Flashback to 1989. Bladder Pain Syndrome/Interstitial Cystitis was treated with a variety of off-label therapies, but the standard treatment against which all therapies were measured was intravesical lavage. Dimethyl sulfoxide (DMSO) had been approved a decade earlier (1978) for treatment of interstitial cystitis and remains to this day the only approved intravesical medication for the disorder by the Food and Drug Administration (FDA). Its use for this condition can be credited to Bruce Stewart of the Cleveland Clinic who persisted with an intravesical trial after failing in a transdermal clinical study of refractory patients in the mid-1960’s. It would be 1996 before sodium pentosan polysulfate became only the second approved medication and sole oral approved therapy for the syndrome.

DMSO, a colorless and odorless organic solvent, would have difficulty attracting a pharmaceutical company to invest in therapeutic trials were it to have come to market today. The garlic odor which is the hallmark of use (possibly resulting from a nonolfactory activation of TRPAA1 receptors [1] makes doing a blinded, placebo controlled trial almost an impossibility, and approval from regulatory authorities unlikely.

The chapter Dr. Wein and I co-authored in 1989 also discusses two intravesical therapies that are rarely if ever used three decades later.

Silver nitrate was first used in the mid nineteenth century for the symptoms of bladder pain syndrome. It was championed at the Mayo Clinic and the evidence of efficacy is noted in the original chapter. It has been used, often unsuccessfully, for the treatment of hemorrhagic cystitis [2]. Pain on instillation which may require sedation, the risk of bladder fibrosis retroperitoneal and renal damage if bladder perforation or reflux are present at the time of administration [3], and the risk of argyrosis [4] have limited if not completely removed it from the BPS armamentarium.

Clorpactin WCS 90 was successfully used in 1855 for the symptoms of BPS. It gained adherents after a number of positive publications in the twentieth century culminating in its dominant position in a classic and seminal publication on interstitial cystitis by Ed Messing and Tom Stamey out of Stanford in 1978. It was in this journal article that glomerulations were established as a keystone in diagnosis in patients with symptoms of bladder pain and voiding dysfunction. A follow up paper from the Stanford group indicating the possibility of ureteral fibrosis in patients with reflux served as a cautionary warning that a cystogram should be performed prior to instillation to rule out this possibility. The last publication I could find on clorpactin, and the only one after 1970, was by Kreder et al. in 2001 indicating that the mechanism of action might be through release of calcitonin gene-related peptide [5]. It’s not clear why this relatively effective intravesical therapy has so fallen out of favor. I think that patients are not predisposed to essentially putting a bleach solution into their bladders. Sodium oxychlorosene, the generic form of the brand, is essentially a relative of Dakin’s solution, an antiseptic solution developed during World War I to treat infected wounds by combining water, baking soda and bleach. Urologists tend to shy away from unapproved therapies that require anesthesia to administer and can cause damage if extravasation or reflux is present. Information on Clorpactin WCS-90 is available from the manufacturer at www.​u-g.​com/​info.​download.​php?​id=​33.

While therapeutically targeting the bladder was certainly reasonable, and remains so today, we did not realize that the disease in many patients has a more decentralized focus and in many patients is a part of a broader chronic pain syndrome that may not respond to treatments focused primarily on the bladder. We did not do randomized placebo-controlled trials to prove efficacy, largely because such trials could not easily be blinded, and thus today are still trying to estimate efficacy of many of these older intravesical solutions without the data necessary to make a valid judgement. Though intravesical and subcutaneous heparin had been considered (see below), intravesical instillation of glycosaminoglycans as a standard treatment option was years away. We had not considered direct intradetrusor application of therapies three decades ago.

Exogenous glycosaminoglycans have been shown to be effective in providing an epithelial permeability barrier in bladders in which the epithelium has been injured with protamine [6]. Heparin, which can mimic the activity of the bladder’s own mucopolysaccharide lining [7], has anti-inflammatory effects as well as actions which 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 [8]. Weaver first reported intravesical heparin for IC treatment [9]. Given intravesically, there is virtually no systemic absorption, even in an inflamed bladder [10]. While uncontrolled studies suggested some beneficial effect for subcutaneous administration [11, 12], 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 reported [13, 14]. Kuo 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 [15].

Parsons has used daily intravesical doses of 40,000 units of heparin in 20 cc sterile water administered by the patient daily and held for 30–60 min. “Reasonable improvement of symptoms” can be expected between 6 months and 2 years after starting therapy [16]. Adding alkalinized lidocaine to the heparin instillation provides better pain relief [17]. The addition of 8 mL of 2% lidocaine and 4 mL of 8.4% sodium bicarbonate may improve results [18]. In fact, a combination of 200 mg 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 [19]. A Japanese study reported high success rates with weekly intravesical instillation of 20,000 units heparin with 5 mL of 4% lidocaine and 25 mL of 7% sodium bicarbonate for 12 weeks [20]. Intravesical alkalinized lidocaine and heparin has been proposed as a treatment for symptom flare [21].

Other glycosaminoglycans administered intravesically include pentosanpolysulfate, hyaluronic acid, chondroitin sulfate, and combinations of hyaluronic acid and chondroitin sulfate [22–26]. While non-placebo controlled trials suggest efficacy, no definitive large scale randomized placebo controlled trials have been reported to show benefit, and none have been approved for a BPS indication in the United States. A comprehensive analysis of glycosaminoglycan layer replenishment therapy with intravesical glycosaminoglycans concluded that despite the fact that GAG intravesical therapy has been in use for over two decades, most of the studies are uncontrolled, poorly done, and with a small number of patients. Large-scale randomized controlled trials are urgently needed to underline the benefit of this type of therapy. Distinct patient groups (well phenotyped) need to be confirmed by definitive diagnostic findings [27]. Another review sadly concludes that “randomized controlled trials have suggested the GAG analogues are at best as good as placebo” [28].

The use of intravesical bacillus Calmette-Guerin (BCG) for interstitial cystitis was first reported by Zeidman and colleagues [29]. 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 to a 27% placebo response [30]. Surprisingly, BCG was tolerated as well as placebo. Even more surprisingly, eight of nine BCG responders continued to have an excellent response in all parameters measured at 27 months of follow-up [31]. It is unclear how BCG achieved this result, but immunologic and/or anti-inflammatory mechanisms have been postulated [32]. A double-blind crossover Swedish study comparing DMSO to BCG failed to substantiate BCG efficacy [33].

A large multicenter randomized controlled trial by NIDDK comparing BCG to placebo found a 12% response rate for placebo compared to a 21% response for BCG. Placebo responders in the trial had the same durability of response (up to 68 weeks) as the BCG responders [34]. 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 [35]. The small response rate in the RCT failed to reach statistical significance at the p = 0.05 level, and this large study of 265 patients suggests that BCG has no place in the treatment of moderate to severe BPS/IC [36].

Resiniferatoxin (RTX), an ultra-potent 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 [37]. Clinical trials for the use of these compounds in bladder pain, 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 [38–40]. A phase 2 safety and proof of concept multicenter, placebo-controlled trial conducted by ICOS Corporation of Bothell, WA found no significant efficacy of a single intravesical administration RTX compared with placebo, although no safety issues were identified [41]. RTX and hydrodistention was effective in relieving the pain of BPS when compared to hydrodistention alone, but was not effective in improving lower urinary tract symptoms [42]. Studies using other concentrations and multiple administrations may be worthwhile [43].