain after cystectomy and continent diversion, discussing 3 such patients. A similar report followed (Irwin and Galloway, 1992). Webster and coworkers (1992) had 10 failures in 14 patients treated with urinary diversion and cystectourethrectomy. Ten patients had persistent pelvic pain, and 4 of them also complained of pouch pain. Only 2 patients had symptom resolution. An English study of 27 patients who underwent cystectomy and bladder replacement with a Kock pouch noted successful treatment of pain in all patients, but follow-up was limited (Christmas et al, 1996a). Parsons suggests that pouch pain will occur in 40% to 50% of patients within 6 to 36 months of surgery (Parsons 2000).

Attempts have been made to improve results by limiting the operation to those without detrusor mastocytosis (Trinka et al, 1993) and those without “neuropathic pelvic pain” (Lotenfoe et al, 1995). Based on the experience of the past decades it is unclear if these efforts will prove any more successful. It would seem that risks of failure peculiar to IC include both the development of pain over time in any continent storage mechanism that is constructed and the risk of phantom pain in the pelvis that persists despite the fact that the stimulus that initially activated the nociceptive neurons (diseased bladder) has been removed (Cross, 1994). Brookoff (1997) has proposed trying a differential spinal anesthetic block before considering cystectomy. If the patient continues to perceive bladder pain after a spinal anesthetic at the T10 level, it can be taken as an indicator that the pain signal is being generated at a higher level in the spinal cord and that surgery on the bladder will not result in pain relief. Some patients with intractable urinary frequency will opt for simple conduit urinary diversion alone, believing that their quality of life will be improved independent of the pain piece of the puzzle. Despite all of the problems, many patients will do well after major surgery and quality of life can measurably improve (Rupp et al, 2000). In the event of neobladder pain after subtotal cystectomy and enterocystoplasty or continent diversion, it appears safe to retubularize a previously used bowel segment to form a urinary conduit for a straightforward urinary diversion without significant risk of conduit pain (Elzawahri et al, 2004).

The Gothenberg experience was recently reviewed, looking at results in 47 patients subjected to reconstructive/extirpative surgery (Rossberger et al, 2007). This included 23 substitution cystoplasties, 12 conduit diversions, and 10 Kock pouches. Twenty-eight of 34 patients with classic Hunner lesions had complete symptom resolution from the initial surgical procedure. Four of the remaining 6 required urinary diversion, cystectomy, or ulcer resection in a trigonal remnant but ultimately did well. Only 3 of 13 patients with non-Hunner disease had successful symptom resolution after reconstructive surgery, 2 of whom required conduit diversion. Peeker’s group concluded that only patients with Hunner lesions that were refractory to standard therapy could be expected to do well after major surgery.

A Thai experience using cystectomy and ileal neobladder in women who failed conservative therapy reported good results in all 35 patients treated (Kochakarn et al, 2007). Spontaneous voiding with minimal residual urine was found in 33 cases, and the remaining 2 cases had spontaneous voiding with residual urine requiring clean intermittent catheterization.

Forty years ago Pool (1967) recognized that “surgical treatment has not been the boon many had hoped it would be. … Diversion of the urine is not the entire answer to the situation. Removal of the lesion in the bladder has been of no benefit. Likewise, removal of almost the entire mobile portion of the bladder proved to be a failure.” Blaivas and associates (2005) and colleagues described results of augmentation enterocystoplasty and continent diversion in 76 consecutive patients with benign disease with a mean 9-year follow-up. All 7 patients with the diagnosis of IC were classified as “failures,” whereas 67 of the remaining 69 patients were cured or improved. When one of the deans of major urologic reconstruction writes, “I find it very difficult to justify such extensive surgery (continent diversion, cystourethrectomy) with such limited results and for these reasons have not been involved in surgery for IC over the past 3 years” (Webster, 1993), it is obvious that one should think carefully and proceed with surgery only after a complete discussion with a very motivated and well-informed patient. Recent reports seem to be more sanguine with regard to these procedures.

Key Points

Surgical Therapy

• Major surgery for bladder pain syndrome is a reasonable alternative for patients with severe symptoms who have failed standard attempts at treatment and when the disease course suggests that spontaneous remission of symptoms is unlikely.

• Patients with a small bladder capacity under anesthesia are less likely to respond to conservative attempts at therapy.

• Patients with a Hunner lesion may have the best results with major surgery.

• If one conceptualizes bladder pain syndrome as two disorders, one of pain and the other of frequency, it becomes easier for the patient and physician to rationalize the decision.

• Conduit urinary diversion can be relied on to resolve the frequency symptoms, and if the patient would consider this alone to make for a successful procedure there is reason to seriously consider this option.

• Diversion, and even cystectomy with diversion, cannot guarantee a pain-free result, and it is critical for the patient to factor this into the decision about this often irrevocable step.

Assessing Treatment Results

The diversity of BPS/IC therapies underscores the lack of understanding about the treatment of this syndrome (Rovner et al, 2000). It has been not only a difficult condition to diagnose but also a difficult condition for which to assess therapeutic impact. There is a 50% incidence of temporary remission unrelated to therapy, with a mean duration of 8 months (Held et al, 1990). A somewhat surprising finding from the Interstitial Cystitis Database was that although there was initial improvement in symptoms partially due to regression to the mean (Sech et al, 1998) and the intervention effect there was no evidence of a long-term change in average symptom severity over the 4-year course of follow-up (Propert et al, 2000). In a chronic, devastating condition with primarily subjective symptomatology, no known cause, and no cure, patients are desperate and often seem to respond to any new therapy (Fig. 12–12). They are often victims of unorthodox health care providers with untested forms of therapy, some medical, some homeopathic, and some even surgical.

Figure 12–12 Selected reported treatment outcomes in uncontrolled studies in the bladder pain syndrome/interstitial cystitis literature: percentage of patients initially improved. Ag nitrate, silver nitrate; BCG, bacillus Calmette-Guérin; DMSO, dimethyl sulfoxide; PPS, sodium pentosan polysulfate; TENS, transcutaneous electrical nerve stimulation.

The Placebo Conundrum

When possible, the results of randomized controlled studies should be used for decision making. Placebo, double-blind studies are optimal in this disorder for which there is no generally effective standard therapy.

Placebo effects influence patient outcomes after any treatment which the clinician and patients believe is effective, including surgery. Placebo effects plus disease natural history and regression to the mean can result in high rates of good outcomes, which may be misattributed to specific treatment effects (Gillespie et al, 1991; Gillespie, 1994; Turner et al, 1994; Propert et al, 2000). Unfortunately, too few BPS treatments have been subjected to a placebo-controlled trial. This is not to say that what seems effective is not, but rather that a high index of skepticism is healthy, even in treatments tested in controlled trials (Schulz et al, 1995).

Although in many diseases an argument can be made against using a true placebo control as opposed to an orthodox treatment of approved or accepted value (Rothman and Michels, 1994), a good case for true placebo comparison can readily be made for BPS. The vagaries of the natural history, the general lack of progression of symptom severity over time, and the fact that it is not life threatening mean that there is little to lose and much to gain by subjecting new treatments to the vigorous scrutiny of placebo control. Many patients who volunteer for such trials have already run the gamut of accepted (although generally unproved) therapies. It has long been recognized in protocols that use subjective criteria for assessment that “improvement” may be expected in up to 35% of placebo-treated patients (Benson and Epstein, 1976). Because the spontaneous remission rate (although temporary) for BPS is 11% (Oravisto and Alfthan, 1976) to 50% (Held et al, 1990), combined with the placebo improvement it can be difficult to prove efficacy.

Even in placebo-controlled trials it is reasonable to surmise that some degree of unblinding may occur as a result of somatic or psychological side effects of the active arm, impairing the validity of the trial results and giving the active arm a slight edge over placebo (DuBeau et al, 2005; Rees et al, 2005). Failure to recognize unblinding can easily bias results of a study and has not been routinely measured in clinical trials (Desbiens, 2002). When occurring late in a study after one would expect onset of a therapeutic effect, unblinding could be the result of side effect profile or drug efficacy. Early in the trial it reflects poor placebo or study design. The degree of blinding needs to be ascertained throughout the trial. This is of specific concern in BPS and any disorder where primary outcomes may be subject to patient-specific psychological and physiologic factors.

The ethics and necessity of placebo-controlled trials have been questioned, especially in situations in which an effective treatment exists and also when delay in treatment has been shown to result in disease progression (Streiner, 1999; Anderson, 2006; Polman et al, 2008). However, there are methodologic concerns with equivalence and noninferiority active agent comparison trials (Streiner, 2007). These include an inability to determine if the treatments are equally good or equally bad, and the possibility that successive noninferiority trials can lead to a gradual decrease in treatment efficacy. Although the use of placebo-controlled trials raises ethical concerns when proven effective treatment exists for the condition under investigation, they are ethically justified, provided that stringent criteria for protecting research subjects are satisfied (Miller et al, 2004).

The value of placebo-controlled trials is aptly illustrated by the recent decisions by pharmaceutical manufacturers not to pursue FDA approval in the United States for seemingly promising intravesical therapies for BPS/IC (Morales et al, 1996; Chancellor and de Groat, 1999) after placebo-controlled trials failed to establish efficacy. These include low concentration hyaluronic acid (Bioniche, Canada), high concentration hyaluronic acid (SKK, Tokyo), and resiniferatoxin (ICOS, Bothell, WA, USA). Nalmefene, an initially promising oral therapy in the 1990s (Stone, 1994), also failed phase 3 trials (IVAX, Miami). Placebo trials are impractical in surgery and it can be difficult to evaluate surgical reports. The many older medications currently used off label might not meet success if tested in the stringent manner in which new molecular entities are tested. The expense of testing therapies currently used off label often requires dependence on the largesse of government agencies such as the NIH (Propert et al, 2002; Sant et al, 2003; Mayer et al, 2005).

Finally, when considering objective changes, the concept of statistical versus clinical significance is paramount. Investigators should, but rarely do, point out differences between statistical improvement and what they consider to be clinically significant improvement (Wein and Broderick, 1994). As Gertrude Stein reportedly stated, “A difference, to be a difference, must make a difference.” An increase in bladder capacity of 30 mL may be statistically significant but clinically irrelevant. Number needed to treat and number needed to harm data (McQuay, 2003) may be particularly important in BPS/IC and typically have not been included in efficacy analysis.

Clinical Symptom Scales

There are three published BPS/IC symptom questionnaires: the University of Wisconsin IC Scale, the O’Leary-Sant IC Symptom Index and IC Problem Index, and the Pelvic Pain and Urgency/Frequency (PUF) Scale.

The University of Wisconsin IC Scale includes 7 PBS/IC symptom items (Table 12–15 ). It has not been validated for identification or diagnosis of BPS/IC. It captures severity of symptom expression (Keller et al, 1994; Goin et al, 1998). BPS/IC patients do not appear to indiscriminately report higher scores than controls for different somatic and general complaints (Porru et al, 2005). Unlike the other two instruments it addresses some quality-of-life issues, and this is an advantage when such issues are subject of investigation. Its most attractive aspects are its clinically apparent face validity and its ease of implementation.

Table 12–15 University of Wisconsin Symptom Instrument

SYMPTOM	SCORE 1-6 (0 = NOT AT ALL) (6 = A LOT)
1. Bladder discomfort
2. Bladder pain
3. Other pelvic discomfort
4. Headache
5. Backache
6. Dizziness
7. Feelings of suffocation
8. Chest pain
9. Ringing in ears
10. Getting up at night to go to the bathroom
11. Aches in joints
12. Swollen ankles
13. Nasal congestion
14. Flu
15. Abdominal cramps
16. Numbness or tingling in fingers or toes
17. Nausea
18. Going to the bathroom frequently during the day
19. Blind spots or blurred vision
20. Heart pounding
21. Difficulty sleeping because of bladder symptoms
22. Sore throat
23. Urgency to urinate
24. Coughing
25. Burning sensation in bladder

From Sirinian E, Azevedo K, Payne CK. Correlation between 2 interstitial cystitis symptom instruments. J Urol 2005;173:835–40.

The O’Leary-Sant indices (Table 12–16 ) are a validated questionnaire that was originally developed by focus groups, subjected to test-retest reliability analysis, and validated by administration to IC patients and asymptomatic controls (O’Leary et al, 1997; Lubeck et al, 2001). The questionnaire centers on 3 questions related to urgency/frequency and 1 on bladder-associated pain. It does not address generalized pelvic pain or symptomatology associated with sexual activity. This is not because these questions were not considered in the formulation of the questionnaire. Of 73 questions in the preliminary instrument covering domains of urinary symptoms, pain, sexual function, menstrual variability, and general health, only the 4 questions now in the instrument were needed to reliably and validly describe the illness experience of those with IC and distinguish these patients from those without the disorder (O’Leary and Sant, 1997).

Table 12–16 O’Leary-Sant Indices

INTERSTITIAL CYSTITIS SYMPTOM INDEX	INTERSTITIAL CYSTITIS PROBLEM INDEX
During the past month …	During the past month how much has each of the following been a problem for you:
Q1. … how often have you felt the strong need to urinate with little or no warning? 0. ____ Not at all 1. ____ Less than 1 time in 5 2. ____ Less than half the time 3. ____ About half the time 4. ____ More than half the time 5. ____ Almost always	Q1. Frequent urination during the day 0. ____ No problem 1. ____ Very small problem 2. ____ Small problem 3. ____ Medium problem 4. ____ Big problem
Q2. … how often have you had to urinate less than 2 hours after you finished urinating? 0. ____ Not at all 1. ____ Less than 1 time in 5 2. ____ Less than half the time 3. ____ About half the time 4. ____ More than half the time 5. ____ Almost always	Q2. Getting up at night to urinate? 0. ____ No problem 1. ____ Very small problem 2. ____ Small problem 3. ____ Medium problem 4. ____ Big problem
Q3. … how often did you most typically get up at night to urinate? 0. ____ None 1. ____ Once 2. ____ 2 times 3. ____ 3 times 4. ____ 4 times 5. ____ 5 times	Q3. Need to urinate with little warning? 0. ____ No problem 1. ____ Very small problem 2. ____ Small problem 3. ____ Medium problem 4. ____ Big problem
Q4. … have you experienced pain or burning in your bladder? 0. ____ Not at all 2. ____ A few times 3. ____ Fairly often 4. ____ Usually 5. ____ Almost always	Q4. Burning, pain, discomfort, or pressure in your bladder? 0. ____ No problem 1. ____ Very small problem 2. ____ Small problem 3. ____ Medium problem 4. ____ Big problem
Add the numerical values of the checked entries.	Add the numerical values of the checked entries.
Total score: _______	Total score: _______

From O’Leary MP, Sant GR, Fowler FJ, et al. The interstitial cystitis symptom index and problem index. Urology 1997;49:58–63.

Another instrument is the PUF questionnaire (Parsons et al, 2002a) (Table 12–17 ). It was specifically designed to include questions that directly reflect a wide variety of the symptoms experienced by patients who are affected by this disorder. One third of the questions address pelvic pain, including pain anywhere in the pelvis: the vagina, labia, lower abdomen, urethra, perineum, testes, penis, or scrotum. A large study utilizing the PUF questionnaire has concluded that up to 23% of American females have BPS/IC (Parsons et al, 2002a). This makes one wary as to the utility and face-validity of the PUF (Ito et al, 2003). A total score of 10 to 14 equals a 74% likelihood of a positive potassium test (PST); 15 to 19 equals 76%; and 20+ equals 91%. To the extent that the PST is suspect, the reliability of PUF data comes into question. Question No. 4 of the PUF is problematic. Patients who are sexually active can gain up to 6 more points than those who are not, and patients who over time begin sexual activity because they are feeling better can actually accumulate a falsely elevated PUF score owing to this anomaly.

Table 12–17 Pelvic Pain and Urgency/Frequency Patient Symptom Scale (PUF)

None of the questionnaires has been shown to be of value in diagnosis (Moldwin and Kushner, 2004), although they may suggest who should be screened further for the syndrome (Kushner and Moldwin, 2006). The O’Leary-Sant and University of Wisconsin instruments correlate strongly in a large population of patients with BPS/IC (Sirinian and Payne, 2001). Both the O’Leary-Sant and University of Wisconsin questionnaires are responsive to change over time and thus good for following the natural history of the disorder and the results of treatment.

Treatment outcome studies have also used the Global Response Assessment (GRA); a balanced patient self-report on overall response to therapy developed for NIDDK-sponsored multicenter therapeutic trials (Sant et al, 2003) (Table 12–18). A one-category change in GRA correlates with a 1.2-point change in the O’Leary-Sant indices and a 3.1-point change in the University of Wisconsin instrument (Propert et al, 2006).

Table 12–18 Global Response Assessment (GRA)

+1: Slightly Improved

+2: Moderately Improved

+3: Markedly Improved

From Sant GR, Propert KJ, Hanno PM, et al. A pilot clinical trial of oral pentosan polysulfate and oral hydroxyzine in patients with interstitial cystitis. J Urol 2003:170:810–15.

Principles of Management

The information currently available in the literature does not lend itself to easily formulating a diagnostic or treatment guideline that would be universally accepted (Hanno and Dmochowski, 2009). Different groups of “experts” would undoubtedly create different “best practices.” The compromise approach constructed by an experienced cross section of urologists and gynecologists from around the world at the International Consultation on Incontinence 2008 meeting in Paris seems reasonable and allows for significant latitude in individual practice and to account for patient preference (Hanno et al, 2009). It is outlined in Figures 12-13 and 12-14 and in Table 12–19.